2732-28-7

Usage

Uses

Used in Pharmaceutical Industry:
1-(2-METHYLPYRIDIN-4-YL)ETHANONE is used as a building block for the synthesis of various pharmaceuticals due to its unique structure and reactivity, contributing to the development of new drugs and therapeutic agents.
Used in Agrochemical Industry:
Similarly, in the agrochemical industry, 1-(2-METHYLPYRIDIN-4-YL)ETHANONE serves as a key component in the synthesis of agrochemicals, potentially enhancing crop protection and yield.
Used in Organic Chemical Production:
1-(2-METHYLPYRIDIN-4-YL)ETHANONE is utilized as an intermediate in the production of other organic chemicals, facilitating the creation of a wide range of chemical compounds for various applications.
Used in Medicinal Chemistry and Drug Development:
Due to its distinctive structural features, 1-(2-METHYLPYRIDIN-4-YL)ETHANONE holds promise in medicinal chemistry, where it may be employed in the design and synthesis of novel drug candidates for various therapeutic areas.

InChI:InChI=1/C8H9NO/c1-6-5-8(7(2)10)3-4-9-6/h3-5H,1-2H3

Synthetic route

4-(1-ethoxyvinyl)-2-methylpyridine → 1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7)

Conditions	Yield
With hydrogenchloride; water at 20℃; for 3h;	82%

N-methoxy-N,2-dimethylisonicotinamide (1211580-90-3) + methyllithium (917-54-4) → 1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7)

Conditions	Yield
In tetrahydrofuran at -78 - 20℃; for 1h; Inert atmosphere;	56.4%
In tetrahydrofuran at -78 - 20℃; for 1h; Inert atmosphere;	56.4%
Stage #1: N-methoxy-N,2-dimethylisonicotinamide; methyllithium In tetrahydrofuran at -78 - 20℃; for 1.5h; Inert atmosphere; Stage #2: With ammonium chloride In tetrahydrofuran	51%
In tetrahydrofuran at -78 - 20℃; for 1.5h; Inert atmosphere;	51%

4-bromo-2-methylpyridine (22282-99-1) + tributyl(1-ethoxyvinyl)stannane (97674-02-7) → 1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In toluene at 80℃; Inert atmosphere;	44%

2-methyl-4-cyanopyridine (2214-53-1) + methylmagnesium bromide (75-16-1) → 1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7)

Conditions	Yield
In tetrahydrofuran; hexane at 0℃; Grignard reaction; Reflux;	25%
Stage #1: 2-methyl-4-cyanopyridine; methylmagnesium bromide In tetrahydrofuran; hexane at 0℃; Heating; Reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; water at 20℃;	25%
Stage #1: 2-methyl-4-cyanopyridine; methylmagnesium bromide In diethyl ether at 20℃; for 16h; Stage #2: With hydrogenchloride In water

2-methyl-4-cyanopyridine (2214-53-1) → 1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7)

Conditions	Yield
With methylmagnesium bromide In water
Product distribution / selectivity;

2-methylisonicotinic acid (4021-11-8) → 1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 20 °C 2.1: tetrahydrofuran / 1.5 h / -78 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 20 °C 2.1: tetrahydrofuran / 1.5 h / -78 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 2 h / 20 °C 2.1: tetrahydrofuran / 1 h / -78 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 12 h / 20 °C 2.1: tetrahydrofuran / 1 h / -78 - 20 °C / Inert atmosphere View Scheme

2,4-lutidine (108-47-4) → 1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium permanganate / water / 14 h / 80 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 2 h / 20 °C 3.1: tetrahydrofuran / 1 h / -78 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: potassium permanganate / water / 14 h / 80 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 12 h / 20 °C 3.1: tetrahydrofuran / 1 h / -78 - 20 °C / Inert atmosphere View Scheme

2-methylpyridine N-oxide (931-19-1) → 1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dimethyl sulfate / 16 h / 20 °C 1.2: 16 h / 20 °C 2.1: tetrahydrofuran; hexane / 0 °C / Heating; Reflux 2.2: 20 °C View Scheme

4-bromo-2-methylpyridine (22282-99-1) → 1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0) / toluene / 16 h / 110 °C / Inert atmosphere 2: hydrogenchloride; water / 3 h / 20 °C View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 2-bromo-1-(2-methylpyridin-4-yl)ethan-1-one hydrobromide (1187669-34-6)

Conditions	Yield
With hydrogen bromide; bromine; acetic acid at 0 - 80℃; for 2h;	96%
With hydrogen bromide; bromine; acetic acid at 0 - 20℃;	80%
With hydrogen bromide; bromine; acetic acid at 0 - 20℃;	80%

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 2-bromo-1-(2-methyl-4-pyridinyl)ethanone (1187785-48-3)

Conditions	Yield
With hydrogen bromide; bromine In acetic acid at 15 - 75℃;	90%
With hydrogen bromide; bromine; acetic acid at 70℃; for 2h;

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 1-(2-methylpyridin-4-yl)ethanol

Conditions	Yield
With dimethylsulfide borane complex; (R)-(+)-2-methyl-CBS-oxazaborolidine In tetrahydrofuran; methanol at 80℃;	80%

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) + (4-bromo-3-fluorophenyl)hydrazine hydrochloride → 4-(1-(2-(4-bromo-3-fluorophenyl)hydrazineylidene)ethyl)-2-methylpyridine

Conditions	Yield
With toluene-4-sulfonic acid In ethanol at 40℃; for 4h;	80%

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 1-(2-methyl-pyridin-4-yl)-ethanone oxime (80882-67-3)

Conditions	Yield
With hydroxylamine hydrochloride In methanol; water at 70 - 80℃; for 4h;	67%
With hydroxylamine hydrochloride In methanol; sodium hydroxide

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) + Cyclopropanecarboxaldehyde (1489-69-6) → 3-cyclopropyl-1-(2-methylpyridin-4-yl)prop-2-en-1-one

Conditions	Yield
With potassium hydroxide In methanol; water at 20℃; for 12h;	29.5%

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 2-bromo-1-(2-methyl-4-pyridinyl)ethanone hydrobromide

Conditions	Yield
With hydrogen bromide; bromine; acetic acid at 15 - 80℃;

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → methyl 2-(2-(2-methylisonicotinoyl)benzofuran-5-yl)acetate (1422053-20-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogen bromide; bromine; acetic acid / 0 - 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 2 h / 20 °C View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → C18H17N3O2S

Conditions	Yield
Multi-step reaction with 2 steps 1: bromine; hydrogen bromide; acetic acid / 2 h / 70 °C 2: ethanol / 1 h / 70 °C View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 1-(2-methylpyridin-4-yl)ethyl 4-methylbenzenesulfonate

Conditions	Yield
Multi-step reaction with 2 steps 1.1: (R)-(+)-2-methyl-CBS-oxazaborolidine; dimethylsulfide borane complex / tetrahydrofuran; methanol / 80 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 2.2: 20 °C View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → methyl 2-methyl-1-(1-(2-methylpyridin-4-yl)ethyl)-1H-indole-3-carboxylate

Conditions	Yield
Multi-step reaction with 3 steps 1.1: (R)-(+)-2-methyl-CBS-oxazaborolidine; dimethylsulfide borane complex / tetrahydrofuran; methanol / 80 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 2.2: 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → methyl 2-methyl-1-(1-(2-methylpiperidin-4-yl)ethyl)-1H-indole-3-carboxylate

Conditions	Yield
Multi-step reaction with 4 steps 1.1: (R)-(+)-2-methyl-CBS-oxazaborolidine; dimethylsulfide borane complex / tetrahydrofuran; methanol / 80 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 2.2: 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C 4.1: platinum(IV) oxide; hydrogen; acetic acid / 40 °C / 2585.81 Torr View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → methyl 1-(1-(1-(2,2-difluoroacetyl)-2-methylpiperidin-4-yl)ethyl)-2-methyl-1H-indole-3-carboxylate

Conditions

Yield

Multi-step reaction with 5 steps 1.1: (R)-(+)-2-methyl-CBS-oxazaborolidine; dimethylsulfide borane complex / tetrahydrofuran; methanol / 80 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 2.2: 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C 4.1: platinum(IV) oxide; hydrogen; acetic acid / 40 °C / 2585.81 Torr 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 1-(1-(1-(2,2-difluoroethyl)-2-methylpiperidin-4-yl)ethyl)-2-methyl-1H-indole-3-carboxylate

Conditions

Yield

Multi-step reaction with 6 steps 1.1: (R)-(+)-2-methyl-CBS-oxazaborolidine; dimethylsulfide borane complex / tetrahydrofuran; methanol / 80 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 2.2: 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C 4.1: platinum(IV) oxide; hydrogen; acetic acid / 40 °C / 2585.81 Torr 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 6.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 80 °C View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 1-(1-(1-(2,2-difluoroethyl)-2-methylpiperidin-4-yl)ethyl)-2-methyl-1H-indole-3-carboxylic acid

Conditions

Yield

Multi-step reaction with 7 steps 1.1: (R)-(+)-2-methyl-CBS-oxazaborolidine; dimethylsulfide borane complex / tetrahydrofuran; methanol / 80 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 2.2: 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C 4.1: platinum(IV) oxide; hydrogen; acetic acid / 40 °C / 2585.81 Torr 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 6.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 80 °C 7.1: sodium hydroxide / water; tetrahydrofuran; methanol / 40 h / 80 °C View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 1-(1-(1-(2,2-difluoroethyl)-2-methylpiperidin-4-yl)ethyl)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide

Conditions

Yield

Multi-step reaction with 8 steps 1.1: (R)-(+)-2-methyl-CBS-oxazaborolidine; dimethylsulfide borane complex / tetrahydrofuran; methanol / 80 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 2.2: 20 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 80 °C 4.1: platinum(IV) oxide; hydrogen; acetic acid / 40 °C / 2585.81 Torr 5.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 6.1: dimethylsulfide borane complex / tetrahydrofuran / 3 h / 80 °C 7.1: sodium hydroxide / water; tetrahydrofuran; methanol / 40 h / 80 °C 8.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 °C 8.2: 20 °C View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 2-(2-methylpyridin-4-yl)-2-oxoacetaldehyde

Conditions	Yield
With hydrogen bromide; dimethyl sulfoxide In water at 55℃; for 16h;
With hydrogen bromide In dimethyl sulfoxide at 55℃; Inert atmosphere;

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 5-(2-methylpyridin-4-yl)-3-(methylthio)-1,2,4-triazine

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen bromide; dimethyl sulfoxide / water / 16 h / 55 °C 2: sodium hydrogencarbonate / ethanol / 1 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogen bromide / dimethyl sulfoxide / 55 °C / Inert atmosphere 2: sodium hydrogencarbonate / ethanol / 1 h / 80 °C View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 5-(2-methylpyridin-4-yl)-3-(methylsulfonyl)-1,2,4-triazine

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen bromide; dimethyl sulfoxide / water / 16 h / 55 °C 2: sodium hydrogencarbonate / ethanol / 1 h / 80 °C 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogen bromide / dimethyl sulfoxide / 55 °C / Inert atmosphere 2: sodium hydrogencarbonate / ethanol / 1 h / 80 °C 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 5-(2-methylpyridin-4-yl)-1,2,4-triazin-3-amine

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen bromide; dimethyl sulfoxide / water / 16 h / 55 °C 2: sodium hydrogencarbonate / ethanol / 1 h / 80 °C 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h / 20 °C 4: ammonium hydroxide / 1,4-dioxane / 1 h View Scheme
Multi-step reaction with 4 steps 1: hydrogen bromide / dimethyl sulfoxide / 55 °C / Inert atmosphere 2: sodium hydrogencarbonate / ethanol / 1 h / 80 °C 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h 4: ammonium hydroxide / 1,4-dioxane / 1 h View Scheme

1-(2-methylpyridin-4-yl)ethan-1-one (2732-28-7) → 6-bromo-5-(2-methylpyridin-4-yl)-1,2,4-triazin-3-amine

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrogen bromide; dimethyl sulfoxide / water / 16 h / 55 °C 2: sodium hydrogencarbonate / ethanol / 1 h / 80 °C 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h / 20 °C 4: ammonium hydroxide / 1,4-dioxane / 1 h 5: trifluoroacetic acid; N-Bromosuccinimide / acetonitrile View Scheme
Multi-step reaction with 5 steps 1: hydrogen bromide / dimethyl sulfoxide / 55 °C / Inert atmosphere 2: sodium hydrogencarbonate / ethanol / 1 h / 80 °C 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h 4: ammonium hydroxide / 1,4-dioxane / 1 h 5: trifluoroacetic acid; N-Bromosuccinimide / acetonitrile / 64 h View Scheme

Upstream product

• 22282-99-1 4-bromo-2-methylpyridine 
• 931-19-1 2-methylpyridine N-oxide 
• 97674-02-7 tributyl(1-ethoxyvinyl)stannane 
• 108-47-4 2,4-lutidine 
• 4021-11-8 2-methylisonicotinic acid 
• 1211580-90-3 N-methoxy-N,2-dimethylisonicotinamide 
• 917-54-4 methyllithium 
• 2214-53-1 2-methyl-4-cyanopyridine 
• 75-16-1 methylmagnesium bromide 

Downstream Products

• 1702539-36-3 1-(2-methylpyridin-4-yl)ethanol 
• 1187669-33-5 N-(3-methylphenyl)-4-(2-methyl-4-pyridinyl)-1,3-thiazol-2-amine 

Relevant academic research and scientific papers

HETEROCYCLIC COMPOUNDS AS TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2 AGONISTS AND METHODS OF USE

The present disclosure provides compounds of Formula (I), useful for the activation of Triggering Receptor Expressed on Myeloid Cells 2 ("TREM2"). This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a neurodegenerative disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula (I).

ANTIBACTERIAL COMPOUNDS

The present invention relates to compounds of general formula (II),to compositions comprising these compounds and to methods of treating Enterobacteriaceae bacterial diseases and infections using the compounds. The compounds find application in the treatment of infection with, and diseases caused by, Enterobacteriaceae.

Casein kinase 1 (CK1) inhibitor for plants (by machine translation)

[Problem] to provide various lead compounds PHA derivatives, and/or circadian rhythm control agent having stronger CK1 inhibitor activity. [Solution] a compound represented by formula I, or a salt thereof or a solvate thereof. (R1 The, H or C1 - 5 A straight-chain, branched or cyclic alkyl group, alkenyl group or alkynyl group, R2 The, H, halogen (F, Cl, Br or I), or a C1 - 4 The alkyl group, the ring A, 5 - 8 membered lactam ring showing; however, R1 And R2 Except H together. )[Drawing] no (by machine translation)

HUMAN PLASMA KALLIKREIN INHIBITORS

Disclosed are compounds of formula I, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also provided are pharmaceutical compositions comprising at least one compound of the invention, and methods involving use of the compounds and compositions of the invention in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.

MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF

Provided are novel compounds of Formula (I): and pharmaceutically acceptable salts thereof, which are useful for treating a variety of diseases, disorders or conditions, associated with methyl modifying enzymes. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I), pharmaceutically acceptable salts thereof, and methods for their use in treating one or more diseases, disorders or conditions, associated with methyl modifying enzymes.

HUMAN PLASMA KALLIKREIN INHIBITORS

Disclosed are compounds of formula (I), as described herein, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also provided are pharmaceutical compositions comprising at least one compound of the invention, and methods involving use of the compounds and compositions of the invention in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.

Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors

The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation.

COMPOUNDS AND METHODS

The present invention relates to novel retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORy.

COMPOUNDS AND METHODS

The present invention relates to no vel retinoid-related orphan receptor gamma (RQRy) modulators and their use in the treatment of diseases mediated by RORy.

4-Pyridylanilinothiazoles that selectively target von Hippel - Lindau deficient renal cell carcinoma cells by inducing autophagic cell death

Renal cell carcinomas (RCC) are refractory to standard therapy with advanced RCC having a poor prognosis; consequently treatment of advanced RCC represents an unmet clinical need. The von Hippel-Lindau (VHL) tumor suppressor gene is mutated or inactivated in a majority of RCCs. We recently identified a 4-pyridyl-2-anilinothiazole (PAT) with selective cytotoxicity against VHL-deficient renal cells mediated by induction of autophagy and increased acidification of autolysosomes. We report exploration of structure-activity relationships (SAR) around this PAT lead. Analogues with substituents on each of the three rings, and various linkers between rings, were synthesized and tested in vitro using paired RCC4 cell lines. A contour map describing the relative spatial contributions of different chemical features to potency illustrates a region, adjacent to the pyridyl ring, with potential for further development. Examples probing this domain validated this approach and may provide the opportunity to develop this novel chemotype as a targeted approach to the treatment of RCC. 2009 American Chemical Society.