CN110028507A - With TRK kinase inhibiting activity compound, preparation method, composition and purposes - Google Patents
With TRK kinase inhibiting activity compound, preparation method, composition and purposes Download PDFInfo
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- CN110028507A CN110028507A CN201910021570.1A CN201910021570A CN110028507A CN 110028507 A CN110028507 A CN 110028507A CN 201910021570 A CN201910021570 A CN 201910021570A CN 110028507 A CN110028507 A CN 110028507A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
One kind having TRK kinase inhibiting activity compound, preparation method, medical composition and its use.The compound is the compound or its pharmaceutically acceptable salt, hydrate, solvate, isotopic compound with Formulas I.Above compound of the invention can be as the main component of pharmaceutical composition, it, can be by the way that needing, the patient of such treatment or prevention gives one kind of therapeutically effective amount or a variety of compounds of the invention or their medicinal salts, stereoisomer or tautomer achieve the purpose that treatment by inhibiting TRK kinase activity to reach treatment tumour purpose.The tumour of the treatment is selected from the common cancers such as breast cancer, cutaneum carcinoma, bladder cancer, oophoroma, lung cancer.
Description
Technical field:
The present invention relates to new compound, the pharmaceutical composition comprising the compound, the method for preparing the compound and it is somebody's turn to do
The purposes of compound in the treatment.More particularly it relates to certain substituted [1,2,4] triazol [4,3-a] pyrazines
Derivative, display have TRK kinase inhibiting activity and can be used for treating pain, inflammation, cancer and certain communicable diseases.
Background technique:
Cancer is derived from the excrescent disease of tissue.Certain cancers are possible to intrusion local organization and are also transferred to
Distal organs.This disease may develop into the widely varied of Different Organs, tissue and cell type.Therefore, term " cancer "
Refer to the set more than 1,000 kinds of various diseases.
Neurotrophic factor tyrosine kinase receptor, also referred to as tropomyosin associated kinase (Trk), be neurotrophy because
The high-affinity receptor of the soluble growth factor activation of sub (NT).NTRK receptor family has 3 members: NTRK1 is (also referred to as
TrkA), NTRK2 (also referred to as TrkB), NTRK3 (also referred to as TrkC).NT includes following albumen: activating the nerve growth of NTRK1
The factor (NGF) activates the NT3 of the derivative neurotrophic factor of the brain-of NTRK2 (BDNF) and NT-4/5 and activation NTRK3.Every kind
NTRK receptor contains extracellular structure (ligand binding site), transmembrane domain and intracellular domain (containing kinase domain).?
Every kind of kinase catalytic autophosphorylation, then activates downstream signaling pathway when being incorporated into ligand.
Under normal circumstances, NTRK wide expression in nerve self-control, and important work is played to the maintenance of these cells survival
With, development and function to nervous system play an important role (Current Opinion in Neurobiology, 11,272-
280(2001)).Nearest lot of documents statement, the overexpression of NTRK, activation, amplification, fusion are formed or are mutated and nerve
Cytoma (PediatrBlood Cancer, 59,226-232 (2012)), secretory breast cancer (Cancer Cell, 2,367-
376 (2002)), colorectal cancer (Science, 300,949-949 (2003)), oophoroma (Cinical
CancerResearch, 9,2248-2259 (2003)), head and neck cancer (PLos ONE7 (1), e30246 (2012)), cancer of pancreas and
Melanoma, androgen-dependent/non-dependent prostate cancer (Prostate, 45,140-148 (2000)) are related.
Trk kinases is activated in malignant tumour by number of mechanisms, the mainly change of structural rearrangement and expression.Trk swashs
The encoding gene NTRK of enzyme, which is reset, generates chimeric oncogene, leads to Trk kinases constitutive activation, is no longer influenced by nerve growth factor
The regulation and control of ligand has carcinogenic risk.Original such as in colon cancer KM12 cell, on No. 1 chromosome long arm
Gene segment rearrangements just have occurred in -3 gene TPM3 of myosin and NTRK1, and TPM3 is broken between 8 exons at No. 7,
NTRK1 is in the 8th exon internal break, and then, TPM3 is directly connected with the NTRK1 for expressing structural region intracellular, exception table
Up to TPM3-TRKA chimeric protein.The change of this gene destroys the interaction of ligand NGF and TrkA in cell, intracellular
TRKA is in overexpression and sustained activation state, and tri- signal paths of PI3K/AKT, Ras/MAPK and PLC γ in downstream
In Showed Very Brisk state.
Reported selective N TRK tyrosine kinase inhibitor, including CEP-751, CEP-701 (Cancer
Research, 59,2395-2341 (1999)), indolocarbazole compound (WO01/14380), oxindole compounds (WO2/
20479, WO02/20513), pyrazolyl fused ring compound (Japanese patent application publication No. 15-231687), isothiazole compounds
(Bioorg.Med.Chem.Lett., 16,3444-3448 (2006)) and other types compound (WO2005/049033,
WO2005/103010,WO2006/082392,WO2006/087530,WO2006087538).Imidazopyridazine framework compound
(WO2007/013673,WO2007/025540,WO2007/147646,WO2008/052734,WO2012/125667).Trk swashs
The mentality of designing of enzyme inhibitor is largely the structure by imitating ATP, reaches with ATP competitive binding site and inhibits kinase catalytic
Active purpose.
The present invention is directed to improve the compound inhibited to TRK, to solve the drug resistance of existing anticancer drug
Can, improve targeting.
Summary of the invention
Researcher of the invention has found structural formula I compound represented TRK kinase inhibiting activity.Therefore, mesh of the invention
Be to provide for compound representated by Formulas I, alloisomerism and its pharmaceutically acceptable salt, hydrate or solvate.
Wherein,
R1For optionally by CN, OH, OMe, NH2、NHMe、N(Me)2、Cl、Br、F、CF3、CONH2、SO2NH2、NHSO2(C1-C4
Alkyl) monosubstituted or polysubstituted phenyl or aromatic heterocyclic；
R2 be selected from be not present, H C1-C4 alkyl；
R3 is optionally by CN, OH, OMe, NH2、NHMe、N(Me)2、Cl、Br、F、CF3、CONH2、SO2NH2, SO2 (C1-C4 alkane
Base), CO (C1-C4 alkyl), NHSO2(C1-C4 alkyl) monosubstituted or polysubstituted phenyl, aromatic heterocyclic；
Or R2 and R3 collectively form substituted four-membered ring, five-membered ring, hexatomic ring.
Preferably, R1 is optional by OH, OMe, Cl, Br, F, CF3、CONH2、SO2NH2、NHSO2(C1-C4 alkyl) singly takes
Generation or polysubstituted phenyl.
Preferably, R1 is optional by OH, OMe, Cl, Br, F, CF3、CONH2、SO2NH2、NHSO2(C1-C4 alkyl) singly takes
Generation or polysubstituted aromatic heterocyclic.
Preferably, R is H or is not present.
Preferably, R3 is optionally by CN, OH, OMe, NH2、NHMe、N(Me)2、Cl、Br、F、CF3、CONH2、SO2NH2、SO2
(C1-C4 alkyl), CO (C1-C4 alkyl), NHSO2(C1-C4 alkyl) monosubstituted or polysubstituted phenyl, aromatic heterocyclic.
Preferably, R2 and R3 collectively forms substituted four-membered ring, five-membered ring, hexatomic ring.
Preferably, R2 and R3 collectively forms substituted four-membered ring, five-membered ring, hexatomic ring, the four-membered ring, five-membered ring, six
Member ring contains 1-2 hetero atom.
Preferably, R2 and R3 collectively forms substituted four-membered ring, five-membered ring, hexatomic ring, the four-membered ring, five-membered ring, six
The substituent group of member ring is selected from C-C4 alkyl, CN, OH, OMe, NH2、NHMe、N(Me)2、Cl、Br、F、CF3、CONH2、SO2NH2、SO2
(C1-C4 alkyl), CO (C1-C4 alkyl), NHSO2(C1-C4 alkyl), it is described be substituted by it is monosubstituted or polysubstituted.
These compounds can be but not limited to following formula (1)-(36) compound:
Second object of the present invention is to provide a kind of pharmaceutical composition containing the compound.The present invention provides medicine
Compositions, it includes pharmaceutical carrier and at least one compounds of the invention or their medicinal salts, alloisomerism, tautomerisms or molten
Immunomodulator compounds.
Third object of the present invention is by inhibiting TRK kinase activity to reach treatment tumour purpose comprising to needs
The patient of such treatment or prevention gives one kind of therapeutically effective amount or a variety of compounds of the invention or their medicinal salts, three-dimensional different
Structure body or tautomer.
The tumour be selected from breast cancer, cutaneum carcinoma, bladder cancer, oophoroma, gastric cancer, prostate cancer, colon cancer, lung cancer, bone
Cancer, the cancer of the brain, the carcinoma of the rectum, the cancer of the esophagus, tongue cancer, gastric cancer, kidney, carcinoma of renal parenchyma, cervical carcinoma, carcinoma of uterine body, carcinoma of endometrium, testis
Cancer, uropoiesis cancer, melanotic cancer, astrocytes cancer, meningioma, Hodgkin lymphoma, non-Hodgkin lymphoma, the white blood of acute lymphoid
Disease, chronic lymphatic leukemia, acute myelogenous leukemia, chronic myelocytic leukemia, adult T-cell leukemia-lymphoma,
Hepatocellular carcinoma, bronchiolar carcinoma, Small Cell Lung Cancer, non-small cell lung cancer, Huppert's disease, basal cell tumor, seminoma,
Rhabdomyosarcoma, chondrosarcoma, muscle tumor, fibrosarcoma.
4th purpose of the invention is to provide compound of formula I, stereoisomer, isotopic compound and its pharmacy
The preparation method of upper acceptable salt or their hydrate or solvate, includes the following steps:
(1) synthesis of intermediate compound IV
Compound II and compound the III ring closure reaction under alkali effect, the reaction at a temperature of 20 DEG C to 100 DEG C into
Row, alkali are selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, cesium carbonate, sodium hydroxide, hydrogen-oxygen
Change potassium, lithium hydroxide；Reaction dissolvent is ethyl alcohol, isopropanol, dioxane, tetrahydrofuran, toluene.
(2) synthesis of intermediate VI
Compound IV reacts under catalyst and ligand effect with compound V, and the reaction is in 20 DEG C to 100 DEG C base catalysis
It carries out, catalyst is selected from PdCl2(PPh3)2、Pd(PPh3)4、Pd(dba)2、Pd(OAc)2、Pd(dppf)2Cl2；Ligand is selected from 2-
Dicyclohexyl phosphine -2', 4', 6'- tri isopropyl biphenyl (XPhos), 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl
(SPhos), the bis- diphenylphosphine -9,9- xanthphos (XantPhos) of 4,5-；Alkali is selected from cesium carbonate, sodium tert-butoxide, tertiary fourth
Potassium alcoholate, potassium phosphate, sodium acetate；Reaction dissolvent is dioxane, DMF, toluene.
(3) synthesis of intermediate VII
Compound VI reacts in the presence of alkali, and the reaction carries out at a temperature of 20 DEG C to 100 DEG C, and alkali is selected from hydroxide
Lithium, sodium hydroxide, potassium hydroxide；Reaction dissolvent be methanol, ethyl alcohol, tetrahydrofuran, methanol/water, ethanol/water, tetrahydrofuran/
Water.
(4) synthesis of intermediate VIII
Compound VII reacts under the action of DPPA, and the reaction carries out at a temperature of 80 DEG C to 100 DEG C, and alkali is selected from three
Ethamine, diisopropylethylamine；Reaction dissolvent is toluene.
(4) the synthesis compound VIII and compound IX of finished product I reacts under condensing agent effect, and the reaction is at 20 DEG C
Base catalysis carries out at a temperature of to 100 DEG C, and condensing agent is selected from CDI, phenyl chloroformate；Alkali is selected from triethylamine, diisopropylethylamine, N-
Methyl morpholine, DMAP；Reaction dissolvent is methylene chloride, DMF, tetrahydrofuran, toluene.
Definition
" pharmaceutically acceptable salt " refers to that those retain the salt of the biological effectiveness of parent compound and characteristic.The salt packet
Include: acid-addition salts are obtained by the free alkali of parent compound with inorganic acid or with reacting for organic acid；The nothing
Machine acid hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid etc.；The organic acid such as acetic acid, oxalic acid,
(D) or (L) malic acid, maleic acid, Loprazolam, ethane sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, benzene sulfonic acid (benzene sulphur
Hydrochlorate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, apple
Acid, mandelic acid, mucus acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid or malonic acid etc.；Preferably hydrochloric acid or (L)-apple
Acid；Or the acid proton present in the parent compound, when being replaced into metal ion or being coordinated with organic base, forming salt is described
Metal ion such as alkali metal ion, alkaline earth ion or aluminium ion；The organic base such as ethanol amine, diethanol amine, three ethyl alcohol
Amine, trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE and the like.
" excipient " refers to the inert substance being added in pharmaceutical composition further to promote compound to be administered.Excipient
Example include but is not limited to calcium carbonate, calcium phosphate, various sugar and all types of starch, cellulose derivative, gelatin, vegetable oil,
Polyethylene glycol, diluent, granulating agent, lubricant, adhesive, disintegrating agent and similar medicament.
" pharmaceutical composition " refer to one or more compounds described herein or its physiologically acceptable salt with
The mixture of other chemical components (such as physiologically acceptable carrier and excipient).The purpose of pharmaceutical composition is intended to promote
Biology is given into compound.
" carrier " refers to when in this article not to be generated bright stimulation to biology and will not eliminate compound to be administered
The carrier or diluent of bioactivity and characteristic.
" method " refers to mode, means, technology and program for completing appointed task comprising but be not limited to chemistry,
Pharmacy, biology, biochemistry and medicine practitioner those of known mode, means, technology and program, or easily by the practitioner
From those of known mode, means, technology and program development mode, means, technology and program.
" alkyl " refers to saturated aliphatic hydrocarbon, including linear chain or branched chain saturated aliphatic hydrocarbon.
" aryl " refers to that the full carbon monocycle of the pi-electron system with total conjugated or condensed ring are polycyclic (also that is, shared adjacent carbons
The ring of atom pair) group.Preferably, aryl has 6 to 12 carbon atoms in ring.
The compound of the present invention can have one or more asymmetric centers；The compound therefore can individual (R)-solid
Isomers or the preparation of (S)-stereoisomer form are prepared with its form of mixtures.Unless otherwise stated, this specification
And the specific compound in claim description or title be intended to include individual enantiomters and its racemic mixture or
Other mixtures.Method for measuring three-dimensional chemical configuration and separating stereoisomer is well known (referring to ＂ in the art
Discussion in the 4th chapter of Advanced Organic Chemistry ＂, the 4th edition, J.March, John Wiley and Sons, New
York, 1992).Therefore, the present invention also covers that any stereoisomeric forms in any ratio of the active ability of c-Met, it is corresponding with adjusting
Enantiomter (d- isomers and l- isomers or (+) isomers and (-) isomers) and its diastereoisomer and its mixing
Object and it is not limited to any stereoisomeric forms in any ratio.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
In following embodiments.
Embodiment 1
(S)-N- (6- ((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -
3- yl) -3- hydroxyl pyrrolidine -1- carbamyl
Step 1:
Compound 1a (14.5g, 100mmol) and compound 1b (12.3g, 100mmol) are dissolved in toluene (100ml) and pyridine
(20ml) in the mixed solvent, is warming up to 100 DEG C, is stirred to react 6 hours, and TLC detection reaction, end of reaction is added dilute hydrochloric acid and quenches
It goes out reaction, organic layer dries, filters, and is concentrated, and column chromatography for separation obtains yellow oil 18.7g, yield 88.0%.
Step 2:
Compound 1c (18.5g, 87.0mmol), compound 1d (15.9g, 87.0mmol), cesium carbonate (42.0g,
130.5mmol)、Pd(dba)2Bis- diphenylphosphine -9,9- the xanthphos of (2.6g, 4.4mmol), 4,5- (2.6g,
It 4.4mmol) is dissolved in DMF (100ml), is warming up to 100 DEG C and is stirred to react 12 hours, TLC detection reaction after completion of the reaction will be anti-
Liquid is answered to pour into water (100ml), ethyl acetate (200mlX2) extracts, and merges organic dry, filtering that is concerned with, concentration, column chromatography for separation
Obtain off-white powder 20.2g, yield 64.6%.
Step 3:
Compound 1e (20.0g, 55.7mmol) is dissolved in ethyl alcohol (100ml) and purified water (50ml), is added at room temperature
Sodium hydroxide (6.7g, 167.0mmol) is stirred to react 12 hours, and ethyl alcohol is removed under reduced pressure after completion of the reaction, adds for TLC detection reaction
Enter ethyl acetate (200ml), adjust PH to 5-6 with dilute hydrochloric acid, organic layer dries, filters, and is concentrated, it is white that column chromatography for separation obtains class
Color solid 15.3g, yield 79.7%.
Step 4:
By compound 1f (2.0g, 5.8mmol), DPPA (2.1g, 7.5mmol), DIPEA (1.1g, 8.7mmol) is dissolved in first
In benzene (100ml), return stirring reacts 12 hours, and TLC detection reaction is added water (20ml) after completion of the reaction, stirs 1 hour,
Stop reaction, layering, organic layer dries, filters, and is concentrated, and column chromatography for separation obtains off-white powder 1.1g, yield 60.1%.
5th step
By compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g, 9.5mmol) is placed in first
In benzene (50ml), reaction 1 hour is stirred at room temperature, compound 1h (278mg, 3.2mmol) then is added, is stirred to react 6 hours,
TLC detection reaction, is concentrated under reduced pressure, column chromatography for separation after completion of the reaction, obtains off-white powder 0.6g, yield 43.8%.MS-
ESI:m/z=430.2 [M+1]
Embodiment 2
(R) -1- (4- acetyl phenyl) -3- (6- (2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol
[4,3-a] pyrazine -3- base) urea
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 4- antifebrin is then added
(432mg, 3.2mmol) is stirred to react 8 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 0.7g, yield 45.8%.MS-ESI:m/z=478.2 [M+1]
Embodiment 3
(R)-N- (6- (2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -4- methyl piperazine -1- carbamyl amine
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 1- methyl piperazine is then added
(320mg, 3.2mmol) is stirred to react 5 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 0.9g, yield 63.5%, MS-ESI:m/z=443.2 [M+1]
Embodiment 4
(R)-N- (6- (2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -4- ethyl piperazidine -1- carbamyl amine
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 1- ethyl piperazidine is then added
(365mg, 3.2mmol) is stirred to react 7 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 0.8g, yield 54.7%, MS-ESI:m/z=457.2 [M+1]
Embodiment 5
(R)-N- (6- (2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -4- isopropyl piperazine -1- carbamyl amine
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 1- isopropyl piperazine is then added
(410mg, 3.2mmol) is stirred to react 6 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 1.0g, yield 66.2%, MS-ESI:m/z=471.2 [M+1]
Embodiment 6
N- (6- ((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -3- methyl piperazine -1- carbamyl amine
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 2- methyl piperazine is then added
(320mg, 3.2mmol) is stirred to react 5 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 1,1g, yield 77.6%, MS-ESI:m/z=443.2 [M+1]
Embodiment 7
(R) -4- amino-N- (6- (2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrrole
Piperazine -3- base) piperazine -1- carbamyl
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 4- tertbutyloxycarbonyl ammonia is then added
Phenylpiperidines (640mg, 3.2mmol) are stirred to react 5 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography point after completion of the reaction
From obtaining off-white powder 1.6g.
By in solid solution methylene chloride (20ml) obtained above, trifluoroacetic acid (2ml) is added at room temperature, is stirred to react
2 hours, saturated sodium bicarbonate solution (10ml) quenching reaction is added, stands, layering, organic phase is dry, and column chromatography for separation obtains
Off-white powder 1.0g, two step total recoverys are 70.5%.MS-ESI:m/z=443.2 [M+1]
Embodiment 8
(S)-N- (6- ((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -
3- yl) -3- hydroxy piperidine -1- carbamyl
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 3- hydroxy piperidine is then added
(323mg, 3.2mmol) is stirred to react 6 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 0.7g, yield 49.3%.
MS-ESI:m/z=444.2 [M+1]
Embodiment 9
(S) -3- amino-N- (6- ((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-
A] pyrazine -3- base) pyrrolidines -1- carbamyl
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 3- tertbutyloxycarbonyl ammonia is then added
Base pyrrolidines (595mg, 3.2mmol) is stirred to react 4 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography point after completion of the reaction
From obtaining off-white powder 1.5g.
By in solid solution methylene chloride (20ml) obtained above, trifluoroacetic acid (2ml) is added at room temperature, is stirred to react
2 hours, saturated sodium bicarbonate solution (10ml) quenching reaction is added, stands, layering, organic phase is dry, and column chromatography for separation obtains
Off-white powder 0.9g, two step total recoverys are 65.5%.MS-ESI:m/z=429.2 [M+1]
Embodiment 10
(R)-N- (6- (2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -3,3- difluoropyrrolidin -1- carbamyl
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 3,3- difluoropyrrolidin is then added
(342mg, 3.2mmol) is stirred to react 7 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 0.8g, yield 55.6%.
MS-ESI:m/z=450.2 [M+1]
Embodiment 11
1- (6- ((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -3- ((1R, 3S) -3- hydroxycyclopent base) urea
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound (1S, 3R) -3- amino is then added
Pentamethylene -1- alcohol (323mg, 3.2mmol) is stirred to react 5 hours, and TLC detection reaction is concentrated under reduced pressure, column layer after completion of the reaction
Analysis separation, obtains off-white powder 0.6g, yield 42.3%.MS-ESI:m/z=444.2 [M+1]
Embodiment 12
1- (6- ((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -3- ((R) -3- oxocyclopentyl) urea
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound (R) -3- amino cyclopentyl is then added
Alkane -1- ketone (317mg, 3.2mmol) is stirred to react 5 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography point after completion of the reaction
From obtaining off-white powder 0.8g, yield 56.6%, MS-ESI:m/z=442.2 [M+1]
Embodiment 13
N- (6- ((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -3,5- lupetidine -1- carbamyl
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 2,6-dimethyl-piperizine is then added
(365mg, 3.2mmol) is stirred to react 5 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 1.0g, yield 68.4%, MS-ESI:m/z=457.2 [M+1]
Embodiment 14
(R)-N- (6- (2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -4- oxo-piperidine -1- carbamyl
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound piperidine -4- ketone is then added
(317mg, 3.2mmol) is stirred to react 6 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 1.1g, yield 77.8%, MS-ESI:m/z=442.2 [M+1]
Embodiment 15
(R)-N- (6- (2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -3- oxo-pyrrolidine -1- carbamyl
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound pyrrolidines -3- ketone is then added
(272mg, 3.2mmol) is stirred to react 4 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 0.7g, yield 51.1%, MS-ESI:m/z=428.2 [M+1]
Embodiment 16
1- ((1R, 3S) -3- amino cyclopentyl) -3- (6- ((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,
4] triazol [4,3-a] pyrazine -3- base) urea
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound (1R, 3S)-ring penta is then added
Alkane -1,3- diamines (320mg, 3.2mmol) is stirred to react 8 hours, and TLC detection reaction is concentrated under reduced pressure, column layer after completion of the reaction
Analysis separation, obtains off-white powder 0.8g, yield 56.4%, MS-ESI:m/z=443.2 [M+1]
Embodiment 17
(((R) -2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] 6- 1- ((R) -3,3- Difluorocyclopentyl) -3-
Triazol [4,3-a] pyrazine -3- base) urea
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 3- tertbutyloxycarbonyl ammonia is then added
Base pyrrolidines (595mg, 3.2mmol) is stirred to react 5 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography point after completion of the reaction
From obtaining off-white powder 1.5g.
By in solid solution methylene chloride (20ml) obtained above, trifluoroacetic acid (2ml) is added at room temperature, is stirred to react
2 hours, saturated sodium bicarbonate solution (10ml) quenching reaction is added, stands, layering, organic phase is dry, and column chromatography for separation obtains
Off-white powder 0.8g, two step total recoverys are 53.9%.MS-ESI:m/z=464.2 [M+1]
Embodiment 18
(R) -1- (6- (2- (2,5- difluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -3- (4- (methyl sulphonyl) phenyl) urea
The method of reference implementation 1, by compound 1g (1.0g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound is then added to methyl sulphonyl benzene
Amine (547mg, 3.2mmol) is stirred to react 8 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
To off-white powder 1.2g, yield 72.9%, MS-ESI:m/z=514.2 [M+1]
Embodiment 19
1- (6- ((R) -2- (2,5- difluorophenyl) -4,4- difluoropyrrolidin -1- base)-[1,2,4] triazol [4,3-a]
Pyrazine -3- base) -3- ((1R, 3S) -3- hydroxycyclopent alkyl) urea
The method of reference implementation 1, by compound (R) -6- (2- (2,5- difluorophenyl) -4,4- difluoropyrrolidin -1- base) -
[1,2,4] triazol [4,3-a] pyrazine -3- amine (preparation of reference compound 1g method) (1.1g, 3.2mmol), CDI (518mg,
3.2mmol), DIPEA (1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, compound is then added
(1S, 3R) -3- Aminocyclopentane -1- alcohol (323mg, 3.2mmol) is stirred to react 6 hours, TLC detection reaction, after completion of the reaction
It is concentrated under reduced pressure, column chromatography for separation obtains off-white powder 0.9g, yield, 58.6%, MS-ESI:m/z=480.2 [M+1]
Embodiment 20
1- (6- ((R) -2- (2,5- difluorophenyl) -4,4- difluoropyrrolidin -1- base)-[1,2,4] triazol [4,3-a]
Pyrazine -3- base) -3- ((R) -3- oxocyclopentyl) urea
The method of reference implementation 1, by compound (R) -6- (2- (2,5- difluorophenyl) -4,4- difluoropyrrolidin -1- base) -
[1,2,4] triazol [4,3-a] pyrazine -3- amine (1.1g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g,
It 9.5mmol) is placed in toluene (50ml), reaction 1 hour is stirred at room temperature, compound (R) -3- Aminocyclopentane -1- is then added
Ketone (317mg, 3.2mmol) is stirred to react 5 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
To off-white powder 0.8g, yield 52.3%, MS-ESI:m/z=478.2 [M+1]
Embodiment 21
(S)-N- (6- ((R) -2- (3- fluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -3- hydroxyl pyrrolidine -1- carbamyl
The method of reference implementation 1, by compound (R) -6- (2- (3- fluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol
[4,3-a] pyrazine -3- amine (0.95g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g, 9.5mmol) are placed in first
In benzene (50ml), reaction 1 hour is stirred at room temperature, compound (S)-pyrrolidines -3- alcohol (278mg, 3.2mmol) then is added, stirs
Reaction 7 hours is mixed, TLC detection reaction is concentrated under reduced pressure, column chromatography for separation after completion of the reaction, obtains off-white powder 0.9g, yield
68.2%, MS-ESI:m/z=412.2 [M+1]
Embodiment 22
(R) -1- (4- acetyl phenyl) -3- (6- (2- (3- fluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-
A] pyrazine -3- base) urea
The method of reference implementation 1, by compound (R) -6- (2- (3- fluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol
[4,3-a] pyrazine -3- amine (0.95g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g, 9.5mmol) are placed in first
In benzene (50ml), reaction 1 hour is stirred at room temperature, compound 4- antifebrin (432mg, 3.2mmol) then is added, is stirred to react
6 hours, TLC detection reaction was concentrated under reduced pressure, column chromatography for separation after completion of the reaction, obtains off-white powder 0.7g, yield
47.6%, MS-ESI:m/z=460.2 [M+1]
Embodiment 23
(R)-N- (6- (2- (3- fluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3- base) -4-
Methyl piperazine -1- carbamyl
The method of reference implementation 1, by compound (R) -6- (2- (3- fluorophenyl) pyrrolidin-1-yl)-[1,2,4] triazol
[4,3-a] pyrazine -3- amine (0.95g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g, 9.5mmol) are placed in first
In benzene (50ml), reaction 1 hour is stirred at room temperature, compound 1- methyl piperazine (320mg, 3.2mmol) then is added, is stirred to react
8 hours, TLC detection reaction was concentrated under reduced pressure, column chromatography for separation after completion of the reaction, obtains off-white powder 1.0g, yield
73.5%, MS-ESI:m/z=425.2 [M+1]
Embodiment 24
(R)-N- (6- (2- (the chloro- 5- fluorophenyl of 2-) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -4- ethyl piperazidine -1- carbamyl
The method of reference implementation 1, by (2- (the chloro- 5- fluorophenyl of 2-) pyrrolidin-1-yl)-[1,2,4] compound (R) -6-
Triazol [4,3-a] pyrazine -3- amine (1.06g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g, 9.5mmol)
It is placed in toluene (50ml), reaction 1 hour is stirred at room temperature, compound 1- methyl piperazine (320mg, 3.2mmol) then is added, stirs
Reaction 5 hours is mixed, TLC detection reaction is concentrated under reduced pressure, column chromatography for separation after completion of the reaction, obtains off-white powder 0.9g, yield
61.2%, MS-ESI:m/z=459.2 [M+1]
Embodiment 25
(R)-N- (6- (2- (the chloro- 5- fluorophenyl of 2-) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine -3-
Base) -4- ethyl piperazidine -1- carbamyl
The method of reference implementation 1, by (2- (the chloro- 5- fluorophenyl of 2-) pyrrolidin-1-yl)-[1,2,4] compound (R) -6-
Triazol [4,3-a] pyrazine -3- amine (1.06g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g, 9.5mmol)
It is placed in toluene (50ml), reaction 1 hour is stirred at room temperature, compound 1- ethyl piperazidine (365mg, 3.2mmol) then is added, stirs
Reaction 5 hours is mixed, TLC detection reaction is concentrated under reduced pressure, column chromatography for separation after completion of the reaction, obtains off-white powder 1.0g, yield
66.1%, MS-ESI:m/z=473.2 [M+1]
Embodiment 26
N- (6- ((R) -2- (2,5- difluorophenyl) -4- oxo-pyrrolidine -1- base)-[1,2,4] triazol [4,3-a] pyrrole
Piperazine -3- base) -3- methyl piperazine -1- carbamyl
The method of reference implementation 1, by compound (R) -1- (3- amino-[1,2,4] triazol [4,3-a] pyrazine -6- base) -
5- (2,5- difluorophenyl) pyrrolidines -3- ketone (1.06g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g,
9.5mmol) be placed in toluene (50ml), be stirred at room temperature reaction 1 hour, then be added compound 2- methyl piperazine (320mg,
3.2mmol), it is stirred to react 5 hours, TLC detection reaction is concentrated under reduced pressure, column chromatography for separation after completion of the reaction, it is solid to obtain off-white color
Body 0.7g, yield 47.8%, MS-ESI:m/z=457.2 [M+1]
Embodiment 27
(R) -4- amino-N- (6- (2- (2,5- difluorophenyl) -4- oxo-pyrrolidine -1- base)-[1,2,4] triazol [4,
3-a] pyrazine -3- base) piperidines -1- carbamyl
The method of reference implementation 1, by compound (R) -1- (3- amino-[1,2,4] triazol [4,3-a] pyrazine -6- base) -
5- (2,5- difluorophenyl) pyrrolidines -3- ketone (1.06g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g,
It 9.5mmol) is placed in toluene (50ml), reaction 1 hour is stirred at room temperature, compound piperidine -4- base t-butyl formate is then added
(640mg, 3.2mmol) is stirred to react 5 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 1.5g.
By in solid solution methylene chloride (20ml) obtained above, trifluoroacetic acid (2ml) is added at room temperature, is stirred to react
2 hours, saturated sodium bicarbonate solution (10ml) quenching reaction is added, stands, layering, organic phase is dry, and column chromatography for separation obtains
Off-white powder 1.1g, two step total recoverys are 75.2%, MS-ESI:m/z=457.2 [M+1]
Embodiment 28
(S)-N- (6- ((R) -2- (2,5- difluorophenyl) -4,4- dimethyl pyrrolidine -1- base)-[1,2,4] triazol
[4,3-a] pyrazine -3- base) -3- hydroxy piperidine -1- carbamyl
The method of reference implementation 1, by compound (R) -6- (2- (2,5- difluorophenyl) -4,4- dimethyl pyrrolidine -1-
Base)-[1,2,4] triazol [4,3-a] pyrazine -3- amine (1.1g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound (S)-piperidin-3-ol is then added
(323mg, 3.2mmol) is stirred to react 8 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 0.9g, yield 59.7%, MS-ESI:m/z=471.2 [M+1]
Embodiment 29
(S) (((R) -2- (2,5- difluorophenyl) -4,4- dimethyl pyrrolidine -1- base)-[1,2,4] 6- -3- amino-N-
Triazol [4,3-a] pyrazine -3- base) pyrrolidines -1- carbamyl
The method of reference implementation 1, by compound (R) -6- (2- (2,5- difluorophenyl) -4,4- dimethyl pyrrolidine -1-
Base)-[1,2,4] triazol [4,3-a] pyrazine -3- amine (1.1g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound (S)-pyrrolidines -3- is then added
Base t-butyl formate (595mg, 3.2mmol) is stirred to react 5 hours, and TLC detection reaction is concentrated under reduced pressure, column layer after completion of the reaction
Analysis separation, obtains off-white powder 1.3g.
By in solid solution methylene chloride (20ml) obtained above, trifluoroacetic acid (2ml) is added at room temperature, is stirred to react
2 hours, saturated sodium bicarbonate solution (10ml) quenching reaction is added, stands, layering, organic phase is dry, and column chromatography for separation obtains
Off-white powder 0.6g, two step total recoverys are 41.0%, MS-ESI:m/z=457.2 [M+1]
Embodiment 30
(R)-N- (6- (2- (2,5- difluorophenyl) -4,4- dimethyl pyrrolidine -1- base)-[1,2,4] triazol [4,3-
A] pyrazine -3- base) -3,3- difluoropyrrolidin -1- carbamyl
The method of reference implementation 1, by compound (R) -6- (2- (2,5- difluorophenyl) -4,4- dimethyl pyrrolidine -1-
Base)-[1,2,4] triazol [4,3-a] pyrazine -3- amine (1.1g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA
(1.2g, 9.5mmol) is placed in toluene (50ml), and reaction 1 hour is stirred at room temperature, and compound 3,3- difluoropyrrolidin is then added
(342mg, 3.2mmol) is stirred to react 7 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 1.0g, yield 63.4%, MS-ESI:m/z=478.2 [M+1]
Embodiment 31
(R)-N- (6- (2- (the fluoro- 2- methoxyphenyl of 5-) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine-
3- yl) -3,5- lupetazin -1- carbamyl
The method of reference implementation 1, by compound (R) -6- (2- (the fluoro- 2- methoxyphenyl of 5-) pyrrolidin-1-yl)-[1,
2,4] triazol [4,3-a] pyrazine -3- amine 1.05g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g,
It 9.5mmol) is placed in toluene (50ml), reaction 1 hour is stirred at room temperature, compound 2,6-dimethyl-piperizine is then added
(365mg, 3.2mmol) is stirred to react 7 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 1.2g, yield 80.0%, MS-ESI:m/z=469.2 [M+1]
Embodiment 32
(R)-N- (6- (2- (the fluoro- 2- methoxyphenyl of 5-) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine-
3- yl) -4- oxo-piperidine -1- carbamyl
The method of reference implementation 1, by compound (R) -6- (2- (the fluoro- 2- methoxyphenyl of 5-) pyrrolidin-1-yl)-[1,
2,4] triazol [4,3-a] pyrazine -3- amine 1.05g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g,
9.5mmol) be placed in toluene (50ml), be stirred at room temperature reaction 1 hour, then be added compound piperidine -4- ketone (317mg,
3.2mmol), it is stirred to react 6 hours, TLC detection reaction is concentrated under reduced pressure, column chromatography for separation after completion of the reaction, it is solid to obtain off-white color
Body 0.9g, yield 62.0%, MS-ESI:m/z=454.2 [M+1]
Embodiment 33
(R)-N- (6- (2- (the fluoro- 2- methoxyphenyl of 5-) pyrrolidin-1-yl)-[1,2,4] triazol [4,3-a] pyrazine-
3- yl) -3- oxo-pyrrolidine -1- carbamyl
The method of reference implementation 1, by compound (R) -6- (2- (the fluoro- 2- methoxyphenyl of 5-) pyrrolidin-1-yl)-[1,
2,4] triazol [4,3-a] pyrazine -3- amine 1.05g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g,
9.5mmol) be placed in toluene (50ml), be stirred at room temperature reaction 1 hour, then be added compound pyrrolidines -3- ketone (272mg,
3.2mmol), it is stirred to react 6 hours, TLC detection reaction is concentrated under reduced pressure, column chromatography for separation after completion of the reaction, it is solid to obtain off-white color
Body 0.8g, yield 56.8%, MS-ESI:m/z=440.2 [M+1]
Embodiment 34
1- ((R) -3,3- difluoro pentamethylene base) -3- (6- ((R) -2- (6- methoxypyridine -2- base) pyrrolidin-1-yl) -
[1,2,4] triazol [4,3-a] pyrazine -3- base) urea
The method of reference implementation 1, by compound (R) -6- (2- (6- methoxypyridine -2- base) pyrrolidin-1-yl)-[1,
2,4] triazol [4,3-a] pyrazine -3- amine (0.96g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g,
It 9.5mmol) is placed in toluene (50ml), reaction 1 hour is stirred at room temperature, compound (R) -3,3- difluoro pentamethylene-is then added
1- amine (387mg, 3.2mmol) is stirred to react 6 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation after completion of the reaction,
Obtain off-white powder 1.1g, yield 74.9%, MS-ESI:m/z=459.2 [M+1]
Embodiment 35
1- ((1R, 3S) -3- amino cyclopentyl) -3- (4- (methyl sulphonyl) phenyl)-[1,2,4] triazol [4,3-a]
Pyrazine -3- base) urea reference implementation 1 method, by compound (R) -6- (2- (6- methoxypyridine -2- base) pyrrolidin-1-yl) -
[1,2,4] triazol [4,3-a] pyrazine -3- amine (0.96g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g,
It 9.5mmol) is placed in toluene (50ml), reaction 1 hour is stirred at room temperature, compound 4- methanesulfonylaniline is then added
(547mg, 3.2mmol) is stirred to react 6 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
Off-white powder 1.0g, yield 61.4%, MS-ESI:m/z=509.2 [M+1]
Embodiment 36
1- ((1R, 3S) -3- amino cyclopentyl) -3- (6- ((R) -2- (6- methoxypyridine -2- base) pyrrolidin-1-yl) -
[1,2,4] triazol [4,3-a] pyrazine -3- base) urea
The method of reference implementation 1, by compound (R) -6- (2- (6- methoxypyridine -2- base) pyrrolidin-1-yl)-[1,
2,4] triazol [4,3-a] pyrazine -3- amine (0.96g, 3.2mmol), CDI (518mg, 3.2mmol), DIPEA (1.2g,
It 9.5mmol) is placed in toluene (50ml), reaction 1 hour is stirred at room temperature, compound 3- t-butoxycarbonyl amino pyrroles is then added
Alkane (595mg, 3.2mmol) is stirred to react 4 hours, and TLC detection reaction is concentrated under reduced pressure, column chromatography for separation obtains after completion of the reaction
To off-white powder 1.5g.
By in solid solution methylene chloride (20ml) obtained above, trifluoroacetic acid (2ml) is added at room temperature, is stirred to react
2 hours, saturated sodium bicarbonate solution (10ml) quenching reaction is added, stands, layering, organic phase is dry, and column chromatography for separation obtains
Off-white powder 0.8g, two step total recoverys are 57.1%.MS-ESI:m/z=438.2 [M+1]
The measurement of 37 bioactivity of embodiment
The evaluation of TrkA kinase inhibiting activity
Use the kinase activity of Enzyme-linked Immunosorbent Assay (ELISA) test valuation TrkA in the presence of the inhibitors.It uses
The solution of poly- (Glu, Ala, Tyr, the 6:3:1) of 0.025mg/ml coats 384 microwell plate of Immulon 4HBX.It will be a variety of
The test compound of concentration, TrkA and 500 μM of the ATP of 2.5nm are incubated for 25 minutes in microwell plate at ambient temperature,
It is shaken simultaneously, the test buffer has 25nm MOPS pH 7.5,0.005% (V/V) TritonX-100 and 5nm
MgCl2 is constituted, and reaction mixture is washed by using the PBS comprising 0.1% (V/V) polysorbas20 come by moving in the plate
Out.Use phosphotyrosine monoclonal antibody specific of the 0.2 μ g/mL in conjunction with horseradish peroxidase and TMB peroxidating
Object zymolyte system (KPL) detects the reaction product of phosphorylation, after 1M phosphoric acid is added, according to absorption feelings at 450 nm
Condition quantifies the color intensity of chromogenic substrate, using S curve calculates IC50Value, concrete outcome are shown in Table 1:
The foregoing is merely presently preferred embodiments of the present invention, the substantial technological context being not intended to limit the invention.
Claims (19)
1. a kind of compound with Formulas I structure, stereoisomer or its pharmaceutically acceptable salt, hydrate, solvate,
Isotopic compound,
Wherein, R1For optionally by CN, OH, OMe, NH2、NHMe、N(Me)2、Cl、Br、F、CF3、CONH2、SO2NH2、NHSO2(C1-
C4 alkyl) monosubstituted or polysubstituted phenyl or aromatic heterocyclic；
R2 is selected from H C1-C4 alkyl；
R3 is optionally by CN, OH, OMe, NH2、NHMe、N(Me)2、Cl、Br、F、CF3、CONH2、SO2NH2, SO2 (C1-C4 alkyl),
CO (C1-C4 alkyl), NHSO2(C1-C4 alkyl) monosubstituted or polysubstituted phenyl, aromatic heterocyclic；
Or R2 and R3 collectively form substituted four-membered ring, five-membered ring, hexatomic ring；
X is selected from CH2、CO、CF2、C(CH3)2。
2. the compound with Formulas I structure, stereoisomer or its pharmaceutically acceptable salt according to claim 1,
Hydrate, solvate, isotopic compound, wherein R1 is optional by OH, OMe, Cl, Br, F, CF3、CONH2、SO2NH2、
NHSO2(C1-C4 alkyl) monosubstituted or polysubstituted phenyl.
3. the compound with Formulas I structure, stereoisomer or its pharmaceutically acceptable salt according to claim 1,
Hydrate, solvate, isotopic compound, wherein R1 is optional by OH, OMe, Cl, Br, F, CF3、CONH2、SO2NH2、
NHSO2(C1-C4 alkyl) monosubstituted or polysubstituted aromatic heterocyclic.
4. the compound according to claim 1 to 3 with Formulas I structure, stereoisomer or its is pharmaceutically acceptable
Salt, hydrate, solvate, isotopic compound, wherein R is H or to be not present.
5. the compound according to claim 1 to 3 with Formulas I structure, stereoisomer or its is pharmaceutically acceptable
Salt, hydrate, solvate, isotopic compound, wherein R3 be optionally by CN, OH, OMe, NH2、NHMe、N(Me)2、Cl、
Br、F、CF3、CONH2、SO2NH2、SO2(C1-C4 alkyl), CO (C1-C4 alkyl), NHSO2(C1-C4 alkyl) is monosubstituted or more
Substituted-phenyl, aromatic heterocyclic.
6. the compound according to claim 1 to 3 with Formulas I structure, stereoisomer or its is pharmaceutically acceptable
Salt, hydrate, solvate, isotopic compound, wherein R2 and R3 collectively forms substituted four-membered ring, five-membered ring, hexa-atomic
Ring；The four-membered ring, five-membered ring, hexatomic ring contain 1-2 hetero atom.
7. according to any compound with Formulas I structure of claim 5-6, stereoisomer or its is pharmaceutically acceptable
Salt, hydrate, solvate, isotopic compound, wherein R2 and R3 collectively forms substituted four-membered ring, five-membered ring, hexa-atomic
Ring, the four-membered ring, five-membered ring, hexatomic ring substituent group be selected from C-C4 alkyl, CN, OH, OMe, NH2、NHMe、N(Me)2、Cl、
Br、F、CF3、CONH2、SO2NH2, SO2 (C1-C4 alkyl), CO (C1-C4 alkyl), NHSO2(C1-C4 alkyl), it is described to be substituted by
It is monosubstituted or polysubstituted.
8. the compound with Formulas I structure, stereoisomer or its pharmaceutically acceptable salt according to claim 1,
Hydrate, solvate, isotopic compound, wherein
Represent such as flowering structure:
9. the compound with Formulas I structure, stereoisomer or its pharmaceutically acceptable salt according to claim 1,
Hydrate, solvate, isotopic compound, wherein
Represent such as flowering structure:
10. the compound according to claim 1-8 with Formulas I structure, stereoisomer or its pharmaceutically may be used
The preparation method of the salt of receiving, hydrate, solvate, isotopic compound, includes the following steps:
(1) synthesis of intermediate compound IV
Compound II and compound III ring closure reaction, reaction under alkali effect carry out at a temperature of 20 DEG C to 100 DEG C；
(2) synthesis of intermediate VI
Compound IV and compound V react under catalyst and ligand effect, the reaction 20 DEG C to 100 DEG C base catalysis into
Row；
(3) synthesis of intermediate VII
Compound VI reacts in the presence of alkali, and the reaction carries out at a temperature of 20 DEG C to 100 DEG C；
(4) synthesis of intermediate VIII
Compound VII reacts under the action of DPPA, and the reaction carries out at a temperature of 80 DEG C to 100 DEG C, alkali be selected from triethylamine,
Diisopropylethylamine；Reaction dissolvent is toluene；
(5) synthesis of finished product I
Compound VIII reacts under condensing agent effect with compound IX, reaction base catalysis at a temperature of 20 DEG C to 100 DEG C
It carries out.
11. preparation method according to claim 10, alkali described in step (1) is selected from triethylamine, diisopropylethylamine, pyrrole
Pyridine, 4-dimethylaminopyridine, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide；Reaction dissolvent is ethyl alcohol, different
Propyl alcohol, dioxane, tetrahydrofuran, toluene.
12. preparation method according to claim 10, catalyst described in step (2) is selected from PdCl2(PPh3)2、Pd
(PPh3)4、Pd(dba)2、Pd(OAc)2、Pd(dppf)2Cl2；Ligand joins selected from 2- dicyclohexyl phosphine -2', 4', 6'- triisopropyl
Benzene (XPhos), 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl (SPhos), the bis- diphenylphosphine -9,9- dimethyl oxygens of 4,5-
Miscellaneous anthracene (XantPhos)；Alkali is selected from cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, potassium phosphate, sodium acetate；Reaction dissolvent is dioxy six
Ring, DMF, toluene.
13. preparation method according to claim 10, in step (3), alkali is selected from lithium hydroxide, sodium hydroxide, hydroxide
Potassium；Reaction dissolvent is methanol, ethyl alcohol, tetrahydrofuran, methanol/water, ethanol/water, tetrahydrofuran/water.
14. preparation method according to claim 10, in step (5), condensing agent is selected from CDI, phenyl chloroformate；Alkali is selected from
Triethylamine, diisopropylethylamine, N-methylmorpholine, DMAP；Reaction dissolvent is methylene chloride, DMF, tetrahydrofuran, toluene.
15. a kind of pharmaceutical composition, it includes compounds a method as claimed in any one of claims 1-8, stereoisomer or pharmaceutically
Acceptable salt, hydrate, solvate, isotopic compound
16. a kind of claim 1-8 any compound, stereoisomer and its pharmaceutically acceptable salt, hydrate,
Solvate, isotopic compound are as TRK kinase inhibitor for treating tumour.
17. a kind of claim 1-8 any compound, stereoisomer and its pharmaceutically acceptable salt, hydrate,
Solvate, isotopic compound are as TRK kinase inhibitor for treating tumour.
18. purposes according to claim 16 or 17, which is characterized in that the tumour is selected from breast cancer, cutaneum carcinoma, bladder
Cancer, oophoroma, gastric cancer, prostate cancer, colon cancer, lung cancer, osteocarcinoma, the cancer of the brain, the carcinoma of the rectum, the cancer of the esophagus, tongue cancer, carcinoma of renal parenchyma, palace
Neck cancer, carcinoma of uterine body, carcinoma of endometrium, carcinoma of testis, uropoiesis cancer, melanotic cancer, astrocytes cancer, meningioma, Hodgkin lymphoma,
Non-Hodgkin lymphoma, acute lymphatic leukemia, chronic lymphatic leukemia, acute myelogenous leukemia, chronic granulocyte
It is leukaemia, adult T-cell leukemia-lymphoma, hepatocellular carcinoma, bronchiolar carcinoma, Small Cell Lung Cancer, non-small cell lung cancer, multiple
Myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, muscle tumor, fibrosarcoma.
19. a kind of compound according to claim 1, stereoisomer and its pharmaceutically acceptable salt, hydrate, molten
Object, isotopic compound are closed in agent, which is characterized in that the compound is selected from the compound of following formula (1)-(36):
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110804059A (en) * | 2019-09-30 | 2020-02-18 | 郑州泰基鸿诺医药股份有限公司 | Carbamate compound, pharmaceutical composition and application thereof |
| CN111039915A (en) * | 2019-12-27 | 2020-04-21 | 北京鑫开元医药科技有限公司 | Raf kinase inhibitor, preparation method, pharmaceutical composition and application thereof |
| CN111303163A (en) * | 2020-05-14 | 2020-06-19 | 北京鑫开元医药科技有限公司 | Compound with JAK kinase inhibitory activity, preparation method, composition and application |
| CN114761408A (en) * | 2019-12-19 | 2022-07-15 | 贝达药业股份有限公司 | KRAS G12C inhibitor and application thereof in medicines |
| WO2023011616A1 (en) * | 2021-08-06 | 2023-02-09 | 正大天晴药业集团股份有限公司 | Use of aminopyrazolopyrimidine compound in treatment of trk kinase-mediated tumor |
Citations (1)
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| CN108794484A (en) * | 2018-04-28 | 2018-11-13 | 北京施安泰医药技术开发有限公司 | [1,2,4] triazol [4,3-a] pyrazines derivatives, its pharmaceutical composition, preparation method and application |
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2019
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794484A (en) * | 2018-04-28 | 2018-11-13 | 北京施安泰医药技术开发有限公司 | [1,2,4] triazol [4,3-a] pyrazines derivatives, its pharmaceutical composition, preparation method and application |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110804059A (en) * | 2019-09-30 | 2020-02-18 | 郑州泰基鸿诺医药股份有限公司 | Carbamate compound, pharmaceutical composition and application thereof |
| CN110804059B (en) * | 2019-09-30 | 2024-03-12 | 郑州泰基鸿诺医药股份有限公司 | Carbamate compound, pharmaceutical composition and application thereof |
| CN114761408A (en) * | 2019-12-19 | 2022-07-15 | 贝达药业股份有限公司 | KRAS G12C inhibitor and application thereof in medicines |
| CN114761408B (en) * | 2019-12-19 | 2023-09-15 | 贝达药业股份有限公司 | KRAS G12C inhibitor and application thereof in medicine |
| CN111039915A (en) * | 2019-12-27 | 2020-04-21 | 北京鑫开元医药科技有限公司 | Raf kinase inhibitor, preparation method, pharmaceutical composition and application thereof |
| CN111303163A (en) * | 2020-05-14 | 2020-06-19 | 北京鑫开元医药科技有限公司 | Compound with JAK kinase inhibitory activity, preparation method, composition and application |
| WO2023011616A1 (en) * | 2021-08-06 | 2023-02-09 | 正大天晴药业集团股份有限公司 | Use of aminopyrazolopyrimidine compound in treatment of trk kinase-mediated tumor |
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Denomination of invention: Compounds with TRK kinase inhibitory activity, preparation method, composition, and use Effective date of registration: 20230829 Granted publication date: 20200901 Pledgee: Industrial Bank Co.,Ltd. Beijing Pinggu Branch Pledgor: BEIJING XINKAIYUAN PHARMACEUTICAL TECHNOLOGY CO.,LTD. Registration number: Y2023110000364 |