WO2024081775A1

WO2024081775A1 - Synthesis of 6-fluoro-2-methylbenzo[d]thiazol-5-yl compounds

Info

Publication number: WO2024081775A1
Application number: PCT/US2023/076675
Authority: WO
Inventors: Eric Michael Woerly; Peter James LINDSAY-SCOTT
Original assignee: Eli Lilly And Company
Priority date: 2022-10-14
Filing date: 2023-10-12
Publication date: 2024-04-18

Abstract

The present invention provides improved reaction schemes and novel reaction intermediates for the synthesis of molecules useful as O-GlcNAcase (OGA) inhibitors.

Description

SYNTHESIS OF 6-FLUORO-2-METHYLBENZOrD1THIAZOL-5-YL COMPOUNDS

The present invention relates to novel methods of synthesizing 6-fluoro-2- methylbenzo[d]thiazol-5-yl compounds, and to intermediates useful in the synthesis of the compounds. The present invention is in the field of synthetic organic chemistry.

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that affects millions of patients worldwide. In view of the currently approved agents on the market which afford only transient symptomatic benefits to the patient, there is a significant unmet need in the treatment of AD.

The oligomerization of the microtubule-associated protein tau into filamentous structures such as paired helical filaments (PHFs) and straight or twisted filaments, which give rise to neurofibrillary tangles (NFTs) and neuropil threads (NTs), is one of the defining pathological features of AD and other tauopathies. The number of NFTs in the brains of individuals with AD has been found to correlate closely with the severity of the disease, suggesting tau has a key role in neuronal dysfunction and neurodegeneration (Nelson et al., J Neuropathol Exp Neurol., 71(5), 362-381(2012)). Tau pathology has been shown to correlate with disease duration in PSP in that cases with a more aggressive disease course have a higher tau burden than cases with a slower progression. (Williams et al., Brain, 130, 1566-76 (2007)).

Past studies (Yuzwa et al., Nat Chem Biol, 4(8), 483-490 (2008)) support the therapeutic potential of O-GlcNAcase (OGA) inhibitors to limit tau hyperphosphorylation, and aggregation into pathological tau, for the treatment of AD and related tau-mediated neurodegeneration disorders. More recently, the OGA inhibitor Thiamet-G has been linked to slowing motor neuron loss in the JNPL3 tau mouse model (Yuzwa et al., Nat Chem Biol, 8, 393-399 (2012)), and to a reduction in tau pathology and dystrophic neurites in the Tg4510 tau mouse model (Graham et al., Neuropharmacology, 19, 307-313 (2014)). Accordingly, OGA inhibitors are recognized as a viable therapeutic approach to reduce the accumulation of hyperphosphorylated, pathological forms of tau.

US 2017/0298082 discloses certain glycosidase inhibitors useful in treating tauopathies such as AD. WO 2018/109198 Al and WO 2018/109202 Al disclose certain

OGA inhibitors useful for treating tauopathies, such as AD and PSP. W02020/068530 provides compounds that are potent inhibitors of OGA, including those with the potential to be sufficiently brain penetrant to effectively treat tauopathies, such as AD and PSP.

Accordingly, the present invention provides improved synthetic routes for the synthesis of molecules useful as OGA inhibitors, and compounds representing synthetic intermediates thereof.

In particular, the present application provides a compound, which is:

and methods of synthesis thereof.

The present application also provides a compound, which is:

and methods of synthesis thereof.

The present application also provides a compound, which is:

and methods of synthesis thereof.

Disclosed herein is also method of synthesizing a compound:

which includes the steps of:

(a) reacting a first compound

with thionyl chloride to yield a second compound

(b) reacting the second compound with N,N-diisopropylethylamine and (2,4-dimethoxyphenyl)methanamine to yield a third compound

(c) reacting the third compound with anisole and an acid, and subsequently treating with base to yield the compound

The present application also provides a method of synthesizing a compound:

which includes a step of reacting a first compound

with p-toluenesulfonic anhydride to yield a second compound

. This reaction may also include 2- methyltetrahydrofuran and triethylamine.

In a further step, the the second compound above may be reacted with 2- nitrobenzenesulfonamide and an inorganic base to yield a third compound

In yet a further step, the method may further include reacting the third compound above with 1 -dodecanethiol and an inorganic base, and subsequently reacting with acetic anhydride, to yield the compound

The present application also provides a method of synthesizing a compound of Formula (I)

wherein X is hydrogen or methyl, which method includes a reaction intermediate generated by any one of the previously- described steps.

The present disclosure furthermore provides a method of synthesizing a compound of Formula (I)

(I), wherein X is hydrogen or methyl,

wherein the method includes an intermediate selected from the group consisting

The present disclosure contemplates all individual enantiomers and diasteromers, as well as mixtures of the enantiomers of said compounds, including racemates.

Individual enantiomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques, chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions" , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds'", Wiley-Interscience, 1994), or supercritical fluid chromatography (SFC) (See for example, T. A. Berger; “Supercritical Fluid Chromatography Primer f Agilent Technologies, July 2015).

The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures known to one of ordinary skill in the art, some of which are illustrated in the schemes, preparations, and examples below. The products of each step in the schemes below can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention. In addition, one of ordinary skill in the art appreciates that compounds of the present disclosure may be prepared by using starting material or intermediate with the corresponding desired stereochemical configuration which can be prepared by one of skill in the art.

Certain abbreviations are defined as follows: “ACN” or “MeCN” refers to acetonitrile; “Ac” refers to acetyl; “AcOH” refers to acetic acid; “AC2O” refers to acetic

anhydride; “BOC” refers to te/7-butoxycarbonyl; “CBz” refers to carbonylbenzyloxy; “DCM” refers to methylene chloride or dichloromethane; “DIPEA” refers to diisopropylethylamine; “DMEA” refers to dimethylethylamine; “DMF” refers to N,N- dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “dppf ’ refers to diphenylphosphinoferrocene; “EDTA” refers to ethylenediaminetetraacetic acid; “ES-MS” or “ES/MS” refers to Electrospray Mass Spectrometry; “EtOAc” refers to ethyl acetate; “EtOH” refers to ethanol or ethyl alcohol; “h” refers to hour or hours; “K0-/-Bu” refers to potassiumter /-butoxi de; “Me” refers to methyl; “min” refers to minute or minutes; “MeOH” refers to methanol; “MHz” refers to megahertz; “mol” refers to mole or moles; “mmol” refers to millimole or millimoles; “MTBE”: refers to methyl tert-butyl ether; “NaBH(OAc)3” refers to sodium triacetoxyborohydride; “NaO-/-Bu” refers to sodium-te/7-butoxide; “NMR” refers to nuclear magnetic resonance; “OAc” refers to acetate or acetoxy; “PG” refers to protecting group; “RT” refers to room temperature; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; “Ts” refers to tosyl, or toluenesulfonyl; “[OC]D²⁰” refers to specific optical rotation at 20 °C and 589 nm, wherein c is the concentration in g/mL.

Scheme 1

Scheme 1 provides a method for preparing l-(2-chloro-5,7-dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl)ethan-l-one from (6-chloropyridine-2,3-diyl)dimethanol. In step A, the alcohol moi eties may be converted to halides through a substitution reaction, such as by using thionyl chloride, oxalyl chloride or a similar chlorinating reagent. The mixture may be

stirred and concentrated under reduced pressure to yield 6-chloro-2,3- bis(chloromethyl)pyridine.

In step B, a non-nucleophilic base such as DIPEA and (2,4- dimethoxyphenyl)methanamine may be added to a solution of 6-chloro-2,3- bis(chloromethyl)pyridine in a suitable solvent (such as dichloromethane). The mixture is stirred (in one aspect, at room temperature for about 72 h) after which it is diluted with the same or a different organic solvent (in this instance, dichloromethane) and washed with water (200 mb). The aqueous layer may then be extracted with organic solvent, as is well known in the art, and the combined organic layers may then be dried, such as over sodium sulfate. After filtration and concentration, the resultant residue may be subjected to a chromatographic process (such as passage through silica gel), and eluted using a variety of solvent systems well know by one skilled in the art (in one aspect, with ethyl acetate/hexanes) to yield 2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine.

In step C, 2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine may be mixed with anisole in the presence of an appropriate acid (in one aspect, trifluoroacetic acid). The mixture may be refluxed for an amount of time, for instance, 1 to 1.5 hours, and concentrated to obtain a residue which upon work-up using an aprotic solvent and subsequent basicifi cation with sodium carbonate may afford 2-chloro-6,7-dihydro-5H- pyrrolo[3,4-b]pyridine, which may be purified as is known in the art.

In step D, acetylation of 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine may be accomplished using acetic anhydride to yield the final product, l-(2-chl oro-5, 7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one. Precipitation may be achieved by addition of a salt (such as sodium chloride), and the compound may be purified by conventional processes.

Alternative synthesis of l-(2-chloro-5,7-dihydro-6H-pyrrolor3,4-b1pyridin-6-yl)ethan-l-one

Scheme 2

Scheme 2 likewise provides a method for preparing l-(2-chloro-5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one from (6-chloropyridine-2,3-diyl)dimethanol, and provides an alternate way to synthesize the desired compound.

In step A, (6-chloropyridine-2,3-diyl)dimethanol may be combined with 2- methyltetrahydrofuran, an amine base such as triethylamine, and p-toluenesulfonic anhydride, stirred, and quenched with saturated aqueous sodium bicarbonate solution, to yield the tosylated product. To isolate (6-chloropyridine-2,3-diyl)bis(methylene) bis(4- methylbenzenesulfonate), the mixture may be filtered, extracted with a non-polar solvent (such as MTBE) and the layers separated. The organic layers are combined and may be washed with brine prior to drying, filtration, and concentration, as is well known in the art, to yield the product.

In step B, (6-chloropyridine-2,3-diyl)bis(methylene) bis(4-methylbenzenesulfonate) and 2-nitrobenzenesulfonamide are combined in organic solvent (such as acetonitrile). Separately, an inorganic base (such as cesium carbonate) is suspended in an organic solvent, (again, such as acetonitrile), and the first solution is added dropwise to the second and mixed. This yields 2-chloro-6-((2-nitrophenyl)sulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine.

In step C, to the foregoing mixture is added 1 -dodecanethiol and a carbonate base such as cesium carbonate. The mixture is stirred and heated, then cooled and filtered. Solids were collected and washed with a non-polar solvent (such as MTBE). The solid is then combined with water and 2-methyltetrahydrofuran, stirred, and extracted, filtered, and concentrated by methods well known in the art, to yield 1 -(2-chl oro-5, 7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)ethan- 1 -one.

Preparation 1 (Example 1)

2-Chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine

Scheme 1, Step A: (6-Chloropyridine-2.3-divl)dimethanol (34.9 g, 201 mmol) was added portion wise to thionyl chloride (210 mL, 2.88 mol) which had been cooled to 0 °C. The mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure to give 6-chloro-2,3-bis(chloromethyl)pyridine (43.7 g, 201 mmol).

Scheme 1, Step B: A solution of 6-chloro-2,3-bis(chloromethyl)pyridine (43.7 g, 201 mmol) in dichloromethane (115 mL) was cooled to 0 °C. To this was slowly added N,N- diisopropylethylamine (110 mL, 631 mmol) and (2,4-dimethoxyphenyl)methanamine (33.0 mL, 220 mmol), keeping the internal temperature below 15 °C. The mixture was stirred at room temperature for 72 h, after which it was diluted with dichloromethane (200 mL) and washed with water (200 mL). The aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were then dried over sodium sulfate, fdtered, and concentrated under reduced pressure. The resultant residue was dissolved in dichloromethane

(100 mL) and passed through silica gel (600 mL), followed by elution with ethyl acetate (1.4 L). The eluent was concentrated under reduced pressure to give 41.4 g of the title compound (68% over two steps). ES-MS m/z 305 (M+H).

(400 MHz, CDCh) 5 7.40 (d, J= 8 Hz, 1H), 7.24 (d, J= 9 Hz, 1H), 7.11 (d, J= 8 Hz, 1H), 6.48 (m, 2H), 4.00 (bs, 2H), 3.94 (bs, 2H), 3.88 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H).

Preparation 2 l-(2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one

Scheme 1, Step C: A mixture of 2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridine (41.4 g, 136 mmol), anisole (16.3 mL, 150 mmol), and trifluoroacetic acid (100 mL) was heated at reflux for 1 h 15 min, then concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate (200 mL) and washed with water (200 mL). The aqueous layer was adjusted to pH = 8 with solid sodium carbonate to afford an aqueous solution of 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (21.0 g, 136 mmol). ESMS m/z 155 (M+H).

Scheme 1, Step D: To the solution of 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (21.0 g, 136 mmol) was added acetic anhydride (19.3 mL, 204 mmol). The mixture was stirred at room temperature for 10 min. The pH of the solution was adjusted to pH = 8 with solid sodium carbonate. The mixture was filtered, sodium chloride (100 g) was added to the filtrate, and the mixture was stirred at room temperature. The resulting solid was collected by vacuum filtration and washed with water (1 x 20 mL). All aqueous layers were combined and extracted with di chloromethane (2 x 300 mL). The previously collected solid was combined

with the organic extracts and dried over magnesium sulfate, fdtered, and concentrated under reduced pressure to give the title compound (13.0 g, 48% over two steps). ES-MS m/z 197 (M+H).

Alternative synthesis of l -(2-chloro-5,7-dihydro-6H-pyrrolor3,4-b1pyridin-6-yl)ethan-l-one

Scheme 2

Preparation 3 (Example 2)

(6-Chloropyridine-2,3-diyl)bis(methylene) bis(4-methylbenzenesulfonate)

Scheme 2, Step A: To a mixture of (6-chloropyridine-2,3-diyl)dimethanol (12.4 g, 71.3 mmol), 2-methyltetrahydrofuran (186 mL), and triethylamine (29.8 m , 214 mmol) at room temperature was added p-toluenesulfonic anhydride (58.2 g, 178 mmol) in six equal portions over 60 min. The mixture was stirred at room temperature for 4.5 h. The reaction was then quenched with saturated aqueous sodium bicarbonate solution (150 mL), and the mixture filtered through celite, which was rinsed with water (30 mL) and MTBE (30 mL). The resulting layers were separated, and the aqueous layer was extracted with MTBE (2 x 100 mL). All organic layers were combined and washed with brine (150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was azeotroped with MeCN (2 x 50 mL) to give the title compound (34.2 g, 94%). ES-MS m/z 482 (M+H). ^lH NMR (400 MHz, CDCh) 8 7.79 (d, J= 8 Hz, 2H), 7.74 (d,

J= 8 Hz, 2H), 7.66 (d, J= 8 Hz, 1H), 7.37 (d, J= 8 Hz, 2H), 7.32 (d, J= 8 Hz, 2H), 7.27 (d, J= 8 Hz, 1H), 5.14 (s, 2H), 5.07 (s, 2H), 2.47 (s, 3H), 2.45 (s, 3H).

Preparation 4 (Example 3) l-(2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one

Scheme 2, Step B: A solution of (6-chloropyridine-2,3-diyl)bis(methylene) bis(4- methylbenzenesulfonate) (34.2 g, 66.7 mmol) and 2-nitrobenzenesulfonamide (14.8 g, 73.2 mmol) was prepared in acetonitrile (342 mL) [Solution 1], Separately, a suspension of cesium carbonate was prepared (43.5 g, 134 mmol) in acetonitrile (342 mL) [Solution 2], Solution 1 was added to Solution 2 at room temperature dropwise at a rate of 1 mL/min. The mixture was stirred at room temperature for 17 h to give crude 2-chloro-6-((2- nitrophenyl)sulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine. ES-MS m/z 340 (M+H).

Scheme 2. Step C: To the foregoing mixture was added 1 -dodecanethiol (24.5 mL, 100 mmol) and cesium carbonate (43.5 g, 134 mmol) in one portion. The mixture was stirred at 75 °C for 4.5 h, then cooled to room temperature and filtered. Solids were collected and washed with MTBE (2 x 50 mL). The solid was then combined with water (150 mL) and 2- methyltetrahydrofuran (150 mL). This mixture was stirred at room temperature for 5 min, and the resulting layers separated. To the aqueous layer was added acetic anhydride (9.46 mL, 100 mmol). This mixture was stirred at room temperature for 5 min, then diluted with 15% aqueous sodium sulfate solution and extracted with 2-methyltetrahydrofuran (4 x 150 mL), followed by extraction with ethyl acetate (2 x 150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was combined with 1 :4 isopropyl acetate: heptane (78 mL). This mixture was stirred at 50 °C for 45 min, then at room temperature for 15 min. The solid was collected by vacuum

filtration to give the title compound (8.9 g, 66% over two steps). ES-MS m/z 197 (M+H). 1H NMR (400 MHz, d6-DMSO) 5 7.86 (d, J = 8 Hz, 1H), 7.45 (d, J = 8 Hz, 1H), 4.83 (d, J = 11.5 Hz, 2H), 4.59 (d, J= 17 Hz, 2H), 2.06 (app d, J= 1.5 Hz, 3H).

Schemes 1 and 2 provide novel and improved synthetic routes for the synthesis of 1- (2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-l -one, relative to previous routes.

In some aspects, this compound is useful as an intermediate for the synthesis of OGA inhibitors. Certain of these OGA inhibitors are disclosed in International Patent Publication No. W02020/068530, and corresponding United States Patents No. 10,752,632 and 10,836,773, all of which are hereby incorporated by reference in their entirety, as is data demonstrating their efficacy as OGA inhibitors.

Specifically, l-(2-chloro-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one may be used to synthesize an OGA inhibitor of Formula (I) below:

In a compound of Formula (I), X is H or methyl.

Such syntheses are described in the patent documents incorporated above, and are recapitulated herein.

Scheme 3 illustrates the synthesis of the compound of Formula (I) when X = H: l-(2- (((3R,5S)-l-((6-fluoro-2-methylbenzo[d]thiazol-5-yl)methyl)-5-methylpyrrolidin-3-yl)oxy)- 5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one.

Scheme 3, step A, shows nucleophilic aromatic substitution of l-(2-chloro-5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one with an appropriately N-protected commercially available hydroxypyrrolidine. The skilled artisan will recognize that a wide array of nucleophilically-stable N-protecting groups may be used, such as Boc, CBz, benzyl, or methyl, as needed for ease of removal. For example, about 1 equivalent of the appropriately N-protected 4-hydroxy-2-methylpyrrolidine may be treated with about 2 equivalents of a suitable strong base, such as NaH, KO-t-Bu, or NaO-/-Bu, in an suitable polar solvent, such as THF, DMF, 1,4-di oxane, or DMSO, at about 0 °C to about RT. About 1.2 equivalents of the desired acylated product of Scheme 1, step A, may be added at about 0 °C to about RT, and the resulting mixture may be stirred at about RT for about 12-24 h. The resulting reaction product may be isolated by techniques well known in the art, such as extraction and chromatography. For example, the reaction mixture may be diluted with water, extracted with an appropriate organic solvent, such as DCM or EtOAc, and the combined organic extracts may be washed sequentially with water, saturated aqueous NaCl, dried over a suitable drying agent, such as NaiSCU or MgSCU, filtered, and the filtrate may be

concentrated under reduced pressure. The resulting residue may be purified by flash chromatography over silica, using a suitable mixture of polar and non-polar organic solvents, such as EtOAc or acetone in hexanes, to obtain the desired product of Scheme 3, step A. The skilled artisan will recognize that different isomers (e. ., cis- or trans-) of the commercially available hydroxypyrrolidine will give different isomers of the product of Scheme 3, step A.

In Scheme 3, step B, the skilled artisan will recognize the removal of the protecting group may be accomplished under an array of conditions well known in the art. For example, wherein PG = BOC, the product of Scheme 3, step A may be dissolved in a suitable organic solvent, such as DCM, and treated with an appropriate acid, such as HC1 dissolved in an organic solvent (e.g., Et2O, 1,4-di oxane), or TFA, and the resulting reaction mixture may be stirred at about RT to about 80 °C from about 30 min to 8 h. The resulting reaction product may be isolated by techniques well known in the art, such as evaporation. For example, the reaction mixture may be subjected to concentration under reduced pressure to obtain the HC1 salt of the product of Scheme 3, step B.

In Scheme 3, step C, N-C bond formation may be accomplished under a variety of methods well known in the art, including nucleophilic displacement of an alkyl halide, transition-metal catalysis, or under reductive amination conditions. For example, about 1 equivalent of an appropriately substituted aldehyde, such as 6-fluoro-2-methyl-l,3- benzothiazole-5-carbaldehyde and about 1 equivalent of the deprotected pyrrolidine hydrochloride (the product of Scheme 3, step B) may be dissolved in a suitable organic solvent, such as DCM, and the resulting solution may be treated with about 2.5-2.75 equivalents of a non-nucleophilic base, such as DIPEA or TEA for about 30 min to about 1 h. About 3 equivalents of a suitable borohydride reducing agent, such as sodium borohydride, sodium tri(acetoxy)borohydride, or sodium cyanoborohydride, may be added, and the resulting mixture may be stirred at about RT for about 12 to 24 h. The resulting reaction product may be isolated by techniques well known in the art, such as extraction and column chromatography. For example, the reaction mixture may be quenched slowly with a saturated aqueous mild basic solution, such as Nal lCO;. The resulting mixture may be extracted with a suitable organic solvent, such as DCM or EtOAc, and the combined organic

extracts may be washed sequentially with water, saturated aqueous NaCl, dried over a suitable drying agent, such as NaiSCh or MgSCh, filtered, and the filtrate may be concentrated under reduced pressure. The resulting residue may be purified by flash chromatography over silica, using a suitable mixture of polar and non-polar organic solvents, such as EtOAc or acetone in hexanes, or methanol in DCM or EtOAc, to obtain the title compound.

Scheme 4

Scheme 4 illustrates the synthesis of a compound of Formula I, wherein X = methyl: 1 -[2-[(3R,5 S)- 1 -[( 1 S)- 1 -(6-fluoro-2-m ethyl- 1 ,3 -benzothiazol-5-yl)ethyl]-5-methyl- pyrrolidin-3-yl]oxy-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethanone.

In Scheme 4, the substituted pyrrolidine as generated in Scheme 3, Step B, or its free base, is dissolved in a suitable solvent, such as acetonitrile, treated with about 0.8 equivalents of 5-[(lR)-l-chloroethyl]-6-fluoro-2-methyl-l,3-benzothiazole and excess cesium carbonate, and stirred for about 21 hours at about 68°C. The product of is then isolated and purified under conditions well known in the art.

Further Examples

Example 4 l-(2-(((3R,5S)-l-((6-fluoro-2-methylbenzo[d]thiazol-5-yl)methyl)-5-methylpyrrolidin-3- yl)oxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one

Scheme 3, step C: To a solution of 6-fluoro-2-methyl-l,3-benzothiazole-5- carbaldehyde (0.19 g, 0.95 mmol) and l-(2-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)-5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one hydrochloride (0.28 g, 0.94 mmol) in DCM (9 mb) is added DTPEA (0.45 mL, 2.6 mmol). The resulting solution is stirred at RT for 40 min. To the solution is added NaBH(OAc)3 (0.65 g, 3.04 mmol). The resulting solution is stirred at RT for 17 h. The reaction mixture is quenched slowly with saturated aqueous NaHCCh (5 mL). The aqueous layer is extracted with DCM (2 x 5 mL). The combined organic extracts are dried over MgSCh, filtered, and concentrated under reduced pressure. The resulting residue is dissolved in DCM and purified via flash chromatography over silica gel, eluting with a gradient of 40-100% acetone in hexanes, to obtain the title compound after solvent evaporation of the desired chromatographic fractions (0.27 g, 65% yield). ES/MS m/z 441 (M+H); [a]_D ²⁰ = +101.4° (c = 0.2, MeOH).

Example 5 l-[2-[(3R,5S)-l-[(lS)-l-(6-fluoro-2-methyl-l,3-benzothiazol-5-yl)ethyl]-5-methyl- pyrrolidin-3-yl]oxy-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethanone

Scheme 4: To a solution of l-(2-(((3R,5S)-5-methylpyrrolidin-3-yl)oxy)-5,7-dihydro-

6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one hydrochloride (0.192 g, 0.644 mmol) in acetonitrile (5.0 mL) is added 5-[(lR)-l-chloroethyl]-6-fluoro-2-methyl-l,3-benzothiazole (0.104 g, 0.452 mmol) and cesium carbonate (1.56 g, 4.79 mmol). The suspension is stirred at 65 °C for 17 h. The crude reaction is cooled to room temperature and filtered through celite. The filtrate is concentrated and purified via flash chromatography (silica gel) eluting with hexanes:(3:l acetone:DCM) [60:40 to 0:100], This material is further purified on a Chiralpak AD-H column with 40% MeOH(0.2% IPAm)/CO2 as the mobile phase to give 1- (2-(((3R,5S)-l-((S)-l-(6-fluoro-2-methylbenzo[d]thiazol-5-yl)ethyl)-5-methylpyrrolidin-3- yl)oxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)ethan-l-one (0.033 g, 0.073 mmol, 16% yield). MS w/z: 455 (M+H). [a]_D ²⁰ = +19.5 ° (c = 0.2, MeOH).

Claims

WE CLAIM:

1. A compound, which is:

2. A compound, which is:

3. A compound, which is:

4. A method of synthesizing a compound:

comprising:

(a) reacting a first compound

with thionyl chloride to yield a second compound

The method according to claim 4, wherein the compound

reacted with acetic anhydride to yield a fourth compound

A method of synthesizing a compound:

comprising: reacting a first compound

p-toluenesulfonic anhydride ield the compound

The method according to claim 6, wherein the first compound is dissolved in 2- methyltetrahydrofuran and triethylamine.

8. The method according to claim 6, further comprising reacting the second compound with 2-nitrobenzenesulfonamide and an inorganic base to yield a third compound

9. The method according to claim 8, further comprising reacting the third compound with 1 -dodecanethiol and an inorganic base, and subsequently reacting with acetic anhydride, to yield the compound

10. A method of synthesizing a compound of Formula (I)

wherein X is hydrogen or methyl, comprising using the method of claim 4 or claim 5 to generate a reaction intermediate.

A method of synthesizing a compound of Formula (I)

wherein X is hydrogen or methyl, comprising using the method of any one of claims 6-9 to generate a reaction intermediate. A method of synthesizing a compound of Formula (I)

wherein X is hydrogen or methyl, wherein the method comprises an intermediate selected from the group consisting

13. The method according to claim 12, wherein the intermediate is

14. The method according to claim 12, wherein the intermediate is

15. The method according to claim 12, wherein the intermediate is