CN109422725A - Drugs for prostate cancer - Google Patents
Drugs for prostate cancer Download PDFInfo
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- CN109422725A CN109422725A CN201710784144.4A CN201710784144A CN109422725A CN 109422725 A CN109422725 A CN 109422725A CN 201710784144 A CN201710784144 A CN 201710784144A CN 109422725 A CN109422725 A CN 109422725A
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- alkyl
- prostate cancer
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to prostate cancer therapy effect compound and its non-toxic pharmaceutically acceptable salt, structure it is shown in formula I:In Formulas I, X is C or N;R1The alkyl replaced for the alkyl or halogen of C1-C3;R2The alkyl or halogen replaced for alkyl, the halogen of C1-C3;R3And R4Independently selected from H, alkyl, substituted alkyl;R3And R4It is connected to form naphthenic base.Such compound not only has strong inhibiting effect to prostate cancer in situ, but also has strong inhibiting effect to the transfer of prostate cancer;And it is less side effects to cause to faint from fear.
Description
Technical field:
The present invention relates to the thio-hydantoin class compounds that two (miscellaneous) aryl of anti-prostate cancer effect replace.
Technical background:
Prostate cancer is a kind of malignant proliferative disease of androgen-dependent, the morbidity with higher in male patient
Rate.Since the individual difference of patients with prostate cancer is larger, reasonable personalized treatment is particularly important in the field.Androgen
Deprive the standard for having become treatment advanced prostate cancer.Medical castration inhibits testis to generate testosterone and protona, but adrenal gland
The androgen generated with prostate cancer tissue still results in prostate cancer progress, this stage is known as castration and resists prostate cancer
(CRPC)。
Androgen receptor (AR) signal path sustained activation is the important of the prostate cancer disease development of androgen insensitivity
Factor.Abiraterone acetate and the miscellaneous Shandong amine of grace based on the research and development of AR target are the newest successful two kinds of breakthrough prostates of research and development
Cancer therapeutic agent.Abiraterone acetate is blocked by inhibiting 17 α of Cytochrome P450-hydroxylase (CYP17) to prostate cancer
The synthesis for developing the androgen to play a crucial role, plays the effect of anti-prostate cancer.The miscellaneous Shandong amine of grace is androgen receptor inhibitor,
Act on androgen receptor signal path.The combination of Reverse transcriptase androgen and androgen receptor, while inhibiting androgen receptor
The displacement of body core and the interaction with DNA, resisting prostate cancer to castration has preferable therapeutic effect.
It is more than 30% prostate cancer crowd although androgen deprivation therapy has become the mainstream therapies of prostate cancer
Drug resistance is generated quickly.(1.Joseph JD, Lu N, Qian J, et al.Cancer Discov.2013;3 (9): 1020-
9.2.Nelson WG, Yegnasubramanian S.Cancer Discov.2013;3 (9): 971-4.3.Buttigliero
C, Tucci M, Bertaglia V, et al.Cancer Treat Rev.2015;41 (10): 884-92.).
More studies have found that, androgen knock out increase model of human prostate carcinoma mouse metastases (Niu Y,
Altuwaijri S, Lai KP, et al.Proc Natl Acad Sci USA 2008;105:12182-12187.), it prompts
Anti-androgen therapy may promote the transfer of prostate cancer.In model of human prostate carcinoma mouse model, androgen receptor inhibitor ratio
Card Shandong amine and the miscellaneous Shandong amine of grace promote transfer (Lin TH, Lee SO, Niu Y, the et al.J Biol Chem of prostate cancer
2013;288:19359-19369.).It is found in clinical test, although abiraterone can significantly reduce PSA level,
Also it can increase Bone tumour (Ryan CJ, Shah S, et al.Clin Cancer Res 2011;17:4854-4861.).
Summary of the invention:
The present inventor is unexpectedly sent out by the further investigation of the thio-hydantoin class compound replaced to two (miscellaneous) aryl
Existing Formulas I compound represented not only has strong inhibiting effect to prostate cancer in situ, but also has to the transfer of prostate cancer
Strong inhibiting effect.
Therefore, the present invention provides Formulas I compound represented and its non-toxic pharmaceutically acceptable salt:
In Formulas I, X is C or N;R1The alkyl replaced for the alkyl or halogen of C1-C3;R2Replace for alkyl, the halogen of C1-C3
Alkyl or halogen;R3And R4Independently selected from H, alkyl, substituted alkyl;R3And R4It is connected to form naphthenic base.
Formulas I compound represented provided by the invention and its non-toxic pharmaceutically acceptable salt, are selected from:
The present invention also provides compound shown in the Formulas I containing effective therapeutic dose and its non-toxic are pharmaceutically acceptable
The pharmaceutical composition of salt and pharmaceutically acceptable excipient.
The present invention also provides Formulas I compound represented and its non-toxic pharmaceutically acceptable salt and its pharmaceutical composition,
Purposes in the preparation of antitumor drugs.
The present invention finally also provides Formulas I compound represented and its non-toxic pharmaceutically acceptable salt and its medicine group
Object is closed, the purposes in antiprostate cancer is being prepared.
Specific embodiment
The following examples can be with the present invention is further described;However, these embodiments are not constituted to of the invention
The limitation of range.
The preparation of 1 4- isothiocyano -2- trifluoromethylbenzonitrile (ii-1) of reference implementation example
23 grams of 4- amino -2- trifluoromethylbenzonitriles are added in 200ml water, is vigorously stirred, is added dropwise in 30 minutes
10ml thiophosgene.It finishes, continues stirring 2 hours.Reaction mixture chloroform is extracted into (3X150ml), merges and extracts
Liquid is dried overnight with anhydrous magnesium sulfate.Solid is filtered off, filtrate decompression is evaporated, obtains 25.3 grams of ii-1.
The preparation of 2 5- isothiocyano -3- trifluoromethyl -2- formonitrile HCN base of reference implementation example-pyridine (ii-2)
The preparation of 2.1 3- trifluoromethylpyridin-N- oxide of reference implementation example
In 20ml methylene chloride, 14.7 grams of 3- trifluoromethylpyridins, 0.025 gram of methyl trioxy- rhenium, stirring is added.
The hydrogen peroxide of 40ml 30% is added dropwise.It finishes, is stirred at room temperature 6 hours.30 milligrams of manganese dioxide are added, continue stirring 1 hour.Add
Enter 500ml methylene chloride, be placed in separatory funnel, wash (2X200ml) with NaCl saturated solution, by organic layer anhydrous slufuric acid
Magnesium is dried overnight.Solid is filtered off, filtrate decompression is evaporated, obtains 14.2 grams of oxide of 3- trifluoromethylpyridin-N-.
The preparation of 2.2 2- itrile group -3- trifluoromethylpyridin of reference implementation example
13 grams of 3- trifluoromethylpyridin-N- oxides 50ml acetonitrile is dissolved, 10 grams of trimethyl cyaniding silicon and 2 are added
Gram triethylamine.Mixture is stirred at room temperature 24 hours.500ml methylene chloride is added, is placed in separatory funnel, uses Na2CO3Saturation
Solution washs (2X200ml), and organic layer is dried overnight with anhydrous magnesium sulfate.Solid is filtered off, filtrate decompression is evaporated.It will residual
Object is separated with silica gel column chromatography, and with ethyl acetate: petroleum ether (1: 2) mixed solvent elutes, component needed for collecting, evaporated under reduced pressure,
Obtain 7.5 grams of 2- itrile group -3- trifluoromethylpyridin.
The preparation of 2.3 2- itrile group -3- trifluoromethyl -5- nitropyridine of reference implementation example
100ml 1,2- dichloroethanes is added in 7 grams of 2- itrile group -3- trifluoromethylpyridins and 11 grams of tetramethyl ammonium nitrate
In, 17 grams of trifluoroacetic anhydride are added, heated sealed is reacted 48 hours to 60 DEG C.500ml ethyl acetate is added, is placed in liquid separation leakage
In bucket, NaHCO is used3Saturated solution washs (2X200ml), and organic layer is dried overnight with anhydrous magnesium sulfate.Solid is filtered off, will be filtered
Liquid evaporated under reduced pressure.Residue is separated with silica gel column chromatography, with ethyl acetate: petroleum ether (1: 4) mixed solvent elutes, and collects institute
Component is needed, evaporated under reduced pressure obtains 1.2 grams of nitropyridine of -3- trifluoromethyl -5- of 2- itrile group.
The preparation of 2.4 2- itrile group -3- trifluoromethyl -5- aminopyridine of reference implementation example
5ml ethyl acetate and 5ml acetic acid are mixed, 1 gram of 2- itrile group -3- trifluoromethyl -5- nitropyridine is added with stirring
With 1.12 grams of iron powders, it is heated to reflux under stirring 15 hours.Solid is filtered off, filtrate decompression is evaporated.By residue silica gel column layer
Analysis separation, with ethyl acetate: petroleum ether (1: 1) mixed solvent elutes, and component needed for collecting, evaporated under reduced pressure obtains 2- itrile group -3- three
0.8 gram of methyl fluoride -5- aminopyridine.
The preparation of 2.5 5- isothiocyano -3- trifluoromethyl -2- formonitrile HCN base of reference implementation example-pyridine (ii-2)
0.8 gram of 2- itrile group -3- trifluoromethyl -5- aminopyridine is added in 20ml water, is vigorously stirred, is dripped in 30 minutes
Add 0.5ml thiophosgene.It finishes, continues stirring 2 hours.Reaction mixture chloroform is extracted into (3X150ml), merges and extracts
Liquid is dried overnight with anhydrous magnesium sulfate.Solid is filtered off, filtrate decompression is evaporated, obtains 0.7 gram of ii-2.Nuclear magnetic resonance spectroscopy:1H-
NMR (400MHz, CDCl3): 7.89 (d, 1H);8.80 (d, 1H).
Reference implementation example the 3 fluoro- 4- of N- methyl -2- [(2,2- dimethyl-acetonitrile-base)-amino]-benzamide (iii-1)
Preparation
The preparation of the fluoro- 4- nitrobenzoic acid of 3.1 2- of reference implementation example
17 grams of periodic acid are added in 250ml acetonitrile, then 1.6 grams of chromium trioxides are added, under stirring in dissolved with vigorous agitation
The fluoro- 4- nitrotoleune of 3 grams of 2- is added.It is stirred to react 1 hour, evaporating solvent under reduced pressure.200ml methylene chloride is added in residue,
(2X60ml) is extracted with water, organic layer is dried overnight with anhydrous magnesium sulfate.Solid is filtered off, filtrate decompression is evaporated, it is fluoro- to obtain 2-
3.2 grams of 4- nitrobenzoic acid.
The preparation of the 3.2 fluoro- 4- nitrobenzamide of N- methyl -2- of reference implementation example
The fluoro- 4- nitrobenzoic acid (2g, 11mmol) of 2- is added in 50ml DMF, -5 DEG C is cooled to, is slowly added to sulfurous
Acyl chlorides (1.5g, 13mmol).It is stirred 1 hour at -5 DEG C, excessive methylamine is added, stirred 1 hour.It is added in this mixture
Then 200ml ethyl acetate is washed with salt water (2X50ml);Organic layer is dried overnight with anhydrous magnesium sulfate.Solid is filtered off, it will
Filtrate decompression is evaporated, and obtains 1.9 grams of the fluoro- 4- nitrobenzamide of N- methyl -2-.
The preparation of the 3.3 fluoro- 4- aminobenzamide of N- methyl -2- of reference implementation example
In the in the mixed solvent of 5ml ethyl acetate and 5ml acetic acid, the fluoro- 4- nitrobenzamide of N- methyl -2- is added
(1.8g, 9.1mmol) and iron powder (3.1g, 56mmol) flows back 1 hour.Solid is filtered off, 100ml water is added in filtrate, then
It is extracted with ethyl acetate;Organic layer is dried overnight with anhydrous magnesium sulfate.Solid is filtered off, filtrate decompression is evaporated, is then used
SiO2Column chromatography for separation, with methylene chloride: acetone (95: 5) elutes, and obtains the fluoro- 4- aminobenzamide 1.6g of N- methyl -2-.
The preparation of reference implementation example 3.4 the fluoro- 4- of N- methyl -2- (1,1- dimethyl-itrile group methyl)-aminobenzamide
By the fluoro- 4- aminobenzamide (960mg, 5.7mmol) of N- methyl -2-, acetone cyanohydrin (3.1ml, 31.4mmol)
80 DEG C are heated to the mixture of magnesium sulfate (500mg), is stirred to react 12 hours.Reaction mixture is cooling, 150ml second is added
Then acetoacetic ester is washed with water (2X50ml).Organic layer is dried overnight with anhydrous magnesium sulfate.Solid is filtered off, by filtrate decompression
It is evaporated, then uses SiO2Column chromatography for separation, with methylene chloride: acetone (95: 5) elutes, and obtains the fluoro- 4- of N- methyl -2- (1,1- bis-
Methyl-itrile group methyl)-aminobenzamide (iii-1) 1.2g.Nuclear magnetic resonance spectroscopy:1H-NMR (400MHz, CDCl3): 1.78
(s, 6H);3.01 (dd, 3H);6.60-6.65 (m, 2H);6.68 (br s, 1H);7.95 (dd, 1H).
The preparation of the fluoro- 4- of 4 2- of reference implementation example [(2,2- dimethyl-acetonitrile-base)-amino]-benzamide (iii-2)
Referring to reference implementation example 3.2 method, by the fluoro- 4- nitrobenzoic acid of 2- with reacted with thionyl chloride after, be added
The fluoro- 4- nitrobenzamide of 2- is made in the ammonia of amount.
The fluoro- 4- ammonia of 2- is made in the fluoro- 4- nitrobenzamide iron powder reducing of 2- referring to the method for reference implementation example 3.3
Yl-benzamide 0.14g.
Referring to the method for reference implementation example 3.4, the fluoro- 4- aminobenzamide of 2- is reacted with acetone cyanohydrin, it is fluoro- that 2- is made
4- (1,1- dimethyl-itrile group methyl)-aminobenzamide (iii-2).Nuclear magnetic resonance spectroscopy:1H-NMR (400MHz, CDCl3):
1.77 (s, 6H);3.00 (dd, 3H);6.60-6.65 (m, 2H);6.65 (br s, 2H);7.97 (dd, 1H).
The preparation of the chloro- 4- of 5 2- of reference implementation example [(2,2- dimethyl-acetonitrile-base)-amino]-benzamide (iii-3)
Referring to the method for reference implementation example 3.1, the chloro- 4- nitrotoleune periodic acid of 2- and chromium trioxide are aoxidized, are made
The chloro- 4- nitrobenzoic acid of 2-.
Referring to the method for reference implementation example 3.2, the chloro- 4- nitrobenzoic acid of 2- is replaced into the fluoro- 4- nitrobenzoic acid of 2-, with Asia
It after chlorosulfuric acid reaction, is then reacted with ammonia, the chloro- 4- nitrobenzamide of 2- is made.
The chloro- 4- ammonia of 2- is made in the chloro- 4- nitrobenzamide iron powder reducing of 2- referring to the method for reference implementation example 3.3
Yl-benzamide.
Referring to the method for reference implementation example 3.4, the chloro- 4- aminobenzamide of 2- is reacted with acetone cyanohydrin, it is chloro- that 2- is made
4- (1,1- dimethyl-itrile group methyl)-aminobenzamide (iii-3).Nuclear magnetic resonance spectroscopy:1H-NMR (400MHz, CDCl3):
1.77 (s, 6H);3.00 (dd, 3H);6.64 (br s, 2H);6.65 (dd, 1H);6.82 (dd, 1H);7.92 (dd, 1H).
The preparation of the bromo- 4- of 6 2- of reference implementation example [(2,2-. dimethyl-acetonitrile-base)-amino]-benzamide (iii-4)
Referring to the method for reference implementation example 3.1, the bromo- 4- nitrotoleune periodic acid of 2- and chromium trioxide are aoxidized, are made
The bromo- 4- nitrobenzoic acid of 2-.
Referring to the method for reference implementation example 3.2, the bromo- 4- nitrobenzoic acid of 2- is replaced into the fluoro- 4- nitrobenzoic acid of 2-, with Asia
It after chlorosulfuric acid reaction, is then reacted with ammonia, the bromo- 4- nitrobenzamide of 2- is made.
The bromo- 4- ammonia of 2- is made in the bromo- 4- nitrobenzamide iron powder reducing of 2- referring to the method for reference implementation example 3.3
Yl-benzamide.
Referring to the method for reference implementation example 3.4, the bromo- 4- aminobenzamide of 2- is reacted with acetone cyanohydrin, it is bromo- that 2- is made
4- (1,1- dimethyl-itrile group methyl)-aminobenzamide (iii-4).Nuclear magnetic resonance spectroscopy:1H-NMR (400MHz, CDCl3):
1.77 (s, 6H);3.00 (dd, 3H);6.64 (br s, 2H);6.69 (dd, 1H);6.79 (dd, 1H);7.91 (dd, 1H).
The 7 fluoro- 4- of N- methyl -2- of reference implementation example { 3- [4- cyano -3- (trifluoromethyl) phenyl] -5,5- dimethyl -4-
Oxo -2- is thio-imidazoles -1- base-benzamide (the miscellaneous Shandong amine of grace) preparation
In 5ml dimethyl acetamide, the fluoro- 4- of N- methyl -2- (1,1- dimethyl-itrile group methyl)-aminobenzoic is added
Amide (iii-1,300mg, 1.3mmol) and 4- isothiocyano -2- trifluoromethylbenzonitrile (ii-1,580mg, 2.6mmol), in
100 DEG C of heating reactions are overnight.Into this mixture, 50ml methanol and 15ml 1N HCl is added.The reflux 1.5 of this mixture is small
When.Reaction mixture is cooled to room temperature, is subsequently poured into 150ml cold water, is extracted with ethyl acetate 150ml.Organic layer is used
Anhydrous magnesium sulfate is dried overnight.Solid is filtered off, filtrate decompression is evaporated, then uses SiO2 column chromatography for separation, with methylene chloride:
Acetone (95: 5) elution, obtains 0.14g.Nuclear magnetic resonance spectroscopy:1H-NMR (400MHz, d6-DMSO): 1.60 (s, 6H);3.03
(d, 3H);6.70 (br s, 1H);7.13 (dd, 1H);7.24 (dd, 1H);7.82 (dd, 1H);8.01 (dd, 1H);8.05 (d,
1H);8.29 (dd, 1H).
The fluoro- 4- of 1 2- of embodiment { 3- [6- cyano -5- (trifluoromethyl) pyridin-3-yl] -5,5- dimethyl -4- oxo -2-
Thio-imidazoles -1- base }-benzamide (I-1) preparation
The method of reference implementation example 7 reacts ii-2 with iii-2, and I-1 is made.Nuclear magnetic resonance spectroscopy:1H-NMR
(400MHz, CDCl3): 1.69 (s, 6H);3.03 (d, 3H);6.68 (br s, 2H);7.15 (dd, 1H);7.24 (dd, 1H);
8.19 (dd, 1H);8.31 (d, 1H);9.05 (d, 1H).
The chloro- 4- of 2 2- of embodiment { 3- [6- cyano -5- (trifluoromethyl) pyridin-3-yl] -5,5- dimethyl -4- oxo -2-
Thio-imidazoles -1- base }-benzamide (I-2) preparation
The method of reference implementation example 7 reacts ii-2 with iii-3, and I-2 is made.Nuclear magnetic resonance spectroscopy:1H-NMR
(400MHz, CDCl3): 1.69 (s, 6H);3.03 (d, 3H);6.68 (br s, 2H);7.31 (dd, 1H);7.38 (dd, 1H);
8.22 (dd, 1H);8.31 (d, 1H);9.05 (d, 1H).
The bromo- 4- of 3 2- of embodiment { 3- [6- cyano -5- (trifluoromethyl) pyridin-3-yl] -5,5- dimethyl -4- oxo -2-
Thio-imidazoles -1- base }-benzamide (I-3) preparation
The method of reference implementation example 7 reacts ii-2 with iii-4, and I-3 is made.Nuclear magnetic resonance spectroscopy:1H-NMR
(400MHz, CDCl3): 1.69 (s, 6H);3.03 (d, 3H);6.68 (br s, 2H);7.22 (dd, 1H);7.25 (dd, 1H);
8.23 (dd, 1H);8.31 (d, 1H);9.05 (d, 1H).
The evaluation of 4 Anticancer effect in vivo of embodiment
It takes male SHO SCID mice (purchased from Shanghai richness all living creatures object development in science and technology Co., Ltd), inoculated with subcutaneous injections 2 ×
106A LNCaP/AR cell.Reach 200mm to tumor average volume3, anesthesia downlink castration operation.Random grouping, 6/group.It will
Sample to be tested grinding is suspended in 0.5% carboxymethylcellulose sodium solution, and stomach-filling is given containing doses drug to be measured
Sodium carboxymethylcellulose suspension is given the conduct of blank sodium carboxymethylcellulose suspension and is compareed, and 1 times/day.After 28 days, measurement
The weight of animals and tumor size.Tumour inhibiting rate is calculated as follows:
It the results are shown in Table 1:
The evaluation result of 1 Anticancer effect in vivo of table
The evaluation of the cause mice convulsion side effect of embodiment 5
Male 7 week old ICR mouse are taken, it is random to be grouped, 10/group.Sample to be tested grinding is suspended in 0.5% carboxymethyl
In sodium cellulosate solution, the sodium carboxymethylcellulose suspension of 400mg/kg dosage drug to be measured is given in stomach-filling, gives blank carboxylic
Sodium carboxymethylcellulose pyce suspension is as control.Observe frequency of fainting from fear in 24 hours.
The evaluation result of the cause mice convulsion side effect of table 2
The evaluation of inhibiting effect on tumor metastasis in 6 body of embodiment
The male nude mouse for taking 6-8 weeks, by 1X106A TRAMP-C1 cell normotopia is injected into bilateral anterior lobe of prostate.Two weeks
Afterwards, it is grouped, intraperitoneal injection, 30mg/kg dosage, 3 times/week, continuous 3 weeks.After putting to death animal, reference literature (The J
Biological Chem 2013;288:19359-19369) method detects transfer stove, calculates transfer stove quantity.
The evaluation result of inhibiting effect on tumor metastasis in 3 body of table
。
Claims (5)
1. Formulas I compound represented and its non-toxic pharmaceutically acceptable salt:
In Formulas I, X is C or N;R1The alkyl replaced for the alkyl or halogen of C1-C3;R2The alkane replaced for alkyl, the halogen of C1-C3
Base or halogen;R3And R4Independently selected from H, alkyl, substituted alkyl;R3And R4It is connected to form naphthenic base.
2. according to claim 1, Formulas I compound represented and its non-toxic pharmaceutically acceptable salt, are selected from:
3. contain the compound claimed in claims 1-2 and its non-toxic pharmaceutically acceptable salt of effective therapeutic dose, and
The pharmaceutical composition of pharmaceutically acceptable excipient.
4. compound described in claim 1-3 and its non-toxic pharmaceutically acceptable salt and its pharmaceutical composition, are preparing
Purposes in anti-tumor drug.
5. compound described in claim 1-3 and its non-toxic pharmaceutically acceptable salt and its pharmaceutical composition, are preparing
Purposes in antiprostate cancer.
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US11325889B2 (en) | 2018-12-19 | 2022-05-10 | Celgene Corporation | Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith |
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US11325889B2 (en) | 2018-12-19 | 2022-05-10 | Celgene Corporation | Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith |
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