 synthesis of mcl-1 inhibitor
专利摘要:
the present invention relates to intermediates and methods for synthesizing compound 1. compound 1 公开号:BR112019019686A2 申请号:R112019019686 申请日:2018-03-29 公开日:2020-04-14 发明作者:Hird Alexander；Stark Andrew；FERRAR Cati；Stewart Craig；HAZRA Debasis；Koek Jan；Ye Qing；Hardy Simon；Zheng Xiaolan 申请人:Astrazeneca Ab； IPC主号:
专利说明:
Descriptive Report of the Invention Patent for SYNTHESIS OF MCL-1 INHIBITOR. Background [001] Myeloid Cell Leukemia 1 (Mcl-1) is an important anti-apoptotic member of the BCL-2 protein family and a central regulator of cell survival. Amplification of the MCL1 gene and / or overexpression of the Mcl-1 protein has been observed in multiple types of cancer and is usually implicated in tumor development. In fact, MCL1 is one of the most frequently amplified genes in human cancer. In many malignancies, Mcl-1 is a critical survival factor and has been shown to mediate drug resistance for a variety of anti-cancer agents. [002] Mcl-1 promotes cell survival by binding to pro-apoptotic proteins such as Bim, Noxa, Bak and Bax and neutralizing their death-inducing activities. Thus, inhibition of Mcl-1 releases these pro-apoptotic proteins, often leading to the induction of apoptosis in Mcl-1-dependent tumor cells to survive. Thus, targeting Mcl-1 therapeutically alone or in combination with other therapies is a promising strategy for treating a plurality of malignancies and for overcoming drug resistance in many human cancers. The compound chemically called (/ A ) - (+) - 17-chloro-5,13,14,22-tetramethyl-28oxa-2,9-dithia-5,6,12,13,22-penta-azaheptacyclo [27.7.1.1 4 ' 7 .0 11 ' 15 .0 16 '21 . Q2024 O 30,35 ] octatrjaconta _ 1 (37), 4 (38), 6,11,14,16,18,20,23,29,31,33,35tridecaene-23-carboxylic (referred to as Compound 1): Compound 1 Petition 870190094446, of 9/20/2019, p. 17/81 2/61 is a potent Mcl-1 inhibitor, as described in more detail below. Therefore, there is a need to develop new methods to synthesize Compound 1 in an efficient manner. Brief Summary [003] Here are provided useful processes and intermediates for the synthesis of Compound 1: s Cl S' N N-N Compound 1 [004] In some embodiments, the following intermediates and any of their salts and their synthesis are disclosed: <^ Ν χΝ · Br H , o, ci · o Petition 870190094446, of 9/20/2019, p. 18/81 3/61 Brief Description of the Drawings [005] Figure 1 illustrates the powder X-ray diffraction diagram of Form A acid (/ A ) -17-chloro-5,13,14,22-tetramethyl-28-oxa-2, 9-dictia- 5.6.12.13.22- penta- azaheptacyclo [27.7.1.1 4 ' 7 .0 11 ' 15 .0 16 '21 0 20 ' 24 .0 30 '35 ] octatriaconta1 (37), 4 (38), 6,11, 14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylic monohydrate. [006] Figure 2 illustrates the differential scanning calorimetry (DSC) and traces of thermogravimetric analysis (TGA) of Form A acid (F A ) -17-chloro-5,13,14,22-tetramethyl-28- oxa-2,9-dithia-5,6,12,13,22penta-azaheptacyclo [27.7.1.1 4 ' 7 O 11 ' 15 O 16 '21 O 20 ' 24 O 30 '35 ] octatriaconta1 (37), 4 ( 38), 6,11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylic monohydrate. Detailed Description [007] In some embodiments, processes and intermediates useful for the synthesis of acid (/ A ) - (+) - 17-chloro-5,13, 14.22- tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-penta-azaheptaciclo [27.7.1.1 vo 11 '.The 15 16' 21 0 20 '24 ° 30' 35] octatriaconta -1 (37), 4 (38), 6,11,14,16, 18,20,23,29,31,33,35-tridecaene-23-carboxylic (Compound 1): Petition 870190094446, of 9/20/2019, p. 19/81 4/61 N-N Compound 1 [008] Compound 1 is a potent Mcl-1 inhibitor as illustrated in Example 1, below, and may be useful in the treatment of cancer, including hematological malignancies such as acute myeloid leukemia, multiple myeloma, mantle cell lymphoma , chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors, for example, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer, neuroblastoma, prostate cancer, melanoma, pancreatic cancer, uterine, endometrial and colon cancer. Due to the structural complexity of Compound 1, achieving an efficient synthesis can be an important aspect in the development of Compound 1 as a potential cancer treatment. Intermediates [009] In some embodiments, (2- (2- (2-bromo-3-chlorophenyl) hydrazone) E / Z hexanedioate) -E (Z / Z) -dimethyl dimethyl (Intermediate 1) is disclosed: Intermediate 1 [0010] In some embodiments, a compound of formula (d) is disclosed: Petition 870190094446, of 9/20/2019, p. 20/81 5/61 where R1 is a protecting group or hydrogen. In some modalities, R1 is p-methoxybenzyl. In some embodiments, the compound of formula (a) is acid (±) -3- (2-carboxyethyl) -6-chloro-7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5- dimethyl-1 H-pyrazol-4-yl) -1-methyl-1 H-indole-2-carboxylic (Intermediate 6): [0011] In some modalities, a compound of formula (e) is disclosed: (e) where R1 is a protecting group or hydrogen. In some embodiments, R1 is p-methoxybenzyl. In some embodiments, the compound of formula (b) is acid (/ A ) -3- (2-Carboxyethyl) -6-chloro-7- (3 - (((4-methoxybenzyl) Petition 870190094446, of 9/20/2019, p. 21/81 6/61 oxy) methyl) -1,5-dimethyl-1 H-pyrazol-4-yl) -1-methyl-1 H-indole-2-carboxylic - (1 / ) - 1- (2-nitrophenyl) ethanamine (salt 1: 1) (Intermediate 7): Intermediate 7 [0012] In some embodiments, 5 - (((4-hydroxynaphthalen-2-yl) thio) methyl) -1-methyl-1H-pyrazol-3-carboxylate (Intermediate 12) is disclosed: O Intermediate 12 [0013] In some embodiments, a 3 - (((3- (hydroxymethyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-ol (Intermediate 13) is disclosed: Intermediate 13 [0014] In some embodiments, 3 - (((3- (chloromethyl) -1methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1 -ol (Intermediate 14) is disclosed: Intermediate 14 Petition 870190094446, of 9/20/2019, p. 22/81 7/61 [0015] In some embodiments, 3 - ((((3 (chloromethyl) -l-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-yl (Intermediate 15) : Cl Intermediate 15 [0016] In some embodiments, 3 - ((((((acetylthio) methyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-yl (Intermediate) 16): Intermediate 16. Synthesis [0017] In some embodiments, a method of synthesizing (2- (2- (2-bromo-3-chlorophenyl) hydrazone) E / Z hexanedioate) -dimethyl (Intermediate 1) is disclosed: , o, Br H o ^ o Intermediate 1 [0018] Comprising the steps of (i) contacting methyl 2-bromo-3-chloroaniline with 2-oxocyclopentane-1-carboxylate with a diazotizing agent in an acidic aqueous system; (ii) add methyl 2oxocyclopentane-1-carboxylate and an aqueous base to the system Petition 870190094446, of 9/20/2019, p. 23/81 8/61 acidic aqueous ma; (iii) isolating the resulting hydrazone; (iv) contacting the hydrazone with an acid solution; and (v) isolation of 2- (2- (2-bromo3-chlorophenyl) hydrazone) (EZZ) -dimethyl hexanedioate (Intermediate 1). In some embodiments, the diazotizing agent is NaNO2, Ca (NO2) 2 or KNO2. In some embodiments, the diazotizing agent is NaNO2. In some embodiments, the acidic aqueous system comprises a protic acid and water. In some embodiments, protic acid is hydrochloric acid. In some embodiments, the aqueous base is potassium acetate, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate or potassium phosphate. In some embodiments, the aqueous base is potassium acetate. In some embodiments, the acidic solution comprises an acid and an alcohol. In some embodiments, the acidic solution comprises concentrated sulfuric acid and methanol, methanesulfonic acid and methanol or p-toluenesulfonic acid and methanol. In some embodiments, the acidic solution comprises concentrated sulfuric acid and methanol. [0019] In some embodiments, a method for synthesizing methyl 7-bromo-6-chloro-3- (3-methoxy-3-oxopropyl) -1 H-indole-2-carboxylate (Intermediate 2): Intermediate 2 [0020] Understanding the steps of (i) contacting (E / Z) -dimethyl 2- (2- (2-bromo-3chlorophenyl) hydrazone) hexanedioate (Intermediate 1) with an acidic solution; and (ii) isolation of methyl 7-bromo-6-chloro-3- (3-methoxy-3-oxopropyl) -1H-indole-2-carboxylate (Intermediate 2). In some embodiments, the acidic solution comprises an acid and an alcohol. In some modalities, the acidic solution comprises Petition 870190094446, of 9/20/2019, p. 24/81 9/61 concentrated sulfuric acid and methanol, methanesulfonic acid and methanol or p-toluenesulfonic acid and methanol. In some embodiments, the acidic solution comprises concentrated sulfuric acid and methanol. In some embodiments, the method of synthesis of Intermediate 2 further comprises the step of heating the acidic solution before isolation of Intermediate 2. [0021] In some embodiments, a method of synthesizing a compound of formula (a) is disclosed: Br (a) in which R1 is a protecting group or hydrogen, comprising the steps of: (i) contacting ethyl 1,5-dimethyl-1H-pyrazol-3-carboxylate with a reducing agent in the presence of a first solvent to form a first solution; (ii) isolating (1,5-dimethyl-1 H-pyrazol-3-yl) methanol; (iii) contacting (1,5-dimethyl-1H-pyrazol-3-yl) methanol with a brominating agent in the presence of a second solvent to form (4bromo-1,5-dimethyl-1H-pyrazol-3-yl )methanol; (iv) isolating (4-bromo-1,5-dimethyl-1H-pyrazol-3-yl) methanol; (v) contacting (4-bromo-1,5-dimethyl-1Hpyrazol-3-yl) methanol with a base, optionally, a phase transfer catalyst, and a precursor of the protecting group in a third solvent; and (v) isolating the compound of formula (a). In some embodiments, the reducing agent is selected from aluminum and lithium hydride (LAH), diisobutylaluminum hydride (DIBAL), lithium borohydride (L1BH4), sodium bis (2-methoxyethoxy) aluminum hydride (Red-AI ®) and sodium borohydride (NaBhk). In some embodiments, the reducing agent is aluminum hydride and lithium. In some embodiments, the first solvent is selected from toluene, THF, 2-methyltetrahydrofuran, MTBE, methanol, ethanol and diethyl ether. In some embodiments, the first solvent is tetrahydrofuran. In some modali Petition 870190094446, of 9/20/2019, p. 25/81 10/61, the second solvent is tetrahydrofuran. In some embodiments, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). In some embodiments, the brominating agent is Nbromosuccinimide. In some embodiments, the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, lithium hydride or potassium hydride. In some embodiments, a phase transfer catalyst, for example BU4N HSO4 or benzyltrimethylammonium chloride, is used. In some embodiments, the base is potassium hydroxide and the phase transfer catalyst is tetrabutylammonium bisulfate. In some embodiments, the precursor to the protecting group is 1- (chloromethyl) -4-methoxybenzene. In some embodiments, R1 is p-methoxybenzyl. In some embodiments, the compound of formula (a) is 4-bromo-3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-1Hpyrazole (Intermediate 3): Intermediate 3 [0022] In some embodiments, a method of synthesizing a compound of formula (b) is disclosed: The 0 B where R1 is a protecting group or hydrogen, comprising the steps of: (I) contacting a compound of formula (a) with a metallising agent in the presence of a solvent; (ii) add 2isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; (iii) adding an Petition 870190094446, of 9/20/2019, p. 26/81 11/61 acidic solvent solution; and (iv) isolating the compound of formula (b). In some embodiments, the metallizing agent is n-butyl lithium. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the acidic solvent solution comprises acetic acid and toluene. In some embodiments, R1 is p-methoxybenzyl. In some embodiments, the compound of formula (a) is 4-bromo-3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-1H-pyrazole (Intermediate 3). In some embodiments, the compound of formula (b) is 3 - ((((4-methoxybenzyl) oxy) methyl) -! , 5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H-pyrazole (Intermediate 4): Intermediate 4 [0023] In some embodiments, a method of synthesizing a compound of formula (c) is disclosed: wherein R1 is a protecting group or hydrogen, comprising the steps of: (i) contacting a compound of formula (b) with 7-bromo-6-chloro-3- (3-methoxy-3-oxopropyl) -1H-indole-2 -methyl carboxylate (Intermediate 2) with a palladium catalyst in the presence of a base and solvent; and (ii) isolating the compound of formula (c). In some embodiments, the palladium catalyst is selected from tetrakis (triphenylphosphine) palladium (O), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium Petition 870190094446, of 9/20/2019, p. 27/81 12/61 (II) and 1,1'-bis dichloride (di-tert-butylphosphino) palladium ferrocene. In some embodiments, the base is potassium carbonate or potassium phosphate. In some embodiments, the palladium catalyst is 1,1'-bis (di-tert-butylphosphine) ferrocene dichloride. In some embodiments, the solvent is dioxane, water or a combination of these. In some embodiments, R1 is p-methoxybenzyl. In some embodiments, the compound of formula (b) is 3 - (((4-methoxybenzyl) oxy) methyl) -1,5dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl) -1 H-pyrazole (Intermediate 4). In some embodiments, the compound of formula (c) is (±) -6chloro-3- (3-methoxy-3-oxopropyl) -7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5 -dimethyl-1H-pyrazol-4 yl) -1H-indole-2-carboxylate (Intermediate 5): Intermediate 5 [0024] In some embodiments, a method of synthesizing a compound of formula (d) is disclosed: wherein R1 is a protecting group or hydrogen, comprising the steps of (i) contacting a compound of formula (c) with a methylating agent in a solvent; (ii) treating the resulting methylated derivative with an ester hydrolysis reagent and (iii) isolating the compound of formula (d). In some embodiments, the compound of formula (c) is Intermediate 5. In some embodiments, the ester hydrolysis reagent is a hydroxide base selected from lithium hydroxide, hydroxy Petition 870190094446, of 9/20/2019, p. 28/81 13/61 potassium oxide and sodium hydroxide. In some embodiments, the methylating agent is selected from methyl iodide, dimethyl sulfate and dimethylformamide-dimethylacetal (DMF-DMA). In some embodiments, the methylating agent is dimethylformamide-dimethylacetal. In some embodiments, the solvent is toluene. [0025] In some embodiments, R1 is p-methoxybenzyl. In some embodiments, the compound of formula (c) is (±) -6-chloro-3- (3-methoxy3-oxopropyl) -7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5 -dimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylate (Intermediate 5). In some embodiments, the compound of formula (d) is (±) -3- (2-carboxyethyl) -6-chloro-7- (3 ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl -1 H-pyrazol-4-yl) -1-methyl-1 H-indol2-carboxylic (Intermediate 6): [0026] In some embodiments, a method of synthesizing a compound of formula (e) is disclosed: where R1 is a protecting group or hydrogen, comprising the steps of: (i) contacting a compound of formula (d) with (1R) -1- (2-nitrophenyl) ethanamine hydrochloride in the presence of a base and a solvent ; and (ii) isolating the compound of formula (e). In some embodiments, the base is sodium hydroxide, potassium hydroxide, diiso Petition 870190094446, of 9/20/2019, p. 29/81 14/61 propylethylamine or triethylamine. In some embodiments, the base is sodium hydroxide. In some embodiments, the solvent is water, THF, methanol, ethanol, isopropanol, n-butanol, methyl ethyl ketone or a combination of these. In some embodiments, the solvent is water, ethanol or a combination of these. In some embodiments, R1 is p-methoxybenzyl. In some embodiments, the compound of formula (d) is (±) -3- (2-carboxyethyl) -6-chloro-7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5- dimethyl-1 H-pyrazol-4-yl) -1-methyl-1 H-indole-2-carboxylic (Intermediate 6). In some embodiments, the compound of formula (e) is (R a ) -3 (2-Carboxyethyl) -6-chloro-7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5- dimethyl-1Hpyrazol-4-yl) -1-methyl-1 H-indole-2-carboxylic - (1 R) -1 - (2-nitrophenyl) ethanamine (salt 1: 1) (Intermediate 7): Intermediate 7 [0027] In some embodiments, a method of synthesizing 6-chloro-7- (3- (hydroxymethyl) -1,5-dimethyl-1 H-pyrazol-4-yl) -3- (3- (Ra) -methyl methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (Intermediate 8): Intermediate 8 comprising the steps of (i) contacting a compound of formula (e) with an acid in the presence of a first solvent; (ii) isolation Petition 870190094446, of 9/20/2019, p. 30/81 15/61 of the free acid component of a compound of formula (e); (iii) treating the free acid with a methylating agent or methanol in a second solvent; (iv) removing the protecting group, optionally in a third solvent; and (v) isolating 6-chloro-7- (3- (hydroxymethyl) -1,5-dimethyl-1Hpyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1 H- (/ a ) -methyl indol-2-carboxylate (Intermediate 8). In some embodiments, the compound of formula (e) is (R a ) -3- (2-carboxyethyl) -6-chloro-7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5 acid -dimethyl-1 H-pyrazol-4-yl) -1-methyl-1 H-indole-2-carboxylic - (1 / ) - 1- (2-nitrophenyl) ethanamine (salt 1: 1) (Intermediate 7 ). In some embodiments, the first solvent is tetrahydrofuran, toluene or a combination of these. In some embodiments, the methylating agent is DMF-DMA. In some embodiments, the second solvent is toluene. In some embodiments, the third solvent is methanol. In some embodiments, the protecting group is removed by acetyl chloride. In some embodiments, the protecting group is removed by acetyl chloride in methanol. In some embodiments, the protecting group is removed by an acid, for example, hydrochloric acid formed in situ by reacting acetyl chloride with methanol. [0028] In some embodiments, a method of synthesizing 6-chloro-7- (3- (hydroxymethyl) -1,5-dimethyl-1 H-pyrazol-4-yl) -3- (3-hydroxypropyl) is disclosed (/ A ) -methyl-1-methyl-1H-indole-2-carboxylate (Intermediate 9): Intermediate 9 comprising the steps of (i) contacting 6-chloro-7- (3- (hydroxymethyl) 1,5-dimethyl-1 H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) - (/ A ) -methyl 1-methyl-1 H-indole-2-carboxylate (Intermediate 8) with a reducing agent in the presence of a solvent; and (ii) isolating 6-chloro-7- (3- (hydroxymethyl) -1.5 Petition 870190094446, of 9/20/2019, p. 31/81 16/61 dimethyl-1 H-pyrazol-4-yl) -3- (3 H) -indol-2-carboxylate of (/ A) -methyl (Intermediate 9 ). In some embodiments, the reducing agent is diisobutyl aluminum hydride. In some embodiments, the solvent is THF, hexane or a combination of these. [0029] In some embodiments, a method of synthesizing methyl 5- (chloromethyl) -1-methyl-1 H-pyrazol-3-carboxylate (Intermediate 10): Intermediate 10 comprising the steps of (i) contacting dimethyl 1-methyl-1 H-pyrazol-3,5-dicarboxylate with a reducing agent in the presence of a solvent; (ii) isolating methyl 3- (hydroxymethyl) -1-methyl-1H-pyrazol-5-carboxylate; (iii) contacting methyl 3- (hydroxymethyl) -1-methyl-1H-pyrazol-5carboxylate with a chlorinating agent; and (iv) isolating methyl 5- (chloromethyl) -1-methyl-1H-pyrazol-3-carboxylate (Intermediate 10). In some embodiments, the solvent is a mixture of methanol and 2-methyltetrahydrofuran. In some embodiments, the reducing agent is sodium borohydride or lithium borohydride. In some embodiments, the reducing agent is sodium borohydride. In some embodiments, the solvent is methanol, ethanol, water, 2-methyltetrahydrofuran, dimethylacetamide, DCM, THF, cyclopentylmethyl ether, acetonitrile or a mixture thereof. In some embodiments, the solvent is a mixture of methanol and 2-methyltetrahydrofuran. [0030] In some embodiments, a method of synthesizing 3- (acetylthio) naphthalen-1-yl acetate (Intermediate 11) is disclosed: OAc Intermediate 11 Petition 870190094446, of 9/20/2019, p. 32/81 17/61 [0031] comprising the steps of (i) contacting sodium 4-hydroxynaphthalene-2-sulfonate with triphenylphosphine and iodine in a solvent; (ii) isolation of 3-mercaptonaftalen-1-ol; (III) contacting 3mercaptonaftalen-1-ol with an acylating agent in the presence of an amine base and a nucleophilic catalyst; and (iv) isolating 3- (acetylthio) naphthalen-1-yl acetate (Intermediate 11). In some embodiments, the solvent is acetonitrile. In some embodiments, the acylating agent is acetic anhydride or acetyl chloride In some embodiments, the acylating agent is acetic anhydride. In some embodiments, the amine base is selected from triethylamine, pyridine or diisopropylethylamine. In some embodiments, the amine base is triethylamine. In some embodiments, the nucleophilic catalyst is selected from 4dimethylaminopyridine, pyridine and N-methylimidazole. In some embodiments, the nucleophilic catalyst is 4-dimethylaminopyridine. [0032] In some embodiments, a method of synthesizing 5 - ((((4-hydroxynaphthalen-2-yl) thio) methyl) -1-methyl-1 H-pyrazol-3-carboxylate (Intermediate 12) is disclosed: Intermediate 12 comprising the steps of (i) contacting methyl 3- (acetylthio) naphthalen-1-yl (Intermediate 11) with methyl 5- (chloromethyl) -1-methyl-1H-pyrazol-3-carboxylate (Intermediate 10 ) in the presence of a base and a solvent; and (ii) isolating 5 - ((((4-hydroxynaphthalen-2-yl) thio) methyl) -1 methyl-1H-pyrazol-3-carboxylate (Intermediate 12). In some embodiments, the base is selected from potassium carbonate, lithium hydroxide, 1,8-diazabicyte [5.4.0] undec-7-ene, sodium hydroxide, hydroxide Petition 870190094446, of 9/20/2019, p. 33/81 18/61 potassium and sodium ethoxide. In some embodiments, the base is potassium carbonate. In some embodiments, the solvent is selected from methanol, ethanol, water and their combinations. In some embodiments, the solvent is methanol. [0033] In some embodiments, a method of synthesizing 3 - (((3- (hydroxymethyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1 ol (Intermediate 13) is disclosed : Intermediate 13 [0034] comprising the steps of (i) contacting methyl 5 - (((4hydroxinaphthalen-2-yl) thio)) -1-methyl-1 H-pyrazol-3-carboxylate (Intermediate 12) reducing agent in a solvent; and (ii) isolating 3 - ((((3- (hydroxymethyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-ol (Intermediate 13). In some embodiments, the reducing agent is diisobutylaluminum hydride. In some embodiments, the solvent is tetrahydrofuran, hexanes or a combination of these. [0035] In some embodiments, a method of synthesizing 3 - (((3- (chloromethyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-ol (Intermediate 14 ): ci Intermediate 14 comprising the steps of (i) contacting 3 - (((3- (hydroxymethyl) -1-methyl1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-ol (Intermediate 13) with an agent Petition 870190094446, of 9/20/2019, p. 34/81 19/61 chlorination; and (ii) isolating 3 - ((((3- (chloromethyl) -1-methyl-1H-pyrazol-5-yl) methyl) thio) naphthalen-1-ol (Intermediate 14). In some embodiments, the solvent is selected from THF, dichloromethane, dimethylformamide and their combinations. In some embodiments, the solvent is dimethylformamide. In some embodiments, the chlorinating agent is methanesulfonyl chloride or thionyl chloride. In some embodiments, the chlorinating agent is methanesulfonyl chloride. In some embodiments, step (i) further comprises lithium chloride. [0036] In some embodiments, a method of synthesizing 3 - ((((3- (chloromethyl) -1-methyl-1H-pyrazol-5-yl) methyl) thio) naphthalen-1-yl (Intermediate) 15): ci Intermediate 15 comprising the steps of (i) contacting 3 - (((3- (chloromethyl) -1-methyl1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-ol (Intermediate 14) with acetic anhydride, optionally an amine base, and a nucleophilic catalyst in a solvent; and (ii) isolating 3 - ((((3- (chloromethyl) -1-methyl-1Hpyazol-5-yl) methyl) thio) naphthalen-1-yl acetate (Intermediate 15). In some embodiments, the amine base is triethylamine. In some embodiments, the nucleophilic catalyst is selected from 4-dimethylaminopyridine, Nmethylimidazole or pyridine. In some embodiments, the nucleophilic catalyst is 4-dimethylaminopyridine. In some embodiments, the solvent is acetonitrile. [0037] In some embodiments, an acetate synthesis method of 3 - ((((3 - ((acetylthio) methyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1 is disclosed -il (Intermediate 16): Petition 870190094446, of 9/20/2019, p. 35/81 20/61 Intermediate 16 comprising the steps of (i) contacting 3 - ((((3- (chloromethyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-yl (Intermediate 15) with potassium thioacetate in a solvent; and (ii) isolate 3 ((((3 - ((acetylthio) methyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-yl acetate (Intermediate 16). In some embodiments, the solvent is acetonitrile. [0038] In some embodiments, a method of synthesizing 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22penta-azaheptacyclo [ 4 27.7.1.1 '.0 7 .0 1115 16' 21 0 20 '24 ° 30' 35] octatriaconta (37), 4 (38), 6,11,14,16,18,20,23,29,31 , (/ A) - (+) - methyl 33,35-tridecaene-23-carboxylate comprising the steps of: (i) contacting 6-chloro-7- (3- (hydroxymethyl) 1,5-dimethyl-1 H-pyrazol-4-yl) -3- (3-hydroxypropyl) -1-methyl- 1 (/ A ) -methyl H-indole-2-carboxylate (Intermediate 9) with a sulfonylating agent in the presence of an aprotic base and a solvent to form a first solution; (ii) adding an iodide salt to the first solution; (iii) isolate 6-chloro-7- [3- (iodomethyl) -1,5-dimethyl-pyrazol-4-iI] -1-methyl-3- (3-methylPetition 870190094446, 09/20/2019, pg 36/81 21/61 methyl sulfonyloxypropyl) indole-2-carboxylate; (iv) contact of 3 - ((((3 - ((acetylthio) methyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-yl (Intermediate 16) with methoxide sodium in methanol to form a second solution; (v) adding methyl 6-chloro-7- [3- (iodomethyl) -1,5-dimethylpyrazol-4-iI] -1-methyl-3- (3-methylsulfonyloxypropyl) indole-2-carboxylate; and (vi) isolating 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9ditia-5,6,12,13,22-penta-azaheptacyclo [27.7.1.1 47 , o 11 · 15 Ό 16 · 21 Ό 20 · 24 . The 30 '35] octatriaconta-1 (37) 4 (38), 6,11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylate (/ A) - (+) - methyl. In some embodiments, the aprotic base is diisopropylethylamine or N-methylmorpholine. In some embodiments, the aprotic base is diisopropylethylamine. In some embodiments, the sulfonylating agent is selected from methanesulfonyl anhydride, methanesulfonyl chloride and p-toluenesulfonic anhydride. In some embodiments, the sulfonylating agent is methanesulfonyl anhydride. In some embodiments, the solvent is an aprotic solvent. In some embodiments, the aprotic solvent is tetrahydrofuran. In some embodiments, the iodide salt is lithium iodide. [0039] In some modalities, a method of synthesis of Compound 1 is disclosed: N-N Compound 1 comprising the steps of (i) contacting (/ A ) - (+) - methyl 17-chloro5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13 , 22-pentaazaheptacycle Petition 870190094446, of 9/20/2019, p. 37/81 22/61 [27.7.1.1 vo 11 '.The 15 16' 21 0 ° 2 '24 .0 30' 35] octatriaconta-1 (37) 4 (38), 6,11,14,16, 18.20.23.29.31.33.35- tridecaene-23-carboxylate with an ester hydrolysis reagent in a solvent and (ii) isolating acid (R a ) - (+) - 17 chloro-5,13,14,22-tetramethyl- 28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacycle [27.7.1.1 4 ' 7 O 11 ' 15 O 16 '21 O 20 ' 24 O 30 '35 ] octatriaconta-1 (37 ), 4 (38), 6.11, 14.16.18.20.23.29.31.33.35-tridecaene-23-carboxylic. In some embodiments, the ester hydrolysis reagent is a hydroxide base selected from lithium hydroxide, sodium hydroxide and potassium hydroxide. In some embodiments, the base is sodium hydroxide. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, DMSO, water and their combinations. [0040] The term isolated means any appropriate method for obtaining a desired compound from the reaction mixture. The isolated term includes extraction, filtration, drying, crystallization, evaporation, chromatography (e.g., HPLC, column chromatography), metal scavenger and the like. The term isolated includes methods for obtaining unpurified and purified compounds from a reaction mixture. In some embodiments, a compound can be isolated from a reaction mixture by extraction and the next step in the reaction can be carried out even when the compound has not been purified or removed from the solvent. One skilled in the art would be able to determine the appropriate means to isolate a desired compound from the reaction mixture. [0041] The term protecting group includes hydroxyl protecting groups, for example, benzyl, p-methoxybenzyl (PMB), tetrahydropyranyl (THP), p-methoxyphenyl (PMP) and t-butyldimethylsilyl (TBDMS), Petition 870190094446, of 9/20/2019, p. 38/81 23/61 one skilled in the art would be able to identify appropriate hydroxyl protecting groups without undue experimentation. [0042] The term precursor to the protecting group includes reagents that add protecting groups to a desired portion. In some embodiments, the precursor to the protecting group is a precursor to the hydroxyl protecting group, for example, benzyl chloride, 4-methoxyphenol, bromomethylpyrazole, dihydropyran, p-methoxyphenol, chloromethylpyrazole, t-butyldimethylchlorosilane, t-butyldimethylchlorosilane and (chloromethyl) -4-methoxybenzene. A person skilled in the art would readily be able to identify the precursor to the appropriate protecting group without undue experimentation. [0043] The term reducing agent includes aluminum and lithium hydride, sodium borohydride, diisobutylaluminum hydride and the like. [0044] The term solvent includes non-polar solvents, aprotic solvents and protic solvents. The term non-polar solvent includes pentane, cyclopentane, hexane, heptane, cyclohexane, benzene, toluene, chloroform, diethyl ether, cyclopentylmethyl ether, tert-butylmethyl ether, tert-amylmethyl ether, dichloromethane and methyl ethyl ketone. The term aprotic solvent includes tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, 2-methyltetrahydrofuran, 1,4-dioxane, dimethylacetamide and dimethylsulfoxide. The term protic solvent includes nbutanol, isopropyl alcohol, n-propanol, ethanol, methanol, acetic acid and water. In some embodiments, the solvent may include a combination Petition 870190094446, of 9/20/2019, p. 39/81 24/61 tions of any of the previous solvents. A person skilled in the art would routinely be able to determine the appropriate solvent or solvent combinations for a particular reaction. [0045] The term brominating agent includes 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) and N-bromosuccinimide (NBS). [0046] The term diazotizing agent includes sodium nitrite (NaNO2), calcium nitrite (Ca (NO2) 2) and potassium nitrite (KNO2). [0047] The term plating agent includes n-butyl lithium (n-BuLi). [0048] The term ester hydrolysis agent includes sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium chloride (NaCI) and lithium iodide (Lil). [0049] The base term includes potassium acetate (KOAc), potassium carbonate (K2CO3), sodium carbonate (Na2COs), potassium phosphate (K3PO4), potassium hydroxide, sodium hydroxide, sodium bis (trimethylsilyl) amide (NaHMDS), lithium bis (trimethylsilyl) amide (LiHMDS), sodium hydride (NaH), t-butyl ammonium bisulfate, n-butyl lithium, t-butyl lithium (t-BuLi), magnesium hydroxide, zinc, lithium, lithium diisopropylamide (LDA), sodium amide (NaNH2), potassium t-butoxide, pyridine, triethylamine (TEA), diisopropylethylamine (DIEA), 1,8-diazabicycle [5.4.0] undec-7- ene (DBU), sodium methoxide (NaOMe) and sodium ethoxide (NaOEt). The base term also includes basic phase transfer catalysts, for example, tetrabutylammonium bisulfate (BU4 HSO4), benzyltrimethylammonium chloride, polyethylene glycol and its derivatives, 18-crown-6 and other crown ethers. [0050] The term acid includes hydrochloric acid (HCI), sulfuric acid (H2SO4), p-toluenesulfonic acid (p-TsOH), methanesulfonic acid and acetic acid. In some embodiments, the acid is concentrated. [0051] The term alcohol includes methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and t-butyl alcohol. [0052] The term reducing agent includes aluminum hydride and lithium Petition 870190094446, of 9/20/2019, p. 40/81 25/61 (LAH), borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, diisobutyl aluminum hydride (DIBAL), lithium borohydride (L1BH4), sodium bis (2-methoxyethoxy) aluminum hydride (Red-AI®) and sodium borohydride (NaBhk). [0053] The term methylating agent includes methyl iodide, dimethyl sulfate and dimethylformamide-dimethylacetal (DMF-DMA). [0054] The term acylating agent includes acetic anhydride and acetyl chloride. [0055] The term nucleophilic catalyst includes dimethylaminopyridine (DMAP), pyridine and N-methylimidazole. [0056] The term amine base includes triethylamine, pyridine and diisopropylethylamine. [0057] The term sulfonylating agent includes tonic anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride and methanesulfonyl anhydride. [0058] The term iodide salt includes lithium iodide, sodium iodide and potassium iodide. [0059] In some embodiments, the term palladium catalyst includes dichloride of 1, T-bis (di-tert-butylphosphino) ferrocene-palladium, [1,1bis (di-tert-butylphosphino) ferrocene] dichloropalladium (ll) (Pd 188, PdCb (dtbpf)), (/ ) diphenylphosphino) - [2.2] -paracyclophane (S-Phanephos), (2-Dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1, T-biphenyl) methanesulfonate [2- (2'-amino1,1'- biphenyl)] palladium (ll) (XPhos-G3-Paladacycle, XPhos-Pd-G3), (2-Dicyclohexylphosphino-2 ', 6'-diisopropoxy-1, T-biphenyl) methanesulfonate [2- (2'-amino -1,1'-biphenyl)] palladium (ll) (RuPhos-G3-Paladacycle, RuPhos-Pd-G3), (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1' biphenyl) methanesulfonate [2 - (2'-amino-1,1 '-biphenyl)] palladium (II) (RuPhos-G3-Paladacycle, RuPhos-Pd-G3), [(2-Di-cyclohexylphosphino-3,6dimethoxy-) methanesulfonate 2 ', 4', 6'-triisopropyl-1, T-biphenyl) -2- (2'-amino-1, T-biphenyl)] palá Petition 870190094446, of 9/20/2019, p. 41/81 26/61 dio (ll) (BrettPhos G3), tBuXPhos-Pd-G3, [(2-Diterc-butylphosphino-2 ', 4', 6'-triisopropyl-1,1 '-biphenyl) -2- ( 2'-amino-1,1 '-biphenyl)] palladium (ll) (tBu XPhos G3), tetrakis (triphenylphosphine) palladium (0) and bis (ditherc-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (ll) [0060 ] In some embodiments, Compound 1 can be synthesized as set out in Schemes 1-VII: Scheme I htemsiáiârw 1 2 A = i) NaNO2, HCI aq; ii) methyl 2-oxocyclopentane-1-carboxylate, Aq KOAc; iii) H2SO4, MeOH B = H2SO4, MeOH Scheme II C = i) L1AIH4, THF; ii) NBS iii) PMBCI, KOH, Bu 4 NHSO 4 , THF D = i) n-BuLi, THF; ii) i-PrOBPin Scheme III Petition 870190094446, of 9/20/2019, p. 42/81 27/61 fetermedlário g E = Pd (di-t-BPF) Cl 2 , K2CO3, 1,4-dioxane, H 2 O F = i) DMF-DMA, PhMe; ii) NaOH aq, MeOH G = (1R) -1- (2-nitrophenyl) ethanamine hydrochloride, NaOH, EtOH, H2O H = i) aq HCI, PhMe, THF; ii) DMF-DMA, PhMe; iii) AcCI, MeOH I = iBu 2 AIH, THF Scheme IV Intermediate 1G J = i) NaBH 4 , MeOH, MeTHF Scheme V o Intermediate 11 K = i) PPh 3 , 12 , MeCN; ii) Ac2O, Et 3 N, DMAP Petition 870190094446, of 9/20/2019, p. 43/81 28/61 | fíWfs§diàfí & 15 iíitenswdiárôo iç L = K2CO3, MeOH M = i-Bu 2 AIH, THF N = MeSO 2 CI, LiCI, DMF O = Ac 2 O, DMAP, MeCN P = KSAc, MeCN Scheme VII ÍRtefwteifistto s tnterme & ârid 16 írrtemseâíárfe 17 Ceréissosío 1 Q = i) intermediate 9, (MeSO2) 2O, i-Pr2NEt; ii) Lil, MeCN; iii) in container 870190094446, of 9/20/2019, p. 44/81 29/61 separated entity, Intermediate 16, NaOMe, MeOH; iv) solution of iii) added to the compound of ii) in MeCN; v) addition in hot DMSO R = NaOH, DMSO, EtOH, H 2 O Examples [0061] Aspects of the present disclosure can be further defined by reference to the following non-limiting examples, which describe in detail the preparation of certain compounds and intermediates of present disclosure and methods for using the compounds of the present disclosure. It will be apparent to those skilled in the art that many modifications, both in materials and methods, can be practiced without departing from the scope of the present disclosure. [0062] Unless otherwise stated: all syntheses were carried out at room temperature, that is, in the range of 17 to 25 ° C, and under an atmosphere of an inert gas, such as nitrogen, unless otherwise specified; evaporations were carried out by rotary evaporation or using Genevac equipment or Biotage v10 evaporator under reduced pressure; Purifications by silica gel chromatography were performed in an automated system Novasep Hipersep® or Teledyne Isco CombiFlash® Rf or Teledyne Isco CombiFlash® Companion® packaged using Kromasil® 60-10-SIL silica (10 pm, 60 A particle size pore) or using prepackaged Silica RediSep Rf Gold ™ Columns (20-40 pm, spherical particles), GraceResolv ™ Cartridges (Davisil® silica) or Silicycle cartridges (40 - 63 pm). Chiral analytical chromatography was performed on a Waters X5 SFC-MS column with UV detection or a Waters UPC2 SFCMS with UV and detection by ELSD or an Agilent 1100 HPLC system with UV detection. Petition 870190094446, of 9/20/2019, p. 45/81 30/61 yields, when present, are not necessarily the maximum achievable; in general, the structures of the isolated compounds were confirmed by NMR spectroscopy; the values of the chemical NMR shifts were measured on the delta scale, using the residual peak of the solvent as an internal standard [the proton magnetic resonance spectra were determined using a 500 MHz Bruker Ultrashield Avance III spectrometer equipped with a QCI cryoprobe, spectrometer 400 MHz Bruker Ultrashield Avance III equipped with a BBFO probe, a Bruker Avance 500 (500 MHz), Bruker Avance 400 (400 MHz), Bruker Avance 300 (300 MHz) or Bruker DRX (300 MHz) instrument]; measurements were taken at 27 ° C unless otherwise specified; the following abbreviations were used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublets; bs, broad sign. in general, the isolated compounds were also characterized by mass spectroscopy after liquid chromatography, using a Waters UPLC equipped with a Waters SQ or QDa mass spectrometer (Temp, column 30 ° C or 40 ° C, UV = 220-300 nm or 210-400 nm or 190-400 nm, Mass Spec = ESI with positive / negative exchange) at a flow rate of 1 mL / min using a solvent system of 97% A + 3% B to 3% A + 97% B over 1.50 min (total processing time with equilibration again for starting conditions, etc., 1.70 min), where A = 0.1% formic acid or 0.05% trifluoroacetic acid in water (for acidic handling) or 0.1% ammonium hydroxide in water (for basic handling) and B = acetonitrile. For acidic analysis the column used was a Waters Acquity HSS T3 (1.8 pm, 2.1 x 50 mm or 2.1 x 30 mm), or a Waters Acquity BEH C18 (1.7 pm, 2.1 x 50 mm or 2.1 x 30 Petition 870190094446, of 9/20/2019, p. 46/81 31/61 mm), for pH-medium analysis, a Waters Acquity BEH C18 column (1.7 pm, 2.1 x 50 mm) was used and for basic analysis a Waters Acquity BEH C18 column (1.7 pm) was used , 2.1 x 50 mm or 2.1 x 30 mm). Alternatively, a solvent gradient of 2 to 98% B was used over 1.5 min (total run time with equilibrium back to starting conditions 2 min), where A = 0.1% formic acid in water and B = 0.1% formic acid in acidic acetonitrile) or A = 0.1% ammonium hydroxide in water and B = acetonitrile (for basic handling). Alternatively, a solvent gradient of 92% A + 5% B + 3% C to 7% A + 90% B + 3% C or 90% A + 5% B + 5 % D to 5% A + 90% B + 5% D over 3.6 min (total cycle time with equilibration back to initial conditions, etc., 5.1 min), where A = water, B = acetonitrile, C = 1% TFA in water and D = 250 mM ammonium acetate in water; the reported molecular ion corresponds to [M + H] +, unless otherwise specified; for molecules with multiple isotopic patterns (Br, Cl, etc.), the reported value is the one obtained with the highest intensity, unless otherwise specified. in general, the purity in wt% of the compounds was determined against an appropriate internal reference standard (eg 1,2,4,5-tetrachloro-3-nitrobenzene, maleic acid or benzyl benzoate) by proton NMR under quantitative conditions. large-scale reactions were carried out in reactors equipped with heat transfer liners and served with appropriate auxiliary equipment; and the following abbreviations were used: MeCN acetonitrile aq. aqueous conc. focused DCM dichloromethane Petition 870190094446, of 9/20/2019, p. 47/81 32/61 di-t-GMP 1,1'-bis (di-tert-butylphosphino) ferrocene DIBAH diisobutylaluminum hydride DMAP 4-dimethylaminopyridine DMF N, N-dimethylformamide DMF-DMA Ν, Ν-dimethylformamide dimethylacetal DMSO dimethylsulfoxide and is. enantiomeric excess ES electrospray mode HPLC high performance liquid chromatography IPA Isopropyl Alcohol LAH lithium and aluminum hydride MS mass spectrometry MTBE tert-butyl methyl ether NBS N-bromosuccinimide NMR nuclear magnetic resonance PMB 4-methoxybenzyl TFA trifluoroacetic acid THF tetrahydrofuran UPLC ultra-performance liquid chromatography % by weight percentage by weight Intermediate 1: (2- (2- (2-bromo-3-chlorophenyl) hydrazone) E / Z hexanedioate) -dimethyl [0063] A mixture of 2-bromo-3-chloroaniline (2.00 kg, 9.69 mol), hydrochloric acid (36% by weight, 4.85 L, 58.1 mol) and water (5 L) stirred for 1 h. The resulting solution was cooled to 0 ° C, then a solution of NaNÜ2 (702 g, 10.2 mol) in water (2.4 L) was gradually added over 1 h at 0-5 ° C. After stirring for 1 h, Petition 870190094446, of 9/20/2019, p. 48/81 33/61 Methyl 2-oxocyclopentane-1-carboxylate (1.38 kg, 9.69 mol) was gradually added at 0-5 ° C. Then, a solution of KOAc (13.3 kg, 136 mol) in water (20 L) was added gradually. The resulting solution was allowed to react for an additional 45 min at 0-5 ° C. The solution was then extracted three times with DCM (12 L per extraction). The combined organic extracts were washed with brine (10 L) and then loaded into another reactor containing a solution of conc. (4.75 kg, 48.5 mol) in MeOH (3.1 kg). The resulting solution was allowed to react for 3 h at 10-20 ° C. The solution was concentrated to about 8 L and then two cycles of addition of MeOH (18 L per cycle) were completed and the solvent was distilled (18 L per cycle) under reduced pressure. The resulting suspension was cooled to 0-10 ° C, stirred for 1 h and then filtered. The solid was washed with MeOH (2 x 2 L) and then dried in an oven under reduced pressure to give E (Z (2- (2- (2-bromo-3-chlorophenyl) hydrazone) hexanedioate) -dimethyl , (Intermediate 1, 3.3 kg, 94% by weight, 82%); m / z (ES +), [M + H] + = 391. 1 H NMR (500 MHz, CHLOROPHOROMY, 27 ° C) δ 1.98 (m, 2H), 2.41 (t, 2H), 2, 59 (t, 2H), 3.66 (s, 3H), 3.87 (s, 3H), 7.05 (dd, 1H), 7.17-7.23 (m, 1H), 7.49 (dd, 1H), 12.48 (s I, 1H). Intermediate 2: 7-Bromo-6-chloro-3- (3-methoxy-3-oxopropyl) -1 methyl H-indole-2carboxylate cr [0064] A solution of (2- (2- (2-bromo-3 -chlorophenyl) hydrazone) E / Z hexanedioate) -dimethyl (Intermediate 1, 3.3 kg, 93.7% by weight, 7.9 mol) in conc. (8.4 kg, 84 mol) and MeOH (26 L) was stirred for 72 h at 80 ° C. The reaction mixture was cooled to 0 ° C. The resulting solids were collected by filtration, washed with Petition 870190094446, of 9/20/2019, p. 49/81 34/61 MeOH (2 L) and then dried in a vacuum oven at 40 ° C to give 2.5 kg of solid. The solid was combined with 3 other batches prepared in the same manner on approximately the same scale, to give a total of 11.9 kg of unpurified product, derived from 13.6 kg (93.7% by weight, 32.5 mol) of the starting material. [0065] Half of the unpurified product was added to MeOH with stirring (36 L). The mixture was heated to 65 ° C and the resulting solution was kept at 65 ° C for 1 h before being cooled to 0 ° C. The resulting suspension was stirred at 0 ° C for 1 hour and then filtered. The filter cake was washed with MeOH (3 L) and dried in a vacuum oven at 40 ° C. This was repeated with the remaining material and the materials were combined to give 9.7 kg of solid. 3.7 kg of this was mixed with charcoal (0.74 kg), DCM (3.4 L) and MeOH (34 L) and the sludge was heated to 65-70 ° C for 1 h. The suspension was cooled to 55 ° C and filtered. The filter cake was washed with DCM (10 L) and then the combined filtrates were concentrated to about 8 L by distillation of the solvent in vacuo. Two cycles of addition of MeOH (10 L) and distillation of the solvent (10 L) under vacuum were completed and then the resulting suspension was combined with other suspensions prepared similarly from the remaining solid. The combined suspension was cooled to 0 ° C and stirred for 1 h before being filtered. The filter cake was washed with MeOH (3 L) and dried in a vacuum oven at 40 ° C to produce 7-bromo-6-chloro-3- (3-methoxy-3-oxopropyl) 1 H-indole-2 methyl carboxylate (Intermediate 2, 9.4 kg, 97.7% by weight, 76%); m / z (ES +), [M + H] + = 374. 1 H NMR (500 MHz, DMSO-cfe, 27 ° C), δ 2.60 (t, 2H), 3.26 (t, 2H) , 3.53 (s, 3H), 3.89 (s, 3H), 7.28 (d, 1H), 7.73 (d, 1H), 11.62 (s I, 1H). Intermediate 3: 4-Bromo-3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-1Hpyrazole Petition 870190094446, of 9/20/2019, p. 50/81 35/61 Br [0066] LAH (1.05 M in THF, 15.0 kg, 17.4 mol) was gradually added to a stirred solution of ethyl 1,5-dimethyl-1H-pyrazol-3-carboxylate (5.33 kg , 31.7 mol) in THF (10.7 L) for 1.5 h at 423 ° C, followed by THF (1.0 L). After 30 min, the solution was cooled to 15 ° C, then, while continuing to cool, a solution of water (0.66 L, 37 mol) in THF (1.9 L) was gradually added over 20 min. Aq. (15% by weight, 0.66 L, 2.8 mol) over a few minutes, followed by water (2.0 L). The resulting suspension was stirred for 20 minutes at 4-11 ° C and then filtered with suction. The collected solids were washed four times with THF (10.7 L per wash) to give (1,5-dimethyl-1H-pyrazol-3-yl) methanol as a solution in the collected filtrates. [0067] The reactor was washed with 1 M HCI, water and THF before loading the filtrates again. Three portions of NBS (1.82 kg per portion, 99.4% by weight, 30.6 mol in total) were loaded, stirring for 7-8 min at 19-27 ° C between portions and then for 45 min, then at 21-28 ° C. A solution prepared from Na2SO 3 (0.81 kg, 99% by weight, 6.4 mol), NaOH (50% by weight in water, 4.6 kg, 57 mol) and water (16 L) was then added and the resulting mixture was stirred for 10 min at 25 -26 ° C. The layers were separated and the bottom layer was washed with THF (16 L). The upper layers were combined and evaporated to dryness to give (4-bromo-1,5-dimethyl-1Hpyrazol-3-yl) methanol as a solid. [0068] This unpurified (4-bromo-1,5-dimethyl-1H-pyrazol-3-yl) methanol was redissolved in THF (18.8 L) and heated with stirring at 50 ° C, then tetrabutylammonium bisulfate ( 0.32 kg, 0.95 mol), 1 (chloromethyl) -4-methoxybenzene (5.4 L, 97.6% by weight, 40 mol) and a THF line wash (2.8 L) were added. Gradu added Petition 870190094446, of 9/20/2019, p. 51/81 36/61 KOH (45% by weight, 13.7 L, 159 mol) over 45 min for the vigorously stirred mixture at 47-57 ° C, before continuing to stir for 4 h at 55-50 ° C. The mixture was then cooled to 20 ° C and kept stirring for 63 hours. The mixture was reheated to 50 ° C, water (18.7 L) was added and the mixture was stirred for 10 min. The bottom layer was removed and the solution remaining in the reactor was cooled to 20 ° C. 4-bromo-3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-1H-pyrazole (0.01 kg, 0.03 mol) was added as a crystallization seed followed by heptane (32 L), gradually over 45 min, during which crystallization started. The suspension was maintained with stirring for 30 min at 20 ° C before gradually charging more heptane (22 L) over 45 min and cooling to 0 ° C. After 17 h, more heptane (11 L) was added. After an additional 1 h at 0 ° C, the suspension was filtered under suction. The filter cake was washed with a cooled (0 ° C) mixture of heptane (17 L) and THF (4.3 L) and then dried in a vacuum oven at 40 ° C to give 4-bromo-3- ( ((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-1H-pyrazole (Intermediate 3, 8.78 kg, 96% by weight, 82%); m / z (ES +), [M + H] + = 325. 1 H NMR (500 MHz, DMSO-cfe, 27 ° C) δ 2.22 (s, 3H), 3.74 (s, 3H), 3.75 (s, 3H), 4.32 (s, 2H), 4.39 (s, 2H), 6.87 - 6.93 (m, 2H), 7.22 - 7.27 (m, 2H). Intermediate 4: 3 - ((((4-Methoxybenzyl) oxy) methyl) -1,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H-pyrazole The 0 B PMBO \ / NN [0069] Butyl lithium (15% by weight in hexane, 7.27 kg, 17.3 mol) was gradually added to a stirred suspension of 4-bromo-3 - ((((4 methoxybenzyl) oxy) methyl) -1 , 5-dimethyl-1 H-pyrazole (Intermediate 3, 5.27 kg, 96% by weight, 15.6 mol) in THF (43 L) at -73 ° C to -66 ° C for Petition 870190094446, of 9/20/2019, p. 52/81 37/61 1.5 h. The resulting solution was stirred for 1.7 h at -77 ° C to -66 ° C, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.4 L, 16 mol), followed by a THF line wash (3.0 L), was added over 15 min. The solution was stirred for 1.5 h at -77 ° C to -63 ° C, then a solution of acetic acid (0.89 L, 16 mol) in toluene (25.3 L) was gradually added over 15 min at -77 ° C to 58 ° C. The mixture was then heated to 20 ° C before heating and distilling the solvent (48 L) to 67-82 ° C (atmospheric pressure). The mixture was cooled to 65 ° C, water (25.5 L) was added and the mixture was stirred for 10 min. The bottom layer was removed and then more solvent (25.4 L) was removed by distillation at 72-119 ° C (atmospheric pressure; final steam temperature 108 ° C). The resulting solution was cooled to 40 ° C and diluted with heptane (50.6 L) over 10 min, during which time the mixture was cooled to 21 ° C and spontaneous crystallization started. 3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (29 g) was then added as a seed. The suspension was stirred at approximately 21 ° C for 0.6 h, cooled to approximately -5 ° C for 1.5 h, then kept overnight (18 h) at that temperature. The suspension was filtered under suction then the filter cake was washed with cold heptane (~ 0 o) before drying in a vacuum oven at 40 ° C to give 3 - (((4-methoxybenzyl) oxy) methyl) - 1,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (Intermediate 4, 4.50 kg, 99% by weight, 77 %); m / z (ES +), [M + H] + = 373. 1 H NMR (500 MHz, DMSO-cfe, 27 ° C) δ 1.23 (s, 12H), 2.34 (s, 3H), 3.68 (s, 3H), 3.73 (s, 3H), 4.40 (s, 2H), 4.42 (s, 2H), 6.85 - 6.91 (m, 2H), 7 , 20 - 7.25 (m, 2H). Intermediate 5: 6-Chloro-3- (3-methoxy-3-oxopropyl) -7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-1H-pyrazol-4-yl) (±) methyl -1H-indole-2-carboxylate Petition 870190094446, of 9/20/2019, p. 53/81 38/61 [0070] 3 - ((((4-Methoxybenzyl) oxy) methyl) -1,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -pyrazole (Intermediate 4, 3.30 kg, 99% by weight, 8.78 mol), 7-bromo-6-chloro-3- (3-methoxy-3-oxopropyl) -1-Methylindol-2-carboxylate ( Intermediate 2, 3.20 kg, 97.7% by weight, 8.35 mol), K2CO3 (1.60 kg, 11.6 mol) and 1,1'-bis (di-tertbutylphosphine) ferrocene-palladium dichloride (0.132 kg, 0.203 mol) were loaded into a 100 L reactor under nitrogen. The top space of the reactor was then evacuated and again filled with nitrogen three times. 1.4Dioxane (26.3 L) and water (3.3 L) were sparged with nitrogen under reduced pressure for 5-10 min, before being added sequentially and the resulting mixture was heated to 80 ° C with stirring for 5 h . The reaction mixture was cooled to 20 ° C and kept overnight (16 h) before diluting with MTBE (33 L) and water (33 L). / V-acetylcysteine (0.165 kg, 1.01 mol) was added and the mixture was stirred for 15 min. The bottom layer, once seated, was removed. The upper layer was then washed sequentially with hydrochloric acid (37% by weight, 2.7 L, 33 mol) in water (30 L) and then water (32 L) to give a 6-chloro-3- MTBE solution (3-methoxy-3oxopropyl) -7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-1H-pyrazol-4-yl) 1 ± H-indole-2-carboxylate ) -methyl (Intermediate 5, 22.9 kg, 19.1% by weight, 97%). Intermediate 6: (±) -3- (2-Carboxyethyl) -6-chloro-7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-1 H-pyrazole-4- il) -1-methyl-1 H-indole-2-carboxylic Petition 870190094446, of 9/20/2019, p. 54/81 39/61 [0071] A 6-chloro-3- (3-methoxy-3-oxopropyl) 7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-d imethyl-1 H- MTBE solution pyrazol-4-yl) -1 (±) -methyl H-indole-2carboxylate (Intermediate 5, 22.94 kg, 19.1% by weight, 8.12 mol) was stirred with a palladium-based scavenger silica functionalized with mercaptopropyl (Quadrasil ™ MP, 1.1 kg) and toluene (44 L) at 20 ° C for 1 h. The suspension was filtered and the residual solids were washed with toluene (13 L). The combined filtrates were concentrated by distillation of the solvent (44 L) at 75-107 ° C. DMFDMA (5.5 L, 41 mol) was then added at 91 ° C. The solution was heated to reflux, maintained for 22 h at approximately 108 ° C, during which four portions of solvent (2, 4.5, 4.5 and 4.4 L) were distilled (immediately after reaching reflux, after 2.0, 3.4 and 4.8 h) and then cooled to 55 ° C. A solution of NaCI (2.2 kg) in water (20 l) was charged, then the resulting biphasic mixture was removed from the vessel and filtered again through a 5 pm in-line filter. The sieved mixture was stirred at 50-53 ° C for 10 min and then, once settled, the bottom layer was removed. MeOH (22 L) and a solution of aq. (3.3 kg, 50% by weight, 41 mol) in water (18 L) were added and the resulting biphasic mixture was stirred at 55 ° C for 3 h. After laying, the layers were removed into separate containers. The bottom layer (containing the product) was then returned to the reactor and stirred at 55 ° C. The solution of acetic acid (4.6 kg, 77 mol) in water (4.4 L) was then gradually added over 25 min, followed by a 3- (2-car acid) crystallization seed Petition 870190094446, of 9/20/2019, p. 55/81 40/61 boxietyl) -6-chloro-7- (3 - ((((4-methoxybenzyl)) oxy) methyl) -1,5-dimethyl-1H-pyrazole- 4-yl) -1-methyl-1H-indole-2-carboxylic (0.02 kg, 0.04 mol). The mixture was kept at 49-56 ° C for 2 h, cooled to 20 ° C for 2 h and then maintained at 20 ° C for 13 h. The resulting suspension was filtered under suction. Water (11 L) was used to wash the reactor and the filter cake, which was then partially dried on the filter, continuing suction for 6 h at room temperature and completely dried in a vacuum oven at 40 ° C to give acid ( ±) -3- (2-carboxyethyl) -6-chloro-7- (3 - ((((4methoxybenzyl) oxy) methyl) -1,5-dimethyl-1 H-pyrazol-4-yl) -1 -methyl- 1 H-indole-2-carboxylic (Intermediate 6, 3.78 kg, 99.0% by weight, 86%); m / z (ES +), [M + H] + = 526. 1 H NMR (500 MHz, DMSO-cfe, 27 ° C) δ 2.01 (s, 3H), 2.50 - 2.57 (m , 2H), 3.18 - 3.29 (m, 2H), 3.40 (s, 3H), 3.68 (s, 3H), 3.82 (s, 3H), 4.08 (d, 1H), 4.14 (d, 1H), 4.19 (d, 1H), 4.21 (d, 1H), 6.64 - 6.69 (m, 2H), 6.69-6.74 (m, 2H), 7.25 (d, 1H), 7.75 (d, 1H), 12.71 (s I, 1H). Intermediate 7: (R a ) -3- (2-carboxyethyl) -6-chloro-7- (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-1 H-pyrazole-4 acid -yl) -1-methyl-1 H-indole-2-carboxylic - (1R) -1- (2-nitrophenyl) ethanamine (salt 1: 1) PMBO [0072] NaOH (50% by weight in water, 0.95 L, 18 mol), followed by a wash with ethanol (1.8 L), was added to a stirred suspension of (±) -3- acid (2 -carboxyethyl) -6-chloro-7- (3 - ((((4-methoxybenzyl) oxy) methyl I) -1,5-d imethyl I-1H-pyrazol-4-i I) -1-methyl-1 H -indol-2-carboxylic (Intermediate 6, 9.38 kg, 97.5 (wt%, 17.4 mol) and (1 / ) 1- (2-nitrophenyl) ethanamine hydrochloride (2.48 kg, 91% by weight, 11.1 mol) in water Petition 870190094446, of 9/20/2019, p. 56/81 41/61 (7.4 kg) and ethanol (64 L) at 20 ° C. While, heating the resulting solution to 78 ° C, spontaneous crystallization of the product (at or below 41 ° C) began. After heating to 78 ° C, three cycles of cooling the suspension to 63 ° C for 1.3 h were completed, heating back to 78 ° C for 0.6 h and maintenance for 10 min. The suspension was then cooled to 63 ° C for 1.2 h, then to 20 ° C for 1.6 h, before being maintained at 20 ° C overnight and then filtered under suction. Ethanol (18 L) was used to wash the reactor and the filter cake. Once well dehumidified, the filter cake was returned to the reactor. (This solid is typically approximately 92% ee of the desired di-acid). Water (7.3 L) and ethanol (66 L) were charged and the reactor contents were heated with stirring at 78 ° C. The resulting suspension was cooled to 63 ° C for 1.3 h, then to 20 ° C for 1.6 h, before being maintained at 20 ° C overnight and then filtered under suction. Ethanol (18 L) was used to wash the reactor and the filter cake. The filter cake was dried in a vacuum oven at 40 ° C to give (R a ) -3- (2-carboxyethyl) -6-chloro-7- (3 - ((((4 methoxybenzyl) oxy) methyl) - 1,5-dimethyl-1 H-pyrazol-4-yl) -1-methyl-1 H-indole-2-carboxylic - (1R) -1- (2-nitrophenyl) ethanamine (salt 1: 1) (Intermediate 7, 5 , 23 kg, 97.5% by weight, 99.0% ee, 7.36 mol) in 42.3% yield; m / z (ES +), [M + H] + = 526 (acid), 167 (amine). 1 H NMR (500 MHz, DMSO-cfe, 27 ° C) δ 1.49 (d, 3H), 2.00 (s, 3H), 2.61 (t, 2H), 3.10 3.22 ( m, 2H), 3.38 (s, 3H), 3.68 (s, 3H), 4.11 (d, 1H), 4.14 (d, 1H), 4.17 (d, 1H), 4.22 (d, 1H), 4.66 (q, 1H), 6.67 - 6.72 (m, 2H), 6.75 - 6.80 (m, 2H), 7.18 (d, 1H), 7.54 - 7.60 (m, 1H), 7.63 (d, 1H), 7.76 - 7.82 (m, 1H), 7.90-7.94 (m, 1H) , 7.93-7.97 (m, 1H), 9.16 (s I, 3H). [0073] Details of the HPLC method for chiral purity analysis: column = Chiralpak AD-H (4.6 x 250 mm, 5 pm); temperature = 25 ° C; mobile phase = 70: 30 hexane: ethanol by volume containing 0.2% TFA, flowing at 1.0 mL / min; UV detection at 254 nm; inj volume. = 10 pl_ Petition 870190094446, of 9/20/2019, p. 57/81 42/61 (this can be adjusted to achieve an appropriate detection limit); retention times of 4.8 and 13.7 min for the R a and S a enantiomers, respectively. Intermediate 8: 6-Chloro-7- (3- (hydroxymethyl) -1,5-dimethyl-1 H-pyrazol-4-yl) 3- (3-methoxy-3-oxopropyl) -1-methyl-1 H- (R a ) -methyl indole-2-carboxylate [0074] Hydrochloric acid (37% by weight, 0.77 L, 9.2 mol) was added to a stirred suspension of (R a ) -3- (2-carboxyethyl) -6-chlorine-7 (3 - ((((4-methoxybenzyl) oxy) methyl) -1,5-dimethyl-1 H-pyrazol-4-yl) -1-methyl-1 H-indole-2-carboxylic - (1R) -1- (2 -nitrophenyl) ethanamine (salt 1: 1) (Intermediate 7, 5.23 kg, 97.5% by weight, 7.36 mol) in THF (20.5 L) and water (20.5 L) at 45 ° Ç. After 5 min, toluene (41 L) was added and the mixture was stirred for 10 min. The lower layer was removed and the upper layer was diluted with toluene (20.5 L) and concentrated by distillation of the solvent (60 L) under reduced pressure (590 mbar) at 48-92 ° C. DMF-DMA (3.45 L, 25.8 mol) was added to the resulting mixture at 90 ° C, yielding a solution that was heated to reflux, held at reflux (98 ° C) for 8 h, then cooled and maintained at 49 ° C for 16 h. DMF-DMA (1.0 L, 7.5 mol) was added and the mixture was refluxed at 100 ° C for an additional 3.6 h before cooling to 50 ° C. Water (12.7 L) was added and the mixture was stirred for 15 min. The bottom layer has been removed. MeOH (20 L) was added to the top layer, followed by a gradual addition of 10 min of acetyl chloride (2.15 L, 29.9 mol) to the stirred solution. The solution was heated to 60 ° C for 21 h and then transferred to containers. Toluene (10 L) and Petition 870190094446, of 9/20/2019, p. 58/81 43/61 K2CO3 (2.56 kg, 18.4 mol) in water (20.5 L) was loaded into the empty reactor and the mixture was heated to 55 ° C. The completed reaction solution was then gradually added back to the reactor over 20 min, followed by a wash with toluene (10 L). Stirring was stopped after a further 10 min at 55 ° C and, once stabilized, the bottom layer was removed. The upper layer was concentrated by distillation of the solvent (21 L) under reduced pressure (540 mbar) at 55-93 ° C. The solution was diluted with heptane (10 L) at 50 ° C and then seeded with 6 chloro-7- (3- (hydroxymethyl) -1,5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy (R a ) -methyl-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (16 g, 0.037 mol). After allowing crystallization to settle for 1 h at 50 ° C, more heptane (20 L) was gradually added over 1 h. The suspension was then cooled to 20 ° C for 2 h and stirred for 65 h before being filtered under suction. The filter cake was washed with heptane (10 L) and then dried in a vacuum oven at 40 ° C to give 6-chloro-7- (3- (hydroxymethyl) -1,5-dimethyl-1H-pyrazol-4-yl ) (R a ) -methyl (3-methoxy-3-oxopropyl) -1-methyl-1H-indol-2-carboxylate (Intermediate 8, 2.85 kg, 98% by weight, 87%); m / z (ES +), [M + H] + = 434. 1 H NMR (500 MHz, DMSO-cfe, 27 ° C) δ 1.95 (s, 3H), 2.57 - 2.64 (m , 2H), 3.17 - 3.33 (m, 2H), 3.44 (s, 3H), 3.57 (s, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 4.13 (dd, 1H), 4.23 (dd, 1H), 4.72 (dd, 1H), 7.26 (d, 1H), 7.72 (d, 1H). Intermediate 9: 6-Chloro-7- (3- (hydroxymethyl) -1,5-dimethyl-1 H-pyrazol-4-yl) 3- (3-hydroxypropyl) -1-methyl-1 H-indole-2- (R a ) -methyl carboxylate [0075] 6-Chlorine-7- (3- (hydroxymethyl) -1,5-d imethyl-1 H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H- (R a ) -methyl indol-2-carboxylate (In Petition 870190094446, of 9/20/2019, p. 59/81 44/61 termediary 8, 2.25 kg, 98% by weight, 5.08 mol) was dissolved in THF (13.3 L) and the resulting solution was cooled to -45 ° C. DIBAH (20.3% by weight in hexane; 11.0 kg, 15.7 mol) was then added over 1.1 h at or below -41 ° C. The reaction mixture was maintained at approximately -45 ° C for an additional 4.4 h, during which time three other portions of DIBAH (20.3% in hexane; 1.32; 0.25 and 0.07 kg; 1, 88; 0.36 and 0.10 mol) were added after 1.4, 2.8 and 3.7 h. IPA (2.2 L, 29 mol) was then added to the reaction mixture, before heating at 20 ° C for 2 h and maintaining at that temperature for 2.5 h. [0076] Meanwhile, in another reactor, sodium tartrate and potassium tetrahydrate (6.47 kg, 22.9 mol) and water (22 L) were loaded. After a few minutes of stirring at 20 ° C, a solution was formed and then isopropyl acetate (22 L) was added. The resulting biphasic mixture was heated to 50 ° C. [0077] The ester reduction reaction mixture was transferred to the vigorously stirred aqueous tartrate and isopropyl acetate mixture at 50 ° C for 20 min, followed by a THF rinse (1.5 L). Vigorous stirring was continued at 50 ° C for 1.9 h. The bottom layer has been removed. The top layer was washed with water (4.45 L), then removed and filtered back to the reactor through a 5 pm in-line filter, followed by an in-line wash with 1.1 L of isopropyl acetate. The solution was concentrated by distillation of the solvent (32 L) at 58-74 ° C (atmospheric pressure) and then cooled to 20 ° C. The solution was transferred to a smaller container, followed by an in-line wash with isopropyl acetate (1.1 L) and then continued to be concentrated (to approximately 9 L) by distilling more solvent (15 L) at 73- 85 ° C (atmospheric pressure). The stirring solution was then cooled to 70 ° C, seeded with 6-chloro-7 (3- (hydroxymethyl) -1,5-d imethyl I-1 H-pyrazol-4-yl) -3- (3- h id roxi propi I) -1-methyl1 H -indole-2-carboxylate (/ a ) -methyl (2 g, 97.9% by weight, 5 mmol), Petition 870190094446, of 9/20/2019, p. 60/81 45/61 cooled to 20 ° C for 1 h and maintained at 20 ° C for 24 h. The resulting suspension was filtered under suction. The filter cake was washed with isopropyl acetate (2.2 L) and then dried in a vacuum oven at 40 ° C to give 6-chloro-7- (3- (hydroxymethyl) -1,5-dimethyl-1 (Ra) -methyl H-pyrazol-4-yl) 3- (3-hydroxypropyl) -1-methyl-1 (Intermediate 9, 1.76 kg, 98.0% by weight, 84%); m / z (ES +), [M + H] + = 406. 1 H NMR (500 MHz, DMSO-cfe, 27 ° C) δ 1.68 - 1.77 (m, 2H), 1.96 (s , 3H), 2.93 - 3.05 (m, 2H), 3.43 (s, 3H), 3.42 - 3.48 (m, 2H), 3.80 (s, 3H), 3, 84 (s, 3H), 4.14 (dd, 1H), 4.23 (dd, 1H), 4.48 (t, 1H), 4.71 (dd, 1H), 7.25 (d, 1H ), 7.71 (d, 1H). Intermediate 10: Methyl 5- (Chloromethyl) -1-methyl-1 H-pyrazol-3-carboxylate [0078] Sodium carbonate (2.14 kg, 20.2 mol) was added to a stirred solution of dimethyl 1-methyl-1 H-pyrazol-3,5-dicarboxylate (7.95 kg, 40.1 mol) in MeOH (80 L) at 20 ± 5 ° C. The suspension was stirred for 0.5 h and then filtered. The filter cake was washed with 2-methylTHF (16 L) and then the filtrates returned to the reactor, followed by 2-methylTHF (24 L). The solution was cooled to 15 ± 3 ° C and sodium borohydride (3.05 kg, 80.7 mol) was loaded in ten portions at 15 ± 3 ° C. The mixture was stirred for 2 h at 18 ± 3 ° C after the addition of NaBH4. It was then gradually quenched by loading acetone (16.4 kg, 283 mol) at 18 ± 3 ° C, then stirred for 1 h at 20 ± 5 ° C. Aq. (37% by weight, ~ 8.6 kg, 87 mol) was then added slowly, keeping the temperature below 30 ° C, to adjust the pH to 2-3, then the mixture was stirred for 1 h. Na2CO 3 aq. (~ 4 L) was then slowly added to adjust the pH to 5-6, then the mixture was stirred for 3 h. The mixture was filtered and the filter cake was washed with DCM (16 L). The filtrates were concentrated to Petition 870190094446, of 9/20/2019, p. 61/81 46/61 approximately 20 L by distillation under reduced pressure, not heating above 40 ° C, then diluted with DCM (40 L) and concentrated again by distillation of the solvent (approx. 40 L) under reduced pressure. DCM (80 L) and purified water (32 L) were charged and the resulting mixture was stirred for at least 10 min. The lower (organic) phase was collected and the upper (aqueous) phase was extracted four times with more DCM (40 L per serving). The combined organic phases were concentrated to approximately 20 L by vacuum distillation below 40 ° C. DCM (80 L) was added and the solution was again concentrated by distillation of the solvent (approx. 40 L). The resulting methyl 5- (hydroxymethyl) -1-methyl-1H-pyrazol-3-carboxylate solution was then diluted with DCM (80 L) and cooled to 10 ± 5 ° C, after which the thionyl chloride (4.80 kg, 40.4 mol) was added gradually, keeping the temperature below 15 ° C. The mixture was then stirred for 1 h at 20 ± 5 ° C. The mixture was concentrated to no more than 20 L by vacuum distillation below 40 ° C, then DCM (64 L) and purified water (80 L) were added. After phase separation, the lower (organic) phase was washed twice with aq. (9% by weight, 80 L per serving) and then with purified water (80 L). The washed organic phase was concentrated to approximately 14 L by vacuum distillation below 40 ° C. Two cycles of slow addition of heptane (40 L) and then vacuum distillation to approximately 24 L at less than 45 ° C were then completed. More heptane (40 L) was added and the resulting suspension was stirred at 20 ± 5 ° C for at least 0.5 h before filtration. The filter cake was washed with heptane (8.0 L) and then dried in a vacuum oven at 45 ° C to give methyl 5- (chloromethyl) -1-methyl-1H-pyrazol-3-carboxylate (Intermediate 10 , 4.87 kg, 64%); m / z (ES +), [M + H] + = 189. 1 H NMR (500 MHz, CDCb, 27 ° C) δ 3.91 (s, 3H), 3.99 (s, 3H), 4, 59 (s, 2H), 6.82 (s, 1H). Petition 870190094446, of 9/20/2019, p. 62/81 47/61 Intermediate 11: 3- (acetylthio) naphthalen-1-yl acetate OAc [0079] A stirred mixture of MeCN (102 L), sodium 4-hydroxynaphthalene2-sulfonate (17.00 kg, 69.05 mol), triphenylphosphine (65.1 kg, 248 mol) and iodine (14.0 kg , 55.2 mol) was heated to 80 ± 5 ° C for 6 h. The mixture was cooled and stirred at 0 ± 5 ° C for at least 2 hours. Residual solids were removed by filtration to give the crude 3-mercaptonaphthalene-1-ol dissolved in the filtrates (also containing a large amount of triphenylphosphine oxide), which were refilled in the reactor followed by DMAP (0.84 kg, 6, 9 mol). Keeping the temperature below 25 ° C, triethylamine (21.0 kg, 207 mol) and then acetic anhydride (17.6 kg, 173 mol) were gradually added. The mixture was stirred for 2 h at 15-20 ° C and then distilled under reduced pressure to less than 85 L, not heating above 45 ° C. DCM (85 L) was added and then the mixture was distilled under reduced pressure to less than 85 L, not heating above 40 ° C. More DCM (170 L) was added and then the mixture was washed with water (170 L), followed by aq. (17% by weight, 170 L). The lower organic phase was distilled under reduced pressure to less than 51 L, not heating above 40 ° C. Then, three cycles of diluting the solution with MeOH (85 L) and distillation under reduced pressure to less than 51 La under 40 ° C were completed to give a methanolic solution of 3- (acetylthio) naphthalen-1-yl (Intermediate 11), 40.9 kg, 31.3% by weight, 49.2 mol) with 71% yield. The solution, which also contains a large amount of triphenylphosphine oxide, was used directly in the preparation of Intermediate 12. Intermediate 12: 5 - ((((4-Hydroxinaftalen-2-yl) thio) methyl) -1-methyl-1H-pyrazol-3-carboxylate Petition 870190094446, of 9/20/2019, p. 63/81 48/61 [0080] 3- (Acetylthio) naphthalen-1-yl acetate (Intermediate 11, 40.9 kg, 31.3% in methanol, 49.2 mol), methanol (64 L) and K2CO3 (13.6 kg, 98.4 mol) were stirred at 15-20 ° C. Methyl 5 (chloromethyl) -1-methyl-1H-pyrazol-3-carboxylate (Intermediate 10, 7.40 kg, 39.2 mol) was added dropwise maintaining the temperature below 25 ° C. The suspension was then stirred for 2 h at 20-25 ° C. In response to the HPLC analysis, four more portions of methyl 5- (chloromethyl) -1-methyl-1 Hpyazol-3-carboxylate (Intermediate 10, 0.46 kg, 2.4 mol, per serving) were loaded, stirred for 1 h at 20-25 ° C after each serving. Purified water (109 L) was gradually added at 15-20 ° C, the resulting mixture was stirred for at least 2 h, then left to settle for at least 3 h. The liquors were removed via tubing, leaving the sticky solids sedimented in the reactor, to which was then added ethanol (25.5 L). The mixture was stirred for at least 1 h at 15 ± 5 ° C before filtering the obtained suspension. The filter cake was washed with ethanol (6.4 L) and then dried in a vacuum oven at 45 ± 5 ° C to give 5 - ((((4-hydroxynaphthalen-2yl) thio) methyl) -1-methyl- 1 methyl H-pyrazol-3-carboxylate (Intermediate 12, 13.05 kg, 99.3% by weight, 81%); m / z (ES +), [M + H] + = 329. 1 H NMR (500 MHz, DMSO, 27 ° C) δ 3.72 (s, 3H), 3.90 (s, 3H), 4, 39 (s, 2H), 6.63 (s, 1H), 6.79 (d, 1H), 7.28 - 7.32 (m, 1H), 7.38 (ddd, 1H), 7.45 (ddd, 1H), 7.72 (d, 1H), 8.07 (d, 1H), 10.55 (s I, 1H). Intermediate 13: 3 - ((((3- (Hydroxymethyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-ol Petition 870190094446, of 9/20/2019, p. 64/81 49/61 [0081] 5 - ((((4-Hydroxynaphthalen-2-yl) thio) methyl) -1-methyl-1 H-pyrazol-3carboxylate (Intermediate 12, 12.7 kg, 99.3% by weight, 38 , 4 mol) was dissolved in THF (254 L) at 30 ± 5 ° C and then the solution was cooled to 15 ± 5 ° C. DIBAH (1 M in hexane, 155 L, 155 mol) was added slowly while maintaining the temperature at 15 ± 5 ° C. The mixture was then stirred for 0.5 h at 20 ± 5 ° C, analyzed by HPLC, and then gradually transferred to aqueous hydrochloric acid (4 M, 114 L, 456 mol) at 5-20 ° C. The biphasic mixture was vacuum distilled at less than 40 ° C to no more than approximately 120 L. The resulting slurry was cooled to 15 ± 5 ° C, then filtered. The filter cake was washed with purified water (25 L) and then refilled in the reactor, together with DCM (57 L) and THF (6.4 L). After stirring the mixture for at least 10 h at 20 ± 5 ° C, it was filtered. The filter cake was washed with DCM (25 L) and then dried in a vacuum oven at 45 ± 5 ° C to give 3 - (((3- (hydroxymethyl) -1-methyl-1 H-pyrazole-5- il) methyl) thio) naphthalen-1-ol (Intermediate 13, 10.45 kg, 95.5% by weight, 87%); m / z (ES +), [M + H] + = 301. 1 H NMR (500 MHz, DMSO-cfe, 27 ° C) δ 3.77 (s, 3H), 4.28 (s, 2H), 4.37 (s, 2H), 4.87 (s I, 1H), 6.14 (s, 1H), 6.81 (d, 1H), 7.35 (d, 1H), 7.39 ( ddd, 1H), 7.47 (ddd, 1H), 7.72 - 7.75 (m, 1H), 8.03 - 8.06 (m, 1H), 10.34 (s, 1H). Intermediate 14: 3 - ((((3- (Chloromethyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-ol s Petition 870190094446, of 9/20/2019, p. 65/81 50/61 [0082] Methanesulfonyl chloride (6.28 kg, 54.8 mol) was gradually added to a stirred mixture of 3 - (((3- (hydroxymethyl) -1methyl-1H-pyrazol-5-yl) methyl ) thio) naphthalen-1-ol (Intermediate 13, 10.30 kg, 95.5% by weight, 32.7 mol), anhydrous lithium chloride (2.91 kg, 68.6 mol) and DMF (51, 5 L) keeping the temperature below 10 ° C. The mixture was stirred for 2 h at 15-20 ° C. EtOAc (155 L) was then added, followed by purified water (155 L) and the mixture was mixed well. The bottom layer was removed and the top layer was washed twice with aq. (17% by weight; 155 L per serving). The top layer was then vacuum distilled to less than 50 L below 35 ° C. Heptane (155 L) was then added slowly to 30 ± 5 ° C before cooling the mixture to 0-5 ° C. After stirring the suspension for at least 1 hour, it was filtered. The filter cake was washed with heptane (10.3 L) and then dried in a vacuum oven at 30-35 ° C to give 3 (((3- (chloromethyl) -1-methyl-1H-pyrazole-5- il) methyl) thio) naphthalen-1-ol (Intermediate 14, 9.72 kg, 95.3% by weight, 89%); m / z (ES +), [M + H] + = 319. 1 H NMR (500 MHz, CDCh, 27 ° C) δ 3.80 (s, 3H), 4.07 (s, 2H), 4, 50 (s, 2H), 6.11 (s, 1H), 6.70 (d, 1H), 7.38 - 7.42 (m, 1H), 7.45 - 7.52 (m, 2H) , 7.52 (b, 1H), 7.68-7.74 (m, 1H), 8.16 - 8.20 (m, 1H). Intermediate 15: 3 - ((((3- (chloromethyl) -1-methyl-1H-pyrazol-5yl) methyl 1) thio) naphthalen-1-yl acetate Cl [0083] Acetic anhydride (3.65 kg, 35.8 mol) was gradually charged to a stirred mixture of 3 - (((3- (chloromethyl) -1-methyl-1H-pyrazole- 5-yl) methyl) thio) naphthalen-1-ol (Intermediate 14, 9.51 kg, 95.3% by weight, 28.4 mol), DMAP (360 g, 2.95 mol) and MeCN (95 L ), keeping the time Petition 870190094446, of 9/20/2019, p. 66/81 51/61 rature below 25 ° C. The mixture was stirred for 2 h at 15-20 ° C. EtOAc (95 L) was then added, followed by aq. (10% by weight, 95 L). After complete mixing, the bottom layer was removed. The top layer was washed with two more portions of aq. (10% by weight, 95 L per serving) and then three cycles of vacuum distillation below 40 ° C to less than 29 L and then addition of MTBE (95 L) were performed. The mixture was vacuum distilled below 40 ° C to less than 48 L, stirred for at least 1 h at about 20 ° C, then cooled to 0-5 ° C. Heptane (95 L) was added slowly and the suspension was stirred at 0-5 ° C for at least 1 hour before filtering. The filter cake was washed with heptane (17 L) and then dried in a vacuum oven at 35-40 ° C to give 3 - (((3- (chloromethyl) -1methyl-1 H-pyrazol-5- acetate) il) methyl) thio) naphthalen-1-yl (Intermediate 15, 8.67 kg, 96.1% by weight, 81%); m / z (ES +), [M + H] + = 361. 1 H NMR (500 MHz, CDCh, 27 ° C) δ 2.46 (s, 3H), 3.82 (s, 3H), 4, 11 (s, 2H), 4.49 (s, 2H), 6.10 (s, 1H), 7.19 (d, 1H), 7.48 - 7.55 (m, 2H), 7.65 - 7.67 (m, 1H), 7.73 - 7.79 (m, 1H), 7.79 - 7.85 (m, 1H). Intermediate 16: 3 - ((((3 - ((acetylthio) methyl) -1-methyl-1H-pyrazol5-yl) methyl) tio) naphthalen-1-yl [0084] Potassium thioacetate (4.15 kg, 36.3 mol) was added to a 3 - ((((3- (chloromethyl) -1-methyl-1H-pyrazol-5yl) methyl) thio acetate mixture) naphthalen-1-yl (Intermediate 15, 8.62 kg, 96.1% by weight, 23.0 mol) and MeCN (86 L), keeping the temperature below 25 ° C. The mixture was stirred for 3 h at 15-20 ° C. EtOAc (86 L) was then added, followed by water (86 L). After complete mixing, the layer Petition 870190094446, of 9/20/2019, p. 67/81 Lower 52/61 has been removed. The top layer was washed with two portions of aq. (15% by weight, 86 L per serving) and then four cycles of vacuum distillation below 40 ° C to less than 29 L and then addition of MTBE (86 L x 3 and 60 L in the final cycle) was performed. The mixture was stirred at 30-35 ° C for at least 1 h, cooled to and then stirred below 10 ° C for at least 1 h, then heptane (86 L) was added slowly. The suspension was cooled to and maintained at 05 ° C for at least 1 h before filtration. The filter cake was washed with heptane (17 L) and then dried in a vacuum oven at 3540 ° C to give 3 - ((((- ((acetylthio) methyl) -1-methyl-1H-pyrazole- acetate). 5yl) methyl) thio) naphthalen-1-yl (Intermediate 16, 8.44 kg, 97% by weight, 89%); m / z (ES +), [M + H] + = 401. 1 H NMR (500 MHz, DMSO-cfe, 27 ° C) δ 2.28 (s, 3H), 2.45 (s, 3H), 3.75 (s, 3H), 3.91 (s, 2H), 4.42 (s, 2H), 6.04 (s, 1H), 7.36 (d, 1H), 7.53 (ddd , 1H), 7.58 (ddd, 1H), 7.82 (d, 1H), 7.85 (d, 1H), 7.90 (d, 1H). Intermediate 17: 17-Chlorine-5,13,14,22-tetramethyl-28-oxa-2,9-dithia- 5,6,12,13,22-penta-azaheptacyclo [27.7.1.1 ν.ο 11 · 15 .Ο 16 · 21 .o 20 · 24 .0 30 · 35 ] octatriaconta-1 (37), 4 (38) , 6,11,14,16,18,20,23,29,31,33,35-tridecaene23-carboxylate of (R a ) - (+) - methyl [0085] A solution of methanesulfonic anhydride (1.20 kg, 6.89 mol) in MeCN (2.5 L) was added to a solution of 6-chloro-7- (3 (h id roximeti I) -1, (Ra) -methyl 5-d imethyl I-1 H-pyrazol-4-yl) -3- (3-h id roxi propyl I) -1-methyl-1Hindol-2-carboxylate (Intermediate 9, 1,19 kg, 97.6%, Petition 870190094446, of 9/20/2019, p. 68/81 53/61 2.86 mol) and / V ^ / V-diisopropylethylamine (1.5 L, 8.6 mol) in THF (8.7 L) over 15 min at 0-30 ° C, followed by an in-line wash with MeCN (0.3 L). The resulting solution was stirred at 20 ° C for 5 h before cooling to approximately -5 ° C. Meanwhile, a Lil solution (1.53 kg, 11.4 mol) was prepared by adding it in portions (0.25 kg per serving) with MeCN (13 L) at less than 30 ° C. The Lil solution was gradually added to the mesylation reaction mixture over 20 min at about -5 ° C, followed by an in-line wash with MeCN (1.2 L). The resulting slurry was heated to 5 ° C and stirred at that temperature for 5 h before being cooled to approximately -15 ° C and maintained for 16 h. Toluene (5.8 L), water (11.6 L) and then a solution of hydrochloric acid (37% by weight, 0.23 L, 2.8 mol) in water (1.1 L) were sequentially added, followed by an in-line wash with water (0.12 L). The temperature of the reaction mixture remained at or below -9 ° C during the additions. The lower layer was removed and water (11.6 L) was added to the upper layer and the resulting mixture was stirred and heated to 0 ° C. The bottom layer was removed and the top layer was washed twice more with water (11.6 L per wash) at approximately 0 ° C, mixing well before settling and removing the bottom layer each time. The washed solution remaining in the reactor was then concentrated by distillation of the solvent (8 L) under reduced pressure (210 to 250 mbar, 30 ° C to 52 ° C), before dilution with MeCN (2.9 L) and reflux for 30 min at 500 mbar in order to completely degass the solution. It was then cooled and held at 0 ° C for 69 h (over the weekend) before repeating the reduced pressure reflux under nitrogen in case of any air intake during the prolonged waiting period. This solution of methyl 6-chloro-7- [3- (iodomethyl) -1,5-dimethyl-pyrazol-4yl] -1-methyl-3- (3-methylsulfonyloxypropyl) indole-2-carboxylate was then cooled to -14 ° C. Petition 870190094446, of 9/20/2019, p. 69/81 54/61 [0086] In parallel, an acetate mixture of 3 - ((((3 - ((acetylthio) methyl) -1-methyl-1 H-pyrazol-5-yl) methyl) thio) naphthalen-1-yl (Intermediate 16, 1.40 kg, 97.8 (% by weight, 3.42 mol) and MeOH (7.25 L) was heated to reflux and held at reflux under nitrogen for 30 min before being cooled to 0 ° C. Methanolic sodium methoxide (25% by weight, 1.6 L, 7.0 mol) was then added gradually over 10 min, before heating the resulting solution to 20 ° C and keeping it there for 1.7 h) A portion of this solution (approx. 0.35 M; 6.6 L, approx. 2.3 mol) was gradually added to the 6-chloro-7- [3 (iodomethyl)-1,5-dimethyl- pyrazol-4-yl] -1-methyl-3- (3-methylsulfonyloxypropyl) indole-2-carboxylate from above at approximately -15 ° C over 20 min The resulting mixture was kept at -10 ° C for 1.4 h. Another portion of the disodium solution of 3 - (((1-methyl-3 (sulfidomethyl) -1H-pyrazol-5-yl) methyl) thio) naphthalen-1-olate (approx. 0, 35 M; 1.5 L , approximately 0.53 mol) was added before keeping the reaction mixture at -10 ° C for 18 h. The mixture was heated to 20 ° C and removed from the reaction vessel, followed by washing with MeOH (0.6 L). The DMSO was charged and heated with stirring to 100 ° C. Then, the intermediate solution (approx. 15 L) was pumped back to the reactor over 2.8 h at 100 ° C, followed by washing with DMSO (0.6 L). After maintaining the reaction mixture at 100 ° C for 0.8 h and then cooling it to just below 60 ° C, toluene (29 L) and water (5.8 L) were added. The temperature of the mixture was adjusted to 50 ° C and then a mixture of aq. (50% by weight, 160 g, 2.02 mol) and water (0.9 L), followed by a wash with water (0.12 L). After 10 min, the bottom layer was removed. The upper layer was washed with a solution of NaCI (1.74 kg) in water (18.6 L) at 53 ° C and then concentrated by distilling the solvent (6 L) at 160 mbar and jacket temperature 85 ° C to give a toluene solution of the crude product (19.2 kg, 6.1% by weight, 1.7 mol). Was Petition 870190094446, of 9/20/2019, p. 70/81 55/61 combined with another solution (18.6 kg, 5.7% by weight, 1.5 mol) prepared from 6-chloro-7- (3- (hydroxymethyl) -1,5-dimethyl-1H -pyrazole- (/ A )-methyl 4-yl) -3- (3-hydroxypropyl) -1-methyl-1H-indol-2-carboxylate (Intermediate 9, 1.19 kg, 98.0% by weight, 2, 87 mol) following the same procedure. The combined solution was purified in portions (0.84 L per serving, 51 servings) by chromatography on a compressed column (20 cm in diameter x 22 cm in length) of Kromasil® silica (3.0 kg, 10 pm in size) particle, 60 pg pore size), eluting with a mixture of toluene and ethanol (approximate volume ratio of 93% toluene: 7% ethanol). The product fractions were evaporated under reduced pressure at 50 ° C in two parts, until distillation ceased, to obtain the product (91 g and 2.40 kg) as a foam. The batches were dissolved in DMSO (148 g and 3.22 kg) to give DMSO solutions of 17-Chlorine-5,13,14,22-tetramethyl-28-oxa-2,9-dithia- 5,6,12,13,22-pentaazaheptacycle [27.7.1.1 4 ' 7 .0 11 ' 15 .0 16 '21 .0 20 ' 24 .0 30 '35 ] octatriaconta-1 (37), 4 (38) , 6,11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylate of (Ra) - (+) - methyl (Intermediate 17, 239 g, 32.2% in weight, 0.112 mol and 5.63 kg, 37.9% by weight, 3.11 mol) in a combined yield of 56%; m / z (ES +), [M + H] + = 686. 1 H NMR (500 MHz, DMSO-cfe, 27 ° C) δ 1.97 (s, 3H), 2.16 - 2.27 (m , 1H), 2.32 - 2.42 (m, 1H), 2.89 (d, 1H), 3.08 (d, 1H), 3.07 - 3.14 (m, 1H), 3, 16 (d, 1H), 3.36 - 3.42 (m, 1H), 3.43 (d, 1H), 3.48 (s, 3H), 3.69 (s, 3H), 3.76 (s, 3H), 3.77 - 3.83 (m, 1H), 3.84 (s, 3H), 4.13 (td, 1H), 4.22 (d, 1H), 4.29 (d, 1H), 4.77 (s, 1H), 6.65 (d, 1H), 7.18 (d, 1H), 7.39 - 7.40 (m, 1H), 7.44 - 7.48 (m, 1H), 7.47 - 7.51 (m, 1H), 7.71 - 7.74 (m, 1H), 7.90 (d, 1H), 8.08 - 8.12 (m, 1H). Compound 1: (/ A ) - (+) - 17-Chloro-5,13,14,22-tetramethyl-28-oxa-2,9ditia-5,6,12,13,22-penta-azaheptacyclo [ 27.7.1.1 47 , o 11 · 15 .0 16 · 21 Ό 20 · 24 . O 30 '35 ] octatriaconta-1 (37), 4 (38), 6,11,14,16,18,20,23,29,31,33,35-tridePetition 870190094446, of 9/20/2019, pg . 71/81 56/61 caeno-23-carboxylic NN [0087] 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22penta-azaheptacyclo [27.7.1.1 4 ' 7 O 11 ' 15 O 16 '21 O 20 ' 24 O 30 '35 ] octatriaconta1 (37), 4 (38), 6,11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylate (/ a) - (+) - methyl (Intermediate 17, 37.9% by weight in DMSO containing 57.3% by weight of DMSO, 2.81 kg, 1.55 mol), DMSO (2.81 kg) and ethanol (1.68 kg) were loaded into a 20 L reactor and the solution was heated with stirring at 50 ° C. NaOH (50% by weight in water; 186 g, 2.33 mol), followed by an in-line wash with water (267 ml), was then added. After 1.5 h, acetic acid (267 ml, 4.66 mol) was added. Aqueous ethanol (34.5% by weight; 3.0 L) was then added, followed by a crystallization seed of acid Form A (/ A ) (+) - 17-chloro-5,13,14,22 -tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacycle [27.7.1.14,7.011,15.016,21.020,24.030,35] octatriaconta1 (37), 4 (38), 6 , 11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylic monohydrate (0.8 g, 0.001 mol). The mixture was stirred at 50 ° C for 4.5 h, then two more portions (4.2 and 1.3 L) of aqueous ethanol (34.5% by weight) were gradually added (over 4.1 and 0, 7 h respectively). The suspension was cooled to 20 ° C over 2 h and maintained at 20 ° C for 17 h. The suspension was filtered under suction and the filter cake was washed twice with aqueous ethanol (34.5% by weight; 2.7 L per wash), before drying in a 40 ° C vacuum oven to obtain the Form A of acid (/ A ) - (+) - 17-chloroPetition 870190094446, of 9/20/2019, p. 72/81 57/61 5,13,14,22-tetramethi l-28-oxa-2,9-d itia-5,6,12,13,22-penta-azaheptacycle [27.7.1.1 4 ' 7 .0 11 ' 15 .0 16 '21 0 20 ' 24 O 30 '35 ] octatriaconta-1 (37), 4 (38), 6,11,14, 16,18,20, 23,29,31,33,35-tridecaene-23-carboxylic monohydrate (Compound 1, 1.01 kg, 99.4% by weight, 99.9% ee, 94%); m / z (ES +), [M + H] + = 672. 1 H NMR (500 MHz, DMSO-cfe, 27 ° C) δ 1.96 (s, 3H), 2.16 - 2.28 (m , 1H), 2.30 - 2.42 (m, 1H), 2.88 (d, 1H), 3.06 (ddd, 1H), 3.12 (d, 1H), 3.18 (d, 1H), 3.42 (d, 1H), 3.41 - 3.48 (m, 1H), 3.51 (s, 3H), 3.72 (s, 3H), 3.75 (s, 3H ), 3.84 (td, 1H), 4.09 (td, 1H), 4.25 (d, 1H), 4.28 (d, 1H), 4.75 (s, 1H), 6.67 (d, 1H), 7.13 (d, 1H), 7.37 - 7.40 (m, 1H), 7.43 - 7.47 (m, 1H), 7.45 - 7.50 (m , 1H), 7.68 - 7.74 (m, 1H), 7.84 (d, 1H), 8.07-8.13 (m, 1H), 13.36 (s I, 1H). [0088] Details of the HPLC method for analyzing chiral purity: column = ChiralPak IE-3, 3 pm 4.6 x 250 mm; temperature = 40 ° C; mobile phase = 50:50 ethane-hexane by volume containing 0.1% TFA, flowing at 0.8 ml / min; UV detection at 305 nm; inj volume. = 10 pL (this can be adjusted to reach an appropriate detection limit); retention times of 8.5 and 11.5 min for the R a and S a enantiomers, respectively. [0089] Form A XRPD is shown in Figure 1 and the results are tabulated below (Table 1). Table 2. XRPD peaks for Form A Angle (2θ ± 0.2 °) Intensity (%) 18.2 100.0 12.5 87.7 14.4 82.7 8.4 75.8 17.2 70.4 26.8 64.4 10.7 59.0 27.7 55.9 30.2 45.6 23.0 42.0 Petition 870190094446, of 9/20/2019, p. 73/81 58/61 20.5 40.5 19.2 39.4 7.0 35.9 25.0 35.3 17.6 34.5 23.7 34.4 19.8 33.4 24.5 31.8 22.0 30.9 20.9 30.8 24.2 28.8 37.6 27.1 31.5 26.9 22.3 26.5 13.9 25.3 13.7 23.9 29.0 23.9 34.5 22.9 26.3 21.3 13.1 20.8 29.4 20.7 15.6 19.8 36.9 17.9 15.1 17.9 36.4 16.7 32.8 16.6 38.2 16.2 28.6 16.1 35.5 14.9 [0090] DSC analysis indicated that Form A undergoes an endothermic desolvation event with a start at about 121 ° C and a peak at about 158 ° C, followed by an endothermic melting / decomposition event with a start at about 181 ° C and a peak at about 194 ° C. TGA indicated that Form A exhibits a mass loss of about 4.0% by heating from about 25 ° C to about 160 ° C. A representative DSC / TGA thermogram of Form A is Petition 870190094446, of 9/20/2019, p. 74/81 59/61 shown in Figure 2. [0091] Analysis of the structure of the isolated crystals confirmed that Form A is a monohydrate form. Crystallographic data: P2 monoclinic spatial group (1), unit cell dimensions: a = 13.83 (3) A, b = 7.578 (14) A, c = 33.57 (6) A, β = 90.23 ( 2) °, V = 3518 (12) A 3 . Powder X-Ray Diffraction Analysis (XRPD) [0092] XRPD analysis was performed using a Bruker D4 diffractometer, which is commercially available from Bruker AXS Inc ™ (Madison, Wisconsin). XRPD spectra were obtained by assembling a sample (approximately 20 mg) of the material for analysis in a single assembly on a single silicon crystal wafer (for example, a Bruker X-ray diffraction sample holder with zero silicon bottom ) and spreading the sample in a thin layer with the aid of a microscope slide. The sample was rotated at 30 revolutions per minute (to improve the counting statistics) and irradiated with X-rays generated by a copper tube with long-fine focus operated at 40 kV and 40 mA with a wavelength of 1, 5406 Angstroms (ie, about 1.54 Angstroms). The sample was exposed for 1 second by an increment of 0.02 degrees 2-theta (continuous scan mode) over the range of 2 degrees to 40 degrees 2-theta in theta-theta mode. The processing time was 31 min, 41 s. [0093] XRPD 20 values may vary within a reasonable range, for example, within the range ± 0.2 ° and such XRPD intensities may vary when measured for essentially the same crystalline form for a variety of reasons, including, for example , preferred orientation. The principles of XRPD are described in publications, such as, for example, Giacovazzo, C. et al. (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, Petition 870190094446, of 9/20/2019, p. 75/81 60/61 John Wiley & Sons, New York, and Klug, Η. P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York. DSC analysis [0094] DSC analysis was performed on samples prepared according to standard methods using a DSC Q SERIES ™ Q1000 calorimeter available from TA Instruments® (New Castle, Delaware). One sample (approximately 2 mg) was weighed in an aluminum sample container and transferred to the DSC. The instrument was purged with nitrogen at 50 mL / min and data were collected between about 22 ° C and 300 ° C, using a dynamic heating rate of about 10 ° C / minute. The thermal data were analyzed using standard software, for example, Universal V.4.5A from TA INSTRUMENTS®. Thermogravimetry Analysis (TGA) [0095] TGA was performed on samples prepared according to standard methods using a Q SERIES ™ Q5000 thermogravimetry analyzer from TA Instruments INSTRUMENTS® (New Castle, Delaware). A sample (approximately 5 mg) was placed in an aluminum sample container and transferred to the TGA oven. The instrument was purged with nitrogen at 50 mL / min and data were collected between 25 ° C and 300 ° C, using a dynamic heating rate of 10 ° C / minute. The thermal data were analyzed using standard software, for example, Universal V.4.5A from TA INSTRUMENTS®. Example 1: In vitro activity of Compound 1 Caspase Activity Assay: This is a cell assay to measure apoptosis induction in MOLP-8 (multiple myeloma), KMS12-BM (multiple myeloma), MV4; 11 (acute myeloid leukemia), and NCIH23 (lung cancer) cells of non-small cells) after 6 h of treatment Petition 870190094446, of 9/20/2019, p. 76/81 61/61 with Mcl-1 inhibitors. On the first day, 3000 (MOLP-8, KMS12-BM, MV4; 11) or 1250 (NCI-H23) cells / well were seeded with 50 µl of growth medium (IMDM + 10% FBS + 2 mM L-Glu for MV4; 11 and RPMI-1640 + 10% FBS + 2 mM L-Glu for all others) in 384-well white microplates and incubated overnight (37 ° C, 5% CO2, 80% RH ). On the second day, the cells were treated with Compound 1 using an ECHO acoustic liquid handler (10-point serial dilution in semi-log, 31.5 μΜ maximum concentration, 0.3% final DMSO concentration). After 6 h of incubation (37 ° C, 5% CO2, 80% RH), 25 μΙ_ of Caspase-GIo 3/7 reagent (Promega) was added to each well and the plates were incubated at room temperature for 30 min protected from light. Luminescence was recorded using an Infinite M200 microplate reader (Tecan) with an integration time of 100 ms. IC50 values were calculated using the GeneData analysis software and are shown in Table 2 below. Table 2. Results of the Caspase Activity test in vitro Cell line Compound ICaspase activity, EC50 (nM) MOLP-8 30 KMS-12-BM 43 MV4; 11 20 NCI-H23 193 Petition 870190094446, of 9/20/2019, p. 77/81
权利要求:
Claims (1) [1] CLAIM 1. Selected compound, characterized by the fact that it presents from: or your salt.
类似技术:
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引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题 US9949965B2|2014-10-17|2018-04-24|Vanderbilt University|Tricyclic indole Mcl-1 inhibitors and uses thereof| KR20180135030A|2016-04-22|2018-12-19|아스트라제네카 아베|Macrocyclic MCL1 inhibitor to treat cancer|CN110845520B|2018-11-22|2021-04-13|苏州亚盛药业有限公司|Macrocyclic indoles as MCL-1 inhibitors| EP3781575A4|2019-01-23|2021-06-02|Ascentage PharmaCo., Ltd.|Macrocyclic fused pyrrazoles as mcl-1 inhibitors| AU2020296918A1|2019-06-21|2022-02-17|Janssen Pharmaceutica Nv|Macrocyclic inhibitors of MCL-1| WO2021005043A1|2019-07-09|2021-01-14|Janssen Pharmaceutica Nv|Macrocyclic spirocycle derivatives as mcl-1 inhibitors| WO2021092053A1|2019-11-08|2021-05-14|Unity Biotechnology, Inc.|Mcl-1 inhibitor macrocycle compounds for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer| WO2021099580A1|2019-11-21|2021-05-27|Janssen Pharmaceutica Nv|Macrocyclic sulfonyl derivatives as mcl-1 inhibitors| WO2021099579A1|2019-11-21|2021-05-27|Janssen Pharmaceutica Nv|Macrocyclic indole derivatives as mcl-1 inhibitors| WO2021165370A1|2020-02-21|2021-08-26|Janssen Pharmaceutica Nv|Macrocyclic indole derivatives as inhibitors of mcl-1| WO2021239862A1|2020-05-29|2021-12-02|Janssen Pharmaceutica Nv|Macrocyclic 7-pyrazol-5-yl-indole derivatives as inhibitors of mcl-1| WO2021255257A1|2020-06-19|2021-12-23|Janssen Pharmaceutica Nv|N-linked macrocyclic 7--indole derivatives as inhibitors of mcl-1| WO2021255258A1|2020-06-19|2021-12-23|Janssen Pharmaceutica Nv|N-linked macrocyclic 4--indole derivatives as inhibitors of mcl-1| WO2022008674A1|2020-07-08|2022-01-13|Janssen Pharmaceutica Nv|Macrocyclic ether containing indole derivatives as inhibitors of mcl-1| WO2022032284A1|2020-08-07|2022-02-10|Zeno Management, Inc.|Macrocyclic compounds|
法律状态:
2021-06-15| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: C07D 231/12 , C07D 403/04 , C07C 245/06 Ipc: C07D 231/12 (2006.01), C07D 403/04 (2006.01), C07C | 2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|
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