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Talorasib

December 11, 2025 2:25 am / Leave a comment

Talorasib

CAS 2648584-48-7

MFC32H34ClFN6O3 MW605.10

[(2S)-4-[(7S)-7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile
Kirsten rat sarcoma viral oncogene homologue (KRAS)inhibitor, antineoplastic, 727W6T7DPK

SYN

CN115385923

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN380619664&_cid=P20-MJ0TAW-52678-1

Preparation Example 1: Synthesis of the compound shown in formula (I)

(1) Synthesis of Compound 1

Synthetic route of compound 1:

Synthesis of compound 1-j

1-Bromo-8-chloronaphthalene (500 mg, 2.07 mmol) was dissolved in THF (20 mL), cooled to -78 °C, and n-BuLi (2.5 M, 1.66 mL, 4.14 mmol) was added dropwise under nitrogen protection. After the addition was complete, the mixture was stirred at -78 °C for 10 min, and then DMF (800 μL, 10.35 mmol) was added dropwise at -78 °C. After the addition was complete, the reaction mixture was stirred at -78 °C for 30 min, then heated to room temperature and stirred for 2 h. The reaction was quenched with 50 mL of saturated ammonium chloride solution and extracted with ethyl acetate (50 mL * 2). The organic phase was washed with saturated brine (50 mL * 2), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (EA/PE = 1/10) to give compound 1-j (330 mg, 84% yield) as a white solid. LC-MS (ESI): m/z=191.0[M+H] ⁺ ; ¹ H NMR (400MHz, CDCL₃):δ11.31(s,1H),8.03(dd,1H,J₁=1.2Hz,J₂=8.4Hz), 7.92(dd,1H,J₁=1.2Hz,J₂＝7.2Hz),7.86(1H,J＝8.4Hz),7.70(dd,1H,J₁=1.2Hz,J₂＝7.6Hz), 7.59(t,1H,J＝7.6Hz), 7.47(t,1H,J＝8Hz).

Synthesis of compound 1-i

At room temperature, NaH (60%, 242 mg, 6.05 mmol) was added to 6 mL of THF. Then, methyl acetoacetate (543 μL, 5.04 mmol) was added under nitrogen atmosphere at room temperature. The mixture was stirred for 30 minutes under nitrogen atmosphere at room temperature, and then n-BuLi (2.5 M, 2.4 mL, 6.05 mmol) was added dropwise at -15 °C to -10 °C. After the addition was complete, the mixture was maintained at this temperature for 30 minutes, and then a 10 mL solution of compound 1-j (320 mg, 1.68 mmol) in THF was added dropwise. After the addition was complete, the mixture was stirred at low temperature (-10 °C to 0 °C) for 2 hours, then quenched with saturated ammonium chloride solution (50 mL), and then extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL * 2), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (EA/DCM = 1/10) to give compound 1-i (510 mg, 99% yield) as a white solid. LC-MS (ESI): m/z = 329.1 [M + Na] ^⁺ ; ^1H NMR (400 MHz, CDCl₂)₃): δ8.06(d,1H,J＝6.4Hz),7.79(d,2H,J＝8Hz),7.58(dd,1H,J₁=7.6Hz,J₂＝1.6Hz),7.53(t,1H,J＝7.6Hz),7.34(t,1H,J＝7.6Hz),6.91(dd,1H,J₁=9.2Hz, J₂=2.4Hz),3.74(s,3H),3.54(s,2H),3.36(dd,1H,J₁=18Hz,J₂＝1.6Hz),3.24(d,1H,J＝3.6Hz),2.85-2.75(m,1H).

Synthesis of compound 1-h

Compound 1-i (510 mg, 1.66 mmol) was dissolved in DCM (18 mL) at room temperature, followed by the addition of DMF-DMA (245 μL, 1.83 mmol) under nitrogen atmosphere at room temperature. After stirring the reaction mixture for 45 minutes at room temperature, BF was added.₃Et₂O (232 μL, 1.83 mmol). After addition, the mixture was stirred at room temperature for 1 hour, then diluted with 100 mL of ethyl acetate. The organic phase was then sequentially quenched with saturated NaHCO3.₃The sample was washed with a solution (100 mL) and saturated saline solution (100 mL * 2), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 1-h (520 mg). The crude product required no purification and was used directly in the next reaction. LC-MS (ESI): m/z = 317.1 [M+1] ⁺ .

Synthesis of compound 1-g

Compound 1-h (520 mg, 1.64 mmol) was dissolved in THF (20 mL) at room temperature, and then tri-sec-butylborohydride (1 M, 1.64 mL, 1.64 mmol) was added dropwise under nitrogen atmosphere at -78 °C. After addition, the mixture was stirred at -78 °C for 1 hour, the reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL * 2), the organic matter was washed with saturated brine (50 mL * 2), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography (PE/EA = 4/1) to give compound 1-g (338 mg, 65% yield) as a yellow oil. LC-MS (ESI): m/z = 319.0 [M+1] ⁺ .

Synthesis of compound 1-f

Compound 1-g (338 mg, 1.06 mmol) was dissolved in methanol (20 mL) at room temperature. Then, under nitrogen atmosphere at 0 °C, sodium methoxide (286 mg, 5.3 mmol) and compound 2-methyl-2-mercaptourea sulfate (265 mg, 0.954 mmol) were added sequentially. After the addition was complete, the mixture was brought to room temperature and stirred for 20 hours. The pH of the reaction solution was adjusted to 5 with 1 N dilute hydrochloric acid, and a solid precipitated. The solid was filtered, the filter cake was washed with water (5 mL * 2), and the solid was collected and dried under vacuum to give crude product 1-f (313 mg) as a white solid. LC-MS (ESI): m/z = 359.1 [M+1] ⁺ .

Synthesis of compound 1-e

Compound 1-f (313 mg, 0.87 mmol) was dissolved in DCM (10 mL) at room temperature. Then, under nitrogen atmosphere in an ice-water bath, DIPEA (431 μL, 2.61 mmol) and trifluoromethanesulfonic anhydride (219 μL, 1.31 mmol) were added sequentially. After addition, the reaction mixture was stirred in an ice-water bath for 2 hours, quenched with saturated sodium bicarbonate solution (50 mL), extracted with DCM (50 mL x 2), and the organic phase was treated with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid column chromatography (EA/PE = 1/10) to give compound 1-e (83 mg, 16% yield in 2 steps) as a white solid. LC-MS (ESI): m/z = 491.0 [M+1] ⁺ .

Synthesis of compound 1-d

Compound 1-e (83 mg, 0.169 mmol) was dissolved in DMF (10 mL) at room temperature, followed by the sequential addition of DIPEA (84 μL, 0.507 mmol) and (S)-2-cyanomethylpiperazine-1-carboxylate hydrochloride (59.9 mg, 0.203 mmol). After addition, the mixture was stirred for 1 hour at 100 °C under nitrogen protection, cooled to room temperature, quenched with saturated brine (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 3), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid column chromatography (EA/PE = 1/1) to give compound 1-d (101 mg, 99% yield) as a white solid. LC-MS (ESI): m/z = 600.2 [M+1] ⁺ .

Synthesis of compound 1-c

Compound 1-d (101 mg, 0.168 mmol) was dissolved in ethyl acetate (10 mL) at room temperature, followed by the addition of MCPBA (85%, 88.4 mg, 0.437 mmol) at room temperature. After addition, the mixture was stirred at room temperature for 2 hours, quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (25 mL x 2), and the organic phase was treated with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid column chromatography (EA/PE = 1/4) to give compound 1-c (88 mg, 82% yield) as a white solid. LC-MS (ESI): m/z = 632.1 [M+1] ⁺ .

Synthesis of compound 1-b

Compound 1-c (88 mg, 0.139 mmol) was dissolved in toluene (10 mL) at room temperature. The reaction mixture was then cooled to 0 °C, and N-methylprolyl (29 μL, 0.243 mmol) and t-BuONa (27 mg, 0.278 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred for 0.5 hours under nitrogen in an ice-water bath, quenched with water (20 mL), and extracted with ethyl acetate (30 mL * 2). The organic phase was treated with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by rapid column chromatography (MeOH/DCM = 1/10) to give compound 1-b (78 mg, 84% yield) as a white solid. LC-MS (ESI): m/z = 667.3 [M+1] ⁺ .

Synthesis of compound 1-a

Compound 1-b (72 mg, 0.108 mmol) was dissolved in methanol (50 mL) at room temperature. The reaction solution was then cooled to -78 °C, purged twice with nitrogen, and then Pd/C (150 mg) and ZnBr were added.₂(24.3 mg, 0.108 mmol), the reaction mixture was purged with hydrogen three times, brought to room temperature, and stirred under hydrogen atmosphere for 5 hours. The reaction mixture was filtered and concentrated to obtain a crude product, which was then purified by a rapid separation column (MeOH/DCM = 1:4) to give compound 1-a (20 mg, 35% yield) as a white solid. LC-MS (ESI): m/z = 533.0 [M+1] ⁺ .

Synthesis of Compound 1

At room temperature, compound 2-fluoroacrylic acid (5.1 mg, 0.0563 mmol) was dissolved in DMF (2 mL). Then, at 0 °C, HATU (25.6 mg, 0.0675 mmol) and DIPEA (18.6 μL, 0.113 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at 0 °C under nitrogen for 20 minutes. Then, a DMF solution of compound 1-a (20 mg, 0.0375 mmol) (3 mL) was added to the above reaction mixture. The mixture was brought to room temperature and stirred for another 5 hours. The reaction mixture was quenched with saturated brine (20 mL), extracted with ethyl acetate (25 mL * 2), washed with saturated brine (50 mL * 3), treated with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by PREP-TLC (MeOH/DCM = 1/10) to obtain compound 1 (6 mg, 26% yield) as a white solid. LC-MS (ESI): m/z=605.2[M+1] ⁺ ; ¹ H NMR (400MHz, CDCl₃): δ7.99-7.93(m,1H),7.83(t,2H,J＝8.8Hz),7.62-7.49(m,2H),7.36(t,1H,J＝7.6Hz),6.5 5-6.44(m,1H),5.51-5.31(m,1H),5.25(d,1H,J＝16.8Hz),5.02-4.93(m,1H),4.82(dd,1H,J₁=2.4Hz, J₂＝13.6Hz),4.48-4.38(m,1H),4.32-4.19(m,1H),4.17-4.04(m,1H),4. 00(d,1H,J＝14Hz),3.87-3.70(m,1H),3.66-3.36(m,2H),3.31-3.16(m ,2H),3.14-2.98(m,1H),2.96-2.69(m,4H),2.59(d,3H,J=18Hz),2.52 -2.34(m,1H),2.15-2.06(m,1H),1.87-1.74(m,2H),0.93-0.76(m,2H).

(2) Resolution of compound 1

Synthesis of compounds 1-1 and 1-2

The challenge lay in obtaining the compound shown in formula (I) through chiral resolution of compound 1. Despite trying various conditions, the two isomers of compound 1 could not be separated on a thin-layer chromatography plate, making separation impossible by thin-layer chromatography. Even in HPLC, the separation of the two isomers of compound 1 was poor, making separation impossible by preparative HPLC. Finally, chiral resolution had to be resorted to. After trying several conditions (as shown in Table 1 below), chiral resolution condition 9 was finally found, which enabled the separation of the compound shown in formula (I) and its diastereomers.

SYN

WO-2021109737-A1

SYN

WO-2022081655-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022081655&_cid=P20-MJ0T2K-48115-1

PAT

Substituted dihydropyranopyrimidine compounds as kras inhibitorsPublication Number: US-2022112204-A1Priority Date: 2020-10-14
Substituted dihydropyranopyrimidine compounds as kras inhibitorsPublication Number: WO-2022081655-A1Priority Date: 2020-10-14
Oxygen-containing heterocyclic compound, preparation method and application thereofPublication Number: WO-2021109737-A1Priority Date: 2019-12-02
Oxygen-containing heterocyclic compound, preparation method and application thereofPublication Number: EP-4015520-A1Priority Date: 2019-12-02

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[1]. Shanghai Yingli Pharmaceutical Co., Ltd. Preparation of oxygen-containing heterocyclic compounds as Ras inhibitor for prevention and/or treatment of Ras mediated diseases. China, CN115385923 A 2022-11-25

///////////talorasib, antineoplastic, 727W6T7DPK

Talogreptide mesaroxetan

December 10, 2025 2:47 am / Leave a comment

Talogreptide mesaroxetan

CAS 1801418-23-4

MF C86H140N22O18 MW1770.17

{MeCOSar}-PEG4-{d-Phe}-Gln-Trp-Ala-Val-Gly-His-{Sta}-Leu-NH2

(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(3S,4S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-6-methyl-1-oxoheptan-4-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]-2-[[(2R)-2-[3-[2-[2-[2-[2-[[5-[(8-methyl-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosan-1-yl)amino]-5-oxopentanoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-3-phenylpropanoyl]amino]pentanediamide

N-{21-[(8-methyl-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosan-1-yl)amino] -17,21-dioxo-4,7,10,13-tetraoxa-16-azahenicosan-1-oyl}-D-phenylalanyl-L-glutaminyl-L-tryptophyl-L-alanyl-Lvalylglycyl-L-histidyl-(3S,4S)-4-amino-3-hydroxy-6-methylheptanoyl-L-leucinamide
diagnostic imaging agent, antineoplastic, ZUN64K4H2X, SAR-BBN

Talogreptide mesaroxetan (CAS 1801418-23-4) is a synthetic peptide, a complex molecule used as a diagnostic imaging agent with potential antitumor effects, targeting G-protein coupled receptors (GRPr) often overexpressed in cancers, allowing for specific tumor visualization in PET scans, particularly for metastatic disease detection, known for its high specificity and contrast for imaging tumors like those expressing GRPr.

Key Characteristics:

Type: A peptide-based diagnostic agent, often labeled with radioisotopes like Copper-64 ($^{64}$Cu) for Positron Emission Tomography (PET) imaging, notes Patsnap Synapse.
Structure: It’s a modified peptide sequence incorporating elements like PEG4 and specific amino acids, MedchemExpress.com.
Function: Binds strongly to GRPr, helping to highlight tumors and metastatic sites.
Application: Used in research to create high-contrast PET scans for better tumor detection and monitoring, showing promise in visualizing lymph node metastasis.

In Simple Terms:
Imagine it as a “smart tracer” that seeks out specific cancer cells. When attached to a radioactive tag, it lights up tumors on a PET scan, helping doctors see cancer more clearly, notes Patsnap Synapse.

Syn

WO2024086891

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024086891&_cid=P10-MIZEJM-53111-1

⁶⁷Cu radioisotope

where R is CH3C(0)-;

(⁶⁷CU-SAR-BBN)

Paper

Molecular Pharmaceutics (2015), 12(8), 2781-2790

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Suvadronabinol

December 9, 2025 2:42 am / Leave a comment

Suvadronabinol

CAS 1225194-84-2

MF C30H43NO6 MW513.7 g/mol

4-{[(2S)-3-methyl-1-oxo-1-{[(6aR,10aR)-6,6,9-trimethyl-3-pentyl6a,7,8,10a-tetrahydro-6H-dibenzo[b,d]pyran-1-yl]oxy}butan-2-yl]amino}-4-oxobutanoic acid

3-{[(2S)-1-{[(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6H,6aH,7H,8H,10aH-benzo[c]isochromen-1-yl]oxy}-3-methyl-1-oxobutan-2-yl]carbamoyl}propanoic acid

4-{[(2S)-3-methyl-1-oxo-1-{[(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-dibenzo[b,d]pyran-1-yl]oxy}butan-2-yl]amino}-4-oxobutanoic acid
cannabinoid receptor agonist, DB 21741, XV9S3R9XJC

Suvadronabinol (DB21741) is a potent, synthetic small-molecule cannabinoid receptor type 1 (CB1) agonist, initially developed for therapeutic potential in areas like appetite stimulation, pain, or weight management, acting similarly to cannabis compounds but with specific design, currently in preclinical research stages, noted for its high selectivity and potency.

Key Characteristics:

Type: Small Molecule Drug.
Mechanism: A highly selective agonist for the cannabinoid receptor type 1 (CB1).
Development: Originally developed by Elsohly Laboratories, it’s in preclinical R&D, with status as an experimental compound.
Molecular Weight: Approximately 513.31 Da.
CAS Number: 1225194-84-2.

Potential Applications (Research Areas):

Appetite Stimulation & Weight Loss: Similar to dronabinol, it targets pathways involved in metabolism and appetite.
Pain Management: As a cannabinoid, it interacts with the endocannabinoid system, which plays a role in pain perception.

Status:

It’s an investigational compound, meaning it’s still under study and not yet approved for medical use.

In essence, Suvadronabinol is a targeted synthetic cannabinoid designed to interact with the body’s CB1 receptors, showing promise in preclinical research for conditions where cannabinoid effects are desired, but it’s not a widely available or established medicine.

SYN

SYN

US20150045282

SYN

WO2010051541

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010051541&_cid=P22-MIXZ0J-96045-1

Example 10: Preparation of THC-valinate-hemisuccinate (15):

Compound 15 was also prepared using scheme II, where the starting material was compound 6 (THC-valinate). Product 15 was purified using column chromatography (>85% yield) and confirmed by mass spectroscopy in the positive ionization mode (M+NlV = 531) (Fig 17). The structure of product 15 was also confirmed by spectral analysis ¹H-NMR and ¹³C-NMR (see Fig 18 for ¹³C-NMR assignments).

Spectral analysis of Δ⁹-THC prodrugs prepared above: Identity and purity of the synthesized prodrugs was established by spectral means including ¹H-NMR, ¹³C-NMR and 2D-NMR such as COSY, HMQC, HMBC, as well as other spectroscopic means (IR₁ UV and MS). The synthetic protocols outlined above yielded prodrugs with ≥95% purity.

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Surzetoclax

December 8, 2025 2:45 am / Leave a comment

Surzetoclax

CAS 2858632-01-4

MF C53H63ClN8O10S, 1039.64

NAMES

4-[(4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12Hpyrazino[2,1-g][1,5,8]benzodioxaazacycloundecin3(4H)-yl]-2-(3,4-dihydro-2Hpyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-[4-({[(2S,5R)-5-methoxyoxan-2-yl]methyl}amino)-3-nitrobenzene-1-sulfonyl]benzamide

4-(14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

D-erythro-Hexitol, 1,5-anhydro-6-[[4-[[[4-[(4aS,10aR)-14-(4-chlorophenyl)-1,2,4a,5,8,9,10a,11,13,15-decahydro-12,12-dimethyl-7H,12H-pyrazino[2,1-g][1,5,8]benzodioxaazacycloundecin-3(4H)-yl]-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl]amino]sulfonyl]-2-nitrophenyl]amino]-3,4,6-trideoxy-2-O-methyl-

1,5-Anhydro-6-[[4-[[[4-[(4aS,10aR)-14-(4-chlorophenyl)-1,2,4a,5,8,9,10a,11,13,15-decahydro-12,12-dimethyl-7H,12H-pyrazino[2,1-g][1,5,8]benzodioxaazacycloundecin-3(4H)-yl]-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl]amino]sulfonyl]-2-nitrophenyl]amino]-3,4,6-trideoxy-2-O-methyl-D-erythro-hexitolB-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, ABBV 453, C3TU3CHH6L, Bcl-2-IN-16

Surzetoclax, also known as ABBV 453; is a highly potent and selective BCL-2 inhibitor with a Ki of approximately 0.07 nM. It induces apoptosis in BCL-2–dependent hematologic cancer cells, showing EC50 values typically below 10 nM in sensitive models. In vivo, Surzetoclax causes rapid tumor regression in xenograft models of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). It is orally bioavailable and demonstrates dose-dependent target engagement with favorable pharmacokinetics. Compared to Venetoclax, Surzetoclax was designed to reduce risks of tumor lysis syndrome and other dose-limiting toxicities.

Surzetoclax is a small molecule drug. The usage of the INN stem ‘-toclax’ in the name indicates that Surzetoclax is a B-cell lymphoma 2 (Bcl-2) inhibitor. Surzetoclax has a monoisotopic molecular weight of 1038.41 Da.

A Study to Assess Adverse Events and Change in Disease Activity of Oral ABBV-453 Alone or in Combination With Subcutaneous and/or Oral Antimyeloma Agents in Adult Participants With Multiple Myeloma (MM)CTID: NCT06953960Phase: Phase 1/Phase 2Status: RecruitingDate: 2025-12-01
A Study to Assess the Adverse Events and Change in Disease Activity in Adult Participants With Relapsed or Refractory Multiple Myeloma Receiving Oral ABBV-453 TabletsCTID: NCT05308654Phase: Phase 1Status: Active, not recruitingDate: 2025-08-14
A Study Assessing Adverse Event and How Oral ABBV-453 Moves Through the Body in Adult Participants With Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)CTID: NCT06291220Phase: Phase 1Status: Active, not recruitingDate: 2025-06-06

SYN

The synthesis of surzetoclax (ABBV-453), a complex, next-generation BCL-2 inhibitor, can be accomplished through a patented 27-step convergent route or a more streamlined, AI-assisted method that involves the modular assembly of three key fragments.

Patented Synthesis (Literature Route)

The published synthesis (described in patent WO 2023/141536 A1) is a 27-step convergent route with a 12-step longest linear sequence. The molecule is assembled from three main components: a 6,11,6-fused tricyclic core, a trans-1,2-disubstituted tetrahydropyran (THP) unit, and a 5,6,7-fused heteroaromatic system.

Key Steps and Intermediates:

Core Tricycle Assembly: The 6,11,6-fused macrocycle is formed by a sequence initiated from dimedone, involving a macrocyclization step using an 11-membered ring bis-triflate intermediate.
THP Fragment Construction: The THP moiety’s synthesis includes an enzymatic resolution step using porcine pancreatic lipase to establish the required stereochemistry.
Heteroaromatic System: The 7-azaindole-oxazepane tricycle is formed via a microwave-assisted, copper-mediated cyclization reaction.
Final Coupling: The fragments are joined through Buchwald–Hartwig and N-sulfonylamide coupling reactions to yield the final surzetoclax molecule.

AI-Assisted Synthesis (ChemAIRS Route)

A more efficient, human-directed AI retrosynthesis approach developed by Chemical.AI offers a more convergent and experimentally practical alternative. This route also uses three fragments but employs different, more efficient coupling strategies.

Key Features of the Revised Route:

Fragment 25a (Core Tricycle): Assembled in 10 steps using more accessible starting materials and a Mizoroki-Heck coupling to incorporate an aryl group.
Fragment 12a (THP Motif): The synthesis is streamlined to four steps from simple building blocks, utilizing a Mitsunobu reaction to introduce the azide precursor instead of the patent’s longer tosylation/displacement sequence.
Fragment 12b (Azaindole-Oxazepane Tricycle): An efficient nickel-photoredox C–N coupling is used to form an intermediate that then undergoes a base-promoted cyclization.
Final Assembly: Fragments 12a and 12b are joined using a palladium-catalyzed amidocarbonylation, followed by deprotection and a final SNAr coupling with fragment 25a to form surzetoclax.

The AI-assisted route achieves greater modularity and adaptability for potential scale-up compared to the patented process.

PAT

1,3,4,7-tetrahydro-2H-pyrrolo[3â€²,2â€²:5,6]pyrido[2,3-b][1,4]oxazepine bcl-2 inhibitors

Publication Number: US-11964990-B2

Priority Date: 2022-01-21

Grant Date: 2024-04-23

PAT

US11964990,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US403063458&_cid=P10-MIWJNM-88215-1

Example 25

4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Example 25A

(S)-(3,4-dihydro-2H-pyran-2-yl)methanol

To a flask containing racemic (3,4-dihydro-2H-pyran-2-yl)methanol (25.8) was added dichloromethane (250 mL) and N,N-dimethylpyridin-4-amine (32.0 g). The flask was placed in an ice bath. After 15 minutes, neat acetyl chloride (16.1 mL) was added, and the reaction was stirred in the ice bath for 1 hour. The reaction mixture was poured into a separatory funnel containing water (200 mL) and the two layers were separated. The aqueous layer was extracted once with dichloromethane (80 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified using flash chromatography (330 g silica column, 0-60% ethyl acetate/heptanes) to afford racemic (3,4-dihydro-2H-pyran-2-yl)methyl acetate. To a flask containing water (1 L) was added potassium phosphate tribasic (4.48 g) and potassium dihydrogen phosphate (4.28 g) and the mixture was stirred until all the solids dissolved. To the solution was added racemic (3,4-dihydro-2H-pyran-2-yl)methyl acetate (10.0 g) in acetone (10 mL) at ambient temperature followed by porcine pancreatic lipase (75 mg). In another flask, the same reaction was set up on twice the scale. The reactions were stirred at ambient temperature for 18 hours then both were combined into a separatory funnel and extracted with 1:1 ethyl acetate/heptanes (2-500 mL). The combined organic layers were discarded, and the aqueous layer was extracted with 9:1 ethyl acetate/heptanes (2×500 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified using flash chromatography (80 g silica column, 0-100% ethyl acetate/heptanes) to afford the title compound. ¹H NMR (500 MHz, CDCl ₃) δ ppm 6.39 (dt, J=6.3, 2.0 Hz, 1H), 4.71 (dddd, J=6.3, 5.0, 2.5, 1.3 Hz, 1H), 3.96-3.88 (m, 1H), 3.76-3.62 (m, 2H), 2.12 (dddt, J=17.3, 10.8, 6.6, 2.4 Hz, 1H), 2.04-1.94 (m, 1H), 1.88 (dd, J=7.3, 5.4 Hz, 1H), 1.82-1.76 (m, 1H), 1.74-1.66 (m, 1H). A small amount of the material was treated with 3-(4-(trifluoromethyl)phenyl)propanoic acid, N,N-dimethylpyridin-4-amine and N ¹-((ethylimino)methylene)-N ³,N ³-dimethylpropane-1,3-diamine hydrochloride to obtain (S)-(3,4-dihydro-2H-pyran-2-yl)methyl 3-(4-(trifluoromethyl)phenyl)propanoate. Analytical chiral supercritical fluid chromatography (ChiralPak AD-H, 5-50% CH ₃OH, 3 mL/minute, 10 minutes method, 150 bar CO ₂) was used to determine the ee of the ester to be 93%. Major enantiomer retention time was 1.26 minutes and that of the minor enantiomer was 1.34 minutes.

Example 25B

(S)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran

To a flask containing sodium hydride (60 weight % in mineral oil, 1.104 g) was added tetrahydrofuran (60.0 mL). The slurry was cooled in an ice bath and a solution of Example 25A (2.100 g) in tetrahydrofuran (3 mL) was added dropwise followed by tetrahydrofuran (2 mL). The reaction was stirred in the ice bath for 15 minutes. Neat (bromomethyl)benzene (3.50 mL) was added, and the ice bath was removed. The reaction was stirred for 18 hours at ambient temperature. The reaction mixture was placed in an ice bath and carefully quenched with dropwise addition of 1:1 water/aqueous saturated ammonium chloride solution (80 mL). The biphasic mixture was extracted with 3:1 ethyl acetate/heptanes (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated. The residue was purified using flash chromatography (80 g silica column, 0-5% ethyl acetate/heptanes) to afford the title compound. ¹H NMR (500 MHz, CDCl ₃) δ ppm 7.40-7.27 (m, 5H), 6.40 (dt, J=6.2, 2.0 Hz, 1H), 4.69 (dddd, J=6.3, 4.9, 2.5, 1.3 Hz, 1H), 4.62 (d, J=12.2 Hz, 1H), 4.58 (d, J=12.2 Hz, 1H), 4.03 (dddd, J=10.4, 6.4, 4.3, 2.3 Hz, 1H), 3.60 (dd, J=10.2, 6.3 Hz, 1H), 3.53 (dd, J=10.2, 4.3 Hz, 1H), 2.10 (dddt, J=17.2, 10.6, 6.5, 2.4 Hz, 1H), 2.02-1.92 (m, 1H), 1.90-1.81 (m, 1H), 1.70 (dtd, J=13.5, 10.4, 5.9 Hz, 1H).

Example 25C

(3R,6S)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol

To a solution of Example 25B (3.60 g) in tetrahydrofuran (50.0 mL) was added dropwise 9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 75.0 mL) at 0° C. over 1 hour. The mixture was then stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath and 10% aqueous sodium hydroxide solution (25 mL) was carefully added to the mixture at 0° C., followed by 30% aqueous hydrogen peroxide solution (32 mL). The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium sulfite solution (40 mL) at 0° C. and concentrated under reduced pressure to remove most of the organic solvent. The residue was extracted with 3:1 ethyl acetate/heptanes (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified using flash chromatography (120 g silica column, 0-60% ethyl acetate/heptanes) to afford the title compound. ¹H NMR (500 MHz, CDCl ₃) δ ppm 7.42-7.27 (m, 5H), 4.59 (d, J=12.2 Hz, 1H), 4.54 (d, J=12.2 Hz, 1H), 4.05 (ddd, J=10.8, 4.9, 2.3 Hz, 1H), 3.71 (td, J=10.2, 5.0 Hz, 1H), 3.53-3.38 (m, 3H), 3.14 (dd, J=10.8, 10.2 Hz, 1H), 2.14 (dtd, J=8.2, 4.7, 4.0, 2.3 Hz, 1H), 1.76-1.66 (m, 1H), 1.51-1.35 (m, 3H). LC/MS (APCI+) m/z 223.53 (M+H) ⁺.

Example 25D

(2S,5R)-2-((benzyloxy)methyl)-5-methoxytetrahydro-2H-pyran

A solution of Example 25C (1.000 g) in tetrahydrofuran (20.0 mL) was cooled in an ice bath. Solid sodium hydride (60 weight % in mineral oil, 0.270 g) was added and the mixture was stirred in the ice bath for 15 minutes. Neat iodomethane (0.400 mL) was added and the reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction was quenched by adding 0.1% aqueous solution of trifluoroacetic acid (4 mL) and water (20 mL), then extracted 5:1 ethyl acetate/heptanes (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated. The residue was purified using flash chromatography (40 g silica column, 0-40% ethyl acetate/heptanes) to afford the title compound. ¹H NMR (600 MHz, CDCl ₃) δ ppm 7.40-7.26 (m, 5H), 4.59 (d, J=12.3 Hz, 1H), 4.54 (d, J=12.3 Hz, 1H), 4.15 (ddd, J=10.8, 4.7, 2.3 Hz, 1H), 3.52-3.39 (m, 3H), 3.36 (s, 3H), 3.32-3.23 (m, 1H), 3.13 (t, J=10.4 Hz, 1H), 2.24-2.16 (m, 1H), 1.76-1.68 (m, 1H), 1.46-1.30 (m, 2H). LC/MS (APCI+) m/z 237.46 (M+H) ⁺.

Example 25E

((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate

A solution of Example 25D (0.97 g) in tetrahydrofuran (10.00 mL) was added to a flask containing Pd(OH) ₂/C (20 weight % Pd, 50% moisture, 50 mg). The flask was purged with nitrogen and a hydrogen balloon was connected. The reaction was stirred at ambient temperature for 24 hours and then the mixture was filtered and concentrated. The residue was dissolved in dichloromethane (15 mL), then N,N-dimethylpyridin-4-amine (0.750 g), N-ethyl-N-isopropylpropan-2-amine (1.500 mL) and 4-methylbenzene-1-sulfonyl chloride (0.800 g) were added sequentially. The reaction was stirred at ambient temperature for 3 hours and then the mixture was poured over water (20 mL) and extracted with dichloromethane (2-20 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated. The residue was purified using flash chromatography (silica, 0-100% ethyl acetate/heptanes) to afford the title compound. ¹H NMR (500 MHz, CDCl ₃) δ ppm 7.79 (d, J=8.5 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 4.04 (ddd, J=10.8, 4.7, 2.3 Hz, 1H), 3.97 (d, J=5.1 Hz, 2H), 3.48 (dtd, J=10.7, 5.1, 2.5 Hz, 1H), 3.34 (s, 3H), 3.25-3.15 (m, 1H), 3.04 (dd, J=10.8, 10.1 Hz, 1H), 2.45 (s, 3H), 2.23-2.15 (m, 1H), 1.74-1.65 (m, 1H), 1.41-1.23 (m, 2H). LC/MS (APCI+) m/z 301.36 (M+H) ⁺.

Example 25F

(2S,5R)-2-(azidomethyl)-5-methoxytetrahydro-2H-pyran

A mixture of Example 25E (1.000 g), N,N-dimethylformamide (6.00 mL) and sodium azide (1.000 g) was heated at 80° C. for 18 hours. The reaction was cooled to ambient temperature and poured over water (30 mL) and extracted with 5:1 ethyl acetate/heptanes (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated to afford the title compound. ¹H NMR (600 MHz, CDCl ₃) δ ppm 4.13 (ddd, J=10.8, 4.7, 2.3 Hz, 1H), 3.44 (dddd, J=10.9, 6.6, 3.9, 2.2 Hz, 1H), 3.36 (s, 3H), 3.30-3.19 (m, 3H), 3.11 (t, J=10.5 Hz, 1H), 2.25-2.17 (m, 1H), 1.73-1.66 (m, 1H), 1.47-1.30 (m, 2H). LC/MS (APCI+) m/z 144.27 (M-N ₂+H) ⁺.

Example 25G

4-((((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide

To a solution of Example 25F (0.57 g) in tetrahydrofuran (6.00 mL) was added water (0.076 mL) and triphenylphosphine (1.10 g) and the reaction was stirred at ambient temperature for 16 hours. To the reaction mixture was added N-ethyl-N-isopropylpropan-2-amine (2.32 mL) and 4-fluoro-3-nitrobenzenesulfonamide (0.73 g) and stirring at ambient temperature was continued for 2 hours. The reaction mixture was purified using flash chromatography (40 g silica column, 10-100% ethyl acetate/heptanes) to afford the title compound. ¹H NMR (600 MHz, CDCl ₃) δ ppm 8.77 (d, J=2.3 Hz, 1H), 8.60 (s, 1H), 7.88 (ddd, J=9.2, 2.3, 0.7 Hz, 1H), 6.95 (d, J=9.2 Hz, 1H), 4.75 (s, 2H), 4.18 (ddd, J=10.8, 4.7, 2.3 Hz, 1H), 3.63-3.55 (m, 1H), 3.47 (ddd, J=13.2, 5.8, 3.7 Hz, 1H), 3.39 (s, 3H), 3.37-3.26 (m, 2H), 3.17 (t, J=10.5 Hz, 1H), 2.27 (dt, J=12.6, 3.4 Hz, 1H), 1.82 (dq, J=13.2, 3.1 Hz, 1H), 1.53-1.48 (m, 1H), 1.42 (tdd, J=13.1, 10.7, 4.1 Hz, 1H). LC/MS (APCI+) m/z 346.39 (M+H) ⁺.

Example 25H

7,7-dimethyl-4,6,7,8-tetrahydro-2H,5H-1,3-benzodioxin-5-one

To a solution of 5,5-dimethylcyclohexane-1,3-dione (15 g) and formaldehyde (19.92 g) in dichloromethane (600 mL) was added boron trifluoride diethyl etherate (40.7 mL) over 10 minutes, and the reaction mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was quenched with the addition of saturated aqueous NaHCO ₃solution, the organic layer was separated, and the aqueous layer was extracted with additional dichloromethane. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was taken up in heptanes/ethyl acetate (5:1), concentrated, treated with heptanes (300 mL), and filtered. The residue was chromatographed over silica gel (ISCO Gold®), eluting with a gradient of 0 to 16% ethyl acetate/heptanes to afford the title compound. ¹H NMR (400 MHz, CDCl ₃) δ ppm 5.13 (s, 2H), 4.43 (t, 2H), 2.28 (t, 2H), 2.22 (s, 2H), 1.08 (s, 6H). MS (DCI+) m/z 183.1 (M+H) ⁺.

Example 251

4′-chloro-2-(hydroxymethyl)-5,5-dimethyl-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one

To a solution of 1-bromo-4-chlorobenzene (30.3 g) in tetrahydrofuran (200 mL) at −78° C. was added ii-butyllithium (2.5M in hexane, 60.6 mL) dropwise, keeping the temperature below −70° C. After stirring at −78° C. for 30 minutes, a solution of Example 25H (24 g) in tetrahydrofuran (75 mL) was added dropwise, keeping the temperature below −60° C. The reaction mixture was stirred at −78° C. for one hour, allowed to warm to ambient temperature and stirred for 12 hours. The reaction mixture was treated with 3 M aqueous HCl (80 mL) and stirred for 2 hours. Most of the organic solvent was removed and the resulting aqueous layer was extracted with ethyl acetate (three times). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed over silica gel (750 g BIOTAGE® SNAP), eluting with a gradient of 5 to 22% ethyl acetate/heptanes to afford the title compound. ¹H NMR (500 MHz, CDCl ₃) δ ppm 7.43-7.32 (m, 2H), 7.28-7.21 (m, 2H), 4.20 (d, 2H), 2.85 (t, 1H), 2.57 (s, 2H), 2.42 (s, 2H), 1.14 (s, 6H). MS (ESI+) m/z 247.2 (M+H) ⁺.

Example 25J

4′-chloro-2-(chloromethyl)-5,5-dimethyl-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one

To a solution of Example 251 (15 g) in dichloromethane (800 mL) was added tetraethylammonium chloride (14.08 g) followed by triethylamine (11.85 mL). The reaction mixture was cooled to 0° C. with an ice/water bath and methane sulfonyl chloride (6.62 mL) was added over 10 minutes. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was washed with saturated aqueous ammonium chloride solution and brine, dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed over silica gel (330 g ISCO Gold®), eluting with a gradient of 0 to 35% ethyl acetate/heptanes to afford the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d ₆) δ ppm 7.60-7.55 (m, 2H), 7.45-7.40 (m, 2H), 4.12 (s, 2H), 2.64 (s, 2H), 2.39 (s, 2H), 1.05 (s, 6H). MS (DCI+) m/z 283.1 (M+H) ⁺.

Example 25K

(R)-4′-chloro-2-(chloromethyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-3-ol

To a solution of (S)-2-methyl-CBS-oxazaborolidine (20.96 g) in anhydrous tetrahydrofuran (230 mL) at −50° C. was added BH ₃-tetrahydrofuran (1.0 M in tetrahydrofuran, 76 mL) over 45 minutes, and the solution was stirred for an additional 40 minutes. A solution of Example 25J (21 g) in anhydrous tetrahydrofuran (230 mL) was added dropwise via an addition funnel over the course of about 60 minutes. After the addition, the reaction mixture was stirred 1.5 hours at −50° C. The reaction mixture was quenched by the dropwise addition of methanol (130 mL) over about 20 minutes at −50° C. The cooling bath was removed, and the reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with saturated aqueous NH ₄Cl solution (250 mL), diluted with water and extracted with ethyl acetate. The organic layer was washed with additional aqueous saturated NH ₄Cl and brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed over silica gel (Teledyne Isco RediSep® Rf GOLD® 330 g), eluting with a gradient of 0 to 20% ethyl acetate/heptanes to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d ₆) δ ppm 7.44-7.36 (m, 2H), 7.21-7.13 (m, 2H), 4.40-4.28 (m, 2H), 3.85 (d, 1H), 2.24 (dt, 1H), 1.82 (d, 1H), 1.74 (ddd, 1H), 1.43 (dd, 1H), 0.94 (s, 3H), 0.89 (s, 3H). MS (DCI+) m/z 284.1 (M+H) ⁺.

Example 25L

tert-butyl (S)-4-(((R)-4′-chloro-3-hydroxy-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-3-(hydroxymethyl)piperazine-1-carboxylate

A solution of (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.71 g), Example 25K (2.15 g), sodium iodide (1.47 g) and potassium carbonate (2.084 g) in acetonitrile (15.08 mL) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed over silica gel (80 g), eluting with a gradient of 0 to 70% 3:1 ethyl acetate:ethanol/heptanes to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d ₆) δ ppm 7.37-7.29 (m, 2H), 7.07-6.99 (m, 2H), 4.95 (d, 1H), 4.80-4.73 (m, 1H), 4.34-4.24 (m, 1H), 3.69-3.58 (m, 4H), 3.29-3.23 (m, 1H), 2.95-2.68 (m, 2H), 2.67-2.58 (m, 1H), 2.34 (d, 1H), 2.06 (dt, 1H), 1.91-1.80 (m, 2H), 1.70 (dd, 1H), 1.61 (td, 1H), 1.40-1.33 (m, 1H), 1.31 (s, 9H), 0.92 (s, 3H), 0.91 (s, 3H). MS (ESI+) m/z 465.4 (M+H) ⁺.

Example 25M

tert-butyl (4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecine-3(4H)-carboxylate

To a solution of Example 25L (100 g) in dichloroethane (2150 mL) was added propane-1,3-diyl bis(trifluoromethanesulfonate) (95 g) followed by N ¹,N ¹,N ⁸,N ⁸-tetramethylnaphthalene-1,8-diamine (122 g) (proton sponge) and the reaction mixture was heated to 50° C. for 20 hours. The reaction mixture was cooled in an ice bath and filtered. The filtrate was washed with 1N aqueous HCl (1 L×3), 1N aqueous NaOH (three times), dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed over silica gel (3 kg) with a gradient of 2 L of 5% ethyl acetate/heptanes, 4 L 10% ethyl acetate/heptanes, then 6-8 L 20% ethyl acetate/heptanes to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d ₆) δ ppm 7.38-7.30 (m, 2H), 7.09-7.01 (m, 2H), 4.03-3.93 (m, 1H), 3.83-3.57 (m, 7H), 3.46-3.36 (m, 2H), 2.66 (d, 2H), 2.19 (d, 1H), 2.06 (d, 1H), 1.92-1.72 (m, 4H), 1.65-1.55 (m, 2H), 1.49-1.33 (m, 2H), 1.32 (s, 9H), 0.94 (s, 3H), 0.94 (s, 3H). MS (ESI+) m/z 505.3 (M+H) ⁺.

Example 25N

(4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,3,4,4a,5,7,8,9,10a,11,12,13,15-tetradecahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecine

To a solution of Example 25M (90 g) in dichloromethane (713 mL) cooled in an ice bath was added trifluoroacetic acid (206 mL) dropwise over about 20 minutes. The ice bath was removed, and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (300 mL). The vigorously stirred solution was neutralized by the addition of saturated aqueous Na ₂CO ₃(350 mL). The organic layer was separated, washed four times with saturated aqueous Na ₂CO ₃, dried over sodium sulfate, filtered, and concentrated to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d ₆) δ 7.45-7.33 (m, 2H), 7.13-7.02 (m, 2H), 3.87 (q, J=8.0 Hz, 1H), 3.79-3.62 (m, 4H), 3.48-3.36 (m, 2H), 2.79-2.53 (m, 4H), 2.19 (d, J=12.1 Hz, 1H), 2.09 (dt, J=17.1, 3.0 Hz, 1H), 1.95, 1.87 (m, 2H), 1.85 (dd, J=6.5, 1.8 Hz, 1H), 1.78-1.70 (m, 1H), 1.63 (dq, J=7.5, 3.9 Hz, 2H), 1.47 (td, J=11.3, 2.8 Hz, 1H), 1.39 (dd, J=12.5, 9.1 Hz, 1H), 0.98 (s, 4H), 0.97 (s, 3H). MS (DCI+) m/z 405.3 (M+H) ⁺.

Example 250

ethyl 2-bromo-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H,7H,15H)-yl)benzoate

A 2 L three-neck round bottom flask equipped with a stir bar, heating mantle, nitrogen inlet and outlet, and a thermocouple was charged with ethyl 2-bromo-4-fluorobenzoate (44.4 g). Anhydrous dimethyl sulfoxide (346 mL) was added to the flask, and mixture stirred at ambient temperature. Example 25N (70 g) was added, followed by potassium hydrogenphosphate (90 g). Once the slurry was mixed thoroughly, the temperature was increased to 60° C., and the slurry was heated under nitrogen for 72 hours. The heating mantle was removed, and the reaction was cooled with an ice/water bath to 8° C. The flask was equipped with a 1 L addition funnel. To this cold reaction slurry was added water (850 mL) dropwise via an addition funnel, and the mixture was sonicated for 30 minutes. The mixture was subjected to mechanical stirring and stirred vigorously for 1 hour at ambient temperature. The precipitate was filtered through a Buchner funnel loaded with filter paper. The filtered solids were washed with water (2×500 mL) and allowed to dry on the filter for 16 hours. The solids were dissolved in ethyl acetate (600 mL), and water (300 mL) was added to the solution. The two-phase solution was stirred for 1 hour. The layers were separated in a separatory funnel, and organic layer washed with water (300 mL) and brine (200 mL). The organic layer was dried with 100 g of magnesium sulfate, filtered and concentrated to afford the crude residue. The residue was dissolved in dichloromethane (100 mL) and purified via normal phase chromatography using a BIOTAGE® Snap Ultra 750 g. silica gel column eluting with a gradient of 0 to 30% ethyl acetate in heptane to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d ₆) δ ppm 7.68 (d, J=8.9 Hz, 1H), 7.46-7.33 (m, 2H), 7.11 (d, J=2.6 Hz, 1H), 7.10-7.07 (m, 2H), 6.91 (dd, J=9.0, 2.5 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.04 (t, J=7.7 Hz, 1H), 3.89-3.64 (m, 7H), 3.59 (d, J=12.0 Hz, 1H), 3.48 (q, J=8.3 Hz, 1H), 2.95 (dd, J=12.2, 10.8 Hz, 1H), 2.86-2.66 (m, 2H), 2.27 (d, J=12.2 Hz, 1H), 2.15-2.06 (m, 1H), 2.01 (d, J=10.6 Hz, 1H), 1.97-1.83 (m, 2H), 1.75-1.57 (m, 3H), 1.40 (dd, J=12.5, 9.1 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H), 0.99 (d, J=1.9 Hz, 6H). LC/MS (APCI+) m/z 631.46 (M+H) ⁺.

Example 25P

5-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide

To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (10 g) in ethyl acetate (200 mL) was added 3-chloroperoxybenzoic acid (21.90 g) at 25° C., then stirred at 25° C. for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL), then quenched by addition of saturated sodium bicarbonate (1000 mL). The biphasic mixture was filtered, and the filter cake was washed with water (100 mL) and then dried in vacuo to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d ₆) δ ppm 8.32 (s, 1H), 8.41-8.22 (m, 1H), 7.86 (s, 1H), 7.47 (s, 1H), 6.50 (d, J=1.8 Hz, 1H).

Example 25Q

5-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine

To a solution of Example 25P (30 g) and 1,1,1,3,3,3-hexamethyldisilazane (29.5 mL) in tetrahydrofuran (300 mL) was added 2,2,2-trichloroacetyl chloride (47.1 mL) at 0° C. The resulting mixture was stirred for 0.5 hours and warmed to 25° C. for another 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford a residue which was triturated with ethyl acetate and petroleum ether (1:10, 100 mL) to afford the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d ₆) δ ppm 12.05 (s, 1H), 8.41 (s, 1H), 7.63-7.54 (m, 1H), 6.51-6.45 (m, 1H).

Example 25R

5-bromo-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

To a solution of Example 25Q (15 g) in N,N-dimethylformamide (150 mL) was added sodium hydride (3.11 g) in portions at 0° C. The resulting mixture was stirred at 0° C. for 1 hour, then a solution of 2-(trimethylsilyl)ethoxymethyl chloride (13.79 mL) in N,N-dimethylformamide (50 mL) was added dropwise. The resulting mixture was stirred at 0° C. for another 2 hours. The reaction mixture was diluted with brine (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford a residue, which was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=10:1) to afford the title compound. ¹H NMR (400 MHz, CDCl ₃) δ ppm 8.15 (s, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.48 (d, J=2.1 Hz, 1H), 5.61 (s, 2H), 3.54 (t, J=7.9 Hz, 2H), 0.92 (t, J=7.9 Hz, 2H), 0.01 (s, 9H).

Example 25S

N-(3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide

To a solution of N-(3-hydroxypropyl)-4-methylbenzenesulfonamide (0.349 g) in anhydrous tetrahydrofuran (5 mL) was added sodium hydride (0.166 g) in portions at 0° C. The resulting mixture was stirred at 0° C. for 0.5 hours, then Example 25R (0.5 g) was added. The reaction mixture was heated to 80° C. and stirred for 12 hours under nitrogen. After cooling, the reaction was diluted with water (100 mL), then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford a residue, which was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=5:1) to afford the title compound. ¹H NMR (400 MHz, CDCl ₃) δ ppm 8.03 (s, 1H), 7.76 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H), 7.15 (d, J=3.5 Hz, 1H), 6.42-6.37 (m, 1H), 5.53 (s, 2H), 4.47-4.41 (m, 2H), 3.55-3.48 (m, 2H), 3.23 (q, J=6.0 Hz, 2H), 2.37 (s, 3H), 2.01 (J=5.7 Hz, 2H), 0.90-0.87 (m, 2H), ), −0.03 (s, 9H).

Example 25T

1-tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepane

To a solution of Example 25S (500 mg) in dimethyl sulfoxide (6 mL) was added potassium carbonate (374 mg), picolinic acid (89 mg) and copper(I) iodide (206 mg) at 20° C. The reaction mixture was stirred at 160° C. under microwave for 2 hours. After cooling to ambient temperature, the reaction was diluted with water (100 mL), then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford a residue, which was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=3:1) to afford the title compound. ¹H NMR (400 MHz, CDCl ₃) δ ppm 8.13 (s, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.31 (d, J=3.5 Hz, 1H), 7.20 (d, J=8.1 Hz, 2H), 6.52 (d, J=3.5 Hz, 1H), 5.58 (s, 2H), 4.03-3.78 (m, 4H), 3.60-3.44 (m, 2H), 2.39 (s, 3H), 1.90 (s, 2H), 0.90 (t, J=8.2 Hz, 2H), −0.05 (s, 9H).

Example 25U

7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepane

To a solution of sodium (0.291 g) in 1,2-dimethoxyethane (0.5 mL) was added naphthalene (1.624 g) under nitrogen. The mixture was stirred at 20° C. for 1 hour until the formation of sodium/naphthalene was complete. Then to the solution of Example 25T (1 g) in anhydrous tetrahydrofuran (10 mL) was added to the above solution at −78° C. The resulting mixture was brought to 20° C. and stirred for 2 hours. The reaction was quenched by addition of water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford a residue, which was purified by preparative-HPLC to afford the title compound. ¹H NMR (400 MHz, CDCl ₃) δ ppm 8.17 (s, 1H), 7.80 (s, 3H), 7.37 (d, J=3.5 Hz, 1H), 6.51 (d, J=3.5 Hz, 1H), 5.59 (s, 2H), 4.38-4.27 (m, 2H), 3.61-3.46 (m, 4H), 2.41 (s, 2H), 0.93-0.86 (m, 2H), −0.06 (s, 9H).

Example 25V

ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H,7H,15H)-yl)-2-(7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate

To an oven dried 2 L three-necked round bottom flask equipped with a mechanical stirrer, a Huber-chilled reflux condenser, Claisen head adapter, nitrogen needle inlet and outlet to bubbler through a septa, and thermocouple was charged Example 25U (79 g), (Example 1N) (26.6 g), and methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) (5.61 g). These solids were put under a heavy flow of nitrogen, and then cesium carbonate (81 g) was added quickly to the reaction flask. The solids were mixed slowly with the mechanical stirrer, and the heavy flow of nitrogen through the reaction flask was continued for 60 minutes. In a separate oven dried 2 L round bottom flask equipped with a stir bar and septum was charged anhydrous toluene (833 mL). This solvent was sparged subsurface with a heavy nitrogen flow for 60 minutes while stirring. The solvent was then transferred via cannula to the three-necked flask, and the reaction was heated to an internal temperature of 110° C. under a flow of nitrogen for 16 hours. The reaction was cooled to ambient temperature, and the flask was charged with water (600 mL), followed by ammonium pyrrolidinedithiocarbamate palladium scavenger (3 g). This mixture was stirred vigorously for 1 hour. The reaction was diluted further with ethyl acetate (400 mL), stirred for 30 minutes, and then filtered through a plug of diatomaceous earth. The filter cake was washed with ethyl acetate (2×500 mL). The filtrate was transferred to a separatory funnel and the layers separated. The organic layer washed with water (200 mL), and then brine (200 mL). The combined aqueous layers were back extracted one time with ethyl acetate (200 mL). The combined organic layers were dried with sodium sulfate (200 g), filtered, and concentrated to produce the crude residue. The residue was dissolved in dichloromethane (200 mL) and purified via normal phase chromatography using a BIOTAGE® Snap Ultra 1.5 kg. silica gel column eluting with a gradient of 0 to 50% ethyl acetate in heptane to afford the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d ₆) δ ppm 7.44 (d, J=8.8 Hz, 1H), 7.40-7.35 (m, 2H), 7.30 (d, J=3.5 Hz, 1H), 7.12-7.07 (m, 2H), 7.03 (s, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.58 (dd, J=8.9, 2.3 Hz, 1H), 6.22 (d, J=3.5 Hz, 1H), 5.43 (s, 2H), 4.47-4.37 (m, 2H), 4.03 (t, J=8.0 Hz, 1H), 3.89-3.69 (m, 7H), 3.66 (q, J=5.7, 4.5 Hz, 3H), 3.59 (t, J=11.1 Hz, 2H), 3.52-3.42 (m, 3H), 2.96-2.87 (m, 1H), 2.85-2.77 (m, 1H), 2.67 (td, J=11.9, 3.0 Hz, 1H), 2.27 (d, J=12.1 Hz, 1H), 2.11 (dt, J=17.4, 3.0 Hz, 1H), 2.02 (d, J=10.8 Hz, 1H), 2.00-1.85 (m, 4H), 1.71 (td, J=11.6, 2.9 Hz, 1H), 1.64 (dd, J=8.7, 4.8 Hz, 2H), 1.40 (dd, J=12.4, 9.1 Hz, 1H), 0.98 (s, 6H), 0.94 (t, J=7.1 Hz, 3H), 0.84-0.79 (m, 2H), −0.08 (s, 9H).

Example 25W

ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H, 7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate

To a 2 L three-necked flask equipped with a mechanical stirrer, heating mantle, Claisen head adapter, reflux condenser, nitrogen inlet and outlet to bubbler, and a thermocouple was charged Example 25V (69 g). The solids were dissolved in anhydrous tetrahydrofuran (330 mL). To this solution at ambient temperature was added ethylenediamine (53.5 mL) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 793 mL). The reaction was heated to 66° C. internal temperature for 24 hours. The heating mantle was removed, and the reaction cooled to 8° C. in an ice/water bath. The mixture was quenched with water (200 mL). The reaction mixture was diluted with ethyl acetate (200 mL) and then partitioned in a separatory funnel. The organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried with sodium sulfate (100 g), filtered and concentrated in vacuo to afford the crude product. The residue was suspended in 1:1 methyl tert-butyl ether:heptane (400 mL), sonicated for 30 minutes then stirred vigorously for 1 hour. The solids were filtered, and the filter cake washed with 1:1 methyl tert-butyl ether heptane (50 mL). The solids were dried on the Buchner funnel to afford the title compound. ¹H NMR (600 MHz, dimethyl sulfoxide-d ₆) δ ppm 11.13 (t, J=2.2 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.40-7.37 (m, 2H), 7.14 (dd, J=3.4, 2.4 Hz, 1H), 7.11-7.07 (m, 2H), 7.02 (d, J=0.7 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.55 (dd, J=8.9, 2.3 Hz, 1H), 6.13 (dd, J=3.4, 1.9 Hz, 1H), 4.44-4.33 (m, 2H), 4.03 (tt, J=7.1, 3.5 Hz, 1H), 3.90-3.69 (m, 4H), 3.68-3.62 (m, 3H), 3.61-3.54 (m, 2H), 3.51-3.44 (m, 1H), 2.92-2.86 (m, 1H), 2.84-2.78 (m, 1H), 2.66 (td, J=11.9, 3.0 Hz, 1H), 2.32-2.28 (m, 1H), 2.26 (d, J=12.1 Hz, 1H), 2.11 (d, J=17.1 Hz, 1H), 2.02 (d, J=10.8 Hz, 1H), 1.98-1.86 (m, 4H), 1.70 (td, J=11.7, 3.0 Hz, 1H), 1.66-1.58 (m, 2H), 1.40 (dd, J=12.5, 9.2 Hz, 1H), 1.36-1.30 (m, 1H), 1.29-1.22 (m, 1H), 0.98 (s, 6H), 0.95 (t, J=7.1 Hz, 3H).

Example 25X

4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H,7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoic acid

To a 5 L three-necked flask equipped with a mechanical stirrer, heating mantle, reflux condenser, Claisen adapter, nitrogen inlet and outlet to bubbler, and a thermocouple was charged Example 25W (58.7 g). The residue was dissolved in 1,4-dioxane (991 mL) and methanol (496 mL) and stirred at ambient temperature for 5 minutes. Then lithium hydroxide (18.99 g) and water (496 mL) were then added, and the reaction was heated to an internal temperature of 75° C. for 16 hours. The heating mantle was removed, and the reaction was cooled to 5° C. in an ice/water bath. The reaction was neutralized to pH 7 by careful addition of 3N aqueous hydrochloric acid (100 mL). The pH was adjusted further to pH 6 with the addition of saturated aqueous ammonium chloride (100 mL). The mixture was diluted with dichloromethane (300 mL) and the layers partitioned in a separatory funnel. The aqueous layer was extracted with dichloromethane (2×100 mL), and the organic layers combined and dried with sodium sulfate (50 g). The solids were filtered, and the filtrate concentrated in vacuo to produce the crude residue. The residue was dissolved in dichloromethane (50 mL) and purified via normal phase chromatography on a silica gel cartridge (Teledyne Isco RediSep® RF GOLD®, 330 g) eluting with 0 to 10% methanol in dichloromethane to afford the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d ₆) δ ppm 12.28 (s, 1H), 11.20 (t, J=2.2 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.43-7.35 (m, 2H), 7.17 (dd, J=3.4, 2.5 Hz, 1H), 7.12-7.06 (m, 2H), 7.01 (d, J=0.7 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.68 (dd, J=8.9, 2.4 Hz, 1H), 6.15 (dd, J=3.3, 1.9 Hz, 1H), 4.34 (t, J=5.5 Hz, 2H), 4.03 (t, J=7.7 Hz, 1H), 3.88-3.75 (m, 3H), 3.74-3.64 (m, 3H), 3.64-3.58 (m, 1H), 3.57 (s, 6H), 3.51-3.43 (m, 1H), 2.92 (t, J=11.4 Hz, 1H), 2.85-2.78 (m, 1H), 2.68 (td, J=12.0, 3.0 Hz, 1H), 2.26 (d, J=12.1 Hz, 1H), 2.11 (d, J=17.4 Hz, 1H), 2.02 (d, J=10.9 Hz, 1H), 1.97 (p, J=5.8 Hz, 1H), 1.95-1.85 (m, 2H), 1.70 (td, J=11.6, 2.9 Hz, 1H), 1.66-1.60 (m, 0H), 1.40 (dd, J=12.5, 9.1 Hz, 1H), 0.98 (s, 6H). LC/MS (APCI+) m/z 712.29 (M+H) ⁺.

Example 25Y

4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

A solution of Example 25G (50 mg) in dichloromethane (0.80 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (0.10 mL), Example 25X (88 mg), N,N-dimethylpyridin-4-amine (37 mg) and N ¹-((ethylimino)methylene)-N ³,N ³-dimethylpropane-1,3-diamine hydrochloride (44 mg) and the mixture was stirred for 18 hours. The reaction mixture was concentrated and purified using reverse-phase HPLC (Luna 10 μm C18(2) 250×50 mm column, 10-100% acetonitrile/water (+0.1% trifluoroacetic acid)) to afford the title compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d ₆) δ ppm 11.93 (s, 1H), 11.22 (t, J=2.3 Hz, 1H), 8.56 (t, J=5.6 Hz, 1H), 8.46 (d, J=2.3 Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J=9.2, 2.4 Hz, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.47-7.41 (m, 2H), 7.19 (dd, J=3.4, 2.5 Hz, 1H), 7.17-7.13 (m, 2H), 6.93-6.88 (m, 2H), 6.74 (d, J=8.0 Hz, 2H), 6.09 (dd, J=3.4, 1.9 Hz, 1H), 4.47 (s, 1H), 4.37 (d, J=13.2 Hz, 1H), 4.24 (t, J=5.5 Hz, 2H), 4.13 (d, J=10.4 Hz, 1H), 4.03 (ddt, J=11.2, 8.7, 5.2 Hz, 2H), 3.92 (t, J=7.3 Hz, 2H), 3.60 (dt, J=11.1, 4.3 Hz, 2H), 3.57-3.52 (m, 4H), 3.46-3.29 (m, 2H), 3.27 (s, 3H), 3.21 (tt, J=10.2, 4.0 Hz, 2H), 3.04 (t, J=10.3 Hz, 1H), 2.22-2.04 (m, 3H), 2.00 (dq, J=12.2, 5.7 Hz, 4H), 1.84-1.76 (m, 1H), 1.74-1.64 (m, 1H), 1.42-1.22 (m, 3H), 1.02 (d, J=12.9 Hz, 6H). LC/MS (APCI+) m/z 1039.65 (M+H) ⁺.

SYN

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Surlorian

December 7, 2025 2:33 am / Leave a comment

Surlorian

CAS 1467605-57-7

MFC18H19NO3S, 329.41

4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl]benzoic acid
ryanodine receptor (RyR) stabilizer, ARM 210, RYCAL DMD, s48168, S 48168, 1033GN605L

Surlorian (ARM210) is a novel drug candidate, specifically a Ryanodine Receptor (RyR) stabilizer developed by RyCarma Therapeutics, designed to treat heart failure by repairing leaky RyRs in heart and skeletal muscles, aiming to improve both cardiac function and muscle weakness by restoring normal calcium regulation. It’s an allosteric modulator, a “Rycal,” that fixes these crucial calcium channels without blocking them, addressing a core issue in heart failure and related muscle diseases.

Key Aspects:

Mechanism: It stabilizes damaged RyR channels, which become leaky due to stress (like in heart failure), preventing unregulated calcium leakage from the sarcoplasmic reticulum (SR).
Target: Acts systemically on RyRs in both cardiac (heart) and skeletal (muscle) cells.
Benefits: Aims to improve heart contraction/relaxation and alleviate skeletal muscle weakness, a common heart failure symptom.
Therapeutic Area: Heart failure, potentially addressing underlying calcium dysregulation.
Status: In clinical development, with Phase II trials underway as of mid-2025, according to AdisInsight.
Chemical Info: Molecular Formula: C18H19NO3S; CAS No: 1467605-57-7.

In essence, Surlorian offers a new approach to heart failure by fixing the fundamental calcium handling problem in muscles, rather than just managing symptoms.

OriginatorARMGO Pharma
DeveloperNational Institute of Neurological Disorders and Stroke; RyCarma Therapeutics; Servier
ClassAntiarrhythmics; Heart failure therapies; Small molecules
Mechanism of ActionRyanodine receptor calcium release channel modulators
Orphan Drug StatusYes – Polymorphic catecholergic ventricular tachycardia; Congenital structural myopathies; Duchenne muscular dystrophy
Phase IIPolymorphic catecholergic ventricular tachycardia
Phase ICardiac-arrhythmias; Congenital structural myopathies; Heart failure
No development reportedDuchenne muscular dystrophy; Limb girdle muscular dystrophies; Sarcopenia; X-linked bulbo-spinal atrophy
04 Sep 2025Chemical structure information added.
02 Apr 2025Surlorian is still in phase I trial for Congenital structural myopathies in USA (PO) (NCT04141670)
02 Apr 2025Phase-I clinical trials in Heart failure (unspecified route), prior to April 2025 (RyCarma Therapeutics pipeline, April 2025)

Treatment of an Inherited Ventricular ArrhythmiaCTID: NCT05122975Phase: Phase 2Status: TerminatedDate: 2024-09-19
S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)CTID: NCT04141670Phase: Phase 1Status: CompletedDate: 2024-08-22

SYN

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=7D2A432BCEB72512228EE7E0314A4982.wapp2nB?docId=US456995370&_cid=P21-MIV3Q0-83794-1

EXAMPLE 1: PREPARATION OF 4-[(7-METHOXY-2,3-DIHYDRO-1,4-BENZOTHIAZEPIN-4(5H)YL)METHYL]BENZOIC ACID

4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was prepared as described below.

Stage 1: 7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (“Amine”)

2-(4-Methoxyphenylthio)ethanamine (1)

4-Methoxythiophenol (50 g, 0.357 mol), 2-chloroethylamine monohydrochloride (39.8 g, 0.343 mol.), K₂CO₃ (78.8 g, 0.57 mol) and diisopropyl ethylamine (32 mL, 0.178 mol) were mixed in tetrahydrofuran (THF). The mixture was degassed for 5 min. under reduced pressure and heated at reflux under argon overnight. The solvent was removed and water was added to the flask. The mixture was extracted with dichloromethane. The organic layers were collected, dichloromethane was removed and conc. HCl was added, followed by of water. The solution was extracted with 1:1 ethyl acetate (EtOAc)/hexane. The aqueous layer was adjusted to pH 10 with 2 M NaOH, and was extracted with dichloromethane. The combined organic solution was dried over anhydrous sodium sulfate. Removal of solvent provided the target compound.

Benzyl 2-(4-methoxyphenylthio)ethylcarbamate (2)

To a flask containing compound 1 (8.0 g, 43.7 mmol), sodium bicarbonate (12.1 g, 144 mmol), water, and dichloromethane was added benzyl chloroformate (8.2 g, 48.1 mmol, diluted in 100 mL of dichloromethane) dropwise at 0° C. After the addition, the mixture was stirred at r.t. for 5 hr. The organic layer was collected and the aqueous solution was extracted with 100 mL of dichloromethane. The combined organic solution was dried over sodium sulfate. The solvent was removed and the resulting solid was triturated with THF/hexane (1:10). The solid was collected and dried leaving the target product.

Benzyl 7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepine-4(5H)-carboxylate (3)

A mixture of compound 2 (7.3 g, 23 mmol), paraformaldehyde (6.9 g 0.23 mol), and p-toluenesulfonic acid (1.45 g, 7.6 mmol) in toluene was stirred at 70° C. overnight. After cooling to r.t., the solid was filtered off. The solution was extracted with saturated sodium carbonate, and the organic layer was dried over anhydrous sodium sulfate to yield the target product as a liquid after removal of the solvent.

7-Methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine hydrobromide (Amine)

Compound 3 (10 g, 30 mmol) was mixed with concentrated HCl, water and dioxane. The mixture was stirred at 100° C. overnight. After cooling to room temperature, most of the solvent and HCl were removed under reduced pressure. Water was added to the solution and the solid was filtered off. The aqueous solution was extracted with EtOAc/hexane (1:1) and basified by adding 15 g of NaOH. The mixture was extracted with dichloromethane. The combined solution was dried over anhydrous sodium sulfate. Removal of solvent provided a liquid that solidified after standing at room temperature (r.t.), to yield the target compound.

Stage 2: −[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid

In Scheme 2, L is a leaving group, which is, by way of example, a halogen or a sulfonate (OSO ₂R′ wherein R′is alkyl or aryl, e.g., OMs (mesylate) or OTs (tosylate)). Amine (4) (1 mmol) was dissolved dichloromethane. To the solution was added alkylation reagent (5) (1 mmol), followed by N,N-diisopropylethylamine (2 mmol). The mixture was stirred at room temperature overnight. The solution was loaded onto a silica gel column directly and eluted with hexane/EtOAc (2:1, v/v) to afforded the desired product.

SYN

WO-2013156505

PAT

Agents for treating disorders involving modulation of ryanodine receptorsPublication Number: US-2014088171-A1Priority Date: 2012-04-18
Agents for treating disorders involving modulation of ryanodine receptorsPublication Number: US-2014378437-A1Priority Date: 2012-04-18
Agents for treating disorders involving modulation of ryanodine receptorsPublication Number: US-8853198-B2Priority Date: 2012-04-18Grant Date: 2014-10-07
Agents for treating disorders involving modulation of ryanodine receptorsPublication Number: WO-2013156505-A1Priority Date: 2012-04-18
Drugs for treating diseases involved in the modulation of ryanodine receptorsPublication Number: JP-2015514736-APriority Date: 2012-04-18
Drugs for treating diseases involved in the modulation of ryanodine receptorsPublication Number: JP-5965542-B2Priority Date: 2012-04-18Grant Date: 2016-08-10
Agents for treating disorders involving modulation of ryanodine receptorsPublication Number: KR-101731459-B1Priority Date: 2012-04-18Grant Date: 2017-04-28
Agents for treating disorders involving modulation of ryanodine receptorsPublication Number: KR-20150003347-APriority Date: 2012-04-18
Agents for treating disorders involving modulation of ryanodine receptorsPublication Number: US-2013281512-A1Priority Date: 2012-04-18

ARM-210 hemifumarate
ZHR6WM1ADJ
UNII-ZHR6WM1ADJ
1467606-11-6
Surlorian fumarate (USAN)

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///////////Surlorian, ryanodine receptor (RyR) stabilizer, ARM 210, RYCAL DMD, s48168, S 48168, 1033GN605L

Sumecigrel, Vicagrel

December 6, 2025 3:05 am / Leave a comment

Sumecigrel, VICAGREL

CAS 1314081-53-2

MF C18H18ClNO4S MW379.858

(S)-2-(2-ACETOXY-6,7-DIHYDROTHIENO(3,2-C)PYRIDINE-5(4H)-YL)-2-(2-CHLOROPHENYL)ACETIC ACID METHYL ESTER
METHYL (.ALPHA.S)-2-(ACETYLOXY)-.ALPHA.-(2-CHLOROPHENYL)-6,7-DIHYDROTHIENO(3,2-C)PYRIDINE-5(4H)-ACETATE
METHYL (2S)-2-(2-ACETYLOXY-6,7-DIHYDRO-4H-THIENO(3,2-C)PYRIDIN-5-YL)-2-(2-CHLOROPHENYL)ACETATE
METHYL (S)-(2-(ACETYLOXY)-6,7-DIHYDROTHIENO(3,2-C)PYRIDIN-5(4H)-YL)(2-CHLOROPHENYL)ACETATE
THIENO(3,2-C)PYRIDINE-5(4H)-ACETIC ACID, 2-(ACETYLOXY)-.ALPHA.-(2-CHLOROPHENYL)-6,7-DIHYDRO-, METHYL ESTER, (.ALPHA.S)-
VICAGREL

methyl (S)-2-(acetyloxy)-6,7-dihydrothieno[3,2- c]pyridin-5(4H)-ylacetate
platelet aggregation inhibitor, 8A63K3TN0U, VICAGREL

Pharmacokinetic/Pharmacodynamic Study of Vicagrel Capsules and Clopidogrel Tablets in Healthy CYP2C19 Normal MetabolizersCTID: NCT07067775Phase: Phase 1Status: CompletedDate: 2025-09-09
Efficacy and Safety Study of Vicagrel in Patients With Acute Coronary Syndrome (ACS) Undergoing Percutaneous Coronary Intervention (PCI)CTID: NCT06577519Phase: Phase 3Status: RecruitingDate: 2024-10-01
PK/PD Study of Vicagrel and Clopidogrel in Healthy Subjects With Different CYP2C19 MetabolizersCTID: NCT05162053Phase: Phase 1Status: CompletedDate: 2023-11-03
A Clinical Trial to Evaluate the Effect of Food on PK and PD of Vicagrel Capsules in Healthy Adult SubjectsCTID: NCT04919551Phase: Phase 1Status: CompletedDate: 2021-11-01
The Efficacy, Safety and Pharmacokinetic of Antiplatelet Therapy for VicagrelCTID: NCT03599284Phase: Phase 2Status: CompletedDate: 2019-09-23
Pharmacokinetics and Pharmacodynamics of Vicagrel in Healthy Adult Subjects of Different CYP2C19
CTID: NCT03942458
Phase: Phase 1
Status: Completed
Date: 2019-09-19

Sumecigrel (also known as

vicagrel) is an investigational small molecule drug classified as a P2Y12 inhibitor and antiplatelet agent. It is currently under clinical development for the treatment of various cardiovascular and peripheral conditions.

Key Information

Therapeutic Class: Antiplatelet agent; P2Y12 inhibitor. These types of drugs work by preventing platelets in the blood from sticking together and forming clots, which is a key process in conditions like heart attack and stroke.
Developer: Jiangsu Vcare PharmaTech.
Clinical Status: It is currently in the pre-registration phase for acute coronary syndrome (ACS). It has also been under investigation for ischemic stroke and peripheral arterial disease.
Synonyms: The drug is also widely referred to by its USAN (United States Adopted Name) and INN (International Nonproprietary Name) designation, vicagrel.

Chemical Details

Formula: C18H18ClNO4SC sub 18 H sub 18 ClNO sub 4 SC18H18ClNO4S.
CAS Number: 1314081-53-2.
UNII: 8A63K3TN0U.

For more detailed information regarding its regulatory status, you can check the official precisionFDA or PubChem databases.

SYN

WO-2011095049

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN85433897&_cid=P22-MITPA1-71386-1

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=EP75374721&_cid=P22-MITPA1-71386-1

Example 3

(2S)-Methyl 2-(2-oxo-7,7a-dihydrothieno[3,2-c]pyridin-5(2H,4H,6H)-yl)-2-(2-chlorophenyl)-acetate (IV-1)

[0036] 58.1 g (0.15 mol) of (R)-methyl 2-(2-chlorophenyl)-2-(4-nitrophenylsulfonyloxy)-acetate ( II-1), 32.3 g (0.17 mol) of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one hydrochloride ( III-1), and 37.8g (0.38 mol) of potassium bicarbonate were added to 500 ml of acetonitrile. The reaction was stirred under a nitrogen atmosphere at room temperature for 26 hrs. The reaction solution was allowed to stand and the insoluble material was filtered off, to obtain a dark red mother liquor. The solvent was evaporated under reduced pressure, and 35.4 g of an oil product was obtained after purification by flash column chromatography (petroleum ether:ethyl acetate = 4:1). Yield 70%. Recrystalization from ethanol afforded 18.1 g of a pure product (IV-1) as a white solid. mp: 146-148°C, ee = 97.5%, [α] _D ¹⁹ = +114.0° (c 0.5, MeOH); ¹H-NMR (300 MHz, CDCl ₃) δ 1.79-1.93 (m, 1 H), 2.30-2.40 (m, 1 H), 2.56-2.70 (m, 1 H), 3.00-3.27 (m, 2 H), 3.72 (s, 3 H), 3.79-3.93 (m, 1 H), 4.12-4.19 (m, 1 H), 4.89 (d, 1 H, J= 5.6 Hz), 6.00 (d, 1 H, J = 5.2 Hz), 7.26-7.50 (m, 4 H); ¹³C-NMR (75 MHz, CDCl ₃) δ 33.9, 34.0, 49.0, 49.7, 51.1, 51.6, 52.2, 52.4, 67.3, 76.6, 77.0, 77.4, 126.6, 126.8, 127.2, 129.8, 130.1, 132.7, 134.8, 167.2, 167.4, 170.8, 198.6; ESI-MS m/ z 338.1 [M+H] ⁺; HRMS Calcd for C ₁₆H ₁₇NO ₃SCl [M+H] ⁺ m/ z 338.0618, found 338.0626.

Reference Example 4

(S)-Methyl 2-(2-benzoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-1)

[0038] (2S)-Methyl 2-(2-chlorophenyl)-2-(2-oxo-5,6,7,7a-tetrahydrothieno[3,2-c]pyridinyl)acetate ( IV– 1) (113 mg) was dissolved in acetonitrile (10 ml), 0.10 ml of triethylamine was added, and 151 mg of benzoic anhydride was added dropwise at 0°C, and then the mixture was warmed to room temperature and reacted for 2 hrs. The reaction solution was poured into water (30 ml), the aqueous phase was extracted with ethyl acetate (50 ml x 3), and the organic phase was washed with saturated aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous sodium sulfate, and evaporated, to obtain a crude product, which was subjected to flash column chromatography (petroleum ether:ethyl acetate = 40 : 3), to obtain (S)-methyl 2-(2-benzoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-1) (77 mg). Yield 52%, mp: 84-86°C, ee = 93.5% (chiral HPLC analysis conditions: Chiralpak IC 4.6 mm x 250 mm; column temperature: 25° C; mobile phase: 90% n-hexane/10% isopropanol/0.1% diethylamine; flow rate: 0.5 ml/min; and detection wavelength: UV 254 nm), [α] _D²⁰ = +34.00° (c 0.50, MeOH); ¹H-NMR (300 MHz, CDCl ₃) δ 2.82-2.93 (m, 4 H), 3.57-3.68 (m, 2 H), 3.73 (s, 3 H), 4.95 (s, 1 H), 6.42 (s, 1 H), 7.26-8.17 (m, 9 H); ¹³C-NMR (75 MHz CDCl ₃) δ 25.0, 48.2, 50.4, 52.2, 67.8, 112.1, 125.9, 127.2, 128.5, 128.6, 129.5, 129.8, 130.0, 130.2, 133.9, 134,7, 149.9, 163.5; ESI-MS m/ z 442.1 [M+H] ⁺; HRMS Calcd for C ₂₃H ₂₁NO ₄SCl [M+H] ⁺m/ z 442.0891, found 442.0880.

Example 5

(S)-Methyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-2)

[0040] Following the method described in Example 4, (2S)-methyl 2-(2-chlorophenyl)-2-(2-oxo-5, 6, 7, 7a-tetrahydrothieno[3,2-c]pyridinyl)acetate (IV-1) (6.5 g) was reacted with acetic anhydride (3.6 ml), to prepare (S)-methyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate ( I-2) (6.8 g). Yield 93%. Recrystallization from ethanol afforded a white solid, mp: 73-75°C, ee = 98.9% (chiral HPLC analysis conditions: Chiralpak IC 4.6 mm x 250 mm; column temperature: 25°C; mobile phase: 92% n-hexane/8% tetrahydrofuran/0.1% diethylamine; flow rate: 0.5 ml/min; and detection wavelength: UV 254 nm), [α] _D²³ = +45.00°(c = 1.0, CH ₃OH); ¹H-NMR (300 MHz, CDCl ₃) δ 2.26 (s, 3 H), 2.65-2.90 (m, 4 H), 3.47-3.69 (m, 2 H), 3.72 (s, 3 H), 4.92 (s, 1 H), 6.26 (s, 1 H), 7.24-7.70 (m, 4 H); ¹³C-NMR (75 MHz, CDCl ₃) δ 20.2, 24.5, 47.6, 49.8, 51.6, 67.3, 111.5, 125.3, 126.6, 128.8, 128.9, 129.3, 129.4, 133.3, 134.2, 149.1, 167.2, 170.7; ESI-MS m/ z 380.0 [M+H] ⁺; HRMS Calcd for C ₁₈H ₁₉NO ₄SCl [M+H] ⁺m/ z 380.0723, found 380.0737.

Reference Example 6

(R)-Methyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-2′)

[0042] Following the method described in Example 4, (2R)-methyl 2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate ( IV-1′) (prepared following Examples 1-3) was reacted with acetic anhydride, to prepare (R)-methyl 2-(2-acetoxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate ( I-2′), ee = 98.2% (chiral HPLC analysis conditions were the same as those in Example 5), [α] _D ²³ =-44.00° (c= 1.0, CH ₃OH).

Reference Example 7

(S)-Methyl 2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-3)

[0043] Following the method described in Example 4, (2S)-methyl 2-(2-chlorophenyl)-2-(2-oxo-7, 7a-dihydrothieno[3.2-c]pyridin-5(2H, 4H,6H)-yl)-acetate ( IV-1) (338 mg) was reacted with propionic anhydride (0.27 ml), to prepare (S)-methyl 2-(2-propanoyloxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate ( I-3) (267 mg).Yield 66%, ee = 96.5% (chiral HPLC analysis conditions were the same as those in Example 4), [α] _D²⁰ = + 36.00°( c 0.50, MeOH); ¹H-NMR (300 MHz, CDCl ₃) δ 1.23 (t, 3 H, J = 7.4 Hz), 2.55 (q, 2 H, J= 7.7 Hz), 2.76-2.78 (m, 2 H), 2.87-2.88 (m, 2 H), 3.53 (d, 1 H, J = 14.2 Hz), 3.65 (d, 1 H, J = 13.6 Hz), 3.72 (s, 3 H), 4.91 (s, 1 H), 6.26 (s, 1 H), 7.26-7.69 (m, 4 H); ¹³C-NMR (75 MHz, CDCl ₃) δ 8.8, 21.1, 25.0, 27.4, 48.2, 50.3, 52.2, 67.8, 106.2, 111.7, 125.6, 127.2, 129.1, 129.5, 129.8, 130.0, 123.7, 149.8, 171.2; ESI-MS m/ z 394.1 [M+H] ⁺; HRMS Calcd for C ₁₉H ₂₁NO ₄SCl [M+H] ⁺m/ z 394.0883, found 394.0880.

PAT

Optically active 2-hydroxytetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereofPublication Number: KR-102215429-B1Priority Date: 2010-02-02Grant Date: 2021-02-16
Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereofPublication Number: EP-3290423-B1Priority Date: 2010-02-02Grant Date: 2021-07-21
Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereofPublication Number: US-2015011583-A1Priority Date: 2010-02-02
Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereofPublication Number: US-2017121341-A1Priority Date: 2010-02-02
Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereofPublication Number: US-2019055260-A1Priority Date: 2010-02-02
Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereofPublication Number: US-8772489-B2Priority Date: 2010-02-02Grant Date: 2014-07-08
Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereofPublication Number: WO-2011095049-A1Priority Date: 2010-02-02

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///////////Sumecigrel, platelet aggregation inhibitor, 8A63K3TN0U, VICAGREL

Soquelitinib

December 5, 2025 8:51 am / Leave a comment

Soquelitinib

CAS 2226636-04-8

MF C25H30N4O4S2, 514.7 g/mol

N-[5-({4-methoxy-2-methyl-5-[(3R)-3-methyl-4-(prop-2-enoyl)-1,4-diazepane-1-carbonyl]phenyl}sulfanyl)-1,3-thiazol-2-yl]cyclopropane-1-carboxamide
tyrosine kinase inhibitor, antineoplastic, CPI818, CPI-000818, CPI596, CP I818, CPI 000818, CP I596, 6I5H17AN3I,

N-[5-[4-methoxy-2-methyl-5-[(3R)-3-methyl-4-prop-2-enoyl-1,4-diazepane-1-carbonyl]phenyl]sulfanyl-1,3-thiazol-2-yl]cyclopropanecarboxamide

Soquelitinib (CPI-818) is an experimental drug which acts as a selective inhibitor of the enzyme interleukin-2-inducible T-cell kinase (ITK). It is in clinical trials for the treatment of T-cell lymphoma.^[1][2]

Soquelitinib is an orally available, small-molecule, irreversible inhibitor of interleukin-2 inducible T-cell kinase (ITK) with potential immunomodulatory and antineoplastic activities. Upon oral administration, soquelitinib selectively and covalently binds to the cysteine residue at position 442 (CYS-442) of ITK, thereby disrupting ITK-mediated signal transduction, while sparing tyrosine-protein kinase TXK (resting lymphocyte kinase, RLK) activity. This may abrogate T-cell receptor (TCR) signaling through ITK and inhibit TCR-induced proliferation of malignant T-cells. Additionally, inhibiting ITK activation may prevent the upregulation of GATA-3, a transcription factor that drives T-helper 2 (Th2) cell differentiation and is overexpressed in certain T-cell lymphomas. Thus, selective inhibition of ITK may inhibit Th2 responses without affecting T-helper 1 (Th1)-dependent immunity. ITK, a member of the Tec family of non-receptor protein tyrosine kinases plays a significant role in the T-cell development, differentiation and production of pro-inflammatory cytokines.

Safety, Tolerability, and Preliminary Efficacy of Soquelitinib in Participants With Moderate to Severe ADCTID: NCT06345404Phase: Phase 1Status: RecruitingDate: 2025-07-22
Study of the ITK Inhibitor Soquelitinib to Reduce Lymphoproliferation and Improve Cytopenias in Autoimmune Lymphoproliferative Syndrome (ALPS)-FAS PatientsCTID: NCT06730126Phase: Phase 2Status: RecruitingDate: 2025-05-31
Soquelitinib vs Standard of Care in Participants With Relapsed/Refractory Peripheral T-cell Lymphoma Not Otherwise Specified, Follicular Helper T-cell Lymphomas, or Systemic Anaplastic Large-cell LymphomaCTID: NCT06561048Phase: Phase 3Status: RecruitingDate: 2025-04-17
A Dose Escalation Study Evaluating CPI-818 in Relapsed/Refractory T-Cell LymphomaCTID: NCT03952078Phase: Phase 1Status: Active, not recruitingDate: 2025-04-16

Syn

Syn

SYN

WO-2023196278-A1

Embodiment B23. A method for an Th2/ITK-mediated disease in a patient in need thereof, the method comprising administering to the patient about 250 mg to about 1,000 mg per day of a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (A) is:

REF

https://www.nature.com/articles/s44386-024-00002-1

Pat

Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: US-2022363676-A1Priority Date: 2016-11-03
Compounds and methods for modulating Interleukin-2-inducible T-cell kinasePublication Number: US-11897874-B2Priority Date: 2016-11-03Grant Date: 2024-02-13
Itk inhibitors for increasing th1 cell activityPublication Number: WO-2023196278-A1Priority Date: 2022-04-05
Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: US-2019375743-A1Priority Date: 2016-11-03
Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: WO-2018089261-A2Priority Date: 2016-11-03
Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: US-11008314-B2Priority Date: 2016-11-03Grant Date: 2021-05-18
Compounds and methods for modulating interleukin-2-inducible t-cell kinasePublication Number: EP-3534899-B1Priority Date: 2016-11-03Grant Date: 2022-06-01

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References

Khodadoust MS, Feldman TA, Yoon DH, Yannakou CK, Radeski D, Kim YH, et al. (November 2020). “Cpi-818, an oral interleukin-2-inducible T-cell kinase inhibitor, is well-tolerated and active in patients with T-cell lymphoma”. Blood. 136: 19–20. doi:10.1182/blood-2020-137782.
Hsu LY, Rosenbaum JT, Verner E, Jones WB, Hill CM, Janc JW, et al. (December 2024). “Synthesis and characterization of soquelitinib a selective ITK inhibitor that modulates tumor immunity”. npj Drug Discovery. 1 (1) 2: 1–4. doi:10.1038/s44386-024-00002-1.

Identifiers

IUPAC name
CAS Number	2226636-04-8
PubChem CID	134517711
DrugBank	DB18749
ChemSpider	129629996
UNII	6I5H17AN3I
KEGG	D12762
Chemical and physical data
Formula	C₂₅H₃₀N₄O₄S₂
Molar mass	514.66 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

//////////////Soquelitinib, tyrosine kinase inhibitor, antineoplastic, CPI818, CPI-000818, CPI596, CP I818, CPI 000818, CP I596, 6I5H17AN3I,

Sitokiren

December 4, 2025 8:26 am / Leave a comment

Sitokiren

CAS 1399849-02-5,

MF C22H32N6O4, 444.5 g/mol

methyl N-[3-[3-[(1R)-1-[cyclopropyl-[(2R)-morpholine-2-carbonyl]amino]ethyl]-6-methylpyrazolo[5,4-b]pyridin-1-yl]propyl]carbamate

methyl [3-(3-{(1R)-1-[(2R)-N-cyclopropylmorpholine-2-carboxamido]ethyl}-6-methyl-1H-pyrazolo[3,4-
b]pyridin-1-yl)propyl]carbamate
renin inhibitor, SPH 3127, C2M78A9V6Z

Sitokiren, also known as SPH3127, isa highly potent, orally active direct renin inhibitor developed by Mitsubishi Tanabe Pharma Corp. that was initially investigated for hypertension and cardiovascular diseases. Recent research has shown it also has a strong anti-inflammatory effect, particularly in the gut, making it a potential candidate for treating conditions like inflammatory bowel disease (IBD).

What it is

Direct renin inhibitor: Sitokiren directly inhibits the enzyme renin, which is the rate-limiting step in the renin-angiotensin-aldosterone system (RAAS).
Chemical properties: It is a small molecule with the chemical formula C22H32N6O4
Developed by: Mitsubishi Tanabe Pharma Corp..
Alternative name: SPH3127 is another name for sitokiren.

How it works

Blocks the RAAS: By inhibiting renin, it prevents the RAAS from over-activating.
Potential benefits: This inhibition may help in managing blood pressure and has also shown promise in suppressing inflammation in the gut, which is a key factor in IBD.

Current research and potential applications

Hypertension: Sitokiren was initially developed for its potential to treat hypertension, and preclinical models have shown it to be more potent than the approved drug aliskiren.
Inflammatory bowel disease (IBD): Studies using sitokiren in mouse models have demonstrated its ability to reduce inflammation and protect against damage in colitis, suggesting it could be a novel therapeutic for IBD.

SPH-3127 is under investigation in clinical trial NCT05359068 (Study to Evaluate the Efficacy and Safety of SPH3127 in Patients With Mild-moderate Essential Hypertension).

SPH3127 is a small-molecule renin inhibitor developed by Shanghai Pharmaceuticals for hypertension and kidney disease. It is believed to be more potent than aliskiren.^[1][2][3]

SYN

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.2c00834

Methyl N-[3-(3-{(1S)-1-[cyclopropyl-((2R)-morpholine-2-carbonyl)amino]ethyl}-6-methyl
pyrazolo[3,4-b]pyridin-1-yl)propyl]carbamate (18-diastereomer). This isomer was separated
from a mixture of the corresponding diastereomers using NH-silica gel column chromatography
as the more polar isomer. 1H NMR (400 MHz, DMSO-d6) : 0.20 (m, 1H), 0.51−0.74 (m, 3H),
1.70 (d, J = 7.0 Hz, 3H), 1.94 (m, 2H), 2.57 (s, 3H), 2.60−2.75 (m, 3H), 2.79 (m, 1H), 2.87 (dd,J = 2.4, 12.5 Hz, 1H), 3.00 (m, 2H), 3.47 (m, 1H), 3.51 (s, 3H), 3.79 (d, J = 10.9 Hz, 1H),
4.30−4.46 (m, 2H), 4.66 (dd, J = 2.1, 9.4 Hz, 1H), 5.84 (q, J = 7.0 Hz, 1H), 7.02 (d, J = 8.2 Hz,
1H), 7.16 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H). MS (APCI) m/z: 445.1 [M + H]+. Purity and
diastereomeric excess measured by chiral HPLC: 98.37%, 81.23% de (column: Chiralpak IC (4.6
mm × 250 mm, elution: hexane/EtOH/diethylamine, 50:50:0.1 (v/v), flow rate: 0.5 mL/min,
column temperature: 25 °C, retention time: 29.40 min).

SYN

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=1B9584CB9AC69299BCC760DE78F64E8B.wapp1nC?docId=US411173755&_cid=P12-MIR5W7-75170-1

SYN

WO-2022048618-A1

SYN

WO-2022047730-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022047730&_cid=P12-MIR63I-81994-1

PAT

Nitrogen-containing saturated heterocyclic compound

Publication Number: US-9278944-B2

Priority Date: 2011-03-16

Grant Date: 2016-03-08

https://patentscope.wipo.int/search/en/detail.jsf?docId=US95781978&_cid=P12-MIR64F-82901-1

PAT

Salt of morpholine derivative and crystalline form thereof, as well as preparation method, pharmaceutical composition and use of the samePublication Number: EP-3398946-B1Priority Date: 2015-12-29Grant Date: 2022-05-04
Nitrogen-containing saturated heterocyclic compoundPublication Number: EP-2687518-B1Priority Date: 2011-03-16Grant Date: 2017-11-01
Nitrogen-containing saturated heterocyclic compoundPublication Number: US-10155731-B2Priority Date: 2011-03-16Grant Date: 2018-12-18
Nitrogen-containing saturated heterocyclic compoundPublication Number: US-2014011807-A1Priority Date: 2011-03-16
Nitrogen-containing saturated heterocyclic compoundPublication Number: US-2016145220-A1Priority Date: 2011-03-16
Methods to treat inflammatory bowel diseasePublication Number: US-2023398123-A1Priority Date: 2020-09-04
Salt of morpholine derivative and crystalline form thereof, as well as preparation method, pharmaceutical composition and use of the samePublication Number: EP-3398946-A1Priority Date: 2015-12-29
Salts of morpholine derivative, crystal forms thereof, processes for producing the same, pharmaceutical compositions including the same, and use thereofPublication Number: US-10519150-B2Priority Date: 2015-12-29Grant Date: 2019-12-31
Salts of morpholine derivative, crystal forms thereof, processes for producing the same, pharmaceutical compositions including the same, and use thereofPublication Number: US-2019016718-A1Priority Date: 2015-12-29
Salt of morpholine derivative and its crystal form, manufacturing method thereof, pharmaceutical composition and use thereofPublication Number: TW-I705065-BPriority Date: 2015-12-29Grant Date: 2020-09-21
Methods to treat inflammatory bowel diseasePublication Number: WO-2022047730-A1Priority Date: 2020-09-04
Application of nitrogen-containing saturated heterocyclic compoundPublication Number: WO-2022048614-A1Priority Date: 2020-09-04
Methods to treat inflammatory bowel diseasePublication Number: WO-2022048618-A1Priority Date: 2020-09-04
Application of nitrogen-containing saturated heterocyclic compoundPublication Number: EP-4209218-A1Priority Date: 2020-09-04
Application of nitrogen-containing saturated heterocyclic compoundPublication Number: US-2023330093-A1Priority Date: 2020-09-04

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References

Iijima, Daisuke; Sugama, Hiroshi; Takahashi, Yoichi; Hirai, Miki; Togashi, Yuko; Xie, Jianshu; Shen, Jingkang; Ke, Ying; Akatsuka, Hidenori; Kawaguchi, Takayuki; Takedomi, Kei; Kashima, Akiko; Nishio, Masashi; Inui, Yosuke; Yoneda, Hikaru; Xia, Guangxin; Iijima, Toru (25 August 2022). “Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor”. Journal of Medicinal Chemistry. 65 (16): 10882–10897. doi:10.1021/acs.jmedchem.2c00834. PMID 35939295. S2CID 251400126.
Zhang, Leduo; Mao, Yu; Gao, Zhiwei; Chen, Xiaoyan; Li, Xin; Liu, Yanjun; Xia, Guangxin (February 2020). “The Nonclinical Pharmacokinetics and Prediction of Human Pharmacokinetics of SPH3127, a Novel Direct Renin Inhibitor”. European Journal of Drug Metabolism and Pharmacokinetics. 45 (1): 15–26. doi:10.1007/s13318-019-00573-9. PMID 31494843. S2CID 201848935.
Jing, Shan; Xu, Ranchi; Yang, Kexu; Liu, Wenfang; Zhang, Leduo; Ke, Ying; Xia, Guangxin; Lin, Yang (April 2021). “Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPH3127: A Phase I, Randomized, Double-Blind, Placebo-Controlled Trial”. Clinical Therapeutics. 43 (4): 735.e1–735.e14. doi:10.1016/j.clinthera.2021.01.025. PMID 33653620. S2CID 232104329.

Legal status

Legal status	Investigational
Identifiers
IUPAC name
CAS Number	1399849-02-5
PubChem CID	117877477
ChemSpider	76799450
UNII	C2M78A9V6Z
ChEMBL	ChEMBL4110551
Chemical and physical data
Formula	C₂₂H₃₂N₆O₄
Molar mass	444.536 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

////Sitokiren, renin inhibitor, SPH 3127, C2M78A9V6Z

Setidegrasib

December 3, 2025 10:09 am / Leave a comment

Setidegrasib

CAS 2821793-99-9

MF C60H65FN12O7S MW1117.30

(2S,4R)-1-[(2S)-2-[4-[4-[[6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(oxan-4-yloxy)quinazolin-8-yl]oxymethyl]phenyl]triazol-1-yl]-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

Kirsten rat sarcoma viral oncogene homologue (KRAS) degradation
inducer, antineoplastic, ASP-3082, ASP 3082, 3NQ4ME292X, KRAS G12D inhibitor 17

Setidegrasib (KRAS G12D inhibitor 17, ASP3082) is a PROTAC KRAS degrader (DC₅₀: 37 nM). Setidegrasib induces the degradation of G12D-mutation KRAS protein. Setidegrasib suppresses p-ERK, p-AKT, p-S6 levels in AsPC-1 cells. Setidegrasib exhibits anti-tumor activity in various cancer xenograft models in mice. Setidegrasib can be used for the study of KRAS(G12D)-mutated solid tumors. (Blue: VHL ligase ligand (HY-168699); Black: linker (HY-168698); Pink: G12D ligand (HY-168700)).

Setidegrasib is a small molecule drug. The usage of the INN stem ‘-rasib’ in the name indicates that Setidegrasib is a Ras protein inhibitor. Setidegrasib has a monoisotopic molecular weight of 1116.48 Da.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022173032&_cid=P21-MIPU3D-50779-1

PAT

Combination of anticancer agents comprising a bifunctional compound with g12d mutant kras inhibitory activityPublication Number: WO-2024033537-A1Priority Date: 2022-08-12
Combination of anticancer agents comprising a bifunctional compound with g12d mutant kras inhibitory activityPublication Number: WO-2024033538-A1Priority Date: 2022-08-12
Quinazoline compound for inducing degradation of g12d-mutation kras proteinPublication Number: WO-2022173032-A1Priority Date: 2021-02-15
Quinazoline compound for inducing degradation of g12d-mutation kras proteinPublication Number: EP-4293024-A1Priority Date: 2021-02-15
Quinazoline compound for inducing degradation of g12d mutant kras proteinPublication Number: US-2024182483-A1Priority Date: 2021-02-15

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[1]. Yoshinari, et al. Preparation of quinazoline-linked (4R)-4-hydroxy-L-prolinamide compounds for inducing degradation of G12D-mutation KRAS protein: World Intellectual Property Organization, WO2022173032[P]. 2022-08-18.[2]. Yoshinari T, et al. Discovery of KRAS(G12D) selective degrader ASP3082. Commun Chem. 2025 Aug 23;8(1):254. [Content Brief]

////////Setidegrasib, antineoplastic, ASP-3082, ASP 3082, 3NQ4ME292X, KRAS G12D inhibitor 17

Sendegobresib

December 2, 2025 2:59 am / Leave a comment

Sendegobresib

CAS 2704617-96-7

MFC37H45F3N6O5, 710.79

2,6-PIPERIDINEDIONE, 3-((4-(4-((4S)-1-((4-(1,6-DIHYDRO-1,4,5-TRIMETHYL-6-OXO-3-PYRIDINYL)-2,6-DIMETHOXYPHENYL)METHYL)-3,3-DIFLUORO-4-PIPERIDINYL)-1-PIPERAZINYL)-3-FLUOROPHENYL)AMINO)-, (3S)-

(3S)-3-[4-[4-[(4S)-1-[[2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridinyl)phenyl]methyl]-3,3-difluoropiperidin-4-yl]piperazin-1-yl]-3-fluoroanilino]piperidine-2,6-dione

bromodomain-containing protein 9 (BRD9) degradation inducer, antineoplastic, AW8PEP3VZ3, CFT 8634, ORPHAN DRUG

Sendegobresib is an orally bioavailable heterobifunctional protein degrader of bromodomain-containing protein 9 (BRD9; sarcoma antigen NY-SAR-29; rhabdomyosarcoma antigen MU-RMS-40.8), with potential antineoplastic activity. Sendegobresib is comprised of an E3 ligase-binding moiety and a BRD9-binding moiety. Upon oral administration, sendegobresib targets and binds to BRD9 with its BRD9-binding moiety. Upon BRD9 binding, the E3 ligase-binding moiety binds to cereblon (CRBN), a component of the CRL4-CRBN E3 ubiquitin ligase complex, which directs proteins for destruction, resulting in the proteasome-mediated degradation of BRD9. This leads to an inhibition of the growth of tumor cells that rely on BRD9 for survival. BRD9, a component of one form of the Brg/Brahma-Associated Factor (BAF) complex, is needed for the survival of certain cancer cells due to mutations.

A Study to Assess the Safety and Tolerability of CFT8634 in Locally Advanced or Metastatic SMARCB1-Perturbed Cancers, Including Synovial Sarcoma and SMARCB1-Null Tumors

CTID: NCT05355753

Phase: Phase 1

Status: Terminated

Date: 2024-12-17

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US355912448&_cid=P11-MINYJY-62955-1

Synthesis of Compound 172

Step-1: To a stirred solution of compound tert-butyl piperazine-1-carboxylate (85.40 g, 536.82 mmol) in DMF (500 mL) was added cesium carbonate (262.4 g, 805.4 mmol) and stirred for 15 min before adding 1,2-difluoro-4-nitro-benzene (100 g, 536.82 mmol). The reaction mixture stirred at RT for 16 h while monitoring by TLC. After completion, the reaction mass was quenched with ice flakes and the precipitated solid was filtered, dried under vacuum to afford tert-butyl 4-(2-fluoro-4-nitro-phenyl) piperazine-1-carboxylate 172-3 (152 g, 88.85% yield, 97.94% purity) as a yellow solid.

Step-2: To a stirred solution of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate 172-3 (50.0 g, 153.69 mmol) in 20 ml dioxane was added 4M dioxane HCl (30 ml) and reaction mixture stirred for 2 h at RT while monitoring by TLC. The solvent was evaporated to dryness under reduced pressure and crude solid was triturated with diethyl ether (75 ml) and n-pentane (100 ml) to afford HCl salt of 1-(2-fluoro-4-nitrophenyl) piperazine 172-4 (36.0 g, 136.2 mmol, 88.62% yield, 99% purity). LCMS (ES ⁺): m/z 226.10 [M+H] ⁺

Step-3: To stirred solution of 1-(2-fluoro-4-nitro-phenyl)piperazine 172-4 (8.0 g, 35.52 mmol) in toluene (200 ml) and ACN (100 ml) was added NaOAc (7.28 g, 88.80 mmol), followed by AcOH (8 ml) and molecular sieves 4 Å (10 g) and stirred for 15 min. After 15 min tert-butyl 3,3-difluoro-4-oxo-piperidine-1-carboxylate (11.49 g, 48.84 mmol, co-distilled with toluene before use) was added and the reaction mixture was allowed to reflux for 12 h, while monitoring by LCMS and TLC. After completion, reaction mixture was cooled to room temperature and filtered through Celite bed. The filtrate was concentrated under vacuum to dryness to afford crude residue 3,3-difluoro-4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate 172-6 (12.2 g, 98.89% purity) which was used for next step without any purification. LCMS (ES ⁺): m/z 443.75 [M+H] ⁺

Step-4: The compound 172-6 (8 g, 18.08 mmol) was dissolved in a mixture of methanol (20 mL), DCE (20 mL) and AcOH (2 ml), allowed to stir for 15 min, before adding sodium cyanoborohydride (5.68 g, 90.41 mmol). After addition, the reaction mixture was stirred for 24 h at room temperature, while monitoring by LCMS and TLC. The reaction mixture was filtered through Celite bed and filtrate was concentrated under vacuum. Crude compound purified by (silica gel mesh 100-200, and product eluted with 30% ethyl acetate in pet ether-neat ethyl acetate) column chromatography to afford tert-butyl-3,3-difluoro-4-[4-(2-fluoro-4-nitro-phenyl)piperazin-1-yl]piperidine-1-carboxylate 172-7 (7.2 g, 15.39 mmol, 85.11% yield, 98% purity). LCMS (ES ⁺): m/z 445.35 [M+H] ⁺

Step-5: To the stirred solution of tert-butyl 3,3-difluoro-4-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)piperidine-1-carboxylate 172-7 (5 g, 11.25 mmol) in ethyl acetate (100 mL) was added 10% Palladium on carbon wet (3.59 g, 33.75 mmol) at RT. The reaction mixture was stirred at RT under H ₂balloon pressure for 12 h was monitored by TLC. After the completion of the reaction, the reaction mixture was filtered-off through Celite and washed with ethyl acetate (200 mL). The filtrate was concentrated to obtain the crude product which was triturated with pentane, decanted the organic layer and the solidified product was filtered, dried well to afford tert-butyl 4-[4-(4-amino-2-fluoro-phenyl)piperazin-1-yl]-3,3-difluoro-piperidine-1-carboxylate 172-8 (3 g, 61.48% yield, 95.56% purity) as pale pink solid. LCMS (ES ⁺): m/z 415.56 [M+H] ⁺

Step-6: To a stirred solution of tert-butyl 4-[4-(4-amino-2-fluoro-phenyl)piperazin-1-yl]-3,3-difluoro-piperidine-1-carboxylate 172-8 (5 g, 12.06 mmol) in DMF (20 mL) taken in a seal tube was added 3-bromopiperidine-2,6-dione (6.95 g, 36.19 mmol) at rt followed by the addition of sodium bicarbonate (6.08 g, 72.38 mmol) and the reaction mixture was allowed to stir at 90° C. for 12 h. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and filtered off through Celite. The filtrate washed with water (2×100 mL), brine (1×25 mL), dried over anhydrous Na ₂SO ₄, filtered and concentrated to get the crude product. The crude product was purified by column chromatography using silica gel (100/200 mesh) and the product eluted at 2-3% MeOH/DCM) to afford (tert-butyl 4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate 172-9 (4.2 g, 56.31% yield, 91.08% purity) as a purple solid. LCMS (ES ⁺): m/z 526.48 [M+H] ⁺

Step-7: To the stirred solution of tert-butyl 4-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2-fluoro-phenyl]piperazin-1-yl]-3,3-difluoro-piperidine-1-carboxylate 172-9 (7 g, 13.32 mmol) in 1,4-dioxane (30 mL) was added 4M HCl in dioxane (30.35 mL, 665.95 mmol, 30.35 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, slowly warmed to RT and stirred at RT for 6 h. After the completion of the reaction, the reaction mixture was concentrated and the residual mass was triturated with diethyl ether (3×100 mL) and the solid precipitated out was dried well to afford 3-[4-[4-(3,3-difluoro-4-piperidyl)piperazin-1-yl]-3-fluoro-anilino]piperidine-2,6-dione 172-10 as HCl salt (5.54 g, 90.05% yield, 91.71% purity) as pale blue solid. LCMS (ES ⁺): m/z 426.22 [M+H] ⁺

Step 8: To a stirred solution of 3-[4-[4-(3,3-difluoro-4-piperidyl)piperazin-1-yl]-3-fluoro-anilino]piperidine-2,6-dione HCl 172-10 (5.65 g, 12.23 mmol) in DCE:MeOH (60:60 ml) were added 4 Å molecular sieves (3 g), acetic acid (0.797 g, 13.27 mmol) and sodium acetate (3.27 g, 39.82 mmol). The resulting solution was stirred for 10 min, then added 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)benzaldehyde 172-11 (4 g, 13.27 mmol) and heated the reaction mixture at 70° C. for 5 h then cooled it at RT and added Silia Bond Cyanoborohydride (3.85 g, 66.37 mmol). The stirring was continued at RT for 16 h, while monitoring the reaction by LCMS and TLC. After 16 h, the reaction mass was filtered through Celite, concentrated and purified by (Devisil silica gel, and product eluted with 1% to 5% MeOH in CH ₂C2) column flash chromatography to afford compound was dissolved in dry DCM (10 ml) and TFA (5 ml) was added at 0° C., stirred it for 30 min. After 30 min, reaction crude was concentrated to dryness and obtained crude was washed with diethyl ether (3×20 ml) to afford 3-[4-[4-[1-[[2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)phenyl]methyl]-3,3-difluoro-4-piperidyl]piperazin-1-yl]-3-fluoro-anilino]piperidine-2,6-dione TFA Compound 172 (3.21 g, 3.83 mmol, 28.85% yield, 98.40% purity) as a light green solid. ¹H NMR (400 MHz, DMSO-d ₆) δ 10.78 (s, 1H), 9.97 (s, 1H), 7.52 (s, 1H), 6.84 (t, J=9.3 Hz, 1H), 6.66 (s, 2H), 6.51 (d, J=15.0 Hz, 1H), 6.42 (d, J=8.5 Hz, 1H), 4.28-4.24 (m, 3H), 3.86 (s, 7H), 3.47 (s, 6H), 2.90 (bs, 9H), 2.76-2.68 (m, 1H), 2.53-2.54 (m, 1H), 2.08 (d, J=10.7 Hz, 9H), 1.91-1.87 (m, 1H). LCMS (ES ⁺): m/z 711.20 [M+H] ⁺

PAT

WO-2021178920

PAT

WO-2022216765

PAT

Enhanced hyt-induced protein degradation using lipid nanoparticle deliveryPublication Number: US-2023414723-A1Priority Date: 2020-10-26
Compounds for targeted degradation of brd9Publication Number: WO-2021178920-A1Priority Date: 2020-03-05
Compounds for targeted degradation of brd9Publication Number: US-2022098194-A1Priority Date: 2020-03-05
Compounds for targeted degradation of brd9Publication Number: US-2023060334-A1Priority Date: 2020-03-05
Compounds for targeted degradation of BRD9Publication Number: US-11691972-B2Priority Date: 2020-03-05Grant Date: 2023-07-04
Selected compounds for targeted degradation of brd9Publication Number: US-2024245677-A1Priority Date: 2021-09-09
Exosome-based cancer assaysPublication Number: US-11938164-B2Priority Date: 2021-04-07Grant Date: 2024-03-26
Exosome-based cancer assaysPublication Number: US-2022331390-A1Priority Date: 2021-04-07
Exosome-based cancer assaysPublication Number: WO-2022216765-A1Priority Date: 2021-04-07
Enhanced hyt-induced protein degradation using lipid nanoparticle deliveryPublication Number: WO-2022093809-A1Priority Date: 2020-10-26
Directed degron molecules and applications thereofPublication Number: WO-2023081400-A1Priority Date: 2021-11-04
Directed degron molecules and applications thereofPublication Number: WO-2023081400-A9Priority Date: 2021-11-04
Directed degron molecules and applications thereofPublication Number: EP-4426687-A1Priority Date: 2021-11-04
Selected compounds for targeted degradation of brd9Publication Number: WO-2023039208-A1Priority Date: 2021-09-09
Selected compounds for targeted degradation of brd9Publication Number: EP-4398904-A1Priority Date: 2021-09-09

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/////////Sendegobresib, antineoplastic, AW8PEP3VZ3, CFT 8634, ORPHAN DRUG

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SYN

Example 25

Example 25A

(S)-(3,4-dihydro-2H-pyran-2-yl)methanol

Example 25B

(S)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran

Example 25C

(3R,6S)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol

Example 25D

(2S,5R)-2-((benzyloxy)methyl)-5-methoxytetrahydro-2H-pyran

Example 25E

((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate

Example 25F

(2S,5R)-2-(azidomethyl)-5-methoxytetrahydro-2H-pyran

Example 25G

4-((((2S,5R)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide

Example 25H

7,7-dimethyl-4,6,7,8-tetrahydro-2H,5H-1,3-benzodioxin-5-one

Example 251

4′-chloro-2-(hydroxymethyl)-5,5-dimethyl-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one

Example 25J

4′-chloro-2-(chloromethyl)-5,5-dimethyl-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one

Example 25K

(R)-4′-chloro-2-(chloromethyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-3-ol

Example 25L

tert-butyl (S)-4-(((R)-4′-chloro-3-hydroxy-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-3-(hydroxymethyl)piperazine-1-carboxylate

Example 25M

tert-butyl (4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecine-3(4H)-carboxylate

Example 25N

(4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,3,4,4a,5,7,8,9,10a,11,12,13,15-tetradecahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecine

Example 250

ethyl 2-bromo-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H,7H,15H)-yl)benzoate

Example 25P

5-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide

Example 25Q

5-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine

Example 25R

5-bromo-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine

Example 25S

N-(3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide

Example 25T

1-tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepane

Example 25U

7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepane

Example 25V

ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H,7H,15H)-yl)-2-(7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate

Example 25W

ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H, 7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate

Example 25X

4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H,7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoic acid

Example 25Y

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