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