TW201211044A - Pyrrolopyrimidine compounds and uses thereof - Google Patents

Abstract

The present invention provides pyrrolopyrimidine compounds and methods of use therefor. In particular, the invention provides certain pyrrolopyrimidine compounds having the activity of inhibiting JAK kinases. The invention also provides the pharmaceutical compositions containing these pyrrolopyrimidine compounds and use of these compounds in the treatment of inflammatory diseases and cancer.

Description

201211044 π, DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to the field of _, and more particularly, to a pyrrolopyrimidine compound having ruthenium kinase inhibitory activity and use thereof. [Prior Art] The JAK (Janus kinase) family belongs to a non-receptor type tyrosine kinase. Specific cytokines bind to cell surface 5:, initiate JAK, and then elicit a series of intracellular signaling cascades. The JAK kinase family and signal transducers and Activat〇rs 〇f Transcription (STATs) are involved in the signaling processes of many cytokines. The JAK/STAT signaling pathway is associated with many inflammatory diseases such as respiratory inflammation, multiple sclerosis, rheumatoid arthritis, asthma, enteritis, occupational, autoimmune diseases, and other inflammatory responses. JAK/STAT signaling pathways, such as the jAK3/STAT signaling pathway, are also associated with certain cancer diseases. Therefore, §_multiple JAK kinase inhibitors have been discovered or studied for the treatment or prevention of inflammatory, cancer-related diseases. The JAK kinase family plays an important role in the regulation of cytokine-dependent proliferation and cellular function in cells involved in the immune response. In mammals, the JAK kinase family contains four subtypes 'JAiU, JAK2, JAK3, and TYK2, respectively. JAK kinase has a molecular weight of 12〇~140kDa ' consisting of 7 conserved JAK homologous domains, one of which is a catalytic domain with catalytic function and the other is a pseudokinase domain with regulatory functions and/or as a binding site for STATs (Scott , Godshall et al. Clin.Diagn.Lab.Immunol, 9 (6): 1153-1159, 2002) The expression of JAK1, JAK2 and TYK2 is relatively extensive. It is believed that JAK3 is mainly expressed in natural killer cells (NK) and non- In dormant tau cells, it may be involved in the lymphoid activation process (Kawamura, M., DW McVicar, et al. " Molecular cloning of L-JAK, a Janus 3 s 201211044 family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. 55 Proc Natl Acad Sci USA 91(14): 6374-8, 1994) The 〇JAK/STAT signaling pathway plays an important role in the pathogenesis of many inflammatory diseases such as asthma, '13⁄4 sex-blocking lung disease, bronchitis, Other similar lower respiratory diseases ("jAK_ STAT signaling in asthma." J / «v, et al., 1279-83, 2002). The JAK/STAT signaling pathway is also associated with certain ocular inflammatory diseases such as iritis, uveitis, dermatitis, conjunctivitis, and chronic allergies. Thus inhibition of jAK kinase is therapeutic for such diseases. Similarly, inhibition of JAK kinase should also have a therapeutic effect in patients with skin inflammation (such as psoriasis, skin sensitization). For psoriasis vulgaris (the most common form of psoriasis), it is generally accepted that activated T lymphocytes are important for the treatment of disorders and their associated plaque repair (Gottlieb, A. B., et al, 4:19). -34, 2005). Psoriasis produces significant immune infiltration (including white blood cells and monocytes) and also produces multiple epidermal layers with stratum corneum hyperplasia. Although the initial activation mechanism of immune cells is still unclear for the onset of psoriasis, it has been reported that its treatment is dependent on a large number of inflammatory cytokines (jC/, in addition to various chemokines and growth factors. 113:1664_1675, 2〇〇4), including many cytokines including 々, -6, -7, -12, -15, -18, -23 and GM-CSF, IFNg, all through JAK Stimulate g# transduction signal 47: 113-74, 2000). Therefore, it is helpful to block the signal transduction pathway of JAK kinase in patients with bovine secret or other cutaneous plague diseases. Signal transduction of JAK at the enzyme level can also be used to treat cancer in humans. The cytokine of the interleukin 6 (IL-6) family, which is capable of initiating the k-transduction factor gpl3〇, is the major survival and growth factor for multiple myeloma cells, while the downstream signal transduction process of gpl3〇 includes JAIG and JAK2. TYK2 and downstream factors STAT3 and MAPK pathways, when JAK2 201211044 inhibitor AG490 and IL-6-dependent multiple myeloma cells were used, JAK2 kinase activity, ERK2 and STAT3 phosphorylation were simultaneously inhibited, and cell proliferation was also inhibited. And lead to apoptosis (De Vos, J., M. Jourdan, et al. oil? / 1〇9(4): 823-8, 2000). However, in some cases, AG490 can induce tumor cell dormancy and protect them from death. Studies have shown that inhibition of JAK2 kinase activity is beneficial for the treatment of myeloid proliferative disease (MPD) (Levin, et al., CW/, vol. 7: 387_397, 2005). MPD includes polycythemia (PV), thrombocytopenia (ET) 'myelomyelopathy combined with myelofibrosis (MMM), chronic myeloid leukemia (CML) 'chronic granulocyte monocytic leukemia (CMML), high hobby Acidic cell hyperplasia syndrome (HES), systemic mast cell disease (SMCD), etc. It is generally believed that MPD is caused by in vivo mutations in hematopoietic stem cells, but the genetic mechanism of the disease axis remains unclear. However, studies have found that most PV patients and a considerable number of anal and Pang Chong human hematopoietic cells exist in the _ weeks. The body of the young (four). It is also pointed out that the use of small = tonic inhibition of Guanna kinase can inhibit the proliferation of remnant cells, suggesting that depletion of enzymes to treat the potential dry spots of PV, ET, MMM. SUMMARY OF THE INVENTION The present invention provides a structural formula _ at least _ compounds:

Vr2 :d

(I) and / or at least - Hexue ± acceptable salts, wherein now 201211044 R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and heterocyclic groups, and R2 is selected from the group consisting of alkyl, aryl, cycloalkyl, hetero a cyclic group, a heteroaryl group, _c(〇)Ra, _C(0)NRcRd, -S(0)nRf, and _S(〇)nNRCRd, or R spear R and the N atom to which it is linked, Forming a 3 to 7 membered heterocyclic ring which may be optionally substituted, the heterocyclic ring additionally optionally containing one or two heteroatoms, and the heterocyclic ring may be further optionally taken to an optional a substituted heteroaryl group or an optionally substituted aromatic ring; and any of the above-mentioned filaments, aryl, cyclod, heterocyclic and heteroaryl groups of R1 and R2 t may be optionally one or more groups Substituted, these groups are selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, -C(0)R. , -C(0)〇Rb, -CN, -C(0)NRcRd, halogen, optionally substituted haloalkyl, optionally substituted heterocyclic, optionally substituted heteroaryl, _NRCRd, _NReC ( 0) 0Rb ^ -NReC(0)NRcRd > -NReS(0)nRf ^ -NReS(0)nNRcRd > N02,- ORb, -S(0)nRf, and _S(〇)nNRcRd; m and n are independently selected from 〇, i and 2; for each of the above, Rb, R<=, Rd, Re and Rf may each Independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted haloalkyl, any The substituted heteroaryl group and the optionally substituted heterocyclic ring, or ^ and Rd, together with the nitrogen atom to which it is bonded, form a heterocyclic ring which may be selected from one or more selected from the group consisting of halogen and lower alkyl. Optionally, the radical, and the lower alkoxy group are optionally substituted, and the heterocyclic ring may additionally optionally contain from 1 to 2 heteroatoms selected from N, 0 and s; and if m is 1, Ri and R2 It cannot be a methyl group at the same time, or when m is 1 and Ri is hydrogen or ethyl, R2 is not an ethyl group. The present invention also provides a composition comprising at least one of said compounds and/or its drug 201211044 a practicable salt, and at least a pharmaceutically acceptable carrier. The present invention also provides an inhibition selected from the group consisting of MKb, JAK2, and TYK2 kinase. A method of kinase kinase comprising contacting an effective amount of at least one of the compounds and/or the heart of the county with at least one of the kinases. In another preferred embodiment, the method is non-treating or bathy. The p-monthly also provides a treatment for inhibiting the green color of the inflammatory sulphate selected from the sputum 2, 3 and τγκ2 enzymes, comprising administering a desired amount of at least the compound and / or dropouts that are acceptable for learning. The present invention also provides a method of treating a cancer associated with a kinase selected from the group consisting of: dish, dish 2, JAK3 and τγΚ2, comprising administering to the individual an effective amount of at least one of said compounds and/or pharmacy thereof Acceptable salt. The test X-month also provides a drug (composition) for inhibiting the activity of the enzyme selected from the group consisting of JAK1, phantom and τπ2, and comprising an effective amount of at least one of the present invention a compound and/or at least one pharmaceutically acceptable salt thereof. The present invention also provides a medicament for the preparation of a compound which inhibits the activity of at least one kinase selected from the group consisting of JAiQ, JAK2, JAK3 and a kinase in the same manner as the compound of the present invention and/or its pharmaceutically acceptable salt. . The present invention also provides a compound of the present invention and/or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating an inflammatory disease or cancer. In another preferred embodiment, the cancer is a cancer associated with the activity of at least one kinase selected from the group consisting of JAKWAK2, JA〇 and τγκ2 kinases. The present invention also provides a compound of the present invention and/or a pharmaceutically acceptable salt thereof, which is used for the preparation of cancer, and which is used in combination with other anti-cancer agents. Treating a cancer associated with the activity of at least one of the 201211044 kinase selected from the group consisting of JAIU, progenitor 2, JAK3 and TYK2 kinase; or the medicament contains other anti-cancer agents. The present invention also provides a method of treating a cancer effective for inhibiting at least one kinase selected from the group consisting of JAK][, JAK2, jak3 and TYK2 kinases, comprising: administering a desired amount of at least one compound of the present invention and a compound a pharmaceutically acceptable salt thereof, and a certain amount of an anti-cancer preparation (or an anti-tumor preparation) administered to a subject in need thereof, wherein the anti-cancer preparation is different from the compound of the present invention and/or its drunk-acceptable salt. [Embodiment] The following words, phrases and symbols used in the "Children's Stomach" are generally as follows unless otherwise stated. The following description of the meanings of abbreviations and terms in the whole text: Not the two letters and symbols _ short line "_" indicates the site of the substituent connection. For example, '-CONH2 is attached to another group through a carbon atom. The base of the burning base contains a linear or branched hydrocarbon of one carbon atom. For example, the base includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. "Low-form base" means a linear or branched hydrocarbon containing M carbon atoms. The term "silk" is a straight or branched chain group attached through an oxygen atom, for example, methyl lactyl, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec Oxyl, tert-butyl lactyl, n-pentyloxy, 2-silyl, isopentyloxy, neopentyloxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy And similar groups. The alkoxy group usually has a carbon atom bonded through an oxygen bridge. Lower alkoxy group refers to a linear or branched alkoxy group in which the alkyl moiety includes from 1 to 4 carbon atoms. A "slim-base" refers to a linear or branched hydrocarbon having one or more c=c double bonds and a carbon number between > For example, alkenyl groups include, but are not limited to, ethylenyl, 2-propyl, 2-butenyl.

201211044

The term "alkynyl" refers to a straight or branched chain containing one or more (five) triple bonds, having a carbon number between HO, such as, for example, but not limited to, an alkenyl group, a 2-propyl group, a 2-butyne. base. The term "annual recording" refers to a cyclic burning hydrocarbon containing m carbon atoms and or a partial sum of money. For example, 'Wei Ke is limited to cyclopropyl, cyclobutyl, cyclofilament, cyclopentyl, cyclohexyl' cyclohexan, cyclofilament and cyclooctyl. The ring may be saturated or may contain one or more double bonds (i.e., partially unsaturated), but not completely co-consumed. "Aryl" includes: a 5-6 membered carbon aromatic ring, such as benzene; a bicyclic ring wherein at least one of the rings is a carbon aromatic ring, such as naphthalene, anthracene and di 2,3,4_tetrahydroquinoline; And a tricyclic ring in which at least one ring is a carbon aromatic ring, such as hydrazine. ' For example, an aryl group includes a 5-6-membered carbon aromatic ring and a 5-7-membered heterocyclic ring. The heterocyclic ring contains 3 or more faces from nitrogen, oxygen and sulfur, provided that the joint is in the carbon ring. on. By replacing the native He Lin, there is free money to form a divalent free radical, which is named as a substituted phenylene group. Ling, such as the UW fine (4) group, by reducing the freely known hydrogen atoms of the divalent free radicals, the name is in the corresponding unit price = base surface plus "subunits" 'for example, there are two linked naphthyl groups Known as Ya Caiji. However, the 疋' square base does not contain, and does not, in any way define the _ loop wire overlap with the following. Thus: as defined herein, if one or more carbon aromatic rings are ring bonded to a heteroaromatic ring, the ring system thereby produced is an aromatic heterocyclic group rather than an aryl group. The term "南素" includes fluorine, chlorine, and fill. The term "arylhetero" refers to: 5 8 diseased hydrocarbons containing _ or more heteroatoms selected from n, 〇 and $, such as μ

9 S 201211044 is a 1-3 _ child' ring whose face is a carbon original hetero atom, in some embodiments neutrons; 8-12 yuan bicyclic aromatic smoke, containing - a hetero atom, in some embodiments In the sample, a hetero atom of N, 0, and S, such as a scorpion; at least one of the rings is an aromatic ring:: = a hetero atom, and the other atoms on the ring are carbon atoms 11-14 70 tricyclic aromatic Smoke, containing one or more selected (four) children; at least one of which is an aromatic ring. - He is a heterogeneous tree of the atomic sinus and a 5.7-dollar ring filament, of which only - one ring contains one or more heteroatoms, for example, 'aromatyl group includes a 5-7 in such a bicyclic ring and The heteroaryl group, the chain bit is on the heteroaromatic ring. When the total number of sulfur and oxygen atoms on the aromatic heterocycle exceeds 丨, these heteroatoms will not be one-by-one: In some embodiments, the total number of sulfur and oxygen atoms in the silk base does not exceed two. In the case of -Beizhi, the 'total number of sulfur atoms and ruthenium atoms in the arylhetero group is not more than the η aryl group', including but not limited to, (the junction point is preferentially labeled as 1), 2 - 吼 base, 3 - pair base, 4 4 record, 2, 3_ turn base, 3, 4 _ square base, 2, 4 _ base, ♦ ♦ base, 1- ah base, 2, 3 · ah base, 2, 4 - microphone Money, iso-Nukey, shot base, 嗟嗤 "Semitate, time base, material base, benzoheptylene, ° Fusi, benzo-based, benzo-salt, dihydro, lotus, weigh a valence, a triazide group, a sulfonyl group, a fluorene group, and a 5,6,7,8 tetraazaisoquinolyl group. A monovalent radical terminated by an anthracene radical by reducing a free valence hydrogen atom Derived divalent aromatic heterocyclic radicals, which are named by adding a "subunit" to the name of the corresponding monovalent radical. For example, a pyridyl group having two attachment sites is referred to as a pyridylene group. The arylhetero group does not include or overlap with the aryl group described above. 201211044 The mechanical aryl group also includes an aromatic heterocyclic group substituted with one or more oxygen (_〇), such as an N-oxo bite group. The "heterocyclic group" refers to a monocyclic aliphatic ring of usually 3-7 yuan, which includes at least 2 carbon atoms and 3 complexes, and the county is selected from oxygen and sulfur (four), and includes the foregoing. Said to a combination of f-heteroatoms. "Heterocyclyl" also includes a heterocyclic ring containing one or more ^, oxygen or sulfur heteroatoms and a 5-6 (tetra) carbon aromatic ring, provided that the attachment site is on the impurity. The heterocycle can be saturated or it can have one or more double bonds (i.e., partially unsaturated). The mash base can be replaced by oxo. The chain point with other atoms can be carbon or heteroatoms. The "heterocyclic group" is different from the "heteroaryl group" described above. The corresponding heterocyclic group includes, for example, (the linking position is preferentially labeled as ibu ratio. each linky, 2_° is trans-base, 2, yoko, 2, fluorenyl, 1 fluorenyl, 2 fluorenyl, 31 bite base 4 - Qianji and 2,5_„ 瓜azinyl. This is also designed in this way, including morpholinyl and 3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ a ring of more than one oxo group, for example, anthracene oxygen ocyanate, oxime oxoline, oxothio morphinyl, and 1,1-dioxo-1-thiomorpholinyl The so-called "optional (_n)", "optional (〇pti〇nal)" or "optional (_naii force) means that the continuation of the event may or may not occur, and the description Including things or situations that occur and do not occur. For example, "optionally substituted alkyl" includes "alkyl" and "substituted alkyl" as defined below. Any one group contains one or more substituents. 'Private dirty-like technology can be understood by humans, but does not include unrealistic high steric hindrance, synthetically infeasible and/or inherently unstable substituents. The 5 used in the "replaced" means specific One or more of the chlorinogens in the atom or group is replaced by a group selected from the specified range, and the valence state of the particular atom is normal. When the oxo generation (such as 〇) is taken, it is thought to be on the designated atom. Two chlorines are substituted. As long as the combination can obtain a stable compound or a useful synthetic intermediate from 201211044, combinations and/or variations of substituents are permissible. Stable compounds or stable structures mean that it is stable to the reaction. Separation from the mixture' and at least useful in subsequent formulation processes. Unless otherwise specified, 'substituents are named into the parent core structure. For example, simply, when a cycloalkylalkyl group is used as a possible substituent, The attachment site of this substituent on the parent nucleus is on the alkyl group. In some embodiments, "substituted by one or more groups" means that two hydrogen atoms in a particular atom or group are specified, respectively. Replacement of the same or different groups selected from the range of groups. In some embodiments, "substituted by one or more groups" means that three hydrogen atoms are applied to a particular atom or group, respectively. Designation Substituting the same or different groups selected from the group. In some embodiments, "substituted by one or more groups" means that four hydrogen atoms in a particular atom or group are specified, respectively. Substituting the same or different groups selected from the range of groups. The compounds, including but not limited to, their optical isomers, such as enantiomers and diastereomeric 'enantiomers. Mixtures, including racemates, mixtures of diastereomers, and other mixtures which can be synthesized by one skilled in the art by routine experimentation. In these cases, single enantiomers or diastereomers, for example, optical The structure of the activity can be obtained by asymmetric synthesis or by resolution of a racemic mixture or a mixture of diastereomers. For the resolution of a racemic mixture or a mixture of diastereomers, it can be separated by conventional methods, for example using splits. The reagent is crystallized; it can also be separated by chromatography, such as a chiral high performance liquid chromatography (HPLC) column. In addition, such compounds comprise Z- and E-type (or meals and-type) compounds containing c=c double bonds. The compounds described herein are in various 1 :isomers. The term "compound" includes all tautomeric forms of the compound. The compounds herein also include their non-crystalline forms, including polycrystalline and clathrates, and the term "salts" also includes all isomers of the salts of the compounds which can be synthesized by those skilled in the art by routine experimentation. Body, other mixtures, Ζ- and Ε-type, tautomers and crystal forms 12 201211044 Formula. The "pharmaceutically acceptable salts" include, but are not limited to, salts formed with inorganic acids such as hydrochlorides, discates, monophosphates, hydrobromides, sulfates, sub-base salts, butanoic acid. Salts, and the like, also include salts with organic acids such as malate, maleate, fumarate, tartrate 'stearate, citrate' acetate' lactate, indeed Acid salt, p-butylic acid salt, 2-hydroxyethyl sulfonate, benzoate, salicylate, stearate and alkanoate such as acetate, HOOC-(CH2)n-CO 〇H wherein η is a salt of 0-4, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. Further, if the compound is a salt formed with an acid, the free base thereof can be obtained by alkalizing the salt solution. Conversely, if the compound is free, the salt, especially the pharmaceutically acceptable salt, can be prepared by conventional procedures for the acid formation from the base, i.e., by dissolving the free base in a suitable organic solvent and treating with an acid. One of ordinary skill in the art can identify a variety of synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable salts. "Solvate" such as "hydrate" is formed by the interaction of a solvent and a compound. The term "compound" shall include solvates of the compound (including hydrates of the compound). Similarly, "salt" also includes solvates of salts (such as salt hydrates). Suitable solvates are pharmaceutically acceptable, such as hydrates, which include monohydrates and hemihydrates. A "chelate" is formed by the coordination of a compound with a metal ion at two (or more) points. The term "compound" shall include a chelate of the compound. Similarly, "salt" also includes salts of chelates. A "non-covalent complex" is formed by the interaction of one compound and another molecule through a non-covalent bond. For example, the composite can be opened by van der Waals forces, hydrogen bonds, and electrostatic interactions (also known as canister bonds). These non-covalent complexes are also included in the term "compound". The term "hydrogen bond" refers to an electronegative atom (also known as a hydrogen bond acceptor) and one is attached to another phase.

13 S 201211044 A form of action on a hydrogen atom (also known as a hydrogen bond donor) on an electronegative atom. Suitable hydrogen bond donors and forks are found in various well-known books on medicinal chemistry (G c pimentel and AL Mccieiian, The Hydrogen Bond, Freeman, San Francisco, 1960; R. Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic Crystals", Accounts of Chemical

Research, 17, pp. 320-326 (1984)). The term "group", "base" or "fragment" as used herein is synonymous and refers to a functional group or a fragment or other molecular fragment attached to a certain bond. The term "active ingredient" means a biologically active chemical. In some aspects, the active ingredient is a chemical that has a medicinal effect. Treatment, treatment, "treatment" or "mitigation" refers to the administration of at least one compound and/or at least one of the symptoms of a disease with eight diseases, or those who are susceptible to a disease. A pharmaceutically acceptable salt used to cure, treat, alleviate, relieve, alter, heal, improve, ameliorate or affect a disease, a symptom of a species, or a constitution that is predisposed to a disease. In the heart of a sinus sinus 搂Λ 贝 贝 贝 贝 一种 一种 一种 一种 一种 一种 心 心 心 心 心 心 心 心In some embodiments, the species may be an inflammatory disease. The term "effective amount" means that the at least one compound and/or at least one pharmaceutically acceptable salt is effective. "Taiwan treatment" & an individual's amount of disease or discomfort. If it is cancer, it can cause any number of visible or detectable changes in the individuals described in the definitions of "^~therapy" and "mitigation"; Reduce the size of the tumor · Inhibition ^ (10) Μ 4 4 less cancer or tumor cells 睹 ^ 16 inhibit or prevent the invasion of tumor cells to the surrounding organs, for example, the tumor Man Yanren soft tissue money; inhibition sister Feng. The transfer, inhibit or prevent the growth of the tumor, - reduce the degree of smuggling - one or more with cancer. ^ ^ rate; improve the quality of life; or the effect of the above two effects right, reduce the incidence and death MKWAK2 The effective amount of MK3 and tearing can be reduced by inhibiting the activity of the scorpion kinase 14 201211044. The effect of in vivo experiments on cancer treatment can be assessed by assessing, for example, survival, time to disease prog (TTP), response rate (Resp〇nse Rates, duration), and/or quality of life. measuring. The skilled person has recognized that an effective amount can vary with the route of administration, the dosage of the excipient, and the combination with other drugs. The term "effective amount" may also mean that the at least one compound and/or at least one pharmaceutically acceptable salt thereof is effective to inhibit the amount of at least one kinase in jAK1, JAK2, JAK3 and TYK2. The term "inhibition" refers to a decrease in the basal activity of a biological activity or biological process. "inhibiting the activity of at least one kinase in JABa, JAK2, JAK3, and TYK2" refers to at least one kinase of JAKh JAK2, JAK3, and TYK2 relative to the absence of the at least one compound and/or at least one pharmaceutically acceptable salt. The activity, directly or indirectly by the at least one compound and/or at least one pharmaceutically acceptable salt, results in a decrease in the activity of at least one kinase of JAK1, JAK2, JAK3 and TYK2. The decrease in activity may be due to direct interaction of the at least one compound and/or at least one pharmaceutically acceptable salt with at least one kinase of JAK1, JAK2, JAK3 and TYK2, or due to the at least one compound and The interaction of at least one pharmaceutically acceptable salt with one or more other factors ultimately affects the activity of at least one of the kinases JAK1, JAK2, JAK3 and TYK2. For example, the at least one compound and/or at least one pharmaceutically acceptable salt can reduce its activity by directly binding to at least one kinase of JAKb JAK2, JAK3 and TYK2, by directly or indirectly affecting other factors. Decreasing at least one kinase activity in JAK1, JAK2, JAK3 and TYK2, or reducing at least one of JAK1, JAK2, JAK3 and TYK2 in cells or organs by direct or indirect reduction of at least one of JAK1, JAK2, JAK3 and TYK2 A kinase activity. The present invention provides at least one compound of structural formula (1):

15 S 201211044 N-R2

R1

(V and/or at least one pharmaceutically acceptable salt thereof, wherein R is far from hydrogen, alkyl, cycloalkyl and heterocyclic, and R is selected from alkyl, aryl, cycloalkyl, heterocyclyl, Heteroaryl, -C(0)Ra, _C(0)NR R > -S(〇)nRf, #〇-S(〇)nNRcRd , or R and R 'and the N atom to which it is attached - Forming a 3 to 7 membered heterocyclic ring which may be optionally substituted 'this heterocyclic ring additionally optionally contains i or 2 heteroatoms, and the heterocyclic ring may be optionally further An optionally substituted heteroaryl group or an optionally substituted aromatic ring; and any one of the above R1 and R2, an alkyl group, an aryl group, a cyclofilament, a heterocyclic group and a heteroaryl group may be optionally - at most Substituted by a group selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted silk, an optionally substituted alkenyl group, an optionally substituted silk, an optionally substituted cycloalkyl group, -C (〇) Ra, -C(0)0Rb, _CN, _C(0)NRCRd, _, optionally substituted functional alkyl, optionally substituted heterocyclic, optionally substituted heteroaryl, _NR <: Rd , _NReqp$a, NReC(0)0Rb, -NReC(0)NRcRd, -NReS(0)nRf, -NReS(0)nNRcRd, .N〇2, -〇Rb, -S(0)nRf, and -S(0)nNRcRd; m and n are independently selected from 0, 1, and 2; for each of the above, Ra, Rb, Re, Rd, 1^, and Rf are independently selected from Hydrogen, optionally substituted succinyl, optionally substituted dilute, optionally substituted indenyl, optionally substituted cyclodyl, optionally substituted aryl, optionally substituted haloalkyl, optionally substituted An aryl group and an optionally substituted heterocyclic ring, 201211044, or Re and Rd', and a chain-bonding atom thereof, form a heterocyclic ring. The heterocyclic ring may be selected from one or more selected from the group consisting of halogen, lower filament, and rhodium. And a lower alkoxy group optionally substituted 'this heterocyclic ring may additionally optionally contain from 1 to 2 heteroatoms selected from N, 0 and s; and if m is 1, R1 and R2 may not be simultaneously Methyl, or when m is 1, and R| is hydrogen or ethyl, R2 is not ethyl hydrazine. In some embodiments, m is 1. In some examples, R is selected from alkyl and ring. Alkyl groups, each alkyl and cycloalkyl group may be optionally substituted with a group selected from the group consisting of an optionally substituted lower-grade, optionally substituted aryl, optionally substituted alkenyl group. , optionally substituted alkynyl group Substituted ring, _C(C〇Il, _QP)〇Rb, -CN, -C(0)NReRd, halogen, optionally substituted haloalkyl, optionally substituted heterocyclic, optionally substituted Aryl, _NRCRd, _NRec(〇)Ra, _NReC(0)0Rb > -NReC(0)NRcRd ^ -NReS(0)nRf ^ -ReS(0)nNRcRd . -N〇2 ^ -ORb, -S (0) nRf, and -S(0)nNRcRd. In some embodiments, R 2 is aryl or heteroaryl, and each aryl or heteroaryl group may be optionally substituted with one or more groups selected from optionally substituted lower alkyl groups. , optionally substituted aryl, optionally substituted dilute, optionally substituted alkynyl, optionally substituted cycloalkyl, _C(0)Ra, -C(0)0Rb, -CN, -C( 0) NReRd, _, optionally substituted functional alkyl, optionally substituted heterocyclic, optionally substituted heteroaryl, -NReRd, -NReCXC^R3, _NReC(0)ORb, -NReC( 0) NRcRd, -NReS(0)nRf, -NReS(0)nNRcRd, -N02, -ORb, -S(0)nRf, and _S(0)nNRcRd. In some embodiments, ' R 2 is alkyl or cycloalkyl, and each alkyl or cycloalkyl group may be optionally substituted with one or more groups selected from the group consisting of an optionally substituted lower alkyl group. , optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl '-C(0)Ra, -C(0)0Rb, -CN, -C( 0) NHeRd, halogen, optionally substituted haloalkyl, any 17 201211044 optionally substituted heterocyclic group, optionally substituted hetero NReC(0)0Rb, -NRec(〇)NRcRd, -NReS(0)nRf, -NReS (0) nNRcRd, -NO!, -ORb, -S(〇)nRf, and _s(〇)nNRcRd 〇 In some implementations, we think that ^(7)!^, _c(〇)NRCRd, 'each of them Ra, Re* Rd are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted a haloalkyl group, an optionally substituted heteroaryl group and an optionally substituted heterocyclic group; or R and R, together with the nitrogen atom to which the chain is bonded, form a heterocyclic ring which is selected one by one or the other Self-priming, low-grade alkyl, transbasic, and low-grade oxygen burning Group optionally substituted 'heterocyclic visiting technology can progress - further optionally comprising i to 2 heteroatoms selected from N, S heteroatom and the square. ..., in some embodiments, R2 is an aryl or heteroaryl group selected from the group consisting of

Wherein each aryl or heteroaryl group may be optionally substituted by one or more groups selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted alkenyl group , optionally substituted block, optionally substituted cycloalkyl, -C(0)Ra, -C(0)0Rb, -CN, _e(Q)NR<:Rd, _, optionally substituted a haloalkyl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group of 201211044, -NRcRd, _NReCX〇)Ra, MReqopRb, .NReaCONR^d, -NK, -NReS(0)nNRcRd '-N02, - 〇Rb, -S(0)nRf, and -S(0)nNRcRd 〇 In some embodiments, R2 is an aryl or heteroaryl group selected from the group consisting of

NReS(0)nRf >

Wherein each aryl or heteroaryl group may be optionally substituted by one or more groups selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted aryl group 'optionally substituted alkenyl group, Optionally substituted, fast-substituted, optionally substituted cycloalkyl, -C(0)Ra, -C(0)0Rb'-CN, -C(Q)NReRd, _, optionally substituted alkyl , optionally substituted heterocyclic group, optionally substituted heteroaryl, NRCpd, _NReC ((7)Ra, _NReC(C)pRb, _NReS(0)nRf > -NReS(〇)nNRcRd, -N02, -ORb , _s(0)nRf, and _S(0)nNRcRd 〇 In some implementations, R2 is

Wherein each aryl or heteroaryl group may be optionally substituted by one or more groups selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted alkenyl group, Optionally substituted alkynyl, optionally substituted cycloalkyl, -C(0)Ra, -C(〇)〇Rb, _CN, _C(0)NReRd, _ 素, optionally substituted _ dai , optionally substituted heterocyclic group, optionally substituted heteroaryl, _NRcRd, _NReC(0)Ra, -NReC(0)0Rb, -NReC(;C〇NRcRd, _NReS(0)nRf, -NReS( 0) nNRcRd, ·Ν02, -ORb ' -S(0)nRf, and _s(〇)nNRCRd. In some implementations, R2 is 20 201211044

Wherein each aryl or heteroaryl group may be optionally substituted by one or more groups' These groups are selected from optionally substituted lower alkyl 'optionally substituted aryl, optionally substituted alkenyl, Optionally substituted alkynyl, optionally substituted cycloalkyl, _C(〇)Ra, -C(0)0Rb, -CN, -C(0)NReRd, halogen, optionally substituted haloalkyl, optionally substituted Heterocyclyl, optionally substituted heteroaryl, -NReRd, -NReC(0)Ra, -NReC(0)0Rb, -NReqCONI^Rd, -NReS(0)nRf, -NReS(0)nNRcRd,- N02, -ORb, -S(0)nRf, and -S(0)nNRcRd 〇 In some embodiments, R1 is selected from the group consisting of a pyridyl group, a propyl group, a propyl group and a cyclopropyl group of Ci_3, each The alkyl, allyl, propyl and cyclopropyl groups of Cw may be optionally substituted by one or more groups selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted aryl group, Optionally substituted alkenyl, optionally substituted fast radical, optionally substituted cycloalkyl, _C(〇)Ra, _CN, -C(0)NReRd, halogen, optionally substituted haloalkyl, optionally Substituted heterocyclic group, optionally substituted heteroaryl, -NRcRd, _NReC(0)NRcRd, -NReS(0)nRf , s(〇)nNRCRd, _Ν〇2, 〇Rb, S(0)nRf, and _s(〇)nNRcRd. In some embodiments, R1 is a fluorenyl group. In some implementations, the carbon atom attached to the Na(10) group is a stereochemistry. The invention also provides at least one compound selected from the group consisting of compounds 1-260 and/or at least one pharmaceutically acceptable salt thereof. The punctured compounds of the present invention and/or the commercially acceptable (iv) commercially viable starting materials are synthesized by known methods in conjunction with the disclosure of the present invention. The synthesis of most of the compounds is shown in the following two routes.

S 21 201211044 Reaction route i

(6) (I) In the present reaction formula and each of the following reaction formulas, "base" indicates the test, and "acid" indicates acid. As shown in Reaction Scheme I, the compound (1) and the compound (2) (m as described above) may be reacted in the presence of a test (eg, K2C03, Na2C〇3, NaH, Et3N, DIPEA, but not limited thereto). Passed to compound (3). Removal of the protecting group under the action of an acid (hydrochloric acid or trifluoroacetic acid, but not limited thereto) gives the compound (4) and continues in the base (e.g., K2C03, Na2C03, Cs2C03, NaH, ί-

The compound (I) is obtained by reacting with Wx and R2X (X is Cl, Br, I, R1 and R2 as described above) in the presence of BuONa, rBuOK, Et3N, DIPEA, but not limited thereto. When r1 or r2 is an aryl or heteroaryl group, a palladium reagent (such as PdC12, Pd(OAc)2, Pd2(dba)3, pd(PPh3)4' but not limited thereto) and a ligand (such as ph3p) are used. iBu3p, binAP, dppf, 1,3-bis(2,6-dipropylphenyl)-hydrazine, ironimidazolium chloride, but not limited thereto can be used as a catalyst to increase the reaction yield.

Reaction Route II 22 201211044

Boc /〇 R1a^f (9)

Boc plus station

Boc (8) NH - R, r2x (6) base (7) R2' N-R_ /~( acid:W - N Boc (10) R2, N-R. N base H (11) (i) As shown in Reaction Scheme 11, the compound (7) (m is defined) and the compound (5) are reacted under the conditions of the reaction scheme I to obtain the compound (8), and the compound (8) can also be passed through the compound (7) and the compound (9). The reaction is prepared (Rla and Rlb may be hydrogen, hydrazino, ring-based, aryl, heteroaryl or R, R, together with a carbon atom to form a alkyl or heterocyclic ring. Compound (8) The compound (6) is reacted under the conditions shown in the reaction scheme to obtain a compound (1〇), and the protecting group is removed by an action of an acid (hydrochloric acid or difluoroacetic acid, but not limited thereto) to obtain a compound, followed by (In the presence of K2C03, Na2C03, Cs2C03, NaH, ί-BuONa, i_BuOK, Et3N, DIPEA, but not limited thereto), react with compound (1) to obtain compound (I). If necessary, use reagent (eg pda2, pd(〇Ac)2, pd2(dba)3, pd(pph3)4, but not limited to) and ligands (eg Ph3p, Bu3p, BINAp, Xantph〇s, dppf, 13_double ( 2,6-dipropylphenyl gasification of oxazolium, but not limited thereto) can increase the reaction yield as a catalyst.

Reaction route III

S 23 201211044 Compound (3) is reacted with lithium aluminum hydride as shown in Reaction Scheme III to give compound (12), which is then reacted with compound (5) under the similar conditions shown in Scheme I to give compound (13). The obtained compound can be further modified by the peripheral position to obtain other target compounds of the present invention. The synthetic chemical modifications described are well known in the art, such as R Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999). L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.

Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions are disclosed. The at least one compound and/or at least one pharmaceutically acceptable salt as used may be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable conditions. The invention further provides a composition comprising the at least one compound and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Compositions comprising at least one of the compounds and/or at least one pharmaceutically acceptable salt can be administered orally, parenterally, inhaled, or implanted. The term "parenteral" as used herein refers to subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intraspinal, intracranial, and intracranial injections or Infusion Techniques 0 Oral compositions can be any acceptable oral dosage, including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. Commonly used tablet carriers include sugar and corn. Lubricants such as stearic acid are often added to tablets. When administered orally in the form of a capsule, the effective diluent may include lactose and dried corn starch. When oral water suspension or milk followed by fine materials, you can generalize the thief money to reduce or float or dissolve in 24 201211044 an oil phase ^ If necessary, you can also add - sweet, flavor, or pigment. ^He contact compound (such as reading or secret milk? - seeing the use of suitable ___ (such as: Tween _ her _ complete p-shot composition can also be prepared into (d) injectable solution or suspension, soluble - non-toxic It can be used for parenteral release, for example, alcohol solution. In the connectables and solvents, (4) can be mannitol, water, forest, and saline = external, sterile low hysteresis Point oils, such as synthetic mono- or di-acid glycerin, usually in a solvent or suspending medium. Fatty acids, such as oleic acid and its glycerin riding organisms, and hearing-acceptable oils such as olive oil or brain oil, In particular, in the case of polyethoxylation, it is possible to prepare a main-spray solution. These oil solutions or suspensions may also contain a long-chain alcohol diluent, dispersant, or slow methylcellulose, or the like. Dispersing agent - The inhalant composition can be prepared according to the known secret formula technique, and can be prepared in physiological saline, 'county plus benzene f-alcohol or other suitable agent, increasing the absorption enhancer of biological concentration, Fluorocarbon, and/or other solubilizers or dispersants known in the art. The composition of the skin may be formulated as a fat, a cream, an emulsion, an ointment, and the like. Suitable carriers for the composition may include: plant or mineral oil, white petrolatum ("white soft stone"), branching Know fat or oily scorpion, animal fat, and high molecular weight alcohols (greater than 12 carbons). A preferred carrier may be one in which the active ingredient can be dissolved. In addition, in addition to adding color or aroma components, Emulsifiers, solubilizers, diluents, and antioxidants may be added as needed. Skin penetration enhancers may also be added to these typical formulations. Examples of such accelerators can be found in U.S. Patents 3,989,816 and 4,444,762. a mixture of mineral oil, self-emulsified beeswax, and water, wherein the mixed active ingredients are dissolved in a small amount of oil, such as almond oil, and then doped therein. An example of such an emulsion is about 40 parts by weight of water, about 2 parts by weight of beeswax, about

25 S 201211044 4 parts by weight of mineral oil, and about 1 part by weight of almond oil. The ointment can be prepared by mixing an active ingredient in a vegetable oil (e.g., almond oil), and a warm soft paraffin, and allowing the mixture to cool. An example of a soft type H is a white soft paraffin comprising about 3 G% by weight of (iv) almond oil and about 70% by weight. "Pharmaceutically acceptable carrier" means that it is compatible with the active ingredient of the composition, and even stabilizes the active ingredient in a good manner in a vehicle, and is not hazardous to the individual to be treated, for example, a cyclodextrin A solubilizing agent, which is capable of forming a specific, more complex, lysate with the at least one compound and/or at least one pharmaceutically acceptable phoenix, can be used as a pharmaceutical carrier to deliver the active compound. Other rhyme _ sub-packages of dioxygenation 11, stearic acid town, cellulose, sodium dodecyl sulfate, and pigments such as D & c yellow i (M & M (D & c YeU〇w # 10). An in vitro assay for early evaluation of the at least one compound and/or at least one pharmaceutically acceptable salt inhibiting the live growth of at least one of JAKWAK2, JAK3 and TYK2, its effect in treating cancer or inflammatory diseases Further, it can be tested by in vivo experiments, for example, 'the compound and/or a scientifically acceptable substance are administered to an animal having a cancer or an inflammatory disease (such as a mouse model)' and then the therapeutic effect is examined. According to the above results, It is also possible to determine the dosage and mode of administration appropriate for the animal (e.g., 'human). This month also provides a kind of inhibition of at least one of JAK1, jAK2, JAK3 and ΤΥΚ2: 3⁄4 method's method includes An effective amount of at least one of said compounds and/or a pharmaceutically acceptable salt thereof is contacted with at least one kinase. The at least one compound and/or at least one pharmaceutically acceptable salt can be used to achieve Have a face or rib effect, for example In the individual towel with cancer. The technique used here refers to the "cell cancer", which is characterized by the uncontrollable or unadjustable cell proliferation of the cell, which is reduced by 4, and the invasiveness of the invaders. Ability, and/or ability to establish a new 26 201211044 growth in an abnormal site. The term "cancer (or tumor)" includes but is not limited to solid tumors and hematological tumors. The term "cancer" encompasses skin, tissues, organs, bone paths, Diseases of cartilage, blood and blood vessels. The term "cancer" further includes primary cancers and metastatic cancers. Non-limiting examples of solid cancers include pancreatic cancer, bladder cancer, colorectal cancer, breast cancer (including metastatic breast cancer), Prostate cancer (including androgen-dependent and non-androgen-dependent prostate cancer), renal cancer (including metastatic renal cell carcinoma), hepatocellular carcinoma, lung cancer (including non-small cell lung cancer (NSCLC) ), bronchoalveolar carcinoma (br〇nchi〇i〇alve〇lar carcinoma (BAC)) and lung adenocarcinoma), Indian cancer (including progressive epidermal cancer or progressive primary peritoneal cancer) Cancer, gastric cancer, esophageal cancer, head and neck cancer (including head and neck squamous cell carcinoma), skin cancer (including malignant melanoma), neuroendocrine system cancer (including metastatic neuroendocrine tumors), brain tumors (including, for example, gliomas, Anaplastic oligodendroglioma, adult glioblastoma multiforme, bone cancer, soft tissue sarcoma, and thyroid cancer. Non-limiting examples of hematological cancer include acute myelitis leukemia (acute myel〇id leukemia) AML)), chronic myelogenous leukemia (CML) (including chronic myeloid leukemia in accelerated phase and chronic myeloid leukemia (CML-BP) in blast phase), acute lymphocytic leukemia (acute) Lymphoblastic leukemia (ALL)), chronic lymphocytic leukemia (CLL), Hodgkin's disease (HD), non-Hodgkin's lymphoma (NHL) (including follicular lymphoma and mantle cell lymphoma), B-cell lymphoma, T-cell lymphoma, multiple myeloma (multiple myeloma (MM)), Waldenstrom's macroglobulinemia, myelodysplastic syndromes (MDS) (including refractory anemia (RA)), RAR Refractory anemia with ringed siderblasts (RARS), refractory s 27 201211044 anemia with excess blasts (RAEB), and excessive bud cell refractory anemia with acute transformation (RAEB in transformation (RAEB- transformation) T)), as well as myeloproliferative syndrome. In some embodiments, examples of cancers that can be treated include, but are not limited to, lung cancer, head and neck cancer, colorectal cancer, salivary gland cancer, colon cancer, breast cancer, ie, nest cancer, prostate cancer, 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 can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in an individual having an inflammatory disease. The term "inflammatory disease" refers to an inflammatory response caused by a case state, especially due to neutrophil chemotaxis. Examples of inflammatory diseases include inflammatory skin diseases (including psoriasis and atopic dermatitis), systemic sderoderma and sclerosis, and inflammatory bowel Disease (inflammat〇ry b〇wd yang detachment, IBD including Crohn's disease and ulcerative colitis), ischemia-reperfusion injury including surgery-induced reperfusion injury, Myocardial ischemia, such as myocardial infarction, cardiac arrest, postoperative reperfusion and constriction, postoperative percutaneous transluminal coronary angioplasty, abnormal aortic nerve-induced angioplasty, and abdominal aortic aneurysm 'Stroke secondary to brain edema, cranial trauma, hypovolemic shock, asphyxia, adult respiratory distress syndrome, acute lung injury (acute_iung injury), Behcet , s disease, dermatomyositis, polymyositis (p〇iymy〇sitis); multiple sclerosis 'MS', dermatitis Is), meningitis, encephalitis, uveitis, osteoarthritis, lupus nephritis 'autoimmune diseases such as rheumatoid arthritis (―咖伽^ arthritis, RA), Sjorgen's syndrome, vasculitis (3) 丨丨 him); leukocyte exudative disease involving disease; sepsis or trauma secondary to the central nervous system ((: 1 ^) inflammatory disease, multiple organs Injury synthesis 28 201211044 sign; alcoholic hepatitis; bacterial pneumonia. Antigen-antibody 纟帛 _ _ disease neon tube ("gbmemlGnephritis", sepsis (sepsis), sarcosis (sarcoidosis); tissue or organ transplantation Caused by immunopathological reactions; pulmonary inflammation, including pleurisy (pleurisy), alveitis (alve〇mis), vasculitis, pneumonia, chronic bronchitis (chr〇nic br〇nchkis), bronchi Bronchiectasis, diffuse panbr〇nchi〇litis, hypersensitivity pneumonitis, idi〇pathic pulmonary fibrosis 'IPF', and Swelling fibrosis (cystic fibr〇sis) and the like. Preferred indications include, but are not limited to, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis (rheumat〇id sp〇ndymis), gouty arthritis And other joint inflammation, multiple sclerosis 'MS', asthma (asthma), systemic lupus erythematosus (systhemic iupus erythrematosus), adult respiratory disorder syndrome (adu丨t respirat〇fy bleeding nor syndrome) , Behcet's disease, psoriasis, chronic pulmonary inflammatory disease, host-induced response, Crohn's disease, uicerative c〇iitis, inflammatory bowel disease 'IBD', Alzheimer's disease, pyresis, and any disease associated with inflammation or related symptoms. The at least one compound and / or at least one pharmaceutically acceptable salt can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in an individual having an autoimmune disease. The term "autoimmune disease" refers to a disease caused by the body's immune response to its own antigen, which causes damage to its own tissues. Autoimmune diseases include, but are not limited to, lupus, myasthenia gravis, mu丨tiple sclerosis (MS), rheumatoid arthritis 'RA, psoriasis (pSOriasis), inflammatosis (inflammatosis), asthma (asthma) and idiopathic thrombocytopenic purpura (idi〇pathie 29 201211044 thrombocytopenic purpura) and myeloproliferative diseases such as myelofibrosis Myelofibrosis disease (PV/ET), such as polycythemia vera/primary to hyperplasia, in some embodiments, the at least one compound and/or at least one pharmaceutically acceptable salt, Can be combined with other training programs (four). In some cases, other therapeutic agents are preparations that are usually taken by a patient with a disease or condition being treated. For example, depending on the disease or condition being treated, the other therapeutic agent can be an anti-immune preparation or an anti-tumor preparation. The at least one compound and / or at least one pharmaceutically acceptable salt may be administered in a single dose with other therapeutic agents or in divided doses. When administered in separate dosage forms, other therapeutic agents can be administered before, concurrently with, or after administration of the at least one compound and/or at least one pharmaceutically acceptable salt. In some embodiments, the at least one compound and/or at least one pharmaceutically acceptable salt thereof can be administered in combination with an anti-immunological agent. Non-limiting examples of anti-immune preparations include adrenal steroid hormone drugs (such as fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide). (triamcinolone acetonide) or budesonide, disease modifying agents (eg antimalarials, meth〇trexate, sulfasalazine, mesalamine, imidazolium) Za (azathioprine), 6-mercaptopurine, metronidazole, intravenous or oral gold, or D-penicillamine (N-penicillamine) non-Cui anti-inflammatory drugs (eg, pair B) Acetominophen, aspirin, sodium salicylate, sodium cromoglycate, magnesium salicylate, choline magnesium salicylate, Salicylsalicylic acid, ibuprofen, naproxen, diclofenac, difluorophenylsalicylic acid 201211044 (out 111111丨331), acetamidine Acetic acid @〇(1〇13(:), fenoprofen about v.11〇卩1*(^11031(^11111), funiprofen, °piroxicam, indomethacin ( Indomethacin), ketoprofen, ketorolac tromethamine 'meclofenamate, meclofenamate sodium, mefenamic acid (mefenamic) Acid), nabumetone, oxaprozin, phenyl butyl nitrone (PB, sulindac, or tolmetin), a COX-2 inhibitor, a cytokine synthesis/release inhibitor (such as an anti-cytokine antibody, an anti-cytokine receptor antibody, etc.). In some embodiments, the at least one compound and/or at least one pharmaceutically acceptable The salt can be used in combination with other anti-cancer agents. The term "anti-cancer agent" as used herein refers to any preparation for treating cancer in a cancer patient. Non-limiting examples of anti-cancer agents include: radiotherapeutic formulations, immunotherapeutic formulations, chemotherapeutic agents for DNA damage, and chemotherapeutic agents that interfere with cell replication. Non-limiting examples of chemotherapeutic agents for DNA damage include inhibitors of local isomerase I (eg, irinotecan, topotecan, and camptothecin, and their analogs) , metabolites, and doxorubicin); local isomerase π inhibitors (eg, etoposide, teniposide, and daunorubicin); alkylation Agents (eg 'melphalan', chlorambucil, busulfan, thiotepa, ifosfamide, nitrosourea nitrogen Carmustine, i〇mustine, semustine, streptozocin, decarbazine, methotrexate , mitomycin C (cyclophosphamide); DNA inserts (eg, cisplatin, oxaliplatin, and carboplatin); DNA inserts and free radical generators such as Bora 31 201211044 bleomycin; and nuclear bit mimics (such as 5-deficient urinary bite (5- Fluorouracil), capecitabine, 2,2-difluorodeoxygenated cell bud (gemcitabine), fludarabine (£111£^313丨116), arabinose (^}^ ^1^1^), 疏基°票吟(11161^卩1〇卩1»*丨1^), thioguanine, pentostatin, and hydroxyurea . Chemotherapeutic agents that interfere with cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin' and related analogs; sedatives (thalidomide) And related analogs (such as CC-5013 and CC-4047); protein-alkaline kinase inhibitors (eg, imatinib mesylate and gefltinib); Proteasome inhibitors (eg, bortezomib); NF-κΒ inhibitors, including ΐκΒ kinase inhibitors; bind to proteins that are overexpressed in neoplasms, thereby downregulating antibodies to cellular replication (eg, trastuzumab) (trastuzumab), rituximab, cetuximab, and bevacizumab; and other proteins or 卩 ' 'known to these eggs will be Inhibition of these proteins or enzymes can inhibit cell replication by increasing, over-expressing or initiating. The following examples are to be considered as purely illustrative and should not be construed as limiting the invention in any way. Temperature, etc.) strive to ensure that it is accurate Sex, but there will be some experimental errors and offsets. Unless otherwise made, the parts are parts by weight and the percentage is percent by weight. The temperature is in degrees Celsius 'pressure is or close to the atmosphere I all mass spectra (four) are from Anjie two ( g Han and 1100. All reagents (except intermediates) used in the present invention are obtained commercially. The names of all compounds (except reagents) are produced by soft mash. In the following examples, the specific conditions are not called experimental methods. According to the general conditions, or according to the conditions recommended by the manufacturer, the following abbreviations are used in the following examples: AIBN N, N,-diazoisobutyronitrile 32 201211044 BINAP 2, 2'-double-( Diphenylphosphino)-1,1'-binaphthalene Boc tert-butoxycarbonyl Boc20 di-tert-butyl dicarbonate i-BuN02 isobutyl nitrite BTC bis(trichloromethyl)carbonate (triphos) DCM dichloride Decane DIPEA Ν, Ν-diisopropylethylamine DMF Ν, Ν-dimethylformamide DMAP 4-dimethylaminopyridine DPPA azide diphenyl phosphate DBU 1,8-diazabicyclo[ 5.4.0] undec-7-ene Et3N triethylamine H hour HATU 2-(7-azobenzotriazole)-Ν Ν,Ν',Ν'-tetramethylurea hexafluorophosphate HMTA hexamethylenetetramine HOAc acetic acid Lawesson's reagent Lawson reagent: 2,4-bis(4-methoxyphenyl)-2,4-di Thiooxy 1,3,2,4-dithiazide mL ml min min MeOH methanol MsCl decane sulfonium chloride NBS Ν-bromobutanediamine imine PE petroleum ether 33 201211044

PdCl2(PPh3)2 bis(triphenyl)phosphine di-palladium palladium

Pd(dppf)Cl2.CH2Cl2[l,r-bis(diphenylphosphino)ferrocene]digassed palladium two gas methane complex

Pd2(dba)3 tris(dibenzylidene-propyl) dimorphism

Pd(PPh3)4 tetrakis(triphenylphosphine)

PdCl2(PPh3)2 bis(triphenylphosphine) di-palladium-palladium PPh3 triphenylphosphine THF tetrahydro-alpha-flana TFA trifluoroacetic acid TBTU benzotriazine σ sit-Ν,Ν,Ν',Ν'-four Mercaptourea tetrafluoroborate intermediate 1 (i?)_3-(7V-cyclopentyl, 7V-(bulk-propyl)amino)pyrrolidine t-butyl carbonate

Boc (Α) cyclopentylamino)pyrrole-small tert-butyl vinegar (and)-3-aminopyrrolidine-1-carbonate tert-butyl ester (1 〇g, 5 3 mm〇1) and cyclopentanone (451 mg , 5.3 mmol) was dissolved in tetrahydrotetramine (20 mL). EtOAc (3. <RTI ID=0.0></RTI> 2 〇 mL of water was added to the reaction solution, and extracted with dioxane (3 X 20 mL). The organic phases were combined, washed with brine (3 mL 5 mL), dried over anhydrous sodium sulfate, filtered and evaporated MS (m/z): 255 (M+H)+ (B) (i?)-3-(7V-cyclopentyl, Λ "-(propargyl-propyl)amino)pyrrolidine_1β The ester was added to (and) _3_(cyclopentylamino)pyrrolidine _ 丨-tert-butyl carbonate (2 〇〇 mg, 0.78 mmol), 3-dipropyne (14 〇 mg, i.18) in 3 mL of B. Methyl) and potassium carbonate (217 mg, 1.57 34 201211044 mmol), and refluxed overnight. The reaction mixture was cooled to room temperature and concentrated to dryness. EtOAc EtOAc The target product was obtained. MS (m/z): 293 (M+H)+ Intermediate 2 (/?)-7V-methyl-1-(7 ugly ratio and [2,3-ί/] bite_ 4-)»tbLoxacin-3-amine

(A) (/?)-l-(7 hambir[2,3-phavidin-4-)pyrrolidine_3_tert-butyl carbonate, tert-butyl (pyridyl)-pyrrolidine-3-carboxylate (250 mg, 丨34 mmd), 4_chloro_7//pyrrolo[2,3♦ pyridine (206 mg, 1.34 mmol), DIPEA (〇35 heart 2 〇1 〇〇1 〇〇 dissolved in 3 (five) ethanol, The mixture was heated to reflux for 16 hours, and the solvent was evaporated to dryness crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss /z): 304 (M+H)+ (B) (8)-methyl-1-(7/Τ-pyrrolo[2,3-pyrimidine·4_)pyrrolidine_3_amine 0°c nitrogen Under the protection, lithium aluminum hydride (143 mg, 3 76 mm 〇1) is slowly dropped into (8) small C7/7-pyrrole [2,3-J] pyridine bite _4 比 咯 炫 _3_ dish acid tert-butyl @干(38〇mg, 丨%面.丨) in a dry tetrahydrofuran solution, the temperature was raised to 65. (: The reaction was continued for 2 hours. Cooled to 〇τ, poured into I5% sodium hydroxide solution, filtered to remove solids, 遽The liquid was concentrated, and the residue was purified by preparative chromatography to afford 178 mg (yield: 66%). MS (m/z): 218 (M+H). Intermediate 3 (i?)-l- Pyrroloindole 2,3_pyrimidine ice) Each amino pyrrolidine hydrochloride

35 S 201211044

Add (/?)-1-(7//-pyrrolo[2,3-pyrimidin-4-)°pyrrol-3-amine to methanol solution of hydrogenated gas (6 凡5 11^) Tert-butyl carbonate (600 mg, 1.97 mmol) was stirred at room temperature for 2 hours. The reaction solution was evaporated to give the hydrochloride salt of the desired product. MS (m/z): 2〇4 (M+H)+. Intermediate 4 propyl-1-(7- and pyrrolo[2,3-ί/]pyrimidine-4-)pyrrolidine-3-amine

Add (8) + (7 benzopyrrole [2,3 Dipidine _4 decapyrrolidine-3-amine hydrochloride (50 mg, 0.24 mmol), propionaldehyde (15 mg, 0.26) in 5 mL of tetrahydrofuran. Methyl acetate and sodium triethoxysulfonate (61 mg, 1.2 mmol) were stirred at room temperature for 20 min. 2 mL of water was added and ethyl acetate (3×1·mL). The organic phases are combined, washed with saturated brine (3×5 mL) dried over anhydrous sodium sulfate, filtered and evaporated to give the desired product. Ms 2 (M+H) + 〇 intermediate 5 (/?)-6- ( 1-(7-((2-(Triethyl decyl)ethoxy)methyl ρ-open-pyrrolo[Μ^鸣(") bite-polypyran-3-amino)-nicotinonitrile 36 201211044

NC

SEM (VIII) 4-Chloro-7-((2-triethylhydrazinyl)ethoxy)methyl)_7lepyrrolo[2,3 of pyrimidine 〇°C, in 4-chloro-7//-pyrrole [2,3_4 pyrimidine (5 g, 326 mm〇1) in tetrahydrofuran (5〇mL) was added to NaH (30%, 4 g, 5〇〇_〇1) and stirred for a few hours followed by [2- (qi Methoxy)ethyl]trimethylnonane (15 g, 9 〇.〇mm〇i). The reaction solution was allowed to warm to room temperature and stirred for 3 hours. 5 mL of water was added and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was chromatographed on a silica gel column to give the objective product. MS (m/z): 284 (M+H)+ (35C1), 286 (M+H)+ (37C1). (B) (8)-1-(7_((2_Triethyldecyl)ethoxy)methylpyrrolopyrimidine_4)pyrazole-3-aminocarbonic acid tert-butyl vinegar in 2〇mL ethanol Add chloro-7-((2-triethylhydrazino)ethoxy)methyl&gt; 7 cups of pyridoxine [2,3 cc (900 mg, 3.17 mmol), (8)-pyrrolidine-3 tert-Butyl aminocarbonate (709 mg, 3.80 mmol) and DIPEA (618 mg, 4.75 mmol) were refluxed for 3 h. The reaction solution was cooled to a warm temperature, and the solvent was evaporated, and then ethyl acetate (1 mL) was added, and brine (3 χ 1 〇 mL) was washed with saturated brine, dried over anhydrous sodium sulfate MS (m/z): 434 (M+H)+ 〇(C) (/?)-6-(1-(7-((2-(triethyl decyl)ethoxy)methylpyrrolo[ Μ呐 咬 _ 4-) β-pyrrolidine-3-amino)-nicotinonitrile in a methanol solution of hydrogenated gas (6 Ν, 5 mL) was added (i?)-l-(7-((2- Triethylsulfonyl)

37 S 201211044 Ethoxy)methyl)·7--0-pyrolo[2,3-c/]pyrimidine_4-). It was stirred at room temperature for 3 hours at a temperature of 3 lbs of tert-butyl hydroxyacetate (7 〇〇 mg, 1.61 mmol). After distilling off the solvent, the residue was dissolved in DMS EtOAc (3 mL), &lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; Mg, 2.41 mmol), stirred at 120 °C for 14 hours. Cool to room temperature and add water (20 mL) to ethyl acetate. The organic phases were combined, dried brine (3 χ 40 mL) dried over anhydrous sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel to give the desired product. MS (m/z): 436 (M+H)+. Intermediate 6 methyl-l-(7_((2_(trimethylmethane)ethoxy)methyl)_7 ugly _»Bilo 丨2,34 kiss lean 4-)pyrrolidine-3-amine

(8)-1-(7-((2-(Trimethylmethyl)ethoxy)methyl)-7-l-pyrrolo[2,3-external, „,pyrrol-3-carboxylate Butyl ester is used as a raw material'. It is prepared by a similar synthesis method to intermediate 2B. Ms (m/z): 348 (M+H)+. Intermediate 7 (/?)-5·bromo-methyl-ΛΚ1-( 7-((2-(Trimethylhydrazinyl)ethoxy)methyl)_7 ugly β betapiro[2,3-4pyrimidin-4-)pyrrolidin-3-)pyrazin-2-amine 38 201211044

Br ct Ν ΗΝ—

SEM

DIPEA

SEM will be 0.575 111111〇1 (Phantom-D-methyl-1-(7-((2-(trimethylmethyl)ethoxy)) sulfhydryl)_7//_pyryl 11 each [2,3- gT] mouth n fixed _4-) ° ratio of each pit 3-amine and 0.689 mmol 2,5-two ratio ° 2 Qin dissolved in NMP, then added 2,876 mmol DIPEA, under microwave conditions at 200 ° C. The reaction was carried out for 45 minutes, cooled, poured into water, EtOAc EtOAcjjjjjjjjjjjj H) +, 506 (M X H) +. Intermediate 8 methyl-7V2-{l-[7-(2-trimethyldecyl-ethoxymethyl)_7 ugly-pyrrolo[2,3- d] spray bite -4-] σ Bilo hospital, 3-}-° than bite-2,5-diamine

(Α) (/?)-Methyl-(5_nitro&quot; than bite-2-)_{1-[7-(2-trimethyldecyl-ethoxymethyl)-7-le And [2,3-pyrimidine glaze]pyrrolidine·3+amine (/?)-methyl-{1-[7-(2-trimethyldecyl-ethoxymethylindole[2, 3 pyrimidine-4+pyrrolidine-3-}-amine (1〇mmol), DIPEA (20 mmol) and 2-bromo-5 nitropyridine (11 mmo丨) dissolved in 50 ml of DMF '100 ° C stirring reaction After 24 hours, cool to room temperature, and then pour into water, acetonitrile 39 201211044 ester extraction 'organic phase combined with water washing, saturated brine wash, concentrated under reduced pressure to dry residue column to obtain the target compound. MS (m / z) : 470 (M+H)+. (B) Methyl _, {1_[7-(2-trimethyl-pyridyl-ethoxymethyl)_7 〇 〇 【 [24 嘧 咬 -4 -4 ·] pyrrole Alkanol-3]-pyridone _2,5-diamine in 10 mmol (8)-fluorenyl _(5_石肖基&quot;比 bit-2_HH7-(2_trimethylsinyl-ethoxymethyl), 7// -pyrrolo[2,3-ί/]pyrimidine_4-]. In a 100 ml methanol solution of pyrrolidine-3-}-amine, the reaction mixture was stirred at room temperature for 18 hours. The target compound is obtained by reduced pressure. MS (m/z): 440 (M+H)+. Intermediate 9 (8)-3-((5-cyanopyridin-2-) Propyl) amino) pyrrolidine small broken stuffed acid tert

(A) (1?) 3-tert-butyl 3-(cyclopropylamino)pyrrolidine-1-carboxylate ( tert-butyl 3-aminopyrrolidine-1-carbonate (400 mg, 2.15 mmol) and (1 Add cyanoborohydride (569 mg, 8.60 mmol) and acetic acid (〇, 2 mL) to a solution of acetoxycyclopropoxy)trimethyldecane (1500 mg, 8.60 mmol) in methanol (30 mL). After refluxing for 1 hour, the reaction mixture was concentrated and then water (20 mL) was evaporated, and the mixture was evaporated to ethyl acetate. The organic phase was combined, washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate The desired product is obtained. Ms (m/z): 227 (M+H) + ° . (B) (/?)- 3-((5-cyanopyridin-2)(cyclopropyl)amino)pyrrolidine _l-tert-butyl carbonate 201211044 is based on 3-(cyclopropyl-based transfer of small tert-butyl carbonate and 6-bromonicotinonitrile. For the synthesis method, see the preparation process of intermediate 2 (A). ms (m/z) : 329 (M+H)+. Intermediate 10 3_(5-Cyanocarbonate tert-butyl carbonate

5 cyanoguanidine (no mg, 〇75 mm〇i) was dissolved in 2 5 w sterol, and 1-tert-butyloxycarbonyl ketopyrrole was added sequentially at room temperature (〗 〖66, 〇·9〇 and Acetic acid (1) xanthene, 1-88 mm 〇 1), after stirring for 1 min, sodium cyanoborohydride (57 mg '0.90 mmol) was added and stirring was continued for two days. The methylation was removed under reduced pressure, and the residue was diluted with EtOAc EtOAc EtOAc EtOAc EtOAc. (M+H)+.

Intermediate II (/?)·3-((5-Fluoro-6-methoxypyrazole_2_)methylamino)pyrrolidine t-butyl carbonate

(A) (/?)-3-((6-Gapent-5-decylpyridin-2-)methylamino)pyrrole rl-tert-butyl carbonate was added 2.2 ml 2,6-two in 10 ml of DMF. The chloro-3-cyano0 ratio bite and 10 mmol of DIPEA, and (8)-l-Boc-3-methylaminopyrrolidine, and the reaction solution was reacted at 100 ° C overnight. After completion, the reaction mixture was diluted with ethyl acetate, washed with water three times, dried, filtered, concentrated, and purified by column chromatography 201211044 to give the desired product MS (m/z): 237 (M+H- BOC) + (B) (and) -3-((5-carbylmethoxy. butyl 2) methylamino) 咕 炫 > 1-tert-butyl carbonate, 0.9 mmol of sodium metal was added to 2 ml of methanol, to be After the bubbles were released, they were slowly added to 20 ml of 0.45 mmol of 0)-3-((6-gas-5-cyanopyridine-2-)decylamino)pyrrolidine-1-carbonate tert-butyl vinegar. The mixture was stirred at room temperature for 3 hours, and then heated to 50 ° C, stirred for 2 hours, and then heated to reflux to react overnight. After completion, the system was concentrated and diluted with ethyl acetate. EtOAc was washed with EtOAc EtOAc (EtOAc). The following intermediates 12-14 can be prepared by those skilled in the art with appropriate intermediates and reagents under appropriate conditions. For specific synthesis methods, reference can be made to the towel body 11(A)R, /

NC

Cfr

Rfr

Boc intermediate 12 intermediate 13 intermediate 14 intermediate 12: (8)-3-((6-cyanoindole-3-)methylamino)pyrrole-1-tert-butyl carbonate intermediate 13 : (^) 3-((6-Trifluoromethylpyridazin-3-)methylamino)pyrrolidine-1-carbonate tert-butyl ester intermediate 14 :(8)-3-((5-methylsulfonylpyridine-2-) Methylamino)pyrrole tert-butyl carbonate intermediate 15 (7) methylcyclopropyl hydrazino) pyrrolidine-1-tert-butyl carbonate

Boc

Boc

HMe ^ (R) l&gt;-S〇2C\ Boc

DIPEA, THF dRj

Boc to the bottom of the coffee's cyanochlorin (77 mg '0.55 mmol) slowly drip into the dissolved (/?) _3_ (amylamine) ° ratio &quot; each burning small carbonic acid tert-butyl (100 mg, 0.5 Mm) and DIPEA (0.10 m Bu 0.60)

The mixture was stirred overnight with EtOAc (EtOAc) m. MS (m/z): 305 (M+H) + ° Intermediate 16 (i〇-3-(7V-methylcyclopropylsulfonylamino)pyrrole-1-butanyl tert-butyl

1 mmol of 2-(trifluoromethyl)benzoic acid was slowly dropped into tetrahydrofuran dissolved in 1 2 mm 〇i TBTU, 2 mmol DIPEA, 1 mmol (8)-3-(methylamino)pyrrolidine-1-carbonate tert-butyl ester. In the solution, the reaction solution was stirred at room temperature overnight, and then concentrated, then water was added, ethyl acetate was evaporated, and then concentrated to give a crude product, and the next reaction was carried out without purification. MS (m/z): 273 (M+H-BOC)+ . Example 1: Synthesis of Compound 1-260 Compound 1 (/?)-7V_(l-(7/T-pyrrolo[2,3-pyrimidin-4-)pyrrolidin-3-)-2-cyano -7V-methylacetamide

(/?)-Denyl-1-(7//-pyrrolo[2,3-(/]pyrimidine_4-)°pyrrolidine-3-amine (75 mg, 0.345

43 S 201211044 mmol) and cyanoacetic acid (35 mg, 0.414 mmol) dissolved in tetrahydrofuran (5 mL), EtOAc (EtOAc, EtOAc (EtOAc) . The precipitated solid was filtered, washed with ethyl acetate and evaporated to drynessielielielielielielielielielielielielielielielielielielielielielielielieliel Compounds 2-8 can be prepared by those skilled in the art with appropriate intermediates and reagents under appropriate conditions. For specific synthetic methods, reference can be made to Compound 1.

44 201211044

Ο

5 Compound 9 Amine - (w turn and pottery · 4 laundering each Μ _ ing base ★, methyl benzene continued brewing

NC

Add (4 benzene to 〇1) one (6 mg, 〇.28 mm〇1) to the solution of (and the base - 辄 辄 3_ 峨 _3~ 物 (4), at room temperature Mix for half an hour. Add water to dilute, and take the acetic acid ^ stroke. Some of her combined 'Feng sulfur _ money, too will evaporate the solvent. The residue was separated and purified by Shishi gum preparation plate to obtain the target product (13.6 mg, 26%). MS (m/Z): 383 (M+H) + Compounds 10-15 can be prepared by those skilled in the art with appropriate intermediates and reagents under appropriate conditions, and the specific synthesis can be referred to compound 9. £ 45 201211044 Compound Structural formula MS (m/z) (Μ+Η)+ Compound structure MS (m/z) (Μ+Η)+ 10 ncO &gt;° ^ Η 383 13 ο7 &gt;° Ν 388 388 11 ο2ν &gt;° 403 14 ~Ν' ο次0 ϊ 325 03 kN Η , 人κ 12 02Ν—/~Λ ΙΝ 403 403 15 0^ο Ν 351 351 Compound 16 (/?)-1-(1-(7//-pyrrole) And [2,3-ί/]pyrimidine-4-)pyrrole&gt;-3-)-3-(3-cyanophenyl)-1-methyl 46 201211044

In the formula, Ί, 4-dioxane" means 1,4 - dioxane. It is added to 1 mL of 1,4 - dioxane (rule HV-methyl-1-(7//-pyrrole) _4_) ° ratio of each of the trimethylamine (50 mg, 0.230 mmol) and 3-cyanophenyl isocyanate (37 mg, 〇257 mm〇i) and refluxed overnight. After the reaction mixture was evaporated, the residue The title product is obtained by flash column chromatography. 362 (M+H)+. Compound 17 can be prepared by a person skilled in the art using appropriate intermediates and reagents under appropriate conditions. For the specific synthesis, reference can be made to compound 16.

Compound 18 transfer [2,3_餐私^狼3_) nasal methyl 2_(trifluoroethyl)benzenecarbamamine 201211044

1 nunoi (external 3-(methyl-2-(trifluoroethyl)phenyl)pyrrolidine) is dissolved in 2 ml of trifluoroacetic acid and 2 ml of a two-gas mixture. Warmly mix for 2 hours, concentrate, dilute with water, adjust the pH to about 9 with sodium bicarbonate solution, extract with ethyl acetate, dry and concentrate to give (/?)-methyl-A4 pyrrolidine-3-)- Crude 2-(trifluoromethyl)benzamide. The obtained crude product (1 mmol), 〇.8 mmol 4-gas-7//-° piroxi[2,3-ί pyrimidine, 2 _1 DIPEa was dissolved in 3 ml of ethanol, and the reaction solution was left at room temperature overnight. Concentration, crude product was separated by flash column chromatography to obtain the target (and) #(1-(7) from pyrrolo[2,3-purpurin-4-)pyrrolidine_3_&gt;Ar-methyl 2 (-r-ethyl) Benzoguanamine. MS (m/z): 39 〇 (M+H) + δ δ 19-22 can be prepared by a person skilled in the art with appropriate intermediates and reagents under appropriate conditions. Reference can be made to compound 18. Compound structure MS (m/z) (M+H)+ Compound structure MS (m/z) (Μ+Η)+ 4 19 ____Ν η 300 21 V. ςΓ Λ3 Ν Ν 418 48

Compound 23 (/?)-ΑΗΗ7πpyrroloindole 2,3-phavidin-4-)pyrrolidin-3-)-2-(1 ugly-imidazole-4-)-7V-methyl

(A) (/?)-2_(1 good-imidazole_4_)_methyl-methyl (1_(7-((2-(trimethylfyl))ethoxy)methyl)-7//-pyrrole And [2,3-&lt;/J-pyrimidine-4-)pyrrole-3-)acetamidamine 0.29 mmol of 2-(1//-imidazole-4-)acetic acid was slowly dropped into the (8)#methyl group ( 7_((2_(tridecylfluorenyl)ethoxy)methyl)-7//-pyrrolo[2,3-c/]pyrimidine) 比 咯 · 3 3 3 3 3 3 3 3 3 3 3 1 TBTU, 0.58 mmol of DIPEA in tetrahydrofuran solution, stirred at room temperature overnight. After the reaction liquid is concentrated, it is diluted with water, extracted with acetic acid, dried, concentrated, and separated by flash column chromatography to obtain the product 0 (B) (8) - Λ 4 Η 7 ugluo and [2, 3 · -4 _) 〇 pyrrolidine Imidazole, seven good methyl acetamide

S 49 201211044 0.11 mmol(8)-2-(lg imidazole-4-)#methyl good (1-(7-((2-(trimethylmethyl)ethoxy)))-7//- The ratio of each [2,3-£/]pyrimidine _4 decyloxan-3-) acetamidine dissolved in 11111 trifluoroacetic acid and 2 ml of dioxane mixed solution, stirring at room temperature for 1.5 hours The solvent was evaporated under reduced pressure, and the residue was crystallised eluted eluted eluted eluted eluted eluted 326 (M+H)+. Compounds 24-28 can be prepared by a person skilled in the art with appropriate intermediates and reagents under appropriate conditions, and the specific synthesis method can refer to compound 23 ^ compound - --- _ structure MS (m/z) (Μ+Η)+ Compound Structure MS (m/z) (M+H)+ 24 - __ 276 27 d〇cf &amp; 338 25 '···· __ (fr όο Ν Ν 328 28 % rfr *3 , N 八 N 364 26 03 , Ν Ν 296 Compound 29 1 _((and)-1 pyrrolo[2,3-(/]pyrimidin-4-)pyrrolidin-3-)-3 -((1/j,2/j)_2-hydroxy-2,3· 50 201211044 dihydro-1 good-茚-1+1-methylurea

(A) 3-((l/?,2J?)-2-yl-based-2,3-dihydro-1--k-methyl-1-((/?)-1_(7_((2•(( Trimethylmethane)ethoxy)methyl)-7-pyrrolopyrene 2,3-d]pyrimidine-4-)pyrrole-3·)urea 0.29 mmol(8) good methyl-1-(7- ((2-(triterpene oxime) ethoxy)methyl)·7//_pyrrole [2,3-&lt;j-pyrimidin-4-decahydro-3-amine is dissolved in 2 ml of tetrahydrofuran, Cool to 〇. 〇, add BTC 'Add 0.35 mmol DIPEA, the mixture is in 〇. (: stir for 30 minutes, warm to room temperature and stir for 3 hours, then cool again to 〇. (3, add 0.35 mmol of amine-2, 3-Dihydro-1 is stirred from the indole-2-ol at room temperature for 24 hours, and the reaction liquid is concentrated to prepare a thin layer to obtain a product. (Β) Η(/?)-1·(7ΡBilo And 丨 2,3- 响 -4- -4-)» than slightly burned hydroxy-nitrogen _1 ugly Bp-1-)-1-methyl gland 3 ((l/?, 2i?)-2-yl group -2,3-monoazinyl-1, (() and seven (7 ((2 (trimethylthene) ethoxy) fluorenyl H//-pyrrolo[2,3-d]pyrimidine) Pyrrol-3-)urea is used as a starting material, and the synthesis process is described in the preparation process of compound 23 (B). MS (m/z): 393 (M+H)+. Compound 3〇-38 can be appropriately determined by those skilled in the art. Intermediates and reagents prepared under suitable conditions, refer to specific synthetic methods Compound 29.

51 S 201211044 Compound Structural Formula MS (m/z) (Μ+Η)+ Compound Structure MS (m/z) (Μ+Η)+ f3c ΓΛ 0, 30 Μ ΝΗ 〇Ν_ Ν Η 405 35 η2ν 〇=&lt ; /Ν~ Ν 358 31 NC F Ά ΝΗ 0=( Μ — Π Ν 03 380 36 Q ΝΗ 0-( Ν — &amp;lV&gt; κι Ν Ν 345 345 32 ΝΗ 0=&lt; /Ν~ &amp; Ν 351 37 0 Ν — &amp; Ν 03, Μ 315

52

Compound 39 (4) good cyclopentyl _ ΛΚ 丙 丙 纠 傅 并 并 并 五 (5)

Boc

^ A

Add _|cyclopentyl group, N_ fast propyl) amino group to 1 mL of rolling methanol solution (6 N). hour. After evaporating the solvent, the solvent was added to ethanol (3 mL), 4_ secret money and (4): mmoi) and DIPEA (53 mg g, 27 preparation of Butterfly K _1}. The final residue was used as the target product. MS (m/z): 310 (M+H)+. 53 s 201211044 Compound 40-62 can be prepared by a person skilled in the art with appropriate intermediates and reagents under appropriate conditions. For the specific synthesis, reference can be made to compound 39. Structural formula MS (m/z) (Μ+Η)+ Compound structure MS (m/z) (Μ+Η)+ 40 Q) N ν κ 312 52 Ν—7 &amp; Ν 03 S Η 297 41 NC Ft &amp; Ν 03 346 53 rt Ν Ν Ν Ν 286 286 42 cT Ν 03 Ν, 350 54 Q __/ Η—7 &amp; Ν 03 S η 324 43 Ν 03 394 55 &lt;1^ ct Ν 03 283 54 201211044

55 201211044

Compound 63

&gt;NHCI\^nnv/CI " 了

DIPEA Ν Κ

(8)-iV-methyl-1-(7//-pyrrolo[2,3y-pyrimidine_4-decahydroramine (please (4) mmol), 2,4-dichloropyrene (0.18 g, 1.21) Methyl) and DIPEA (0 25 〇1 ~ 1Λ, · 'J g, 1.94 mmol) were dissolved in DMF (6 mL) and stirred at 110 ° C for 16 hours. Add 5 (7) hydrazine to the reaction solution. Extraction (2 x 8 mL). The organic phases were combined, washed with brine (2 χ 3 〇mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (DCM/Me〇H = 12 /1) Purification to give the title compound. MS 330 〇1+1^+ Compounds 64-102 can be prepared by a person skilled in the art with appropriate intermediates and reagents under appropriate conditions, and the specific synthesis method can be referred to compound 63. 56 201211044 Compound Structural Formula MS (m/z) (M+H)+ Compound Structural Formula MS (m/z) (M+H)+ 64 NC & Λ) Μ Ν Ν 271 271 84 NC dR) N nu〇&gt; 321 65 \ J & Ν N0C&gt; Ν Ν Μ Η 256 85 Cl Qn. N— 03 330 (35C1) 332 (37C1) 66 rfr &amp; Ν 313 313 86 OMe N~~~ Π N Ν N ^ H 406 67 Ν Π Ν 03 S' 329 (35C1) 331 (37C1) 87 NCv c, /N' ct Nfc Ν N 372 (35C 1) 374 (37C1) 68 Ν~ a Ν NU〇373 (79Br) 375 (81Br) 88 θ' SN3 Ν- Π N Ν N 335 57 201211044 69 cT N 03 421 89 dR) N NuO&gt; 398(79Br) 400 (8,Br) 70 N02 N~~~ a N 03 340 90 v \^N ,N' &amp; N 03 354 (35C1) 356 (37C1) 71 CN N~~~ a N 03 S person s 320 91 N 03 320 72 CN ci N— Ci NNNH 368 (35C1) 3 7 0 (37C1) 92 Ν'— N 03 319 73 NC MN isi N IN H 3 6 8 (35C1) 370 (37C1) 93 EN Λ /N- ct N 03 326 74 o2n Cl N — rt N 03 S person K 3 74 (35C1) 376 (37C1) 94 7- NU〇374(79Br) 376(8,Br) 58 201211044 75 02N N~ ct N 03 S' 354 95 % /N~ cf &lt;X&gt; NH 326 % Q NC 76 /N^ &amp; 320 96 N~ a N 365 tjy tl} NH 77 o2n , N- 0Ri Λο NH 354 97 \ 02N nh ct N 03 351 78 〇2^ /nh2 QN~ &amp; Λ〇S' 355 98 0 ct~ N 03 348 79 N- rt Λ〇NN 3 8 0 (35C1) 382 (37C1) 99 NV f&gt;Br /N^ ct N 03 398 (79Br) 400(81Br) NCx N 03 80 N 03 346 100 334 s 59 201211044

Compound 103 (/?)-4-((1-(7好"Bilo and bite_4_) «Beloved) (曱基)amino)_3_1Benzyl

(8) Good methyl small (7//-pyrrolo[2,3-^|pyrimidine-4-)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) was taken in EtOAc (10 mL). Water (5 〇 mL) was added to the reaction solution.

60 201211044 Extraction with acetic acid (2 x M) mL). The organic phases were combined, washed with brine (2×5 mL), dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (yield: methane / methanol / ammonia = 60 / 1 / 0.3) to give the desired product _4 g, 52%). MS (m/z) m (M+H)+. Compound 104-1丨8 can be prepared by a person skilled in the art with appropriate intermediates and reagents under appropriate conditions. For the specific synthesis, reference can be made to compound 103. —— Compound structure MS (m/z) (M+H)+ Compound structure MS (m/z) (M+H)+ 104 NC ct Ν 319 319 112 N^c. (^Γ NvQ IN H 353 (35C1) 355 (37C1) — NC F NC CN 105 cf N 337 113 cf V 344 03 NK vj〇&gt;, person a -_-^106 ct N 03 355 114 cf NH 397 (79Br) 399 (81Br) 201211044 107 NC &lt;^~no2 N— &amp; 364 115 v N— 0R) H 03 397 (79Br) 399 (8,Br) 108 FN — cf N 03 355 116 NC ri N, N ΝΛ&gt; NN n H 353 (35C1) 355 (37C1) 109 NK V/~cp3 cf N NU〇387 117 F cf) N 03 391 110 ;ctf FN— &amp;) Nfc NNMH 371 (35C1) 373 (37C1) 118 F^cn N~ N 03 , human H 355 111 NC /v &amp; H 03 V human n 369 62 201211044 Compound 119 (and) _3_((1-(7 ugly-pyrroloindole 2,3_&lt;/]pyrimidin-4)pyrrole Burn _3_) (methyl) amino) benzonitrile

(Α)(/?)-3-(methyl(1-(7-((2-(trimethylmethyl))ethoxy)methyl)pyrrolo[23_pyrimidin-4-)pyrrolidine -3-)Amino)benzonitrile will be (8) good methyl-1-(7-((2-(trimethylmethyl)ethoxy)) sulfonyl). Pyrrolidine-3-amine (50 mg, 0-14 mmol), 3-indolizonitrile (39 mg, 0.21 mmol), Pd2 (dba) 3 (1 mg, 0.002 mmol), BINAP (5 mg, 0.008 mmol) Sodium tert-butoxide (27 mg, 0·28 mmo) was mixed in toluene (2 mL) and refluxed for 6 hours under nitrogen. The reaction was cooled to room temperature and diluted with water. 〇mL) extraction. The organic phase was washed with brine and brine (3×10 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel (DCM/MeOH. = 20/1) Product. MS (m/z): 449 (M+H)+ ° (Β) (Λ)-3_((1-(7/ί-«Biluo[2,3-rf] pain -4--4- ) 0 比洛烧-3·)(methyl)amino)benzene is guessed as (8)_3-(f-based (1-(7-((2-(trimethylmethyl))ethoxy)methyl)) More than argon [2,3 ^ ° pyridine-4-) ° pyrrolidine-3-) amino) benzonitrile as raw material, for the synthesis method see compound 23 (b) Preparation process. MS (m/z): 319 (M+H)+.

63 S 201211044 (Dream methyl '- (A Grinding) phenyl) small scale and [a ah called scale burning _3_ amine

(A) ((4)-methyl _ _ (A) phenyl) small (7 ((2 (trimethyl yl) ethoxy) methyl)-7^ piroxi[2,3-&lt;;/] 唆 唆 4 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 十 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 -) * each xanthene-3-amine (1〇〇mg '〇.287 mm〇1), Bu Dunbing (methyl stone base) benzene (1) xanthene, 0.861 mmol), potassium carbonate (158 mg, U42 mm〇1) dissolved in Heat to 120 ° C in 2 ml of DMF and react overnight [cooling] into water, extract with ethyl acetate, concentrate, and prepare a thin layer to obtain the product. (B) (8) Nasal methyl nasal (4-(methylsulfonyl)phenyl)-1-(7 ugly-pyrrolo[23-rf]pyrimidine_4_)pyrazole-3-amine (8) nasal sputum 4-((indenyl)phenyl)_1_(7-((2·(trimethylglucenyl)ethoxy)indolyl)-7//-pyrrolo[2,3-4-pyrimidine-4-)pyrrole The alk-3-amine is used as a raw material, and the synthesis method can be referred to the preparation process of the compound 2?(8). MS (m/z): 372 (M+H)+. Compounds 121-124 can be prepared by those skilled in the art with appropriate intermediates and reagents under appropriate conditions. For specific synthetic methods, reference can be made to compound Π0. MS MS Compound Structural Formula (m/z) (M+H)+ Compound. Structural Formula (m/z) (M+H)+

64 201211044 121 qcn oN, 03 Ν κ 320 123 F\ F Ν~ Ν 363 363 —.........................,-a 4' CF3 Ν^λ Ν*-7 122 ϊ 426 124 cf 360 Χ Λ) Ν Ν ^ Μ 化合物 Compound 125 ) Pyrrolidine-3-)-#-methyl-1 ugly pyrazolo[3,4- (8) -iV-(lC^e is better than [2,3 called feeding beer 4

(A)(/?)-iV,4-monomethyl_5·breaking base_乡_(7((2(trimethyl)yl)ethoxy)methyl)pyrrolo[2,3·ί /|Urhime bite ·4·) Pyrrole singe ratio bite 2·amine will 〇·287 咖〇1(8)·#曱基]-(7-((2-(trimethylglycosyl)ethoxy)methyl)- 7//-transfer [2,3-c/j pyrimidine-4-) pyrrolidine·3_amine, 〇347 mm〇丨2_gas_4methyl_5 nitropyridine, 丨435 mmol DIPEA, 1.5 The ml nmp was mixed and placed in a reaction flask, and reacted under microwave conditions for 2 minutes at 2 ° C. 'cooled to room temperature, poured into water, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain product. (Yield 86.3%). (B) (8)-Methyl-methyl (1-(7-((2-(trimethyl)methyl)))))) - - - - - - - - - - - - - - - - - - Burn -3-)- 1/Γ-0 than saliva and [3,4-cJ0 than bite-5-amine will be 0.248 mmol (Λ)-#,4-dimethyl-5-nitro-//-( 1-(7-((2-(trimethylhydrazino)ethoxy) decyl)-7//-pyrrolo[2,3-pyrimidin-4-)°pyrazine-3-)pyridine 2-Amine is dissolved in a mixture of 20 ml of ethanol and 5 ml of water, 0.752 mmol of iron powder and 1.495 mmol of NH4C1 are added, and the mixture is heated to reflux for 2 hours, filtered under cooling, and the residue obtained by concentration of the filtrate is dissolved in U ml of acetic acid and 2 5 The solvent was mixed with water, and 0.304 mmol of NaN02 was slowly added, and the mixture was stirred at room temperature overnight. Ammonia water was added, ethyl acetate was extracted and concentrated, and the product was isolated by column chromatography (yield 33.0%). (C) (and) _ exhaust (1-(7-pyrroloindole 2,3-//]pyrimidin-4-)pyrrolidin-3-)-7V-methyl-1open-pyrene[3 , 4-cb-batch-5-amine (8)-methyl---(1-(7-((2-(trimethylmethyl))ethoxy)methyl)_7//0 ratio [2, 3_4 pyrimidine. _4-)t each calcination ratio [3,4 inch than pyridine-5-amine as raw material, the synthesis method see compound 23 (B) preparation process. MS (m / z): 335 (M +H)+. Compound 126 W-6-((l-(7/^比比和丨2,3咄嘴咬-4-)»pyrrolidine-3-)(ethyl)amino)-nicotinonitrile

(Α)(Λ)-6-(Ethyltrimethylsulfonyl)ethoxy)methyl)_7 ugly/pyrrolopyrene 234 66 201211044 Mouth bite -4-) β 比洛烧-3-) Amino) Smoke guessed at 0 °C 'NaH (55 mg, 2.3 mmol) was added in portions to 〇/?)-6-(1-(7-((2-(trimethylglycosyl)ethoxy)methyl)) 7//-pyrrolo[2,3-c/]pyrimidine_4_).pyrrolidine-3-amine (carbonitrile) (2 mg, 0·46 mmol) in DMF (5_0 mL). After the reaction mixture was stirred at room temperature for 3 hrs, ethyl bromide (60 mg, 0.55 mmol) was added dropwise and stirring was continued at room temperature for 3 min. The reaction was quenched with aq. EtOAc (3 mL) The organic phase was combined, washed with saturated brine, filtered and evaporated. The residue was purified by silica gel column chromatography to give the desired product. MS (m/z): 464 (M+H)+. (3⁄4)(8)-0-((1-(7 ugly pyrroindole 2,; μ 咬 _4_) β-pyrrolidine·3_)(ethyl)amino)benzonitrile with (8)_6·(ethyl (1 -(7-((2_(tridecylfluorenyl)ethoxy)methyl)_7 from 〇 咯 并 [2,3-i/j ° 密定-4-) °pyrrol-3- ) Amino) nicotinonitrile is used as a raw material. For the synthesis method, see the preparation of compound 23 (Β). MS (m/z): 334 (Μ+Η)+. Compounds 127-133 can be prepared by one of ordinary skill in the art with the corresponding intermediates and reagents under appropriate conditions. Compound Structural Formula MS (m/z) (M+H)+ Compound Structural Formula MS (m/z) (M+H)+ 127 NC / Ν--/ cf) N Λ&gt; fsi NNH 345 131 N-/ &amp ; N 03 343

S 67 201211044 128 N—/ &amp; N NuQ NN Ν 344 344 132 NC F cf N 03 369 129 F Μ —/ NNNNH 379 133 NC N—/ Ni〇NH 351 130 &gt;y/ F N-7 cf K| IN NH 361 Compound 134 pyrrolo[2,3-ί/]pyrimidine-4-)pyrrole-3-)-iV-methyl-5-morpholinepyrazine-2-amine

68 201211044 (8) (4) Explosion 5_morphine like you (three Xieji thief base) methyl) -7-open-pyrolo[2,3-rf]pyrimidine_4_)pyrrole _3)pyridin-2-amine _9 Axis 〇 1(8)-5-漠# Methyl yam (trimethyl sulphate) ethoxy) fluorenyl) _, '['3 «pyrimidin-4-)pyrrolidin-3-) η azine _ 2_amine and (5 mi morpholine dissolved in 〇5 NMP, under the condition of money, reacted for 2 hours in muscle. Cooled, poured into human water, extracted σ with ethyl acetate and organic layer, dried 'waves and purified by chromatography Product (grab). (Β)(8)iV-(i_(7 ugly-pyrrolo[2,3^嚷 _4) 吼洛烧-3_^methyl-5 morphineline pyrazin-2-amine (8)- Methyl-5-morphine H-(l-(7-((2_(trimethylglycosyl)ethoxy)methyl)) is more than [2,3-ί/] mouth bite - ten ten bil The -3-)»pyrazine-2-amine is used as a raw material. For the synthesis method, refer to the preparation process of the compound 23 (B). MS (m/z): 381 (M+H)+. The compound 135-138 can be specialized in the field. The skilled person prepares the corresponding intermediate and reagent under appropriate conditions, and the specific synthesis method can refer to compound 134.

69 ^ 201211044

Compound 139 % morphine-3-)-TV2 〆-dimethylpyrimidine- (and)-7\^-(1-(7-pyrido- 2,3-pyrimidin-4-) 2,4 -diamine (Cl, Ν Ν

, N', M

MeNH2/THF Microwave

In the formula, "microwave" means a microwave reactor. Will (7?)-_/V-(l-(7//-n ratio[2,3-ί/] π 密-4-) 〇 n 疋 疋 疋 疋 3- 3- 3- 3- 3- 3- 3- 3- - gas-TV-methylpyrimidin-4-amine (26.0 mg, 0.08 mmol) dissolved in methylamine in tetrahedral solution (2.0 M, 5.0 mL, 10.0 mmol) in a microwave reactor (InitatorTM Bi 〇 s ' at 110. (: stirring for 45 minutes. The reaction solution is evaporated to remove the solvent, and the residue is purified by purification to give the desired product. (m/z): milk (M+H)+. Compound M0-M1 can be used in the field The skilled person prepares the corresponding intermediates and reagents under appropriate conditions, and the specific synthesis method can refer to the compound Up. Compound structure Ms Compound structure MS (m/z)

Compound 142 (i?)-2-(l-(W-tondepyridinium 2,3_4 pyridyl-4_)pyrrole-3-)(methyl)amino·5·cyanopyrimidine

In the formula, 'microwave' means a microwave reactor. C^HV-(l-(7//~n ratio p and [2,3-ί/] ρ 密-4-) β 比洛院-3-)-5-漠善曱基鸣. Dine-2-amine (50.0 mg, 0.134 mmol), zinc cyanide (15.7 mg, 0.134 mmol), tetrakis(triphenylphosphine)! Bar (15.4 mg, 〇.〇 134 mmol) mixed in 5 mL of DMF In a microwave reactor (InitatorTM

Biotage) was mixed for 40 minutes at 120 °C. I5 mL of water was added to the reaction mixture, and ethyl acetate (20 mL) was evaporated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated and evaporated. ]VIS (m/z): 321 (M+H)+.

71 S 201211044 Compound 143

(4) (Trimethylmethane) ethoxy)methyl oxime [a pyrimidine _4_) pyroxazepine-3-) pyrazin-2-amine (8)-5-dimethomethyl-do (1 -(7_((2_(三曱基石基基)ethoxy)methyl m♦ each [2,3 ¢/] 咬-4-) is more than p) -3-) ° azine-2- Amine (55 mg, 1〇mm〇1), ethanol sodium (68%, 10 mmol) dissolved in 10.5 ml of ethanol, heated to reflux, reacted for 5 days. After cooling, diluted with water, ethyl acetate was extracted and dried. Separation and purification by gel column chromatography (pE/Et〇Ac=1/l) successively obtained two products's structurally shouted, respectively: firstly, compound 136 was obtained, and 5 ethoxy groups were used. -(7-((2-(trimethylsulfanyl)ethoxy)fyl)l each [23 but densely bite _4_) 〇 0 0 炫 炫 嗓 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺z): 470 (M+l)+, 21 mg, 41.1%), then compound 143(8)#methyl#(1-(7-((2-(trimethyl)))))比 „ [2,3_^ 嘧 _ 4 4 4 4 _ _ _ _ 十 十 十 十 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , (/?)-7V-(l-(7 ugly-pyrrolo[2,3-flT]pyrimidine_4·)pyrrole-3_)_yy_methylpyrazine-2-amine (8) good methyl- (1-(7-((2-(tridecyl) fluorenyl) Oxy)methyl)u 匕 并 [2,3 body close -4-). Bieryuan-3 decaazine-2-amine as raw material, the synthesis method see compound 23 (B) preparation. MS (m/z): 296 (M+H)+. Compound 144

72 201211044 (i?)-iV-(H7 ugly-pyrrolo[2,3-rf]pyrimidin-4-)pyrrolidine-3-; HV-methyl-3,4,-bipyridyl-6-amine

(8)-7V-(l-(7-Pyrylpyrrolo[2,3_jj-[i]-[4])pyrrolidine_3_)_5_峨峨曱pyridinyl-2-amine (90.0 mg, 〇_21 mm〇i), pyridine · 4_ Boric acid (28 4 mg, 〇23 mmol), PdC^dppf CHsCl2 (17.2 mg, 0.02 mmol) and potassium carbonate (0.058 g) were mixed in DMF (5.0 mL) and stirred under n. 16 hours. The reaction solution was cooled to room temperature and then extracted with EtOAc EtOAc. The organic phases were combined, washed with saturated brine (0× 5.0 mL) dried over anhydrous sodium sulfate, filtered and evaporated. The residue was subjected to flash column chromatography to give the aimed product. MS (m/z): 372 (M+H)+. Compounds 145-150 can be prepared by one skilled in the art using appropriate intermediates and reagents under appropriate conditions. Field Compound Structural Formula MS (m/z) (M+H)+ Compound Structural Formula MS' (m/z) (M+H)+ 145 CT 371 148 Nk~q cf) CN N 420 N Η 73 201211044

Compound 151 7V-((/?)-l-(7/^Biluo[2,3 哟H)pyrrolidin-3-)-TV-methyl-5-(1 and-pyrazole-4-) Pyrazin-2-amine

In the formula, "Dioxane" means 1,4-dioxane. (A)(/?)-7V-mercapto_5_(1H pyrazole_4+乂(1_(7((2_(trimethylmethyl)ethoxy)methyl))) 3-&lt;/] squirting bit 4_) 吼洛烧_3 decaazine amide 2 (8)-5-bromo-from methyl #(Bu(7-((2-(trimethylmethyl))) Oxy) indenyl)-7//-pyrrolo[2,3-&lt;^]°岔-4-)° ratio η#3_)ϋ 嗓-2-amine (64 mg, 0.127 mmol) ), 4-° ratio ° sitt acid ° vinegar vinegar (37 mg, 0.19 mmol), Pd (PPh3) 4 (29 mg, 0.0254 mmol), cesium carbonate (124 mg '0.381 mmol), 1,4- After mixing dioxane (3 ml) and water (0.3 ml), nitrogen protection

74 201211044 Heated to reflux under s蒦 and reacted for 14 hours. After cooling to room temperature, it was diluted with ethyl acetate and water, ethyl acetate was evaporated, washed with brine, dried, concentrated, and purified by column chromatography. (B) A4 (and) -1- (7-open-pyrrolo[2,3-4-pyrimidine_4·) pyrrolidine-3_)-AL methyl_5_(1 good_〇bazole-4-) »比"秦-2-amine (8)-existing methyl-5-(1Η-pyrazole-4-)_^(1-(7-((2-(trimethylmethyl))ethoxy)methyl) H 乐 。 each [2, 3 melidine-4 decimole _3-) azine 2 amine as raw material, the synthesis method see compound 23 (9) preparation process.] viS (m / z): 362 (Μ+Η)+. Compound 152 can be prepared by a person skilled in the art with appropriate intermediates and reagents under appropriate conditions. For a specific synthesis method, reference can be made to compound 151. Compound Structure / Formula MS (m/z) (M+H ) + 152 ηνΛ NNH 362 Compound 153 iV-((i?)-l-(7 such as biluo and mouth bite than 洛? _3_) 5_(1 good·salt methylpyrazine-2-amine

75 S 201211044

(A) 5-(1 from imidazole small; methyl nasal ((magic small (7_((2_(trimethylmethyl))ethoxy)methyl)-7/Γ-»比比和[2,3 -&lt;/]pyrimidine-4-)pyrrole _3_)pyrazin-2-amine (and)-5-bromo-from fluorenyl#(1_(7_((2-(trimethylmethyl))) Oxy)methyl)-7//-pyrrolo[2,3-J]♦ -4-)° ratio b to each, 3-)D ratio. Qin-2-amine (50 mg, 0.0991 mmol) ), rice bran (14 mg, 0.198 mmol), copper (9.4 mg, 0.050 mm〇i), carbonic acid (32 mg, 0.0991 mmol), l, l-phenanthroline (9 mg, 0.050 mmol) and 2 ml of NMP were mixed in a microwave tube and reacted under microwave conditions for 45 minutes at 18 ° C. After the reaction was completed, it was diluted with ethyl acetate and water, and extracted with ethyl acetate to wash with saturated brine, and dried. Concentrated and purified by flash column chromatography to give 20 mg of brown oil (yield: 41%) 〇(B) ((/?) small (7 ugly-pyrrolo[2,3-&lt;/] pyrimidine·4_ Pyrrolidine-3-)-5-(1 from imidazole-1-)-methylpyrazin-2-amine 5-(1//-imilin-1曱基# ((8)]-(7_(( 2-((tridecylfluorenyl)ethoxy)methyl.Biloze[2,3-c?]pyrimidine-4-).Byrox-3-)pyrazine·2·amine as raw material, synthesis method See Preparation of Compound 23 (9). MS (m/z): 362 (Μ+Η)+· Compound 154 Pyrrole [2, 3-4 pyrimidine·4 decitex _3·) also methylpyrimidine-4 -amine

76

201211044 will (and) - do (1-(7//-. Biluo [2,3-pyrimidin-4-). Biha Xuan ^3-)-2-chloro-iV-methyl" pyridine 4-Amine (30 mg, 0.09 mmol) and palladium on carbon (10 wt.%, 20.0 mg) were mixed in 3 mL of methanol and stirred at room temperature under a hydrogen atmosphere for 4 hours. The palladium carbon was filtered off and the filtrate was evaporated to dryness. The residue was purified by silica gel chromatography (DCM / MeOH = 15 / 1) to give the desired product. MS (m/z): 2% (M+H)'s sigma I55 159 can be prepared by a person skilled in the art with appropriate intermediates and reagents under appropriate conditions. For specific hydration, reference can be made to compound 154.

77 S 201211044 157 NC 7~- N 334 NuO Ν 化合物 Compound 160 (8)-TV-(l-(7 is better than [2,3-4-pyrimidine-4-)pyrrolidine-3-)-7V-methyl -5-(2 good-tetrazine salium 5-) pyridine-2-amine

(8)-6-((1-(7//-pyrho[2,3-4-pyrimidin-4-).pyrrol-3-)(fluorenyl)amino)-smoke (100mg, 0.31mmol) Ammonium gasification (84 mg, 1.57 mmol) and azide steel (1 〇 8 mg, 1.66 mmol) were mixed in DMF (5.0 mL) at 丨2〇. (The mixture was stirred for 16 hours. The solvent was evaporated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The preparation can be carried out under appropriate conditions. For the specific synthesis method, reference can be made to the compound 16〇.

78

201211044 Compound 162 W)-iV-(l-(7-Dan-pyrrolo[2,3-&lt;/|pyrimidin-4-)pyrrolidin-3-)-5-hexynyl-iV-methylpyrobites - 2-amine

(A)CR)-7V-(l-(7-ugly-pyrrolo[2,3-phavidin-4-)pyrrolidin-3-)-iV-methyl-5-((trimethylfyl) Ethynyl)pyridin-2-amine (8)#(1-(7//-pyrrolo[2,3-pyrimidin-4-)pyrrolidin-3-)-5-bromo#methylpyridine-2- Amine (0.22 g, 0.58 mmol), trimethyl oxaacetylene (0.22 mL, 1.6 mmol), triethylamine (0.24 mL, 1.5 mmol), cuprous iodide (5.0 mg, 0.03 mmol), PdCl2 (PPh3) 2 ( 8.0 mg, 0. 01 mmol) and PPh3 (3.0 mg, EtOAc) were combined in DMF (3.0 mL) and stirred at 90 C for 4 hr under nitrogen. The reaction solution was cooled to room temperature, and water (3 mL) was added, and ethyl acetate (2 χ 10 mL) was extracted. The organic phases were combined, washed with brine (2×6 mL), dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography to give the desired product. MS (m/z): 295 (M+H)+. s 79 201211044 (B) (J?HV-(l-(7 heart ratios and [2,3-4 pyrimidin-4-) pyrrolidines B快基-7V_methylbite-2-amine will (8)-exhaustion (1-(7//-.biluo[2,3-compound-4-). Biluo»善methyl_ 5·((Trimethyldecyl)ethynyl)acridin-2-amine (26 mg, 0.06 mmol) and potassium carbonate (2 〇.〇mg) mixed in f alcohol (4·〇mL) It is more than 6 hours at room temperature. The solvent is distilled off and the residue is purified by column chromatography to give the desired product. MS (m/z): 319 (M+H)+. Compound 163 (/?HV-(l-( 7--pyrrolo[2,3-phavidin-4-)pyrrolidine,3,) AL methyl-3-open imidazo[4,5,pyridin-5-amine

Methylpyridine-2,5,6· (A)(/?)-7V2-(l-(7 ugly-咣 并[2,3 sylvite _4_) pyrrole, 3) ^2. amine will (8), (1 detection - material and [2, 3 life secret bite) scale burning, methyl chlorinated · nitroguanidine

2,6-diamine (320 mg, 0.90 mmol) and carbon (10 wt·%, ι〇η, A ' υυ mg) were mixed in 35 mL of ethanol at room temperature in an atmospheric hydrogen atmosphere. When the cake is 1 (tetra) carbon, the filtrate is distilled off to obtain the target product. MS (m/z): 325 (M+H)+. (B trace _ reminder-scale and [2, 3-4 do -4 ten than slightly burned, 3 cut methyl _3 from taste spit and [4, 5-6] Pyridin-5-amine will (Fantasy-#2-(1-(7-Lepyrrolo[2,3-pyrimidin-4-)pyrrolidine, fly,)^2〇^ _ 3,) -#-picolin-2,5,6-triamine (35 mg, 0.11 mm〇l), triethyl orthoformate (0.58 mL, 3 4 ς , · · 45 mmol) and p-toluene acid 201211044 monohydrate (62 mg, 0.33 mmol) was mixed with methanol (3.0 mL) in a microwave reactor (InitatorTM Biotage) at 150. (: stirring for 5 minutes. The reaction solution was evaporated and the residue was purified by silica gel chromatography. Purification to give the desired product: MS (m/z): 335 (M+H)+. Compound 164 (and)-5-((1-(7 from pyrroloindole 2,3-ί/)pyrimidine-4-) Palladium-3-)(methyl)aminoimidazo[4,5-sentylpyridine-2 (3-cut-emergence

(8)-7V2-(l-(7i/-.bibromo[2,3-c/]pyrimidin-4 decitex-3-)-7V2-methylbitone-2,5,6-di The amine (35 mg, 0.11 mmol) and 1, hydrazine-dimethyl carbamide (21 mg, 0.13 mmol) were mixed in tetrahydrofuran (3.0 mL) and refluxed for 1 hour. The solvent was evaporated and the residue was evaporated. Purification by gel column chromatography to obtain the desired product. MS 〇η/ζ): 351 〇VI+H)+. Compound 165 (i〇-3_(l-(7吼吼和丨2,3·...pyrimidine_4 Ten ratios _3_)_6_cyano-2.oxo-2,3_dihydro-1open-imidazolium 4,5-sequence acridine

(A)(i?)-6-(l_(7 is better than 并[2,3_^/] pyridine bite_本) 吼洛烧j amino)_5 amino nicotinonitrile to (8)-6-(l-(7/ /-t each [2, 3-4 pyrimidine-4-)pyrrolidin-3-amino)-5-nitronicotinonitrile is the original 201211044 material 'synthesis method, see the preparation process of compound 163 (A). MS (m/z): 321 (Μ+Η)+·(Β)(8)-3-(1-(7-pyrido[2,3-(/]pyrimidine-4-)pyrrolidine-3 -)-6-cyano-2-oxo, 2,3 虱-1 ugly-flavored and [4,5-Z&gt;]nt bite with (8)-6-(1-(7//-« ratio咯[2,3_4 pyrimidine _4 decarotane respective amino group)_5_aminonicotinonitrile as raw material 'Synthesis method See the preparation process of compound 164. MS (m/z): 347 (M+H)+. Compound 166 (8) _4_((1-(7-pyrido[2,3 岣 咬 _4_) pyrrole _3_) (methyl)amino)_3·amino stupid

(8) _4-((1-(7//-pyrrolo[2,3_4 pyrimidine_4_) „ 咯 院 _3_) (methyl)amino) _3 · indeed basic carbonitrile as raw material 'synthesis method see compound 163 ( A) Preparation process. MS (m/z): 334 (M+H)+. Compound 167 (/?) good (1-(7 good-0 than Luo and [2,3_4 mouth 唆_4 ten billo烧_3_)_7V_Methylazolo[4,5-6]pyridine-5-amine

In (i?)-7V2-(l-(7//-° ratio p and [2,3_4 mouth bite-4-)° Β·$Ί3-)-7ν2-methyl. Concentrated sulfuric acid (23 uL) was added to a 0.6 mL aqueous solution of triamine (50 mg, 〇_15 mmol), and the mixture was allowed to stand at room temperature for 1 hour and then cooled to 0. (:, adding 0.1 mL of sodium nitrite (17 mg, 0.25 mmol) in water, and the solution was stirred. The reaction solution was further stirred at 0 ° C for 1 hour, and adjusted to pH = 5 with 10% aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate (3×10 mL). The organic phase was combined, washed with brine, and then washed with brine (2 χ 10 mL), dried over anhydrous sodium sulfate, filtered and evaporated. (m/z): 336 (Μ+Η)+· Compound 168 (External 6-((1-(7-Pyropyrrolo[2,3_ 岣 咬 咬 咯 _ _ _ _ _ _ _) Methyl ester

Add (8) each to (5 liters of hydrogen chloride in methanol (6 Μ)) ((1_(7 such as 咯比和[2 3_^嘴咬-4-) ° ratio 11 each burn -3-) (methyl) amino) smoke Bet (31.9 mg, 0.1 mmol), sandalwood at 65 °C for 14 hours. The solvent of the reaction mixture was evaporated, and the residue was purified by silica gel column chromatography. Ms (m/z): 353 (M+H)+. Compound 169 (8)-0-((1-(7-pyrido[2,3 pyrimidinyl)pyrrolidine·3_)(methyl)amino) Nicotinamide

83 S 201211044

κ

(8)-6-((l-(7 from pyrrolo[2,3-4]pyrimidine]pyrrolidine_3_χmethyl)amino)nicotinonitrile (31.9 mg, 0.1 mmol), aerobic sodium oxide solution (1.0 M , 0.7 mL, 0.7 mmol) and an aqueous hydrogen peroxide solution (30%, 0.3 mL) were mixed in methanol (1.0 mL), stirred at room temperature for 2 hours and then added to 10 ° /. The aqueous solution of NaAzO3 was not detected until no peroxide was detected. The reaction mixture was concentrated and extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered and evaporated. MS (m/z): 338 (M+H)+. Compound 170 W)-6_((l-(7--pyrrolo[2,3-4-pyrimidine_410 syllabary_3_)) Amino) nicotinic acid

(8)-6-((1-(77/-pyrrolo[2,3-4-pyrimidin-4-) t-alkane-3-)(indolyl)amino)nicotinonitrile (160 mg, 0·5 Concentrated hydrochloric acid (5 〇 mL) was added to mmol) and stirred at 100 ° C for 14 hours. The reaction mixture was evaporated to give the title compound. MS (m/z): 339 (μ+Η)+· 84 201211044 Compound πι (8)-6_((l-(w_Scale[2,34 vs_4_)transformed methyl)Amino)propyl Tobacco amine

(8) Each ((1-(7) was added sequentially from a solution of pyrrolo[2,3-tweet _4 deca-butyr (methyl)amino)nicotinic acid (33.8 mg, 0.1 mmol) in DMF (2 mL) Cyclopropylamine (5 71 tons, 〇 2 mmol) 'DIPEA (26 mg, 〇·2 curry 1) and HATU (38. 〇mg, 〇丨 〇丨, stirring at room temperature for 16 hours. Evaporate the solvent, The residue is purified by silica gel column chromatography to give the desired product. MS (m/z): 378 (M+H)+. Compounds 172-209 can be carried out by one skilled in the art using appropriate intermediates and reagents under appropriate conditions. For the specific synthesis method, refer to 彳 ,, compound 171. Compound structure MS (m / z) (M + H) + compound structure MS (m / z) (M + H) + 172 ^ HN-Bn N , 13⁄4 ——NK — 428 191 V rfr Η 432 —--1

S 85 201211044

86 201211044 178 〇=&gt;O~-f Qn &amp; N 03 446 197 o Q ct N 03 428 179 cfr &amp;} NNNH 475 198 VN~~ N 03 S person K 415 180 (&gt;F 0R) N ΝΛ&gt ; NN 441 199.矽N — NNN 421 181 Q zn~ cf N 03 414 200 , p Qn Φ NU〇472 182 O^'^PNMNMH 459 201 pp 〇=θ~ΟΗ 0R, N 6c&gt; NN 509 (35C1) 511 (37C1) 87 201211044 183 O^0~〇\ Qn /N- &amp;) &amp; ^ H 444 202 hn-^0H dR, N 0C&gt; NNH 475 184 HO . Talk about FN-Cf) N 03 487 203 Let F N-0&quot; N03 487 185 QQ Cl F &amp;&amp; NH 46 5 (35C1) 467 (37C1) 204 〇PFN~ d(R) &amp;} N π 487 186 0=/0- cf N 03 428 205 〇^£ Q^ci /n' ct) NNNMH 491 (35C1) 493 (37C1) 88

Compound 210 (i?)-iV-(6-((l-(7i/-pyrrolo[2,3-rf]pyrimidin-4-)pyrrolidin-3-)methylamino)pyridine-3-) Sulfaguanamine £ 89 201211044

(A) (/?)-TV-(6-(methyl(1-(7-((2-(dimethyl)yl)ethoxy)methyl)_7 ugly-pyrrolo[2,3_ Pyrimidine-4-)pyrrole-3-)amino)pyridine-3-)ethylsulfonamide 0.3 mmol of ethyl sulphate was added to dissolve in 0 25 mmol(8)-#2-methyl-#- (1-(7-((2-(trimethylglycosyl)ethoxy)methyl) in a mixed solution of pyridine-2,5-diamine, 0.3 mmol triethylamine, 5 ml dichloromethane, room The mixture was stirred under temperature for 18 hours. The reaction mixture was concentrated and then evaporated to give a purple solid (yield: 42%). (B) (i- HV-(6-(-)-pyrpyridinium 2,3- 4-pyrimidin-4-)pyrrolidin-3-)methylamino)pyridin-3-)ethylsulfonamide (i〇-7V_(6-(indolyl)-(1-(7-((2-())矽 )) ethoxy) fluorenylpyrrolo[2,3&lt;pyrimidin-4-)pyrrolidin-3-)amino)pyridine-3-)ethylsulfonamide as a starting material, for the synthesis method see compound 23 ( Preparation Process of B) MS (m/z): 402 (Μ+Η)+· Compounds 211-229 can be prepared by a person skilled in the art with appropriate intermediates and reagents under appropriate conditions. 210. MS Compound Structural Formula MS (m/z) Compound Structural Formula (m/z) (M+H)+ (M+H)+ 201211044 211 HN cf' N 03 V person a 464 221 %° Φ &amp;} NH 482 212 ci' N 03 , person H 468 222 \P z1'- c1RI buckle. 478 213 &amp;} NH 486 223 i^N cf NV, 498 214 rfr 13⁄4 NNNH 456 224 \'p HpT i^N /N^ rt ά) NK 498 215 Q4 ci^ H 13⁄4 NNNH 451 225 V HP^c, ,N- & N iV) N fj 498 216 v&lt;? HN 〇Q /n' &amp; N 13⁄4 NK 414 226 fy F rfr 13⁄4 Μ NNH 432

S 91 201211044 217 V HN 〇 Ν 388 388 227 Λ /n' ct Λ} Ν N 448 218 /ν~ cf Ν 03, person n 416 228 op. '·HN /N' cf, N 03 382 219 hnmU dF N 03 , human il 482 229 V&lt;] HN , N' cf N 03 378 220 i^N cf N 03 V human k 482 Compound 230 (/?)- 7V5-(4-fluorobenzyl)-;V2-(l-(7--0-pyrolo[2,3-rf]pyrimidin-4-de-pyrrolidine-3-)-A^-methyl-bite -2,5-diamine 92 201211044

(A)(8)-jin 1-(4-fluorobenzyl)-V_methyl_λ^(1-(7-((2_(trimethylmethyl)ethoxy)methyl)-W-nb Luohe [2,3_4 pyrimidine _4_)pyrrolidine_3_)pyrazine 2,1_diamine will be 〇.2〇mmol(8)-ΛΑ2-mercaptotrimethylmethyl)ethoxy)methyl)-7 //-pyrrolo[2,3-JJ pyrimidine ice)pyrrolidine_3_)pyridine_2,5-diamine, 0.24 mmol potassium carbonate and 0.24 mmol of I gas in 5 ml of DMF in 8〇〇c The reaction was stirred for 18 hours. After cooling to room temperature, it was poured into water and extracted with ethyl acetate. The organic phase was combined with water, washed with saturated brine, and concentrated under reduced pressure to dryness. ). (9) (8) _λγ5_(4-fluoro-knot group> Ά(1·(7 ugly ratio 咯[2,3-岣 啶 _ 4 4 户 户 户 户 户 3 3 3 3 3 3 3 3 3 3 3 -2 -2 -2 -2 -2 -2 -2 -2 , , , , , , , , , , , Diamine (8)-#-(4-fluoro-benzyl)-'methyl_#2_(1_(7-((2(trimethylfyl)ethoxy)methyl))))) 3-♦ close bite -4-). Compared with peach _3 ten bite _2, 1_diamine as raw material, the synthesis method can be found in the preparation process of compound 23 (B). MS 418 (M+Hf compound 231 (/? )-6-((1 傅·“叫和丨2,3-rf]细_4_) 烧烧_3·)Methylamino)_cis dimethyl acridine-3_ oxime amine 93 1 201211044

SEM

(A) 6-Chloro-TV, AL dimethylpyridine-3-sulfonamide in 2 ml of tetrahydrofuran, sequentially added 1 111111 〇 16-gas ° than bite -3- scutellaria, 2 mmol three Ethylamine and 2 mmol of decylamine were stirred at room temperature for 30 minutes and then ended. The system was diluted with ethyl acetate, washed with saturated aq. water, dried, filtered, and concentrated to give a crude product of &lt;RTI ID=0.0&gt;&gt; (B) (and HV nasal dimethyl-H methyl (1-(7-((2-(trimethylmethyl))ethoxy)methyl)) 7 ugly 吼 并 [2,3垌Pyridinium _4_) pyrrolidine _3_) amino) cycline _3_ continuation of decylamine to / under the dish in 2 mliV-mercapto 吼 *1 in each of the sputum, 1 mmol of 6-chlorodimethyl pyridine Indoleamine, 2.5 mmol DIPEA and 0.5 〇 ( 1 (8) # 曱 小 small (7_((2_(trimethyl sulphate) ethoxy) methyl 吼 吼 各 [2,3__. fixed clock ratio 嘻 _ 3 amine microwave Under the conditions of 200. (: 1 hour reaction. After the reaction is completed, it is cooled to room temperature. The system is diluted with ethyl acetate, washed with saturated brine, dried, filtered, condensed, purified by flash column chromatography to obtain the target product. (6) (8) Na book scales and 丨 π · Correction scales to fly base) solution dimethyl 11 than bite-3-continued amine

S 94 201211044 Compound 23 (B) preparation process. MS (m/z): 4〇2 (Μ+Η)+· Compound 232-259 can be prepared by a person skilled in the art with appropriate intermediates and reagents under appropriate conditions, and the specific synthesis method can be referred to the compound 231. Compound Structural Formula MS (m/z) (M+H)+ Compound Structural Formula MS (m/z) (M+H)+ HV &gt; 〇〇^)X 232 /N~ ct N 506 246 N— N 458 233 HN^(] rt N 506 247 0 〇)=\ /n_ 0R&gt; N 428 03 NHN n . ΓΓ NH , 234 d, N 374 248 /N~ &amp; N 445 03 , person N 03 V person κ r^] MeO—' b Q 235 (1r ά&gt; N N 428 249 ct 13⁄4 N N M H 472

S 95 201211044 236 i&gt; rfr &amp;) NN 414 250 / NN i^N /N_ AN 03 454 237 〆〇- dR, N 432 251 〇HV^N /N_ &amp; N 03 443 238 &amp; N 430 252 \ C) h: φ Λ &gt; NNNH 444 239 \ &lt;r 388 253 \s&quot;〇-f °Q dR&gt; NNN 468 240 Φ &amp;} NN 402 254 .吖 cf 482

S 201211044 rP 〇&gt;=\ °^nV 〇% 241 Qn N— 458 255 Q dR, N&amp; NH 496 242 〇C°0 0 )=\ i^N ^r N 03 , person κ 430 256 〇aF 〇 JS; % N - &amp; Ni) NH 496 plant OH HN j \_^N \ 243 dR&gt; 418 257 /N_ ct N 458 03 , human n N Π 244 V-OH HN j(8) °〇% cf~ 432 258 °W ^NH % 0r N 440 isxy NH 245 ^iS) r~OH \^NN — ct N 03 432 259 P ,N~ &amp; NH 458 s 97 201211044 Compound 260 (/?)-6_((1 Futuan [2,3, bite clock than Luo Shao _3_) methylamino) fun base · 3 atmosphere base

Dissolve 〇43 mm〇i in a mixed solvent of 0.4 ml of concentrated hydrochloric acid and 2 ml of glacial acetic acid (magic-&amp; ((1-(7-foot) pirox [2,3-_bit-4). Hyun _3_) methylamino)·2—decyloxy glacial nitrogen base ^ bite back

Purification by phase chromatography gave the desired product. MS Ο/ζ): 336 (;Μ+Η)+. Example 2 Analysis of JAK1/2/ using Z'-LYTETM Kinase Assay Kit-Tyr 6 Peptide (Invitrogen, Cat. No. PV4122) Kit 3 kinase activity. The TYK2 kinase activity was analyzed using the Kitacin ugly (10) Kyrgyzstan-Tyr 3 Peptide (Invitrogen, Cat. No. PV3192) kit. Recombinant human JAK1/2/3 or TYK2 kinase from Invitrogen (Cat No. PV4774/PV4210/PV3855/PV4790); 20 μί total reaction solution as follows, containing 2.5 pL of test compound dissolved in 4% DMS0, 5 μί enzyme/substrate mix Buffer (containing 3.2, 0.04, 0.2, 8 gg/mL recombinant human JAK1/2/3 or ΤΥΚ2 kinase, 4 μΜ Tyr 6 or Tyr 3 reaction substrate peptide) or Tyr 6 or Tyr 3 basified substrate buffer ( Invitrogen, Cat.No·PV3192, with 1.33χ

98 S 201211044 kinase buffer dilution), 2.5 of this ATP solution (3〇〇/ΐ〇〇/4〇/ΐ〇〇μΜ, JAK1/2/3 or TYK2 kinase) or ι ·33 x kinase bufferer nvitr〇gen , (3) N〇pv3l89, 5 X kinase slow filament, diluted with water). The components in the reaction well (total volume 10μ1) were thoroughly mixed in a 384-well plate and the chamber was incubated for 1 hour, adding 5 μ [to the oiler (10) solution (for the ΑΚ1, JAK2, JAK3 reaction, the reagent A ( Devei〇pmem 邱 职 职 a, pv3297) diluted in reaction buffer (Devei〇pment Buffer) with 丨: 64. For the τγΚ2 reaction, the reagent a (PV3192) was diluted 1:2048 in the reaction buffer) , mix well and incubate for 丨 hours at room temperature. Finally, the reaction was terminated by the addition of 5 μί stop solution (lnvitr0gen, Cat. No, PV3094). The components of the wells were thoroughly mixed, and the fluorescent signals of coumarin (Ex 400 nm, Em 445 nm) and luciferin (Ex 400 nm, Em 520 nm) were respectively detected by Wallac 1420 VICTOR 3 Multilabel Counter. All compounds were diluted 3 times in 8 concentration ranges (ιμΜ~〇.〇〇〇3μΜ). Most of the compounds disclosed herein are capable of inhibiting at least one kinase of the JAK1, JAK2, JAK3, and ΤΥΚ2 kinases, ic50 &lt; i.〇um. Example 3 Cell assay To detect IL6-induced phosphorylated STAT3 levels, HepG2 cells (SIBS) were resuspended in serum-free DMEM medium, seeded in 96-well plates at 5.4 M03 per well and incubated overnight in a cell culture incubator. Compounds of various concentrations were added the next day, and after incubation for 30 minutes, human recombinant IL6 was added for a final concentration of 10 ng/ml for 15 minutes. Subsequently, the cells were fixed with 2% paraformaldehyde at room temperature for 45 minutes, incubated with ice-cold methanol for 30 minutes, washed with PBS, and the cells were incubated with rabbit anti-phospho-STAT3 (Y705) (Cell Signaling Technologies) - overnight at 4 ° C, the next day. Washed first and then incubated with goat anti-rabbit IgG Alexa 488 secondary antibody for 90 minutes. Add 7.5 uM propidium iodide (containing lOOpg/ml RNaseA) for 60 minutes in the dark and read 99 201211044 plate with Acumen X3 (TPP Labtech) instrument. In order to detect IL3-induced phosphorylated STAT5 levels, TF1 cells (ATCC) were resuspended in RPMI-1640 medium containing 10% FBS, seeded in 96-well plates at 1χ1〇3 cells per well and incubated for 3 hours in a cell culture incubator. . Compounds of various concentrations were then incubated for 30 minutes and stimulated with human recombinant IL3 at a final concentration of 10 ng/ml for 30 minutes. The cells were fixed with 2% paraformaldehyde at room temperature for 45 minutes, incubated with ice-cold methanol for 30 minutes, washed with PBS, and the cells were incubated with rabbit anti-phospho-STAT5 (Y694) (Cell Signaling Technologies) for 4 days at the end of the day. Washed first and then incubated with goat anti-rabbit IgG Alexa 488 secondary antibody for 90 minutes. Add 7.5 uM propidium iodide (containing 100 pg/ml RNaseA) for 60 minutes in the dark and read the plate with an Acumen X3 (TPP Labtech) instrument. To detect IL4-induced disc acidified STAT6 levels, Ramos cells (ATCC) were resuspended in RPMI-1640 medium containing 10% FBS, seeded in 96-well plates at 1xl〇3 cells per well and incubated for 3 hours in the cell culture incubator. Subsequent addition of various concentrations of compounds, incubation for 30 minutes, and stimulation with human recombinant IL3 at a final concentration of 10 ng/ml for 30 minutes. The cells were fixed with 2% poly-furfural for 45 minutes at room temperature, incubated with ice-cold methanol for 30 minutes, washed with PBS, and the cells were incubated with rabbit anti-phospho-STAT6 (Y641) (Cell Signaling Technologies) - anti-4X overnight, followed by washing 'After incubation with goat anti-rabbit IgG Alexa 488 secondary antibody for 90 minutes. Add 7.5 uM propidium iodide (containing lOOpg/ml RNaseA) for 60 minutes in the dark and read the plate with an Acumen X3 (TPP Labtech) instrument. The percent inhibition is calculated using the following formula: Inhibition rate (%) = 100 - ((Inhibitor treatment well - cell well) / (Stimulator treatment well - Cell well)) X100 Here: Inhibitor treatment well represents both compound and irritant Fine treatment of (IL-6, IL-3 or IL-4)

S 100 201211044 Percent cell activation; cell wells represent percentage of cell activation with no compound and no stimulant (IL-6, IL-3 or IL-4), stimulator treated wells represent only stimulators (IL 6, il_3 Or iL_4) The percentage of cell activation treated. The majority of the compounds of the present invention are capable of inhibiting at least one kinase in the JAK3 and TYK2 kinases, 1 (:5〇&lt;1〇〇_.- and .Ij7, of a certain compound) The data are listed in the table below. Compound No. JAK1 (enzyme, IC5〇, μΜ) JAK2 (enzyme, ic5〇, μΜ) JAK3 (enzyme, ICs〇, μΜ) Η ΊΤ7'4&gt;7; Γ PSTAT3 (IC5〇, μΜ) PSTAT5 (ICs〇, μΜ) pSTAT6 (ic5〇, μΜ) 47 0.119 0.098 0.157 0.824 1.486 1.149 105 0.0140 0.0487 0.3594 0.009 1.680 NT 142 Γ 0.0094 0.055 0.497 Factory 〇.〇65 __^066 Γ 0.3364 199 0.01^ &quot; ~ 〇 075 0.050 7.549 NT 206 0.002 0.0005 0.047 0.0239 0.6928 0 180 234 0.0051 0.0411 0.0863 0.337 0.857 0.385 All documents mentioned in the present application are hereby incorporated by reference in its entirety as if it is the same as the reference. In addition, it should be understood that those skilled in the art can make various changes or modifications in the above-mentioned period of the present invention, and this formula is also in the scope of the patent application scope of the towel. Simple description] (none) Element symbol description] (none)

S 101

Claims (1)

201211044 VII, the scope of application for patents: L a structural formula _ at least - a compound: R; (I) and/or at least one pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl and heterocyclic groups, and R is selected from the group consisting of an alkyl group, an aryl group, a cycloalkyl group, and a heterocyclic group. , heteroaryl, &lt;(〇)1^, -C(0)NRcRd, -S(〇)nRf, ^nS(〇)nNRcRd, or R1 and R2, together with the N atom of the chain, form a 3 to 7 membered heterocyclic ring which may be optionally substituted, which heterocyclic ring additionally optionally contains 1 or 2 heteroatoms, and which may be further optionally substituted into an optionally substituted hetero An aryl group or an optionally substituted aromatic ring; and any one of the above R1 and R2, an alkyl group, an aryl group, a cycloalkyl group, a heterocyclic group and a heteroaryl group may be optionally substituted by one or more groups, These groups are selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted block, optionally substituted cycloalkyl, -C(0)Ra, - C(0)〇Rb, -CN, -C(0)NRcRd, halogen, optionally substituted haloalkyl, optionally substituted heterocyclic, optionally substituted heteroaryl, -NRcRd, -NReC(0) Ra, -NReC(〇)〇Rb, (9)NRCRd, NReS(0)nRf, _NReS(0)nNRcRd -N〇2, -0Rb, _s(〇)nRf, and -S(0)nNRcRd; 102 s 201211044 m and η are independently selected from 〇, 丨 and 2; for each of the above, Ra, Rb, Re, Rd, Re and Rf, each independently selected from the group consisting of chloro 'optionally substituted alkyl, optionally substituted fluorenyl, optionally substituted alkynyl, optionally substituted fen-group, optionally substituted aryl, An optionally substituted haloalkyl group, an optionally substituted heteroaryl group and an optionally substituted heterocyclic ring, or Re and Rd' together with the nitrogen atom to which it is bonded form a heterocyclic ring which may be one or more a group selected from the group consisting of dentin, a lower alkyl group, a hydroxyl group, and a lower alkoxy group, which may additionally optionally contain 1 to 2 hetero atoms selected from N, fluorene and s; m is 1 'R1 and R2 cannot be methyl at the same time, or when m is 1 and R1 is hydrogen or ethyl, R2 is not an ethyl group. 2. The at least one compound of claim 1, and / or at least one pharmaceutically acceptable salt, wherein m is 1. 3. The at least one compound of claim 1 or 2, and/or at least one pharmaceutically acceptable salt, wherein R is selected from the group consisting of a pit group and a cycloalkyl group, and each of the alkyl group and the cycloalkyl group is optional. Substituted by one or more groups selected from the group consisting of an optionally substituted lower alkyl, an optionally substituted aryl 'optionally substituted alkenyl, an optionally substituted fast group, an optionally substituted ring Base, _C(C〇Ra, &lt;(0)00, -CN, -C(0)NReRd, dentate, optionally substituted alkyl, optionally substituted heterocyclic, optionally substituted Miscellaneous NReC(0)ORb, -NReC(0)NRcRd, _NTS(0)nRf, _Res(〇)nNRCRd, _N〇2, -0Rb, -S(0)nRf, and _s(〇)nNRcRd. The at least one compound of any one of claims 1 to 3, and/or at least one pharmaceutically acceptable salt, wherein R is an aryl or heteroaryl group, and each aryl or heteroaryl group may be any Optionally substituted with a plurality of groups selected from the group consisting of an optionally substituted lower alkyl group, optionally a 103 S 201211044 substituted aryl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, Substituted substituted cycloalkyl, -C(0)Ra, -C(0)0Rb, -C N, -C(0)NRcRd, halogen, optionally substituted haloalkyl, optionally substituted heterocyclic, optionally substituted heteroaryl, ?^^^^, -NReC(0)Ra ' -NReC( 0) 0Rb, -NReC(0)NRcRd, -NRes(〇)nRf, -NReS(0)nNRcRd, -N〇2, -〇Rb, -S(0)nRf, and -S(0)nNRcRd 〇5 The at least one compound of any one of claims 1 to 3, and/or at least one pharmaceutically acceptable salt, wherein R 2 is an alkyl group or a cycloalkyl group, and each alkyl group or cycloalkyl group may be optionally selected. The ground is substituted with one or more groups selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted alkenyl group, an optionally substituted fast group, an optionally substituted ring Affiliation '-C(0)Ra, -C(0)0Rb, -CN, -C(0)NRcRd, halogen, optionally substituted haloalkyl, optionally substituted heterocyclic, optionally substituted Heteroaryl, _]^. Ruler (1, _NReC(0)Ra, -NReC(0)0Rb, -NReC(0)NRcRd, -NRes(〇)nRf, _NReS(0)nNRcRd, -N〇 2. -ORb, -S(0)nRf, and -S(0)nNRcRd. 6. At least one compound of any one of claims 1 to 3, and/or at least one pharmaceutically acceptable salt' among them R2 is -C(〇)Ra, -C(0)NRcRd, or -S(0)nNRcRd, and each of Ra, Re and Rd is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted an alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted dentate alkyl group, an optionally substituted heteroaryl group, and an optionally substituted heterocyclic group, or Re Together with Rd, and the nitrogen atom to which it is bonded, form a heterocyclic ring which may be optionally substituted by one or more groups selected from the group consisting of an element, a lower alkyl group, a hydroxyl group, and a lower alkyl fluorenyl group. This heterocyclic ring may further optionally contain up to two heteroatoms selected from the group consisting of N, fluorene and S. 7. The at least one compound of any one of claims 1 to 4, and/or at least one pharmaceutically acceptable salt, wherein R2 is an aryl or heteroaryl group selected from the group consisting of S 104 201211044 Each aryl or heteroaryl group may be optionally substituted by one or more groups selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted alkenyl group, Optionally substituted alkynyl, optionally substituted cycloalkyl, -C(0)Ra, -C(0)0Rb, -CN, -C(0)NRcRd, halogen S 105 201211044, optionally substituted tooth Alkenyl, optionally substituted heterocyclic, optionally substituted heteroaryl, -NRcRd, -NReC(0)Ra, -NReC(0)ORb, -NReC(〇)NRcRd ' -NReS(0)nRf , -NReS(0)nNRcRd, -N02, -ORb, -S(0)nRf, and -S(0)nNRcRd. 8. At least one compound and/or at least one pharmaceutically acceptable salt according to claim 7, wherein R2 is an aryl or heteroaryl group selected from the group consisting of Each aryl or heteroaryl group may be optionally substituted by one or more groups selected from the group consisting of an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted alkenyl group, and any Substituted substituted alkynyl, optionally substituted cycloalkyl, -C(0)Ra, -C(0)0Rb, -CN, -C(0)NRcRd, halogen, optionally substituted haloalkyl, optionally substituted Heterocyclic group, optionally substituted heteroaryl group, -NRcRd, -NRec(〇)Ra, -NReC(0)0Rb, -NReC(0)NRcRd, -NReS(0)nRf, -NReS(0)nNReRd , -N〇2, -〇Rb, -S(0)nRf, and -S(0)nNRcRd. 9. At least one compound of claim 8, and/or at least one pharmaceutically acceptable salt 'wherein R2 is, which may be optionally substituted with one or more groups selected from the group consisting of Substituted lower alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -C(0)Ra, -C(0)0Rb, -CN, -C(0)NReRd, _ 素, optionally substituted dentate alkyl, optionally substituted heterocyclic, optionally substituted heteroaryl, -NReRd, -NReC(0)Ra, -NReC (0) 0Rb, _ NReC(0)NRcRd, -NReS(0)nRf, -NReS(0)nNRcRd, -N〇2, -ORb, -S(〇)nRf, and _s(0)nNRcRd 〇10 The at least one compound of claim 8, and/or the at least one pharmaceutically acceptable salt 'wherein R2 is _^^, which may be optionally substituted by one or more groups, these groups 106 S 201211044 Group selected from optionally substituted lower alkyl, optionally substituted aryl 'optionally substituted alkenyl' optionally substituted alkynyl' optionally substituted cycloalkyl, -C(0)Ra, -C (0) 0Rb, _CN, _C(0)NReRd, halogen, optionally substituted haloalkyl, optionally substituted Ring group, optionally substituted heterog*, -NReRd, -NReC(0)Ra, -NReq〇pilb, _NReC(〇)NRcRd, -NReS(0)nRf, -NReS(0)nNRcRd, -N〇 2. Ice, S(0)nRf, and -S(0)nNRcRd. 11. The at least one compound of any one of claims 1 to 10, and/or at least one pharmaceutically acceptable salt, wherein R1 is selected from the group consisting of alkyl, allyl, propargyl and cyclopropyl of Cu3 The alkyl, allyl, propargyl and cyclopropyl groups of each Cw may be optionally substituted by one or more groups' These groups are selected from optionally substituted lower alkyl groups, optionally substituted An aryl group, an optionally substituted dilute group, an optionally substituted fast group, an optionally substituted ring group, _C(〇)Ra, _C(0)0Rb, -CN, -C(0)NReRd, halogen, Optionally substituted haloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -NRcRd, _NReC(0)0Rb, -NReC(0)NRcR' '-NReS(0)nRf, -NReS (0) nNRcRd, _N02, -〇Rb, -S(〇)nRf, and -S(〇)nNRcRd. 12. At least one compound as claimed in claim ii, and/or at least one pharmaceutically acceptable salt, wherein R1 is methyl. 13. The at least one compound of any one of 12, and/or at least one pharmaceutically acceptable salt, wherein the absolute stereochemistry of the carbon atom attached to the -NCR^R2) group is a configuration . I4 is at least one compound selected from the group consisting of Compounds 1 to 260, and/or at least one pharmaceutically acceptable salt. A composition comprising at least one compound according to any one of claims 1 to 14 and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 107 S 201211044 16. A medicament for inhibiting activity of at least one kinase selected from the group consisting of JAK1, JAK2, JA-magic and τγκ2 kinase, characterized by comprising an effective amount of at least one compound as claimed in claim 1 and/or At least one pharmaceutically acceptable salt thereof. Use of the compound of the present invention, and/or a pharmaceutically acceptable salt thereof, characterized in that the preparation for inhibiting at least one selected from the group consisting of JAK1 'JAK2, Dish 3 and TYK2 kinase A drug that is active in a kinase. Use of a compound according to any one of claims 1 to 3, and/or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the treatment of an inflammatory disease or cancer. The use according to claim 17, characterized in that the cancer is a cancer associated with activity of at least one kinase selected from the group consisting of JAK1, JAK2, JAK3 and TYK2 kinases. Use of a compound according to any one of claims 1 to 14, and/or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for cancer, and the medicament is combined with other anticancer agents The medicament or the medicament described contains other anti-cancer agents for the treatment of cancer associated with activity of at least one kinase selected from the group consisting of JAK, JAK3 and TYK2 kinases. 108 201211044 IV. Designated representative map: (1) The representative representative of the case is: (none). (2) A brief description of the symbol of the representative figure: (none). 5. If there is a chemical formula in this case, please reveal the chemical formula that best shows the invention's characteristics: 2