CN105712998B - Azaindole derivatives, preparation method and medical application thereof - Google Patents
Azaindole derivatives, preparation method and medical application thereof Download PDFInfo
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Abstract
The invention relates to azaindole derivatives, a preparation method and application thereof in medicines. Specifically, the invention relates to a novel derivative shown in a general formula (I), a medicinal salt thereof or a medicinal composition containing the derivative and a preparation method thereof. The invention also relates to application of the derivative and pharmaceutically acceptable salts thereof or a pharmaceutical composition containing the derivative in preparation of a therapeutic agent, in particular a Janus kinase 3(JAK3) inhibitor, and in preparation of a medicament for treating and/or preventing inflammation-related diseases. Wherein, each substituent group in the general formula (I) is the same as the definition in the specification.
Description
Technical Field
The invention relates to a novel azaindole derivative, a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, and a preparation method thereof. The invention also relates to application of the derivatives and pharmaceutically acceptable salts thereof or a pharmaceutical composition containing the derivatives in preparation of a therapeutic agent, a Janus kinase 3 inhibitor and a medicament for treating and/or preventing inflammation-related diseases.
Background
janus kinase/signal transduction and transcription activator (Janus-activated kinase and activators of transcription, JAK/STAT) is a cell signaling pathway closely related to cell factors discovered in recent years. When cytokines, such as interferons, growth hormones, interleukins, etc., bind to their receptors, JAKs phosphorylate cytokine receptors and further phosphorylate and activate STAT proteins recruited by the phosphorylated cytokine receptors. Activated STATs leave the receptor and form dimers, which are then transferred to the nucleus and bind to DNA resulting in gene transcription, thereby effecting intracellular signal transduction. Many JAK/STAT pathways are expressed in leukocytes, and are involved in many important biological processes such as proliferation, differentiation, apoptosis, and immune regulation of cells, and if their functions are disturbed or deregulated (usually genetic or acquired genetic defects), immune deficiency syndrome and cancer will result. Targeting the module in JAK/STAT is therefore an effective means of treating such diseases.
Janus kinase (JAK) is a non-receptor tyrosine protein kinase, and inhibitors thereof can be used for preventing and treating diseases mediated by JAK, such as hematological diseases, tumors (breast cancer, pancreatic cancer, small cell lung cancer and the like), rheumatoid arthritis, psoriasis and the like. There are 4 family members of Janus kinases, JAK1, JAK2, TYK2 and JAK3, the first 3 of which are widely present in various tissues and cells, while JAK3 is only present in the bone marrow and lymphatic system. Therefore, JAK3 is a very attractive target for suppressing immune responses.
Tofacitinib (CP-690550) is the only novel oral JAK3 inhibitor developed by Peucedanum and approved by FDA at present, and is used for treating rheumatoid arthritis. However, tofacitinib clinically causes some adverse effects, such as severe infection and increased risk of cancer and heart failure. These adverse reactions may be due to the potent inhibitory effect of tofacitinib on JAK1, JAK2 and JAK 3. In addition, tofacitinib has a short half-life in humans and needs to be taken twice a day. Therefore, the development of more potent and more specific inhibitors of JAK3 would provide better treatments for patients with inflammation and other diseases modulated by JAK 3. Through continuous efforts, the present inventors designed compounds having a structure represented by general formula (I), and found that compounds having such a structure exhibit excellent effects and actions.
Disclosure of Invention
the present invention aims to provide a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof:
Wherein:
A1、A2And A3Each independently selected from N or CR3But not N at the same time;
R1And R2Each independently selected from H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally substituted with one OR more groups selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -OR4、-OC(O)NR5R6、-C(O)OR4、-C(O)NR5R6、-C(O)R4、-NR5R6、-NR5C(O)R4、-NR4C(O)NR5R6、-S(O)mR4or-NR5S(O)mR4Substituted with the substituent(s);
R3Selected from H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or substituent (W):
l is independently selected from the group consisting of a bond, -CH2-、-CH(CH3)-、-C(CH3)2-、-CH(OH)-、-C(O)-、-CH2O-、-OCH2-、-SCH2-、-CH2S-、-N(R5)-、-N(R5)C(O)-、-C(O)N(R5)-、-N(R5)CON(R6)-、-O-、-S(O)m-、-N(R5)S(O)2-or-S (O)2N(R5)-；
Ring B is independently selected from cycloalkyl, heterocyclyl, aryl OR heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally substituted with one OR more groups selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -OR4、-OC(O)NR5R6、-C(O)OR4、-C(O)NR5R6、-C(O)R4、-NR5R6、-NR5C(O)R4、-NR4C(O)NR5R6、-S(O)mR4or-NR5S(O)mR4substituted with the substituent(s);
Z is independently selected from H, NHR7CN、
Ra、Rband RcEach independently selected from H, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally substituted with one OR more groups selected from halogen, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -OR4、-OC(O)NR5R6、-C(O)OR4、-C(O)NR5R6、-C(O)R4、-NR5R6、-NR5C(O)R4、-NR4C(O)NR5R6、-S(O)mR4or-NR5S(O)mR4Substituted with the substituent(s);
RaAnd RbChemical bonds can be formed;
R4、R5And R6Each independently selected from H, C1-C8 alkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl, or monocyclic aryl;
R7Independently selected from H or C0-C3 alkyl; and is
m is 0, 1 or 2.
In one embodiment of the present invention, a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof:
Wherein:
R1、R2and R3Is as defined in claim 1.
In another embodiment of the present invention, a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt thereof, which is a compound of formula (IV) or (V) or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt thereof:
wherein R is3Is as defined in claim 1.
Typical compounds of the invention include, but are not limited to:
Or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof.
The invention further relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
Another aspect of the invention relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a Janus kinase 3 inhibitor.
Another aspect of the present invention relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of a disease associated with inflammation.
The present invention also relates to a method for the treatment and/or prevention of inflammation-related diseases, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, mixture thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
Another aspect of the present invention relates to a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, as a medicament for treating and/or preventing inflammation-related diseases.
Detailed Description
unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group including straight and branched chain groups of 1 to 20 carbon atoms, such as straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and the various branched chain isomers thereof, and the like. Alkyl groups may be optionally substituted or unsubstituted. The range of carbon atoms can also be expressed in terms of "Cx-Cy" where x and y are integers, e.g., C1-C8 indicates that any number of carbon atoms from 1 to 8 can be included in the carbon chain. x may be 0, for example C0 alkyl, which represents a bond. This carbon number range representation is also applicable to other carbon-containing substituents in this specification.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. It comprises 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted.
"Heterocyclyl" means a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) but excludes the ring moiety of-O-, -O-S-or-S-, and the remaining ring atoms are carbon. Preferably 3 to 12 ring atoms of which 1 to 4 are heteroatoms, more preferably the heterocyclyl ring comprises 3 to 10 ring atoms, most preferably a 5-or 6-membered ring of which 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, most preferably 1 to 2 are heteroatoms. . Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azetidinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
"Spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group with one atom (called the spiro atom) shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2),The remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiroheterocyclyl radicals include
"fused heterocyclyl" means a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
And the like. The heterocyclic group may be optionally substituted or unsubstituted.
"aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
The aryl group may be substituted or unsubstituted.
"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Preferably 5 to 10 membered. More preferably, heteroaryl is 5-or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and the like, which heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Heteroaryl groups may be optionally substituted or unsubstituted.
"halogen" means fluorine, chlorine, bromine or iodine.
"cyano" means-CN.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
examples
The preparation of the compounds of formula (I) or pharmaceutically acceptable salts thereof according to the present invention can be accomplished by the following exemplary procedures described in the examples and the associated publications used by those skilled in the art, which are not intended to limit the scope of the present invention.
the structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDC 1)3) Or deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS), chemical shift is 10-6(ppm) is given as a unit.
MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6110) or Shimadzu SQD (ESI) mass spectrometer (manufacturer: Shimadzu, model: 2020).
HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5 μm, column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm, 5 μm column).
the thin layer chromatography silica gel plate adopts Qingdao ocean GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses Qingdao ocean silica gel of 200-300 meshes as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Beijing coupled Chemicals, and the like.
In the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction uses a GCD-500G high-purity hydrogen generator and a BLT-2000 medium-pressure hydrogenation instrument of Beijing Jiawei scientific and technological Limited.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-SP type microwave reactor.
In the examples, the reaction temperature was room temperature and the temperature range was 20 ℃ to 30 ℃ unless otherwise specified.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents, A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound.
The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include a: dichloromethane and methanol systems; b: the volume ratio of the solvent in the petroleum ether and ethyl acetate system is adjusted according to different polarities of the compounds, and a small amount of triethylamine, an acidic or basic reagent and the like can be added for adjustment.
Example 1
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-yl) acryloyl amide
First step of
Tert-butyl 1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-ylcarbamate
The compound 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine 1a (154mg, 1.0mmol), tert-butylpiperidin-3-ylcarbamate 1b (200mg, 1.0mmol), N-diisopropylethylamine (387mg, 3.0mmol) and 1, 4-dioxane (5mL) were mixed and reacted by microwave heating to 120 ℃ for 0.5 hour. Cooling to room temperature, and desolventizing under reduced pressure. Water (20mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL. times.3). The organic phases were combined and washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 30/1) to give the objective product tert-butyl 1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-ylcarbamate 1c (210mg, white solid) in yield: 66 percent.
MS m/z(ESI):318[M+1]
second step of
1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-amine
the compound tert-butyl 1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-ylcarbamate 1c (210mg,0.66mmol), trifluoroacetic acid (3mL) and dichloromethane (10mL) were mixed and stirred at room temperature for 1 hour. Desolventizing under reduced pressure gave the trifluoroacetate salt of the desired product 1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-amine 1d (500mg, crude), yield: is more than 100 percent. The product was used in the next reaction without further purification.
MS m/z(ESI):218[M+1]
The third step
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-yl) acryloyl amide
The mixture 1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-amine 1d (500mg, crude), N-diisopropylethylamine (2mL) and dichloromethane (10mL) were cooled to 0 deg.C, a solution of acryloyl chloride (255mg, 0.66mmol) in dichloromethane (0.5mL) was added, and the reaction mixture was stirred at 0 deg.C for 1 hour. The solution was removed under reduced pressure and the residue was purified by preparative TLC (dichloromethane/methanol ═ 10/1) to give the desired product N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-3-yl) acryloylamide (20mg, white solid) in yield: 11 percent.
MS m/z(ESI):272[M+1]
1H NMR(400MHz，DMSO-d6)δ11.66(s,1H),8.17(d,J＝7.3Hz,1H),8.12(s,1H),7.18(s,1H),6.71(s,1H),6.27(dd,J＝17.1,10.0Hz,1H),6.13(dd,J＝17.1,2.3Hz,1H),5.60(dd,J＝10.0,2.3Hz,1H),4.56(d,J＝9.8Hz,1H),4.43(d,J＝13.1Hz,1H),3.82-3.76(m,1H),3.22-3.17(m,1H),3.05(dd,J＝12.8,9.5Hz,1H),1.97-1.94(m,1H),1.85-1.81(m,1H),1.60-1.54(m,2H)。
Example 2
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) acryloyl amide
Example 2 was synthesized according to the procedure of example 1, except that in the first step tert-butylpiperidin-3-ylcarbamate was substituted with tert-butylpiperidin-4-ylcarbamate.
MS m/z(ESI):272[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.14(s,1H),8.05(d,J＝7.8Hz,1H),7.18(s,1H),6.59(s,1H),6.19(dd,J＝17.2,10.0Hz,1H),6.09(d,J＝18.9Hz,1H),5.58(d,J＝11.9Hz,1H),4.58(d,J＝13.2Hz,2H),4.05-3.92(m,1H),3.27-3.22(m,2H),1.88(d,J＝10.0Hz,2H),1.45-1.37(m,2H)。
Example 3
1- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-1-yl) prop-2-en-1-one
First step of
tert-butyl 5- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -3, 4-dihydropyridine-1 (2H) -carboxylate
The mixture is 4-chloro-7H-pyrrolo [2,3-d ]]Pyrimidine 1a (1.0g, 6.5mmol), tert-butyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyridine-1 (2H) -carboxylate 3a (1.0g, 6.5mmol), sodium carbonate (1.4g, 13.0mmol), PdCl2(dppf) (475mg, 0.65mmol), 1, 4-dioxane (20mL) and water (10mL) were heated to 95 ℃ and stirred under nitrogen overnight. After the reaction mixture was cooled to room temperature, water (50mL) was added and the mixture was extracted with ethyl acetate (30 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 50/1) to give the desired product tert-butyl 5- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -3, 4-dihydropyridine-1 (2H) -carboxylate 3b (1.3g, light yellow oil), yield: 65 percent.
MS m/z(ESI):301[M+1]
Second step of
Tert-butyl 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidine-1-carboxylate
The mixture tert-butyl 5- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -3, 4-dihydropyridine-1 (2H) -carboxylate (1.3g, 4.3mmol)3b, 10% palladium on carbon (260mg) and methanol (50mL) were catalytically hydrogenated at 2 atmospheres for 16 hours. Filtration was carried out, and the filter cake was washed with methanol (20 mL. times.2). The filtrate was desolventized under reduced pressure to give the target product tert-butyl 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidine-1-carboxylate 3c (1.3g), yield: 98 percent. The product was used in the next reaction without purification.
MS m/z(ESI):303[M+1]
The third step
4- (piperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine
To a mixture of tert-butyl 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidine-1-carboxylate 3c (1.3g, 4.3mmol) and methanol (30mL) was added dropwise a solution of hydrogen chloride in dioxane (4N). The reaction solution was stirred at room temperature for 0.5 hour and desolventized under reduced pressure to give the hydrochloride of the objective 4- (piperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine 3d (0.75g), yield: 81 percent. The product was used in the next reaction without purification.
MS m/z(ESI):203[M+1]
the fourth step
1- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-1-yl) prop-2-en-1-one
Synthesized using 4- (piperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine 3d (202mg, 1.0mmol) as a starting material according to the synthesis method of 1 in example 1 to give the title product 1- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-1-yl) prop-2-en-1-one 3(20mg) in yield: 10 percent.
MS m/z(ESI):257[M+1]
1H NMR(400MHz,CD3OD)δ8.96(s,1H),7.87(s,1H),7.22-7.18(m,1H),6.91-6.76(m,1H),6.32-6.24(m,1H),5.85-5.75(m,1H),4.74(d,J＝12.2Hz,0.5H),4.45(d,J＝14.1Hz,0.5H),4.29(d,J＝13.1Hz,1H),3.73-3.67(m,0.5H),3.53-3.49(m,1H),3.35-3.22(m,1H),2.91(t,J＝12.6Hz,0.5H),2.28-2.18(m,2H),2.04-2.01(m,1H),1.80-1.74(m,1H)。
Example 4
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-1-yl) prop-2-en-1-one
Example 4 was synthesized with reference to the procedure of example 3, but in the first step tert-butyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate was substituted for tert-butyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyridine-1 (2H) -carboxylate.
MS m/z(ESI):257[M+1]
1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.66(s,1H),7.51(s,1H),6.87(dd,J＝16.7,10.5Hz,1H),6.70(s,1H),6.13(d,J＝16.7Hz,1H),5.68(d,J＝10.4Hz,1H),4.59(d,J＝12.2Hz,1H),4.20(d,J＝13.0Hz,1H),3.48-3.41(m,1H),3.33-3.24(m,1H),2.84(t,J＝12.3Hz,1H),1.91-1.71(m,4H)。
Example 5
1- (3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one
First step of
N-methyl-N- (piperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
The compound 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine 1a (130mg, 0.85mmol), tert-butyl 3- (methylamino) piperidine-1-carboxylate 5a (182mg, 0.85mmol), potassium carbonate (352mg, 2.55mmol), sodium iodide (255mg, 1.7mmol) and water (6mL) were mixed and reacted for 1 hour with microwave heating to 100 ℃. The residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 10/1) to give the desired product N-methyl-N- (piperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine 5b (89mg, white solid), yield: 45 percent.
MS m/z(ESI):232[M+1]
Second step of
1- (3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one
Synthesized using N-methyl-N- (piperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine 5b (89mg, 0.38mmol) as a starting material according to the synthesis method of 1 in example 1 to give the title product 1- (3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) prop-2-en-1-one 5(29mg, colorless oil) in yield: 26 percent.
MS m/z(ESI):286[M+1]
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.15-8.14(m,1H),7.18(s,1H),6.92-6.70(m,1H),6.58-6.55(m,1H),6.13-6.10(m,1H),5.70-5.60(m,1H),4.71-4.51(m,2H),4.40-4.36(m,0.5H),3.92-3.88(m,0.5H),3.17-2.89(m,5H),1.97-1.76(m,3H),1.59-1.56(m,1H)。
Example 6
N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) acryloyl amide
First step of
3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline
The compound 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine 1a (306mg, 2.0mmol), 3-aminophenylboronic acid 6a (274mg, 2.0mmol), potassium carbonate (828mg, 6mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (280mg, 0.4mmol), 1, 4-dioxane (20mL) and water (4mL) were mixed, heated to 100 ℃ under nitrogen and stirred for 15 hours. It is cooled to room temperature, filtered, the filtrate is desolventized under reduced pressure, and the residue is diluted with 20mL of water and extracted with ethyl acetate (20 mL. times.3). The organic phases were combined and washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 15/1) to give the desired product 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline 6b (205mg, orange oil), yield: 48 percent.
MS m/z(ESI):211[M+1]
Second step of
N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) acryloyl amide
Using 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline 6b (205mg, 0.97mmol) as a starting material, the title product, N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) acryloylamide 6(130mg, yellow solid) was synthesized according to the synthesis method of 1 in example 1, yield: 50 percent.
MS m/z(ESI):265[M+1]
1H NMR(400MHz,DMSO-d6)δ12.29(s,1H),10.41(s,1H),8.84(s,1H),8.64(s,1H),8.25(s,0.5H),7.93(d,J＝7.7Hz,1H),7.83(d,J＝8.0Hz,1H),7.70(s,1H),7.54(t,J＝7.9Hz,1H),6.96(d,J＝3.2Hz,1H),6.48(dd,J＝16.9,10.0Hz,1H),6.32(d,J＝16.8Hz,1H),5.81(d,J＝10.1Hz,1H)。
example 7
(E) -N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyano-3-cyclopropylacryloyl amide
First step of
N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyanoacetamide
the compound 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline 6b (150mg, 0.71mmol), 2-cyanoacetic acid (73mg, 0.85mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (323mg, 0.85mmol), N, N-diisopropylethylamine (275mg, 2.13mmol) and N, N-dimethylformamide (10mL) were mixed. Stirred at room temperature for 1 hour. The reaction solution was diluted with water (30mL), extracted with ethyl acetate (30mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and desolventization under reduced pressure was carried out to obtain the objective product N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyanoacetamide 7a (186mg, grass green solid), yield: 94 percent. The product was used in the next reaction without purification.
MS m/z(ESI):278[M+1]
Second step of
(E) -N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyano-3-cyclopropylacryloyl amide
The compound N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyanoacetamide 7a (24mg, 0.08mmol), cyclopropanecarboxaldehyde (11mg, 0.16mmol), piperidine (20mg, 0.24mmol), acetic acid (0.1mL) and isopropanol (5mL) were mixed and stirred at room temperature for 15 hours. The solution was removed under reduced pressure and the residue was purified by preparative HPLC to give the desired product (E) -N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyano-3-cyclopropylacryloylamide hydrochloride (11mg, yellow solid) in yield: 41 percent.
MS m/z(ESI):330[M+1]
1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),10.53(s,1H),8.98(s,1H),8.55(s,1H),7.92-7.88(m,3H),7.62(t,J＝7.9Hz,1H),7.29(d,J＝11.1Hz,1H),7.10(s,1H),2.00-1.98(m,1H),1.41-1.25(m,2H),1.15-0.98(m,2H)。
example 8
N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) acryloyl amide
First step of
4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline
The compound 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine 1a (1.5g, 9.8mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline 8a (2.57g, 11.7mmol), sodium carbonate (3.11g, 29.3mmol), tetratriphenylphosphine palladium (0.904g, 0.782mmol), 1, 4-dioxane (40mL) and water (20mL) were mixed and stirred under reflux under nitrogen overnight. Cooling to room temperature, and desolventizing under reduced pressure. The residue was diluted with 30mL of water and extracted with ethyl acetate (80 mL. times.3). The organic phases were combined and washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure, and the residue was recrystallized from petroleum ether and ethyl acetate to give the desired product 4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline 8b (1.2g, brown solid), yield: 59 percent.
MS m/z(ESI):211[M+1]
Second step of
N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) acryloyl amide
using 4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline 8b (210mg, 1.0mmol) as a starting material, the title product, N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) acryloylamide 8(130mg, yellow solid) was synthesized according to the synthesis method of 1 in example 1, yield: 49 percent.
MS m/z(ESI):265[M+1]
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),10.41(s,1H),8.80(s,1H),8.21(d,J＝8.4Hz,2H),7.89(d,J＝8.5Hz,2H),7.64(s,1H),6.95(d,J＝3.2Hz,1H),6.50(dd,J＝17.0,10.2Hz,1H),6.31(d,J＝16.8Hz,1H),5.81(d,J＝10.4Hz,1H)。
Example 9
(E) -N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyano-3-methacryloylamide
First step of
n- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyanoacetamide
Synthesized using 4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline 8b (1.2g, 0.71mmol) as a starting material according to the synthesis method of 7a in example 7 to give the title product N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyanoacetamide 9a (1.1g, yellow solid) in yield: and 69 percent.
MS m/z(ESI):278[M+1]
Second step of
(E) -N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyano-3-methacryloylamide
The compound N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyanoacetamide 9a (320mg, 1.15mmol), acetaldehyde (408mg, 9.23mmol), piperidine (330mg, 4.04mmol) and acetic acid (5mL) were mixed and stirred at room temperature for 3 hours. Yellow precipitate was formed, filtered, the filter cake was washed with ethanol and dried to obtain 208mg of crude product. 100mg of the crude product was recrystallized from petroleum ether, acetone and methanol to give the desired product (E) -N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyano-3-methacryloylamide 9(45mg, grey solid), yield: 26 percent.
MS m/z(ESI):304[M+1]
1H NMR(400MHz，DMSO-d6)δ12.23(s,1H),10.48(s,1H),8.81(s,1H),8.23(d,J＝7.6Hz,2H),7.87(d,J＝7.6Hz,2H),7.75-7.58(m,2H),6.95(s,1H),2.19(s,3H)。
Example 10
(E) -N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyano-3-cyclopropylacryloyl amide
(E) -N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyano-3-cyclopropylacryloyl amide
The compound N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyanoacetamide 9a (80mg, 0.29mmol), cyclopropanecarboxaldehyde (80mg, 1.15mmol), piperidine (82mg, 1.0mmol) and isopropanol (10mL) were mixed and stirred at room temperature for 3 hours. The solution was removed under reduced pressure and the residue was purified by preparative HPLC to give the desired product (E) -N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyano-3-cyclopropylacryloyl amide 10(30mg, yellow solid), yield: 31 percent.
MS m/z(ESI):330[M+1]
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.30(s,1H),8.80(s,1H),8.22(d,J＝8.2Hz,2H),7.84(d,J＝8.2Hz,2H),7.65(s,1H),7.14(d,J＝10.9Hz,1H),6.95(s,1H),2.05-1.92(m,1H),1.33-1.29(m,2H),1.06-1.03(m,2H)。
Example 11
N- (1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl) acryloylamide
First step of
2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine
The compound 2-bromo-5H-pyrrolo [2,3-b ] pyrazine 11a (300mg, 1.5mmol) and N, N-dimethylformamide (10mL) were mixed, cooled to 0 ℃ and sodium hydride (60%, 90mg, 2.25mmol) was added portionwise. Stirred at room temperature for 0.5 hour. The reaction system was cooled to 0 deg.C, (2- (chloromethoxy) ethyl) trimethylsilane (500mg, 3.0mmol) was slowly added, stirred at room temperature for 1 hour, quenched with water, and extracted with ethyl acetate (20 mL. times.3). The organic phases were combined and washed with water (20mL × 3) and saturated brine (20mL × 3) in this order, dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 50/1) to give the desired product 2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine 11b (330mg, clear oil), yield: 67%.
MS m/z(ESI):328[M+1]
Second step of
Tert-butyl 1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-ylcarbamate
The compounds 2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazine 11b (330mg, 1.0mmol), tert-butylpiperidin-3-ylcarbamate (200mg, 1.0mmol), bis (dibenzylideneacetone) palladium (92mg, 0.1mmol), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (95mg, 0.2mmol), sodium tert-butoxide (288mg, 3.0mmol) and 1, 4-dioxane (6mL) were mixed, heated to 100 ℃ by microwave and reacted for 0.5 hour. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 6/1) to give the desired product tert-butyl 1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-ylcarbamate 11c (270mg, brown oil) in yield: 60 percent.
MS m/z(ESI):448[M+1]
The third step
1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-amine
The compound tert-butyl 1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl carbamate 11c (270mg, 0.6mmol) and a 1, 4-dioxane solution of hydrogen chloride gas (10mL) were mixed and stirred at room temperature for 1 hour. Desolventizing under reduced pressure gave the hydrochloride salt of the desired product 1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-amine 11d (310mg, crude) in yield: is more than 100 percent. The product was used in the next reaction without purification.
MS m/z(ESI):348[M+1]
The fourth step
N- (1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl) propenylamide
synthesized using 1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-amine 11d (310mg, crude) as a starting material according to the synthesis method of 1 in example 1 to give the title product N- (1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl) acryloylamide 11e (238mg, yellow solid) in two-step yield: 98 percent.
MS m/z(ESI):402[M+1]
The fifth step
N- (1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl) acryloylamide
After mixing the compound N- (1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl) acryloylamide 11e (238mg, 0.59mmol) and dichloromethane (10mL), trifluoroacetic acid (5mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was desolventized under reduced pressure, and the residue was dissolved in methylene chloride (5mL) and methanol (5mL), and aqueous ammonia (3mL) was added thereto and the mixture was stirred at room temperature for 1 hour. Desolventizing under reduced pressure and purifying the residue by preparative HPLC to give the desired product N- (1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl) acryloylamide 11(30mg, yellow solid), yield: 18 percent.
MS m/z(ESI):272[M+1]
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.14(d,J＝7.3Hz,1H),8.00(s,1H),7.57(s,1H),6.31(s,1H),6.27(dd,J＝17.0Hz,10.0Hz,1H),6.11(d,J＝17.0Hz,1H),5.60(d,J＝10.0Hz,1H),4.11(d,J＝10.3Hz,1H),3.97(d,J＝12.6Hz,1H),3.85-3.79(m,1H),3.00-2.95(m,1H),2.85-2.76(m,1H),1.92-1.87(m,1H),1.82-1.77(m,1H),1.62-1.55(m,1H),1.51-1.43(m,1H)。
Example 12
N- (1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-4-yl) acryloylamide
example 12 was synthesized according to the procedure of example 11, except that tert-butylpiperidin-3-ylcarbamate was substituted with tert-butylpiperidin-4-ylcarbamate in the second step.
MS m/z(ESI):272[M+1]
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.06-8.03(m,2H),7.57(s,1H),6.32(s,1H),6.20(dd,J＝17.1,9.9Hz,1H),6.09(d,J＝16.9Hz,1H),5.58(d,J＝9.9Hz,1H),4.18-4.15(m,2H),3.89-3.87(m,1H),2.99(t,J＝11.7Hz,2H),1.86-1.83(m,2H),1.51-1.43(m,2H)。
Example 13
1- (4- (5H-pyrrolo [3,2-b ] pyrazin-2-yl) piperidin-1-yl) prop-2-en-1-one
Example 13 was synthesized with reference to the procedure of example 3, but in the first step 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and tert-butyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyridine-1 (2H) -carboxylate were substituted with 2-bromo-5H-pyrrolo [2,3-b ] pyrazine and tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate.
MS m/z(ESI):257[M+1]
1H NMR(400MHz,CD3OD)δ8.19(s,1H),7.75(d,J＝3.4Hz,1H),6.83(dd,J＝16.8,10.7Hz,1H),6.59(d,J＝3.4Hz,1H),6.23(d,J＝16.8Hz,1H),5.76(d,J＝10.7Hz,1H),4.75(d,J＝12.7Hz,1H),4.28(d,J＝13.3Hz,1H),3.43-3.25(m,1H),3.28-3.07(m,1H),2.98-2.71(m,1H),2.02-1.94(m,2H),1.91-1.82(m,2H)。
Example 14
N- (3- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) phenyl) acryloylamide
Example 14 was synthesized according to the procedure of example 6, except that in the first step 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine was substituted with 2-bromo-5H-pyrrolo [2,3-b ] pyrazine.
MS m/z(ESI):265[M+1]
1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),10.31(s,1H),8.80(s,1H),8.42(s,1H),7.92(s,1H),7.84-7.81(m,2H),7.46(t,J＝7.9Hz,1H),6.69(s,1H),6.48(dd,J＝16.9,10.0Hz,1H),6.30(d,J＝16.7Hz,1H),5.79(d,J＝10.2Hz,1H)。
Example 15
(E) -N- (3- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) phenyl) -2-cyanobutan-2-enamide
Example 15 was synthesized according to the procedure of example 9, except that in the first step 4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline was substituted with 3- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) aniline.
MS m/z(ESI):304[M+1]
1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),10.38(s,1H),8.81(s,1H),8.41(s,1H),7.93(s,1H),7.87(d,J＝7.6Hz,1H),7.78(d,J＝7.9Hz,1H),7.74-7.69(m,1H),7.48(t,J＝7.9Hz,1H),6.69(s,1H),2.19(d,J＝6.8Hz,3H)。
Example 16
(E) -N- (3- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) phenyl) -2-cyano-3-cyclopropylacryloyl amide
Example 16 was synthesized according to the procedure of example 10, except that in the first step N- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyanoacetamide was substituted with N- (3- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) phenyl) -2-cyanoacetamide.
MS m/z(ESI):330[M+1]
1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),10.20(s,1H),8.81(s,1H),8.36(s,1H),7.93(s,1H),7.86(d,J＝7.8Hz,1H),7.79(d,J＝7.9Hz,1H),7.47(t,J＝7.9Hz,1H),7.15(d,J＝11.0Hz,1H),6.68(d,J＝3.2Hz,1H),2.02-1.95(m,1H),1.32-1.30(m,2H),1.05-1.03(m,2H)。
Example 17
n- (4- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) phenyl) acryloylamide
Example 17 was synthesized according to the procedure of example 6, except that in the first step 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and 3-aminophenylboronic acid were substituted with 2-bromo-5H-pyrrolo [2,3-b ] pyrazine and 4-aminophenylboronic acid.
MS m/z(ESI):265[M+1]
1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),10.31(s,1H),8.82(s,1H),8.11(d,J＝7.9Hz,2H),7.88(s,1H),7.82(d,J＝8.0Hz,2H),6.66(s,1H),6.56-6.42(m,1H),6.29(d,J＝17.0Hz,1H),5.79(d,J＝10.0Hz,1H)。
Example 18
N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) cyanoamides
To a mixture of 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline 6b (127mg, 0.6mmol), sodium bicarbonate (152mg, 1.8mmol), and toluene (10mL) was added a toluene solution (0.5mL) of cyanogen bromide (127mg, 1.2mmol), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (20 mL. times.3). The organic phases were combined and washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure, and the residue was separated by preparative HPLC to give the desired product N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) cyanoamide 18(70mg, yellow solid) in yield: 49 percent.
MS m/z(ESI):236[M+1]
1H NMR(400MHz，DMSO-d6)δ12.45(s,1H),10.45(s,1H),8.89(s,1H),7.86(d,J＝7.6Hz,1H),7.81(s,1H),7.74(s,1H),7.59(t,J＝7.6Hz,1H),7.16(d,J＝8.0Hz,1H),6.90(s,1H)。
Example 19
N- (3- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) phenyl) cyanoamide
Example 19 was synthesized by reference to the procedure of example 18, but substituting 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline with 3- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) aniline.
MS m/z(ESI):236[M+1]
1H NMR(400MHz，CD3OD)δ8.71(s,1H),7.82(d,J＝3.4Hz,1H),7.70(d,J＝9.2Hz,2H),7.51(t,J＝7.9Hz,1H),7.09(d,J＝8.0Hz,1H),6.71(d,J＝3.5Hz,1H)。
Example 20
(E) -N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl) -2-cyanobutan-2-enamide
Example 20 was synthesized according to the procedure of example 9, except that in the first step 4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline was substituted with 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline.
MS m/z(ESI):304[M+1]
1H NMR(400MHz，CD3OD)δ8.69(s,1H),8.34(s,1H),7.80(d,J＝7.6Hz,1H),7.66(d,J＝8.1Hz,1H),7.59–7.54(m,1H),7.51–7.43(m,2H),6.88(s,1H),2.15(d,J＝6.8Hz,3H)。
Examples 21 and 22
cis-N- (- (1R,3S) -3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexyl) acrylamides and trans-N- (- (1R,3S) -3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexyl) acrylamides
First step of
5- (tert-Butoxycarbonylamino) cyclohex-1-enyl triflate and 3- (tert-butoxycarbonylamino) cyclohex-1-enyl triflate
To a solution of LDA (10.3mmol) in tetrahydrofuran (5mL) at-78 deg.C was added a solution of tert-butyl 3-carbonyl cyclohexyl carbamate (2g, 9.38mmol) in tetrahydrofuran (15 mL). The reaction was warmed to room temperature, stirred for 30 minutes, cooled to-78 ℃ and added a solution of trifluoro-N-phenyl-N- (trifluoromethanesulfonyl) methanesulfonamide (4.63g, 12.2mmol) in tetrahydrofuran (25 mL). The reaction solution was warmed to room temperature and stirred for 3 hours. Ethyl acetate (300mL) was added for dilution and washed with water (2X 200mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, desolvation under reduced pressure was carried out, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 20/1 to 10/1) to obtain the desired products 5- (tert-butoxycarbonylamino) cyclohex-1-enyl trifluoromethanesulfonate 21b-1 and 3- (tert-butoxycarbonylamino) cyclohex-1-enyl trifluoromethanesulfonate 21b-2(3g, white solid), yield: 93 percent.
MS m/z(ESI):368[M+Na+]
Second step of
Tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enylcarbamate and tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-2-enylcarbamate
compounds of 5- (tert-Butoxycarbonylamino) cyclohex-1-enyltrifluoromethanesulfonate 21b-1 and 3- (tert-butoxycarbonylamino) cyclohex-1-enyltrifluoromethanesulfonate 21b-2(3g, 8.7mmol),4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolane) (2.87g, 11.3mmol), potassium acetate (2.56g, 26mmol), Pd (dppf) Cl2(0.64g, 0.87mmol) and 1, 4-dioxane (50mL) were combined and heated to reflux with stirring overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was desolventized under reduced pressure, diluted with water (100mL) and extracted with dichloromethane (3X 100 mL). The organic phases were combined and washed with water (100mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, desolvation under reduced pressure was carried out, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 10/1) to obtain the target products tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enylcarbamate 21c-1 and tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-2-enylcarbamate 21c-2(2.36g, pale yellow solid), yield: 84 percent.
MS m/z(ESI):346[M+Na+]
The third step
Tert-butyl 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohex-2-enylcarbamate and tert-butyl 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohex-3-enylcarbamate
Mixing the mixture of tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enyl carbamate 21c-1 and tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-2-enyl carbamate 21c-2(988mg, 3.06mmol), 4-chloro-7H-pyrrolo [2,3-d ] pyrrole]Pyrimidine (391mg, 2.5mmol), sodium carbonate (810mg, 7.64mmol), Pd (PPh)3)4(236mg, 0.204mmol), dioxane (25mL) and water (12mL) were heated to reflux with stirringStirring overnight. The reaction mixture was cooled to room temperature, diluted with water (20mL) and extracted with ethyl acetate (3X 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether ═ 3/1) to give the desired product, tert-butyl 3- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) cyclohex-2-enylcarbamate 21d-1 and tert-butyl 3- (7H-pyrrolo [2, 3-d)]pyrimidin-4-yl) cyclohex-3-enyl carbamate 21d-2(530mg, white solid), yield: 66 percent.
MS m/z(ESI):315[M+1]
the fourth step
Tert-butyl 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexyl carbamate
Using tert-butyl 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohex-2-enylcarbamate 21d-1 and tert-butyl 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohex-3-enylcarbamate 21d-2(530mg, 1.7mmol) as starting materials, the title product, tert-butyl 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexylcarbamate 21e (226mg, white solid), was synthesized according to the synthesis method of 3c in example 3 to give the title product: 42 percent.
MS m/z(ESI):317[M+1]
The fifth step
3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexylamine
The mixture of tert-butyl 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexylcarbamate 21e (226mg, 0.72mmol), dioxane solution of hydrochloric acid (8mL) and methanol (25mL) was stirred at room temperature for 3 hours. Desolventizing under reduced pressure gave the title product, hydrochloride 21f (180mg, white solid) of 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexylamine, yield: 99 percent.
MS m/z(ESI):217[M+1]
The sixth step
cis-N- (- (1R,3S) -3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexyl) acrylamides and trans-N- (- (1R,3S) -3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexyl) acrylamides
using hydrochloride 21f (120mg, 0.48mmol) of 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexylamine as a starting material, the title products, cis-N- (- (1R,3S) -3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexyl) acryloylamide 21(26mg, white solid) and trans-N- (- (1R,3S) -3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexyl) acryloylamide 22(36mg, white solid), were synthesized according to the synthesis method of 1 in example 1 to give: 48 percent.
MS m/z(ESI):271[M+1]
21：1H NMR(400MHz,CD3OD)δ8.80(s,1H),7.73(s,1H),7.02(s,1H),6.35(dd,J＝17.0,10.2Hz,1H),6.19(d,J＝17.0Hz,1H),5.60(d,J＝10.2Hz,1H),4.27(s,1H),3.67–3.44(m,1H),2.04–1.85(m,4H),1.75–1.60(m,4H)。
22：1H NMR(400MHz，DMSO-d6)δ12.02(s,1H),8.65(s,1H),8.17(s,1H),7.49(s,1H),6.70(s,1H),6.17–6.13(m,2H),5.56(s,1H),3.86(s,1H),3.27(s,1H),1.94–1.25(m,8H)。
Example 23
N- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexyl) cyanoamide
Example 23 was synthesized according to the procedure for example 18, except that 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline was substituted with 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexylamine.
MS m/z(ESI):242[M+1]
1H NMR(400MHz，DMSO-d6)δ12.04(s,1H),8.66(s,1H),7.50(s,1H),6.93(s,1H),6.69(d,J＝9.3Hz,1H),3.72–3.69(m,0.5H),3.48-3.43(m,0.5H),3.28-3.19(m,1H),2.04–1.53(m,8H)。
Example 24
2- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexylamino) acetonitrile
3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexylamine 21f (91mg, 0.36mmol), bromoacetonitrile (87mg, 0.72mmol), potassium carbonate (150mg, 1.08mmol) and acetonitrile (20mL) were mixed and stirred at room temperature for 6 hours. The residue was separated by preparative HPLC under reduced pressure to give the desired product 2- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) cyclohexylamino) acetonitrile (20mg, as a milky white solid) in yield: 21 percent.
MS m/z(ESI):256[M+1]
1H NMR(400MHz，CD3OD)δ8.65(s,1H),7.45(s,1H),6.77(s,1H),3.73(s,2H),3.65–3.60(m,0.5H),3.30–3.25(m,1H),2.94-2.91(m,0.5H),2.19–1.64(m,8H)。
Example 25
N- (3- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) cyclohexyl) acryloyl amide
Example 25 was synthesized by reference to the procedures of examples 21 and 22, but substituting 2-bromo-5H-pyrrolo [2,3-b ] pyrazine for 4-chloro-7H-pyrrolo [23-d ] pyrimidine.
MS m/z(ESI):271[M+1]
1H NMR(400MHz，DMSO-d6)δ11.92(s,1H),8.17(s,1H),8.11–8.04(m,1H),7.82(s,1H),6.55(s,1H),6.42(dd,J＝17.0,10.2Hz,0.5H),6.20(dd,J＝17.1,10.0Hz,0.5H),6.08(dd,J＝17.0,11.4Hz,1H),5.57(t,J＝10.7Hz,1H).4.18(br,0.5H),3.85–3.77(m,0.5H),3.24–3.19(m,0.5H),2.99–2.94(m,0.5H),2.01–1.85(m,3H),1.71–1.48(m,3.5H),1.25–1.20(m,0.5H)。
Example 26
N- (1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl) cyanoamide
First step of
1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-amine
The mixture was stirred at room temperature overnight for tert-butyl 1- (5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl carbamate 11c (300mg, 0.67mmol), trifluoroacetic acid (2mL) and dichloromethane (10 mL). 20% sodium hydroxide solution (10mL) was added under ice-cooling and stirred at room temperature for 1 hour. Extraction with dichloromethane and methanol (10/1, 110mL × 4), organic drying over anhydrous sodium sulfate, filtration to remove the drying agent, and desolventization under reduced pressure gave the desired product 1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-amine 26a (100mg, crude), yield: and 69 percent.
MS m/z(ESI):218[M+1]
Second step of
N- (1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl) cyanoamide
Using 1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-amine 26a (100mg, 0.46mmol) as a starting material, synthesis was performed according to the synthetic method of example 18 to give the title product N- (1- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) piperidin-3-yl) cyanoamide 26(4mg, black solid) in yield: 4 percent.
MS m/z(ESI):243[M+H]
1H NMR(400MHz,CD3OD)δ7.86(s,1H),7.43(s,1H),6.29(s,1H),4.53(s,1H),3.97(d,J＝12.8Hz,1H),3.68(d,J＝12.7Hz,1H),3.13–2.91(m,2H),1.94–1.90(m,1H),1.85–1.80(m,1H),1.68–1.44(m,2H)。
Example 27
N- (3- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) cyclohexyl) cyanoamide
Example 27 was synthesized by reference to the procedure of example 18, but substituting 3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) aniline with 3- (5H-pyrrolo [2,3-b ] pyrazin-2-yl) cyclohexylamine.
MS m/z(ESI):242[M+1]
1H NMR(400MHz,CD3OD)δ8.19(s,1H),7.75(s,1H),6.61(s,1H),3.78(s,0.5H),3.24(t,J＝10.5Hz,1H),3.00(t,J＝10.7Hz,0.5H),2.22(d,J＝12.6Hz,0.5H),2.13–2.04(m,1.5H),1.98-1.91(m,2H),1.82-1.69(m,2.5H),1.65-1.58(m,1H),1.46–1.39(m,0.5H)。
Activity inhibition assay for JAK3
The experimental methods for assessing the effect of the compounds of the invention on Janus kinase 3(JAK3) activity using an in vitro kinase assay are summarized below:
The in vitro activity of JAK3 was determined by detecting the phosphorylation level of a substrate in the kinase reaction using a Homogeneous Time Resolved Fluorescence (HTRF) kinase detection kit. The reaction buffer contained the following components: 50mM HEPES (pH 7.0), 5mM MgCl2And 1mM DTT; human recombinant JAK3 catalytic domain protein purchased from Invitrogen (amino acid sequence 781-1184, cat # PV3855) diluted to 0.5ng/μ L kinase solution with reaction buffer; substrate reaction solution comprising 140nM biotinylated tyrosine kinase substrate (Cisbio, cat # 62TK0PEC) and 3.5. mu.M ATP diluted in reaction buffer; the detection buffer solution comprises Eu diluted to 0.125 ng/mu L by reaction buffer solution3+labeled caged antibody (Cisbio, cat # 61T66KLB) and 8.75nM streptavidin labeled XL665(Cisbio, cat # 610 SAXLB).
Compounds were dissolved in 100% DMSO diluted to 1mM and then 3-fold serial dilutions were made in DMSO to a minimum concentration of 0.05 μ M, with 40-fold dilutions using reaction buffer at each concentration point.
mu.L of the compound solution and 2. mu.L of JAK3 kinase solution were added to a 384-well assay plate (Corning, cat. No. 3674), mixed well, and incubated at room temperature for 15 minutes. Subsequently, 4. mu.L of the substrate reaction solution was added and the reaction mixture was incubated at room temperature for 30 minutes. Then, 10. mu.L of a detection buffer equal in volume to the reaction was added, mixed well and left to stand at room temperature for 30 minutes, and then the progress of the reaction was detected at wavelengths of 620nm and 665nm using an Envision plate reader (Perkin Elmer). The 665/620 ratio is directly related to the degree of phosphorylation of the substrate, thereby detecting the JAK3 kinase activity. In this experiment, the JAK3 kinase protein-free group was used as a negative control (100% inhibition), and the JAK3 kinase protein-free group was used as a positive control (0% inhibition). The percent inhibition of JAK3 activity by a compound can be calculated using the following formula:
Percent inhibition of 100-100 ═ (signal value at the specified concentration of test compound-negative control signal value)/(positive control signal value-negative control signal value)
Compound IC50Values were calculated from 10 concentration points using XLfit (ID Business Solutions ltd., UK) software by the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hillslope))
Wherein Y is the percent inhibition, X is the logarithm of the concentration of the test compound, Bottom is the maximum percent inhibition, and Top is the minimum percent inhibition.
| Compound numbering | IC50(nM) | Compound numbering | IC50(nM) |
| 1. | A | 2. | C |
| 3. | B | 4. | B |
| 5. | A | 6. | A |
| 7. | B | 8. | B |
| 9. | B | 10. | B |
| 11. | C | 12. | C |
| 13. | B | 14. | A |
| 15. | A | 16. | A |
| 17. | C | 18. | B |
| 19. | A | 20. | A |
| 21. | A | 22. | A |
| 23. | B | 24. | C |
| 25. | C | 26. | B |
| 27. | C |
A < 100 nM; b100 to 500 nM; c > 500nM
And (4) conclusion: the compound of the invention has obvious inhibitory effect on the activity of Janus kinase 3(JAK 3).
Claims (13)
1. A compound of formula (IV) or a pharmaceutically acceptable salt thereof:
(IV)
Wherein:
R3is a substituent W:
(W)
L is a chemical bond;
ring B is cyclohexyl, wherein the cyclohexyl is optionally substituted with one or more groups selected from hydrogen, halogen, cyano and C1-C8Alkyl is substituted by a substituent;
Z is independently selected from NHCN andAnd are and
Ra、RbAnd RcAre independently selected fromFrom H, halogen, cyano and alkyl having 1 to 20 carbon atoms, wherein the alkyl is optionally substituted by one or more groups selected from halogen, cyano and C1-C8Alkyl substituents.
2. A compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein:
(V)
R3Is a substituent W:
(W)
L is a chemical bond;
Ring B is piperidinyl, wherein the piperidinyl is optionally substituted with one or more groups selected from hydrogen, halogen, cyano and C1-C8An alkyl group; and
Z is NHCN.
3. A compound represented by the formula:
。
4. A compound represented by the formula:
。
5. A compound represented by the formula:
。
6. A compound represented by the formula:
。
7. a compound represented by the formula:
。
8. A compound represented by the formula:
。
9. a compound represented by the formula:
。
10. A compound represented by the formula:
。
11. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 11 in the manufacture of a Janus kinase 3 inhibitor.
13. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment and/or prevention of a disease associated with inflammation.
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