Sosimerasib

Cas 2839563-01-6

MF C36H39ClFN7O4 MW688.2 g/mol

• (2R,4aR,8M)-11-chloro-6-[2-(dimethylamino)ethyl]-10-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-3-(prop-2-enoyl)-2,3,4,4a,6,8-hexahydro-1Hpyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
• (4R,7R)-16-chloro-9-[2-(dimethylamino)ethyl]-15-(2-fluoro-6-hydroxyphenyl)-4-methyl-12-(4-methyl-2-propan-2-yl-3-pyridinyl)-5-prop-2-enoyl-2,5,9,12,14-pentazatetracyclo[8.8.0.02,7.013,18]octadeca-1(10),13,15,17-tetraene-8,11-dione
• 1H-Pyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione, 11-chloro-6-[2-(dimethylamino)ethyl]-10-(2-fluoro-6-hydroxyphenyl)-2,3,4,4a,6,8-hexahydro-2-methyl-8-[4-methyl-2-(1-methylethyl)-3-pyridinyl]-3-(1-oxo-2-propen-1-yl)-, (2R,4aR,8R)-

(4R,7R)-16-chloro-9-[2-(dimethylamino)ethyl]-15-(2-fluoro-6-hydroxyphenyl)-4-methyl-12-(4-methyl-2-propan-2-yl-3-pyridinyl)-5-prop-2-enoyl-2,5,9,12,14-pentazatetracyclo[8.8.0.0^2,7.0^13,18]octadeca-1(10),13,15,17-tetraene-8,11-dione

(2R,4aR,8M)-11-chloro-6-[2-(dimethylamino)ethyl]-10-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-3-(prop-2-enoyl)-2,3,4,4a,6,8-hexahydro-1Hpyrazino[1′,2′:4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
Kirsten rat sarcoma viral oncogene homolog inhibitor, antineoplastic, HBI-2438, JMKX1899, HBI 2438, JMKX 1899, 2VHH89PP6W

Sosimerasib is an orally active KRAS^G12C inhibitor. Sosimerasib can be used in research related to non-small cell lung cancer.

Sosimerasib (also known as HBI-2438 or JMKX1899) is an orally active, covalent small molecule inhibitor that targets the KRAS G12C mutation. Developed natively in China, it secured conditional marketing approval from the National Medical Products Administration (NMPA) in February 2026, making it China’s first domestically discovered and registered KRAS G12C inhibitor.

The drug is designed to selectively lock the mutant KRAS protein in its inactive, GDP-bound state, preventing downstream oncogenic signaling pathways that drive tumor growth.

Mechanism and Clinical Indications

Sosimerasib specifically binds to the cysteine residue at position 12 of the mutated KRAS protein. It has shown distinct clinical advantages, including central nervous system (CNS) penetration, which makes it effective against brain metastases. Its primary therapeutic applications include:

• Non-Small Cell Lung Cancer (NSCLC): It is indicated for patients with locally advanced or metastatic non-squamous NSCLC harboring the KRAS G12C mutation, particularly those who have progressed after receiving standard platinum-based chemotherapy or immune checkpoint inhibitors.
• Colorectal Cancer (CRC) and Solid Tumors: It is being clinically evaluated as a monotherapy or combination treatment for other advanced solid tumors, showing promising anti-tumor activity in KRAS G12C-mutated colorectal cancer.

Efficacy Data

Data presented across recent oncology conferences highlight substantial therapeutic efficacy:

• NSCLC Outcomes: In a pivotal Phase II trial involving 145 previously treated patients, a once-daily 500 mg dose of sosimerasib achieved an Objective Response Rate (ORR) of 52.4% and a Disease Control Rate (DCR) of 87.6%. The median progression-free survival (PFS) was documented at 7.2 months.
• Colorectal Cancer Outcomes: Data from the 2026 ASCO Annual Meeting for advanced CRC patients demonstrated a confirmed ORR of 31.6% and a median PFS of 8.3 months.

Safety and Side Effects

Sosimerasib possesses a manageable safety profile, with rare occurrences of treatment discontinuations (around 1.8% to 2.1%) due to toxicity. The most common treatment-related adverse events (TRAEs) include:

• Elevated liver enzymes (Alanine aminotransferase/ALT and Aspartate aminotransferase/AST increases)
• Anaemia
• Decreased white blood cell count or elevated gamma-glutamyl transferase

Commercial and Development Background

The compound was originally discovered by Shanghai Jiyu Pharmaceutical Technology. It is being co-developed and commercialized through partnerships with HUYA Bioscience International (Huyabio) and Zhejiang Hangyu Pharmaceutical. Within the Chinese market, it joins foreign-developed alternatives like sotorasib (Amgen) and adagrasib (Bristol Myers Squibb), marking a major milestone for independent biomedical innovation in the region. Ongoing Phase III trials are evaluating sosimerasib in combination regimens (such as with the FAK inhibitor IN10018) as a first-line treatment option.

PAT

[US20220389029]

https://patentscope.wipo.int/search/en/detail.jsf?docId=US380594568&_cid=P20-MUT7JP-65582-1

Embodiment 29: Preparation of Compound 29

Step 1: Preparation of Compound 29-1

Compound 25-3 (700 mg, 1 mmol) and cesium carbonate (977 mg, 3 mmol) were dissolved in N,N-dimethylformamide (20 mL), and compound 26-1 (432 mg, 3 mmol) was added thereto at room temperature (25° C.). After the addition was completed, under nitrogen atmosphere, the system was heated to 120° C. and stirred for 2 hours. The system was filtered and concentrated to obtain a crude product, the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=1/10) to obtain compound 29-1.

MS (ESI) m/z (M+H) +=778.2.

Step 2: Preparation of Compound 29-2

Compound 29-1 (150 mg, 0.2 mmol), hydrochloric acid (6N, 7 mL) were added to a mixed solution of methanol (0.6 mL) and tetrahydrofuran (6 mL). The system was heated to 55° C. and stirred for 10 min. The system was concentrated to obtain crude product compound 29-2, which was directly used in the next reaction without further purification.

MS (ESI) m/z (M+H) +=634.2.

Step 3: Preparation of Compound 29

Compound 29-2 (140 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL), and the system was cooled to 0° C., triethylamine (0.3 mL, 2.1 mmol) and acryloyl chloride (27 mg, 0.3 mmol) were added dropwise thereto, the reaction was carried out at 0° C. for 0.5 hours. The system was quenched with methanol and then concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), potassium carbonate (140 mg) was added thereto, after the addition was completed, the system was stirred at room temperature (20° C.) for 30 min. The pH of the system was adjusted to 6 with hydrochloric acid, the mixture was extracted with dichloromethane (20 mL) and water (20 mL); and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, the crude product was purified by high performance liquid chromatography (separation conditions: chromatographic column Welch Xtimate® C18 21.2×250 mm, 10 μm; column temperature: 25° C., mobile phase: water (10 mM/L NH 4HCO 3)-acetonitrile; acetonitrile 40%-60% 9 min; flow rate 30 mL/min) to obtain compound 29.

MS (ESI) m/z (M+H) +=688.2.

Step 4: Preparation of Compounds 29A and 29B

Diastereoisomeric compound 29 was purified by SFC («Column_3»; mobile phase: [CO 2-ethanol (0.1% ammonia)]; ethanol %: 25%; flow rate: 60 mL/min; column temperature: 38° C.). After concentration, compound 29A and compound 29B were obtained.

Compound 29A:

1H NMR (400 MHz, DMSO-d 6) δ 10.06 (brs, 1H), 8.37 (d, J=4.9 Hz, 1H), 8.18 (s, 1H), 7.29-7.05 (m, 2H), 6.97 (dd, J=16.8, 10.6 Hz, 0.75H), 6.79 (dd, J=16.7, 10.7 Hz, 0.25H), 6.69-6.46 (m, 2H), 6.07 (dd, J=16.8, 2.5 Hz, 1H), 5.68 (dd, J=10.5, 2.4 Hz, 1H), 4.95 (d, J=13.9 Hz, 0.25H), 4.82-4.66 (m, 0.75H), 4.54 (d, J=14.0 Hz, 1H), 4.40-4.12 (m, 2H), 3.94 (dd, J=20.5, 4.4 Hz, 1H), 3.68 (dd, J=14.2, 4.4 Hz, 1H), 3.14-2.90 (m, 1H), 2.43-2.34 (m, 2H), 2.27-2.08 (m, 2H), 1.97-1.82 (m, 9H), 1.56-1.45 (m, 3H), 0.97 (dd, J=6.6, 2.2 Hz, 3H), 0.78 (t, J=6.0 Hz, 3H).

MS (ESI) m/z (M+H) +=688.3.

SFC 100% ee. Retention time was 3.559 min.

Separation conditions: chromatographic column: «Column_2»; mobile phase: [CO 2-ethanol (0.05% DEA)]; ethanol %: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min; column temperature: 35° C.

Compound 29B:

1H NMR (400 MHz, DMSO-d 6) δ 10.18 (brs, 1H), 8.45 (d, J=4.9 Hz, 1H), 8.26 (s, 1H), 7.29-7.20 (m, 2H), 7.04 (dd, J=16.8, 10.4 Hz, 0.75H), 6.86 (dd, J=17.6, 10.4 Hz, 0.25H), 6.72-6.60 (m, 2H), 6.14 (d, J=16.4 Hz, 1H), 5.75 (d, J=10.7 Hz, 1H), 5.03 (d, J=13.8 Hz, 0.25H), 4.80 (d, J=7.8 Hz, 0.75H), 4.61 (d, J=14.1 Hz, 1H), 4.43-4.30 (m, 1H), 4.28-4.15 (m, 1H), 4.04-3.89 (m, 1H), 3.75 (dd, J=14.5, 4.4 Hz, 1H), 3.28-3.10 (m, 2H), 2.75-2.65 (m, 1H), 2.39-2.28 (m, 1H), 2.28-2.17 (m, 1H), 2.06-1.96 (m, 6H), 1.81 (d, J=9.5 Hz, 3H), 1.53 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

MS (ESI) m/z (M+H) +=688.3.

HPLC retention time was 5.269 min.

Separation conditions: chromatographic column: Waters XBridge 4.6*100 mm, 3.5 μm; column temperature: 40° C.; mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL/min. SFC 100% ee. Retention time was 4.349 min.

Separation conditions: chromatographic column: «Column_2»; mobile phase: [CO 2-ethanol (0.05% DEA)]; ethanol %: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min; column temperature: 35° C.

PAT

US20230227472

https://patentscope.wipo.int/search/en/detail.jsf?docId=US402823590&_cid=P20-MUT7F9-60174-1

Step 3: Preparation of Compound 29

Compound 29-2 (140 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL), and the system was cooled to 0° C., triethylamine (0.3 mL, 2.1 mmol) and acryloyl chloride (27 mg, 0.3 mmol) were added dropwise thereto, the reaction was carried out at 0° C. for 0.5 hours. The system was quenched with methanol and then concentrated to obtain a crude product. The crude product was dissolved in methanol (5 mL), potassium carbonate (140 mg) was added thereto, after the addition was completed, the system was stirred at room temperature (20° C.) for 30 min. The pH of the system was adjusted to 6 with hydrochloric acid, the mixture was extracted with dichloromethane (20 mL) and water (20 mL); and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, the crude product was purified by high performance liquid chromatography (separation conditions: chromatographic column Welch Xtimate® C18 21.2×250 mm, 10 μm; column temperature: 25° C., mobile phase: water (10 mM/L NH 4HCO 3)-acetonitrile; acetonitrile 40%-60% 9 min; flow rate 30 mL/min) to obtain compound 29.

MS (ESI) m/z (M+H) +=688.2.

Step 4: Preparation of Compounds 29A and 29B

Diastereoisomeric compound 29 was purified by SFC («Column_3»; mobile phase: [CO 2-ethanol (0.1% ammonia)]; ethanol %: 25%; flow rate: 60 mL/min; column temperature: 38° C.). After concentration, compound 29A and compound 29B were obtained.

Compound 29A:

1H NMR (400 MHz, DMSO-d 6) δ 10.06 (brs, 1H), 8.37 (d, J=4.9 Hz, 1H), 8.18 (s, 1H), 7.29-7.05 (m, 2H), 6.97 (dd, J=16.8, 10.6 Hz, 0.75H), 6.79 (dd, J=16.7, 10.7 Hz, 0.25H), 6.69-6.46 (m, 2H), 6.07 (dd, J=16.8, 2.5 Hz, 1H), 5.68 (dd, J=10.5, 2.4 Hz, 1H), 4.95 (d, J=13.9 Hz, 0.25H), 4.82-4.66 (m, 0.75H), 4.54 (d, J=14.0 Hz, 1H), 4.40-4.12 (m, 2H), 3.94 (dd, J=20.5, 4.4 Hz, 1H), 3.68 (dd, J=14.2, 4.4 Hz, 1H), 3.14-2.90 (m, 1H), 2.43-2.34 (m, 2H), 2.27-2.08 (m, 2H), 1.97-1.82 (m, 9H), 1.56-1.45 (m, 3H), 0.97 (dd, J=6.6, 2.2 Hz, 3H), 0.78 (t, J=6.0 Hz, 3H).

MS (ESI) m/z (M+H) +=688.3.

SFC 100% ee. Retention time was 3.559 min.

Separation conditions: chromatographic column: «Column_2»; mobile phase: [CO 2-ethanol (0.05% DEA)]; ethanol %: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min; column temperature: 35° C.

Compound 29B:

1H NMR (400 MHz, DMSO-d 6) δ 10.18 (brs, 1H), 8.45 (d, J=4.9 Hz, 1H), 8.26 (s, 1H), 7.29-7.20 (m, 2H), 7.04 (dd, J=16.8, 10.4 Hz, 0.75H), 6.86 (dd, J=17.6, 10.4 Hz, 0.25H), 6.72-6.60 (m, 2H), 6.14 (d, J=16.4 Hz, 1H), 5.75 (d, J=10.7 Hz, 1H), 5.03 (d, J=13.8 Hz, 0.25H), 4.80 (d, J=7.8 Hz, 0.75H), 4.61 (d, J=14.1 Hz, 1H), 4.43-4.30 (m, 1H), 4.28-4.15 (m, 1H), 4.04-3.89 (m, 1H), 3.75 (dd, J=14.5, 4.4 Hz, 1H), 3.28-3.10 (m, 2H), 2.75-2.65 (m, 1H), 2.39-2.28 (m, 1H), 2.28-2.17 (m, 1H), 2.06-1.96 (m, 6H), 1.81 (d, J=9.5 Hz, 3H), 1.53 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

MS (ESI) m/z (M+H) +=688.3.

HPLC retention time was 5.269 min.

Separation conditions: chromatographic column: Waters XBridge 4.6*100 mm, 3.5 μm; column temperature: 40° C.; mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; acetonitrile: 5%-95% 7 min; flow rate: 1.2 mL/min. SFC 100% ee. Retention time was 4.349 min.

Separation conditions: chromatographic column: «Column_2»; mobile phase: [CO 2-ethanol (0.05% DEA)]; ethanol %: 5%-40% 5 min, 40% 2.5 min, 5% 2.5 min; flow rate: 2.5 mL/min; column temperature: 35° C.

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References

[1]. Jia Zhong, et al. Sosimerasib monotherapy in patients with previously treated KRAS G12C–mutated non-small cell lung cancer: Primary results of a phase 2 study. Journal of Clinical Oncology Volume 43, Number 16_suppl June 2025.

///////////sosimerasib, anax labs, Kirsten rat sarcoma viral oncogene homolog inhibitor, antineoplastic, HBI-2438, JMKX1899, HBI 2438, JMKX 1899, 2VHH89PP6W

#sosimerasib, #anax labs, #Kirsten rat sarcoma viral oncogene homolog inhibitor, #antineoplastic, #HBI-2438, #JMKX1899, #HBI 2438, #JMKX 1899, #2VHH89PP6W