Pyrrolopyrimidine compounds, composition and use thereof

专利摘要:
"PYROLPYRIMIDINE COMPOUNDS, COMPOSITION AND USE OF THEM". The present invention relates to pyrrolpyrimidine compounds of formula I(I) capable of inhibiting JAK kinases, wherein R 1 , R 2 and m are defined in the description. The invention further relates to pharmaceutical compositions containing such pyrrolopyrimidine compounds, and the use of such pyrrolopyrimidine compounds in the treatment of disorders or diseases, such as inflammatory diseases and cancer.
公开号:BR112013003864B1
申请号:R112013003864-0
申请日:2011-08-18
公开日:2021-08-31
发明作者:Wei-guo Su；Wei Deng；Jinshui Li；Jianguo Ji
申请人:Hutchison Medipharma Limited；
IPC主号:

专利说明:

Technical Field
[001] The present invention relates to the pharmaceutical field. For example, the present invention relates to certain pyrrolpyrimidine compounds, a composition containing said compound, and the use thereof. These pyrrolpyrimidine compounds can effectively inhibit the activity of JAK kinases. Background of the Technique
[002] The Janus kinase family (JAK) is one of the well recognized families of non-receptor tyrosine kinases. The JAK family can be activated by binding a cytokine to a cell surface receptor. Activated Jak can then initiate intracellular signaling cascades. The Jak family and signal transducers and activators of transcription (STATs) are involved in signaling pathways for a wide range of cytokines.
[003] It has been shown that the JAK/STAT pathway plays an important role in inflammatory diseases such as inflammatory diseases of the respiratory tract, multiple sclerosis, rheumatoid arthritis, asthma, inflamed bowel disease, allergies, autoimmune diseases. nes and other immunological reactions. The JAK/STAT pathway, eg JAK3/STAT, also play a role in cancers.
[004] Inhibitors of the Jak family are widely explored and published for the treatment or prevention of inflammatory diseases or cancers.
[005] The Janus kinase family of protein tyrosine kinases (JAKs) may play a role in cytokine-dependent regulation of the proliferation and function of cells involved in the immune response. Four members of the JAK family of mammals have been reported: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase, leukocyte; JAKL; L-JAK and Janus kinase-3) and TYK2 (also known as protein tyrosine kinase 2). JAK proteins can range in size from 120 to 140 kDa and comprise seven conserved JAK homology (JH) domains; one of which may be a functional catalytic kinase domain, and another may be a pseudokinase domain potentially serving a regulatory function and/or serving as a docking site for STATs (Scott, Godshall et al. Clin.Diagn.Lab.Immunol , 9(6): 1153-1159, 2002). Although JAK1, JAK2 and TYK2 can be ubiquitously expressed, it has been reported that JAK3 is expressed, for example, in natural killer (NK) cells and in non-resting T cells, suggesting a role in lymphoid activation (Kawamura, M., DW McVicar, et al. "Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes." Proc Natl Acad Sci USA 91(14): 6374-8, 1994) .
[006] The JAK/STAT pathway is known to play a role in the pathogenesis of the asthma response, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. ("JAK-STAT signaling in asthma." J Clin Invest 109(10): 1279-83, 2002). It has also been understood that the JAK/STAT pathway plays a role in inflammatory eye diseases/conditions including, but not limited to, iritis, uveitis, scleritis, conjunctivitis, as well as chronic allergic responses. Therefore, inhibition of JAK kinases may have a beneficial role in the therapeutic treatment of these diseases.
[007] We can also imagine that inhibition of JAK kinases has therapeutic benefits in patients suffering from autoimmune skin disorders such as psoriasis, and skin sensitization. In psoriasis vulgaris, the most common form of psoriasis, it is generally believed that activated T lymphocytes may be important for the maintenance of the disease and its associated psoriatic plaques (Gottlieb, AB, et al., Nat Rev Drug Disc., 4:19-34, 2005). Psoriatic plaques may contain a significant immunological infiltrate, including leukocytes and monocytes, as well as multiple epidermal layers with increased proliferation of keratinocytes. Although the initial activation of immune cells in psoriasis may occur by a defined diseased mechanism, it has been remarked that their maintenance is dependent on numerous inflammatory cytokines, in addition to various chemokines and growth factors (JCI, 113:1664-1675, 2004). Many of them, including interleukins -2, -4, -6, -7, -12, -15, -18, and -23 as well as GM-CSF and IFNy, can signal through Janus kinases (JAK) (Adv Pharmacol 47: 113-74, 2000). Thus, blocking signal transduction at the level of JAK kinases may result in therapeutic benefits in patients suffering from psoriasis or other autoimmune skin disorders.
[008] Blocking signal transduction at the level of JAK kinases may also promise the development of treatments for human cancers. Interleukin 6 family cytokines (IL-6_, which can activate the gp130 signal transducer, may be important survival and growth factors for human multiple myeloma (MM) cells. pathways of JAK1, JAK2 and TYK2 and downstream effectors STAT3 and mitogen-activated protein kinase (MAPK) In IL-6-dependent MM cell lines treated with the JAK2 inhibitor tyrphostin AG490, JAK2 kinase activity and a phosphorylation of ERK2 and STAT3 can be inhibited. In addition, cell proliferation can be suppressed and apoptosis can be induced (De Vos, J., M. Jourdan, et al., "JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen- activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells.” Br J Haematol 109(4): 823-8, 2000). induce numbness of tumor cells is and can then protect them from death.
[009] It has been suggested that inhibition of JAK2 tyrosine kinase may be beneficial for patients with myeloproliferative disorder (Levin, et al., Cancer Cell, vol. 7: 387-397, 2005). Myeloproliferative disorders (MPD) can include polycythemia rubra (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES) , and systemic mast cell disease (SMCD). Although myeloproliferative disorders (such as PV, ET, and MMM) are believed to be caused by acquired somatic mutation in hematopoietic progenitors, the genetic basis for these diseases is not yet known. However, hematopoietic cells from the vast majority of PV patients and a significant number of patients with ET and MMM have been reported to have a recurrent somatic activating mutation in the JAK2 tyrosine kinase. It has also been reported that inhibition of JAK2V617F kinase with a small molecule inhibitor led to inhibition of proliferation of hematopoietic cells, suggesting that JAK2 tyrosine kinase may be a potential target for pharmacological inhibition in patients with PV, ET and MMM. summary
[0010] The invention offers at least one compound of formula (I):

[0011] and/or at least one pharmaceutically acceptable salt thereof
[0012] where
[0013] R1 is selected from hydrogen, alkyl, cycloalkyl and heterocycle,
[0014] R2 is selected from aryl, heterocycle, heteroaryl, - C(O)NRcRd, -S(O)nRf, and -S(O)nNRcRd,
[0015] or R1 and R2 together with the N atom to which they are attached form an optionally substituted 3- to 7-membered ring, which optionally comprises one or two additional heteroatoms and which is further optionally fused to a heteroaryl ring optionally substituted or an optionally substituted aryl ring;
[0016] and each of said above alkyl, aryl, cycloalkyl, heterocycle, heteroaryl in R1 and R2 is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl , optionally substituted cycloalkyl, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, -NRcRd, -NReC (O)Ra, -NReC(O)ORb, -NReC(O)NRcRd, -NReS(O)nRf, -NReS(O)nNRcRd, , -NO2, -ORb, -S(O)nRf, and -S (O)nNRcRd;
[0017] m and n are independently chosen from 0, 1, and 2;
[0018] for each occurrence, Ra, Rb, Rc, Rd, Re and Rf are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, haloalkyl optionally substituted, optionally substituted heteroaryl and optionally substituted heterocycle,
[0019] or Rc and Rd, with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups chosen from halo, lower alkyl, hydroxy, and lower alkoxy, where the ring heterocycle further optionally comprises one or two additional heteroatoms chosen from N, O and S;
[0020] where each optionally substituted group above may be unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently chosen from C1-C4 alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, aryl- C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1- C4 alkyl, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), - N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo, -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 al- quil)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 phenyl, - C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, - SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1 -C4 alkyl), -SO2 NH(phenyl), -NHSO2(C1-C4 alkyl), - NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl), in which each of phenyl, aryl, heterocycle, and heteroaryl is optionally substituted with one or more groups chosen from halo, cycloalkyl, heterocycle, C1C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -NH2, -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC( O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), -SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl) ), - SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl).
[0021] The invention also provides a composition comprising at least one compound and/or at least one pharmaceutically acceptable salt described in this report and at least one pharmaceutically acceptable carrier.
The invention also provides a method for inhibiting the activity of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 comprising contacting at least one kinase with an effective amount of at least one compound and/or at least one salt pharmaceutically acceptable described in this report.
The invention also provides a method for treating in an individual an inflammatory disease responsive to inhibition of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 comprising administering to the individual in need thereof an effective amount of at least one compound and/or at least one pharmaceutically acceptable salt described in this report.
The invention also offers a method for treating in an individual a cancer responsive to inhibition of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 comprising administering to the individual in need thereof an effective amount of at least one compound and /or at least one pharmaceutically acceptable salt described in this report.
[0025] The invention also offers the use of at least one compound and/or at least one pharmaceutically acceptable salt described in this report, in the preparation of a medicament for treating an inflammatory disease or a cancer responsive to the inhibition of at least one chosen kinase among JAK1, JAK2, JAK3 and TYK2.
[0026] The invention also provides a drug or pharmaceutical composition for treating an inflammatory disease or a cancer responsive to the inhibition of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2, which comprises at least one compound and/or at least a pharmaceutically acceptable salt described in this report and at least one pharmaceutically acceptable carrier. Detailed Description
[0027] As used in this report, the following words, expressions and symbols generally have the meanings specified below, except to the extent that the context in which they are used indicates otherwise. The following abbreviations and terms have the meanings indicated throughout the text:
[0028] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is bonded through the carbon atom.
[0029] The term "alkyl" in this report refers to a straight or branched chain hydrocarbon containing 1-10 carbon atoms, such as 1-6 carbon atoms, or else such as 1-4 carbon atoms. carbon. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. "Lower alkyl" refers to a straight or branched chain hydrocarbon containing 1-4 carbon atoms.
[0030] By "alkoxy" is meant a straight or branched chain alkyl group having the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy , sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, among others. Alkoxy groups usually have 1 to 6 carbon atoms attached through the oxygen bridge. "Lower alkoxy" refers to straight or branched chain alkoxy, where the alkyl portion contains 1-4 carbon atoms.
[0031] The term "alkenyl" in this report refers to a straight or branched chain C2-10 hydrocarbon containing one or more C=C double bonds. For example, "alkenyl" refers to a C2-6 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl.
[0032] The term "alkynyl" in this report refers to a straight or branched chain C2-10 hydrocarbon containing one or more C=C triple bonds. As a further example, "alkynyl" refers to a C2-6 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.
The term "cycloalkyl" refers to saturated and partially unsaturated monocyclic, bicyclic or tricyclic hydrocarbon rings having 3 to 12 carbons, such as having 3 to 8 carbons. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The ring can be saturated or have one or more double bonds (ie, partially unsaturated), but not fully conjugated, and not aromatic, as defined in this report.
[0034] "Arila" covers:
[0035] 5- and 6-membered carbocyclic aromatic rings, eg benzene;
[0036] bicyclic ring systems where at least one ring is carbocyclic and aromatic, for example naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and
[0037] tricyclic ring systems where at least one ring is carbocyclic and aromatic, eg fluorene.
[0038] For example, aryl includes 5- and 6-membered aromatic rings fused to a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, provided the point of attachment is on the carbocyclic aromatic ring . Divalent radicals formed from substituted benzene derivatives and having the free valences on the ring atoms are termed substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-ila" by removing a hydrogen atom from the carbon atom with the free valence are named with the addition of "-idene" to the name of the corresponding univalent radical, for example , a naphthyl group with two attachment points is called naphthylidene. Aryl, however, does not encompass or in any way coincide with heteroaryl, defined separately below. Therefore, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined earlier in this report.
The term "halo" includes fluorine, chlorine, bromine, and iodine, and the term "halogen" includes fluorine, chlorine, bromine, and iodine.
[0040] The term "heteroaryl" refers to
[0041] 5- to 8-membered monocyclic aromatic rings containing one or more, for example, 1 to 4, or, in some embodiments, 1 to 3, heteroatoms selected from N, O, and S, with the ring atoms remainder being carbon;
[0042] 8- to 12-membered bicyclic rings containing one or more, for example, from 1 to 6, or, in some embodiments, from 1 to 4, or in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and where at least one heteroatom is present in an aromatic ring; and
[0043] 11 to 14-membered tricyclic rings containing one or more, for example, from 1 to 6, or in some embodiments, from 1 to 4, or in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and where at least one heteroatom is present in an aromatic ring.
[0044] For example, heteroaryl includes a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring. For such fused bicyclic heteroaryl ring systems where only one of the rings contains one or more heteroatoms, the point of attachment may be on the heteroaromatic ring.
[0045] When the total number of S and O atoms in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is at most 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is at most 1.
[0046] Examples of heteroaryl groups include, but are not limited to, (numbered from the binding position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4- pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline.
[0047] Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-il" by removing a hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, by For example, a pyridyl group with two attachment points is a pyridylidene. Heteroaryl neither encompasses nor coincides with heteroaryl, as defined above.
[0048] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.
[0049] By "heterocycle" is meant a monocyclic, bicyclic or tricyclic 4- to 12-membered, saturated or partially unsaturated ring, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen . "Heterocycle" also refers to a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S fused to a 5- and 6-membered aromatic ring, provided the point of attachment is on the heterocyclic ring. Rings can be saturated or can have one or more double bonds (i.e., partially unsaturated). The heterocycle can be substituted with oxo. The point of attachment can be a carbon or a heteroatom in the heterocyclic ring. A heterocycle is not a heteroaryl as defined in this report.
Suitable heterocycles include, for example (numbered from the binding position assigned priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl , 3-piperidinyl, 4-piperidinyl, and 2,5-piperazinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered where oxygen is assigned priority 1). Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.
[0051] By "optionally" or "optionally" is meant that the event or circumstance subsequently described may or may not occur, and that the report includes instances where the event or circumstance does occur and instances where it does not. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as described below. Those skilled in the art will understand that, with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically impractical and/or inherently unstable.
[0052] The term "substituted", as used in this report, means that any one or more hydrogens in the indicated atom or group is replaced by a choice within the indicated group, provided that the normal valence of the indicated atom is not exceeded. When a substituent is oxo (ie, =O) then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permitted only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure indicates a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent that has at least practical utility. Unless otherwise specified, the name of the substituents appears in the core structure name. For example, it should be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
[0053] In some embodiments, "substituted with one or more groups" refers to the fact that two hydrogens on the indicated atom or group are independently replaced by two choices within the indicated group of substituents. In some embodiments, "substituted with one or more groups" refers to the fact that three hydrogens on the indicated atom or group are independently replaced by three choices within the indicated group of substituents. In some embodiments, "substituted with one or more groups" refers to the fact that four hydrogens on the indicated atom or group are independently replaced by four choices within the indicated group of substituents.
[0054] The compounds described in this invention include, but are not limited to, where possible, their optical isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, insofar as they can be made by the person skilled in the art by routine experimentation. In these situations, simple enantiomers or diastereomers, that is, optically active forms, can be obtained by asymmetric synthesis or by resolution of racemates or mixtures of diastereomers. The resolution of racemates or mixtures of diastereomers, if possible, can be carried out, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral chromatography column high pressure liquid (HPLC). In addition, such compounds include the Z- and E- forms (or the cis- and trans- forms) of compounds with carbon-carbon double bonds. When the compounds described in this invention exist in various tautomeric forms, the term "compound" is intended to include, insofar as they can be made without undue experimentation, all tautomeric forms of the compound. Such compounds also include crystalline forms including polymorphs and clathrates, as they can be made by the person skilled in the art without undue experimentation. Similarly, the term "salt" is intended to include all isomers, racemates, other mixtures, Z- and E-forms, tautomeric forms and crystalline salt forms of the compound, as they can be made by the person skilled in the art without undue experimentation. .
"Pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids, such as hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and similar salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC-(CH2)n-COOH where n is 0-4, and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
[0056] Furthermore, if a compound described in this invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures. for the preparation of acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methodologies that can be used without undue experimentation to prepare pharmaceutically acceptable non-toxic addition salts.
[0057] A "solvate", such as a hydrate", is formed by the interaction of a solvent and a compound. The term "compound" is intended to include solvates, including hydrates, of compounds, insofar as they can be made by the person skilled in the art without undue experimentation. Similarly, "salts" include solvates, such as hydrates, of salts, as they can be made by the person skilled in the art without undue experimentation. Suitable solvates are pharmaceutically acceptable solvates. , such as hydrates, including monohydrates and semihydrates, as they can be made by the person skilled in the art without undue experimentation.
[0058] A "chelate" is formed by coordinating a compound to a metal ion at two (or more) points. The term "compound" is intended to include chelates of compounds. Similarly, "salts" include salt chelates.
[0059] A "non-covalent complex" is formed by the interaction of a compound and another molecule where a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term "compound".
[0060] The term "hydrogen bonding" refers to a form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second relatively electronegative atom (also known as a bond donor hydrogen). Suitable hydrogen bond donors and acceptors are well known in medicinal chemistry (GC Pimentel and AL McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic Crystals", Accounts of Chemical Research, 17, pages 320-326 (1984)).
[0061] As used in this report the terms "group", "radical" or "fragment" are synonymous and are intended to indicate functional groups or fragments of molecules that can be attached to a bond or other fragments of molecules.
[0062] The term "active agent" is used to indicate a chemical substance that has biological activity. In some embodiments, an "active agent" is used to indicate a chemical having pharmaceutical utility.
"Treating", "treating", or "treatment" or "relief" refers to administering at least one compound and/or at least one pharmaceutically acceptable salt described in this invention to a subject having a disease or disorder , or has a symptom of a disease or disorder, or has a predisposition to a disease or disorder, for the purpose of curing, healing, alleviating, calming, altering, remedying, improving, reducing, or affecting a cancer, the symptoms of the disease or disorder, or the predisposition to the disease or disorder. In some modalities, the disease or disorder could be cancer. In some embodiments, the disease or disorder can be an inflammatory disease.
The term "effective amount" refers to an amount of at least one compound and/or at least one pharmaceutically acceptable salt described in this invention effective to "treat", as defined above, a disease or disorder in an individual. The effective amount can cause any of the observable or measurable changes in an individual already described in the definitions of "treating", "treating", "treatment" and "relief" given above. For example, in the case of cancer, the effective amount may reduce the number of cancer or tumor cells; reduce tumor size; inhibit or stop tumor cell infiltration into peripheral organs including, for example, tumor spread into soft tissue and bone; inhibit and stop tumor metastasis; inhibit and stop tumor growth; alleviate to some extent one or more of the symptoms associated with cancer, reduce morbidity and mortality; improve the life quality; or a combination of such effects. An effective amount can be an amount sufficient to lessen the symptoms of a disease responsive to inhibition of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2. For cancer therapy, in vivo efficacy can, for example, be measured by assessing survival time, time for disease to progress (TTP), response rates (RR), duration of response, and/ or the quality of life. Effective amounts may vary, as is known to those skilled in the art, depending on the route of administration, the excipient used, and the concurrent of other agents. An effective amount can also be an amount sufficient for a pharmaceutical composition comprising at least one compound and/or at least one pharmaceutically acceptable salt to meet regulatory requirements, such as SFDA, USFDA, or European approval, to "treat ", as defined above, a disease or disorder in a human patient. An effective amount may also be an amount sufficient for a pharmaceutical composition comprising at least one compound and/or at least one pharmaceutically acceptable salt to show efficacy in a randomized double-blind clinical trial to "treat", as defined above, a disease or disorder in a human being.
[0065] The term "effective amount" also refers to an amount of at least one compound and/or at least one pharmaceutically acceptable salt described in this invention effective to inhibit the activity of at least one kinase chosen from JAK1, JAK2 , JAK3 and TYK2.
[0066] The term "inhibition" indicates a reduction in the basal activity of a biological activity or process. "Inhibition of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2" refers to a reduction in the activity of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 as a direct or indirect response to the presence of at least a compound and/or at least one pharmaceutically acceptable salt described in this report, in relation to the activity of the at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 in the absence of the at least one compound and/or the at least one pharmaceutically acceptable salt the same. The reduction in activity may be due to the direct interaction of the at least one compound and/or at least one pharmaceutically acceptable salt described in this invention with the at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2, or due to the interaction of at least one compound and/or at least one pharmaceutically acceptable salt described in this invention with one or more other factors which in turn affect the activity of the at least one kinase. For example, the presence of at least one compound and/or at least one pharmaceutically acceptable salt described in this report can decrease the activity of at least one kinase by directly binding to at least one kinase, making (directly or indirectly) with another factor decreasing the activity of the at least one kinase, or decreasing (directly or indirectly) the amount of the at least one kinase present in the cell or body.
[0067] The invention offers at least one compound of formula (I):

[0068] and/or at least one pharmaceutically acceptable salt thereof
[0069] where
[0070] R1 is selected from hydrogen, alkyl, cycloalkyl and heterocycle,
[0071] R2 is selected from aryl, heterocycle, heteroaryl, -C(O)NRcRd, -S(O)nRf, and -S(O)nNRcRd,
[0072] or R1 and R2, together with the N atom to which they are attached, form an optionally substituted 3- to 7-membered ring, which optionally comprises one or two additional heteroatoms and which is further optionally fused to a heteroaryl ring optionally substituted or an optionally substituted aryl ring;
[0073] and each of said above alkyl, aryl, cycloalkyl, heterocycle, heteroaryl in R1 and R2 is optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl , optionally substituted cycloalkyl, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, -NRcRd, -NReC (O)Ra, -NReC(O)ORb, -NReC(O)NRcRd, -NReS(O)nRf, -NReS(O)nNRcRd, , -NO2, -ORb, -S(O)nRf, and -S (O)nNRcRd;
[0074] m and n are independently chosen from 0, 1, and 2;
[0075] for each occurrence, Ra, Rb, Rc, Rd, Re and Rf are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl , optionally substituted haloalkyl, optionally substituted heteroaryl and optionally substituted heterocycle,
[0076] or Rc and Rd, with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups chosen from halo, lower alkyl, hydroxy, and lower alkoxy, where the heterocycle ring optionally further comprises one or two additional heteroatoms chosen from N, O and S;
[0077] wherein each of the groups optionally substituted above may be unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently chosen from C1-C4 alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -C1-C4 alkyl- O- C1-C4 alkyl, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo, -CO2H, -C(O)OC1-C4 alkyl, -CON (C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1 -C4 alkyl)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1- C4 phenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, -SO2(C1-C4 alkyl), -SO2(phenyl), - SO2(C1-C4 haloalkyl), - SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl), in which each of phenyl, aryl, heterocycle, and heteroaryl is optionally substituted with one or more groups chosen from halo, cycloalkyl, heterocycle, C1-C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -NH2, -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(C1-C4 alkyl), -CONH(C1-C4 alkyl) ), -CONH2, -NHC(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(C1-C4 alkyl), - SO2(C1-C4 alkyl), -SO2(phenyl) , -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), - NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl).
[0078] In some modes, m is 1.
[0079] In some embodiments, R1 is selected from alkyl and cycloalkyl, each being optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, - C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, -NRcRd, -NReC(O)Ra, - NReC(O)ORb, -NReC(O)NRcRd, -NReS(O)nRf, -NReS(O)nNRcRd, , -NO2, -ORb, -S(O)nRf, and -S(O)nNRcRd.
[0080] In some embodiments, R1 is alkyl optionally substituted with alkenyl, alkynyl or cycloalkyl.
[0081] In some embodiments, R1 is cycloalkyl.
[0082] In some embodiments, R2 is aryl or heteroaryl, each being optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -C( O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, -NRcRd, -NReC(O)Ra, -NReC(O) ORb, -NReC(O)NRcRd, -NReS(O)nRf, -NReS(O)nNRcRd, , -NO2, -ORb, -S(O)nRf, and -S(O)nNRcRd.
[0083] In some embodiments, R2 is -C(O)NRcRd, or S(O)nNRcRd, where Ra, Rc, and Rd are each independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted haloalkyl, optionally substituted heteroaryl, and optionally substituted heterocycle,
[0084] or Rc and Rd, with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups chosen from halo, lower alkyl, hydroxy, and lower alkoxy, where the heterocycle ring optionally further comprises one or two additional heteroatoms chosen from N, O and S.
[0085] In some embodiments, R2 is -C(O)NRcRd, where Rc and Rd are each independently chosen from alkylz; phenyl optionally substituted with CN, halo, alkyl and haloalkyl; OH-substituted indanyl; and tetrahydropyranylz.
[0086] In some embodiments, R2 is -S(O)nNRcRd, where n is 2, Rc and Rd are each independently chosen from H and alkyl, or Rc and Rd, with the nitrogen to which they are attached , form pyrrolidinyl.
[0087] In some embodiments, R2 is -S(O)nRf, where n is 2, Rf is alkyl; or phenyl optionally substituted with one or more groups chosen from halo, -CN, -NO2 and ORb, where Rb is -H or alkyl; or cycloalkyl.
[0088] In some embodiments, R1 and R2, together with the N atom to which they are attached, form an indolinyl, or imidazolonyl fused to pyridine, wherein said indolinylz and pyridine are optionally substituted with -CN.
[0089] In some embodiments, R2 is aryl or heteroaryl chosen from

[0090] each being optionally substituted with one or more groups chosen from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted haloalkyl, -C(O)Ra, - C(O)ORb, -CN, - C(O)NRcRd, halo, optionally substituted heterocycle, optionally substituted heteroaryl, -NRcRd, -NReC(O)Ra, -NReC(O)ORb, - NReC(O)NRcRd, -NReS(O)nRf, -NReS(O)nNRcRd, , -NO2, -ORb, -S(O)nRf, and -S(O)nNRcRd.
[0091] In some embodiments, R2 is aryl or heteroaryl chosen from

[0092] each being optionally substituted with one or more groups chosen from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted haloalkyl, -C(O)Ra, - C(O)ORb, -CN, - C(O)NRcRd, halo, optionally substituted heterocycle, optionally substituted heteroaryl, -NRcRd, -NReC(O)Ra, -NReC(O)ORb, - NReC(O)NRcRd, -NReS(O)nRf, -NReS(O)nNRcRd, , -NO2, -ORb, -S(O)nRf, and -S(O)nNRcRd.
[0093] In some modalities, R2 is

[0094] which is optionally substituted with one or more groups chosen from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted haloalkyl, -C(O)Ra, -C(O) ORb, -CN, -C(O)NRcRd, halo, optionally substituted heterocycle, optionally substituted heteroaryl, -NRcRd, -NReC(O)Ra, -NReC(O)ORb, -NReC(O)NRcRd, -NReS(O )nRf, -NReS(O)nNRcRd, , -NO2, -ORb, -S(O)nRf, and -S(O)nNRcRd.
[0095] In some modalities,
R2 is which is optionally substituted with one or more groups chosen from:
[0096] -CN;
[0097] halo;
[0098] haloalkyl;
[0099] -NO2;
[00100] amino;
[00101] -S(O)nRf, where n is 2 and Rf is alkyl or haloalkyl;
[00102] phenyl optionally substituted with one or more groups chosen from -CN, alkyloxy and halo;
[00103] indanyl optionally substituted with -OH; tetrazolyl; and
[00104] -C(O)NRcRd, where Rc and Rd are each independently chosen from -H; alkyl optionally substituted with -OH; alkoxy; phenyl optionally substituted with halo; and indanyl optionally substituted with -OH.
[00105] In some embodiments, R2 is

[00106] which is optionally substituted with one or more groups chosen from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted haloalkyl, -C(O)Ra, -C( O)ORb, -CN, -C(O)NRcRd, halo, optionally substituted heterocycle, optionally substituted heteroaryl, -NRcRd, -NReC(O)Ra, -NReC(O)ORb, -NReC(O)NRcRd, -NReS (O)nRf, -NReS(O)nNRcRd, , -NO2, -ORb, -S(O)nRf, and -S(O)nNRcRd.
[00107] In some modalities, R2
, which is optionally replaced with one or more groups chosen from:
[00108] -CN;
[00109] alkynyl;
[00110] halo;
[00111] -NO2;
[00112] alkyl;
[00113] amino;
[00114] haloalkyl;
[00115] phenyl optionally substituted with -CN;
[00116] heteroaryl selected from tetrazolyl, thienyl, pyridinyl and pyrazolyl, said heteroaryl is optionally substituted with alkyl;
[00117] -ORb, where Rb is -H or alkyl;
[00118] -S(O)nRf where n is 2 and Rf is alkyl;
[00119] COORb where Rb is -H or alkyl;
[00120] -C(O)NRcRd , where Rc and Rd are each independently chosen from -H; cycloalkyl optionally substituted with OH; alkyl optionally substituted with one or more groups chosen from --OH and phenyl; phenyl optionally substituted with one or more groups chosen from alkyl, alkoxy and halo; pyridinyl; and thiazolyl;
[00121] NReS(O)nRf, where n is 2, Re is -H, Rf is alkyl; cycloalkyl; benzyl optionally substituted with one or more groups chosen from halo and alkyl; phenyl optionally substituted with halo; thienyl; or pyridinyl;
[00122] -NReC(O)Ra, where Re is -H, Ra is cycloalkyl; phenyl optionally substituted with halo; or alkyl substituted with ORb, where Rb is alkyl;
[00123] NRcRd, where Rc and Rd are benzyl, each optionally substituted with halo; and
[00124] -S(O)nNRcRd , where n is 2, Rc and Rd are each independently chosen from -H; alkyl optionally substituted with one or more groups chosen from alkynyl, cycloalkyl, tetrahydrofuranyl, and phenyl optionally substituted with one or more groups chosen from halo and -ORb, where Rb is -H or alkyl; cycloalkyl optionally substituted with -OH; indanyl optionally substituted with -OH; tetrahydropyranyl; tetrahydrofuranyl; oxetanil; pyrazolyl optionally substituted with alkyl; and phenyl optionally substituted with halo; or Rc and Rd, with the nitrogen to which they are attached, form a heterocycle ring selected from pyrrolidinyl, piperazinyl and morpholinyl.
[00125] In some embodiments, R2 is pyrazinyl optionally substituted with one or more groups chosen from: -CN, alkoxy, morpholino, pyrazolyl, imidazolyl, and -NRcRd, where Rc and Rd are each independently chosen from cycloalkyl and alkyl, each being optionally substituted with -OH.
[00126] In some embodiments, R2 is pyridazinyl optionally substituted with one or more groups chosen from -CN, halo, and haloalkyl.
[00127] In some embodiments, R2 is pyrimidinyl optionally substituted with one or more groups chosen from -CN, halo, -NO2, -ORb, and -NRcRd, where Rb, Rc and Rd are each independently chosen from - H and alkyl.
[00128] In some embodiments, R1 is selected from C1-3 alkyl, allyl, propargyl, and cyclopropyl, each being optionally substituted with one or more groups chosen from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted cycloalkyl, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd, halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, -NRcRd, -NReC(O)Ra, -NReC(O)ORb, -NReC(O)NRcRd, -NReS(O)nRf, -NReS(O)nNRcRd, -NO2, -ORb, -S(O)nRf, and - S(O)nNRcRd.
[00129] In some embodiments, R1 is methyl.
[00130] In some embodiments, the absolute stereocenter hence the -N(R1)(R2) group is the R isomer.
[00131] The invention also offers at least one compound chosen from compounds 1 to 260 and/or at least one pharmaceutically acceptable salt thereof.
The compounds described in this invention, and/or the pharmaceutically acceptable salts thereof, can be synthesized from commercially available starting materials by methods well known in the literature, together with the description in this patent application. The following schemes illustrate methods for preparing most of the compounds disclosed in this invention.

[00133] As shown in scheme I, a compound of formula (1) can be reacted with a compound of formula (2), where m has the definition given in this report, in the presence of a base such as, but not limited to, K2CO3 , Na2CO3, NaH, Et3N or diisopropylethylamine (DIPEA), to give a compound of formula (3). In the presence of an acid, such as, but not limited to, HCl or CF3CO2H, the N-Boc group in the compound of formula (3) can be deprotected to give the compound of formula (4) which can subsequently react with R1X and R2X, where X is Cl, Br or I, R1 and R2 have the definition given in this report, in the presence of a base such as, but not limited to, K2CO3, Na2CO3, Cs2CO3, NaH, t-BuONa, t-BuOK, Et3N, or diisopropylethylamine (DIPEA), to give the compound of formula (I). When R1 or R2 is an aryl or heteroaryl, a palladium-based reagent, such as, but not limited to, PdCl2, Pd(OAc)2 Pd2(dba)3 or Pd(PPh3)4, and a linker , such as, but not limited to, Ph3P, tBu3P, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP), 1,1'-bis(diphenylphosphino)ferrocene (dppf) or 1, 3-bis(2,6-dipropylphenyl)-1H-imidazol-3-ium can be used as a catalyst to improve the reaction efficiency. Scheme II

[00134] As shown in scheme II, a compound of formula (7), where m has the definition given above, can be reacted with a compound of formula (5) under the conditions described in scheme I to give a compound of formula (8) . Alternatively, a compound of formula (8) can also be prepared by reacting a compound of formula (7) with a compound of formula (9), where R1a and R1b are selected from H, alkyl, cycloalkyl, aryl heteroaryl, or R1a and R1b together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl ring. A compound of formula (8) can be reacted with a compound of formula (6) under conditions described in scheme I to give a compound of formula (10). In the presence of an acid, such as, but not limited to, HCl or CF3CO2H, the N-Boc group in the compound of formula (10) can be deprotected to give a compound of formula (11) which can further react with a compound of formula (1) in the presence of a base, such as, but not limited to, K2CO3, Na2CO3, Cs2CO3, NaH, t-BuONa, t-BuOK, Et3N, or diisopropylethylamine (DIPEA), to give the compound of formula (I ). If required, for example when R1 or R2 is an aryl or heteroaryl, a palladium-based reagent such as, but not limited to, PdCl2, Pd(OAc)2 Pd2(dba)3 or Pd(PPh3)4, and a linker, such as, but not limited to, Ph3P, tBu3P, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos), 1,1'-bis(diphenylphosphino)ferrocene (dppf) or 1,3-bis(2,6-dipropylphenyl)-1H-imidazol-3-ium chloride, can be used as a catalyst to improve the reaction efficiency. Scheme III

[00135] Scheme III shows that a compound of formula (3) can react with LiAlH4 to give a compound of formula (12) which can further react with a compound of formula (5) under conditions similar to those described in scheme I to give a compound of formula (13).
[00136] The compounds obtained in this way can be further modified in their peripheral positions to give the desired compounds. Synthetic chemical transformations are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons (1999); L. Fieser & M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley & Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons (1995) and subsequent editions.
[00137] Before being used, the at least one compound and/or at least one pharmaceutically acceptable salt described in this invention can be purified by column chromatography, high performance liquid chromatography, crystallization, or other suitable methods.
The invention also provides a composition comprising at least one compound and/or at least one pharmaceutically acceptable salt described in this invention, and at least one pharmaceutically acceptable carrier.
[00139] A composition comprising at least one compound and/or at least one pharmaceutically acceptable salt described in this invention, may be administered in various known ways, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. The term "parenteral" as used in this report includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
An oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions. Commonly used vehicles for tablets include lactose and cornstarch. Lubricating agents, such as magnesium stearate, are also typically added to tablets. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oil phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents may be added.
[00141] A sterile injectable composition (eg an aqueous or oleaginous suspension) can be formulated according to techniques known in the literature using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents . The sterile injectable intermediate may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the pharmaceutically acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally employed as a solvent or suspending medium (eg synthetic monoglycerides or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives are useful in the injectable intermediate, as well as pharmaceutically acceptable natural oils such as olive oil or castor oil, especially in their polyoxyethylated versions. Such oily solutions or suspensions may also contain a long-chain alcohol-type diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
[00142] A composition for inhalation can be prepared according to techniques well known in the pharmaceutical formulation literature and can be prepared as solutions in saline solution, employing benzyl alcohol or other suitable preservatives, absorption promoters to increase the bioavailability, fluorocarb - us, and/or other solubilizing or dispersing agents known in the literature.
[00143] A topical composition can be formulated in the form of an oil, cream, lotion, ointment, among others. Suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C12). In some embodiments, the pharmaceutically acceptable vehicle is a vehicle in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants can also be included as well as color or fragrance imparting agents, if desired. Additionally, transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in US Patents 3,989,816 and 4,444,762.
[00144] Creams can be formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of oil, such as almond oil, is mixed. An example of such a cream is a cream that includes about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil, and about 1 part almond oil. Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. An example of such an ointment is an ointment that includes about 30% by weight of almond oil and about 70% by weight of white soft paraffin.
[00145] A pharmaceutically acceptable vehicle refers to a vehicle that is compatible with the active principles of the composition (and in some embodiments, capable of stabilizing the active principles) and is not harmful to the individual to be treated. For example, solubilizing agents such as cyclodextrins (which form more soluble specific complexes with the at least one compound and/or at least one pharmaceutically acceptable salt described in this invention) can be used as pharmaceutical excipients for delivery of the principles. active. Examples of other vehicles include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10.
[00146] Suitable in vitro assays can be used to preliminarily assess the effectiveness of the at least one compound and/or at least one pharmaceutically acceptable salt described in this invention in inhibiting the activity of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 . The at least one compound and/or at least one pharmaceutically acceptable salt described in this invention can be examined for its effectiveness in treating cancer or inflammatory diseases by in vivo assays. For example, the compounds described in this invention, and/or the pharmaceutically acceptable salts thereof, can be administered to an animal (e.g., mouse model) with cancer or an inflammatory disease and their therapeutic effects can be evaluated. Based on the results, the appropriate dosage range and route of administration for animals, such as humans, can also be determined.
[00147] The invention offers a method to inhibit the activity of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2. The method comprises contacting the at least one kinase with an amount of at least one compound and/or at least one pharmaceutically acceptable salt described in this invention effective to inhibit the activity of the at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 .
[00148] The at least one compound and/or at least one pharmaceutically acceptable salt described in this invention can be used to obtain a beneficial therapeutic or prophylactic effect, for example, in individuals with cancer. As used in this report, the term "cancer" refers to a cellular disorder characterized by uncontrolled or unregulated cell proliferation, reduced cell differentiation, inadequate ability to invade neighboring tissue, and/or ability to establish regrowth at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and blood-borne tumors. The term "cancer" encompasses diseases of the skin, tissues, organs, bones, cartilage, blood, and vessels. The term "cancer" also covers primary and metastatic cancers.
[00149] Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, for example, metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, primary or progressive epithelial peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; skin cancer, including, for example, malignant melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; soft tissue sarcoma; and thyroid carcinoma.
[00150] Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myelogenous leukemia (CML), including accelerated CML and blast phase CML (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), (refractory anemia with excess blasts (RAEB), and transforming RAEB (RA-EB-T), and myeloproliferative syndromes.
[00151] In some modalities, examples of cancer to be treated include, but are not limited to, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, breast cancer. prostate, stomach cancer, kidney cancer, liver cancer, brain cancer, bone cancer, and leukemia.
The at least one compound and/or at least one pharmaceutically acceptable salt described in this invention can be used to obtain a beneficial therapeutic or prophylactic effect, for example, in individuals with an inflammatory disease or an inflammatory disorder. The term "inflammatory disease" or "inflammatory disorder" refers to disease states that result in inflammation, typically caused by neutrophil chemotaxis. Examples of such disorders include inflammatory skin diseases, including psoriasis and atopic dermatitis; systemic scleroderma; responses associated with inflamed bowel disease (IBD) (such as Crohn's disease and ulcerative colitis); reperfusion disorders of ischemia including surgical tissue reperfusion injury, myocardial ischemic conditions such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery and constriction after percutaneous transluminal coronary angioplasty, stroke, and abdominal aortic aneurysms; cerebral edema secondary to stroke; head trauma, hypovolemic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behcet's disease; dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis (RA), Sjorgen syndrome, vasculitis; diseases involving leukocyte diapedesis; inflammatory disorders of the central nervous system (CNS), syndrome of multiple organ damage secondary to sepsis or trauma; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex mediated diseases including glomerulonephritis; sepsis; sarcoidosis; immunopathological responses to tissue/organ transplantation; lung inflammation, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis; etc. Preferred indications include, without limitation, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other arthritic conditions, multiple sclerosis (MS), asthma, systemic lupus erythematosus, adult respiratory distress syndrome, disease of Behcet, psoriasis, chronic inflammatory lung disease, graft versus host disease, Crohn's disease, ulcerative colitis, inflamed bowel disease (IBD), Alzheimer's disease, and pyrexia, along with any disease or disorder that is related to inflammation and related disorders.
The at least one compound and/or at least one pharmaceutically acceptable salt described in this invention can be used to obtain a beneficial therapeutic or prophylactic effect, for example, in individuals with an autoimmune disease. The term "autoimmune disease" refers to a disease or disorder arising from and/or directed against the individual's own tissues or organs, or a cosegregation or manifestation thereof, or a condition resulting therefrom. Examples of autoimmune diseases include, but are not limited to, lupus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, inflamed bowel disease, asthma and idiopathic thrombocytopenic purpura, and myeloid proliferative disorders, such as such as myelofibrosis, PV / ET (post-polycythemia / essential thrombocythemia and myelofibrosis).
In some embodiments, the at least one compound and/or at least one pharmaceutically acceptable salt described in this invention is administered in conjunction with another therapeutic agent. In some embodiments, the other therapeutic agent is an agent that is normally administered to patients with the disease or condition being treated. For example, the other therapeutic agent can be an anti-inflammatory agent or an anti-neoplastic agent, depending on the disease or condition being treated. The at least one compound and/or at least one pharmaceutically acceptable salt described in this invention can be administered with the other therapeutic agent in a single dosage form or as a separate dosage form. When administered as a separate dosage form, the other therapeutic agent can be administered prior to, concurrently with, or after administration of the at least one compound and/or at least one pharmaceutically acceptable salt described in this invention.
In some embodiments, at least one compound and/or at least one pharmaceutically acceptable salt described in this invention is administered in conjunction with an anti-inflammatory agent. Non-limiting examples of anti-inflammatory agents include corticosteroids (eg, fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide), disease modifying agents (eg, antimalarials, methotrexate, sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine, metronidazole, injectable and oral gold, or D-penicillamine), non-steroidal anti-inflammatory drugs (eg, acetaminophen, aspirin, sodium salicylate, sodium cromoglycate, magnesium salicylate, salicylate choline magnesium, salicylsalicylic acid, ibuprofen, naproxen, diclofenac, diflunisal, etodolac, fenoprofen calcium, fluriprofen, piroxicam, indomethacin, ketoprofen, ketorolac tromethamine, meclofenamate, meclofenamate sodium, oxa butyl, mefenamic acid nitrone (PBN), sulindac, or tolmetin), COX-2 inhibitors, inhibitors of cytokine synthesis/release (eg, antibodies anticytokine, anticytokine receptor antibodies, among others).
In some embodiments, at least one compound and/or at least one pharmaceutically acceptable salt described in this invention is administered in conjunction with an antineoplastic agent. As used in this report, the term "antineoplastic agent" refers to any agent that is administered to an individual with cancer for the purpose of treating cancer. Non-limiting examples of antineoplastic agents include: radiotherapy; immunotherapy; DNA damaging chemotherapeutic agents; and chemotherapeutic agents that disrupt cell replication.
[00157] Non-limiting examples of DNA-damaging chemotherapeutic agents include topoisomerase I inhibitors (for example, irinotecan, topotecan, camptothecin and analogues or metabolites thereof, and doxorubicin); topoisomerase II inhibitors (for example, etoposide, teniposide, and daunorubicin); alkylating agents (for example melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (for example, cisplatin, oxaliplatin, and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside mimetics (eg, 5-fluorouracil, capecitibine, gemcitabine, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).
[00158] Chemotherapeutic agents that disrupt cell replication include: paclitaxel, docetaxel, and related analogues; vincristine, vinblastine, and related analogues; thalidomide and related analogs (for example, CC-5013 and CC-4047); protein tyrosine kinase inhibitors (for example, imatinib mesylate and gefitinib); proteasome inhibitors (for example bortezomib); NF-kappa B inhibitors, including kinase I kappa B inhibitors; antibodies that bind to overexpressed proteins in cancers and thus down-regulate cell replication (eg, trastuzumab, rituximab, cetuximab, and bevacizumab); and other protein or enzyme inhibitors are known to be upregulated, overexpressed or activated in cancers, and whose inhibition downregulates cell replication. EXAMPLES
[00159] The examples below are merely exemplary and should not be considered limiting in any way. Striving to ensure accuracy with respect to numbers used (eg quantities, temperature etc.) but some experimental errors and deviations must be taken into account. Unless otherwise indicated, parts are part by weight, temperature is in degrees Centigrade, and pressure is atmospheric pressure or a pressure close to atmospheric. All MS data were verified with agilent 6120 and/or agilent 1100. All reagents, except intermediates, used in this invention are commercially available. All compound names except reagents were generated by Chemdraw 8.0.
[00160] In the following examples, the abbreviations below are used: AIBN a,a'-azo-isobutyronitrile BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Boc tert-butoxycarbonyl Boc2O di-t-butyl -dicarbonate i-BuNO2 isobutyl nitrite BTC bis(trichloromethyl)carbonate DCM dichloromethane DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMAP 4-dimethylaminopyridine DPPA diphenylphosphoryl azide DBU 1,8-diazabicyclo[5.4.0] undec-7-ene Et3N triethylamine h hour HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HMTA hexamethylenetetramine HOAc acetic acid Lawesson reagent: 2,4- Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane mL milliliter(s) min minute(s) MeOH methanol MsCl methanesulfonyl chloride NBS N-bromosuccinimide PE petroleum ether Pd(dppf) Cl2 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride Pd(dppf)ChCH2Ch 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride complex dichloromethane Pd2(dba)3 tris( dibenzylideneacetone) dipalladium (0) Pd(PPh3)4 tetracys(triphenylphosphine)palladium (0) PdCl2(PPh3)2 bis(triphenylphosphine)palladium (II) dichloride PPh3 triphenylphosphine THF tetrahydrofuran TFA trifluoroacetic acid TBTU o-benzotriazol-1-yl tetrafluoroborate -N,N,N',N'- tetramethyluronium Intermediate 1 (R)-tert-butyl 3-(cyclopentyl(prop-2-ynyl)amino)pyrrolidine-1-carboxylate
(A) (R)-butyl 3-(cyclopentylamino)pyrrolidine-1-carboxylate
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.0 g, 5.3 mmol) and cyclopentanone (451 mg, 5.3 mmol) in THF (20 mL) was NaBH(OAc)3 (1.13 g, 5.3 mmol) is slowly added and then the solution stirred at room temperature overnight. The reaction was quenched with H2O (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined extracts were washed with brine (3 x 5 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the title compound. MS (m/z): 255 (M+H)+. (B) (R)-tert-butyl 3-(cyclopentyl(prop-2-ynyl)amino)pyrrolidine-1-carboxylate
A mixture of (R)-tert-butyl 3-(cyclopentylamino)pyrrolidine-1-carboxylate (200mg, 0.78mmol), 3-bromo-1-propyne (140mg, 1.18mmol) and K2CO3 (217 mg, 1.57 mmol) in acetonitrile (3 mL) was stirred at reflux overnight. Volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc = 4:1) to give the title compound. MS (m/z): 293 (M+H)+. Intermediate 2 (R)-N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine
(A) (R)-tert-butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate
A mixture of (R)-tert-butyl pyrrolidin-3-ylcarbamate (250 mg, 1.34 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (206 mg, 1.34 mmol) and DIPEA (0.35 mL, 2.01 mmol) in EtOH (3 mL) was stirred at reflux temperature for 16 hours. Volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (15 mL), and filtered. The filtrate was washed with brine (3 x 5 mL), dried over anhydrous Na 2 SO 4 , and concentrated to give the title compound (360 mg, 88% yield). MS (m/z): 304 (M+H)+. (B) (R)-N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine
[00164] In an atmosphere of N2, to a solution of (R)-tert-butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate (380 mg, 1.34 mmol) in anhydrous THF (10 mL) was slowly added mixed lithium aluminum hydride (143 mg, 3.76 mmol) at 0°C. After the addition was complete, the reaction mixture was stirred at 65°C for 2 hours. The reaction mixture was then cooled to 0°C, quenched with aqueous NaOH (15%), and filtered to remove solid. The filtrate was concentrated under reduced pressure. The residue was purified by preparatory TLC to give the title compound (178 mg, 66% yield). MS (m/z): 218 (M+H)+. Intermediate 3 (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine hydrochloride

[00165] (R)-tert-butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate (600 mg, 1.97 mmol) was treated with HCl (in MeOH , 6N, 5 mL) at room temperature for 2 hours. Volatiles were removed under reduced pressure to give the hydrochloride salt of (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine. MS (m/z): 204 (M+H)+. Intermediate 4 (R)-N-propyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine

[00166] A mixture of (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine hydrochloride (50 mg, 0.24 mmol), propionaldehyde (15 mg) , 0.26 mmol) and NaBH(OAC) 3 (61 mg, 1.2 mmol) in THF (5 mL) was stirred at room temperature for 20 minutes. It was then quenched with water (2ml) and extracted with EtOAc (3x10ml). The combined extracts were washed with brine (3 x 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound. MS (m/z): 246 (M+H)+. Intermediate 5 (R)-6-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylamino)nicotinonitrile
(A) 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 32.6 mmol) in THF (50 mL) was added NaH (30%, 4 g, 50.0mmol) ) at 0°C. The reaction mixture was stirred at 0°C for 1 hour before the addition of (2-(chloromethoxy)ethyl)-trimethylsilane (15 g, 90.0mmol). The reaction was stirred at room temperature for 3 hours. It was then treated with water (5ml) and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by chromatography to give the title compound. MS (m/z): 284 (M+H)+ (35Cl), 286 (M+H)+ (37Cl). (B) (R)-tert-butyl 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate
[00168] A solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(900 mg, 3.17 mmol), (R)-tert -butyl pyrrolidin-3-ylcarbamate (709 mg, 3.80 mmol) and DIPEA (618 mg, 4.75 mmol) in EtOH (20 mL) was stirred at reflux temperature for 3 hours. Volatiles were removed under reduced pressure and the residue dissolved in EtOAc (100 mL), washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound. MS (m/z): 434 (M+H)+. (C) (R)-6-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylamino)nicotinonitrile
[00169] A solution of (R)-tert-butyl 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3- ilcarbamate (700 mg, 1.61 mmol) in HCl (in MeOH, 6N, 5 mL) was stirred at room temperature for 3 hours. Volatiles were removed under reduced pressure. The residue was dissolved in DMSO (3 ml). 6-chloronicotinonitrile (323 mg, 2.41 mmol), KI (10 mg, 0.06 mmol) and DIPEA (311 mg, 2.41 mmol) were then added. The reaction mixture was stirred at 120°C for 14 h, cooled to room temperature, diluted with H2O (20 mL), and extracted with EtOAc (3 x 40 mL). The combined extracts were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound. MS (m/z): 436 (M+H)+. Intermediate 6 (R)-N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine

[00170] The title compound was prepared according to the procedures used for intermediate 2(B) using (R)-tert-butyl 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H -pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate. MS (m/z): 348 (M+H)+. Intermediate 7 (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) pyrrolidin-3-yl)pyrazin-2-amine

[00171] DIPEA (2.876 mmol) was added to the solution of (R)-N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrrolidin-3-amine (0.575mmol) and 2,5-dibromopyrazine (0.689mmol) in NMP (2ml). Then the solution was heated at 200°C for 45 minutes in a microwave reactor. After cooling, it was poured into water, and extracted with EtOAc. The combined organic layer was concentrated, and the resulting residue was purified by column chromatography to give (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine in 57.5% yield. MS (m/z): 504 (M+H)+, 506 (M+H)+. Intermediate 8 (R)-N2-Methyl-N2-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}- pyridine-2,5-diamine
(R)-Methyl-(5-nitro-pyridin-2-yl)-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin -3-yl}-amine
[00172] A mixture of (R)-Methyl-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}- amine (10mmol), DIPEA (20mmol) and 2-bromo-5-nitro-pyridine (11mmol) in DMF (50ml) was stirred at 100°C for 24 hours. After cooling, it was poured into water and extracted with EtOAc. The organic layer was washed with water and brine in sequence, then concentrated to give the crude product. The crude product was purified by column chromatography to give the title compound. (B) (R)-N2-Methyl-N2-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl} -pyridine-2,5-diamine
To a solution of (R)-methyl-(5-nitro-pyridin-2-yl)-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin -4-yl]-pyrrolidin-3-yl}-amine (10 mmol) in methanol (100 mL) was added Raney-Ni. The mixture was stirred at room temperature for 18 hours in 1 atm of H2. After filtered it was concentrated to give the title compound. Intermediate 9 (R)-tert-butyl 3-((5-cyanopyridin-2-yl)(cyclopropyl)amino)pyrrolidine-1-carboxylate
(A) (R)-tert-butyl 3-(cyclopropylamino)pyrrolidine-1-carboxylate
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (400 mg, 2.15 mmol), (1-ethoxycyclopropoxy)trimethylsilane (1500 mg, 8.60 mmol) in methanol (30 mL) was added sodium cyanoborohydride (569 mg, 8.60 mmol) and acetic acid (0.2 mL). The mixture was stirred at reflux for 10 hours. Volatiles were removed under reduced pressure. The residue was treated with water (20ml) and extracted with ethyl acetate (3x30ml). The combined extracts were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the title compound. MS (m/z): 227 (M+H)+. (B) (R)-tert-butyl 3-((5-cyanopyridin-2-yl)(cyclopropyl)amino)pyrrolidine-1-carboxylate
The title compound was prepared according to the procedures of Intermediate 2(A) using (R)-tert-butyl 3-(cyclopropylamino)pyrrolidine-1-carboxylate and 6-bromonicotinonitrile under similar conditions MS (m /z): 329 (M+H)+. Intermediate 10 tert-butyl 3-(5-cyanoindolin-1-yl)pyrrolidine-1-carboxylate

To a solution of indoline-5-carbonitrile (110 mg, 0.75 mmol) in 2.5 mL of MeOH was added tert-butyl 3-oxopyrrolidine-1-carboxylate (166 mg, 0.90 mmol) and HOAc (0.11 mL, 1.88 mmol) subsequently. After stirring at room temperature for 10 minutes, NaCNBH3 (57 mg, 0.90 mmol) was added and the mixture was then stirred at room temperature for 2 days. Volatiles were removed in vacuo. The residue was diluted with EtOAc, then washed with a 1N NaOH solution and brine, dried over Na 2 SO 4 , and evaporated in vacuo to give the crude title compound to be used in the next step without further purification. Intermediate 11 (R)-tert-butyl 3-((5-cyano-6-methoxypyridin-2-yl)(methyl)amino)pyrrolidine-1-carboxylate
(A) (R)-tert-butyl 3-((6-chloro-5-cyanopyridin-2-yl)(methyl)amino)pyrrolidine-1-carboxylate
To a solution of 2,6-dichloronicotinonitrile (2.2 mmol) and DIPEA (10 mmol) in DMF (10 mL) was added (R)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate with stirring at room temperature. The reaction mixture was stirred at 100°C overnight. Then the mixture was diluted with EtOAc, washed 3 times with water, dried, filtered and concentrated. The crude product was purified by flash chromatography to give the title compound. (B) (R)-tert-butyl 3-((5-cyano-6-methoxypyridin-2-yl)(methyl)amino)pyrrolidine-1-carboxylate
To a solution of (R)-tert-butyl 3-((6-chloro-5-cyanopyridin-2-yl)(methyl)amino)pyrrolidine-1-carboxylate (0.45mmol) in MeOH (20 mL) was added to a solution of NaOMe (0.9 mmol) in MeOH (2 mL). The reaction mixture was stirred at room temperature for 3 hours, then heated to 50°C, stirred for a further 2 hours, and then stirred at reflux overnight. The mixture was concentrated, diluted with EtOAc, washed with brine, dried, filtered, and concentrated to give the title compound.
[00179] Intermediates 12-14 below were prepared according to the procedures used for intermediate 11(A) using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.
Intermediate 15 (R)-tert-butyl 3-(N-methylcyclopropanesulfonamido)pyrrolidine-1-carboxylate

To a solution of (R)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (100 mg, 0.5 mmol) in 2.5 mL of THF was added cyclopropanesulfonyl chloride (77 mg, 0 .55 mmol) and DIPEA (0.10 mL, 0.60 mmol) at room temperature. The mixture was stirred at room temperature overnight. Water was added, then extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and evaporated in vacuo to give the crude title product which was used in the next step without further purification. MS (m/z): 305 (M+H)+. Intermediate 16 (R)-tert-butyl 3-(N-methylcyclopropanesulfonamido)pyrrolidine-1-carboxylate

To a solution of (R)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1mmol), TBTU (1.2mmol), DIPEA (2mmol) and 2-(acid) were slowly added trifluoromethyl)benzoic (1 mmol). The mixture was stirred at room temperature overnight. She was then focused. The residue was diluted with water, and extracted with EtOAc. The combined extracts were concentrated to give the title compound to be used in the next step without further purification. Example 1: Synthesis of Compounds 1-260 Compound 1 (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-cyano-N- methylacetamide

[00182] To a solution of (R)-N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (75 mg, 0.345 mmol) and 2-acid cyanoacetic (35 mg, 0.414 mmol) in THF (5 mL) were added HATU (157 mg, 0.414 mmol) and DIPEA (0.12 mL, 0.69 mmol). The reaction mixture was stirred at room temperature for 20 hours. The precipitate was filtered, washed with EtOAc, and dried under reduced pressure to give the title compound (45 mg, 46%). MS (m/z): 285 (M+H)+.
The compounds below were prepared according to the procedures used for compound 1 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.


To a solution of (R)-N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (30 mg, 0.138 mmol) in THF (2 mL) 4-cyanobenzene-1-sulfonyl chloride (42 mg, 0.208 mmol) and DIPEA (36 mg, 0.28 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 hour. The reaction mixture was then diluted with water, and extracted with EtOAc. The organic layers were combined, dried, and concentrated. The residue was purified by preparatory TLC to give the title compound (13.6 mg, 26%). MS (m/z): 383 (M+H)+.
The compounds below were prepared according to the procedures used for compound 9 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.



[00186] A solution of (R)-N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (50 mg, 0.230 mmol) and 3-isocyanatobenzonitrile ( 37mg, 0.257mmol) in 1,4-dioxane (1ml) was refluxed overnight. Volatiles were removed in vacuo and the residue was purified by flash chromatography to give the title compound. MS (m/z): 362 (M+H)+.
The compound below was prepared according to the procedures used for compound 16 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.


[00188] A solution of (R)-tert-butyl 3-(N-methyl-2-(trifluoromethyl)benzamido)pyrrolidine-1-carboxylate (1mmol) in TFA (2ml) and DCM (2ml) was stirred at room temperature for 2 hours, concentrated and diluted with water. It was then basified with an aqueous NaHCO3 solution until it reached a pH=~9, and extracted with EtOAc. The combined extracts were dried, filtered, and concentrated to give (R)-N-methyl-N-(pyrrolidin-3-yl)-2-(trifluoromethyl)benzamide.
[00189] To a solution of (R)-N-methyl-N-(pyrrolidin-3-yl)-2-(trifluoromethyl)benzamide (1 mmol) and 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (0.8 mmol) in EtOH (3 mL) was added DIPEA (2 mmol) with stirring at room temperature. The reaction mixture was refluxed overnight. The mixture was then concentrated, and purified by flash chromatography to give the title compound. MS (m/z): 390 (M+H)+.
[00190] The compounds below were prepared according to the procedures used for compound 18 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.

(A) (R)-2-(1H-imidazol-4-yl)-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3 -d]pyrimidin-4-yl)pyrrolidin-3-yl)acetamide.
To a solution of (R)-N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin- 3-amine (0.29 mmol), TBTU (0.35 mmol) and DIPEA (0.58 mmol) in THF was slowly added 2-(1H-imidazol-4-yl)acetic acid (0.29 mmol) ). The mixture was stirred at room temperature overnight, then concentrated, diluted with water, and extracted with EtOAc. The combined extracts were dried, filtered and concentrated. The residue was purified by flash chromatography to give the title compound. (B) (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-(1H-imidazol-4-yl)- N-methylacetamide.
[00192] A solution of (R)-2-(1H-imidazol-4-yl)-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole[ 2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)acetamide (0.11mmol) in TFA (1ml) and DCM (2ml) was stirred at room temperature for 1.5 hour. Volatiles were removed under reduced pressure. The residue was dissolved in MeOH (2ml) and treated with ethane-1,2-diamine (0.2ml) at room temperature overnight. Volatiles were then removed under reduced pressure and the residue was purified by flash chromatography to give the title compound. MS (m/z): 326 (M+H)+.
[00193] The compounds below were prepared according to the procedures used for compound 23 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.

3-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-1-methyl-1-((R)-1- (7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)urea.
[00194] To a solution of (R)-N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin- 3-amine (0.29 mmol) in anhydrous THF (2 mL) were subsequently added BTC and DIPEA (0.35 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes and at room temperature for 3 hours. It was then cooled to 0°C, (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (0.35 mmol) was added, and the mixture was stirred. at room temperature for 24 hours. It was then purified by preparatory TLC to give the title compound. (B) 1-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-3-((1R,2R)-2-hydroxy-2 ,3-dihydro-1H-inden-1-yl)-1-methylurea.
[00195] The title compound was prepared according to the procedure used for compound 23(B) using 3-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1- yl)-1-methyl-1-((R)-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3 -yl)urea. MS (m/z): 393 (M+H)+.
The compounds below were prepared according to the procedures used for compound 29 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.



[00197] (R)-tert-butyl 3-(cyclopentyl(prop-2-ynyl)amino)pyrrolidine-1-carboxylate (80 mg, 0.27 mmol) was stirred with HCl (in MeOH, 6N, 1 mL) at room temperature for 2 hours, then concentrate under reduced pressure. The residue was dissolved in EtOH (3 mL) and treated with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (42 mg, 0.27 mmol) in the presence of DIPEA (53 mg, 0.41 mmol) at reflux temperature for one night. Volatiles were removed and the residue was purified by preparatory HPLC to give the title compound. MS (m/z): 310 (M+H)+.
The compounds below were prepared according to the procedures used for compound 39 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.




[00199] A mixture of methyl (R)-N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.20 g, 0.92 mmol) , 2,4-dichloropyrimidine (0.18 g, 1.21 mmol) and DIPEA (0.25 g, 1.94 mmol) in DMF(6 mL) was stirred at 110°C for 16 hours. The mixture was poured into water (5ml) and extracted with ethyl acetate (2x8ml). The combined extracts were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (v. DCM/MeOH = 12/1) to give the title compound. MS (m/z): 330 (M+H)+.
The compounds below were prepared according to the procedures used for compound 65 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.






[00201] A mixture of methyl (R)-N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.50 g, 2.3 mmol) , 3,4-difluorobenzonitrile (0.48 g, 3.45 mmol) and DIPEA (0.59 g, 4.6 mmol) in DMSO (10 mL) was stirred at 90°C overnight. The mixture was poured into water (50ml) and extracted with ethyl acetate (2x50ml). The combined extracts were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound (0.404 g, 52% yield). MS (m/z): 337 (M+H)+.
The compounds below were prepared according to the procedures used for compound 103 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.




[00203] Under an atmosphere of N2, a mixture of (R)-N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4 -yl)pyrrolidin-3-amine (50 mg, 0.14 mmol), 3-bromobenzonitrile (39 mg, 0.21 mmol), Pd2(dba)3 (1 mg, 0.002 mmol), BINAP (5 mg, 0.008 mmol) and t-BuONa (27 mg, 0.28 mmol) in toluene (2 mL) was stirred at reflux for 6 hours, cooled to room temperature, diluted with EtOAc (50 mL), washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparatory TLC (DCM: MeOH = 20:1) to give the title compound. MS (m/z): 449 (M+H)+. (B) (R)-3-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)-benzonitrile.
The title compound was prepared according to the procedures used for compound 23 (B) using (R)-3-(methyl(1-(7-((2-(trimethylsilyl)ethoxy)methyl)) -7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)amino)benzonitrile. MS (m/z): 319 (M+H)+.
(R)-N-methyl-N-(4-(methylsulfonyl)phenyl)-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrrolidin-3-amine.
[00205] A mixture of (R)-N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3 -amine (100 mg, 0.287 mmol) and 1-fluoro-4-(methylsulfonyl)benzene (150 mg, 0.861 mmol) and K2CO3 (158 mg, 1.142 mmol) in DMF (2 mL) was stirred at 120 °C by a overnight and then cooled to room temperature, poured into water, and extracted with EtOAc. The EtOAc layer was concentrated, and purified by preparatory TLC to give the title compound. (B) (R)-N-methyl-N-(4-(methylsulfonyl)phenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine.
The title compound was prepared according to the procedures used for compound 23(B) using (R)-N-methyl-N-(4-(methylsulfonyl)phenyl)-1-(7-( (2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine.MS (m/z): 372 (M+H)+.
The compounds below were prepared according to the procedures used for compound 120 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.

(R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-1H-pyrazol[3,4-c]pyridin-5 -amine (A) (R)-N,4-dimethyl-5-nitro-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)pyrrolidin-3-yl)pyridin-2-amine.
A solution of (R)-N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3 -amine (0.287 mmol), 2-chloro-4-methyl-5-nitropyridine (0.347 mmol), and DIPEA (1.435 mmol) in NMP (1.5 mL) was stirred at 200 °C for 30 minutes in a micro reactor -waves and then cooled to room temperature. The solution was poured into water, extracted with EtOAc, concentrated, and purified by column chromatography to give the title compound in 86.3% yield. (B) (R)-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3 -yl)-1H-pyrazol[3,4-c]pyridin-5-amine.
[00209] To a solution of (R)-N,4-dimethyl-5-nitro-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3-d ]pyrimidin-4-yl)pyrrolidin-3-yl)pyridin-2-amine (0.248 mmol) in ethanol (20 mL) and water (5 mL), iron powder (0.752 mmol) and NH4Cl (1.495) were added mmol). The mixture was stirred at reflux temperature for 2 hours, cooled, and filtered. The filtrate was concentrated, and dissolved in CH3COOH (1.5 mL) and water (2.5 mL). NaNO 2 (0.304 mmol) was then slowly added, and the mixture was stirred at room temperature overnight, which was subsequently treated with NH 3 .H 2 O and extracted with EtOAc (3 x 20 mL). The combined extracts were concentrated and the residue was purified by column chromatography to give the title compound in 33.0% yield. (C) (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-1H-pyrazol[3,4-c] pyridin-5-amine.
The title compound was prepared according to the procedures used for compound 23(B) using (R)-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-1H-pyrazol[3,4-c]pyridin-5-amine.MS (m/z): 335 (M+H)+. Compound 126 (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(ethyl)amino)-nicotinonitrile
midin-4-yl)pyrrolidin-3-yl)amino)nicotinonitrile.
To a solution of (R)-6-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3 -ylamino)nicotinonitrile (200 mg, 0.46 mmol) in DMF (5.0 mL) was added NaH (55 mg, 2.3 mmol) gradually at 0°C. The reaction mixture was stirred at room temperature for 30 minutes, bromoethane (60 mg, 0.55 mmol) was then added dropwise and the reaction mixture was stirred at room temperature for a further 30 minutes. The reaction mixture was quenched with saturated NH 4 Cl (10 mL) and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound. MS (m/z): 464 (M+H)+. (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(ethyl)amino)-nicotinonitrile.
[00212] The title compound was prepared according to the procedures used for compound 23 (B) using (R)-6-(ethyl(1-(7-((2-(trimethylsilyl)ethoxy)methyl)) -7H-pyrrole[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)amino)nicotinonitrile. MS (m/z): 334 (M+H)+.
The compounds below were prepared according to the procedures used for compound 126 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.

(R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-5-morpholinopyrazin-2-amine (R)- N-methyl-5-morpholino-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl) pyrazin-2-amine.
A solution of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrrolidin-3-yl)pyrazin-2-amine (0.099mmol) and morpholine (1.5ml) in NMP (0.5ml) was stirred at 195°C for 2 hours in a microwave reactor . After cooling to room temperature, it was poured into water, and extracted with EtOAc. The combined organic extracts were concentrated and the residue was purified by column chromatography over silica gel to give the title compound. (B) (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-5-morpholinopyrazin-2-amine.
The title compound was prepared according to the procedures used for compound 23(B) using (R)-N-methyl-5-morpholino-N-(1-(7-((2-( trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine. MS (m/z): 381 (M+H)+.
The compounds below were prepared according to the procedures used for compound 134 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.
.
[00217] A mixture of (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-chloro-N-methylpyrimidin-4-amine (26.0 mg, 0.08 mmol) and methylamine (in THF, 2.0 M, 5.0 mL, 10.0 mmol) was stirred at 110 °C for 45 minutes in an Initator® Biotage microwave reactor . Volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography to give the title compound. MS (m/z): 325 (M+H)+.
[00218] The compounds below were prepared according to the procedures used for compound 139 using the corresponding reagent under appropriate conditions which will be recognized by the person skilled in the art.

[00219] A mixture of (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-5-bromo-N-methylpyrimidin-2-amine (50.0 mg, 0.134 mmol), dicyanozinc (15.7 mg, 0.134 mmol) and tetrakis(triphenylphosphine)palladium (15.4 mg, 0.0134 mmol) in 5 mL of DMF was stirred at 120 °C for 40 minutes in an InitatorTM Biotage microwave reactor. The reaction mixture was distributed between 15 ml of water and 20 ml of ethyl acetate. The organic layer was washed with brine, dried, concentrated and the residue was purified by preparatory TLC to give the title compound. MS (m/z): 321 (M+H)+. Compound 143 (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methylpyrazin-2-amine

[00220] A solution of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrrolidin-3-yl)pyrazin-2-amine (55mg, 0.10mmol) and sodium ethoxide (680mg, 10mmol) in EtOH (10.5ml) was stirred at reflux temperature by 5 days. It was then treated with water and extracted with EtOAc (2 x 30 mL). The combined extracts were concentrated and the residue was purified by chromatography on silica gel (PE/EtOAc=1/1). The first compound from the column was collected and confirmed to be (R)-5-ethoxy-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)-methyl)-7H -pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine [MS (m/z), 470 (M+1)+, 21 mg, 41.1% of yield) and the last compound from the column was isolated and concentrated to give the title compound (22 mg, 47.8% yield). MS (m/z), 426 (M+1)+ (B) (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)- N-methylpyrazin-2-amine.
[00221] The title compound was prepared according to the procedures used for compound 23(B) using (R)-N-methyl-N-(1- (7-((2-(trimethylsilyl)ethoxy)) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine. MS (m/z): 296 (M+H)+. Compound 144 (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-3,4'-bipyridin-6-amine

[00222] Under an N2 atmosphere, a mixture of (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-5-iodo-N -methylpyridin-2-amine (90.0 mg, 0.21 mmol), pyridin-4-yl boronic acid (28.4 mg, 0.23 mmol), PdCWppf-C^Ck (17.2 mg, 0, 02 mmol) and K2CO3 (0.058 g) in DMF (5.0 mL) was stirred at 110°C for 16 hours. Then it was cooled to room temperature, diluted with water (5.0 mL) and extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with brine (3 x 5.0 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. The residue was purified by flash chromatography to give the title product. MS (m/z): 372 (M+H)+.
[00223] The compounds below were prepared according to the procedures used for compound 144 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.

(R)-N-methyl-5-(1H-pyrazol-4-yl)-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine.
[00224] Under an atmosphere of N2, a mixture of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2, 3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine (64mg, 0.127mmol), pinacol 4-pyrazoleboronic acid ester (37mg, 0.19mmol), Pd(PPh3) 4 (29mg, 0.0254mmol), Cs 2 CO 3 (124mg, 0.381mmol) in 1,4-dioxane (3ml) / water (0.3ml) was stirred at reflux for 14 hours. Then it was cooled to room temperature, diluted with EtOAc and H2O, and extracted with EtOAc. The combined extracts were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography to give the title compound. (B) N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-5-(1H-pyrazol-4-yl) )pyrazin-2-amine.
The title compound was prepared according to the procedures used for compound 23(B) using (R)-N-methyl-5-(1H-pyrazol-4-yl)-N-(1- (7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine. MS (m/z): 362 (M+H)+.
The compound below was prepared according to the procedures used for compound 151 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.

(A) 5-(1H-imidazol-1-yl)-N-methyl-N-((R)-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3 -d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine.
[00227] A mixture of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrrolidin-3-yl)pyrazin-2-amine (50 mg, 0.0991 mmol), imidazole (14 mg, 0.198 mmol), CuI (9.4 mg, 0.050 mmol), Cs2CO3 (32 mg, 0.0991 mmol), and 1,10-phenanthroline (9 mg, 0.050 mmol), in NMP (2 mL) was stirred at 180°C for 45 minutes in a microwave reactor. Then it was cooled to room temperature and diluted with H2O, extracted with EtOAc, washed with brine, dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give the title compound (20 mg, 41%). (B) N-((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-5-(1H-imidazol-1-yl)- N-methylpyrazin-2-amine.
The title compound was prepared according to the procedures used for compound 23(B) using 5-(1H-imidazol-1-yl)-N-methyl-N-((R)-1- (7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine. MS (m/z): 362 (M+H)+. Compound 154 (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methylpyrimidin-4-amine

[00229] In a hydrogen atmosphere, a mixture of (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-chloro-N -methylpyrimidin-4-amine (30 mg, 0.09 mmol), Pd/C (10 wt%, 20.0 mg) was stirred in 3.0 mL of methanol at room temperature for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by preparatory TLC (DCM/MeOH = 15/1) to give the title compound. MS (m/z): 296 (M+H)+.
[00230] The compounds below were prepared according to the procedures used for compound 154 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.


[00231] A mixture of (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinonitrile (100mg, 0, 31mmol), ammonium chloride (84mg, 1.57mmol) and sodium azide (108mg, 1.66mmol) in N,N-dimethylformamide (5.0ml) was stirred at 120°C for 16 hours. Volatiles were removed in vacuo and the residue was purified by silica gel chromatography to give the title compound. MS (m/z): 363.0 (M+H)+.
The compound below was prepared according to the procedures used for compound 160 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.

(A) (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-5-((trimethylsilyl)ethynyl)pyridin- 2-amine.
[00233] Under an N2 atmosphere, a mixture of (■)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-5-bromo-N -methylpyridin-2-amine (0.22 g, 0.58 mmol), ethynyltrimethylsilane (0.22 mL, 1.6 mmol), Et3N (0.24 mL, 1.5 mmol), CuI (5.0 mg , 0.03 mmol), PdCl2(PPh3)2 (8.0 mg, 0.01 mmol) and PPh3 (3.0 mg, 0.01 mmol) in DMF (3.0 mL) was stirred at 90°C for 4 hours. The reaction was then cooled to room temperature, diluted with water (3 mL), extracted with ethyl acetate (2 x 10 mL). The combined extracts were washed with brine (2 x 6 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give the title compound. MS (m/z): 295 (M+H)+. (B) (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-5-ethynyl-N-methylpyridin-2-amine.
A mixture of (■)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-5-((trimethylsilyl)ethynyl )pyridin-2-amine (26 mg, 0.06 mmol) and K2CO3 (20.0 mg) in MeOH (4.0 mL) was stirred at room temperature for 16 hours. Volatiles were removed and the residue was purified by silica gel chromatography to give the title compound. MS (m/z): 319 (M+H)+.
(A) (R)-N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methyl-pyridine-2,5,6-triamine
[00235] A solution of (R)-N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methyl-5-nitropyridine-2,6 -diamine (320 mg, 0.90 mmol) in ethanol (35 mL) was degassed and purged with N2. Pd/C (10%, 100 mg) was added, degassed and purged with H2 and then stirred in a hydrogen atmosphere at room temperature for 20 hours. The catalyst was removed by filtration and the filtrate was concentrated to give the title product. MS (m/z): 325 (M+H)+. (B) (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-3H-imidazo[4,5-b] pyridin-5-amine.
[00236] A solution of (R)-N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5,6-triamine (35mg, 0.11mmol), triethoxymethane (0.58ml, 3.45mmol) and 4-methylbenzenesulfonic acid monohydrate (62mg, 0.33mmol) in methanol (3.0ml) was stirred at 150 °C for 5 minutes in an Initator® Biotage microwave reactor. Volatiles were removed and the residue was purified by chromatography to give the title product. MS (m/z): 335 (M+H)+. Compound 164 (R)-5-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)-1H-imidazo[4,5-b ]pyridin-2(3H)-one

[00237] A solution of (R)-N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5,6-triamine (35 mg, 0.11 mmol,) and 1,1'-carbonyldiimidazole (21 mg, 0.13 mmol) in tetrahydrofuran (3.0 mL) was stirred at reflux for 1 hour. Volatiles were removed and the residue was purified by chromatography to give the title compound. MS (m/z): 351 (M+H)+. Compound 165 (R)-3-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridine-6-carbonitrile
(A) (R)-6-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylamino)-5-aminonicotinonitrile.
[00238] The title compound was prepared according to the procedure used for compound 163(A) using (R)-6-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl )pyrrolidin-3-ylamino)-5-nitronicotinonitrile. MS (m/z): 321 (M+H)+. (B) (R)-3-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridine-6-carbonitrile.
[00239] The title compounds were prepared according to the procedure used for compound 164 using R)-6-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylamino )-5-aminonicotinonitrile. MS (m/z): 347 (M+H)+. Compound 166 (R)-4-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)-3-aminobenzonitrile

The title compound was prepared according to the procedures used for compound 163 using (R)-4-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin -3-yl)(methyl)amino)-3-nitrobenzonitrile. MS (m/z): 334 (M+H)+. Compound 167 (R)-N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N-methyl-3H-[1,2,3]triazol[ 4,5-b]pyridin-5-amine

[00241] To a suspension of (R)-N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5,6- triamine (50 mg, 0.15 mmol) in water (0.6 mL) was added concentrated sulfuric acid (23 uL). The mixture was stirred at room temperature for 1 hour. It was cooled to 0°C and aqueous sodium nitrite (17 mg, 0.25 mmol, in 0.1 mL of water) was added. The reaction mixture was stirred at 0 °C for 1 hour. It was then neutralized to pH 5 with aqueous NaHCO3 (10%) and extracted with EtOAc (3 x 10 mL). The combined extracts were washed with brine (2 x 10 mL), concentrated, and the residue was purified by chromatography to give the title compound. MS (m/z): 336 (M+H)+. Compound 168 (R)-Methyl 6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinate

[00242] A solution of (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinonitrile (31.9 mg , 0.1 mmol) in hydrogen chloride (6M in MeOH, 5.0 ml) was stirred at 65°C for 14 hours. Volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography to give the title compound. MS (m/z): 353 (M+H)+. Compound 169 (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinamide

[00243] A solution of (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinonitrile (31.9 mg , 0.1 mmol), aqueous sodium hydroxide (1.0 M, 0.7 mL, 0.7 mmol,) and hydrogen peroxide (30% in H2O, 0.3 mL) in MeOH (1.0 mL ) was stirred at room temperature for 2 hours and then treated with aqueous Na2S2O3 (10%) until it was no longer possible to detect the peroxide. Volatiles were removed under reduced pressure and the residue was extracted with EtOAc (3 x 20 mL). The combined extracts were washed with brine, concentrated and the residue was purified by silica gel chromatography to give the title compound. MS (m/z): 338 (M+H)+. Compound 170 (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinic acid

[00244] A solution of (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)nicotinonitrile (160 mg, 0 .5 mmol) in concentrated hydrochloric acid (5.0 ml) was stirred at 100°C for 14 hours. Volatiles were removed under reduced pressure to give the title compound. MS (m/z): 339 (M+H)+. Compound 171 (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)-N-cyclopropylnicotinamide

To a solution of (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino) nicotinic acid (33, 8mg, 0.1mmol) in DMF (2ml) were added cyclopropylamine (5.71mg, 0.2mmol), DIPEA (26mg, 0.2mmol) and HATU (38.0mg, 0.1mmol) ). The reaction mixture was stirred at room temperature for 16 hours. Volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography to give the title compound. MS (m/z): 378 (M+H)+.
The compounds below were prepared according to the procedures used for compound 171 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.





(R)-N-(6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)pyridin-3-yl)ethanesulfonamide midin- (R)-ethanesulfonic acid 4-yl]-pyrrolidin-3-yl}-amino)-pyridin-3-yl]-amide.
[00247] To a solution of (R)-N2-methyl-N2-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin- 3-yl}-pyridine-2,5-diamine (0.25 mmol) in DCM (5 mL) were subsequently added ethanesulfonyl chloride (0.3 mmol) and Et3N (0.3 mmol). The solution was stirred at room temperature for 18 hours and then concentrated. The crude product was purified by preparatory TLC to give the title compound in 42% yield. (B) (R)-N-(6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)-pyridin-3-yl )ethanesulfonamide.
[00248] The title compounds were prepared according to the procedure used for compound 23(B) using [6-(methyl-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrole[2,3 (R)-ethanesulfonic acid -d]pyrimidin-4-yl]-pyrrolidin-3-yl}-amino)-pyridin-3-yl]-amide. MS (m/z): 402 (M+H)+.
[00249] The compounds below were prepared according to the procedures used for compound 210 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.


Compound 230 (R)-N5-(4-fluorobenzyl)-N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5 -diamine (R)-N5-(4-fluorobenzyl)-N2-methyl-N2-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrrolidin-3-yl)pyridine-2,5-diamine.
To a solution of (R)-N2-methyl-N2-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )pyrrolidin-3-yl)pyridine-2,5-diamine (0.20mmol) in DMF (5ml) were added K 2 CO 3 (0.24mmol) and 1-Chloromethyl-4-fluoro-benzene (0.24mmol) ) at ambient temperature. The mixture was stirred at 80°C for 18 hours, poured into water and extracted with EtOAc. The organic layer was washed with water and brine in sequence, then concentrated. The residue was purified by preparatory TLC to give the title compound in 30% yield. (B) (R)-N5-(4-fluorobenzyl)-N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine- 2,5-diamine.
[00251] The title compounds were prepared according to the procedure used for compound 23(B) using (R)-N5-(4-fluorobenzyl)-N2-methyl-N2-(1-(7-((2) -(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyridine-2,5-diamine. MS (m/z): 418 (M+H)+. Compound 231 (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)-N,N-dimethylpyridine-3-sulfonamide
(A) 6-chloro-N,N-dimethylpyridine-3-sulfonamide.
[00252] A solution of 6-chloropyridine-3-sulfonyl chloride (1 mmol), dimethylamine (2 mmol) and Et3N (2 mmol) in THF (2 mL) was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with brine, dried, filtered, and concentrated to give the title compound in 95% yield. (B) (R)-N,N-dimethyl-6-(methyl(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl )pyrrolidin-3-yl)amino)pyridine-3-sulfonamide.
To a solution of 6-chloro-N,N-dimethylpyridine-3-sulfonamide (1 mmol) and DIPEA (2.5 mmol) in NMP (2 mL) was added (R)-N-methyl-1- (7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.5mmol). The reaction mixture was stirred at 200°C for 60 minutes in a microwave reactor. After cooling to room temperature, the mixture was diluted with EtOAc, washed with brine, dried, filtered, and concentrated. The residue was purified by chromatography with MeOH/H2O to give the yellow title compound in 8% yield. (C) (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)-N,N-dimethylpyridine-3- sulfonamide.
The title compounds were prepared according to the procedure used for compound 23(B) using (R)-N,N-dimethyl-6-(methyl(1-(7-((2-(trimethylsilyl)) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)amino)pyridine-3-sulfonamide.MS (m/z): 402 (M+H)+.
The compounds below were prepared according to the procedures used for compound 231 using the corresponding intermediates and reagents under appropriate conditions which can be recognized by the person skilled in the art.





[00256] (R)-6-((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)(methyl)amino)-2-methoxynicotinonitrile (0.43mmol) ) was dissolved in the mixture of HCl (concentrated, 0.4 ml) and TFA (2.0 ml). The mixture was then refluxed for 7 hours, concentrated under reduced pressure, and purified by preparatory HPLC to give the title compound. MS (m/z): 336 (M+H)+. Example 2 Enzyme Assay
[00257] Assays of JAK1/2/3 kinases are performed in vitro using the "Kit-Tyr 6 Peptide" (Invitrogen, Cat. No. PV4122). TYK2 kinase assays are performed in vitro using the "Z’-LYTE® Kinase Assay Kit-Tyr 3 Peptide" (Invitrogen, Cat. No. PV3192). Recombinant human JAK1/2/3 or TYK2 catalytic domains are from Invitrogen (Cat. No. PV4774/PV4210/PV3855/PV4790); all reactions (20 µL) are initiated with the addition of 2.5 µL of test compound in 4% DMSO solution, 5 µL of substrate kinase/peptide mixture (3.2, 0.04, 0.2 or 8 mg/μL for the catalytic domains of recombinant human JAK1/2/3, 4 μM for the peptide Z-LYTE® Tyr 6 or for the peptide Z-LYTE® Tyr 3) or phospho-peptide solution (Invitrogen , Cat. No. PV3192, diluted with 1.33x kinase buffer), 2.5 µL of ATP solution (300/100/40/100 µM, JAK1/JAK2/JAK3/TYK2) or 1.33 x kinase buffer ( Invitrogen, Cat. No. PV3189, 5x diluted with distilled water). The 384-well assay plate (Corning, Cat. No. 3575) is mixed and incubated at room temperature for 1 hour. 5 μL of the development solution (diluted development reagent A (Cat. No. PV3297) is diluted 1/64 with development buffer (Cat. No. PV3127) for the JAK1, JAK2 and JAK3 assay; the development reagent A (Cat. No. PV3297) is diluted 1/2048 with the development buffer (Cat. No. PV3127) for the TYK2 assay.The development reagent is then added to each well, mixed and incubated at room temperature for an additional 1 The kinase reaction is then stopped by the addition of 5 μL of Stop Reagent (Invitrogen, Cat. No. PV3094), and the plate is read with the Wallac 1420 VICTOR3 Multilabel Counter (PerkinElmer®) at 445 nm and 520 nm All compounds are initially tested at 8 different concentrations (1 µM down to 0.0003 µM) using a 1:3 serial dilution scheme.
[00258] Most of the compounds disclosed in this invention inhibited at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 with IC50 < 1.0 uM. Example 3 Cell Assays
[00259] For the determination of IL-6-induced STAT3 phosphorylation, HepG2 cells (SIBS) are seeded in 96-well plates at 5.4x103 cells per well in serum-free DMEM medium overnight and incubated in the presence or absence of various concentrations of the compound diluted for 30 minutes at 37°C, 5% CO2. Cells were stimulated by adding 10 ng/ml of recombinant human IL-6 to each well for 15 minutes at 37°C, 5% CO 2 . Cells are then fixed in 2% paraformaldehyde for 45 minutes at room temperature and incubated in ice-cold methanol for 30 minutes. After being washed in PBS, cells are incubated with rabbit anti-phospho-STAT3 primary antibody (Y705) (Cell Signaling Technologies, 1:1000 in antibody dilution solution) overnight at 4°C. Alexa 488 goat anti-rabbit IgG secondary antibody (Invitrogen, 1:1000 dilution in PBS) is added for 90 minutes before PBS washes. The cells are subsequently incubated in a solution of 7.5uM propidium iodide, 100mg/ml RNaseA and PBS for 60 minutes in the dark. Plates are read on an Acumen X3 instrument (TPP Labtech).
For the determination of IL-3 induced STAT5 phosphorylation, TF-1 cells (ATCC) are plated in 96-well plates at 1x104 cells per well in RPMI-1640 medium with 10% FBS at 37°C, 5% CO2 for 3 hours. Cells were incubated in the presence or absence of various concentrations of the diluted compound for 30 minutes at 37°C, 5% CO 2 . Cells were stimulated by adding 10 ng/ml of recombinant human IL-3 to each well for 30 minutes at 37°C, 5% CO 2 . Cells are then fixed in 2% paraformaldehyde for 45 minutes at room temperature and incubated in ice-cold methanol for 30 minutes. After being washed in PBS, cells are incubated with rabbit anti-phospho-STAT5 primary antibody (Y694) (Cell Signaling Technologies, 1:1000 in antibody dilution solution) overnight at 4°C. Alexa 488 goat anti-rabbit IgG secondary antibody (Invitrogen, 1:1000 dilution in PBS) is added for 90 minutes before PBS washes. Cells are counted subsequent to incubation in a solution of 7.5uM propidium iodide, 100mg/ml RNaseA and PBS for 60 minutes in the dark. Plates are read on an Acumen X3 instrument (TPP Labtech).
[00261] For the determination of IL-4 induced STAT6 phosphorylation, Ramos cells (ATCC) are plated in 96-well plates at 1x104 cells per well in RPMI-1640 medium with 10% FBS at 37°C, 5% of CO2 for 3 hours. Cells were incubated with compounds for 30 minutes before stimulation with interleukin-4 (10ng/ml final) for another 30 minutes. Cells are then fixed in 2% paraformaldehyde for 45 minutes and incubated in ice-cold methanol for 30 minutes. After being washed in PBS, cells are incubated with rabbit anti-phospho-STAT6 primary antibody (Y641) (Cell Signaling Technologies, 1:1000 in antibody dilution solution) overnight at 4°C. Alexa 488 goat anti-rabbit IgG secondary antibody (Invitrogen, 1:1000 dilution in PBS) is added for 90 minutes before PBS washes. Cells are counted subsequent to incubation in a solution of 7.5uM propidium iodide, 100mg/ml RNaseA and PBS for 60 minutes in the dark. Plates are read on an Acumen X3 instrument (TPP Labtech).
[00262] Percent inhibition is calculated using the following formula: Inhibition (%) = 100-((inhibitor-cell treatment) / (stimulator - cell)) x100
[00263] where: inhibitor treatment represents the percentage of cell activation of wells treated with both the compound and the stimulator (IL-6, IL-3 or IL-4); cell represents the percentage of cell activation of wells not treated with compound or stimulator (IL-6, IL-3 or IL-4). Stimulator represents the percentage of cell activation of wells treated with only the stimulator (IL-6, IL-3 or IL-4).
Most of the compounds disclosed in this invention inhibited at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2 in cellular assays with IC50 < 10.0 uM.
[00265] For example, in the JAK1 kinase assay above, the present compounds have the following percent inhibition at a concentration of 0.3 uM (IR%):
[00266] IV% values for compounds 1, 3, 6, 7, 10, 12, 14, 15, 16, 17, 20, 21, 24, 27, 28, 29, 30, 31, 33, 38 , 40, 41, 42, 45, 46, 47, 48, 49, 52, 53, 55, 56, 59, 60, 61, 62, 63, 64, 67, 68, 70, 71, 72, 73, 74 , 77, 79, 80, 81, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 101, 102, 103, 104, 105 , 106, 107, 108, 111, 112, 114, 115, 117, 119, 121, 122, 123, 124, 126, 127, 129, 131, 132, 133, 134, 136, 138, 144, 147, 150 , 152, 153, 154, 155, 156, 157, 158, 159, 161, 162, 163, 164, 167, 168, 170, 171, 174, 176, 177, 178, 179, 180, 182, 183, 184 , 185, 186, 187, 190, 191, 192, 195, 197, 199, 201, 202, 204, 205, 206, 207, 208, 209, 210, 212, 214, 218, 219, 220, 222, 223 , 224, 225, 226, 227, 229, 230, 234, 235, 236, 237, 238, 239, 240, 242, 243, 244, 245, 246, 247, 248, 249, 251, 252, 253, 254 , 255, 256, 259, 260, 261, 262, range from 50% to less than 100%;
[00267] IV% values for compounds 4, 5, 8, 9, 11, 13, 19, 35, 43, 44, 39, 54, 57, 58, 65, 66, 75, 76, 78, 88 , 100, 109, 110, 113, 116, 118, 120, 130, 135, 141, 142, 146, 148, 151, 160, 165, 166, 169, 172, 173, 175, 188, 189, 193, 194 , 196, 198, 200, 203, 213, 221, 228, 232, 250, 257, range from 20% to less than 50%.
[00268] In addition, in the above JAK1 kinase assay, the IC50 values for compounds 1, 16, 21, 30, 33, 36, 37, 42, 67, 68, 77, 86, 104, 105, 106, 119, 121, 122, 123, 124, 125, 127, 128, 144, 154, 155, 161, 202, 214, 215, 217, 218, 219, 233, 234, 236, 237, 238, 239, 241, 242, 243, 245, 246, 247, 251, 252, 253, 254, 259, range in the range from 0.001 µM to less than 0.1 µM.
[00269] In the above JAK2 kinase assay, the IC50 values for compounds 1, 40, 41, 42, 46, 47, 48, 60, 61, 62, 63, 64, 66, 67, 71, 73, 80 , 81, 84, 86, 87, 91, 92, 93, 94, 98, 99, 102, 103, 104, 111, 114, 121, 122, 123, 124, 125, 126, 128, 129, 131, 134 , 153, 155, 156, 157, 159, 161, 162, 163, 164, 168, 171, 174, 176, 179, 182, 184, 185, 187, 190, 192, 201, 202, 204, 208, 209 , 210, 212, 236, 241, 242, range from 0.001 µM to less than 0.1 µM;
IC50 values for compounds 3, 6, 7, 10, 12, 16, 17, 30, 49, 52, 53, 55, 56, 57, 58, 68, 70, 72, 77, 79, 83, 85, 89, 90, 96, 97, 101, 107, 108, 115, 130, 136, 147, 154, 158, 160, 167, 170, 178, 195, 207, 217, 218, 239, 243, 252, 259, range from 0.1 µM to less than 1 µM.
[00271] In the above JAK3 kinase assay, IC50 values for compounds 42, 63, 66, 67, 121, 126, 129, 134, 162, 182, 208, 209, 236, range from 0.001 uM to less than 0.1 µM;
IC50 values for compounds 1, 17, 25, 40, 41, 48, 60, 62, 64, 70, 71, 73, 77, 79, 80, 81, 84, 86, 87, 91, 92, 93, 94, 96, 97, 98, 99, 102, 103, 104, 107, 111, 114, 131, 153, 156, 159, 163, 164, 168, 171, 174, 179, 184, 187, 190, 201, 202, 210, range from 0.1 µM to less than 1 µM.
[00273] The experimental data of some compounds tested in examples 2 and 3 are presented in the table below.

权利要求:
Claims (19)
[0001]
1. Compound characterized by the fact that it has the formula (I):
[0002]
2. Compound according to claim 1, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R 1 is alkyl or alkyl substituted by alkenyl, alkynyl or cycloalkyl.
[0003]
3. A compound according to claim 1, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R 1 is cycloalkyl.
[0004]
A compound according to any one of claims 1 to 3, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R2 is aryl or heteroaryl, each of which is optionally substituted with one or more groups chosen from optionally substituted C1-C4 alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -C(O)Ra, -C(O)ORb, -CN, -C(O)NRcRd , halo, optionally substituted haloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, -NRcRd, -NReC(O)Ra, -NReC(O)ORb, -NReC(O)NRcRd, -NReS(O)nRf, -NReS (O)nNRcRd, -NO2, -ORb, -S(O)nRf, and -S(O)nNRcRd; where each optionally substituted group above may be unsubstituted or independently substituted as defined in claim 1.
[0005]
A compound according to any one of claims 1 to 4, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R2 is aryl or heteroaryl selected from
[0006]
6. A compound according to claim 5, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R2 is aryl or heteroaryl chosen from
[0007]
7. A compound according to claim 6, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R2 is
[0008]
8. A compound according to claim 7, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R2 is
[0009]
9. A compound according to claim 5, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R2 is
[0010]
10. A compound according to claim 9, and/or at least one pharmaceutically acceptable salt thereof, characterized in D2.-O, in that R2 is
[0011]
11. Compound according to claim 5, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R 2 is pyrazinyl optionally substituted with one or more groups chosen from: -CN, alkoxy, morpholino, pyrazolyl, imi - dazolyl, and -NRcRd, where Rc and Rd are each independently chosen from cycloalkyl and alkyl, each optionally being substituted with -OH.
[0012]
12. A compound according to claim 5, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R 2 is pyridazinyl optionally substituted with one or more groups chosen from -CN, halo, and haloalkyl.
[0013]
13. A compound according to claim 5, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R2 is pyrimidinyl optionally substituted with one or more groups chosen from -CN, halo, -NO2, -ORb, and -NRcRd, where Rb, Rc and Rd are each independently chosen from -H and alkyl.
[0014]
A compound according to any one of claims 1 to 13, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R1 is selected from C1-3 alkyl, allyl, propargyl, and cyclopropyl.
[0015]
A compound according to any one of claims 1 to 14, and/or at least one pharmaceutically acceptable salt thereof, characterized in that R1 is methyl.
[0016]
16. A compound according to any one of claims 1 to 15, and/or at least one pharmaceutically acceptable salt thereof, characterized in that the absolute stereocenter carrying the -N(R1)(R2) group is the isomer A.
[0017]
17. A compound according to claim 1 or at least one pharmaceutically acceptable salt thereof, characterized in that said compound is selected from:
[0018]
18. Composition characterized in that it comprises at least one compound as defined in any one of claims 1 to 17, and/or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
[0019]
19. Use of at least one compound as defined in any one of claims 1 to 17, and/or at least one pharmaceutically acceptable salt thereof, characterized in that it is in the preparation of a medicine to treat an inflammatory disease or a cancer responsive to inhibition of at least one kinase chosen from JAK1, JAK2, JAK3 and TYK2.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-07-02| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-08-06| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-06-01| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-07-20| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-08-31| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 18/08/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

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申请号 | 申请日 | 专利标题

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CN201010257786.7A|CN102372717B|2010-08-20|2010-08-20|Pyrrolopyrimidine compound and use thereof|

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CNPCTCN2010076187|2010-08-20|

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PCT/CN2010/076187|WO2012022045A1|2010-08-20|2010-08-20|Pyrrolopyrimidine compounds and uses thereof|

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CN2010102577867|2010-08-20|

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PCT/CN2011/078575|WO2012022265A1|2010-08-20|2011-08-18|Pyrrolopyrimidine compounds and uses thereof|

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