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HK1213881B - Pyrrolo [2, 3-d] pyrimidine derivatives as inhibitors of janus-related kinases (jak) - Google Patents

Pyrrolo [2, 3-d] pyrimidine derivatives as inhibitors of janus-related kinases (jak) Download PDF

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Publication number
HK1213881B
HK1213881B HK16101741.2A HK16101741A HK1213881B HK 1213881 B HK1213881 B HK 1213881B HK 16101741 A HK16101741 A HK 16101741A HK 1213881 B HK1213881 B HK 1213881B
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Hong Kong
Prior art keywords
methyl
pyrrolo
cis
pyrimidin
cyclobutyl
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HK16101741.2A
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Chinese (zh)
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HK1213881A1 (en
Inventor
M.F.布朗
A．E．芬维克
M.E.弗拉纳甘
A.冈萨雷斯
T.A.约翰逊
N．凯拉
M．J．米顿-弗莱
J．W．斯特罗巴克
R．E．特布林克
J．D．特祖皮克
R．J．昂瓦拉
M．L．瓦兹奎兹
M．D．帕里克
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辉瑞大药厂
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Priority claimed from PCT/IB2014/058889 external-priority patent/WO2014128591A1/en
Publication of HK1213881A1 publication Critical patent/HK1213881A1/en
Publication of HK1213881B publication Critical patent/HK1213881B/en

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Description

Pyrrolo [2,3-D ] pyrimidine derivatives as janus-related kinase (JAK) inhibitors
Technical Field
The present invention provides pharmaceutically active pyrrolo [2,3-d ] pyrimidines and analogs. Such compounds are useful for inhibiting Janus (Janus) kinases (JAKs). The invention also relates to compositions comprising such compounds and methods of making such compounds, as well as methods for treating and preventing conditions mediated by JAK.
Background
Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified as tyrosine and serine/threonine kinases. Inappropriate kinase activity due to mutations, over-expression or inappropriate regulation, dysregulation or dysregulation, and overproduction or under-production of growth factors or cytokines has been implicated in a number of diseases including, but not limited to, cancer, cardiovascular disease, allergy, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders (e.g., alzheimer's disease). Inappropriate kinase activity triggers a number of biological cellular responses that are associated with cell growth, cell differentiation, survival, apoptosis, mitosis, cell cycle control and cell motility involved in the above and related diseases.
Thus, protein kinases have become an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of intracellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play an important role in cytokine signaling (Kisseleva et al, Gene,2002,285, 1; Yamaoka et al Genome Biology 2004,5, 253). When cytokines bind to their receptors, cytokines activate JAKs, which in turn phosphorylate cytokine receptors, thus creating docking sites for signaling molecules, notably the signaling conductors and the activator of transcription (STAT) family members that ultimately lead to gene expression. Many cytokines are known to activate the JAK family. These cytokines include the IFN family (IFN-. alpha., IFN-. beta., IFN-. omega., restrictors, 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 γ 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), single chain families (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G-protein coupled receptors (AT 1).
There remains a need for novel compounds that can effectively and selectively inhibit specific JAK enzymes, particularly JAK1 (as opposed to JAK 2). JAK1 is a member of the janus family of protein kinases consisting of JAK1, JAK2, JAK3 and TYK 2. JAK1 is expressed to varying degrees in all tissues. Many cytokine receptors signal transmission via JAK kinases in the following combinations: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/TYK2, or JAK2/JAK 2. In this regard, JAK1 is the most widely paired JAK kinase and is required for signaling by the gamma-common (IL-2R γ) cytokine receptor, the IL-6 receptor family, the I, II and type III receptor families, and the IL-10 receptor family. Animal studies have shown that JAK1 is essential for the development, production and homeostasis of the immune system. Modulation of immune activity by inhibition of JAK1 kinase activity has proven useful in the treatment of a variety of immune disorders (Murray, p.j., j.immunol.,178, 2623-2629 (2007); Kisseleva, t., et al, Gene,285, 1-24 (2002); O' Shea, j.j., et al, Cell,109, (suppl.) S121-S131 (2002)) while avoiding JAK 2-dependent signaling of Erythropoietin (EPO) and Thrombopoietin (TPO) (Neubauer h., et al, Cell,93(3),397-409 (1998); Parganas e., et al, Cell,93(3),385-95 (1998)).
Summary of the invention
The present invention provides a compound of formula I having the structure shown below:
or a pharmaceutically acceptable salt thereof, wherein R1Is hydrogen or C1-C4An alkyl group, wherein the alkyl group is further optionally substituted with one or more substituents selected from the group consisting of: halo, hydroxy, methoxy, amino, CF3And C3-C6A cycloalkyl group; r2And R3Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, C3-C6Cycloalkyl radical, C1-C6Linear or branched perfluoroalkyl radical, C1-C6Straight or branched alkoxy, C1-C6Linear or branched perfluoroalkoxy, halogen, cyano, hydroxy, amino, carboxy, aminocarbonyl, aryl, heteroaryl, (aryl) C1-C6Straight or branched alkyl, (heteroaryl) C1-C6Straight or branched alkyl, (heterocyclyl) C1-C6Straight or branched alkyl, (C)1-C6Straight or branched alkyl) aryl, (C)1-C6Straight or branched alkyl) heteroaryl, (C)1-C6Straight or branched alkyl) heterocyclic group, (C)1-C6Linear or branched alkoxy) carbonyl (C)1-C6Straight or branched alkyl) amino-carbonylamino or (C)1-C6Straight or branched alkyl) aminocarbonyl; r4Is selected from hydrogen, deuterium, C1-C6Straight or branched alkyl, C1-C6Linear or branched perfluoroalkyl, aryl and alkylaryl groups; x is selected from-NH-and-CRaRb- - -, in which (a) RaAnd RbIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, (aryl) C1-C6Straight or branched alkyl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, (heteroaryl) C1-C6Straight or branched alkyl, (heterocyclyl) C1-C6A linear or branched alkyl group, or (b) RaAnd RbTogether form an inclusion- - (CR)cRd)jA chain of (A) wherein RcAnd RdIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, halo, CN, CF3Hydroxyl group, CONH2Or SO2CH3(ii) a Y is-A-R5Wherein A is a bond, - - (CH)2)k- - (or- -) - (CD)2)k-, and R5Is C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, or-NRa’Rb’Or is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of 5 to 11 atoms having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the alkyl group, C3-C6The cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of: deuterium, halo, C1-C6Straight or branched alkyl, CN, hydroxy, CF3、--ORe、--NReRf、--S(O)pReAnd C3-C6Cycloalkyl radicals, in whichThe alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CONH2And SO2CH3Wherein (a) Ra’And Rb’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl or (C)1-C6Straight or branched alkyl) heteroaryl, wherein said alkyl and cycloalkyl groups may optionally be substituted with one or more Rc’Substituted, or (b) Ra’And Rb’Together form an inclusion- - (CR)c’Rd’)jA chain of (A) wherein Rc’And Rd’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, halo, CN, hydroxy, CF3、CONH2、--ORe、--NReRfOr- -S (O)pRe(ii) a Wherein R iseAnd RfIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl or C3-C6Cycloalkyl, wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CF3And CONH2(ii) a 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 other aspects, the invention also provides:
a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I;
a method of treating a condition or disorder including myositis, vasculitis, pemphigus, crohn's disease, lupus, nephritis, psoriasis, multiple sclerosis, major depressive disorder, allergy, asthma, Sjogren's disease, dry eye syndrome, transplant rejection, cancer, inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, acute respiratory disease, or cachexia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
a method of treating a condition or disorder including atopic dermatitis, eczema, psoriasis, scleroderma, lupus, pruritus, other pruritus, allergic reactions (including allergic dermatitis in mammals), allergic diseases in horses (including stinging allergy), eczema in summer, scrapie (sweet spot), chronic emphysema in horses, inflammatory airway diseases, recurrent airway obstruction, airway hyperresponsiveness and chronic obstructive pulmonary disease, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; and
methods of preparing the compounds of the invention. The invention will be further understood by the following description, given by way of example only. The invention relates to pyrrolo [2,3-d ] pyrimidine derivatives. In particular, the present invention relates to pyrrolo [2,3-d ] pyrimidine compounds useful as inhibitors of JAK, particularly JAK 1. While the invention is not so limited, various aspects of the invention will be understood from the following discussion and examples.
The term "alkyl", alone or in combination, means of formula CnH2n+1The acyclic saturated hydrocarbon group of (1) may be a straight chain or a branched chain. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl. Unless otherwise specified, alkyl groups contain 1 to 6 carbon atoms. The carbon atom content of alkyl groups and various other hydrocarbon-containing moieties is indicated by a prefix denoting either the upper or lower value of the carbon atom in that moiety, in other words, the prefix Ci-CjDenotes a moiety having an integer of "i" to "j" (containing) carbon atoms. Thus, for example, C1-C6Alkyl means an alkyl group having 1 to 6 carbon atoms, inclusive.
As used herein, the term "hydroxyl" means an OH group. Operation of the artThe term "heterocyclyl" means a saturated or partially saturated (i.e., non-aromatic) heterocyclic ring and which may be attached through a ring nitrogen atom (when the heterocyclic ring is attached to a carbon atom), or through a ring carbon atom (in all cases). Likewise, when substituted, a substituent may be located on a ring nitrogen atom (if the substituent is attached through a carbon atom) or on a ring carbon atom (in all cases). Specific examples include ethylene oxide, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1, 4-bisAlkyl, morpholinyl, piperazinyl, azepanyl, oxepinyl, oxazepanyl and diazaAnd (4) a base.
The term "aryl" means an aromatic monocyclic or bicyclic hydrocarbon which may be attached through a ring carbon atom. Likewise, when substituted, the substituent may be located on a ring carbon atom. Specific examples include phenyl, tolyl, xylyl, trimethylphenyl, and naphthyl. Examples of aryl substituents include alkyl, hydroxy, halo, nitrile, alkoxy, trifluoromethyl, carboxamido, SO2Me, benzyl and substituted benzyl.
The term "heteroaryl" means an aromatic heterocyclic ring, and it may be attached through a ring carbon atom (in all cases) or through a ring nitrogen atom having a suitable valence (when the heterocyclic ring is attached to a carbon atom). Likewise, when substituted, a substituent may be attached at a ring carbon atom (in all cases) or at a ring nitrogen atom having an appropriate valence number (if the substituent is attached through a carbon atom). Specific examples include thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, and the like,Azolyl radical, isoOxazolyl, thiazolyl, isothiazolyl, triazolyl,Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. The term "cycloalkyl" means CnH2n-1The monocyclic saturated hydrocarbon group of (1). Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Unless otherwise specified, cycloalkyl groups contain 3 to 8 carbon atoms.
The terms "halo" and "halogen" mean fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
The term "mammal" means a human, livestock, or companion animal.
The term "companion animal" means an animal that is kept as a pet or household animal. Examples of companion animals include dogs, cats and rodents (including hamsters, guinea pigs, gerbils, etc.), rabbits, ferrets and birds.
The term "livestock" means an animal that is raised or nursed in an agricultural environment to prepare a product (e.g., food or fiber) or for its labor. In some embodiments, the livestock are suitable for consumption by a mammal (e.g., a human). Examples of livestock animals include cows, goats, horses, pigs, sheep (including lambs) and rabbits, and birds (e.g., chickens, ducks and turkeys).
The term "treating" means slowing the symptoms associated with a disease, disorder, or condition, or stopping the further development or worsening of those symptoms. Depending on the disease and condition of the patient, "treatment" in the present application may include one or more of curative, palliative and prophylactic treatment. Treatment may also include administration of the pharmaceutical formulations of the present invention in combination with other treatments.
The term "therapeutically effective" refers to the ability of an agent to prevent a disease or ameliorate the severity of a disease, while avoiding the adverse side effects normally associated with alternative treatments. The phrase "therapeutically effective" is to be understood as being equivalent to the phrase "effective for treatment, prevention, or alleviation" and both are intended to define the amount of the individual agents used in the combination therapy to achieve the goal of improvement in the severity and frequency of cancer, cardiovascular disease, or pain and inflammation, relative to treatment with each agent itself, while avoiding the adverse side effects typically associated with alternating therapy.
By "pharmaceutically acceptable" is meant suitable for use in mammals, companion animals, or livestock animals.
If a substituent is described as "independently selected" from a group, then each substituent is selected independently of the other. Thus, each substituent may be the same or different from the others.
Description
The present invention relates to novel compounds which are selective JAK1 modulators useful in the treatment of diseases and disorders associated with dysregulation of JAK 1. The invention further provides pharmaceutical compositions comprising said JAK1 modulators and methods of treating and/or preventing said diseases and disorders. Accordingly, the present invention provides a compound of formula I having the structure shown below:
or a pharmaceutically acceptable salt thereof, wherein R1Is hydrogen or C1-C4An alkyl group, wherein the alkyl group is further optionally substituted with one or more substituents selected from the group consisting of: halo, hydroxy, methoxy, amino, CF3And C3-C6A cycloalkyl group; r2And R3Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, C3-C6Cycloalkyl radical, C1-C6Linear or branched perfluoroalkyl radical, C1-C6Straight or branched alkoxy, C1-C6Straight or branched chainFluoroalkoxy, halogen, cyano, hydroxy, amino, carboxy, aminocarbonyl, aryl, heteroaryl, (aryl) C1-C6Straight or branched alkyl, (heteroaryl) C1-C6Straight or branched alkyl, (heterocyclyl) C1-C6Straight or branched alkyl, (C)1-C6Straight or branched alkyl) aryl, (C)1-C6Straight or branched alkyl) heteroaryl, (C)1-C6Straight or branched alkyl) heterocyclic group, (C)1-C6Linear or branched alkoxy) carbonyl (C)1-C6Straight or branched alkyl) amino-carbonylamino or (C)1-C6Straight or branched alkyl) aminocarbonyl; r4Is selected from hydrogen, deuterium, C1-C6Straight or branched alkyl, C1-C6Linear or branched perfluoroalkyl, aryl and alkylaryl groups; x is selected from-NH-and-CRaRb- - -, in which (a) RaAnd RbIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, (aryl) C1-C6Straight or branched alkyl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, (heteroaryl) C1-C6Straight or branched alkyl, (heterocyclyl) C1-C6A linear or branched alkyl group, or (b) RaAnd RbTogether form an inclusion- - (CR)cRd)jA chain of (A) wherein RcAnd RdIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, halo, CN, CF3Hydroxyl group, CONH2Or SO2CH3(ii) a Y is-A-R5Wherein A is a bond, - - (CH)2)k- - (or- -) - (CD)2)k-, and R5Is C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, or-NRa’Rb’Or 1 to 3 independently selected from oxygen,An unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of 5 to 11 atoms of heteroatoms of nitrogen and sulfur, wherein said alkyl, C3-C6The cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of: deuterium, halo, C1-C6Straight or branched alkyl, CN, hydroxy, CF3、--ORe、--NReRf、--S(O)pReAnd C3-C6Cycloalkyl, wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CONH2And SO2CH3Wherein (a) Ra’And Rb’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl or (C)1-C6Straight or branched alkyl) heteroaryl, wherein said alkyl and cycloalkyl groups may optionally be substituted with one or more Rc’Substituted, or (b) Ra’And Rb’Together form an inclusion- - (CR)c’Rd’)jA chain of (A) wherein Rc’And Rd’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, halo, CN, hydroxy, CF3、CONH2、--ORe、--NReRfOr- -S (O)pRe(ii) a Wherein R iseAnd RfIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl or C3-C6Cycloalkyl, wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CF3And CONH2(ii) a 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 present invention provides a toolA compound of formula IA having the structure shown below:
or a pharmaceutically acceptable salt thereof, wherein Y is-A-R5Wherein A is a bond, - - (CH)2)k- - (or- -) - (CD)2)k-, and R5Is C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, or-NRa’Rb’Or is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of 5 to 11 atoms having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the alkyl group, C3-C6The cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of: deuterium, halo, C1-C6Straight or branched alkyl, CN, hydroxy, CF3、--ORe、--NReRf、--S(O)pReAnd C3-C6Cycloalkyl, wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CONH2And SO2CH3Wherein (a) Ra’And Rb’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl or (C)1-C6Straight or branched alkyl) heteroaryl, wherein said alkyl and cycloalkyl groups may optionally be substituted with one or more Rc’Substituted, or (b) Ra’And Rb’Together form an inclusion- - (CR)c’Rd’)jA chain of (A) wherein Rc’And Rd’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, halo, CN, hydroxy, CF3、CONH2、--ORe、--NReRfOr- -S (O)pRe(ii) a Wherein R iseAnd RfIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl or C3-C6Cycloalkyl, wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CF3And CONH2(ii) a j is 2,3, 4 or 5; k is 1,2, 3 or 4; and p is 0, 1 or 2.
In one embodiment, the present invention provides a compound of formula IA wherein A is a bond, and R5Is C1-C6Straight or branched alkyl, C3-C6Cycloalkyl or aryl. In another embodiment, the invention provides a compound of formula IA wherein A is a bond or- - (CH)2)k-, and R5Is C3-C6Cycloalkyl, wherein said C3-C6The cycloalkyl group is further optionally substituted with one or more substituents selected from the group consisting of: halogen radical, C1-C6A straight or branched alkyl group and CN, wherein said alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CONH2And SO2CH3(ii) a Wherein k is 1,2 or 3. In yet another embodiment, the invention provides a compound of formula IA, wherein A is a bond or- - (CH)2)k-, and R5Is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of 5 to 11 atoms having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the alkyl group, C3-C6The cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of: deuterium, halo, C1-C6Straight or branched alkyl, CN, hydroxy, CF3、--NRa’Rb’、--ORe、--S(O)pReAnd C3-C6A cycloalkyl group; wherein k is 1,2 or 3.
In another embodiment, the present invention provides a compound of formula IB having the structure shown below:
or a pharmaceutically acceptable salt thereof, wherein (a) Ra’And Rb’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl or (C)1-C6Straight or branched alkyl) heteroaryl, wherein said alkyl and cycloalkyl groups may optionally be substituted with one or more RcSubstituted, or (b) Ra’And Rb’Together form an inclusion- - (CR)c’Rd’)jA chain of (A) wherein Rc’And Rd’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, halo, CN, hydroxy, CF3、CONH2、--ORe、--NReRfOr- -S (O)pRe(ii) a Wherein R iseAnd RfIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl or C3-C6Cycloalkyl, wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CF3And CONH2(ii) a Or (c) Ra’And Rb’Together form an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of 5 to 11 atoms having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein said monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting ofSubstituted with a substituent of the group (b): deuterium, halo, C1-C6Straight or branched alkyl, CN, hydroxy, CF3、--NRa’Rb’、--ORe、--S(O)pReAnd C3-C6A cycloalkyl group; j is 2,3, 4 or 5; and p is 0, 1 or 2.
In another embodiment, the present invention provides a compound of formula IC having the structure shown below:
or a pharmaceutically acceptable salt thereof, wherein (a) Ra’And Rb’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl or (C)1-C6Straight or branched alkyl) heteroaryl, wherein said alkyl and cycloalkyl groups may optionally be substituted with one or more RcSubstituted, or (b) Ra’And Rb’Together form an inclusion- - (CR)c’Rd’)jA chain of (A) wherein Rc’And Rd’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, halo, CN, hydroxy, CF3、CONH2、--ORe、--NReRfOr- -S (O)pRe(ii) a Wherein R iseAnd RfIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl or C3-C6Cycloalkyl, wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CF3And CONH2(ii) a Or (c) Ra’And Rb’Together form a heterocomplex having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfurAn unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of 5 to 11 atoms, wherein said monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of: deuterium, halo, C1-C6Straight or branched alkyl, CN, hydroxy, CF3、--NRa’Rb’、--ORe、--S(O)pReAnd C3-C6A cycloalkyl group; j is 2,3, 4 or 5; and p is 0, 1 or 2.
In another embodiment, the invention provides a compound of formula ID having the structure:
or a pharmaceutically acceptable salt thereof, wherein
Y is-AR5Wherein A is a bond or- - (CH)2)k-, and R5Is C1-C6Straight or branched alkyl, C3-C6Cycloalkyl, aryl, or an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of 5 to 11 atoms having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the alkyl, C3-C6The cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of: deuterium, halo, C1-C6Straight or branched alkyl, CN, hydroxy, CF3、--NRa’Rb’、--ORe、--S(O)pReAnd C3-C6Cycloalkyl, wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CONH2And SO2CH3Wherein (a) Ra’And Rb’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched chain alkyl、C3-C6Cycloalkyl, aryl, (aryl) C1-C6Straight or branched alkyl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, (heteroaryl) C1-C6Straight or branched alkyl, (heterocyclyl) C1-C6Straight or branched chain alkyl, wherein said alkyl and cycloalkyl groups may optionally be substituted by one or more Rc’Substituted, or (b) Ra’And Rb’Together form an inclusion- - (CR)c’Rd’)jA chain of (A) wherein Rc’And Rd’Independently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl, aryl, (C)1-C6Straight or branched alkyl) aryl, heteroaryl, (C)1-C6Straight or branched alkyl) heteroaryl, halo, CN, hydroxy, CF3、CONH2、--ORe、--NReRfOr- -S (O)pRe(ii) a Wherein R iseAnd RfIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl or C3-C6Cycloalkyl, wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CF3And CONH2(ii) a 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 a compound of formula ID wherein R5Is C1-C6Straight or branched alkyl or C3-C6A cycloalkyl group.
In another embodiment, the invention provides a compound of formula ID wherein A is a bond or- - (CH)2)k-, and R5Is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of 5 to 11 atoms having 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the alkyl group, C3-C6The cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of: deuterium, halo, C1-C6A straight or branched alkyl group,CN, hydroxy, CF3、--NRa’Rb’、--ORe、--S(O)pReAnd C3-C6A cycloalkyl group; wherein R iseAnd RfIndependently of one another is hydrogen, deuterium, C1-C6Straight or branched alkyl or C3-C6Cycloalkyl, wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more substituents selected from the group consisting of: halo, CN, hydroxy, CF3And CONH2(ii) a k is 1,2 or 3; and p is 0, 1 or 2. In another embodiment, the invention provides a compound of formula I wherein R is5Is an unsaturated ring structure containing 5 to 11 atoms in total having 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur. In other embodiments, the invention provides compounds of formula I wherein R5Is furyl, thienyl, pyrrolyl, pyrazolyl,Oxazolyl, azetidinyl, piperidinyl or thiazolyl, and which is optionally substituted with 1 or 2 methyl groups.
In another embodiment, the present invention provides a compound 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 } -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-1-sulfonamide;
1-cyclopropyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -methanesulfonamide;
n- { cis-3- [ (butanesulfonyl) methyl ] cyclobutyl } -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine;
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;
(1R,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;
(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-3-yl) methane-sulfonamide;
1- (3, 3-difluorocyclobutyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methane-sulfonamide;
trans-3- (cyanomethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutanesulfonamide;
cis-3- (cyanomethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutane-sulfonamide;
n- [ cis-3- ({ [ (3, 3-difluorocyclobutyl) methyl ] sulfonyl } methyl) cyclobutyl ] -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine;
(1S,5S) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -3-azabicyclo [3.1.0] hexane-3-sulfonamide;
(1R,5R) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) 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-7H-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;
n- (cis-3- { [ (3-chloro-4-fluorophenyl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine;
n- (cis-3- { [ (2-cyclopropylethyl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine;
N-methyl-N- [ cis-3- ({ [1- (propan-2-yl) pyrrolidin-3-yl ] sulfonyl } methyl) cyclobutyl ] -7H-pyrrolo [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-4-yl) amino ] cyclobutyl } -methanesulfonamide;
cis-3- (cyanomethyl) -3-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -cyclobutanesulfonamide;
trans-3- (cyanomethyl) -3-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutanesulfonamide;
n- (2-cyanoethyl) -N-methyl-N' - { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } sulfuric acid diamide (sulfuric diamide);
n- { (1S,3R) -3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclopentyl } propane-1-sulfonamide;
3- (2-hydroxypropan-2-yl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } benzene-sulfonamide;
n- (cyclopropylmethyl) -N' - { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } sulfuric acid diamide;
n- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -4- (1H-pyrazol-3-yl) 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;
2- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] pyridine-4-carbonitrile;
(1S,3S) -3- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] cyclopentanecarbonitrile;
(1R,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 } -methanesulfonamide;
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-4-amine; and the number of the first and second groups,
2-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -1, 3-thiazole-5-sulfonamide; or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound selected from the group consisting of:
1- (3, 3-difluorocyclobutyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methanesulfonamide;
trans-3- (cyanomethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutanesulfonamide;
n- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } propane-1-sulfonamide;
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 } propane-1-sulfonamide; or a pharmaceutically acceptable salt thereof.
In other embodiments, the present invention provides compounds selected from the group consisting of:
(3R) -3-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } pyrrolidine-1-sulfonamide;
(1R,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;
(1S,5S) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) 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-4-yl) amino ] cyclobutyl } sulfuric acid 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.
In another embodiment, the present invention provides a 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;
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-7H-pyrrolo [2,3-d ] pyrimidin-4-amine; and
(3S) -1- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] pyrrolidine-3-carbonitrile;
or a pharmaceutically acceptable salt thereof.
In yet another embodiment, the present invention provides a compound selected from the group consisting of:
(1R,3R) -3- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] cyclopentanecarbonitrile;
(1S,3S) -3- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] cyclopentanecarbonitrile;
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-7H-pyrrolo [2,3-d ] pyrimidin-4-amine; and
n- { cis-3- [ (butanesulfonyl) methyl ] cyclobutyl } -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine; or a pharmaceutically acceptable salt thereof.
Particularly preferred embodiments include 2-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -1, 3-thiazole-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-3-ylmethanesulfonamide; 1- (3, 3-difluorocyclobutyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -methanesulfonamide; 3, 3-difluoro-N- { 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; (1S,5S) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -3-azabicyclo [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-carbonitrile; or a pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical or veterinary composition comprising a compound of formula I, IA, IB, IC or ID, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also provides a method of treating a disorder or condition associated with dysregulation of JAKs, particularly JAK1, in a subject, comprising administering to the subject a therapeutically effective amount of a compound having the structure of formula I, IA, IB, IC or ID, or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder or condition treated in this method is selected from rheumatoid arthritis, myositis, vasculitis, pemphigus, Crohn's disease, ulcerative colitis, Alzheimer's disease, lupus, nephritis, psoriasis, atopic dermatitis, autoimmune thyroid disease, multiple sclerosis, major depression, allergy, asthma, Sjogren's disease, dry eye syndrome, organ transplant rejection, xeno transplantation, type I diabetes and diabetic complications, cancer, leukemia, T-cell acute lymphocytic leukemia, adult T-cell leukemia, activated B-cell-like, diffuse large B-cell lymphoma, inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, chronic obstructive pulmonary disease, acute respiratory disease and cachexia, the method comprises the step of administering to the subject an effective amount of a composition comprising a compound of formula I, IA, IB, IC or ID. In some embodiments, a therapeutically effective amount according to the method is 0.01 mg/kg body weight/day to 100 mg/kg body weight/day. In some other embodiments, a therapeutically effective amount according to the method is 0.1 mg/kg body weight/day to 10 mg/kg body weight/day. In carrying out the process, 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-4-yl) amino ] cyclobutyl } -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-difluoro-N- { 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; (1S,5S) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -3-azabicyclo [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-carbonitrile; or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of treating or preventing a disorder or condition selected from atopic dermatitis, eczema, scleroderma, pruritus, other pruritus, allergic reactions including allergic dermatitis in mammals, allergic diseases in horses including bite allergies, summer eczema, marcke itch (sweet itch), chronic emphysema in horses, inflammatory airway diseases, recurrent airway obstruction, and airway hyperresponsiveness, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I, IA, IB, IC, or ID, or a pharmaceutically acceptable salt thereof.
In some embodiments, a therapeutically effective amount according to the method is 0.01 mg/kg body weight/day to 100 mg/kg body weight/day. In some other embodiments, a therapeutically effective amount according to the method is 0.1 mg/kg body weight/day to 10 mg/kg body weight/day. According to said method, the mammal to be treated with the compound of the invention is selected from the group consisting of companion animals, dogs and livestock. In some embodiments, the compound of formula I, IA, IB, IC or ID, or a pharmaceutically acceptable salt thereof, according to the methods may be administered by oral, parenteral or topical routes. In carrying out the process, 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-4-yl) amino ] cyclobutyl } -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-difluoro-N- { 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; (1S,5S) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -3-azabicyclo [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-carbonitrile; or a pharmaceutically acceptable salt thereof.
Compounds having the same molecular formula but differing in the nature or order of their atomic bonds or the spatial arrangement of the atoms are referred to as "isomers". Isomers in which the atoms differ in their spatial arrangement are referred to as "stereoisomers". It will be clear to those skilled in the art that the compounds of formula I, IA, IB, IC or ID may exist as cis-and trans-achiral diastereomers.
All isomers (e.g., cis-, trans-, or diastereoisomers) of the compounds described herein, alone or in any mixture thereof, are encompassed within the scope of the compounds. All such forms, including enantiomers, diastereomers, cis (cis), trans (trans), ipsilateral (syn), contralateral (anti), solvates (including hydrates), tautomers, and mixtures thereof, are contemplated within the scope of the compounds. Stereoisomeric mixtures, for example mixtures of diastereomers, can be separated in a known manner into their corresponding isomers using suitable separation methods. Diastereomeric mixtures can be separated into individual diastereomers, for example, by fractional crystallization, chromatography, solvent partition, and similar procedures. This separation can take place at the level of one of the starting compounds or at the compound of the formula I, IA, IB, IC or ID itself. Enantiomers can be separated by formation of diastereomeric salts (e.g., salt formation with an enantiomerically pure chiral acid), or by chromatography (e.g., HPLC) using a chromatography matrix with chiral ligands.
In terms of therapeutic use for treating a disorder in a mammal, a compound of the present invention or a pharmaceutical composition thereof may be administered orally, parenterally, topically, rectally, mucosally, or intestinally. Parenteral administration includes indirect injection to produce a systemic effect or direct injection to the site of disease. Topical administration includes treatments of the skin or organs, such as the eye or ear, that are readily accessible by topical application. Transdermal delivery to produce a systemic effect is also included. Rectal administration includes the form of suppositories. Preferred routes of administration are oral and parenteral.
Pharmaceutically acceptable salts of the compounds of formula I, IA, IB, IC or ID include acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate (camsylate), citrate, cyclohexylamine sulfonate (cyclamate), edisylate (edisylate), ethanesulfonate (esylate), formate, fumarate, glucoheptonate (gluceptate), gluconate (gluconate), glucuronate (glucuronate), hexafluorophosphate, salicylate (hibenzate), hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate (isethionate), lactate, malate, dicarboxylate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate (2-napsylate), nicotinate, nitrate, orotate (orate), Oxalate, palmitate, pamoate (pamoate), phosphate/hydrogen/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate (xinofoate).
Suitable base salts are formed from bases which form non-toxic salts. Examples thereof include salts of aluminum, arginine, N-dibenzylethylenediamine (benzathine), calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine (meglumine), ethanolamine (olamine), potassium, sodium, trometamol (tromethamine) and zinc.
Hemisalts of acids and bases, e.g., hemisulfate and hemicalcium salts, may also be formed. A review of suitable Salts is found in Stahl and Wermuth's Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).
Pharmaceutically acceptable salts of compounds of formula I, IA, IB, IC or ID can be prepared by one of three methods: (i) reacting a compound of formula I, IA, IB, IC or ID with a desired acid or base; (ii) removing an acid or base labile protecting group from a suitable precursor of a compound of formula I, IA, IB, IC or ID, or subjecting a suitable cyclic precursor (e.g. a lactone or lactam) to a ring opening reaction using a desired acid or base; or (iii) converting one salt of a compound of formula I, IA, IB, IC or ID to another salt by reaction with a suitable acid or base or by use of a suitable ion exchange column. All three reactions are usually carried out in solution. The resulting salt may be precipitated and collected by filtration or may be recovered by evaporating the solvent. The degree of ionization of the resulting salt can vary from fully ionized to nearly unionized.
The pharmaceutical compositions of the present invention may be manufactured by processes known in the art, for example by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, freeze-drying or spray-drying processes.
The pharmaceutical compositions used according to the invention can be prepared in a customary manner using one or more pharmaceutically acceptable carriers which include excipients and auxiliaries and facilitate processing of the active compounds into preparations which can be used pharmaceutically. Suitable formulations depend on the route of administration chosen. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore encompassed within the scope of the present invention. Such excipients and carriers are disclosed, for example, in "Remington's Pharmaceutical Sciences", Mack pub. The preparation of the invention can be designed into short-acting type, quick-release type, long-acting type and controlled-release type. Thus, the pharmaceutical formulations may also be formulated in a controlled or sustained release form.
Pharmaceutical compositions suitable for use in the present invention include compositions which contain a sufficient amount of the active ingredient to achieve the desired purpose (i.e., control or treat a disorder or disease). More particularly, a therapeutically effective amount means an amount of a compound that is effective to prevent, alleviate or ameliorate symptoms/signs of disease or prolong the survival of the subject being treated.
The amount of active ingredient (compound of the invention) in the pharmaceutical compositions and unit dosage forms thereof can be widely varied or adjusted depending upon the mode of administration, the potential of the particular compound, and the desired concentration. Determination of a therapeutically effective amount is within the ability of those skilled in the art. Typically, the amount of active ingredient is from 0.01% to 99% by weight of the composition.
In general, a therapeutically effective dose of the active ingredient will range from about 0.01 to about 100 mg/kg body weight/day, preferably from about 0.1 to about 10 mg/kg body weight/day, more preferably from about 0.3 to 3 mg/kg body weight/day, and still more preferably from about 0.3 to 1.5 mg/kg body weight/day. It will be understood that the dosage may vary depending on the requirements of the individual subject and the severity of the disorder or disease being treated.
The desired dose may conveniently be presented in single or divided doses administered at suitable intervals (e.g. in two, three, four or more sub-doses per day). The sub-doses themselves may be further divided, for example, into a number of discrete loosely divided doses for administration; such as multiple inhaled doses generated by an insufflator or in a manner that administers drops to the eye.
Furthermore, it will be appreciated that in order to rapidly achieve the desired plasma concentration, the initial dose administered may be increased beyond the upper limit. Conversely, the starting dose may be lower than the optimal dose, and the daily dose during the treatment period may be gradually increased according to the particular condition. If desired, the daily dose may also be divided into multiple doses, for example, two to four times daily.
The present compounds relate to pyrrolo [2,3-d ] pyrimidine compounds useful as inhibitors of janus kinases (JAK-i). These compounds 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 colitis, alzheimer's disease, lupus, nephritis, psoriasis, atopic dermatitis, autoimmune thyroid disease, multiple sclerosis, major depression, allergy, asthma, sjogren's disease, dry eye syndrome, organ transplant rejection, xeno organ transplantation, type I diabetes and diabetic complications, cancer, leukemia, T-cell acute lymphocytic leukemia, adult T-cell leukemia, activated B-cell diffuse large B-cell lymphoma, inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, chronic obstructive pulmonary disease, acute respiratory disease, cachexia and other indications for which immunosuppression/immunomodulation is desired, comprising the step of administering to a subject an effective amount of a compound of the invention.
There is a substantial need for safe and effective agents for controlling JAK-associated disorders, such as atopic dermatitis in humans and animals. The market for the treatment of atopic dermatitis in animals is currently predominantly corticalSteroids, which cause distressing and undesirable side effects in animals, particularly companion animals such as dogs. Antihistamines can also be used, but less effectively. Canine formulation of cyclosporin (atopca)TM) Is currently marketed for atopic dermatitis, but it is expensive and begins to be slow in efficacy. Further, ATOPICATMThere is a problem of gastrointestinal tolerance. The compounds of the invention are JAK inhibitors and have selective potency against JAK 1. These compounds are expected to provide an alternative to the use of steroids and to provide a solution to chronic itching and inflammation that persists in atopic dermatitis or that slowly recedes after removal of allergens or pathogens (e.g., fleas in flea-allergic dermatitis).
The compounds of the present invention may be administered alone or in combination with one or more additional agents that modulate the immune system of a mammal or with an anti-inflammatory agent in a pharmaceutically acceptable form. Such agents may include, but are not limited to, cyclosporin A (e.g., Sandimmune)TMOr NeoralTM) Rapamycin (rapamycin), FK-506(tacrolimus), leflunomide (leflunomide), deoxyspergualin (deoxyspergualin), mycophenolate mofetil (e.g. Cellcept)TM) Azathioprine (e.g., Imuran)TM) Rilizumab (daclizumab) (e.g., Zenapax)TM) OKT3 (e.g. Orthocolone)TM) AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids such as prednisolone or dexamethasone. These agents may be administered in the same or separate dosage forms, by the same or different routes of administration, and on the same or different schedules of administration, according to standard pharmaceutical practice known to those skilled in the art.
Accordingly, the present invention provides a method of treating or preventing a disease, condition or disorder associated with JAK in a subject (e.g., a human or non-human mammal) comprising administering to the subject an effective amount of one or more compounds described herein. Suitable subjects that can be treated include domestic or wild animals, companion animals such as dogs, cats, horses, etc.; livestock, including cattle and other ruminants, swine, poultry, rabbits, and the like; primates, such as monkeys, e.g., rhesus monkeys (rhesus monkeys) and stone crab monkeys (Cynomolgus monkeys) (also known as Cynomolgus or Cynomolgus monkeys), marmosets (marmosets), tamarins (tamarins), chimpanzees (chimpanzees), macaques, and the like; and rodents such as rats, mice, gerbils, guinea pigs, and the like. In one embodiment, the compound is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier.
Conditions for which selective targeting of the JAK pathway or modulation of JAK kinases (particularly JAK1) is expected to have therapeutic utility include arthritis, asthma, autoimmune diseases, cancer or tumors, diabetes, certain eye diseases, disorders or conditions, inflammation, intestinal inflammation, allergy or conditions, neurodegenerative diseases, psoriasis, and transplant rejection. Conditions that may benefit from the selective inhibition of JAK1 are discussed in more detail below.
Accordingly, the compounds of formula I, IA, IB, IC or ID, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are useful for treating a number of conditions or disorders such as:
arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis;
autoimmune diseases or disorders, including single organ or single cell type autoimmune disorders, such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis from pernicious anemia, autoimmune encephalomyelitis, autoimmune testitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves ' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, those involving systemic autoimmune disorders (e.g. systemic lupus erythematosus, rheumatoid arthritis, schroemeria syndrome, lewy's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid), and autoimmune diseases, And other autoimmune diseases of the O-cell (humoral) or T-cell type (including Cogan's syndrome), ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I diabetes or juvenile onset diabetes or thyroiditis;
cancers or tumors, including cancers of the digestive/gastrointestinal tract, colorectal, liver, skin (including mast cell and squamous cell), breast and breast, ovarian, prostate, lymphoma, leukemia (including acute and chronic myelogenous leukemias), kidney, lung, myoma, bone, bladder, brain, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, myeloma (including multiple myeloma), myeloproliferative disorders, proliferative diabetic retinopathy or disorders associated with angiogenesis (including solid tumors);
diabetes, including type I diabetes or diabetic complications;
an ocular disease, disorder or condition, comprising an autoimmune disease of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis (including Behcet's disease uveitis and lens-induced uveitis), keratitis, herpes viral keratitis, keratoconus, corneal endothelial dystrophy, leukoplakia, ocular pemphigus, moren's ulcer, scleritis, grev's (Grave's) eye pathology, Vogt-Koyanagi-Harada syndrome, dry eye, blister, iridocyclitis, sarcoidosis, endocrine eye disease, sympathetic eye inflammation, allergic conjunctivitis, or ocular neovascularization;
an intestinal inflammation, allergy or disorder, comprising crohn's disease and/or ulcerative colitis, inflammatory bowel disease, chylomicron, proctitis, eosinophilic gastroenteritis, or mastocytosis;
neurodegenerative diseases, including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, neurodegenerative diseases caused by cerebral ischemia or traumatic injury, stroke, glutamate neurotoxicity or hypoxia; ischemia/reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia or platelet aggregation;
a skin disease, condition or disorder, including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus or other pruritus;
allergic reactions, including allergic dermatitis (including horse allergic diseases such as sting allergy), summer eczema, horse itch (sweet itch), horse chronic emphysema, inflammatory airway diseases, recurrent airway obstruction, airway hyperreactivity or chronic obstructive pulmonary disease in mammals;
asthma and other obstructive airways diseases including chronic or refractory asthma, late asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma or dust mite asthma;
transplant rejection, including pancreatic islet transplant rejection, bone marrow transplant rejection, graft versus host disease, organ and cell transplant rejection (e.g., bone marrow, cartilage, cornea, heart, intervertebral disc, pancreatic islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea) or xenogeneic organ transplant; and
another embodiment provides a method of selectively inhibiting a JAK1 enzyme, comprising contacting the JAK enzyme with a non-therapeutic or therapeutically effective amount of one or more compounds of the invention. The method may occur in vivo or in vitro. In vitro contacting may include screening assays to determine the efficacy of the one or more compounds against the selected enzyme at various amounts or concentrations. In vivo contact with a therapeutically effective amount of the one or more compounds may comprise treating the disease, disorder or condition or preventing organ transplant rejection in the contacted animal. The effect of the 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 the methods described in the examples and the methods disclosed in WO99/65908, WO99/65909, WO01/42246, WO02/00661, WO02/096909, WO2004/046112 and WO 2007/012953.
Chemical synthesis
The following reaction schemes and written description provide general details regarding the preparation of the compounds of the present invention.
Sulfonamides
A compound of formula I (wherein p is 2, X is NH, Y is AR)5And A is a bond) can be prepared according to reaction scheme 1.
Scheme 1
Those skilled in the art will appreciate that the sensitive functional group (PG) may need to be protected and deprotected during synthesis of the compounds of the invention. Protection and deprotection can be achieved using conventional methods, for example, "Protective Groups in organic Synthesis", T.W.Greene and P.G.M.Wuts, John Wiley&Sons Inc (1999) and the references cited therein. Thus, in scheme 1, step 1, a compound of formula II (wherein Q is1Is halogen) is treated with a protecting agent to give a compound of formula III, wherein PG1Is an arylsulfonyl protecting group such as phenylsulfonyl or, preferably, p-toluenesulfonyl ("tosyl"). The protecting group may be introduced by reacting a compound of formula II with an arylsulfonyl chloride, preferably tosyl chloride, in the presence of a base, for example aqueous sodium hydroxide, and an organic solvent, for example acetone. The reaction is generally carried out at 0 ℃ to about 50 ℃, preferably about 23 ℃ (room temperature). Alternatively, a base (e.g., sodium hydride and potassium tert-butoxide) can be used with a suitable solvent (e.g., N-dimethylformamide or tetrahydrofuran). Several compounds of the formula II are known from the literature and have been described aboveThe method is used for preparing the product. For example, compounds of formula II (wherein Q1Is Cl and R2And R3Is hydrogen) has been reported, for example, in WO 2007012953.
In scheme 1, step 2, the protected compound of formula III is mixed with 1-2 equivalents of the amine of formula IV in the presence of 1-3 equivalents of a base and a protic solvent to provide the compound of formula V. Suitable bases include triethylamine, diisopropylethylamine and potassium carbonate, while suitable solvents include methanol, ethanol, diisopropyl alcohol and water or mixtures thereof. The reaction is generally carried out at about 23 ℃ to about 150 ℃, preferably about 75 ℃. It is understood that the amine of formula IV contains a second amino group and is protected with a protecting group PG2Protection, and PG2Can not lose PG1Is removed under the conditions of (1). Suitable protecting groups PG2Comprising a tert-butoxycarbonyl group ("Boc") and a benzyloxycarbonyl group ("Cbz"), preferably benzyloxycarbonyl.
In step 3 of reaction scheme 1, no removal of PG is caused1Under conditions such that the protecting group PG is removed from the compound of formula V2To form a primary amine (or salt thereof) of formula VI. When PG is used2Is benzyloxycarbonyl, which can be removed by hydrogenolysis, wherein the compound of formula V is exposed to hydrogen or a hydrogen transfer agent (e.g., cyclohexene) in the presence of a hydrogenation catalyst (e.g., palladium hydroxide) using a solvent (e.g., methanol, acetic acid, or preferably ethanol). Or, when PG2Is a benzyloxycarbonyl group which 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 suitable solvent such as ethyl acetate, at a temperature of from about-20 ℃ to about 40 ℃ (preferably less than 25 ℃). The latter deprotection method is preferred, wherein n is 1 and R2、R3And R4Is hydrogen, R1Is methyl, PG1Is tosyl and PG2Is benzyloxycarbonyl, and provides the amine dihydrobromide salt of formula VI. When PG is used2Is a tert-butoxycarbonyl group which may be protected by reaction of an excess of an acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as dichloromethane or 1, 4-bisAlkane) to remove.
In scheme 1, step 4, the primary amine (or salt thereof) of formula VI is a sulfonic acid derivative that can be activated by the reaction of formula VIII (wherein Q is2Is halogen, O-alkyl or O-aryl) in the presence of a base to convert to a sulfonamide derivative of formula VII. Most commonly, VIII is a sulfonyl chloride derivative, wherein Q2Is Cl. Many sulfonyl chlorides are available from commercial sources. Furthermore, a number of methods for preparing sulfonyl chlorides exist and are known to those skilled in the art and are disclosed in textbooks such as "Advanced Organic Chemistry", j&Sons (1985). Typically, the amine of formula VI is a sulfonyl chloride derivative of formula VIII (wherein Q is2Is Cl) in the presence of at least one equivalent of a base, such as triethylamine or diisopropylamine, in a suitable solvent, such as dichloromethane, tetrahydrofuran or acetonitrile. When the salt form of the amine is used, an additional equivalent of base is used for each equivalent of acid forming the salt. For example, when a dihydrobromide salt is used, an additional two equivalents of base are used. The reaction can be carried out from about-20 ℃ to about 50 ℃, preferably starting at about 0 ℃, and warming the reaction to about 23 ℃ (room temperature).
Finally, in scheme 1, step 5, the sulfonamide derivative of formula VII is deprotected to provide a compound of formula I (wherein p is 2, X is NH, Y is AR)5And A is a bond). Two methods are generally used and the choice of method depends on the compatibility of the 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 comprising water and an alcohol, such as methanol or ethanol. The reaction can also be carried out in a mixture of water and tetrahydrofuran and optionally an alcohol, for example methanol or ethanol. The reaction may be carried out at a temperature of from about 23 ℃ to about 100 ℃ (typically about 60 ℃). The second method, which is preferred in the presence of hydroxyl-sensitive functional groups (e.g., nitriles) in the molecule, involves dissolving a compound of formula VII with an excess of tetrabutylammonium fluoride (4-25 equivalents)In an agent such as 1, 2-dimethoxyethane or preferably tetrahydrofuran. Deprotection is carried out at a temperature of from about 0 ℃ to about 60 ℃ (preferably about 23 ℃).
A compound of formula II (wherein Q)1Is halogen) is commercially available or is already known in the chemical literature. For example, 4-chloro-7H-pyrrolo [2,3-d]Pyrimidines, wherein Q1Is Cl and R2And R3Are both hydrogen and are readily commercially available compounds.
The compounds of formula IV are known in the chemical literature or can be prepared by standard chemical reactions known to those skilled in the art.
Another preparation of the compounds of the invention (where p is 2, X is NH and Y is AR)5And a is a bond) is shown in reaction scheme 2.
Scheme 2
In scheme 2, step 1, a compound of formula IX is mixed with a benzyloxycarbamate derivative of formula X in the presence of a base (1-5 equivalents) to give a benzyloxycarbamate derivative of formula XI. The reaction is carried out in a solvent (e.g. water or an alcohol, e.g. ethanol) and optionally with the addition of a miscible cosolvent (e.g. tetrahydrofuran). Suitable bases include potassium carbonate, cesium carbonate, triethylamine and diisopropylethylamine. The reaction is carried out at a temperature of about 23 ℃ to about 100 ℃. When n is 1, R2、R3And R4Is hydrogen, and R1In the case of methyl, the preferred conditions are to carry out the reaction in water, start the reaction at about 23 ℃ using potassium carbonate (3 equivalents) as the base, and then raise the temperature to about 95 ℃.
In scheme 2, step 2, a benzyloxycarbamate derivative of formula XI is deprotected by exposure to hydrogen or a hydrogen transfer agent (e.g., cyclohexene) in the presence of a hydrogenation catalyst (e.g., palladium hydroxide). Meanwhile, under the condition of deprotection, 7H-pyrrolo [2,3-d]Of pyrimidine ringsThe chlorine atom in the 2-position is replaced with hydrogen to form the amine hydrochloride salt of formula XII. The reaction is carried out in a solvent (e.g., methanol or ethanol) at a temperature of about 50 ℃ to about 80 ℃. When R is2、R3And R4Is hydrogen, and R1In the case of methyl, the preferred conditions are the use of palladium hydroxide as catalyst in ethanol at about 78 ℃ and cyclohexene (about 20 equivalents) as hydrogen transfer agent.
Finally, in step 3, scheme 2, amine hydrochloride of formula XII is reacted with an activated sulfonic acid derivative of formula VIII (wherein Q2Is halogen, O-alkyl or O-aryl) in the presence of at least two equivalents of a base to form a sulfonamide of formula I (wherein p is 2, X is NH, Y is AR)5And A is a bond). Most commonly, VIII is a sulfonyl chloride derivative, wherein Q2Is Cl. Suitable bases include triethylamine, diisopropylethylamine and potassium carbonate. Suitable solvents include N, N-dimethylformamide, and mixtures of tetrahydrofuran and water. The reaction may be carried out at a temperature of about-20 ℃ to about 50 ℃ (preferably about 23 ℃). Alternatively, the amine hydrochloride of formula XII is first treated 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 suitable aprotic solvent, such as tetrahydrofuran. Next, after about 1 hour, about 1.2 equivalents of a sulfonyl chloride of formula VIII (wherein Q is2Is Cl) to give, after work-up, a sulfonamide of the formula I (where p is 2, X is NH and Y is AR)5And A is a bond). The reaction may be carried out at a temperature of about-20 ℃ to about 50 ℃ (preferably about 23 ℃).
The compounds of formula IX are commercially available or are already known in the chemical literature. For example, 2, 4-dichloro-7H-pyrrolo [2,3-d ]]Pyrimidines (wherein R2And R3Both hydrogen) are commercially available. The synthesis of which is disclosed in PCT International publication WO 2007/012953.
Thioamides
A compound of formula I (wherein p is 2, X is NH, and Y is NRaRb) Can be prepared according to reaction scheme 3.
In reaction scheme 3, step 1, an amine (or salt thereof) of formula VI (wherein PG1Is an arylsulfonyl protecting group such as phenylsulfonyl or preferably tosyl) is converted to a compound of formula XIIIAn oxazolidinone derivative. First, a solution of N-chlorosulfonyl isocyanate (1 eq.) is slowly added to a solution of 2-bromoethanol (1 eq.) at a temperature of about-40 ℃ to about 10 ℃ (preferably about 0 ℃). Then, after 0.5 to 2 hours, a solution of the amine of formula VI (1 equivalent) and a base (e.g. triethylamine or diisopropylethylamine) (about 3 equivalents, plus one equivalent per mole of acid forming the salt) is slowly added and the reaction is allowed to warm to about 23 ℃ for about 10 to 24 hours. Suitable solvents for the reaction include chloroform or preferably dichloromethane.
In reaction scheme 3, step 2, of formula XIIIOxazolidinone derivatives with 1-3 equivalents of a compound of formula HNRaRbIn the presence of a base (2-5 equivalents) to give the sulfamide derivative of formula XIV. Suitable bases include triethylamine and diisopropylethylamine. The reaction is preferably carried out in a pressurized vessel with heating to about 90 ℃ to about 150 ℃ using a suitable solvent (e.g., N-dimethylformamide or acetonitrile).
In scheme 3, step 3, deprotection of a compound of formula XIV removes the arylsulfonyl protecting group PG1To give a sulfamide derivative of formula I (wherein p is 2, X is NH, and Y is NR)aRb). The reaction can be carried out in one of the two general methods mentioned in step 5 of reaction scheme 1. Likewise, the choice of deprotection method depends on the compatibility of the conditions with other functional groups within the molecule. Alternatively, the sulfamide of formula XIV can be obtained directly from the amine of formula VI (or a salt thereof)And (4) obtaining. Thus, in scheme 3, step 4, the amine of formula VI (or salt thereof) is treated as described in scheme 1, step 4 as Cl-SO2NRaRbWith a base such as triethylamine or diisopropylethylamine. Formula Cl-SO2NRaRbThe sulfamoyl chloride of (A) can thus be represented by the formula HNRaRbThe amines of (a) were prepared according to the procedure disclosed in W.R.Bowman and R.J.Marmon, "Comprehensive Organic Functional groups formulations, Volume 2", Pergamon (1995).
A compound of formula I (wherein p is 2, X is NH, and Y is NR)aRb) They can also be obtained directly from amines of the formula XII (or salts thereof). Thus, in scheme 3, step 5, the amine of formula XII (or salt thereof) is prepared according to the formula Cl-SO as described in scheme 1, step 42NRaRbWith a base such as triethylamine or diisopropylethylamine. The amine of formula XII is obtained as described in reaction scheme 2. The amine of formula XII (or salt thereof) may be prepared by removing the arylsulfonyl protecting group PG of the compound of formula VI (see scheme 1)1And obtaining the compound. Deprotection reactions can be carried out by one of the two general deprotection methods mentioned in step 5 of scheme 1. The choice of deprotection method depends on the compatibility of the conditions with other functional groups in the molecule.
Sulfonamide
A compound of formula I (wherein p is 2 and X is CH)2And Y is NRaRb) Can be prepared according to reaction scheme 4.
Scheme 4
In scheme 4, step 1, a compound of formula III (see scheme 1) is reacted with an aminoalcohol of formula XV in the presence of a base and a polar solvent to provide a compound of formula XVI. Suitable bases include triethylamine and diisopropylethylamine, while suitable solvents include methanol, diisopropyl alcohol and acetone. The reaction is generally carried out at about 23 ℃ to about 70 ℃. Preferably, a catalytic amount (about 1 mol%) of potassium iodide is added to the reaction.
In reaction scheme 4, step 2, a compound of formula XVI is converted to a compound of formula XVII (wherein LG is a leaving group such as bromo, iodo, methanesulfonate, or preferably p-toluenesulfonate). Methods for introducing such leaving groups are known to those skilled in the art and are disclosed in textbooks such as "Advanced Organic Chemistry", j. In the case where LG is a p-toluenesulfonate group, the compound of formula XVI is treated with p-toluenesulfonyl chloride in the presence of a base such as triethylamine, diisopropylethylamine or N, N-dimethylaminopyridine in an aprotic solvent such as dichloromethane or tetrahydrofuran. The reaction is carried out at a temperature of about-10 ℃ to about 40 ℃, preferably starting at about 0 ℃, and the reaction is allowed to warm to about 23 ℃.
In scheme 4, step 3, the compound of formula XVII is combined with a salt of thioacetic acid, preferably potassium thioacetate, to give a thioester derivative of formula XVIII. The reaction is carried out in a polar solvent, such as N, N-dimethylformamide or N-methylpyrrolidine, at a temperature of from about 23 ℃ to about 80 ℃ (preferably about 55 ℃).
In scheme 4, step 4, the thioester derivative of formula XVIII is converted to the sulfonic acid derivative of formula XIX by reaction with an aqueous solution of hydrogen peroxide (typically 30% by weight). The reaction is carried out in an acidic solvent (e.g., formic acid or acetic acid) at a temperature of from about 0 ℃ to about 40 ℃ (preferably about 23 ℃).
In scheme 4, step 5, the sulfonic acid derivative of formula XIX is converted to the sulfonyl chloride derivative of formula XX. Several methods for performing this functional group transformation have been disclosed in the literature. A preferred method is to treat the compound of formula XIX with an excess (3-15 equivalents) of thionyl chloride in the presence of a catalytic amount of N, N-dimethylformamide in an aprotic solvent such as dichloromethane or chloroform. The reaction may be carried out at about-20 ℃ to about 100 ℃, preferably the reaction is initiated at about 0 ℃ followed by a temperature increase to about 75 ℃.
Alternatively, in reaction scheme 4, step 6, the thioester derivative of formula XVIII can be directly converted to the sulfonyl chloride derivative of formula XX by treatment with a chlorinating agent. Several methods for performing this functional group transformation have been disclosed in the literature. The chlorinating agent comprises chlorine gas and N-chlorosuccinimide, and the reaction is usually carried out in the presence of an acid (e.g., hydrochloric acid or acetic acid). Mixed aqueous solvent systems are often used, such as water and dichloromethane and water and acetonitrile.
In reaction scheme 4, step 7, a sulfonyl chloride derivative of formula XX is reacted with 1-3 equivalents of a compound of formula HNRaRbTo form a sulfonamide derivative of formula XXI. The reaction is carried out in the presence of at least one equivalent of a base (e.g., triethylamine or diisopropylethylamine) at a temperature of about-20 ℃ to about 50 ℃ (preferably, the reaction is initiated from about 0 ℃ and the reaction is allowed to warm to about 23 ℃). The reaction is carried out in an aprotic solvent (e.g., tetrahydrofuran or dichloromethane).
Finally, in scheme 4, step 8, the arylsulfonyl protecting group PG is removed1To form a compound of formula I (wherein p is 2 and X is CH)2And Y is NRaRb). The reaction can be carried out by one of the two general deprotection methods mentioned in step 5 of reaction scheme 1. The choice of deprotection method depends on the compatibility of the conditions with other functional groups in the molecule. The amino alcohols of the formula XV are already known in the chemical literature or can be prepared by methods known to the person skilled in the art.
Sulfones, sulfoxides and thioethers
A compound of formula I (wherein p is 0, 1 or 2 and X is CH)2Y is AR5And A is a bond) can be prepared according to reaction scheme 5.
Scheme 5
In reaction scheme 5, step 1, a compound of formula XVII (reference reactionReaction scheme 4) with 1-2 equivalents of formula R5The thiol of SH is treated in the presence of 1-2 equivalents of a base to give a thioether of the formula XXIII. Suitable bases include sodium hydride, sodium bis (trimethylsilyl) amide, 1, 5-diazabicyclo [4.3.0]Non-5-ene (DBN), and preferably 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (DBU). The reaction is carried out in a solvent such as N, N-dimethylformamide or N-methylpyrrolidinone at a temperature of from about 0 ℃ to about 50 ℃ (preferably about 23 ℃).
In scheme 5, step 2, a compound of formula XXIII is deprotected to remove the arylsulfonyl protecting group PG1To form a compound of formula XXIV. The reaction can be carried out by one of the two general deprotection methods mentioned in step 5 of reaction scheme 1. The choice of deprotection method depends on the compatibility of the conditions with other functional groups in the molecule.
In scheme 5, step 3, a thioether of formula XXIV is oxidized to give a sulfone of formula I (wherein p is 2 and X is CH)2Y is AR5And A is a bond). Several methods have been found in the literature, and all involve the use of oxidizing agents, such as meta-chloroperoxybenzoic acid, hydrogen peroxide or potassium peroxymonosulfate complex saltsThe preferred method is to use 2 equivalents of potassium monopersulfate complex saltA compound of formula XXIV is treated in a solvent mixture of tetrahydrofuran, ethanol and water at a temperature of about 23 ℃. The thioether of formula XXIV may also be oxidized under milder conditions, for example using between 1 equivalent of chloroperoxybenzoic acid in a solvent such as methylene chloride at a temperature of about 0 deg.C to provide the sulfoxide of formula I (where p is 1 and X is CH2Y is AR5And A is a bond).
It is noted that the order of steps 2 and 3 in scheme 5 may optionally be reversed such that the oxidation step is performed before the deprotection step.
Of the formula ICompound (wherein p is 0 and X is CH)2Y is AR5And A is a bond) is prepared by removing the arylsulfonyl protecting group PG in a compound of formula XXIII in step 4 of reaction scheme 51And obtaining the compound. The reaction can be carried out by one of the two general deprotection methods mentioned in step 5 of reaction scheme 1. Likewise, the choice of deprotection method depends on the compatibility of the conditions with other functional groups within the molecule.
In scheme 5, step 5, a compound of formula XXIII is alternatively prepared from a thioacetate derivative of formula XVIII. First, the thioacetate of formula XVIII is dissolved in a solvent, such as ethanol, methanol or water (or a mixture thereof). A suitable base, such as potassium carbonate or cesium carbonate (about 2 equivalents) is added and a nitrogen bubble is bubbled through the solution to remove oxygen. Followed by addition of formula R5Alkylating agents of LG, wherein LG is a leaving group, such as a bromo, iodo, mesylate or p-toluenesulfonate group. The reaction is carried out at a temperature of from about-20 ℃ to about 30 ℃. Preferably, the reaction starts at about 0 ℃ and then warms up to about 23 ℃.
A plurality of formulae R5Thiols of SH with formula R5Alkylating agents for LG are commercially available from commercial sources. Furthermore, there are a number of methods for preparing such compounds which are known to the person skilled in the art and are known from textbooks, such as "Advanced Organic Chemistry", j&Sons(1985)。
It will be appreciated that some of the compounds of the invention may be obtained by functional group conversion at a later stage of the synthesis, for example, after performing steps 4 or 5 of reaction scheme 1, step 3 of reaction scheme 2, steps 2,3 or 4 of reaction scheme 3, steps 7 or 8 of reaction scheme 4, and steps 2,3, 4 or 5 of reaction scheme 5, the group R is allowed to react4Or R5Carrying out chemical modification. Such functional group conversion may comprise one or more steps, for example, reduction of the ester to an alcohol, reoxidation to an aldehyde, addition of an organomagnesium reagent to form a secondary alcohol, reoxidation to a ketone, and finally, addition of an organomagnesium reagent to yield a tertiary alcohol.
In carrying out the synthesis of the compounds of the invention, it will be understood by those skilled in the art that prior to purification treatment, it may be necessary to sample and analyze the reaction mixture to monitor the progress of the reaction and to determine whether the reaction should be continued or whether purification treatment may be carried out to obtain the desired product. Common methods of analyzing the reaction mixture include Thin Layer Chromatography (TLC), liquid chromatography/mass spectrometry (LCMS), and Nuclear Magnetic Resonance (NMR).
It will also be appreciated by those skilled in the art that the compounds of the invention may be prepared as mixtures of diastereomers or geometric isomers (e.g., cis and trans substitutions on the cyclohexane ring). These isomers can be separated by standard chromatographic techniques, such as forward chromatography on silica gel, reverse phase preparative high pressure liquid chromatography or supercritical fluid chromatography. It will also be appreciated by those skilled in the art that some of the compounds of the invention are chiral and may thus be prepared as racemic or non-racemic (scalemic) mixtures of enantiomers. Several methods for the separation of enantiomers exist and are known to those skilled in the art. The customary enantiomeric separation is preferably performed by supercritical fluid chromatography using a chiral stationary phase.
Experimental part
Unless specifically mentioned, the reaction is carried out under a nitrogen atmosphere. Silica gel chromatography using 250-400 mesh silica gel pressurized nitrogen (-10-15 psi) was used to drive the solvent through the column ("flash chromatography"). When indicated, the solution and reaction mixture were concentrated under vacuum using rotary evaporation.
Example 1:2, 2, 2-trifluoro-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } ethanesulfonamide
Step 1: [ cis-3- (methylamino) cyclobutyl ] carbamic acid benzyl ester and [ trans-3- (methylamino) cyclobutyl ] carbamic acid benzyl ester
A33% solution of methylamine in absolute ethanol (1000mL, 9.13mol) was added to stirring (3-oxo) at 0 deg.CCyclobutyl) benzyl carbamate (WO2012/75381 a1 and WO2012/09678 a1) (200g, 0.913mol) and acetic acid (88mL) in a mixture of ethanol (1000mL) the reaction mixture is stirred at 0 ℃ for 1.5 hours, then at room temperature for 2 hours, lithium borohydride (41g, 2.05mol) is added portionwise to the reaction mixture at-70 ℃ after the addition is complete, the reaction mixture is stirred at-70 ℃ for 1 hour, then allowed to warm to room temperature for 12 hours, water (400mL) is added to the reaction mixture to quench the reaction, concentrated under vacuum to remove ethanol, the aqueous layer is acidified to pH 2 with concentrated hydrochloric acid, washed with ethyl acetate (2 × 1000mL), basified with 10% sodium hydroxide to pH 9-10, then extracted with dichloromethane (3 × 1000mL), the combined organic layers are washed with brine (1000mL), dried with sodium sulfate, and concentrated to give a crude brown liquid, this crude product is cooled to dichloromethane (0 mL) and added to a solution of HCl in dichloromethane (4M) and the resulting solution is added to HClThe resulting solution in alkane (300 mL). The mixture was stirred at 0 ℃ for 30 minutes, followed by stirring at room temperature for 12 hours. The reaction mixture was filtered and the residual solid was recrystallized from a mixture of methanol and methyl tert-butyl ether to give a white solid of cis-isomer (111.09g, 52%).1HNMR：(400MHz，D2O): 7.33-7.38(m, 5H), 5.02(s, 2H), 3.83-3.87(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): c13H18N2O2The theoretical value of (A); 234.137, Experimental value (M + H)+)；235.1。
The trans isomer was separated from the mother liquor using supercritical fluid chromatography.
Step 2: { cis-3- [ (2-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) (methyl) amino ] cyclobutyl } carbamic acid benzyl ester
To a solution of potassium carbonate (20.47g, 148mmol) in water (180mL) was added [ cis-3- (methylamino) cyclobutyl]Benzyl carbamate (13.57g, 50.2mmol), then 2 was added at room temperature,4-dichloro-7H-pyrrolo (2,3-d) pyrimidine (9.0g, 47.9 mmol). After the addition was complete, the reaction mixture was stirred at 95 ℃ overnight. The mixture was filtered to collect the solid. The filter cake was washed with water and dried under vacuum to give the title compound (16.5g, 89.7%) as a yellow solid.1HNMR(400MHz，DMSO-d6): 11.81(sm, 1H), 7.65(d, 1H), 7.38(m, 5H), 7.16(m, 1H), 6.67(d, 1H), 5.02(s, 2H), 4.81(m, 1H), 3.85(m, 1H), 3.25(s, 3H), 2.53(m, 2H), 2.25(m, 2H). LC/MS (exact mass): c19H20ClN5O2The theoretical value of (A); 385.131, Experimental value (M + H)+)；386.1。
And step 3: cis-N-methyl-N-7H-pyrrolo [2,3-d ] pyrimidin-4-cyclobutane-1, 3-diamine hydrochloride
{ cis-3- [ (2-chloro-7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) (methyl) -amino]Cyclobutyl } carbamate (13.0g, 34.0mmol), Pd (OH)2A mixture of (40.3g, 40.8mmol) and cyclohexene (72.5mL, 0.71mol) in ethanol (300mL) was stirred at reflux for 3 h. The reaction mixture is passed throughThe pad was filtered and washed with methanolA pad. The filtrate was concentrated in vacuo to afford the title compound (4.8g, 66%) as a white solid.1H NMR(400MHz，DMSO-d6): 11.68(br, 1H), 8.11(s, 1H), 7.67(br, 2H), 7.17(d, 1H), 6.65(d, 1H), 5.08(m, 1H), 3.45(m, 1H), 3.26(s, 3H), 2.31(m, 4H). LC/MS (exact mass): c11H15N5The theoretical value of (A); 217.133, Experimental value (M + H)+)；218.1。
And 4, step 4: 2,2, 2-trifluoro-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } ethanesulfonamide
At room temperature, in cis-N-methyl-N-7H-pyrrolo [2,3-d]Pyrimidin-4-yl cyclobutanesTo a solution of alkyl-1, 3-diamine hydrochloride (100mg, 0.39mmol) in tetrahydrofuran (0.8mL) were added lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran) (0.9mL, 0.9mmol) and chlorotrimethylsilane (94mg, 0.88 mmol). The reaction mixture was stirred for 45 minutes, followed by the slow addition of 2,2, 2-trifluoroethanesulfonyl chloride (86mg, 0.47 mmol). The mixture was stirred at room temperature for 18 hours, then partitioned between dichloromethane and water. The aqueous layer was extracted twice with dichloromethane and the combined organic layers were concentrated to give the crude product as a brown solid. The crude material was purified by silica gel chromatography, eluting with a mixture of dichloromethane and methanol (93:7), to afford the title compound as a white solid (93mg, 65%).1H NMR(400MHz，DMSO-d6): 11.61(br.s., 1H), 8.20(d, 1H), 8.08(s, 1H), 7.13(d, 1H), 6.60(d, 1H), 4.80-4.94(m, 1H), 4.34(q, 2H), 3.58-3.71(m, 1H), 3.23(s, 3H), 2.55-2.67(m, 2H), 2.17-2.30(m, 2H). LC/MS (exact mass): c13H16F3N5O2Theoretical value of S; 363.098, Experimental value (M + H)+)；363.9。
The following compounds, examples 2-7, were prepared from cis-N-methyl-N-7H-pyrrolo [2,3-d ] pyrimidin-4-cyclobutane-1, 3-diamine hydrochloride (example 1, step 3) in analogy to the procedure described in example 1, step 4, substituting the sulfonyl chloride shown for 2,2, 2-trifluoroethane sulfonyl chloride.
Example 2: n- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -propane-1-sulfonamide
This compound was prepared using 1-propanesulfonyl chloride. The crude compound was purified by silica gel chromatography eluting with a mixture of dichloromethane and methanol (93:7) to afford the title compound as a brown solid (78% yield).1H NMR(400MHz，DMSO-d6)：11.60(br s，1H)，8.08(s，1H)，7.46(d，1H)，7.12(d，1H)，6.61(d，1H)，4.81-4.94(m，1H)，3.47-3.62(m，1H)，3.23(s，3H)，2.87-2.96(m，2H)，2.52-2.63(m，2H)，2.14-2.27(m，2H)，1.60-1.73(m2H), 0.96(t, 3H). LC/MS (exact mass): c14H21N5O2Theoretical value of S; 323.142, Experimental value (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
This compound was prepared using 2-methyl-1-propanesulfonyl chloride. The crude compound was purified by silica gel chromatography eluting with a mixture of dichloromethane and methanol (93:7) to afford the title compound as a white solid (52%).1H NMR(400MHz，DMSO-d6): 11.64(br s, 1H), 8.12(s, 1H), 7.51(d, 1H), 7.03-7.26(m, 1H), 6.65(d, 1H), 4.82-5.02(m, 1H), 3.52-3.70(m, 1H), 3.26(s, 3H), 2.87(d, 2H), 2.55-2.67(m, 2H), 2.18-2.30(m, 2H), 2.11(dt, 1H), 1.04(d, 6H). LC/MS (exact mass): c15H23N5O2Theoretical value of S; 337.157, Experimental value (M + H)+)；338.0。
Example 4A and example 4B: cis-and trans-3- (cyanomethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutanesulfonamide
These compounds were prepared using a mixture (. about.1: 1) of cis-and trans-3- (cyanomethyl) cyclobutanesulfonyl chloride. The crude mixture of cis and trans isomers was purified by silica gel chromatography eluting with a gradient of dichloromethane and methanol (100:0 to 10:1) to give the mixture of the title compounds (420mg) as a white solid (67%). Cis and trans isomers were separated by supercritical fluid chromatography.
Cis-isomer 4A: 160mg (21%).1H NMR (400MHz, methanol-d)4)：8.12(s，1H)，7.13-7.12(d，1H)，6.69-6.69(d，1H)，4.92-4.89(m，1H)，3.84-3.78(m，1H)，3.76-3.67(m，1H)，3.36(s，3H)，2.79-2.73(m，2H) 2.65-2.64(m, 3H), 2.58-2.52(m, 2H), 2.32-2.19(m, 4H). LC/MS (exact mass): c17H22N6O2Theoretical value of S; 374.152, Experimental value (M + H)+)；375.3。
Trans-isomer 4B: 155mg (20%).1H NMR (400MHz, methanol-d)4): 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, 1H), 3.36(s, 3H), 2.85-2.62(m, 7H), 2.31-2.23(m, 4H). LC/MS (exact mass): c17H22N6O2Theoretical value of S; 374.152, Experimental value (M + H)+)；374.9。
A mixture of cis-and trans-3- (cyanomethyl) cyclobutanesulfonyl chlorides was prepared by the following method:
step 1: [3- (benzyloxy) cyclobutyl ] acetonitrile
Diethyl cyanomethylphosphonate (1.21g, 3.40mmol) was added to a cold suspension of sodium hydride (125mg, 3.12mmol) in tetrahydrofuran (12mL) at 0 ℃. The mixture was stirred at room temperature for 1 hour, followed by addition of a solution of 3- (benzyloxy) cyclobutanone (500mg, 2.84mmol) in tetrahydrofuran (8 mL). The mixture was stirred at room temperature overnight, followed by addition of water to quench the reaction. The mixture was extracted with ethyl acetate (3 × 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 give the title compound (450mg, 80%) as a yellow oil.
Step 2: [3- (benzyloxy) cyclobutyl ] acetonitrile
[3- (benzyloxy) cyclobutylidene group]A mixture of acetonitrile (10.2g, 51mmol) and 10% Pd/C (2.0g) in dry tetrahydrofuran was pressurized to 50psi with hydrogen and stirred at room temperature for 3 days. The mixture was then filtered and concentrated under vacuum. 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 (7g, 70%) as a colorless oil.1H NMR(400MHz，CDCl3)：7.36-7.28(m，5H)，4.44-4.43(m，2H)，4.30-4.09(m，1H)，3.98-3.95(m，1H)，2.64-2.45(m，4H)，1.81-1.759(m，2H)。
And step 3: (3-Hydroxycyclobutyl) acetonitrile
At 0 ℃ in a [3- (benzyloxy) cyclobutyl group]To a solution of acetonitrile (1g, 5.00mmol) in acetonitrile (15mL) was added iodotrimethylsilane (1.5g, 7.50mmol) dropwise. The mixture was stirred at room temperature overnight. To the mixture was added triethylamine to quench the reaction, which was concentrated and then purified by silica gel chromatography eluting with a gradient of petroleum ether and ethyl acetate (1:0 to 1:1) to give the title compound (340mg, 62%) as a yellow oil.1H NMR(400MHz，CDCl3)：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)。
And 4, step 4: 4-Methylbenzenesulfonic acid 3- (cyanomethyl) cyclobutyl ester
To a solution of (3-hydroxycyclobutyl) acetonitrile (333mg, 3.0mmol) in dry dichloromethane (25mL) was added 4-dimethylaminopyridine (732mg, 6.0 mmol). The mixture was stirred at room temperature for 5 minutes, followed by addition of p-toluenesulfonyl chloride (859mg, 4.5 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was washed with water (2X 15 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of petroleum ether and ethyl acetate (10:0 to 7:3) to give the title compound (520mg, 65% yield) as a colorless oil.
And 5: thioacetic acid S- [3- (cyanomethyl) cyclobutyl ] ester
A mixture of 3- (cyanomethyl) cyclobutyl 4-methylbenzenesulfonate (1.5g, 5.7mmol) and potassium thioacetate (1.29g, 3.00mmol) was heated in N, N-dimethylformamide (8mL) at 80 deg.C overnight, the mixture was diluted with ethyl acetate (15mL), washed with water (30mL) and brine (2 × 30mL), dried over sodium sulfate and concentrated, the residue was purified by preparative thin layer chromatography using a mixture of petroleum ether and ethyl acetate (3:1)The material was eluted to afford the title compound (750mg, 78%) as a colorless oil.1H NMR(400MHz，CDCl3)：4.12-3.92(m，1H)，2.86-2.77(m，2H)，2.71-2.47(m，2H)，2.42-2.37(m，2H)，2.30-2.29(m，3H)，1.97-1.90(m，1H)。
Step 6: 3- (cyanomethyl) cyclobutanesulfonyl chloride
A mixture of N-chlorosuccinimide (1.6g, 12.0mmol) in concentrated HCl (3mL) and acetonitrile (12mL) was stirred at room temperature for 10 minutes. At 0 deg.C, thioacetic acid S- [3- (cyanomethyl) cyclobutyl]A solution of the ester (507mg, 3.0mmol) in acetonitrile (3mL) was stirred for 10 min, the mixture was diluted with aqueous sodium bicarbonate (50mL) and extracted with methyl tert-butyl ether (3 × 50mL), the combined organic layers were dried over anhydrous sodium sulfate and concentrated the crude product was purified by silica gel chromatography eluting with a mixture of petroleum ether and ethyl acetate (100:0 to 50:50) to give the title compound (400mg, 69%) as a yellow oil.1H NMR(400MHz，CDCl3)：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 [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methanesulfonamide
The compound is composed of [3- (cyanomethyl) oxetan-3-yl]Methanesulfonyl chloride. The crude compound was purified by preparative thin layer chromatography eluting with ethyl acetate to afford the title compound as a white solid (32%).1H NMR (400MHz, methanol-d)4): 8.13(s, 1H), 7.14-7.13(m, 1H), 6.71-6.70(m, 1H), 5.06-5.05(m, 1H), 4.85-4.81(m, 2H), 4.52-4.50(m, 2H), 3.77-3.75(m, 1H), 3.63(m, 2H), 3.39(s, 3H), 3.29-3.26(m, 2H), 2.85-2.78(m, 2H), 2.38-2.30(m, 2H). LC/MS (exact mass): c17H22N6O3Theoretical value of S; 390.147, Experimental value (M + H)+)；391.0。
[3- (cyanomethyl) oxetan-3-yl ] methanesulfonyl chloride
Step 1: 4-Methylbenzenesulfonic acid [3- (cyanomethyl) oxetan-3-yl ] methyl ester
This compound was synthesized according to the procedure of example 4, step 4, using [3- (hydroxymethyl) -3-oxetanyl]Acetonitrile instead of (3-hydroxycyclobutyl) acetonitrile. The crude compound was purified by silica gel chromatography eluting with a mixture of petroleum ether and ethyl acetate (1:0 to 1:1) to afford the title compound as a white solid (10%).1H NMR(400MHz，CDCl3)：7.82-7.80(m，2H)，7.41-7.39(m，2H)，4.54-4.35(m，4H)，4.31(s，2H)，2.79(s，2H)，2.45(s，3H)。
Step 2: [3- (cyanomethyl) oxetan-3-yl ] methyl thiocyanate
A solution of [3- (cyanomethyl) oxetan-3-yl ] methyl 4-methylbenzenesulfonate (150mg, 0.53mmol) and potassium thiocyanate (104mg, 1.07mmol) in ethanol (10mL) was stirred. The reaction was heated to 85 ℃ and stirred for 16 hours. The solvent was evaporated to give a crude white solid of the title compound.
And step 3: [3- (cyanomethyl) oxetan-3-yl ] methanesulfonyl chloride
Chlorine gas was bubbled through a solution of [3- (cyanomethyl) oxetan-3-yl ] methyl thiocyanate (0.53mmol, crude product) in water (10mL) at 0 ℃ for 30 minutes. The reaction mixture was extracted with methyl tert-butyl ether (2X 20 mL). The combined organic layers were dried over sodium sulfate and concentrated to give the title compound (20mg, 18%).
Example 6: n- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -1-oxetan-3-ylmethanesulfonamide
This compound is prepared using oxetan-3-ylmethanesulfonyl chloride. The crude compound was purified by silica gel chromatography with a mixture of dichloromethane and methanolMaterial (85:15) was eluted to give the title compound as a white solid (23%).1H NMR (400MHz, methanol-d)4): 8.13(m, 1H), 7.13(d, J ═ 4Hz, 1H), 6.70-6.69(m, J ═ 4Hz, 1H), 4.93-4.91(m,1H), 4.84-4.83(m, 2H), 4.63-4.59(m, 2H), 3.74-3.68(m, 1H), 3.58-3.56(m, 1H), 3.47-3.45(m, 2H), 3.37(s, 3H), 2.79-2.77(m, 2H), 2.32-2.29(m, 2H). LC/MS (exact mass): c15H21N5O3Theoretical value of S; 351.136, Experimental value (M + H)+)；352.1。
Oxetan-3-ylmethanesulfonyl chloride
Step 1: oxetan-3-ylmethyl thiocyanate
This compound was prepared according to the procedure of example 5 step 2 substituting 4-methylbenzenesulfonic acid oxetan-3-ylmethyl ester (WO2012/117000a1) for 4-methylbenzenesulfonic acid [3- (cyanomethyl) oxetan-3-yl ] methyl ester to give a crude title compound as a white solid (100%).
Step 2: oxetan-3-ylmethanesulfonyl chloride
The crude form of this compound was prepared (25% yield) according to the procedure of example 5, step 3, substituting oxetan-3-yl methyl thiocyanate for [3- (cyanomethyl) oxetan-3-yl ] methyl thiocyanate.
Examples 7A and 7B: cis-and trans-3- (cyanomethyl) -3-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutanesulfonamide
These compounds are prepared by using a mixture (. about.1: 1) of cis-and trans-3- (cyanomethyl) -3-methylcyclobutanesulfonyl chloride. The crude mixture of cis-and trans-isomers was purified by silica gel chromatography eluting with a gradient of petroleum ether to ethyl acetate (10:1 to 1:15) to give the title compound as a mixture (70mg) as a light brown solid (28%). The cis and trans isomers were then separated by Supercritical Fluid Chromatography (SFC).
Cis-isomer (7A): 26mg (10%); SFC retention time 7.11 minutes;1h NMR (400MHz, methanol-d)4): 8.13(s, 1H), 7.13-7.13(d, 1H), 6.69(d, 1H), 4.93-4.86(m, 1H), 3.91-3.87(m, 1H), 3.71-3.65(m, 1H), 3.37-3.33(m, 3H), 2.77-2.75(m, 2H), 2.68(s, 2H), 2.41-2.36(m, 2H), 2.26-2.21(m, 2H), 1.34(m, 3H). LC/MS (exact mass): c18H24N6O2Theoretical value of S; 388.168, Experimental value (M + H)+)；389.1。
Trans-isomer (7B)24mg (10%); SFC retention time 11.35 min;1h NMR (400MHz, methanol-d)4): 8.13(s, 1H), 7.14(d, 1H), 6.69(d, 1H), 4.93-4.86(m, 1H), 3.96-3.86(m, 1H), 3.72-3.65(m, 1H), 3.36-3.31(m, 3H), 2.77-2.75(m, 2H), 2.71(s, 2H), 2.34-2.26(m, 6H), 1.33(m, 3H). LC/MS (exact mass): c18H24N6O2Theoretical value of S; 388.168, Experimental value (M + H)+)；389.0。
The mixture of cis-and trans-3- (cyanomethyl) -3-methylcyclobutanesulfonyl chloride was prepared as follows:
step 1: 1-methyl-3-methylenecyclobutanecarbonitrile
Lithium bis (trimethylsilyl) amide (450mL, 1M) was added dropwise to a solution of 3-methylenecyclobutanecarbonitrile (35.0g, 373.0mmol) in tetrahydrofuran (200mL) at-78 ℃ under stirring at-78 ℃ for 1 hour, iodomethane (30mL, 448mmol) was added to the reaction after 1 hour, the mixture was warmed to room temperature and stirred overnight, aqueous ammonium chloride (380mL) was added to the reaction mixture to quench the reaction and extracted with methyl tert-butyl ether (3 × 400mL), the combined organic layers were dried over sodium sulfate and concentrated, the crude product was purified by distillation under reduced pressure to afford the title compound (20g, 50%) as a clear oil.1H NMR(400MHz，CDCl3)：4.90-4.89(m，2H)，3.24-3.20(m，2H)，2.67-2.62(m，2H)，1.50(s，3H)。
Step 2: 1-methyl-3-methylenecyclobutanecarboxylic acid
To a solution of 1-methyl-3-methylenecyclobutanecarbonitrile (10.0g, 93.3mmol) in water (50mL) and ethanol (50mL) was added potassium hydroxide (25.6g, 466.6 mmol.) the reaction mixture was heated at reflux and stirred overnight, the ethanol was removed under reduced pressure, the solution was cooled to less than 10 deg.C and acidified to pH 1 with concentrated hydrochloric acid, the aqueous layer was extracted with ethyl acetate (3 × 150mL), the combined organic layers were dried over sodium sulfate and concentrated to give the title compound (9g, 77%).1H NMR(400MHz，CDCl3)：11.90(s，1H)，4.88-4.85(m，2H)，3.23-3.17(m，2H)，2.53-2.41(m，2H)，1.45(s，3H)。
And step 3: 1-methyl-3-methylenecyclobutanecarboxylic acid ethyl ester
Thionyl chloride (11.0mL, 143mmol) was added dropwise to a solution of 1-methyl-3-methylenecyclobutanecarboxylic acid (6g, 47.6mmol) in dichloromethane (30mL) at 0 ℃, the solution was stirred at 0 ℃ for 1 hour, 3 drops of N, N-dimethylformamide were added to the solution, the solution was stirred at 0 ℃ for 30 minutes, the solvent was evaporated, dichloromethane (20mL) and ethanol (125mL) were added to the residue, the resulting solution was stirred at room temperature for 16 hours, the solvent was evaporated, water (20mL) was added to the residue, the aqueous layer was extracted with dichloromethane (4 × 20mL), 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 afford the title compound (5g, 68%).1H NMR(400MHz，CDCl3)：4.85-4.83(m，2H)，4.17-4.12(m，2H)，3.18-3.12(m，2H)，2.48-2.42(m，2H)，1.41(s，3H)，1.27-1.23(m，3H)。
And 4, step 4: (1-methyl-3-methylenecyclobutyl) methanol
A mixture of ethyl 1-methyl-3-methylenecyclobutanecarboxylate (4.55g, 29.5mmol) and lithium aluminum hydride (2.8g, 72mmol) in tetrahydrofuran (50mL) was stirred at room temperature overnight. Adding Na to the reaction mixture2SO4·10H2O (3.7g, 11.5mmol), the resulting mixture was stirred at room temperature for 1h, the solids were removed by filtration, the filtrate was concentrated in vacuo, the residue was extracted with dichloromethane (3 × 50mL), the combined organic extracts were dried over sodium sulfate and concentrated to give the title compound (2.6g, 79%) as a colorless oil.1H NMR(400MHz，CDCl3)：4.79-4.78(m，2H)，3.48(s，2H)，2.53-2.48(m，2H)，2.36-2.27(m，2H)，1.16(s，3H)。
And 5: 4-Methylbenzenesulfonic acid (1-methyl-3-methylenecyclobutyl) methyl ester
This compound was prepared according to the procedure of example 4, step 4, substituting (1-methyl-3-methylenecyclobutyl) methanol for (3-hydroxycyclobutyl) acetonitrile. The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether and ethyl acetate (20:1 to 4:1) to afford the title compound (70%).1H NMR(400MHz，CDCl3)：7.79(d，2H)，7.34(d，2H)，4.79-4.78(m，2H)，3.90(s，2H)，2.51-2.47(m，2H)，2.44(s，3H)，2.35-2.31(m，2H)，1.15(s，3H)。
Step 6: (1-methyl-3-methylenecyclobutyl) acetonitrile
A mixture of methyl 4-methylbenzenesulfonate (1-methyl-3-methylenecyclobutyl) methyl ester (2.5g, 9.4mmol), potassium cyanide (1.3g, 19mmol) and N, N-dimethylformamide (8mL) was stirred at 70 deg.C overnight, water (10mL) and methyl tert-butyl ether (20mL) were added to the mixture, the organic layer was separated, the aqueous layer was extracted with methyl tert-butyl ether (3 × 30mL), the combined organic layers were washed with saturated aqueous sodium bicarbonate (15mL), dried over sodium sulfate, and concentrated.1H NMR(400MHz，CDCl3)：4.88-4.87(m，2H)，2.62-2.54(m，2H)，2.50(s，2H)，1.33(s，3H)。
And 7: (1-methyl-3-oxocyclobutyl) acetonitrile
Bubbling ozone gas into the (1-methyl) at-78 deg.C3-Methylenecyclobutyl-3-yl acetonitrile (1.08g, 8.91mmol) in dichloromethane (30mL) over a period of 10 min. After flushing the solution with nitrogen, dimethyl sulfide (10mL) was added dropwise to the solution at-78 ℃. The solution was stirred at-78 ℃ for 30 minutes and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography eluting with a gradient of petroleum ether and ethyl acetate (20:1 to 8:1) to give the title compound (920mg, 84%) as a colorless oil.1H NMR(400MHz，CDCl3)：3.11-3.06(m，2H)，2.96-2.91(m，2H)，2.69(s，2H)，1.53(s，3H)。
And 8: (3-hydroxy-1-methylcyclobutyl) acetonitrile
To a solution of (1-methyl-3-oxocyclobutyl) acetonitrile (400mg, 3.25mmol) in tetrahydrofuran (15mL) was added sodium cyanoborohydride (246mg, 6.5 mmol). the mixture was stirred at room temperature for 3h, acetone (2mL) was added, followed by evaporation of the solvent, water (10mL) was added to the residue, the aqueous layer was extracted with dichloromethane (4 × 15mL), the combined organic layers were dried over sodium sulfate and concentrated the crude product was purified by chromatography on silica eluting with a gradient of petroleum ether and ethyl acetate (10:1 to 1:1) to give the title compound (300mg, 74%) as a colorless oil.1H NMR(400MHz，CDCl3)：4.38-4.34(m，2H)，2.46-2.27(m，4H)，1.94-1.86(m，2H)，1.33-1.12(m，3H)。
And step 9: 4-Methylbenzenesulfonic acid 3- (cyanomethyl) -3-methylcyclobutyl ester
This compound was prepared according to the procedure of example 7, step 5, using (3-hydroxy-1-methylcyclobutyl) acetonitrile instead of (1-methyl-3-methylenecyclobutyl) methanol. The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether and ethyl acetate (20:1 to 4:1) to afford the title compound (36%).1H NMR(400MHz，CDCl3)：7.77(d，2H)，7.35(d，2H)，4.89-4.81(m，1H)，2.45(s，3H)，2.43-2.34(m，3H)，2.26-2.21(m，1H)，2.15-2.11(m，2H)，1.33(s，3H)。
Step 10: thioacetic acid S- [3- (cyanomethyl) -3-methylcyclobutyl ] ester
This compound was prepared according to the procedure of example 4, step 5, using 4-methylbenzenesulfonic acid 3- (cyanomethyl) -3-methylcyclobutyl ester instead of 4-methylbenzenesulfonic acid 3- (cyanomethyl) cyclobutyl ester, in 89% yield (crude product).1H NMR(400MHz，CDCl3)：3.12(s，1H)，2.46-2.30(m，4H)，2.19(s，2H)，1.29(s，1H)，1.26-1.24(m，1H)，1.18-1.14(m，1H)，1.13(s，3H)。
Step 11: 3- (cyanomethyl) -3-methylcyclobutanesulfonyl chloride
This compound was synthesized according to the procedure of example 4, step 6, using S- [3- (cyanomethyl) -3-methylcyclobutyl ] thioacetic acid]Ester substitution of Thioacetic acid S- [3- (cyanomethyl) -cyclobutyl]Esters. The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether and ethyl acetate (90:10 to 30:70) to afford the title compound as a yellow liquid (66%).1HNMR(400MHz，CDCl3)：4.45-4.38(m，1H)，2.67-2.55(m，4H)，2.46-2.40(m，2H)，1.42-1.40(m，3H)。
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) isonicotinic carbonitriles
A60% suspension of sodium hydride in mineral oil (8.36g, 210.0mmol) was suspended in tetrahydrofuran (100 mL). A solution of benzylthiol (21.5g, 173mmol) in tetrahydrofuran (50mL) was then added dropwise. A thick slurry formed during the addition. 4-cyano-2-chloropyridine (12.5g, 90.2mmol) was added and the resulting mixture was stirred at room temperature for 3 hours. After careful addition of water to quench the reaction, the mixture was partitioned between water and diethyl ether. The ether layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure. Heptane was added to the residue, rapidly forming a solid. The solid was collected by filtration, washed with heptane, and dried to give the title compound as an off-white solid (33.02g, 84%).1H NMR(400MHz，CDCl3): 8.61(d, 1H), 7.25-7.46(m, 6H), 7.16-7.22(m, 1H), 4.47(s, 2H). LC/MS (exact mass): c13H10N2Theoretical value of S; 226.056, Experimental value (M + H)+)；227.1。
Step 2: 4-cyanopyridine-2-sulfonyl chloride
To a mechanically stirred mixture of 2- (benzylthio) isonicotinonitrile (8.92g, 39.4mmol) in dichloromethane (139mL) and water (31mL) was added sulfuryl chloride (22.5mL, 278mmol) dropwise, maintaining the temperature of the mixture below 3 ℃. After the addition was complete, the mixture was stirred for 30 minutes and continued to be cooled in an ice bath. A slurry of water (50mL) and ice (20g) was added. The aqueous layer was extracted twice with dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude title compound.
And step 3: 4-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } pyridine-2-sulfonamide
A solution of 4-cyanopyridine-2-sulfonyl chloride (9.7g, 47.9mmol) in N, N-dimethylformamide (10mL) was added at room temperature to the solution of cis-N-methyl-N-7H-pyrrolo [2,3-d ] amide]Pyrimidine-4-cyclobutane-1, 3-diamine hydrochloride (8.0g, 36.8mmol) and 4-dimethylaminopyridine (150mg, 0.03mmol) in N, N-dimethylformamide (90 mL). Diisopropylethylamine (13mL, 77mmol) was added and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (200mL) and saturated aqueous sodium bicarbonate was added. Water was added to dissolve the precipitated solid. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed 4 times with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added a 1:1 mixture of ethyl acetate and hexane. The solid was collected by filtration and then dissolved in dichloromethane and a minimum amount of methanol. The resulting solution was passed through a short column of silica gel eluting with 5% methanol in dichloromethane. The solvent was evaporated to give a solid, to which was added a 10% methanol/dichloromethane solution. The mixture was briefly stirred and then allowed to stand overnight. Filtering the solid with twoMethyl chloride was washed and dried to give the title compound (5.58g, 39%) as an off-white solid.1H NMR(400MHz，DMSO-d6): 11.62(br.s., 1H), 9.02(d, 1H), 8.52(d, 1H), 8.38(s, 1H), 8.17(dd, 1H), 8.07(s, 1H), 7.10-7.15(m, 1H), 6.59(dd, 3.41Hz, 1H), 4.80-4.91(m, 1H), 3.58-3.71(m, 1H), 3.19(s, 3H), 2.25-2.36(m, 2H), 2.10(m, 2H). LC/MS (exact mass): c17H17N7O2Theoretical value of S; 383.116, Experimental value (M + H)+)；384.1。
Example 9: 3- (1-hydroxy-1-methylethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } benzenesulfonamide
Step 1: 3- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } amino) sulfonyl ] benzoic acid methyl ester
Triethylamine (6.7mL, 49mmol) was added portionwise to a suspension of cis-N-methyl-N-7H-pyrrolo [2,3-d ] pyrimidin-4-cyclobutane-1, 3-diamine hydrochloride (1.8g, 8.29mmol) in N, N-dimethylformamide (100mL) at 0 ℃. Methyl 3- (chlorosulfonyl) benzoate (2.3g, 9.9mmol) was added at 0 ℃. The resulting mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum. The residue was chromatographed on silica gel eluting with a methanol/dichloromethane gradient (3% to 10%) to give the title compound (1.6g, 47%) as a yellow solid.
Step 2: 3- (hydroxymethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } benzenesulfonamide
Lithium aluminium hydride (0.25g, 6.7mmol) was added to a solution of methyl 3- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } amino) sulfonyl ] benzoate (800mg, 1.92mmol) in tetrahydrofuran (120mL) at 0 ℃. The reaction was warmed to 25 ℃ and stirred for 3 hours. Water (2mL) was added to quench the reaction and stirred for 15 min. The reaction mixture was filtered. The filter cake was stirred in tetrahydrofuran (50mL) and filtered again. The combined filtrates were concentrated to dryness to give the title compound (430mg, 58%) as a yellow solid.
And step 3: 3-formyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } benzenesulfonamide
To a solution of 3- (hydroxymethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } benzenesulfonamide (400mg, 1.03mmol) in chloroform (50mL) and methanol (5mL) was added manganese dioxide (0.89g, 10.0 mmol). The reaction mixture was stirred at 25 ℃ overnight. The reaction mixture was filtered and the filter cake was washed with chloroform (3X 25 mL). The combined filtrates were concentrated. The residue was chromatographed on silica gel, eluting with a methanol/dichloromethane gradient (2% to 8%) to give the title compound (240mg, 60%) as an oil.
And 4, step 4: 3- (1-hydroxyethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } benzenesulfonamide
At 0 ℃ under nitrogen at 3-formyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) amino]Cyclobutyl } benzenesulfonamide (260mg, 0.68mmol) in tetrahydrofuran (20mL) was added methylmagnesium bromide (1.8mL, 5.4mmol) to a solution of the reaction in tetrahydrofuran (20mL) the reaction was stirred at 25 ℃ overnight, followed by addition of aqueous ammonium chloride (10mL) to quench the reaction mixture was extracted with ethyl acetate (3 × 25mL), the combined organic layers were dried over sodium sulfate and concentrated the residue was purified by preparative high performance liquid chromatography to afford the title compound (60mg, 22%) as a white solid.1H NMR(400MHz，DMSO-d6): 11.6(s, 1H), 8.08(s, 1H), 8.03(d, 1H), 7.86(s, 1H), 7.70(m, 1H), 7.55(m, 2H), 7.15(m, 1H), 6.61(m, 1H), 5.44(m, 1H), 4.85(m, 1H), 3.56(m, 1H), 3.18(s, 3H), 2.18(m, 2H), 2.04(m, 2H), 1.32(d, 3H). LC/MS (exact mass): c19H23N5O3Theoretical value of S; 401.152, Experimental value (M + H)+)；402.2。
And 5: 3-acetyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } benzenesulfonamide
In 3- (1-hydroxyethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino]Cyclobutyl } benzenesulfonamide (60mg, 0.15mmol) in chloroform (30mL) and methanol (5mL) was added manganese dioxide (190mg, 2.2mmol) and the reaction mixture was stirred at 45 ℃ overnight then the reaction mixture was filtered, the filter cake was washed with chloroform (3 × 25mL) the combined filtrates were concentrated and the residue was purified by preparative high performance liquid chromatography to give the title compound (15mg, 25%) as a white solid.1H NMR(400MHz，DMSO-d6): 11.58(s, 1H), 8.31(s, 1H), 8.21(m, 2H), 8.16(m, 2H), 7.76(m, 1H), 7.09(d, 1H), 6.56(s, 1H), 4.82(m, 1H), 3.54(m, 1H), 3.14(s, 3H), 2.81(m, 3H), 2.26(m, 2H), 1.98(m, 2H). LC/MS (exact mass): c19H21N5O3Theoretical value of S; 399.136, Experimental value (M + H)+)；400.1。
Step 6: 3- (1-hydroxy-1-methylethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } benzenesulfonamide
At 0 ℃ under nitrogen at 3-acetyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) amino]Cyclobutyl } benzenesulfonamide (240mg, 0.58mmol) in tetrahydrofuran (20mL) was added methylmagnesium bromide (2.4mL, 7.2 mmol). the reaction was stirred at 25 ℃ for 2 hours, aqueous ammonium chloride (10mL) was added to quench the reaction mixture was extracted with ethyl acetate (3 × 25 mL). the combined organic layers were dried over sodium sulfate and concentrated.1H NMR(400MHz，DMSO-d6): 11.6(s, 1H), 8.05(s, 1H), 7.97(m, 2H), 7.67(m, 2H), 7.52(m, 1H), 7.12(m, 1H), 6.57(m, 1H), 5.29(s, 1H), 4.85(m, 1H), 3.53(m, 1H), 3.15(s, 3H), 2.24(m, 2H), 1.98(m, 2H), 1.44(s, 6H). LC/MS (exact mass): c20H25N5O3Theoretical value of S;415.168, Experimental value (M + H)+)；416.0。
Example 10: 1-cyclopropyl-N- { trans-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methanesulfonamide
The compound is prepared from [ trans-3- (methylamino) -cyclobutyl]Benzyl carbamate (example 1, step 1) was prepared according to procedures analogous to those described in example 1, steps 2 and 3 to give trans-N-methyl-N-7H-pyrrolo [2, 3-d)]Pyrimidine-4-cyclobutane-1, 3-diamine hydrochloride. To a solution of the hydrochloride (60mg, 0.28mmol) obtained in THF (10mL) were added potassium carbonate (76mg, 0.55mmol), H2O (5mL) and cyclopropylmethanesulfonyl chloride (52mg, 0.33 mmol). The mixture was stirred for 2 hours, diluted with dichloromethane, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative high performance liquid chromatography to afford the title compound as a white solid (7 mg; 8%).1H NMR (400MHz, methanol-d)4): 8.14(s, 1H), 7.16(d, 1H), 6.72(d, 1H), 5.44-5.40(m, 1H), 4.07-4.06(m, 1H), 3.41(s, 3H), 3.01-2.99(m, 2H), 2.81-2.74(m, 2H), 2.54-2.49(m, 2H), 1.15-1.13(m, 1H), 0.720-0.69(m, 2H), 0.42-0.41(m, 2H). LC/MS (exact mass): c15H21N5O2Theoretical value of S; 335.142, Experimental value (M + H)+)；336.1。
Example 11: n- { (1S,3R) -3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclopentyl } propane-1-sulfonamide
This compound was synthesized according to the procedure for example 10 using (1S,3R) -N-benzyl-N' -methylcyclopentane-1, 3-diamine in place of [ trans-3- (methylamino) -cyclobutyl ] -N]Benzyl carbamate, using (1R,3S) -N-methyl-N-7H-pyrrolo [2, 3-d)]Pyrimidine-4-cyclopentane-1, 3-diamine hydrochloride in place of trans-N-methyl-N-7H-pyrrolo [2,3-d]Pyrimidine-4-cyclobutane-1, 3-diamine hydrochloride and the preparation using propane-1-sulfonyl chloride instead of cyclopropylmethanesulfonyl chlorideThe title compound was an off-white solid (11%). The crude compound was purified by preparative high performance liquid chromatography.1H NMR (400MHz, methanol-d)4): 8.08(s, 1H), 7.08(s, 1H),. 6.65(s, 1H), 5.27-5.23(m, 1H), 3.81-3.76(m, 1H), 3.31(s, 3H), 2.33-2.29(m, 1H), 2.13-2.04(m, 1H), 1.98-1.92(m, 2H), 1.82-1.75(m, 4H), 1.06(t, 3H), 0.42-0.41(m, 2H). LC/MS (exact mass): c15H23N5O2Theoretical value of S; 337.157, Experimental value (M + H)+)；337.8。
(1S,3R) -N-benzyl-N' -methylcyclopentane-1, 3-diamine was prepared according to the following method:
step 1: [ (1R,3S) -3-Aminocyclopentyl ] carbamic acid benzyl ester
Trifluoroacetic acid (15mL, 190mmol) was added to a solution of tert-butyl (1R,3S) -cyclopentane-1, 3-diyl biscarbamate (prepared as described in WO2011/086053a 1) (5.02g, 15.0mmol) in dichloromethane (75mL) at room temperature. The reaction was stirred for 2 hours and then concentrated to give the title compound as a pale brown oil (6.70g, crude).
Step 2: [ (1R,3S) -3- (benzylamino) cyclopentyl ] carbamic acid benzyl ester
Sodium triacetoxyborohydride (4.38g, 20.0mmol) was added to the reaction mixture consisting of [ (1R,3S) -3-aminocyclopentyl group at room temperature]Benzyl carbamate (5.23g, 15.0mmol) and benzaldehyde (1.7mL, 16.0mmol) in dichloromethane (75mL) the mixture was stirred for 21 hours followed by the addition of 1M aqueous sodium hydroxide (75mL) to make the solution basic the aqueous layer was extracted with dichloromethane (2 × 25mL), the combined organic layers were washed with brine (50mL), 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 afford the title compound as a yellow oil (3.47g, 71%).1H NMR(400MHz，CDCl3)：7.35-7.31(m，5H)，7.30-7.26(m，5H)，5.07(s，2H)，4.17-4.07(m，1H)，3.76-3.68(m，2H)，3.27-3.20(m，1H)，2.02-1.51(m，6H)。
And step 3: (1S,3R) -N-benzyl-N' -methylcyclopentane-1, 3-diamine
Lithium aluminum hydride (1.02g, 26.9mmol) was added portionwise to a solution of [ (1R,3S) -3- (benzylamino) cyclopentyl ] aluminum hydride at room temperature]Benzyl carbamate (3.47g, 10.7mmol) in solution in tetrahydrofuran (70mL) the reaction mixture was heated to reflux for 3.5 hours the mixture was then cooled in an ice bath, water (1.0mL), 15% aqueous sodium hydroxide (1.0mL) and water (3.0mL) were added in order to quench the reaction, the suspension was diluted with ethyl acetate and filtered through Celite, the filtrate was concentrated, the residue was taken up in 0.5M aqueous hydrochloric acid, the mixture was washed with diethyl ether (2 × 20mL), and the aqueous solution was made basic with sodium hydroxide (pH 11). the resulting mixture was extracted with dichloromethane (3 × 25mL), 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 give the title compound as a yellow oil (204mg, 9%).1H NMR(400MHz，CDCl3): 7.33-7.20(m, 5H), 3.74(s, 2H), 3.19-3.13(m, 1H), 3.08-3.02(m, 1H), 2.39(s, 3H), 2.09-2.03(m, 1H), 1.87-1.81(m, 2H), 1.67-1.54(m, 2H), 1.46-1.39(m, 1H). LC/MS (exact mass): c13H20N2The theoretical value of (A); 204.163, Experimental value (M + H)+)；205.1。
Example 12: 1- (3, 3-Difluorocyclobutyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methanesulfonamide
Step 1: [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] carbamic acid benzyl ester
4-chloro-7- [ (4-methylphenyl) sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidine (15g, 48.7mmol) and [ cis-3- (methylamino) cyclobutyl ]]Benzyl carbamate (17.2g, 63.5mmol) was combined with isopropanol (180mL) and diisopropylethylamine (28mL, 161 mmol). The resulting slurry was heated at 75 ℃ for 6 hours. The reaction is cooled to roomWarm, filter, rinse with isopropanol (150mL), and dry in an oven at 50 ℃ to give the title compound (23.5g, 95%) as a white solid.1H NMR(400MHz，DMSO-d6)：8.38(s，1H)，8.03(d，2H)，7.45(d，1H)，7.38-7.28(m，4H)，7.26(s，1H)，7.25(d，1H)，6.61(d，1H)，5.08(s，2H)，4.96(d，1H)，4.77(m，1H)，3.88(m，1H)，3.23(s，3H)，2.71(m，2H)，2.36(s，3H)，2.18(m，2H)。
Step 2: cis-N-methyl-N- {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } cyclobutane-1, 3-diamine dihydrobromide salt
[ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl group)]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Benzyl carbamate (15.2g, 30.1mmol) suspended ethyl acetate (45mL) and acetic acid (45 mL). A solution of 4M HBr in acetic acid (45mL, 180mmol) was added slowly to the slurry, maintaining the temperature below 25 ℃. The resulting slurry was stirred at room temperature for 2 hours. The solid was collected by filtration, washed with ethyl acetate (450mL), and dried at 40 ℃ to give the title compound (16 g; 100%) as a white solid.1H NMR(400MHz，DMSO-d6): 8.31(s, 1H), 8.20(s, 2H), 7.97(d, 2H), 7.72(d, 1H), 7.44(d, 2H), 7.08(d, 1H), 4.93(m, 1H), 3.54(m, 1H), 3.30(s, 3H), 2.50(m, 4H), 2.35(s, 3H). LC/MS (exact mass): c18H21N5O2Theoretical value of S; 371.142, Experimental value (M + H)+)；372.1。
And step 3: ({ [ (3, 3-Difluorocyclobutyl) methyl ] thio } methyl) benzene
A mixture of 4-methylbenzenesulfonic acid (3, 3-difluorocyclobutyl) methyl ester (see WO2010/032200A1) (4g, 14.5mmol), iminothiocarbamic acid benzyl ester (benzyl imidothiocarbamate) (3.53g, 17.4mmol), sodium hydroxide solution (1.45g, 36.2mmol, dissolved in 16mL of water) and N, N-dimethylformamide (16mL) was stirred at 60 ℃ for 16 h. Water (40mL) and ethyl acetate (150mL) were added. The organic layer was washed with water (40mL), the layers were separated, dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel with petroleum etherAnd a gradient of ethyl acetate (100:0 to 95:5) to give the title compound as a colorless oil (3.2g, 81%).1H NMR(400MHz，CDCl3)：7.34-7.24(m，5H)，5.71(s，2H)，2.71-2.61(m，2H)，2.57-2.55(m，2H)，2.30-2.14(m，3H)。
And 4, step 4: (3, 3-Difluorocyclobutyl) methanesulfonyl chloride
This compound was synthesized according to the procedure for step 2 of example 8 using S- [3- (cyanomethyl) -3-methylcyclobutyl ] thioacetic acid]The ester was prepared instead of 2- (benzylthio) isonicotinonitrile to give the title compound as a colorless oil (93%).1H NMR(400MHz，CDCl3)：3.88-3.86(m，2H)，3.03-2.94(m，3H)，2.61-2.49(m，2H)。
And 5: 1- (3, 3-Difluorocyclobutyl) -N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] methanesulfonamide
A solution of (3, 3-difluorocyclobutyl) methanesulfonyl chloride (2.5g, 12.19mmol) in 10mL of dichloromethane at 0 deg.C was added dropwise to the mixture of cis-N-methyl-N- {7- [ (4-methylphenyl) sulfonyl group]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } cyclobutane-1, 3-diamine dihydrobromide (3.25g, 6.10mmol) and triethylamine (3.08g, 30.49mmol) in dichloromethane (150mL) over 15 minutes the reaction was stirred at room temperature for 4 hours water (50mL) was added and the organic layer was separated the aqueous layer was extracted with dichloromethane (2 × 150mL), the separated organic layers were combined and dried over sodium sulfate the crude compound was purified by silica gel chromatography eluting with a gradient of dichloromethane and methanol (100:0 to 90:10) to give the title compound as a white solid (2.0g, 61%). LC/MS (accurate mass C): C23H27F2N5O4S2The theoretical value of (A); 539.147, Experimental value (M + H)+)；540.1。
Step 6: 1- (3, 3-Difluorocyclobutyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methanesulfonamide
1- (3, 3-difluorocyclobutyl)-N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]A solution of methanesulfonamide (2g, 3.71mmol) and lithium hydroxide monohydrate (780mg, 18.6mmol) in ethanol (40mL) and water (20mL) was stirred at 60 deg.C for 4h, the ethanol was evaporated, the residual aqueous layer was neutralized to pH 7 with hydrochloric acid, followed by extraction with dichloromethane (2 × 200mL), the combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by preparative high performance liquid chromatography to afford the title compound (800mg, 56%) as a white solid.1H NMR (400MHz, methanol-d)4): 8.15(s, 1H), 8.13(s, 1H), 7.16-7.15(m, 1H), 6.73-6.62(m, 1H), 4.95-4.88(m, 1H), 3.73-3.71(m, 1H), 3.38(s, 3H), 3.28-3.26(m, 2H), 2.87-2.78(m, 4H), 2.63-2.61(m, 1H), 2.56-2.48(m, 2H), 2.35-2.28(m, 2H). LC/MS (exact mass): c16H21F2N5O2Theoretical value of S; 385.138, Experimental value (M + H)+)；386.1。
The following compounds, examples 13-14, were prepared from cis-N-methyl-N- {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } cyclobutane-1, 3-diamine dihydrobromide salt (example 12 step 2) using the indicated sulfonyl chloride instead of (3, 3-difluorocyclobutyl) methanesulfonyl chloride and using the deprotection procedure described in example 12 step 6 according to a similar procedure described in example 12 step 5.
Example 13: 3, 3-difluoro-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutanesulfonamide
This compound was prepared using 3, 3-difluorocyclobutanesulfonyl chloride according to the procedure described in PCT publication WO 2011/068881. The crude compound was purified by silica gel chromatography eluting with a gradient of petroleum ether and ethyl acetate (80:20 to 10:90) to afford the title compound as an off white solid (22% for the 2 steps).1H NMR (400MHz, methanol-d)4)：8.13(s，1H)，7.13(d，1H)，6.70(d，1H)，4.86-4.81(m，1H)，3.78-3.72(m，2H)，3.35(s, 3H), 3.01-2.93(m, 4H), 2.78-2.76(m, 2H), 2.32-2.25(m, 2H). LC/MS (exact mass): c15H19F2N5O2Theoretical value of S; 371.123, Experimental value (M + H)+)；372.1。
Example 14: 1-cyclopropyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methanesulfonamide
This compound was prepared using cyclopropylmethanesulfonyl chloride as a white solid (73% total in 2 steps).1H NMR(400MHz，DMSO-d6): 11.64(br.s., 1H), 8.11(s, 1H), 7.53(d, 1H), 7.12-7.19(m, 1H), 6.64(m, 1H), 4.84-4.97(m, 1H), 3.54-3.70(m, 1H), 3.26(s, 3H), 2.93(d, 2H), 2.55-2.66(m, 2H), 2.29-2.22(m, 2H), 0.96-1.09(m, 1H), 0.53-0.64(m, 2H), 0.29-0.39(m, 2H). LC/MS (exact mass): c15H19F2N5O2Theoretical value of S; 335.142, Experimental value (M + H)+)；336.0。
Example 15: 1-cyclopropyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } azetidine-3-sulfonamide
Step 1: 3- ({ [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] amino } sulfonyl) azetidine-1-carboxylic acid tert-butyl ester
cis-N-methyl-N- {7- [ (4-methylphenyl) sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } cyclobutane-1, 3-diamine dihydrobromide salt (7.0g, 18.8mmol) was obtained as the free base by stirring in excess of 1N aqueous sodium hydroxide solution for 3 minutes and then extracted into dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The remaining free base was taken up in dichloromethane (200mL), cooled to 0 deg.C and treated with triethylamine (13mL, 94mmol) and tert-butyl 3- (chlorosulfonyl) azetidine-1-carboxylate. The reaction was stirred at room temperatureFor 10 minutes. The crude mixture was washed with water and brine, then dried over sodium sulfate and concentrated to give the crude product as a white solid. The solid was crystallized from a mixture of dichloromethane and diethyl ether to give the title compound as a white solid (9.61g, 90%).1H NMR (400MHz, methanol-d)4): 8.19(s, 1H), 7.92-8.01(m, 2H), 7.54(d, 1H), 7.35(d, 2H), 6.86(d, 1H), 4.76-4.65(m, 1H), 4.18(br.s., 2H), 3.99-4.10(m, 3H), 3.66-3.78(m, 1H), 3.25(s, 3H), 2.64-2.78(m, 2H), 2.37(s, 3H), 2.10-2.25(m, 2H), 1.41(s, 9H). LC/MS (exact mass): c26H34N6O6S2The theoretical value of (A); 590.198, Experimental value (M + H)+)；591.45。
Step 2: n- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] azetidine-3-sulfonamide
Acetyl chloride (0.20mL, 2.8mmol) was added to the solution at 0 deg.C from 3- ({ [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl)]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Amino } sulfonyl) azetidine-1-carboxylic acid tert-butyl ester (1.64g, 2.78mmol) in a solution formed in anhydrous dichloromethane (18mL) and methanol (7 mL.) the reaction mixture was stirred at room temperature for 16 h.the white precipitate was filtered off and placed in saturated aqueous sodium bicarbonate solution (20 mL.) the resulting solution was extracted with dichloromethane (3 × 20mL), the combined organic layers were dried over sodium sulfate and concentrated to give the title compound (810mg, 60%) as a white solid21H26N6O4S2The theoretical value of (A); 490.146, Experimental value (M + H)+)；491.0。
And step 3: 1-cyclopropyl-N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] azetidine-3-sulfonamide
N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Azetidine-3-sulfonamide (810mg, 1.65mmol), methanol (10)mL), molecular sieves, and [ (1-ethoxycyclopropyl) oxy](trimethyl) silane (0.53mL, 2.64mmol) was mixed in a sealable reaction vessel flushed with nitrogen and acetic acid (1.28mL, 8.26mmol) was added to the vessel, the vessel was sealed and then heated at 80 ℃ for 2 hours after the mixture was cooled to room temperature, sodium cyanoborohydride (273mg, 4.13mmol) was added, the vessel was sealed again and heated slowly to 40 ℃ for 1.5 hours the crude mixture was filtered through a pad of Celite, rinsed with methanol, the filtrate was concentrated and the residue was taken up in saturated aqueous sodium bicarbonate, the resulting solution was extracted with dichloromethane (5 × 20mL), the combined organic layers were dried over sodium sulfate and concentrated to give the title compound (576mg, 74%) as a white solid.1H NMR (400MHz, methanol-d)4): 8.23(s, 1H), 7.95-8.05(m, 2H), 7.58(d, 1H), 7.39(d, 2H), 6.90(d, 1H), 4.69-4.83(m, 1H), 3.94-4.09(m, 1H), 3.65-3.75(m, 3H), 3.54-3.64(m, 2H), 3.29(s, 3H), 2.67-2.79(m, 2H), 2.41(s, 3H), 2.15-2.29(m, 2H), 2.02-2.15(m, 1H), 0.43-0.51(m, 2H), 0.29-0.39(m, 2H). LC/MS (exact mass): c24H30N6O4S2The theoretical value of (A); 530.177, Experimental value (M + H)+)；531.0。
And 4, step 4: 1-cyclopropyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } azetidine-3-sulfonamide
A solution of cesium carbonate (976mg, 3.0mmol) in water (5mL) was added to a solution of 1-cyclopropyl-N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Azetidine-3-sulfonamide (530mg, 1.0mmol) in ethanol (10mL) the reaction mixture was heated at reflux for 16 h after removal of the solvent, the residue was taken up in water and extracted with a mixture of dichloromethane and methanol (96: 4; 3 × 10mL), the combined organic layers were dried over sodium sulfate and concentrated the crude solid was crystallized from methanol to afford the title compound (225mg, 59%) as a white solid.1H NMR (400MHz, methanol-d)4)：8.10(s，1H)，7.09(d，1H)，6.66(d，1H)，4.88-4.80(m，1H)，4.03-3.96(m1H), 3.73-3.65(m, 3H), 3.61-3.57(m, 2H), 3.32(s, 3H), 2.77-2.68(m, 2H), 2.28-2.19(m, 2H), 2.08-2.03(m, 1H), 0.46-0.41(m, 2H), 0.34-0.31(m, 2H). LC/MS (exact mass): c17H24N6O2Theoretical value of S; 376.168, Experimental value (M + H)+)；377.0。
Example 16: n- (cyclopropylmethyl) -N' - { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } sulfuric acid diamide
Step 1: n- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]-2-oxo-1, 3-Azolidine-3-sulfonamides
To a solution of chlorosulfonyl isocyanate (1.76mL, 20.6mmol) in methylene chloride (150mL) at 0 deg.C was added dropwise a solution of 2-bromoethanol (1.43mL, 20.6mmol) in methylene chloride (80 mL). After 30 minutes at 0 ℃ cis-N-methyl-N- {7- [ (4-methylphenyl) sulfonyl group was added dropwise]-7H-pyrrolo [2,3-d]A solution of pyrimidin-4-yl } cyclobutane-1, 3-diamine dihydrobromide (11.0g, 20.6mmol) and triethylamine (10.42g, 103.2mmol) in dry dichloromethane (80mL) and the reaction mixture was allowed to warm to room temperature overnight the reaction solution was dissolved in dichloromethane (1L), washed with 1M aqueous hydrochloric acid (2 × 800mL) and brine (500mL), the solution was dried over sodium sulfate and concentrated to afford the title compound as a white solid (8.5g, 79%).1H NMR(400MHz，CD3OD): 8.22(s, 1H), 8.00(d, 2H), 7.58(d, 1H), 7.38(d, 2H), 6.91(d, 1H), 4.88(m, 1H), 4.45-4.41(m, 2H), 4.06-4.02(m, 2H), 3.75(m, 1H), 3.29(s, 3H), 2.72-2.69(m, 2H), 2.40(s, 3H), 2.30-3.27(m, 2H). LC/MS (exact mass): c21H24N6O6S2The theoretical value of (A); 520.120, Experimental value (M + H)+)；521.4。
Step 2: n- (cyclopropylmethyl) -N' - [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] sulfuric acid diamide
N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]-2-oxo-1, 3-A solution of oxazolidine-3-sulfonamide (150mg, 0.29mmol), cyclopropanemethylamine (51mg, 0.72mmol) and triethylamine (116mg, 1.15mmol) in acetonitrile (3mL) was stirred with microwave heating at 100 ℃ for 15 min. The reaction mixture was concentrated to give the crude title compound (146mg, 100% crude yield) as a yellow oil. LC/MS (exact mass): c22H28N6O4S2The theoretical value of (A); 504.161, Experimental value (M + H)+)；505.2。
And step 3: n- (cyclopropylmethyl) -N' - { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } sulfuric acid diamide
N- (cyclopropylmethyl) -N' - [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]A solution of sulfuric acid diamide (146mg, 0.29mmol) and lithium hydroxide monohydrate (48mg, 1.15mmol) in ethanol (5mL) and water (2.5mL) was stirred at 100 ℃ for 1 hour. The reaction mixture was concentrated in vacuo and the crude product was purified by preparative high performance liquid chromatography to give the title compound (14mg, 14%) as a white solid.1H NMR (400MHz, methanol-d)4): 8.12(s, 1H), 7.13(d, 1H), 6.90(d, 1H), 4.90-4.86(m, 1H), 3.63-3.59(m, 1H), 3.37(s, 3H), 2.85-2.83(m, 2H), 2.78-2.71(m, 2H), 2.33-2.26(m, 2H), 1.05-1.03(m, 1H), 0.57-0.52(m, 2H), 0.30-0.25(m, 2H). LC/MS (exact mass): c15H22N6O2Theoretical value of S; 350.152, Experimental value (M + H)+)；351.2。
The following compounds, examples17-18 is N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] group]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]-2-oxo-1, 3-The oxazolidine-3-sulfonamide (example 16 step 1) was prepared according to a method analogous to that described in example 16 step 2 using the indicated amine instead of cyclopropanemethylamine and using the deprotection method described in example 16 step 3.
Examples 17A and 17B: (R) -and (S) -3-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } pyrrolidine-1-sulfonamide
These compounds are prepared using racemic pyrrolidine-3-carbonitrile hydrochloride. The crude racemic mixture was purified by high performance liquid chromatography to give a white solid (60mg, 52% in 2 steps). Enantiomers were separated by supercritical fluid chromatography.
Enantiomer a (17A): 24mg (21%);1H NMR(400MHz，CD3OD): 8.13(s, 1H), 7.13(d, J ═ 3.2Hz, 1H), 6.69(d, 1H, J ═ 3.6Hz, 1H), 4.87 to 4.84(m, 1H), 3.73 to 3.67(m, 1H), 3.65 to 3.57(m, 1H), 3.53 to 3.50(m, 2H), 3.48 to 3.44(m, 2H), 3.405(s, 3H), 2.77 to 2.75(m, 2H), 2.42 to 2.20(m, 4H). LC/MS (exact mass): c16H21N7O2Theoretical value of S; 375.148, Experimental value (M + H)+) (ii) a 376.1. Chiral HPLC retention time ═ 5.97 min.
Enantiomer B (17B): 25mg (21%);1H NMR(400MHz，CD3OD): 8.13(s, 1H), 7.13(d, J ═ 3.2Hz, 1H), 6.69(d, 1H, J ═ 3.6Hz, 1H), 4.87 to 4.84(m, 1H), 3.73 to 3.67(m, 1H), 3.65 to 3.57(m, 1H), 3.53 to 3.50(m, 2H), 3.48 to 3.44(m, 2H), 3.405(s, 3H), 2.77 to 2.75(m, 2H), 2.42 to 2.20(m, 4H). LC/MS (exact mass): c16H21N7O2Theoretical value of S; 375.148, Experimental value (M + H)+)；376.1. Chiral HPLC retention time ═ 5.16 min.
Example 18: 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
The compound uses 2-methyl-2, 4,5, 6-tetrahydropyrrolo [3,4-c]Pyrazole hydrochloride. The crude compound was purified by high performance liquid chromatography to afford the title compound as an off-white solid (24% total in 2 steps).1H NMR (400MHz, methanol-d)4): 8.08(s, 1H), 7.38(s, 1H), 7.10(d, 1H), 6.66(d, 1H), 4.87-4.86(m, 1H), 4.42-4.41(m, 4H), 3.87(s, 3H), 3.71-3.67(m, 1H), 3.31(s, 3H), 2.68-2.61(m, 2H), 2.27-2.22(m, 3H). LC/MS (exact mass): c17H22N8O2Theoretical value of S; 402.159, Experimental value (M + H)+) (ii) a 403.2 and (M + Na); 425.1.
example 19: n- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -6-oxa-3-azabicyclo [3.1.1] heptane-3-sulfonamide
Step 1: n- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] -6-oxa-3-azabicyclo [3.1.1] heptane-3-sulfonamide
N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]-2-oxo-1, 3-Azolidine-3-sulfonamide (208mg, 0.40mmol), 6-oxa-3-azabicyclo [3.1.1]A mixture of heptane (50mg, 0.50mmol), triethylamine (220. mu.L, 1.58mmol) and acetonitrile (15mL) was heated in a 20mL microwave bottle in a microwave reactor at 120 ℃ for 1 hour. The excess solvent was evaporated and the resulting oil was taken up in dichloromethane. The solution is passed through an aqueous ammonium chloride solutionAnd a saline flush. The crude material was dried over sodium sulfate and concentrated to give an oil. This oil was chromatographed on silica gel, eluting with a methanol/dichloromethane gradient (0:100 to 5:100) to give a foam of the title compound (82mg, 30%).1H NMR(CDCl3): 8.38(s, 1H), 8.04(d, 2H), 7.48(d, 1H), 7.28(d, 2H), 6.63(d, 1H), 4.78-4.69(m, 1H), 4.62(d, 1H), 4.47(d, 1H), 3.69-3.61(m, 1H), 3.58(d, 3H), 3.26-3.17(m, 1H), 3.24(s, 3H), 2.83-.275(m, 2H), 2.37(s, 3H), 2.18-2.11(m, 2H), 2.04(d, 1H), 1.18(t, 1H). LC/MS (exact mass): c23H28N6O5S2The theoretical value of (A); 532.156, Experimental value (M + H)+)；533。
Step 2: n- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -6-oxa-3-azabicyclo [3.1.1] heptane-3-sulfonamide
N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]-6-oxa-3-azabicyclo [3.1.1]Heptane-3-sulfonamide (229mg, 0.43mmol) was added to a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (6.5mL, 6.4 mmol). The reaction was stirred at room temperature for 10 hours. The mixture was concentrated and the residue was chromatographed on silica gel, eluting with a mixture of methanol and ethyl acetate (1: 9). A yellow oil was isolated and triturated 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 washed with brine, dried over sodium sulfate and concentrated to give an off-white solid. This solid was triturated with ether followed by isopropanol to give the title compound as a white solid (14mg, 9%).1H NMR(CD3OD)8.08(s, 1H), 7.09(d, 1H), 6.66(s, 1H), 4.90-4.81(m, 1H), 4.62(d, 2H), 3.86-8.84(m, 1H), 3.66(t, 1H), 3.56-3.49(m, 3H), 3.33(s, 3H), 3.19-3.13(m, 1H), 2.75-2.70(m, 2H), 2.32-2.24(m, 2H), 2.05-2.03(d, 1H). LC/MS (exact mass): c16H22N6O3Theoretical value of S; 378.147, Experimental value (M + H)+)；379.5。
The following compounds, examples 20-24, are prepared from N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]-2-oxo-1, 3-The oxazolidine-3-sulfonamide (example 16 step 1) was prepared according to a method analogous to that described in example 16 step 2 using the indicated amine instead of cyclopropanemethylamine and using the deprotection method described 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
This compound was prepared using azetidine-3-carbonitrile. The crude compound was purified by high performance liquid chromatography to afford the title compound as a white solid (23% in 2 steps).1H NMR(400MHz，CD3OD): 8.10(s, 1H), 7.11(d, 1H), 6.68(d, 1H), 4.80(m, 1H), 4.02(m, 2H), 3.90(m, 2H), 3.58(m, 2H), 3.32(s, 3H), 2.72(m, 2H), 2.25(m, 2H). LC/MS (exact mass): c15H19N7O2Theoretical value of S; 361.132, Experimental value (M + H)+)；362.1。
Example 21: n- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -4- (1H-pyrazol-3-yl) piperidine-1-sulfonamide
This compound was used to prepare 4- (1H-pyrazol-3-yl) piperidine. The crude compound was purified by silica gel chromatography eluting with a mixture of dichloromethane and methanol (9: 1). The isolated material was triturated with ether followed by ethyl acetate to give the title compound as a white solid (10% in 2 steps).1H NMR(300MHz，CD3OD)：8.09(s，1H)，7.48(s，1H)，7.12-7.05(m，1H)，6.71-6.60(m，1H)，6.22-6.08(m，1H)，4.92-4.73(m, 1H), 3.80-3.55(m, 3H), 3.41(s, 3H), 2.90-2.65(m, 5H), 2.38-2.19(m, 2H), 2.09-1.90(m, 2H) and 1.83-1.65(m, 2H). LC/MS (exact mass): c19H26N8O2Theoretical value of S; 430.190, Experimental value (M + H)+)；431.1。
Example 22: n- (2-cyanoethyl) -N-methyl-N' - { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } sulfuric acid diamide
This compound was prepared using 3-methylaminopropionitrile. The crude compound was purified by high performance liquid chromatography to afford the title compound (7% in 2 steps). LC/MS (exact mass): c15H21N7O2Theoretical value of S; 363.148, Experimental value (M + H)+)；364.0。
Examples 23 and 27: (1S,5S) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -3-azabicyclo [3.1.0] hexane-3-sulfonamide and (1R,5R) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -3-azabicyclo [3.1.0] hexane-3-sulfonamide
These compounds were prepared using racemic 3-azabicyclo [3.1.0] hexane-1-carbonitrile. The crude racemic compound was purified by silica gel chromatography eluting with a gradient of dichloromethane and methanol (30:1 to 5:1) as a white solid (92mg, 21% over 2 steps). The title enantiomer was isolated by supercritical fluid chromatography.
Enantiomer 23: 41mg (9%); SFC retention time 4.28 min;1h NMR (400MHz, methanol-d)4): 8.13(s, 1H), 7.13(d, 1H), 6.70(d, 1H), 4.61(s, 1H), 3.57-3.72(m, 2H), 3.43-3.51(m, 3H), 3.36(s, 3H), 2.70-2.77(m, 2H), 2.24-2.38(m, 3H), 1.41-1.48(m, 1H), 1.32(t, 1H). LC/MS (exact mass): c17H21N7O2Theoretical value of S; 387.148, Experimental value (M + H)+)；388.1。
Enantiomer 27: 40mg (9%); SFC retention time 4.84 min1H NMR (400MHz, methanol-d)4): 8.13(s, 1H), 7.13(d, 1H), 6.70(d, 1H), 4.61(s, 1H), 3.57-3.72(m, 2H), 3.43-3.51(m, 3H), 3.36(s, 3H), 2.70-2.77(m, 2H), 2.24-2.38(m, 3H), 1.41-1.48(m, 1H), 1.32(t, 1H). LC/MS (exact mass): c17H21N7O2Theoretical value of S; 387.148, Experimental value (M + H)+)；388.1。
Racemic 3-azabicyclo [3.1.0] hexane-1-carbonitrile is prepared by the following method.
Step 1: racemic rac-1-formyl-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester
1,1, 1-Triacetoxy-1, 1-dihydro-1, 2-benzodioxole (benzidoxol) -3(1H) -one (6.5g, 15.2mmol) was added to the mixture consisting of racemic 1- (hydroxymethyl) -3-azabicyclo [3.1.0]Hexane-3-carboxylic acid tert-butyl ester (Synlett2009, 921) (2.5g, 11.7mmol) in anhydrous dichloromethane (60 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (60mL) and washed with saturated aqueous sodium sulfite, saturated sodium bicarbonate (30mL), and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated to give the title compound as a colorless oil (1.7g, 68%).1H NMR(400MHz，CDCl3)：9.01(d，1H)，3.83(d，1H)，3.68(t，1H)，3.59(dd，1H)，3.50-3.36(m，1H)，2.25-2.09(m，1H)，1.63(t，1H)，1.43(s，9H)，1.19-1.06(m，1H)。
Step 2: racemic 1- [ (hydroxyimino) methyl ] -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester
Potassium carbonate (3.89g, 28.2mmol) and hydroxylamine hydrochloride (671mg, 9.7mmol) were added to the mixture at room temperature from racemic 1-formyl-3-azabicyclo [3.1.0]Hexane-3-carboxylic acid tert-butyl ester (1.7g, 8.05mmol) in anhydrous dichloromethane (40mL) with stirringStirring for 16 hours. The mixture was diluted with ethyl acetate (80mL) and washed with water (30mL) 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 give the title compound as a yellow oil (1.6g, 88%).1H NMR(400MHz，CDCl3)：7.18(s，1H)，3.74-3.55(m，3H)，3.44-3.40(m，1H)，1.74-1.72(m，1H)，1.44(s，9H)，1.10(t，1H)，0.86-0.83(m，1H)。
And step 3: racemic 1-cyano-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester
In the racemic 1- [ (hydroxyimino) methyl group]-3-azabicyclo [3.1.0]To a solution of tert-butyl hexane-3-carboxylate (925mg, 4.09mmol) in anhydrous tetrahydrofuran (100mL) was added methyl N- (triethylammoniumsulfonyl) carbamate (2.92g, 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 give the title compound as a colorless oil (570mg, 67%).1H NMR(400MHz，CDCl3)：3.84(dd，1H)，3.64(dd，1H)，3.50(d，1H)，3.46(dd，1H)，2.21-2.12(m，1H)，1.44(s，9H)，0.96(t，1H)。
And 4, step 4: racemic 3-azabicyclo [3.1.0] hexane-1-carbonitrile
A solution of racemic tert-butyl 1-cyano-3-azabicyclo [3.1.0] hexane-3-carboxylate in trifluoroacetic acid (1mL) and dichloromethane (10mL) was stirred at room temperature for 1 hour. The solvent was removed to give the title compound (205mg, 100%) as a brown oil.
Example 24: racemic 3-cyano-N- { trans-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } pyrrolidine-1-sulfonamide
This compound was prepared according to the procedure for example 10 using 3-cyanopyrrolidine-1-sulfonyl chloride instead of cyclopropylmethanesulfonyl chloride. Crude productPurification by preparative high performance liquid chromatography gave the title compound as an off-white solid (5%).1H NMR(400MHz，CD3OD): 8.13(s, 1H), 7.14(d, 1H), 6.67(d, 1H), 5.45-5.41(m, 1H), 4.00-3.64(m, 1H), 3.62-3.52(m, 1H), 3.51-3.47(m, 2H), 3.45-3.39(m, 2H), 3.369(s, 3H), 2.78-2.70(m, 2H), 2.53-2.47(m, 2H), 2.39-2.36(m, 1H), 2.27-2.24(m, 1H). LC/MS (exact mass): c16H21N7O2Theoretical value of S; 375.148, Experimental value (M + H)+)；375.9。
Racemic 3-cyanopyrrolidine-1-sulfonyl chloride
A solution of racemic pyrrolidine-3-carbonitrile (53mg, 0.4mmol) and triethylamine (101g, 1mmol) in dry dichloromethane (1.0mL) was added dropwise to a stirred solution of sulfuryl chloride (64.8mg, 0.48mmol) in dichloromethane (3.0mL) at-78 deg.C. The reaction was stirred at-78 ℃ for 30 minutes, then allowed to warm to room temperature for 1 hour. The reaction solution was washed with 1M aqueous hydrochloric acid (5mL) and brine (5mL), dried over sodium sulfate and concentrated to give the title compound as a colorless oil (68mg, crude product).
Example 25: n- (cis-3- { [ (4, 4-difluoropiperidin-1-yl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Step 1: cis/trans-3- [ (tert-butoxycarbonyl) amino ] cyclobutanecarboxylic acid ethyl ester
Di (tert-butyl) dicarbonate (15.8g, 72.3mmol) is added dropwise to a solution of a mixture of cis-and trans-3-aminocyclobutanecarboxylic acid ethyl ester hydrochloride (cis/trans ═ 10:1) (WO2009/60278) (10g, 55.7mmol) and triethylamine (19.4mL, 139.1mmol) in dichloromethane (370mL) at 0 ℃. After the addition was complete, the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the resulting residue was chromatographed on silica gel, eluting with a gradient (10:1 to 3:1) of petroleum ether and ethyl acetate to give the title mixture as a white solid(19g，92％)。1H NMR(400MHz，CDCl3)：4.77(s，1H)，4.13(q，3H)，2.68-2.82(m，1H)，2.60(d，2H)，1.99-2.17(m，2H)，1.43(s，9H)，1.25(t，3H)。
Step 2: cis/trans- [3- (methylamino) cyclobutyl ] methanol
Lithium aluminum hydride (9.14g, 240.4mmol) was suspended in dry tetrahydrofuran (350 mL). The mixture was cooled to 0 ℃ and a solution of cis/trans-3- [ (tert-butoxycarbonyl) amino group was added dropwise thereto]A solution of ethyl cyclobutanecarboxylate (cis/trans ═ 10:1) (11.7g, 48.1mmol) in dry tetrahydrofuran (170 mL). After the addition was complete, the resulting mixture was heated at reflux overnight. After cooling to room temperature, the reaction was diluted with tetrahydrofuran (1.5L) and then cooled to 0-5 ℃. Adding small amount of Na2SO4·10H2O until no gas is produced. The mixture was filtered to remove solids, and the solids were rinsed with more tetrahydrofuran (500 mL). The filtrate was concentrated to dryness to give the title mixture (cis/trans ═ 10:1) as an oil (10g,>100％)。1HNMR(400MHz，CDCl3)：3.58(d，J＝3.8Hz，2H)，3.06-3.17(m，1H)，2.34-2.43(m，3H)，2.32(s，3H)，1.48-1.57(m，2H)。
and step 3: cis/trans- [3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] methanol
Potassium iodide (173mg) and triethylamine (13mL, 93.8mmol) were added to a solution of cis/trans- [3- (methylamino) cyclobutyl ] methanol (6.0g, 52.1mmol) in acetone (250 mL). 4-chloro-7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidine (14.4g, 46.9mmol) is then added and the resulting mixture is heated at reflux overnight. After evaporation of the solvent under reduced pressure, the residue was diluted with dichloromethane (500 mL). The solution was washed sequentially with water (300mL), 2% citric acid (300mL) and brine (300mL), then dried over sodium sulfate. After filtration, the solution was filtered and concentrated to give the title mixture as a pale solid (15.3g, 85%). A portion (5.0g) of the cis/trans- [3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) -cyclobutyl ] methanol mixture was separated using supercritical fluid chromatography using a Chiralpak-AD column:
cis isomer, 4.6 g:1h NMR (400MHz, methanol-d)4): 8.20(s, 1H), 7.98(d, 2H), 7.53(d, 1H), 7.34(d, 2H), 6.83(d, 2H), 4.99-4.95(m, 1H), 3.56(d, J ═ 5.6Hz, 1H), 3.24(s, 3H), 2.36(s, 3H), 2.34-2.28(m, 2H), 2.24-2.19(m, 1H), 2.11-2.03(m, 2H). LC/MS (exact mass): c19H22N4O3Theoretical value of S: 386.14, Experimental value (M + H)+)：387.3。
Trans isomer, 0.4 g:1h NMR (400MHz, methanol-d)4): 8.20(s, 1H), 7.98(d, 2H), 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): c19H22N4O3Theoretical value of S: 386.14, Experimental value (M + H)+)：387.3。
And 4, step 4: cis-4-methylbenzenesulfonic acid [3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] methyl ester
At 0 ℃ in the presence of cis- [3- (methyl {7- [ (4-methylphenyl) sulfonyl group]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]To a solution of methanol (20g, 51.8mmol) and N, N-dimethylaminopyridine (12.6g, 103.6mmol) in dichloromethane (500mL) was added p-toluenesulfonyl chloride (14.8g, 77.7 mmol.) the reaction mixture was stirred at room temperature for 16 hours, then washed with water (500mL), the combined aqueous washes were extracted with dichloromethane (2 × 800mL), the combined organic layers were dried, filtered and concentrated under vacuum, the residue was chromatographed on silica gel with a gradient of dichloromethane and methanol (100:0 to 95:5) to give the title compound (23g, 82%) as a white solid LC/MS (exact mass): C26H28N4O5S2Theoretical value of (2): 540.150, Experimental value (M + H)+)：541.3。
And 5: thioacetic acid S- { [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] methyl } ester
To a solution of potassium thioacetate (678mg, 5.93mmol) in N, N-dimethylformamide (5mL) was added dropwise 4-methylbenzenesulfonic acid [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] at room temperature]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]A solution of methyl ester (2.0g, 3.70mmol) in N, N-dimethylformamide (6mL) was formed over a period of 5 minutes, then the mixture was heated at 50-55 deg.C overnight, the mixture was cooled to room temperature, the mixture was poured into saturated aqueous sodium bicarbonate (60mL) to quench the reaction, the mixture was extracted with ethyl acetate (3 × 30mL), the combined organic layers were washed with water (3 × 30mL) and brine (30mL), washed with Na2SO4After drying, 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 give the title compound (1.2g, 73%) as a yellow solid.1H NMR(400MHz，CDCl3): 8.39(s, 1H), 8.04(d, 2H), 7.45(d, 1H), 7.27(d, 2H), 6.63(d, 1H), 4.98-4.88(m, 1H), 3.22(s, 3H), 3.02-3.00(m, 2H), 2.45-2.44(m, 2H), 2.47(m, 3H), 2.22(m, 3H), 2.21-2.24(m, 1H), 1.92-1.87(m, 2H). LC/MS (exact mass): c21H24N4O3S2Theoretical value of (2): 444.129, Experimental value (M + H)+)：445.1。
Step 6: [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] methanesulfonic acid
S- { [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] thioacetic acid at room temperature]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]To a solution of methyl } ester (580mg, 1.31mmol) in formic acid (10mL) was added 30% aqueous hydrogen peroxide (0.7mL, 6.92 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into 33% aqueous sodium hydrogensulfate solution (1.12mL), followed by stirring for 10 minutes.Then 33% aqueous sodium hydroxide (1.8mL) was added to adjust to pH 5. The resulting mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with water (10mL), and dried under vacuum at about 60 ℃ to give the title compound (634mg, crude) as a white solid. LC/MS (exact mass): c19H22N4O5S2The theoretical value of (A); 450.103, Experimental value (M + H)+)；451.3。
And 7: cis- [3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] methanesulfonyl chloride
Thionyl chloride (0.3ml, 3.33mmol) was added dropwise to the mixture of cis- [3- (methyl {7- [ (4-methylphenyl) sulfonyl ] carbonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Methanesulfonic acid (150mg, 0.33mmol) in dichloromethane (20mL) over a period of 5 minutes 2 drops of N, N-dimethylformamide were added to the solution, the solution was then heated at 75 ℃ for 2 hours, the mixture was cooled and the solvent evaporated, the residue was washed with dry dichloromethane (3 × 10mL) to give the crude title compound (170mg) as a yellow solid LC/MS (exact mass): C19H21ClN4O4S2The theoretical value of (A); 468.069, Experimental value (M + H)+)；469.2。
And 8: n- (cis-3- { [ (4, 4-difluoropiperidin-1-yl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
A mixture of 4, 4-difluoropiperidine (77mg, 0.64mmol) and triethylamine (97mg, 0.96mmol) in tetrahydrofuran (20mL) was added dropwise at 0 deg.C to a solution of cis- [3- (methyl {7- [ (4-methylphenyl) sulfonyl group]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Methanesulfonyl chloride (150mg, 0.320mmol) in tetrahydrofuran (10 mL). The mixture was allowed to warm to room temperature overnight. The solvent was evaporated and the residue taken up in ethyl acetate (80 mL). The solution was washed with brine (30mL), dried over sodium sulfate and concentrated to give the crude title compound (134mg) as a white solid. LC/MS (exact mass): c24H29F2N5O4S2The theoretical value of (A); 553.651, Experimental value (M + H)+)；554.3。
And step 9: n- (cis-3- { [ (4, 4-difluoropiperidin-1-yl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N- (cis-3- { [ (4, 4-difluoropiperidin-1-yl) sulfonyl]Methyl } cyclobutyl) -N-methyl-7- [ (4-methylphenyl) sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-amine (134mg, 0.24mmol) and lithium hydroxide monohydrate (51mg, 1.21mmol) were mixed in a mixture of ethanol (14mL) and water (7mL), followed by heating at 50 ℃ overnight. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (30mL), 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 give the title compound (31mg, 32.3%) as a white solid.1H NMR (400MHz, methanol-d)4): 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): c17H23F2N5O2Theoretical value of S; 399.154, Experimental value (M + H)+)；400.3。
Examples 26 to 29 the following compounds were prepared from cis- [3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] methanesulfonyl chloride (example 25 step 7) using the appropriate amine in place of 4, 4-difluoropiperidine in step 8 according to the procedure of example 25 step 8 (sulfonylation) and step 9 (deprotection).
Example 26: 1- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] -4- (trifluoromethyl) piperidin-4-ol
The title compound (31mg) was prepared using 4- (trifluoromethyl) piperidin-4-ol in the sulfonylation step and deprotected using the method of example 25, step 9. This compound was purified using preparative thin layer chromatography eluting with a mixture of ethyl acetate and methanol (20: 1).1H NMR (400MHz, methanol-d)4): 8.13(s, 1H), 7.13(d, J ═ 3.6, 1H), 6.70(d, J ═ 3.6, 1H), 5.10 to 5.08(m, 1H), 3.74 to 3.71(m, 2H), 3.36(m, 3H), 3.32 to 3.27(m, 2H), 3.19 to 3.13(m, 2H), 2.62 to 2.54(m, 3H), 2.25 to 2.21(m, 2H), 1.86 to 1.84(m, 4H). LC/MS (exact mass): c18H24F3N5O3Theoretical value of S; 447.155, Experimental value (M + H)+)；448.3。
Examples 28 and 29: (3R) and (3S) -1- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] pyrrolidine-3-carbonitrile
The title compound (all 330mg) was prepared using concentrated pyrrolidine-3-carbonitrile as a non-racemic mixture of 80:20 of (3R) -pyrrolidine-3-carbonitrile and (3S) -pyrrolidine-3-carbonitrile enantiomers in a sulfonylation step and deprotected using the procedure of example 19, step 2. The compound was purified by silica gel chromatography eluting with a gradient (10:1 to 1:10) of petroleum ether and ethyl acetate. LC/MS M/z 375.2(M + 1). Separation of enantiomers by preparative supercritical fluid chromatography:
3R-enantiomer (28): 178 mg.1H NMR(400MHz，CDCl3): 8.31(s, 1H), 7.06(d, 1H), 6.58(d, 1H), 5.19-5.10(m, 1H), 3.77-3.75(m, 1H), 3.61-3.54(m, 3H), 3.33(s, 3H), 3.21-3.19(m, 3H), 2.69-2.66(m, 3H), 2.36-2.31(m, 2H), 2.14-2.11(m, 2H). LC/MS (exact mass): c17H22N6O2Theoretical value of S; 374.15, Experimental value (M + H)+) (ii) a 375.2. Chiral HPLC retention time ═ 2.65 min.
3S-enantiomer (29))：31mg。1H NMR(400MHz，CDCl3): 8.31(s, 1H), 7.06(d, 1H), 6.58(d, 1H), 5.19-5.10(m, 1H), 3.77-3.75(m, 1H), 3.61-3.54(m, 3H), 3.33(s, 3H), 3.21-3.19(m, 3H), 2.69-2.66(m, 3H), 2.36-2.31(m, 2H), 2.14-2.11(m, 2H). LC/MS (exact mass): c17H22N6O2Theoretical value of S; 374.15, Experimental value (M + H)+) (ii) a 375.2. Chiral HPLC retention time 2.53 min.
Example 30: n- { cis-3- [ (butanesulfonyl) methyl ] cyclobutyl } -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Step 1: n- { cis-3- [ (butylthio) methyl ] cyclobutyl } -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Cis-4-methylbenzenesulfonic acid [3- (methyl {7- [ (4-methylphenyl) sulfonyl ] from step 4 of example 25]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]A solution of the methyl ester (23g, 42.6mmol) was stirred in N-methylpyrrolidine (100mL), then 1, 8-diazabicycloundec-7-ene (12.8g, 85.2mmol) and 1-butanethiol (7.8g, 85.2mmol) were added to the reaction mixture, the reaction mixture was stirred at room temperature for 16 hours, water (200mL) and ethyl acetate (500mL) were added, the aqueous layer was extracted with ethyl acetate (2 × 500mL), 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 give the title compound (11.8g, 91%). LC/MS (exact mass): C16H24N4Theoretical value of S; 304.172, Experimental value (M + H)+)；305.3。
Step 2: n- { cis-3- [ (butanesulfonyl) methyl ] cyclobutyl } -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N- { cis-3- [ (butylthio) methyl group]Cyclobutyl } -N-methyl-7H-pyrrolo [2, 3-d)]Pyrimidin-4-amine (12g, 39.5mmol) was dissolved in a mixture of tetrahydrofuran (200mL), ethanol (200mL) and water (200 mL). Adding potassium hydrogen peroxymonosulfate complex salt (48.6g, 79.0mmol) and reactingThe mixture was stirred at room temperature for 1 hour, then the mixture was filtered, the solids were washed with a mixture of tetrahydrofuran (40mL), ethanol (40mL) and water (20mL), the filtrate was treated with 10% aqueous sodium hydrogen sulfate (200mL) and stirred at room temperature for 20 minutes, saturated aqueous sodium bicarbonate was added to adjust the pH to-7, the mixture was extracted with dichloromethane (3 × 800mL), the combined organic layers were dried and concentrated under vacuum, the crude residue was chromatographed on silica gel, eluting with a gradient of dichloromethane and methanol (100:0 to 95:5), to give the title compound (11.4g, 86%).1H NMR (400MHz, methanol-d)4): 8.13(s, 1H), 7.13-7.12(m, 1H), 6.70-6.69(m, 1H), 5.13-5.10(m, 1H), 3.42(s, 3H), 3.33(m, 2H), 3.11-3.07(m, 2H), 2.65-2.63(m, 3H), 2.29-2.25(m, 2H), 1.86-1.78(m, 2H), 1.55-1.50(m, 2H), 1.03-0.99(m, 3H). LC/MS (exact mass): c16H24N4O2Theoretical value of S; 336.162, Experimental value (M + H)+)；337.3。
Example 31: N-methyl-N- (trans-3- ((propylsulfonyl) methyl) cyclobutyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
From cis-and trans-4-methylbenzenesulfonic acid [3- (methyl {7- [ (4-methylphenyl) sulfonyl group]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Starting from the methyl ester (cis/trans ═ 10:1) (example 25, step 4), a mixture of the cis and trans isomers of the title compound was prepared according to analogous procedures as in example 30, steps 1 and 2, using propane-1-thiol instead of butane-1-thiol in step 2 (50 mg). 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): c15H22N4O2Theoretical value of S; 322.15, Experimental value (M + H)+)；323.2。
Subsequently, cis and trans isomers were separated by preparative supercritical fluid chromatography.
Trans isomer (31), 12 mg:1h NMR (400MHz, methanol-d)4): 8.12(s, 1H), 7.13-7.12(m, 1H), 6.69-6.66(m, 1H), 5.45-5.41(m, 1H), 3.46-3.44(m, 2H), 3.36(s, 3H), 3.11-3.09(m, 2H), 2.88-2.86(m, 1H), 2.75-2.67(m, 2H), 2.40-2.38(m, 2H), 1.91-1.86(m, 2H), 1.12-1.10(m, 3H). LC/MS (exact mass): c15H22N4O2Theoretical value of S; 322.15, Experimental value (M + H)+)；323.2。
Cis isomer, 36 mg:1h NMR (400MHz, methanol-d)4): 8.12(s, 1H), 7.13-7.12(m, 1H), 6.70-6.69(m, 1H), 5.10-5.20(m, 1H), 3.36(s, 3H), 3.33-3.32(m, 2H), 3.08-3.04(m, 2H), 2.64-2.61(m, 3H), 2.24-2.22(m, 2H), 1.90-1.84(m, 2H), 1.13-1.09(m, 3H). LC/MS (exact mass): c15H22N4O2Theoretical value of S; 322.15, Experimental value (M + H)+)；323.2。
Example 32: n- (cis-3- { [ (2-cyclopropylethyl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Step 1: n- (cis-3- { [ (2-cyclopropylethyl) thio ] methyl } cyclobutyl) -N-methyl-7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Nitrogen bubbling through thioacetic acid S- { [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] at 0 deg.C]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Methyl } ester (example 25 step 5) (190mg, 0.43mmol) and potassium carbonate (129mg, 0.94mmol) in a mixture of methanol (10mL) over 2 minutes followed by 2-cyclopropylethyl 4-methylbenzenesulfonate (159mg, 1.53mmol) and the solution stirred at room temperature for 6 hours dichloromethane (30mL) and water (20mL) were added, the aqueous layer was extracted with dichloromethane (2 × 20mL), the combined organic layers were washed with brine, dried over sodium sulfate and concentrated the crude product was purified by preparative thin layer chromatography eluting with ethyl acetate-petroleum ether (1:2) to give the title compound as a white solid (62mg, 31%). LC/MS (neat)Exact mass): c24H30N4O2S2The theoretical value of (A); 470.18, Experimental value (M + H)+)；471.1。
Step 2: n- (cis-3- { [ (2-cyclopropylethyl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N- (cis-3- { [ (2-cyclopropylethyl) thio]-methyl } cyclobutyl) -N-methyl-7- [ (4-methylphenyl) sulfonyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-amine (24mg, 0.051mmol) and Potassium hydrogen peroxymonosulfate Complex salt (49mg, 0.079mmol) in a mixture of tetrahydrofuran (1.2mL), water (0.6mL) and ethanol (1.2mL) was stirred at room temperature for 20 minutes, aqueous sodium bisulfate was added followed by dichloromethane (20mL), the aqueous layer was extracted with dichloromethane (2 × 20mL), the combined organic layers were extracted with brine, dried over sodium sulfate and concentrated the crude material was used directly in the next step LC/MS (exact mass): C24H30N4O4S2The theoretical value of (A); 502.17, Experimental value (M + H)+)；503.3。
And step 3: n- (cis-3- { [ (2-cyclopropylethyl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N- (cis-3- { [ (2-cyclopropylethyl) sulfonyl]Methyl } cyclobutyl) -N-methyl-7- [ (4-methylphenyl) sulfonyl]-7H-pyrrolo [2,3-d]A mixture of pyrimidin-4-amine (49mg, 0.097mmol) and lithium hydroxide (30mg, 1.3mmol) in water (5mL) and ethanol (10mL) was stirred at 50 ℃ for 2 hours. Next, methylene chloride (20mL) was added and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by reverse phase high performance liquid chromatography eluting with a gradient of water and acetonitrile (95:5 to 5:95) to afford the title compound (14mg, 40%) as a white solid.1H NMR (400MHz, methanol-d)4)：8.12(s，1H)，7.13(d，2H)，6.70(d，2H)，5.12-5.09(m，1H)，3.34(s，3H)，3.34-3.33(m，2H)，3.20-3.17(m，2H)，2.64-2.61(m，3H)，2.26-2.22(m，2H)，1.75-1.69(m，2H)，0.89-0.86(m，2H)，0.56-0.52(m, 2H), 0.18-0.17(m, 2H). LC/MS (exact mass): c17H24N4O2Theoretical value of S; 348.16, Experimental value (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 ] thio } methyl) cyclobutyl ] -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Nitrogen bubbling through thioacetic acid S- { [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] at 0 deg.C]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Methyl } ester (example 25 step 5) (250mg, 0.56mmol) and potassium carbonate (194mg, 1.41mmol) in a mixture of methanol (100mL) over a period of 2 minutes followed by the addition of methyl 4-methylbenzenesulfonate (3, 3-difluorocyclobutyl) ester (prepared as described in WO 2004/032834) (310mg, 1.12 mmol). The mixture was stirred at room temperature for 6h, filtered, and concentrated to give the title compound as a white solid (270mg, crude). LC/MS (exact mass): c17H22F2N4Theoretical value of S; 352.15, Experimental value (M + H)+)；353.2。
Step 2: n- [ cis-3- ({ [ (3, 3-difluorocyclobutyl) methyl ] sulfonyl } methyl) cyclobutyl ] -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N- [ cis-3- ({ [ (3, 3-difluorocyclobutyl) methyl]Thio } methyl) cyclobutyl]-N-methyl-7H-pyrrolo [2,3-d]A mixture of pyrimidin-4-amine (45mg, 0.13mmol) and potassium hydrogen peroxymonosulfate complex salt (157mg, 0.26mmol) in a mixture of tetrahydrofuran (20mL), water (10mL) and ethanol (20mL) was stirred at room temperature for 20 minutes, followed by the addition of aqueous sodium bisulfite, followed by the addition of dichloromethane (20mL), the aqueous layer was extracted with dichloromethane (2 × 20mL), the combined organic layers were extracted with brine, dried over sodium sulfate, and concentratedGradient (95:5 to 5:95) elution afforded the title compound as a white solid (34mg, 39%).1H NMR (400MHz, methanol-d)4): 8.29(s, 1H), 7.42(d, 1H), 7.03(d, 1H), 4.86(m, 1H), 3.51(s, 3H), 3.39-3.33(m, 4H), 2.84(m, 1H), 2.76-2.71(m, 4H), 2.53(m, 2H), 2.37-2.34(m, 2H). LC/MS (exact mass): c17H22F2N4O2Theoretical value of S; 384.14, Experimental value (M + H)+)；385.1。
Examples 34A and 34B: (1R,3R) and (1S,3S) - [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] cyclopentanecarbonitrile
The title compound mixture of (1R,3R) and (1S,3S) -3- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] cyclopentanecarbonitrile was prepared from thioacetic acid S- { [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] methyl } ester (example 25 step 5) according to the procedures of example 30 steps 1 and 2.
The title compound (180mg) was isolated using preparative supercritical fluid chromatography using a Chiralpak AS column:
(1R,3R) enantiomer 34A: 60mg of the total weight of the powder,1h NMR (400MHz, methanol-d)4): 8.12(s, 1H), 7.13-7.12(d, 1H), 6.70-6.69(d, 1H), 5.17-5.11(m, 1H), 3.86-3.78(m, 1H), 3.41-3.36(m, 5H), 3.15-3.11(m, 1H), 2.63-2.53(m, 4H), 2.37-2.13(m, 6H), 2.03-1.91(m, 1H). LC/MS (exact mass): c17H22F2N4O2Theoretical value of S; 373.16, Experimental value (M + H)+)；374.1。
(1S,3S) enantiomer 34B: 27mg, LC/MS (accurate mass): c17H22F2N4O2Theoretical value of S; 373.16, Experimental value (M + H)+)；374.1。
The intermediate, 3-cyanocyclopentyl 4-methylbenzenesulfonate, used in step-1 was prepared according to the following procedure:
4-Methylbenzenesulfonic acid 3-cyanocyclopentyl ester
4-methylbenzene-1-sulfonyl chloride (6.9g, 36mmol) and N, N-dimethylpyridin-4-amine (100mg) were added to a solution of the compound 3-hydroxycyclopentanecarbonitrile (J.Org.chem.2007,72,7423) (2g, 18mmol) and triethylamine (5.5g, 54mmol) in dichloromethane (100 mL.) the reaction mixture was stirred at room temperature for 15 hours, followed by addition of saturated aqueous sodium bicarbonate (20mL) to the mixture to quench the reaction, the mixture was extracted with dichloromethane (4 × 50mL), 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 (0.5g, 11% yield). LC/MS (exact mass): C13H15NO3Theoretical value of S; 265.08, Experimental value (M + 23); 287.9.
example 35: racemic N-methyl-N- [ cis-3- ({ [1- (propan-2-yl) pyrrolidin-3-yl ] sulfonyl } methyl) cyclobutyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Step 1: 3- ({ [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] methyl } thio) pyrrolidine-1-carboxylic acid tert-butyl ester
Cis-4-methylbenzenesulfonic acid [3- (methyl {7- [ (4-methylphenyl) sulfonyl ] from step 4 of example 25 was stirred]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]A solution of methyl ester (2g, 3.7mmol) in N-methylpyrrolidine (40mL) was then added to the reaction mixture 1, 8-diazabicycloundecen-7-ene (1.13g, 7.4mmol) and tert-butyl 3-mercapto-pyrrolidine-1-carboxylate (1.13g, 5.6 mmol). the reaction mixture was stirred at room temperature for 16 hours, water (200mL) and ethyl acetate (500mL) were added, the aqueous layer was extracted with ethyl acetate (2 × mL), the combined organic layers were dried and concentrated in vacuo to afford the title compound as a white solid (2).6g, 118%). LC/MS (exact mass): c28H37N5O4S2The theoretical value of (A); 571.23, Experimental value (M + H)+)：572.1。
Step 2: n-methyl-7- [ (4-methylphenyl) sulfonyl ] -N- { cis-3- [ (pyrrolidin-3-ylsulfanyl) methyl ] cyclobutyl } -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
At the position of 3- ({ [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl group)]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Methyl } thio) pyrrolidine-1-carboxylic acid tert-butyl ester (2.6g, 4.5mmol) in methanol (15mL) was added 3M hydrochloric acid in methanol (40 mL). The resulting solution was stirred at room temperature for 1 hour. The solution was concentrated to give the crude product, which was purified by silica gel chromatography eluting with a gradient of dichloromethane and methanol (100:0 to 85:15) to give the title compound as a colorless oil (1.7g, 52%).1H NMR (400MHz, methanol-d)4): 8.21(s, 1H), 7.99(d, 2H), 7.56(d, 1H), 7.37(d, 2H), 6.88(d, 1H), 4.95-4.87(m, 1H), 3.29(s, 1H), 3.27(s, 3H), 3.21-3.17(m, 1H), 3.04-3.96(m, 1H), 2.92-29(m, 1H), 2.72-2.01(m, 3H), 2.50-2.43(m, 2H), 2.39(s, 3H), 2.29-2.15(m, 2H), 2.03-2.01(m, 2H), 1.98-1.65(m, 1H). LC/MS (exact mass): c23H29N5O2S2The theoretical value of (A); 471.18, experimental value (M + 23): 494.
and step 3: n-methyl-7- [ (4-methylphenyl) sulfonyl ] -N- [ cis-3- ({ [1- (propan-2-yl) pyrrolidin-3-yl ] thio } methyl) cyclobutyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
In the presence of N-methyl-7- [ (4-methylphenyl) sulfonyl]-N- { cis-3- [ (pyrrolidin-3-ylthio) methyl]Cyclobutyl } -7H-pyrrolo [2, 3-d)]To a solution of pyrimidin-4-amine (472mg, 1mmol) in dichloromethane (50mL) was added acetone (174mg, 3mmol),Molecular sieves (40mg) and sodium cyanoborohydride (189mg, 3 mmol). The resulting solution is in the chamberStirring at room temperature for 1 hour, followed by dilution with dichloromethane (70mL) and water (70mL), extraction of the aqueous layer with dichloromethane (2 × 50mL), washing of the combined organic layers with brine (100mL), drying of the organic layers over anhydrous sodium sulfate and concentration to give the title compound (500mg, 97% yield) as a colorless oil, LC/MS (exact mass): C26H35N5O2S2The theoretical value of (A); 513.22, Experimental value (M + H)+)；514.1。
And 4, step 4: n-methyl-7- [ (4-methylphenyl) sulfonyl ] -N- [ cis-3- ({ [1- (propan-2-yl) pyrrolidin-3-yl ] sulfonyl } methyl) cyclobutyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N-methyl-7- [ (4-methylphenyl) sulfonyl]-N- [ cis-3- ({ [1- (propan-2-yl) pyrrolidin-3-yl]Thio } methyl) cyclobutyl]-7H-pyrrolo [2,3-d]A mixture of pyrimidin-4-amine (500mg, 1.0mmol) and potassium hydrogen peroxymonosulfate complex salt (1.23g, 2.0mmol) in tetrahydrofuran (20mL), water (10mL) and ethanol (20mL) was stirred at room temperature for 30 minutes, the reaction solution was diluted with ethyl acetate (100mL) and water (50mL), the aqueous layer was extracted with ethyl acetate (3 × 50mL), the combined organic layers were washed with brine (100mL), dried over sodium sulfate and concentrated to give the title compound as a colorless oil (420mg, 90%). LC/MS (exact mass): C26H35N5O4S2The theoretical value of (A); 545.21, Experimental value (M + H)+)：546.3。
And 5: N-methyl-N- [ cis-3- ({ [1- (propan-2-yl) pyrrolidin-3-yl ] sulfonyl } methyl) cyclobutyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N-methyl-7- [ (4-methylphenyl) sulfonyl]-N- [ cis-3- ({ [1- (propan-2-yl) pyrrolidin-3-yl]Sulfonyl } methyl) cyclobutyl]-7H-pyrrolo [2,3-d]A mixture of pyrimidin-4-amine (330mg, 0.6mmol) and lithium hydroxide (126mg, 3mmol) was stirred in a mixture of water (5mL) and ethanol (10mL) at 50 ℃ for 2 hours. The mixture was then concentrated and the residue 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 eluting with a gradient of water and acetonitrile (95:5 to 5:95)To give the title compound as a white solid (89mg, 38%).1H NMR(400MHz，CDCl3): 8.32(s, 1H), 7.07(d, 1H), 6.57(d, 1H), 5.13(m, 1H), 3.57(m, 1H), 3.33(s, 3H), 3.05-3.22(m, 3H), 2.92(m, 1H), 2.78-2.87(m, 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): c19H29N5O2Theoretical value of S; 391.20, Experimental value (M + H)+)；392.3。
Example 36: n- (cis-3- { [ (3-chloro-4-fluorophenyl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Step 1: n- (cis-3- { [ (3-chloro-4-fluorophenyl) thio ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
To a solution of 3-chloro-4-fluorosulphenol (93mg, 0.55mmol) in tetrahydrofuran (1.5mL) were added 50% aqueous sodium hydroxide (44mg, 0.55mmol) and ethanol (1.5 mL). The mixture was stirred at room temperature for 1 hour. Cis-4-methylbenzenesulfonic acid [3- (methyl {7- [ (4-methylphenyl) sulfonyl ] from step 4 of example 25]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]A solution of methyl ester (200mg, 0.37mmol) in tetrahydrofuran (1.5mL) was added to the reaction mixture. The combined mixture was heated at 40 ℃ overnight. The reaction mixture was concentrated and purified on a silica gel column eluting with a gradient of heptane and ethyl acetate (90:10 to 0:100) to give the title compound (69mg, 49.6%).1H NMR(400MHz，CDCl3)：8.18(s，1H)，7.39(dd，1H)，7.28(s，1H)，7.03-7.08(m，1H)，7.00(d，1H)，6.52(d，1H)，4.97-5.07(m，1H)，3.35(m，2H)，3.23(s，3H)，2.89(s，1H)，2.43-2.52(m，2H)，2.19-2.30(m，2H)。
Step 2: n- (cis-3- { [ (3-chloro-4-fluorophenyl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
In the presence of N- (cis-3- { [ (3-chloro-)4-fluorophenyl) thio group]Methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d]To a solution of pyrimidin-4-amine (75mg, 0.2mmol) in dichloromethane (10mL) was added 3-chloroperbenzoic acid (107 mg). The reaction was stirred at room temperature overnight, then concentrated. The crude residue was chromatographed on silica gel, eluting with a gradient (80:20) of dichloromethane and 2M ammonia in methanol to afford the title compound (48mg, 59.2%).1H NMR (400MHz, methanol-d)4): 8.31(s, 1H), 8.02(m, 1H), 7.81-7.83(m, 1H), 7.37-7.27(m, 1H), 7.09(d, 1H), 6.65(s, 1H), 5.18-5.10(m, 1H), 4.15-4.09(m, 1H), 3.32(m, 5H), 2.59-2.54(m, 2H), 2.44-2.42(m, 2H). LC/MS (exact mass): c18H18ClFN4O2Theoretical value of S; 408.08, Experimental value (M + H)+)；409。
Example 37: 2- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] pyridine-4-carbonitrile
Step 1: 2- ({ [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] methyl } thio) pyridine-4-carbonitrile
1, 8-diazabicycloundec-7-ene (24.6g, 161mmol) and 2-mercapto-isonicotinic carbonitrile (16.1g, 118mmol) were added to the residue obtained from methanesulfonic acid [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ]]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]-methyl ester (50g, 110mmol) in N-methylpyrrolidine (250 mL). The reaction mixture was heated at 50 ℃ overnight. Additional 2-mercaptoisonicotinine carbonitrile (8.1g, 59mmol) was added to complete the reaction. The mixture was cooled to about 0 ℃, followed by dropwise addition of water to the reaction mixture to quench the reaction. The solid was collected by filtration, washed with water and dried under vacuum at 50 ℃ to give the title compound as a bright yellow solid (45.8g, 82.8%). LC/MS (exact mass): c25H24N6O2S2The theoretical value of (A); 504.14, Experimental value (M + H)+)；505.1。
Step 2: 2- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) thio ] pyridine-4-carbonitrile
At the 2- ({ [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl group { [ S ]]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]Methyl } thio) pyridine-4-carbonitrile (45.3g, 89.8mmol) in tetrahydrofuran (180mL) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (269 mL). The reaction mixture was heated to reflux for 6 hours, then cooled to room temperature. Water was added dropwise over 45 minutes. The solid was collected by filtration and rinsed with a mixture of 20% tetrahydrofuran (33mL) and water (97 mL). The wet cake was dried under vacuum at 50 ℃ to afford the title compound as a brown solid (25g, 79%). LC/MS (exact mass): c18H18N6S2The theoretical value of (A); 350.13, Experimental value (M + H)+)；351.1。
And step 3: 2- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] pyridine-4-carbonitrile
Potassium hydrogen peroxymonosulfate complex salt (236.8g, 385.2mmol) was slowly added to 2- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ]) at 0 deg.C]Pyrimidin-4-yl) amino]Cyclobutyl } methyl) thio group]Pyridine-4-carbonitrile (22.5g, 64.2mmol) was dissolved in a mixture of methanol (337mL) and water (56 mL). The reaction was stirred at3 ℃ for 20 hours. To the reaction mixture was added 10% aqueous sodium hydrogensulfate solution (40mL) to quench the reaction. The resulting slurry was stirred at room temperature for 2 hours. 10% aqueous potassium carbonate solution was added until the pH was 4 to 5. The material was filtered and washed with water. The wet cake was dried under vacuum at 40 ℃ to give an off-white solid. This material was taken up in tetrahydrofuran (50mL) and heated at reflux for 3 h. The mixture was cooled to room temperature and filtered to collect the solid, which was dried under vacuum at 40 ℃ to give the title compound as a pale brown powder (17.3g, 70.46%).1HNMR(400MHz，CDCl3): 11.97(s, 1H), 8.95(d, 1H), 8.33-8.28(m, 2H), 7.81(d, 1H), 7.1(d, 1H), 6.54(d, 1H), 5.13-5.08(m, 1H), 3.63(m, 2H), 3.30(s, 3H), 2.54-2.48(m, 3H), 2.09-2.07(m, 2H). LC/MS (accurate)Mass): c18H18N6O2S2The theoretical value of (A); 382.12, Experimental value (M + H)+)；383.1。
Example 38: 2-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -1, 3-thiazole-5-sulfonamide
Step 1: 2-methyl-N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclobutyl ] -1, 3-thiazole-5-sulfonamide
Triethylamine (62.0g, 0.613mol) was added to the reaction mixture consisting of cis-N-methyl-N-7H-pyrrolo [2,3-d ]]Pyrimidine-4-cyclobutane-1, 3-diamine hydrochloride (22.2.g, 0.102mol) in dichloromethane (250 mL). A solution of 2-methylthiazole-5-sulfonyl chloride (28.0g, 0.142mol) in dichloromethane (250mL) was added to the reaction mixture at room temperature for 30 minutes. After 1.5 hours, the solvent was removed under reduced pressure and the resulting solid was dissolved in 4:1 ethyl acetate: dichloromethane (400 mL). The solution was filtered through a 40g pad of silica gel, rinsing with ethyl acetate (800mL) and dichloromethane (100 mL). The solvent in the filtrate was removed under reduced pressure to obtain a solid (59 g). The solid was purified by silica gel column chromatography with a 1:1 dichloromethane: ethyl acetate to pure ethyl acetate elution gave the title compound (44.4g, 81%); m/z (CI)533[ M + H]+。
Step 2: 2-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -1, 3-thiazole-5-sulfonamide
A solution of lithium hydroxide (12.1g, 0.505mol) in water (290mL) was added to 2-methyl-N- [ cis-3- (methyl {7- [ (4-methylphenyl) sulfonyl ] group]-7H-pyrrolo [2,3-d]Pyrimidin-4-yl } amino) cyclobutyl]-1, 3-thiazole-5-sulfonamide (43.8g, 82.2mmol) in isopropanol (435mL) and the mixture was heated to 60 ℃ overnight. After cooling to room temperature, the reaction mixture was filtered and washed with water (145 mL). The pH of the filtrate was adjusted to 6-7 using 6M aqueous hydrochloric acid. The reaction slurry was concentrated under reduced pressure. Adding water(370mL), the mixture was cooled to 0 ℃. The resulting material was collected by filtration, washed with ice water (150ml) and then dried under vacuum at 60 ℃ overnight to give the title compound (25.0g, 80%);1H NMR(DMSO-d6)：11.66-11.71(1H)，8.44-8.47(1H)，8.11-8.08(2H)，7.16-7.17(1H)，6.63-6.65(1H)，4.86-4.94(1H)，3.58-3.68(1H)，3.22(3H)，2.74(3H)，2.40-2.46(2H)，2.10-2.18(2H)。m/z(CI)379[M+H]+。
biological evaluation
JAK Caliper enzyme assay at 1mM ATP
The test article was dissolved in dimethyl sulfoxide (DMSO) to a stock concentration of 30 mM. Using DMSO, 11 semilog serial dilutions were made, with a maximum concentration of 600 μ M. The test compound plate also included positive control wells containing known inhibitors to define 100% inhibition, and negative control wells containing DMSO to define no inhibition. The compound plates were diluted 1 to 60 to give the highest concentration of final assay compound of 10 μ M and DMSO concentration of 2%.
Test items and assay controls were added to 384-well plates. The reaction mixture contained 20mM HEPES (pH 7.4), 10mM magnesium chloride, 0.01% Bovine Serum Albumin (BSA), 0.0005% tween 20, 1mM ATP and 1 μ M peptide substrate. The JAK1 and TYK2 assays contained 1 μ M IRStide peptide (5FAM-KKSRGDYMTMQID), while the JAK2 and JAK3 assays contained 1 μ M JAKtide peptide (FITC-KGGEEEEYFELVKK). These assays were primed by the addition of 20nM JAK1, 1nM JAK2, 1 nMUK 3, or 1nM TYK2 and incubation at room temperature for the following times: JAK1 was incubated for 3 hours, JAK2 for 60 minutes, JAK3 for 75 minutes or TYK2 for 135 minutes. The enzyme concentration and incubation time for each new enzyme preparation were optimized and slightly modified over time to ensure 20% -30% phosphorylation. To the assay solution were added 10mM EDTA, 0.1% coating agent and 100mM HEPES (pH 7.4) at final concentration to stop the assay reaction. The assay plates were placed on a caliper life Science Lab Chip 3000(LC3000) instrument and each well was sampled using appropriate separation conditions to measure unphosphorylated and phosphorylated peptides.
TABLE 1.1 JAK Caliper at mM ATPTMData from enzyme assays
STAT3 phosphorylation assay induced by HWB INF α
Test articles were made up in 100% DMSO as 30mM stock, then diluted to 5 mM. 10 2.5-fold serial dilutions were made in DMSO, with a maximum concentration of 5 mM. mu.L of each of the above test article solutions was added to 96. mu.L of PBS for further dilution to a maximum concentration of 200. mu.M.
mu.L of HWB followed by 5. mu.L of the test article solution prepared above to a maximum concentration of 10. mu.M was added to each well of a 96-well polypropylene plate (VWR 82007-292). The plate was mixed and incubated at 37 ℃ for 45 minutes.5. mu.L of human IFN α (Universal Type I IFN, R.sub.&D Systems # 11200-2; final concentration 5000U/ml) or D-PBS (unstimulated control), mixed and incubated at 37 ℃ for 15 minutes. Add 1000. mu.L/well lysis/fixation Buffer [ BD Phosflow 5X Lyse/Fix Buffer (BD #558049) to all wells]To quench the reaction and mix and incubate at 37 ℃ for 20 minutes; in FACS buffer [ D-PBS (Invitrogen cat #14190), containing 0.1% BSA and 0.1% sodium azide]After rinsing, 400 μ L of ice-cold 90% methanol/water was added to each well and incubated on ice for 30 minutes. An additional wash was performed with ice-cold FACS buffer and the total samples were finally suspended in 250 μ L/well of the desired Alexa Fluor 647 conjugated anti-phospho-STAT 3(pY705) antibody (BD #557815) (1:125 fold dilution in FACS buffer). All samples were incubated overnight at 4 ℃ and transferred to 96-well polypropylene U-plates (Falcon #353077) and examined by flow cytometry. The ICs of examples 1 to 9, 11 to 23, and 25 to 38 were obtained50Values ranged from 22 to 2610 nM.
In vitro canine T cell proliferation assay
T cell activation plays an important role in a variety of inflammatory conditions and autoimmune diseases, as well as asthma, allergy and pruritus. Since T cell activation may be triggered in part by cytokines that signal through the JAK-STAT pathway, JAK inhibitors may be effective against such diseases involving aberrant T cell activation.
The method comprises the following steps: canine whole blood was collected from 29 beagle (beagle) dogs and 23 mixed breed dogs in heparin sodium tubes. Whole blood (20. mu.L) was placed in 96-well plates (Costar 3598) containing 180. mu.L of medium (RPMI 1640, Gibco #21870-076 containing 1% heat-inactivated fetal bovine serum, Gibco # 10082-39; 292. mu.g/ml L-glutamine, Gibco 250030-081; 100. mu.g/ml penicillin and 100. mu.g/ml streptomycin, Gibco #15140-122) and containing either a vector control or test compound (0.001 to 10. mu.M), concanavalin A (ConA; 1. mu.g/ml, Sigma C5275), and canine interleukin-2 (IL-2; 50ng/ml, R & D Systems 1815-CL/CF). Wells containing whole blood, vehicle control-containing medium and no ConA or IL-2 were used as background controls. The plates were incubated at 37 ℃ for 48 hours. Tritiated thymidine (PerkinElmer, Net027A-005MC) was added at 0.4. mu. Ci/well and incubation was continued for 20 hours. Plates were frozen, then thawed, washed, and filtered using a Brandel MLR-96 cell harvester and pre-wetted filter pad (Wallac 1205-. The filters were dried at 60 ℃ for 1 hour (Precision 16EG oven) and placed in a filtration sample bag (Wallac 1205-. The sealed filters were counted on a LKB Wallac1205Betaplate liquid scintillation counter. Data were collected using a Gterm Betaplate program v1.1 and converted to percent inhibition using the following equation calculation:
_________________________
data in percent inhibition form are graphically represented using GraphPad Prism 4.0 and IC is fitted using point-to-point analysis50Curve line.
In this experiment, the IC of example 385048.5 nM. This data indicates that the compounds of the invention are effective in inhibiting T cell proliferation, a major feature of diseases caused by dysregulation of JAK.

Claims (12)

1. A compound 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 } -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-1-sulfonamide;
1-cyclopropyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -methanesulfonamide;
n- { cis-3- [ (butanesulfonyl) methyl ] cyclobutyl } -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine;
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;
(1R,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;
(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-3-yl) methane-sulfonamide;
1- (3, 3-difluorocyclobutyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methane-sulfonamide;
trans-3- (cyanomethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutanesulfonamide;
cis-3- (cyanomethyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutane-sulfonamide;
n- [ cis-3- ({ [ (3, 3-difluorocyclobutyl) methyl ] sulfonyl } methyl) cyclobutyl ] -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine;
(1S,5S) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -3-azabicyclo [3.1.0] hexane-3-sulfonamide;
(1R,5R) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) 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-7H-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;
n- (cis-3- { [ (3-chloro-4-fluorophenyl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine;
n- (cis-3- { [ (2-cyclopropylethyl) sulfonyl ] methyl } cyclobutyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine;
N-methyl-N- [ cis-3- ({ [1- (propan-2-yl) pyrrolidin-3-yl ] sulfonyl } methyl) cyclobutyl ] -7H-pyrrolo [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-4-yl) amino ] cyclobutyl } -methanesulfonamide;
cis-3- (cyanomethyl) -3-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -cyclobutanesulfonamide;
trans-3- (cyanomethyl) -3-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutanesulfonamide;
n- (2-cyanoethyl) -N-methyl-N' - { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } sulfuric acid diamide;
n- { (1S,3R) -3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclopentyl } propane-1-sulfonamide;
3- (2-hydroxypropan-2-yl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } benzene-sulfonamide;
n- (cyclopropylmethyl) -N' - { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } sulfuric acid diamide;
n- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -4- (1H-pyrazol-3-yl) 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;
2- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] pyridine-4-carbonitrile;
(1S,3S) -3- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] cyclopentanecarbonitrile;
(1R,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 } methanesulfonamide;
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-4-amine; and
2-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -1, 3-thiazole-5-sulfonamide; or a pharmaceutically acceptable salt thereof.
2. A compound which is 2-methyl-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -1, 3-thiazole-5-sulfonamide, or a pharmaceutically acceptable salt thereof.
3. A compound which is N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -propane-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
4. A compound which 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.
5. A compound which is 1- (3, 3-difluorocyclobutyl) -N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methanesulfonamide, or a pharmaceutically acceptable salt thereof.
6. A compound which 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.
7. A compound which is (3R) -1- [ ({ cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } methyl) sulfonyl ] pyrrolidine-3-carbonitrile, or a pharmaceutically acceptable salt thereof.
8. A compound which is 3, 3-difluoro-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } cyclobutanesulfonamide or a pharmaceutically acceptable salt thereof.
9. A compound which is (1S,5S) -1-cyano-N- { cis-3- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclobutyl } -3-azabicyclo [3.1.0] hexane-3-sulfonamide, or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. A veterinary composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition selected from rheumatoid arthritis, myositis, vasculitis, pemphigus, crohn's disease, ulcerative colitis, alzheimer's disease, lupus, nephritis, psoriasis, atopic dermatitis, autoimmune thyroid disease, multiple sclerosis, major depression, allergy, asthma, sjogren's disease, dry eye syndrome, organ transplant rejection, type I diabetes and diabetic complications, T-cell acute lymphocytic leukemia, adult T-cell leukemia, diffuse large B-cell lymphoma, inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, chronic obstructive pulmonary disease and acute respiratory disease.
HK16101741.2A 2013-02-22 2014-02-11 Pyrrolo [2, 3-d] pyrimidine derivatives as inhibitors of janus-related kinases (jak) HK1213881B (en)

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