Phosphodiesterase 3 (PDE3) inhibitors

Abstract

The present invention describes a novel PDE3 inhibitor for use in the treatment of cardiovascular diseases, including mucinoma mitral valve disease, congestive heart failure and / or asymptomatic heart failure, in an animal, in particular a canine.

Description

Technical Field

[0001] This invention describes novel multimodal cardiotonic agents that inhibit phosphodiesterase 3 (PDE3) and reduce the likelihood of arrhythmias induced by calcium hypersensitivity; methods for their preparation; compositions thereof; and methods for treating cardiovascular diseases in animals, including myxomatous mitral valve disease, congestive heart failure, and / or asymptomatic heart failure. Background Technology

[0002] Congestive heart failure (CHF) is a leading cause of death in patients with heart disease. Phosphodiesterases (PDEs) are a class of intracellular enzymes responsible for the hydrolysis of cyclic adenosine monophosphate (c-AMP) and cyclic guanosine monophosphate (c-GMP), participating in the regulation of important cellular functions such as secretion, contraction, metabolism, and growth. Based on their structure and substrate specificity, PDEs can be divided into eleven distinct families, defined as PDE1 to PDE11.

[0003] Each PDE isoenzyme possesses a conserved C-terminal catalytic domain and a unique N-terminal regulatory domain. These isoenzymes are found in various tissues and cells of animals, such as smooth muscle, brain, heart, lung, platelets, and lymphocytes. Of all PDE isoforms, PDE3 is primarily expressed in cardiac muscle and platelets. The PDE3 family in mammals consists of two isoforms (A and B) that have similar pharmacological properties but can be distinguished based on their expression profiles and affinity for cGMP. PDE3A is present in platelets, kidneys, vascular smooth muscle, heart, and oocytes. PDE3B is located in adipocytes, hepatocytes, vascular smooth muscle, developing sperm, kidneys, B cells, T lymphocytes, and macrophages. PDE3 is specific for c-AMP and has no effect on c-GMP or calmodulin. Therefore, inhibition of PDE3 isoenzymes in cardiovascular tissues leads to high levels of c-AMP, which in turn produces inotropic effects, driving myocardial contraction (inotropic contractility) and smooth muscle vasodilation.

[0004] Myxomatous mitral valve disease (MMVD) is a leading cause of cardiovascular disease in dogs. MMVD leads to mitral regurgitation, which promotes sodium and water retention, activation of the neurohormonal system, volume overload, and ultimately congestive heart failure (CHF). The medical terms MMVD used in this article include mitral valve disease (MVD), degenerative mitral valve disease (DMVD), chronic valvular disease (CVD), chronic valvular heart disease (CVHD), and atrial and ventricular valvular insufficiency (AVVI). The pathological mechanisms of MMVD involve the differentiation and activation of the normally resting mitral valve into a more active myofibroblast phenotype, mediating numerous 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 common cause of canine congestive heart failure (CHF). MMVD is most prevalent in small breeds such as Cavalier King Charles Spaniels, Chihuahuas, Maltese, Pekingese, Toy Poodles, and Miniature Poodles. The natural history of the disease is adult onset, progression with age, and in severe cases, the final development of CHF (Chronic Chin Fever). Current treatments for MMVD include the use of angiotensin-converting enzyme inhibitors, diuretics, vasodilators, and positive inotropic agents.

[0005] Early citations (1985-1988) described benzothiazolinones (US4562190A), thiadiazinones (US4916128A), and pyridazinones (US4647564A) as agents possessing antihypertensive, antithrombotic, cardiotonic, and positive inotropic properties suitable for treating heart failure. These early citations did not present PDE3 inhibition data. Additionally, many non-spirocyclic cardiotonic agents are described in the Journal of Medicinal Chemistry (JMC), Vol. 35, 1992, pp. 163-172; the PDE3 IC50 of these cardiotonic agents... 50 The values ​​ranged from approximately 0.17 to 66.0 μM (Table IX), among which the reported IC50 values ​​for pimobendan were... 50 The concentration was 0.56 μM (560 nM). According to JMC citations, subtle changes in molecular structure can have drastically different effects on the inhibitory and / or calcium-sensitizing properties of enzymes (PDEs and ATPases). For example, studies have shown that PDE3 IC50... 50Indolidan at a concentration of 0.52 μM lacks calcium sensitizing properties, and introducing a sulfur atom into the pyridazine ring is beneficial for obtaining the desired activity, and substitution of the indole ketone moiety also appears to be essential. This is evidenced by the alkyl substitutions on the indole ring in Table IV. According to JMC, adding a sulfur-containing spirocyclic ring to indole increases calcium sensitizing activity by 30-fold, but its potency as a positive inotropic agent in vivo is low. Therefore, it is believed that the conditions for achieving calcium sensitizing activity are: 1) the indole ketone and heterocyclic moieties of the molecule must be relatively coplanar; 2) the heterocyclic moiety must contain a sulfur (or selenium) atom; and 3) a substituent (preferably a bulky group) is required at the 3-position of the indoline ring. In contrast, we have demonstrated that the sulfur atom and / or bulky group are not necessary to obtain this dual activity. Furthermore, it has been found that adding a halogen atom at the 7-position of the oxyindole molecule can induce calcium sensitizing properties and / or enhance PDE3 inhibition. Therefore, the compounds of the present invention exhibit the desired PDE3 inhibitory activity at nanomolar concentrations and are calcium sensitizers, as seen in the positive effects observed in contractility assays. As described in the European Journal of Medicinal Chemistry (1996), Vol. 31, pp. 805–8120; by Nadler G. et al., for pyridazinones and thiadiazinones with a single chiral center, PDE inhibitory activity is typically found in one enantiomer (e.g., thiadiazinones in the (S) configuration and pyridazinones in the (R) configuration), while myofibril calcium sensitization is found in the opposite configuration. To date, research and development of these bimodal positive inotropic agents appear to have drastically decreased, as no new compounds have been truly described for at least 28 years or more.

[0006] In fact, the most commonly used positive inotropic compound currently available for animal heart failure is pimoxendan, a racemic mixture. Pimoxendan is a benzimidazole-pyridazinone derivative that has been used to treat dilated cardiomyopathy (DCM) or congestive heart failure (CHF) caused by DMVD in animals for approximately 20 years. The positive inotropic effect of pimoxendan is mediated by a combination of increased c-AMP-mediated PDE3 inhibition and increased intracellular calcium sensitization of the myocardial contractile apparatus. Pimoxendan was first described in US Patent 4361563A, which was first published in the equivalent Australian patent application AU197950279A in February 1980. Pimoxendan is administered orally to dogs at a dose of 0.5 mg / kg / day, twice daily. Pimobendan is safe and well-tolerated, but its long-term, twice-daily (every 12 hours) administration can lead to several common safety issues in animals, such as tachycardia or abnormal heartbeat, bleeding or bruising, gastrointestinal disturbances, jaundice, rash, and skin redness. It is also known to induce valvular disease in patients with asymptomatic heart failure (MVD). Furthermore, pimoxemandan should not be used in cases of hypertrophic cardiomyopathy or aortic stenosis. Long-term BID administration can also lead to poor adherence. As with many marketed products, there is always a need for newer, safer, and more effective drugs to treat the corresponding disease classes. This invention describes novel bimodal cardiotonic agents that inhibit PDE3 at nanomolar concentrations and have a positive effect on contractility (a measure of calcium sensitization). These novel bimodal cardiotonic agents can be used for the effective treatment of cardiovascular diseases, including MMVD, CHF, and / or asymptomatic heart failure, and / or inhibition of platelet aggregation in animals (preferably canines). Summary of the Invention

[0007] In one aspect of the invention, there is a novel PDE3 receptor antagonist that can be used to treat mitral valve disease and congestive heart failure in animals (particularly canines). In another aspect, there is a PDE3 inhibitor compound (Example #) selected from the group consisting of:

[0008] 8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (1);

[0009] 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(thiazo-2-yl)-3,4-dihydroquinoline-2(1H)-one (2);

[0010] 8-(2-methoxythiazo-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (4);

[0011] 7-Chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (6);

[0012] 7-(4-chlorophenyl)-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (7);

[0013] 7'-Chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (8);

[0014] 8-(4-chlorophenyl)-6-(6-oxo-1,6-dihydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (9);

[0015] 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (12);

[0016] 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one (13);

[0017] 3,3-Dimethyl-5-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-(thiazo-4-yl)indololin-2-one (17);

[0018] 9-(6-methoxypyridin-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-1,3,4,5-tetrahydro-2H-benzo[b]aza -2-keto(18);

[0019] 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19);

[0020] 7-Bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (23);

[0021] 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (24);

[0022] 7-Chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (25);

[0023] 7-Fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (26);

[0024] 7-Fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (27);

[0025] 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (28);

[0026] 4-Chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazolyl-2(3H)-one (29);

[0027] 6-(2-amino-4-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (30);

[0028] 6-(2-amino-4-fluorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (31);

[0029] 7-Bromo-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (32);

[0030] (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (33);

[0031] 6-(4-fluoro-2-(methylamino)benzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (34);

[0032] 8-Chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-2(1H)-one (35);

[0033] 6-(8-chloro-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (35a);

[0034] 7-Chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (36);

[0035] 6-(4-fluoro-2-(3-hydroxyazacyclobutane-1-yl)benzo[d]thiazolyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (37);

[0036] 2-Amino-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazolyl-4-onitrile (38);

[0037] 7-Chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindololin-1-one (39);

[0038] 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-2-oxo-1,2-dihydroquinoline-8-nitrile (40);

[0039] 2-Hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-8-nitrile (40a);

[0040] 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindololin-1-one (41);

[0041] 4-Chloro-1-methyl-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (42);

[0042] 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclobutane-1,3'-indoline]-2'-one (43);

[0043] 7-Chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (44);

[0044] 6-(8-bromo-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (45);

[0045] 6-(4-fluoro-2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)benzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (46);

[0046] 6-(7-chloro-3-methyl-1H-indazol-5-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (47);

[0047] 6-(8-Cyclopropyl-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (48);

[0048] 6-(2-(3-methoxyazacyclobutane-1-yl)benzo[d]thiazolyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (49);

[0049] 7-Fluoro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (50);

[0050] (S)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindololin-2-one (51);

[0051] 4-Chloro-6-(6-oxo-1,6-dihydropyridazin-3-yl)benzo[d]thiazolyl-2(3H)-one (52);

[0052] 5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-2-oxoindoline-7-nitrile (53);

[0053] 4-Methyl-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one (55);

[0054] 4-Chloro-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one (56);

[0055] 5-(7-fluoro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57);

[0056] 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (58);

[0057] 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (59);

[0058] 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (61);

[0059] 5-(7-chloro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (62);

[0060] 6-Methyl-5-(7-(4-(methanesulfonyl)phenyl)-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (63);

[0061] 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (66);

[0062] 5-(3,3-dimethyl-2-oxo-7-(thiazo-4-yl)indololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (68);

[0063] 5-(7-(4-chlorophenyl)-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (71);

[0064] 5-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (72);

[0065] 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (73);

[0066] 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (74);

[0067] 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (75);

[0068] 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (76);

[0069] 5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7-nitrile (77);

[0070] (S)-5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (78);

[0071] 5-(7-chloro-1-oxoisoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (79);

[0072] 5-(7-chloro-3,3-dimethyl-1-oxoisoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (80);

[0073] 5-(8-chloro-2-hydroxyquinoline-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (81);

[0074] 5-(7-chloro-2,2-dioxy-1,3-dihydrobenzo[c]isothiazo-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (82);

[0075] 6-Methyl-5-(8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (83);

[0076] 4-Chloro-6-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]oxazol-2(3H)-one (84);

[0077] 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (85);

[0078] 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indololin-2-one (86);

[0079] 6-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,4-dihydro-1,8-naphthidin-2(1H)-one (87);

[0080] 4-Chloro-6-(5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)benzo[d]thiazol-2(3H)-one (88); and 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-1,3,4-thiadiazol-2(3H)-one (89), their stereoisomers, and their veterinary-acceptable salts.

[0081] On the other hand, there are PDE3 inhibitors (example #), selected from the group consisting of: 8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (1);

[0082] 7-Chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (6);

[0083] 7'-Chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (8);

[0084] 8-(4-chlorophenyl)-6-(6-oxo-1,6-dihydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (9);

[0085] 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (12);

[0086] 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one (13);

[0087] 9-(6-methoxypyridin-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-1,3,4,5-tetrahydro-2H-benzo[b]aza -2-keto(18);

[0088] 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19);

[0089] 7-Bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (23);

[0090] 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (24);

[0091] 7-Chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (25);

[0092] 7-Fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (26);

[0093] 7-Fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (27);

[0094] 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (28);

[0095] 6-(2-amino-4-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (30);

[0096] 6-(2-amino-4-fluorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (31);

[0097] 7-Bromo-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (32);

[0098] (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (33);

[0099] 6-(4-fluoro-2-(methylamino)benzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (34);

[0100] 8-Chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-2(1H)-one (35);

[0101] 6-(8-chloro-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (35a);

[0102] 7-Chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (36);

[0103] 6-(4-fluoro-2-(3-hydroxyazacyclobutane-1-yl)benzo[d]thiazolyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (37);

[0104] 2-Amino-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazolyl-4-onitrile (38);

[0105] 7-Chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindololin-1-one (39);

[0106] 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-2-oxo-1,2-dihydroquinoline-8-nitrile (40);

[0107] 2-Hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-8-nitrile (40a);

[0108] 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindololin-1-one (41);

[0109] 4-Chloro-1-methyl-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (42);

[0110] 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclobutane-1,3'-indoline]-2'-one (43);

[0111] 7-Chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (44);

[0112] 4-Chloro-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one (56);

[0113] 5-(7-fluoro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57);

[0114] 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (58);

[0115] 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (59);

[0116] 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (61);

[0117] 5-(7-chloro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (62);

[0118] 6-Methyl-5-(7-(4-(methanesulfonyl)phenyl)-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (63);

[0119] 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (66);

[0120] 5-(7-(4-chlorophenyl)-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (71);

[0121] 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (73);

[0122] 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (74);

[0123] 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (75);

[0124] 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (76);

[0125] 5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7-nitrile (77);

[0126] (S)-5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (78);

[0127] 5-(7-chloro-1-oxoisoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (79);

[0128] 5-(7-chloro-3,3-dimethyl-1-oxoisoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (80);

[0129] 6-Methyl-5-(8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (83);

[0130] 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (85); and

[0131] 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indoline-2-one (86), their stereoisomers and their veterinary-acceptable salts.

[0132] On the other hand, there are PDE3 inhibitors (example #), which are selected from the group consisting of the following:

[0133] 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (12);

[0134] 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19);

[0135] 7-Bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (23);

[0136] 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (24);

[0137] 7-Chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (25);

[0138] 7-Fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (26);

[0139] 7-Fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (27);

[0140] 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (28);

[0141] 6-(2-amino-4-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (30);

[0142] 6-(2-amino-4-fluorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (31);

[0143] 7-Bromo-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (32);

[0144] (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (33);

[0145] 4-Chloro-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one (56);

[0146] 5-(7-fluoro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57);

[0147] 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (58);

[0148] 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (61);

[0149] 5-(7-chloro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (62);

[0150] 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (66);

[0151] 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (73);

[0152] 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (74);

[0153] 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (75);

[0154] 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (76);

[0155] 5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7-nitrile (77);

[0156] (S)-5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (78);

[0157] 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (85); and

[0158] 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indoline-2-one (86), their stereoisomers and their veterinary-acceptable salts.

[0159] On the other hand, there are PDE3 inhibitors (example #), which are selected from the group consisting of the following:

[0160] 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19);

[0161] 7-Bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (23);

[0162] 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (24);

[0163] 7-Chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (25);

[0164] 5-(7-fluoro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57);

[0165] 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (61);

[0166] 5-(7-chloro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (62);

[0167] 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (73);

[0168] 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (74);

[0169] 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (75);

[0170] 5-(7-bromo-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (76); and

[0171] 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indoline-2-one (86), their stereoisomers and their veterinary-acceptable salts.

[0172] On the other hand, there are PDE3 inhibitors (example #), which are selected from the group consisting of the following:

[0173] 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19);

[0174] 7-Bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (23);

[0175] 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (24);

[0176] 5-(7-fluoro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57);

[0177] 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (61);

[0178] 5-(7-chloro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (62);

[0179] 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (73);

[0180] 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (74);

[0181] 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (75); and

[0182] 5-(7-bromo-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (76), their stereoisomers and their veterinary-acceptable salts.

[0183] On the other hand, there are PDE3 inhibitors (example #), which are selected from the group consisting of the following:

[0184] 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19);

[0185] 5-(7-fluoro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57);

[0186] 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (61);

[0187] 5-(7-chloro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (62); and

[0188] 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (73), their stereoisomers and their veterinary-acceptable salts.

[0189] On the other hand, there are PDE3 inhibitors (example #), which are selected from the group consisting of the following:

[0190] 7-Bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (23);

[0191] 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (24);

[0192] 7-Chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (25);

[0193] 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (74);

[0194] 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (75);

[0195] 5-(7-bromo-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (76); and

[0196] 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indoline-2-one (86), their stereoisomers and their veterinary-acceptable salts.

[0197] On the other hand, there are PDE3 inhibitors (example #), which are selected from the group consisting of the following:

[0198] 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19);

[0199] 7-Bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (23);

[0200] 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (24);

[0201] 5-(7-fluoro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57);

[0202] 5-(7-chloro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (62); and

[0203] 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (75), their stereoisomers and their veterinary-acceptable salts.

[0204] On the other hand, there are PDE3 inhibitors, which are selected from the group consisting of the following:

[0205] 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19);

[0206] 5-(7-fluoro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57); and

[0207] 5-(7-chloro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (62), their stereoisomers and their veterinary-acceptable salts.

[0208] On the other hand, there are PDE3 inhibitors (example #), which are selected from the group consisting of the following:

[0209] 7-Bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (23);

[0210] 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (24); and

[0211] 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (75), their stereoisomers and their veterinary-acceptable salts.

[0212] On the other hand, there are PDE3 inhibitors 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (19), its stereoisomers, and its veterinary-acceptable salts.

[0213] On the other hand, there is the PDE3 inhibitor 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indoline-2-one (23), its stereoisomers, and its veterinary-acceptable salts.

[0214] On the other hand, there is the PDE3 inhibitor 7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (24), its stereoisomers, and its veterinary-acceptable salts.

[0215] On the other hand, there is the PDE3 inhibitor 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (25), its stereoisomers, and its veterinary-acceptable salts.

[0216] On the other hand, there are PDE3 inhibitors 5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (57), its stereoisomers, and its veterinary-acceptable salts.

[0217] On the other hand, there is PDE3 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (61), its stereoisomers, and its veterinary-acceptable salts.

[0218] On the other hand, there is the PDE3 inhibitor 5-(7-chloro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (62), its stereoisomers, and its veterinary-acceptable salts.

[0219] On the other hand, there is the PDE3 inhibitor 6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (73), its stereoisomers and its veterinary-acceptable salts.

[0220] On the other hand, there is the PDE3 inhibitor 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (74), its stereoisomers, and its veterinary-acceptable salts.

[0221] On the other hand, there is the PDE3 inhibitor 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (75), its stereoisomers, and its veterinary-acceptable salts.

[0222] On the other hand, there is the PDE3 inhibitor 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (76), its stereoisomers, and its veterinary-acceptable salts.

[0223] On the other hand, there is the PDE3 inhibitor 7-chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indoline-2-one (86), its stereoisomers, and its veterinary-acceptable salts.

[0224] In another aspect of the invention, there is a composition comprising a compound of the invention selected from the group consisting of examples #1, 2, 4, 6 to 9, 12 to 13, 17 to 19, 23 to 53, 55 to 59, 61 to 63, 66, 68, and 71 to 89, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising a compound of the invention selected from the group consisting of examples #1, 6, 8, 12 to 13, 18 to 19, 23 to 28, 30 to 43, 56 to 59, 61 to 63, 66, 71, 73 to 80, 83, and 85 to 86, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising a compound of the invention selected from the group consisting of examples #12, 19, 23 to 28, 30 to 33, 56 to 58, 61 to 62, 66, 73 to 78, 85, and 86, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising a compound of the invention selected from the group consisting of examples #19, 23, 24, 57, 61 to 62 and 73 to 76, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising any one of the compounds selected from the group consisting of examples #19, 57, 61, 62 and 73, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising a compound of the invention selected from the group consisting of examples #23, 24, 25, 74, 75, 76 and 86, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising a compound of the invention selected from the group consisting of examples #23, 24, 74, 75 and 76, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising a compound of the invention selected from the group consisting of examples #19, 57 and 62, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising a compound of the invention selected from the group consisting of Examples #23, 24, and 75, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising Example #19, its stereoisomer, and a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising Example #23, its stereoisomer, and a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising Example #24, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising Example #25, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising Example #57, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a composition comprising Example #61, its stereoisomer, or a veterinary-acceptable salt thereof.In another aspect, a composition is provided, comprising Example #62, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, a composition is provided, comprising Example #73, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, a composition is provided, comprising Example #74, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, a composition is provided, comprising Example #75, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, a composition is provided, comprising Example #76, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, a composition is provided, comprising Example #86, its stereoisomer, and a veterinary acceptable salt thereof. In another aspect, a composition is provided, comprising Example #86, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, the composition further comprises at least one veterinary acceptable excipient. In yet 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 ACE inhibitors, furosemide, and spironolactone. In another respect, each of the compositions described herein may be in solid or liquid form. Preferably, the compositions described herein are in solid form; for example, tablets or capsules that can be administered orally. Oral compositions may be film-coated tablets or flavored chewable tablets.

[0225] In another aspect of the invention, there is a method of treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering therapeutic amounts of compounds of the invention, stereoisomers thereof, or veterinary-acceptable salts thereof selected from the group consisting of examples #1, 2, 4, 6 to 9, 12 to 13, 17 to 19, 23 to 53, 55 to 59, 61 to 63, 66, 68, and 71 to 89. In another aspect, there is a method of treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering therapeutic amounts of compounds of the invention, stereoisomers thereof, or veterinary-acceptable salts thereof selected from the group consisting of examples #1, 6, 8, 12 to 13, 18 to 19, 23 to 28, 30 to 43, 56 to 59, 61 to 63, 66, 71, 73 to 80, 83, and 85 to 86. In another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering therapeutic amounts of compounds of the present invention selected from the group consisting of examples #12, 19, 23 to 28, 30 to 33, 56 to 58, 61 to 62, 66, 73 to 78, 85, and 86, their stereoisomers, or their veterinary acceptable salts. In another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering therapeutic amounts of compounds of the present invention selected from the group consisting of examples #19, 23, 24, 57, 61 to 62, and 73 to 76, their stereoisomers, or their veterinary acceptable salts. In another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering therapeutic amounts of compounds of the present invention selected from the group consisting of examples #19, 57, 61, 62, and 73, their stereoisomers, or their veterinary acceptable salts. In another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of a compound of the present invention selected from the group consisting of examples #23, 24, 25, 74, 75, 76, and 86, its stereoisomers, or a veterinary-acceptable salt thereof. In another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of a compound of the present invention selected from the group consisting of examples #23, 24, 74, 75, and 76, its stereoisomers, or a veterinary-acceptable salt thereof. In yet another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of a compound of the present invention selected from the group consisting of examples #19, 57, and 62, its stereoisomers, or a veterinary-acceptable salt thereof. On the other hand, it is a method of treating animals with MMVD, CHF and / or asymptomatic heart failure by administering a therapeutic amount of a compound of the invention selected from the group consisting of examples #23, 24 and 75, its stereoisomers or veterinary acceptable salts thereof.In another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #19, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #23, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #24, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #25, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, a method is provided for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #57, its stereoisomer, or a veterinary-acceptable salt thereof. In another aspect, there is a method for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #61, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, there is a method for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #62, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, there is a method for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #73, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, there is a method for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #74, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, there is a method for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #75, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, it is a method of treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #76, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect, it is a method of treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of Example #86, its stereoisomer, or a veterinary acceptable salt thereof. In another aspect of treating animals with MMVD, CHF, and / or asymptomatic heart failure by administering a therapeutic amount of any of the compounds of the present invention, it is a method of co-administering at least one additional pharmaceutical agent selected from the group consisting of ACE inhibitors, furosemide, and spironolactone.

[0226] In another aspect of the invention, is the use of compounds of the invention, their stereoisomers, or veterinary-acceptable salts thereof, selected from the group consisting of Examples #1, 2, 4, 6 to 9, 12 to 13, 17 to 19, 23 to 53, 55 to 59, 61 to 63, 66, 68, and 71 to 89, for the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. In another aspect, is the use of compounds of the invention, their stereoisomers, or veterinary-acceptable salts thereof, selected from the group consisting of Examples #1, 6, 8, 12 to 13, 18 to 19, 23 to 28, 30 to 43, 56 to 59, 61 to 63, 66, 71, 73 to 80, 83, and 85 to 86, for the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. In another aspect, the use of compounds of the present invention, their stereoisomers, or veterinary-acceptable salts thereof, selected from the group consisting of Examples #12, 19, 23 to 28, 30 to 33, 56 to 58, 61 to 62, 66, 73 to 78, 85, and 86, for the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. In another aspect, the use of compounds of the present invention, their stereoisomers, or veterinary-acceptable salts thereof, selected from the group consisting of Examples #19, 23, 24, 57, 61 to 62, and 73 to 76, for the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. In another aspect, the use of compounds of the present invention, their stereoisomers, or veterinary-acceptable salts thereof, selected from the group consisting of Examples #19, 57, 61, 62, and 73, for the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. In another aspect, the use of compounds of the present invention, stereoisomers thereof, or veterinary-acceptable salts thereof, selected from the group consisting of Examples #23, 24, 25, 74, 75, 76, and 86, for the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. In another aspect, the use of compounds of the present invention, stereoisomers thereof, or veterinary-acceptable salts thereof, selected from the group consisting of Examples #23, 24, 74, 75, and 76, for the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. In another aspect, the use of compounds of the present invention, stereoisomers thereof, or veterinary-acceptable salts thereof, selected from the group consisting of Examples #19, 57, and 62, for the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, it is the use of compounds of the present invention, stereoisomers thereof, or veterinary acceptable salts thereof selected from the group consisting of examples #23, 24 and 75, in the preparation of a medicament for treating animals suffering from MMVD, CHF and / or asymptomatic heart failure.On the other hand, there is the use of Example #19, its stereoisomer or a veterinary-acceptable salt thereof, to prepare a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, there is the use of Example #23, its stereoisomer or a veterinary-acceptable salt thereof, to prepare a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, there is the use of Example #24, its stereoisomer or a veterinary-acceptable salt thereof, to prepare a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, there is the use of Example #25, its stereoisomer or a veterinary-acceptable salt thereof, to prepare a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, there is the use of Example #57, its stereoisomer or a veterinary-acceptable salt thereof, to prepare a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, there is the use of Example #61, its stereoisomer or a veterinary-acceptable salt thereof, to prepare a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, there is the use of Example #62, its stereoisomer or a veterinary-acceptable salt thereof, to prepare a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, there is the use of Example #73, its stereoisomer or a veterinary-acceptable salt thereof, to prepare a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, there is the use of Example #74, its stereoisomer or a veterinary-acceptable salt thereof, to prepare a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, there is the use of Example #75, its stereoisomer or a veterinary-acceptable salt thereof, to prepare a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On the other hand, there is the use of Example #76, its stereoisomer, or a veterinary-acceptable salt thereof in the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. On yet another aspect, there is the use of Example #86, its stereoisomer, or a veterinary-acceptable salt thereof in the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure. In yet another aspect, there is the use of any compound of the present invention in the preparation of a medicament for treating animals suffering from MMVD, CHF, and / or asymptomatic heart failure, together with at least one additional pharmaceutical agent selected from the group consisting of ACE inhibitors, furosemide, and spironolactone.

[0227] manual

[0228] definition

[0229] For the purposes of this invention, as described and claimed herein, the following terms and phrases are defined as follows:

[0230] Unless otherwise stated, as used herein, “additional veterinary agent (or pharmaceutical agent)” means other veterinary or pharmaceutical compounds or products (i.e., drugs) that provide a therapeutically effective amount of the agent and are used to treat MMVD, CHF, and / or asymptomatic heart failure in animals (preferably canines).

[0231] As used herein, unless otherwise stated, “animal” means a single animal as a mammal. Specifically, a mammal is a human or non-human vertebrate belonging to the class Mammalia. Non-exclusive examples of non-human mammals include companion animals. Non-exclusive examples of companion animals include: cats (Felidae), dogs (Canidae), and horses (Equidae). Preferred companion animals are canids.

[0232] Unless otherwise stated, as used herein, “asymptomatic (silent, preclinical) heart failure” means any cardiac contractile disorder or disease caused by MMVD.

[0233] Unless otherwise stated or required, "compounds of the present invention" refers to the PDE3 receptor antagonists (inhibitors) described herein as Examples #1 to #89, their stereoisomers, and / or their veterinary acceptable salts. The compound example numbers have an ambiguous relationship to their specific example names and structures.

[0234] As used herein, “comprises” or “comprising” means inclusive, that is, it will be understood to include not only the listed components that it directly refers to, but also other unspecified components or elements.

[0235] Unless otherwise stated, "congestive heart failure" or "heart failure" refers to an overt pathological process in which the heart is unable to meet the body's blood supply needs, and is often accompanied by pulmonary effusion due to elevated pressure in the heart and pulmonary arteries. The term also encompasses any disorder or disease of cardiac contractility. Clinically, it typically results from changes in cardiac cells and molecular components, as well as mediators that drive homeostatic control, leading to cardiac enlargement and deterioration of cardiac function.

[0236] Unless otherwise stated, “mixogenic mitral valve disease (MMVD)” refers to the overt pathological process of mitral valve degeneration. 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 and ventricular valvular insufficiency (AVVI).

[0237] As used herein, “stereoisomer” specifically refers to the compounds of the present invention having at least one chiral carbon; and exists as enantiomers (S and R optical isomers) that are mirror images of each other, have the same chemical properties, but are not overlapping. Mixtures of (S) and (R) enantiomers are racemic. For example, Examples #33 and #51 are (R) and (S) isomers of Example #24 (racemic), respectively.

[0238] Unless otherwise stated, “therapeutic effective amount” means the amount of the compound of the present invention that (i) treats MMVD, CHF and / or asymptomatic heart failure in animals; (ii) alleviates, improves or eliminates one or more symptoms of MMVD, CHF and / or asymptomatic heart failure in animals; or (iii) prevents or delays the onset of MMVD, CHF and / or asymptomatic heart failure in animals.

[0239] Unless otherwise stated, as used herein, "treatment / treating / treat" refers to alleviating, stopping, or slowing the progression of MMVD, CHF, and / or asymptomatic heart failure in animals. As used herein, these terms also encompass, depending on the animal's condition, prevention of the onset of symptoms or symptom onset, or symptoms associated with symptoms or symptom onset, including reducing the severity of symptoms or symptom onset or associated symptoms. Therefore, treatment can refer to administering the compounds of this invention to animals that have not been diagnosed with CHF at the time of administration.

[0240] Unless otherwise stated, "veterinary acceptable" means a substance or composition that is chemically and / or toxicologically compatible with an animal receiving the substance or composition. The term also covers "pharmaceutically or pharmaceutically acceptable"; and the terms are used interchangeably.

[0241] As stated herein, "and veterinary acceptable salts" also means "or veterinary acceptable salts". In some cases, the stereoisomers of the examples or the veterinary acceptable salts of the examples or their stereoisomers may be used in compositions or medicines for the treatment of MMVD, CHF and / or asymptomatic heart failure in animals.

[0242] Myxomatous mitral valve disease (MMVD) is the most common acquired heart disease in older dogs and a cause of new-onset heart murmurs. A heart murmur is the sound heard with each heartbeat and is caused by turbulent blood flow within the heart. MMVD is a pathological process that can affect the mitral valve. MMVD primarily affects smaller dogs in their later years, but can also affect larger dogs. Some smaller dogs are affected earlier than others, with the Cavalier King Charles Spaniel being the most prominent breed described to date.

[0243] 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 throughout the body. When the left ventricle contracts, the mitral valve closes, preventing blood from flowing back into the left atrium. A healthy mitral valve is thin and flexible, anchored in place by chordae tendineae (CTs). Myxomatous degeneration occurs when the valve thickens and forms nodules that prevent complete closure, allowing blood to flow back into the left atrium (mitral regurgitation). Over time, the atria and ventricles compensate by dilating, and the regurgitation gradually worsens. As the regurgitation increases, atrial pressure increases. In some cases, the CT may rupture, causing the mitral valve to partially lose its anchorage (mitral valve prolapse). The increased pressure is transmitted to the lungs, leading to chronic heart failure (CHF).

[0244] A heart murmur is usually the earliest sign of MMVD. After a murmur is detected, MMVD symptoms may not appear for three to four years. Typically, the initial external signs of worsening MMVD are cough or shortness of breath, which may be due to airway pressure caused by an enlarged heart and / or fluid congestion in the lungs, pericardium, and heart.

[0245] Current medications may slow the progression of MMVD to CHF, especially in the early stages of the disease. Treatments administered to control MMVD, CHF, and / or asymptomatic heart failure include, but are not limited to: furosemide, pimobendan, ACE inhibitors (e.g., enalapril), and spironolactone. Furosemide is a potent diuretic that removes excess water from the body, thereby reducing pulmonary congestion. Pimobendan helps the heart work more efficiently, helps reduce cardiac remodeling, and has been shown to prolong survival in patients with MMVD. ACE inhibitors and spironolactone block harmful compensatory mechanisms that contribute to severe heart disease and have been shown to prolong survival. Side effects of these medications include allergic reactions, staggering, loss of appetite, drowsiness, diarrhea, and syncope. Other medications that can be used to control CHF symptoms include hydrochlorothiazide, amlodipine, torsemide, and digoxin.

[0246] Despite the development of new drugs and treatments, uncertainty remains regarding when to treat and what constitutes the optimal intervention for some of these animals. In 2009, an objective grading system for classifying heart disease based on risk factors and clinical and radiological signs was developed.

[0247] Heart failure is classified into different stages, which are defined by different grading systems, such as the International Small Animal Cardiac Health Council (ISACHC), the New York Heart Association (NYHA) functional classification system, and the grading system currently used according to the 2009 consensus statement of the American College of Veterinary Internal Medicine (ACVIM). To eliminate any ambiguity between grading systems, the grading systems described below will be considered synonymous.

[0248] According to the International Small Animal Heart Health Committee (ISACHC) classification system: Grade I: Asymptomatic (also known as occult or preclinical); Grade IA: No evidence of underlying heart disease compensation (no volume overload or pressure overload detected on imaging or echocardiography); Grade IB: Clinical signs of underlying heart disease compensation (volume overload or pressure overload detected on imaging or echocardiography); Grade II: Mild to moderate heart failure with clinical signs at rest or during mild exercise (requiring treatment); Grade III: Late heart failure; clinical signs of severe congestive heart failure; Grade IIIA: Can be treated at home; and Grade IIIB: Requires hospitalization.

[0249] The New York Heart Association (NYHA) functional classification system is as follows: Class I: Patients with asymptomatic heart disease (e.g., those with chronic valvular heart disease (CVHD) but no obvious clinical signs even during exercise); Class II: Patients with heart disease who only have clinical signs during strenuous exercise; Class III: Patients with heart disease who have clinical signs due to daily activities or mild exercise; and Class IV: Patients with heart disease who have severe clinical signs even at rest.

[0250] The ACVIM system describes four basic phases of heart disease and failure: Phase A: Patients at high risk of developing heart disease but currently without a definitive structural heart disease symptom; Phase B: Patients with structural heart disease (e.g., a typical mitral regurgitation murmur) but who have never presented with clinical signs of heart failure (Phase B is further subdivided into Phase B1 and Phase B2 by the expert panel due to its significant clinical implications for prognosis and treatment). Phase B1: Asymptomatic patients without imaging or echocardiographic evidence of cardiac remodeling in response to CVHD. Phase B2: Asymptomatic patients with hemodynamically significant valvular regurgitation confirmed by imaging or echocardiographic findings such as left ventricular enlargement. Phase C: Patients with a history or current clinical sign of heart failure associated with structural heart disease. Phase D: Patients with end-stage disease who present with clinical signs of heart failure due to CVHD that are refractory to standard treatment.

[0251] Cardiac pathology begins in ISACHC I, NYHA I, and ACVIM B2 stages, characterized by a heart murmur or enlarged heart chambers, but without clinical symptoms (ISACHHC I or asymptomatic / silent / preclinical). Clinical symptoms become apparent as the disease progresses (ISACHHC I or III, NYHA II, III, or IV, ACVIM B2 and D stages).

[0252] The compounds of this invention have an affinity for PDE3 and can provide veterinarians with potential new drugs for the treatment of MMVD, CHF, and / or asymptomatic heart failure in animals.

[0253] The compounds of the present invention can be used as PDE3 antagonists for the treatment of MMVP, CHF, and / or asymptomatic heart failure in animals (particularly canines). Another aspect of the invention is a veterinary composition comprising a therapeutically effective amount of the compound of the present invention and a veterinary-acceptable salt thereof. Yet another aspect of the invention is a veterinary composition comprising a therapeutically effective amount of the compound of the present invention, a veterinary-acceptable salt thereof, and a veterinary-acceptable excipient. The compounds of the present invention (including the compositions and processes used therein) can also be used to manufacture medicaments for the therapeutic applications described herein.

[0254] The compounds of the present invention can be administered alone or in formulations suitable for the specific intended use and the animal species to be treated. Generally, they will be administered as a formulation in combination with one or more veterinary-acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compounds of the present invention or their salts or any additional veterinary formulations. The selection of excipients depends heavily on a variety of factors, such as the specific route of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. In addition to excipients, the dosage of the compounds of the present invention and the administration regimen for treating diseases or conditions with the compound depend on a variety of factors, including the animal's age, weight, sex, and medical condition, the severity of the disease, the route of administration, and the frequency, and therefore can vary considerably.

[0255] In one aspect, the veterinary composition comprises the compounds of the present invention with veterinary-acceptable excipients. Concentration ranges will vary depending on the composition (e.g., oral or injectable). The active agent (i.e., the compounds of the present invention (e.g., examples #19, #23, #24, #57, #62, #75, etc.) ranges from about 0.005 to 10 mg / kg; or about 0.01 to 10 mg / kg; or about 0.1 to 10 mg / kg; or about 0.1 to 5 mg / kg; or about 0.2 to 5 mg / kg; or about 0.2 to about 2.5 mg / kg. The preferred route of administration is oral. The concentration ranges and preferred concentration ranges are considered to be therapeutically effective doses. Furthermore, the dose ranges and preferred dose ranges may be higher or lower than the concentrations described herein.

[0256] Formulations can be prepared using conventional dissolution and mixing procedures. Such compositions and their preparation methods can be found, for example, in 'Remington's Veterinary Sciences', 19th edition (Mack Publishing Company, 1995); and 'Veterinary Dosage Forms: Tablets', Volume 1, by H. Lieberman, L. Lachman, and Marcel Dekker, NY, 1980 (ISBN 0-8247-6918-X).

[0257] Typical formulations are prepared by mixing the compounds of the present invention with at least one veterinary-acceptable 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 or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific excipient depends on the manner and purpose of applying the compounds of the present invention. Solvents are typically selected based on those deemed safe for animal administration by those skilled in the art. Formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, and other known additives to provide an elegant presentation of the medicine (i.e., the compounds of the present invention or their veterinary compositions) or to aid in the manufacture of veterinary products (i.e., pharmaceuticals). The compounds of the present invention are typically formulated into veterinary dosage forms to provide an easily controlled dosage form.

[0258] Methods of administering the compounds of the present invention include oral and injectable administration (e.g., parenteral and subcutaneous).

[0259] The compounds of the present invention can be administered orally in the form of capsules, pellets, tablets, powders, lozenges, chewable tablets, microparticles and nanoparticles, gels, solid solutions, films, sprays, or liquids. This is a preferred method of administration, and therefore it is desirable to develop compounds for oral administration. Such formulations may include soft or hard capsules and tablets, chewable tablets, which typically contain excipients such as water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methylcellulose, glycerin, magnesium stearate, pregelatinized starch, sodium glycolate starch, animal-derived flavorings (chicken, liver, beef, etc.), non-animal-derived flavorings (e.g., vegetable, fruit, yeast, etc.), and other known pharmaceutical excipients designated as fillers, disintegrants, stabilizers, antioxidants, preservatives, etc. Liquid forms include suspensions, solutions, syrups, infusions, and elixirs. Liquid formulations can also be prepared by reconstitution of solids (e.g., from sachets or lyophilized powders).

[0260] Injectable formulations can be prepared as sterile solutions, which may contain other substances, such as sufficient salt 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 fatty acid derivatives of propylene glycol), and organic solvents (such as pyrrolidone-2-one, benzyl alcohol, and glyceryl formal). Formulations are prepared by dissolving or suspending the compounds of the present invention, alone or together with additional veterinary agents, in a liquid excipient such that the final formulation contains about 0.01 to 30% by weight of the active ingredient.

[0261] Suitable devices for injectable administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques. Injectable formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably pH 3 to 9). However, for some applications, they may be better formulated as sterile non-aqueous solutions or dry powders for use with suitable mediators (such as sterile, pyrogen-free water). Injectable formulations can be readily prepared under sterile conditions, for example by lyophilization, using standard veterinary techniques well known to those skilled in the art. The solubility of the compounds of the present invention used to prepare injectable formulations can be improved by using appropriate formulation techniques, such as the incorporation of solubilizers.

[0262] The compounds of the present invention are intended to be administered once or twice daily. Preferably, once daily. Alternatively, the compounds of the present invention may be administered once or twice every 2, 3, 4, 5, 6, or 7 days.

[0263] The compositions of the present invention can be administered alone as described above, or in combination with at least one additional veterinary agent to provide a wider range of veterinary uses. These additional veterinary agents (including pharmaceutical agents) can be administered concurrently with the compounds of the present invention, or at any time during animal treatment.

[0264] The following list of adjunctive pharmaceutical (veterinary) cardiovascular agents that can be used in conjunction with the compounds of the present invention to treat heart diseases in animals (e.g., MMVD, CHF, and / or asymptomatic heart failure) is intended to illustrate possible combinations and not to impose any limitations on them. Non-limiting examples of adjunctive medicinal (veterinary) agents include: diuretics (e.g., furosemide, chlorothiazide, indapamide, triamterene, hydrochlorothiazide, etc.) that reduce edema and effusion; aldosterone antagonists (e.g., spironolactone, eplerenone, etc.) that reduce aldosterone-mediated myocardial fibrosis, may slow the progression of heart disease, and prevent sodium reabsorption (sodium reabsorption promotes water loss); and ACE inhibitors (e.g., enalapril, ramipril, benazepril, imidapril, etc.) that inhibit the action of angiotensin-converting enzyme, producing balanced vasodilation by vasodilation.

[0265] Veterinary compositions intended for use on animals can be packaged in various ways depending on the method of administration of the compounds or combinations thereof. Generally, articles for dispensing include containers in which a suitable form of the veterinary composition is deposited. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. Containers may also include anti-interference components to prevent accidental contact with the packaged contents. Additionally, the container is provided with a label describing the contents. The label may also include appropriate warnings.

[0266] The compounds of the present invention (including the compositions and processes used therein) can also be used to manufacture medicaments for the therapeutic applications described herein.

[0267] The structures of the compounds in the following examples were confirmed by one or more of the following methods: proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance (¹H NMR) spectra were determined using a Bruker spectrometer operating at a field strength of 400 MHz. Chemical shifts are reported in parts per million (PPM, δ) relative to the low-field shift of the internal standard tetramethylsilane or the residual protonated NMR solvent. Mass spectrometry (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 1.7 μm 2.1 × 50 mm column, with gradient conditions of 0.1% acetonitrile / TFA in water; or similar instruments (Waters Acquity or Shimadzu), columns (Waters Acquity BEH C8 column, Waters YMC Triart C18, Waters Xbridge C18 / Agilent Zorbax C18, or Waters Xbridge C18), and gradient conditions of mobile phase (A: 0.05% formic acid in water; B: 0.05%). ACN: Formic acid in water (90:10); or A: Ammonium acetate in 10mM water; B: ACN; or A: Ammonium acetate in 5mM water; B: Ammonium acetate in 5mM ACN (90:10); or A: Formic acid in 0.1% water; B: Formic acid in 0.1% ACN).

[0268] The compounds of the present invention can be synthesized via synthetic routes that include methods similar to those known in the field of chemistry, particularly those described herein. Starting materials are generally available from commercial sources (such as Aldrich Chemicals (Milwaukee, Wis.)) or readily prepared using methods known to those skilled in the art (e.g., by methods commonly described in the following literature: Louis F. Fieser and Mary Fieser, “Reagents for Organic Synthesis”, 1; 19, Wiley, New York (1967, 1999 edition), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed., Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)). For illustrative purposes, the reaction schemes described below confirm potential routes for the synthesis of the compounds and key intermediates of the present invention. More detailed descriptions of the individual reaction steps can be found in the Examples section. Those skilled in the art will understand that the compounds of the present invention can be prepared by means other than those described herein, by modifying the methods described herein and / or modifying methods known in the art (e.g., the art described herein), or by using standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 edition or later).

[0269] 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 a structural feature of a molecule that makes it impossible for the molecule to be superimposed on its mirror image (e.g., “R” and “S” enantiomers). Examples 7, 9, 15, 25, 27, 32, 44, 52, 59, 61, 66, 72, 84 to 86, and 88 to 89 do not contain chiral carbons. The R and S configurations are based on knowledge of known chiral inversion / retention chemistry. Unless otherwise stated, it is intended that the stereoisomeric forms of the compounds of the present invention, as well as racemic mixtures thereof, constitute part of the present invention. Racemic mixtures of enantiomers can be separated into their individual enantiomeric forms based on their physicochemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. A more detailed description of techniques that can be used to separate stereoisomers of compounds from racemic mixtures can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley and Sons, Inc. (1981). Those skilled in the art will understand that, in the separation from racemic mixtures, a stereoisomer that is enriched relative to another stereoisomer may be more active and / or may exhibit beneficial effects.

[0270] This document describes examples and general steps for the preparation and isolation of the compounds of the present invention. However, it should be understood that, as fully described herein and as set forth in the claims, the present invention is not intended to be limited to the details of the following preparation methods or modes.

[0271] In the schemes and examples described herein, the following reactants and various abbreviations include: acetic acid (AcOH); acetonitrile (Acn or MeCN); aluminum chloride (AlCl3); carbonyl diimidazole (CDI); dichloromethane (DCM); CH2Cl2); N,N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO); 1,1'-bis(diphenylphosphine)ferrocene (dppf); ethyl acetate (EtOAc); ethanol (EtOH); ethyl magnesium bromide (EtMgBr); [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-hexafluorophosphate ammonium (HATU); hydrochloric acid (HCl). High-performance liquid chromatography (HPLC); Isopropyl magnesium chloride·lithium chloride (iPrMgCl·LiCl); Potassium carbonate (K2CO3); Tripotassium phosphate (K3PO4); Bis(trimethylsilyl)aminopotassium (KHMDS); Potassium acetate (KOAc); Potassium thiocyanate (KSCN); Lithium borohydride (LiBH4); Liquid chromatography-mass spectrometry (LCMS); Bis(trimethylsilyl)aminolithium (LiHMDS); Lithium hydroxide (LiOH); Methanol (MeOH); 2-Methyltetrahydrofuran (MeTHF); Sodium carbonate (Na2CO3); Sodium bicarbonate (NaHCO3); Sodium nitrite (NaNO2); Sodium sulfate (N a2SO4); N-bromosuccinimide (NBS); n-Butyllithium (n-Buli); 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(ll)(Pd(dppf)Cl2); Tris(dibenzylpyrone)dipalladium(O)(Pd2(dba)3); [1 [1,1′-bis(di-tert-butylphosphino)-ferrocene]-dichloropalladium(II) (Pd-118,Pd(dtbpf)Cl2); [1,1′-bis(diphenylphosphino)-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); 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3); and zinc cyanide (Zn(CN2)).

[0272] Veterinary-acceptable salts of the compounds of the present invention can also be prepared using conventional methods. For example, the free alkaline solution can be treated with a suitable acid (pure acid or dissolved in a suitable solvent), and the resulting salt can be separated by filtration or by evaporation of the reaction solvent under reduced pressure. For a review of suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0273] The compounds of the present invention can be used in their natural form or as salts. In cases where the formation of stable, non-toxic acid salts or salt reduction is desired, administration of the compounds as veterinary-acceptable salts may be appropriate. Veterinary acceptable salts of the compounds of the present invention include, but are not limited to: acetates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphor sulfonates, citrates, ethylenediaminetetraacetate, etoglutarate, ethanesulfonates, formates, fumarates, gluconate, gluconate, glucuronide, glycerol phosphates, hexafluorophosphates, hydroxybenzoylbenzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydroxyethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, nitrates, orotate, oxalate, palmitate, pamoate, phosphates / hydrogen phosphates / dihydrogen phosphates, sucrose salts, stearates, succinates, tartrates, toluenesulfonates, and trifluoroacetates.

[0274] For illustrative purposes, the reaction schemes described below demonstrate potential routes for synthesizing the compounds of the present invention. Those skilled in the art will understand that other suitable starting materials, reagents, and synthetic routes may be used to prepare the intermediates and compounds of the present invention.

[0275] Example

[0276] The following examples provide a more detailed description of each compound and the process conditions for preparing the compounds of the present invention. However, it should be understood that, as fully described herein and as set forth in the claims, the present invention is not intended to be limited to the details of the following preparation methods.

[0277] Examples #35 and #40 exist as tautomers, in which the hydrogen atoms and double bonds of the quinoline ring spontaneously interconvert and are in equilibrium.

[0278] Preparation of Example #3 (8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one) and Example #12 (8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one)

[0279]

[0280] Step 1: Add 2-chloropropionyl chloride (4.25 g, 34 mmol, 2 equivalents) to a solution of 3,4-dihydroquinoline-2(1H)-one (2.5 g, 17 mmol) in 1,2-dichloroethane (25 mL), followed by the addition of aluminum trichloride (9 g, 68 mmol, 4 equivalents) in triplicate over 10 minutes with stirring. The mixture was then heated to 50 °C under an inert nitrogen atmosphere. After 3.5 hours, the reaction was determined to be complete based on LCMS analysis. The reaction mixture was poured directly into an ice-filled beaker. After the ice melted, the mixture was poured into a separatory funnel. Dichloromethane (100 mL) was added, and the product was extracted. The organic phase was washed again with saturated NaHCO3 aqueous solution (1 × 50 mL) and brine (1 × 50 mL). The organic layer was dried and concentrated to obtain 6-(2-chloropropionyl)-3,4-dihydroquinoline-2(1H)-one (2.75 g, 11.6 mmol), which can be used directly in the next step.

[0281] Step 2: Over 20 minutes, add potassium tert-butoxide (1.7 g, 15.1 mmol) in three equal portions to a stirred DMSO (40 mL) solution. Let the mixture stir for another 20 minutes. Over 10 minutes, add diethyl malonate (2.4 g, 15.1 mmol) dropwise to a DMSO (5 mL) solution. Stir the solution for 20 minutes, then add 6-(2-chloropropionyl)-3,4-dihydroquinoline-2(1H)-one (2.75 g, 11.6 mmol) to a DMSO (10 mL) solution. Then warm the reaction mixture to 35 °C and stir for 3 hours. Cool the mixture to room temperature and add acetic acid (1.2 g, 20 mmol). Then partition the mixture between ethyl acetate (150 mL) and water (100 mL). Wash the organic layer 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)propyl-2-yl)malonate (3.5 g, 9.7 mmol).

[0282] Step 3: Add 6N HCl (100 mL) and dioxane (20 mL) to diethyl 2-(1-oxo-1-(2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)propyl-2-yl)malonate (3.5 g, 9.7 mmol). Then heat the reaction mixture at 90 °C for 16 hours. Pour the reaction mixture into a beaker containing ice water. After the ice melts, pour the mixture into a separatory funnel and extract the product using dichloromethane (4 × 50 mL). Dry the combined organic washes with sodium sulfate and concentrate to give crude 3-methyl-4-oxo-4-(2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)butyric acid (1.8 g, 6.9 mmol).

[0283] Step 4: Ethanol (30 mL) was added to 3-methyl-4-oxo-4-(2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)butyric acid (1.8 g, 6.9 mmol), followed by the addition of hydrazine monohydrate (1.75 g, 35 mmol). The solution was heated at 65 °C for 4 hours. The mixture was poured into ice water (200 mL), forming a beige precipitate. The precipitate was collected by vacuum filtration and dried to provide the product 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (1.35 g, 5.2 mmol).

[0284] Step 5: Add NBS (1.1 g, 6.2 mmol) to a DMF (20 mL) solution of 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (1.35 g, 5.2 mmol). Stir the mixture at 55 °C for 10 h. Stir at 55 °C for 3 h, then add a second portion of NBS (0.55 g, 3.1 mmol). Pour the reaction mixture into ice water (150 mL). Collect the beige precipitate by filtration and wash with water (3 x 50 mL). After drying, obtain the crude product 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (Example #3; 1.45 g, 4.3 mmol). The pure product was obtained by rapid column chromatography (MeOH in 3.5% CH2Cl2). ¹H NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 9.31 (s, 1H), 7.82 (d, 1H), 7.65 (d, 1H), 3.34–3.45 (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).

[0285] 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-dihydroquinoline-2(1H)-one (120 mg, 0.36 mmol). Next, (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 purgings and purged with nitrogen. Finally, 1,1-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (60 mg, 0.06 mmol) was added. The mixture was then heated at 75 °C for 3 hours. The reaction was filtered through a diatomaceous earth column. The column was washed with dichloromethane (20 mL). The organic phase was washed with water (1 × 10 mL). The organic phase was concentrated. The crude residue was dissolved in DMF (4.5 mL) and purified by reversed-phase HPLC. After lyophilization, compound #12 (68 mg, 0.18 mmol) was obtained. 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 min; HPLC purity = 98.20%.

[0286] Example #1, the preparation of 8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one was carried out in a similar manner to Example #12, but in step 6 (2-methoxypyridin-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid to obtain the compound of Example #1. 1H NMR (400MHz, DMSO-d6): δ10.92(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,1H),6.85(s,1H),3.90(s,3H),3.43-3.22(m,1H),2.98(br t,2H),2.66(dd,1H),2.58-2.52(m,1H),2.22(d,1H),1.06(d,3H).

[0287] Example #2, the preparation of 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(thiazol-2-yl)-3,4-dihydroquinoline-2(1H)-one was carried out in a similar manner to Example 12, but in step 6, thiazol-2-ylboronic acid was used instead of (3-fluorophenyl)boronic acid to obtain the compound of Example #2. 1H NMR (400MHz, DMSO-d6): δ11.12(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,1H),3.03(t,2H),2.70(dd,1H),2.61-2.52(m,1H),1.30(br d,1H),1.09(d,3H).

[0288] Example #4, the preparation of 8-(2-methoxythiazol-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one was carried out in a similar manner to Example #12, but in step 6, 2-methoxythiazol-5-ylboronic acid was used instead of (3-fluorophenyl)boronic acid to obtain the compound of Example #4. 1H NMR (400MHz, DMSO-d6): δ10.93(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,1H),2.58-2.52(m,1H),2.23(d,1H),1.06(d,3H).

[0289] Example #13, the preparation of 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one was carried out in a similar manner to Example #12, but in step 6, 3-pyridylboronic acid was used instead of (3-fluorophenyl)boronic acid to obtain the compound of Example #13. 1H NMR (400MHz, DMSO-d6): δ 10.91 (s, 1H). 9.34(s,1H),8.64-8.53(m,2H),7.90-7.75(m,1H),7.74-7.61(m,1H),7.60-7.36(m,2H),3.66- 3.39(m,2H),3.17-2.90(m,2H),2.82-2.60(m,1H),2.56-2.51(m,1H),2.22(d,1H),1.07(d,3H).

[0290] Example #17, the preparation of 3,3-dimethyl-5-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-(thiazo-4-yl)indoline-2-one was carried out in a manner similar to step 6 of Example #12, but with thiophene-4-boronic acid instead of (3-fluorophenyl)boronic acid and with 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one instead of Example #47, to obtain the compound of Example #17. 1H NMR (400MHz, DMSO-d6): δ10.91(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=7.2Hz,3H).

[0291] Example #18, 9-(6-methoxypyridin-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-1,3,4,5-tetrahydro-2H-benzo[b]aza The preparation of 2-ones was carried out in a manner similar to step 6 of Example #12, but using (2-methoxypyridin-5-yl)boronic acid and 9-bromo-7-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3,4,5-tetrahydro-2H-benzo[b]aza -2-keto, to give compound #18. ¹H NMR (400 MHz, DMSO-d6): δ 8.96 (s, 1H). 8.21–8.14 (d, 1H), 7.76–7.70 (m, 2H), 7.61–7.56 (d, 1H), 6.94–6.87 (d, 1H), 3.92–3.87 (s, 3H), 3.50–3.42 (m, 1H), 3.05–3.00 (m, 1H), 2.81–2.74 (br, t, 2H), 2.73–2.64 (dd, 1H), 2.30–2.24 (m, 2H), 2.19–2.10 (m, 2H), 1.76–1.71 (m, 1H), 1.07–1.11 (d, 3H).

[0292] Example #63, the preparation of 6-methyl-5-(7-(4-(methanesulfonyl)phenyl)-2-oxoindoline-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was carried out in a manner similar to that of Example #12, but in step 6, (4-(methanesulfonyl)phenyl)boronic acid was used instead of (3-fluorophenyl)boronic acid and 5-(7-bromo-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was used instead of 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one was obtained. 1H NMR (400MHz, DMSO-d6): δ11.62(s,1H),10.63(brs,1H),8.01(d,J=8.0Hz,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=7.2Hz,3H).

[0293] Example #68, the preparation of 5-(3,3-dimethyl-2-oxo-7-(thiazol-4-yl)indololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was carried out in a manner similar to that of Example #12, but in step 6, 4-thiazol-boric acid was used instead of (3-fluorophenyl)boric acid and 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one was used instead of Example 76 to obtain the compound of Example #68. 1H NMR (400MHz, DMSO-d6): δ11.65(s,1H),10.17(s,1H),9.30(d,J=1.8Hz,1H),8.36(d,J=1.8Hz,1H), 8.14(d,J=1.6Hz,1H),7.80(d,J=1.6Hz,1H),4.92-4.82(m,1H),1.51(d,J=7.2Hz,3H),1.35(s,6H).

[0294] Example #71, the preparation of 5-(7-(4-chlorophenyl)-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was carried out in a manner similar to that of Example #12, but in step 6, 4-chlorophenyl-boronic acid was used instead of (3-fluorophenyl)boronic acid and 5-(7-bromo-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was used instead of 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one was obtained. 1HNMR (400MHz, DMSO-d6): δ11.59(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=7.2Hz,3H).

[0295] Example #6, the preparation of 7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indoline-2-one was carried out according to the following steps:

[0296]

[0297] Step 1: A slurry of AlCl3 (7.9 g, 59.39 mmol) and DMF (1.4 ml, 18.02 mmol) was heated at 70 °C for 15 minutes, then cooled to 40 °C. 7-Chloro-2,3-dihydro-1H-indol-2-one (1.0 g, 5.98 mmol) and 3-methyloxacyclopentane-2,5-dione (886 mg, 7.78 mmol) were slowly added. The resulting mixture was heated at 70 °C for 1 hour, poured into ice-cooled water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was ground with diethyl ether-pentane to give 4-(7-chloro-2-oxoindololin-5-yl)-3-methyl-4-oxobutyric acid (800 mg, 47%) as a brown gel. This was transferred to the next step without further purification. MS(ESI): m / z 282.0[M+1]+.

[0298] Step 2: Add hydrazine monohydrate (0.27 mL, 5.69 mmol) to a stirred solution of 4-(7-chloro-2-oxoindoline-5-yl)-3-methyl-4-oxobutyric acid (400.0 mg, 1.42 mmol) in ethanol (20.0 mL). Heat the resulting mixture at 80 °C for 16 hours. Crude LCMS showed the formation of two peaks with product masses (undesired:desired = 4:1). Evaporate the reaction mixture under reduced pressure, dissolve the residue in EtOH and stir while cooling. Filter and discard the resulting solid [containing the predominantly undesired isomer]. Concentrate the filtrate under reduced pressure and purify the crude material by combiflash column chromatography (EtOAc in 60 to 70% hexane) followed by reversed-phase preparative HPLC to give compound #6 (40 mg, 10%) as a grayish-white solid. 1H NMR (400MHz, DMSO-d6): δ10.95(s,1H),10.92(s,1H),7.62-760(m,2H),3.64(s,2H) ),3.38-3.34(m,1H),2.69-2.63(m,1H),2.22(d,J=16Hz,1H),1.04(d,J=8Hz,3H).

[0299] The preparation of Example #44 (7-chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one) was carried out in a similar manner to Example #6, but with 7-chloro-2,3-dimethyl-1H-indololin-2-one instead of 7-chloro-2,3-dihydro-1H-indololin-2-one and succinic anhydride instead of 3-methyloxacyclopentane-2,5-dione, to obtain the compound of Example #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).

[0300] Preparation of Example #39 (7-chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-2,3-dihydro-1H-isoindol-1-one)

[0301]

[0302] Step 1. Diethyl malonate (58 mg, 0.35 mmol) in DMSO (1 mL) was added dropwise over 10 minutes to a stirred solution of potassium tert-butoxide (38.7 mg, 0.35 mmol) in dimethyl sulfoxide (5 mL), and the mixture was stirred at room temperature for 40 minutes. Then, 5-(2-bromopropionyl)-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 reaction mixture was slowly warmed to room temperature and stirred for 3 hours. After completion, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (EtOAc in 30 to 50% hexane) to give 1,3-diethyl-2-[1-(7-chloro-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-1-oxopropyl-2-yl]malonate (55 mg, 54%) as a yellow solid. MS (ESI): m / z 382 [M+1]+.

[0303] Step 2. A solution of 1,3-diethyl-2-[1-(7-chloro-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-1-oxopropyl-2-yl]malonate (220 mg, 0.58 mmol) in 6N hydrochloric acid aqueous solution (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 twice with toluene. The crude product was ground with diethyl ether to obtain 4-(7-chloro-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-methyl-4-oxobutyric acid (90 mg, 55%), a brown gel, which was sent to the next step without further purification. MS (ESI): m / z 282.0 [M+1]+.

[0304] Step 3. At room temperature, hydrazine monohydrate (0.1 mL, 1.14 mmol) was added to a stirred solution of 4-(7-chloro-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-methyl-4-oxobutyric acid (80.0 mg, 0.28 mmol) in ethanol (10 mL). The resulting mixture was heated at 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure, and the crude product was purified by reversed-phase preparative HPLC to give compound #39 (9 mg) as a grayish-white 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), 2.77–2.66 (m, ¹H), 2.32–2.25 (m, ¹H), 1.08 (d, J = 7.2 Hz, 3H). Example #7, the preparation of 7-(4-chlorophenyl)-5-(6-oxo-1,6-dihydropyridazin-3-yl)indoline-2-one was carried out according to the following steps:

[0305] Step 1: Potassium phosphate (500 mg, 2.36 mmol) was added to a stirred solution of 7-bromo-2,3-dihydro-1H-indol-2-one (200.0 mg, 0.94 mmol) in 1,4-dioxane (5.0 mL) and water (2.0 mL), followed by the addition of 4-chlorophenylboronic acid (222 mg, 1.42 mmol), and the resulting mixture was purged with argon for 10 min. Pd(dppf)Cl2.CH2Cl2 (77.0 mg, 0.09 mmol) was added, and the reaction mixture was heated at 100 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (EtOAc in 10 to 15% hexane) to give 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]+.

[0306] Step 2: N-bromosuccinimide (52.0 mg, 0.53 mmol) was added in portions to a stirred solution of 7-(4-chlorophenyl)-2,3-dihydro-1H-indole-2-one (100.0 mg, 0.41 mmol) in trifluoroacetic acid (3.0 mL), and the reaction mixture was stirred at room temperature for 16 hours. After completion, the volatiles were 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 substance was purified by combiflash column chromatography (EtOAc in 10 to 15% hexane) to give 5-bromo-7-(4-chlorophenyl)-2,3-dihydro-1H-indole-2-one (60 mg, 45%) as a grayish-white solid. MS (ESI): m / z 323.8 [M+1]+.

[0307] Step 3: Add pinacol diboronic acid ester (238 mg, 0.93 mmol) 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), followed by potassium acetate (153 mg, 1.55 mmol), and purge the resulting mixture with argon for 10 min. Add Pd(dppf)Cl2.CH2Cl2 (64 mg, 0.07 mmol), and heat the reaction mixture at 85 °C for 16 h. After completion, dilute the reaction mixture with water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude substance was purified by combiflash column chromatography (EtOAc in 30 to 40% hexane) to give 7-(4-chlorophenyl)-5-(tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydro-1H-indol-2-one (200 mg, 69%), as a grayish-white solid. MS (ESI): m / z 370.3 [M+1]+.

[0308] Step 4: Potassium phosphate (288.0 mg, 1.35 mmol) was added to a stirred solution of 7-(4-chlorophenyl)-5-(tetramethyl-1,3,2-dioxaborane-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), followed by the addition of 6-bromo-2,3-dihydropyridazin-3-one (143.0 mg, 0.81 mmol), and the resulting mixture was purged with argon for 10 min. Pd(dppf)Cl2.CH2Cl2 (44.0 mg, 0.05 mmol) was added, and the reaction mixture was heated at 100 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (EtOAc in 50 to 60% hexane) to give compound #7 (10 mg, 6%) as a grayish-white 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).

[0309] Example #9, the preparation of 8-(4-chlorophenyl)-6-(6-oxo-1,6-dihydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one was carried out in a similar manner to Example #7, but 7-bromo-2,3-dihydro-1H-indole-2-one was replaced with 6-bromo-3,4-hydroquinolone to obtain the compound of Example #9. 1H NMR (400MHz, DMSO-d6): δ13.11(s,1H),9.01(s,1H),8.08(d,J=9.6Hz,1H),7.76(s,1H),7.55 -7.53(m,3H),7.46-7.44(m,2H),6.96(d,J=9.6Hz,1H),3.01-2.98(m,2H),2.52-2.48(m,2H).

[0310] Example #8, the preparation of 7'-chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one was carried out according to the following steps:

[0311]

[0312] Step 1. A slurry of anhydrous AlCl3 (20.97 g, 157.23 mmol) and DMF (0.004 mL, 47.17 mmol) was heated at 70 °C for 15 minutes and then cooled to 40 °C. Spiro[cyclopropane-1,3'-indoline]-2'-one (2.5 g, 15.72 mmol) and 3-methyldihydrofuran-2,5-dione (2.15 g, 18.89 mmol) were slowly added. The resulting mixture was heated at 70 °C for 2 hours, then poured into ice-cooled water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was ground with diethyl ether-pentane to give 3-methyl-4-oxo-4-{2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-5'-yl}butyric acid (3.0 g, crude product, mixture of products), a brown gel. It was sent to the next step without further purification. MS (ESI): m / z 274.2 [M+1]+.

[0313] Step 2. Add hydrazine monohydrate (1.41 mL, 43.96 mmol) to a stirred solution of 3-methyl-4-oxo-4-{2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-5'-yl}butyric acid (3.0 g, 10.99 mmol) in ethanol (30.0 mL). Heat the resulting mixture at 80 °C for 16 hours. Crude LCMS showed the formation of two peaks with product mass (undesired:desired = 4:1). Evaporate the reaction mixture under reduced pressure, dissolve the residue in EtOH and stir while cooling. Filter and discard the resulting solid [containing the predominantly undesired isomer]. The filtrate was concentrated under reduced pressure, and the crude material was purified by combiflash column chromatography (EtOAc in 60 to 70% hexane) to give 5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2'-one (270 mg, 7% of both steps), as a grayish-white solid. MS (ESI): m / z 270.2 [M+1]+.

[0314] Step 3. At room temperature, NCS (200.99 mg, 1.51 mmol) was added 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). The resulting reaction mixture was heated at 70 °C for 3 hours. After completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (EtOAc in 50 to 60% hexane) to give the compound of Example #8. 1H NMR (400MHz, DMSO-d6): δ11.16(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=16.8Hz,1H),1.71-170(m,2H),1.55-154(m,2H),1.03(d,J=7.2Hz,3H).

[0315] Example #19 Preparation of (6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one)

[0316]

[0317] Step 1. At 0 °C, 4-methylmorpholine (0.23 mL, 2.08 mmol) was added to a stirred solution of 1-(4-methoxyphenyl)cyclopropane-1-carboxylic acid (200 mg, 1.04 mmol) in DMF (5 mL), followed by HATU (395.64 mg, 1.041 mmol), and the resulting mixture was stirred at 0 °C for 10 min. 6-(3,4-diaminophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one (227 mg, 1.04 mmol) was added, and the resulting mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water and extracted with MeOH in 10% DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 semi-solid [a mixture of two positional isomers]. It was used in the next step without further purification. MS (ESI): m / z 392.9 and 393.3 [M+1]+ .

[0318] 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 obtained was purified by reversed-phase preparative HPLC to give compound #19 (110 mg, 58%) as a grayish-white solid. 1HNMR (400MHz, DMSO-d6): δ11.79&11.74(s,1H),10.85&10.83(s,1H),7.86&7 .69(s,1H),7.66&7.56(d,J=8.2Hz,1H),7.49&7.33(d,J=8.2Hz,1H),7.35-7. 31(m,2H),6.94(m,2H),3.76(s,3H),3.46&3.37(m,1H),2.72&2.68(m,1H),2. 25&2.20(m,1H),1.60–1.57(m,2H),1.33–1.30(m,2H),1.08(d,J=6.8Hz,3H). LCMS: Retention time = 2.20 min; HPLC purity = 99.72%. Note: 1H NMR indicates that the product is a mixture of isomers.

[0319] Example #21 Preparation of (5-methyl-6-(1-methyl-2-(phenylamino)-1H-benzo[d]imidazol-6-yl)-4,5-dihydropyridazine-3(2H)-one)

[0320]

[0321] Step 1. At room temperature, phenyl isothiocyanate (1.2 mL, 10.00 mmol) in N,N-dimethylformamide (15 mL) 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 N,N-dimethylformamide (15 mL), and the contents were stirred at room temperature. After 2 hours, N,N'-diisopropylmethanediimide (1.86 mL, 12.00 mmol) was added to the reaction mixture, and the contents were stirred overnight at 70 °C. The reaction mixture was then cooled to room temperature and purified directly by reversed-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).

[0322] Step 2. At 0°C, a sodium hydride dispersion in 60% mineral oil (138 mg, 3.44 mmol) was added to a tetrahydrofuran (20 mL) solution of 3-(2-anilino-3H-benzimidazol-5-yl)-4-methyl-4,5-dihydro-1H-pyridazin-6-one (1.00 g, 3.13 mmol) and stirred for 1 hour. Iodomethane (0.214 mL, 3.44 mmol) was then added, and the mixture was stirred overnight. The resulting mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was concentrated under reduced pressure, and the residue was purified by reversed-phase preparative HPLC to give compound #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).

[0323] Preparation of Example #24 (7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one)

[0324]

[0325] Step 1. Anhydrous aluminum chloride (10.4 g, 77.54 mmol) was added to a stirred solution of 3,3-dimethyl-2,3-dihydro-1H-indole-2-one (5.0 g, 31.02 mmol) in 1,2-dichloroethane (150 mL) at 0 °C, and the mixture was stirred at 10 °C for 30 min. Propionyl chloride (5.8 g, 62.04 mmol) was added dropwise to the reaction mixture and the mixture was stirred at 80 °C for 16 h. After completion, the reaction mixture was diluted with ice-cooled water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (EtOAc in 30 to 40% hexane) to give 3,3-dimethyl-5-propionyl-2,3-dihydro-1H-indole-2-one (3 g, 44%) as a grayish-white solid. MS(ESI): m / z 218.0 [M+1] + .

[0326] Step 2. At -78°C, a solution of 3,3-dimethyl-5-propionyl-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, 1 M in THF) in THF (30 mL), 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 the mixture was stirred again at -78°C for 1 hour. After completion, the reaction mixture was quenched with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (EtOAc in 40-50% hexane) to give ethyl 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-methyl-4-oxobutyrate (900 mg, 32%), as a grayish-white solid. MS (ESI): m / z 304.0 [M+1] + .

[0327] Step 3. At 0 °C, ethyl 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-methyl-4-oxobutyrate (700 mg, 2.31 mmol) was added dropwise to a stirred solution of 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-methyl-4-oxobutyrate (700 mg, 2.31 mmol) in EtOH (20 mL) and MeOH (5 mL), and the mixture was 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 ethyl acetate in 50% hexane. The organic fraction was discarded. The aqueous fraction was acidified with 2N HCl to pH approximately 4 and extracted with MeOH in 10% ethyl acetate. The combined organic layers were 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-oxobutyric acid (470 mg, 74%), a white solid. MS (ESI): m / z 274.4 [M⁻¹] + .

[0328] Step 4. Add hydrazine monohydrate (89.7 mg, 1.79 mmol) to a stirred solution of 4-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-methyl-4-oxobutyric acid (470 mg, 1.71 mmol) in ethanol (15 mL) and stir at 80 °C for 16 hours. After completion, remove the volatiles under reduced pressure and purify the crude product by combiflash column chromatography (ethyl acetate in 60-70% hexane) to give 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 grayish-white solid. MS (ESI): m / z 271.9 [M+1] + .

[0329] 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), N-chlorosuccinimide (27 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was poured into ice water. The resulting solid was filtered, washed with diethyl ether, and dried under vacuum to give compound #24 (20 mg, 35%) as a white solid. ¹H NMR (400MHz, 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 min; HPLC purity = 98.00%. The enantiomers of Example #24 are Example #33 and Example #51. Example #33 was the (R)-isomer and was separated by HPLC (Chiralpak IG column 250 × 4.6 mm, 5 μm; mobile phase (hexane / DCM / EtOH / isopropylamine (50 / 25 / 25 / 0.1)) at a flow rate of 1.0 mL / min). The HPLC retention times for Example #33 and Example #24 were 5.88 min and 6.63 min, respectively.

[0330] Example #23, the preparation of 7-bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one was carried out in a similar manner to Example #24, but 7-bromo-3,3-dimethylindololin-2-one was used instead of 7-chloro-3,3-dimethylindololin-2-one to obtain the compound of Example #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).

[0331] Example #26 Preparation of (7-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one)

[0332]

[0333] 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 diisopropylamino (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 min. Iodomethane (1.8 mL, 66.2 mmol) was added, and the reaction mixture was stirred at room temperature for 5 h. After completion, the reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc in 10 to 20% hexane) to give 7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indolin-2-one (2.7 g, 46%) as a white solid. MS(ESI): m / z 180.1[M+1]+.

[0334] 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-chloropropionyl chloride (1.86 mL, 18.75 mmol, 1.25 equivalents) were slowly added to the AlCl3 melt, and the mixture was heated to 70 °C for 4 hours. After completion, the reaction mixture was allowed to reach ambient temperature, slowly poured into crushed ice, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc in 10 to 20% hexane) to give 5-(2-chloropropionyl)-7-fluoro-3,3-dimethyldihydroindolin-2-one (1.4 g, 35%) as a yellow solid. MS (ESI): m / z 270.2 [M+1]+.

[0335] Step 3. Over 10 minutes, diethyl malonate (1.2 gm, 7.55 mmol) in DMSO (12 mL) was added dropwise to a stirred solution of potassium tert-butoxide (850 mg, 7.55 mmol) in DMSO (20 mL). The solution was stirred for 20 minutes, and then 5-(2-chloropropionyl)-7-fluoro-3,3-dimethylindolin-2-one (1.4 gm, 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 quenched with acetic acid (0.6 mL, 10 mmol) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate in 30 to 40% hexane) to give diethyl 2-(1-(7-fluoro-3,3-dimethyl-2-oxoindoline-5-yl)-1-oxoprop-2-yl)malonate (800 mg, 27%), as a grayish-white solid. MS (ESI): m / z 394.1 [M+1]+.

[0336] Step 4. A solution of diethyl 2-(1-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-1-oxopropyl-2-yl)malonate (800 mg, 2.03 mmol) in 6N HCl (50 mL) and dioxane (15 mL) was heated to 90 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-3-methyl-4-oxobutyric acid (600 mg, crude) as a colorless gel. MS (ESI): m / z 294.3 [M+1]+.

[0337] Step 5. Add hydrazine monohydrate (3 mL) to a stirred solution of 600 mg crude 4-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-3-methyl-4-oxobutyric acid (20 mL) in ethanol (3 mL), and heat to 90 °C for 16 hours. After completion, quench the reaction mixture with water and extract with MeOH in 10% DCM. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by column chromatography (1 to 5% DCM with MeOH) to give compound #26 (340 mg, 54% of both steps) as a grayish-white solid. ¹H NMR (400MHz, 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 min; HPLC purity = 96.27%.

[0338] Preparation of Example #27 (7-fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one)

[0339]

[0340] Step 1. N-bromosuccinimide (4 g, 22.63 mmol) was added in portions to a stirred solution of 7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indolin-2-one (2.7 g m, 15.08 mmol) in trifluoroacetic acid (30 mL), 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 and water, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (ethyl acetate in 30 to 40% hexane) to give 5-bromo-7-fluoro-3,3-dimethylindolin-2-one (2 g, 52%) as a grayish-white solid. MS (ESI): m / z 257.6 [M+1]+.

[0341] Step 2. Add pinacol diboronic acid ester (2.37 g, 9.33 mmol) to a stirred solution of 5-bromo-7-fluoro-3,3-dimethylindolin-2-one (2 g, 7.72 mmol) in dioxane (5 mL), followed by the addition of KOAc (1.51 g, 15.44 mmol), and purge the resulting mixture with argon for 10 min. Add Pd(dppf)Cl2·DCM (630 mg, 0.772 mmol), and heat the reaction mixture at 95 °C for 16 h. After completion, dilute the reaction mixture with water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by combiflash column chromatography (EtOAc in 30 to 40% hexane) to give 7-fluoro-3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indoline-2-one (1.5 g, 63%), as a grayish-white solid. MS (ESI): m / z 305.9 [M+1]+.

[0342] Step 3.7-Fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one

[0343] 6-Bromo-2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indoline-2-one (1.5 g, 4.92 mmol) was added to a stirred solution of a mixture of 7-fluoro-3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indoline-2-one (1.5 g, 4.92 mmol) in 1,4-dioxane (15 mL) and water (5 mL), followed by the addition of K3PO4 (2.61 g, 12.3 mmol), and the resulting mixture was purged with argon for 10 min. Pd-118 (321 mg, 0.49 mmol) was added, and the reaction mixture was heated in a sealed tube at 100 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with MeOH in 10% DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was purified by combiflash column chromatography (MeOH in 1 to 5% DCM) to give compound #27 (220 mg, 17%) as a grayish-white 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 min; HPLC purity = 98.01%.

[0344] Preparation of Example #28 (7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one)

[0345]

[0346] Step 1. A slurry of AlCl3 (7.5 g, 56.44 mmol) and DMF (1.3 mL, 16.93 mmol) was heated at 70 °C for 15 minutes, then cooled to 40 °C. 7'-Fluorospiro[cyclopropane-1,3'-indoline]-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 at 70 °C for 8 hours, poured into crushed ice, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained therefrom was ground with diethyl ether-pentane to give a mixture of 4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-3-methyl-4-oxobutyric acid and 4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-2-methyl-4-oxobutyric acid (800 mg, crude, desired:undesired = 1:4), as a brown gel. It was sent to the next step without further purification. MS (ESI): m / z 291.7 [M+1]+.

[0347] Step 2. Add hydrazine monohydrate (0.66 mL, 13.74 mmol) to a stirred solution of 4-(7'-fluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-3-methyl-4-oxobutyric acid (800.0 mg, 2.75 mmol) in ethanol (20.0 mL). Heat the resulting mixture at 80 °C for 16 hours. Crude LCMS showed the formation of two peaks with product masses (undesired:desired = 4:1). Evaporate the reaction mixture under reduced pressure, dissolve the residue in EtOH and stir while cooling. Filter and discard the resulting solid [containing the predominantly undesired isomer]. Concentrate the filtrate under reduced pressure and purify by reversed-phase preparative HPLC to give compound #28 (60 mg, 4% of both steps) as a grayish-white 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 min; HPLC purity = 99.66%. Example #30: Preparation of 6-(2-amino-4-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one).

[0348]

[0349] Step 1: 6-(4-amino-3-chlorophenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one

[0350] NCS (1.31 g, 9.8 mmol) was added to a solution of 3-(4-aminophenyl)-4-methyl-4,5-dihydro-1H-pyridazin-6-one (2.0 g, 9.8 mmol) in DMF (15 mL). The reaction mixture was heated to 45 °C and stirred overnight. The reaction mixture was then cooled to room temperature, diluted with water, and extracted with EtOAc:MeOH (90:10 2 × 100 mL). The combined organic phases were dried (Na₂SO₄) and concentrated under vacuum. The crude feedstock was separated chromatographically (40 g Redi-Sep column) and eluted with 100% hexane to 60:40 EtOAc:hexane to give an intermediate (1.52 g, 65%) as a solid. LC / MS M+H = 238.

[0351] Step 2: Potassium thiocyanate (3.3 g, 33.6 mmol) was added to a solution of 6-(4-amino-3-chlorophenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (2.0 g, 8.4 mmol) in AcOH (50 mL), which was then slightly cooled in an ice bath. The contents were stirred at room temperature for 15 minutes. Next, bromine (0.45 mL, 8.4 mmol) dissolved in AcOH (2 mL) was added dropwise, and the reaction was stirred overnight at room temperature. The reaction was neutralized with saturated NaHCO3, and the resulting precipitate was filtered and air-dried to give an intermediate (2.9 g, 97%) as an orange solid. 500 mg of the crude product was purified by SFC chromatography to give compound #30 (253 mg) as a solid. LC / MS M+H=295; 1H NMR (400MHz, DMSO-d6): δ10.94(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).

[0352] Example 31: Preparation of 6-(2-amino-4-fluorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one

[0353]

[0354] Step 1: Ethyl 4-(3,4-difluorophenyl)-3-methyl-4-oxobutyrate

[0355] A 1M solution of KHMDS in THF (22.0 mL, 22.0 mmol) was added to a round-bottom flask containing 25 mL of THF, and the mixture was cooled to -78 °C. Next, 10 mL of 1-(3,4-difluorophenyl)prop-1-one (3.75 g, 22.0 mmol) in THF was added dropwise, and the reaction mixture was stirred at -78 °C for 1 hour. Then, 10 mL of ethyl 2-bromoacetate (4.8 g, 28.6 mmol) in THF was slowly added, and the reaction mixture was warmed to 0 °C while stirring for 1 hour. The reaction was quenched with 1N HCl and extracted with EtOAc (2 × 75 mL). The combined organic phases were dried (Na₂SO₄) and concentrated under vacuum. The crude product was separated by chromatography (120 g Redi-Sep column) and eluted with 100% hexane to EtOAc:hexane at a ratio of 10:90 to give an intermediate (3.9 g, 69%) as a clear oil. LC / MS M+H = 257.

[0356] Step 2: 6-(3-fluoro-4-hydrazinophenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one

[0357] Hydrazine hydrate (0.5 mL, 15.6 mmol) was added to a solution of ethyl 4-(3,4-difluorophenyl)-3-methyl-4-oxo-butyrate (1.0 g, 3.9 mmol) in 15 mL of 2-MeTHF. The reaction was heated to 110 °C under microwave irradiation for 6 hours. The crude mixture was then cooled in an ice bath with stirring, and the resulting precipitate was filtered, washed with cold EtOH, and air-dried to give an intermediate (0.7 g, 76%) as a colorless solid. LC / MS M+H = 237.

[0358] Step 3: 6-(4-amino-3-fluorophenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one

[0359] 10% Pd / C (200 mg) was added to a solution of 6-(3-fluoro-4-hydrazinophenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (750 mg, 3.2 mmol) in MeOH (200 mL) and AcOH (1 mL). The reaction mixture was hydrogenated at 20 psi on a Palermo shaker at room temperature for 2 h and then filtered through diatomaceous earth. The mother liquor was concentrated under vacuum to give an intermediate as a semi-solid (0.67 g, 95%). LC / MS M+H = 222.

[0360] Step 4: Potassium thiocyanate (1.9 g, 19.9 mmol) was added to a solution of 6-(4-amino-3-fluorophenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (1.1 g, 4.9 mmol) in AcOH (35 mL), which was then slightly cooled in an ice bath. The contents were stirred at room temperature for 15 minutes. Next, bromine (0.25 mL, 4.9 mmol) dissolved in AcOH (1 mL) was added dropwise, and the reaction was stirred overnight at room temperature. The reaction was neutralized with saturated NaHCO3 and extracted with EtOAc:MeOH (100 mL, 90:10). The concentrate was then used to give a crude product (1.2 g, 88%) as a gel. 100 mg of the crude product was purified by reversed-phase chromatography, eluting over 20 minutes with a mixture of 95:5:0.1 water:MeCN:TFA to 80:20:0.1 MeCN:water:TFA to give compound #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 (br s, 2H), 7.50 (d, 1H), 3.39 (q, 1H), 2.71–2.67 (m, 1H), 2.23 (d, 1H), 1.08 (d, 3H).

[0361] Preparation of Example #32 (7-bromo-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one)

[0362]

[0363] 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. Diisopropylaminolithium (23.5 mL, 47.17 mmol, 2.0 M in THF / heptane / ethylbenzene) was added, and the mixture was stirred at -78 °C for 15 min. Iodomethane (2.9 mL, 47.17 mmol) was added, and the reaction mixture was stirred at room temperature for 5 h. After completion, the reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc in 10 to 20% hexane) to give 5-bromo-3,3-dimethyldihydroindolin-2-one (2.3 g, 41%) as a white solid. MS(ESI):m / z240[M+1]+.

[0364] Step 2. Add pinacol diboronate (2.9 g, 11.5 mmol) to a stirred solution of 5-bromo-3,3-dimethylindololin-2-one (2.3 g, 9.58 mmol) in dioxane (15 mL), followed by KOAc (1.8 g, 19.16 mmol), and purge the resulting mixture with argon for 10 min. Then add Pd(dppf)Cl2.DCM (0.783 g, 0.958 mmol) and heat the reaction mixture at 95 °C for 16 h. After completion, dilute the reaction mixture with water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by combiflash chromatography (EtOAc in 30 to 40% hexane) to give 3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2,3-dihydro-1H-indol-2-one (1.45 g, 53%), as a grayish-white solid. MS (ESI): m / z 288 [M+1]+.

[0365] Step 3. 6-Bromo-2,3-dihydro-1H-indol-2-one (640 mg, 2.23 mmol) was added to a stirred solution of a mixture of 3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-2,3-dihydro-1H-indol-2-one (10 mL) and water (5 mL), followed by the addition of K3PO4 (1.2 g, 5.57 mmol), and the resulting mixture was purged with argon for 10 min. 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 h. After completion, the reaction mixture was diluted with water and extracted with MeOH in 10% DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was purified by combiflash column chromatography (MeOH in 1 to 5% DCM) to give 3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)-2,3-dihydro-1H-indol-2-one (170 mg, 30%) as a grayish-white solid. MS (ESI): m / z 256 [M+1]+.

[0366] Step 4. N-bromosuccinimide (142 mg, 0.8 mmol) was added in portions 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), and the resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with water and extracted with MeOH in 10% DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product thus obtained (Example #32) was purified by combi flash chromatography (MeOH in 1 to 5% DCM) to give compound #32 (65 mg, 29%) as a grayish-white solid. ¹H NMR (400MHz, DMSO-d6): δ 13.15 (br s, ¹H), 10.85 (br s, ¹H), 8.07 (d, J = 10Hz, ¹H), 7.86 (s, ¹H), 7.83 (s, ¹H), 6.98 (d, J = 11.2Hz, ¹H), 3.31 (s, 6H). LCMS: Retention time = 2.17 min; HPLC purity [at 254 nm] = 98.61%.

[0367] Preparation of Example #34 (6-(4-fluoro-2-(methylamino)benzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one)

[0368]

[0369] Step 1. At 0 °C, 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 added to copper powder (195 mg, 2.9 mmol) in a mixture of concentrated HCl (10.0 mL) and water (3.0 mL). Next, excess NaNO2 (750 mg, 10.8 mmol) dissolved in 3 mL of water was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Next, the reaction mixture was diluted with water (25 mL), filtered, and air-dried to give 6-(2-chloro-4-fluorobenzo[d]thiazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (598 mg, 56%) as a solid. LC / MS M+H = 298.

[0370] 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), N-methylamine (0.2 g, 2.0 mmol; 33 wt% in EtOH) was added. The reaction mixture was heated at 80 °C for 2 hours and then cooled to room temperature. The crude product was purified by reversed-phase chromatography, eluting over 20 minutes with a mixture of 95:5:0.1 water:MeCN:TFA to 75:25:0.1 MeCN:water:TFA to give compound #34 (32 mg, 54%) as a solid. LC / MS M+H=293; 1H NMR (400MHz, DMSO-d6): δ10.94(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).

[0371] Example #37, the preparation of 6-(4-fluoro-2-(3-hydroxyazacyclobutane-1-yl)benzo[d]thiazo-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one was carried out in a similar manner to Example #34, but in step 2, 3-hydroxyazacyclobutane HCl and K2CO3 from IPA were used instead of N-methylamine to obtain the compound of Example #37. 1H NMR (400MHz, DMSO-d6): δ10.97(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).

[0372] Example #46, the preparation of 6-(4-fluoro-2-(3-hydroxyazacyclobutane-1-yl)benzo[d]thiazo-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one was carried out in a similar manner to Example #34, but in step 2, (1-methylpyrazol-4-yl)methylamine from IPA was used instead of N-methylamine to obtain the compound of Example #46. 1H NMR (400MHz, DMSO-d6): δ10.95(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).

[0373] Preparation of Example #35 (8-chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-2(1H)-one)

[0374]

[0375] Step 1. Dissolve 2-chloroaniline (1.0 g, 7.8 mmol) in ethyl acetate (50 mL). Add solid sodium bicarbonate (2.0 equivalents), followed by 3-ethoxy-acryloyl chloride (1.2 g, 9.4 mmol, 1.2 equivalents) at room temperature. Stir the mixture for 3 hours, then quench by adding water (10 mL). Pour the reaction mixture into a separatory funnel. Collect the organic layer and wash with water (2 × 15 mL). Collect the organic phase and dry it with sodium sulfate. Remove the volatiles by rotary evaporation to provide (E)-N-(2-chlorophenyl)-3-ethoxyacrylamide, which is used directly in the next step.

[0376] Step 2. Add (E)-N-(2-chlorophenyl)-3-ethoxyacrylamide (0.80 g, 3.5 mmol) to cold sulfuric acid (5 mL). Warm the solution to room temperature and stir at room temperature for 3 hours. Pour the reaction mixture into ice water (50 mL), producing a precipitate. Collect the precipitate by suction filtration, wash with water, and then dry overnight to prepare 8-chloroquinoline-2(1H)-one (0.771 g, 4.3 mmol).

[0377] Step 3. Aluminum chloride (2.3 g, 17.2 mmol) was added in portions to a solution of 2-chloropropionyl chloride (1.6 g, 12.9 mmol) in DCM (10 mL) while maintaining the temperature below 30 °C. 8-Chloroquinoline-2(1H)-one (0.771 g, 4.3 mmol) was added while maintaining the temperature below 30 °C. The mixture was stirred and refluxed for 15 hours, cooled, and poured into ice water. The precipitate was filtered off, washed with water, and dissolved in DCM (2 mL). The organic solution was stirred at 0 °C and filtered. The precipitate was dried to give 0.79 g (2.7 mmol) of 8-chloro-6-(2-chloropropionyl)quinoline-2(1H)-one.

[0378] Step 4. Under a nitrogen atmosphere, add t-BuOK (490 mg, 4.4 mmol) to anhydrous DMSO (25 mL). Stir the mixture at 30 °C for 30 min. Diethyl malonate (656 mg, 4.4 mmol) is diluted with DMSO (5 mL) and added dropwise to the stirred mixture over a 1-hour period. The reaction solution is stirred at 30 °C for another hour. 8-Chloro-6-(2-chloropropionyl)quinoline-2(1H)-one (790 mg, 2.7 mmol) is added to the reaction mixture in three portions over a 15-minute period. The reaction is then stirred at 40 °C for 2 hours. The reaction mixture is cooled to room temperature and quenched by adding acetic acid (2 mL). Water (100 mL) and dichloromethane (50 mL) are added to the reaction mixture in a separatory funnel. The layers are mixed and partitioned. The organic phase is collected and washed with brine (3 × 20 mL). The organic phase was dried over sodium sulfate and concentrated to obtain the crude product 2-(1-(8-chloro-2-oxo-1,2-dihydroquinoline-6-yl)-1-oxopropyl-2-yl)malonate, which was used directly in the next step.

[0379] Step 5. Diethyl 2-(1-(8-chloro-2-oxo-1,2-dihydroquinoline-6-yl)-1-oxopropyl-2-yl)malonate (2.7 mmol) was suspended in a 1:1 solution (10 mL) of dioxane / water. Sodium hydroxide (0.540 g, 13.5 mmol) was added to the mixture. The mixture was heated at 60 °C for 12 hours. The reaction mixture was allowed to cool to room temperature, and then AcOH (15 mmol) was added. The reaction mixture was stirred for 10 minutes, frozen, and lyophilized to obtain a crude mixture of diacid and inorganic salt.

[0380] The mixture was suspended in EtOH, and hydrazine monohydrate (0.30 g, 6 mmol) was added to the mixture. The reaction was heated at 65 °C overnight. The reaction mixture was allowed to cool to room temperature. Volatile components were evaporated off under low pressure using rotary evaporation to give a white solid. Water (20 mL) was added to the solid, and insoluble substances were filtered off to give a crude product (0.4 g), a brown solid. Purification by reversed-phase HPLC gave compound #35 (156 mg, 0.56 mmol). 1 H NMR(400MHz,DMSO-d6)δppm 1.05-1.13(m,3H)2.24-2.31(m,1H)2.68-2.77(m,1H)3.41-3.51(m,1H)6. 61-6.68(m,1H)8.01-8.10(m,3H)11.03-11.07(m,1H)11.22-11.27(m,1H).

[0381] Example #35 exists as the tautomer 6-(8-chloro-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (#35a), as shown below:

[0382]

[0383] Preparation of Example #36 (7-chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one)

[0384]

[0385] Step 1. At room temperature, 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 mixed with 2-chloro-3-fluoroaniline (10.0 g, 68.7 mmol) in concentrated hydrochloric acid (6.9 mL) 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 ethyl acetate. The organic layer was concentrated under reduced pressure to give (E)-N-(2-chloro-3-fluorophenyl)-2-(hydroxyimino)acetamide (10 g), which was sent to the next step without further purification. MS (ESI): m / z 217.2 [M+1] + .

[0386] Step 2. The (E)-N-(2-chloro-3-fluorophenyl)-2-(hydroxyimino)acetamide (10 g, 46.17 mmol) in concentrated sulfuric acid (30 mL) was stirred at 80 °C for 3 hours. The reaction mixture was poured into ice 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 (ethyl acetate in 20 to 40% hexane) to give 7-chloro-6-fluoroindoline-2,3-dione (5.6 g, 26%, after two steps) as a grayish-white solid. MS (ESI): m / z 200.2 [M+1] + .

[0387] Step 3. At room temperature, hydrazine monohydrate (2.81 g, 56.12 mmol) was added to a stirred solution of 7-chloro-6-fluoroindoline-2,3-dione (5.6 g, 28.06 mmol) in ethylene glycol (50 mL), and the mixture was stirred at 130 °C for 4 hours, and then at room temperature for 16 hours. Water (50 mL) and concentrated hydrochloric acid (5 mL) were added to the reaction mixture, and the mixture was stirred at 50 °C for 1 hour. The reaction mixture was poured into ice 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 (EtOAc in 30 to 40% hexane) to give 7-chloro-6-fluoroindoline-2-one (3.9 g, 75%) as a brown solid. MS (ESI): m / z 186.2 [M+1] + .

[0388] Step 4. At room temperature, 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), and the reaction mixture was cooled to -78 °C. Then, LDA (2 M in THF, 21 mL, 42.03 mmol) was added. The reaction mixture was stirred at -78 °C for 15 min, followed by the addition of iodomethane (2.6 mL, 42.03 mmol). After the addition, the reaction mixture was allowed to reach room temperature and stirred for 2 h. The reaction mixture was quenched 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 combi flash chromatography (ethyl acetate in 20-30% hexane) to give 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] + .

[0389] Step 5. At room temperature, n-bromosuccinimide (3.75 g, 21.06 mmol) was added in portions to a stirred solution of 7-chloro-6-fluoro-3,3-dimethylindololin-2-one (3.0 g, 14.04 mmol) in concentrated sulfuric acid (30 mL), and the mixture was stirred for 1 hour. The reaction mixture was poured into ice 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 combi flash chromatography (ethyl acetate in 30 to 40% hexane) to give 5-bromo-7-chloro-6-fluoro-3,3-dimethylindololin-2-one (3.8 g, 92%) as a grayish-white solid. MS (ESI): m / z 292.2 [M+1] + .

[0390] Step 6. At 0°C, add iPrMgCl·LiCl (10.52 mL, 2 equivalents, 1.3 M in THF) to a stirred nBuLi (13.4 mL, 28.32 mmol, 2 M in THF) in 30 mL of THF and stir for 10 min. Add a solution of 5-bromo-7-chloro-6-fluoro-3,3-dimethylindolin-2-one (2 g, 7.08 mmol) in 10 mL of THF to the reaction mixture and stir for 1 h. Cool the reaction mixture to -78°C and add propionaldehyde (2.47 g, 42.47 mmol), stirring at -78°C for 2 h. Quench the reaction mixture with saturated ammonium chloride and extract with ethyl acetate. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by combiflash chromatography (ethyl acetate in 30-40% hexane) to give 7-chloro-6-fluoro-5-(1-hydroxypropyl)-3,3-dimethylindolin-2-one (0.85 g, 44%), as a liquid. MS (ESI): m / z 272.2 [M+1] + .

[0391] Step 7. At room temperature, add Dys-Martin oxidant (5.308 mg, 12.51 mmol) to a stirred solution of 7-chloro-6-fluoro-5-(1-hydroxypropyl)-3,3-dimethylindoline-2-one (1.7 g, 6.25 mmol) in dichloromethane (50 mL), and then stir at room temperature for 16 hours. Filter the reaction mixture through a diatomaceous earth bed and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to give a crude compound, which is purified by combiflash column chromatography (ethyl acetate in 40 to 50% hexane) to give 7-chloro-6-fluoro-3,3-dimethyl-5-propionylindoline-2-one (0.5 g, 30%) as a liquid. MS (ESI): m / z 270.2 [M+1] + .

[0392] Step 8. At room temperature, n-bromosuccinimide (660 mg, 3.71 mmol) was added in portions to a stirred solution of 7-chloro-6-fluoro-3,3-dimethyl-5-propionylindololin-2-one (500 mg, 0.37 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred for 16 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (ethyl acetate in 20 to 30% hexane) to give 5-(2-bromopropionyl)-7-chloro-6-fluoro-3,3-dimethylindololin-2-one (0.6 g, 92%) as a yellow solid. MS (ESI): m / z 348.2 [M+1]+ .

[0393] Step 9. At room temperature, potassium tert-butoxide (251 mg, 2.24 mmol) was added in three portions (7 mL) to a stirred solution of DMSO, and the mixture was stirred for 20 minutes. A solution of diethyl malonate (238 mg, 3.75 mmol) in DMSO (1 mL) was added to the reaction mixture, and the mixture was stirred for 20 minutes. A solution of 5-(2-bromopropionyl)-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 the mixture was stirred for 3 hours. After completion, the reaction 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 substance was purified by Combi flash column chromatography (ethyl acetate in 5 to 10% hexane) to give diethyl 2-(1-(7-chloro-6-fluoro-3,3-dimethyl-2-oxoindoline-5-yl)-1-oxopropane-2-yl)malonate (0.24 g, 33%), as a grayish-white solid. MS (ESI): m / z 428.2 [M+1] + .

[0394] Step 10. At room temperature, concentrated hydrochloric acid (7.0 mL, 6 N) was added to a stirred solution of compound 1 (240.0 mg, 0.56 mmol) in 3 mL of 1,4-dioxane, and the mixture was stirred at 90 °C for 16 hours. The reaction mixture was diluted with ice water and extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure to give 4-(7-chloro-6-fluoro-3,3-dimethyl-2-oxoindoline-5-yl)-3-methyl-4-oxobutyric acid (200 mg, crude), a grayish-white solid, which was transferred to the next step. MS (ESI): m / z 328.2 [M+1] + .

[0395] Step 11. At room temperature, hydrazine monohydrate (0.2 mL, 3.05 mmol) was added to a stirred solution of 4-(7-chloro-6-fluoro-3,3-dimethyl-2-oxoindoline-5-yl)-3-methyl-4-oxobutyric acid (200.0 mg, 0.61 mmol) in ethanol (4 mL). The reaction mixture was stirred at 80 °C for 16 hours. After completion, the reaction mixture was cooled at room temperature and concentrated under reduced pressure. The crude product was purified by reversed-phase preparative HPLC to give compound #36 (35.8 mg, 25% of both steps) as a white solid (99.36% purity). 1H NMR (400MHz, DMSO-d6): δ11.17(s,1H),11.02(s,1H),7.50(d,J=6.8Hz,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=7.16Hz,3H).

[0396] Preparation of Example #38 (2-amino-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)benzo[d]thiazolyl-4-nitrile)

[0397]

[0398] Step 1. 6-(4-amino-3-bromophenyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one. The preparation of this intermediate was carried out in a similar manner to that of the intermediate in Step 1 of Example #30, but with NBS used instead of NCS. LC / MS M+H = 282.

[0399] Step 2.6-(2-amino-4-bromobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one. The preparation of this intermediate was carried out in a similar manner to that of the intermediate in Step 2 of Example #30. LC / MS M+H = 339.

[0400] Step 3. Under microwave irradiation, a mixture of 6-(2-amino-4-bromobenzo[d]thiazolyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (100 mg, 0.3 mmol), Zn(CN)₂ (42 mg, 0.35 mmol), and Pd(dppf)Cl₂ (22 mg, 0.03 mmol) in DMF (4 mL) was heated to 150 °C for 2 hours. The reaction mixture was then cooled, extracted 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 by reversed-phase chromatography, eluting over 20 minutes with a ratio of 95:5:0.1 water:MeCN:TFA to 75:25:0.1 MeCN:water:TFA to give compound #38 (15 mg, 13%) as a solid. 1H NMR (400MHz, DMSO-d6): δ11.0(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).

[0401] Preparation of Example #40 (6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-2-oxo-1,2-dihydroquinoline-8-nitrile)

[0402]

[0403] Step 1. Add 2-chloropropionyl chloride (1.27 g, 10.2 mmol) to a solution of 3,4-dihydroquinoline-2(1H)-one (1.0 g, 6.8 mmol) in 20 mL of 1,2-dichloroethane, and then add aluminum trichloride (3.6 g, 27 mmol) in triplicate over 15 minutes. Heat the mixture to 60 °C under a nitrogen atmosphere for five hours. Cool the reaction to room temperature and pour it into ice water (100 mL). Remove the volatiles by rotary evaporation under low pressure, which forms a precipitate. Collect the precipitate by filtration and wash with water (2 × 25 mL). After drying, weigh 0.8 g of the crude product 6-(2-chloropropionyl)-3,4-dihydroquinoline-2(1H)-one and use it directly in the next step.

[0404] Step 2. Dissolve 6-(2-chloropropionyl)-3,4-dihydroquinoline-2(1H)-one (0.80 g, 3.4 mmol) in DMF (5 mL) and add NBS (1.2 g, 6.8 mmol). Warm the solution at 80 °C for 12 hours. Pour the reaction mixture into ice water (50 mL) and collect the precipitate by vacuum filtration. Wash the precipitate with water (3 × 20 mL) and dry to provide the product 8-bromo-6-(2-chloropropionyl)-3,4-dihydroquinoline-2(1H)-one (0.94 g, 3.0 mmol).

[0405] Step 3. Benzoyl peroxide (catalytic amount) was added to a solution of 8-bromo-6-(2-chloropropionyl)-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 solids were partitioned 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-chloropropionyl)-3,4-dihydroquinoline-2(1H)-one (0.54 g, 1.7 mmol) was obtained by rapid column chromatography using a gradient of ethyl acetate in hexane.

[0406] Step 4. Under a nitrogen atmosphere, add t-BuOK (280 mg, 2.5 mmol) to anhydrous DMSO (15 mL). Stir the mixture at 30 °C for 30 min. Diethyl malonate (410 mg, 2.5 mmol) is diluted with DMSO (5 mL) and added dropwise to the stirred mixture over a 1-hour period. The reaction solution is stirred at 30 °C for another 1 hour. 8-Bromo-6-(2-chloropropionyl)-3,4-dihydroquinoline-2(1H)-one (540 mg, 1.7 mmol) is added to the reaction mixture in three portions over 15 minutes. The reaction is then stirred at 40 °C for 2 hours. The reaction mixture is cooled to room temperature and quenched by adding acetic acid (2 mL). Water (50 mL) and dichloromethane (30 mL) are added to the reaction mixture in a separatory funnel. The layers are mixed and partitioned. The organic phase is collected and washed with brine (3 × 20 mL). The organic phase was dried over sodium sulfate and concentrated to obtain the crude product 2-(1-(8-bromo-2-oxo-1,2-dihydroquinoline-6-yl)-1-oxopropyl-2-yl)malonate, which was used directly in the next step.

[0407] Step 5. Diethyl 2-(1-(8-bromo-2-oxo-1,2-dihydroquinoline-6-yl)-1-oxopropyl-2-yl)malonate (1.7 mmol) was suspended in a 1:1 solution of dioxane / water (10 mL). Sodium hydroxide (0.340 g, 8.5 mmol) was added to the mixture. The mixture was heated at 60 °C for 12 hours. The reaction mixture was cooled to room temperature, and then AcOH (10 mmol) was added. 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 mixture was heated at 65 °C overnight. The reaction mixture was cooled to room temperature. The volatile components were evaporated off under low pressure using rotary evaporation to give a white solid. Water (20 mL) was added to the solid, and insoluble substances were filtered off to give crude product (0.21 g), a brown solid. Purification was performed by reversed-phase HPLC to give pure product 8-bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-2(1H)-one (171 mg, 0.51 mmol).

[0408] Step 6. 8-Bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-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-necked round-bottom flask, followed by the addition of DMF (10 mL). Nitrogen was bubbled into the reaction mixture for 10 minutes. P(tBu)3 (100 mg, 0.025 mmol) was added as a solution in hexane (1 mg). The reaction mixture was then stirred at 50 °C for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and 30 mL of ice water was added with stirring. The precipitate was collected by filtration and purified by reversed-phase HPLC to give compound #40 (8 mg, 0.029 mmol) as a beige solid. 1H NMR (400MHz, DMSO-d6) δppm 1.10 (d, J=7.34Hz, 3H) 2.11-2.35 (m, 1H) 2.61-2.86 (m, 2H) 3.34-3.61 (m, 1H) 6.73 (br s, 1H) 8.34 (br s, 1H) 8.43 (br s,1H)11.11(s,1H)11.81(br s,1H).

[0409] Example #40 exists as the tautomer 2-hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-8-nitrile (#40a), as shown below:

[0410]

[0411] Preparation of Example #41 (7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-2,3-dihydro-1H-isoindol-1-one)

[0412]

[0413] Step 1. Over 10 minutes, add a solution of diethyl malonate (260 mg, 1.97 mmol) in DMSO (2 mL) to a stirred solution of potassium tert-butoxide (221 mg, 1.98 mmol) in dimethyl sulfoxide (5 mL) with stirring, and stir at room temperature for 40 minutes. Under an argon atmosphere at 0 °C, add a solution of 5-(2-bromopropionyl)-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (500 mg, 1.52 mmol) in DMSO (5 mL) dropwise over 10 minutes. Slowly warm the resulting reaction mixture to room temperature and stir for 3 hours. After completion, quench the reaction mixture with a saturated aqueous ammonium chloride solution at 0 °C and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by combiflash chromatography (EtOAc in 30 to 50% hexane) to give 1,3-diethyl-2-[1-(7-chloro-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-1-oxopropyl-2-yl]malonate (320 mg, 51%), as a yellow solid. MS (ESI): m / z 410 [M+1]+.

[0414] Step 2. A solution of 1,3-diethyl-2-[1-(7-chloro-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-1-oxopropyl-2-yl]malonate (130 mg, 0.318 mmol) in 6N hydrochloric acid aqueous solution (5 mL) was heated at 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure, and the residue was co-distilled twice with toluene. The crude product was ground with diethyl ether to obtain 4-(7-chloro-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-methyl-4-oxobutyric acid (90 mg, crude), a brown gel-like substance, which was sent to the next step without further purification. MS (ESI): m / z 310.1 [M+1]+.

[0415] Step 3. At room temperature, hydrazine monohydrate (0.06 mL, 1.16 mmol) was added to a stirred solution of 4-(7-chloro-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-methyl-4-oxobutyric acid (90 mg, 0.29 mmol) in ethanol (5 mL). The resulting mixture was heated at 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure, and the obtained crude product was purified by reversed-phase preparative HPLC to give compound #41 (12 mg) as a grayish-white solid (purity 97.52%). 1H NMR (400MHz, DMSO-d6): δ11.15(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=7.2Hz,3H).

[0416] Preparation of Example #42 (4-chloro-1-methyl-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one)

[0417]

[0418] Step 1. A methylamine solution (10 mL, 20 mmol, 2 M 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, the volatiles were removed under reduced pressure, and the crude product was purified by combiflash chromatography (EtOAc in 20 to 40% hexane) to give 3-chloro-N-methyl-2-nitrobenzylamine (0.91 g, 85%) as a grayish-white solid. MS (ESI): m / z 187.0 [M+1] + .

[0419] Step 2. At 0 °C, ammonium formate (6.8 g, 107.53 mmol) was added to a stirred solution of 3-chloro-N-methyl-2-nitroaniline (2.0 g, 10.75 mmol) in methanol (30 mL), and the mixture was stirred at 0 °C for 20 min. Zinc powder (7.1 g, 107.53 mmol) was added in portions to the reaction mixture at 0 °C, and the mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was filtered, washed with ethyl acetate, and the combined filtrates were evaporated under reduced pressure. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (EtOAc in 40 to 60% hexane) to give 3-chloro-N-methyl-2-nitroaniline. 1 1,2-methylbenzene diamine (3.95 g, 67%), a grayish-white solid. MS (ESI): m / z 157.0 [M+1] + .

[0420] Step 3. At 0°C, to 3-chloro-N 1 Toluene-1,2-diamine (1.3 g, 8.33 mmol) was added to a stirred solution of dichloromethane (10 mL) with triethylamine (1.39 mL, 10.0 mmol). Triphosgene (3.71 g, 12.5 mmol) was added in portions under cooling. The reaction mixture was allowed to reach room temperature and stirred for 5 hours. After completion, the volatiles were removed under reduced pressure, and the residue was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (EtOAc in 30 to 50% hexane) to give 4-chloro-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.5 g, 31%) as a grayish-white solid. MS (ESI): m / z 183.0 [M+1] + .

[0421] Step 4. A slurry of aluminum chloride (7.33 g, 54.95 mmol) and DMF (1.41 mL, 18.13 mmol) was heated at 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 dropwise while maintaining the temperature below 40 °C. 2-Chloropropionyl chloride (0.52 mL, 6.87 mmol) was added dropwise, and the mixture was stirred at 80 °C for 2 hours. After completion, the reaction mixture was poured into crushed ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (EtOAc in 40 to 60% hexane) to give 4-chloro-6-(2-chloropropionyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.19 g, 11%), as a grayish-white solid. MS (ESI): m / z 273.0 [M+1] + .

[0422] Step 5. Over 10 minutes, add a solution of diethyl malonate (4.41 g, 27.57 mmol) in DMSO (30 mL) with potassium tert-butoxide (3.09 g, 27.57 mmol) in DMSO (25 mL) with stirring, and stir at room temperature for 40 minutes. Under an argon atmosphere at 0 °C, add a solution of 4-chloro-6-(2-chloropropionyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (5 g, 18.38 mmol) in DMSO (25 mL) with stirring, over 10 minutes. Slowly warm the resulting reaction mixture to room temperature and stir for 3 hours. After completion, quench the reaction mixture with a saturated aqueous ammonium chloride solution at 0 °C and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by combiflash chromatography (EtOAc in 30 to 50% hexane) to give diethyl 2-(1-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-oxopropyl-2-yl)malonate (3 g, 48%), as a grayish-white solid. MS (ESI): m / z 397.0 [M+1] + .

[0423] Step 6. A stirred solution of 2-(1-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-oxopropyl-2-yl)malonate (3 g, 7.56 mmol) in 50 mL of 6N hydrochloric acid was heated at 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure, and the residue was co-distilled twice with toluene. The crude product was ground with diethyl ether to give 4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-methyl-4-oxobutyric acid (1.2 g, crude), a brown gel-like substance, which was sent to the next step without further purification. MS (ESI): m / z 295.0 [M-1] + .

[0424] Step 7. At room temperature, hydrazine monohydrate (0.34 mL, 6.76 mmol) was added to a stirred solution of 4-(7-chloro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-methyl-4-oxobutyric acid (500.0 mg, 1.69 mmol, crude) in ethanol (20 mL). The resulting mixture was heated at 90 °C for 16 hours. After completion, the volatiles were removed under reduced pressure, and the obtained crude product was purified by reversed-phase preparative HPLC to give compound #42 (18 mg, 4% of both steps) as a grayish-white solid (purity 93.65%). 1H NMR (400MHz, DMSO-d6, 100℃): δ10.63(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=6.4Hz,3H).

[0425] Preparation of Example #43 (7'-fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)spiro[cyclobutane-1,3'-indoline]-2'-one)

[0426]

[0427] 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. Next, n-BuLi (17.0 mL, 26.5 mmol) was slowly added, and the reaction mixture was stirred at -78 °C for about 30 minutes. 1,3-Dibromopropane (2.0 mL, 19.9 mmol) was slowly added, and the reaction mixture was warmed to room temperature while stirring overnight. The reaction mixture was quenched with 0.1 N HCl (75 mL) and extracted with EtOAc (2 × 75 mL). The combined organic phases were dried (Na₂SO₄) and concentrated under vacuum. The crude feedstock was separated by chromatography (80g Redi-Sep column) and eluted with 100% hexane to a 30:70 EtOAc:hexane mixture to give 7'-fluorospiro[cyclobutane-1,3'-indoline]-2'-one as a solid. LC / MS M+H = 192.

[0428] 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, then cooled to 40 °C. Next, 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 slowly added. The reaction mixture was heated to 70 °C for 2 hours, and then slowly poured into ice water. The mixture was filtered and air-dried to give 4-(7'-fluoro-2'-oxospiro[cyclobutane-1,3'-indoline]-5'-yl)-3-methyl-4-oxobutyric acid, a mixture of positional isomers. LC / MS M+H = 306.

[0429] Step 3. Add hydrazine hydrate (0.2 mL, 1.9 mmol) to a solution of crude 4-(7'-fluoro-2'-oxo-spiro[cyclobutane-1,3'-indoline]-5'-yl)-3-methyl-4-oxo-butyric acid (150 mg, 0.49 mmol) in EtOH (15 mL). Heat the reaction mixture to 80 °C for 18 hours. Cool the reaction mixture in an ice bath, filter, and wash with cold EtOH. Dry the precipitate under vacuum. Purify the crude positional isomer mixture by reversed-phase chromatography, eluting with 95:5:0.1 water:MeCN:TFA to 80:20:0.1 MeCN:water:TFA, and collect the minor positional isomers as compound #43. 1H NMR (400MHz, DMSO-d6): δ10.95-10.93(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).

[0430] Example #50: The preparation of 7-fluoro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indoline-2-one was carried out in a similar manner to Example #6, but with 4-(7-fluoro-2-oxoindoline-5-yl)-3-methyl-4-oxobutyric acid instead of 4-(7-chloro-2-oxoindoline-5-yl)-3-methyl-4-oxobutyric acid to obtain the compound of Example #50. ¹H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 10.93 (s, 1H), 7.51–7.47 (m, 2H), 3.61 (s, 2H), 3.37 (q, 1H), 2.68–2.64 (m, 1H), 2.22 (d, 1H), 1.05 (d, 3H).

[0431] Example #74, the preparation of 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was carried out in a similar manner to Example #57, but 7-fluoro-3,3-dimethylindololin-2-one was used instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to obtain the compound of Example #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).

[0432] Preparation of Example #57 (5-(7-fluoro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one)

[0433]

[0434] Step 1. Dimethylformamide (7.7 mL, 99.27 mmol) was added dropwise to anhydrous aluminum chloride (47.12 g, 330.91 mmol), and the mixture was stirred at 70 °C for 15 minutes. The resulting mixture was cooled to 40 °C, and 7-fluoro-2,3-dihydro-1H-indole-2-one (5 g, 49.64 mmol) and 2-bromopropionyl chloride (5.1 mL, 49.64 mmol) were slowly added, and the mixture was stirred at 70 °C for 2 hours. After completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (EtOAc in 30 to 40% hexane) to give 5-(2-bromopropionyl)-7-fluoro-2,3-dihydro-1H-indole-2-one (3 g, 32%) as a brown solid. MS(ESI): m / z 286.1 [M+1] + Alternatively, 5-(2-chloropropionyl)-7-fluoro-2,3-dihydro-1H-indole-2-one can be prepared using 2-chloropropionyl chloride instead of 2-bromopropionyl chloride, followed by step 2 to prepare the compound of Example 57.

[0435] Step 2. Under an argon atmosphere at room temperature, [(methoxymethylthio)amino]amine (1.12 g, 10.53 mmol) was added to a stirred solution of 5-(2-bromopropionyl)-7-fluoro-2,3-dihydro-1H-indole-2-one (3 g, 10.53 mmol) in ethanol (30 mL). The resulting mixture was heated at 80 °C for 16 hours. After completion, the reaction mixture was evaporated to dryness, and the crude product obtained was purified by column chromatography (EtOAc in 50 to 60% hexane) to give compound #57 (1 g, 34%) as a brown solid. ¹H NMR (400MHz, 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 = 6.8Hz, 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 resolved by HPLC (column I-cellulose Z 150 × 4.6 mm, 3 μm; mobile phase (hexane / ethanol / isopropylamine (70 / 30 / 0.1); flow rate 1.0 mL / min). The HPLC retention times for Example #57 and Example #78 were 4.22 min and 5.11 min, respectively.

[0436] Example #55, the preparation of 4-methyl-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one was carried out in a similar manner to Example #57, but 7-fluoro-2,3-dihydro-1H-indol-2-one was used instead of 4-methylbenzo[d]thiazol-2(3H)-one to give the compound of Example #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). Example #56, the preparation of 4-chloro-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one was carried out in a similar manner to Example #57, but with 4-chlorobenzo[d]thiazol-2(3H)-one instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to give the compound of Example #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).

[0437] Example #58, the preparation of 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was carried out in a similar manner to Example #57, but 7'-chlorospiro[cyclopropane-1,3'-indoline]-2'-one was used instead of 7-fluoro-2,3-dihydro-1H-indoline-2-one to obtain the compound of Example #58. 1H NMR (400MHz, DMSO-d6): δ11.65(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=4.2Hz,2H),1.45(d,J=7.1Hz,3H).

[0438] Example #65, the preparation of 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 carried out in a similar manner to Example #57, but with 8-bromo-3,4-dihydroquinolone instead of 7-fluoro-2,3-dihydro-1H-indole-2-one to give the compound of Example #65. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 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).

[0439] Example #67, (6R)-5-(8-chloro-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was prepared in a manner similar to that of Example #57, but 7-fluoro-2,3-dihydro-1H-indole-2-one was replaced with 8-chloro-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one to obtain the compound of Example #67. 1H NMR (400MHz, DMSO-d6): δ11.68(brs,1H),9.81(brs,1H),7.73(brs,2H),4.81(brs,1H),2.47(s,2H),1.45(d,J=6.4Hz,3H),1.28(brs,6H).

[0440] Example #75, the preparation of 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was carried out in a similar manner to Example #57, but 7-chloro-3,3-dimethylindololin-2-one was used instead of 7-fluoro-2,3-dihydro-1H-indol-2-one to obtain the compound of Example #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).

[0441] Example #76, the preparation of 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was carried out in a similar manner to Example #57, but 7-bromo-3,3-dimethylindololin-2-one was used instead of 7-fluoro-2,3-dihydro-1H-indololin-2-one to give the compound of Example #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).

[0442] Preparation of Example #61 (5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one)

[0443]

[0444] Step 1. Dimethylformamide (0.5 mL, 7.66 mmol) was added dropwise to anhydrous aluminum chloride (3.41 g, 25.55 mmol), and the mixture was stirred at 70 °C for 15 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 slowly added, and the mixture was stirred at 70 °C for 2 hours. After completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was purified by combiflash column chromatography (EtOAc in 40-50% hexane) to give 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] + .

[0445] 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), [(methoxymethane-thioyl)amino]amine (117 mg, 1.1 mmol) was added, 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 (EtOAc in 60 to 70% hexane) to give compound #61 (120 mg, 35%) as a grayish-white solid. 1 ¹H NMR (400MHz, 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 min; HPLC purity = 98.56%.

[0446] Example #59, the preparation of 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was carried out in a similar manner to Example #61, but 7-chloro-3,3-dimethyl-2,3-dihydro-1H-indololin-2-one was used instead of 7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indololin-2-one to obtain the compound of Example #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 Hz, 11.8 Hz, 1H), 4.20 (s, 2H), 1.30 (s, 6H).

[0447] Example #66, the preparation of 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was carried out in a similar manner to Example #61, but 7-bromo-3,3-dimethylindololin-2-one was used instead of 7-chloro-3,3-dimethyl-2,3-dihydro-1H-indololin-2-one to give the compound of Example #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).

[0448] Example #72, 5-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) The preparation of (-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one was carried out in a manner similar to that of Example #61, but using 1,3,4,5-tetrahydro-2H-benzo[b]aza The 2-one was replaced with 7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one to give compound #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 (br t, 2H), 2.16 (br m, 4H).

[0449] Preparation of Example #62 (5-(7-chloro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one)

[0450]

[0451] Step 1. Dimethylformamide (3.05 mL, 39.52 mmol) was added dropwise to anhydrous aluminum chloride (16 g, 119.76 mmol), and the mixture was stirred at 70 °C for 15 min. The resulting mixture was cooled to 40 °C, and 7-chloro-2,3-dihydro-1H-indole-2-one (2 g, 11.97 mmol) and 2-chloropropionyl chloride (1.3 mL, 15.56 mmol) were slowly added, and the mixture was stirred at 70 °C for 2 h. After completion, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The combined organic layers were 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 (EtOAc in 30 to 40% hexane) to give 7-chloro-5-(2-chloropropionyl)-2,3-dihydro-1H-indole-2-one (900 mg, 29%) as a brown solid. MS(ESI): m / z 257.9 [M+1] + .

[0452] Step 2. Add [(methoxymethylthioyl)-amino]amine (186.18 mg, 1.76 mmol) to a stirred solution of 7-chloro-5-(2-chloropropionyl)-2,3-dihydro-1H-indole-2-one (500 mg, 1.76 mmol) in acetonitrile (10 mL), and stir the resulting mixture at room temperature for 5 minutes. Add acetic acid (0.1 mL), and heat the reaction mixture at 80 °C for 4 hours. After completion, dilute the reaction mixture with water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude product thus obtained by combiflash column chromatography (EtOAc in 50 to 60% hexane) to give compound #62 (150 mg, 26%) as a brown solid. 1 ¹H NMR (400MHz, 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 min; HPLC purity = 98.46%.

[0453] Example #73 (6-methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) Preparation of (-7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one

[0454]

[0455] Step 1. Under an argon atmosphere at room temperature, hydroxylamine hydrochloride (260 mg, 3.74 mmol) was added to a stirred solution of 8-methyl-1,2,3,4-tetrahydronaphthyl-1-one (500 mg, 3.12 mmol) in methanol (10 mL), followed by sodium acetate (307 mg, 3.74 mmol). The resulting mixture was stirred at 60 °C for 4 hours. After completion, the reaction mixture was cooled to ambient temperature, and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to give N-[(1E)-8-methyl-1,2,3,4-tetrahydronaphthyl-1-yl]-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] + .

[0456] Step 2. Phosphorus pentoxide (1.79 g, 6.31 mmol) was added to the stirred phosphoric acid solution (1.8 mL), and the resulting mixture was heated at 100 °C for 0.5 h. N-[(1E)-8-methyl-1,2,3,4-tetrahydronaphthyl-1-ylidene]hydroxylamine (460 mg, 2.63 mmol) was added, and the mixture was stirred again at 100 °C for 2.5 h. After completion, the reaction mixture was poured into ice-cold water. The resulting solid was filtered, washed with water, and dried under reduced pressure to give 9-methyl-2,3,4,5-tetrahydro-1H-1-benzoza-2-one (400 mg, 86%) as a brown solid. MS (ESI): m / z 176.2 [M+1] + .

[0457] Step 3. Dimethylformamide (0.58 mL, 7.44 mmol) was added dropwise to anhydrous aluminum chloride (3.3 g, 24.81 mmol), and the mixture was 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-benzoza-2-one (400 mg, 2.48 mmol) and 2-chloropropionyl 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 water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was purified by combiflash column chromatography (EtOAc in 30-40% hexane) to give 7-(2-chloropropionyl)-9-methyl-2,3,4,5-tetrahydro-1H-1-benzoza-2-one (400 mg, 66%), as a brown solid. MS (ESI): m / z 266.3 [M+1] + .

[0458] Step 4. Add [(ethoxymethylthio)amino]amine (100 mg, 0.94 mmol) to a stirred solution of 7-(2-chloropropionyl)-9-methyl-2,3,4,5-tetrahydro-1H-1-benzoza-2-one (250 mg, 0.94 mmol) in acetonitrile (5 mL) and stir for 5 minutes at room temperature. Add AcOH (0.1 mL) and heat the resulting mixture at 80 °C for 16 hours. Cool the reaction mixture to room temperature and remove the volatiles under reduced pressure. Purify the crude product thus obtained by combiflash column chromatography (EtOAc in 40 to 60% hexane) to give compound #73 (60 mg, 21%) as a grayish-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 min; HPLC purity = 96.28%.

[0459] Preparation of Example #77 (5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7-nitrile)

[0460]

[0461] Step 1. A slurry of anhydrous AlCl3 (31.4 g, 235.8 mmol) and DMF (5.4 mL, 70.7 mmol) was heated at 70 °C for 15 min, then cooled to 40 °C. 7-Bromoindololin-2-one (5.0 g, 23.58 mmol) and 2-chloropropionyl chloride (2.7 mL, 28.30 mmol) were slowly added. The resulting mixture was heated at 70 °C for 4 h. The reaction mixture was cooled to ambient temperature, poured into crushed ice, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (EtOAc in 40 to 60% hexane) to give 7-bromo-5-(2-chloropropionyl)indololin-2-one (4.1 g, 48%) as a brown solid. MS (ESI): m / z 302.0 [M+1]+.

[0462] Step 2. At room temperature, acetic acid (2.0 mL) and hydrazinothiocarbamate O-methyl ester (0.39 g, 3.64 mmol) were added to a stirred solution of 7-bromo-5-(2-chloropropionyl)indoline-2-one (1.0 g, 3.63 mmol) in acetonitrile (10.0 mL). The resulting reaction mixture was heated at 90 °C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (EtOAc in 60 to 70% hexane) to give 5-(7-bromo-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (1.1 g, 24%) as a grayish-white solid. MS (ESI): m / z 340.05 [M+1]+.

[0463] Step 3. At room temperature, zinc cyanide (62.3 mg, 0.53 mmol) was added to a stirred solution of 5-(7-bromo-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (150 mg, 0.44 mmol) in DMF (4.0 mL). The reaction mixture was degassed for 5 min, 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 heated in a microwave (MW) at 140 °C for 0.5 h. After completion, the reaction mixture was diluted with cold water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by normal-phase preparative HPLC to give compound #77 (65 mg, 36%) as a grayish-white solid. 1H NMR (400MHz, DMSO-d6): δ 11.73 (s, 1H), 11.58 (bs, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 4.76 (q, J = 8.3Hz, 1H), 3.64 (s, 2H), 1.46 (d, J = 7.1Hz, 3H).

[0464] Preparation of Example #79 (7-chloro-5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2,3-dihydro-1H-isoindol-1-one)

[0465]

[0466] Step 1. DIPEA (18 mL, 101.1 mmol) was added to a stirred solution of 5-bromo-7-chloro-2-(4-methoxybenzyl)isoindoline-1-one (7.5 g, 20.5 mmol) in MeOH (150 mL), followed by the addition of Pd(dppf)Cl2·DCM (1.6 g, 2.18 mmol). The resulting mixture was purged with argon for 10 min and heated at 90 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was purified by combiflash column chromatography (EtOAc in 10 to 20% hexane) to give 7-chloro-2-(4-methoxybenzyl)-5-propionylisoindoline-1-one (3.2 g, 45%) as a white solid. MS(ESI): m / z 344[M+1]+.

[0467] Step 2. LiBH4 (158 mg, 7.22 mmol) was added to a stirred solution of 7-chloro-2-(4-methoxybenzyl)-5-propionyl isoindoline-1-one (1 g, 2.89 mmol) in THF-EtOH (15 mL; 2:1 ratio), and the mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (EtOAc in 30 to 40% hexane) to give 7-chloro-5-(hydroxymethyl)-2-(4-methoxybenzyl)isoindoline-1-one (500 mg, 54%) as a grayish-white solid. MS (ESI): m / z 318 [M+1]+.

[0468] Step 3. At 0 °C, add Dys-Martin oxidant (3.9 g, 9.4 mmol) to a stirred solution of 7-chloro-5-(hydroxymethyl)-2-(4-methoxybenzyl)isoindoline-1-one (1.5 g, 4.7 mmol) in DCM (25 mL) and stir for 16 hours at room temperature. Filter the reaction mixture through a short diatomaceous earth pad and wash with ethyl acetate. Concentrate the combined filtrate under reduced pressure and purify by combiflash column chromatography (ethyl acetate in 20 to 30% hexane) to give 7-chloro-2-(4-methoxybenzyl)-1-oxoisoindoline-5-carboxaldehyde (1.0 g, 67%) as a grayish-white solid. MS (ESI): m / z 316 [M+1]+.

[0469] Step 4. Under ice-cold conditions, EtMgBr (4.4 mL, 8.9 mmol, 2 M in THF) was added to a stirred solution of 7-chloro-2-(4-methoxybenzyl)-1-oxoisoindoline-5-carboxaldehyde (700 mg, 2.2 mmol) in 10 mL of THF, and the mixture was stirred at room temperature for 6 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combi flash chromatography (ethyl acetate in 30 to 40% hexane) to give 7-chloro-5-(1-hydroxypropyl)-2-(4-methoxybenzyl)isoindoline-1-one (320 mg, 41%) as a grayish-white solid. MS (ESI): m / z 346 [M+1]+.

[0470] Step 5. At 0 °C, add Dys-Martin oxidant (1.3 g, 3.18 mmol) to a stirred solution of 7-chloro-5-(1-hydroxypropyl)-2-(4-methoxybenzyl)isoindoline-1-one (550 mg, 1.5 mmol) in DCM (15 mL) and stir for 16 hours at room temperature. Filter the reaction mixture through a short diatomaceous earth pad and wash with ethyl acetate. Concentrate the combined filtrate under reduced pressure and purify by combiflash column chromatography (ethyl acetate in 20 to 30% hexane) to give 7-chloro-2-(4-methoxybenzyl)-5-propionylisoindoline-1-one (400 mg, 73%) as a grayish-white solid. MS (ESI): m / z 344 [M+1]+.

[0471] Step 6. At room temperature, NBS (872 mg, 4.89 mmol) was added in portions to a stirred solution of 7-chloro-2-(4-methoxybenzyl)-5-propionyl isoindoline-1-one (420 mg, 1.22 mmol) in THF (10 mL) and stirred for 16 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (ethyl acetate in 50 to 60% hexane) to give 5-(2-bromopropionyl)-7-chloro-2-(4-methoxybenzyl)isoindoline-1-one [contaminated with dibromo-substituted compounds] (280 mg, 54%) as a white solid. MS (ESI): m / z 423 [M+1]+.

[0472] Step 7. A stirred solution of 5-(2-bromopropionyl)-7-chloro-2-(4-methoxybenzyl)isoindoline-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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (EtOAc in 70 to 90% hexane) to give 5-(2-bromopropionyl)-7-chloroisoindoline-1-one (135 mg, 63%) as a grayish-white solid. MS (ESI): m / z 303 [M+1]+.

[0473] Step 8. Add hydrazinoyl thiocarbamate O-methyl ester (63 mg, 0.59 mmol) to a stirred solution of 5-(2-bromopropionyl)-7-chloroisoindoline-1-one (150 mg, 0.49 mmol) in EtOH (15 mL), and heat under reflux at 90 °C for 16 hours. After completion, remove the volatiles under reduced pressure, and dilute the residue with water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by combiflash column chromatography (EtOAc in 70 to 90% hexane) to give compound #79 (20.5 mg) as a grayish-white solid (98.22% purity). 1HNMR (400MHz, DMSO-d6): δ11.90(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=7.2Hz,3H).

[0474] Preparation of Example #80 (7-chloro-3,3-dimethyl-5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2,3-dihydro-1H-isoindol-1-one)

[0475]

[0476] Step 1. At room temperature, NBS (4 g, 22.91 mmol) was added in portions 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), and the resulting mixture was refluxed for 16 hours. After completion, the volatiles were removed under reduced pressure. The crude product was ground with pentane-hexane (1:1) to give the desired product, methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate (5 g, crude), as a brown solid, which could be used in the next step without further purification. MS (ESI): m / z 340 [M+1] + .

[0477] Step 2. Add 4-methoxybenzylamine (3.8 mL, 29.4 mmol) to a stirred solution of methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate (5 g, 14.70 mmol) and TEA (6.1 mL, 43.76 mmol) in DMF (50 mL) and stir for 5 hours at room temperature. After completion, dilute the reaction mixture with water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by combiflash column chromatography (EtOAc in 20-30% hexane) to give 5-bromo-7-chloro-2-(4-methoxybenzyl)isoindoline-1-one (3.3 g, 61% of both steps), as a grayish-white solid. MS (ESI): m / z 366 [M+1] + .

[0478] Step 3. Under an argon atmosphere at 0°C, NaH (493 mg, 12.32 mmol, 60% in mineral oil) was added to a stirred solution of 5-bromo-7-chloro-2-(4-methoxybenzyl)isoindoline-1-one (1.5 g, 4.11 mmol) in THF, and the resulting mixture was stirred at room temperature for 30 minutes. Iodomethane (1.0 ml, 16 mmol) was added, and the resulting mixture was heated at 70°C for 3 hours. After completion, the reaction mixture was quenched with an aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were 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 (ethyl acetate in 10 to 20% hexane) to give 5-bromo-7-chloro-2-(4-methoxybenzyl)-3,3-dimethylisoindoline-1-one (900 mg, 56%) as a white solid. MS(ESI): m / z 394[M+1] + .

[0479] Step 4. 5-Bromo-7-chloro-2-(4-methoxybenzyl)-3,3-dimethylisoindolin-1-one (500 mg, 1.27 mmol) was heated at 80 °C for 16 hours in a stirred solution of TFA (10 mL). After completion, the volatiles were removed under reduced pressure, the residue was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (ethyl acetate in 70 to 90% hexane) to give 5-bromo-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindolin-1-one (230 mg, 66%) as a grayish-white solid. MS (ESI): m / z 274 [M+1] + .

[0480] Step 5. Under an argon atmosphere at -78°C, add iPrMgCl·LiCl (0.7 mL, 0.91 mmol, 1.3 M, THF) to a stirred solution of nBuLi (1.5 mL, 0.75 mmol, 2 M in THF) in 5 mL THF. Add a solution of 5-bromo-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (200 mg, 0.735 mmol) in 10 mL THF to the reaction mixture, and warm the resulting mixture to room temperature while stirring for 1 hour. Cool the reaction mixture to -78°C, add propionaldehyde (0.32 mL, 4.41 mmol), and stir at -78°C for 2 hours. After completion, quench the reaction mixture with an aqueous solution of ammonium chloride and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by combiflash column chromatography (EtOAc in 40 to 60% hexane) to give 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] + .

[0481] Step 6. At 0 °C, add Dys-Martin oxidant (1.54 g, 3.63 mmol) 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) and stir for 16 hours at room temperature. Filter the reaction mixture through a short diatomaceous earth pad and wash with ethyl acetate. Concentrate the combined filtrates under reduced pressure and purify by combiflash column chromatography (EtOAc in 50 to 60% hexane) to give 7-chloro-3,3-dimethyl-5-propionyl-2,3-dihydro-1H-isoindol-1-one (325 mg, 72%) as a white solid. MS (ESI): m / z 252 [M+1] + .

[0482] Step 7. At room temperature, NBS (266 mg, 1.45 mmol) was added fractionally to a stirred solution of 5-(2-bromopropionyl)-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (150 mg, 0.60 mmol) in THF (5 mL), 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (ethyl acetate in 40 to 60% hexane) to give 5-(2-bromopropionyl)-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] + .

[0483] Step 8. Add hydrazinoyl thiocarbamate O-methyl ester (97 mg, 0.912 mmol) to a stirred solution of 5-(2-bromopropionyl)-7-chloro-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (250 mg, 0.76 mmol) in EtOH (10 mL), and heat under reflux at 90 °C for 16 hours. After completion, remove the volatiles under reduced pressure, and dilute the residue with water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by PREP-HPLC to give compound #80 (35 mg, 15%) as a grayish-white solid (97.59% purity). 1 H NMR (400MHz, DMSO-d6): δ11.90(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).

[0484] Preparation of Example #84 (4-chloro-6-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]oxazol-2(3H)-one)

[0485]

[0486] Step 1. At 0 °C, 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), and the resulting mixture was stirred at room temperature for 16 hours. The resulting solid was filtered, washed with DCM, and dried. The solid residue was partitioned between a saturated aqueous solution of NaHCO3 and DCM. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-amino-5-bromo-3-chlorophenol (1.3 g, 41%) as a brown powder. MS (ESI): m / z 221.6 [M⁻¹] + .

[0487] 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 layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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] + .

[0488] Step 3. In a microwave-safe dish, 5-(tetramethyl-1,3,2-dihydro-1,3-benzoxazol-2-one (200 mg, 0.81 mmol) was added to a stirred solution of 6-bromo-4-chloro-2,3-dihydro-1,3-benzoxazol-2-one (200 mg, 0.81 mmol) in 1,4-dioxane (4 mL) and water (1 mL), followed by the addition of K3PO4 (430 mg, 2.02 mmol), and the resulting mixture was purged with argon for 10 min. Pd(dtbpf)Cl2 (53 mg, 0.08 mmol) was added, and the reaction mixture was heated at 100 °C for 1 h under microwave irradiation. After completion, the reaction mixture was diluted with water and extracted with MeOH in 10% DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase preparative HPLC to obtain compound #84 (30 mg, 12%), a grayish-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 min; HPLC purity = 93.25%.

[0489] Preparation of compound #85 (5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one)

[0490]

[0491] For the preparation of 5-bromo-7-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-2-one, see steps 1 to 2 of Example #87. Then, 5-(4,4,5,5-tetramethyl-1,3,2-dihydro-1H-indol-2-one (150 mg, 0.55 mmol) was added 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), followed by the addition of K3PO4 (292 mg, 1.37 mmol), and the resulting mixture was purged with argon for 10 minutes. Pd(dtbpf)Cl2 (36 mg, 0.5 mmol) was added, and the reaction mixture was heated at 100 °C for 1 hour under microwave irradiation. Afterward, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (MeOH in 3 to 10% DCM) to give compound #85 (50 mg, 28%) as a grayish-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 min; HPLC purity = 96.99%.

[0492] Example #86, the preparation of 7-chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indololin-2-one was carried out in a similar manner to Example #85, but 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one was replaced with pyrimidin-5-boronic acid to give the compound of Example #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).

[0493] Preparation of Example #87 (6-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,4-dihydro-1,8-naphthidium-2(1H)-one)

[0494]

[0495] 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. Diisopropylaminolithium (29.8 mL, 59.67 mmol, 2.0 M in THF / heptane / ethylbenzene) was added, and the mixture was stirred at -78 °C for 15 min. Iodomethane (3.76 mL, 59.67 mmol) was added, and the reaction mixture was stirred at room temperature for 5 h. After completion, the reaction mixture was quenched with an aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (EtOAc in 10 to 20% hexane) to give 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] + .

[0496] Step 2. N-bromosuccinimide (892 mg, 9.18 mmol) was added fractionally to a stirred solution of 7-chloro-3,3-dimethyl-2,3-dihydro-1H-indole-2-one (1.5 g, 7.65 mmol) in trifluoroacetic acid (15 mL), 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 and water, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography (EtOAc in 10 to 20% hexane) to give 5-bromo-7-chloro-3,3-dimethyl-2,3-dihydro-1H-indole-2-one (800 mg, 38%) as a yellow solid. MS (ESI): m / z 274.1 & 276.1 [M+1] + .

[0497] Step 3. Add pinacol diboronic acid ester (558 mg, 2.2 mmol) 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), followed by the addition of KOAc (360 mg, 3.66 mmol), and purge the resulting mixture with argon for 10 min. Add Pd(dppf)Cl2·dcm (150 mg, 0.183 mmol), and heat the reaction mixture at 95 °C for 16 h. After completion, dilute the reaction mixture with water and extract with ethyl acetate. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product obtained was purified by combiflash column chromatography (EtOAc in 30 to 40% hexane) to give 7-chloro-3,3-dimethyl-5-(tetramethyl-1,3,2-dioxaboran-2-yl)-2,3-dihydro-1H-indol-2-one (300 mg, 51%), as a brown solid. MS (ESI): m / z 322.2 [M+1]+.

[0498] Step 4. To a stirred solution of 7-chloro-3,3-dimethyl-5-(tetramethyl-1,3,2-dioxaborin-2-yl)-2,3-dihydro-1H-indol-2-one (100 mg, 0.3 mmol) in dioxane (4 mL) and water (1 mL), 6-bromo-3,4-dihydro-1H-1,8-naphthid-2-one (106 mg, 0.46 mmol) was added, followed by the addition of K3PO4 (360 mg, 3.66 mmol), and the resulting mixture was purged with argon for 10 min. Pd(dtbpf)Cl2 (150 mg, 0.183 mmol) was added, and the reaction mixture was heated at 100 °C for 1 h under microwave irradiation. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase preparative HPLC to obtain compound #87 (40 mg, 38%), a grayish-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 min; HPLC purity = 99.16%.

[0499] Example #25: The preparation of 7-chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)dihydroindololin-2-one was carried out in a similar manner to Example #87, but with 6-bromopyridazin-3(2H)-one instead of 6-bromo-3,4-dihydro-1H-1,8-naphthidin-2-one to obtain the compound of Example #25. ¹H NMR (400 MHz, DMSO-d6): δ 8.06 (d, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 6.98 (d, 1H), 1.32 (s, 1H).

[0500] The instance number, compound name (mass ([M+1]+)) and corresponding chemical structure are as follows.

[0501] Instance # and Name (Quality):

[0502] #1. 8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (364);

[0503] #2. 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(thiazolyl-2-yl)-3,4-dihydroquinoline-2(1H)-one (340);

[0504] #3. 8-Bromo-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (336);

[0505] #4. 8-(2-methoxythiazo-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (370);

[0506] #5. 5-Methyl-6-(1-Methyl-2-((4-(methanesulfonyl)phenyl)amino)-1H-benzo[d]imidazol-6-yl)-4,5-dihydropyridazine-3(2H)-one (412);

[0507] #6. 7-Chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (278);

[0508] #7. 7-(4-chlorophenyl)-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (337);

[0509] #8. 7'-Chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (304);

[0510] #9. 8-(4-chlorophenyl)-6-(6-oxo-1,6-dihydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (351);

[0511] #10. 6-(2-(benzo[d]thiazol-6-ylamino)-1-methyl-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (390);

[0512] #11. 8-Bromo-4,4-dimethyl-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (364);

[0513] #12. 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (352);

[0514] #13. 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one (334);

[0515] #14. 8-(6-methoxypyridin-3-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one (364);

[0516] #15. 4-Methyl-6-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazolyl-2(3H)-one (261);

[0517] #16. 6-(1-Cyclopropyl-2-((4-(Methylsulfonyl)phenyl)amino)-1H-Benz[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (438);

[0518] #17. 3,3-Dimethyl-5-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-(thiazo-4-yl)indololin-2-one (352);

[0519] #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]aza -2-one (378);

[0520] #19. 6-(2-(1-(4-methoxyphenyl)cyclopropyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (375);

[0521] #20. 7-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-9-(thiazolyl-2-yl)-1,3,4,5-tetrahydro-2H-benzo[b]aza -2-one (354);

[0522] #21. 5-Methyl-6-(1-Methyl-2-(phenylamino)-1H-benzo[d]imidazol-6-yl)-4,5-dihydropyridazine-3(2H)-one (334);

[0523] #22. 6-(2-(benzo[d]thiazol-6-yloxy)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (377);

[0524] #23. 7-Bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (350);

[0525] #24. 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (306);

[0526] #25. 7-Chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (289);

[0527] #26. 7-Fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (290);

[0528] #27. 7-Fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (274);

[0529] #28. 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one (288);

[0530] #29. 4-Chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazolyl-2(3H)-one (296);

[0531] #30. 6-(2-amino-4-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (295);

[0532] #31. 6-(2-amino-4-fluorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (279);

[0533] #32. 7-Bromo-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one (334);

[0534] #33.(R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (306);

[0535] #34. 6-(4-fluoro-2-(methylamino)benzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (292);

[0536] #35. 8-Chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-2(1H)-one (290);

[0537] #36. 7-Chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (324);

[0538] #37. 6-(4-fluoro-2-(3-hydroxyazacyclobutane-1-yl)benzo[d]thiazolyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (335);

[0539] #38. 2-Amino-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazolyl-4-onitrile (285);

[0540] #39. 7-Chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindololin-1-one (278);

[0541] #40. 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-2-oxo-1,2-dihydroquinoline-8-nitrile (280);

[0542] #41. 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindololin-1-one (306);

[0543] #42. 4-Chloro-1-methyl-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (293);

[0544] #43. 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclobutane-1,3'-indoline]-2'-one (301);

[0545] #44. 7-Chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (291);

[0546] #45. 6-(8-bromo-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (334);

[0547] #46. 6-(4-fluoro-2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)benzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (373);

[0548] #47. 6-(7-chloro-3-methyl-1H-indazol-5-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (277);

[0549] #48. 6-(8-cyclopropyl-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (295);

[0550] #49. 6-(2-(3-methoxyazacyclobutane-1-yl)benzo[d]thiazolyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one (330);

[0551] #50. 7-Fluoro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (261);

[0552] #51. (S)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindololin-2-one (305);

[0553] #52. 4-Chloro-6-(6-oxo-1,6-dihydropyridazin-3-yl)benzo[d]thiazolyl-2(3H)-one (280);

[0554] #53. 5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-2-oxoindoline-7-nitrile (268);

[0555] #54.(R)-7-fluoro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one (261);

[0556] #55. 4-Methyl-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one (293);

[0557] #56. 4-Chloro-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one (313);

[0558] #57. 5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (279);

[0559] #58. 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (322);

[0560] #59. 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (293);

[0561] #60.(R)-5-(2-hydroxy-8-methylquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (287);

[0562] #61. 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (310);

[0563] #62. 5-(7-chloro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (294);

[0564] #63. 6-Methyl-5-(7-(4-(methanesulfonyl)phenyl)-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (415);

[0565] #64. 5-(9-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (324);

[0566] #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 (354);

[0567] #66. 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (354);

[0568] #67.(6R)-5-(8-chloro-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (338);

[0569] #68. 5-(3,3-dimethyl-2-oxo-7-(thiazo-4-yl)indololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (372);

[0570] #69. 5-(7-bromo-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (340);

[0571] #70. 6-Methyl-5-(2-oxo-7-phenylindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (337);

[0572] #71. 5-(7-(4-chlorophenyl)-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (372);

[0573] #72. 5-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one (275);

[0574] #73. 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (304);

[0575] #74. 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (307);

[0576] #75. 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (324);

[0577] #76. 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (368);

[0578] #77. 5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7-nitrile (286);

[0579] #78.(S)-5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (279);

[0580] #79. 5-(7-chloro-1-oxoisoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (296);

[0581] #80. 5-(7-chloro-3,3-dimethyl-1-oxoisoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (324);

[0582] #81. 5-(8-chloro-2-hydroxyquinoline-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (308);

[0583] #82. 5-(7-chloro-2,2-dioxy-1,3-dihydrobenzo[c]isothiazolyl-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (332);

[0584] #83. 6-Methyl-5-(8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (289);

[0585] #84. 4-Chloro-6-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]oxazol-2(3H)-one (300);

[0586] #85. 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (328).

[0587] #86. 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indololin-2-one (274);

[0588] #87. 6-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,4-dihydro-1,8-naphthidin-2(1H)-one (340);

[0589] #88. 4-Chloro-6-(5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)benzo[d]thiazol-2(3H)-one (286); and

[0590] #89. 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-1,3,4-thiadiazol-2(3H)-one (296).

[0591] The chemical structures of the corresponding compounds for Examples 1 to 89 are shown below.

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600] Pimobendan, also known as dihydropyridazinone vasodilator, has the chemical name 6-(2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, and its structure is shown below.

[0601]

[0602] Pimobendan is rapidly absorbed upon oral administration, with a bioavailability of approximately 60-65%. The time to peak concentration and elimination half-life of pimobendan are approximately 2 hours and 1.6 hours, respectively. The time to peak concentration and elimination half-life of the demethylated metabolite are approximately 3.2 hours and 5 hours, respectively. Pimobendan exerts a positive inotropic effect by enhancing the affinity of calcium ions for binding to cardiac troponin C in cardiomyocytes and inhibiting PDE3. Inhibition of PDE3 also leads to arterial and venous dilation, thereby improving cardiac output without increasing myocardial oxygen consumption, and is therefore used to treat canine myxomatous mitral valve disease or congestive heart failure secondary to dilated cardiomyopathy. Cardiac troponin I (cTnI) is a heart-specific protein and a specific and sensitive biomarker of myocardial injury. In healthy animals, the concentration of cardiac troponin in the blood should be almost zero; therefore, any significant elevation indicates some degree of myocardial injury. Monitoring the effects of PDE3 candidates on circulating cTnI in the blood can provide early warning of any risk of cardiomyocyte damage and aid in safety assessments in future studies. Additionally, cTnI can serve as a prognostic biomarker because it is closely associated with canine mortality.

[0603] Biological methods:

[0604] cPDE3A assay (fluorescence polarization)

[0605] The canine PDE3A assay kit was purchased from BPS Bioscience (San Diego, CA) and contains canine PDE3A recombinase, FAM-loop-3',5'-AMP (20 μM), PDE3 assay buffer, binding agent, binding agent diluent, and a microtiter 96-well plate. The compound was initially dissolved in DMSO. Subsequently, the stock solution concentration was diluted in cPDE3 assay buffer (10× stock solution) and serially diluted to obtain a concentration response curve starting at 10 μM (total concentration ≥7). After serial dilution, the compound solution (finally 0.1% DMSO) was transferred to the assay plate (96 wells), where the contents were titrated according to BPS... The protocol (catalog number 79735) dispensed the remaining canine PDE3A assay reagents using a final enzyme concentration of 5 pg / μL. The inhibitory effect of each compound on canine PDE3A enzyme activity was assessed using measurements of fluorescence polarization changes. The 50% inhibitory concentration (IC50) was calculated and reported. 50)nM. Compared to the current cPDE3 inhibitors of this invention, pimobendan has a cPDE3 IC50 value. 50 The value is approximately 1530 nM. The cPDE3 inhibition data (IC50) of the compounds of this invention are... 50 (In nanomoles (nM)) as shown in Table 1.

[0606] Human iPS cardiomyocyte contractility assay

[0607] Frozen people cardiomyocytes ( Thaw with Cellular Dynamics Inc. and administer via 5 to 6 μL droplets, or at a concentration of 7 to 10 × 10⁻⁶ μL. 6 Cells / mL were seeded onto plates coated with human fibronectin. The center of each well in a Biosystems Cytoview 24-well microelectrode array plate. Cells were cultured in a humidified incubator at 37°C with 5% CO2. After culturing for at least seven days with the maintenance medium changed every 2 to 3 days, the cells were then... Cells were paced at 2 Hz for approximately 48 hours using the field potential application in the Axis Navigator software on the Biosystems Maestro Pro instrument, and then returned to spontaneous pacing for at least 10 minutes in the contractility application (i.e., ...). (Positive contractile variability protocol of the Biosystems program). Before adding the test sample to the plate, a baseline of three minutes was recorded, followed by recording spontaneous pulsations for at least sixty minutes, with three-minute records every ten minutes. Readings were taken at 3, 13, 23, 33, 43, and 53 minutes. The compound was dissolved in DMSO and tested at a final concentration of 30 μM (0.3% final concentration of DMSO). After baseline recording, the compound solution was transferred to a cell plate on the instrument. The contractile response of each compound relative to the mediator control (DMSO) was assessed. A "+" sign in Table 1 indicates a statistically significant change in contractility (as defined by the change in mean %δ pulsation amplitude) at the last time point (53 minutes). An "*" sign indicates a contractile change that was not significantly different from the mediator at the last time point. Significance was obtained at earlier time points for these changes.

[0608] Table 1. cPDE3 inhibitory effect (IC50) 50 (in nM) and contractile force

[0609]

[0610]

[0611] NT – Untested

[0612] As can be observed in Table 1, the compounds of the present invention exhibit a significantly greater affinity for cPDE3 than other known cPDE3 inhibitors. On average, the IC50 of the compounds of the present invention for the cPDE3 receptor is [missing information]. 50 The binding affinity (27.1 nM (2408 / 89)) was approximately 57 times greater than that of pimoxendan (1530 / 27). For Examples 19, 57, 61, 62, and 73, the average cPDE3IC 50 It is approximately 13.5, which is about 113 times that of pimoxendan. For Examples 23, 24, 74, 75, and 76, the compounds with longer terminal half-lives have an average cPDE3IC. 50 The concentration is approximately 10.5 nM, which is about 129 times higher than that of pimoxemandil. Therefore, lower doses of any of the compounds of the present invention can lead to increased levels of cPDE3 inhibition, increased c-AMP levels, and subsequent positive inotropic effects, thereby driving myocardial contraction and smooth muscle dilation. As potent inotropic agents, the compounds of the present invention can be used to treat CHF, MMVD, and / or asymptomatic heart failure in animals, particularly canines.

[0613] Myocardial contractility represents the innate ability of the myocardium to contract. This ability to produce changes in force during contraction arises from a gradual increase in the degree of binding between different types of tissues (i.e., between myosin filaments and actin tissues). Contractility is an inherent property of these myocardial fibers. The degree of binding depends on the concentration of intracellular calcium ions and the responsiveness of myofibrils to calcium. Within the intact heart, the action / response of the sympathetic nervous system is driven by the precisely timed release of catecholamines, a process that determines the concentration of calcium ions in the myocardial cell cytosol. Factors leading to enhanced contractility are achieved through an increase in intracellular calcium ions (Ca) during contraction. 2+ The measurable relative increase in contractility is a characteristic of the myocardium, similar to the term "inotropic contractility." Contractility can be iatrogenically altered by the administration of positive inotropic drugs. Drugs that actively exert catecholamine effects (such as norepinephrine, epinephrine, and pimoxim) are considered to have positive inotropic effects. Therefore, an increase in contractility generally leads to an increase in cardiac output. Human myocardial cells synchronized after prolonged pacing (2Hz) for several days allow for the measurement of contractility or drug-induced impedance changes. Pimoxim increases myocardial cell contractility in a dose-dependent manner, as defined by the change in mean %δ beat amplitude. With enhanced contractility, left ventricular pressure will increase. The myocardial cell contractility of the compounds of the present invention (as defined by the change in mean %δ beat amplitude) has been determined to have a positive inotropic effect (i.e., stronger myocardial contractility).

[0614] Furthermore, Example #57 (30 μM) was tested using adult primary ventricular cardiomyocytes isolated from human donor hearts in a contractile amplitude (CA) assay to determine the effect of this compound on a single (Ca) pathway. 2+ Sensitization or inhibition of PDE3) or dual (Ca) 2+ The potential of sensitizing and inhibiting PDE3 to exert a positive inotropic effect was explored. Cardiomyocytes were continuously perfused (2 mL / min) at 35°C in a buffer (mediator) solution (HEPES (10 mM), NaCl (145 mM), KCl (4 mM), MgCl2 1 mM, CaCl2 (1.8 mM), and glucose (11.1 mM)) plus 0.1% DMSO. Cells were equilibrated for at least 5 minutes and stimulated at 1.0 Hz with a stimulation intensity of 1.5 × 100 μM IBMX (3-isobutyl-1-methylxanthine), a non-selective PDE inhibitor, was used. The treatment and stimulation times were 300 seconds at 1.0 Hz. MyoBLAZER was used. TM Data was collected using software (v2.9.2). Equilibrated cells (n=12) were stimulated with a suprathreshold voltage at a pacing frequency of 1 Hz (bipolar pulses lasting 3 ms). Starting at 1 V, the amplitude of the stimulation pulse was increased until the cardiomyocytes began to generate systolic-diastolic cycles. Contractile force amplitude was calculated based on the average of the last 20 systolic transients. The contractile force amplitudes for the mediator, IBMX, and IBMX + Example #57 were 100, 136.8, and 267.6, respectively. Significant differences in CA were observed between the mediator and IBMX; between the mediator and IBMX + Example #57; and between IBMX and IBMX + Example #57. IBMX increased CA by inhibiting PDE; however, the increase in CA was even greater in the presence of Example #57. Additionally, CA measurements were used to assess the effect of calcium concentration EC50 on Example #57. 50 The potential to apply displacement. For ECMO cells without instance #57. 50 It is 1286μM, including EC from instance #57. 50 The concentration was 821 μM. According to the second CA study, the contractility of myocytes was dose-dependent on calcium concentration. The contractility values ​​at 100 μM, 1000 μM, and 10,000 μM CaCl2 were 3.11, 56.31, and 228.61, respectively. With the addition of 30 μM of example #57, the contractility values ​​increased to 40.17, 182.67, and 284.27, respectively. Overall, these contractility studies clearly demonstrate the presence of an additive effect of calcium sensitization independent of PDE3 inhibition, thus supporting bimodal cardiotonic activity.

[0615] Finally, the plasma half-lives of many compounds in dogs were evaluated. Beagles were administered an oral dose (0.1 mg / kg) of the corresponding compound, equivalent to approximately 1 mg per dog. Pimobendan was administered at a dose of 0.3 mg / kg. Plasma samples were obtained over a 72-hour period, and plasma half-lives were calculated. Table 2 presents the canine plasma half-lives (t1 / 2) in hours.

[0616] Table 2. Half-life (hours) of canine plasma compounds

[0617] Example # t1 / 2(hr) Example # t1 / 2(hr) 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 57 10 75 50 58 7 76 40 59 5.2 85 9 61 8.5 86 96 Pimobendan 0.4

[0618] As can be observed in Table 2, the compounds of the present invention have a much longer half-life than pimoxendan. Therefore, it is likely that the compounds of the present invention can be administered once daily (instead of twice daily as pimoxendan), or even once every few days (e.g., twice weekly).

[0619] NT-proBNP is a standard circulating biomarker of canine MMVD secreted by ventricular cardiomyocytes in response to stretching from excessive volume or pressure load. It is a well-established diagnostic and prognostic biomarker for myocardial wall stress and can be used as a biomarker for acute changes in left ventricular load status. In some internal studies, NT-proBNP has been evaluated as a biomarker showing a 30% reduction in NT-proBNP, which is associated with other factors indicating a reduction in myocardial wall stress and improved quality of life. In one instance, Case No. 26 reduced NT-proBNP levels by 49% and 62% over a 12-hour period at doses of 0.03 and 0.1 mg / kg, respectively. In contrast, a labeled dose of pimoxemandib was associated with a 41% reduction in NT-proBNP 24 hours after administration. This positive pharmacological effect suggests a clinically relevant reduction in myocardial stress, potentially delaying the progression of heart disease.

Claims

1. A compound selected from the group consisting of: 8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(thiazolyl-2-yl)-3,4-dihydroquinoline-2(1H)-one; 8-(2-methoxythiazo-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 7-Chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 7-(4-chlorophenyl)-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one; 7'-Chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one; 8-(4-chlorophenyl)-6-(6-oxo-1,6-dihydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 3,3-Dimethyl-5-(4-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-7-(thiazo-4-yl)indololin-2-one; 9-(6-methoxypyridin-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-1,3,4,5-tetrahydro-2H-benzo[b]aza -2-keto; 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)indololin-2-one; 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 7-Chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one; 7-Fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 7-Fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one; 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one; 7-Chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 4-Chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazolyl-2(3H)-one; 6-(2-amino-4-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 6-(2-amino-4-fluorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 7-Bromo-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one; (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 6-(4-fluoro-2-(methylamino)benzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 8-Chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-2(1H)-one; 6-(8-chloro-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 7-Chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 6-(4-fluoro-2-(3-hydroxyazacyclobutane-1-yl)benzo[d]thiazolyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 2-Amino-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazolyl-4-onitrile; 7-Chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindololin-1-one; 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-2-oxo-1,2-dihydroquinoline-8-nitriles; 2-Hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)quinoline-8-nitrile; 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindolin-1-one; 4-Chloro-1-methyl-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclobutane-1,3'-indoline]-2'-one; 6-(8-bromo-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 6-(4-fluoro-2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)benzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one; 6-(7-chloro-3-methyl-1H-indazol-5-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 6-(8-Cyclopropyl-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 6-(2-(3-methoxyazacyclobutane-1-yl)benzo[d]thiazolyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 7-Fluoro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; (S)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindolin-2-one; 4-Chloro-6-(6-oxo-1,6-dihydropyridazin-3-yl)benzo[d]thiazolyl-2(3H)-one; 5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-2-oxoindoline-7-nitrile; 4-Methyl-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one; 4-Chloro-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one; 5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-Methyl-5-(7-(4-(methanesulfonyl)phenyl)-2-oxoindoline-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(3,3-dimethyl-2-oxo-7-(thiazo-4-yl)indololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-(4-chlorophenyl)-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7-nitrile; (S)-5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-1-oxoisoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-1-oxoisoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(8-chloro-2-hydroxyquinoline-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2,2-dioxy-1,3-dihydrobenzo[c]isothiazolyl-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-Methyl-5-(8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 4-Chloro-6-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]oxazol-2(3H)-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indololin-2-one; 6-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,4-dihydro-1,8-naphthidium-2(1H)-one; 4-Chloro-6-(5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)benzo[d]thiazol-2(3H)-one; and 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-1,3,4-thiadiazole-2(3H)-one, their stereoisomers, and their veterinary-acceptable salts.

2. The compound according to claim 1, wherein the compound is selected from the group consisting of: 8-(2-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 8-(2-methoxythiazo-5-yl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 7-Chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 7'-Chloro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one; 8-(4-chlorophenyl)-6-(6-oxo-1,6-dihydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-8-(pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 9-(6-methoxypyridin-3-yl)-7-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-1,3,4,5-tetrahydro-2H-benzo[b]aza -2-keto; 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)indololin-2-one; 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 7-Chloro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one; 7-Fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 7-Fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one; 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one; 7-Chloro-3,3-dimethyl-5-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 6-(2-amino-4-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 6-(2-amino-4-fluorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 7-Bromo-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one; (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 6-(4-fluoro-2-(methylamino)benzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 8-Chloro-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)quinoline-2(1H)-one; 6-(8-chloro-2-hydroxyquinoline-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 7-Chloro-6-fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 6-(4-fluoro-2-(3-hydroxyazacyclobutane-1-yl)benzo[d]thiazolyl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 2-Amino-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzo[d]thiazolyl-4-onitrile; 2-Hydroxy-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)quinoline-8-nitrile; 7-Chloro-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindololin-1-one; 6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-3-yl)-2-oxo-1,2-dihydroquinoline-8-nitriles; 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)isoindolin-1-one; 4-Chloro-1-methyl-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclobutane-1,3'-indoline]-2'-one; 4-Chloro-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one; 5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-Methyl-5-(7-(4-(methanesulfonyl)phenyl)-2-oxoindoline-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-(4-chlorophenyl)-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7-nitrile; (S)-5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-1-oxoisoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-1-oxoisoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-Methyl-5-(8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; and 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indoline-2-one, their stereoisomers, and their veterinary-acceptable salts.

3. The compound according to claim 2, wherein the compound is selected from the group consisting of: 8-(3-fluorophenyl)-6-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-3,4-dihydroquinoline-2(1H)-one; 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)indololin-2-one; 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 7-Fluoro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 7-Fluoro-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one; 7'-Fluoro-5'-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)spiro[cyclopropane-1,3'-indoline]-2'-one; 6-(2-amino-4-chlorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 6-(2-amino-4-fluorobenzo[d]thiazolyl-6-yl)-5-methyl-4,5-dihydropyridazine-3(2H)-one; 7-Bromo-3,3-dimethyl-5-(6-oxo-1,6-dihydropyridazin-3-yl)indololin-2-one; (R)-7-chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 4-Chloro-6-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)benzo[d]thiazol-2(3H)-one; 5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7'-chloro-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(6-methyl-2-oxo-3,6-dihydro-2H-1,3,4-thiadiazin-5-yl)-2-oxoindoline-7-nitrile; (S)-5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one; and 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indoline-2-one, their stereoisomers, and their veterinary-acceptable salts.

4. The compound according to claim 3, wherein 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-tetrahydropyridazin-3-yl)indololin-2-one; 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 6-Methyl-5-(9-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; and 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indoline-2-one, their stereoisomers, and their veterinary-acceptable salts.

5. The compound according to claim 4, wherein the compound 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-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2-oxoindoline-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]aza) -7-yl)-3,6-dihydro-2H-1,3,4-thiadiazine-2-one, their stereoisomers, and their veterinary-acceptable salts.

6. The compound according to claim 4, wherein the compound is selected from the group consisting of: 7-Bromo-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 5-(7-fluoro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-3,3-dimethyl-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-bromo-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; and 7-Chloro-3,3-dimethyl-5-(pyrimidin-5-yl)indoline-2-one, their stereoisomers, and their veterinary-acceptable salts.

7. The compound according to claim 4, wherein the compound 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)indololin-2-one; 7-Chloro-3,3-dimethyl-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)indololin-2-one; 5-(7-fluoro-2-oxoindololin-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; 5-(7-chloro-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; and 5-(7-chloro-3,3-dimethyl-2-oxoindoline-5-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, their stereoisomers, and their veterinary-acceptable salts.

8. A composition comprising the compound according to any one of claims 1 to 7, its stereoisomer, or a veterinary acceptable salt thereof.

9. The composition of claim 8, comprising the compound of any one of claims 3, 4, 5, 6 or 7, its stereoisomer or a veterinary acceptable salt thereof.

10. The composition according to claim 8 or 9, further comprising an additional pharmaceutical substance selected from the group consisting of: ACE inhibitors, furosemide, or spironolactone.

11. The composition according to claim 9 or 10, further comprising a veterinary acceptable excipient.

12. A method of treating animals suffering from myxomatous mitral valve disease, congestive heart failure, and / or asymptomatic heart failure by administering a therapeutic amount of the compound, stereoisomer thereof, or veterinary acceptable salt thereof, according to any one of claims 1 to 7, to animals in need.

13. The method of claim 12, wherein the compound, its stereoisomer, or a veterinary acceptable salt thereof, is administered to the animal in need of the method according to any one of claims 3, 4, 5, 6, or 7.

14. The method according to claims 11 to 13, wherein at least one additional pharmaceutical substance selected from the group consisting of ACE inhibitors, furosemide, and spironolactone is administered to the animal in need of the method.

15. Use of any one of claims 1 to 7 or any one of claims 3, 4, 5, 6 or 7, its stereoisomer or a veterinary acceptable salt thereof for the preparation of a medicament for the treatment of myxomatous mitral valve disease, congestive heart failure and / or asymptomatic heart failure in animals in need.

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