CN110407852A - Double aromatic ring derivative egf inhibitors of a kind of Thienopyrimidine and preparation method thereof and purposes - Google Patents
Double aromatic ring derivative egf inhibitors of a kind of Thienopyrimidine and preparation method thereof and purposes Download PDFInfo
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Abstract
The present invention discloses a kind of selective depressant of the clinical mutant of EGFR protein tyrosine kinase, and with the structure such as formula (I and II), it is a kind of double aromatic rings template compounds containing Thienopyrimidine, also disclose the preparation method and its application as the selective depressant of the clinical mutant of EGFR protein tyrosine kinase of such compound, especially for the inhibiting effect of the EGF-R ELISA EGFR of T790M variation, related disease such as kidney is over-expressed in treatment and EGF-R ELISA EGFR, lung cancer, prostate cancer, cancer of pancreas, breast cancer and spongiocytoma.
Description
Technical field
The present invention relates to the double aromatic ring derivatives of Thienopyrimidine.
Background technique
Skin growth factor EGFR (epithelial growth factor receptor) is the cross-film sugar of a 170kDa
Protein receptor tyrosine kinase, is activated by epidermal growth factor, influences the growth and differentiation of cell.EGF or TGFα are to EGFR's
In conjunction with the tyrosine-kinase enzyme activity of activated receptor.Tyrosine residue Tyr1068, Tyr1148 of EGFR carboxyl terminal and
Tyr1173 is the major site of the autophosphorylation occurred after EGF is combined.Once it is activated, EGFR1068 and 1173 phosphorus
The tyrosine residue of acidification can mediate combination of the Grb2 to EGFR.In addition, the tyrosine residue of 1173 phosphorylations is SHC
Principal binding sites on EGFR.EGFR is widely distributed in many normal and malignant epithelial cells, overexpression and oneself
I activates may be related with the occurrence and development of many tumours.Being currently used primarily in various human cancers includes incidence
The research of squamous carcinoma, lung cancer, breast cancer and bladder cancer etc..
Protein tyrosine kinase (protein tyrosine kinase, PTK) is γ-phosphoric acid transfer on a kind of catalysis ATP
Kinases onto protein-tyrosine residue.Perhaps my growth factor receptor protein includes that EGF-R ELISA passes through phosphorylation
It works, EGF-R ELISA EGFR tyrosine kinase makes EGF-R ELISA phosphorylation.Clinically, EGFR junket ammonia
Acid kinase inhibitor has been used for the treatment of cancer, the first generation reversible EGFR tyrosine kinase inhibitor Gefitinib and Ai Luo
For Buddhist nun.Significant clinical response (50-80%) is shown to the viral people for there are these specific activated mutants in body.So
And the patient for generating the mutation of secondary and medicine for these drugs understands the recurrence in some months by cancer.Second generation EGFR junket
Histidine kinase inhibitor includes linatinib, replaces Buddhist nun up to gram, Afatinib all contains electrophilic group in the structure of these drugs
Michael receptor.Wherein by taking Afatinib is pharmaceutical representative as an example, allyl amide structure plays the anti-tumor activity of Afatinib
Vital effect, it is (new as the catalytic site of Michael receptor and EGFR cysteine residue (Cys797)
The sulfydryl of core) Michael addition reaction occurs, to make kinase-dead, irreversibly inhibit the activity of tyrosine kinase, thus
With good tolerance.Researchers demonstrate this from molecular level by the crystal of culture inhibitor and receptor completely
The presence of a little covalent bonds, and it was found that Afatinib is by the way that the Cys 803 of Cys 805 and HER4 with HER2 are acted on and then
Strength inhibits these enzymes.Afatinib is to Wild type EGFR and L858R/ to be shown to Wild type EGFR testing in vitro
The inhibiting effect of T790M double-mutant has better effect compared with Gefitinib, Erlotinib and Lapatinib.This
Outside, Afatinib is higher than 30 times of Lapatinib to the inhibiting effect of DER4.Third generation EGFR tyrosine kinase inhibitor Austria is uncommon to be replaced
Buddhist nun also reaches nanomole to the inhibiting effect of tri- saltant type of L858R/T790M/C797S.Buddhist nun is replaced so that Austria is uncommon, is further opened
Sending has the EGFR tyrosine kinase inhibitor of high inhibition effect to saltant type, meanwhile, research and development are efficient, low toxicity with resistance to
The anti-cancer agent of pharmacological property is particularly significant in current medical research and development field.
Summary of the invention
The present invention devises a series of inhibitor small molecules for the EGFR tyrosine kinase for inhibiting T790M to make a variation, and finds
There is the compound of high inhibitory activity to T790M variation EGFR, and the compound has cancer cell and apparent inhibits to make
With the compound is the compound and α of double aromatic rings containing Thienopyrimidine, beta-unsaturated carboxylic acid amide structure.The chemical combination
Object can realize that high activity inhibits to T790M/L858R variant EGFR, and can inhibit or kill the tumour of EGFRT790M variation
Cell, while there is very high inhibitory activity effect to Wild type EGFR.
The present invention provides the compound of the double aromatic ring derivatives of Thienopyrimidine shown in formula (I and II) or its solid are different
Structure body or its pharmaceutically acceptable salt, such compound contain double aromatic rings and α, and beta-unsaturated carboxylic acid amide structure can
As a kind of irreversible EGFR inhibitor,
Wherein: A is optional following any
X1N or CR can be selected5；
R1H, halogen, CN, NO can be selected2, CF3, CHF2, C1-C6Alkyl, C1-C6Naphthenic base, C1-C6Allylic alkylation, C1-C6Alkynes
Alkyl, C1-C6Oxyalkyl, C1-C6Amine alkyl；
R2H, C can be selected1-C6Alkyl, C1-C6Naphthenic base, C1-C6Allylic alkylation, C1-C6Alkynes alkyl, C1- C6Oxyalkyl, C1-
C6Amine alkyl, C1-C6Alkyl carbonyl, C1-C6Alkene carbonyl；
R3H, CN, NO can be selected2, CF3, CHF2, C1-C6Alkyl, C1-C6Naphthenic base, C1-C6Allylic alkylation, C1-C6Alkynes alkyl,
C1-C6Oxyalkyl, C1-C6Amine alkyl；
R4H, halogen, CN, C can be selected1-C6Alkyl, C1-C6Naphthenic base, C1-C6Alkenyl, C1-C6Alkynyl, C1-C6Oxyalkyl,
CF3, CHF2；
R5H, C can be selected1-C6Alkyl, C1-C6Naphthenic base, C1-C6Alkenyl, C1-C6Alkynyl, C1-C6Alkoxy, C1-C6Amine alkane
Base；
It is excellent selectively, the compound include with as 1 structure of table compound:
The compound of 1 general structure of table (I and II) includes one kind of number 501-508
The synthesis and preparation of 1 general formula I and II compound of Scheme
The present invention also provides a kind of preparation methods of above-mentioned EGFR protein tyrosine kinase selective depressant, such as
Shown in Scheme 1.The following steps are included: starting material I-1 obtains intermediate II -1 through coupling reaction, intermediate II -1 is passed through
Two step nucleophilic displacement of fluorine obtain logical formula (I) compound represented, starting material I ' -1 obtains intermediate II through coupling reaction ' -1, in
Mesosome II ' -1 obtains logical formula (II) compound represented by two step nucleophilic displacement of fluorine (as shown in Scheme 1).
The present invention also provides compounds above-mentioned or base stereoisomer or its pharmaceutically acceptable salt to prepare
Purposes in anti-tumor drug, EFGR kinase inhibitor.
Described pharmaceutical composition is the form of tablet, capsule, granule, spray or injection.
The pharmaceutically acceptable carrier is selected from one of filler, disintegrating agent, adhesive and lubricant or a variety of.
Including but not limited to any and whole solvent, decentralized medium, coating, absorption delaying agent etc., such medium and medicament are used for
Pharmaceutically active substances are in the well-known of this field.
The present invention also provides the double aromatic rings egf inhibitors of the Thienopyrimidine and pharmaceutically acceptable
Purposes of the salt as protein tyrosine kinase inhibitor；
Further, the protein tyrosine kinase inhibitor is epidermal growth factor receptor inhibitor；
It is highly preferred that the epidermal growth factor receptor inhibitor is to the T790M EGF-R ELISA to make a variation
Inhibitor.
The double aromatic rings egf inhibitors of Thienopyrimidine and pharmaceutically acceptable salt or its pharmaceutical composition
Purposes of the object in the drug that preparation over-expresses related disease for treating EGF-R ELISA.
Further, the tumour is liver cancer, lung cancer, prostate cancer, cancer of pancreas, breast cancer and astrocytoblast
Tumor.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other diversified forms, replacement or change can also be made.
Below by way of the specific embodiment of form of implementation, above content of the invention is remake further specifically
It is bright.But this should not be understood the range of the above-mentioned theme of the hair present invention only in example below.It is all real based on invention above content institute
Existing technology all belongs to the scope of the present invention.
Specific embodiment
The present invention is further illustrated below by way of specific embodiment.
Synthesize and prepare general formula I and II compound starting material I-1 and I ' -1 through coupling reaction obtain intermediate II -1 and
II ' -1, intermediate II -1 and II ' -1 obtain general formula (I and II) compound represented by two step nucleophilic displacement of fluorine.It is worth explanation
It is that general formula (I and II) compound includes but is not limited to following compounds enumerated.
Embodiment 1:2- 1'-N, and TMSDMA N dimethylamine base ethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-four
Hydrogen -6'- quinoxaline } -4- (1 "-methyl-1 H-3 "-indoles) thiophene [2,3-D] pyrimidine (compound 501)
The preparation of the chloro- 4- of 2- (1 '-methyl-1 H-3 '-indoles) thiophene [2,3-D] pyrimidine:
2,4- dichloro-thiophene [2,3-D] pyrimidine (0.82g, 4mmol) is dissolved in glycol dimethyl ether (20mL), Yu Bing
The lower stirring of bath, is added portionwise ferric trichloride (0.77g, 4.59mmol), is stirred to react at room temperature later 15 minutes.Then it is added dropwise
N- methyl indol (0.68g, 5.2mmol) is heated to 60 DEG C later and is stirred to react 24 hours.Stop reaction, be down to 0 DEG C, is added
3.5mL methanol and 9mL water, are then stirred to react 3 hours at room temperature again.A large amount of solids are precipitated, filters, washs filter cake with methanol,
Drying obtains yellow solid 0.81g, yield: 68%.LC/MS (ESI): m/z 300 (M+H)+。
The preparation of the fluoro- 2- methoxyl group -5- nitrobenzene amido tert-butyl acrylate of 4-:
By the fluoro- 2- methoxyl group -5- nitroaniline (50g, 0.269mol) of 4-, Boc acid anhydrides (58.62g, 0.269 mol) is molten
It in acetonitrile (1L), is warming up to 55 DEG C and reacts 7 hours, vacuum rotary steam falls acetonitrile, ethyl acetate (500mL) dissolution is added, then
Stirring is lower to be added dropwise petroleum ether (100mL), solid is precipitated, filtering obtains yellow solid 61.5g, yield: 81%
The preparation of N- (2- dimethyl aminoethyl) sweet acid ethyl ester:
Glyoxylic acid hydrate (60g, 0.652mol) is dissolved in methanol (500mL), is stirred at room temperature 30 minutes, then
It is cooled to 0 DEG C, N is added dropwise, 10%Pd/C is added after stirring 30 minutes in N- dimethyl-ethylenediamine (57g, 0.646mol)
(8.2g), then plus methanol (10mL) is replaced three times with hydrogen, and reaction 24 hours is stirred at room temperature.Stop reaction, filters out palladium
Charcoal, a small amount of methanol wash filter cake, and filtrate decompression is concentrated to get crude product N- (2- dimethyl aminoethyl) sweet acid.By gained crude product N-
(2- dimethyl aminoethyl) sweet acid is dissolved in ethyl alcohol (500mL), and the lower addition concentrated sulfuric acid (8mL) is then stirred at room temperature, and reflux 16 is small
When, decompression evaporates ethyl alcohol, and ethyl acetate (500mL) dissolution is added, 250mL water is then added, is transferred to Ph with 15%NaOH solution
It is 11, then layering extraction, aqueous layer with ethyl acetate (2*50mL) extraction is washed with saturated salt solution, anhydrous magnesium sulfate is dry,
It is concentrated to get brown color oil 102.2g, yield: 90%.LC/MS (ESI): m/z 175 (M+H)+。
The system of 4- (N, N- dimethyl-N '-ethyl acetate ethylenediamine base) -2- methoxyl group -5- nitrobenzene amido tert-butyl acrylate
It is standby:
The fluoro- 2- methoxyl group -5- nitrobenzene amido tert-butyl acrylate (40g, 0.14mol) of 4- is dissolved in DMAC (600mL),
Stir at room temperature, be added N- (2- dimethyl aminoethyl) sweet acid ethyl ester (26.7g, 12 mmol) and DIPEA (23.4g,
0.18mol), it is heated to 60 DEG C later, is stirred to react 6 hours.Fully reacting is detected through TLC.Stop reaction, be cooled to room temperature,
Reaction solution is slowly poured into the ice water that stirred, a large amount of solids are precipitated, is filtered, filtration cakes torrefaction obtains light yellow solid
54.2g, yield: 88%.LC/MS (ESI): m/z 441 (M+H)+。
1- (N, N- dimethylaminoethyl) -3- oxo -4-boc amido -7- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
The preparation of quinoline
By 4- (N, N- dimethyl-N '-ethyl acetate ethylenediamine base) -2- methoxyl group -5- nitrobenzene amido tert-butyl acrylate
(44g, 0.1mol) is dissolved in methanol (600mL), is added 5%Pd/C (0.15g), three times with hydrogen displacement, later in 40Psi hydrogen
Under gas atmospheric pressure, it is stirred to react 3 hours.Fully reacting is detected through TLC.Stop reaction, filters out palladium charcoal, a small amount of methanol washing filter
Cake, filtrate decompression concentration obtain yellow solid 24.4g through quick post separation, yield: 67%.LC/MS (ESI): m/z 365 (M+
H)+。
1- (N, N- dimethylaminoethyl) -3- oxo -4- amino -7- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
The preparation of quinoline
By 1- (N, N- dimethylaminoethyl) -3- oxo -4-boc amido -7- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'-
Quinoxaline (21.6g, 59.2mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (600mL), stirs at room temperature, is added 4M HCL (160mL),
It is stirred to react 10 hours.Fully reacting is detected through TLC.Stop reaction.With saturation Na2CO3Solution tune pH 7~9, uses methylene chloride
(500mL) extraction, it is dry, it is concentrated under reduced pressure to give yellow solid 14.37g, yield: 92%.LC/MS (ESI): m/z 265 (M+H)+。
1- (N, N- dimethylaminoethyl) -4- amino -7- methoxyl group -1 ', the system of 2 ', 3 ', 4 '-tetrahydro -6'- quinoxalines
It is standby:
By 1- (N, N- dimethylaminoethyl) -3- oxo -4- amino -7- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
Quinoline (13.2g, 50mmol) is dissolved in THF (20mL), is stirred at 0 DEG C, and LiAlH is added4, then it is stirred to react at 0 DEG C
30 minutes, 80 DEG C are then heated to, is stirred to react 4 hours.Fully reacting is detected through TLC.Stop reaction.It is cooled to 0 DEG C, is instilled
Then concentrated hydrochloric acid (6mL) and water (20mL) is added in water (0.5mL) quenching reaction, stir 30 minutes, and solid is precipitated, and filters, filter cake
Dry, gained crude product obtains yellow-brown solid 8.53g through quick post separation, yield: 68%.LC/MS (ESI): m/z 251 (M+
H)+。
2- [4 '-fluoro- 5 '-nitro -2 '-methoxyl group] anilino- -4- (1 "-methyl-1 H-3 "-indoles) thiophene [2,3-D] is phonetic
The preparation of pyridine:
The chloro- 4- of 2- (1- methyl-1 H-3- indoles) thiophene [2,3-D] pyrimidine (299mg, 1mmol) is dissolved in 20 mL dioxies
In six rings, stirs 1- (N, N- dimethylaminoethyl) -4- amino -7- methoxyl group -1 ' is added at room temperature, 2 ', 3 ', 4 '-four
Hydrogen -6'- quinoxaline (275mg, 1.1mmol) and p-methyl benzenesulfonic acid (215mg, 1.1mmol) are heated to 85 DEG C later, and stirring is anti-
It answers 7 hours.LCMS detects fully reacting.Stop reaction, be cooled to room temperature, 5mL water is added and 40%NaOH is adjusted to pH=9.It crosses
Filter washs filter cake with methanol, and drying obtains yellow solid, 472mg, yield: 92%.LC/MS (ESI): m/z 514 (M+H)+。
2- { 1'-N, N- dimethylaminoethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
Quinoline } -4- (1 "-methyl-1 H-3 "-indoles) thiophene [2,3-D] pyrimidine (compound 501) preparation:
By 2- [1'-N, N- dimethylaminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (1 " -
Methyl-1 H-3 "-indoles) thiophene [2,3-D] pyrimidine (195mg, 0.38mmol) and DIPEA (0.073mL, 0.42 mmol) be dissolved in
It in methylene chloride (5mL), is stirred at 0 DEG C, then it is molten to be dissolved in DCM (1mL) for dropwise addition acryloyl chloride (34.5mg, 0.38mmol)
Liquid is stirred to react 2 hours later.Fully reacting is detected through TLC.Stop reaction, is added DCM (25mL), is then saturated with 50mL
NaHCO3Washing, water layer are extracted with DCM (2*25mL), anhydrous MgSO4Dry, concentration, crude product obtains Huang by quick post separation
Color solid 101mg, yield: 47%.1H NMR(400MHz,DMSO-d6)δ8.89(s,1H), 8.17(d,1H),7.59(d,
1H),7.31-7.44(m,3H),7.12-7.19(m,3H),6.43-6.48(m,2H), 6.09(m,1H),5.74(m,1H),
3.74-3.86(m,10H),3.45(m,2H),2.50(m,2H),2.21(s, 6H).LC/MS (ESI): m/z 568 (M+H)+。
Embodiment 2:2- 1'-N, N- dimethylaminoethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-four
Hydrogen -6'- quinoxaline } and -4- (1 "-methyl -4- azepine -3 "-indoles) thiophene [3,2-D] pyrimidine (compound 502)
The preparation of the chloro- 4- of 2- (1 '-methyl-1 H-3 '-indoles) thiophene [3,2-D] pyrimidine:
2,4- dichloro-thiophene [3,2-D] pyrimidine (0.82g, 4mmol) is dissolved in glycol dimethyl ether (20mL), Yu Bing
The lower stirring of bath, is added portionwise ferric trichloride (0.77g, 4.59mmol), is stirred to react at room temperature later 15 minutes.Then it is added dropwise
N- methyl indol (0.68g, 5.2mmol) is heated to 60 DEG C later and is stirred to react 24 hours.Stop reaction, be down to 0 DEG C, is added
3.5mL methanol and 9mL water, are then stirred to react 3 hours at room temperature again.A large amount of solids are precipitated, filters, washs filter cake with methanol,
Drying obtains yellow solid, 0.86g, yield: 72%.LC/MS (ESI): m/z 300 (M+H)+。
2- [1'-N, N- dimethylaminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (1 "-first
Base -7 "-azepine -1H-3 "-indoles) thiophene [3,2-D] pyrimidine preparation:
The chloro- 4- of 2- (1- methyl -7- azepine -1H-3- indoles) thiophene [3,2-D] pyrimidine (299mg, 1mmol) is dissolved in
In 20mL dioxane, stirs 1- (N, N- dimethylaminoethyl) -4- amino -7- methoxyl group -1 ' is added at room temperature, 2 ', 3 ',
4 '-tetrahydro -6'- quinoxalines (275mg, 1.1mmol) and p-methyl benzenesulfonic acid (215mg, 1.1 mmol), are heated to 85 DEG C later,
It is stirred to react 7 hours.LCMS detects fully reacting.Stop reaction, be cooled to room temperature, 5mL water and 40%NaOH solution tune is added
To pH=9.Filtering washs filter cake with methanol, and drying obtains yellow solid, 442mg, yield: 86%.LC/MS (ESI): m/z
514(M+H)+。
2- { 1'-N, N- dimethylaminoethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
Quinoline } -4- (1 "-methyl -7 "-azepine -1H-3 "-indoles) thiophene [3,2-D] pyrimidine (compound 502) preparation:
By 2- [1'-N, TMSDMA N dimethylamine aminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (1 " -
Methyl -7 "-azepine -1H-3 "-indoles) thiophene [3,2-D] pyrimidine (390mg, 0.76mmol) and DIPEA (0.146 mL,
It 0.84mmol) is dissolved in methylene chloride (10mL), is stirred at 0 DEG C, acryloyl chloride (69mg, 0.76mmol) is then added dropwise and is dissolved in
DCM (2mL) solution, is stirred to react 2 hours later.Fully reacting is detected through TLC.Stop reaction, is added DCM (50mL), then
NaHCO is saturated with 100mL3Washing, water layer are extracted with DCM (2*50mL), anhydrous MgSO4Dry, concentration, crude product passes through quick
Post separation obtains yellow solid 231mg, yield: 54%.1H NMR(400MHz,DMSO-d6)δ8.89 (s,1H),8.17(d,
1H),7.59(d,1H),7.31-7.44(m,3H),7.12-7.19(m,3H),6.43-6.48(m, 2H),6.09(m,1H),
5.74(m,1H),3.74-3.86(m,10H),3.45(m,2H),2.50(m,2H),2.21 (s,6H).LC/MS (ESI): m/z
568(M+H)+。
Embodiment 3:2- 1'-N, N- dimethylaminoethyl -4'- crotonoyl amido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-four
Hydrogen -6'- quinoxaline } -4- (3 "-pyrazoles [1,5-a] pyridine) thiophene [2,3-D] pyrimidine (compound 503)
2- { 1'-N, N- dimethylaminoethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
Quinoline } -4- (3 "-pyrazoles [1,5-a] pyridine) thiophene [2,3-D] pyrimidine (compound 503) preparation:
By 2- [1'-N, N- dimethylaminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (3 " -
Pyrazoles [1,5-a] pyridine) Thienopyrimidine (390mg, 0.76mmol) and DIPEA (0.146mL, 0.84mmol) be dissolved in dichloro
It in methane (10mL), is stirred at 0 DEG C, crotonyl chloride (79mg, 0.76 mmol) is then added dropwise and is dissolved in DCM (2mL) solution, it
After be stirred to react 2 hours.Fully reacting is detected through TLC.Stop reaction, is added DCM (50mL), is then saturated with 100mL
NaHCO3Washing, water layer are extracted with DCM (2*50mL), anhydrous MgSO4Dry, concentration, crude product is obtained by quick post separation
Yellow solid 199mg, yield: 45%.1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.17(d,1H), 7.59(d,
1H),7.31-7.44(m,3H),7.12-7.19(m,3H),6.72(m,1H),6.43(s,1H),6.26(m, 1H),3.74-
3.86(m,10H),3.45(m,2H),2.50(m,2H),2.21(s,6H),1.89(m,3H).LC/MS (ESI): m/z 582 (M
+H)+。
Embodiment 4:2- 1'-N, N- dimethylaminoethyl -4'- crotonoyl amido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-four
Hydrogen -6'- quinoxaline } -4- (3 "-pyrazoles [1,5-a] pyridine) thiophene [3,2-D] pyrimidine (compound 504)
2- { 1'-N, N- dimethylaminoethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
Quinoline } -4- (3 "-pyrazoles [1,5-a] pyridine) thiophene [3,2-D] pyrimidine (compound 504) preparation:
By 2- [1'-N, N- dimethylaminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (3 " -
Pyrazoles [1,5-a] pyridine) Thienopyrimidine (390mg, 0.76mmol) and DIPEA (0.146mL, 0.84mmol) be dissolved in dichloro
It in methane (10mL), is stirred at 0 DEG C, crotonyl chloride (79mg, 0.76 mmol) is then added dropwise and is dissolved in DCM (2mL) solution, it
After be stirred to react 2 hours.Fully reacting is detected through TLC.Stop reaction, is added DCM (50mL), is then saturated with 100mL
NaHCO3Washing, water layer are extracted with DCM (2*50mL), anhydrous MgSO4Dry, concentration, crude product is obtained by quick post separation
Yellow solid 230mg, yield: 52%.1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.17(d,1H), 7.59(d,
1H),7.31-7.44(m,3H),7.12-7.19(m,3H),6.72(m,1H),6.43(s,1H),6.26(m, 1H),3.74-
3.86(m,10H),3.45(m,2H),2.50(m,2H),2.21(s,6H),1.89(m,3H).LC/MS (ESI): m/z 582 (M
+H)+。
Embodiment 5:2- 1'-N, N- dimethylaminoethyl -4'- crotonoyl amido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-four
Hydrogen -6'- quinoxaline } -4- (3 "-pyrazoles [1,5-a] pyridine) thiophene [2,3-D] pyrimidine (compound 505) preparation:
2- { 1'-N, N- dimethylaminoethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
Quinoline } -4- (3 "-pyrazoles [1,5-a] pyridine) thiophene [2,3-D] pyrimidine (compound 505) preparation:
By 2- [1'-N, N- dimethylaminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (3 " -
Pyrazoles [1,5-a] pyridine) Thienopyrimidine (390mg, 0.76mmol) and DIPEA (0.146mL, 0.84mmol) be dissolved in dichloro
It in methane (10mL), is stirred at 0 DEG C, acryloyl chloride (69mg, 0.76 mmol) is then added dropwise and is dissolved in DCM (2mL) solution, it
After be stirred to react 2 hours.Fully reacting is detected through TLC.Stop reaction, is added DCM (50mL), is then saturated with 100mL
NaHCO3Washing, water layer are extracted with DCM (2*50mL), anhydrous MgSO4Dry, concentration, crude product is obtained by quick post separation
Yellow solid 213mg, yield: 46%.1H NMR(400MHz,DMSO-d6)δ8.85-8.89(m,2H),8.17 (d,1H),
7.59(d,1H),7.31-7.44(m,3H),7.12-7.19(m,3H),6.43(s,1H),5.22(m,1H), 3.74-3.86
(m,10H),3.45(m,2H),2.91(s,6H),2.50(m,2H),2.21(s,6H).LC/MS (ESI): m/z 611 (M+H)+。
Embodiment 6:2- 1'-N, N- dimethylaminoethyl -4'- crotonoyl amido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-four
Hydrogen -6'- quinoxaline } -4- (3 "-pyrazoles [1,5-a] pyridine) thiophene [3,2-D] pyrimidine (compound 506) preparation:
2- { 1'-N, N- dimethylaminoethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
Quinoline } -4- (3 "-pyrazoles [1,5-a] pyridine) thiophene [3,2-D] pyrimidine (compound 506) preparation:
By 2- [1'-N, N- dimethylaminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (3 " -
Pyrazoles [1,5-a] pyridine) Thienopyrimidine (390mg, 0.76mmol) and DIPEA (0.146mL, 0.84mmol) be dissolved in dichloro
It in methane (10mL), is stirred at 0 DEG C, acryloyl chloride (69mg, 0.76 mmol) is then added dropwise and is dissolved in DCM (2mL) solution, it
After be stirred to react 2 hours.Fully reacting is detected through TLC.Stop reaction, is added DCM (50mL), is then saturated with 100mL
NaHCO3Washing, water layer are extracted with DCM (2*50mL), anhydrous MgSO4Dry, concentration, crude product is obtained by quick post separation
Yellow solid 195mg, yield: 42%.1H NMR(400MHz,DMSO-d6)δ8.85-8.89(m,2H),8.17 (d,1H),
7.59(d,1H),7.31-7.44(m,3H),7.12-7.19(m,3H),6.43(s,1H),5.22(m,1H), 3.74-3.86
(m,10H),3.45(m,2H),2.91(s,6H),2.50(m,2H),2.21(s,6H).LC/MS (ESI): m/z 611 (M+H)+。
Embodiment 7:2- 1'-N, and TMSDMA N dimethylamine base ethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-four
Hydrogen -6'- quinoxaline } -4- (1 "-methyl -7 "-azepine -1H-3 "-indoles) thiophene [2,3-D] pyrimidine (compound 507) preparation:
The preparation of the chloro- 4- of 2- (1 '-methyl -7 '-azepine -1H-3 '-indoles) thiophene [2,3-D] pyrimidine:
By 1- methyl -3- (4,4,5,5- tetramethyl -1,3,2- dioxy borine -2- base) -1H- pyrrolo- [2,3-B] pyridine
(0.74g, 2.87mmol) and 2,4- dichloro-thiophene [2,3-D] pyrimidine (0.70g, 3.44mmol) are dissolved in glycol dimethyl ether
In (20mL), then stirring be added dichloro di-t-butyl-(4- dimethylaminophenyl) phosphine palladium (II) (0.31g,
0.19mmol), 2M sodium carbonate solvent (3.2mL, 6.3mmol) under nitrogen protection, is stirred and heated to 80 DEG C and reacts 4 hours.Through
TLC detects fully reacting.Stop reaction, water (1mL) is added to dilute.Ethyl acetate (25mL) extracts 2 times, anhydrous MgSO4It is dry,
Concentration, crude product obtain yellow solid 560mg by quick post separation, yield: 65%.LC/MS (ESI): m/z 301 (M+H)+。
2- [1'-N, N- dimethylaminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (1 "-first
Base -7 "-azepine -1H-3 "-indoles) thiophene [2,3-D] pyrimidine preparation:
The chloro- 4- of 2- (1 '-methyl -7 '-azepine -1H-3 '-indoles) thiophene [2,3-D] pyrimidine (300mg, 1mmol) is molten
In 20mL dioxane, stirs 1- (N, N- dimethylaminoethyl) -4- amino -7- methoxyl group -1 ' is added at room temperature, 2 ',
3 ', 4 '-tetrahydro -6'- quinoxalines (275mg, 1.1mmol) and p-methyl benzenesulfonic acid (215mg, 1.1 mmol), are heated to 85 later
DEG C, it is stirred to react 7 hours.LCMS detects fully reacting.Stop reaction, be cooled to room temperature, 5mL water is added and 40%NaOH is adjusted to
PH=9.Filtering washs filter cake with methanol, and drying obtains yellow solid, 473mg, yield: 92%.LC/MS (ESI): m/z 515
(M+H)+。
2- { 1'-N, N- dimethylaminoethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
Quinoline } -4- (1 "-methyl -7 "-azepine -1H-3 "-indoles) thiophene [2,3-D] pyrimidine (compound 507) preparation:
By 2- [1'-N, N- dimethylaminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (1 " -
Methyl -7 "-azepine -1H-3 "-indoles) thiophene [2,3-D] pyrimidine (195mg, 0.38mmol) and DIPEA (0.073 mL,
It 0.42mmol) is dissolved in methylene chloride (5mL), is stirred at 0 DEG C, it is molten that acryloyl chloride (34.5mg, 0.38mmol) is then added dropwise
In DCM (1mL) solution, it is stirred to react later 2 hours.Fully reacting is detected through TLC.Stop reaction, is added DCM (25mL), so
NaHCO is saturated with 50mL afterwards3Washing, water layer are extracted with DCM (2*25mL), anhydrous MgSO4Dry, concentration, crude product passes through quick
Post separation obtains yellow solid 101mg, yield: 47%.1H NMR(400MHz,DMSO-d6)δ8.89 (s,1H),8.39-8.51
(m,2H),7.31(d,1H),7.06-7.17(m,4H),6.43-6.48(m,2H),6.09 (m,1H),5.74(m,1H),
3.74-3.86(m,7H),3.59(s,3H),3.45(m,2H),2.50(m,2H), 2.21(s,6H).LC/MS (ESI): m/z
569(M+H)+。
Embodiment 8:2- 1'-N, N- dimethylaminoethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-four
Hydrogen -6'- quinoxaline } -4- (1 "-methyl -7 "-azepine -1H-3 "-indoles) thiophene [3,2-D] pyrimidine (compound 508) preparation:
The preparation of the chloro- 4- of 2- (1 '-methyl -7 '-azepine -1H-3 '-indoles) thiophene [3,2-D] pyrimidine:
By 1- methyl -3- (4,4,5,5- tetramethyl -1,3,2- dioxy borine -2- base) -1H- pyrrolo- [2,3-B] pyridine
(0.74g, 2.87mmol) and 2,4- dichloro-thiophene [3,2-D] pyrimidine (0.70g, 3.44mmol) are dissolved in glycol dimethyl ether
In (20mL), then stirring be added dichloro di-t-butyl-(4- dimethylaminophenyl) phosphine palladium (II) (0.31g,
0.19mmol), 2M sodium carbonate solvent (3.2mL, 6.3mmol) under nitrogen protection, is stirred and heated to 80 DEG C and reacts 4 hours.Through
TLC detects fully reacting.Stop reaction, water (1mL) is added to dilute.Ethyl acetate (25mL) extracts 2 times, anhydrous MgSO4It is dry,
Concentration, crude product obtain yellow solid 585mg by quick post separation, yield: 68%.LC/MS (ESI): m/z 301 (M+H)+。
2- [1'-N, N- dimethylaminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (1 "-first
Base -7 "-azepine -1H-3 "-indoles) thiophene [3,2-D] pyrimidine preparation:
The chloro- 4- of 2- (1 '-methyl -7 '-azepine -1H-3 '-indoles) thiophene [3,2-D] pyrimidine (300mg, 1mmol) is molten
In 20mL dioxane, stirs 1- (N, N- dimethylaminoethyl) -4- amino -7- methoxyl group -1 ' is added at room temperature, 2 ',
3 ', 4 '-tetrahydro -6'- quinoxalines (275mg, 1.1mmol) and p-methyl benzenesulfonic acid (215mg, 1.1 mmol), are heated to 85 later
DEG C, it is stirred to react 7 hours.LCMS detects fully reacting.Stop reaction, be cooled to room temperature, 5mL water is added and 40%NaOH is adjusted to
PH=9.Filtering washs filter cake with methanol, and drying obtains yellow solid, 457mg, yield: 89%.LC/MS (ESI): m/z 515
(M+H)+。
2- { 1'-N, N- dimethylaminoethyl -4'- acrylamido -7'- methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydro -6'- quinolines
Quinoline } -4- (1 "-methyl -7 "-azepine -1H-3 "-indoles) thiophene [3,2-D] pyrimidine (compound 508) preparation:
By 2- [1'-N, N- dimethylaminoethyl -7 '-methoxyl group -1 ', 2 ', 3 ', 4 '-tetrahydros -6 '-quinoxaline] -4- (1 " -
Methyl -7 "-azepine -1H-3 "-indoles) thiophene [3,2-D] pyrimidine (390mg, 0.76mmol) and DIPEA (0.146 mL,
It 0.84mmol) is dissolved in methylene chloride (10mL), is stirred at 0 DEG C, acryloyl chloride (69mg, 0.76mmol) is then added dropwise and is dissolved in
DCM (2mL) solution, is stirred to react 2 hours later.Fully reacting is detected through TLC.Stop reaction, is added DCM (50mL), then
NaHCO is saturated with 100mL3Washing, water layer are extracted with DCM (2*50mL), anhydrous MgSO4Dry, concentration, crude product passes through quick
Post separation obtains yellow solid 237mg, yield: 55%.1H NMR(400MHz,DMSO-d6)δ8.89 (s,1H),8.39-8.51
(m,2H),7.31(d,1H),7.06-7.17(m,4H),6.43-6.48(m,2H),6.09 (m,1H),5.74(m,1H),
3.74-3.86(m,7H),3.59(s,3H),3.45(m,2H),2.50(m,2H), 2.21(s,6H).LC/MS (ESI): m/z
569(M+H)+。
The measurement of embodiment 9:EGFR kinase inhibiting activity and relevant mutational site Percentage bound
To compound 501-508 made from above-described embodiment 1-8, aforesaid compound is measured to EGFR using FRET technology
Kinase inhibiting activity, the inhibitory activity use IC50This index is to expression, IC50That is the activity inhibited 50% of EGFR kinases
When compound concentration.
Simultaneously using TR-FRET technology to the EGFR- of compound 501- 508 made from the compounds of this invention embodiment 1-8
T790M kinase activity inhibiting effect is measured, and also uses IC50This index is to expression.It is public using Life technologies
Take charge of Z '-LYTETMKinase Assay Kits (PV3193), and the EGFR-T790M selected in Tyrosine 4Peptide swashs
Enzyme solution carries out active determination test.Measurement result is shown in Table 2
The EGFR inhibitory activity and EGFR of 2 embodiment compound of tableT790MPercentage bound measurement
Embodiment 10: chemical combination of the present invention measures (mtt assay detection) to the inhibitory activity of cancer cell line
Cell strain: Non-small cell lung carcinoma adenocarcinoma cell strain NCI-H1975 (EGFR-T790M high expression), people's non-small cell
Pneumonocyte strain A549 (EFGR high expression).
Method: it is double that cell strain NCI-H1975 and A549 are placed in 20%FBS (fetal calf serum) (Gibco)+1640+1%
It is anti-to be cultivated.Then the good NCI-H1975 cell of growth conditions is taken, 5000/hole is inoculated in 96 porocyte plates respectively, sets
Hatch to educate in 37 DEG C, the incubator containing 5%CO2 makes cell adherent completely for 24 hours.Old culture solution is discarded, every hole sequentially adds 100
The culture solution of μ L untested compound Han 0.3,1,3,10,30,100,300,1000,3000 and 10000nmol/L, solvent control
The every hole of group is added 100 culture solutions of the μ L containing 0.1%DMSO, every group of 3 multiple holes, old culture solution is discarded after 72h, under the conditions of being protected from light
Every hole is added 100 μ L and contains 0.5mgmL-1The culture solution of MTT is placed in cell incubator and continues to be incubated for 4h, discards supernatant, every hole
100 μ LDMSO are added, vibrates, measures each hole absorbance value under 492nm wavelength with microplate reader.According to each compound various concentration
To the inhibiting rate of detailed intracellular growth, the IC in following table is obtained through conversion50(nM)。
3 compound of table acts on lung cancer cell line
| NCI-H1975 | A549 | |
| Sample number into spectrum | IC50(nM) | IC50(nM) |
| 501 | 19 | 1.4 |
| 502 | 27 | 3.2 |
Claims (10)
1. one kind has the double aromatic rings egf inhibitors of the Thienopyrimidine of general structure (I and II) and pharmaceutically may be used
The salt of receiving
Wherein: A is optional following any
X1N or CR can be selected5；
R1H, halogen, CN, NO can be selected2, CF3, CHF2, C1-C6Alkyl, C1-C6Naphthenic base, C1-C6Allylic alkylation, C1-C6Alkynes alkyl,
C1-C6Oxyalkyl, C1-C6Amine alkyl；
R2H, C can be selected1-C6Alkyl, C1-C6Naphthenic base, C1-C6Allylic alkylation, C1-C6Alkynes alkyl, C1-C6Oxyalkyl, C1-C6Amine alkane
Base, C1-C6Alkyl carbonyl, C1-C6Alkene carbonyl；
R3H, CN, NO can be selected2, CF3, CHF2, C1-C6Alkyl, C1-C6Naphthenic base, C1-C6Allylic alkylation, C1-C6Alkynes alkyl, C1-C6
Oxyalkyl, C1-C6Amine alkyl；
R4H, halogen, CN, C can be selected1-C6Alkyl, C1-C6Naphthenic base, C1-C6Alkenyl, C1-C6Alkynyl, C1-C6Oxyalkyl, CF3,
CHF2；
R5H, C can be selected1-C6Alkyl, C1-C6Naphthenic base, C1-C6Alkenyl, C1-C6Alkynyl, C1-C6Alkoxy, C1-C6Amine alkyl.
2. the double aromatic rings egf inhibitor of Thienopyrimidine according to claim 1 and pharmaceutically acceptable
Salt, which is characterized in that the compound of the general structure (I or II) includes one kind of number 501-508
3. a kind of prepare the double aromatic rings egf inhibitors of Thienopyrimidine described in claims 1 or 2 and pharmacy
The method of upper acceptable salt.It is characterized by comprising following steps:
(1) compound I-1 and I-2 obtains compound II-1 by coupling reaction, and compound I ' -1 and I-2 are obtained by coupling reaction
To compound II ' -1:
Wherein: A is optional following any
X1N or CR can be selected5；
R4H, halogen, CN, C can be selected1-C6Alkyl, C1-C6Naphthenic base, C1-C6Alkenyl, C1-C6Alkynyl, C1-C6Alkoxy, CF3,
CHF2；
R5H, C can be selected1-C6Alkyl, C1-C6Naphthenic base, C1-C6Alkenyl, C1-C6Alkynyl, C1-C6Alkoxy, C1-C6Amine alkyl；
(2) compound II-1 and II-2 obtains compound III-1 by substitution reaction, and compound II ' -1 and II-2 pass through substitution
Reaction obtains compound III ' -1:
(3) compound III-1 and III-2 obtains compound I by necleophilic reaction, and compound III ' -1 and III-2 pass through nucleophilic
Reaction obtains compound II:
4. a kind of pharmaceutical composition, which is characterized in that include the double aromatic rings tables of Thienopyrimidine described in claims 1 or 2
Epidermal growth factor inhibitors and pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
5. pharmaceutical composition according to claim 4, which is characterized in that described pharmaceutical composition is tablet, capsule, particle
The form of agent, spray or injection.
6. pharmaceutical composition according to claim 4, which is characterized in that the pharmaceutically acceptable carrier is selected from filling
One of agent, disintegrating agent, adhesive and lubricant are a variety of.
7. claim 1 and the double aromatic rings egf inhibitor of Thienopyrimidine described in 2 and can pharmaceutically connect
Purposes of the salt received as protein tyrosine kinase inhibitor.
8. purposes according to claim 7, it is characterised in that: the protein tyrosine kinase inhibitor is epidermal growth factor
Sub- acceptor inhibitor.
9. claim 1 and the double aromatic rings egf inhibitor of Thienopyrimidine described in 2 and can pharmaceutically connect
Pharmaceutical composition described in any one of the salt received or claim 4 to 6 is in preparation for treating EGF-R ELISA
Over-express the purposes in the drug of related disease.
10. purposes according to claim 9, it is characterised in that: the EGF-R ELISA over-expresses related disease
Disease is selected from one of kidney, lung cancer, prostate cancer, cancer of pancreas, breast cancer and spongiocytoma or a variety of.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022101184A1 (en) | 2020-11-11 | 2022-05-19 | Bayer Aktiengesellschaft | N-[2-({4-[3-(anilino)-4-oxo-4,5,6,7-tetrahydro-1h-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl)oxy)ethyl]prop-2-enamide derivatives and similar compounds as egfr inhibitors for the treatment of cancer |
| WO2023213882A1 (en) | 2022-05-04 | 2023-11-09 | Bayer Aktiengesellschaft | Irreversible mutegfr inhibitors |
| WO2024028316A1 (en) | 2022-08-02 | 2024-02-08 | Bayer Aktiengesellschaft | 1h-pyrrolo[3,2-b]pyridine derivatives as irreversible inhibitors of mutant egfr for the treatment of cancer |
-
2019
- 2019-08-27 CN CN201910796922.0A patent/CN110407852A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022101184A1 (en) | 2020-11-11 | 2022-05-19 | Bayer Aktiengesellschaft | N-[2-({4-[3-(anilino)-4-oxo-4,5,6,7-tetrahydro-1h-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl)oxy)ethyl]prop-2-enamide derivatives and similar compounds as egfr inhibitors for the treatment of cancer |
| WO2023213882A1 (en) | 2022-05-04 | 2023-11-09 | Bayer Aktiengesellschaft | Irreversible mutegfr inhibitors |
| WO2024028316A1 (en) | 2022-08-02 | 2024-02-08 | Bayer Aktiengesellschaft | 1h-pyrrolo[3,2-b]pyridine derivatives as irreversible inhibitors of mutant egfr for the treatment of cancer |
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