CN107973783B - Alternylpyrimidine derivatives as ERK inhibitors - Google Patents

Alternylpyrimidine derivatives as ERK inhibitors Download PDF

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CN107973783B
CN107973783B CN201610921874.XA CN201610921874A CN107973783B CN 107973783 B CN107973783 B CN 107973783B CN 201610921874 A CN201610921874 A CN 201610921874A CN 107973783 B CN107973783 B CN 107973783B
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汤剑秋
王路路
朱岩
孔凡胜
沈永铭
刘崇皓
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The application belongs to the field of medicinal chemistry, and particularly relates to a novel aniline pyrimidine derivative serving as an ERK inhibitor and pharmaceutically acceptable salts thereof, and particularly relates to a compound shown in a formula I and pharmaceutically acceptable salts thereof, a pharmaceutical composition thereof and a method for treating diseases benefiting from ERK inhibition.

Description

Alternylpyrimidine derivatives as ERK inhibitors
Technical Field
The application belongs to the field of medicinal chemistry, and particularly relates to an aniline pyrimidine derivative serving as an ERK inhibitor, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a method for treating ERK-mediated diseases or application thereof.
Background
Protein kinases constitute a large family of structurally related enzymes responsible for controlling a variety of signal transduction processes within cells. Protein kinases are thought to evolve from a common ancestral gene due to their conservation in structure and catalytic function. Almost all kinases contain similar catalytic domains with 250-300 amino acids. The kinases can be categorized into families (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.) by their phosphorylating substrates.
The processes involved in tumor growth, progression and metastasis are mediated by signaling pathways that are activated in cancer cells. The ERK pathway plays an important role in regulating mammalian cell growth by relaying extracellular signals from ligand-binding cell surface tyrosine kinase receptors (e.g., erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase). Activation of the ERK pathway is via a cascade of phosphorylation events starting with activation of Ras. Activation of Ras causes recruitment and activation of Raf, a serine-threonine kinase. The activated Raf then phosphorylates and activates MEK1/2, which in turn phosphorylates and activates one or both of ERK1 and ERK 2. One or both of ERK1 and ERK2, when activated, phosphorylates several downstream targets involved in numerous cellular events including cytoskeletal changes and transcriptional activation. The ERK/MAPK pathway is one of the most important pathways for cell proliferation, and is often activated in many tumors.
Numerous studies have shown that in proliferative diseases such as cancer, genetic mutations and/or overexpression of protein kinases in the Ras/Raf/MEK/ERK pathway can lead to uncontrolled cell proliferation and tumor formation. For example, some cancers contain mutations that will result in continued activation of the pathway due to continued production of growth factors. Other mutations can lead to a defect in the inactivation of activated GTP-bound Ras complex, again resulting in mutations in the Ras gene upstream of one or both of ERK1 and ERK2 activation of the MAP kinase pathway in several cancers including colorectal, melanoma, breast and pancreatic tumors. In many human tumors, high Ras activity is accompanied by increased ERK activity.
ERK has been a major goal of drug development given that numerous upstream (e.g., RAS, raf) and downstream (e.g., ATF2, c-Fos, c-Myc) signaling proteins in the Raf/Ras/MEK/ERK pathway have been implicated in numerous disorders including, but not limited to, cancer.
Disclosure of Invention
The application provides a compound shown in a formula I and pharmaceutically acceptable salts thereof:
Wherein R 1 is selected from H, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, Methanesulfonyl, ethanesulfonyl, and an isopropylsulfonyl or cyclopropylsulfonyl group;
R 2 is selected from H, methyl or hydroxymethyl;
R 3 is selected from H or hydroxymethyl.
In some embodiments, the R 1 is selected from H,Or methanesulfonyl.
In some embodiments, the compound of formula I is selected from:
In another aspect of the present application there is provided a pharmaceutical composition comprising a compound of formula I as disclosed herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Optionally, the pharmaceutical compositions of the present application may further contain one or more additional therapeutic agents.
In another aspect, the application provides a method of treating a disease that benefits from ERK inhibition, comprising administering to a subject in need thereof a compound of formula I according to the application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
In another aspect, the application provides the use of a compound of formula I according to the application, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease benefiting from ERK inhibition.
In some embodiments, the disorder that benefits from ERK inhibition is selected from the group consisting of cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease, and heart disease.
In some embodiments, the cancer is selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome (MDS), acute Myelogenous Leukemia (AML), and colorectal cancer. In further embodiments, the cancer is melanoma or colorectal cancer.
In some embodiments, the disease is mediated by ERK1 and/or ERK 2.
Definition part
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As pharmaceutically acceptable salts, for example, salts with inorganic acids, salts with organic acids, salts with acidic amino acids, and the like.
Pharmaceutically acceptable salts of the application can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free base form with a stoichiometric amount of an appropriate acid in water or an organic solvent or a mixture of both.
Certain compounds of the application may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present application. Certain compounds of the present application may exist in polycrystalline or amorphous form.
The pharmaceutical compositions of the application may be prepared by combining a compound of the application or a salt thereof with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels or microspheres, aerosols and the like.
Typical routes of administration of the compounds of the application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, or intravenous administration.
The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, and freeze-drying methods.
For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the application to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries or suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is admixed with solid excipients, the resulting mixture is optionally milled, if desired with other suitable auxiliaries, and the mixture is then processed into granules, giving tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners and/or flavoring agents, and the like. Such as microcrystalline cellulose, dextrose solution, acacia syrup, gelatin solution, sucrose and/or starch paste; talc, starch, magnesium stearate, calcium stearate and/or stearic acid; lactose, sucrose, starch, mannitol, sorbitol and/or dicalcium phosphate; silicon dioxide; crosslinked sodium carboxymethyl cellulose, pre-crosslinked starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl cellulose, and/or crosslinked polyvinylpyrrolidone, and the like. The cores of the drags may optionally be coated according to methods well known in the usual pharmaceutical practice, in particular with enteric coatings.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In some embodiments, a compound of formula (i) or a pharmaceutically acceptable salt thereof described herein may be administered by any suitable route and method, such as by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound of formula (I) is from about 0.0001 to 20mg/Kg of body weight/day, for example from 0.001 to 10mg/Kg of body weight/day.
In some embodiments, the frequency of dosage of the compound of formula (i) is determined by the needs of the individual patient, e.g., 1 or 2 times per day, or more times per day. The administration may be intermittent, for example, wherein the patient receives a daily dose of the compound of formula (I) for a period of several days, followed by a period of several days in which the patient does not receive a daily dose of the compound of formula (I).
The compounds of the present application can be prepared by the following general procedure, the preparation of which is described in detail in the examples.
Scheme 1:
In the scheme 1, the compound A1 and the compound A2 undergo a grignard reaction to obtain a compound A3, the compound A3 and the compound A4 undergo a condensation reaction under alkaline conditions to obtain a compound A5, the compound A5 and the compound A6 undergo a condensation reaction to obtain a compound A7, the compound A7 and the compound A8 undergo a condensation reaction to obtain a compound A9, the nitro group of the compound A9 is reduced to obtain a compound a10, and the compound a10 and the compound a11 undergo a reaction to obtain the target compound I.
In some embodiments of the application, the person skilled in the art may prepare according to, rather than strictly following, the steps of scheme 1, and depending on the structure of the final product, may add, subtract or change the order of the steps to scheme 1, which is also within the scope of the application, e.g. the step of condensation of compound A3 with compound A4 to give compound A5 may not occur when R 1 is selected from H.
For clarity, the application is further illustrated by examples. The embodiments are not limited to defining or specifying the scope of the application.
Examples
The following specific examples are put forth so as to enable those skilled in the art to more clearly understand and practice the present application. They should not be considered as limiting the scope of the application, but merely as being illustrative and representative thereof.
Example A ((2- (methylamino) ethyl) amino) methanol (A8-3)
To a 250mL three-necked flask under nitrogen atmosphere was added a compound of formula A8-2 (10 g,0.135 mol), trioxymethylene (4.23 g,0.047 mol), carbon tetrachloride (80 mL), and the mixture was completely dissolved by magnetic stirring. Heated to 50 ℃ and reacted for 2 hours. Cooling to room temperature, concentrating under reduced pressure, adding ethyl acetate into the concentrate, extracting with saturated sodium carbonate solution in layers, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate, and purifying the concentrate by column chromatography (ethyl acetate/petroleum ether) to obtain compound A8-3 (9.4 g, 67.2%). MS: [ m+h ] + =105
Example B (methyl (2- (methylamino) ethyl) amino) methanol (A8-4)
To a 250mL three-necked flask under nitrogen atmosphere was added a compound of formula A8-1 (10 g,0.114 mol), trioxymethylene (3.6 g,0.040 mol), carbon tetrachloride (80 mL), and the mixture was completely dissolved by magnetic stirring. Heated to 50 ℃ and reacted for 2 hours. Cooling to room temperature, concentrating under reduced pressure, adding ethyl acetate into the concentrate, extracting with saturated sodium carbonate solution in layers, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate, and purifying the concentrate by column chromatography (ethyl acetate/petroleum ether) to obtain compound A8-4 (11.3 g, 83.9%). MS: [ m+h ] + =119
Example C ((2- (methylamino) ethyl) amino) dimethanol (A8-5)
To a 250mL three-necked flask under nitrogen atmosphere was added a compound of formula A8-2 (10 g,0.135 mol), trioxymethylene (8.46 g,0.094 mol), carbon tetrachloride (80 mL), and the mixture was completely dissolved by magnetic stirring. Heated to 50 ℃ and reacted for 2 hours. Cooling to room temperature, concentrating under reduced pressure, adding ethyl acetate into the concentrate, extracting with saturated sodium carbonate solution in layers, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, vacuum filtering, concentrating the filtrate, and purifying the concentrate by column chromatography (ethyl acetate/petroleum ether) to obtain compound A8-5 (11.8 g, 65.5%). MS: [ m+h ] + =135
Example 1N- (5- ((4- (1H-indol-3-yl) pyrimidin-2-yl) amino) -4-methoxy-2- (methyl (2- (methylamino) ethyl) amino) phenyl) acrylamide (I-1)
The flow is as follows:
Step 1
To a 3L three-necked flask under nitrogen atmosphere, compound A2 (150 g,1.28 mol) and dried dichloroethane (1.5L) were successively added and dissolved by magnetic stirring. The temperature of the ice salt bath is reduced to 0 ℃, methyl magnesium bromide (640 mL, 3M) is slowly added dropwise, the temperature is controlled to be between-5 ℃ and 5 ℃ in the dripping process, and after the dripping is finished, the temperature is increased to the room temperature for continuous reaction for 0.5h. The reaction mixture was cooled to 0℃and then Compound A1 (267 g,1.79 mol) was added dropwise, and after the completion of the addition, the mixture was warmed to room temperature and reacted for 16 hours. After the completion of the reaction, the reaction mixture was quenched by pouring into ice water (2.5L), extracting with methylene chloride (300 ml×3), and the organic phases were combined, washed with saturated brine (300 ml×3), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE/ea=10/1 to PE/ea=4/1) to give compound A3 (70.0 g, 23.8%). MS: [ m+h ] + =230
Step 2
To a 500mL three-necked flask, compound A3 (25 g,0.109 mol), compound A6 (20.3 g,0.109 mol), tsOH monohydrate (31.1 g) and 2-pentanol (250 mL) were added and stirred to dissolve completely. Slowly heating to 105 ℃, and reacting for 20h. After the reaction was completed, the reaction mixture was cooled to room temperature, a large amount of solids were precipitated, and the resulting precipitate was suction-filtered, and the cake was washed with 2-pentanol (50 mL). The resulting solid was slurried sequentially with dichloromethane (50 mL), methanol (50 mL) and purified for 30min. Suction filtration gave compound A7-1 (14.9 g, 36.05%). MS: [ m+h ] + =380
Step 3
Compound A7-1 (10 g,0.026 mol), potassium carbonate (10.8 g,0.078 mol), compound A8-1 (3.4 g,0.039 mol) and N-methylpyrrolidone (200 mL) were added to a 500mL three-necked flask and stirred magnetically uniformly. Heating in an oil bath to 50 ℃ and reacting for 5h. Cooling to room temperature, suction filtering, pouring the filtrate into water (1L), precipitating a large amount of solid, suction filtering, eluting the filter cake with ethyl acetate (50 mL), and vacuum drying the filter cake to constant weight to obtain the compound A9-1 (29.1 g, 83.5%). MS: [ m+h ] + =448
Step 4
Compound A9-1 (20.0 g,0.045 mol), zn (29.3 g,0.45 mol), dichloromethane (200 mL) and methanol (200 mL) were added to a 1L three-necked flask and stirred magnetically. Cooling to 0 ℃, slowly dropwise adding a saturated ammonium chloride aqueous solution (200 mL) for 10 minutes, and continuing to react for 2 hours after the dropwise adding is finished, wherein the color of the solution becomes pale yellow. After the reaction, a saturated sodium carbonate solution (200 mL) was added dropwise to the reaction system, stirred and suction-filtered, the resulting mother liquor was extracted with dichloromethane (500 mL), and the organic phase was washed with saturated sodium chloride (500 ml×3). Dried over anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated to give compound a10-1 (17.5 g, 93.1%). MS: [ m+h ] + =418
Step 5
Compound A10-1 (15 g,0.036 mol), DIEA (9.3 g,0.072 mol) and methylene chloride (400 mL) were charged into A1L three-necked flask and dissolved by magnetic stirring. The nitrogen replaces the air of the system for three times, and the temperature of the reaction liquid is reduced to-20 to-10 ℃. Within the above temperature range, acryloyl chloride (3.9 g,0.043 mol) was added dropwise over about 20 minutes. After the dripping is finished, the reaction is carried out for 20min at the temperature of minus 20 to minus 10 ℃. After the reaction, water (300 mL) was added to the reaction system, the solution was separated, the organic phase was washed with saturated brine (200 mL. Times.2), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and the concentrate was purified by column chromatography (DCM/MeOH=50/1 to 20/1) to give the compound I-1(8.1g,47.6％).MS：[M+H]+＝472;1H NMR(DMSO-d6):δ9.82(s,1H),9.32(s,1H),8.23(d,2H),8.04(m,1H),7.78(s,1H),7.44(s,1H),7.31(m,2H),7.24(m,1H),6.81(s,1H),6.37(m,2H),5.71(m,1H),3.89(s,3H),2.89(m,2H),2.70(s,3H),2.27(s,3H).
Referring to the preparation method of example 1, according to the difference of the compound groups, the compound A8-1 in step 3 of example 1 is replaced to obtain the following compound:
example 6N- (4-methoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- (methylsulfonyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-6)
The flow is as follows:
Starting from compound A3 obtained in example 1.
Step 2
To a 1L three-necked flask, compound A3 (32.0 g,0.14 mol) and DMF (300 mL) were added under nitrogen atmosphere, and the mixture was completely dissolved by magnetic stirring. The nitrogen was replaced three times with air, the ice salt bath was cooled to 0deg.C, naH (14.0 g,0.42 mol) was added in portions, a slight exotherm was observed, and after the addition was completed, the reaction was maintained at 0deg.C for 30min. T=0 ℃, methanesulfonyl chloride (32.1 g,0.28 mol) is added dropwise, and the temperature T= -5 ℃. After the completion of the dropwise addition, the reaction was carried out at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was poured into water (2L) to precipitate a large amount of solid, which was filtered off with suction, and dried under vacuum to give Compound A5-1 (23.7 g, 55.11%).
Then the reaction is carried out in the steps 2 to 5 of the reference example 1 to obtain the compound I-6.MS：[M+H]+＝550;1H NMR(DMSO-d6):δ9.72(s,1H),8.52(m,1H),8.20(m,1H),8.03(m,1H),7.69(s,1H),7.41(m,2H),7.17(m,1H),6.81(s,1H),6.39(m,2H),5.68(m,1H),3.89(s,3H),3.32(s,3H),2.82(m,2H),2.71(s,3H),2.29(m,5H).
Referring to the preparation method of example 6, according to the difference of the compound groups, the compound A8-1 in step 4 of example 6 was replaced to obtain the following compound:
Example 11N- (4-methoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- ((4- (1- (trifluoroethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-11)
The flow is as follows:
Starting from compound A3 obtained in example 1.
Step 2
To a 1L three-necked flask, compound A3 (32.0 g,0.14 mol) and DMF (300 mL) were added under nitrogen atmosphere, and the mixture was dissolved by mechanical stirring. Reducing the temperature to 0 ℃ by an ice salt bath, adding NaH (8.4 g,0.209 mol) in batches, controlling the temperature T= -5 ℃ after the addition, maintaining the temperature T= -5 ℃ to continue to react for 0.5 hour, and dropwise adding trifluoroethyl triflate (54.0 g,0.236 mol) at the temperature T= -5 ℃ and continuing to react for 2 hours after the dropwise addition. The reaction solution was poured into ice water (1L), a large amount of solids was precipitated, ethyl acetate (1L) was added, the mixture was shaken and separated, the organic phase was washed with saturated brine (500 ml. Times.3), dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain compound A5-2 (38.0 g, 88%).
Then the reaction is carried out in the steps 2 to 5 of the reference example 1 to obtain the compound I-11.MS：[M+H]+＝554;1H NMR(DMSO-d6):δ9.62(s,1H),8.49(m,1H),8.05(m,2H),7.60(s,1H),7.28(m,2H),7.09(m,1H),6.76(s,1H),6.37(m,2H),5.62(m,1H),3.77(s,3H),3.25(s,3H),2.75(m,5H),2.29(m,5H).
Referring to the preparation method of example 11, according to the difference of the compound groups, the compound A8-1 in step 4 of example 11 was replaced to obtain the following compound:
experimental example 1 inhibition test of ERK
The inhibitory activity of the compounds of the application against ERK was detected using a Z' -LYTE kinase assay kit, which was determined using Ser/Thr 3 peptide substrate. For ATP Km of ERK2, detection was performed at a concentration of 0.47 ng/. Mu.L of ERK2 enzyme at 100. Mu.M ATP. The compounds were diluted at 100 times the desired concentration in DMSO at 1:3 dilution, followed by further dilution with 20mM HEPES buffer (1:25) to prepare a 4X test solution. The final concentration of the compound solution to be tested was 1%. The volume of detection solution per well plate was 20. Mu.L. The activity detection reaction is carried out for 1 hour, the enzyme content in the supernatant is detected by an enzyme-labeled instrument, the obtained data are analyzed and calculated to obtain the IC50 of each compound, and the experimental results are shown as follows:
numbering of compounds IC50 Numbering of compounds IC50 Numbering of compounds IC50
I-1 A I-6 B I-11 A
I-2 B I-7 A I-12 C
I-3 B I-8 C I-13 A
I-4 A I-9 A I-14 B
I-5 B I-10 C I-15 C
In vitro ERK2IC50 data for the compounds of the application are represented by the following symbols: a (IC 50. Ltoreq.50 nM), B (50 nM < IC 50. Ltoreq.100 nM), C (100 nM < IC 50. Ltoreq.200 nM).

Claims (8)

1. Compounds of formula I a pharmaceutically acceptable salt:
wherein R 1 is selected from trifluoromethyl,
R 2 is selected from methyl or hydroxymethyl;
R 3 is selected from H or hydroxymethyl.
2. The compound of formula I according to claim 1, wherein R 1 is selected from the group consisting of
3. The compound of formula I according to claim 1, and pharmaceutically acceptable salts thereof, selected from:
4. a pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 3 and pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.
5. Use of a compound according to any one of claims 1-3, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the treatment of a disease that benefits from ERK inhibition.
6. The use according to claim 5, wherein the disease benefiting from ERK inhibition is selected from the group consisting of cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease and heart disease.
7. The use according to claim 6, wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer, thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome, acute myelogenous leukemia, and colorectal cancer.
8. The use according to claim 7, wherein the cancer is selected from melanoma or colorectal cancer.
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WO2020102686A1 (en) * 2018-11-16 2020-05-22 California Institute Of Technology Erk inhibitors and uses thereof
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