Patent Description:
The patent <CIT> disclosed synthetic approaches to obtain compounds of formula (Ia). However, the synthetic approaches disclosed in patent <CIT> are not suitable for large scale production due to the following issues:.

One object of the invention therefore is to find an efficient synthetic approach which can be applied on a technical scale.

Based on current invention of new process, above issues were nicely addressed and further advantages were provided as following;.

Another aspect of the present invention relates to a novel intermediate of compound (V):
<CHM>.

Compare to compound (Va) which is used in prior patent <CIT> , compound (V) used in this invention is the key intermediate in the synthesis and manufacture of pharmaceutically active compound of formula (Ia) and/or (I) as described herein. The tert-butyl ester group in compound of formula (V) can perfectly avoid the basic hydrolysis step and can be removed together with Boc group in one step. Herein, the four-step synthesis was reduced to three steps.

Another aspect of the present invention relates the salt formation of compound (Ia). After systematic screen of different salt formation, HCl salt of compound (Ia) was selected because of the excellent stability and efficient formation and isolation property.

As used herein, the term "halogen" signifies fluorine, chlorine, bromine or iodine, particularly fluorine or chlorine.

The term "diastereomer" denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another.

The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flow ability and solubility of compounds. It is for example described in <NPL>; or in <NPL>.

The present invention provides a process for preparing the compounds of formula (I) as outlined in the scheme <NUM> exemplified for the compound with R<NUM> is fluorine; R<NUM> is fluorine or nitrile group.

The whole synthesis comprises the following steps:.

Another embodiment of this invention is that compound of formula (Ia) can also be synthesized in analogy to Scheme <NUM> after neutralization of the compound of formula (I).

A detailed description of present invention of process steps is as following:
Step a) the formation of compound of formula (IV),
<CHM>
via nucleophilic aromatic substitution between compound of formula (II),
<CHM>
and compound (III),
<CHM>.

The formation of compound of formula (IV) is usually performed in the presence of a suitable base in a suitable organic solvent, followed by a recrystallization procedure. The conversion as a rule is performed under a heating condition.

The suitable base is selected from TEA, DIPEA, DBU, pyridine, K<NUM>CO<NUM> and Cs<NUM>CO<NUM>; particularly the base is TEA.

The suitable organic solvent is selected from DMF, DMSO, DMAc, Toluene, DCM, CHCl<NUM>, benzene, THF, MeTHF, IPA, t-BuOH and ACN; particularly the organic solvent is ACN.

The reaction is performed at <NUM> - <NUM>; particularly at <NUM> - <NUM>.

The solid formation of the product via crystallization can be performed in the same solvent system as used in the reaction. The suitable solvent used both in the reaction and the crystallization is a mixture of ACN and the base, wherein the base is selected from TEA and DIPEA, particularly the base is TEA. The suitable volume ratio of TEA/ACN is <NUM>/<NUM> to pure TEA; particularly the volume ratio is <NUM>/<NUM>.

In prior art (e.g., <CIT>), DMSO is used as the solvent. DMSO containing reaction mixture has potential explosion risk and could decompose at high temperature which makes it not a good solvent for scale-up. In addition, column purification is required during the work up stage , however recrystallization in the solvent of ACN/TEA in this step of present invention could surprisingly address above issue, which also results in cleaner reaction and a work-up procedure without solvent change.

Step b) the formation of compound of formula (VI),
<CHM>
via Suzuki-Miyaura coupling reaction between compound of formula (IV) and compound (V),
<CHM>.

This step is critical for the whole process in terms of yield and purity improvement. In prior art (e.g., <CIT>), a compound (Va) was used with additional two more steps to deprotect Boc group and hydrolyze the ester group with tedious isolation and column purification procedure. In present invention, compound (V) was used and ester hydrolysis step was successfully avoided.

In prior art (e.g., <CIT>), flash column chromatography was used, which cannot meet the requirement of large scale production. In present invention, different purification and isolation methods were tried, however direct crystallization of the crude compound of formula (VI) under various conditions was never successful which either gave no precipitation or precipitation with low purity or low yield. Finally, the acid-base workup procedure with carefully selected pH value and solvent system surprisingly gives an efficient and reliable process for technical scale production. Following recrystallization surprisingly gives more than <NUM>% percent purity product with high yield (more than <NUM>%).

The formation of compound of formula (VI) is synthesized in the presence of a suitable catalyst and a suitable base in a suitable solvent. The conversion as a rule is performed under a heating condition.

The suitable catalyst is selected from Palladium(II) analogues with Phosphine Ligands, Nickel Catalyst and Palladium Precatalyst; particularly the catalyst is XPhos Pd G2, SPhos Pd G2, P(Cy3)Pd G3, APhos Pd G3, cataC-Pd G2 and cataC-Pd G3; more particularly the catalyst is cataC-Pd G2.

The suitable base used in the reaction is selected from NaOtBu, KOtBu, NaOH, KOH, MeONa, MeOK, Cs<NUM>CO<NUM>, K<NUM>CO<NUM>, K<NUM>PO<NUM>, KHCO<NUM>, Na<NUM>CO<NUM> and NaHCO<NUM>; particularly the base is K<NUM>CO<NUM> or Na<NUM>CO<NUM>.

The suitable solvent used in the reaction is a mixture of water and an organic solvent. The organic solvent is selected from MeTHF, THF, Dioxane, Toluene, Benzene, DMF, DMSO, DMAc, DCM, CHCl<NUM>, IPA, MeOH and EtOH; particularly the solvent is Dioxane.

The ratio of water to the organic solvent is surprisingly important to this reaction. Reducing the amount of water and increasing reaction temperature will unpredictably increase the yield and the purity of product. The suitable volume ratio of water to organic solvent is from <NUM>/<NUM> to <NUM>/<NUM>; particularly the ratio is <NUM>/<NUM>.

The purification of compound of formula (VI) is achieved via an acid-base work-up with a suitable acid and base in a suitable solvent at a suitable final PH; and recrystallization of formula (VI) is performed in a suitable organic solvent.

The acid used in the acid-base work-up is selected from HCl, HBr, H<NUM>SO<NUM>, H<NUM>PO<NUM>, MSA, toluene sulfonic acid and camphor sulfonic acid, particularly the acid is HCl. The base used in the acid-base work-up is selected from NaOH, KOH, KHCO<NUM>, K<NUM>CO<NUM>, NaHCOs and Na<NUM>CO<NUM>; particularly the base is NaOH. The suitable final pH range is from <NUM> to <NUM>; particularly the pH is <NUM> to <NUM>.

The suitable solvent for acid-base work-up is a selected from EtOH, MeOH, THF, IPAc, MTBE, EA, Toluene, benzene and DCM; particular the organic solvent is DCM and Toluene.

The suitable solvent for recrystallization of compound of formula (VI) was selected from acetone, ACN, MeOH, EtOH and IPA; particularly the solvent is EtOH.

Step c) the formation of compound of formula (I),
<CHM>
via deprotection of formula (VI).

In present invention, the deprotection of Boc group and hydrolysis of ester group is performed in one step. The compound of formula (I) is synthesized in the presence of a suitable acid in a suitable organic solvent.

The suitable acid used in the reaction is selected from TFA, HCl, H<NUM>PO<NUM> and CH<NUM>COOH and HCOOH; particularly the acid is HCl.

The organic solvent is selected from MeTHF, THF, DCM, CHCl<NUM>, EA, IPAc, IPA, MeOH and EtOH; particularly the solvent is THF or EA.

In another embodiment, the present invention relates to the synthetic process of
<CHM>
and its salt
<CHM>.

The present invention relates to (i) process for the preparation of a compound of the formula (I),
<CHM>.

A further embodiment of present invention is (ii) the process according to (i), wherein R<NUM> is hydrogen, fluoro or chloro; R<NUM> is hydrogen, fluoro, chloro or cyano.

A further embodiment of present invention is (iii) the process according to (i) to (ii), wherein the formation of compound of formula (IV) in step a) is performed in the presence of a base in an organic solvent; wherein the base is selected from TEA, DIPEA, DBU, pyridine, K<NUM>CO<NUM> and Cs<NUM>CO<NUM> particularly the base is TEA; wherein the solvent which is selected from DMF, DMSO, DMAc, Toluene, DCM, CHCl<NUM>, benzene, THF, MeTHF, IPA, t-BuOH and ACN, particularly the organic solvent is ACN.

A further embodiment of present invention is (iv) the process according to (i) to (iii), wherein the suitable volume ratio of TEA/ACN is <NUM>/<NUM> to pure TEA; particularly the volume ratio is <NUM>/<NUM>.

A further embodiment of present invention is (v) the process according to (i) to (iv), wherein the formation of compound of formula (VI) in step b) is performed in the presence of a catalyst, a base in a solvent; wherein the catalyst is selected from Palladium(II) analogues with Phosphine Ligands, Nickel Catalyst and Palladium Precatalyst; particularly the catalyst is XPhos Pd G2, SPhos Pd G2, P(Cy3)Pd G3, APhos Pd G3, cataC-Pd G2 and cataC-Pd G3; more particularly the catalyst is cataC-Pd G2.

A further embodiment of present invention is (vi) the process according to (i) to (v), wherein the base is selected from NaOtBu, KOtBu, NaOH, KOH, MeONa, MeOK, Cs<NUM>CO<NUM>, K<NUM>CO<NUM>, K<NUM>PO<NUM>, KHCO<NUM>, Na<NUM>CO<NUM> and NaHCO<NUM>; particularly the base is K<NUM>CO<NUM> or Na<NUM>CO<NUM>.

A further embodiment of present invention is (vii) the process according to (i) to (vii), wherein the solvent is a mixture of water and an organic solvent, wherein the organic solvent is selected from MeTHF, THF, Dioxane, Toluene, Benzene, DMF, DMSO, DMAc, DCM, CHCl<NUM>, IPA, MeOH and EtOH; particularly the solvent is Dioxane.

A further embodiment of present invention is (viii) the process according to (i) to (vii), wherein ratio of water to the organic solvent is <NUM>/<NUM> to <NUM>/<NUM>; particularly the ratio is <NUM>/<NUM>.

A further embodiment of present invention is (ix) the process according to (i) to (viii), wherein the compound of formula (VI) was purified via an acid-base work-up process in a solvent at a final PH; wherein the acid used in the process is selected from HCl, HBr, H<NUM>SO<NUM>, H<NUM>PO<NUM>, MSA, toluene sulfonic acid and camphor sulfonic acid, particularly the acid is HCl; wherein the base used in the process is selected from NaOH, KOH, KHCO<NUM>, K<NUM>CO<NUM>, NaHCOs and Na<NUM>CO<NUM>; particularly the base is NaOH.

A further embodiment of present invention is (x) the process according to (i) to (ix), wherein the solvent is selected from EtOH, MeOH, THF, IPAc, MTBE, EA, Toluene, benzene and DCM; particular the organic solvent is DCM and Toluene.

A further embodiment of present invention is (xi) the process according to (i) to (x), wherein the final PH range is from <NUM> to <NUM>; particularly the pH is <NUM> to <NUM>.

A further embodiment of present invention is (xii) the process according to (i) to (xi), wherein the compound of formula (VI) was further recrystallized in a solvent after acid-base work-up , wherein the solvent is selected from acetone, ACN, MeOH, EtOH and IPA; particularly the solvent is EtOH.

A further embodiment of present invention is (xiii) the process according to (i) to (xii), the formation of compound of formula (I) in step c) is performed in the presence of an acid in a solvent; wherein the acid is selected from TFA, HCl, H<NUM>PO<NUM> and CH<NUM>COOH and HCOOH, particularly the acid is HCl; wherein solvent is selected from MeTHF, THF, DCM, CHCl<NUM>, EA, IPAc, IPA, MeOH and EtOH, particularly the solvent is THF or EA.

To a <NUM> L glass flask was charged (<NUM>,<NUM>-dichloro-<NUM>-cyano-<NUM>-fluoro-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl)(methyl)carbamate (<NUM>, <NUM> mmol), (3aS, 6aS)-<NUM>-methyloctahydropyrrolo[<NUM>,<NUM>-b]pyrrole (<NUM>, <NUM> mmol, compound (III)), TEA (<NUM>, <NUM>) and ACN (<NUM>, <NUM>). The reaction mixture was heated to <NUM> - <NUM> and stirred for <NUM> hours.

After reaction completion, the reaction mixture was cooled to <NUM> - <NUM> over <NUM> hours. The resulting suspension was stirred at <NUM> - <NUM> for <NUM> hours, then filtered and the solid was collected and washed with ACN (<NUM>, three times). Combine and concentrate the organic solution and the solid was recrystallization in <NUM> ACN and <NUM> TEA. After filtration, the solid was collected. Two portion of wet solid was combine and dried in vacuum oven to afford <NUM> of tert-butyl N-[<NUM>-chloro-<NUM>-cyano-<NUM>-fluoro-<NUM>-[ (3aS,6aS)-<NUM>-methyl-<NUM>,<NUM>,3a,<NUM>,<NUM>,6a-hexahydropyrrolo[<NUM>,<NUM>-c]pyrrol-<NUM>-yl]-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl]-N-methyl-carbamate (Example <NUM>). The purity was <NUM>%, the yield was <NUM> %, and MS m/e = <NUM>[M+H] +.

The Compound (V) was prepared according to following scheme:
<CHM>.

To a <NUM> L three neck glass flask with N<NUM> protected was charged <NUM>-bromo-<NUM>-fluoronicotinic acid (<NUM>, <NUM> mmol, <NUM> eq), DCM (<NUM>, <NUM>), DMF (<NUM>, <NUM>) and oxalyl chloride (<NUM>, <NUM>, <NUM> mmol, <NUM> eq). The mixture was stirred at <NUM> over <NUM> hours. The result mixture was concentrated under vacuum to afford crude product of formula (Vc) (<NUM>, <NUM> mmol, <NUM> % yield). The crude product was used in the next step directly.

To a <NUM> L three neck glass flask with N<NUM> protected was charged tert-butyl (E)-<NUM>-(dimethylamino)acrylate (<NUM>, <NUM> mmol, <NUM> eq), toluene (<NUM>, <NUM>) and Et3N (<NUM>, <NUM>, <NUM> mmol, <NUM> eq). The mixture was heated to <NUM> and <NUM>-bromo-<NUM>-fluoronicotinoyl chloride (<NUM>, <NUM> mmol, <NUM> eq) was added. The result mixture was stirred at <NUM> <NUM> hours.

After reaction completion, the reaction mixture was cooled to room temperature. The resulting mixture was poured to <NUM> of ice water. After phase separation, the organic layer was washed by <NUM> of brine twice and then dried over Na<NUM>SO<NUM>. The organic layer was concentrated and mixed with n-heptane (<NUM>, <NUM>). The result suspension was filtered and the filter cake was dried under vacuum overnight. Tert-butyl (Z)-<NUM>-(<NUM>-bromo-<NUM>-fluoronicotinoyl)-<NUM>-(dimethylamino)acrylate (<NUM>, <NUM> mmol, <NUM> % yield) was obtained as a pale-yellow powder.

To a <NUM> L three neck glass flask with N<NUM> protection was charged tert-butyl (Z)-<NUM>-(<NUM>-bromo-<NUM>-fluoronicotinoyl)-<NUM>-(dimethylamino)acrylate (<NUM>, <NUM> mmol, <NUM> eq), THF (<NUM>, <NUM>) and DBU (<NUM>, <NUM>, <NUM> mmol). The mixture was cooled to <NUM> and methanamine (<NUM>, <NUM> mmol, <NUM> eq) was added. The result mixture was stirred at <NUM> for <NUM> hours.

After reaction was completed, the reaction mixture was concentrated under vacuum. The resulting residue was mixed with ethanol (<NUM>, <NUM>) and water (<NUM>, <NUM>). The resulting suspension was filtered and the filter cake was washed by <NUM> water, dried under vacuum, and tert-butyl <NUM>-bromo-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-dihydro-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (<NUM>, <NUM> mmol, <NUM> % yield) was obtained.

To a <NUM> in L three neck glass flask with N<NUM> protection was charged with Pd<NUM>(dba)<NUM> (<NUM>, <NUM>µmol, <NUM> eq), xPhos (<NUM>, <NUM> mmol, <NUM> eq), and toluene (<NUM>, <NUM>). The result mixture was stirred at room temperature for <NUM> hour. KOAc (<NUM>, <NUM> mmol, <NUM> eq), tert-butyl <NUM>-bromo-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-dihydro-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (<NUM>, <NUM> mmol, e1 eq), <NUM>,<NUM>,<NUM>',<NUM>',<NUM>,<NUM>,<NUM>',<NUM>'-octamethyl-<NUM>,<NUM>'-bi(<NUM>,<NUM>,<NUM>-dioxaborolane) (<NUM>, <NUM> mmol, <NUM> eq) and toluene (<NUM>, <NUM>) were added into the mixture. The result mixture was stirred at <NUM> for <NUM> hours.

After reaction was completed, the reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting suspension was filtered and the filter cake was washed by <NUM> DCM and <NUM> toluene mixture. The filtrate was concentrated to give the crude product. And the crude product was triturated in <NUM> of MTBE/ Heptane (v/v=<NUM>/<NUM>) at room temperature for <NUM> hours, then filtered. And the filter cake was washed with <NUM> of MTBE/heptane(v/v=<NUM>/<NUM>) and <NUM> heptane, then dried under vacuum to give tert-butyl <NUM>-methyl-<NUM>-oxo-<NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolan-<NUM>-yl)-<NUM>,<NUM>-dihydro-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (<NUM>, <NUM> mmol, <NUM> % yield) as an off-white solid. MS (ESI): <NUM>([M+H]+). <NUM>H NMR (<NUM>, CDCl<NUM>) δ ppm <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

To a <NUM> L three neck glass flask with N<NUM> protection was charged with tert-butyl (<NUM>-chloro-<NUM>-cyano-<NUM>-fluoro-<NUM>-((3aS,6aS)-<NUM>-methylhexahydropyrrolo[<NUM>,<NUM>-b]pyrrol-<NUM>(<NUM>)-yl)-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl)(methyl)carbamate (<NUM>, <NUM> mmol) and tert-butyl <NUM>-methyl-<NUM>-oxo-<NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolan-<NUM>-yl)-<NUM>,<NUM>-dihydro-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (<NUM>, <NUM> mmol), CataC-Pd G2 (<NUM>, <NUM> mmol), <NUM>,<NUM>-dioxane (<NUM>), potassium carbonate (<NUM>, <NUM> mmol) and water (<NUM>). The reaction mixture was heated to <NUM> - <NUM> and stirred for <NUM> hour.

After reaction was completed, the reaction mixture was cooled to room temperature. The resulting suspension was filtered and the filter cake was washed with <NUM> dioxane. The filtrate was concentrated and then dissolved in <NUM> dioxane. The solution was added to <NUM> water slowly over <NUM> hour and precipitate formed. The suspension was filtered, the filter cake was washed by <NUM> water two times and dried, and then dissolved in the mixture of <NUM> DCM and <NUM> MeOH. The organic layer was extracted by <NUM> <NUM>. 1N HCl aqueous solution four times. The aqueous solution was neutralized to pH = <NUM> by NaOH 2N solution. Then, the aqueous solution was extracted by <NUM>, DCM three times. The combined organic layer was washed with brine, dried over Na<NUM>SO<NUM>, concentrated to afford crude product. The crude product was dissolved in <NUM> EtOH at <NUM> and then slowly cool to room temperature over <NUM> hours. The precipitate was formed and was collected through filtration. The wet solid was dried in oven over <NUM> and afford <NUM> of ethyl <NUM>-[<NUM>-[tert-butoxycarbonyl(methyl)amino]-<NUM>-cyano-<NUM>-fluoro-<NUM>-[ (3aS,6aS)-<NUM>-methyl-<NUM>,<NUM>,3a,<NUM>,<NUM>,6a-hexahydropyrrolo[<NUM>,<NUM>-c]pyrrol-<NUM>-yl]-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl]-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate. The purity was <NUM>% and the yield was <NUM>% and the MS (ESI): <NUM>([M+H]+).

To a <NUM> L three neck glass flask with N<NUM> protection was charged with tert-butyl <NUM>-(<NUM>-((tert-butoxycarbonyl)(methyl)amino)-<NUM>-cyano-<NUM>-fluoro-<NUM>-((3aS,6aS)-<NUM>-methylhexahydropyrrolo[<NUM>,<NUM>-b]pyrrol-<NUM>(<NUM>)-yl)-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl)-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-dihydro-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (<NUM>, <NUM> mmol), THF (<NUM>, <NUM>) and HCl (<NUM>, <NUM>% wt% aqueous solution, <NUM>, <NUM> mmol). The reaction mixture was stirred at room temperature for <NUM> hours. The reaction mixture was concentrated and then re-dissolved in <NUM> ethanol. The suspension was stirred at room temperature over <NUM> hours. After filtration, the wet cake was suspended in <NUM> ethanol. The result suspension was filtered and dried in oven at <NUM> over <NUM> hours to afford <NUM> HCl salt of <NUM>-[<NUM>-cyano-<NUM>-fluoro-<NUM>-(methylamino)-<NUM>-[ (3aS,6aS)-<NUM>-methyl-<NUM>,<NUM>,3a,<NUM>,<NUM>,6a-hexahydropyrrolo[<NUM>,<NUM>-c]pyrrol-<NUM>-yl]-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl]-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylic acid. The purity was <NUM>% and the yield was <NUM>%. MS (ESI): <NUM> ([M+H]+). <NUM>H NMR (<NUM>, DMSO-d6) δ ppm <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> ~ <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> ~ <NUM> (m, <NUM>), <NUM> ~ <NUM> (m, <NUM>), <NUM> (br d, J=<NUM>, <NUM>), <NUM> ~ <NUM> (m, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (br s, <NUM>). <NUM>F NMR (<NUM>, DMSO-d<NUM>) δ ppm -<NUM> (s, <NUM> F). Cl ion test (Dionex Interion HPLC): <NUM> and <NUM> in two separate tests. Cl ratio; average: <NUM>.

To a <NUM> glass flask was charged with tert-butyl (<NUM>,<NUM>-dichloro-<NUM>,<NUM>-difluoro-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl)(methyl)carbamate (<NUM>, <NUM> mmol), (3aS, 6aS)-<NUM>-methyloctahydropyrrolo[<NUM>,<NUM>-b]pyrrole (<NUM>, <NUM> mmol), Et<NUM>N (<NUM>) and ACN (<NUM>). The reaction mixture was heated to <NUM> - <NUM> and stirred for <NUM> hours.

After reaction was completed, the reaction mixture was cooled to room temperature over <NUM> hours. The resulting suspension was stirred at room temperature for <NUM> hours, then filtered and the collected solid was washed with ACN (<NUM>, three times). The wet solid was dried in vacuum oven to afford <NUM> of tert-butyl N-[<NUM>-chloro-<NUM>-cyano-<NUM>-fluoro-<NUM>-[ (3aS,6aS)-<NUM>-methyl-<NUM>,<NUM>,3a,<NUM>,<NUM>,6a-hexahydropyrrolo[<NUM>,<NUM>-c]pyrrol-<NUM>-yl]-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl]-N-methylcarbamate (Example <NUM>). The purity was <NUM>%, the yield was <NUM> %, and MS (ESI): <NUM> ([{<NUM>C1}M+H] +), <NUM> ([{<NUM>Cl}M+H] +).

The formation of Compound of formula (VI) is essential to the scale up and quality control of formula (I), which requires a comprehensive design for the choice of reaction condition to achieve optimized product recovery and quality.

In the following tests, to each <NUM> tube was added tert-butyl (<NUM>-chloro-<NUM>,<NUM>-difluoro-<NUM>-((3aS,6aS)-<NUM>-methylhexahydropyrrolo[<NUM>,<NUM>-b]pyrrol-<NUM>(<NUM>)-yl)-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl)(methyl)carbamate (<NUM>, <NUM> mmol), tert-butyl <NUM>-methyl-<NUM>-oxo-<NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolan-<NUM>-yl)-<NUM>,<NUM>-dihydro-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (<NUM>, <NUM> mmol), Cata C Xium @RA-PdG2, potassium bicarbonate (<NUM>, <NUM> mmol), <NUM>,<NUM>-dioxane (<NUM>, <NUM> V) and water. The reaction mixture was heated to <NUM> and stirred for <NUM> hours. The result was summarized in Table <NUM>.

Based on the above data, lower Pd catalyst (entry <NUM> compare to entry <NUM>) has cleaner product. Lower water content (entry <NUM> compare to entry <NUM> and entry <NUM>) has better conversion and purity. 2v water and <NUM>. 05eq Pd catalyst is the best reaction condition based on current result.

To a <NUM> L three neck glass flask with N<NUM> protection was charged with tert-butyl (<NUM>-chloro-<NUM>,<NUM>-difluoro-<NUM>-((3aS,6aS)-<NUM>-methylhexahydropyrrolo[<NUM>,<NUM>-b]pyrrol-<NUM>(<NUM>)-yl)-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl)(methyl)carbamate (<NUM>, <NUM> mmol), tert-butyl <NUM>-methyl-<NUM>-oxo-<NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolan-<NUM>-yl)-<NUM>,<NUM>-dihydro-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (<NUM>, <NUM> mmol), CataC-Pd G2 (<NUM>, <NUM> mmol), potassium bicarbonate (<NUM>, <NUM> mmol), <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>). The reaction mixture was heated to <NUM> - <NUM> and stirred for <NUM> hours.

After reaction was completed, the reaction mixture was cooled to room temperature. The resulting suspension was concentrated and then dissolved in <NUM> ethanol and <NUM> <NUM>. 1N HCl aqueous solution. The solution was washed by <NUM> toluene three times and then added to <NUM> water slowly over <NUM> hour and precipitate was formed. The suspension was filtered and washed by <NUM> water two times. The filter cake was dried and then dissolved in <NUM> DCM and <NUM> MeOH. The organic layer was extracted by <NUM> <NUM>. 1N HCl aqueous solution four times. The aqueous solution was neutralized to pH = <NUM> by NaOH 2N solution. Then, the aqueous solution was extracted by <NUM> DCM three times. The combined DCM layer was washed with brine and dried over Na<NUM>SO<NUM>, concentrated to afford crude product. The crude product was dissolved in <NUM> EtOH at <NUM> and then slowly cool to room temperature over <NUM> hours. The precipitate was formed and was collected through filtration. The wet solid was dried in oven over <NUM> and afford <NUM> of tert-butyl <NUM>-[<NUM>-[tert-butoxycarbonyl(methyl)amino]-<NUM>,<NUM>-difluoro-<NUM>-[ (3aR,6aR)-<NUM>-methyl-<NUM>,3a,<NUM>,<NUM>,<NUM>,6a-hexahydro-<NUM>-cyclopenta[b]pyrrol-<NUM>-yl]-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl]-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate. The purity is <NUM>% and the yield is <NUM>% and the MS (ESI): <NUM> ([M+H]+).

To a <NUM> L three neck glass flask with N<NUM> protection was charged with tert-butyl <NUM>-[<NUM>-[tert-butoxycarbonyl(methyl)amino]-<NUM>,<NUM>-difluoro-<NUM>-[ (3aR,6aR)-<NUM>-methyl-<NUM>,3a,<NUM>,<NUM>,<NUM>,6a-hexahydro-<NUM>-cyclopenta[b]pyrrol-<NUM>-yl]-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl]-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylate (<NUM>, <NUM> mmol), THF (<NUM>) and HCl (<NUM>, <NUM>, <NUM> mol). After being stirred at room temperature for <NUM> hours, the reaction mixture was concentrated and then dissolved in <NUM> ethanol and <NUM> water. The suspension was heated to <NUM> over <NUM> hours and then slowly cooled to room temperature over <NUM> hours. After filtration, the filter cake was dissolved in <NUM> ethanol and suspension formed. The result suspension was filtered and dried in oven at <NUM> over <NUM> hours to afford <NUM> HCl salt of <NUM>-[<NUM>-cyano-<NUM>-fluoro-<NUM>-(methylamino)-<NUM>-[ (3aS,6aS)-<NUM>-methyl-<NUM>,<NUM>,3a,<NUM>,<NUM>,6a-hexahydropyrrolo[<NUM>,<NUM>-c]pyrrol-<NUM>-yl]-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl]-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylic acid. The purity is <NUM>% and the yield is <NUM>%.

<NUM>H NMR (<NUM>, DMSO-d6) δ ppm: <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> ~ <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> ~ <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM> ( s, <NUM>), <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (m, <NUM>), <NUM> ~ <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>); MS (ESI): <NUM> ([M+H] +), <NUM> ([M/<NUM>+H] +). Cl ion test (Dionex Interion HPLC): <NUM> and <NUM> in two separate tests; average: <NUM>.

Freebase of Example <NUM>: <NUM>-[<NUM>-cyano-<NUM>-fluoro-<NUM>-(methylamino)-<NUM>-[(3aS,6aS)-<NUM>-methyl-<NUM>,<NUM>,3a,<NUM>,<NUM>,6a-hexahydropyrrolo[<NUM>,<NUM>-c]pyrrol-<NUM>-yl]-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl]-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylic acid; initial purity: <NUM>%.

HCl salt compound (Example <NUM>): <NUM>-[<NUM>-cyano-<NUM>-fluoro-<NUM>-(methylamino)-<NUM>-[(3aS,6aS)-<NUM>-methyl-<NUM>,<NUM>,3a,<NUM>,<NUM>,6a-hexahydropyrrolo[<NUM>,<NUM>-c]pyrrol-<NUM>-yl]-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl]-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylic acid; hydrochloride; initial purity: <NUM>%.

Freebase of Example <NUM>: <NUM>-[<NUM>,<NUM>-difluoro-<NUM>-(methylamino)-<NUM>-[ (3aS,6aS)-<NUM>-methyl-<NUM>,<NUM>,<NUM> a,<NUM>,<NUM>,6a-hexahydropyrrolo [<NUM>,<NUM>-c]pyrrol-<NUM>-yl] -<NUM>-pyrido [<NUM>,<NUM>-b] indol-<NUM>-yl]-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylic acid; initial purity: <NUM>%.

HCl salt compound (Example <NUM>): <NUM>-[<NUM>,<NUM>-difluoro-<NUM>-(methylamino)-<NUM>-[ (3aS,6aS)-<NUM>-methyl-<NUM>,<NUM>,3a,<NUM>,<NUM>,6a-hexahydropyrrolo[<NUM>,<NUM>-c]pyrrol-<NUM>-yl]-<NUM>-pyrido[<NUM>,<NUM>-b]indol-<NUM>-yl]-<NUM>-methyl-<NUM>-oxo-<NUM>,<NUM>-naphthyridine-<NUM>-carboxylic acid; hydrochloride; initial purity: <NUM>%.

Condition: <NUM> of compound in <NUM> vial with sealed cap. Keep in oven at certain temperature for certain days. Then, the purity of solid was checked by UPLC. The result was summarized in Table <NUM>:.

Claim 1:
Process for the preparation of a compound of the formula (I),
<CHM>
wherein R<NUM> is hydrogen or halogen; R<NUM> is hydrogen, halogen or cyano; n is <NUM>-<NUM>, particularly n is <NUM>-<NUM>, more particularly n is <NUM>;
comprising any of the following steps:
Step a) the formation of compound of formula (IV),
<CHM>
via nucleophilic aromatic substitution between compound of formula (II),
<CHM>
and compound (III),
<CHM>
Step b) the formation of compound of formula (VI),
<CHM>
via Suzuki-Miyaura coupling reaction between compound of formula (IV) and compound (V),
<CHM>
Step c) the formation of compound of formula (I),
<CHM>
via deprotection of formula (VI).