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Preparation of Example 59: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-2-yl)-2- (3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5- tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
The title compound was prepared according to General Procedure D using 2-chloro-6-(trifluoromethyl)pyridine as the coupling partner. The experiment afforded the title compound, N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. The sample was analyzed using LCMS Method F: retention time = 1.51 min.; observed ion = 948.4 (M-H).1H NMR (METHANOL-d4, 500 MHz) Shift 8.66 (s, 1H), 8.4-8.4 (m, 3H), 8.22 (t, 1H, J=7.9 Hz), 7.88 (d, 1H, J=7.7 Hz), 7.28 (br d, 1H, J=8.0 Hz), 7.20 (d, 1H, J=7.7 Hz), 6.7-6.8 (m, 1H), 6.61 (dd, 2H, J=2.2, 8.2 Hz), 6.67 (br t, 2H, J=54.7 Hz), 4.5-4.6 (m, 2H), 3.61 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.2 (m, 3H), 3.1-3.2 (m, 1H), 2.41 (br dd, 2H, J=3.7, 7.3 Hz), 1.34 (br d, 1H, J=5.4 Hz), 0.99 (br dd, 1H, J=1.9, 3.7 Hz)
WO 2020/084492 and WO 2020/254985 disclose certain Capsid Inhibitor compounds including the two compounds shown below which will be referred to in this application as the compounds of Formula la and Formula lb.
Teprosulvose (CAS 1983131-47-0) is a novel synthetic glycolipid, specifically a sulfoquinovosylacylpropanediol (SQAP). It is primarily developed for use in veterinary medicine as a radiosensitizer, intended to enhance the effectiveness of radiation therapy in treating malignant tumors.
Structure: It consists of a glucose derivative (6-deoxy-6-sulfo-$\alpha$-D-glucopyranoside) linked via a propyl bridge to a long-chain fatty acid (stearic acid/octadecanoic acid).
Regulatory Data
Teprosulvose is currently in the investigational stage, primarily focused on veterinary oncology.
USAN/INN Status: The name "Teprosulvose" was officially adopted by the USAN Council in 2024 (File LM-156).
Classification: Radiosensitizer.
Target Application: Adjuvant therapy for malignant tumors in animals (e.g., canine or feline cancers).
Current Status: It has not yet received full FDA or EMA approval for human use. In the U.S., it is typically handled under Investigational New Animal Drug (INAD) protocols for clinical trials in veterinary patients.
Note: Because it is a specialized veterinary investigative agent, detailed safety data (LD50, pharmacokinetics) is generally found in specific FDA Freedom of Information (FOI) summaries or peer-reviewed veterinary oncology journals rather than standard human drug databases.
INN List 131 (WHO): Teprosulvose was officially included in the World Health Organization's International Nonproprietary Names (INN) list in 2024. This confirms its unique status as a distinct drug substance.
USAN Council: The United States Adopted Names Council assigned the name in 2024, classifying it as a radiosensitizer.
FDA Status: It is currently under investigation (INAD) for canine oral melanoma and other solid tumors in veterinary medicine. Human clinical trial data is not yet widely available as the primary focus remains on the "Veterinary First" pathway.
Mechanism of Action: It is a potent inhibitor of DNA polymerase $\alpha$ and $\beta$. By inhibiting the repair of radiation-induced DNA damage, it effectively "locks in" the damage to tumor cells while sparing normal tissue due to differential uptake.
PAT
US Patent 10,206,942 (and related continuations): Covers the use of SQAP compounds in combination with radiation.
WO 2017/023812: International filing regarding the composition and therapeutic application of these glycolipids.
Tigemocoxib is a small molecule drug. The usage of the INN stem '-coxib' in the name indicates that Tigemocoxib is a selective cyclo-oxygenase inhibitor. Tigemocoxib has a monoisotopic molecular weight of 334.06 Da.
Tigemocoxib (also known as SC-75416) is a selective cyclo-oxygenase 2 (COX-2) inhibitor and nonsteroidal anti-inflammatory drug (NSAID) designed for reducing pain and inflammation. Initially developed as an orally bioavailable clinical lead for treating acute, postoperative, and chronic inflammatory pain, it acts by targeting the COX-2 enzyme
(S)-6-Chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1- benzopyran-3-carboxylic acid To a solution of 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 8) (11.4 g, 34.1 mmol) and (S)-(-)-2-amino-3-phenyl-1-propanol (2.57 g, 17.00 mmol) was added n-heptane (200 mL) and the mixture set aside for 16 h. The resulting suspension was filtered yielding a solid (3.8 g). This solid was recrystallized from 2-butanone (20 mL) and n-heptane (200 mL) yielding upon filtration a white solid (3.0 g). This solid was dissolved in ethyl acetate (100 mL) and washed with 1 N hydrochloric acid (50 mL) and brine (2 × 50 mL), dried over MgSO4 and concentrated in vacuo yielding a white solid. This solid was recrystallized from n-heptane yielding the title compound of high optical purity as a crystalline solid (1.7 g, 30%): mp 175.4-176.9 °C. 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.52 (s, 1H), 7.12 (s,
1 H), 5.83 (q, 1H, J = 7.1 Hz), 1.48 (s, 9H). Anal. Calc'd for C15H14O3F3Cl : C, 53.83; H, 4.22; N, 0.0; Cl, 10.59. Found: C, 53.78; H, 4.20; N, 0.0; Cl, 10.65. This compound was determined to have an optical purity of greater than 90% ee. Chiral purity was determined as describe in Example 66.
Step 1. Preparation of 4-tert-butylsalicylaldehyde. A five liter three-neck round bottom flask equipped with overhead mechanical stirrer and condenser was charged with trifluoroacetic acid (2.4 L). A mixture of 3-tert-butylphenol (412 g, 2.8 mole) and HMTA (424 g, 3.0 mole) was added portion-wise causing an exotherm. With cooling, the temperature was maintained under 80 °C. The reaction was heated at 80 °C for one hour, then cooled, and water (2 L) added. After 0.5 hour additional water (4 L) was added and the mixture was extracted with ethyl acetate (6 L). The organic extract was washed with water and brine. The resulting organic phase was divided into 2 L volumes and each diluted with water (1 L), and solid NaHCO3 added until the mixture was neutralized. The organic phases were isolated and combined, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. This oil was distilled at 95 °C (0.8 mm) yielding the desired salicylaldehyde as an oil (272.9 g, 56 %) which was of sufficient purity to be used without further purification.
Step 2. Preparation of ethyl 7-(1,1-dimethylethyl)-2- (trifluoromethyl)-2H-1-benzopyran-3-carboxylate. A one liter three-neck flask was charged with 4-tert-butylsalicylaldehyde (Step 1) (100.0 g, 0.56 mole), dimethylformamide (110 mL), and potassium carbonate (79.9 g, 0.58 mole) causing the temperature of the mixture to rise to 40 °C. Ethyl 4,4,4-trifluorocrotonate (118.0 g, 0.70 mole) in dimethylformamide (110 mL) was added and the mixture heated to 60 °C at which time the reaction temperature rose to 70 °C. The reaction was cooled to 60 °C, maintained at 60
°C (with addedheating) for 8.5 hours and cooled to room temperature. Ethyl acetate (600 mL) and 3 N HCl (600 mL) were added, mixed, and the layers separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The combined organic phases were washed with brine-water (1:1), brine, dried over MgSO4, filtered and concentrated in vacuo, yielding a semi-solid. Hexane (600 mL) was added with mixing and the mixture was filtered. The filtrate was washed with brine, dried over
MgSO4, filtered and concentrated in vacuo yielding a solid. This solid was dissolved in hot ethanol (600 mL). Water (190 mL) was added which induced crystallization. Filtration of the mixture and drying of the product provided the desired ester as a crystalline solid (131.3 g, 71%): mp 91.0-94.9 °C. This material was of suitable purity to be used in subsequent steps without further purification.
Step 3. Preparation of ethyl 6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate. A one liter three-neck flask equipped with mechanical stirrer and gas inlet tube was charged with the ester (Step 2) (100 g, 0.3 mole) and acetic acid (300 mL). While cooling (water bath) the reaction mixture, chlorine gas (37.6 g, 0.53 mole) was added which caused the temperature to rise to 48 °C. After stirring for two hours, the reaction was cooled in an ice-water bath to 15 °C. Zinc powder (19.5 g, 0.3 mole) was added in one portion which caused the temperature to rise to 72 °C. After cooling to room temperature additional zinc powder (5.0 g, 0.08 mole) was added and the mixture was stirred for 0.5 hour longer. The crude mixture was filtered through diatomaceous earth and was concentrated in vacuo yielding an oil. The oil was dissolved in ethyl acetate (700 mL) washed with brine-water (1:1, 1 L) and brine (0.5 L). The resulting aqueous phase was extracted with ethyl acetate (700 mL). This ethyl acetate phase was washed with brine-water (1:1, 1 L) and brine (0.5 L). The combined organic phases were dried over
MgSO4, filtered and concentrated in vacuo yielding the title compound as a yellow oil (116 g, 106 %). This material, which contained some entrained ethyl acetate, was of suitable purity to be used in subsequent steps without further purification.
Step 4. Preparation of 6-chloro-7-(1,1-dimethylethyl)-2- (trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid. To a solution of the ester (Step 3) (116 g, 0.3 mole) in methanol (500 mL) and tetrahydrofuran (500 mL) in a one liter flask was added aqueous sodium hydroxide (2.5 N, 240 mL, 0.6 mole). After stirring overnight, the pH of the solution was adjusted to 1 with concentrated hydrochloric acid and the solution was extracted with ethyl acetate. The ethyl acetate phase was dried over MgSO4, filtered and concentrated in vacuo yielding a solid. This solid was dissolved in hot ethanol (500 mL). Water (500 mL) was added and upon cooling to room temperature crystals formed which were collected by vacuum filtration. The crystals were washed with ethanol-water (3:7, 3 X 200 mL) and dried providing the title acid as a crystalline solid (91.6 g, 91 %) : mp 194.9-196.5 °C. 1H NMR (acetone-d6/300 MHz) 7.86 (s, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 5.83 (q, 1H, J = 7.1 Hz), 1.48 (s, 9H). Anal. Calc'd for C15H14ClF3O3: C, 53.83; H, 4.22; Cl, 10.59. Found: C, 53.92; H, 4.24; Cl, 10.50
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
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).
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 (3x15 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%.
