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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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CC-90010


str1

CC-90010

C21 H21 N O4 S, 383.46

CAS 1706738-98-8

1(2H)-Isoquinolinone, 4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-2-methyl-

  • 4-[2-(Cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-2-methyl-1(2H)-isoquinolinone
  • 4-[2-(Cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one
  • 4-[2-(Cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one

Quanticel Pharmaceuticals Inc, Michael John BennettJuan Manuel BetancortAmogh BoloorStephen W. KaldorJeffrey Alan StaffordJames Marvin Veal

Image result for QUANTICEL

Celgene  (now a wholly owned subsidiary of  Bristol-Myers Squibb ) , following its acquisition of  Quanticel , is developing CC-90010, an oral inhibitor of BET (bromodomain and extraterminal) proteins, for the potential treatment of solid tumors and non-Hodgkin’s lymphoma.  In August 2019, a phase I trial for diffuse astrocytoma, grade III anaplastic astrocytoma and recurrent glioblastoma was planned

PATENT

WO2018075796 claiming solid composition comprising a bromodomain inhibitor, preferably 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one in crystalline form A.

PATENT

WO2015058160 (compound 89, page 103).

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=9B64008287A0D105A68DDF31141C7419.wapp1nA?docId=WO2015058160&tab=PCTDESCRIPTION

Example 89: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

Step 1 : 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one

[00344] A suspension of 4-bromo-2-methylisoquinolin-l-one (100 mg, 0.42 mmol), bis(pinacolato)diboron (214 mg, 0.84 mmol), Pd(dppf)Cl2 (31 mg, 0.04 mmol) and potassium acetate (104 mg, 1.05 mmol) in dioxane (2 mL) under nitrogen was warmed up to 90 °C for 135 minutes. It was then cooled down to room temperature and diluted with ethyl acetate (8 mL). The mixture was washed with aqueous saturated solution of NaHC03 (8 mL) and brine (8 mL). The organic phase was separated, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purifed by normal phase column chromatography (10-90% EtOAc/Hexanes) to give the title compound (44 mg, 37%). 1H NMR (CDC13, 400 MHz) δ 8.43 (d, J = 7.9 Hz, 1 H), 8.40 (dd, J = 8.2 Hz, 0.9 Hz, 1 H), 7.68 (s, 1 H), 7.65 (ddd, J = 8.2, 8.2, 1.1 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 3.63 (s, 3H), 1.38 (s, 12H). LCMS (M+H)+ 286. Step 2: 4-[2-(cyclopropylmethox -5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

[00345] The title compound was prepared in a manner similar to Example 18, step 3, substituting 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene for 4-bromo-2-methylisoquinolin-l(2H)-one and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one for N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. 1H NMR (DMSO-d6, 400 MHz) δ 0.09 (m, 2 H), 0.29 (m, 1H), 0.35 (m, 1H),

0.94 (m, 1H), 3.22 (s, 3H), 3.57 (s, 3H), 3.95 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.37 (d, J =

8.8 Hz, 1H), 7.53 (m, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.8,

2.4 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H). LCMS (M+H)+ 384.

[00346] Alternatively, 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one can be prepared as described below.

Step 1 : 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one

[00347] A mixture of 4-bromo-2-methylisoquinolin-l-one (8.0 g, 33.6 mmol),

bis(pinacolato)diboron (17.1 g, 67.2 mmol), KOAc (6.6 g, 67.2 mmol), Pd2(dba)3 (3.1 g, 3.36 mmol) and X-Phos (1.6 g, 3.36 mmol) in anhydrous dioxane (200 mL) was stirred at 60 °C for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (PE : EA = 15 : 1) to give the title compound (6.0 g, 62 %) as a solid.

Step 2: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one

[00348] The title compound from Step 1 (5.0 g, 17.5 mmol), 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene (6.4 g, 21 mmol), K3PO4 (9.3 g, 43.9 mmol) and Pd(dppf)Cl2 (1.4 g, 1.75 mmol) in a dioxane/water (100 mL / 10 mL) mixture were stirred at 60 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EA : DCM = 1 : 4).

Appropriate fractions were combined and concentrated under reduce pressure. The resultant solid was recrystallized from DCM / MTBE (1 : 1, 50 mL) to give the title compound (4.0 g, 60 %) as a white solid. 1H NMR: (CDC13, 400 MHz) δ 8.51 (dd, Ji = 8.0 Hz, J2 = 0.8 Hz, 1 H), 7.98 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.53 (m, 2 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.10 (m, 2 H), 3.88 (m, 2 H), 3.66 (s, 3 H), 3.09 (s, 3 H), 1.02-0.98 (m, 1 H), 0.44-0.38 (m, 2 H), 0.11-0.09 (m, 2 H). LCMS: 384.1 (M+H)+

Patent

WO-2020023438

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020023438&tab=PCTDESCRIPTION&_cid=P10-K6HCMJ-20465-1

A process for preparing bromodomain inhibitor, particularly 4-[2(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one (having HPLC purity of 99%; compound 1; (hereafter referred to as C-90010)) and its hydrates, solvates, prodrugs and salts comprising the reaction of a substituted 4-(methylsulfonyl)phenol compound with a quinoline derivative, followed by purification is claimed. Also claimed are novel intermediates of CC-90010 and their processes for preparation. Further claimed are novel crystalline form of CC-90010. CC-90010 is known and disclosed to be a bromodomain containing protein inhibitor, useful for treating cancer.

Scheme 10: Synthesis of Compound 1

[0090] Acetonitrile (1.6L) was charged to a mixture of Compound 2 (156.7g, 460 mmol), Compound 3 (lOOg, 420 mmol) and potassium phosphate tribasic (223g, l.OSmol). Agitation

was begun and water (400mL) charged to the batch. The system was vacuum purged three times with nitrogen and charged with Pd(PPh3)2Cl2 (2.9g, 4 mmol) and the system vacuum purged three times with nitrogen. The batch was heated to about 65 to about 75 °C (or any temperature in between and including these two values) and contents stirred for at least about 16 hours until reaction was complete by HPLC analysis. The batch was cooled to about 60 to about 70 °C (or any temperature in between and including these two values), agitation halted and the mixture allowed to settle. The bottom aqueous layer was removed. Water (150mL) and acetonitrile (700mL) were charged at about 60 to about 70°C (or any temperature in between and including these two values). Ecosorb C-941 (15g) and Celite (lOg) were charged to the reaction vessel at about 60 to about 70°C (or any temperature in between and including these two values). After lh, the mixture was filtered to remove solids. The solids were washed twice each with 18% water in acetonitrile (500 mL) at about 60 to about 70°C (or any temperature in between and including these two values). The filtrates were combined and concentrated under atmospheric pressure to a final volume of 1.5L. The batch was cooled to about 60 to about 65°C (or any temperature in between and including these two values) and seeded with Compound 1 (1 g). After lh, water (500 mL) was charged over at least 1 hour at about 60 to about 65°C (or any temperature in between and including these two values). The slurry was cooled to about 15 to about 25°C (or any temperature in between and including these two values) over 4 hours. The product was collected by suction filtration. The wet cake was washed with 45% water in acetonitrile (500mL) twice. The product was dried under vacuum at about 40°C with nitrogen purge. Yield: 139g of 1.

[0091] The above procedure for coupling Compound 3 and Compound 2 to produce

Compound 1 may be modified in any of the ways that follow. Reaction solvents: Different reaction solvents from acetonitrile can be used, including tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, and isopropanol. Boronic ester: Different boronic esters from Compound 2 can be used, including pinacolato ester compound 7, and the free boronic acid of Compound 2. Examples of boronic esters can be found in Lennox et al., Chem. Soc. Rev., 43: 412 (2014). Carbon treatment: Different carbon treatments from Ecosorb C-941 could be used. Different amounts of carbon, from 0.01 to 0.5X weight can be used. The carbon can be eliminated. Different amounts of Celite, from 0.01 to 0.5X weight can be used.

Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used.

The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1); cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCk(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy3 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5);

Pd(PPh3)2Cb (Cas# 13965-03-2). Examples of catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

VI. Purification of Compound 1 fCC-900101 bv crystallization from formic acid and water

[0092] Described herein are methods of purifying Compound 1 by crystallization from formic acid and water. Also described are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1 and two metastable forms, Form 4

The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1); cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCh(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy3 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5);

Pd(PPh3)2Cl2 (Cas# 13965-03-2). Examples of catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

VI. Purification of Compound 1 (CC-90010! bv crystallization from formic acid and water

[0092] Described herein are methods of purifying Compound 1 by crystallization from formic acid and water. Also described are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1 and two metastable forms, Form 4

33 -a

and Form 5. Supporting data (XRPD, DSC, photomicroscopy) for all three forms is provided in the examples below.

[0093] The stmcture of Compound 1 (CC-90010) is shown below:

Example 1: Synthesis of Compound 1

[0217] Synthesis of compound 1 was accomplished according to Scheme 1 below. Referring to Scheme 1, synthesis commenced with bromination of starting material 4-(methylsulfonyl)phenol 4, to produce compound 5. Compound 5 was O-alkylated with (bromomethyl)cyclopropane to produce compound 6. Boronate Compound 2 was then formed by borylation of Compound 6 with Pd catalyst and bis(pinacolato)diboron to produce transient Compound 7, which was subsequenctly treated with diethanolamine (DBA) to afford cross-coupling partner Compound 2. Cross-coupling partner Compound 3 was formed in one pot starting from commercially available Compound 8. Compound 8 was N-methylated and brominated to afford Compound 3. Compounds 2 and 3 were cross-coupled (Norio, M. and Suzuki, A., Chem. Rev., 95(7), 2457-2483 (1995)) to afford the target compound 1.

Scheme 1: Synthesis of compound 1

1.1: Bromination of 4

[0218] The bromination of Compound 4 to produce Compound 5 itself is simple, however stopping at the mono-brominated Compound 5 was challenging. The bis-brominated Compound 5-a (see Scheme 2 below) is a particularly pernicious impurity as it couples downstream to form a di ffi cult-to-purge impurity.

Scheme 2: Bromination of Compound 4

[0219] The key to high purity with reasonable yield was to exploit the solubility differences of the starting material Compound 4 (46 mg/ml at 20 °C) and the product Compound 5 (8 mg/ml) in CH2CI2. These solubility differences are summarized in Table 3 below.

[0220] This solubility difference is exploited by performing the reaction at a high

concentration to drive Compound 5 out of solution once formed, thereby minimizing its ability to react further with the brominating reagent to form Compound 5-a diBr. The reaction is seeded with Compound 5 to initiate its crystallization.

[0221] In Fig. 22 (Conversion of Compound 4 to Compound 5: Effect of Sulfuric Acid) it can be seen that in the absence of acid the initial reaction to Compound 5 is rapid, however the conversion plateaus at about 30% Compound 5. The main side product was found to be the impurity Compound 5-a diBr (see Fig. 23: Conversion of Compound 5 and Compound 5-a diBr: No H2SO4). Addition of increasing amounts of sulfuric acid leads to a higher conversion to desired Compound 5.

[0222] Fig. 24 (Compound 4 to Compound 5 Reaction Profile: Portion-wise Addition of NBS, Seeding) depicts further reaction control. The portion-wise addition ofNBS after addition of catalytic sulfuric acid minimizes the temperature rise, and the addition of Compound 5 after an initial NBS charge promotes the reactive crystallization of Compound 5. After about 6 to 7 hours of reaction it can be seen that the major product is Compound 5, with only a small (<5%) of the di-brominated impurity formed. In contrast, in a reaction where Compound 4 and all of the NBS were charged followed by the addition of 4 volumes of methylene chloride, a rapid exotherm resulted and undesired Compound 5-a diBr was found to be the major product.

[0223] Thus, the reaction was run under a high concentration in CH2CI2 with a portion-wise solid addition of NBS (to control both availability of the electrophile and the exotherm). An end of reaction slurry sample typically showed not more than 5% of the starting material Compound 4 remaining. After filtration the crude cake was washed with cold CH2CI2 and the OkCk-washed filter cake contained not more than 0.5% by weight dibrominated Compound 5-a. It also contained a large amount of HPLC-silent succinimide.

[0224] The following procedure was carried out: Compound 4 (25g, 145mmol) followed by CH2CI2 (lOOmL) were added to a reaction vessel and agitated. The batch was adjusted to 17 °C to 23 °C. Sulfuric acid was charged (2.7mL, Slmmol) to the batch maintaining 17 °C to 23°C. The batch was stirred at 17 °C to 23 °C for 10 minutes to 20 minutes. The first portion of A-bromosuccimide (NBS) was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23°C and stirred for at least 30 min. The second portion of NBS was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23°C and stirred for at least 30 min. The batch was seeded with

Compound 5 (0.02wt) and stirred for ca. 30 min at 17 °C to 23 °C to induce crystallization.

[0225] The third portion of NBS was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23 °C and stirred for at least 30 min. NBS (6.5g, 36.5 mmol) was charged to the batch at 17 °C to 23 °C and stirred for at least 30 min. Additional CH2CI2 was charged (50mL) to the batch while maintaining 17 °C to 23 °C to aid in agitation and transfer for filtration. The batch was stirred at 17 °C to 23 °C until complete by HPLC analysis (~20 – 40 h). The product was collected by suction filtration. The filter cake was slurry washed with CH2CI2 (3 x 50mL) at 17 °C to 23 °C (target 20 °C). The filter cake was slurry washed with purified water (3.0vol) at 65 °C to 75 °C for 2 to 3 hours. Then, the filter cake was slurry washed with purified water (3 x 1.0 vol, 3 x 1.0 wt) at 17 °C to 23°C. The wet cake was dried under vacuum with nitrogen bleed at 60 °C. Yield: 27g 5 (74% molar) >97% by weight. ¾ NMR (500 MHz, de-DMSO) 8.01 (1H, d, 4J = 2.1 Hz, RO-Ar meta- H ), 7.76 (1H, dd, J = 8.6 and 4J = 2.1 Hz, RO-Ar meta-H ), 7.14 (1H, d, J = 8.6 Hz, RO-Ar ortho- H), 3.38 (1H, br s, OH), 3.20 (3H, s,

CHJ); MS (ES-) calc. 249/251; found 249/251. Melting point (MP): (DSC) 188 °C.

[0226] The above procedure allowed for the following modifications. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as acetonitrile, tetrahydrofuran, or 2- methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from about 2X vol to about 20 X vol (with respect to Compound 4). Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Different amounts of the brominating reagent can be used, from about 0.8 equiv to about 1.9 equiv. Bromination reagent addition: The brominating reagent can be added all at once, portion wise in about 2 to about 20 portions, or continuously. The addition times can vary from about 0 to about 72 hours. Temperature: Reaction temperatures from about 0 °C to about 40 °C could be used. Acids: Different acids can be envisioned, including benzenesulfonic acid, para-toluenesulfonic acid, triflic acid, hydrobromic acid, and trifluoroacetic acid. Isolation: Instead of directly filtering the product and washing with methylene chloride and water, at the end of reaction an organic solvent capable of dissolving Compound 5 could be charged, followed by an aqueous workup to remove succinimide, and addition of an antisolvent or solvent exchange to an appropriate solvent to crystallize Compound 4. Drying: A temperature range of about 10 to about 60 °C could be used for drying.

[0227] An alternative process to Compound 5 has also been developed. This process is advantageous in that it does not use a chlorinated solvent, and provides additional controls over the formation of the Compound 5-a dibromo impurity. See Oberhauser, T. J Org. Chem 1997, 62, 4504-4506. The process is as follows. Compound 4 (10 g, 58 mmol) and acetonitrile (100 ml) were charged to the reactor and agitated. The batch was cooled to -20 °C. Triflic acid (CF3SO3H or TfOH, 5.5 mL, 62 mmol) was charged while maintaining a batch temperature of -10 to -25 °C. N-bromosuccinimide was charged (NBS, 11.4 g, 64 mmol), stirred at -10 to -25 °C for 30 minutes, then warmed to 20 °C over 3 to 4 hours. Agitation was continued at 15 °C to 25 °C until reaction completion. If the reaction conversion plateaued before completion, the reaction was cooled to -5 to -15 °C, and additional NBS was added, the amount based off of unreacted starting material, followed by warming to 15 °C to 25 °C and reacting until complete.

[0228] After reaction completion, the batch was warmed to 40 °C to 50 °C and concentrated under reduced pressure to 40 mL. The batch was cooled to -5 °C to -15 °C and the resulting product solids were filtered off. The solids were slurry washed three times, each with 20 mL water, for at least 15 minutes. The final cake was dried at 50 °C to 60 °C under reduced pressure to furnish 10 g of 5 containing less than 0.1% MeCN, 0.07% water, and 0.1% triflic acid (TfOH) by weight.

[0229] Alternatives to the above procedure employing MeCN and TfOH are as follows. Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination Reagent Stoichiometry: Different amounts of the brominating reagent can be used, from about 0.8 equiv to about 2 equiv. Drying: A temperature range of about 10 °C to about 60 °C could be used for drying.

[0230] The impurity 5-a is was prepared and characterized as follows. 10 g of Compound 4 and sulfuric acid (35 mol%) were dissolved in MeOH (10 vol). The mixture was set to stir at 20 °C to 25 °C for 5-10 min and 2.0 equivalents of NBS were charged in one portion. The resulting yellow mixture was stirred for three days at 20-25 °C. The batch was concentrated under reduced pressure and the resulting solid was slurried in water at 95-100 °C for 3 hours. After a second overnight slurry in CH2CI2 at room temperature, the batch was filtered and dried to give a white solid 5-a (15.0 g, 78%). ¾ NMR (500 MHz, de-DMSO), 8.05 (2H, s, ArH), 3.40 (1H, br s, HO-Ar), 3.28 (3H, s, CH3); MS (ES) calc. 327/329/331; found

327/329/331; MP (DSC): 226 °C (onset 221 °C, 102 J/g); lit. 224-226 °C.

1.2: O-alkylation of 5 to produce 6

[0231] Compound 6 was prepared according to Scheme 7 below.

Scheme 7: O-alkylation of 5 to produce 6

[0232] Compound 5 (100 g, 398 mmol) and methyl ethyl ketone (MEK, 700 mL) were charged to the reaction vessel and agitated. Potassium carbonate (K2CO3, 325 mesh 82.56 g, 597 mmol) was then charged to the stirred reaction vessel at 15 °C to 25 °C.

Bromomethylcyclopropane (64.4 mL, 664 mmol) was charged to the reaction vessel over at least 1 hour, maintaining the temperature between 15 °C to 25 °C. MEK (200 mL) was added into the reactor and the reactor heated to 65 to 75 °C. The contents of the reaction vessel were stirred at 65 to 75°C for approximately 10 hours until reaction was complete by HPLC analysis. Water (3.0 vol, 3.0wt) was charged to the vessel maintaining the temperature at 65 to 75 °C. The batch was stirred at 65 to 75 °C. The phases were allowed to separate at 65°C to 75 °C and the lower aqueous phase was removed. Water (300 mL) was charged to the vessel maintaining the temperature at 65 °C to 75 °C. The batch was agitated for at least 10 minutes at 65 to 75 °C. The phases were allowed to separate at 65 °C to 75 °C and the lower aqueous phase was removed. The water wash was repeated once. The temperature was adjusted to 40 to 50°C. The mixture was concentrated to car. 500 mL under reduced pressure. The mixture was distilled under reduced pressure at up to 50 °C with MEK until the water content was <1.0% w/w. n-heptane (500mL) was charged to the vessel maintaining the temperature at 40 to 50 °C. The mixture was continuously distilled under vacuum with n-heptane (300mL), maintaining a 1L volume in the reaction vessel. Compound 6 seeds (0.0 lwt) were added at 40 to 50 °C. The mixture was continuously distilled under reduced pressure at up to 50 °C with n-heptane (300mL) while maintaining 1L volume in the reactor. The batch was cooled to 15 to 25 °C and aged for 2 hours. The product was collected by suction filtration. The filter cake was washed with a solution of 10% MEK in n-heptane (5vol) at 15 to 25°C. The filter cake was dried under reduced pressure at up to 40 °C under vacuum with nitrogen flow to afford 95g of 6. 1H NMR (500 MHz, de-DMSO) 8.07 (1H, d, 4J = 2.2 Hz, ArH), 7.86 (1H, d, J = 8.7 Hz, meta-ArH), 7.29 (1H, d, J = 8.8 Hz, ortho-AiK),

4.04 (2H, d, J = 6.9 Hz, OCH2CH), 3.21 (3H, s, CH3), 1.31-1.24 (1H, m, OCH), 0.62- 0.58 (2H, m, 2 x CHCHaHb), 0.40-0.37 (2H, m, 2 x CHC¾Hb); MS (ES+) calc. 305/307; found 305/307; MP: (DSC) 93 °C.

[0233] The following modifications of the above reaction, synthesis of 6 from 5, may be employed as well. Solvent: Different solvents could be used, for example acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, or 2-methyl tetrahydrofuran. Reaction volume: Reaction volumes of 3 to 30 volumes with respect to 3 could be used. Base: Different inorganic bases, such as cesium carbonate or phosphate bases (sodium, potassium, or cesium) could be used. Also, organic bases, such as trimethylamine or diisopropyldiimide could be used. Base particle size: Different particle sizes of potassium carbonate from 325 mesh could be used. Reaction temperature: A lower temperature, such

as 50 °C could be used. A higher temperature, such as about 100 °C could be used. Any temperature above the boiling point of the solvent could be run in a pressure vessel.

Isolation: Different solvent ratios of MEK to n-heptane could be used. Different amounts of residual water can be left. Different amounts of seeds, from 0 to 50% could be used.

Seeding could take place later in the process and/or at a lower temperature. An un-seeded crystallization can be employed. A different isolation temperature, from 0 °C to 50 °C could be used. A different wash could be used, for example a different ratio of MEK to n-heptane. A different antisolvent from n-heptane could be used, such as hexane, pentane, or methyl tert-butyl ether. Alternatively, the batch could be solvent exchanged into a solvent where Compound 3 has a solubility of less than 100 mg/ml and isolated from this system. Drying: A temperature range of 10 to 60 °C could be used for drying.

[0234] Compound 10, shown below may also be formed as a result of O-alkylation of unreacted 4 present in product 5, or alternatively from or via a palladium mediated proteodesbromination or proteodesborylation in subsequent chemistry discussed in Example 1.3 below.

[0235] Preparation of methylsulfonylphenyl(cyclopropylmethyl) ether 10: Compound 4 (0.86 g, 5.0 mmol) and K2CO3 (1.04 g, 7.5 mmol) were slurried in acetone (17 mL, 20 vols). Cyclopropylmethyl bromide (0.73 mL, 7.5 mmol) was added in several small portions over ~1 minute and the reaction mixture heated to 50 °C for 48 hours, then cooled to 25 °C. Water (5.0 mL) was added with stirring and the acetone was evaporated on a rotary evaporator from which a fine white solid formed which was filtered off and returned to a vessel as a damp paste. A 1 : 1 mixture of MeOH/ water (8 mL) was added and heated to 40 °C with stirring. After 1 hour, the white solid was filtered off. Some residual solid was washed out with fresh water that was also rinsed through the cake, which was then isolated and left to air dry over the two days to give a dense white solid 10 (1.00 g, 88%). ¾ NMR (500 MHz, CDCb) 7.85

(2H, d, J = 8.8 Hz, RO-Ar ortho-H), 7.00 (2H, d, J = 8.8 Hz, RO-Ar meta- H), 3.87 (2H, d, J = 7.0 Hz, OCH2CH), 3.02 (3H, s, CHs), 1.34-1.23 (1H, m, OCH2CH), 0.72-0.60 (2H, m, 2 x CHCHflHb), 0.42-0.31 (2H, m, 2 x CHCH^.

1.3: Synthesis and Isolation Coupling Partner Boronic Ester 2

[0236] The final bond forming step to Compound 1 is a Suzuki-Miyaura coupling between Compounds 2 and 3, as shown in Scheme 3 below (Norio, M. and Suzuki, A., Chem. Rev., 95(7), 2457-2483 (1995)). Early studies demonstrated that the boronic ester of the isoquinolinone Compound 3-a had poor physical attributes and solid phase stability (Kaila, N. et al., J. Med Chem., 57: 1299-1322 (2014)). The pinacolatoboronate of the O-alkyl phenol, Compound 7, had acceptable solid phase stability and could be isolated via crystallization.

Scheme 3: Suzuki-Miyaura coupling between 2 and 3

[0237] Process robustness studies for the isolation of Compound 7, however, indicated that Compound 7 has poor solution stability, decomposing primarily to the proteodeborylated compound 10, as shown in Scheme 4 below. This was particularly problematic as the isolation process involved a solvent exchange from 2-MeTHF (2-methyl tetrahydrofuran) to iPrOAc (isopropyl acetate), which is not a fast unit operation on scale.

Scheme 4: Modification of 7

[0238] A search for a more stable boronic ester was undertaken. Early attempts targeted making N-methyliminodiacetic acid (MID A) boronate Compound 2-a (E. Gilis and M. Burke,“Multi step Synthesis of Complex Boronic Acids from Simple MIDA Boronates,” J Am. Chem. Soc., 750(43): 14084-14085 (2008)), however, all attempts resulted in product decomposition. Applicant then turned to a relatively obscure boronate formed by the addition of diethanolamine to Compound 7 (Bonin et al., Tetrahedron Lett., 52: 1132-1135 (2011)). Addition of diethanolamine to a solution of Compound 7 led to rapid ester formation and concomitant crystallization of Compound 2.

[0239] The discovery of boronic ester Compound 2 allowed for a simple, fast, high-yielding, high-purity process comprising the following procedure. Tetrahydrofuran (THF, 1500mL) was charged to a flask containing Compound 6 (100g, 328 mmol), bis(pinacolato)diboron (90.7g, 357 mmol) and cesium acetate (CsOAc, 158g, 822 mmol). The system was vacuum purged three times with nitrogen. Pd(PPh3)2Cl2 (13.8g, 20 mmol) was charged to the reaction and the system was vacuum purged three times with nitrogen. The reaction was then heated to 55 to 65°C.

[0240] The batch was stirred for approximately 8 hours until reaction was complete by HPLC analysis. The batch was cooled to 15 to 25 °C (target 20 °C ) and charged with silica gel (20g) and Ecosorb C-941 (20g). After lh, the mixture was filtered to remove solid. The residual solids were washed twice, each with THF (300mL). The filtrate and washes were combined. In a separate vessel, diethanolamine (34.5mL, 360 mmol) was dissolved in THF (250 mL). The diethanolamine solution in THF (25mL) was then charged to the batch. After 10 minutes, the batch was seeded with 2 (1 g) and aged for 1 to 2 hours. The remaining of the diethanolamine solution in THF was charged to the batch over at least 2 hours and the slurry was stirred for at least 2 hours. The product 2 was collected by suction filtration. The wet cake was washed thrice with THF (200mL). The material was dried under vacuum at 40 °C with nitrogen purge yielding 94.6g of 2.

[0241] The reaction to synthesize Compound 2 from Compound 6 described above may be modified as follows. Solvent: Different solvents from THF could be used, such as 1,4 dioxane or 2-methyltetrahydrofuran. Reaction volume: The reaction volume can be varied from 4 to 50 volumes with respect to compound 2. Catalyst and base: Different palladium catalyst and bases can be used for the borylation. Examples can be found in Chow et al., RSC Adv., 3 : 12518-12539 (2013). Borylation reaction temperature: Reaction temperatures from room temperature (20 °C) to solvent reflux can be used. Carbon/ Silica treatment:

The treatment can be performed without silica gel. The process can be performed without a carbon treatment. Different carbon sources from Ecosorb C-941 can be used. Different amounts of silica, from 0.01X to IX weight equivalents, can be used. Different amounts of Ecosorb C-941, from 0.01X to IX weight equivalents, can be used. Crystallization: A different addition rate of diethanolamine can be used. Different amounts of diethanolamine, from 1.0 to 3.0 molar equivalents can be used. A different cake wash with more or less THF can be used. Different amount of seeds from 0.0001X wt to 50X wt can be used.

Alternatively, the process can be unseeded. Drying: A temperature range of 10 °C to 60 °C could be used for drying.

[0242] The subsequent Suzuki-Miyaura coupling between Compounds 2 and 3 also proceeded well, providing over 20 kg of crude compound 1 with an average molar yield of 80% and LCAP of 99.7%.

1.4: Synthesis of Coupling Partner 3

[0243] Cross-coupling partner 3 was prepared by two different processes corresponding to Schemes 8 and 9 shown below.

Scheme 8: Process A for preparation of 3

[0244] According to Process A, Compound 9 (100g, 628 mmol) was dissolved in acetonitrile (450 mL) at room temperature. In a separate vessel, N-bromosuccinimide (NBS, 112g, 628 mmol) was suspended in acetonitrile (1 L). Compound 9 in acetonitrile was charged to the NBS slurry over at least 45 minutes. The contents of the reaction vessel were warmed to 45 °C to 55 °C and the batch stirred until the reaction was complete by HPLC analysis. The batch was cooled to 35 °C to 45 °C and ensured dissolution. Norit SX plus carbon (lOg) was charged to the mixture and the reaction mixture adjusted to 55 °C to 60 °C. The mixture was stirred at 55 °C to 60 °C for about lh and the mixture filtered at 55 °C to 60 °C to remove solids. The solids were washed with acetonitrile (500mL) at 55 °C to 60 °C. The volume of the combined filtrate was reduced to 900 mL by distilling off acetonitrile under reduced pressure. The batch with Compound 3 (lg) and stirred at 35 °C to 45 °C for at least 60 minutes. The contents of the reaction vessel were cooled to 15 °C to 25 °C over at least 1 hour. Water (2000 mL) was charged to the reaction vessel over at least 90 minutes and the slurry aged for at least 60 minutes. The product was collected by suction filtration. The cake was washed with a premixed 5% solution of acetonitrile in water (300mL). The wet cake was dried under vacuum at 40 °C with nitrogen purge. Yield: 120g of 3.

[0245] The above procedure, Process A for this synthesis of 3, may be practiced with alternative reagents and conditions as follows. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as methylene chloride, chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as tetrahydrofuran, or 2-methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from 2X vol to 40 X vol (with respect to Compound 9). Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent Stoichiometry: Different amounts of the brominating reagent can be used, from 0.8 equiv to 2 equiv. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 °C to 60 °C could be used for drying.

Scheme 9: Process B for preparation of 3

[0246] According to Process B, Compound 3 can be formed starting from 8 via non-isolated compound 9 as follows. Compound 8 (80 g, 55 mmol), cesium carbonate (CS2CO3, 215 g, 66 mmol), and acetonitrile (800 mL) were charged to the reactor. The temperature was adjusted from 15 to 25 °C and iodomethane charged to the reactor (Mel, 86 g, 0.61 mol) while maintaining a batch temperature below 25 °C. The batch was heated to 40 °C and agitated for 10 hours to form Compound 9. The batch was cooled to 25 °C, filtered into a fresh reactor to remove solids, and the solids washed twice with acetonitrile. The combined organic layers were concentrated via atmospheric distillation to about 320 mL.

[0247] In a separate reactor N-bromosuccinimide (NBS, 98.1 g, 0.55 mol) was charged to acetonitrile (800 mL) and agitated. The batch containing Compound 9 was transferred to the NBS solution while maintaining a batch temperature of 15 to 25 °C. The batch was heated to 45 to 55 °C and agitated for at least 4 hours to allow for reaction completion to Compound 3. Upon reaction completion, Norit SX Plus activated carbon (8 g) was charged, and agitated at 45 to 55 °C for one hour. The batch was filtered into a fresh vessel, the Norit SX plus cake was washed with 400 ml of 45 to 55 °C acetonitrile. The acetonitrile layers were combined, cooled to 35 to 45 °C, and distilled under reduced pressure to 720 mL. The batch was adjusted to a temperature of 40 °C, charged with Compound 3 seeds (0.8 g), agitated for one hour, cooled to 15 to 25 °C over at least on hour, then charged with water (1600 mL) over at least two hours. The mixture was agitated for an additional one to two hours, filtered, the cake washed with a premixed 5% solution of acetonitrile in water (240 mL). The wet cake was dried under vacuum at 40°C with nitrogen purge. Yield: 52 g of 3.

[0248] Process B to synthesize Compound 3, described above, may be modified as follows. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as methylene chloride, chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as tetrahydrofuran, or 2-methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from 2X vol to 40 X vol (with respect to Compound 8).

Alkylating reagent: Alternative methylating reagents to methyl iodide can be used such as dimethylsulfate. Alkylating reagent stoichiometry: 1 to 10 molar equivalents of methyl iodide may be used. Base: Different inorganic bases, such as potassium carbonate or phosphate bases (sodium, potassium, or cesium) could be used. Brominating agents:

Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Different amounts of the brominating reagent can be used, from 0.8 equiv to 2 equiv. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. Seeding levels from 0.0001% to 50% can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying.

1.5: Cross-coupling of 2 and 3 to Produce Target Compound 1

[0249] 1 is synthesized by Suzuki cross-coupling of 3 and 2 according to Scheme 10 and as described below.

Scheme 10: Synthesis of 1

[0250] Acetonitrile (1.6L) was charged to a mixture of Compound 2 (156.7g, 460 mmol), Compovmd 3 (lOOg, 420 mmol) and potassium phosphate tribasic (223 g, l.OSmol). Agitation was begun and water (400mL) charged to the batch. The system was vacuum purged three times with nitrogen and charged with Pd(PPh3)2Cl2 (2.9g, 4 mmol) and the system vacuum

purged three times with nitrogen. The batch was heated to 65 to 75°C and contents stirred for at least 16 hours until reaction was complete by HPLC analysis. The batch was cooled to 60 to 70°C, agitation halted and the mixture allowed to settle. The bottom aqueous layer was removed. Water (150mL) and acetonitrile (700mL) were charged at 60 to 70°C. Ecosorb C-941 (15g) and Celite (lOg) were charged to the reaction vessel at 60 to 70°C. After lh, the mixture was filtered to remove solids. The solids were washed twice each with 18% water in acetonitrile (500 mL) at 60 to 70°C. The filtrates were combined and concentrated under atmospheric pressure to a final volume of 1.5L. The batch was cooled to 60 to 65°C and seeded with Compound 1 (1 g). After lh, water (500 mL) was charged over at least 1 hour at 60 to 65°C. The slurry was cooled to 15 to 25°C over 4 hours. The product was collected by suction filtration. The wet cake was washed with 45% water in acetonitrile (500mL) twice. The product was dried under vacuum at 40°C with nitrogen purge. Yield: 139g of 1.

[0251] The above procedure for coupling Compound 3 and Compound 2 to produce

Compound 1 may be modified in any of the ways that follow. Reaction solvents: Different reaction solvents from acetonitrile can be used, including tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, and isopropanol. Boronic ester: Different boronic esters from Compound 2 can be used, including pinacolato ester compound 7, and the free boronic acid of Compound 2. Examples of boronic esters can be found in Lennox, Alister, J.J., Lloyd-Jones, Guy C. Chem. Soc. Rev., 2014, 43, 412. Carbon treatment: Different carbon treatments from Ecosorb C-941 could be used. Different amounts of carbon, from 0.01 to 0.5X weight can be used. The carbon can be eliminated. Different amounts of Celite, from 0.01 to 0.5X weight can be used. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1);

cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCk(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy3 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5); Pd(PPh3)2Cl2 (Cas# 13965-03-2). Examples of

catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

1.6: Crystallization of 1

[0252] The final isolation of Compound 1 requires a polish filtration. For this, the batch must be completely soluble. Unfortunately, Compound 1 has low solubility in almost all

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Class 3 and common Class 2 (e.g. THF, MeCN) solvents (ICH

Harmonized Guideline“Impurities: Guideline for Residual Solvents Q3C(R6)” October 20, 2016). A reasonable solubility was obtained in a warm MeCN-water mix, but this is not an optimal system (requires a heated filtration, MeCN has a residual solvent limit of only 410 ppm). Additional solvents with reasonable solubility (>50 mg/ml) include N-methyl-2- pyrrolidone (NMP) and dimethylacetamide (DMAc); but the development of isolations from these solvents required large volumes and raised residual solvent limit concerns (530 ppm or less for NMT and 1090 ppm or less for DMAc).

catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.

Table 4: Catalyst screen summary

1.6: Crystallization of 1

[0252] The final isolation of Compoxmd 1 requires a polish filtration. For this, the batch must be completely soluble. Unfortunately, Compound 1 has low solubility in almost all

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Class 3 and common Class 2 (e.g. THF, MeCN) solvents (ICH

Harmonized Guideline“Impurities: Guideline for Residual Solvents Q3C(R6)” October 20, 2016). A reasonable solubility was obtained in a warm MeCN-water mix, but this is not an optimal system (requires a heated filtration, MeCN has a residual solvent limit of only 410 ppm). Additional solvents with reasonable solubility (>50 mg/ml) include N-methyl-2- pyrrolidone (NMP) and dimethylacetamide (DMAc); but the development of isolations from these solvents required large volumes and raised residual solvent limit concerns (530 ppm or less for NMT and 1090 ppm or less for DMAc).

[0253] Formic acid is one ICH Class 3 solvent in which Compound 1 is highly soluble, having a solubility greater than 250 mg/ml at 20 °C. The solubility curve of Compound 1 in formic acid-Water is quite steep (see Figure 7), which enables a volumetrically efficient process.

[0254] Initial attempts to recrystallize crude Compound 1 involved dissolving in formic acid, polish filtering, and charging polish filtered water to about 20% supersaturation, followed by seeding with the thermodynamically most stable form (Form 1), followed by slow addition of water to the final solvent ratio, filtration, washing, and drying. Applicant observed that during the initial water charge, if the batch self-seeded it formed a thick slurry. X-ray diffraction (XRD), differential scanning calorimetry (DSC), and photomicroscopy demonstrated that a metastable form was produced. Once seeded with Form 1, the batch converted to the desired form (Form 1) prior to the addition of the remaining water. This process worked well during multiple lab runs, consistently delivering the desired form and purity with about 85% yield.

[0255] Unfortunately, upon scale-up, the batch did not convert to Form 1 after seeding. Additional water was charged and the batch began to convert to the desired form (mix of Form 1 and the metastable form by X-ray powder diffraction (XRPD)). When additional water was charged, the XRPD indicated only the metastable form. After a few hours with no change, Applicant continued the water charge to the final solvent ratio, during which time the batch eventually converted to Form 1. This process is summarized in Figure 8.

[0256] It was subsequently found by closer analysis of the plant and laboratory retains that a new metastable form was formed during scale up, with a similar, but different XRPD pattern. This form (metastable B) could be reproduced in the laboratory, but only when the batch has a high formic acid:water ratio and is seeded with Form 1. Without Form 1 seeds, metastable A is the kinetic form. Both metastable forms converted to Form 1 with additional water and/or upon drying, leading Applicant to believe that the metastable forms are formic acid solvates. These findings are summarized in Figure 9.

[0257] While there is little risk in not being able to control the final form, there is a risk of forming a difficult-to-stir slurry which can lead to processing issues. The crystallization procedure was therefore modified to keep a constant formic acid-water ratio. This was performed by charging 2.4X wt. formic acid and 1.75X wt. water (final solvent composition)

to the crystallizer with 0.03X wt. Form 1 seeds, and performing a simultaneous addition of Compound 1 in 6. IX wt. formic acid and 4.4X wt. water. The batch filtered easily and was washed with formic acid/water, then water, and dried under reduced pressure to yield 8.9 kg of Compound 1 (92% yield) with 99.85% LCAP and N.D. formic acid.

Example 2: Exemplary high throughput experimentation reaction

[0258] The following procedure is an exemplary high throughput experimentation reaction.

[0259] An overview of the reaction is shown below in Scheme 5:

Scheme 5: Reaction conditions tested for cross-coupling reaction of 2 and 3

[0260] Pd catalysts were dosed into the 24-well reactor vial as solutions (100 pL of 0.01 M solution in tetrahydrofuran (THF) or dichloroethane (DCE) depending upon the solubility of the ligand). Plates of these ligands are typically dosed in advance of the reaction, the solvent is removed by evacuation in an evaporative centrifuge and plates are stored in the glovebox. The catalysts screened in the coupling are the following: XPhos, SPhos, CataCXium A, APhos, P(Cy)3, PEPPSI-IPent. For the first five ligands, these were initially screened as the Buchwald Pd G2/G3 precatalysts.

[0261] To the plates was then added a stock solution of Compound 3 (10 pmol) and Compound 2 (12 pmol) dissolved in the following solvents: dimethylformamide (DMF),

tetrahydrofuran (THF), butanol (/r-BuOH), and toluene. The base was then added as a stock solution (30 mmol) in 20 mL of water.

[0262] A heatmap summarizing catalyst performance is shown in Figs. 10A and 10B. High performance liquid chromatography (HPLC) yields for this screening span from <5% up to -85%. Larger circles indicate higher yield. Lighter circles indicate higher cleanliness.

[0263] A similarly designed screening of base and solvent also indicate that a range of alcoholic solvents (methanol, ethanol, propanol, 2-butanol, 2-propanol, and /-amyl alcohol) are also all viable in this coupling chemistry. Bases such as potassium phosphate, potassium carbonate, potassium acetate, and potassium hydroxide were all successful in achieving the coupling. Fig. 10B shows a heatmap with HPLC yields ranging from -50 – 95%. Larger, darker circles indicate higher yield.

[0264] This chemistry from microvial screening has been scaled to a laboratory process. To a 3 -necked jacketed 250 mL flask equipped with overhead stirring, nitrogen inlet, and thermocouple was added Compound 3 (1.0 eq, 4.00 grams), Compound 2 (1.2 eq, 1.71 x wt), potassium carbonate (3.0 eq, 1.74 x wt). The reactor was inerted three times and then degassed 2-propanol (24 x vol.) followed by degassed water (6 x vol) was then added.

Stirring was then initiated at 300 rpms. The reactor was then stirred and blanketed with nitrogen for 1 hour. The catalyst was then added (0.01 eq, 0.028 x wt) and stirring continued (300 rpms) and the reactor was heated into the Tj = 65 °C.

[0265] After 2 hours, with full conversion confirmed analytically, trioctylphosphine (0.1 eq, 0.16 x wt) dosed, and reaction mixture allowed to cool slowly to room temperature hours.

The reaction mixture was then filtered, washed with 2-propanol (4 x vol), 2-propanol: water (4: 1, 4 x vol), and then with water (4 x vol). Note: If 2 is dimer present in cake, an additional ethyl acetate (EtOAc) wash (4 x vol) can be added for purging. The cake was then transferred to a vacuum oven to dry overnight at 40 °C, -40 cm Hg, under nitrogen flow. After transfer to a bottle, 6.03 grams of 1 were isolated, 98.6% assay, 91% overall yield.

Scheme 6: Alternative reagents and solvents for cross-coupling

[0266] Based on the previously delineated results, it was expected that a variety of monodentate (PPI13 [triphenylphosphine], PBu3 [tributylphosphine], etc) and bidentate phosphines (dppf [1,1 ‘-bis(diphenylphosphino)ferrocene], BINAP [2,2 -bis(diphenylphosphino)- 1 , 1 -binaphthyl], Xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene], dppe [l,2-bis(diphenylphosphino)ethane], etc) ligated to any number of Pd sources (Pd halides, Pd(H) precatalyts, Pd(0) sources) could reasonably be employed to arrive at the Compound 1 crude material. A range of organic solvents ranging from non-polar (heptane, benzene), protic (alcohols), polar aprotic (dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetonitrile) as well as a variety of esters and ketones (acetone, 2-butanone, ethylacetate) should also serve as effective solvents for this reactivity. Finally, inorganic bases of varying strength (phosphates, carbonates, acetates, etc) along with organic variants such as triethylamine, l,8-diazabicyclo(5.4.0)undec-7-ene, and others in a wide pKa range are viable as stoichiometric basic additives.

Example 3: Exemplary Compound 5 process

[0267] The purpose of this example was to describe an exemplary process for making Compound 5.

[0268] Charge 4 (lOg, 58mmol) and acetonitrile (lOOmL) to a reaction vessel and start the stirrer. Adjust the batch to -18 °C to -22 °C (target -20 °C). Charge triflic acid (5.5mL, 62mmol) to the batch maintaining -10 °C to -25 °C (target -20 °C). Stir the batch at -10 °C to -25 °C (target -20 °C) for 10 to 20 minutes. Charge NBS (11.38g, 64mmol) to the batch at -10 °C to -25 °C (target -20 °C) and stir for ca. 30 min at -10 °C to -25 °C (target -20 °C). Warm the batch to 20 °C over 3-4 hours (reaction will occur when internal temp is between 5 °C and 15 °C). Stir the batch at 15 °C to 25 °C (target 20 °C) for approximately 1 hour and sample for reaction completion.

[0269] If Compound 4 relative to Compound 5 is more than 5%:

[0270] Cool the bath to -5 °C to -15 °C (target -10 °C) (cooling below 0 °C to ensure selectivity). Charge NBS to the batch according to the follow formula: Mass of NBS = (% Compound 4 x lOg). Warm the batch to 20 °C over 1-2 hours. Stir the batch at 15 °C to 25 °C (target 20 °C) for approximately 1 hour and check reaction for completion. Proceed to next line.

[0271] If Compound 4 relative to Compound 5 is less than 5%:

[0272] Warm the batch to 40 °C to 50 °C (target 48 °C). Concentrate the batch under reduced pressure to a final volume of ~40mL. Cool the batch to -15 °C to -5 °C (target -10 °C) and stir for ca. lh. Filter the batch by suction filtration. Slurry wash the filter cake with purified water (3 x 20mL) at 15 °C to 25 °C (target 20 °C) for 10 to 15 minutes each wash. Remove a sample of the filter cake for analysis by ¾ NMR. Continue washing cake until the residual succimide is below 1.0%mol% relative to 5. Dry the filter cake at up to 60°C under vacuum and nitrogen purge. Analyse the 5 by HPLC analysis (97%w/w to 99%w/w). Expected yield: 60-85% theory (90-110% w/w).

Example 4: Purification of Compound 1 (CC-90010) by crystallization from formic acid and water.

[0273] This example describes a method for the purification of Compound 1 by

crystallization from formic acid and water. Also detailed are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1.

[0274] Figure 11 shows XH NMR of Compound 1 (CC-90010). Solvent: d6DMSO; and Figure 12 shows microscopy of Compound 1 (CC-90010) Form I. Figure 13 shows XRPD of Compound 1 (CC-90010) Form I, with peak information detailed in Table 6:

PATENT

US 20190008852

WO 2018081475

US 20180042914

WO 2016172618

WO 2015058160

/////////CC-90010, solid tumors , non-Hodgkin’s lymphoma, PHASE 1, CANCER, QUANTICEL

CS(=O)(=O)c4cc(C1=CN(C)C(=O)c2ccccc12)c(OCC3CC3)cc4

Zanubrutinib, ザヌブルチニブ , занубрутиниб , زانوبروتينيب ,


Zanubrutinib (USAN/INN).png

Image result for Zanubrutinib

ChemSpider 2D Image | zanubrutinib | C27H29N5O3

Zanubrutinib, BGB-3111

Formula
C27H29N5O3
CAS
1691249-45-2
Mol weight
471.5509

FDA , 2019/11/14, Brukinsa

ザヌブルチニブ ,

занубрутиниб [Russian]
زانوبروتينيب [Arabic]
(7S)-7-(1-Acryloyl-4-piperidinyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
Pyrazolo[1,5-a]pyrimidine-3-carboxamide, 4,5,6,7-tetrahydro-7-[1-(1-oxo-2-propen-1-yl)-4-piperidinyl]-2-(4-phenoxyphenyl)-, (7S)-

Antineoplastic, Bruton’s tyrosine kinase inhibitor, Mantle cell lymphoma

Zanubrutinib, sold under the brand name Brukinsa, is for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.[3]

It was approved for medical use in the United States in November 2019.[4][3][5][6]

Zanubrutinib is classified as a Bruton’s tyrosine kinase (BTK) inhibitor. It is administered orally.

History

Efficacy was evaluated in BGB-3111-206 (NCT03206970), a phase II open-label, multicenter, single-arm trial of 86 patients with mantle cell lymphoma (MCL) who received at least one prior therapy.[5] Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity.[5] Efficacy was also assessed in BGB-3111-AU-003 (NCT 02343120), a phase I/II, open-label, dose-escalation, global, multicenter, single-arm trial of B‑cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib administered orally at 160 mg twice daily or 320 mg once daily.[5][6]

The primary efficacy outcome measure in both trials was overall response rate (ORR), as assessed by an independent review committee.[5] In trial BGB-3111-206, FDG-PET scans were required and the ORR was 84% (95% CI: 74, 91), with a complete response rate of 59% (95% CI 48, 70) and a median response duration of 19.5 months (95% CI: 16.6, not estimable).[5] In trial BGB-3111-AU-003, FDG-PET scans were not required and the ORR was 84% (95% CI: 67, 95), with a complete response rate of 22% (95% CI: 9, 40) and a median response duration of 18.5 months (95% CI: 12.6, not estimable).[5] Trial 1 was conducted at 13 sites in China, and Trial 2 was conducted at 25 sites in the United States, United Kingdom, Australia, New Zealand, Italy, and South Korea.[6]

The U.S. Food and Drug Administration (FDA) granted zanubrutinib priority reviewaccelerated approvalbreakthrough therapydesignation, and orphan drug designation.[3][5][7]

The FDA approved zanubrutinib in November 2019, and granted the application for Brukinsa to BeiGene USA Inc.[3][5][8]

PAPER

https://www.x-mol.com/paper/5799457

Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase Journal of Medicinal Chemistry ( IF 6.054 ) Pub Date: 2019-08-19 , DOI: 10.1021 / acs.jmedchem.9b00687

Yunhang Guo, Ye Liu, Nan Hu, Desheng Yu, Changyou Zhou, Gongyin Shi, Bo Zhang, Min Wei, Junhua Liu, Lusong Luo, Zhiyu Tang, Huipeng Song, Yin Guo, Xuesong Liu, Dan Su, Shuo Zhang, Xiaomin Song , Xing Zhou, Yuan Hong, Shuaishuai Chen, Zhenzhen Cheng, Steve Young, Qiang Wei, Haisheng Wang, Qiuwen Wang, Lei Lv, Fan Wang, Haipeng Xu, Hanzi Sun, Haimei Xing, Na Li, Wei Zhang, Zhongbo Wang, Guodong Liu, Zhijian Sun, Dongping Zhou, Wei Li, Libin Liu, Lai Wang, Zhiwei Wang

Aberrant activation of Bruton’s tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.
PATENT
WO 2014173289
WO 2018033135
PATENT
WO 2018033853

Bruton’s tyrosine kinase (Btk) belongs to the Tec tyrosine kinase family (Vetrie et al., Nature 361: 226-233, 1993; Bradshaw, Cell Signal. 22: 1175-84, 2010). Btk is primarily expressed in most hematopoietic cells such as B cells, mast cells and macrophages (Smith et al., J. Immunol. 152: 557-565, 1994) and is localized in bone marrow, spleen and lymph node tissue. Btk plays important roles in B-cell receptor (BCR) and FcR signaling pathways, which involve in B-cell development, differentiation (Khan, Immunol. Res. 23: 147, 2001). Btk is activated by upstream Src-family kinases. Once activated, Btk in turn phosphorylates PLC gamma, leading to effects on B-cell function and survival (Humphries et al., J. Biol.Chem. 279: 37651, 2004).

[0003] These signaling pathways must be precisely regulated. Mutations in the gene encoding Btk cause an inherited B-cell specific immunodeficiency disease in humans, known as X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. 27: 199-227, 2009). Aberrant BCR-mediated signaling may result in dysregulated B-cell activation leading to a number of autoimmune and inflammatory diseases. Preclinical studies show that Btk deficient mice are resistant to developing collagen- induced arthritis. Moreover, clinical studies of Rituxan, a CD20 antibody to deplete mature B-cells, reveal the key role of B-cells in a number of inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis (Gurcan et al, Int. Immunopharmacol. 9: 10-25, 2009). Therefore, Btk inhibitors can be used to treat autoimmune and/or inflammatory diseases.

[0004] In addition, aberrant activation of Btk plays an important role in pathogenesis of B-cell lymphomas indicating that inhibition of Btk is useful in the treatment of hematological malignancies (Davis et al, Nature 463: 88-92, 2010). Preliminary clinical trial results showed that the Btk inhibitor PCI-32765 was effective in treatment of several types of B-cell lymphoma (for example, 54thAmerican Society of Hematology (ASH) annual meeting abstract, Dec. 2012: 686 The Bruton’s Tyrosine Kinase (Btk) Inhibitor, Ibrutinib (PCI- 32765), Has Preferential Activity in the ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-Cell Lymphoma (DLBCL): Interim Results of a Multic enter, Open-Label, Phase I Study). Because Btk plays a central role as a mediator in multiple signal transduction pathways, inhibitors of Btk are of great interest as anti-inflammatory and/or anti-cancer agents {Mohamed et al., Immunol. Rev. 228: 58-73, 2009; Pan, Drug News perspect 21: 357-362, 200%; Rokosz et al., Expert Opin. Ther. Targets 12: 883-903, 2008; Uckun et al., Anti-cancer Agents Med. Chem. 7: 624-632, 2007; Lou et al, J. Med. Chem. 55(10): 4539-4550, 2012).

[0005] International application WO2014173289A disclosed a series of fused heterocyclic compounds as Btk inhibitors. In particular, WO2014173289A disclosed

(S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[l,5-a]pyrimi dine-3-carboxamide (hereinafter C

Compound 1

[0006] Compound 1 is a potent, specific and irreversible BTK kinase inhibitor. The data generated in preclinical studies using biochemical, cell based and animal studies suggested that Compound 1 could offer significant benefit in inhibiting tumor growth in B-cell malignancies. As Compound 1 was shown to be more selective than ibrutinib for inhibition of BTK vs. EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC, it is expected to give rise to less side-effects than ibrutinib in clinic. In addition, Compound 1 showed significantly less inhibition of rituximab-induced antigen-dependent cell-mediated cytotoxicity (ADCC) than ibrutinib due to weaker ITK inhibition, and therefore may provide better efficacy when combined with rituximab or other ADCC-dependent antibody in treating B-cell malignancies.

[0007] Preclinical safety evaluation has demonstrated that Compound 1 was safer than ibrutinib in terms of the overall tolerance and severe toxicities in both rat and dog single and repeat dose toxicity studies up to 28 days. Additionally, Compound 1 had better bioavailability without accumulation issues observed for ibrutinib. These unique characteristics warrant further evaluation of Compound 1 in clinical studies.

[0008] However, Compound 1 was found to be an amorphous form according to the preparation method for Compound 27 in WO 2014173289A, which was further confirmed by the X-Ray Powder Diffraction pattern of FIG. 7A. The amorphous form was shown to have a low glass transition temperature as shown in FIG. 7B, indicating some difficulties in the drug formulation with the amorphous form, such as low stability and hard to purify. Therefore, it’s necessary to develop a new form of Compound 1 which possesses characteristics such as high melting point and better stability, suitable for drug formulation.

Scheme 1: Preparation of Compound 1 and deuterium-labeled Compound 1

Deuterium-Labeled Compound 1

Step 15: Synthesis of

(S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolori,5-a1pyrimi dine-3-carboxamide (Compound 1

[0105] Under N2 atmosphere, ACN (12.0 v), water (12.5 v), BG-13 (8.0 Kg, 1.0 eq), and NaHC03 (2.5 eq.) were added to a reactor. The mixture was then cooled to -5-0 °C. To the mixture, the solution of acryloyl chloride (1.1 eq.) in MeCN (0.5 v) was added dropwise and

stirred until the reaction was completed. EA (6.0 v) was then added to the reactor, and stirred. The organic phase was collected. The aqueous layer was further extracted with EA (3.0 v). The organic phases were combined and washed with brine. The organic layer was collected and concentrated.

[0106] The residue was purified by silica gel (2 wt) column, eluted with 3% w/w methanol in DCM (21.0 v). The Compound 1 solution was collected and concentrated under vacuum. The residue was precipitated from EA/MTBE (2.0 v). The cake was collected by centrifugation as the product.

Step 15: Synthesis of (S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)

-4,5,6,7-tetrahydropyrazolori,5-a1pyrimidine-3-carboxamide (Compound 1, alternative method)

[0107] A mixture of CHsCN (10.0 v), purified water (5.0 v), NaOH (1.5 eq.) and BG-13 (1.0 eq.) was stirred to get a clear solution. EtOAc (6.0 v) was then charged to the reaction and separated. The organic phase was collected and washed with 15% brine (3.0 v) twice. The organic phase prepared above was concentrated and the solvent was swapped to CH3CN (residue volume: NMT 5.0 v). CH3CN (7.5 v) and purified water (12.5 v) were charged and cooled to 15-20°C. L-(+)-tartaric acid (0.5 eq) and NaHCCb (2.5 eq.) were charged to the reaction mixture. A solution of acryloyl chloride (1.1 eq.) in CH3CN (0.5 v) was charged drop-wise to the reaction mixture. After the reaction was completed, EtOAc (6.0 v) was charged to the reaction mixture and organic layer was collected. Aqueous phase was further extracted with EA (3.0 v). The organic layers were combined, washed with 15% brine (5.0 v) and concentrated. The solvent was swapped to DCM (volume of residue: 1.5-2.0 v) and purified by silica gel column (silica gel: 100-200 mush, 2.0 w/ w; eluent: 3%> w/ w MeOH in DCM (about 50 v). The collected solution was concentrated and swapped to EtOAc (4.0 v). MTBE (6.4 v) was charged drop-wise to residue at 50°C. The mixture was then cooled to 5°C and the cake was collected centrifugation.

Step 16: Preparation of Crystalline Form A of Compound 1

[0108] The above cake of Compound 1 was dissolved in 7.0 volumes of DCM, and then swapped to solvent EA. After recrystallization from EA/MTBE, the cakes was collected by centrifugation, and was dried under vacuum. This gave 4.44 Kg product (Yield: 70.2%).

[0109] The product was then characterized by X-ray powder diffraction (XRPD) pattern method, which was generated on a PANalytical Empyrean X-ray powder diffractometer with the XRPD parameters as follows: X-Ray wavelength (Cu, ka, Kal (A): 1.540598, Ka2(A): 1.544426; Ka2/Kal intensity ratio: 0.50); X-Ray tube setting (45 Kv, 40mA); divergence slit (automatic); scan mode (Continuous); scan range (°2TH) (3°-40); step size (°2TH) (0.0131); scan speed (°/min) (about 10). The XRPD result found the resultant product as a crystalline shown in FIG. 1.

[0110] The differential scanning calorimetry (DSC) curves shown as in FIG. 2 was generated on a TA Q2000 DSC from TA Instruments. The DSC parameters used includes: temperature (25°C-desired temperature); heating rate (10°C/min) ; method (ramp); sample pan (aluminum, crimped); purge gas (N2). DSC result showed a sharp melting point at 139.4°C (onset temperature).

[0111] The thermo-gravimetric analysis (TGA) curves shown as in FIG. 3 was generated on a TA Q5000 TGA from TA Instruments. The TGA parameters used includes: temperature

(RT-desired temperature); heating rate (10°C/min); method (ramp); sample pan (platinum, open); purge gas (N2). TGA result showed is anhydrous with no weight loss even up to 110 °C.

[0112] The proton nuclear magnetic resonance ^H-NMR) shown as in FIG. 4 was collected on a Bruker 400M NMR Spectrometer in DMSO-de. ¾-NMR (DMSO-de) δ 7.50 (d, J= 8.6 Hz, 2H), 7.46-7.38 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.08 (d, J= 7.6 Hz, 2H), 7.05 (d, J= 8.8 Hz, 2H), 6.85-6.72 (m, 1H), 6.67 (s, 1H), 6.07 (dd, J= 16.8, 2.2 Hz, 1H), 5.64 (dd, J= 10.4 Hz, 2.2 Hz, 1H), 4.55-4.38 (m, 1H), 4.17-3.94 (m, 2H), 3.33-3.22 (m, 2H), 3.08-2.88 (m, 1H), 2.67-2.51 (m, 1H), 2.36-2.15 (m, 1H), 2.12-1.82 (m, 2H), 1.79-1.65 (m, 1H), 1.63-1.49 (m, 1H), 1.38-1.08 (m, 2H).

[0113] The carbon nuclear magnetic resonance (13C-NMR) shown as in FIG. 5 was collected on a Bruker 400M NMR Spectrometer in DMSO-de. 13C-NMR spectra for Crystalline Form A of Compound 1.

PATENT
 WO 2019108795

Step 15: Synthesis of (S)-7-(1-acrvlovlpiperidin-4-vl)-2-(4-phenoxvphenyl)-4.5.6.7-tetrahvdropvrazolo[1.5-a1pvrimidine-3-carboxamide (Compound 1)

[0119] Under N2 atmosphere, ACN (12.0 v), water (12.5 v), BG-13 (8.0 Kg, 1.0 eq), and NaHCO3 (2.5 eq.) were added to a reactor. The mixture was then cooled to -5-0 °C. To the mixture, the solution of acryloyl chloride (1.1 eq.) in MeCN (0.5 v) was added dropwise and stirred until the reaction was completed. EA (6.0 v) was then added to the reactor, and stirred. The organic phase was collected. The aqueous layer was further extracted with EA (3.0 v). The organic phases were combined and washed with brine. The organic layer was collected and concentrated.

[0120] The residue was purified by silica gel (2 wt) column, eluted with 3% w/w methanol in DCM (21.0 v). The Compound 1 solution was collected and concentrated under vacuum. The residue was precipitated from EA/MTBE (2.0 v). The cake was collected by centrifugation as the product.

Step 15: Synthesis of (S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl) -4.5.6.7-tetrahvdropvrazolori.5-a1pvrimidine-3-carboxamide (Compound 1. alternative method)

[0121] A mixture of CH3CN (10.0 v), purified water (5.0 v), NaOH (1.5 eq.) and BG-13 (1.0 eq.) was stirred to get a clear solution. EtOAc (6.0 v) was then charged to the reaction and separated. The organic phase was collected and washed with 15% brine (3.0 v) twice. The organic phase prepared above was concentrated and the solvent was swapped to CH3CN (residue volume: NMT 5.0 v). CH3CN (7.5 v) and purified water (12.5 v) were charged and cooled to 15-20°C. L-(+)-tartaric acid (0.5 eq) and NaHCO3 (2.5 eq.) were charged to the reaction mixture. A solution of acryloyl chloride (1.1 eq.) in CH3CN (0.5 v) was charged drop-wise to the reaction mixture. After the reaction was completed, EtOAc (6.0 v) was charged to the reaction mixture and organic layer was collected. Aqueous phase was further extracted with EA (3.0 v). The organic layers were combined, washed with 15% brine (5.0 v) and concentrated. The solvent was swapped to DCM (volume of residue: 1.5-2.0 v) and purified by silica gel column (silica gel: 100-200 mush, 2.0 w/ w; eluent: 3% w/ w MeOH in DCM (about 50 v). The collected solution was concentrated and swapped to EtOAc (4.0 v). MTBE (6.4 v) was charged drop-wise to residue at 50°C. The mixture was then cooled to 5°C and the cake was collected centrifugation.

References

  1. ^ “Zanubrutinib (Brukinsa) Use During Pregnancy”Drugs.com. 3 January 2020. Retrieved 26 January 2020.
  2. ^ “Zanubrutinib”DrugBank. Retrieved 15 November 2019.
  3. Jump up to:a b c d “FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage”U.S. Food and Drug Administration (FDA) (Press release). 14 November 2019. Retrieved 15 November 2019.  This article incorporates text from this source, which is in the public domain.
  4. ^ “Brukinsa (zanubrutinib) FDA Approval History”Drugs.com. 14 November 2019. Archived from the original on 15 November 2019. Retrieved 15 November 2019.
  5. Jump up to:a b c d e f g h i “FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma”U.S. Food and Drug Administration (FDA)(Press release). 15 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019.  This article incorporates text from this source, which is in the public domain.
  6. Jump up to:a b c “Drug Trials Snapshots Brukinsa”U.S. Food and Drug Administration (FDA). 14 November 2019. Retrieved 26 January 2020.  This article incorporates text from this source, which is in the public domain.
  7. ^ “Zanubrutinib Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 28 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019.  This article incorporates text from this source, which is in the public domain.
  8. ^ “Drug Approval Package: Brukinsa”U.S. Food and Drug Administration (FDA). 27 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.

External links

Zanubrutinib
Zanubrutinib.svg
Clinical data
Trade names Brukinsa
Other names BGB-3111
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • US: N (Not classified yet) [1]
Routes of
administration
By mouth
Drug class Bruton’s tyrosine kinase(BTK) inhibitor
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
PubChem SID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C27H29N5O3
Molar mass 471.5509 g·mol−1
3D model (JSmol)

/////////////////Zanubrutinib, FDA 2019, ザヌブルチニブ , занубрутиниб زانوبروتينيب BGB-3111

CK-101


N-[3-[2-[2,3-Difluoro-4-[4-(2-hydroxyethyl)piperazin-1-yl]anilino]quinazolin-8-yl]phenyl]prop-2-enamide.png

CK-101, RX-518

CAS 1660963-42-7

MF C29 H28 F2 N6 O2
MW 530.57
2-Propenamide, N-[3-[2-[[2,3-difluoro-4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-8-quinazolinyl]phenyl]-

N-[3-[2-[[2,3-Difluoro-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]amino]quinazolin-8-yl]phenyl]acrylamide

N-(3-(2-((2,3-Difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide

EGFR-IN-3

UNII-708TLB8J3Y

708TLB8J3Y

AK543910

Suzhou NeuPharma (Originator)
Checkpoint Therapeutics

Non-Small Cell Lung Cancer Therapy
Solid Tumors Therapy

PHASE 2 Checkpoint Therapeutics, Cancer, lung (non-small cell) (NSCLC), solid tumour

RX518(CK-101) is an orally available third-generation and selective inhibitor of certain epidermal growth factor receptor (EGFR) activating mutations, including the resistance mutation T790M, and the L858R and exon 19 deletion (del 19) mutations, with potential antineoplastic activity.

In August 2019, Suzhou Neupharma and its licensee Checkpoint Therapeutics are developing CK-101 (phase II clinical trial), a novel third-generation, covalent, EGFR inhibitor, as a capsule formulation, for the treatment of cancers including NSCLC and other advanced solid tumors. In September 2017, the FDA granted Orphan Drug designation to this compound, for the treatment of EGFR mutation-positive NSCLC; in January 2018, the capsule was being developed as a class 1 chemical drug in China.

CK-101 (RX-518), a small-molecule inhibitor of epidermal growth factor receptor (EGFR), is in early clinical development at Checkpoint Therapeutics and Suzhou NeuPharma for the potential treatment of EGFR-mutated non-small cell lung cancer (NSCLC) and other advanced solid malignancies.

In 2015, Suzhou NeuPharma granted a global development and commercialization license to its EGFR inhibitor program, excluding certain Asian countries, to Coronado Biosciences (now Fortress Biotech). Subsequently, Coronado assigned the newly acquired program to its subsidiary Checkpoint Therapeutics.

In 2017, the product was granted orphan drug designation in the U.S. for the treatment of EGFR mutation-positive NSCLC.

There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.

[0003] The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.

[0004] The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. In particular, the identification of compounds that specifically inhibit the function of a kinase which is essential for processes leading to cancer would be beneficial.

[0005] While such compounds are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance, such as a kinase inhibitor, can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties

can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers. For example, polymorphism has been evaluated in many multi-million dollar and even multi-billion dollar drugs, such as warfarin sodium, famotidine, and ranitidine. Polymorphism can affect the quality, safety, and/or efficacy of a drug product, such as a kinase inhibitor. Thus, there still remains a need for polymorphs of kinase inhibitors. The present disclosure addresses this need and provides related advantages as well.

PATENT

WO2015027222

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015027222

PATENT

WO-2019157225

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019157225&tab=PCTDESCRIPTION&_cid=P10-JZNKMN-12945-1

Crystalline form II-VIII of the compound presumed to be CK-101 (first disclosed in WO2015027222 ), for treating a disorder mediated by epidermal growth factor receptor (EGFR) eg cancer.

SCHEME A

Scheme B

General Procedures

Example 1: Preparation of the compound of Formula I (N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide)

[0253] To a solution of l,2,3-trifluoro-4-nitrobenzene (2.5 g, 14 mmol, 1.0 eq.) in DMF (20 mL) was added K2C03 (3.8 g, 28 mmol, 2.0 eq.) followed by 2-(piperazin-l-yl)ethanol (1.8 g, 14 mmol, 1.0 eq.) at 0 °C and the mixture was stirred at r.t. overnight. The mixture was poured into ice-water (200 mL), filtered and dried in vacuo to afford 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-l-yl)ethanol (2.7 g, 67.5%).

[0254] To a solution of 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-l-yl)ethanol (2.7 g, 9.0 mmol) in MeOH (30 mL) was added Pd/C (270 mg) and the resulting mixture was stirred at r.t.

overnight. The Pd/C was removed by filtration and the filtrate was concentrated to afford 2-(4-(4-amino-2,3-difluorophenyl)piperazin-l-yl)ethanol (2.39 g, 99% yield) as off-white solid.

[0255] To a solution of 8-bromo-2-chloroquinazoline (15.4 g, 63.6 mmol, 1 eq. ) and (3-aminophenyl)boronic acid (8.7 g, 63.6 mmol, 1 eq.) in dioxane/H20 (200 mL/20 mL) was added Na2C03 (13.5 g, 127.2 mmol, 2 eq.), followed by Pd(dppf)Cl2 (2.6 g, 3.2 mmol, 0.05 eq.) under N2, then the mixture was stirred at 80 °C for 12 h. Then the solution was cooled to r.t.,

concentrated and the residue was purified via column chromatography (PE/EA=3 :2, v/v) to afford 3-(2-chloroquinazolin-8-yl)aniline as yellow solid (8.7 g, 53.7% yield).

[0256] To a solution of 3-(2-chloroquinazolin-8-yl)aniline (8.7 g, 34 mmol, 1 eq.) in DCM ( 200 mL ) cooled in ice-bath was added TEA (9.5 mL, 68 mmol, 2 eq. ), followed by acryloyl chloride (4.1 mL, 51 mmol, 1.5 eq.) dropwise. The resulting mixture was stirred at r.t. for 1 h, then washed with brine, dried over anhydrous N2S04 concentrated and the residue was purified via column chromatography (PE/EA=l : 1, v:v) to afford N-(3-(2-chloroquinazolin-8-yl)phenyl)acryl amide as yellow solid(6.6 g, 65% yield).

[0257] To a suspension of 2-(4-(4-amino-2,3-difluorophenyl)piperazin-l-yl)ethanol (83 mg,

0.32 mmol, 1 eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100 mg, 0.32 mmol, 1 eq.) in n-BuOH (5 mL) was added TFA (68 mg, 0.64 mmol, 2 eq.) and the resulting mixture was stirred at 90 °C overnight. The mixture was concentrated, diluted with DCM (20 mL) , washed with Na2C03 solution (20 mL), dried over anhydrous Na2S04, concentrated and the residue was purified via column chromatography (MeOH/DCM=l/30, v:v) to afford N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide as a yellow solid(l6.3 mg, 9.5% yield). LRMS (M+H+) m/z calculated 531.2, found 531.2. 1H NMR

(CD3OD, 400 MHz) d 9.21 (s, 1 H), 7.19-8.01 (m, 10 H), 8.90 (s, 1 H), 6.41-6.49 (m, 3 H), 5.86 (m, 1 H), 3.98-4.01 (m, 3 H), 3.70-3.76 (m, 3 H), 3.40-3.49 (m, 2 H), 3.37-3.39 (m, 4 H), 3.18 (m, 2H).

Example 2. Preparation of Form I of the compound of Formula I

[0258] Crude compound of Formula I (~30 g, 75% of weight based assay) was dissolved in ethyl acetate (3 L) at 55-65 °C under nitrogen. The resulting solution was filtered via silica gel pad and washed with ethyl acetate (3 L><2) at 55-65 °C. The filtrate was concentrated via vacuum at 30-40 °C to ~2.4 L. The mixture was heated up to 75-85 °C and maintained about 1 hour.

Then cooled down to 50-60 °C and maintained about 2 hours. The heat-cooling operation was repeated again and the mixture was then cooled down to 20-30 °C and stirred for 3 hours. The resulting mixture was filtered and washed with ethyl acetate (60 mL><2). The wet cake was dried via vacuum at 30-40 °C to get (about 16 g) of the purified Form I of the compound of Formula I.

Example 3. Preparation of Form III of the compound of Formula I

[0259] The compound of Formula I (2 g) was dissolved in EtOH (40 mL) at 75-85 °C under nitrogen. n-Heptane (40 mL) was added dropwise into reaction at 75-85 °C. The mixture was stirred at 75-85 °C for 1 hour. Then cooled down to 50-60 °C and maintained about 2 hours. The heat-cooling operation was repeated again and continued to cool the mixture down to 20-30 °C and stirred for 3 hours. The resulting mixture was filtered and washed with EtOH/n-Heptane (1/1, 5 mL><2). The wet cake was dried via vacuum at 30-40 °C to get the purified Form III of the compound of Formula I (1.7 g).

Example 4. Preparation of Form IV of the compound of Formula I The crude compound of Formula I (15 g) was dissolved in ethyl acetate (600 mL) at 75-85 °C under nitrogen and treated with anhydrous Na2S04, activated carbon, silica metal scavenger for 1 hour. The resulting mixture was filtered via neutral Al203 and washed with ethyl acetate (300 mL><2) at 75-85 °C. The filtrate was concentrated under vacuum at 30-40 °C and swapped with DCM (150 mL). n-Heptane (75 mL) was added into this DCM solution at 35-45 °C, and then the mixture was cooled down to 20-30 °C slowly. The resulting mixture was filtered and washed with DCM/n-Heptane (2/1, 10 mL><3). The wet cake was dried via vacuum at 35-40 °C to get the purified Form IV of the compound of Formula I (9.6 g).

Example 5. Preparation of Form V of the compound of Formula I

[0260] Polymorph Form III of the compound of Formula I was dried in oven at 80 °C for 2 days to obtain the polymorph Form V.

Example 6. Preparation of Form VI of the compound of Formula I

[0261] The compound of Formula I (1 g) was dissolved in IPA (20 mL) at 75-85 °C under nitrogen. n-Heptane (20 mL) was added dropwise into reaction at 75-85 °C. The mixture was stirred at 45-55 °C for 16 hours. Then heated up to 75-85 °C and maintained about 0.5 hour.

Then cooled down to 45-55 °C for 0.5 hour and continued to cool the mixture down to 20-30 °C and stirred for 3 hours. Filtered and washed with IPA/n-Heptane (1/1, 3 mL><2). The wet cake was dried via vacuum at 75-80 °C for 2 hours to get the purified Form VI of the compound of Formula I.

Example 7. Preparation of Form VIII of the compound of Formula I

[0262] The polymorph Form VI of the compound of Formula I was dried in oven at 80 °C for 2 days to obtain the polymorph Form VIII.

Example 8. X-ray powder diffraction (XRD)

[0263] X-ray powder diffraction (XRD) patterns were obtained on a Bruker D8 Advance. A CuK source (=1.54056 angstrom) operating minimally at 40 kV and 40 mA scans each sample between 4 and 40 degrees 2-theta. The step size is 0.05°C and scan speed is 0.5 second per step.

Example 9. Thermogravimetric Analyses (TGA)

[0264] Thermogravimetric analyses were carried out on a TA Instrument TGA unit (Model TGA 500). Samples were heated in platinum pans from ambient to 300 °C at 10 °C/min with a nitrogen purge of 60mL/min (sample purge) and 40mL/min (balance purge). The TGA temperature was calibrated with nickel standard, MP=354.4 °C. The weight calibration was performed with manufacturer-supplied standards and verified against sodium citrate dihydrate desolvation.

Example 10. Differential scanning calorimetry (DSC)

[0265] Differential scanning calorimetry analyses were carried out on a TA Instrument DSC unit (Model DSC 1000 or 2000). Samples were heated in non-hermetic aluminum pans from ambient to 300 °C at 10 °C/min with a nitrogen purge of 50mL/min. The DSC temperature was calibrated with indium standard, onset of l56-l58°C, enthalpy of 25-29J/g.

Example 11. Hygroscopicity (DVS)

[0266] The moisture sorption profile was generated at 25°C using a DVS Moisture Balance Flow System (Model Advantage) with the following conditions: sample size approximately 5 to 10 mg, drying 25°C for 60 minutes, adsorption range 0% to 95% RH, desorption range 95% to 0% RH, and step interval 5%. The equilibrium criterion was <0.01% weight change in 5 minutes for a maximum of 120 minutes.

Example 12: Microscopy

[0267] Microscopy was performed using a Leica DMLP polarized light microscope equipped with 2.5X, 10X and 20X objectives and a digital camera to capture images showing particle shape, size, and crystallinity. Crossed polars were used to show birefringence and crystal habit for the samples dispersed in immersion oil.

Example 13: HPLC

[0256] HPLCs were preformed using the following instrument and/or conditions.

///////////////CK-101 , CK 101 , CK101 , phase II , Suzhou Neupharma, Checkpoint Therapeutics ,  Orphan Drug designation, EGFR mutation-positive NSCLC, NSCLC, CANCER, SOLID TUMOUR,  China, RX-518, AK543910

OCCN1CCN(CC1)c5ccc(Nc2nc3c(cccc3cn2)c4cccc(NC(=O)C=C)c4)c(F)c5F

FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor


FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor 

FDA also approves drug for second indication in a type of lung cancer

The U.S. Food and Drug Administration today granted accelerated approval to Rozlytrek (entrectinib), a treatment for adult and adolescent patients whose cancers have the specific genetic defect, NTRK (neurotrophic tyrosine receptor kinase) gene fusion and for whom there are no effective treatments.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” said FDA Acting Commissioner Ned Sharpless, M.D. “Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.”

This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated. The approval marks a new paradigm in the development of cancer drugs that are “tissue agnostic.” It follows the policies that the FDA developed in a guidance document released in 2018. The previous tissue agnostic indications approved by the FDA were pembrolizumab for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib for NTRK gene fusion tumors in 2018.

“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK-fusion-positive tumors by relying on efficacy information obtained primarily in adults. The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

The ability of Rozlytrek to shrink tumors was evaluated in four clinical trials studying 54 adults with NTRK fusion-positive tumors. The proportion of patients with substantial tumor shrinkage (overall response rate) was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for nine months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid and colon/rectum.

Rozlytrek was also approved today for the treatment of adults with non-small cell lung cancer whose tumors are ROS1-positive (mutation of the ROS1 gene) and has spread to other parts of the body (metastatic). Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.

Rozlytrek’s common side effects are fatigue, constipation, dysgeusia (distorted sense of taste), edema (swelling), dizziness, diarrhea, nausea, dysesthesia (distorted sense of touch), dyspnea (shortness of breath), myalgia (painful or aching muscles), cognitive impairment (confusion, problems with memory or attention, difficulty speaking, or hallucinations), weight gain, cough, vomiting, fever, arthralgia and vision disorders (blurred vision, sensitivity to light, double vision, worsening of vision, cataracts, or floaters). The most serious side effects of Rozlytrek are congestive heart failure (weakening or damage to the heart muscle), central nervous system effects (cognitive impairment, anxiety, depression including suicidal thinking, dizziness or loss of balance, and change in sleep pattern, including insomnia and excessive sleepiness), skeletal fractures, hepatotoxicity (damage to the liver), hyperuricemia (elevated uric acid), QT prolongation (abnormal heart rhythm) and vision disorders. Health care professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Rozlytrek. Women who are pregnant or breastfeeding should not take Rozlytrek because it may cause harm to a developing fetus or newborn baby.

Rozlytrek was granted accelerated approval. This approval commits the sponsor to provide additional data to the FDA. Rozlytrek also received Priority ReviewBreakthrough Therapy and Orphan Drug designation. The approval of Rozlytrek was granted to Genentech, Inc.

link http://s2027422842.t.en25.com/e/es?s=2027422842&e=244904&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=46563b1749694ceb96d9f79a6d5cd8a7&elqaid=9150&elqat=1

///////////////Rozlytrek, entrectinib, accelerated approval, priority ReviewBreakthrough Therapy,  Orphan Drug designation, fda 2019, Genentech, cancer

BQ-788


BQ-788.svg

ChemSpider 2D Image | BQ-788 | C34H50N5NaO7

Image result for bq-788

Image result for bq-788

BQ-788

  • Molecular FormulaC34H50N5NaO7
  • Average mass663.780 Da

SP ROT +3.8 ° Conc: 1.032 g/100mL; methanol; Wavlenght: 589.3 nm, Development of an efficient strategy for the synthesis of the ETB receptor antagonist BQ-788 and some related analogues
Peptides (New York, NY, United States) (2005), 26, (8), 1441-1453., https://doi.org/10.1016/j.peptides.2005.03.022

FOR FREE FORM +19.6 °, Conc: 0.998 g/100mL; : N,N-dimethylformamide; 589.3 nm

CAS 156161-89-6 [RN]
CAS 173326-37-9 FREE ACID
2,6-Dimethylpiperidinecarbonyl-γ-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle
BQ 788 sodium salt
BQ788
D-Norleucine, N-(((2R,6S)-2,6-dimethyl-1-piperidinyl)carbonyl)-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, monosodium salt
D-Norleucine, N-((cis-2,6-dimethyl-1-piperidinyl)carbonyl)-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, monosodium salt
D-Norleucine, N-[[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl]-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, sodium salt (1:1)
MFCD00797882
N-[N-[N-[(2,6-Dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl]-1-(methoxycarbonyl)-D-tryptophyl]-D-norleucine sodium salt
 
Sodium N-{[(2R,6S)-2,6-dimethylpiperidin-1-yl]carbonyl}-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-(methoxycarbonyl)-D-tryptophanamide
2,6-Dimethylpiperidinecarbonyl-γ-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle

BQ-788 is a selective ETB antagonist.[1]

presumed to be under license from Banyu , was investigating BQ-788, a selective endothelin receptor B (ETRB) antagonist, for treating metastatic melanoma. By December 2009, the drug was in validation.

Also claimed is their use as an ETBR antagonist and for treating cancers, such as brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma and squamous cell carcinoma. Represent a first filing from ENB Therapeutics Inc and the inventors on these deuterated forms of BQ-788. Melcure SarL ,

SYN

By Brosseau, Jean-Philippe et alFrom Peptides (New York, NY, United States), 26(8), 1441-1453; 2005

CONTD…………

PAPER

https://pubs.acs.org/doi/pdf/10.1021/jo00130a028

N-(cw-2,6-Dimethylpiperidinocarbonyl)-y-methylleucylD-l-(methoxycarbonyl)tryptophanyl-D-norleucine Sodium Salt (1, BQ-788). To a solution of 15 (3.5 g, 5.5 mmol) in methanol (50 mL) was slowly added 5% aqueous NaHCOs (300 mL) over a period of 30 min. The solution was stirred until clarity was achieved (30 min, 23 °C). The solution was diluted with water (200 mL), and the resulting solution was passed through a C18 (60 mL) cartridge preequilbrated in water. BQ-788 (1) was eluted with methanol (2 x 50 mL), concentrated under reduced pressure, resuspended in water (50 mL), and lyophilized to quantitatively yield compound 1 as a white powder:

HPLC £r = 16.4 (gradient A, > 99%);

NMR (400 MHz, DMSO-d6) ó 0.80 (s, 9H), 0.74-0.85 (m, 3H), 1.00 (d, 3H), 1.02 (d, 3H), 1.10-1.25 (m, 6H), 1.30-1.55 (m, 6H), 1.60-1.75 (m, 2H), 2.92 (dd, 1H), 3.12 (dd, 1H), 3.78 (m, 1H), 3.95 (s, 3H), 4.08 (m, 1H), 4.13 (m, 1H), 4.29 (m, 1H), 4.50 (m, 1H), 5.98 (d, 1H), 7.22 (t, 1H), 7.32 (t, 1H), 7.50 (s, 1H), 7.58 (br d, 1H), 7.65 (d, 1H), 8.05 (d, 1H), 8.15 (br d, 1H) ESMS m/z 640.6 (M).

PATENT

WO-2019140324

Novel deuterated analogs of a substituted heterocyclic compound, particularly BQ-788 , processes for their preparation and compositions and combinations comprising them are claimed.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019140324&tab=PCTDESCRIPTION&_cid=P22-JYJK98-13819-1

PAPER

https://www.sciencedirect.com/science/article/abs/pii/S0196978105001415

Image result for bq-788

PAPER

By He, John X.; Cody, Wayne L.; Doherty, Annette M., From Journal of Organic Chemistry (1995), 60(25), 8262-6

Journal of medicinal chemistry (1996), 39(12), 2313-30.

References

  1. ^ Okada, M; Nishikibe, M (Winter 2002). “BQ-788, a selective endothelin ET(B) receptor antagonist”. Cardiovascular drug reviews20 (1): 53–66. PMID 12070534.
BQ-788
BQ-788.svg
Names
Systematic IUPAC name

Sodium N-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-(methoxycarbonyl)-D-tryptophanamide
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
C34H50N5NaO7
Molar mass 663.792 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////BQ-788, BQ 788, BQ788, ETBR antagonist, cancers,  brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma, squamous cell carcinoma, PEPTIDE

CCCC[C@H](C(=O)O)NC(=O)[C@@H](Cc1cn(c2c1cccc2)C(=O)OC)NC(=O)[C@H](CC(C)(C)C)NC(=O)N3[C@@H](CCC[C@@H]3C)C

Fluazolepali, 氟唑帕利 , Fluzoparib


Fluazolepali

CAS  2170504-09-1

Fluzoparib; SHR-3162, (HS10160)

  • HS 10160
  • SHR 3162

An orally available inhibitor of poly(ADP-ribose) polymerase 1 and 2 (PARP-1/2) for treatment of solid tumors (Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China)

Fluazolepali, developed by Hengrui and Howson, is intended for the treatment of recurrent ovarian cancer, triple-negative breast cancer, advanced gastric cancer and other advanced solid tumors. Currently, the drug has been introduced into China for recurrent ovarian cancer. Clinical stage.

In February 2019, a randomized, double-blind, controlled, multicenter, phase III clinical study (CTR20190294) of flazopril capsule versus placebo for maintenance of recurrent ovarian cancer was initiated in China and was sponsored by Hengrui Medicine.

Jiangsu Hansoh Pharmaceutical , in collaboration with  Jiangsu Hengrui Medicine , is developing an oral capsule formulation of fluazolepali (fluzoparib; SHR-3162), a small molecule inhibitor to PARP-1 and PARP-2, for the treatment of solid tumors including epithelial ovarian, fallopian tube or primary peritoneal, breast and gastric cancer.

  • Originator Jiangsu Hengrui Medicine Co.
  • Class Antineoplastics
  • Mechanism of Action Poly(ADP-ribose) polymerase 1 inhibitors; Poly(ADP-ribose) polymerase 2 inhibitors
  • Phase II Ovarian cancer
  • Phase I Breast cancer; Fallopian tube cancer; Gastric cancer; Peritoneal cancer; Solid tumours
  • 09 Jul 2019 Jiangsu HengRui Medicine initiates a phase I trial in Solid tumors in China (NCT04013048) [14C]-Fluzoparib
  • 01 Jul 2019 Jiangsu HengRui Medicine plans a phase I drug-drug interaction trial (In volunteers) in China (PO) (NCT04011124)
  • 12 Jun 2019 Jiangsu HengRui Medicine completes a phase I trial in Gastric cancer (Combination therapy, Recurrent, Metastatic disease, Second-line therapy or greater, Late-stage disease) in China (PO) (NCT03026881)

Fluzoparib (SHR 3162) is a selective poly [ADP-ribose] polymerase 1 (PARP1) and poly [ADP-ribose] polymerase 2 inhibitor (PARP2), being developed by Jiangsu HengRui Medicine, for the treatment of cancer. PARP enzymes play a vital role in repair of DNA damage and maintaining genomic stability. Fluzoparib inhibits PARP enzymes and induces DNA-double strands breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Clinical development for ovarian cancer, breast cancer, fallopian tube cancer, peritoneal cancer, gastric cancer and solid tumours is underway in China and Australia.

An orally available inhibitor of poly (ADP-ribose) polymerase (PARP) types 1 and 2, with potential antineoplastic activity. Upon oral administration, fluzoparib inhibits PARP 1 and 2 activity, which inhibits PARP-mediated repair of damaged DNA via the base excision repair (BER) pathway, enhances the accumulation of DNA strand breaks, promotes genomic instability, and leads to an induction of apoptosis. The PARP family of proteins catalyze post-translational ADP-ribosylation of nuclear proteins, which then transduce signals to recruit other proteins to repair damaged DNA. PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. Check for active clinical trials using this agent. (NCI Thesaurus)

PATENT

WO-2019137358

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019137358&tab=FULLTEXT&_cid=P20-JYI5A2-54836-1

Process for preparing heterocyclic compounds (presumed to be fluazolepali ) and its intermediates as PARP inhibitors useful for treating cancer.

Example 1

The compound and 5.0kg of 10% palladium on carbon 250g, 80L of methanol was added to the kettle at 0.4MPa, 24h 25 ℃ hydrogenation reaction. The palladium carbon was removed by filtration, the filter cake was washed with methanol, and the filtrate was collected, evaporated to dryness under reduced pressure, and ethyl acetate (20 L) was added to the concentrate, and the mixture was stirred and evaporated, and then cooled to 0° C. ~3, stirring, filtration, filter cake and then adding 20 L of ethyl acetate, pulping at room temperature for 3 to 4 h, filtration, vacuum drying at 45 ° C for 6-8 h to obtain 5.5 kg of compound 3 solid, yield 91.7%, HPLC purity 99.69%.
Example 2
According to the method of Example 19 of CN102686591A, 2 g of the compound 3 and 2.79 g of the compound 4 were charged to obtain 3.6 g of the compound of the formula I in a yield of 87.8%.
Example 3
At room temperature, 2.0 g of compound 2 (prepared according to the method disclosed in WO2009025784) was dissolved in 30 mL of isopropanol, and concentrated sulfuric acid was added dropwise with stirring to adjust the pH to 3, and stirred at room temperature without solid precipitation; the reaction solution was poured into 150 mL of n-hexane. After stirring at room temperature, no solid precipitated, and the sulfate solid of Compound 2 could not be obtained.
Example 4
1. At room temperature, 1.11 g of compound 2 was dissolved in 10 mL of isopropanol, and 15% phosphoric acid/isopropanol solution was added dropwise with stirring to adjust the pH to 3, stirred at room temperature, filtered, and the filter cake was washed with isopropyl alcohol and dried under vacuum. Compound 2 phosphate solid 1.46 g, yield 87.1%, HPLC purity 99.72%.
Example 5
At room temperature, 1.28 g of compound 2 was dissolved in 10 mL of isopropanol, and 20% acetic acid/isopropanol solution was added dropwise with stirring to adjust the pH to 3, and stirred at room temperature without solid precipitation; the reaction solution was poured into 100 mL of n-hexane, and continued. After stirring at room temperature, no solid precipitated, and the acetate solid of Compound 2 could not be obtained.
Example 6
1.05g of compound 2 was dissolved in 10mL of isopropanol at room temperature, and the pH was adjusted to 3 by adding 15% citric acid/isopropanol solution while stirring. At room temperature, no solid precipitated; the reaction solution was poured into 100 mL of n-hexane. After stirring at room temperature, no solid precipitated, and the citrate solid of Compound 2 could not be obtained.
Example 7
1.12 g of compound 2 was dissolved in 10 mL of isopropanol at room temperature, and 0.74 g of maleic acid was added thereto with stirring. The mixture was stirred at room temperature, filtered, and the filter cake was washed with isopropyl alcohol and dried in vacuo to obtain the maleate salt of compound 2. 1.51 g, yield 84.6%.

PATENT

WO2019109938

claiming synergistic combination comprising PARP inhibitor fluazolepali and apatinib mesylate .

PATENT

WO 2018005818

WO 2018129553

WO 2018129559

WO 2018208968

WO 2018213732

WO 2018191277

WO 2018201096

WO 2018085469

WO 2018085468

WO 2019090227

WO 2019133697

WO 2019067978

WO 2019071123

WO 2019090141

///////////Fluazolepali, Jiangsu Hansoh Pharmaceutical,  Jiangsu Hengrui Medicine, fluzoparib,  SHR-3162, 氟唑帕利 , Phase II,  Ovarian cancer, HS10160, CHINA, HS 10160

https://med.sina.com/article_detail_103_2_64751.html

CC-90009


str1

2-(4-Chlorophenyl)-N-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl]-2,2-difluoroacetamide.png

CC-90009

CC-90009-AML-001

CAS 1860875-51-9

461.8 g/mol, C22H18ClF2N3O4

2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

  • 4-Chloro-N-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α,α-difluorobenzeneacetamide
  • Benzeneacetamide, 4-chloro-N-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α,α-difluoro-

Phase 1 Clinical, Acute myelogenous leukemia, Protein cereblon modulator

Useful for treating chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or acute myeloid leukemia.

Celgene is developing CC-90009, a cereblon E3 ligase modulator, for treating AML; in January 2019, data from a phase I trial were expected later that year.

  • 0iginator Celgene Corporation
  • Class Antineoplastics
  • Mechanism of Action CRBN protein modulators; Ubiquitin protein ligase complex modulators
  • Phase I Acute myeloid leukaemia
  • 28 Mar 2019 No recent reports of development identified for clinical-Phase-Unknown development in Acute-myeloid-leukaemia in USA (IV)
  • 01 Sep 2016 Phase-I clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) in Canada (IV) (NCT02848001)
  • 04 Aug 2016 Celgene plans a phase I trial for Acute Myeloid Leukaemia in USA and Canada (NCT02848001)

In September 2016, Celgene initiated a phase I dose-finding trial of CC 90009 in patients with relapsed or refractory acute myeloid leukaemia (NCT02848001; CC-90009-AML-001). The open-label study intends to enrol 60 patients in the US and Canada

CC-90009 is a cereblon modulator. CC-90009 specifically binds to CRBN, thereby affecting the activity of the ubiquitin E3 ligase complex. This leads to the ubiquitination of certain substrate proteins and induces the proteasome-mediated degradation of certain transcription factors, including Ikaros (IKZF1) and Aiolos (IKZF3), which are transcriptional repressors in T-cells. This reduces the levels of these transcription factors, and modulates the activity of the immune system, which may include the activation of T-lymphocytes. .

Development Overview

cereblon modulator CC-90009A modulator of cereblon (CRBN), which is part of the cullin 4-RING E3 ubiquitin ligase complex (CRL4-CRBN E3 ubiquitin ligase; CUL4-CRBN E3 ubiquitin ligase), with potential immunomodulating and pro-apoptotic activities. Upon administration, CC-90009 specifically binds to CRBN, thereby affecting the activity of the ubiquitin E3 ligase complex. This leads to the ubiquitination of certain substrate proteins and induces the proteasome-mediated degradation of certain transcription factors, including Ikaros (IKZF1) and Aiolos (IKZF3), which are transcriptional repressors in T-cells. This reduces the levels of these transcription factors, and modulates the activity of the immune system, which may include the activation of T-lymphocytes. In addition, this downregulates the expression of other proteins, including interferon regulatory factor 4 (IRF4) and c-myc, which plays a key role in the proliferation of certain cancer cell types. CRBN, the substrate recognition component of the E3 ubiquitin ligase complex, plays a key role in the ubiquitination of certain proteins. Check for active clinical trials using this agent. (NCI Thesaurus)

WO 2017120446,

PATENT

WO2016007848

US 20170348298

WO 2017120415

WO 2017120446

WO 2017120437

PATENT

WO2017214014

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017214014&tab=PCTDESCRIPTION

Provided herein are methods of treating, preventing, managing, and/or ameliorating a hematologic malignancy with 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of

stereoisomers, an isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Further provided is a compound for use in methods of treating, preventing, managing, and/or ameliorating a hematologic malignancy, wherein the compound is 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, an isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

The term Compound 1 refers to”2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide” having the structure:

and its stereoisomers or mixture of stereoisomers, isotopologues, pharmaceutically acceptable salts, tautomers, solvates, hydrates, co-crystals, clathrates, or polymorphs thereof. In certain embodiments, Compound 1 refers to 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide and its tautomers. In certain embodiments, Compound 1 refers to a polymorph of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-

oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide. In certain embodiments, Compound 1 refers to polymorph Form C of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide. In one embodiment, the stereoisomer is an enantiomer.

PATENT

WO-2019136016

Novel isotopologs of the compound presumed to be CC-90009 , processes for their preparation and compositions comprising them are claimed.

str2

Patent ID Title Submitted Date Granted Date
US2017199193 METHODS FOR TREATING CANCER AND THE USE OF BIOMARKERS AS A PREDICTOR OF CLINICAL SENSITIVITY TO THERAPIES 2017-01-06
US2018224435 METHODS FOR MEASURING SMALL MOLECULE AFFINITY TO CEREBLON 2018-02-02
US2018353496 FORMULATIONS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE 2018-07-19
US2017196847 FORMULATIONS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE 2017-01-06
US2017348298 TREATMENT OF A HEMATOLOGIC MALIGNANCY WITH 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE 2017-06-05
Patent ID Title Submitted Date Granted Date
US2018221361 ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF 2018-04-09
US9968596 Antiproliferative compounds and methods of use thereof 2017-10-02 2018-05-15
US2017197934 SOLID FORMS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE, AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES 2017-01-06
US9499514 ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF 2015-07-09 2016-01-14
US9808451 ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF 2016-09-23

////////CC-90009 , CC 90009  , CC90009, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, phase I, CANCER, CC-90009-AML-001

Clc1ccc(cc1)C(F)(F)C(=O)NCc2ccc3C(=O)N(Cc3c2)C4CCC(=O)NC4=O

Selinexor


Skeletal formula of selinexor

Selinexor.png

Selinexor

セリネクソル

KPT-330

UNII-31TZ62FO8F

(Z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-N‘-pyrazin-2-ylprop-2-enehydrazide

Formula
C17H11F6N7O
CAS
1393477-72-9
Mol weight
443.306

FDA, APPROVED 2019/7/3, Xpovio

CAS : 1393477-72-9 (free base)   1421923-86-5 (E-isomer)   1621865-82-4 (E-isomer)   Unknown (HCl)

Treatment of cancer, Antineoplastic, Nuclear export inhibitor

Selinexor (INN, trade name Xpovio; codenamed KPT-330) is a selective inhibitor of nuclear export used as an anti-cancer drug. It works by quasi-irreversibly binding to exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis.[1] It is the first drug with this mechanism of action.[2][3]

Selinexor was granted accelerated approval by the U.S. Food and Drug Administration in July 2019, for use as a drug of last resort in people with multiple myeloma. In clinical trials, it was associated with a high incidence of severe side effects, including low platelet counts and low blood sodium levels.[3][4]

Selinexor is an orally available, small molecule inhibitor of CRM1 (chromosome region maintenance 1 protein, exportin 1 or XPO1), with potential antineoplastic activity. Selinexor modifies the essential CRM1-cargo binding residue cysteine-528, thereby irreversibly inactivates CRM1-mediated nuclear export of cargo proteins such as tumor suppressor proteins (TSPs), including p53, p21, BRCA1/2, pRB, FOXO, and other growth regulatory proteins. As a result, this agent, via the approach of selective inhibition of nuclear export (SINE), restores endogenous tumor suppressing processes to selectively eliminate tumor cells while sparing normal cells. CRM1, the major export factor for proteins from the nucleus to the cytoplasm, is overexpressed in a variety of cancer cell types.

Selinexor has been used in trials studying the treatment of AML, Glioma, Sarcoma, Leukemia, and Advanced, among others.

 Selinexor, also known as KPT-330, is an orally bioavailable, potent and selective XPO1/CRM1 Inhibitor. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Selinexor potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis. Selinexor has strong activity against primary AML cells while sparing normal stem and progenitor cells.

SYN

Medical uses

Selinexor is restricted for use in combination with the steroid dexamethasone in people with relapsed or refractory multiple myelomawhich has failed to respond to at least four or five other therapies (so-called “quad-refractory” or “penta-refractory” myeloma),[5] for whom no other treatment options are available.[3][4] It is the first drug to be approved for this indication.[6]

Adverse effects

In the clinical study used to support FDA approval, selinexor was associated with high rates of pancytopenia, including leukopenia(28%), neutropenia (34%, severe in 21%), thrombocytopenia (74%, severe in 61% of patients), and anemia (59%).[4][7] The most common non-hematological side effects were gastrointestinal reactions (nausea, anorexia, vomiting, and diarrhea), hyponatremia (low blood sodium levels, occurring in up to 40% of patients), and fatigue.[7][8] More than half of all patients who received the drug developed infections, including fatal cases of sepsis.[7] However, these data are from an open-label trial, and thus cannot be compared to placebo or directly attributed to treatment.

Mechanism of action

Schematic illustration of the Ran cycle of nuclear transport. Selinexor inhibits this process at the nuclear export receptor (upper right).

Like other so-called selective inhibitors of nuclear export (SINEs), selinexor works by binding to exportin 1 (also known as CRM1). CRM1 is a karyopherin which performs nuclear transport of several proteins, including tumor suppressorsoncogenes, and proteins involved in governing cell growth, from the cell nucleus to the cytoplasm; it is often overexpressed and its function misregulated in several types of cancer.[1] By restoring nuclear transport of these proteins to normal, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell proliferation. This ultimately leads to cell cycle arrest and death of cancer cells by apoptosis.[1][2][7] In vitro, this effect appeared to spare normal (non-malignant) cells.[1][8]

Because CRM1 is a pleiotropic gene, inhibiting it affects many different systems in the body, which explains the high incidence of adverse reactions to selinexor.[2] Thrombocytopenia, for example, is a mechanistic and dose-dependent effect, occurring because selinexor causes a buildup of the transcription factor STAT3 in the nucleus of hematopoietic stem cells, preventing their differentiation into mature megakaryocytes (platelet-producing cells) and thus slowing production of new platelets.[2]

Chemistry

Selinexor is a fully synthetic small-molecule compound, developed by means of a structure-based drug design process known as induced-fit docking. It binds to a cysteine residue in the nuclear export signal groove of exportin 1. Although this bond is covalent, it is not irreversible.[1]

History

Selinexor was developed by Karyopharm Therapeutics of Newton, Massachusetts, a pharmaceutical company devoted entirely to the development of drugs that target nuclear transport. It was approved by the FDA on July 3, 2019, on the basis of a single uncontrolled clinical trial. The decision was controversial, and overruled the previous recommendation of an FDA Advisory Panel which had voted 8–5 against approving the drug, due to concerns about efficacy and toxicity.[3]

Research

Under the codename KPT-330, selinexor was tested in several preclinical animal models of cancer, including pancreatic cancerbreast cancernon-small-cell lung cancerlymphomas, and acute and chronic leukemias.[9] In humans, early clinical trials (phase I) have been conducted in non-Hodgkin lymphomablast crisis, and a wide range of advanced or refractory solid tumors, including colon cancerhead and neck cancermelanomaovarian cancer, and prostate cancer.[9] Compassionate use in patients with acute myeloid leukemia has also been reported.[9]

The pivotal clinical trial which served to support approval of selinexor for people with relapsed/refractory multiple myeloma was an open-label study of 122 patients known as the STORM trial.[7] In all of the enrolled patients, selinexor was used as fifth-line or sixth-line therapy after conventional chemotherapytargeted therapy with bortezomibcarfilzomiblenalidomidepomalidomide, and a monoclonal antibody (daratumumab or isatuximab)[5]; nearly all had also undergone hematopoietic stem cell transplantation to no effect.[7] The overall response rate was 25%, and no patients had a complete response.[7] However, the response rate was higher in patients with high-risk myeloma (cytogenetic abnormalities associated with a worse prognosis).[5] The median time to progression was 2.3 months overall and 5 months in patients who responded to the drug.[2]

As of 2019, phase I/II and III trials are ongoing,[3][9] including the use of selinexor in other cancers and in combinations with other drugs used for multiple myeloma.[2]

PATENT

WO 2013019561

WO 2013019548

US 9079865

PATENT

WO 2016025904 A

https://patents.google.com/patent/WO2016025904A1/tr

International Publication No. WO 2013/019548 describes a series of compounds that are indicated to have inhibitory activity against chromosomal region maintenance 1 (CRM1, also referred to as exportin 1 or XPO1) and to be useful in the treatment of disorders associated with CRM1 activity, such as cancer. (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N’-(pyrazin-2-yl)acrylohydrazide (also referred to as selinexor) is one of the compounds disclosed in International Publication No. WO 2013/019548. Selinexor has the chemical structure shown in Structural Formula I:

Example 1. Preparation of Selinexor Lot No.1305365 (Form A).

[00274] Selinexor for Lot No. 1305365 was made in accordance with the following reaction scheme:

[00275] A solution of propane phosphonic acid anhydride (T3P®, 50% in ethyl acetate, 35Kg) in THF (24.6Kg) was cooled to about -40 °C. To this solution was added a solution of KG1 (13.8Kg) and diisopropylethylamine (12.4Kg) in tetrahydrofuran (THF, 24.6Kg). The resulting mixture was stirred at about -40°C for approximately 2.5 hours.

[00276] In a separate vessel, KJ8 (4.80Kg) was mixed with THF (122.7Kg), and the resulting mixture cooled to about -20°C. The cold activated ester solution was then added to the KJ8 mixture with stirring, and the reaction was maintained at about -20°C. The mixture was warmed to about 5°C, water (138.1Kg) was added and the temperature adjusted to about 20°C. After agitating for about an hour, the lower phase was allowed to separate from the mixture and discarded. The upper layer was diluted with ethyl acetate (EtOAc). The organic phase was then washed three times with potassium phosphate dibasic solution (~150Kg), then with water (138.6Kg).

[00277] The resulting organic solution was concentrated under reduced pressure to 95L, EtOAc (186.6Kg) was added and the distillation repeated to a volume of 90L. Additional EtOAc (186.8Kg) was added and the distillation repeated a third time to a volume of 90L. The batch was filtered to clarify, further distilled to 70L, then heated to about 75°C, and slowly cooled to 0 to 5°C. The resulting slurry was filtered and the filter cake washed with a mixture of EtOAc (6.3Kg) and toluene (17.9Kg) before being dried in a vacuum oven to provide selinexor designated Lot No. 1305365 (Form A).

Example 2. Preparation of Selinexor Lot No.1341-AK-109-2 (Form A).

[00278] The acetonitrile solvate of selinexor was prepared in accordance with Example 6.

[00279] The acetonitrile solvate of selinexor (2.7g) was suspended in a mixture of isopropanol (IPA, 8mL) and water (8mL), and the resulting mixture heated to 65 to 70 °C to effect dissolution. The solution was cooled to 45 °C, and water (28mL) was added over 15 minutes, maintaining the temperature between 40 and 45 °C. The slurry was cooled to 20 to 25 °C over an hour, then further cooled to 0 to 5 °C and held at that temperature for 30 minutes before being filtered. The filter cake was washed with 20% v/v IPA in water and the product dried under suction overnight, then in vacuo (40°C).

Example 3. Preparation of SelinexorSelinexorSelinexor Lot No. PC-14-005 (Form A).

[00280] The acetonitrile solvate of selinexor (Form D) was prepared in accordance with the procedure described in Example 6.

[00281] The acetonitrile solvate of selinexor (1.07Kg) was suspended in a mixture of IPA (2.52Kg) and water (3.2Kg) and the mixture heated to 70 to 75 °C to dissolve. The temperature was then adjusted to 40 to 45 °C and held at that temperature for 30 minutes. Water (10.7Kg) was added while maintaining the temperature at 40 to 45 °C, then the batch was cooled to 20 to 25 °C and agitated at that temperature for 4 hours before being further cooled to 0 to 5 °C. After a further hour of agitation, the slurry was filtered and the filter cake washed with a cold mixture of IPA (0.84Kg) and water (4.28Kg) before being dried.

Example 4. Preparation of SelinexorSelinexorSelinexor Lot No. PC-14-009 (Form A).

[00282] The acetonitrile solvate of selinexor (Form D) was prepared in accordance with the procedure described in Example 6.

[00283] The acetonitrile solvate of selinexor (1.5Kg) was suspended in IPA (3.6Kg) and water (4.5Kg) and warmed to 37 to 42 °C with gentle agitation. The suspension was agitated at that temperature for 4 hours, and was then cooled to 15 to 20 °C over 1 hour. Water (15.1Kg) was added, maintaining the temperature, then the agitation was continued for 1 hour and the batch was filtered. The filter cake was washed with a mixture of IPA (1.2Kg) and water (6Kg), then dried under a flow of nitrogen.

Example 5. Preparation of Selinexor Lot Nos.1339-BS-142-1, 1339-BS-142-2 and PC-14-008 (Form A).

[00284] A reactor, under nitrogen, was charged with KG1 (1Kg, 1.0 Eq), KJ8 (0.439 Kg, 1.4 Eq) and MeTHF (7L, 7 parts with respect to KG1). Diisopropylethylamine (0.902Kg, 2.45 Eq with respect to KG1) was added to the reaction mixture at -20 °C to -25 °C with a MeTHF rinse. To the reaction mixture, 50% T3P® in ethyl acetate (2.174Kg, 1.2 Eq with respect to KG1) was then charged, maintaining the temperature at -20 °C to -25 °C with a MeTHF rinse. After the completion of the addition, the reaction mixture was stirred briefly

and then warmed to 20 °C to 25 °C. Upon completion, the reaction mixture was washed first with water (5L, 5 parts with respect to KG1) and then with dilute brine (5L, 5 parts with respect to KG1). The organic layer was concentrated by vacuum distillation to a volume of 5 L (5 parts with respect to KG1), diluted with acetonitrile (15L, 15 parts with respect to KG1) at approximately 40 °C and concentrated again (5L, 5 parts with respect to KG1). After solvent exchange to acetonitrile, the reaction mixture was then heated to approximately 60 °C to obtain a clear solution. The reaction mixture was then cooled slowly to 0-5 °C, held briefly and filtered. The filter cake was washed with cold acetonitrile (2L, 5 parts with respect to KG1) and the filter cake was then dried under a stream of nitrogen to provide the acetonitrile solvate of selinexor (Form D) as a slightly off-white solid.

[00285] Form D of selinexor (0.9Kg) was suspended in IPA (2.1Kg, 2.7L, 3 parts with respect to Form D) and water (2.7Kg, 2.7L, 3 parts with respect to Form D) and warmed to approximately 40 °C. The resulting suspension was agitated for about 4 hours, selinexor, cooled to approximately 20 °C, and diluted with additional water (9Kg, 10 parts with respect to Form D). The mixture was stirred for a further 4-6 hours, then filtered, and the cake washed with a mixture of 20% IPA and water (4.5L, 5 parts with respect to Form D). The filter cake was then dried under vacuum to provide selinexor designated Lot No. PC-14-008 as a white crystalline powder with a >99.5% a/a UPLC purity (a/a=area to area of all peaks; UPLC-ultra performance HPLC).

Example 6. Preparation of Selinexor Lot No.1405463 (Form A).

[00286] Selinexor Lot No. 1405463 was prepared in accordance with the following reaction scheme:

 .

[00287] A reactor was charged with KG1 (15.8Kg), KJ8 (6.9Kg) and MeTHF (90Kg). Diisopropylethylamine (14.2Kg) was added to the reaction mixture over approximately 35 minutes at about -20 °C. Following the addition of the diisopropylethylamine, T3P® (50%

solution in EtAOc, 34.4Kg) was added maintaining the temperature at -20 °C. The mixture stirred to complete the reaction first at -20 °C, then at ambient temperature.

[00288] Upon completion of the reaction, water (79Kg) was added over about 1 hour. The layers were separated and the organic layer was washed with a mixture of water (55Kg) and brine (18Kg), The mixture was filtered, and the methyl-THF/ethyl acetate in the mixture distillatively replaced with acetonitrile (volume of approximately 220L). The mixture was warmed to dissolve the solids, then slowly cooled to 0 to 5 °C before being filtered. The filter cake was washed with acetonitrile to provide the acetonitrile solvate of

selinexorSelinexorSelinexor (Form D).

[00289] The acetonitrile solvate of selinexorSelinexorSelinexor was dried, then mixed with isopropanol (23Kg) and water (55Kg). The slurry was warmed to about 38 °C and held at that temperature for approximately 4 hours before being cooled to 15 to 20 °C. Water (182Kg) was added. After a further 5 hours of agitation, the mixture was filtered and the filter cake washed with a mixture of isopropanol (14Kg) and water (73Kg), before being dried under vacuum (45 °C). The dried product was packaged to provide

selinexorSelinexorSelinexor Lot No. 1405463 (Form A).

Example 7. Polymorphism Studies of Selinexor.

[00290] A comprehensive polymorphism assessment of selinexor was performed in a range of different solvents, solvent mixtures and under a number of experimental conditions based on the solubility of selinexor. Three anhydrous polymorphs of

selinexorSelinexorSelinexor were observed by XRPD investigation, designated Form A, Form B and Form C. Form A is a highly crystalline, high-melting form, having a melting point of 177 °C, and was observed to be stable from a physico-chemical point of view when exposed for 4 weeks to 25 °C/97% relative humidity (RH) and to 40 °C/75% RH. A solvated form of selinexor was also observed in acetonitrile, designated Form D. A competitive slurry experiment confirmed Form A as the stable anhydrous form under the conditions investigated, except in acetonitrile, in which solvate formation was observed. It was further found that in acetonitrile, below 50 °C, only Form D is observed, at 50 °C both Form A and Form D are observed, and at 55 °C, Form A is observed .

PATENT

CN 106831731

https://patents.google.com/patent/CN106831731A/en

Selinexor is an orally bioavailable selective nuclear export inhibitors, 2012 for the first time in clinical, so far carried out a total of 21 trials, indications include chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphatic leukemia, prostate cancer, melanoma, non-small cell lung cancer, glioma, neuroblastoma into, gynecological cancer, diffuse large B-cell lymphoma, squamous cell carcinoma, colorectal cancer and the like. May 2014, FDA granted orphan drug designation Selinexor treatment of acute myeloid leukemia and diffuse large B-cell lymphoma, in June 2014, EMA is also granted orphan drug designation Selinexor treatment of both diseases. January 2015, received FDA orphan drug to treat multiple myeloma identified.

[0003] Currently, the synthesis process has been disclosed, the following reaction equation:

Figure CN106831731AD00041

[0006] wherein the compound is 5 Selinexor drug.

[0007] In this method, however, easy to produce Intermediate 1-2 double bond is easily reversed when synthetically produced from trans impurities, in addition to more difficult to impact yield; Intermediate 3 Intermediate 4 Synthesis APIs 5 when required ultra-low temperature, and the product was purified by column required, only a yield of 20%.

SUMMARY

[0008] The object of the present invention to provide a novel compound Selinexor drug synthesis of 5, in order to solve technical problems.

[0009] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0010] A, Compound 7

[0011] Compound 6, dichloromethane and ethyl acetate mixture, stirred and dissolved, compound 4, T3P (n-propyl phosphoric anhydride) and DIPEA (N, N- diisopropylethylamine) at a low temperature; the reaction was stirred for 25-35min at a low temperature, dichloromethane and water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0012] B, Synthesis of Compound 8

[0013] the compound obtained in Step 7, and mixed sodium iodide acetic acid, warmed to 110-120 ° C, the reaction 2.5-3.5h; After completion of the reaction, the system cooled to room temperature, water and dichloromethane were added, stirred for 8 after -15min, standing layered organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in DMF (dimethyl fumarate) to give compound in DMF 8;

Synthesis [0014] C, of Compound 5

[0015] Compound 1, DBAC0 (triethylenediamine), the DMF mixed and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 3-4 hours; the reaction after completion, water and ethyl acetate were added to the system, the organic phase is evaporated to dryness and petroleum ether and recrystallized from ethyl acetate to give compound 5.

[0016] Preferably, said step A, the low temperature is 0-2 ° C.

[0017] Preferably, said step B in DMF, the crude compound 8 concentration of less than 1%.

[0018] The novel synthetic methods of the present invention Selinexor drug, the chemical equation is as follows:

Figure CN106831731AD00051

[0020] The present invention has the following advantages: novel synthetic method Selinexor drug of the present invention to overcome the conventional synthesis process, is easy to produce trans impurities, more difficult in addition, the influence the yield and the need for ultra-low temperature, and the product requires problems purified by column, the yield is very low, reducing the synthetic steps, increased yield, there is provided a new process for the synthesis of the drug Selinexor.

[0021] In addition to the above-described objects, features and advantages of the present invention as well as other objects, features and advantages. Below the invention will be described in further detail present.

Example 1

[0024] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0025] A, Compound 7

[0026] 50ml three □ flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 0 ° C; the system at 0 ° C the reaction was stirred for 30min, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0027] B, Synthesis of Compound 8

[0028] 50ml three-necked flask, added the compound obtained in Step 7,40ml of glacial acetic acid and 1.38g of sodium iodide was heated to 115. (:, The reaction 3H; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and IOOml dichloromethane, after stirring IOmin, standing separation, the organic phase was washed with saturated sodium bicarbonate and saturated washed with sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8;

Synthesis [0029] C, of Compound 5

[0030] After 50ml 3-necked flask was added 0.2g compound 1,0.24gDBAC0,20mlDMF, dissolved with stirring, dropwise adding to the reaction system in DMF compound obtained in Step 8, after the addition was complete, stirring continued for 3.5 hours; after completion of the reaction, 20ml water was added to the system and 50ml ethyl acetate, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.158g of compound 5, yield 50.9%.

[0031] Example 2

[0032] – new type Se Iinexor drug synthesis, comprising the steps of:

Synthesis [0033] A, Compound 7

[0034] 50ml three □ flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 1 ° C; system at 1 ° C the reaction was stirred for 35min, 50ml of dichloromethane and 30ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0035] B, Synthesis of Compound 8

Three-neck flask [0036] 50ml of addition of the compound obtained in Step 7,40ml glacial acetic acid and 1.38g of sodium iodide was heated to 120. (:, The reaction for 2.5 h; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 60ml water and 120ml dichloromethane was added, after stirring for 15min, allowed to stand for separation, the organic phase was washed with saturated sodium bicarbonate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, 12mLDMF was dissolved in DMF to give a solution of compound 8;

Synthesis [0037] C, of Compound 5

[0038] After 50ml 3-necked flask was added 0.2g compound 1,0.24gDBAC0,20mlDMF, dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring continued for 3 hours; after completion of the reaction, 25ml of water and 50ml of ethyl acetate was added to the system, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.152g of compound 5, yield 49.0% billion

[0039] Example 3

[0040] – novel synthetic method of Se species I inexor drug, comprising the steps of:

Synthesis [0041] A, Compound 7

Three [0042] 50ml of flask, 15ml of dichloromethane and 0.2g compound 6,15ml ethyl acetate, stirred and dissolved, was added 0.3g of compound 4 and 3gT3P, 0.75gDIPEA at 2 ° C; system from 0 ° C the reaction was stirred for 25min, 40ml of dichloromethane and 35ml of water were added after the completion of the reaction, liquid separation, the organic phase was evaporated to dryness to give crude compound 7, crude without purification cast down;

[0043] B, Synthesis of Compound 8

Three-neck flask [0044] 50ml of addition of the compound obtained in Step 7,35ml glacial acetic acid and 1.38g of sodium iodide was heated to 110. (:, The reaction for 3.5 h; After completion of the reaction, cooled to room temperature system, the system will be transferred to 500ml flask, 50ml of water was added and dichloromethane IOOml After Smin of stirring, standing separation, the organic phase was washed with saturated sodium bicarbonate and washed with saturated sodium chloride, dried over anhydrous sodium sulfate and distilled to give crude compound 8, was dissolved in IOmL DMF to give DMF solution of compound 8;

Synthesis [0045] C, of Compound 5

[0046] 50ml three-neck flask was added 0.2g compound 1,0.24gDBA⑶, 20mlDMF, and dissolved with stirring, dropwise adding to the reaction system of the compound obtained in DMF step 8, after the addition was complete, stirring was continued for 4 hours; after completion of the reaction, 20ml of water and 40ml ethyl acetate were added to the system, the organic phase is evaporated to dryness and petroleum ether to ethyl acetate to give 0.155g of compound 5, yield 49.9% billion

PATENT

WO 2017118940

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017118940&tab=PCTDESCRIPTION

The drug compound having the adopted name “Selinexor” has chemical name:(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-IH-l,2,4-triazol-1 -yl)-N’-(pyrazin-2yl) acrylohydrazide as below.

Figure imgf000003_0001

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE™ compound. Selinexor functions by binding with and inhibiting the nuclear export protein XP01 (also called CRM1 ), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. Over 1 ,200 patients have been treated with Selinexor in company and investigator-sponsored Phase 1 and Phase 2 clinical trials in advanced hematologic malignancies and solid tumors. Karyopharm has initiated four later-phase clinical trials of Selinexor, including one in older patients with acute myeloid leukemia (SOPRA), one in patients with Richter’s transformation (SIRRT), one in patients with diffuse large B-cell lymphoma (SADAL) and a single-arm trial of Selinexor and lose-dose dexamethasone in patients with multiple myeloma (STORM). Patients may receive a twice-weekly combination of Selinexor in combination with low dose dexamethasone. Randomized 1 :1 , Selinexor will be dosed either at 60mg + dexamethasone or at 100 mg + dexamethasone.

US 8999996 B2 discloses Selinexor and a pharmaceutically acceptable salt thereof, pharmaceutical compositions and use for treating disorders associated with CRM1 activity. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Selinexor by reacting (Z)-3-(3- (3,5-

bis(trifluoromethyl)phenyl)-IH-l,2,4-triazol-l-yl)acrylic acid in 1 :1 CH2CI2: AcOEt with 2-Hydrazinopyrazine at -40 °C followed by addition of T3P[Propylphosphonic anhydride] (50%) and DIPEA. After 30 minutes, the reaction mixture was concentrated and the crude oil was purified by preparative TLC using 5% MeOH in CH2CI2 as mobile phase (under ammonia atmosphere) to afford 40 mg of Selinexor with purity: 95.78%. However, it is not disclosed about the nature of the compound obtained therein.

WO 2016025904 A1 discloses various crystalline forms of Selinexor namely Form A, Form B, Form C, Form D, compositions and MoU thereof for the treatment of disorder associated with CRM1 activity and their preparative processes.

Prior art process for the preparation of Selinexor suffers from disadvantages interms of process such as the use of lengthy procedures to practice and resulting in low yields, which may not be viable at industrial scale. Synthetic product obtained therein has very low purity and contains significant amounts of unreacted starting materials and trans-isomer of Selinexor, which are further purified by time consuming and expensive chromatographic separations leading to loss of yield. Hence, there remains a need for improved process for the preparation of Selinexor which is industrially viable and reproducible. Particularly, it is desirable to have a process avoiding purification steps still meeting desired pharmaceutical quality.

EXAMPLES

Example-1 : Preparation of isopropyl (Z)-3-(3-(3,5-bis(trifluoromethyl) phenyl)-1 H- -triazol-1 -yl)acrylate

Figure imgf000061_0001

3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazole (250 g) was dissolved in tetrahydrofuran (2 I) under nitrogen atmosphere at 27°C and cooled to -5°C. 1 ,4- diazabicyclo[2.2.2]octane (DABCO, 1 99.5 g) was added to the reaction mixture at -5°C and stirred at the same temperature for 40 minutes. Isopropyl (Z)-3- iodoacrylate (234.8 g in 500 mL of tetrahydrofuran) was added drop wise to the reaction mixture in 1 hour 1 0 minutes at -5°C and stirred at the same temperature for 2 hours. After the completion of the reaction, the reaction mixture was added to ice cold water (2 I) and separated the organic layer. The aqueous layer was extracted with ethyl acetate (2 x 1 I). The combined organic layer was washed with brine solution (1 I) and dried over sodium sulphate. The dried solution was evaporated completely under vacuum at 40°C to obtain crude product with HPLC purity of 93.53% The crude product was triturated with hexane (700 mL) and stirred for 20 minutes at -30°C and filtered the solid. Trituration of crude product with hexane was repeated for three times and dried under vacuum to obtain the title compound with HPLC purity of 97.46% and trans-isomer content of 0.66%. Yield: 297 g Example-2: Preparation of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4- triazol-1 -yl)acr lic acid.

Figure imgf000062_0001

To a mixture of tetrahydrofuran (300 mL) and water (300 mL), Isopropyl (Z)-3-(3- (3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylate (30 g) was added and cooled to 0°C. Lithium hydroxide monohydrate (16.03 g) under cooling condition at 0°C was added to the reaction mixture and stirred the reaction mixture at same temperature for 7 hours. After completion of the reaction, 2 N HCI (180 mL) was added to adjust the pH of the reaction mixture to 2 and extracted it with ethyl acetate (300 mL). Organic layer was dried over sodium sulphate and evaporated under vacuum at 40°C. The crude compound was stirred with hexane (150 mL) and filtered the solid. Dried the compound under vacuum at 40°C for 0.5 hour to obtain the title compound with HPLC purity of 97.25% with trans-isomer content of 3 %. Yield: 24 g

Example-3: Purification of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4- tria

Figure imgf000062_0002

A mixture of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid (24 g) and acetone (240 mL) was stirred for complete dissolution at 30°C. Dicyclohexyl amine (1 5 mL) was added drop wise for 20 minutes under stirring at the same temperature. Acetone (50 mL) was added to the reaction mixture and stirred for 2 hours at 27°C. Filtered the solid and washed with hot acetone (150 mL) and dried in vacuum drier at 30°C for 1 hour to obtain the Dicyclohexyl amine salt of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid. To the above salt, dichloromethane (150 mL) and water (1 00 mL) was added and stirred for complete dissolution at 30and adjusted the pH of the solution with 2 N sulphuric acid (100 mL) to 2. Filtered the reaction mixture and washed the product with water (1 00 mL) and then with hexane (150 mL). The solid was dried under vacuum at 40°C for 0.5 hour to obtain title compound with HPLC purity 99.98% with no detectable content of trans-isomer. Yield: 17 g

Example-4: Preparation of Selinexor

Figure imgf000063_0001

(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1 H-1 ,2,4-triazol-1 -yl)acrylic acid (10 g) was combined with a mixture of acetonitrile (1 00 mL) and ethyl acetate (50 mL) then added the 2-hydrazinylpyrazine (3.76 g) and stirred for 5 min. Reaction mixture was cooled to 0°C and diisopropyl ethyl amine (16.63 ml) and then Propylphosphonic anhydride (T3P, 33.31 mL) was added at 0°C and stirred the reaction mixture for 2.5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with cold water (100 mL) and extracted the product with ethyl acetate (2 x 150 mL). The combined organic layer was dried over sodium sulphate and evaporated the solvent under vacuum at 40°C to obtain the crude product as yellow syrup. The obtained crude product was combined with dichloromethane (1 00 mL) and filtered the solid and washed with dichloromethane (2 x 50 mL). The solid was dried under vacuum at 40°C to obtain the title compound with purity by HPLC of 99.86%. Yield : 7 g

PATENT
WO 2018129227

References

  1. Jump up to:a b c d e Fung HY, Chook YM (2014). “Atomic basis of CRM1-cargo recognition, release and inhibition”Semin Cancer Biol27: 52–61. doi:10.1016/j.semcancer.2014.03.002PMC 4108548PMID 24631835.
  2. Jump up to:a b c d e f Gandhi UH, Senapedis W, Baloglu E, Unger TJ, Chari A, Vogl D; et al. (2018). “Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma”. Clin Lymphoma Myeloma Leuk18 (5): 335–345. doi:10.1016/j.clml.2018.03.003PMID 29610030.
  3. Jump up to:a b c d e Feuerstein, Adam (2019-07-03). “FDA approves new multiple myeloma drug despite toxicity concerns”STAT. Retrieved 2019-07-06.
  4. Jump up to:a b c Mulcahy, Nick (2019-07-03). “FDA Approves Selinexor for Refractory Multiple Myeloma”Medscape. Retrieved 2019-07-06.
  5. Jump up to:a b c Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA; et al. (2018). “Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond”Leukemia32 (2): 252–262. doi:10.1038/leu.2017.329PMC 5808071PMID 29257139.
  6. ^ Barrett, Jennifer (2019-07-03). “New Treatment for Refractory Multiple Myeloma Granted FDA Approval”Pharmacy Times. Retrieved 2019-07-07.
  7. Jump up to:a b c d e f g “XPOVIO Prescribing Information” (PDF). Newton, MA: Karyopharm Therapeutics. 2019-07-03. Retrieved 2019-07-06.
  8. Jump up to:a b Chen C, Siegel D, Gutierrez M, Jacoby M, Hofmeister CC, Gabrail N (2018). “Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia”. Blood131 (8): 855–863. doi:10.1182/blood-2017-08-797886PMID 29203585.
  9. Jump up to:a b c d Parikh K, Cang S, Sekhri A, Liu D; et al. (2014). “Selective inhibitors of nuclear export (SINE)—a novel class of anti-cancer agents”J Hematol Oncol7: 78. doi:10.1186/s13045-014-0078-0PMC 4200201PMID 25316614.

REFERENCES

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2: Crochiere ML, Hannus S, Hansen K, Becker F, Baloglu E, Lee M, Kauffman M, Shacham S, Landesman Y. XPO1 target occupancy measurements confirm the selinexor recommended phase 2 dose. Oncotarget. 2017 Nov 30;8(66):110503-110516. doi: 10.18632/oncotarget.22801. eCollection 2017 Dec 15. PubMed PMID: 29299164; PubMed Central PMCID: PMC5746399.

3: Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, Giralt S, Mateos MV, Leleu X, Anderson KC. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia. 2017 Jan 16. doi: 10.1038/leu.2017.329. [Epub ahead of print] Review. PubMed PMID: 29257139.

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8: Chen Y, Zhang L, Huang J, Hong X, Zhao J, Wang Z, Zhang K. Dasatinib and chemotherapy in a patient with early T-cell precursor acute lymphoblastic leukemia and NUP214-ABL1 fusion: A case report. Exp Ther Med. 2017 Nov;14(5):3979-3984. doi: 10.3892/etm.2017.5046. Epub 2017 Aug 28. PubMed PMID: 29067094; PubMed Central PMCID: PMC5647690.

9: Body S, Esteve-Arenys A, Miloudi H, Recasens-Zorzo C, Tchakarska G, Moros A, Bustany S, Vidal-Crespo A, Rodriguez V, Lavigne R, Com E, Casanova I, Mangues R, Weigert O, Sanjuan-Pla A, Menéndez P, Marcq B, Picquenot JM, Pérez-Galán P, Jardin F, Roué G, Sola B. Cytoplasmic cyclin D1 controls the migration and invasiveness of mantle lymphoma cells. Sci Rep. 2017 Oct 24;7(1):13946. doi: 10.1038/s41598-017-14222-1. PubMed PMID: 29066743; PubMed Central PMCID: PMC5654982.

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12: Garg M, Kanojia D, Mayakonda A, Ganesan TS, Sadhanandhan B, Suresh S, S S, Nagare RP, Said JW, Doan NB, Ding LW, Baloglu E, Shacham S, Kauffman M, Koeffler HP. Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin. Sci Rep. 2017 Aug 29;7(1):9749. doi: 10.1038/s41598-017-10325-x. PubMed PMID: 28852098; PubMed Central PMCID: PMC5575339.

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Selinexor
Skeletal formula of selinexor
Clinical data
Trade names Xpovio
Pregnancy
category
  • Known to cause fetal harm
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Protein binding 95%
Metabolism Hepatic oxidation, glucuronidation, and conjugation, by CYP3A4UGTand GST
Elimination half-life 6–8 h
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
Chemical and physical data
Formula C17H11F6N7O
Molar mass 443.313 g·mol−1
3D model (JSmol)

Karyopharm’s Selinexor Receives Fast Track Designation from FDA for the Treatment of Patients with Penta-Refractory Multiple Myeloma

NEWTON, Mass., April 10, 2018 (GLOBE NEWSWIRE) — Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to the Company’s lead, oral Selective Inhibitor of Nuclear Export (SINE) compound selinexor for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy.  The FDA’s statement, consistent with the design of Karyopharm’s Phase 2b STORM study, noted that the three prior lines of therapy include regimens comprised of an alkylating agent, a glucocorticoid, Velcade® (bortezomib), Kyprolis® (carfilzomib), Revlimid® (lenalidomide), Pomalyst® (pomalidomide) and Darzalex® (daratumumab).  In addition, the patient’s disease must be refractory to at least one proteasome inhibitor (Velcade or Kyprolis), one immunomodulatory agent (Revlimid or Pomalyst), glucocorticoids and to Darzalex, as well as to the most recent therapy.  The Company expects to report top-line data from the STORM study at the end of April 2018.

ChemSpider 2D Image | selinexor | C17H11F6N7O

The FDA’s Fast Track program facilitates the development of drugs intended to treat serious conditions and that have the potential to address unmet medical needs.  A drug program with Fast Track status is afforded greater access to the FDA for the purpose of expediting the drug’s development, review and potential approval.  In addition, the Fast Track program allows for eligibility for Accelerated Approval and Priority Review, if relevant criteria are met, as well as for Rolling Review, which means that a drug company can submit completed sections of its New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be submitted for review.

“The designation of Fast Track for selinexor represents important recognition by the FDA of the potential of this anti-cancer agent to address the significant unmet need in the treatment of patients with penta-refractory myeloma that has continued to progress despite available therapies,” said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm.  “We are fully committed to working closely with the FDA as we continue development of this potential new, orally-administered treatment for patients who currently have no other treatment options of proven benefit.”

About the Phase 2b STORM Study

In the multi-center, single-arm Phase 2b STORM (Selinexor Treatment oRefractory Myeloma) study, approximately 122 patients with heavily pretreated, penta-refractory myeloma receive 80mg oral selinexor twice weekly in combination with 20mg low-dose dexamethasone, also dosed orally twice weekly.  Patients with penta-refractory disease are those who have previously received an alkylating agent, a glucocorticoid, two immunomodulatory drugs (IMiDs) (Revlimid® (lenalidomide) and Pomalyst® (pomalidomide)), two proteasome inhibitors (PIs) (Velcade® (bortezomib) and Kyprolis® (carfilzomib)), and the anti-CD38 monoclonal antibody Darzalex® (daratumumab), and their disease is refractory to at least one PI, at least one IMiD, Darzalex, glucocorticoids and their most recent anti-myeloma therapy.  Overall response rate is the primary endpoint of the study, with duration of response and clinical benefit rate being secondary endpoints.  All responses will be adjudicated by an Independent Review Committee (IRC).

About Selinexor

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,300 patients have been treated with selinexor, and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), in combination with low-dose dexamethasone (STORM) and as a potential backbone therapy in combination with approved therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

About Karyopharm Therapeutics

Karyopharm Therapeutics Inc. (Nasdaq:KPTI) is a clinical-stage pharmaceutical company focused on the discovery, development and subsequent commercialization of novel first-in-class drugs directed against nuclear transport and related targets for the treatment of cancer and other major diseases. Karyopharm’s SINE compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). In addition to single-agent and combination activity against a variety of human cancers, SINE compounds have also shown biological activity in models of neurodegeneration, inflammation, autoimmune disease, certain viruses and wound-healing. Karyopharm, which was founded by Dr. Sharon Shacham, currently has several investigational programs in clinical or preclinical development.

/////////Selinexor, FDA 2019, セリネクソル  ,KPT-330, KPT 330 , KPT330,  AML, Glioma, Sarcoma, Leukemia, Fast Track, CANCER

Picropodophyllin


Picropodophyllin.png

Image result for Picropodophyllin

2D chemical structure of 477-47-4

Picropodophyllin

Picropodophyllotoxin

CAS 477-47-4

AXL1717, NSC 36407, BRN 0099161

414.4 g/mol, C22H22O8

(5R,5aR,8aS,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one

Furo(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6(5aH)-one, 5,8,8a,9-tetrahydro-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-, (5R-(5-alpha,5a-alpha,8a-alpha,9-alpha))-

5-19-10-00665 (Beilstein Handbook Reference)

Axelar is developing picropodophyllin, a small-molecule IGF-1 receptor antagonist for the treatment of cancer including NSCLC and malignant astrocytoma. In February 2019, a phase Ia study was planned to initiate for solid tumor in March 2019.

Picropodophyllin is a cyclolignan alkaloid found in the mayapple plant family (Podophyllum peltatum), and a small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF1R) with potential antineoplastic activity. Picropodophyllin specifically inhibits the activity and downregulates the cellular expression of IGF1R without interfering with activities of other growth factor receptors, such as receptors for insulin, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor and mast/stem cell growth factor (KIT). This agent shows potent activity in the suppression o f tumor cell proliferation and the induction of tumor cell apoptosis. IGF1R, a receptor tyrosine kinase overexpressed in a variety of human cancers, plays a critical role in the growth and survival of many types of cancer cells.

Picropodophyllotoxin is an organic heterotetracyclic compound that has a furonaphthodioxole skeleton bearing 3,4,5-trimethoxyphenyl and hydroxy substituents. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor, an insulin-like growth factor receptor 1 antagonist and a plant metabolite. It is a lignan, a furonaphthodioxole and an organic heterotetracyclic compound.

Picropodophyllin has been investigated for the treatment of Non Small Cell Lung Cancer.

One of the largest challenges in pharmaceutical drug development is that drug compounds often are poorly soluble, or even insoluble, in aqeous media. Insufficient drug solubility means insufficient bioavailability, as well as poor plasma exposure of the drug when administered to humans and animals. Variability of plasma exposure in humans is yet a problem when developing drugs which are poorly soluble, or even insoluble, in aqeous media.

It is estimated that between 40% and 70 % of all new chemical entities identified in drug discovery programs, are insufficiently soluble in aqeous media (M. Lindenberg, S et al: European Journal of Pharmaceutics and Biopharmaceuticals, vol. 58, no.2, pp. 265-278, 2004). Scientists have investigated various ways of solving the problem with poor drug solubility in order to enhance bioavailability of poorly absorbed drugs, aiming at increasing their clinical efficacy when administered orally.

Technologies such as increase of the surface area and hence dissolution may sometimes solve solubility problems. Other techniques that may also solve bioavailability problems are addition of surfactants and polymers. However, each chemical compound has its own unique chemical and physical properties, and hence has its own unique challenges when being formulated into a pharmaceutical product that can exert its clinical efficacy.

Picropodophyllin is an insulin-like growth factor-1 receptor inhibitor fiGF-lR inhibitor) small-molecule compound belonging to the class of compounds denominated cyclolignans, having the chemical structure:

The patent applicant is presently entering clinical phase II development with its development compound picropodophyllin (AXL1717). However, picropodophyllin is poorly soluble in aqueous media. In a phase I clinical study performed by the applicant in 2012 (Ekman S et al; Acta Oncologica, 2016; 55: pp. 140-148), it was discovered that picropodophyllin, when administered as an oral suspension to lung cancer patients, resulted in unacceptable variability in drug exposure. A large variability in plasma exposure of the active drug picropodophyllin occurred not only within certain patients, but also between several patients.

Yet a problem with administering picropodophyllin as an aqeous solution, is that due to the poor solubility in aqueous media, it is difficult or even impossible to reach the required therapeutic doses.

The compound picropodophyllin is furthermore physically unstable, and transforms from amorphous picropodophyllin into crystalline picropodophyllin. Yet a stability problem with picropodophyllin is that it is chemically unstable in solution.

Image result for Picropodophyllin AND podophyllotoxin

Product case, WO02102804

Patent

WO-2019130194

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019130194&tab=PCTDESCRIPTION&_cid=P10-JXYAA3-53049-1

Novel amorphous forms of picropodophyllin , processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating cancers, such as neurologic cancer, lung cancer, breast cancer, head and neck cancer, gastrointestinal cancer, genitourinary cancer, gynecologic cancer, hematologic cancer, musculoskeletal cancer, skin cancer, endocrine cancer, and eye cancers. , claiming picropodophyllin derivatives as modulators of insulin-like growth factor-1 receptor (IGF-1), useful for treating cancers, assigned to Axelar AB ,

CLIP

Image result for Picropodophyllin

CLIP

https://pubs.rsc.org/en/content/articlelanding/2004/cc/b312245j/unauth#!divAbstract

Image result for Picropodophyllin

http://www.rsc.org/suppdata/cc/b3/b312245j/b312245j.pdf

dH(CDCl3; 300 MHz; Me4Si): 2.64-2.78 (1 H, m, 3-H), 3.23 (1 H, dd, J 4.4 and 8.2, 2-H), 3.81 (6 H, s, 2 x OMe), 3.85 (3 H, s, OMe), 4.09 (1 H, d, J 4.4, 1-H), 4.38–4.59 (3 H, m, 11-H2 and 4-H), 5.91 (1 H, d, J 1.5, OCH2O), 5.93 (1 H, d, J 1.5, OCH2O), 6.35 (1 H, s, 5-H/8-H), 6.46 (1 H, s, 2’-H and 6’-H) and 7.07 (1 H, s, 5-H/8-H).

CLIP

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PAPER

Organic Letters (2018), 20(6), 1651-1654

https://pubs.acs.org/doi/abs/10.1021/acs.orglett.8b00408

Abstract Image

A nickel-catalyzed reductive cascade approach to the efficient construction of diastereodivergent cores embedded in podophyllum lignans is developed for the first time. Their gram-scale access paved the way for unified syntheses of naturally occurring podophyllotoxin and other members.

Synthesis of (−)-Podophyllotoxin (1)

https://pubs.acs.org/doi/suppl/10.1021/acs.orglett.8b00408/suppl_file/ol8b00408_si_001.pdf

The residue was purified by flash column chromatography (petroleum ether/EtOAc = 4 : 1 → petroleum ether/EtOAc = 2 : 1) on silica gel to afford 1 (8.6 mg, 87% yield) as a white solid; Rf = 0.23 (petroleum ether/EtOAc = 1 : 1); [α]20 D = –115.00 (c = 1.00, CHCl3) [ref.13: [α]20 D = –101.7 (c = 0.55, EtOH)]; Mp. 167–168 °C; 1H NMR (400 MHz, CDCl3): δ = 7.11 (s, 1H), 6.51 (s, 1H), 6.37 (s, 2H), 5.98 (s, 1H), 5.96 (s, 1H), 4.77 (t, J = 8.4 Hz, 1H), 4.60 (t, J = 8.0 Hz, 1H), 4.59 (d, J = 4.4 Hz, 1H), 4.08 (dd, J = 9.6, 8.8 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 6H), 2.84 (dd, J = 14.0, 4.4 Hz, 1H), 2.83−2.74 (m, 1H), 2.13 (d, J = 8.0 Hz, 1H, −OH) ppm; 13C NMR (100 MHz, CDCl3): δ = 174.6, 152.5 (2C), 147.7, 147.6, 137.1, 135.5, 133.3, 131.0, 109.7, 108.4 (2C), 106.3, 101.4, 72.6, 71.4, 60.7, 56.2 (2C), 45.2, 44.1, 40.6 ppm.

https://pubs.acs.org/doi/suppl/10.1021/acs.orglett.8b00408/suppl_file/ol8b00408_si_002.pdf

PAPER

Organic Letters (2017), 19(24), 6530-6533

https://pubs.acs.org/doi/abs/10.1021/acs.orglett.7b03236

Abstract Image

he first catalytic enantioselective total synthesis of (−)-podophyllotoxin is accomplished by a challenging organocatalytic cross-aldol Heck cyclization and distal stereocontrolled transfer hydrogenation in five steps from three aldehydes. Reversal of selectivity in hydrogenation led to the syntheses of other stereoisomers from the common precursor.

https://pubs.acs.org/doi/suppl/10.1021/acs.orglett.7b03236/suppl_file/ol7b03236_si_001.pdf

(-)-Picropodophyllin 4. The lactone 5 (0.2 g, 0.38 mmol) was taken in 1-pentanol (5 mL) in a double neck RB flask at rt. Water (0.14 mL, 7.6 mmol) was added to above mixture and it was then degassed with argon followed by addition of Pd/C (0.04 g, 20% by wt.) and HCO2Na (0.78g, 11.4 mmol). The reaction mixture was heated at 40 °C for 12 h. On completion, the reaction mixture was diluted with EtOAc (200 mL), filtered through a celite pad and solvent was removed under vacuum. This crude mixture was dissolved in THF (3.8 mL), TBAF (1.9 mL, 1.9 mmol, 1M in THF) was added and stirred for 6 h at 27 °C. On completion, EtOAc (250 mL) was added, washed with water (100 mL), brine and dried over Na2SO4. After removal of solvent, the crude product was purified by column chromatography (hexanes-EtOAc, 3:2) to get the title compound as a white solid (0.082 g, 52%): Rf 0.32 (hexanes/EtOAc, 1:1); [α]25 D = -10.6 (c = 0.4, CHCl3) [lit. -10 (c = 0.3, CHCl3), -11 (c = 0.41, CHCl3)]3a,b;

Mp 214-216 °C; 1H NMR (600 MHz, CDCl3) δ 7.05 (s, 1H), 6.47 (s, 2H), 6.41 (s, 1H), 5.95 (d, J = 14.1 Hz, 2H), 4.5 (m, 2H), 4.44 (t, J = 8.0 Hz, 1H), 4.15 (d, J = 4.1 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 6H), 3.24 (dd, J = 8.7, 5.0 Hz, 1H), 2.75 (m, 1H), 2.12 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 177.6, 153.7, 147.5, 147.1, 139.3, 137.4, 131.9, 130.6, 109.3, 105.9, 105.5, 101.2, 69.8, 69.6, 60.9, 56.3, 45.4, 44.1, 42.7; HRMS (ESI-TOF) m/z 437.1219 [(M+Na)+ ; calcd for C22H22O8Na+ : 437.1212].

PAPER

The Journal of organic chemistry (2000), 65(3), 847-60.

https://pubs.acs.org/doi/abs/10.1021/jo991582+

Abstract Image

REF

Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1932), 65B, 1846.

Justus Liebigs Annalen der Chemie (1932), 499, 59-76.

Justus Liebigs Annalen der Chemie (1932), 494, 126-42.

Journal of the American Chemical Society (1954), 76, 5890-1

Helvetica Chimica Acta (1954), 37, 190-202.

 Journal of the American Chemical Society (1988), 110(23), 7854-8.

//////////////Picropodophyllin, AXL1717, NSC 36407, BRN 0099161, Picropodophyllotoxin, AXELAR, PHASE 1, CANCER, neurologic cancer, lung cancer, breast cancer, head and neck cancer, gastrointestinal cancer, genitourinary cancer, gynecologic cancer, hematologic cancer, musculoskeletal cancer, skin cancer, endocrine cancer, eye cancers,  NSCLC, malignant astrocytoma, SOLID TUMOUR

COC1=CC(=CC(=C1OC)OC)C2C3C(COC3=O)C(C4=CC5=C(C=C24)OCO5)O

Podofilox, Podophyllotoxin, Wartec, Condyline, Condylox

J Org Chem 2000,65(3),847

The formylation of 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) with BuLi and DMF gives the 6-formyl derivative (II), which is reduced with NaBH4 in ethanol to yield the corresponding carbinol (III). The cyclization of (III) with dimethyl acetylenedicarboxylate (V) in hot acetic acid (through the nonisolated intermediate (IV)) affords dimethyl 1,4-epoxy-6,7-(methylenedioxy)naphthalene-2,3-dicarboxylate (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the (1R*,2S*,3R*,4S*)-tetrahydro derivative (VII). The reduction of (VII) with LiAlH4 in refluxing ethyl ether affords the corresponding bis carbinol (VIII), which is treated with acetic anhydride to afford the diacetate (IX). The enzymatic monodeacetylation of (VIII) with PPL enzyme in DMSO/buffer gives (1R,2R,3S,4S)-2-(acetoxymethyl)-1,4-epoxy-3-(hydroxymethyl)-6,7-(methylenedioxy)-1,2,3,4-tetrahydronaphthalene (X), which is silylated with TBDMS-Cl and imidazole in DMF yielding the silyl ether (XI). The hydrolysis of the acetoxy group of (XI) with K2CO3 in methanol affords the carbinol (XII), which is oxidized with oxalyl chloride in dichloromethane affording the carbaldehyde (XIII). The exchange of the silyl protecting group of (XIII) (for stability problems) provided the triisopropylsilyl ether (XIV), which is treated with sodium methoxide in methanol to open the epoxide ring yielding the hydroxy aldehyde (XV). The protection of the hydroxy group of (XV) with 2-(trimethylsilyl)ethoxymethyl chloride and DIEA in dichloromethane provides the corresponding ether (XVI). The carbinol (III) can also be obtained directly from 6-bromo-1,3-benzodioxole-5-carbaldehyde dimethyl acetal (I) by reaction with formaldehyde and BuLi in THF.

The oxidation of the aldehyde group of (XVI) with NaClO2 in tert-butanol affords the corresponding carboxylic acid (XVII), which is condensed with 2-oxazolidinone (XVIII) by means of carbonyldiimidazole (CDI) in THF to give the acyl imidazolide (XIX). The arylation of (XIX) with 3,4,5-trimethoxyphenylmagnesium bromide (XX) in THF yields the expected addition product (XXI), which is cyclized by means of TBAF in hot THF to afford the tetracyclic intermediate (XXII). Isomerization of the cis-lactone ring of (XXII) with LDA in THF affords intermediate (XXIII) with its lactone ring with the correct trans-conformation. Finally, this compound is deprotected with ethyl mercaptane and MgBr2 in ethyl ether to provide the target compound.

Synthesis 1992,719

The intermediate trans-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetra-hydronaphtho[2,3-d][1,3]benzodioxole-6-carboxylic acid ethyl ester (XI) has been obtained by several different ways: (a) The condensation of benzophenone (XXXVIII) with diethyl malonate (XXXIX) by means of t-BuOK gives the alkylidenemalonate (XL), which is hydrogenated with H2 over Pd/C to the alkylmalonate hemiester (XLI). The reaction of (XLI) with acetyl chloride affords the mixed anhydride (XLII), which is finally cyclized to the target (XI) by means of SnCl4. (b) The cyclization of the malonic ester derivative (XLIII) by means of Ti(CF3–CO2)3 gives the 5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho [2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLIV), which is finally oxidized and decarboxylated with NBS and NaOH in methanol to afford the target intermediate (XI). (c) The cyclization of the benzylidenemalonate (XLV) with the aryllithium derivative (XLVI) gives the 8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLVII), which is demethylated with TFA and oxidized with CrO3 and pyridine to the target compound (XI). (d) The cyclopropanation of the chalcone (XLVIII) with (ethoxycarbonyl) (dimethylsulfonium)methylide (XLIX) gives the cyclopropanecarboxylate (L), which is finally rearranged with BF3/Et2O to the target intermediate (IX).

The cyclization of 3,4,5-trimethoxycinnamic acid ethyl ester (LI) with malonic acid ethyl ester potassium salt (LII) by means of Mn(OAc)3 gives the tetrahydrofuranone (LIII), which is acylated with 1,3-benzodioxol-5-ylcarbonyl chloride (LIV) yielding the tetrahydrofuranone (LV). Finally, this compound is rearranged and decarboxylated with SnCl4 to the target intermediate (XI).

The cyclization of 6-[1-hydroxy-1-(3,4,5-trimethoxyphenyl)methyl]-1,3-benzodioxol-5-carbaldehyde dimethylacetal (LVI) by means of AcOH gives 5-(3,4,5-trimethoxyphenyl)-1,3-dioxolo[4,5-f]isobenzofuran (LVII), which is submitted to a Diels-Alder cyclization with acetylenedicarboxylic acid dimethyl ester (LVIII) yielding the epoxy derivative (LIX). The selective reduction of (LIX) with LiBEt3H and H2 affords the carbinol (LX), which is treated with H2 over RaNi in order to open the epoxide ring to give the diol (LXI) with the wrong configuration at the secondary OH group. The treatment of (LXI) with aqueous acid isomerizes the secondary OH group to (LXII) with the suitable configuration. Finally, this compound is cyclized with DCC to the desired target compound.

The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with dimethyl maleate (LXIII) gives the expected adduct (LXIV), which by thermal extrusion of CO2 yields the dihydronaphthodioxole (LXV). This compound is then converted to dihydroxycompound (X), which is finally cyclized by means of ZnCl2 to provide the target compound. The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with dimethyl fumarate (LXVI) gives the expected adduct (LXVII), which by hydrogenation with H2 over Pd/C yields the tricarboxylic acid derivative (LXVIII). The reaction of (LXVIII) with Pb(OAc)4 affords the acetoxy derivative (LXIX), which is selectively reduced with LiBEt3H providing the diol (LXI) with the wrong configuration at the secondary OH group. The treatment of (LXI) with aqueous acid isomerizes the secondary OH group to give the previously described (X) with the suitable configuration.

The reaction of benzocyclobutane derivative (LXX) with isocyanate (LXXI) by means of Ph3SnOAc gives the carbamate (LXXII), which is cyclized by a thermal treatment with LiOH yielding the tetracyclic carboxylic acid (LXXIII). The opening of the oxazinone ring of (LXXIII) in basic medium affords the tricyclic amino acid (LXXIV), which is finally cyclized to the target compound by reaction with sodium nitrite in acidic medium (pH = 4).

J Chem Soc Chem Commun 1993,1200

The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with the chiral dihydrofuranone (II) in hot acetonitrile gives the pentacyclic anhydride (III), which is opened with warm acetic acid yielding the carboxylic acid (IV). Hydrogenation of the benzylic double bond of (IV) with H2 over Pd/C affords (V), which is treated with lead tetraacetate and acetic acid in THF to give the acetoxy compound (VI). The hydrolysis of the acetoxy group and the menthol hemiacetal group with HCl in hot dioxane yields the diol (VII), which is treated with diazomethane in ether/methanol affording the aldehyde (VIII). The reduction of the aldehyde group of (VIII) with LiEt3BH in THF gives the diol (IX) as a diastereomeric mixture, which is treated with HCl in THF to afford the diol (X) with the right conformation. Finally, this compound is lactonized to the target compound with ZnCl2 in THF.

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SELPERCATINIB


img

Selpercatinib.png

SELPERCATINIB

LOXO 292

CAS: 2152628-33-4
Chemical Formula: C29H31N7O3
Molecular Weight: 525.613

CEGM9YBNGD

UNII-CEGM9YBNGD

 6-(2-hydroxy-2-methylpropoxy)-4-(6-{6-[(6-methoxypyridin- 3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Selpercatinib is a tyrosine kinase inhibitor with antineoplastic properties.

A phase I/II trial is also under way in pediatric patients and young adults with activating RET alterations and advanced solid or primary CNS tumors.

Loxo Oncology (a wholly-owned subsidiary of Eli Lilly ), under license from Array , is developing selpercatinib, a lead from a program of RET kinase inhibitors, for treating cancer, including non-small-cell lung cancer, medullary thyroid cancer, colon cancer, breast cancer, pancreatic cancer, papillary thyroid cancer, other solid tumors, infantile myofibromatosis, infantile fibrosarcoma and soft tissue sarcoma

In 2018, the compound was granted orphan drug designation in the U.S. for the treatment of pancreatic cancer and in the E.U. for the treatment of medullary thyroid carcinoma.

Trk is a high affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophic factor (NT). The Trk receptor family has three members, namely TrkA, TrkB and TrkC. Among the neurotrophic factors are (1) nerve growth factor (NGF) which activates TrkA, (2) brain-derived neurotrophic factor (BDNF) and NT4/5 which activate TrkB, and (3) NT3 which activates TrkC. Trk is widely expressed in neuronal tissues and is involved in the maintenance, signaling and survival of neuronal cells.
The literature also shows that Trk overexpression, activation, amplification and/or mutations are associated with many cancers including neuroblastoma, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, multiple myeloma, astrocytoma. And medulloblastoma, glioma, melanoma, thyroid cancer, pancreatic cancer, large cell neuroendocrine tumor and colorectal cancer. In addition, inhibitors of the Trk/neurotrophin pathway have been shown to be effective in a variety of preclinical animal models for the treatment of pain and inflammatory diseases.
The neurotrophin/Trk pathway, particularly the BDNF/TrkB pathway, has also been implicated in the pathogenesis of neurodegenerative diseases, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. The modulating neurotrophic factor/Trk pathway can be used to treat these and related diseases.
It is believed that the TrkA receptor is critical for the disease process in the parasitic infection of Trypanosoma cruzi (Chagas disease) in human hosts. Therefore, TrkA inhibitors can be used to treat Chagas disease and related protozoal infections.
Trk inhibitors can also be used to treat diseases associated with imbalances in bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastasis. Bone metastases are a common complication of cancer, up to 70% in patients with advanced breast or prostate cancer and about 15 in patients with lung, colon, stomach, bladder, uterine, rectal, thyroid or kidney cancer Up to 30%. Osteolytic metastases can cause severe pain, pathological fractures, life-threatening hypercalcemia, spinal cord compression, and other neurostress syndromes. For these reasons, bone metastases are a serious cancer complication that is costly. Therefore, an agent that can induce apoptosis of proliferating bone cells is very advantageous. Expression of the TrkA receptor and TrkC receptor has been observed in the osteogenic region of the fractured mouse model. In addition, almost all osteoblast apoptosis agents are very advantageous. Expression of the TrkA receptor and TrkC receptor has been observed in the osteogenic region of the fractured mouse model. In addition, localization of NGF was observed in almost all osteoblasts. Recently, it was demonstrated that pan-Trk inhibitors in human hFOB osteoblasts inhibit tyrosine signaling activated by neurotrophic factors that bind to all three Trk receptors. This data supports the theory of using Trk inhibitors to treat bone remodeling diseases, such as bone metastases in cancer patients.
Developed by Loxo Oncology, Larotrectinib (LOXO-101) is a broad-spectrum antineoplastic agent for all tumor patients expressing Trk, rather than tumors at an anatomical location. LOXO-101 chemical name is (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)pyrazolo[1,5-a] Pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, the structural formula is as follows. LOXO-101 began treatment of the first patient in March 2015; on July 13, 2016, the FDA granted a breakthrough drug qualification for the inoperable removal or metastatic solid tumor of adults and children with positive Trk fusion gene mutations; Key entry was completed in February 2017; in November 2018, the FDA approved the listing under the trade name Vitrakvi.
Poor absorption, distribution, metabolism, and/or excretion (ADME) properties are known to be the primary cause of clinical trial failure in many drug candidates. Many of the drugs currently on the market also limit their range of applications due to poor ADME properties. The rapid metabolism of drugs can lead to the inability of many drugs that could be effectively treated to treat diseases because they are too quickly removed from the body. Frequent or high-dose medications may solve the problem of rapid drug clearance, but this approach can lead to problems such as poor patient compliance, side effects caused by high-dose medications, and increased treatment costs. In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites.
Although LOXO-101 is effective as a Trk inhibitor in the treatment of a variety of cancers and the like, it has been found that a novel compound having a good oral bioavailability and a drug-forming property for treating a cancer or the like is a challenging task. Thus, there remains a need in the art to develop compounds having selective inhibitory activity or better pharmacodynamics/pharmacokinetics for Trk kinase mediated diseases useful as therapeutic agents, and the present invention provides such compounds.
SYN
WO 2018071447

PATENT

WO2018071447

PATENT

US 20190106438

PATENT

WO 2019075108

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019075108&tab=PCTDESCRIPTION

Compounds of Formula I-IV, 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula I); 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula II); 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula III); and 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula IV) are inhibitors of RET kinase, and are useful for treating diseases such as proliferative diseases, including cancers.

[0007] Accordingly, provided herein is a compound of Formula I-IV:

and pharmaceutically acceptable salts, amorphous, and polymorph forms thereof.

PATENT

WO 2019075114

PATENT

WO-2019120194

Novel deuterated analogs of pyrazolo[1,5-a]pyrimidine compounds, particularly selpercatinib , processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating pain, inflammation, cancer and certain infectious diseases.

Example 2(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl-2,3,3-d 3)-pyrazolo[ 1,5-a] pyrimidin-3-yl) -3-hydroxypyrazole prepared pyrrolidine-1-carboxamide (compound L-2) a.

[0163]

[0164]
Use the following route for synthesis:

[0165]
Patent ID Title Submitted Date Granted Date
US10137124 Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors 2018-01-03
US10172851 Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors 2018-01-03
US10112942 Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors 2017-12-29

/////////////SELPERCATINIB, non-small-cell lung cancer, medullary thyroid cancer, colon cancer, breast cancer, pancreatic cancer, papillary thyroid cancer, other solid tumors, infantile myofibromatosis, infantile fibrosarcoma, soft tissue sarcoma, LOXO, ELI LILY,  ARRAY, LOXO 292, orphan drug designation

N#CC1=C2C(C3=CC=C(N4CC(C5)N(CC6=CC=C(OC)N=C6)C5C4)N=C3)=CC(OCC(C)(O)C)=CN2N=C1

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