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Delocamten

April 30, 2026 2:33 am / Leave a comment

Delocamten

CAS 2417411-02-8

MFC19H21F2N3O3 MW377.4 g/mol

Pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, 6-fluoro-7-(2-fluoro-5-methylphenyl)-5,6,7,8-tetrahydro-3-(tetrahydro-2H-pyran-4-yl)-, (6S,7S)-

(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(oxan-4-yl)-5,6,7,8-tetrahydro-1H-pyrido[2,3-d]pyrimidine-2,4-dione

(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(oxan-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
cardiac myosin inhibitor, MYK-224; BMS-986435, MYK 224, BMS 986435, IE5886BN8T

Delocamten (development code MYK-224) is a small-molecule cardiac myosin inhibitor developed by Bristol Myers Squibb for hypertrophic cardiomyopathy.^[1][2][3]

Delocamten is a small molecule drug. Delocamten is under investigation in clinical trial NCT06122779 (Study to Evaluate Safety, Tolerability and Drug Levels of BMS-986435/MYK-224 in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF)). Delocamten has a monoisotopic molecular weight of 377.16 Da.

SYN

US20250282779,

Example 1-3: Preparation of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2, 4 (1H, 3H)-dione (3)

Step 7. Synthesis of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2, 4 (1H, 3H)-dione (3). A mixture of crude 3G (1.0 g, 2.53 mmol) in CH ₃CN (15 mL) was put into a microwave reactor with stirring at 120° C. for 30 min. Subsequently, the mixture was concentrated and the residue was purified by preparative HPLC (column: C18 silica gel; mobile phase: CH3CN:H ₂O=20:80 (v v) increasing to CH3CN:H ₂O=80:20 (v v) within 40 min; detector: UV 254 nm) to give compound 3 (302 mg, 32%), as a white solid, which was identified as Form 1 polymorph (see Example 2). LC-MS (ES, m/z): 378 [M+H] ⁺; ¹H NMR (300 MHz, d-DMSO): δ 10.20 (s, 1H), 7.38-7.05 (m, 3H), 6.45 (s, 1H), 5.11-4.81 (m, 3H), 3.89 (dd, J=10.8, 3.9 Hz, 2H), 3.34-3.27 (m, 3H), 2.76-2.48 (m, 4H), 2.28 (s, 3H), 1.39-1.36 (m, 2H); ¹⁹F NMR (376 MHz, d ⁶-DMSO): δ −123.51 (t, J=86.5 Hz), −191.57 (d, J=129.34 Hz).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020092208&_cid=P10-MOKV4B-54959-1

Example 1-3: Preparation of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3- (tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2, 4 (1H, 3H)-dione (3).

Scheme 3

[0165] Step 1. Synthesis of (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfinamide (3B). The reaction mixture was filtered and the filtrate was diluted with ether (150 mL). Subsequently, the resulting suspension was filtered. The filtrate was concentrated and the residue was dried in vacuo to give 3B (8.7 g, 97%) as a yellow oil. LC-MS (ES, m/z): 242 [M+H] ⁺ ; ¹ H NMR (400 MHz, d ⁶ -DMSO): d 8.87 (s, 1H), 7.76 (m, 1H), 7.29 (m, 1H), 7.03 (m, 1H), 2.37 (d, J = 1.0 Hz, 3H), 1.27 (s, 9H).

[0166] Step 2. Synthesis of ethyl (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(2-fluoro-5-methylphenyl)propanoate (3C). To a solution of 3B (4 g, 16.6 mmol), ethyl 2- fluoroacetate (2.6 g, 24.6 mmol), and TMEDA (4.8 mL) in anhydrous THF (40 mL) was added LiHMDS (1 M in THF, 24.6 mL, 24.6 mmol) dropwise at -78 ^o C over 30 min under an atmosphere of Ar. After stirring at -78 ^o C for 1 h, the reaction was quenched by adding 1 N aq.

HCl (50 mL), while maintaining the inner temperature of the mixture at < -20 ^o C. Subsequently, the mixture was concentrated to remove most of the organic solvent and then extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (100 mL) and dried over anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to give crude 3C (6.0 g) as a yellow oil, which was used for the next step without further purification. LC-MS (ES, m/z): 348 [M+H] ⁺ .

[0167] Step 3. Synthesis of (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(2-fluoro-5-methylphenyl)propanoic acid (3D). To a solution of 3C (6.0 g, 17.3 mmol) in THF (40 mL) was added 1N aq. NaOH (34.6 mL, 34.6 mmol) at rt. After stirring at rt for 1 h, the reaction mixture was added ice water (50 mL). The resulting mixture was extracted with EtOAc (100 mL x 2). The aqueous layer was adjusted to pH 5 with sat. aq. citric acid, followed by extraction with EtOAc (100 mL x 3). Subsequently, the combined organic extracts were washed with brine (100 mL) and dried over anhydrous Na ₂ SO ₄ . The solvent was removed and the residue was purified by preparative HPLC (Column: LC-MS (ES, m/z): 320 [M+H] ⁺ ; ¹ H NMR (400 MHz, d ⁶ -DMSO): d 13.57 (br, 1H), 7.55 (dd, J = 7.5, 2.2 Hz, 1H), 7.23– 6.94 (m, 2H), 6.04 (d, J = 10.8 Hz, 1H), 5.37– 4.86 (m, 2H), 2.29 (s, 3H), 1.12 (s, 9H).

[0168] Step 4. Synthesis of (R)-N-((1S,2R)-2-fluoro-1-(2-fluoro-5-methylphenyl)-3-oxo-3- (2,4,6-trioxo-1-(tetrahydro-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylpropane-2-sulfinamide (3E). A solution of 3D (700 mg, 2.19 mmol), 2-2 (698 mg, 3.29 mmol), and HATU (1.25 g, 3.29 mmol) in DMF (10 mL) was added DIEA (849 mg, 6.57 mmol) at 0 ^o C under an atmosphere of Ar. aq. sodium bicarbonate (30 mL) and the resulting solution was extracted with ethyl acetate (50 mL x3). The combined organic extracts were washed with brine (50 mL x 2) and dried over anhydrous Na ₂ SO ₄ . The solvent was removed and the residue was dried in vacuo to give crude 3E (1.3 g) as a white solid, which was used for the next step without further purification. LC-MS (ES, m/z): 514 [M+H] ⁺ ; ¹ H NMR (400 MHz, d ⁶ -DMSO): d 12.16 (br, 1H), 7.66– 7.45 (m, 1H), 7.23– 6.98 (m, 2H), 6.37 (m, 1H), 6.13 (d, J = 10.7 Hz, 1H), 5.22 (m, 1H), 4.79 (m, 1H), 3.94 (m, 2H), 3.35 (t, J = 11.7 Hz, 2H), 2.52– 2.39 (m, 2H), 2.29 (s, 3H), 1.49 (d, J = 12.2 Hz, 2H), 1.04 (s, 9H).

[0169] Step 5. Synthesis of (R)-N-((1S,2S)-2-fluoro-1-(2-fluoro-5-methylphenyl)-3-(2,4,6- trioxo-1-(tetrahydro-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylpropane-2-sulfinamide (3F). A solution of crude 3E (1.3 g, 2.53 mmol) in AcOH (10 mL) was added NaBH3CN (398 mg, 6.33 mmol) at 0 ^o C under an atmosphere of Ar. After stirring at rt for 1 h, the reaction mixture was added ice water (20 mL) and the resulting solution was extracted with EtOAc (50 mL x 3). Next, the combined organic extracts were washed with brine (50 mL) and

dried over anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to give crude 3F (1.3 g) as a white solid, which was used for the next step without further purification. LC-MS (ES, m/z): 500 [M+H] ⁺ ; ¹ H NMR (400 MHz, d ⁶ -DMSO): d 11.31 (d, J = 28.1 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 7.27– 6.84 (m, 2H), 6.11– 5.78 (m, 2H), 5.08– 4.43 (m, 3H), 3.87 (m, 3H), 2.29 (s, 6H), 1.99 (s, 1H), 1.53– 1.28 (m, 2H), 1.10 (d, J = 2.1 Hz, 10H).

[0170] Step 6. Synthesis of 5-((2S,3S)-3-amino-2-fluoro-3-(2-fluoro-5-methylphenyl)propyl)-1-(tetrahydro-2H-pyran-4-yl)pyrimidine-2, 4, 6 (1H, 3H, 5H)-trione (3G). A solution of crude 3F (1.3 g, 2.60 mmol) in ethanol (10 mL) was added thionyl chloride (334 mg) at 0 ^o C. After stirring at rt for 1 h, the reaction mixture was concentrated and the residue was dried in vacuo to give crude 3G (1.0 g) as a white solid, which was used for the next step without further purification. LC-MS (ES, m/z): 396 [M+H] ⁺ .

[0171] Step 7. Synthesis of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2, 4 (1H, 3H)-dione (3). A mixture of crude 3G (1.0 g, 2.53 mmol) in CH ₃ CN (15 mL) was put into a microwave reactor with stirring at 120 ^o C for 30 min. Subsequently, the mixture was concentrated and the residue was purified by preparative HPLC (column: C18 silica gel; mobile phase: CH3CN:H2O = 20:80 (v/v) increasing to CH3CN:H2O = 80:20 (v/v) within 40 min; detector: UV 254 nm) to give compound 3 (302 mg, 32%), as a white solid, which was identified as Form 1 polymorph (see Example 2). LC-MS (ES, m/z): 378 [M+H] ⁺ ; ¹ H NMR (300 MHz, d ⁶ -DMSO): d 10.20 (s, 1H), 7.38– 7.05 (m, 3H), 6.45 (s,1H), 5.11– 4.81 (m, 3H), 3.89 (dd, J = 10.8, 3.9 Hz, 2H), 3.34– 3.27 (m, 3H), 2.76–2.48 (m, 4H), 2.28 (s, 3H), 1.39–1.36 (m, 2H); ¹⁹ F NMR (376 MHz, d ⁶ -DMSO): d -123.51 (t, J = 86.5 Hz), -191.57 (d, J = 129.34 Hz).

PAT

Tetrahydropyran (thp)-substituted bicyclic-pyrimidinedione compoundsPublication Number: EP-4464321-A2Priority Date: 2018-10-29
Tetrahydropyran-substituted bicyclic pyrimidinedione compounds (THP)Publication Number: ES-2986923-T3Priority Date: 2018-10-29Grant Date: 2024-11-13
Substituted 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4-diones for treating cardiac diseasesPublication Number: US-2024025894-A1Priority Date: 2018-10-29
Substituted 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4-diones for treating cardiac diseasesPublication Number: US-12344607-B2Priority Date: 2018-10-29Grant Date: 2025-07-01
Substituted 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4-diones for treating cardiac diseasesPublication Number: US-2025282779-A1Priority Date: 2018-10-29
Tetrahydropyran (THP) Substituted Bicyclic Pyrimidinedione CompoundsPublication Number: CN-113056465-APriority Date: 2018-10-29
Tetrahydropyrane (THP) -substituted bicyclic pyrimidinedione compoundsPublication Number: CN-119977963-APriority Date: 2018-10-29
Tetrahydropyran (thp)-substituted bicyclic-pyrimidinedione compoundsPublication Number: EP-3873904-B1Priority Date: 2018-10-29Grant Date: 2024-07-10
Substituted 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4-diones for treating cardiac diseasesPublication Number: US-11034693-B2Priority Date: 2018-10-29Grant Date: 2021-06-15
Substituted 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4-diones for treating cardiac diseasesPublication Number: US-2022106314-A1Priority Date: 2018-10-29
Tetrahydropyran (THP)-Substituted Bicyclic-Pyrimidinedione CompoundsPublication Number: JP-2024063091-APriority Date: 2018-10-29
Tetrahydropyran (thp)-substituted bicyclic-pyrimidinedione compoundsPublication Number: TW-202426449-APriority Date: 2018-10-29
Tetrahydropyrane (THP) -substituted bicyclic pyrimidinedione compoundsPublication Number: CN-113056465-BPriority Date: 2018-10-29Grant Date: 2025-01-28
Tetrahydropyran (thp)-substituted bicyclic-pyrimidinedione compoundsPublication Number: US-2020165247-A1Priority Date: 2018-10-29
BICYCLIC PYRIMIDINODIONA COMPOUNDS REPLACED WITH TETRAHYDROPYRAN, POLYMORPHIC FORM OF THE SAME AND THE USE OF THE SAME FOR THE TREATMENT OF HCMPublication Number: AR-116880-A1Priority Date: 2018-10-29
Substituted 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4-diones for treating cardiac diseasesPublication Number: US-2022340569-A1Priority Date: 2018-10-29
Tetrahydropyran (thp)-substituted bicyclic-pyrimidinedione compoundsPublication Number: EP-3873904-A1Priority Date: 2018-10-29
CRYSTALLINE FORMS OF (6S,7S)-6-FLUORO-7-(2-FLUORO-5-METHYLPHENYL)- 3-(TETRAHYDRO-2H-PYRAN-4-YL)-5,6,7,8-TETRAHYDROPYRIDO[2,3- d]PYRIMIDINE-2,4(1H,3H)-DIONEPublication Number: WO-2024026058-A8Priority Date: 2022-07-29
Crystalline forms of (6s,7s)-6-fluoro-7-(2-fluoro-5-methylphenyl)- 3-(tetrahydro-2h-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidine-2,4(1h,3h)-dionePublication Number: EP-4561697-A1Priority Date: 2022-07-29
Methods of Administering Myosin InhibitorsPublication Number: US-2023338378-A1Priority Date: 2022-04-26
Methods of treatment with myosin modulatorPublication Number: US-2023158027-A1Priority Date: 2019-11-10
tetrahydropyran-substituted bicyclic pyrimidinedione compounds (thp)Publication Number: BR-112021008077-A2Priority Date: 2018-10-29
CRYSTALLINE FORMS OF (6S,7S)-6-FLUORO-7-(2-FLUORO-5-METHYLPHENYL)-3-(TETRAHYDRO-2H-PYRAN-4-YL)-5,6,7,8-TETRAHYDROPYRIDO[2,3-d]PYRIMIDINE-2,4(1H,3H)-DIONEPublication Number: US-2025034129-A1Priority Date: 2023-07-28
CRYSTALLINE FORMS OF (6S,7S)-6-FLUORO-7-(2-FLUORO-5-METHYLPHENYL)-3-(TETRAHYDRO-2H-PYRANO-4-IL)-5,6,7,8-TETRAHYDROPYRIDE[2 ,3-D]PYRIMIDINE-2,4(1H,3H)-DIONEPublication Number: AR-130058-A1Priority Date: 2022-07-29
Crystalline forms of (6s,7s)-6-fluoro-7-(2-fluoro-5-methylphenyl)- 3-(tetrahydro-2h-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidine-2,4(lh,3h)-dionePublication Number: WO-2024026058-A1Priority Date: 2022-07-29
Crystalline form of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionePublication Number: CN-119855816-APriority Date: 2022-07-29
Crystalline forms of (6s,7s)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2h-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1h,3h)-dionePublication Number: TW-202412788-APriority Date: 2022-07-29

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References

Lehman, Sarah J.; Crocini, Claudia; Leinwand, Leslie A. (June 2022). “Targeting the sarcomere in inherited cardiomyopathies”. Nature Reviews Cardiology. 19 (6): 353–363. doi:10.1038/s41569-022-00682-0. ISSN 1759-5010. PMC 9119933. PMID 35304599.
Sebastian, Sneha Annie; Padda, Inderbir; Lehr, Eric J.; Johal, Gurpreet (September 2023). “Aficamten: A Breakthrough Therapy for Symptomatic Obstructive Hypertrophic Cardiomyopathy”. American Journal of Cardiovascular Drugs. 23 (5): 519–532. doi:10.1007/s40256-023-00599-0. PMID 37526885. S2CID 260348901.
Packard, Elizabeth; de Feria, Alejandro; Peshin, Supriya; Reza, Nosheen; Owens, Anjali Tiku (December 2022). “Contemporary Therapies and Future Directions in the Management of Hypertrophic Cardiomyopathy”. Cardiology and Therapy. 11 (4): 491–507. doi:10.1007/s40119-022-00283-5. PMC 9652179. PMID 36243823.

////////delocamten, ANAX LAB, cardiac myosin inhibitor, MYK-224; BMS-986435, MYK 224, BMS 986435, IE5886BN8T

Ulacamten

March 20, 2026 2:42 am / Leave a comment

Ulacamten

CAS 2830607-59-3

MF C21H25F2N3O3 MW405.4 g/mol

5-[(3,4-difluorophenyl)methyl]-8-(4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde

5-[(3,4-difluorophenyl)methyl]-8-[(1r,4r)-4-methylcyclohexyl]-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde
cardiac myosin inhibitor, CK-586, CK-4021586, CK 586, CK 4021586, X325G97HZJ

Ulacamten (also known as CK-586 or CK-4021586) is an investigational drug developed by Cytokinetics that acts as a cardiac myosin inhibitor (CMI). It is currently being studied for the treatment of heart failure with preserved ejection fraction (HFpEF), a condition where the heart muscle is too stiff to fill properly

Key Characteristics and Development

Mechanism of Action: Unlike earlier CMIs like mavacamten or aficamten, ulacamten is highly selective. It binds to the regulatory light chain (RLC) of myosin and only inhibits the “two-headed” form of cardiac myosin, potentially allowing for more precise control over heart muscle contraction.
Clinical Status: As of March 2026, it is in Phase 2 clinical trials (specifically the AMBER-HFpEF study) to evaluate its safety, tolerability, and optimal dosage in patients with symptomatic HFpEF.
Administration: It is designed as an orally active small molecule intended for once-daily dosing.
Potential Benefits: Preclinical studies suggest it can reduce excessive myocardial contractility and improve left ventricular relaxation (diastolic function) without significantly compromising the heart’s overall pumping ability.

AMBER-HFpEF: Assessment of CK-4021586 in a Multi-Center, Blinded Evaluation of Safety and Tolerability Results in HFpEFCTID: NCT06793371Phase: Phase 2Status: RecruitingDate: 2026-01-12
A Single and Multiple Ascending Dose Study of CK-4021586 in Healthy Adult ParticipantsCTID: NCT05877053Phase: Phase 1Status: CompletedDate: 2025-05-01

SYN

compound 4 [WO2022187501A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022187501&_cid=P12-MMYAAW-13612-1

Example 1

Synthesis of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde

(Compound 4)

Step 1: Synthesis of 1-(tert-butyl) 3-ethyl 3-((3,4-difluorobenzyl)amino)azetidine-1,3-dicarboxylate:

[0147] To a solution of 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (4.0 g, 16.4 mmol, 1.0 equiv) and 3,4-difluorobenzaldehyde (2.4 g, 19.6 mmol, 1.2 equiv) in DCE (40.0 mL) at 0 ˚C were added STAB (7.0 g, 32.8 mmol, 2.0 equiv) and AcOH (2.0 g, 32.8 mmol, 2.0 equiv). The resulting mixture was stirred at rt overnight, adjusted the pH to 8 with ammonium hydroxide, added water (50.0 mL) and extracted with DCM (50.0 mL) twice. The combined organic layers were washed with brine (50 mL) twice, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to afford 6.0 g of 1-tert-butyl 3-ethyl 3-(3,4-difluorobenzyl)amino)azetidine-1,3-dicarboxylate as a yellow oil. LRMS (ES) m/z 315 (M+H-56).

Step 2: Synthesis of 1-(tert-butyl) 3-ethyl 3-(2-bromo-N-(3,4-difluorobenzyl)acetamido)azetidine-1,3-dicarboxylate:

[0148] To a solution of 1-tert-butyl 3-ethyl 3-[[(3,4-difluorophenyl)methyl]amino]azetidine-1,3-dicarboxylate (6.0 g, 16.2 mmol, 1.0 equiv) in DCM (60.0 mL) at 0 ˚C were added a solution of K ₂ CO ₃ (3.4 g, 24.3 mmol, 1.50 equiv) in water (30 mL), and then bromoacetyl bromide (3.9 g, 19.4 mmol, 1.2 equiv) dropwise over a period of 10 min. The resulting mixture was stirred at rt overnight and extracted with DCM (50.0 mL) twice. The combined organic layers were washed with brine (100 mL) twice, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to afford 8.0 g of 1-(tert-butyl) 3-ethyl 3-(2-bromo-N-(3,4-difluorobenzyl)acetamido)azetidine-1,3-dicarboxylate as a yellow oil. LRMS (ES) m/z 435 (M+H-56).

Step 3: Synthesis of tert-butyl 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate:

[0149] To a solution of 1-(tert-butyl) 3-ethyl 3-(2-bromo-N-(3,4-difluorobenzyl)acetamido)azetidine-1,3-dicarboxylate (8.0 g, 16.3 mmol, 1.0 equiv) in ACN (80 mL) were added TEA (4.9 g, 48.4 mmol, 3.0 equiv) and trans-(1r,4r)-4-methylcyclohexan-1-amine (2.8 g, 24.7 mmol, 1.5 equiv). The resulting mixture was stirred at rt for 1 h, gradually warmed to 80 ˚C, and stirred at 80 ˚C overnight. The mixture was cooled to rt, concentrated under reduced pressure, and triturated with a mixture of PE and EA (7/1; 80 mL) to afford 7 g (~80% purity) of tert-butyl 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate as an off-white solid. LRMS (ES) m/z 422 (M+H-56).

Step 4: Synthesis of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione:

[0150] To a stirred solution of tert-butyl 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate (7.0 g, 14.7 mmol, 1.0 equiv) in DCM (70.0 mL) was added TFA (18.0 mL). The resulting mixture was stirred at rt for 3h, diluted with water (100.0 mL), adjusted the pH to 13-14 with aqueous NaOH solution (2 N), and extracted with DCM (100 mL) twice. The combined organic layers were washed with brine (100.0 mL) twice, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to afford 4.5 g (~80% purity) of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-2,5,8-triazaspiro[3.5]nonane-6,9-dione as a yellow semi-solid. LRMS (ES) m/z 378 (M+H).

Step 5: Synthesis of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde (Compound 4):

[0151] A solution of tert-butyl 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate (1.5 g, 4.0 mmol, 1.0 equiv) in ethyl formate (15.0 mL) was stirred at 80
^o C overnight. The mixture was cooled to rt, concentrated under reduced pressure, and purified by C18 column chromatography, eluted with a mixture of water (0.05% NH
₄ HCO
₃ )/CH
₃ CN (3:2) to afford 1.3 g (81%) of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde as an amorphous white solid. An experimental X-ray powder diffraction (XRPD) pattern of this amorphous white solid is shown in FIG. 1 LRMS (ES) m/z 406 (M+H);
¹ H NMR (300 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.47 – 7.29 (m, 2H), 7.10 (ddd, J = 9.4, 4.4, 2.0 Hz, 1H), 4.82 (s, 2H), 4.50 (d, J = 9.6 Hz, 1H), 4.15-4.28 (m, J = 3H), 4.01 (s, 2H), 3.96 (d, J = 10.8 Hz, 1H), 1.80 – 1.69 (m, 2H), 1.65 – 1.48 (m, 4H), 1.35 (d, J = 10.9 Hz, 1H), 1.13 – 0.93 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=EP459206402&_cid=P12-MMYAID-19733-1

5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde, also called compound 1, having the structure shown below,

Example 1

Synthesis of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde (Compound 1)

Step 6: Synthesis of 5-[(3,4-difluorophenyl)methyl]-6,9-dioxo-8-[(1r,4r)-4-methylcyclohexyl]-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde (Compound 1):

[0165] To a solution of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde (4.0 kg, 10.60 mol, 1 equiv) in MeCN (20 L) at r.t. were added 2,2,2-trifluoroethyl formate (1.63 kg, 12.72 mol, 1.2 equiv) and DIPEA (3.42 kg, 26.50 mol, 2.5 equiv) . The resulting mixture was stirred overnight at rt. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (10 L). The resulting mixture was quenched with NH ₄Cl (6 L, sat.) and water (6 L), extracted with EtOAc (3×15 L). The combined organic layers were washed with NH ₄Cl (aq.) (10 L) and brine (10 L), dried over anhydrous Na ₂SO ₄, concentrated under reduced pressure to give a crude brown oil, the crude oil was re-crystallized from cyclohexane and EtOAc (5:1, 4L, 80 °C to r.t.), filtered to afford 3 kg (1 ^st batch) 5-[(3,4-difluorophenyl)methyl]-6,9-dioxo-8-[(1r,4r)-4-methylcyclohexyl]-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde light yellow solid. The filtrate was concentrated under reduced pressure, re-crystallized with petroleum ether and EtOAc (10:1, 3 L, rt) to afford 800 g (2 ^nd batch) of light yellow solid. Two batches were combined, dried to afford 3.8 kg of Form I (m.p. at 133 °C) 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde light yellow solid. The overall yield of this step is 97%.

PAT

Cardiac sarcomere inhibitorsPublication Number: US-12286437-B2Priority Date: 2021-03-04Grant Date: 2025-04-29
Cardiac sarcomere inhibitorsPublication Number: US-11919909-B2Priority Date: 2021-03-04Grant Date: 2024-03-05
Cardiac sarcomere inhibitorsPublication Number: US-2024309011-A1Priority Date: 2021-03-04
Cardiac sarcomere inhibitorsPublication Number: WO-2022187501-A1Priority Date: 2021-03-04
Cardiac sarcomere inhibitorsPublication Number: US-2022306642-A1Priority Date: 2021-03-04
cardiac sarcomere inhibitorPublication Number: CN-117083275-APriority Date: 2021-03-04
Cardiac sarcomere inhibitorsPublication Number: EP-4301760-A1Priority Date: 2021-03-04
Crystalline forms of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehydePublication Number: US-2024132498-A1Priority Date: 2022-09-02
Crystalline forms of 5- (3, 4-difluorobenzyl) -8- ((1 r,4 r) -4-methylcyclohexyl) -6, 9-dioxo-2, 5, 8-triazaspiro [3.5] nonane-2-carbaldehydePublication Number: CN-119998292-APriority Date: 2022-09-02
Crystalline forms of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehydePublication Number: WO-2024050539-A1Priority Date: 2022-09-02
Crystalline forms of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehydePublication Number: EP-4581034-A1Priority Date: 2022-09-02
Cardiac sarcomere inhibitorsPublication Number: TW-202302594-APriority Date: 2021-03-04

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REF

Cardiac myosin inhibitor, CK-586, minimally reduces systolic function and ameliorates obstruction in feline hypertrophic cardiomyopathy

Publication Name: Scientific Reports

Publication Date: 2024-05-27

PMCID: PMC11130313

PMID: 38802475

DOI: 10.1038/s41598-024-62840-3

///////////////ulacamten, ANAX, cardiac myosin inhibitor, CK-586, CK-4021586, CK 586, CK 4021586, X325G97HZJ

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