Phosphodiesterase 3 (PDE3) inhibitors

Description

1 / 152 “PHOSPHODIESTERASE 3 (PDE3) INHIBITOR COMPOUNDS, COMPOSITION COMPRISING THE SAME AND USE OF THE COMPOUNDS TO TREAT CARDIOVASCULAR DISEASES” FIELD OF THE INVENTION

[001] The present invention describes novel multimodal cardiotonic agents that inhibit phosphodiesterase 3 (PDE3) and reduce the potential for arrhythmia due to calcium sensitization; processes for their preparation, compositions and methods of use for the treatment of cardiovascular diseases, including myxomatous mitral valve disease, congestive heart attack and / or asymptomatic heart attack in animals. BACKGROUND

[002] Congestive heart attack (CHF) is a leading cause of death in patients with heart disease. Phosphodiesterases are a class of intracellular enzymes responsible for the hydrolysis of cyclic adenosine monophosphate (c-AMP) and cyclic guanosine monophosphate (c-GMP), which are involved in the regulation of important cellular functions such as secretion, contraction, metabolism, and growth. Based on structure and substrate specificity, PDE enzymes can be grouped into eleven different families, defined as PDE1 to PDE11.

[003] Each PDE isoenzyme has a conserved C-terminal catalytic domain and a unique N-terminal regulatory domain. These isoenzymes are found in different animal tissues and cells, such as smooth muscle, brain, heart, lung, platelets, lymphocytes, and others. Among all PDE subtypes, PDE3 is predominantly expressed in cardiac muscle and platelets. The mammalian PDE3 family consists of two isoforms (A and B) that have properties Petition 870250099203, dated 10 / 30 / 2025, page 176 / 342 2 / 152 PDE3A isoenzymes are pharmacologically similar, but can be differentiated based on their expression profiles and affinity for cGMP. PDE3A is found in platelets, kidneys, vascular smooth muscle, heart, and oocytes. PDE3B is located in adipocytes, hepatocytes, vascular smooth muscle, developing spermatozoa, kidneys, B cells, T lymphocytes, and macrophages. PDE3 is specific for cAMP and has no effect on cGMP or calmodulin. Therefore, inhibition of the PDE3 isoenzyme in cardiovascular tissues leads to high levels of cAMP and consequent inotropic effects, thus boosting cardiac muscle contraction (inotropy) and smooth muscle vasodilation.

[004] Myxomatous mitral valve disease (MMVD) is the leading cause of cardiovascular disease in dogs. MMVD causes mitral valve incompetence, leading to mitral regurgitation, which promotes sodium and water retention, activation of neurohormonal systems, volume overload, and eventual congestive heart attack (CHF). Synonymous medical terms for MMVD used in this document include mitral valve disease (MVD), degenerative mitral valve disease (DMVD); chronic valvular disease (CVD); chronic valvular heart disease (CVHD); and atrial ventricular valve insufficiency (AVVI). The pathology of MMVD involves the differentiation and activation of the normally quiescent mitral valve into a more active myofibroblast phenotype, which mediates many of the histological and molecular changes in the valve tissue. MMVD is present in approximately 30% of all dogs over 10 years of age and is the most frequent cause of CHF in dogs.MMVD is most prevalent in small dogs, such as Cavalier King Charles Spaniels, Chihuahuas, Maltese, Pekingese, toy and miniature poodles. The natural history of the disease is onset in adulthood, variable progression with aging, and eventual development of CHF in dogs with severe disease. Petition 870250099203, dated 10 / 30 / 2025, page 177 / 342 Current treatments for MMVD include the use of angiotensin-binding agonists, diuretics, vasodilators, and positive inotropes.

[005] Previous citations (1985-1988) describe benzothiazolones (US4562190A), thiadiazines (US4916128A), and pyridazinones (US4647564A) as agents with useful properties as antihypertensives, antithrombotics, cardiotonics, and positive inotropes that can be used to treat heart attack. PDE3 inhibitory data were not presented in these previous citations. In addition, several non-spirocyclic cardiotonic agents were described in the Journal of Medicinal Chemistry (JMC), Vol. 35, 1992, pp. 163-172; with PDE3 IC50 values ​​ranging from 0.17 to 66.0 μM (Table IX), with a reported IC50 for pimobendan of 0.56 μM (560 nM). According to the JMC citation, small changes in molecular structure can have very different effects on enzyme inhibition (PDE and ATPase) and / or on calcium sensitization properties.For example, it was demonstrated that indolidan with a PDE3 IC50 value of 0.52 μM had no calcium-sensitizing properties, and that the introduction of a sulfur atom into the pyridazine ring favored the desired activity, and that the substitution of the indolone moiety also appeared essential. This was demonstrated in Table IV with the alkyl substitutions on the indole ring. According to the JMC, the addition of a sulfur-containing spirocyclic ring to indole increased the calcium-sensitizing activity by 30 times, but was less potent as an inotropic agent in vivo. Therefore, it was taught that the requirements to obtain calcium-sensitizing effects were: 1) the indolone and heterocyclic parts of the molecule must be able to achieve relative coplanarity; 2) the heterocyclic part must contain a sulfur (or selenium) atom; and 3) substituents (preferably bulky groups) are needed at position 3 of the indolone ring. In contrast, we have shown that the S atom and / or... Petition 870250099203, dated 10 / 30 / 2025, pp. 178 / 342 4 / 152 bulky groups are not necessary to achieve this dual activity. Furthermore, it has been found that the addition of a halogen atom at position 7 of an oxindole-containing molecule can induce calcium sensitizing properties and / or increase PDE3 inhibition. Thus, the compounds of the invention have the desired PDE3 inhibitory activity at nanomolar concentrations and are calcium sensitizers, as observed with the positive effect in contractility assays. As described in the European Journal of Medicinal Chemistry (1996), Vol 31, p. 805-8120; by Nadler G., et al., for pyridazinone and thiadiazine cardiotonic agents with a chiral center, the PDE inhibitory activity generally resides in one enantiomer (e.g., the (S) configuration for thiadiazines and the (R) configuration for pyridazinones) and myofibrillar calcium sensitization resides in the opposite configurations, respectively.To date, research and development of these dual-modality inotropes appears to have slowed dramatically, as no new compounds have actually been described for at least 28 years or more.

[006] In fact, the most commonly used inotropic compound for heart attack in animals today is pimobendan, which is a racemate. Pimobendan is a benzimidazole-pyridazinone derivative that has been used to treat congestive heart attack (CHF) resulting from dilated cardiomyopathy (DCM) or DMVD in animals for about 20 years. The positive inotropic effects of pimobendan are mediated by a combination of increased c-AMP-mediated PDE3 inhibition and sensitization of the cardiac contractile apparatus to intracellular calcium. Pimobendan was first described in US patent US4361563A, first published in February 1980 in an equivalent Australian patent application (AU197950279A). Pimobendan is administered orally twice daily to dogs. Petition 870250099203, dated 10 / 30 / 2025, page 179 / 342 5 / 152 at a dose of 0.5 mg / kg / day. Pimobendan is safe and well tolerated, but should be administered chronically twice daily (every 12 hours), which can lead to some common safety problems in animals, such as accelerated or abnormal heartbeats, bleeding or bruising, gastrointestinal disturbances, jaundice, rash and skin redness, and is known to induce valvular lesions in patients with asymptomatic MVD. Furthermore, pimobendan should not be used in cases of hypertrophic cardiomyopathy or aortic stenosis. Chronic BID dosing can also lead to failures in administration compliance. As with many marketed products, there is always a need for newer, safer, and more effective medications to treat the respective classes of diseases.The present invention describes novel bimodal cardiotonic agents that inhibit PDE3 at nanomolar concentrations and have a positive effect on contractility, a measure of calcium sensitization, for the useful treatment of cardiovascular diseases, including MMVD, CHF and / or asymptomatic heart attack, and / or inhibition of platelet aggregation, in an animal, preferably canine. SUMMARY OF THE INVENTION

[007] In one aspect of the invention, the novel PDE3 receptor antagonists are useful for the treatment of mitral valve disease and congestive heart attack in animals, primarily canines. In one aspect, the PDE3 inhibitor compounds (Example No.) are selected from the group consisting of: 8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4dihydroquinolin-2(1H)-one (1); 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(thiazol-2-yl)-3,4-dihydroquinolin-2(1H)-one (2); Petition 870250099203, dated 10 / 30 / 2025, p. 180 / 342 6 / 152 8-(2-methoxythiazol-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-3,4-dihydroquinolin-2(1H)-one (4); 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2-ona (6); 7-(4-chlorophenyl)-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (7); 7'-chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)spiro[cyclopropane1,3'-indoline]-2'-one (8); 8-(4-chlorophenyl)-6-(6-oxo-1,6-di-hydropyridazine-3-yl)-3,4-di-hydroquinoline-2(1H)one (9); 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-3,4-dihydroquinolin-2(1H)-one (12); 6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropindazine-3-yl)-8-(pindin-3-yl)-3,4-dihydroquinolin-2(1H)-ona (13); 3,3-dimethyl-5-(4-methyl-6-oxo-1,6-di-hydropyridazine-3-yl)-7-(thiazol-4-yl)indolin-2ona (17); 9-(6-methoxypyridine-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)1,3,4,5-tetra-hydro-2H-benzo[b]azepin-2-one (18); 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19); 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (23); 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (24); 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (25); 7-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (26); Petition 870250099203, dated 10 / 30 / 2025, p. 181 / 342 7 / 152 7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (27); 7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)spiro[cyclopropane1,3'-indoline]-2'-one (28); 4-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)benzo[d]thiazol-2(3H)one (29); 6-(2-amino-4-chlorobenzo[d]thiazol-6-yl)-5-methyl-4,5-di-hidropyridazin-3(2H)-ona (30); 6-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-5-methyl-4,5-di-hidropyridazin-3(2H)-ona (31); 7-bromo-3,3-dimethyl-5-(6-oxo-1,6-di-hidropyridazin-3-yl)indolin-2-one (32); (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3yl)indolin-2-ona (33); 6-(4-fluoro-2-(methylamino)benzo[d]thiazol-6-yl)-5-methyl-4,5-di-hidropyridazin3(2H)-ona (34); 8-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)quinolin-2(1H)-one (35); 6-(8-chloro-2-hidroxyquinolin-6-yl)-5-methyl-4,5-di-hidropyridazin-3(2H)-ona (35a); 7-chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3yl)indolin-2-ona (36); 6-(4-fluoro-2-(3-hidroxiazetidin-1-yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihidropyridazin-3(2H)-ona (37); 2-amino-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)benzo[d]thiazole-4carbonitrila (38); 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)isoindolin-1 -one (39); 6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)-2-oxo-1,2-di-hidroquinolinaPetição 870250099203, de 30 / 10 / 2025, pág. 182 / 342 8 / 152 8-carbonitrila (40); 2-hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)quinoline-8carbonitrila (40a); 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)isoindolin1-one (41); 4-chloro-1 -methyl-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)-1,3-di-hydro2H-benzo[d]imidazol-2-one (42); 7'-Huoro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)spiro[cyclobutane1,3'-indoline]-2'-ona (43); 7-chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)indolin-2-one (44); 6-(8-bromo-2-hidroxyquinolin-6-yl)-5-methyl-4,5-di-hidropyridazin-3(2H)-ona (45); 6-(4-fluoro-2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)benzo[d]thiazol-6-yl)-5-methyl4,5-di-hydropyridazin-3(2H)-one (46); 6-(7-chloro-3-methyl-1H-indazol-5-yl)-5-methyl-4,5-di-hidropyridazin-3(2H)-ona (47); 6-(8-cyclopropyl-2-hidroxyquinoline-6-yl)-5-methyl-4,5-di-hidropyridazine-3(2H)ona (48); 6-(2-(3-methoxy-azetidine-1-yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-di-hidropyridazine3(2H)-ona (49); 7-fluoro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)indolin-2-ona (50); (S)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3yl)isoindolin-2-ona (51); 4-chloro-6-(6-oxo-1,6-di-hydropyridazin-3-yl)benzo[d]thiazol-2(3H)-one (52); 5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-2-oxoindoline-7-carbonitrila (53); Petition 870250099203, 30 / 10 / 2025, pág. 183 / 342 9 / 152 4-methyl-6-(6-methyl-2-oxo-3,6-di-hydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol2(3H)-one (55); 4-chloro-6-(6-methyl-2-oxo-3,6-di-hydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol2(3H)-one (56); 5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin-2-one (57); 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-di-hydro-2H1,3,4-thiadiazin-2-one (58); 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (59); 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazin-2-one (61); 5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin-2-one (62); 6-methyl-5-(7-(4-(methylsulfonyl)phenyl)-2-oxoindolin-5-yl)-3,6-di-hydro-2H-1,3,4thiadiazin-2-one (63); 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazin-2-one (66); 5-(3,3-dimethyl-2-oxo-7-(thiazol-4-yl)indolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazin-2-one (68); 5-(7-(4-chlorophenyl)-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin-2ona (71); 5-(2-oxo-2,3,4,5-tetra-hydro-1 H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4thiadiazin-2-one (72); 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetra-hydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiazin-2-one (73); Petition 870250099203, of 30 / 10 / 2025, p. 184 / 342 10 / 152 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazin-2-one (74); 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin2-one (75); 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazin-2-one (76); 5-(6-methyl-2-oxo-3,6-di-hydro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7carbonitrile (77); (S)-5-(7-fluoro-2-oxondolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (78); 5-(7-chloro-1-oxoisoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (79); 5-(7-chloro-3,3-dimethyl-1-oxoisoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazine-2-ona (80); 5-(8-chloro-2-hydroxyquinoline-6-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (81); 5-(7-chloro-2,2-dioxide-1,3-di-hydrobenzo[c]isothiazol-5-yl)-6-methyl-3,6-di-hydro2H-1,3,4-thiadiazine-2-one (82); 6-methyl-5-(8-methyl-2-oxo-1,2,3,4-tetra-hydroquinolin-6-yl)-3,6-di-hydro-2H-1,3,4thiadiazine-2-one (83); 4-chloro-6-(2-oxo-2,3-di-hydro-1 H-pyrrole[2,3-b]pyridine-5-yl)benzo[d]oxazol2(3H)-one (84); 5-(7-chloro-3,3-dimethyl-2-oxoendolin-5-yl)-1,3-di-hydro-2H-pyrrole[2,3-b]pyridine-2one (85); 7-chloro-3,3-dimethyl-5-(pyrimidine-5-yl)indolin-2-ona (86); Petition 870250099203, dated 10 / 30 / 2025, p. 185 / 342 11 / 152 6-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,4-di-hydro-1,8-natfiridin-2(1H)-one (87); 4-chloro-6-(5-oxo-4,5-di-hidro-1,3,4-thiadiazol-2-yl)benzo[d]thiazol-2(3H)-ona (88); And 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-1,3,4-thiadiazol-2(3H)-ona (89), estereoisomer do mesmo and known veterinary aceitáveis ​​do mesmo.

[008] In another aspect, the PDE3 inhibitors (Example n°) are selected from the group that consists of: 8-(2-methoxipyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)-3,4di-hidroquinolin-2(1H)-ona (1); 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)indolin-2-one (6); 7'-chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)espiro[cyclopropane1,3'-indolin]-2'-one (8); 8-(4-chlorophenyl)-6-(6-oxo-1,6-di-hidropyridazin-3-yl)-3,4-di-hidroquinolin-2(1H)ona (9); 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)-3,4-dihidroquinolin-2(1H)-ona (12); 6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one (13); 9-(6-methoxypyridine-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)1,3,4,5-tetra-hydro-2H-benzo[b]azepin-2-one (18); 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19); 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (23); Petition 870250099203, dated 10 / 30 / 2025, p. 186 / 342 12 / 152 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (24); 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (25); 7-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (26); 7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (27); 7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)espiro[cyclopropane1,3'-indolin]-2'-one (28); 6-(2-amino-4-chlorobenzo[d]thiazol-6-yl)-5-methyl-4,5-di-hidropyridazin-3(2H)-ona (30); 6-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-5-methyl-4,5-di-hidropyridazin-3(2H)-ona (31); 7-bromo-3,3-dimethyl-5-(6-oxo-1,6-di-hidropyridazin-3-yl)indolin-2-one (32); (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3yl)indolin-2-ona (33); 6-(4-fluoro-2-(methylamino)benzo[d]thiazol-6-yl)-5-methyl-4,5-di-hidropyridazin3(2H)-ona (34); 8-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)quinolin-2(1H)-one (35); 6-(8-chloro-2-hidroxyquinolin-6-yl)-5-methyl-4,5-di-hidropyridazin-3(2H)-ona (35a); 7-chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3yl)indolin-2-ona (36); 6-(4-fluoro-2-(3-hidroxiazetidin-1-yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihidropyridazin-3(2H)-ona (37); 2-amino-6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)benzo[d]thiazol-4Petição 870250099203, de 30 / 10 / 2025, pág. 187 / 342 13 / 152 carbonitrila (38); 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)isoindolin-1 -one (39); 6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)-2-oxo-1,2-di-hydroquinoline8-carbonitrila (40); 2-hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)quinoline-8carbonitrila (40a); 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)isoindolin1-one (41); 4-chloro-1 -methyl-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)-1,3-di-hydro2H-benzo[d]imidazol-2-one (42); 7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)spiro[cyclobutane1,3'-indolin]-2'-ona (43); 7-chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2-ona (44); 4-chloro-6-(6-methyl-2-oxo-3,6-di-hydro-2H-1,3,4-thiadiazine-5-yl)benzo[d]thiazol2(3H)-one (56); 5-(7-fluoro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (57); 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-6-methyl-3,6-di-hydro-2H1,3,4-thiadiazine-2-one (58); 5-(7-fluoro-3,3-dimethyl-2-oxonindolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (59); 5-(7-chloro-3,3-dimethyl-2-oxoendolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (61); 5-(7-chloro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (62); 6-methyl-5-(7-(4-(methylsulfonyl)phenyl)-2-oxendolin-5-yl)-3,6-di-hydro-2H-1,3,4Petition 870250099203, dated 10 / 30 / 2025, p. 188 / 342 14 / 152 thiadiazine-2-ona (63); 5-(7-bromo-3,3-dimethyl-2-oxoendolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (66); 5-(7-(4-chlorofenil)-2-oxoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4-tiadiazin-2ona (71); 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetra-hidro-1H-benzo[b]azepin-7-il)-3,6-dihidro-2H-1,3,4-tiadiazin-2-ona (73); 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4tiadiazin-2-ona (74); 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4-tiadiazin2-ona (75); 5-(7-bromo-3,3-dimetil-2-oxoindolin-5-il)-6-metil-3,6-di-hydro-2H-1,3,4tiadiazin-2-ona (76); 5-(6-methyl-2-oxo-3,6-di-hidro-2H-1,3,4-tiadiazin-5-il)-2-oxoindoline-7carbonitrila (77); (S)-5-(7-fluoro-2-oxoindolin-5-il)-6-metil-3,6-di-hydro-2H-1,3,4-tiadiazin-2-ona (78); 5-(7-chloro-1-oxoisoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4-tiadiazin-2-ona (79); 5-(7-chloro-3,3-dimethyl-1-oxoisoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4tiadiazin-2-ona (80); 6-methyl-5-(8-methyl-2-oxo-1,2,3,4-tetra-hydroquinolin-6-yl)-3,6-di-hydro-2H-1,3,4thiadiazine-2-one (83); 5-(7-chloro-3,3-dimethyl-2-oxoendolin-5-yl)-1,3-di-hydro-2H-pyrrole[2,3-b]pyridine-2one (85); and Petition 870250099203, dated 10 / 30 / 2025, p. 189 / 342 15 / 152 7-chloro-3,3-dimethyl-5-(pyrimidine-5-yl)indolin-2-one (86), stereoisomer of mesmo and veterinary acetyáveis ​​salts of mesmo.

[009] In another aspect, a PDE3 inhibitor (Example No.) is selected from the group comprising: 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-3,4-dihydroquinolin-2(1H)-one (12); 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19); 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (23); 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (24); 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (25); 7-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (26); 7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (27); 7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)spiro[cyclopropane1,3'-indoline]-2'-one (28); 6-(2-amino-4-chlorobenzo[d]thiazol-6-yl)-5-methyl-4,5-di-hydropyridazin-3(2H)-ona (30); 6-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-5-methyl-4,5-di-hydropyridazine-3(2H)-one (31); 7-bromo-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (32); (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3yl)indolin-2-ona (33); Petition 870250099203, dated 10 / 30 / 2025, p. 190 / 342 16 / 152 4-chloro-6-(6-methyl-2-oxo-3,6-di-hydro-2H-1,3,4-thiadiazine-5-yl)benzo[d]thiazol2(3H)-one (56); 5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin-2-one (57); 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-di-hydro-2H1,3,4-thiadiazin-2-one (58); 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazin-2-one (61); 5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin-2-one (62); 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazin-2-one (66); 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetra-hydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiazin-2-one (73); 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3I6-di-hidiO-2H-1,3,4thiadiazin-2-one (74); 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin2-one (75); 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazin-2-one (76); 5-(6-methyl-2-oxo-3,6-di-hidro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7carbonitrila (77); (S)-5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona (78); 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2one (85); and Petition 870250099203, 30 / 10 / 2025, pág. 191 / 342 17 / 152 7-chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indolin-2-ona (86), estereoisomer do mesmo and known veterinary aceitáveis ​​do mesmo.

[010] In another aspect, it is a PDE3 inhibitor (Example n°) selected from the group that consists of: 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihidropyridazin-3(2H)-ona (19); 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)indolin-2ona (23); 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)indolin-2ona (24); 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (25); 5-(7-fluoro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (57); 5-(7-chloro-3,3-dimethyl-2-oxoendolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (61); 5-(7-chloro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (62); 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetra-hydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (73); 5-(7-fluoro-3,3-dimethyl-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazine-2-one (74); 5-(7-chloro-3,3-dimethyl-2-oxonindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine2-one (75); 5-(7-bromo-3,3-dimethyl-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazine-2-one (76); and 7-chloro-3,3-dimethyl-5-(pyrimidine-5-yl)indolin-2-one (86), stereoisomer of the Petition 870250099203, dated 10 / 30 / 2025, p. 192 / 342 18 / 152 same and you know vets will accept the same.

[011] In another aspect, is a PDE3 inhibitor (Example No.) selected from the group comprising: 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19); 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (23); 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (24); 5-(7-fluoro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (57); 5-(7-chloro-3,3-dimethyl-2-oxoendolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (61); 5-(7-chloro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (62); 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetra-hydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (73); 5-(7-fluoro-3,3-dimethyl-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazine-2-one (74); 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin2-one (75); and 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4thiadiazin-2-one (76), stereoisomer thereof and veterinary acceptable salts thereof.

[012] In another aspect, PDE3 inhibitors (Example No.) are selected from the group consisting of: Petition 870250099203, dated 10 / 30 / 2025, pp. 193 / 342 19 / 152 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (19); 5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57); 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (61); 5-(7-chloro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (62); and 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetra-hydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (73), stereoisomer of the mesnaries do mesnarius aceitá and sais veteri

[013] In another aspect, PDE3 inhibitors (Example No.) are selected from the group comprising: 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (23); 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (24); 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (25); 5-(7-fiuorG-3,3-dimethyl-2-oxondolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazine-2-one (74); 5-(7-chloro-3,3-dimethyl-2-oxonindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine2-one (75); 5-(7-bromo-3,3-dimethyl-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazine-2-one (76); and 7-chloro-3,3-dimethyl-5-(pyrimidine-5-yl)indolin-2-one (86), stereoisomer of the Petition 870250099203, dated 10 / 30 / 2025, p. 194 / 342 20 / 152 same and you know vets will accept the same.

[014] In another aspect, PDE3 inhibitors (Example No.) are selected from the group comprising: 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19); 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (23); 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona (24); 5-(7-fluoro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (57); 5-(7-chloro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one (62); and 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin2-one (75), stereoisomer thereof and acceptable veterinary salts thereof.

[015] In another aspect, PDE3 inhibitors are selected from the group consisting of: 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (19); 5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57); and 5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (62), stereoisomers thereof and acceptable veterinary salts thereof.

[016] In another aspect, PDE3 inhibitors (Example no. are selected Petition 870250099203, dated 10 / 30 / 2025, pp. 195 / 342 21 / 152 of the group consisting of: 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2one (23); 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2one (24); and 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin2-one (75), stereoisomer thereof and acceptable veterinary salts thereof.

[017] In another aspect, there is the PDE3 inhibitor 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)one (19), stereoisomer thereof and acceptable veterinary salts thereof.

[018] In another aspect, there is the PDE3 inhibitor 7-bromo-3,3-dimethyl-5-(4methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one (23), stereoisomer thereof and acceptable veterinary salts thereof.

[019] In another aspect, there is the PDE3 inhibitor 7-chloro-3,3-dimethyl-5-(4-methyl6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one (24), stereoisomer thereof and acceptable veterinary salts thereof.

[020] In another aspect, there is the PDE3 inhibitor 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indolin-2-one (25), stereoisomer thereof and acceptable veterinary salts thereof.

[021] In another aspect, there is the PDE3 inhibitor 5-(7-fluoro-2-oxoindolin-5-yl)6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57), stereoisomer thereof and acceptable veterinary salts thereof.

[022] In another aspect, there is PDE3 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)3,6-dihydro-2H-1,3,4-thiadiazin-2-one (61), a stereoisomer thereof and acceptable veterinary salts thereof. Petition 870250099203, dated 10 / 30 / 2025, pp. 196 / 342 22 / 152

[023] In another aspect, there is the PDE3 inhibitor 5-(7-chloro-2-oxoindolin-5-yl)6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (62), stereoisomer thereof and acceptable veterinary salts thereof.

[024] In another aspect, there is the PDE3 inhibitor 6-methyl-5-(9-methyl-2-oxo2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (73), stereoisomer thereof and acceptable veterinary salts thereof.

[025] In another aspect, there is the PDE3 inhibitor 5-(7-fluoro-3,3-dimethyl-2oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (74), stereoisomer thereof and acceptable veterinary salts thereof.

[026] In another aspect, there is the PDE3 inhibitor 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (75), stereoisomer thereof and acceptable veterinary salts thereof.

[027] In another aspect, there is the PDE3 inhibitor 5-(7-bromo-3,3-dimethyl-2oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (76), stereoisomer thereof and acceptable veterinary salts thereof.

[028] In another aspect, the PDE3 inhibitor is 7-chloro-3,3-dimethyl-5-(pyrimidin5-yl)indolin-2-one (86), a stereoisomer thereof, and an acceptable veterinary salt thereof.

[029] In another aspect of the invention, it is a composition comprising a compound of the invention selected from the group consisting of Examples Nos. 1, 2, 4, 69, 12-13, 17-19, 23-53, 55-59, 61-63, 66, 68 and 71-89, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a composition comprising a compound of the invention selected from the group consisting of Examples Nos. 1, 6, 8, 12-13, 18-19, 23-28, 30-43, 56-59, 61-63, 66, 71, 73-80, 83 and 8586, a stereoisomer thereof and acceptable veterinary salts thereof. In another Petition 870250099203, dated 10 / 30 / 2025, pp. 197 / 342 Aspect 23 / 152 is a composition comprising a compound of the invention selected from the group consisting of Examples Nos. 12, 19, 23-28, 30-33, 56-58, 61-62, 66, 73-78, 85 and 86, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a composition comprising a compound of the invention selected from the group consisting of Examples Nos. 19, 23, 24, 57, 61-62 and 73-76, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a composition comprising any of the compounds selected from Examples Nos. 19, 57, 61, 62 and 73, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a composition comprising a compound of the invention selected from the group consisting of Examples Nos. 23, 24, 25, 74, 75, 76 and 86, a stereoisomer thereof and acceptable veterinary salts thereof.In another aspect, it is a composition comprising a compound of the invention selected from the group consisting of Examples Nos. 23, 24, 74, 75 and 76, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a composition comprising a compound of the invention selected from the group consisting of Examples Nos. 19, 57 and 62, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a composition comprising a compound of the invention selected from the group consisting of Examples Nos. 23, 24 and 75, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a composition comprising Example 19, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a composition comprising Example 23, a stereoisomer thereof and acceptable veterinary salts thereof.In another aspect, it is a composition comprising Example No. 24, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a composition comprising... Petition 870250099203, dated 10 / 30 / 2025, pp. 198 / 342 24 / 152 Example No. 25, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a composition comprising Example No. 57, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a composition comprising Example No. 61, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a composition comprising Example No. 62, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a composition comprising Example No. 73, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a composition comprising Example No. 74, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a composition comprising Example No. 75, a stereoisomer thereof, and acceptable veterinary salts thereof.In another aspect, it is a composition comprising Example No. 76, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a composition comprising Example No. 86, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a composition comprising Example No. 86, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, the composition further comprises at least one acceptable veterinary excipient. In another aspect, the composition further comprises at least one additional pharmaceutical agent. In another aspect, the at least one additional pharmaceutical agent is selected from the group consisting of an ACE inhibitor, furosemide, and spironolactone. In another aspect, each of the compositions described in this document may be in a solid or liquid form.Preferably, the compositions described here are in solid form, for example, a tablet or a capsule, which can be administered orally. The oral composition may be a... Petition 870250099203, dated 10 / 30 / 2025, pp. 199 / 342 25 / 152 coated tablet or one flavored chewable tablet.

[030] In another aspect of the invention, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack, by administering a therapeutic amount of a compound of the invention selected from the group consisting of Exemplo Nos. 1, 2, 4, 6-9, 12-13, 17-19, 23-53, 55-59, 61-63, 66, 68 and 71-89, a stereoisomer thereof or an acceptable veterinary salt thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack, by administering a therapeutic amount of the compound of the invention selected from the group consisting of Examples Nos. 1, 6, 8, 12-13, 18-19, 23-28, 30-43, 56-59, 61-63, 66, 71, 73-80, 83 and 85-86, a stereoisomer thereof or an acceptable veterinary salt thereof.In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack by administering a therapeutic amount of a compound of the invention selected from the group consisting of Examples Nos. 12, 19, 23-28, 30-33, 56-58, 61-62, 66, 73-78, 85 and 86, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack by administering a therapeutic amount of a compound of the invention selected from the group consisting of Examples Nos. 19, 23, 24, 57, 61-62 and 73-76, a stereoisomer thereof and acceptable veterinary salts thereof.In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack, by administering a therapeutic amount of a compound of the invention selected from the group consisting of Examples Nos. 19, 57, 61, 62 and 73, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a method of treating... Petition 870250099203, dated 10 / 30 / 2025, pp. 200 / 342 26 / 152 an animal with MMVD, CHF and / or asymptomatic heart attack, by administering a therapeutic amount of a compound of the invention selected from the group consisting of Examples Nos. 23, 24, 25, 74, 75, 76 and 86, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack, by administering a therapeutic amount of a compound of the invention selected from the group consisting of Examples Nos. 23, 24, 74, 75 and 76, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack, by administering a therapeutic amount of a compound of the invention selected from the group consisting of Examples Nos. 19, 57 and 62, a stereoisomer thereof and acceptable veterinary salts thereof.In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack by administering a therapeutic amount of a compound of the invention selected from the group consisting of Examples Nos. 23, 24 and 75, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack by administering a therapeutic amount of Example No. 19, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack by administering a therapeutic amount of Example No. 23, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack, by administering a therapeutic amount of Example No. 24. Petition 870250099203, dated 10 / 30 / 2025, pp. 201 / 342 27 / 152 stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack by administering a therapeutic amount of Example No. 25, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack by administering a therapeutic amount of Example No. 57, a stereoisomer thereof and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack by administering a therapeutic amount of Example No. 61, a stereoisomer thereof and acceptable veterinary salts thereof.In another aspect, it is a method of treating an animal with MMVD, CHF, and / or asymptomatic heart attack by administering a therapeutic amount of Example No. 62, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF, and / or asymptomatic heart attack by administering a therapeutic amount of Example No. 73, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF, and / or asymptomatic heart attack by administering a therapeutic amount of Example No. 74, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect, it is a method of treating an animal with MMVD, CHF and / or asymptomatic heart attack, by administering a therapeutic amount of Example No. 75, a stereoisomer thereof and acceptable veterinary salts thereof.In another aspect, it is a method of treating an animal with MMVD, CHF, and / or asymptomatic heart attack, through the administration of a therapeutic amount of... Petition 870250099203, dated 10 / 30 / 2025, pp. 202 / 342 28 / 152 Example No. 76, a stereoisomer thereof, and an acceptable veterinary salt thereof. In another aspect, it is a method of treating an animal with MMVD, CHF, and / or asymptomatic heart attack by administering a therapeutic amount of Example No. 86, a stereoisomer thereof, and acceptable veterinary salts thereof. In another aspect of treating an animal with MMVD, CHF, and / or asymptomatic heart attack by administering a therapeutic amount of any of the compounds of the invention, it is a method of co-administering at least one additional pharmaceutical agent selected from the group consisting of an ACE inhibitor, furosemide, and spironolactone.

[031] In another aspect of the invention, is the use of a compound of the invention selected from the group consisting of Examples Nos. 1, 2, 4, 6-9, 12-13, 17-19, 23-53, 55-59, 61-63, 66, 68 and 71-89, stereoisomer thereof and acceptable veterinary salts thereof to prepare a medicament for treating an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of a compound of the invention selected from the group consisting of Examples Nos. 1, 6, 8, 12-13, 18-19, 23-28, 30-43, 56-59, 61-63, 66, 71, 73-80, 83 and 85-86, a stereoisomer thereof and acceptable veterinary salts thereof to prepare a medicament for treating an animal with MMVD, CHF and / or asymptomatic heart attack.In another aspect, it is the use of a compound of the invention selected from the group consisting of Examples Nos. 12, 19, 23-28, 30-33, 56-58, 61-62, 66, 73-78, 85 and 86, a stereoisomer thereof and acceptable veterinary salts thereof to prepare a medicament for treating an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of a compound of the invention selected from the group consisting of Examples Nos. 19, 23, 24, 57, 61-62 and 73-76, a stereoisomer thereof and acceptable veterinary salts thereof, to prepare a medicament for treating an animal. Petition 870250099203, dated 10 / 30 / 2025, pp. 203 / 342 29 / 152 animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of a compound of the invention selected from the group consisting of Examples Nos. 19, 57, 61, 62 and 73, a stereoisomer thereof and acceptable veterinary salts thereof, to prepare a medicament to treat an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of a compound of the invention selected from the group consisting of Examples Nos. 23, 24, 25, 74, 75, 76 and 86, a stereoisomer thereof and acceptable veterinary salts thereof, to prepare a medicament to treat an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of a compound of the invention selected from the group consisting of Examples Nos. 23, 24, 74, 75 and 76, a stereoisomer thereof and acceptable veterinary salts thereof, to prepare a medicament for treating an animal with MMVD, CHF and / or asymptomatic heart attack.In another aspect, it is the use of a compound of the invention selected from the group consisting of Examples Nos. 19, 57 and 62, their stereoisomers or an acceptable veterinary salt, to prepare a medicament for treating an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of a compound of the invention selected from the group consisting of Examples Nos. 23, 24 and 75, their stereoisomers or an acceptable veterinary salt, to prepare a medicament for treating an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of Example No. 19, its stereoisomer or an acceptable veterinary salt to prepare a medicament for treating an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of Example No. 23, its stereoisomer or an acceptable veterinary salt to prepare a medicament for treating an animal with MMVD, CHF and / or asymptomatic heart attack.In another aspect, it is the use of Example 24, a stereoisomer of the same, and veterinary salts. Petition 870250099203, dated 10 / 30 / 2025, pp. 204 / 342 30 / 152 acceptable aspects thereof for preparing a medicament to treat an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of Example No. 25, a stereoisomer thereof and acceptable veterinary salts thereof for preparing a medicament to treat an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of Example No. 57, a stereoisomer thereof and acceptable veterinary salts thereof for preparing a medicament to treat an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of Example No. 61, a stereoisomer thereof and acceptable veterinary salts thereof for preparing a medicament to treat an animal with MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of Example No. 62, a stereoisomer thereof, and acceptable veterinary salts thereof to prepare a medicament for treating an animal with MMVD, CHF, and / or asymptomatic heart attack.In another aspect, it is the use of Example No. 73, a stereoisomer thereof, and acceptable veterinary salts thereof to prepare a medicament for treating an animal with MMVD, CHF, and / or asymptomatic heart attack. In another aspect, it is the use of Example No. 74, a stereoisomer thereof, and acceptable veterinary salts thereof to prepare a medicament for treating an animal with MMVD, CHF, and / or asymptomatic heart attack. In another aspect, it is the use of Example No. 75, a stereoisomer thereof, and acceptable veterinary salts thereof to prepare a medicament for treating an animal with MMVD, CHF, and / or asymptomatic heart attack. In another aspect, it is the use of Example No. 76, a stereoisomer thereof, and acceptable veterinary salts thereof to prepare a medicament for treating an animal with MMVD, CHF, and / or asymptomatic heart attack. In another aspect, it is the use of Example No. 86, a stereoisomer thereof, and acceptable veterinary salts thereof to prepare a medicament for treating an animal with. Petition 870250099203, dated 10 / 30 / 2025, pp. 205 / 342 31 / 152 MMVD, CHF and / or asymptomatic heart attack. In another aspect, it is the use of any of the compounds of the invention to prepare a medicament with at least one other additional pharmaceutical agent selected from the group consisting of an ACE inhibitor, furosemide and spironolactone to treat an animal with MMVD, CHF and / or asymptomatic heart attack. DESCRIPTION DEFINITIONS

[032] For the purposes of the invention, as described and claimed herein, the following terms and phrases are defined as follows:

[033] “Veterinary agent(s) (or pharmaceutical agent(s))”, as used in this document, unless otherwise indicated, refers to other veterinary or pharmaceutical compounds or products (i.e., drugs) that provide a therapeutically effective amount of said agent(s) that are useful for the treatment of MMVD, CHF and / or asymptomatic heart attack in an animal, preferably canine.

[034] “Animal(s)”, as used in this document, unless otherwise indicated, refers to an individual animal that is a mammal. Specifically, mammal refers to a vertebrate animal that is human or non-human, which are members of the taxonomic class Mammalia. Non-exclusive examples of non-human mammals include pets. Non-exclusive examples of pets include: cat (feline), dog (canine), and horse (equine). The preferred pet is the canine.

[035] “Asymptomatic (occult, preclinical) heart attack”, as used in this document unless otherwise indicated, refers to any contractile disorder or disease of the heart resulting from MMVD. Petition 870250099203, dated 10 / 30 / 2025, pp. 206 / 342 32 / 152

[036] “Compound(s) of the invention”, unless otherwise indicated or claimed, refers to the PDE3 receptor antagonists (inhibitors) described herein as Examples Nos. 1 to 89, their stereoisomers and / or acceptable veterinary salts. The numbers of the Compound Example are erroneously correlated with the name and structure of the specific Example.

[037] “Includes” or “comprising”, as used in this document, refers to an inclusive meaning, that is, it will be considered as including not only the listed components to which it directly refers, but also other unspecified components or elements.

[038] “Congestive heart attack” or “heart attack,” unless otherwise indicated, refers to a manifest process in which the heart is unable to keep up with the demands of blood supply to the body and usually results in fluid accumulation in the lungs resulting from increased cardiac and pulmonary pressures. The term(s) also refers to any contractile disorder or disease of the heart. Clinical manifestations are, as a rule, the result of alterations in the cellular and molecular components of the heart and in the mediators that drive homeostatic control, leading to increased heart size and deterioration of cardiac function.

[039] “Myxomatous mitral valve disease (MMVD)”, unless otherwise indicated, refers to the manifest process of degeneration of the mitral valve. MMVD is usually detected as a heart murmur by auscultation. MMVD also includes synonymous medical terms, including: mitral valve disease (MVD); degenerative mitral valve disease (DMVD); chronic valvular disease (CVD); chronic valvular heart disease (CVHD); and atrial ventricular valvular insufficiency (AVVI). Petition 870250099203, dated 10 / 30 / 2025, pp. 207 / 342 33 / 152

[040] “Stereoisomer(s)”, as used in this document, refers specifically to compounds of the invention that have at least one chiral carbon and exist as enantiomers (S and R optical isomers) that are mirror images of each other, chemically identical, but not superimposable. The mixture of the (S) and (R) enantiomers is racemic. For example, Example 33 and Example 51 are the (R) and (S) isomers, respectively, of Example 24 (racemate).

[041] “Therapeutically effective amount”, unless otherwise indicated, refers to an amount of a compound of the invention that (i) treats MMVD, CHF and / or asymptomatic heart attack in an animal, (ii) attenuates, improves or eliminates one or more symptoms of MMVD, CHF and / or asymptomatic heart attack in an animal, or (iii) prevents or delays the onset of MMVD, CHF and / or asymptomatic heart attack in an animal.

[042] “Treatment”, “treating”, “treats” and similar terms, as used in this document, unless otherwise indicated, refer to relieving, interrupting or delaying the progression of MMVD, CHF and / or asymptomatic heart attack in an animal. As used in this document, these terms also encompass, depending on the animal’s condition, the prevention of the onset of a disorder or condition, or of symptoms associated with a disorder or condition, including the reduction of the severity of a disorder or condition or of the symptoms associated with it. Thus, treatment may refer to the administration of a compound of the invention to an animal that, at the time of administration, has not been diagnosed with CHF.

[043] “Acceptable for veterinary use”, unless otherwise indicated, refers to a substance or composition that is chemically and / or toxicologically compatible with the animal receiving that substance or composition. The term Petition 870250099203, dated 10 / 30 / 2025, pp. 208 / 342 34 / 152 also includes “pharmaceutical” or “pharmaceutically” as acceptable; and is used interchangeably.

[044] As described in this document, “and acceptable veterinary salt(s)” also equally describes “or acceptable veterinary salt(s)”. In some cases, a stereoisomer of the Example or an acceptable veterinary salt of the Example or a stereoisomer thereof may be used in a composition or medicament to treat MMVD, CHF and / or asymptomatic heart attack in an animal.

[045] Myxomatous mitral valve disease (MMVD) is the most common type of acquired heart disease and new heart murmurs in older dogs. A heart murmur is a sound heard with each heartbeat and is caused by turbulent blood flow in the heart. MMVD is a manifestation of a process that can affect the mitral valve. MMVD primarily affects small breed dogs later in life, but can affect larger breed dogs. Some smaller breed dogs are affected earlier in life than others, with the Cavalier King Charles Spaniel being the most prominent breed described to date.

[046] The mitral valve is the valve between the left atrium and the left ventricle. Oxygenated blood from the lungs enters the left atrium, passes through the mitral valve into the left ventricle, and is then pumped to the body. The mitral valve closes when the left ventricle contracts, preventing blood from flowing back into the left atrium. A healthy mitral valve is thin and flexible and is anchored in place by chordae tendineae (CT). Myxomatous degeneration is a process that occurs when the valve becomes thickened with the formation of small nodules that prevent the valves from closing completely, allowing blood to flow back (mitral regurgitation) into the left atrium. Over time, Petition 870250099203, dated 10 / 30 / 2025, pp. 209 / 342 35 / 152 The atria and ventricles compensate for the increase, and the leak progressively worsens. As the leak volume increases, atrial pressure rises. In some cases, the CT may rupture, causing a partially unanchored mitral valve (mitral valve prolapse). The increased pressure is transmitted to the lungs, leading to CHF.

[047] A heart murmur is generally the first way in which MMVD can be detected. After a murmur is detected, MMVD symptoms may not appear for three to four years. In general, the first external sign of worsening MMVD is coughing or increased respiratory effort, which may be due to airway pressure caused by an enlarged heart and / or fluid congestion in the lungs, pericardium, and heart.

[048] Current medications can slow the progression of MMVD to CHF, particularly in the early stages of the disease. Treatments are administered to manage MMVD, CHF, and / or asymptomatic heart attack, including, but not limited to: furosemide, pimobendan, ACE inhibitors (e.g., enalapril), and spironolactone. Furosemide is a potent diuretic that removes water from the body, thus decreasing pulmonary fluid congestion. Pimobendan helps the heart work more effectively, aids in reducing cardiac remodeling, and has been shown to improve survival in patients with MMVD. ACE inhibitors and spironolactone block the deleterious compensatory mechanisms that occur in severe heart disease and also prolong survival. Side effects of these medications include allergic reaction, staggering, loss of appetite, lethargy, diarrhea, and fainting.Other medications that can be used to control CHF symptoms include hydrochlorothiazide, amlodipine, torsemide, and digoxin. Petition 870250099203, dated 10 / 30 / 2025, pp. 210 / 342 36 / 152

[049] Despite the development of new drugs and treatment regimens, there is still uncertainty about when to treat and what the best interventions are for some of these animals. In 2009, an objective classification system was developed to categorize heart diseases based on risk factors and clinical and imaging diagnostic signs.

[050] Heart attack is divided into different stages, which have been defined by different classification systems, for example, the International Small Animal Cardiac Health Council (ISACHC), the New York Heart Association (NYHA) functional classification systems, and the classification currently used according to the American College of Veterinary Internal Medicine (ACVIM) Consensus Statements, 2009. To eliminate any ambiguity between classification systems, the classification systems described below should be considered synonymous.

[051] Classification according to the International Small Animal Heart Health Council (ISACHC) System: Class I: asymptomatic (also known as occult or preclinical); Class IA: no evidence of compensation for underlying heart disease (no volume or pressure overload detected radiographically or echocardiographically); Class IB: clinical signs of compensation for underlying heart disease (volume overload or pressure overload detected radiographically or echocardiographically); Class II: mild to moderate heart attack with clinical signs at rest or with light exercise (treatment required); Class III: advanced heart attack; clinical signs of severe congestive heart attack; Class IIIA: home treatment possible; and Class IIIB: requires hospitalization.

[052] New York Heart Association functional classification system Petition 870250099203, dated 10 / 30 / 2025, pp. 211 / 342 37 / 152 (NYHA): Class I: describes patients with asymptomatic heart disease (e.g., chronic valvular heart disease (CVHD) is present but there are no evident clinical signs, even with exercise); Class II: describes patients with heart disease that causes clinical signs only during strenuous exercise; Class III: describes patients with heart disease that causes clinical signs with routine daily activities or light exercise; and Class IV: describes patients with heart disease that causes severe clinical signs even at rest.

[053] The ACVIM system describes four basic stages of heart disease and heart attack: Stage A: patients at high risk of developing heart disease but who currently have no identifiable structural heart disorder; Stage B: patients with structural heart disease (e.g., the typical murmur of mitral valve regurgitation is present) but who have never developed clinical signs caused by heart attack (due to important clinical implications for prognosis and treatment, the panel subdivided Stage B into Stage B1 and B2). Stage B1: asymptomatic patients who have no radiographic or echocardiographic evidence of cardiac remodeling in response to CVHD. Stage B2: asymptomatic patients who present with hemodynamically significant valvular regurgitation, as evidenced by radiographic or echocardiographic findings of left-sided heart enlargement.Stage C: Patients with past or present clinical signs of heart attack associated with structural heart disease. Stage D: Patients with end-stage disease with clinical signs of heart attack caused by CVHD that are refractory to standard therapy.

[054] Heart pathology begins with ISACHC Class I, NYHA Class I, and ACVIM stage B2, in which there is a heart murmur or enlargement of the heart chamber, but no clinical symptoms are present (ISACHC Class I or asymptomatic / Petition 870250099203, dated 10 / 30 / 2025, pp. 212 / 342 38 / 152 occult / preclinical stage). Clinical symptoms manifest during the course of disease progression (ISACHC Class II or III, NYHA class II, III or IV, ACVIM stage C and D).

[055] The compounds of the invention have an affinity for PDE3 and may provide a potentially novel drug to veterinarians for the treatment of MMVD, CHF and / or asymptomatic heart attack in animals.

[056] The compounds of the invention are useful as PDE3 antagonists for the treatment of MMVP, CHF and / or asymptomatic heart attack in animals, especially canines. Another aspect of the invention is a composition for veterinary use comprising a therapeutically effective amount of a compound of the invention and acceptable veterinary salts thereof. Another aspect of the invention is a composition for veterinary use comprising a therapeutically effective amount of a compound of the invention, acceptable veterinary salts and an acceptable veterinary excipient. The compounds of the invention (including the compositions and the processes used therein) can also be used in the manufacture of a medicament for the therapeutic applications described in this document.

[057] The compounds of the invention may be administered alone or in a formulation appropriate for the specific intended use and for the animal species to be treated. In general, it will be administered as a formulation in association with one or more acceptable veterinary excipients. The term “excipient” is used in this document to describe any ingredient other than the compound of the invention, or its salt, or any additional veterinary agent. The choice of excipient(s) will depend, in large part, on factors such as the specific mode of administration, the effect of the excipient(s) on solubility and stability, and the nature of the dosage form. In addition to the excipient(s), the amount of the compound Petition 870250099203, dated 10 / 30 / 2025, pp. 213 / 342 39 / 152 of the invention that is administered and the dosage regimen for the treatment of a condition or disorder with the compound depend on several factors, including the age, weight, sex and medical condition of the animal, the severity of the disease, the route and frequency of administration and, therefore, may vary widely.

[058] In one aspect, the composition for veterinary use comprises a compound of the invention with an acceptable veterinary excipient. The concentration range varies according to the composition (e.g., oral or injectable). The range of the active agent (i.e., compound of the invention (e.g., Ex. No. 19, No. 23, No. 24, No. 57, No. 62, No. 75 and the like) is from about 0.005 to 10 mg / kg; or from about 0.01 to 10 mg / kg; or from about 0.1 to 10 mg / kg; or from about 0.1 to 5 mg / kg; or from about 0.2 to 5 mg / kg; or from about 0.2 to about 2.5 mg / kg.

[059] The formulations can be prepared using conventional dissolution and mixing procedures. Such compositions and methods for their preparation can be found, for example, in “Remington's Veterinary Sciences”, 19th edition (Mack Publishing Company, 1995); and “Veterinary Dosage Forms”: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, NY, 1980 (ISBN 0-8247-6918-X).

[060] A typical formulation is prepared by mixing a compound of the invention with at least one acceptable veterinary excipient. Suitable excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic materials or Petition 870250099203, dated 10 / 30 / 2025, pp. 214 / 342 40 / 152 hydrophobic, gelatin, oils, solvents, water and the like. The specific excipient(s) will depend on the medium and purpose for which the compound of the invention is being applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe for administration to a mammal. Formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrance agents, flavoring agents and other additives known to provide an elegant presentation of the drug (i.e., a compound of the invention composition for veterinary use thereof) or to aid in the manufacture of the pharmaceutical product (i.e., medicament).In general, the compound of the invention will be formulated in veterinary dosage forms to provide an easily controllable dosage form for administration.

[061] The methods by which the compound of the invention can be administered include oral and injectable (e.g., parenteral and subcutaneous).

[062] The compounds of the invention can be administered orally in capsules, boluses, tablets, powders, lozenges, chewables, multi- and nanoparticles, gels, solid solutions, films, sprays or liquid form. This is a preferred method of administration and, therefore, it is desirable to develop the compound for oral administration. These formulations may include soft or hard capsules and tablets, soft or hard palatable chewables, which typically comprise an excipient, for example, water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methylcellulose, glycerol, magnesium stearate, pregelatinized starch, sodium starch glycolate, animal-derived flavoring (chicken, liver, meat). Petition 870250099203, dated 10 / 30 / 2025, pp. 215 / 342 41 / 152 bovine and similar), flavoring of non-animal origin (e.g., vegetables, fruits, yeasts and similar) and other known pharmaceutical excipients that are designated as fillers, disintegrants, stabilizers, antioxidants and preservatives and similar. Liquid forms include suspensions, solutions, syrups, drains and elixirs. Liquid formulations may also be prepared by reconstituting a solid, for example, from a sachet or lyophilized powder.

[063] Injectable formulations may be prepared in the form of a sterile solution which may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with blood. Acceptable liquid excipients include vegetable oils such as sesame oil and cottonseed oil, glycerides such as triacetin, esters such as benzyl benzoate, isopropyl myristate and propylene glycol fatty acid derivatives, as well as organic solvents such as pyrrolidine-2-one, benzyl alcohol and glycerol formaldehyde. The formulations are prepared by dissolving or suspending the compounds of the invention alone or with an additional veterinary agent in the liquid excipient(s) such that the final formulation contains from 0.01 to 30% by weight of the active ingredient.

[064] Suitable devices for administering injectables include needle injectors (including microneedle injectors), needleless injectors, and infusion techniques. Injectable formulations are normally aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (preferably with a pH of 3 to 9), but for some applications, they may be more appropriately formulated as a sterile non-aqueous solution or as a dry powder form. Petition 870250099203, dated 10 / 30 / 2025, pp. 216 / 342 42 / 152 to be used in conjunction with a suitable vehicle, such as sterile, pyrogen-free water. The preparation of injectable formulations under sterile conditions, for example by lyophilization, can be readily performed using standard veterinary techniques well known to those skilled in the art. The solubility of a compound of the invention used in the preparation of an injectable solution can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

[065] The compound of the invention should be administered once or twice a day. Preferably once a day. In addition, the compound of the invention can also be administered once or twice every 2, 3, 4, 5, 6 or 7 days.

[066] The composition of the invention can be administered alone, as described above, or in combination with at least one other additional veterinary agent, thus providing a broader spectrum of veterinary utility. These at least one other additional veterinary agent, including pharmaceutical agents, can be dosed simultaneously with the compound of the invention or at any time during the treatment of the animal.

[067] The following list of additional pharmaceutical (veterinary) cardiovascular agents with which the compound of the invention may be used to treat heart disease (e.g., MMVD, CHF, and / or asymptomatic heart attack) in an animal is intended to illustrate possible combinations but does not impose any limitations. Non-limiting examples of additional pharmaceutical (veterinary) agents include: diuretics (e.g., furosemide, chlorothiazide, indapamide, triamterene, hydrochlorothiazide, and the like) to reduce edema and effusion; aldosterone antagonists (e.g., spironolactone, eplerenone, and the like) to reduce aldosterone-mediated myocardial fibrosis and possibly delay progression. Petition 870250099203, dated 10 / 30 / 2025, pp. 217 / 342 43 / 152 of heart disease and block the reabsorption of aldosterone, spironolactone, eplerenone and similar drugs) to reduce aldosterone-mediated myocardial fibrosis, possibly slowing the progression of heart disease and blocking sodium reabsorption, which stimulates water loss; and an ACE inhibitor (e.g., enalapril, ramipril, benazepril, imidapril and similar drugs) to inhibit the action of angiotensin-converting enzyme, producing balanced vasodilation through relaxation of blood vessels.

[068] The veterinary composition for application to an animal may be packaged in various ways, depending on the method used to administer the compound of the invention or its combination. Generally, a distribution article includes a container that has the veterinary composition deposited therein in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders and the like. The container may also include a tamper-evident seal to prevent indiscreet access to the contents of the package. In addition, the container has a label deposited on it describing the contents of the container. The label may also include appropriate warnings.

[069] The compounds of the invention (including the compositions and processes used therein) can also be used in the manufacture of a medicament for the therapeutic applications described in this document.

[070] The structures of the compounds in the examples below have been confirmed by one or more of the following methods: proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance (1H NMR) spectra were determined with a Bruker spectrometer operating at a field intensity of 400 megahertz (MHz). Chemical shifts Petition 870250099203, dated 10 / 30 / 2025, pp. 218 / 342 44 / 152 are reported in parts per million (PPM, δ) relative to an internal tetramethylsilane standard or residual protonated NMR solvents. Mass spectra (MS) data were obtained using an Agilent 1200 Series LC / MS system equipped with an Agilent 6125 or 6140 single quadrupole mass spectrometer and a Waters BEH C8 1.7μm 2.1x50 mm column using gradient conditions of 0.1% TFA in acetonitrile / water; or similar instrumentation (Waters Acquity or Shimadzu), column (Waters Acquity BEH C8, Waters YMC Triart C18, Waters Xbridge C18 / Agilent Zorbax C18 or Waters Xbridge C18) and using mobile phase gradient conditions (A: 0.05% formic acid in water; B: 0.05% formic acid in ACN:water (90:10); or A: 10 mM ammonium acetate in water; B: ACN; or A: 5 mM ammonium acetate in water; B: 5 mM ammonium acetate in ACN:water (90:10); or A: 0.1% formic acid in water; B: 0.1% formic acid in ACN).

[071] The compounds of the invention can be synthesized by synthetic routes that include processes analogous to those well known in chemical techniques, particularly in light of the description contained herein. Starting materials are generally available from commercial sources, such as Chemicals (Milawykee, Wis.), or are readily prepared using methods well known to those skilled in the art (for example, prepared by methods generally described in Louis F. Fieser and Mary Fieser, “Reagents for Organic Synthesis”, 1; 19, Wiley, New York (edition 1967–1999), or Beilsteins Hebuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available in the Beilstein online database)). For illustrative purposes, the reaction schemes described below demonstrate possible routes for synthesizing the compounds of the invention and the main intermediates.A more detailed description of the individual steps of the reaction can be found in the Examples section. The person. Petition 870250099203, dated 10 / 30 / 2025, pp. 219 / 342 45 / 152 experienced individuals will understand that the compounds of the invention can be produced by methods other than those described in this document, by adapting the methods described in this document and / or by adapting methods known in the art, for example, the technique described in this document, or by using standard textbooks such as “Comprehensive Organic Transformations - A Guide to Functional Group Transformations”, RC Larock, Wiley-VCH (1999 or later editions).

[072] Many of the compounds of the present invention described herein contain at least one asymmetric or chiral center and therefore exist in different stereoisomeric forms. Chirality refers to the structural characteristic of a molecule that makes it impossible to superimpose it onto its mirror image (e.g., “R” and “S” enantiomers). Examples numbered 7, 9, 15, 25, 27, 32, 44, 52, 59, 61, 66, 72, 84-86 and 88-89 do not contain a chiral carbon. The R and S configurations are based on knowledge of known chiral inversion / retention chemistry. Unless otherwise specified, the stereoisomeric forms of the compounds of the invention, as well as their racemic mixtures, are intended to be part of the present invention. Racemic mixtures of enantiomers can be separated into their individual enantiomeric forms by the skilled craftsman based on their physicochemical differences using methods well known to those versed in the art, such as chromatography and / or fractional crystallization.A more detailed description of the techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley and Sons, Inc. (1981). One skilled in the art will understand that a stereoisomer may be more active and / or may exhibit beneficial effects when enriched relative to the other stereoisomeric form when separated from the racemic mixture. Petition 870250099203, dated 10 / 30 / 2025, pp. 220 / 342 46 / 152

[073] Useful general examples and procedures for the preparation and isolation of the compounds of the invention are described in this document. It should be understood, however, that the invention, as described in its entirety in this document and as mentioned in the claims, is not intended to be limited by the details of the schemes or preparation methods that follow.

[074] In the schemes and examples described in this document, the following reagents and various abbreviations are included: acetic acid (AcOH); acetonitrile (Acn or MeCN); aluminum chloride (AlCh); carbonyldi-imidazole (CDI); dichloromethane (DCM); CH2CL2); N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO); 1,1'-bis(diphenylphosphino)ferrocene (dppf); ethyl acetate (EtOAc); ethanol (EtOH); ethylmagnesium bromide (EtMgBr); [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethyl-azanium hexafluorophosphate (HATU); hydrochloric acid (HCl); high-performance liquid chromatography (HPLC); isopropylmagnesium chloride; lithium chloride (iPrMgCl).LiCl); potassium carbonate (K2CO3); tripotassium phosphate (K3PO4); potassium bis(trimethylsilyl)amide (KHMDS); potassium acetate (KOAc); potassium thiocyanate (KSCN); lithium borohydride (LiBH4); liquid chromatography mass spectrometry (LCMS); lithium bis(trimethylsilyl)amide (LiHMDS); lithium hydroxide (LiOH); methanol (MeOH); 2-methyltetrahydrofuran (MeTHF); sodium carbonate (Na2CO3); sodium bicarbonate (NaHCO3); sodium nitrite (NaNO2); sodium sulfate (Na2SO4); N-bromosuccinimide (NBS); n-butylyl (n-Buly); N-chlorosuccinimide (NCS); hydrazine (NH2NH2); nuclear magnetic resonance (NMR); N,N-diisopropylethylamine (DIPEA); p-methoxybenzyl (PMB); room temperature (RT); triethylamine (TEA); trifluoroacetic acid (TFA); tetrahydrofuran (THF); thin-layer chromatography (TLC); palladium (Pd); palladium on carbon (Pd / C); [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2); tris(dibenzylideneacetone)dipalladium(II) (Pd2(dba)3);. Petition 870250099203, dated 10 / 30 / 2025, pp. 221 / 342 47 / 152 [1,1'-Bis(di-tert-butylphosphine)-ferrocene]dichloropalladium(II) (Pd-118, Pd(dtbpf)Cb); [1,1'-bis(diphenyl-phosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1; Pd(dppf)Cl2.DCM); potassium tert-butoxide (t-BuOK); tri-tert-butylphosphine (P(tBu)3)); water (H2O); 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos); palladium(ll) 2dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl[2-(2'-amino-1,1'biphenyl)]methane sulfonate (XPhos Pd G3); and zinc cyanide (Zn(CN2)).

[075] Acceptable veterinary salts of the compounds of the invention can also be prepared in a conventional manner. For example, a solution of a free base can be treated with the appropriate acid, pure or in a suitable solvent, and the resulting salt can be isolated by filtration or by evaporation under reduced pressure of the reaction solvent. For a review of suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[076] The compound of the invention can be used in its native form or as a salt. In cases where it is desired to form a stable and non-toxic acidic or basic salt, administration of the compound as an acceptable veterinary salt may be suitable. "Pharmaceutically acceptable salt," as used in this document unless otherwise indicated, refers to any salt suitable for pharmaceutical use in an animal, preferably acetate, ascorbate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, ethoglutarate, esilate, formate, fumarate, gluceptate, gluconate, glucuronate, glycerophosphate, hexafluorophosphate, hydroxybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, Petition 870250099203, dated 10 / 30 / 2025, pages 222 / 342 48 / 152 stearate, succinate, tartrate, tosylate or trifluoroacetate salt.

[077] For illustrative purposes, the reaction schemes described below provide potential routes for synthesizing the compounds of the present disclosure, as well as key intermediates. Those skilled in the art will understand that other suitable starting materials, reagents, and synthetic routes can be used to prepare the intermediates and compounds of the invention. EXAMPLES

[078] The following examples provide a more detailed description of each compound and the process conditions for the preparation of said compounds of the invention. It should be understood, however, that the invention, as described in its entirety in this document and as mentioned in the claims, is not intended to be limited by the details of the following preparation methods.

[079] Examples No. 35 and No. 40 exist as tautomers in which the hydrogen atom and the double bond of the quinolinyl ring spontaneously interconvert and are in a state of equilibrium.

[080] Preparation of Example No. 3 (8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one) and Example No. 12 (8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 223 / 342 49 / 152

[081] Step 1: To a solution of 1,2-dichloroethane (25 mL) of 3,4-dihydroquinoline-2(1H)-one (2.5 g, 17 mmol) was added 2-chloropropanoyl chloride (4.25 g, 34 mmol, 2 eq) followed by the addition of aluminum trichloride (9 g, 68 mmol, 4 eq) in three equal portions over 10 minutes, while stirring. The mixture in an inert nitrogen atmosphere was then heated to 50 °C. After 3.5 hours, the reaction was considered complete based on LCMS analysis. The reaction mixture was poured directly into a beaker with ice. After the ice melted, the mixture Petition 870250099203, dated 10 / 30 / 2025, pp. 224 / 342 50 / 152 was poured into a separatory funnel. Methylene chloride (100 mL) was added and the product was extracted. The organic phase was washed again with saturated aqueous NaHCO3 (1 x 50 mL) and brine (1 x 50 mL). The organic layer was dried and concentrated to give 6-(2-chloropropanoyl)-3,4-dihydroquinoline-2(1H)-one (2.75 g, 11.6 mmol), which was used directly in the next step.

[082] Step 2: Potassium tert-butoxide (1.7 g, 15.1 mmol) was added in three equal portions over 20 minutes to a stirred solution of DMSO (40 mL). The mixture was stirred for a further 20 minutes. A solution of diethylmalonate (2.4 g, 15.1 mmol) in DMSO (5 mL) was added dropwise over 10 minutes. The solution was stirred for 20 minutes before the addition of 6-(2-chloropropanoyl)-3,4-dihydroquinoline-2(1H)-one (2.75 g, 11.6 mmol) as a solution in DMSO (10 mL). The reaction mixture was then heated to 35 °C and stirred for 3 hours. The mixture was cooled to room temperature and acetic acid (1.2 g, 20 mmol) was added. The mixture was then divided between ethyl acetate (150 mL) and water (100 mL). The organic layer was washed with water (4 x 70 mL). The organic phase was dried (Na2SO4) and concentrated to give crude diethyl 2-(1-oxo-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)propan-2-yl)malonate (3.5 g, 9.7 mmol).

[083] Step 3: Diethyl 2-(1-oxo-1-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)propan-2yl)malonate (3.5 g, 9.7 mmol) was added to 6N HCl (100 mL) and dioxane (20 mL). The reaction was then heated to 90 °C for 16 hours. The reaction mixture was poured into a beaker with ice water. After the ice melted, the mixture was poured into a separatory funnel and the product was extracted with methylene chloride (4 x 50 mL). The combined organic washes were dried with sodium sulfate and concentrated to obtain crude 3-methyl-4-oxo-4-(2-oxo-1,2,3,4-tetrahydroquinolin-6yl)butanoic acid (1.8 g, 6.9 mmol). Petition 870250099203, dated 10 / 30 / 2025, pp. 225 / 342 51 / 152

[084] Step 4: Ethanol (30 mL) was added to 3-methyl-4-oxo-4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)butanoic acid (1.8 g, 6.9 mmol) followed by the addition of hydrazine monohydrate (1.75 g, 35 mmol). The solution was heated to 65 °C for 4 hours. The mixture was poured into ice water (200 mL), causing the formation of a beige precipitate. The precipitate was collected by suction filtration to give the product, 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2(1H)-one (1.35 g, 5.2 mmol) after drying.

[085] Step 5: To a DMF solution (20 mL) of 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2(1H)-one (1.35 g, 5.2 mmol) was added NBS (1.1 g, 6.2 mmol). The mixture was stirred at 55 °C for 10 hours. A second portion of NBS (0.55 g, 3.1 mmol) was added with stirring at 55 °C for a further 3 hours. The reaction was then poured into ice-cold water (150 mL). The beige precipitate was collected by suction filtration and washed with water (3 x 50 mL). After drying, the crude product, 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)3,4-dihydroquinolin-2(1H)-one (Example No. 3; 1.45 g, 4.3 mmol) was obtained. The pure product was obtained by flash column chromatography (3.5% MeOH in CH2Cl2). 1H NMR (400 MHz, DMSO-d6): δ 10.97 (s,1H), 9.31 (s,1H), 7.82 (d,1H), 7.65 (d,1H), 3,343.45 (m,1H), 2.98 (t,2H), 2.67 (dd, 1H), 2.52-2.55 (m, 2H), 2.18-2.28 (m, 1H), 1.05 (d,3H).

[086] Step 6: Dioxane (4 mL) and water (0.5 mL) were added to 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)3,4-dihydroquinolin-2(1H)-one (120 mg, 0.36 mmol). Then, (3-fluorophenyl)boronic acid (80 mg, 0.57 mmol) and sodium bicarbonate (165 mg, 1.9 mmol) were added. The mixture was then degassed by several vacuum purges, replenishing with nitrogen. Finally, 1,1-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (60 mg, 0.06 Petition 870250099203, dated 10 / 30 / 2025, pp. 226 / 342 52 / 152 mmol). The mixture was then stirred at 75 °C for 3 hours. The reaction was filtered through a Celite buffer. The buffer was washed with methylene chloride (20 mL). The organic phase was washed with water (1 x 10 mL). The organic phase was concentrated. The crude residue was dissolved in DMF (4.5 mL) and purified using reverse-phase HPLC to obtain the compound of Example No. 12 (68 mg, 0.18 mmol) after lyophilization. 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H), 9.03 (s, 1H), 7.68 (s, 1H), 7.54-7.48 (m, 2H), 7.27-7.23 (m, 3H), 3.44-3.40 (m, 1H), 2.99-2.96 (m, 2H), 2.68-2.62 (m, 1H), 2.55-2.50 (m, 2H), 2.39-2.19 (m, 1H), 1.06 (d, J = 7.2 Hz, 3H). LCMS: Retention time = 2.51 minutes; HPLC purity = 98.20%

[087] The preparation of Example No. 1, 8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2(1H)-one, was conducted similarly to Example No. 12, but using boronic acid (2-methoxypyridin-4-yl) instead of boronic acid (3-fluorophenyl) in Step 6 to obtain the compound of Example No. 1. 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H), 9.23 (s, 1H), 8.24 (d, 1H), 7.83 - 7.60 (m, 1H), 7.01 (dd, 1H), 7.49 (d, 1H), 4.39 (br s, 1 H), 6.85 (s, 1 H), 3.90 (s, 3 H), 3.43 - 3.22 (m, 1 H), 2.98 (br t, 2 H), 2.66 (dd, 1 H), 2.58 - 2.52 (m, 1 H), 2.22 (d, 1 H), 1.06 (d, 3H).

[088] The preparation of Example No. 2, 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(thiazol-2-yl)-3,4-dihydroquinolin-2(1H)-one, was conducted similarly to Example No. 12, but using thiazol-2-ylboronic acid instead of (3-fluorophenyl)boronic acid in Step 6 to obtain the compound of Example No. 2. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 10.95 (s, 1H), 9.43 (d, 1H), 8.42 (d, 1H), 8.13 - 7.93 (m, 1H), 7.72 - 7.67 (m, 1H), 3.66 - 3.39 (br, m, 1 H), 3.03 (t, 2 H), 2.70 (dd, 1 H), 2.61 - 2.52 (m, 1 H), 1.30 (br d, 1 H), 1.09 (d, 3 H).

[089] The preparation of Example No. 4, 8-(2-methoxythiazol-5-yl)-6-(4-methyl-6-oxo Petition 870250099203, dated 10 / 30 / 2025, pp. 227 / 342 53 / 152 The synthesis of 1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2(1H)-one was conducted similarly to Example No. 12, but using 2-methoxythiazol-5-yl boronic acid instead of (3-fluorophenyl)boronic acid in Step 6 to obtain the compound of Example No. 4. 1H NMR (400 MHz, DMSO-d6): δ 10.93 (s, 1H), 9.38 (s, 1H), 7.82 - 7.61 (m, 1H), 7.55 (d, 1H), 7.26 (s, 1H), 4.07 (s, 3H), 3.57 - 3.37 (m, 2H), 3.07 - 2.85 (m, 2H), 2.80 - 2.59 (m, 1 H), 2.58 - 2.52 (m, 1 H), 2.23 (d, 1 H), 1.06 (d, 3 H).

[090] The preparation of Example No. 13, 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one, was conducted similarly to Example No. 12, but using 3-pyridinylboronic acid instead of (3-fluorophenyl)boronic acid in Step 6 to obtain the compound of Example No. 13. 1H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H). 9.34 (s, 1 H), 8.64 - 8.53 (m, 2 H), 7.90 - 7.75 (m, 1 H), 7.74 - 7.61 (m, 1 H), 7.60 - 7.36 (m, 2 H), 3.66 - 3.39 (m, 2 H), 3.17 - 2.90 (m, 2 H), 2.82 - 2.60 (m, 1 H), 2.56 - 2.51 (m, 1 H), 2.22 (d, 1 H), 1.07 (d, 3 H).

[091] The preparation of Example No. 17, 3,3-dimethyl-5-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-(thiazol-4-yl)indolin-2-one, was conducted similarly to Example No. 12, Step 6, but with thiophene-4-boronic acid instead of (3-fluorophenyl)boronic acid and Example No. 47 instead of 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2(1H)-one to obtain the compound of Example No. 17. 1H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1H), 10.12 (s, 1H), 9.29 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.78 (s, 1H), 3.57-3.54 (m, 1H), 2.74-2.68 (m, 1H), 2.32-2.24 (m, 1H), 1.34 (s, 6H), 1.10 (d, J = 7.2 Hz, 3H).

[092] The preparation of Example No. 18, 9-(6-methoxypyridin-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one, was conducted similarly to Example No. 12, Step 6, but using (2 Petition 870250099203, dated 10 / 30 / 2025, pp. 228 / 342 54 / 152 methoxypyridin-5-yl)boronic and 9-bromo-7-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3yl)-1,3,4,5-tetra-hydro-2H-benzo[b]azepin-2-one to obtain the compound of Example 18. (400 MHz, DMSO-d6): δ 8.96 (s, 1 H). 8.21 - 8.14 (d, 1 H), 7.76 - 7.70 (m, 2 H), 7.61 - 7.56 (d, 1 H), 6.94 - 6.87 (d, 1 H), 3.92 - 3.87 (s, 3 H), 3.50 - 3.4 m (3.1 H), 3.00 (m, 1 H), 2.81 - 2.74 (br, t, 2 H), 2.73 - 2.64 (dd, 1 H), 2.30 - 2.24 (m, 2 H), 2.19 - 2.10 (m, 2 H), 3 H).

[093] The preparation of Example No. 63, 6-methyl-5-(7-(4-(methylsulfonyl)phenyl)-2oxoindolin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one, was conducted similarly to Example No. 12, but with (4-(methylsulfonyl)phenyl)boronic acid instead of (3-fluorophenyl)boronic acid in Step 6 and 5-(7-bromo-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-one instead of 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-3,4-dihydroquinoline-2(1H)-one to obtain the compound of Example No. 63. 1H NMR (400 MHz, DMSO-d6): δ 11.62 (s, 1H), 10.63 (brs, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.79-7.77 (m, 3H), 7.66 (s, 1H), 4.85-4.80 (m, 1H), 3.64 (s, 2H), 3.26 (s, 3H), 1.48 (d, J = 7.2 Hz, 3H).

[094] The preparation of Example No. 68, 5-(3,3-dimethyl-2-oxo-7-(thiazol-4yl)indolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, was conducted similarly to Example No. 12, but for 4-thiazolboronic acid instead of (3-fluorophenyl)boronic acid and Example 76 instead of 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinolin-2(1H)-one in Step 6 to provide the compound of Example No. 68. 1H NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 10.17 (s, 1H), 9.30 (d, J = 1.8 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H), 4.92-4.82 (m, 1H), 1.51 (d, J = 7.2 Hz, 3H), 1.35 (s, 6H).

[095] The preparation of Example No. 71, 5-(7-(4-chlorophenyl)-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, was conducted in a manner similar to Petition 870250099203, dated 10 / 30 / 2025, pp. 229 / 342 55 / 152 Example No. 12, but with 4-chlorophenylboronic acid instead of (3-fluorophenyl)boronic acid and 5-(7-bromo-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-one instead of 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3yl)-3,4-dihydroquinoline-2(1H)-one in Step 6 to obtain the compound of Example No. 71. 1H NMR (400 MHz, DMSO-d6): δ 11.59 (s, 1H), 10.53 (s, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.52 (s, 4H), 4.83-4.78 (m, 1H), 3.62 (s, 2H), 1.47 (d, J = 7.2 Hz, 3H).

[096] Preparation of Example No. 6, 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one was prepared according to the following steps:

[097] Step 1: A paste of AlCh (7.9 g, 59.39 mmol) and DMF (1.4 ml, 18.02 mmol) was heated to 70 °C for 15 minutes and then cooled to 40 °C. 7-chloro-2,3-dihydro-1H-indol-2-one (1.0 g, 5.98 mmol) and 3-methyloxolane-2,5-dione (886 mg, 7.78 mmol) were slowly added. The resulting mixture was heated to 70 °C for 1 hour, poured into ice-cooled water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was ground with ethyl ether-pentane to obtain 4-(7-chloro-2-oxoindolin-5-yl)-3-methyl-4-ethyl ether-pentane acid. Petition 870250099203, dated 10 / 30 / 2025, pages 230 / 342 56 / 152 oxobutanoic acid (800 mg, 47%) as brown gum. It was taken to the next step without further purification. MS (ESI): m / z 282.0 [M+1]+.

[098] Step 2: Hydrazine monohydrate (0.27 mL, 5.69 mmol) was added to a stirred solution of 4-(7-chloro-2-oxoindolin-5-yl)-3-methyl-4-oxobutanoic acid (400.0 mg, 1.42 mmol) in ethanol (20.0 mL). The resulting mixture was heated at 80 °C for 16 hours. The crude LCMS showed the formation of two peaks with the mass of the product (undesired:desired = 4:1). The reaction mixture was evaporated under reduced pressure, the residue was absorbed in EtOH and stirred under cooling. The solid thus formed was filtered and discarded [contains the main undesired isomer]. The filtrate was concentrated under reduced pressure and the gross mass was purified by combiflash column chromatography (60-70% EtOAc in hexane) followed by preparative reverse-phase HPLC to obtain the compound of Example No. 6 (40 mg, 10%) as a whitish solid.1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.92 (s, 1H), 7.62760 (m, 2H), 3.64 (s, 2H), 3.38-3.34 (m, 1H), 2.69-2.63 (m, 1H), 2.22 (d, J = 16 Hz, 1H), 1.04 (d, J = 8 Hz, 3H).

[099] The preparation of Example No. 44 (7-chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one) was conducted similarly to Example No. 6, but with 7-chloro-2,3-dimethyl-1H-indol-2-one instead of 7-chloro-2,3-dihydro-1H-indol-2-one and succinic anhydride instead of 3-methyloxolane-2,5-dione to obtain the compound of Example No. 44. 1H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 10.87 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 2.93 (t, 2H), 2.43 (t, 2H), 1.30 (s, 6H).

[0100] Preparation of Example No. 39 (7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-2,3-dihydro-1H-isoindol-1-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 231 / 342 57 / 152

[0101] Step 1. To a stirred solution of potassium tert-butoxide (38.7 mg, 0.35 mmol) in dimethyl sulfoxide (5 mL) was added a solution of diethyl malonate (58 mg, 0.35 mmol) in DMSO (1 mL), dropwise, over 10 minutes, and stirred at room temperature for 40 minutes. A solution of 5-(2-bromopropanoyl)-7-chloro-2,3-dihydro-1H-isoindol-1-one (80 mg, 0.27 mmol) in DMSO (1 mL) was added dropwise over 10 minutes at 0 °C under an argon atmosphere. The resulting mixture was slowly heated to room temperature and stirred for 3 hours. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution at 0 °C and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by combiflash chromatography (30-50% EtOAc in hexane) to obtain 1,3-diethyl 2-[1-(7-chloro-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-1-oxopropan-2-yl]propanedioate (55 mg, 54%) as a yellow solid. MS (ESI): m / z 382[M+1]+. Petition 870250099203, dated 10 / 30 / 2025, pages 232 / 342 58 / 152

[0102] Step 2. A solution of diethyl 1,3-diethyl-2-[1-(7-chloro-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-1-oxopropan-2-yl]propanedioate (220 mg, 0.58 mmol) in 6N aqueous hydrochloric acid (8 mL) was heated at 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure and the residue was co-distilled with toluene twice. The crude product was triturated with diethyl ether to obtain 4-(7-chloro-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-methyl-4-oxobutanoic acid (90 mg, 55%) as a brown gum, which was carried to the next step without further purification. MS (ESI): m / z 282.0 [M+1]+.

[0103] Step 3. To a stirred solution of 4-(7-chloro-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-methyl-4-oxobutanoic acid (80.0 mg, 0.28 mmol) in ethanol (10 mL) was added hydrazine monohydrate (0.1 mL, 1.14 mmol) at room temperature. The resulting mixture was heated to 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure and the crude product obtained was purified by preparative reverse-phase HPLC to obtain the compound of Example 39 (9 mg) as a whitish solid (99.89% purity). 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 8.74 (s, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 4.37 (s, 2H), 3.46-3.43 (m, 1H), 2,772.66 (m, 1H), 2.32-2.25 (m, 1H), 1.08 (d, J = 7.2 Hz, 3H).

[0104] The preparation of Example No. 7, 7-(4-chlorophenyl)-5-(6-oxo-1,6-dihydropyridazin-3-yl)indolin-2-one, was prepared according to the following steps: Petition 870250099203, dated 10 / 30 / 2025, pp. 233 / 342 59 / 152

[0105] Step 1: To a stirred solution of 7-bromo-2,3-dihydro-1H-indol-2one (200.0 mg, 0.94 mmol) in 1,4-dioxane (5.0 ml) and water (2.0 ml) was added potassium phosphate (500 mg, 2.36 mmol) followed by 4-chlorophenylboronic acid (222 mg, 1.42 mmol) and the resulting mixture was purged with argon for 10 minutes. Pd(dppf)Cl2.CH2Cl2 (77.0 mg, 0.09 mmol) was added and the reaction mixture was heated at 100 °C for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (1015% EtOAc in hexane) to obtain 7-(4-chlorophenyl)-2,3-dihydro-1H-indol-2-one (160 mg, 70%) as a brown solid. MS (ESI): m / z 244.02 [M+1]+.

[0106] Step 2: To a stirred solution of 7-(4-chlorophenyl)-2,3-dihydro-1Hindol-2-one (100.0 mg, 0.41 mmol) in trifluoroacetic acid (3.0 ml) was added a portion of N-bromo succinimide (52.0 mg, 0.53 mmol) and the reaction mixture was stirred at room temperature for 16 hours. After completion, the volatiles were Petition 870250099203, dated 10 / 30 / 2025, pages 234 / 342 60 / 152 removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mass was purified by combiflash column chromatography (10-15% EtOAc in hexane) to obtain 5-bromo-7-(4-chlorophenyl)2,3-dihydro-1H-indol-2-one (60 mg, 45%) as a whitish solid. MS (ESI): m / z 323.8 [M+1]+.

[0107] Step 3: To a stirred solution of 5-bromo-7-(4-chlorophenyl)-2,3-dihydro-1H-indol-2-one (250.0 mg, 0.77 mmol) in 1,4-dioxane (5.0 ml) was added bis(pinacolate)-diboron (238 mg, 0.93 mmol) followed by potassium acetate (153 mg, 1.55 mmol) and the resulting mixture was purged with argon for 10 minutes. Pd(dppf)Cl2.CH2Cl2 (64 mg, 0.07 mmol) was added and the reaction mixture was heated to 85 °C for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mass was purified by combiflash column chromatography (3040% EtOAc in hexane) to obtain 7-(4-chlorophenyl)-5-(tetramethyl-1,3,2-dioxaborolan-2yl)-2,3-dihydro-1H-indol-2-one (200 mg, 69%) as a whitish solid. MS (ESI): m / z 370.3 [M+1]+.

[0108] Step 4: To a stirred solution of 7-(4-chlorophenyl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (200.0 mg, 0.54 mmol) in 1,4-dioxane (10.0 ml) and water (2.0 ml) was added potassium phosphate (288.0 mg, 1.35 mmol) followed by 6-bromo-2,3-dihydropyridazin-3-one (143.0 mg, 0.81 mmol) and the resulting mixture was purged with argon for 10 minutes. Pd(dppf)Cl2.CH2Cl2 (44.0 mg, 0.05 mmol) was added and the reaction mixture was heated at 100 °C for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. Petition 870250099203, dated 10 / 30 / 2025, pages 235 / 342 61 / 152 The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (50-60% EtOAc in hexane) to obtain the compound of Example No. 7 (10 mg, 6%) as a whitish solid. 1H NMR (400 MHz, DMSO-d6): δ 13.10 (s, 1H), 10.49 (s, 1H), 8.01 (s, 1H), 7.74 (s, 1H), 7.65 (s, 1H), 7.52 (s, 4H), 6.95 (d, J = 10 Hz, 1H), 3.63 (s, 2H).

[0109] The preparation of Example 9, 8-(4-chlorophenyl)-6-(6-oxo-1,6-dihydropyridazin-3-yl)-3,4-dihydroquinolin-2(1H)-one, was conducted similarly to Example 7, but with 6-bromo-3,4-hydroquinolone instead of 7-bromo-2,3-dihydro1H-indol-2-one to obtain the compound of Example 9. 1H NMR (400 MHz, DMSOd6): δ 13.11 (s, 1H), 9.01 (s, 1H), 8.08 (d, J = 9.6 Hz, 1H), 7.76 (s, 1H), 7.55-7.53 (m, 3H), 7.46-7.44 (m, 2H), 6.96 (d, J = 9.6 Hz, 1H), 3.01-2.98 (m, 2H), 2.52-2.48 (m, 2H).

[0110] The preparation of Example No. 8, 7'-chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one, was prepared according to

[0111] Step 1. A paste of anhydrous AlCh (20.97 g, 157.23 mmol) and DMF (0.004 mL, 47.17 mmol) was heated to 70 °C for 15 minutes and then cooled to 40 °C. Petition 870250099203, dated 10 / 30 / 2025, pp. 236 / 342 62 / 152 °C. Spiro[cyclopropane-1,3'-indolin]-2'-one (2.5 g, 15.72 mmol) and 3-methyldihydrofuran-2,5-dione (2.15 g, 18.89 mmol) were added slowly. The resulting mixture was heated to 70 °C for 2 hours and then poured into ice-cooled water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was triturated with ethyl ether-pentane to obtain 3-methyl~4-oxo~4-{2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indol]5'-yl}butanoic acid (3.0 g, crude, mixture of products) as a brown gum. It was taken to the next stage without further purification. MS (ESI): m / z 274.2 [M+1]+.

[0112] Step 2. Hydrazine monohydrate (1.41 mL, 43.96 mmol) was added to a stirred solution of 3-methyl-4-oxo-4-{2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-5'-yl}butanoic acid (3.0 g, 10.99 mmol) in ethanol (30.0 mL). The resulting mixture was heated at 80 °C for 16 hours. The crude LCMS showed the formation of two peaks with the mass of the product (undesired:desired = 4:1). The reaction mixture was evaporated under reduced pressure, the residue was absorbed in EtOH and stirred under cooling. The solid thus formed was filtered and discarded [contains the main undesired isomer]. The filtrate was concentrated under reduced pressure and the gross mass was purified by combiflash column chromatography (60-70% EtOAc in hexane) to obtain 5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2'-one (270 mg, 7% in two steps) as a white solid. MS (ESI): m / z 270.2 [M+1]+.

[0113] Step 3. To a stirred solution of 5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2'-one (270.0 mg, 1.00 mmol) in DMF (5.0 mL) was added NCS (200.99 mg, 1.51 mmol) at room temperature. The resulting reaction mixture was heated to 70 °C for 3 hours. After the Petition 870250099203, dated 10 / 30 / 2025, pages 237 / 342 63 / 152 In conclusion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (50-60% EtOAc in hexane) to obtain the compound of Example 8. 1H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 10.90 (s, 1H), 7.61 (s, 1H), 7.35 (s, 1H), 3.41-3.38 (m, 1H), 2.68-2.62 (m, 1H), 2.22 (d, J = 16.8 Hz, 1H), 1.71-170 (m, 2H), 1.55-154 (m, 2H), 1.03 (d, J = 7.2 Hz, 3H).

[0114] Preparation of Example No. 19 (6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1Hbenzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one) —o (18)

[0115] Step 1. To a stirred solution of 1-(4-methoxyphenyl)cyclopropane-1-carboxylic acid (200 mg, 1.04 mmol) in DMF (5 mL) at 0 °C, 4-methylmorpholine (0.23 mL, 2.08 mmol) was added followed by HATU (395.64 mg, 1.041 mmol) and the resulting mixture was stirred at 0 °C for 10 minutes. 6-(3,4-diaminophenyl)5-methyl-2,3,4,5-tetrahydropyridazin-3-one (227 mg, 1.04 mmol) was added and the resulting mixture Petition 870250099203, dated 10 / 30 / 2025, pp. 238 / 342 64 / 152 was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain N-[2-amino-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl]-1-(4-methoxyphenyl)cyclopropane-1-carboxamide (200 mg, crude) as a yellow semisolid [mixture of two regio isomers]. It was used in the next step without further purification. MS (ESI): m / z 392.9 and 393.3 [M+1]+.

[0116] Step 2. A stirred solution of N-[2-amino-4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl]-1-(4-methoxyphenyl)cyclopropane-1-carboxamide (200 mg, 0.53 mmol) in acetic acid (5 mL) was heated at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The crude product thus obtained was purified by reversed-phase pre-HPLC to obtain the compound of Example 19 (110 mg, 58%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.79 and 11.74 (s, 1H), 10.85 and 10.83 (s, 1H), 7.86 and 7.69 (s, 1H), 7.66 and 7.56 (d, J = 8.2 Hz, 1H), 7.49 and 7.33 (d, J = 8.2 Hz, 1H), 7.35 7.31 (m, 2H), 6.94 (m, 2H), 3.76 (s, 3H), 3.46 and 3.37 (m, 1H), 2.72 and 2.68 (m, 1H), 2.25 and 2.20 (m, 1H), 1.60 - 1.57 (m, 2H), 1.33 - 1.30 (m, 2H), 1.08 (d, J = 6.8 Hz, 3H). LCMS: Retention time = 2.20 minutes; HPLC purity = 99.72%. Note: 1H NMR indicated that the product is a mixture of isomers.

[0117] Preparation of Example No. 21 (5-methyl-6-(1-methyl-2-(phenylamino)-1Hbenzo[d]imidazol-6-yl)-4,5-dihydropyridazine-3(2H)-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 239 / 342 65 / 152

[0118] Step 1. Isothiocyanatobenzene (1.2 mL, 10.00 mmol) in N,N-dimethylformamide (15 mL) at room temperature was added to a solution of 3(3,4-diaminophenyl)-4-methyl-4,5-dihydro-1H-pyridazin-6-one (2.183 g, 10.00 mmol) in / V, / V-dimethylformamide (15 mL) and the contents were stirred at room temperature. After 2 hours, A / ,A / -diisopropylmethanedimine (1.86 mL, 12.00 mmol) was added to the reaction mixture and the contents were stirred at 70 °C overnight. The reaction mixture was then cooled to room temperature and purified directly by reverse-phase chromatography to give 3-(2-anilino-3H-benzimidazol-5-yl)-4-methyl-4,5-dihydro-1H-pyridazin-6-one (m / z [M+H] = 320).

[0119] Step 2. A 60% sodium hydride dispersion in mineral oil (138 mg, 3.44 mmol) was added to a tetrahydrofuran solution (20 mL) of 3-(2anilino-3H-benzimidazol-5-yl)-4-methyl-4,5-dihydro-1H-pyridazin-6-one (1.00 g, 3.13 mmol) at 0 °C and stirred for 1 hour. Methyl iodide (0.214 mL, 3.44 mmol) was added and the mixture was stirred overnight. The resulting mixture was diluted with Petition 870250099203, dated 10 / 30 / 2025, pages 240 / 342 66 / 152 ethyl acetate and washed with water and brine. The organic layer was concentrated under reduced pressure and the residue was purified by reverse-phase preparative HPLC to obtain the compound of Example 21. dH (d6-DMSO) 10.83 (s, 1H), 9.00 (s, 1H), 7.87 (d, 2H), 7.71 (s, 1H), 7.55 (d, 1H), 7.25-7.40 (m, 3H), 6.97 (t, 1H), 3.75 (s, 3H), 3.45-3.60 (m, 1H), 2.70 (dd, 1H), 2.26 (d, 1H), 1.12 (d, 3H).

[0120] Preparation of Example No. 24 (7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one)

[0121] Step 1. To a stirred solution of 3,3-dimethyl-2,3-dihydro-1H-indol-2-one (5.0 g, 31.02 mmol) in 1,2-dichloroethane (150 mL) at 0 °C, anhydrous aluminum chloride (10.4 g, 77.54 mmol) was added and stirred at 10 °C for 30 minutes. Propionyl chloride (5.8 g, 62.04 mmol) was added dropwise to the reaction mixture and stirred at 80 °C for 16 hours. After completion, the reaction mixture was diluted with ice-cooled water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (30-40% EtOAc). Petition 870250099203, dated 10 / 30 / 2025, pp. 241 / 342 67 / 152 in hexane) to obtain 3,3-dimethyl-5-propanoyl-2,3-dihydro-1H-indol-2-one (3 g, 44%) as a white solid. MS (ESI): m / z 218.0 [M+1]+.

[0122] Step 2. A solution of 3,3-dimethyl-5-propanoyl-2,3-dihydro-1H-indol-2-one (2 g, 9.20 mmol) in THF (30 mL) was added to a stirred solution of LiHMDS (11.1 mL, 11.1 mmol, 1M in THF) in THF (30 mL) at -78 °C and the resulting mixture was stirred at -78 °C for 1 hour. A solution of ethyl 2-bromoacetate (1.85 g, 11.05 mmol) in THF (30 mL) was added dropwise over 20 minutes and stirred for a further 1 hour at -78 °C. After completion, the reaction mixture was slaked with 1N HCl and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (4050% EtOAc in hexane) to obtain ethyl 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-methyl-4-oxobutanoate (900 mg, 32%) as a white solid. MS (ESI): m / z 304.0 [M+1]+.

[0123] Step 3. To a stirred solution of ethyl 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-methyl-4-oxobutanoate (700 mg, 2.31 mmol) in EtOH (20 mL) and MeOH (5 mL) at 0 °C, LiOH.H2O (11.5 mL, 11.54 mmol, 1M in H2O) was added dropwise and stirred at room temperature for 16 hours. After completion, the reaction mixture was evaporated under reduced pressure, the residue was diluted with water and extracted with 50% ethyl acetate in hexane. The organic part was discarded. The aqueous part was acidified with 2N HCl to pH ~4 and extracted with 10% MeOH in ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-methyl-4-oxobutanoic acid (470 mg, 74%) as a white solid. MS (ESI): m / z 274.4 [M-1]+. Petition 870250099203, dated 10 / 30 / 2025, pages 242 / 342 68 / 152

[0124] Step 4. Hydrazine monohydrate (89.7 mg, 1.79 mmol) was added to a stirred solution of 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-methyl-4-oxobutanoic acid (470 mg, 1.71 mmol) in ethanol (15 mL) and stirred at 80 °C for 16 hours. After completion, volatiles were removed under reduced pressure and the crude product was purified by combiflash column chromatography (60-70% ethyl acetate in hexane) to obtain 3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-2,3-dihydro-1H-indol-2-one (200 mg, 43%) as a white solid. MS (ESI): m / z 271.9 [M+1]+.

[0125] Step 5. To a stirred solution of 3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-2,3-dihydro-1H-indol-2-one (50 mg, 0.18 mmol) in DMF (1 mL) was added N-chlorosuccinimide (27 mg, 0.2 mmol) and stirred at room temperature for 1 hour. After completion, the reaction mixture was poured into ice water. The solid thus formed was filtered, washed with diethyl ether, and dried under vacuum to obtain the compound of Example 24 (20 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.92 (s, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 3.42-3.37 (m, 1H), 2.71-2.65 (m, 1H), 2.22 (d, J = 16.8 Hz, 1H), 1.30 (s, 6H), 1.06 (d, J = 7.2 Hz, 3H). LCMS: Retention time = 1.56 minutes; HPLC purity = 98.00%. The enantiomers of Example No. 24 are Example No. 33 and Example No. 51.Example 33 is the (R) isomer and was solved by HPLC (Chiralpak IG 250x4.6 mm, 5 μ column; mobile phase (hexane / DCM / EtOH / isopropylamine (50 / 25 / 25 / 0.1) at a flow rate of 1.0 mL / minute). The HPLC retention time for Examples 33 and 24 was 5.88 and 6.63 minutes, respectively.

[0126] The preparation of Example No. 23, 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one, was conducted similarly to Example No. 24, but with 7-bromo-3,3-dimethylindolin-2-one instead of 7-chloro-3,3 Petition 870250099203, dated 10 / 30 / 2025, pp. 243 / 342 69 / 152 dimethylindolin-2-one to obtain the compound of Example No. 23. 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H), 10.83 (s, 1H), 7.74 (s, 2H), 3.42-3.38 (m, 1H), 2.70-2.65 (m, 1H), 2.22 (d, J = 16.8 Hz, 1H), 1.29 (s, 6H), 1.05 (d, J = 7.2 Hz, 3H).

[0127] Preparation of Example No. 26 (7-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one)

[0128] Step 1. Lithium chloride (4.2 g, 99.34 mmol) was added to a stirred solution of 7-fluoroindolin-2-one (5 g, 33.11 mmol) in dry THF (50 mL), and the resulting mixture was cooled to -78 °C. Lithium diisopropylamide (33.1 mL, 66.2 mmol, 2.0 M in THF / heptane / ethylbenzene) was added, and the mixture was stirred at -78 °C for 15 minutes. Methyl iodide (1.8 mL, 66.2 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. After completion, the reaction mixture was slaked with an aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Gross product Petition 870250099203, dated 10 / 30 / 2025, pp. 244 / 342 70 / 152 was purified by column chromatography (10-20% EtOAc in hexane) to obtain 7fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (2.7 g, 46%) as a white solid. MS (ESI): m / z 180.1 [M+1]+.

[0129] Step 2. DMF (3.78 mL, 49.54 mmol) was added dropwise to anhydrous AlCl3 (19.98 g, 150.12 mmol) and the resulting mixture was stirred at 70 °C for 15 minutes and then cooled to 40 °C. 7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (2.7 g, 15.08 mmol) and 2-chloropropanoyl chloride (1.86 mL, 18.75 mmol, 1.25 eq.) were slowly added to the AlCl3 melt and heated to 70 °C for 4 hours. After completion, the reaction mixture was left at room temperature, slowly poured over crushed ice, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (10-20% EtOAc in hexane) to obtain 5-(2-chloropropanoyl)-7-fluoro-3,3-dimethylindolin-2-one (1.4 g, 35%) as a yellow solid. MS (ESI): m / z 270.2 [M+1]+.

[0130] Step 3. To a stirred solution of potassium tert-butoxide (850 mg, 7.55 mmol) in DMSO (20 mL) was added diethylmalonate (1.2 g, 7.55 mmol) in DMSO (12 mL), dropwise over 10 minutes. The solution was stirred for 20 minutes and 5-(2-chloropropanoyl)-7-fluoro-3,3-dimethylindolin-2-one (1.4 g, 5.8 mmol) in DMSO (5 mL) was added. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was slaked with acetic acid (0.6 mL, 10 mmol) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (30-40% ethyl acetate in hexane) to obtain 2-(1-(7-fluoro-3,3-dimethyl diethyl malonate). Petition 870250099203, dated 10 / 30 / 2025, pages 245 / 342 71 / 152 2-oxoindolin-5-yl)-1-oxopropan-2-yl) (800 mg, 27%) as a white solid. MS (ESI): m / z 394.1 [M+1]+.

[0131] Step 4. A solution of diethyl 2-(1-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-1-oxopropan-2-yl)malonate (800 mg, 2.03 mmol) in 6N HCl (50 ml) and dioxane (15 ml) was heated at 90 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-3-methyl-4-oxobutanoic acid (600 mg, crude) as a colorless gum. MS (ESI): m / z 294.3 [M+1]+.

[0132] Step 5. To a stirred solution of 4-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-3-methyl-4-oxobutanoic acid (600 mg, crude) in ethanol (20 mL) was added hydrazine monohydrate (3 mL) and heated at 90 °C for 16 hours. After completion, the reaction mixture was quenched with water and extracted with 10% MeOH in DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (1-5% MeOH in DCM) to obtain the compound of Example 26 (340 mg, 54% in two steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 10.92 (s, 1H), 7.61 (s, 1H), 7.50-7.48 (m, 1H), 3.40-3.38 (m, 1H), 2.689-2.66 (m, 1H), 2.24-2.20 (m, 1H), 1.29 (s, 6H), 1.05 (bs, 3H). Retention time = 6.11 minutes; HPLC purity = 96.27%

[0133] Preparation of Example No. 27 (7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indolin-2-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 246 / 342 72 / 152

[0134] Step 1. To a stirred solution of 7-fluoro-3,3-dimethyl-2,3-dihydro-1Hindol-2-one (2.7 g, 15.08 mmol) in trifluoroacetic acid (30 mL) was added N-bromosuccinimide (4 g, 22.63 mmol) in portions and the reaction mixture was stirred at room temperature for 16 hours. After completion, the trifluoroacetic acid was evaporated under reduced pressure. The residue was diluted with ethyl acetate, water, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by combined flash column chromatography (30-40% ethyl acetate in hexane) to obtain 5-bromo-7-fluoro-3,3-dimethylindolin-2-one (2 g, 52%) as a whitish solid. MS (ESI): m / z 257.6 [M+1 ]+.

[0135] Step 2. To a stirred solution of 5-bromo-7-fluoro-3,3-dimethylindolin-2-one (2 g, 7.72 mmol) in dioxane (5 mL) was added bis(pinacolate)diboron (2.37 g, 9.33 mmol) followed by KOAc (1.51 g, 15.44 mmol) and the resulting mixture was purged with argon for 10 minutes. Pd(dppf)Cl2.DCM (630 mg, 0.772 mmol) was added and the reaction mixture was heated at 95 °C for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, Petition 870250099203, dated 10 / 30 / 2025, pp. 247 / 342 73 / 152 filtered and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography (30-40% EtOAc in hexane) to obtain 7-fluoro-3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (1.5 g, 63%) as a whitish solid. MS (ESI): m / z 305.9 [M+1]+.

[0136] Stage 3. 7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazin-3-yl)indolin2-one

[0137] To a stirred solution of 7-fluoro-3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (1.5 g, 4.92 mmol) in a mixture of 1,4-dioxane (15 mL) and water (5 mL) was added 6-bromo-2,3-dihydropyridazin-3-one (1.29 g, 7.38 mmol) followed by K3PO4 (2.61 g, 12.3 mmol) and the resulting mixture was purged with argon for 10 minutes. Pd-118 (321 mg, 0.49 mmol) was added and the reaction mixture was heated in a sealed tube at 100 °C for 16 hours. After completion, the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by combined flash column chromatography (1-5% MeOH in DCM) to obtain the compound of Example 27 (220 mg, 17%) as a whitish solid.1H NMR (400 MHz, DMSO-d6): δ 13.16 (s, 1H), 11.04 (s, 1H), 8.06 (d, J = 9.9 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J = 11.7 Hz, 1H), 6.99 (d, J = 9.9 Hz, 1H), 1.32 (s, 6H). LCMS: Retention time = 1.80 minutes; HPLC purity = 98.01%.

[0138] Preparation of Example No. 28 (7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indolin]-2'-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 248 / 342 74 / 152

[0139] Step 1. A fluid paste of AlCh (7.5 g, 56.44 mmol) and DMF (1.3 mL, 16.93 mmol) was heated to 70 °C for 15 minutes and then cooled to 40 °C. 7'-fluorospiro[cyclopropane-1,3'-indolin]-2'-one (1.0 g, 5.64 mmol) and 3-methyldihydrofuran-2,5-dione (590 mg, 7.34 mmol) were slowly added. The resulting mixture was heated to 70 °C for 8 hours, poured onto crushed ice, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was triturated with ethyl ether-pentane to obtain a mixture of 4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3-methyl-4-oxobutanoic acid and 4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-2-methyl-4-oxobutanoic acid (800 mg, crude, desired : undesired = 1:4) as brown gum. It was carried to the next step without further purification. MS (ESI): m / z 291.7 [M+1]+.

[0140] Step 2. To a stirred solution of 4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-3-methyl-4-oxobutanoic acid (800.0 mg, 2.75 mmol) in ethanol (20.0 mL) was added hydrazine monohydrate (0.66 mL, 13.74 Petition 870250099203, dated 10 / 30 / 2025, pp. 249 / 342 (75 / 152 mmol). The resulting mixture was heated at 80 °C for 16 hours. The crude LCMS showed the formation of two peaks with the mass of the product (undesired:desired = 4:1). The reaction mixture was evaporated under reduced pressure, the residue was absorbed in EtOH and stirred under cooling. The solid thus formed was filtered and discarded [it contained the main undesired isomer]. The filtrate was concentrated under reduced pressure and purified by reverse-phase HPLC preparation to obtain the compound of Example 28 (60 mg, 4% in two steps) as a whitish solid. 1H NMR (400 MHz, DMSO-d6): δ 10.90 (bs, 2H), 7.48 (d, J = 12 Hz, 1H), 7.26 (s, 1H), 3.38 (t, J = 7.0 Hz, 1H), 2.68-2.62 (m, 1H), 2.24-2.20 (m, 1H), 1.71-1.69 (m, 2H), 1.54-1.53 ​​(m, 2H), 1.04 (d, J = 7.2 Hz, 3H). LCMS: Retention time = 2.11 minutes; HPLC purity = 99.66%

[0141] Preparation of Example No. 30 (6-(2-amino-4-chlorobenzo[d]thiazol-6-yl)5-methyl-4,5-dihydropyridazine-3(2H)-one)

[0142] Step 1: 6-(4-amino-3-chlorophenyl)-5-methyl-4,5-dihydropyridazin-3(2H) Petition 870250099203, dated 10 / 30 / 2025, p. 250 / 342 76 / 152 ona

[0143] To a solution of 3-(4-aminophenyl)-4-methyl-4,5-dihydro-1H-pyridazin-6one (2.0 g, 9.8 mmol) in DMF (15 mL) was added NCS (1.31 g, 9.8 mmol). The reaction was heated to 45 °C and stirred overnight. Then, the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc:MeOH (90:10 2 x 100 mL). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (40 g Redi-Sep column) with 100% hexane elution to 60:40 EtOAc:hexane to obtain the intermediate as a solid (1.52 g, 65%). LC / MS M+H = 238.

[0144] Step 2: To a solution of 6-(4-amino-3-chlorophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (2.0 g, 8.4 mmol) in AcOH (50 mL), slightly cooled in an ice bath, potassium thiocyanate (3.3 g, 33.6 mmol) was added. The contents were stirred at room temperature for 15 minutes. Then, bromine (0.45 mL, 8.4 mmol), dissolved in AcOH (2 mL), was added dropwise and the reaction was stirred at room temperature overnight. The reaction was neutralized with saturated NaHCO3 and the resulting precipitate was filtered and air-dried to obtain the intermediate as an orange solid (2.9 g, 97%). 500 mg of the crude product were purified using SFC chromatography to obtain the compound of Example 30 (253 mg) as a solid. LC / MS M+H = 295; 1H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.06 (s, 1H), 8.02 (br s, 2H), 7.71 (s, 1H), 3.40 (q, 1H), 2.70-2.66 (m, 1H), 2.23 (d, 1H), 1.07 (d, 3H).

[0145] Preparation of Example No. 31: 6-(2-amino-4-fluorobenzo[d]thiazol-6-yl)5-methyl-4,5-di-hydropyridazin-3(2H)-one Petition 870250099203, of 30 / 10 / 2025, p. 251 / 342 77 / 152

[0146] Step 1: 4-(3,4-difluorophenyl)-3-methyl-4-oxobutanoate of ethyl

[0147] A 1M solution of KHMDS in THF (22.0 mL, 22.0 mmol) was added to THF (25 mL) in a round-bottom flask and cooled to -78°C. Then, 1-(3,4-difluorophenyl)propan-1-one (3.75 g, 22.0 mmol) in 10 mL of THF was added dropwise and the reaction mixture was stirred at -78°C for 1 hour. Ethyl 2-bromoacetate (4.8 g, 28.6 mmol) in 10 mL of THF was added slowly and the reaction mixture was allowed to warm to 0°C while stirring for 1 hour. The reaction was quenched with 1N HCl and extracted with EtOAc (2 x 75 mL). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. The crude product was chromatographed (120 g Redi-Sep column) with 100% hexane elution at a 10:90 EtOAc:hexane ratio to obtain the intermediate as a clear oil (3.9 g, 69%). LC / MS M+H = 257. Petition 870250099203, dated 10 / 30 / 2025, pages 252 / 342 78 / 152

[0148] Step 2: 6-(3-fluoro-4-hydrazineylphenyl)-5-methyl-4,5-dihydropyridazin3(2H)-one

[0149] To a solution of ethyl 4-(3,4-difluorophenyl)-3-methyl-4-oxo-butanoate (1.0 g, 3.9 mmol) in 2-MeTHF (15 mL) was added hydrazine hydrate (0.5 mL, 15.6 mmol). The reaction was heated at 110 °C for 6 hours under microwave irradiation. Then, the crude mixture was cooled in an ice bath while stirring and the resulting precipitate was filtered, washed with cold EtOH and air-dried to obtain the intermediate as a colorless solid (0.7 g, 76%). LC / MS M+H = 237.

[0150] Step 3: 6-(4-amino-3-fluorophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)one

[0151] To a solution of 6-(3-fluoro-4-hydrazineylphenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (750 mg, 3.2 mmol) in MeOH (200 mL) and AcOH (1 mL) was added 10% Pd / C (200 mg). The reaction mixture was hydrogenated at room temperature in a Parr shaker at 20 psi for 2 hours and then filtered through celite. The mother liquor was concentrated under vacuum to obtain the intermediate as a semi-solid. (0.67 g, 95%). LC / MS M+H = 222.

[0152] Step 4: To a solution of 6-(4-amino-3-fluorophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (1.1 g, 4.9 mmol) in AcOH (35 mL), slightly cooled in an ice bath, potassium thiocyanate (1.9 g, 19.9 mmol) was added. The contents were stirred at room temperature for 15 minutes. Then, bromine (0.25 mL, 4.9 mmol), dissolved in AcOH (1 mL), was added dropwise and the reaction was stirred at room temperature overnight. The reaction was neutralized with saturated NaHCO3 and extracted with EtOAc:MeOH (100 mL, 90:10) to obtain the crude product (1.2 g, 88%) as a gum after concentration. 100 mg of the crude product were purified using reverse-phase chromatography with a 95:5:0.1 elution ratio. Petition 870250099203, dated 10 / 30 / 2025, pp. 253 / 342 79 / 152 water:MeCN:TFA to 80:20:0.1 of MeCN:water:TFA for 20 minutes to obtain the compound of Example 31 (31 mg) as a solid. LC / MS M+H = 279; 1H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 7.95 (s, 1H), 7.91 (brs, 2H), 7.50 (d, 1H), 3.39 (q, 1H), 2.71-2.67 (m, 1H), 2.23 (d, 1H), 1.08 (d, 3H).

[0153] Preparation of Example No. 32 (7-bromo-3,3-dimethyl-5-(6-oxo-1,6-di-

[0154] Step 1. Lithium chloride (2.9 g, 70.75 mmol) was added to a stirred solution of 5-bromoindolin-2-one (5 g, 23.58 mmol) in dry THF (50 mL), and the resulting mixture was cooled to -78 °C. Lithium diisopropylamide (23.5 mL, 47.17 mmol, 2.0 M in THF / heptane / ethylbenzene) was added and stirred at -78 °C for 15 minutes. Methyl iodide (2.9 mL, 47.17 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. After completion, the reaction mixture was scavenged with an aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over Petition 870250099203, dated 10 / 30 / 2025, pp. 254 / 342 80 / 152 anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (10-20% EtOAc in hexane) to obtain 5-bromo-3,3-dimethylindolin-2-one (2.3 g, 41%) as a white solid. MS (ESI): m / z 240 [M+1]+.

[0155] Step 2. To a stirred solution of 5-bromo-3,3-dimethylindolin-2-one (2.3 g, 9.58 mmol) in dioxane (15 mL) was added bis(pinacolate)diboron (2.9 g, 11.5 mmol) followed by KOAc (1.8 g, 19.16 mmol) and the resulting mixture was purged with argon for 10 minutes. Pd(dppf)Cl2.DCM (0.783 g, 0.958 mmol) was added and the reaction mixture was heated at 95 °C for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by combined flash chromatography (30-40% EtOAc in hexane) to obtain 3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (1.45 g, 53%) as a whitish solid. MS (ESI): m / z 288 [M+1]+.

[0156] Step 3. To a stirred solution of 3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (640 mg, 2.23 mmol) in a mixture of 1,4-dioxane (10 mL) and water (5 mL) was added 6-bromo-2,3-dihydropyridazin-3-one (585 mg, 3.34 mmol) followed by K3PO4 (1.2 g, 5.57 mmol) and the resulting mixture was purged with argon for 10 minutes. Xphos (213 mg, 0.446 mmol) and Xphos Pd G3 (175 mg, 0.223 mmol) were added and the reaction mixture was heated in a sealed tube at 100 °C for 16 hours. After completion, the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was Petition 870250099203, dated 10 / 30 / 2025, pages 255 / 342 81 / 152 purified by combined flash column chromatography (1-5% MeOH in DCM) to obtain 3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)-2,3-dihydro-1H-indol-2-one (170 mg, 30%) as a whitish solid. MS (ESI): m / z 256 [M+1]+.

[0157] Step 4. To a stirred solution of 3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)-2,3-dihydro-1H-indol-2-one (170 mg, 0.667 mmol) in DMF (5 mL) was added N-bromosuccinimide (142 mg, 0.8 mmol) in portions and the resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (Example No. 32) thus obtained was purified by combined flash chromatography (1-5% MeOH in DCM) to obtain the compound of Example No. 32 (65 mg, 29%) as a whitish solid. 1H NMR (400 MHz, DMSO-d6): δ 13.15 (br s, 1H), 10.85 (br s, 1H), 8.07 (d, J = 10 Hz, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 6.98 (d, J = 11.2 Hz, 1H), 3.31 (s, 6H). LCMS: Retention time = 2.17 minutes; HPLC purity [at 254 nm] = 98.61%

[0158] Preparation of Example No. 34 (6-(4-fluoro-2(methylamino)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 256 / 342 82 / 152

[0159] Step 1. 3-(2-amino-4-fluoro-1,3-benzothiazol-6-yl)-4-methyl-4,5-dihydro-1H-pyridazin-6-one (1.0 g, 3.6 mmol) was loaded into a mixture of copper powder (195 mg, 2.9 mmol) in concentrated HCl (10.0 mL) and water (3.0 mL) at 0 °C. Then, an excess of NaNO₃ (750 mg, 10.8 mmol) dissolved in 3 mL of water was added slowly. The reaction was allowed to reach room temperature and stirred for 3 hours. Next, the reaction mixture was diluted with water (25 mL), filtered, and air-dried to obtain 6-(2-chloro-4-fluorobenzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)one as a solid (598 mg, 56%). LC / MS M+H = 298.

[0160] Step 2. To a solution of 3-(2-chloro-1,3-benzothiazol-6-yl)-4-methyl-4,5-dihydro-1H-pyridazin-6-one (55 mg, 0.2 mmol) in EtOH (5 mL) was added N-methylamine (0.2 g, 2.0 mmol; 33% by weight in EtOH). The reaction mixture was heated to 80 °C for 2 hours and then cooled to room temperature. The crude product was purified using reversed-phase chromatography with elution from 95:5:0.1 water:MeCN:TFA to 75:25:0.1 MeCN:water:TFA for 20 minutes to obtain the Petition 870250099203, dated 10 / 30 / 2025, pp. 257 / 342 83 / 152 compound of Example No. 34 (32 mg, 54%) as a solid. LC / MS M+H = 293; 1H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.34 (br s, 1H), 7.96 (s, 1H), 7.51 (d, 1H), 3.39 (q, 1H), 2.98 (s, 3H), 2.71-2.67 (m, 1H), 2.23 (d, 1H), 1.08 (d, 3H).

[0161] The preparation of Example 37, 6-(4-fluoro-2-(3-hydroxy-azetidine-1-yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one, was conducted similarly to Example 34, but using 3-hydroxy-azetidine-HCl and K2CO3 in IPA instead of N-methylamine in Step 2 to obtain the compound of Example 37. 1H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 8.06 (s, 1H), 7.55 (d, 1H), 4.72-4.66 (m, 1H), 4.40-4.36 (m, 2H), 3.96-3.92 (m, 2H), 3.40 (q, 1H), 2.71-2.67 (m, 1H), 2.24 (d, 1H), 1.08 (d, 3H).

[0162] The preparation of Example 46, 6-(4-fluoro-2-(3-hydroxy-azetidin-1-yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, was conducted similarly to Example 34, but using (1-methylpyrazol-4-yl)methanamine in IPA instead of N-methylamine in Step 2 to obtain the compound of Example 46. 1H NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 8.61 (t, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.52 (d, 1H), 7.44 (s, 1H), 4.43 (d, 2H), 3.80 (s, 3H), 3.39 (q, 1H), 2.72-2.68 (m, 1H), 2.24 (d, 1H), 1.08 (d, 3H).

[0163] Preparation of Example No. 35 (8-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinolin-2(1H)-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 258 / 342 84 / 152

[0164] Step 1. 2-Chloroaniline (1.0 g, 7.8 mmol) was dissolved in ethyl acetate (50 mL). Solid sodium bicarbonate (2.0 equiv.) was added, followed by the addition of 3-ethoxyacryloyl chloride (1.2 g, 9.4 mmol, 1.2 equiv.) at room temperature. The mixture was stirred for 3 hours and then cooled by the addition of water (10 mL). The reaction was poured into a separatory funnel. The organic layer was collected and washed with water (2 x 15 mL). The organic phase was collected and dried over sodium sulfate. Volatiles were removed by rotary evaporation to provide (E)-N-(2-chlorophenyl)-3-ethoxyacrylamide, which was used directly in the next step.

[0165] Step 2. (E)-N-(2-chlorophenyl)-3-ethoxyacrylamide (0.80 g, 3.5 mmol)) was added to cold sulfuric acid (5 mL). The solution was allowed to warm to room temperature, where it was stirred for 3 hours. The reaction mixture was poured into ice water (50 mL), resulting in the formation of a precipitate. The precipitate was collected by suction filtration and washed with water before drying in an oven overnight to prepare 8-chloroquinoline-2(1H)-one (0.771 g, 4.3 mmol). Petition 870250099203, dated 10 / 30 / 2025, pp. 259 / 342 85 / 152

[0166] Step 3. Aluminum chloride (2.3 g, 17.2 mmol) was added in portions to a solution of 2-chloropropanoyl chloride (1.6 g, 12.9 mmol) in DCM (10 mL) while the temperature was maintained below 30 °C. 8-chloroquinoline-2(1H)one (0.771 g, 4.3 mmol) was added while the temperature was maintained below 30 °C. The mixture was stirred and refluxed for 15 hours, cooled, and poured into ice water. The precipitate was filtered, washed with water, and absorbed in DCM (2 mL). The organic solution was stirred at 0 °C and filtered. The precipitate was dried, yielding 0.79 g (2.7 mmol) of 8-chloro-6-(2-chloropropanoyl)quinoline-2(1H)-one.

[0167] Step 4. Anhydrous DMSO (25 mL) was added to t-BuOK (490 mg, 4.4 mmol) in a N2 atmosphere. The mixture was stirred for 30 minutes at 30 °C. Diethyl malonate (656 mg, 4.4 mmol) was diluted with DMSO (5 mL) and added to the stirred mixture dropwise over a period of 1 hour. The reaction solution was stirred for another hour at 30 °C. 8-chloro-6-(2-chloropropanoyl)quinoline-2(1H)-one (790 mg, 2.7 mmol) was added in three portions to the reaction mixture over a period of 15 minutes. The reaction was then stirred for 2 hours at 40 °C. The reaction mixture was cooled to room temperature and quenched with the addition of acetic acid (2 mL). Water (100 mL) and methylene chloride (50 mL) were added to the reaction in a separatory funnel. The layers were mixed and left to separate. The organic phase was collected and washed with brine (3 x 20 mL).The organic phase was dried over sodium sulfate and concentrated to give the crude product, diethyl 2-(1-(8-chloro-2oxo-1,2-dihydroquinolin-6-yl)-1-oxopropan-2-yl malonate), which was used directly in the next step.

[0168] Step 5. Diethyl 2-(1-(8-chloro-2-oxo-1,2-dihydroquinolin-6-yl)-1-oxopropan-2-yl)malonate (2.7 mmol) was suspended in a 1:1 dioxane / water solution (10 mL). Sodium hydroxide (0.540 g, 13.5 mmol) was added to the mixture. The mixture Petition 870250099203, dated 10 / 30 / 2025, pp. 260 / 342 86 / 152 was heated to 60 °C for 12 hours. The reaction mixture was allowed to cool to room temperature before the addition of AcOH (15 mmol). The reaction mixture was stirred for 10 minutes, frozen, and lyophilized to give a crude mixture of diacid and inorganic salts.

[0169] The mixture was suspended in EtOH and hydrazine monohydrate (0.30 g, 6 mmol) was added to the mixture. The reaction was heated to 65 °C overnight. The reaction mixture was allowed to cool to room temperature. The volatile components were evaporated by low-pressure rotary evaporation, resulting in a white solid. Water (20 mL) was added to the solid and the insoluble material was filtered to give the crude product as a brown solid (0.4 g). Purification by reverse-phase HPLC to obtain the compound of Example 35 (156 mg, 0.56 mmol). 1H NMR (400 MHz, DMSO-ra) δ ppm 1.05 - 1.13 (m, 3 H) 2.24 - 2.31 (m, 1 H) 2.68 - 2.77 (m, 1 H) 3.41 - 3.51 (m, 1 H) 6.61 - 6.68 (m, 1 H) 8.01 - 8.10 (m, 3 H) 11.03 - 11.07 (m, 1 H) 11.22 - 11.27 (m, 1 H).

[0170] Example 35 exists as a tautomer, 6-(8-chloro-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (No. 35a), shown below:

[0171] Preparation of Example No. 36 (7-chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 261 / 342 87 / 152

[0172] Step 1. To a stirred solution of chloral hydrate (15.9 g, 96.18 mmol) and sodium sulfate (54.6 g, 384.72 mmol) in water (70 mL) was added 2-chloro-3-fluoroaniline (10.0 g, 68.7 mmol) in concentrated hydrochloric acid (6.9 mL) at room temperature and stirred for 1 hour. Hydroxylamine hydrochloride (6.68 g, 96.18 mmol) was added to the reaction mixture and the resulting mixture was heated at 80 °C for 16 hours. The reaction mixture was poured into water and extracted with acetate. Petition 870250099203, dated 10 / 30 / 2025, pp. 262 / 342 88 / 152 ethyl. The organic layer was concentrated under reduced pressure to obtain (E)-N(2-chloro-3-fluorophenyl)-2-(hydroxyimino)acetamide (10 g), which was carried over to the next step without further purification. MS (ESI): m / z 217.2 [M+1]+.

[0173] Step 2. A stirred solution of (E)-N-(2-chloro-3-fluorophenyl)-2(hydroxyimino)acetamide (10 g, 46.17 mmol) in concentrated sulfuric acid (30 mL) at 80 °C for 3 hours. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combined flash chromatography (20-40% ethyl acetate in hexane) to obtain 7-chloro-6-fluoroindoline-2,3-dione (5.6 g, 26%, after two steps) as a white solid. MS (ESI): m / z 200.2 [M+1]+.

[0174] Step 3. To a stirred solution of 7-chloro-6-fluoroindoline-2,3-dione (5.6 g, 28.06 mmol) in ethylene glycol (50 mL) was added hydrazine monohydrate (2.81 g, 56.12 mmol) at room temperature and stirred for 4 hours at 130 °C and then at room temperature for 16 hours. Water (50 mL) and concentrated hydrochloric acid (5 mL) were added to the reaction mixture and stirred at 50 °C for 1 hour. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (30-40% EtOAc in hexane) to obtain 7-chloro-6-fluoroindolin-2-one (3.9 g, 75%) as a brown solid. MS (ESI): m / z 186.2 [M+1]+.

[0175] Step 4. Lithium chloride (2.67 g, 63.05 mmol) was added to a stirred solution of 7-chloro-6-fluoroindolin-2-one (3.9 g, 21.02 mmol) in tetrahydrofuran (40 mL) at room temperature, and the reaction mixture was cooled to -78 °C, followed by the addition of LDA (2M in THF, 21 mL, 42.03 mmol). The reaction mixture was left Petition 870250099203, dated 10 / 30 / 2025, pp. 263 / 342 89 / 152 under stirring at -78 °C for 15 minutes, followed by the addition of methyl iodide (2.6 mL, 42.03 mmol). After the addition, the reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction mixture was tempered with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combined flash chromatography (20-30% ethyl acetate in hexane) to obtain 7-chloro-6-fluoro-3,3-dimethylindolin-2-one (1.5 g, 33%) as a brown solid. MS (ESI): m / z 214.2 [M+1]+.

[0176] Step 5. To a stirred solution of 7-chloro-6-fluoro-3,3-dimethylindolin-2-one (3.0 g, 14.04 mmol) in concentrated sulfuric acid (30 mL) was added n-bromo-succinimide (3.75 g, 21.06 mmol) in portions at room temperature and stirred for 1 hour. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combined flash chromatography (30-40% ethyl acetate in hexane) to obtain 5-bromo-7-chloro-6-fluoro-3,3-dimethylindolin-2-one (3.8 g, 92%) as a white solid. MS (ESI): m / z 292.2 [M+1]+.

[0177] Step 6. To a stirred nBuLi (13.4 mL, 28.32 mmol, 2M in THF) in THF (30 mL) iPrMgCl.LiCl (10.52 mL, 2 equivalents, 1.3M in THF) at 0 °C was added and stirred for 10 minutes. A solution of 5-bromo-7-chloro-6-fluoro-3,3-dimethylindolin-2-one (2 g, 7.08 mmol) in THF (10 mL) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was cooled to -78 °C and propionaldehyde (2.47 g, 42.47 mmol) was added, stirred at -78 °C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under... Petition 870250099203, dated 10 / 30 / 2025, pp. 264 / 342 90 / 152 reduced pressure. The crude product was purified by combined flash chromatography (30-40% ethyl acetate in hexane) to obtain 7-chloro-6-fluoro-5-(1-hydroxypropyl)3,3-dimethylindolin-2-one (0.85 g, 44%) as liquid. MS (ESI): m / z 272.2 [M+1]+.

[0178] Step 7. To a stirred solution of the compound 7-chloro-6-fluoro-5-(1-hydroxypropyl)-3,3-dimethylindolin-2-one (1.7 g, 6.25 mmol) in dichloromethane (50 mL) was added Dess martin periodinane (5.308 mg, 12.51 mmol) at room temperature and then stirred at room temperature for 16 hours. The reaction mixture was filtered over a celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude compound, which was purified by combined flash column chromatography (40-50% ethyl acetate in hexane) to obtain 7-chloro-6-fluoro-3,3-dimethyl-5-propionilyndolin-2-one (0.5 g, 30%) as liquid. MS (ESI): m / z 270.2 [M+1]+.

[0179] Step 8. To a stirred solution of 7-chloro-6-fluoro-3,3-dimethyl-5-propionylindolin-2-one (500 mg, 0.37 mmol) in tetrahydrofuran (20 mL) n-bromo succinimide (660 mg, 3.71 mmol) was added in portions at room temperature and stirred for 16 hours. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography (20-30% ethyl acetate in hexane) to obtain 5-(2-bromopropanoyl)-7-chloro-6-fluoro-3,3-dimethylindolin-2-one (0.6 g, 92%) as a yellow solid. MS (ESI): m / z 348.2 [M+1]+.

[0180] Step 9. Three portions of potassium tert-butoxide (251 mg, 2.24 mmol) at room temperature were added to a stirred solution of DMSO (7 mL) and stirred for 20 minutes. A solution of diethyl malonate (238 mg, Petition 870250099203, dated 10 / 30 / 2025, pp. 265 / 342 91 / 152 A solution of 5-(2-bromopropanoyl)-7-chloro-6-fluoro-3,3-dimethylindolin-2-one (600 mg, 1.72 mmol) in DMSO (2 mL) was added to the reaction mixture and stirred for 20 minutes. A solution of 5-(2-bromopropanoyl)-7-chloro-6-fluoro-3,3-dimethylindolin-2-one (600 mg, 1.72 mmol) in DMSO (2 mL) was added to the reaction mixture and stirred for 3 hours. After the reaction was complete, it was quenched with acetic acid (176 mg, 2.93 mmol). The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mass was purified by combi flash column chromatography (5-10% ethyl acetate in hexane) to obtain diethyl 2-(1-(7-chloro-6-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-1-oxopropan-2-yl) malonate (0.24 g, 33%) as a white solid. MS (ESI): m / z 428.2 [M+1]+.

[0181] Step 10. To a stirred solution of compound 1 (240.0 mg, 0.56 mmol) in 1,4-dioxane (3 mL) was added concentrated hydrochloric acid (7.0 mL, 6N) at room temperature and stirred for 16 hours at 90 °C. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layer was concentrated under reduced pressure to obtain 4-(7-chloro-6-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-3-methyl-4-oxobutanoic acid (200 mg, crude) as a white solid which was forwarded to the next step. MS (ESI): m / z 328.2 [M+1]+.

[0182] Step 11. Hydrazine monohydrate (0.2 mL, 3.05 mmol) was added to a stirred solution of 4-(7-chloro-6-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-3-methyl-4-oxobutanoic acid (200.0 mg, 0.61 mmol) in ethanol (4 mL) at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative reverse-phase HPLC to obtain the compound of Example 36 (35.8 mg, 25% in two steps) as a white solid (99.36% purity). 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 11.02 Petition 870250099203, dated 10 / 30 / 2025, pp. 266 / 342 92 / 152 (s, 1H), 7.50 (d, J = 6.8 Hz, 1H), 3.18-3.13 (m, 1H), 2.72-2.66 (m, 1H), 2.27-2.22 (m, 1H), 1.29 (s, 6H), 1.06 (d, J = 7.16 Hz, 3H).

[0183] Preparation of Example No. 38 (2-amino-6-(4-methyl-6-oxo-1,4,5,6-tetra-

[0184] Step 1. 6-(4-amino-3-bromophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)one. The preparation of this intermediate was conducted similarly to that of the intermediate in Step 1 of Example 30, but using NBS instead of NCS. LC / MS M+H = 282.

[0185] Step 2. 6-(2-amino-4-bromobenzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one. The preparation of this intermediate was carried out similarly to that of the intermediate in Step 2 of Example 30. LC / MS M+H = 339.

[0186] Step 3. A mixture of 6-(2-amino-4-bromobenzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (100 mg, 0.3 mmol), Zn(CN)2 (42 mg, 0.35 mmol) and Pd(dppf)Cb (22 mg, 0.03 mmol) in DMF (4 mL) was heated to 150 °C for 2 hours under microwave irradiation. The reaction mixture was subsequently cooled, extracted Petition 870250099203, dated 10 / 30 / 2025, pp. 267 / 342 93 / 152 with EtOAc:MeOH (100 ml, 95:5) and washed with water. The organic phase was dried (Na2SO4), concentrated under reduced pressure, and the crude product was purified using reversed-phase chromatography with elution from 95:5:0.1 water:MeCN:TFA to 75:25:0.1 MeCN:water:TFA for 20 minutes to obtain the compound of Example 38 (15 mg, 13%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 11.0 (s, 1H), 8.40-8.36 (m, 3H), 7.98 (s, 1H), 3.43 (q, 1H), 2.73-2.68 (m, 1H), 2.24 (d, 1H), 1.08 (d, 3H).

[0187] Preparation of Example No. 40 (6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-2-oxo-1,2-dihydroquinoline-8-carbonitrile)

[0188] Step 1. To a solution of 1,2-dichloroethane (20 mL) of 3,4-dihydroquinoline-2(1H)-one (1.0 g, 6.8 mmol) and 2-chloropropanoyl chloride (1.27 g, 10.2 mmol) was added aluminum trichloride (3.6 g, 27 mmol) in three equal portions. Petition 870250099203, dated 10 / 30 / 2025, pp. 268 / 342 94 / 152 for 15 minutes. The mixture was heated to 60 °C in a nitrogen atmosphere for five hours. The reaction was cooled to room temperature and poured into ice water (100 mL). Volatiles were removed by rotary evaporation at low pressure, which caused the formation of a precipitate. The precipitate was collected by suction filtration and washed with water (2 x 25 mL). After drying, the crude product, 6-(2-chloropropanoyl)-3,4-dihydroquinolin-2(1H)-one, weighed 0.8 g and was used as is in the next step.

[0189] Step 2. 6-(2-chloropropanoyl)-3,4-dihydroquinolin-2(1H)-one (0.80 g, 3.4 mmol) was dissolved in DMF (5 mL) and NBS (1.2 g, 6.8 mmol) was added. The solution was heated to 80 °C for 12 hours. The reaction was poured into ice-cold water (50 mL) and the precipitate was collected by suction filtration. The precipitate was washed with water (3 x 20 mL) and dried to give the product, 8-bromo-6-(2-chloropropanoyl)3,4-dihydroquinolin-2(1H)-one, (0.94 g, 3.0 mmol).

[0190] Step 3. Benzoyl peroxide (catalytic amount) was added to a solution of 8-bromo-6-(2-chloropropanoyl)-3,4-dihydroquinoline-2(1H)-one (0.94 g, 3.0 mmol) and NBS (0.67 g, 3.8 mmol). The mixture was refluxed for 5 hours. The volatiles were evaporated and the residual solid was divided between water (25 mL) and ethyl acetate (50 mL). The organic phase was washed with water (25 mL), dried, and concentrated. The product, 8-bromo-6-(2-chloropropanoyl)-3,4-dihydroquinoline-2(1H)-one (0.54 g, 1.7 mmol), was obtained after flash column chromatography using an ethyl acetate-hexane gradient.

[0191] Step 4. Anhydrous DMSO (15 mL) was added to t-BuOK (280 mg, 2.5 mmol) in a N2 atmosphere. The mixture was stirred for 30 minutes at 30 °C. Diethyl malonate (410 mg, 2.5 mmol) was diluted with DMSO (5 mL) and added to the stirred mixture dropwise over a period of 1 hour. The reaction solution was stirred. Petition 870250099203, dated 10 / 30 / 2025, pp. 269 / 342 95 / 152 for one more hour at 30 °C. 8-bromo-6-(2-chloropropanoyl)-3,4-dihydroquinoline-2(1H)-one (540 mg, 1.7 mmol) was added in three portions to the reaction mixture over 15 minutes. The reaction was then stirred for 2 hours at 40 °C. The reaction mixture was cooled to room temperature and quenched with the addition of acetic acid (2 mL). Water (50 mL) and methylene chloride (30 mL) were added to the reaction in a separatory funnel. The layers were mixed and left to partition. The organic phase was collected and washed with brine (3 x 20 mL). The organic phase was dried over sodium sulfate and concentrated to give the crude product, diethyl 2(1-(8-bromo-2-oxo-1,2-dihydroquinolin-6-yl)-1-oxopropan-2-yl malonate), which was used directly in the next step.

[0192] Step 5. Diethyl 2-(1-(8-bromo-2-oxo-1,2-dihydroquinolin-6-yl)-1-oxopropan-2-yl)malonate (1.7 mmol) was suspended in a 1:1 dioxane / water solution (10 mL). Sodium hydroxide (0.340 g, 8.5 mmol) was added to the mixture. The mixture was heated to 60 °C for 12 hours. The reaction mixture was allowed to cool to room temperature before the addition of AcOH (10 mmol). The reaction mixture was stirred for 10 minutes, then frozen and lyophilized to give a mixture of white solids. The mixture was suspended in EtOH (10 mL) and hydrazine monohydrate (0.175 g, 3.5 mmol) was added to the mixture. The reaction was heated to 65 °C overnight. The reaction mixture was allowed to cool to room temperature. The volatile components were evaporated by rotary evaporation at low pressure, resulting in a white solid. Water (20 mL) was added to the solid and the insoluble material was filtered to give the crude product as a brown solid (0.21 g).Reverse-phase HPLC purification resulted in the pure product, 8-bromo-6-(4-methyl-6oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinolin-2(1H)-one (171 mg, 0.51 mmol).

[0193] Step 6. 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3 Petition 870250099203, dated 10 / 30 / 2025, pp. 270 / 342 96 / 152 il)quinolin-2(1H)-one (171 mg, 0.51 mmol), Zn(CN)2 (117 mg, 1.0 mmol), Pd2(dba)3 (47 mg, 0.051 mmol), and zinc powder (32 mg, 0.5 mmol) were added to a three-tube round-bottom flask, followed by the addition of DMF (10 mL). Nitrogen gas was bubbled into the reaction mixture for 10 minutes. P(tBu)s (100 mg, 0.025 mmol) was added as a solution in hexanes (1 mg). The reaction mixture was then stirred in a nitrogen atmosphere at 50 °C for 5 hours. The reaction mixture was cooled to room temperature, and 30 mL of ice-cold water were added while stirring. The precipitate was collected by suction filtration and purified by reversed-phase HPLC to obtain the compound of Example 40 (8 mg, 0.029 mmol) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (d, J=7.34 Hz, 3 H) 2.11 - 2.35 (m, 1 H) 2.61 - 2.86 (m, 2 H) 3.34 - 3.61 (m, 1 H) 6.73 (br s, 1 H) 8.34 (br s, 1 H) 8.43 (br s, 1 H) 11.11 (s, 1 H) 11.81 (br s, 1 H).

[0194] Example 40 exists as a tautomer, 2-hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-8-carbonitrile (No. 40a), as shown below:

[0195] Preparation of Example No. 41 (7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-2,3-dihydro-1H-isoindole-1-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 271 / 342 97 / 152

[0196] Step 1. To a stirred solution of potassium tert-butoxide (221 mg, 1.98 mmol) in dimethyl sulfoxide (5 mL) was added a solution of diethyl malonate (260 mg, 1.97 mmol) in DMSO (2 mL), dropwise, over 10 minutes, and stirred at room temperature for 40 minutes. A solution of 5-(2-bromopropanoyl)-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (500 mg, 1.52 mmol) in DMSO (5 mL) was added dropwise over 10 minutes at 0 °C under an argon atmosphere. The resulting mixture was slowly heated to room temperature and stirred for 3 hours. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution at 0 °C and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by combiflash chromatography (30-50% EtOAc in hexane) to obtain 1,3-diethyl 2-[1-(7-chloro-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-1-oxopropan-2-yl]propanedioate (320 mg, 51%) as a yellow solid. MS (ESI): m / z 410 [M+1]+.

[0197] Step 2. A solution of 2-[1-(7-chloro-3,3-dimethyl-1-oxo-2,3-dihydro Petition 870250099203, dated 10 / 30 / 2025, pp. 272 / 342 98 / 152 1H-isoindol-5-yl)-1-oxopropan-2-yl]propanedioate of 1,3-diethyl (130 mg, 0.318 mmol) in 6N aqueous hydrochloric acid (5 mL) was heated at 90 °C for 16 hours. After completion, volatiles were removed under reduced pressure and the residue was co-distilled with toluene twice. The crude product was triturated with diethyl ether to obtain 4-(7-chloro-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-methyl-4-oxobutanoic acid (90 mg, crude) as a brown gum, which was carried to the next step without further purification. MS (ESI): m / z 310.1 [M+1]+.

[0198] Step 3. To a stirred solution of 4-(7-chloro-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-methyl-4-oxobutanoic acid (90 mg, 0.29 mmol) in ethanol (5 mL) was added hydrazine monohydrate (0.06 mL, 1.16 mmol) at room temperature. The resulting mixture was heated to 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure and the crude product obtained was purified by preparative reverse-phase HPLC to obtain the compound of Example 41 (12 mg) as a whitish solid (97.52% purity). 1H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 8.82 (s, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 3.51-3.48 (m, 1H), 2.78-2.72 (m, 1H), 2.32-2.25 (m, 1H), 1.46 (s, 6H), 1.08 (d, J = 7.2 Hz, 3H).

[0199] Preparation of Example No. 42 (4-chloro-1-methyl-6-(4-methyl-6-oxo-1,4,5,6tetrahydropyridazin-3-yl)-1,3-dihydro-2H benzo[d]imidazol-2-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 273 / 342 99 / 152

[0200] Step 1. A methylamine solution (10 mL, 20 mmol, 2M in THF) was added to a stirred solution of 1-chloro-3-fluoro-2-nitrobenzene (1.0 g, 5.71 mmol) in EtOH (2 mL) and stirred at 90 °C for 16 hours. After completion, volatiles were removed under reduced pressure and the crude product was purified by combiflash chromatography (20-40% EtOAc in hexane) to obtain 3-chloro-A / -methyl-2-nitroaniline (0.91 g, 85%) as a white solid. MS (ESI): m / z 187.0 [M+1]+.

[0201] Step 2. To a stirred solution of 3-chloro-A / -methyl-2-nitroaniline (2.0 g, 10.75 mmol) in methanol (30 mL) at 0 °C, ammonium formate (6.8 g, 107.53 mmol) was added and stirred at 0 °C for 20 minutes. Zinc powder (7.1 g, 107.53 mmol) was added in portions to the reaction mixture at 0 °C and stirred at room temperature. Petition 870250099203, dated 10 / 30 / 2025, pp. 274 / 342 100 / 152 for 16 hours. After completion, the reaction mixture was filtered, washed with ethyl acetate, and the combined filtrate was evaporated under reduced pressure. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (40-60% EtOAc in hexane) to obtain 3-chloro-N1-methylbenzene-1,2-diamine (3.95 g, 67%) as a white solid. MS (ESI): m / z 157.0 [M+1]+.

[0202] Step 3. To a stirred solution of 3-chloro-N1-methylbenzene-1,2-diamine (1.3 g, 8.33 mmol) in dichloromethane (10 mL) was added triethylamine (1.39 mL, 10.0 mmol) at 0 °C. Triphosgene (3.71 g, 12.5 mmol) was added in portions under cooling conditions. The reaction mixture was allowed to reach room temperature and stirred for 5 h. After completion, the volatiles were removed under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (30-50% EtOAc in hexane) to obtain 4-chloro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.5 g, 31%) as a white solid. MS (ESI): m / z 183.0 [M+1]+.

[0203] Step 4. A paste of aluminum chloride (7.33 g, 54.95 mmol) and DMF (1.41 mL, 18.13 mmol) was heated to 80 °C for 15 minutes. The resulting mixture was cooled to room temperature and 4-chloro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 g, 5.5 mmol) was added in portions, maintaining the temperature below 40 °C during the addition. 2-chloropropanoyl chloride (0.52 mL, 6.87 mmol) was added dropwise and stirred at 80 °C for 2 hours. After completion, the reaction mixture was poured into water with crushed ice and extracted with acetate. Petition 870250099203, dated 10 / 30 / 2025, pp. 275 / 342 101 / 152 ethyl. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (40-60% EtOAc in hexane) to obtain 4chloro-6-(2-chloropropanoyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.19 g, 11%) as a white solid. MS (ESI): m / z 273.0 [M+1]+.

[0204] Step 5. To a stirred solution of potassium tert-butoxide (3.09 g, 27.57 mmol) in DMSO (30 mL) was added a solution of diethyl malonate (4.41 g, 27.57 mmol) in DMSO (25 mL), dropwise, over 10 minutes, and stirred at room temperature for 40 minutes. A solution of 4-chloro-6-(2-chloropropanoyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (5 g, 18.38 mmol) in DMSO (25 mL) was added dropwise over 10 minutes at 0 °C under an argon atmosphere. The resulting mixture was slowly heated to room temperature and stirred for 3 hours. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution at 0 °C and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by combiflash chromatography (30-50% EtOAc in hexane) to obtain diethyl 2-(1-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-oxopropan-2-yl)malonate (3 g, 48%) as a white solid. MS (ESI): m / z 397.0 [M+1]+.

[0205] Step 6. A stirred solution of diethyl 2-(1-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-oxopropan-2-yl)malonate (3 g, 7.56 mmol) in 6N aqueous hydrochloric acid (50 mL) was heated at 90 °C for 16 hours. After completion, volatiles were removed under reduced pressure and the residue was co-distilled with toluene twice. The crude product was triturated with diethyl ether to obtain 4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-methyl-4 Petition 870250099203, dated 10 / 30 / 2025, pp. 276 / 342 102 / 152 oxobutanoic acid (1.2 g, crude) as brown gum, which was carried over to the next step without further purification. MS (ESI): m / z 295.0 [M-1]+.

[0206] Step 7. To a stirred solution of 4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1 / 7-benzo[d]imidazol-5-yl)-3-methyl-4-oxobutanoic acid (500.0 mg, 1.69 mmol, crude) in ethanol (20 mL) was added hydrazine monohydrate (0.34 mL, 6.76 mmol) at room temperature. The resulting mixture was heated at 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure and the crude product obtained was purified by preparative reverse-phase HPLC to obtain the compound of Example No. 42 (18 mg, 4% in two steps) as a whitish solid (93.65% purity). 1H NMR (400 MHz, DMSO-O6, 100 °C): δ 10.63 (s, 1H), 10.35 (brs, 1H), 7.44-7.41 (m, 2H), 3.44 (m, 1H), 3.34 (s, 3H), 2.71-2.67 (m, 1H), 2.33-2.2 (m, 1H), 1.06 (d, J = 6.4 Hz, 3H).

[0207] Preparation of Example No. 43 (7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)spiro[cyclobutane-1,3'-indoline]-2'-one)

[0208] Step 1. 7-fluoroindolin-2-one (2.0 g, 13.2 mmol) and LiCl (1.7 g, 39.7 mmol) were added to THF (50 mL) and the mixture was cooled to -78 °C. In Petition 870250099203, dated 10 / 30 / 2025, pp. 277 / 342 103 / 152 then, n-BuLi (17.0 mL, 26.5 mmol) was added slowly and the reaction mixture was stirred at -78 °C for approximately 30 minutes. 1,3-Dibromopropane (2.0 mL, 19.9 mmol) was added slowly and the reaction mixture was left at room temperature, with stirring overnight. The reaction mixture was tempered with 0.1 N HCl (75 mL) and extracted with EtOAc (2 x 75 mL). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (80 g Redi-Sep column) with 100% hexane elution at a 30:70 EtOAc:hexane ratio to obtain 7'-fluorospiro[cyclobutane-1,3'-indolin]-2'-one as a solid. LC / MS M+H = 192.

[0209] Step 2. DMF (0.55 mL, 7.1 mmol) was added dropwise to anhydrous AlCl3 (3.3 g, 24.0 mmol), the mixture was stirred at 70 °C for approximately 15 minutes and then cooled to 40 °C. Then, 7'fluorospiro[cyclobutane-1,3'-indoline]-2'-one (500 mg, 1.6 mmol) and 3-methyltetrahydrofuran-2,5-dione (450 mg, 3.9 mmol) were added slowly. The reaction mixture was heated to 70 °C for 2 hours and then slowly poured into ice water, filtered, and air-dried to obtain 4-(7'-fluoro-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-3-methyl-4-oxobutanoic acid as a mixture of regional isomers. LC / MS M+H = 306.

[0210] Step 3. To a solution of crude 4-(7'-fluoro-2'-oxo-spiro[cyclobutane-1,3'-indoline]-5'-yl)-3-methyl-4-oxo-butanoic acid (150 mg, 0.49 mmol) in EtOH (15 mL) was added hydrated hydrazine (0.2 mL, 1.9 mmol). The reaction was heated at 80 °C for 18 hours. The reaction mixture was cooled in an ice bath, filtered, and washed with ice-cold EtOH. The precipitate was dried under vacuum. The crude regioisomeric mixture was purified using reversed-phase chromatography with elution from 95:5:0.1 water:MeCN:TFA to 80:20:0.1 MeCN:water:TFA, collecting the smaller regioisomer as the compound of Example 43. 1H NMR (400 MHz, DMSO-d6): δ 10.95-10.93 Petition 870250099203, dated 10 / 30 / 2025, pp. 278 / 342 104 / 152 (m, 2H), 7.85 (s, 1H), 7.49 (d, 2H), 3.46 (q, 1H), 2.72-2.68 (m, 1H), 2.49-2.33 (m, 5H), 2.29-2.15 (m, 3H), 1.08 (d, 3H).

[0211] The preparation of Example 50, 7-fluoro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one, was conducted similarly to Example 6, but with 4-(7-fluoro-2-oxoindolin-5-yl)-3-methyl-4-oxobutanoic acid instead of 4-(7-chloro-2-oxoindolin-5-yl)-3-methyl-4-oxobutanoic acid to obtain the compound of Example 50. 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 10.93 (s, 1H), 7.517.47 (m, 2H), 3.61 (s, 2H), 3.37 (q, 1H), 2.68-2.64 (m, 1H), 2.22 (d, 1H), 1.05 (d, 3H).

[0212] The preparation of Example No. 74, 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, was conducted similarly to Example No. 57, but for 7-fluoro-3,3-dimethylindolin-2-one instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to obtain the compound of Example No. 74. 1H NMR (400 MHz, DMSO-d6): δ 11.66 (s, 1H), 11.09 (s, 1H), 7.65 (s, 1H), 7.55 (d, 1H), 4.73 (q, 1H), 1.47 (d, 3H), 1.31 (s, 6H).

[0213] Preparation of Example No. 57 (5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl3,6-dihydro-2H-1,3,4-thiadiazine-2-one)

[0214] Step 1. Dimethyl formamide (7.7 mL, 99.27 mmol) was added dropwise to anhydrous aluminum chloride (47.12 g, 330.91 mmol) and stirred at 70 °C for 15 minutes. The resulting mixture was cooled to 40 °C and 7-fluoro-2,3-dihydro-1H-indol-2-one (5 g, 49.64 mmol) and 2-bromopropanoyl chloride (5.1 mL, 49.64 mmol) were added slowly and stirred at 70 °C for 2 hours. After completion, the mixture Petition 870250099203, dated 10 / 30 / 2025, pp. 279 / 342 105 / 152 of the reaction was diluted with ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (30-40% EtOAc in hexane) to obtain 5-(2-bromopropanoyl)-7-fluoro-2,3-dihydro-1H-indol-2-one (3 g, 32%) as a brown solid. MS (ESI): m / z 286.1 [M+1]+. Alternatively, 2-chloropropanoyl chloride can be substituted for 2-bromopropanoyl chloride to produce 5-(2-chloropropanoyl)-7-fluoro-2,3-dihydro-1H-indol-2-one, followed by step 2 to obtain the compound of Example 57.

[0215] Step 2. To a stirred solution of 5-(2-bromopropanoyl)-7-fluoro-2,3-dihydro-1H-indol-2-one (3 g, 10.53 mmol) in ethanol (30 mL) was added [(methoxymethiomethiol)amino]amine (1.12 g, 10.53 mmol) at room temperature under an argon atmosphere. The resulting mixture was heated to 80 °C for 16 hours. After completion, the reaction mixture was evaporated to dryness and the crude product obtained was purified by column chromatography (50-60% EtOAc in hexane) to obtain the compound of Example No. 57 (1 g, 34%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 11.66 (br s, 1H), 11.10 (br s, 1H), 7.57-7.56 (m, 2H), 4.72-4.70 (m, 1H), 3.63 (s, 2H), 1.46 (d, J = 6.8 Hz, 3H). LCMS: Retention time = 1.92 minutes; m / z 278.0 [M-1]+; HPLC purity = 97.5%. Example 78 is the (S) isomer of Example 57 and was solved by HPLC (Z-cellulose I-column 150x4.6mm, 3μ; mobile phase (hexane / ethanol / isopropylamine (70 / 30 / 0.1); flow rate of 1.0 mL / minute)).The HPLC retention time for Examples No. 57 and No. 78 was 4.22 and 5.11 minutes, respectively.

[0216] The preparation of Example No. 55, 4-methyl-6-(6-methyl-2-oxo-3,6-dihydro2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one, was conducted in a similar manner. Petition 870250099203, dated 10 / 30 / 2025, pp. 280 / 342 106 / 152 to Example No. 57, but with 4-methylbenzo[d]thiazol-2(3H)-one instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to obtain the compound of Example No. 55. 1H NMR (400 MHz, DMSO-d6): δ 11.93 (s, 1H), 11.62 (s, 1H), 7.83 (s, 1H), 7.55 (s, 1H), 4.72-4.66 (m, 1H), 2.36 (s, 3H), 1.47 (d, J = 7.2, 3H).

[0217] The preparation of Example No. 56, 4-chloro-6-(6-methyl-2-oxo-3,6-dihydro2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one, was conducted similarly to Example No. 57, but with 4-chlorobenzo[d]thiazol-2(3H)-one instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to obtain the compound of Example No. 56. 1H NMR (400 MHz, DMSO-d6): δ 12.47 (s, 1H), 11.76 (s, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 4.75-4.70 (m, 1H), 1.47 (d, J = 7.2 Hz, 3H).

[0218] Preparation of Example No. 58, 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, was conducted similarly to Example No. 57, but for 7'-chlorospiro[cyclopropane-1,3'-indolin]-2'-one instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to obtain the compound of Example No. 58. 1H NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 11.25 (s, 1H), 7.67 (s, 1H), 7.40 (s, 1H), 4.75-4.69 (m, 1H), 1.75-1.70 (m, 2H), 1.56 (d, J = 4.2 Hz, 2H), 1.45 (d, J = 7.1 Hz, 3H).

[0219] The preparation of Example No. 65, 5-(8-bromo-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, was conducted similarly to Example No. 57, but with 8-bromo-3,4-dihydroquinolone instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to obtain the compound of Example No. 65. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.75 (s, 1H), 7.89 (br s 1H), 7.71 (d, 1H), 7.46 (s, 1H), 4.12 (d, 1H), 2.98 (m, 2H), 2.61 (dd, 2H), 1.59 (d, 3H).

[0220] Preparation of Example No. 67, (6R)-5-(8-chloro-4,4-dimethyl-2-oxo1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thidiazin-2-one, was Petition 870250099203, dated 10 / 30 / 2025, pp. 281 / 342 107 / 152 conducted similarly to Example No. 57, but with 8-chloro-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to obtain the compound of Example No. 67. 1H NMR (400 MHz, DMSO-d6): δ 11.68 (brs, 1H), 9.81 (brs, 1H), 7.73 (brs, 2H), 4.81 (brs, 1H), 2.47 (s, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.28 (brs, 6H).

[0221] The preparation of Example No. 75, 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, was conducted similarly to Example No. 57, but with 7-chloro-3,3-dimethylindolin-2-one instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to obtain the compound of Example No. 75. 1H NMR (400 MHz, DMSO-d6): δ 11.66 (s, 1H), 11.02 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 4.76-4.73 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H), 1.31 (s, 6H).

[0222] The preparation of Example No. 76, 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, was conducted similarly to Example No. 57, but with 7-bromo-3,3-dimethylindolin-2-one instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to obtain the compound of Example No. 76. 1H NMR (400 MHz, DMSO-d6): δ 11.66 (s, 1H), 10.91 (s, 1H), 7.80 (d, J = 1.3, 1H), 7.77 (d, J = 1.2, 1H), 4.78-4.73 (m, 1H), 1.47 (d, J = 7.1 Hz, 3H), 1.30 (s, 6H).

[0223] Preparation of Example No. 61 (5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)3,6-dihydro-2H-1,3,4-thiadiazine-2-one)

[0224] Step 1. Dimethyl formamide (0.5 mL, 7.66 mmol) was added dropwise to anhydrous aluminum chloride (3.41 g, 25.55 mmol) and stirred at 70 °C for 15 Petition 870250099203, dated 10 / 30 / 2025, pp. 282 / 342 108 / 152 minutes. The resulting mixture was cooled to 40 °C and 7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (500 mg, 2.55 mmol) and 2-chloroacetyl chloride (0.26 mL, 3.32 mmol) were added slowly and stirred at 70 °C for 2 hours. After completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (40-50% EtOAc in hexane) to obtain 7-chloro-5-(2-chloroacetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (300 mg, 43%) as a yellow solid. MS (ESI): m / z 269.8 [M-1]+.

[0225] Step 2. To a stirred solution of 7-chloro-5-(2-chloroacetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (300 mg, 1.1 mmol) in acetonitrile (10 mL) was added [(methoxymethyl)thioyl)amino]amine (117 mg, 1.1 mmol) and the reaction mixture was stirred at room temperature for 5 minutes. AcOH (0.1 mL) was added and the resulting mixture was heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (60-70% EtOAc in hexane) to obtain the compound of Example No. 61 (120 mg, 35%) as a whitish solid. 1H NMR (400 MHz, DMSO-d6): δ 11.56 (s, 1H), 11.03 (s, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 4.21 (s, 2H), 1.30 (s, 6H). LCMS: Retention time = 2.48 minutes; HPLC purity = 98.56%

[0226] The preparation of Example No. 59, 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one, was conducted similarly to Example No. 61, but with 7-fluoro-3,3-dimethylindolin-2-one instead of 7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one to obtain the compound of Example No. 59. 1H NMR (400 MHz, DMSO-d6): δ 11.56 (s, 1H), 11.09 (s, 1H), 7.65 (s, 1H), 7.56 (dd, J = 0.8 Petition 870250099203, dated 10 / 30 / 2025, pp. 283 / 342 109 / 152 Hz, 11.8Hz, 1H), 4.20 (s, 2H), 1.30 (s, 6H).

[0227] The preparation of Example No. 66, 5-(7-bromo-3,3-dimethyl-2-oxoindolin5-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one, was conducted similarly to Example No. 61, but with 7-bromo-3,3-dimethylindolin-2-one instead of 7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one to obtain the compound of Example No. 66. 1H NMR (400 MHz, DMSO-d6): δ 11.57 (s, 1H), 10.91 (s, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 4.21 (s, 2H), 1.30 (s, 6H).

[0228] The preparation of Example No. 72, 5-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one, was conducted similarly to Example No. 61, but for 1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one instead of 7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one to obtain the compound of Example 72. 1H NMR (400 MHz, DMSO-d6): δ 11.57 (s, 1H), 9.72 (s, 1H), 7.76 7.64 (m, 2H), 7.03 (d, 1H), 4.21 (s, 2H), 2.73 (brt, 2H), 2.16 (br m, 4H).

[0229] Preparation of Example No. 62 (5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-one)

[0230] Step 1. Dimethyl formamide (3.05 mL, 39.52 mmol) was added dropwise to anhydrous aluminum chloride (16 g, 119.76 mmol) and stirred at 70 °C for 15 minutes. The resulting mixture was cooled to 40 °C and 7-chloro-2,3-dihydro-1H-indol-2-one (2 g, 11.97 mmol) and 2-chloropropanoyl chloride (1.3 mL, 15.56 mmol) were added slowly and stirred at 70 °C for 2 hours. After completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The layer Petition 870250099203, dated 10 / 30 / 2025, pp. 284 / 342 Combined organic matter 110 / 152 was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (30-40% EtOAc in hexane) to obtain 7-chloro-5-(2-chloropropanoyl)-2,3-dihydro-1H-indol-2-one (900 mg, 29%) as a brown solid. MS (ESI): m / z 257.9 [M+1]+.

[0231] Step 2. To a stirred solution of 7-chloro-5-(2-chloropropanoyl)-2,3-dihydro-1H-indol-2-one (500 mg, 1.76 mmol) in acetonitrile (10 mL) was added [(methoxymethiothioyl)amino]amine (186.18 mg, 1.76 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. Acetic acid (0.1 mL) was added and the reaction mixture was heated to 80 °C for 4 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (50-60% EtOAc in hexane) to obtain the compound of Example No. 62 (150 mg, 26%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 11.66 (br s, 1H), 11.03 (br s, 1H), 7.68 (s, 1H), 7.65 (s, 1H), 4.75-4.70 (m, 1H), 3.66 (s, 2H), 1.45 (d, J = 6.8 Hz, 3H).LCMS: Retention time = 2.01 minutes; HPLC purity = 98.46%.

[0232] Preparation of Example No. 73 (6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thidiazin-2-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 285 / 342 111 / 152

[0233] Step 1. To a stirred solution of 8-methyl-1,2,3,4-tetrahydronaphthalen-1-one (500 mg, 3.12 mmol) in methanol (10 mL) was added hydroxylamine hydrochloride (260 mg, 3.74 mmol) followed by sodium acetate (307 mg, 3.74 mmol) at room temperature under an argon atmosphere, and the resulting mixture was stirred at 60 °C for 4 hours. After completion, the reaction mixture was cooled to room temperature and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to obtain N-[(1E)-8-methyl-1,2,3,4-tetrahydronaphthalen-1-ylidene]-hydroxylamine (460 mg, 84%) as a yellow solid. It was used in the next step without further purification. MS (ESI): m / z 176.2 [M+1]+.

[0234] Step 2. Phosphoric acid solution (1.8 mL) was added to a stirred solution of phosphoric acid (1.8 mL) and the resulting mixture was heated at 100 °C for 0.5 hours. N-[(1E)-8-methyl-1,2,3,4-tetrahydronaphthalen-1-ylidene]hydroxylamine (460 mg, 2.63 mmol) was added and stirred at 100 °C for a further 2.5 hours. After completion, the reaction mixture was poured into ice water. The solid thus formed was filtered, washed with water and dried under reduced pressure to obtain 9-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (400 mg, 86%) as a brown solid. MS (ESI): m / z 176.2 [M+1]+.

[0235] Step 3. Dimethylformamide (0.58 mL, 7.44 mmol) was added dropwise. Petition 870250099203, dated 10 / 30 / 2025, pp. 286 / 342 112 / 152 dropwise to anhydrous aluminum chloride (3.3 g, 24.81 mmol) and stirred at 70 °C for 15 minutes. The resulting mixture was cooled to 40 °C and 9-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (400 mg, 2.48 mmol) and 2-chloropropanoyl chloride (0.3 mL, 2.98 mmol) were added. The resulting mixture was heated at 70 °C for 2 hours. After completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (30-40% EtOAc in hexane) to obtain 7-(2-chloropropanoyl)-9-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin2-one (400 mg, 66%) as a brown solid. MS (ESI): m / z 266.3 [M+1]+.

[0236] Step 4. To a stirred solution of 7-(2-chloropropanoyl)-9-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (250 mg, 0.94 mmol) in acetonitrile (5 mL) was added [(ethoxymethanethiol)amino]amine (100 mg, 0.94 mmol) and stirred at room temperature for 5 minutes. AcOH (0.1 mL) was added and the resulting mixture was heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (40-60% EtOAc in hexane) to obtain the compound of Example No. 73 (60 mg, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.64 (s, 1H), 9.24 (s, 1H), 7.56 (s, 2H), 4.74-4.69 (m, 1H), 2.71-2.67 (m, 2H), 2.27 (s, 3H), 2.15-2.05 (m, 4H), 1.48 (d, J = 6.8 Hz, 3H). LCMS: Retention time = 2.47 minutes; HPLC purity = 96.28%.

[0237] Preparation of Example No. 77 (5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazine-5-yl)-2-oxoindoline-7-carbonitrile) Petition 870250099203, dated 10 / 30 / 2025, pp. 287 / 342 113 / 152

[0238] Step 1. A paste of anhydrous AlCh (31.4 g, 235.8 mmol) and DMF (5.4 mL, 70.7 mmol) was heated to 70 °C for 15 minutes and then cooled to 40 °C. 7-bromoindolin-2-one (5.0 g, 23.58 mmol) and 2-chloropropanoyl chloride (2.7 mL, 28.30 mmol) were added slowly. The resulting mixture was heated to 70 °C for 4 hours. The reaction mixture was cooled to room temperature, poured onto crushed ice, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography (4060% EtOAc in hexane) to obtain 7-bromo-5-(2-chloropropanoyl)indolin-2-one (4.1 g, 48%) as a brown solid. MS (ESI): m / z 302.0 [M+1]+.

[0239] Step 2. To a stirred solution of 7-bromo-5-(2-chloropropanoyl)indolin-2-one (1.0 g, 3.63 mmol) in acetonitrile (10.0 mL) were added acetic acid (2.0 mL) and O-methylhydrazine-carbothioate (0.39 g, 3.64 mmol) at room temperature. The resulting reaction mixture was heated at 90 °C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. Petition 870250099203, dated 10 / 30 / 2025, pp. 288 / 342 114 / 152 The crude product was purified by combi flash column chromatography (60-70% EtOAc in hexane) to obtain 5-(7-bromo-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (1.1 g, 24%) as a whitish solid. MS (ESI): m / z 340.05 [M+1]+.

[0240] Step 3. To a stirred solution of 5-(7-bromo-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (150 mg, 0.44 mmol) in DMF (4.0 mL), zinc cyanide (62.3 mg, 0.53 mmol) was added at room temperature. The reaction mixture was degassed for 5 minutes, followed by the addition of Pd2(dba)3 (12.19 mg, 0.013 mmol) and dppf (2.46 mg, 0.004 mmol). The resulting mixture was microwaved (MW) for 0.5 hours at 140 °C. After completion, the reaction mixture was diluted with cold water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The gross mass was purified by normal-phase pre-HPLC to obtain the compound of Example No. 77 (65 mg, 36%) as a whitish solid. 1H NMR (400 MHz, DMSO-d6): δ 11.73 (s, 1H), 11.58 (bs, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 4.76 (q, J = 8.3 Hz, 1H), 3.64 (s, 2H), 1.46 (d, J = 7.1 Hz, 3H).

[0241] Preparation of Example No. 79 (7-chloro-5-(6-methyl-2-oxo-3,6-dihydro2H-1,3,4-thiadiazin-5-yl)-2,3-dihydro-1H-isoindol-1-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 289 / 342 115 / 152

[0242] Step 1. To a stirred solution of 5-bromo-7-chloro-2-(4-methoxybenzyl)isoindolin-1-one (7.5 g, 20.5 mmol) in MeOH (150 mL) was added DIPEA (18 ml, 101.1 mmol) followed by Pd(dppf)Cl2.DCM (1.6 g, 2.18 mmol) and the resulting mixture was purged with argon for 10 minutes and heated at 90 °C for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by combi flash column chromatography (10-20% EtOAc in hexane) to obtain 7-chloro-2-(4-methoxybenzyl)-5-propionylisoindolin-1-one (3.2 g, 45%) as a white solid. MS (ESI): m / z 344 [M+1 ]+. Petition 870250099203, dated 10 / 30 / 2025, pp. 290 / 342 116 / 152

[0243] Step 2. To a stirred solution of 7-chloro-2-(4-methoxybenzyl)-5-propionylisoindolin-1-one (1 g, 2.89 mmol) in THF-EtOH (15 mL); 2:1) was added LiBH4 (158 mg, 7.22 mmol) and stirred at RT for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography (30-40% EtOAc in hexane) to obtain 7-chloro-5-(hydroxymethyl)-2-(4-methoxybenzyl)isoindolin-1-one (500 mg, 54%) as a whitish solid. MS (ESI): m / z 318 [M+1]+.

[0244] Step 3. To a stirred solution of 7-chloro-5-(hydroxymethyl)-2-(4-methoxybenzyl)isoindolin-1-one (1.5 g, 4.7 mmol) in DCM (25 mL) was added Dess martin periodinane (3.9 g, 9.4 mmol) at 0 °C and stirred at RT for 16 hours. The reaction mixture was filtered through a small celite block and washed with ethyl acetate. The combined portion of the filtrate was concentrated under reduced pressure and purified by combiflash column chromatography (20-30% ethyl acetate in hexane) to obtain 7-chloro-2-(4-methoxybenzyl)-1-oxoisoindolin-5-carbaldehyde (1.0 g, 67%) as a whitish solid. MS (ESI): m / z 316 [M+1]+.

[0245] Step 4. To a stirred solution of 7-chloro-2-(4-methoxybenzyl)-1-oxoisoindoline-5-carbaldehyde (700 mg, 2.2 mmol) in THF (10 mL) was added EtMgBr (4.4 mL, 8.9 mmol, 2M in THF) under ice conditions and stirred at RT for 6 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combined flash column chromatography (30-40% ethyl acetate in hexane) to obtain 7-chloro-5-(1-hydroxypropyl)-2-(4-methoxybenzyl)isoindoline Petition 870250099203, dated 10 / 30 / 2025, pp. 291 / 342 117 / 152 1-one (320 mg, 41%) as a whitish solid. MS (ESI): m / z 346 [M+1]+.

[0246] Step 5. To a stirred solution of 7-chloro-5-(1-hydroxypropyl)-2-(4-methoxybenzyl)isoindolin-1-one (550 mg, 1.5 mmol) in DCM (15 mL) was added Dess martin periodinane (1.3 g, 3.18 mmol) at 0 °C and stirred at RT for 16 hours. The reaction mixture was filtered through a small celite block and washed with ethyl acetate. The combined portion of the filtrate was concentrated under reduced pressure and purified by combiflash column chromatography (20-30% ethyl acetate in hexane) to obtain 7-chloro-2-(4-methoxybenzyl)-5-propionylisoindolin-1-one (400 mg, 73%) as a whitish solid. MS (ESI): m / z 344 [M+1]+.

[0247] Step 6. To a stirred solution of 7-chloro-2-(4-methoxybenzyl)-5-propionylisoindolin-1-one (420 mg, 1.22 mmol) in THF (10 mL) was added NBS (872 mg, 4.89 mmol) in a portion at RT and stirred for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography (50-60% ethyl acetate in hexane) to obtain 5-(2-bromopropanoyl)-7-chloro-2-(4-methoxybenzyl)isoindolin-1-one [contaminated with the substituted di-bromo compound] (280 mg, 54%) as a white solid. MS (ESI): m / z 423 [M+1]+.

[0248] Step 7. A stirred solution of 5-(2-bromopropanoyl)-7-chloro-2-(4-methoxybenzyl)isoindolin-1-one (300 mg, 0.71 mmol) in TFA (5 mL) was heated at 80 °C for 16 hours. After completion, the volatiles were removed under reduced pressure, the residue was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography. Petition 870250099203, dated 10 / 30 / 2025, pages 292 / 342 118 / 152 combiflash (70-90% EtOAc in hexane) to obtain 5-(2-bromopropanoyl)-7-chloroisoindolin-1-one (135 mg, 63%) as a whitish solid. MS (ESI): m / z 303 [M+1]+.

[0249] Step 8. To a stirred solution of 5-(2-bromopropanoyl)-7-chloroisoindolin-1-one (150 mg, 0.49 mmol) in EtOH (15 ml) was added O-methyl hydrazinocarbothioate (63 mg, 0.59 mmol) and heated under reflux at 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (70-90% EtOAc in hexane) to obtain the compound of Example No. 79 (20.5 mg) as a whitish solid (98.22% purity). 1H NMR (400 MHz, DMSO-d6): δ 11.90 (s, 1H), 8.79 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 4.84-4.79 (m, 1H), 4.39 (s, 2H), 1.49 (d, J = 7.2 Hz, 3H).

[0250] Preparation of Example No. 80 (7-chloro-3,3-dimethyl-5-(6-methyl-2-oxo-3,6dihydro-2H-1,3,4-thidiazin-5-yl)-2,3-dihydro-1H-isoindol-1-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 293 / 342 119 / 152

[0251] Step 1. To a stirred solution of methyl 4-bromo-2-chloro-6-methylbenzoate (5 g, 19.09 mmol) and benzoyl peroxide (0.63 g, 3.82 mmol) in carbon tetrachloride (20 mL), NBS (4 g, 22.91 mmol) was added in portions at room temperature and the resulting mixture was refluxed for 16 hours. After completion, the volatiles were removed under reduced pressure. The crude product was triturated with pentane-hexane (1:1) to obtain the desired product methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate (5 g, crude) as a brown solid which was carried to the next step without further purification. MS (ESI): m / z 340 [M+1]+.

[0252] Step 2. To a stirred solution of 4-bromo-2-(bromomethyl)-6 Petition 870250099203, dated 10 / 30 / 2025, pp. 294 / 342 Methyl chlorobenzoate (5 g, 14.70 mmol) and TEA (6.1 mL, 43.76 mmol) in DMF (50 mL) were added to 4-methoxybenzylamine (3.8 mL, 29.4 mmol) and stirred at room temperature for 5 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (20-30% EtOAc in hexane) to obtain 5-bromo-7-chloro-2-(4-methoxybenzyl)isoindolin-1-one (3.3 g, 61% in two steps) as a whitish solid. MS (ESI): m / z 366 [M+1]+.

[0253] Step 3. To a stirred solution of 5-bromo-7-chloro-2-(4-methoxybenzyl)isoindolin-1-one (1.5 g, 4.11 mmol) in THF, NaH (493 mg, 12.32 mmol, 60% in mineral oil) was added at 0 °C under an argon atmosphere and the resulting mixture was stirred at room temperature for 30 minutes. Methyl iodide (1.0 ml, 16 mmol) was added and the resulting mixture was heated to 70 °C for 3 hours. After completion, the reaction mixture was slaked with an aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (10-20% ethyl acetate in hexane) to obtain 5-bromo-7-chloro-2-(4-methoxybenzyl)-3,3-dimethylisoindolin-1-one (900 mg, 56%) as a white solid. MS (ESI): m / z 394 [M+1]+.

[0254] Step 4. A stirred solution of 5-bromo-7-chloro-2-(4-methoxybenzyl)3,3-dimethylisoindolin-1-one (500 mg, 1.27 mmol) in TFA (10 mL) was heated at 80 °C for 16 hours. After completion, the volatiles were removed under reduced pressure, the residue was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and Petition 870250099203, dated 10 / 30 / 2025, pp. 295 / 342 121 / 152 concentrated under reduced pressure. The crude product was purified by combiflash chromatography (70-90% ethyl acetate in hexane) to obtain 5-bromo-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (230 mg, 66%) as a whitish solid. MS (ESI): m / z 274 [M+1]+.

[0255] Step 5. To a stirred mixture of nBuLi (1.5 mL, 0.75 mmol, 2M in THF) in THF (5 mL) was added iPrMgCl.LiCl (0.7 mL, 0.91 mmol, 1.3M in THF) at -78 °C under an argon atmosphere. A solution of 5-bromo-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (200 mg, 0.735 mmol) in THF (10 mL) was added to the reaction mixture and the resulting mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was cooled to -78 °C and propionaldehyde (0.32 mL, 4.41 mmol) was added and stirred at -78 °C for 2 hours. After completion, the reaction mixture was quenched with an aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by combiflash column chromatography (40-60% EtOAc in hexane) to obtain 7-chloro-5-(1-hydroxypropyl)-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (80 mg, 43%) as a white solid. MS (ESI): m / z 254 [M+1]+.

[0256] Step 6. To a stirred solution of 7-chloro-5-(1-hydroxypropyl)-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (460 mg, 1.82 mmol) in DCM (10 mL) was added Dess martin periodinane (1.54 g, 3.63 mmol) at 0 °C and stirred at RT for 16 hours. The reaction mixture was filtered through a small celite block and washed with ethyl acetate. The combined portion of the filtrate was concentrated under reduced pressure and purified by combiflash column chromatography (50-60% EtOAc in hexane) to obtain 7-chloro-3,3-dimethyl-5-propanoyl-2,3-dihydro-1H-isoindol-1-one (325 mg, 72%) as a white solid. MS (ESI): m / z 252 [M+1]+. Petition 870250099203, dated 10 / 30 / 2025, pp. 296 / 342 122 / 152

[0257] Step 7. To a stirred solution of 5-(2-bromopropanoyl)-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (150 mg, 0.60 mmol) in THF (5 mL) was added NBS (266 mg, 1.45 mmol) in a portion at room temperature and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (40-60% ethyl acetate in hexane) to obtain 5-(2-bromopropanoyl)-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (100 mg, 50%) as a white solid. MS (ESI): m / z 330 [M+1]+.

[0258] Step 8. To a stirred solution of 5-(2-bromopropanoyl)-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (250 mg, 0.76 mmol) in EtOH (10 ml) was added O-methyl hydrazinocarbothioate (97 mg, 0.912 mmol) and heated under reflux at 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by PREP-HPLC to obtain the compound of Example 80 (35 mg, 15%) as a whitish solid (97.59% purity). 1H NMR (400 MHz, DMSO-d6): δ 11.90 (s, 1H), 8.88 (s, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 4.87-4.82 (m, 1H), 1.50-1.46 (m, 9H).

[0259] Preparation of Example No. 84 (4-chloro-6-(2-oxo-2,3-dihydro-1Hpyrrolo[2,3-b]pyridin-5-yl)benzo[d]oxazol-2(3H)-one) Petition 870250099203, dated 10 / 30 / 2025, pp. 297 / 342 123 / 152

[0260] Step 1. Bromine (1.08 mL, 20.98 mmol) was added dropwise to a stirred solution of 2-amino-3-chlorophenol (2 g, 13.97 mmol) in DCM (100 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 16 hours. The solid thus formed was filtered, washed with DCM, and dried. The solid residue was divided between a saturated aqueous solution of NaHCO3 and DCM. The organic layer was washed with water, brine, and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-amino-5-bromo-3-chlorophenol (1.3 g, 41%) as a brown powder. MS (ESI): m / z 221.6 [M1]+.

[0261] Step 2. CDI (4.58 g, 28.24 mmol) was added to a stirred solution of 2-amino-5-bromo-3-chlorophenol (1.3 g, 5.88 mmol) in THF (20 mL) and the resulting mixture was heated at 65 °C for 2 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-bromo-4-chloro-2,3-dihydro-1,3-benzoxazol-2-one (800 mg, 54%) as a brown powder. MS (ESI): m / z 246.0 [M-1]+.

[0262] Step 3. To a stirred solution of 6-bromo-4-chloro-2,3-dihydro-1,3 Petition 870250099203, dated 10 / 30 / 2025, pp. 298 / 342 124 / 152 benzoxazol-2-one (200 mg, 0.81 mmol) in 1,4-dioxane (4 mL) and water (1 mL) in a microwave-safe container was added 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)1H,2H,3H-pyrrolo[2,3-b]pyridin-2-one (316 mg, 1.22 mmol) followed by K3PO4 (430 mg, 2.02 mmol) and the resulting mixture was purged with argon for 10 minutes. Pd(dtbpf)Cl2 (53 mg, 0.08 mmol) was added and the reaction mixture was heated under microwave irradiation at 100 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by reversed-phase preparation HPLC to obtain the compound of Example 84 (30 mg, 12%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.35 (br s, 1H), 11.10 (s, 1H), 8.38 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 7.53 (s, 1H), 3.60 (s, 2H).LCMS: Retention time = 1.85 minutes; HPLC purity = 93.25%.

[0263] Preparation of Example No. 85 (5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one)

[0264] Refer to Steps 1-2 of Example No. 87 for the preparation of 5-bromo-7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one. Then, to a stirred solution of 5-bromo-7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (150 mg, 0.55 mmol) in dioxane (4 mL) and water (1 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (214 mg, 0.82 mmol) followed by K3PO4 (292 mg, 1.37 mmol) and the resulting mixture was purged with Petition 870250099203, dated 10 / 30 / 2025, pp. 299 / 342 125 / 152 argon for 10 minutes. Pd(dtbpf)Cl2 (36 mg, 0.5 mmol) was added and the reaction mixture was heated under microwave irradiation at 100 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography (3-10% MeOH in DCM) to obtain the compound of Example 85 (50 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 10.84 (s, 1H), 8.37 (s, 1H), 7.89 (s, 1H), 7.64 (s, 1H), 7.53 (s, 1H), 3.60 (s, 2H), 1.32 (s, 6H). LCMS: Retention time = 2.42 minutes; HPLC purity = 96.99%

[0265] The preparation of Example No. 86, 7-chloro-3,3-dimethyl-5-(pyrimidine-5yl)indolin-2-one, was conducted similarly to Example No. 85, but for pyrimidine-5-boronic acid instead of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one to obtain the compound of Example No. 86. 1H NMR (400 MHz, DMSO-d6) δ: 10.97 (br-s, 1H), 9.18 - 9.14 (m, 3H), 7.84 (m, 1H), 7.78 (m, 1H), 1.34 (s, 6H).

[0266] Preparation of Example No. 87 (6-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)3,4-dihydro-1,8-naphthyridine-2(1H)-one) Petition 870250099203, dated 10 / 30 / 2025, pages 300 / 342 126 / 152

[0267] Step 1. Lithium chloride (3.79 g, 89.50 mmol) was added to a stirred solution of 7-chloro-2,3-dihydro-1H-indol-2-one (5 g, 29.83 mmol) in dry THF (50 mL), and the resulting mixture was cooled to -78 °C. Lithium diisopropylamide (29.8 mL, 59.67 mmol, 2.0 M in THF / heptane / ethylbenzene) was added and stirred at -78 °C for 15 minutes. Methyl iodide (3.76 mL, 59.67 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. After completion, the reaction mixture was slaked with an aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography (10-20% EtOAc). Petition 870250099203, dated 10 / 30 / 2025, pages 301 / 342 127 / 152 in hexane) to obtain 7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (2.8 g, 48%) as a yellow solid. MS (ESI): m / z 196.2 [M+1]+.

[0268] Step 2. To a stirred solution of 7-chloro-3,3-dimethyl-2,3-dihydro-1Hindol-2-one (1.5 g, 7.65 mmol) in trifluoroacetic acid (15 mL) was added N-bromo succinimide (892 mg, 9.18 mmol) in portions and the reaction mixture was stirred at room temperature for 16 hours. After completion, the trifluoroacetic acid was evaporated under reduced pressure. The residue was diluted with ethyl acetate, water, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (10-20% EtOAc in hexane) to obtain 5-bromo-7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (800 mg, 38%) as a yellow solid. MS (ESI): m / z 274.1 & 276.1 [M+1]+.

[0269] Step 3. To a stirred solution of 5-bromo-7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (500 mg, 1.83 mmol) in dioxane (5 mL) was added bis(pinacolate)diboron (558 mg, 2.2 mmol) followed by KOAc (360 mg, 3.66 mmol) and the resulting mixture was purged with argon for 10 minutes. Pd(dppf)Cl2.dcm (150 mg, 0.183 mmol) was added and the reaction mixture was heated at 95 °C for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product thus obtained was purified by combiflash column chromatography (30-40% EtOAc in hexane) to obtain 7-chloro-3,3-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (300 mg, 51%) as a brown solid. MS (ESI): m / z 322.2 [M+1]+.

[0270] Step 4. To a stirred solution of 7-chloro-3,3-dimethyl-5-(tetramethyl Petition 870250099203, dated 10 / 30 / 2025, pp. 302 / 342 128 / 152 1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (100 mg, 0.3 mmol) in dioxane (4 mL) and water (1 mL) was added, followed by 6-bromo-3,4-dihydro-1H-1,8-naphthyridine-2-one (106 mg, 0.46 mmol) and K3PO4 (360 mg, 3.66 mmol). The resulting mixture was purged with argon for 10 minutes. Pd(dtbpf)Cl2 (150 mg, 0.183 mmol) was added, and the reaction mixture was heated under microwave irradiation at 100 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by reversed-phase preparation HPLC to obtain the compound of Example 87 (40 mg, 38%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 10.54 (s, 1H), 8.43 (s, 1H), 7.94 (s, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 2.96-2.92 (m, 2H), 2.57-2.54 (m, 2H), 1.33 (s, 6H).LCMS: Retention time = 2.12 minutes; HPLC purity = 99.16%.

[0271] The preparation of Example 25, 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indolin-2-one, was conducted similarly to Example 87, but with 6-bromopyridazin-3(2H)-one instead of 6-bromo-3,4-dihydro-1H-1,8naphtiridin-2-one to obtain the compound of Example 25. 1H NMR (400 MHz, DMSOd6): δ 8.06 (d, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 6.98 (d, 1H), 1.32 (s, 1H).

[0272] The example number, the names of the compounds (mass ([M+1]+)) and their respective chemical structures are described below. EXAMPLE OF NUMBER AND NAME (MASS): No. 1. 8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)3,4-dihydroquinolin-2(1H)-one (364); No. 2. 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(thiazol-2-yl)-3,4-dihydroquinolin-2(1H)-one (340); Petition 870250099203, dated 10 / 30 / 2025, pp. 303 / 342 129 / 152 n° 3. 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-3,4-dihydroquinolin-2(1H)-one (336); n° 4. 8-(2-methoxythiazol-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)3,4-di-hydroquinoline-2(1 H)-one (370); n° 5. 5-methyl-6-(1-methyl-2-((4-(methylsulfonyl)phenyl)amino)-1 H-benzo[d]imidazol6-yl)-4,5-di-hydropyridazine-3(2H)-ona (412); n° 6. 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2-ona (278); n° 7. 7-(4-chlorophenyl)-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (337); n° 8. 7'-chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3yl)spiro[cyclopropane-1,3'-indoline]-2'-ona (304); n° 9. 8-(4-chlorophenyl)-6-(6-oxo-1,6-di-hydropyridazine-3-yl)-3,4-di-hydroquinoline2(1H)-one (351); n° 10. 6-(2-(benzo[d]thiazol-6-ylamino)-1-methyl-1H-benzo[d]imidazol-6-yl)-5methyl-4,5-di-hydropyridazine-3(2H)-one (390); n° 11. 8-bromo-4,4-dimethyl-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)3,4-di-hydroquinolin-2(1 H)-one (364); No. 12. 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)-3,4-dihydroquinolin-2(1H)-one (352); No. 13. 6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one (334); No. 14. 8-(6-methoxypyridin-3-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)3,4-di-hydroquinolin-2(1 H)-one (364); No. 15. 4-methyl-6-(6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)benzo[d]thiazol-2(3H)one (261); Petition 870250099203, of 30 / 10 / 2025, p. 304 / 342 130 / 152 No. 16. 6-(1-cyclopropyl-2-((4-(methylsulfonyl)phenyl)amino)-1H-benzo[d]imidazol-6yl)-5-methyl-4,5-di-hydropyridazin-3(2H)-one (438); n° 17. 3,3-dimethyl-5-(4-methyl-6-oxo-1,6-di-hydropyridazin-3-yl)-7-(thiazol-4yl)indolin-2-one (352); n° 18. 9-(6-metoxipiridin-3-il)-7-(4-metil-6-oxo-1,4,5,6-tetra-hidropiridazin-3-il)1,3,4,5-tetra-hidro-2H-benzo[b]azepin-2-ona (378); n° 19. 6-(2-(1-(4-metoxifenil)ciclopropil)-1H-benzo[d]imidazol-6-il)-5-methyl-4,5di-hidropiridazin-3(2H)-ona (375); n° 20. 7-(4-methyl-6-oxo-1,4,5,6-tetra-hidropiridazin-3-il)-9-(tiazol-2-il)-1,3,4,5tetra-hidro-2H-benzo[b]azepin-2-ona (354); n° 21. 5-methyl-6-(1-methyl-2-(phenilamino)-1H-benzo[d]imidazol-6-il)-4,5-dihidropiridazin-3(2H)-ona (334); n° 22. 6-(2-(benzo[d]tiazol-6-iloxi)-1 H-benzo[d]imidazol-6-il)-5-methyl-4,5-dihidropiridazin-3(2H)-ona (377); n° 23. 7-bromo-3,3-dimetil-5-(4-metil-6-oxo-1,4,5,6-tetra-hydropyridazin-3il)indolin-2-ona (350); n° 24. 7-chloro-3,3-dimetil-5-(4-metil-6-oxo-1,4,5,6-tetra-hydropyridazin-3il)indolin-2-ona (306); n° 25. 7-chloro-3,3-dimetil-5-(6-oxo-1,6-di-hydropyridazin-3-il)indolin-2-ona (289); n° 26. 7-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3yl)indolin-2-ona (290); n° 27. 7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-one (274); n° 28. 7′-fluoro-5′-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3 Petition 870250099203, dated 10 / 30 / 2025, p. 305 / 342 131 / 152 il)spiro[cyclopropane-1,3'-indoline]-2'-one (288); n° 29. 4-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)benzo[d]thiazol2(3H)-one (296); n° 30. 6-(2-amino-4-chlorobenzo[d]thiazol-6-yl)-5-methyl-4,5-di-hydropyridazine3(2H)-ona (295); n° 31. 6-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-5-methyl-4,5-di-hydropyridazine3(2H)-one (279); n° 32. 7-bromo-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona (334); n° 33. (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3yl)indolin-2-ona (306); No. 34. 6-(4-fluoro-2-(methylamino)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihidropyridazin-3(2H)-one (292); n° 35. 8-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)quinolin-2(1 H)ona (290); n° 36. 7-chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin3-yl)indolin-2-one (324); n° 37. 6-(4-fluoro-2-(3-hidroxiazetidin-1 -yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihidropyridazin-3(2H)-ona (335); n° 38. 2-amino-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)benzo[d]thiazol4-carbonitrila (285); n° 39. 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)isoindolin-1-one (278); No. 40. 6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)-2-oxo-1,2-dihidroquinoline-8-carbonitrila (280); Petition 870250099203, 30 / 10 / 2025, pág. 306 / 342 132 / 152 n° 41. 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3yl)isoindolin-1-ona (306); n° 42. 4-chloro-1-methyl-6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropiridazin-3-il)-1,3-dihidro-2H-benzo[d]imidazol-2-ona (293); n° 43. 7'-fluoro-5'-(4-metil-6-oxo-1,4,5,6-tetra-hydropyridazin-3il)spiro[ciclobutane-1,3'-indolin]-2'-ona (301); n° 44. 7-chloro-3,3-dimetil-5-(6-oxo-1,4,5,6-tetra-hydropyridazin-3-il)indolin-2ona (291); n° 45. 6-(8-bromo-2-hidroxiquinolin-6-il)-5-methyl-4,5-di-hidropiridazin-3(2H)ona (334); n° 46. 6-(4-fluoro-2-(((1-metil-1 H-pirazol-4-il)metil)amino)benzo[d]tiazol-6-il)5-metil-4,5-di-hydropyridazin-3(2H)-ona (373); n° 47. 6-(7-chloro-3-methyl-1 H-indazol-5-il)-5-methyl-4,5-di-hidropiridazin-3(2H)ona (277); n° 48. 6-(8-ciclopropil-2-hidroxiquinolina-6-il)-5-methyl-4,5-di-hidropiridazin3(2H)-ona (295); n° 49. 6-(2-(3-metoxiazetidin-1 -il)benzo[d]tiazol-6-il)-5-metil-4,5-dihydropyridazin-3(2H)-ona (330); n° 50. 7-fluoro-5-(4-metil-6-oxo-1,4,5,6-tetra-hydropyridazin-3-il)indolin-2-ona (261); n° 51. (S)-7-chloro-3,3-dimetil-5-(4-metil-6-oxo-1,4,5,6-tetra-hydropyridazin-3il)isoindolin-2-ona (305); n° 52. 4-chloro-6-(6-oxo-1,6-di-hydropyridazin-3-il)benzo[d]tiazol-2(3H)-ona (280); n° 53. 5-(4-metil-6-oxo-1,4,5,6-tetra-hydropyridazin-3-il)-2-oxoindoline-7 Petition 870250099203, on 10 / 30 / 2025, page. 307 / 342 133 / 152 carbonitrila (268); n° 54. (R)-7-fluoro-5-(4-metil-6-oxo-1,4,5,6-tetra-hydropyridazin-3-il)indolin-2ona (261); n° 55. 4-methyl-6-(6-methyl-2-oxo-3,6-di-hidro-2H-1,3,4-tiadiazin-5il)benzo[d]tiazol-2(3H)-ona (293); n° 56. 4-chloro-6-(6-methyl-2-oxo-3,6-di-hidro-2H-1,3,4-tiadiazin-5il)benzo[d]tiazol-2(3H)-ona (313); n° 57. 5-(7-fluoro-2-oxoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4-tiadiazin-2ona (279); No. 58. 5-(7'-chloro-2'-oxospiro[cyclopropano-1,3'-indoline]-5'-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (322); No. 59. 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazin2-one (293); No. 60. (R)-5-(2-hydroxy-8-methylquinolin-6-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazin-2-one (287); No. 61. 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazin2-one (310); No. 62. 5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin-2ona (294); No. 63. 6-methyl-5-(7-(4-(methylsulfonyl)phenyl)-2-oxoindolin-5-yl)-3,6-di-hydro-2H1,3,4-thiadiazin-2-one (415); No. 64. 5-(9-chloro-2-oxo-2,3,4,5-tetra-hydro-1 H-benzo[b]azepin-7-yl)-6-methyl-3,6di-hydro-2H-1,3,4-thiadiazin-2-one (324); No. 65. 5-(8-bromo-2-oxo-1,2,3,4-tetra-hydroquinolin-6-yl)-6-methyl-3,6-di-hydro2H-1,3,4-thiadiazin-2-one (354); Petition 870250099203, of 30 / 10 / 2025, p. 308 / 342 134 / 152 No. 66. 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazin2-one (354); No. 67. (6R)-5-(8-chloro-4,4-dimethyl-2-oxo-1,2,3,4-tetra-hydroquinolin-6-yl)-6methyl-3,6-di-hydro-2H-1,3,4-thiadiazin-2-one (338); No. 68. 5-(3,3-dimethyl-2-oxo-7-(thiazol-4-yl)indolin-5-yl)-6-methyl-3,6-di-hydro-2H1,3,4-thiadiazin-2-one (372); No. 69. 5-(7-bromo-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin-2ona (340); No. 70. 6-methyl-5-(2-oxo-7-phenylindolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazin-2ona (337); No. 71. 5-(7-(4-chlorophenyl)-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazin-2-one (372); No. 72. 5-(2-oxo-2,3,4,5-tetra-hydro-1 H-benzo[b]azepin-7-yl)-3,6-di-hydro-2H1,3,4-thiadiazin-2-one (275); No. 73. 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetra-hydro-1 H-benzo[b]azepin-7-yl)-3,6di-hydro-2H-1,3,4-thiadiazin-2-one (304); n° 74. 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4tiadiazin-2-ona (307); n° 75. 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4tiadiazin-2-ona (324); n° 76. 5-(7-bromo-3,3-dimetil-2-oxoindolin-5-il)-6-metil-3,6-di-hydro-2H-1,3,4tiadiazin-2-ona (368); n° 77. 5-(6-methyl-2-oxo-3,6-di-hidro-2H-1,3,4-tiadiazin-5-il)-2-oxoindoline-7carbonitrila (286); n° 78. (S)-5-(7-fluoro-2-oxoindolin-5-il)-6-metil-3,6-di-hydro-2H-1,3,4-tiadiazinPetição 870250099203, on 10 / 30 / 2025, pág. 309 / 342 135 / 152 2-ona (279); n° 79. 5-(7-chloro-1-oxoisoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4-tiadiazin-2ona (296); n° 80. 5-(7-chloro-3,3-dimethyl-1-oxoisoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4tiadiazin-2-ona (324); n° 81. 5-(8-chloro-2-hidroxiquinolin-6-il)-6-methyl-3,6-di-hidro-2H-1,3,4-tiadiazin2-ona (308); No. 82. 5-(7-chloro-2,2-dioxide-1,3-di-hydrobenzo[c]isothiazol-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (332); No. 83. 6-methyl-5-(8-methyl-2-oxo-1,2,3,4-tetra-hydroquinolin-6-yl)-3,6-di-hydro-2H1,3,4-thiadiazin-2-one (289); No. 84. 4-chloro-6-(2-oxo-2,3-di-hydro-1 H-pyrrole[2,3-b]pyridin-5yl)benzo[d]oxazol-2(3H)-one (300); No. 85. 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-1,3-dihydro-2H-pyrrolo[2,3b]pyridin-2-one (328). n° 86. 7-chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indoline-2-one (274); No. 87. 6-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,4-di-hydro-1,8-natphyridin-2(1 H)one (340); No. 88. 4-chloro-6-(5-oxo-4,5-di-hydro-1,3,4-thiadiazol-2-yl)benzo[d]thiazol-2(3H)one (286); en° 89. 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-1,3,4-thiadiazol-2(3H)-one (296).

[0273] The respective chemical structures of the compounds of Examples 1 to 89 are described below. Petition 870250099203, dated 10 / 30 / 2025, pp. 310 / 342 136 / 152 Petition 870250099203, dated 10 / 30 / 2025, pp. 311 / 342 137 / 152 Petition 870250099203, dated 10 / 30 / 2025, pp. 312 / 342 138 / 152 Petition 870250099203, dated 10 / 30 / 2025, pp. 313 / 342 139 / 152 Petition 870250099203, dated 10 / 30 / 2025, pp. 314 / 342 140 / 152 Petition 870250099203, dated 10 / 30 / 2025, pp. 315 / 342 141 / 152 O=S=O Petition 870250099203, dated 10 / 30 / 2025, pp. 316 / 342 142 / 152 Petition 870250099203, dated 10 / 30 / 2025, pp. 317 / 342 143 / 152

[0274] Pimobendan, a dihydropyridazinone inodilator / vasodilator, has the chemical name 6-(2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one and the structure shown below. Petition 870250099203, dated 10 / 30 / 2025, pp. 318 / 342 144 / 152

[0275] Pimobendan is rapidly absorbed when administered orally, with a bioavailability of approximately 60 to 65%. The tmax and elimination half-life of pimobendan are approximately 2 hours and 1.6 hours, respectively. The desmethyl metabolite has a tmax and elimination half-life of approximately 3.2 hours and 5 hours, respectively. Pimobendan acts as a positive inotropic agent by sensitizing the affinity of calcium for binding to troponin C in cardiac myocytes and inhibiting PDE3. Inhibition of PDE3 also results in arterial dilation and venodilation, thus improving cardiac output without increasing myocardial oxygen consumption and is therefore used in the treatment of congestive heart attack secondary to myxomatous mitral valve disease or dilated cardiomyopathy in dogs. Cardiac troponin I (cTnI) is a protein unique to the heart and is a specific and sensitive biomarker of myocardial damage.In healthy animals, the concentration of cardiac troponin in the blood should be practically zero; therefore, any significant elevation indicates some degree of myocardial damage. Monitoring the effect of PDE3 ceidates on circulating cTnI can provide an alert to any concerns about cardiomyocyte damage and help inform safety assessments in future studies. Furthermore, cTnI can be used as a prognostic biomarker due to its strong association with mortality in dogs. BIOLOGICAL METHODS: cPDE3A assay (fluorescent polarization) Petition 870250099203, dated 10 / 30 / 2025, pp. 319 / 342 145 / 152

[0276] The canine PDE3A assay kit was purchased from BPS Bioscience (San Diego, CA), which included recombinant canine PDE3A enzyme, FAM-cyclic-3',5'-AMP (20μM), PDE3 assay buffer, binding agent, binding agent diluent, and 96-well microtiter plates. The compounds were initially dissolved in DMSO. The stock concentration was subsequently diluted in cPDE assay buffer (10X stock) and serially diluted to provide a concentration response curve from 10 μM (>7 total concentrations). After serial dilution, the compound solution (final DMSO of 0.1%) was transferred to an assay plate (96 wells), where the remaining reagents for the canine PDE3A assay were dispensed according to the BPS Bioscience® protocol procedure (catalog no. 79735) using a final enzyme concentration of 5 pg / μL.Each compound was evaluated for inhibition of canine PDE3A enzyme activity using measurement of fluorescent polarization changes. The 50% inhibition concentration (IC50) nM was calculated and reported. Compared to current cPDE3 inhibitors of the invention, pimobendan exhibited a cPDE3 IC50 value of approximately 1530 nM. The cPDE3 inhibitory data (IC50) in nanomolar (nM) for the compounds of the invention are shown in Table 1. Contractility assay of human iPS cardiomyocytes

[0277] Frozen human iCell® cardiomyocytes (FujiFilm® Cellular Dynamics Inc.) were thawed and placed in the center of each well of a 24-well Axion® Biosystems cytoview microelectrode array plate, coated with human fibronectin in a 5-6 μL droplet at a density of 7-10 x 10⁶ cells / mL. The cells were maintained in culture in a humidified incubator at 37°C with 5% CO₂. After at least seven days in culture with maintenance medium changes every 2-3 days, the cells were stimulated at 2 Hz. Petition 870250099203, dated 10 / 30 / 2025, pages 320 / 342 146 / 152 for approximately 48 hours on the Axion® Biosystems Maestro Pro instrument using the field potential application in the Axis Navigator software before reverting to spontaneous beating for at least 10 minutes on the contractility application (i.e., Axion® Biosystems procedure for the Positive Inotropy Protocol). A three-minute baseline recording was made before adding the test articles to the plate, followed by spontaneous beating recording for at least sixty minutes, with three-minute recordings every ten minutes. Readings were taken at 3, 13, 23, 33, 43, and 53 minutes. The compounds were dissolved in DMSO and tested at a final concentration of 30 μM with a final DMSO concentration of 0.3%. The compound solutions were transferred to the cell plates in the instrument after baseline recording. Each compound was evaluated for its contractility response in relation to vehicle control (DMSO).Statistically significant changes in contractility at the last time point (53 minutes), as defined by changes in mean beat amplitude delta %, are described with a “+” notation in Table 1. Changes in contractility at the last time point that were not significant relative to the vehicle were described with “*”. For these, significance was obtained at earlier time points. TABLE 1. cPDE3 INHIBITION (IC50) IN nM AND CONTRACTILITY Ex. No. IC50 Ex. No. IC50 Ex. No. IC50 1 (+) 29.2 31 (*) 5.5 61 (*) 14.8 2 (+) 23.5 32 (+) 26.7 62 (+) 11.2 3 (+) 3.2 33 (+) 3.2 63 (+) 30.5 4 (+) 24.8 34 (NT) 3.7 64 (+) 3.2 Petition 870250099203, dated 10 / 30 / 2025, pages 321 / 342 147 / 152 5 (+) 4.9 35 (NT) 3.2 65 (+) 4.3 6 (*) 6.2 36 (NT) 3.6 66 (+) 24.4 7 (+) 40.6 37 (NT) 6.1 67 (+) 48.3 8 (+) 3.9 38 (+) 7.4 68 (+) 118 9 (+) 13.6 39 (NT) 10.5 69 (+) 10.9 10 (+) 7.3 40 (+) 12 70 (+) 80.7 11 (+) 51.3 41 (NT) 15.4 71 (+) 90.4 12 (+) 90.9 42 (+) 16.2 72 (+) 28.2 13 (+) 44.4 43 (NT) 35.5 73 (+) 4.9 14 (+) 50.2 44 (+) 94 74 (+) 13.3 15 (+) 17.6 45 (+) 3.2 75 (+) 9.7 16 (+) 5 46 (NT) 3.4 76 (+) 15.2 17 (+) 62.4 47 (NT) 4 77 (+) 41.6 18 (+) 42.1 48 (+) 18 78 (+) 7.8 19 (*) 22.2 49 (NT) 48.6 79 (NT) 20.3 20 (+) 32.4 50 (+) 4.9 80 (NT) 20.6 21 (+) 22.7 51 (*) 336 81 (*) 3.2 22 (+) 33.1 52 (NT) 24.7 82 (NT) 26.4 23 (+) 9.1 53 (*) 32.7 83 (+) 3.2 24 (+) 5.4 54 (NT) 7.4 84 (+) 112 Petition 870250099203, dated 10 / 30 / 2025, pages 322 / 342 148 / 152 25 (+) 15.7 55 (+) 3.8 85 (+) 49.7 26 (+) 7.4 56 (+) 3.6 86 (+) 115 27 (*) 38.3 57 (+) 14.2 87 (+) 3.4 28 (+) 3.4 58 (+) 8.4 88 (NT) 29.2 29 (+) 3.2 59 (+) 22.2 89 (+) 25.3 30 (+) 4 60 (+) 4.7 pimobendan (+) 1530 NT - Not tested

[0278] As can be seen in Table 1, the compounds of the invention have a much higher affinity for cPDE3 than other known cPDE3 inhibitors. On average, the compounds of the invention have an IC50 binding affinity (27.1 nM (2408 / 89)) to the cPDE3 receptor that is about 57 times greater than pimobendan (1530 / 27). For examples 19, 57, 61, 62 and 73, the average cPDE3 IC50 is about 13.5, which is about 113 times greater than pimobendan. For examples 23, 24, 74, 75 and 76, compounds with a longer terminal half-life, the average cPDE3 IC50 is about 10.5 nM, about 129 times greater than that of pimobendan. Therefore, lower doses of either of the compounds in the invention may lead to higher levels of cPDE3 inhibition and higher levels of cAMP and subsequent inotropic effects, thereby boosting cardiac muscle contraction and smooth muscle dilation.As strong inotropes, the compounds of the invention may be useful for the treatment of CHF, MMVD and / or asymptomatic heart attack in animals, especially canines.

[0279] Myocardial contractility represents the innate ability of the heart muscle to contract. The ability to produce changes in force during Petition 870250099203, dated 10 / 30 / 2025, pp. 323 / 342 149 / 152 Contraction results from incremental degrees of binding between different types of tissues, that is, between myosin filaments and actin tissue. Contractility is an intrinsic property of these myocardial fibers. The degree of binding depends on the concentration of calcium ions in the cell and also on the responsiveness of the myofilament to calcium. In an intact heart in vivo, the action / response of the sympathetic nervous system is driven by precisely timed releases of a catecholamine, a process that determines the concentration of calcium ions in the cytosol of cardiac muscle cells. Factors that cause an increase in contractility work by causing an increase in intracellular calcium ions (Ca2+) during contraction. A measurable relative increase in contractility is a property of the myocardium similar to the term "inotropy". Contractility can be altered iatrogenically by the administration of inotropic agents.Drugs that positively mimic the effects of catecholamines, such as norepinephrine, epinephrine, and pimobendan, which increase contractility, are considered to have a positive inotropic effect. Thus, an increase in contractility generally results in an increase in cardiac output. Human cardiomyocytes that are chronically stimulated (2 Hz) for several days synchronize so that pharmacologically induced contractility or impedance changes can be measured. Pimobendan increases cardiomyocyte contractility in a dose-dependent manner, as defined by changes in mean delta beat amplitude. By contracting more, there will be an increase in left ventricular pressure. The cardiomyocyte contractility of the compounds of the invention, as defined by changes in mean delta beat amplitude, has been determined to have a positive inotropic effect (i.e., a stronger cardiac muscle contraction force). Petition 870250099203, dated 10 / 30 / 2025, pp. 324 / 342 150 / 152

[0280] In addition, Example No. 57 (30μM) was tested in a contractility amplitude (CA) assay using adult human primary ventricular cardiomyocytes dissociated from human donor hearts to determine the compound's potential to exert its positive inotropic effect by a single (Ca2+ sensitization or PDE3 inhibition) or dual (Ca2+ sensitization and PDE3 inhibition) mechanism of action. Cardiomyocytes were incubated at 35°C under continuous perfusion (2 mL / minute) in a buffer solution (vehicle) (HEPES (10 mM), NaCl (145 mM), KCl (4 mM), MgCl2 1 mM), CaCl2 (1.8 mM) and dextrose (11.1 mM)) plus 0.1% DMSO). Cells were equilibrated for a minimum of 5 minutes and stimulated at 1.0 Hz with a stimulation intensity of 1.5x. A non-selective PDE inhibitor IBMX (3-isobutyl-1-methylxanthine) of 100 μM was used. The treatment time and stimulation were 300 seconds at 1.0 Hz. Data were collected using MyoBLAZERT™ software (v2.9.2).Balanced cells (n=12) were stimulated with suprathreshold voltage at a stimulation frequency of 1 Hz (3 ms bipolar pulse duration). Starting at 1V, the amplitude of the stimulating pulse was increased until cardiomyocytes began to generate contraction-relaxation cycles. Contractility amplitude was calculated from the average of the last 20 contractility transients. Contractility amplitude for the vehicle, IBMX, and IBMX with Example #57 was 100, 136.8, and 267.6, respectively. The differences in CA between vehicle and IBMX; vehicle and IBMX+Exam #57; and IBMX and IBMX+Exam #57 were significantly different. IBMX increased CA by inhibiting PDE; However, there was an even greater increase in CA in the presence of Ex n° 57. Furthermore, the CA assay was used to evaluate the potential of Ex n° 57 to exert a change in the EC50 calcium concentration. The EC50 for cardiomyocytes without Ex n° 57 was 1286 μM, while the EC50 with Ex n° 57 was 821 μM.In this second study of. Petition 870250099203, dated 10 / 30 / 2025, pages 325 / 342 151 / 152 CA, myocyte contractility was dose-dependent on calcium concentration. Contractility at 100 μM, 1000 μM, and 10,000 μM of CaCl2 was 3.11, 56.31, and 228.61, respectively. With the addition of 30 μM of Ex n° 57, the respective contractility values ​​increased to 40.17, 182.67, and 284.27. Overall, these contractility studies clearly show that there is an additive effect of calcium sensitization, independent of PDE3 inhibition, thus supporting dual-modality cardiotonic activity.

[0281] Finally, the plasma half-life was evaluated for several compounds in dogs. Beagle dogs received an oral dose (0.1 mg / kg) of the respective compound, representing a dose amount of approximately 1 mg / dog. Pimopendan was administered at a dose of 0.3 mg / kg. Plasma samples were obtained over a 72-hour period and the plasma half-life was calculated. The plasma half-lives of the dogs (t½) in hours are presented in Table 2. TABLE 2. COMPOUND HALF-LIFE OF DOG PLASMA (HOURS) Example number t½ (hours) Example number t½ (hours) 12 10.4 62 5 19 16 66 10.2 23 94 68 12 24 50 71 5.4 25 50 72 3.9 55 3.2 73 7.5 56 15 74 55 Petition 870250099203, dated 10 / 30 / 2025, pp. 326 / 342 152 / 152 57 10 75 50 58 7 76 40 59 5.2 85 9 61 8.5 86 96 pimobendan 0.4

[0282] As can be seen in Table 2, the compounds of the invention have a much longer half-life than pimobendan. Therefore, it is likely that the compounds of the invention can be dosed once a day (instead of twice a day, like pimobendan) or even once every few days (e.g., twice a week).

[0283] NT-proBNP is a standard circulating biomarker of canine MMVD secreted by ventricular cardiomyocytes in response to stretch from volume or pressure overload. It is a well-defined diagnostic and prognostic biological indicator of myocardial wall stress and can be used as a biomarker for acute changes in left ventricular loading conditions. In some internal studies, NT-proBNP was evaluated as a biomarker that showed a 30% reduction in NT-proBNP, which was associated by others to indicate a reduction in cardiac wall stress and improved quality of life. In one example, Example No. 26 reduced NT-proBNP levels by 49% and 62% at doses of 0.03 and 0.1 mg / kg, respectively, over a 12-hour period. In contrast, the labeled dose of pimobendan showed a 41% reduction in NT-proBNP 24 hours after dosing.This positive pharmacological effect suggests a clinically relevant reduction in myocardial stress, which may delay the progression of heart disease. Petition 870250099203, dated 10 / 30 / 2025, pp. 327 / 342

Claims

1 / 14 CLAIMS 1. Compound, CHARACTERIZED hair made is selected from the group consisting of: 8-(2-methoxypyridine-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydrohydrolyne-1,3hydropyridazine( H)-one; 6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-8-(thiazol-2-yl)-3,4-dihydroquinolin-2(1 H)-one; 8-(2-methoxythiazol-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-3,4-dihydroquinolin-2(1 H)-one; 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2-one; 7-(4-chlorophenyl)-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona; 7'-chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)spiro[cyclopropane1,3'-indolin]-2'-one; 8-(4-chlorophenyl)-6-(6-oxo-1,6-di-hydropyridazine-3-yl)-3,4-di-hydroquinoline-2(1H)one; 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-3,4-dihydroquinolin-2(1 H)-one; 6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinolin-2(1 H)-one;3,3-dimethyl-5-(4-methyl-6-oxo-1,6-di-hydropyridazine-3-yl)-7-(thiazol-4-yl)indolin-2ona; 9-(6-methoxypyridine-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)1,3,4,5-tetra-hydro-2H-benzo[b]azepin-2-one; 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; Petition 870250099203, dated 10 / 30 / 2025, p. 328 / 342 2 / 14 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2ona; 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2one; 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona; 7-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2one; 7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-one; 7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)spiro[cyclopropane1,3'-indoline]-2'-one; 7-chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2-one;4-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)benzo[d]thiazol-2(3H)one; 6-(2-amino-4-chlorobenzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 6-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)one; 7-bromo-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-one; (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3yl)indolin-2-one; 6-(4-fluoro-2-(methylamino)benzo[d]thiazol-6-yl)-5-methyl-4,5-di-hydropyridazin3(2H)-one; 8-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)quinolin-2(1H)-one; 6-(8-chloro-2-hydroxyquinolina-6-yl)-5-methyl-4,5-di-hydropyridazine-3(2H)-one; 7-chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropiridazin-3yl)indolin-2-one; Petition 870250099203, of 30 / 10 / 2025, p. 329 / 342 3 / 14 6-(4-fluoro-2-(3-hidroxi-azetidina-1-yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 2-amino-6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropiridazine-3-yl)benzo[d]thiazol-4carbonitrila;7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)isoindolin-1-one; 6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-2-oxo-1,2-di-hydroquinolina-8-carbonitrila; 2-hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)quinolina-8-carbonitrila; 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)isoindolin-1-one; 4-chloro-1 -methyl-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)-1,3-di-hydro2H-benzo[d]imidazol-2-one; 7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)espiro[cyclobutane1,3'-indoline]-2'-one; 6-(8-bromo-2-hydroxyquinolina-6-yl)-5-methyl-4,5-di-hydropyridazine-3(2H)-one; 6-(4-fluoro-2-(((1-methyl-1 H-pyrazol-4-yl)methyl)amino)benzo[d]thiazol-6-yl)-5-methyl4,5-dihydropyridazine-3(2H)-one; 6-(7-chloro-3-methyl-1H-indazol-5-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 6-(8-cyclopropyl-2-hydroxyquinolina-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)one;6-(2-(3-methoxy-azetidine-1-yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-di-hydropyridazine3(2H)-one; 7-fluoro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2-one; (S)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3 Petition 870250099203, dated 30 / 10 / 2025, p. 330 / 342-1 indone) 4 / isone 4-chloro-6-(6-oxo-1,6-di-hydropyridazine-3-yl)benzo[d]thiazol-2(3H)-one; 5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)-2-oxendoline-7carbonitrile; 4-methyl-6-(6-methyl-2-oxo-3,6-di-hydro-2H-1,3,4-thiadiazine-5-yl)benzo[d]thiazol2(3H)-ona; 4-chloro-6-(6-methyl-2-oxo-3,6-di-hydro-2H-1,3,4-thiadiazine-5-yl)benzo[d]thiazol2(3H)-one; 5-(7-fluoro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one; 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-6-methyl-3,6-di-hydro-2H1,3,4-thiadiazine-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxendolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoendolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one;5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin-2-one; 6-methyl-5-(7-(4-(methylsulfonyl)phenyl)-2-oxoindoline-5-yl)-3,6-di-hydro-2H-1,3,4thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazin-2ona; 5-(3,3-dimethyl-2-oxo-7-(thiazol-4-yl)indolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazin-2-one; 5-(7-(4-chlorophenyl)-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin-2ona; 5-(2-oxo-2,3,4,5-tetra-hydro-1H-benzo[b]azepin-7-yl)-3,6-di-hydro-2H-1,3,4thiadiazin-2-one; 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetra-hydro-1H-benzo[b]azepin-7-yl)-3,6-di Petition 870250099203, of 30 / 10 / 2025, p. 331 / 342 5 / 14 hydro-2H-1,3,4-thiadiazin-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazin2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazin-2-one;5-(6-methyl-2-oxo-3,6-di-hidro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7carbonitrila; (S)-5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona; 5-(7-chloro-1-oxoisoindolin-5-yl)-6-methyl-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona; 5-(7-chloro-3,3-dimethyl-1-oxoisoindolin-5-yl)-6-methyl-3,6-di-hidro-2H-1,3,4thiadiazin-2-ona; 5-(8-chloro-2-hidroxyquinolin-6-yl)-6-methyl-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona; 5-(7-chloro-2,2-dioxido-1,3-di-hidrobenzo[c]isothiazol-5-yl)-6-methyl-3,6-di-hidro2H-1,3,4-thiadiazin-2-ona; 6-methyl-5-(8-methyl-2-oxo-1,2,3,4-tetra-hidroquinolin-6-yl)-3,6-di-hidro-2H-1,3,4thiadiazin-2-ona; 4-chloro-6-(2-oxo-2,3-di-hidro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]oxazol2(3H)-ona; 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-1,3-di-hidro-2H-pyrrolo[2,3-b]pyridin-2ona; 7-chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indolin-2-one; 6-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,4-di-hidro-1,8-naphthyridin-2(1H)-ona;4-chloro-6-(5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)benzo[d]thiazol-2(3H)-one; and Petition 870250099203, dated 10 / 30 / 2025, page 332 / 342 6 / 14 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-1,3,4-thiadiazol-2(3H)-one, stereoisomers thereof and acceptable veterinary salts thereof.

2. Compound, in accordance with indication 1, CHARACTERIZED by which it is selected from the group consisting of: 8-(2-methoxipyridin-4-yl)-6-(4-methyl·6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)-3,4di-hidroquinolin-2(1 H)-ona; 8-(2-methoxythiazol-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)-3,4-dihidroquinolin-2(1 H)-ona; 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)indolin-2-ona; 7'-chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)espiro[cyclopropane1,3'-indolin]-2'-one; 8-(4-chlorophenyl)-6-(6-oxo-1,6-di-hydropyridazin-3-yl)-3,4-di-hydroquinolin-2(1H)one; 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)-3,4-dihydroquinolin-2(1 H)-one; 6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihidroquinolin-2(1 H)-ona; 9-(6-methoxipyridin-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)1,3,4,5-tetra-hidro-2H-benzo[b]azepin-2-ona;6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2one; 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2one; Petition 870250099203, dated 10 / 30 / 2025, p. 333 / 342 7 / 14 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-one; 7-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2one; 7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-one; 7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)spiro[cyclopropane1,3'-indoline]-2'-one; 7-chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)indolin-2-one; 6-(2-amino-4-chlorobenzo[d]thiazol-6-yl)-5-methyl-4,5-di-hydropyridazine-3(2H)-one; 6-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-5-methyl-4,5-di-hydropyridazine-3(2H)one; 7-bromo-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona;(R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3yl)indolin-2-one; 6-(4-fluoro-2-(methylamino)benzo[d]thiazol-6-yl)-5-methyl-4,5-di-hydropyridazin3(2H)-one; 8-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)quinolin-2(1H)-one; 6-(8-chloro-2-hydroxyquinolina-6-yl)-5-methyl-4,5-di-hydropyridazine-3(2H)-one; 7-chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3yl)indolin-2-one; 6-(4-fluoro-2-(3-hydroxy-azetidine-1-yl)benzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 2-amino-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)benzo[d]thiazole-4-carbonitrila; 2-hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)quinoline-8-carbonitrila; Petition 870250099203, 30 / 10 / 2025, pág. 334 / 342 8 / 14 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazine-3-yl)isoindolin-1-ona; 6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazine-3-yl)-2-oxo-1,2-di-hidroquinolina8-carbonitrila;7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)isoindolin1-one; 4-chloro-1 -methyl-6-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)-1,3-di-hydro2H-benzo[d]imidazol-2-one; 7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3-yl)espiro[cyclobutane1,3'-indoline]-2'-one; 4-chloro-6-(6-methyl-2-oxo-3,6-di-hidro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol2(3H)-ona; 5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona; 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-di-hidro-2H1,3,4-thiadiazin-2-ona; 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona; 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona; 5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona; 6-methyl-5-(7-(4-(methylsulfonyl)phenyl)-2-oxoindolin-5-yl)-3,6-di-hidro-2H-1,3,4thiadiazin-2-ona; 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hidro-2H-1,3,4-thiadiazin-2ona;5-(7-(4-chlorofenil)-2-oxoindolin-5-il)-6-metil-3,6-di-hydro-2H-1,3,4-tiadiazin-2ona; 6-metil-5-(9-metil-2-oxo-2,3,4,5-tetra-hydro-1H-benzo[b]azepin-7-il)-3,6-dihidro-2H-1,3,4-tiadiazin-2-ona; Petition 870250099203, on 10 / 30 / 2025, page. 335 / 342 9 / 14 5-(7-fluoro-3,3-dimetil-2-oxoindolin-5-il)-6-metil-3,6-di-hydro-2H-1,3,4tiadiazin-2-ona; 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4-tiadiazin-2-ona; 5-(7-bromo-3,3-dimetil-2-oxoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4-tiadiazin-2-ona; 5-(6-methyl-2-oxo-3,6-di-hidro-2H-1,3,4-tiadiazin-5-il)-2-oxoindolina-7carbonitrila; (S)-5-(7-fluoro-2-oxoindolin-5-il)-6-methyl-3,6-di-hidro-2H-1,3,4-tiadiazin-2-ona; 5-(7-chloro-1-oxoisoindolin-5-il)-6-metil-3,6-di-hydro-2H-1,3,4-tiadiazin-2-ona; 5-(7-chloro-3,3-dimetil-1-oxoisoindolin-5-il)-6-metil-3,6-di-hydro-2H-1,3,4tiadiazin-2-ona; 6-metil-5-(8-metil-2-oxo-1,2,3,4-tetra-hydroquinolin-6-il)-3,6-di-hidro-2H-1,3,4tiadiazin-2-ona;5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; and 7-chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indolin-2-one, stereoisomers thereof and acceptable veterinary salts thereof.

3. Compound, in accordance with indication 2, CHARACTERIZED by which it is selected from the group consisting of: 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)-3,4-dihidroquinolin-2(1 H)-ona; 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)indolin-2 Petição 870250099203, de 30 / 10 / 2025, pág. 336 / 342 10 / 14 on; 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)indolin-2ona; 7-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)indolin-2ona; 7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indolin-2-one; 7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazin-3-yl)espiro[cyclopropane1,3'-indolin]-2'-one; 6-(2-amino-4-chlorobenzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 6-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one;7-bromo-3,3-dimethyl-5-(6-oxo-1,6-di-hydropyridazine-3-yl)indolin-2-ona; (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hydropyridazine-3yl)indolin-2-one; 4-chloro-6-(6-methyl-2-oxo-3,6-di-hydro-2H-1,3,4-thiadiazine-5-yl)benzo[d]thiazol2(3H)-one; 5-(7-fluoro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one; 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-yl)-6-methyl-3,6-di-hydro-2H1,3,4-thiadiazine-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoendolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one; 5-(7-chloro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoendolin-5-yl)-3,6-di-hydro-2H-1,3,4-thiadiazine-2one; 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetra-hydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one; Petition 870250099203, dated 10 / 30 / 2025, p. 337 / 342 11 / 14 5-(7-fluoro-3,3-dimethyl-2-oxonindolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazine-2-one;5-(7-chloro-3,3-dimethyl-2-oxoendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine 2-one; 5-(7-bromo-3,3-dimethyl-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazine-2-one; 5-(6-methyl-2-oxo-3,6-di-hydro-2H-1,3,4-thiadiazine-5-yl)-2-oxonondoline-7carbonitrile; (S)-5-(7-fluoro-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoendolin-5-yl)-1,3-di-hydro-2H-pyrrole[2,3-b]pyridine-2 ona; and 7-chloro-3,3-dimethyl-5-(pyrimidine-5-yl)indolin-2-one, stereoisomers of the same and veterinary acceptance of the same.; 4. Compound, in accordance with indication 3, CHARACTERIZED by the fact that it is a compound selected from the group consisting of: 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)indolin-2 ona; 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetra-hidropyridazin-3-yl)indolin-2 ona; 5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona; 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona; 5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-di-hidro-2H-1,3,4-thiadiazin-2-ona; 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetra-hidro-1H-benzo[b]azepin-7-yl)-3,6-di Petição 870250099203, de 30 / 10 / 2025, pág.338 / 342 12 / 14 hydro-2H-1,3,4-thiadiazine-2-ona; 5-(7-fluoro-3,3-dimethyl-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazine-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4-thiadiazine2-one; 5-(7-bromo-3,3-dimethyl-2-oxendolin-5-yl)-6-methyl-3,6-di-hydro-2H-1,3,4thiadiazine-2-one; and 7-chloro-3,3-dimethyl-5-(pyrimidine-5-yl)indolin-2-one, stereoisomers of the same and veterinary acceptance of the same.

5. Compound according to claim 4, CHARACTERIZED by the fact that it is selected from the group consisting of 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; and 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one, stereoisomers thereof and veterinary acceptable salts thereof.

6. Compound according to claim 4, CHARACTERIZED in that it is selected from the group consisting of 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one; 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2-one; Petition 870250099203, dated 10 / 30 / 2025, pp. 339 / 342 13 / 14 5-(7-fluoro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4thiadiazin-2-one; and 7-chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indolin-2-one, stereoisomers thereof and veterinary acceptable salts thereof.

7. Compound according to claim 4, CHARACTERIZED by the fact that it is selected from the group consisting of 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2one; 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indolin-2one; 5-(7-fluoro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; and 5-(7-chloro-3,3-dimethyl-2-oxoindolin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, stereoisomers thereof and acceptable veterinary salts thereof.

8. Composition CHARACTERIZED by the fact that it comprises a compound, as defined in any one of claims 1 to 7, a stereoisomer thereof or an acceptable veterinary salt thereof.

9. Composition, according to claim 8, CHARACTERIZED by Petition 870250099203, dated 10 / 30 / 2025, pp. 340 / 342 14 / 14, in that it comprises a compound, as defined in any one of claims 3 to 7, a stereoisomer thereof or an acceptable veterinary salt thereof.

10. Composition, according to claim 8 or 9, CHARACTERIZED in that it further comprises an additional pharmaceutical agent selected from the group consisting of an ACE inhibitor, furosemide or spironolactone.

11. Composition according to claim 9 or 10, CHARACTERIZED in that it further comprises an acceptable veterinary excipient.

12. Use of a compound, as defined in any one of claims 1 to 7, or of a compound, as defined in any one of claims 3 to 7, a stereoisomer thereof, or an acceptable veterinary salt thereof, CHARACTERIZED in that it is for preparing a medicament for the treatment of myxomatous mitral valve disease, congestive heart failure and / or asymptomatic heart failure in an animal in need thereof.

13. Use according to claim 12, CHARACTERIZED in that a compound, as defined in any one of claims 3 to 7, a stereoisomer thereof or an acceptable veterinary salt thereof is formulated for administration to an animal in need thereof.

14. Use according to claims 12 or 13, CHARACTERIZED in that at least one additional pharmaceutical agent selected from the group consisting of an ACE inhibitor, furosemide and a spironolactone is formulated to be administered to an animal in need thereof. Petition 870250099203, dated 10 / 30 / 2025, pp. 341 / 342