Novel ATP-sensitive potassium channel enhancers, their preparation and use

Abstract

The present disclosure relates to compounds of general formula (I), or pharmaceutically acceptable salts, solvates, and / or hydrates thereof, processes for their preparation, the use of said compounds for use as medicaments, and their use in the treatment and / or prevention of diseases or disorders, such as metabolic disorders (e.g., hyperinsulinism, e.g., congenital hyperinsulinism). The present disclosure also relates to pharmaceutical compositions comprising a compound of general formula (I) and a pharmaceutically acceptable carrier, and their use as medicaments, particularly in the treatment of diseases or disorders, such as metabolic disorders (e.g., hyperinsulinism, e.g., congenital hyperinsulinism).

Description

[Technical Field]

[0001] Priority claims This application claims priority to Dutch Patent Application No. N2033343, filed October 18, 2022. The entire contents of the aforementioned application are incorporated herein by reference in their entirety.

[0002] The present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt, solvate, and / or hydrate thereof, a process for preparing the compound, the compound's use as a medicament, and its use in the treatment and / or prevention of a disease or disorder. In one embodiment, the disease or disorder is hyperinsulinism, particularly congenital hyperinsulinism. The present invention also relates to a pharmaceutical composition comprising a compound of general formula (I) and a pharmaceutically acceptable carrier, and its use as a medicament, particularly its use in the treatment of a disease or disorder such as hyperinsulinism or congenital hyperinsulinism. [Background technology]

[0003] K ATP The channel is composed of four pore-forming inwardly rectifying potassium channel subunits, Kir6.1 or Kir6.2, and four regulatory sulfonylurea receptor subunits, SUR1 or SUR2. Assembly of these subunits in various combinations results in tissue-specific K channel activity. ATP Channel isoforms are produced. For example, pancreatic β-cell type K ATP The channel has a combination of SUR1 subunit and Kir6.2 subunit (SUR1 / Kir6.2). The combination of SUR2A / Kir6.2 and the combination of SUR2B / Kir6.2 or Kir6.1 are present in cardiac and smooth muscles, respectively. Each SUR subunit contains 17 transmembrane domains and two intracellular nucleotide binding domains (NBDs) clustered into three regions. Kir6.x is a K - It contains two transmembrane domains that provide the selectivity P loop.

[0004] In some embodiments, KATP The channel (SUR1 / Kir6.2) is dysfunctionally closed in certain patients. Furthermore, the beta cells are electrically active, which leads to inappropriate insulin release independent of plasma glucose concentration. Therefore, the therapeutic strategy is to ATP Using a channel opener (KCO), ATP The goal is to open the channels and return the β-cell to an inactive state. KCO hyperpolarizes the cell membrane and inhibits calcium influx into the cell, thereby bringing about quiescence in the β-cell.

[0005] KCO has been previously used to inhibit insulin secretion and thus to treat type 1 and type 2 diabetes or to lower blood pressure. KCO has also been used to treat CHI patients. However, the known KCOs are ATP Due to the ubiquitous distribution of the channels, they are not tissue specific, which leads to undesirable side effects. Therefore, the use of KCOs has been limited so far due to their moderate potency and limited selectivity.

[0006] Currently available KCOs include first-generation benzopyrans, benzothiadiazines, cyanoguanidines, pyridyl nitrates, and thioformamides, as well as second-generation cyclobutenediones, dihydropyridines, and tertiary carbinols.

[0007] Diazoxide, a benzothiazidine, is a ATPDiazoxide is a channel opener and the first-line treatment for patients with CHI. Diazoxide was first approved for medical use in 1973 and is used as a vasodilator to treat acute hypertension and hypoglycemia. However, diazoxide is not tissue-specific and is primarily active at SUR1-containing channels. Furthermore, its activity shifts to SUR2-containing channels in the presence of intracellular MgADP. Diazoxide's side effects are numerous and include Na+ and fluid retention, hirsutism, and anorexia, as well as life-threatening complications such as heart failure, pulmonary hypertension, hyperuricemia, bone marrow damage, depression, and anemia. The vasodilatory effects of diazoxide are mediated by membrane hyperpolarization and Ca(2+) upregulation in arterial smooth muscle cells. 2+ SUR2-containing K resulting in reduced influx ATP It is mediated by binding to and activation of the K channel in beta cells. ATP In addition to the channel, diazoxide also inhibits K channels in peripheral tissues containing the SUR2 subunit. ATP It has been shown that diazoxide can activate the channel, which may explain many of the off-target side effects of diazoxide, including salt and water retention, hirsutism, bitter taste, and rarely pulmonary hypertension.

[0008] Furthermore, without being bound by theory, diazoxide ATP While the channels are functional, they may only be effective in cases where mutations in the ABCC8 and KCNJ11 genes are present. This means that diazoxide may not respond to patients with the most severe cases of CHI. Patients with milder forms of the disease may respond somewhat to diazoxide but suffer from the side effects described above. Therefore, treatment with diazoxide may still result in life-threatening hypoglycemia in one-third of responsive patients.

[0009] Alternatives to diazoxide and other KCOs include glucagon, somatostatin analogs, nifedipine, GLP1 receptor antagonists, and sirolimus (primarily for Ca delivery to β-cells). 2+Other drugs, such as steroids (which act by reducing the influx of steroids), have been administered. However, these drugs also have many side effects, such as gastrointestinal symptoms, gallstone formation, suppression of pituitary hormones, necrotizing enterocolitis, hypotension, immunosuppression, thrombocytosis, and impaired immune response.

[0010] Other treatments for CHI include surgery, which is performed when medical therapy is insufficient. Partial or near-total pancreatectomy can be considered depending on whether the CHI is localized or diffuse and whether it is clearly non-responsive to medications requiring surgical intervention.

[0011] Additional treatments involve modifying the insulin levels already present in the plasma. These methods target downstream pathways of insulin and use molecules that act as insulin antagonists or insulin receptor antagonists. This can lead to additional undesirable effects. Such molecules are typically administered by injection, but this is not the preferred method because children with some forms of CHI may be too obese to undergo injections.

[0012] Therefore, there remains a need to provide potent and well-tolerated compounds that are able to selectively bind to SUR1 / Kir6.2 and inhibit glucose-stimulated insulin secretion. Summary of the Invention [Means for solving the problem]

[0013] A first aspect of the present disclosure is a compound represented by the following formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A is C(R'), each of B and D is independently N, A and B or A and D are connected via a double bond or a single bond, and each of R1, R2, R5, and R6 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR A , fluorine, chlorine, bromine, iodine, nitro, or cyano, wherein A and B form a double bond, and R x is hydrogen, or A and D form a double bond, and R y is hydrogen, and R3 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(R B )(R C ), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; R' is absent, hydrogen, or C1-C6 alkyl; each R4 is independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, fluorine, chlorine, bromine, or iodine; and R A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; B and R Ceach is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, where each of the alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7, or R B and R C and together, one or more R 7 and each R 7 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR A , fluorine, chlorine, bromine, iodine, nitro, or cyano.

[0014] In one embodiment, B is N. In one embodiment, D is N. In one embodiment, A is C. In one embodiment, R5 is hydrogen. In one embodiment, R6 is hydrogen. In one embodiment, each of R1 and R2 is independently hydrogen, fluorine, chlorine, bromine, iodine, nitro, or cyano. In one embodiment, R1 is hydrogen, fluorine, chlorine, bromine, iodine, nitro, or cyano. In one embodiment, R1 is hydrogen, fluorine, chlorine, bromine, iodine, or cyano. In one embodiment, R1 is hydrogen, fluorine, or chlorine. In one embodiment, R1 is hydrogen. In one embodiment, R1 is fluorine. In one embodiment, R1 is chlorine. In one embodiment, R1 is bromine. In one embodiment, R1 is iodine. In one embodiment, R1 is cyano. In one embodiment, R2 is hydrogen, fluorine, chlorine, bromine, iodine, nitro, or cyano. In one embodiment, R2 is hydrogen, fluorine, chlorine, bromine, iodine, or cyano. In one embodiment, R2 is hydrogen, fluorine, or chlorine. In one embodiment, R2 is hydrogen. In one embodiment, R2 is fluorine. In one embodiment, R2 is chlorine. In one embodiment, R2 is bromine. In one embodiment, R1 is iodine. In one embodiment, R2 is cyano.

[0015] In one embodiment, R3 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(R B )(R C ), each of which is optionally substituted with one or more R7. In one embodiment, R3 is C1-C6 heteroalkyl optionally substituted with one or more R7. In one embodiment, R3 is C1-C6 haloalkyl optionally substituted with one or more R7. In one embodiment, R3 is cycloalkyl optionally substituted with one or more R7. In one embodiment, R3 is heterocyclyl optionally substituted with one or more R7.

[0016] In one embodiment, R3 is N(R B )(R C In one embodiment, R B and R C and together form one or more R 7 In one embodiment, R B is hydrogen. In one embodiment, R C is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R7. C is C1-C6 alkyl optionally substituted with one or more R7. In one embodiment, R C is a C1-C6 heteroalkyl optionally substituted with one or more R7. C is a C1-C6 haloalkyl optionally substituted with one or more R7. Cis cycloalkyl (e.g., monocyclic cycloalkyl, bicyclic cycloalkyl) optionally substituted with one or more R7. In one embodiment, R C is cycloalkyl substituted with one or more R7, where R7 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR A , fluorine, chlorine, bromine, iodine, nitro, or cyano. C is heterocyclyl optionally substituted with one or more R7.

[0017] In one embodiment, the compound of Formula (I) is not 3-(tert-butylamino)-7-chloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide or a pharmaceutically acceptable salt thereof.

[0018] In one embodiment, the compound of formula (I) has the following formula (Ia): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A is C, B and D are each independently N, A and B or A and D are connected via a double bond or a single bond, R1 and R2 are hydrogen, fluorine, chlorine, bromine, and iodine, wherein A and B form a double bond, and R x is H, or A and D form a double bond, and R y is H and R3 is [ka] wherein R4 is selected from the group consisting of C1-C3 alkyl optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro and hydroxy, ethynyl, C1-C2 alkoxy, (methoxy)-C1-C2 alkyl, cyano, fluoro, (methylsulfonyl)-C1-C2 alkyl, (dimethylamino)-C1-C2 alkyl, and n-methylcarbamoyl, with the proviso that the compound is not 3-(tert-butylamino)-7-chloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide.

[0019] The present inventors have surprisingly found that the compounds described herein selectively bind to SUR1 / Kir6.2 and exhibit remarkable potency in inhibiting glucose-stimulated insulin secretion. Without being bound by theory, the specific binding of such compounds to their targets results in reduced off-target effects. Furthermore, the compounds according to the present invention exhibit excellent bioavailability, stability, and safety, and can be administered orally.

[0020] The present invention includes any tautomeric forms, metabolites, or prodrugs of the compounds of the present invention. The present invention further includes unsolvated and solvated forms, including hydrated forms, of the compounds of the present invention.

[0021] A second aspect of the present invention relates to a process for preparing a compound according to formula (I).

[0022] A third aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically active amount of a compound according to formula (I) and a pharmaceutically acceptable carrier.

[0023] A final aspect of the present invention relates to the use of the above compounds and pharmaceutical compositions thereof as medicaments, in particular the use of the above compounds and pharmaceutical compositions thereof as medicaments for the treatment of diseases or disorders, such as metabolic disorders (e.g., hyperinsulinism (HI) or congenital hyperinsulinism (CHI)), cancer, or neurological or cardiovascular disorders. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 shows the inhibition of insulin by diazoxide in a GSIS assay. [Figure 2] FIG. 1 shows the inhibition of insulin by compound 42 in a GSIS assay. [Figure 3] FIG. 1 shows the inhibition of insulin by compound 54 in a GSIS assay. DETAILED DESCRIPTION OF THE INVENTION

[0025] Described herein are compounds, compositions, and their related uses and formulations for treating diseases or disorders such as CHI. In a first aspect, the disclosure features a compound of formula (I):

[0026] A first aspect of the present disclosure is a compound represented by the following formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A is C(R'), each of B and D is independently N, A and B or A and D are connected via a double bond or a single bond, and each of R1, R2, R5, and R6 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR A , fluorine, chlorine, bromine, iodine, nitro, or cyano, wherein A and B form a double bond, and R x is hydrogen, or A and D form a double bond, and R y is hydrogen, and R3 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(R B )(R C), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more R4; R' is absent, hydrogen, or C1-C6 alkyl; each R4 is independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, fluorine, chlorine, bromine, or iodine; and R A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; B and R C each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, where each of the alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7, or R B and R C and together, one or more R 7 and each R 7 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR A , fluorine, chlorine, bromine, iodine, nitro, or cyano.

[0027] In one embodiment, B is N. In one embodiment, D is N. In one embodiment, A is C. In one embodiment, R5 is hydrogen. In one embodiment, R6 is hydrogen. In one embodiment, each of R1 and R2 is independently hydrogen, fluorine, chlorine, bromine, iodine, nitro, or cyano. In one embodiment, R1 is hydrogen, fluorine, chlorine, bromine, iodine, nitro, or cyano. In one embodiment, R1 is hydrogen, fluorine, chlorine, bromine, iodine, or cyano. In one embodiment, R1 is hydrogen, fluorine, or chlorine. In one embodiment, R1 is hydrogen. In one embodiment, R1 is fluorine. In one embodiment, R1 is chlorine. In one embodiment, R1 is bromine. In one embodiment, R1 is iodine. In one embodiment, R1 is cyano. In one embodiment, R2 is hydrogen, fluorine, chlorine, bromine, iodine, nitro, or cyano. In one embodiment, R2 is hydrogen, fluorine, chlorine, bromine, iodine, or cyano. In one embodiment, R2 is hydrogen, fluorine, or chlorine. In one embodiment, R2 is hydrogen. In one embodiment, R2 is fluorine. In one embodiment, R2 is chlorine. In one embodiment, R2 is bromine. In one embodiment, R1 is iodine. In one embodiment, R2 is cyano.

[0028] In one embodiment, R3 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(R B )(R C ), each of which is optionally substituted with one or more R7. In one embodiment, R3 is C1-C6 heteroalkyl optionally substituted with one or more R7. In one embodiment, R3 is C1-C6 haloalkyl optionally substituted with one or more R7. In one embodiment, R3 is cycloalkyl optionally substituted with one or more R7. In one embodiment, R3 is heterocyclyl optionally substituted with one or more R7.

[0029] In one embodiment, R3 is N(R B )(R C In one embodiment, R B and R C and together form one or more R 7 In one embodiment, R B is hydrogen. In one embodiment, R C is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R7. C is C1-C6 alkyl optionally substituted with one or more R7. In one embodiment, R C is a C1-C6 heteroalkyl optionally substituted with one or more R7. C is a C1-C6 haloalkyl optionally substituted with one or more R7. C is cycloalkyl (e.g., monocyclic cycloalkyl, bicyclic cycloalkyl) optionally substituted with one or more R7. In one embodiment, R C is cycloalkyl substituted with one or more R7, where R7 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR A , fluorine, chlorine, bromine, iodine, nitro, or cyano. C is heterocyclyl optionally substituted with one or more R7.

[0030] In one embodiment, the compound of Formula (I) is not 3-(tert-butylamino)-7-chloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide or a pharmaceutically acceptable salt thereof.

[0031] In one embodiment, the compound of formula (I) has the following formula (Ia): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A is C, B and D are each independently N, A and B or A and D are connected via a double bond or a single bond, R1 and R2 are hydrogen, fluorine, chlorine, bromine, and iodine, wherein A and B form a double bond, and R x is H, or A and D form a double bond, and R y is H and R3 is [ka] wherein R4 is selected from the group consisting of C1-C3 alkyl, ethynyl, C1-C2 alkoxy, (methoxy)-C1-C2 alkyl, cyano, fluoro, (methylsulfonyl)-C1-C2 alkyl, (dimethylamino)-C1-C2 alkyl, and n-methylcarbamoyl, optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro and hydroxy, with the proviso that the compound is not 3-(tert-butylamino)-7-chloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide. Regarding these compounds, the present inventors surprisingly found that they selectively bind to SUR1 / Kir6.2 and exhibit remarkable potency in inhibiting glucose-stimulated insulin secretion. The highly specific binding of these compounds to their targets results in reduced off-target effects. Furthermore, the compounds according to the present invention exhibit excellent bioavailability, stability, and safety, and can be administered orally.

[0032] In another embodiment, the compound of formula (I) has the following formula (Ib): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A, B, D, R1, R2, R5, R6, R x R y , R A , R B , R C , and R 7 has the same meaning as in formula (I).

[0033] In another embodiment, the compound of formula (I) has the following formula (Ic): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A, B, D, R1, R2, R5, R6, R x R y , R A , R B , R C , and R 7 has the same meaning as in formula (I), m is an integer of 0 to 12, and n is an integer of 0 to 4.

[0034] In another embodiment, the compound of formula (I) has the following formula (Id): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R1, R2, R5, R x , and R 7 has the same meaning as in formula (I), m is an integer of 0 to 12, and n is an integer of 0 to 4.

[0035] In another embodiment, the compound of formula (I) has the following formula (Ie): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R, R, R x , and R7 has the same meaning as in formula (I), m is an integer of 0 to 12, and n is an integer of 0 to 4.

[0036] In another embodiment, the compound of formula (I) has the following formula (If): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R, R, R x , and R 7 has the same meaning as in formula (I), m is an integer of 0 to 12, and n is an integer of 0 to 4.

[0037] In another embodiment, the compound of formula (I) has the following formula (Ig): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R1, R2, R5, R x , and R 7 has the same meaning as in formula (I), m is an integer of 0 to 12, and n is an integer of 0 to 4.

[0038] In another embodiment, the compound of formula (I) has the following formula (Ih): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R, R, R x , R B , R C , and R 7 has the same meaning as in formula (I).

[0039] In another embodiment, the compound of formula (I) has the following formula (Id): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R1, R2, R5, R B , R x , and R 7 has the same meaning as in formula (I), m is an integer of 0 to 12, and n is an integer of 0 to 4.

[0040] In one embodiment, the compounds of formula (I) described herein exhibit improved properties compared to compounds in the art. Known compounds cause severe side effects due to a lack of channel specificity. Furthermore, the response of patients suffering from HI, particularly CHI, varies significantly among patients, so that compounds already known in the prior art generally do not offer significant benefit to the patient population. This is believed to be due to the low specificity of the known compounds. Because the compounds of the present invention have high specificity, the response of patients suffering from HI, particularly CHI, is significantly improved.

[0041] It should be noted that with respect to the compounds according to the present invention, the compounds include all of their acid addition and base salts, tautomeric forms, metabolites, or prodrugs. The present invention further includes unsolvated and solvated forms, including hydrated forms, of the compounds of the present invention.

[0042] Preferred compounds according to the present invention are those in which the compound is according to general formula (I):

[0043] A is carbon (C), B and D are nitrogen (N); A and B or A and D are connected via a double or single bond, R1 and R2 are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine; A and B form a double bond, and R x is H, or A and D form a double bond, and R y is H, R3 is independently [ka] is selected from the group consisting of:

[0044] A second aspect of the present invention relates to a method for preparing a compound according to the present invention, said method comprising the steps of: a) providing a first compound according to formula (X) [ka] (In the formula, A is carbon (C), B and D are nitrogen (N); A and B or A and D are connected via a double or single bond, R1 and R2 are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine; A and B form a double bond, and R x is H, or A and D form a double bond, and R y is H, R4 is independently selected from the group consisting of fluorine, chlorine, bromine, and iodine, and is preferably chlorine; b) providing a second compound according to the formula H-R3, wherein R3 is [ka] wherein R4 is selected from the group consisting of C1-C3 alkyl optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro and hydroxy, ethynyl, C1-C2 alkoxy, (methoxy)-C1-C2 alkyl, cyano, fluoro, (methylsulfonyl)-C1-C2 alkyl, (dimethylamino)-C1-C2 alkyl, and n-methylcarbamoyl; c) reacting the first compound with the second compound under conditions that result in the formation of a compound of the invention.

[0045] In certain embodiments, the reaction is carried out in a solvent comprising a polar aprotic solvent such as dichloromethane, tetrahydrofuran, or dioxane, preferably dioxane.

[0046] In a preferred embodiment, the reaction is carried out at a temperature of 20°C to 200°C, preferably at a temperature of 30°C to 160°C.

[0047] In a preferred embodiment, the reaction is carried out in the presence of a base, preferably a sterically hindered base, more preferably a sterically hindered amine base, such as triethylamine or N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine.

[0048] A third aspect of the present invention relates to a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition according to the present invention also comprises, in addition to the compound according to the present invention, a pharmaceutically acceptable carrier and / or excipient.

[0049] Examples of categories of additives include, but are not limited to, binders, disintegrants, lubricants, glidants, fillers, and diluents. Those skilled in the art can select one or more of the above additives through routine experimentation without undue burden so that the granules and / or solid oral dosage forms have specific desired properties. The amount of each additive used can vary within the range conventional in the art.

[0050] The following references, incorporated herein by reference in their entireties, disclose techniques and excipients used to formulate oral dosage forms: See "The Handbook of Pharmaceutical Excipients," 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003), and "Remington: The Science and Practice of Pharmacy," 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2000).

[0051] A final aspect of the invention relates to the use of a compound or pharmaceutical composition according to the invention in the treatment of a subject, in particular a human subject, suffering from hyperinsulinism (HI), more particularly congenital hyperinsulinism (CHI).

[0052] In one embodiment, the compounds of the present disclosure are compounds shown in Table 1.

[0053] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0054] In one embodiment, the compound of formula (I) is [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0055] In a preferred embodiment, the compound of formula (I) is [ka] or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment, the compound of Formula (I) is Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 2 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 3 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 4 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 5 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 6 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 7 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 8 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 9 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 10 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 11 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 12 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 13 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 14 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 15 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 16 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 17 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 18 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 19 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 20 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 21 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 22 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula (I) is compound 23 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula (I) is compound 24 or a pharmaceutically acceptable salt thereof.In one embodiment, the compound of Formula (I) is Compound 25 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 26 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 27 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 28 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 29 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 30 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 31 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 32 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 33 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 34 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 35 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 36 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 37 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 38 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 39 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 40 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 41 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 42 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 43 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 44 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 45 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 46 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula (I) is compound 47 or a pharmaceutically acceptable salt thereof.In one embodiment, the compound of Formula (I) is Compound 48 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 49 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 50 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 51 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 52 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 53 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 54 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 55 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 56 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 57 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 58 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 59 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 60 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 61 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 62 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 63 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 64 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 65 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 66 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 67 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 68 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 69 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula (I) is compound 70 or a pharmaceutically acceptable salt thereof.In one embodiment, the compound of Formula (I) is Compound 71 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 72 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 73 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 74 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 75 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula (I) is Compound 76 or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the compounds of Formula (I) provided herein are not compounds disclosed in WO97 / 49692A, De Tullio P. et al. J Med Chem., 2003, 46:1, pp. 3342-3353. In some embodiments, the compounds provided herein do not include any of the compounds disclosed in Sharma BK et al., Int J Chem Sci., 2009, 7:2, pp. 655-671. In some embodiments, the compounds provided herein do not include any of the compounds disclosed in J. et al., ACS Catalysis. 2022, 12, pp. 6857-6873. In some embodiments, the compounds provided herein do not include any of the compounds disclosed in Vlaar, T. et al., Angew Chem Int Ed., 2012, 51, pp. 13058-13061. In some embodiments, the compounds provided herein do not include any of the compounds disclosed in De Tullio, P. et al., J Med Chem., 2005, 48, pp. 4990-5000.

[0058] In one embodiment, the compound is selected from the group consisting of WO1997049692A1, WO2002074945A1, WO2003087089A1, WO2003091245A1, WO2005063742A2, WO2006045799A2, WO2007125048A1, WO2010093243A1, WO2013130411A1, WO2014046172A1, WO201908 4271A1, WO2021236818A1, US4035374A, US20070254862A1, DE2757922A1, DE2757999A1, EP105732A2, EP112142A2, EP172968A1, EP355612A2, JP6284823B2, JP51054576A, or JP60072868A.

[0059] In one embodiment, the compound is selected from the group consisting of WO2003087089A1, WO2003091245A1, WO2004087053A2, WO2005058348A1, WO2005063742A2, WO2007053514A2, WO2007081521A2, WO2007136125A1, WO2009006483A1, WO2017098421A1, WO2 The compound is not a compound disclosed in WO2019084271A1, WO2021236818A1, WO1997049692A1, US4035374A, EP105732A2, EP112142A2, EP355612A2, EP386931A1, JP2015214525A, JP2016011275A, JP3254698A, or JP60112781A.

[0060] In one embodiment, the compound is selected from the group consisting of WO2006025857A2, WO2006069806A1, WO2000037474A1, WO2001002410A1, WO2002000222A1, WO2002000665A1, WO2002050085A1, WO2003045954A1, WO2003045955A1, WO2003105896A1, WO2004005 299A1, WO2005013962A1, WO2006045799A2, WO2006088798A2, WO2007020286A2, WO2007125048A1, WO2009000038A1, WO2022125784A1, WO1997026265A1, DK200400395A, or US20070254862A1.

[0061] In one embodiment, the compound is not a compound disclosed in WO2000037474A1, WO2001002410A1, WO2002000222A1, WO2002050085A1, WO2003045954A1, WO2003045955A1, WO2003087089A1, WO2003091245A1, WO2003105896A1, WO1999003861A1, WO1999032494A1, or DK200400395A.

[0062] definition Specific Chemical Definitions Definitions of specific functional groups and chemical terms are set forth in more detail below. Chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thThe general principles of organic chemistry and specific functional groups are generally defined as described therein. Also, general principles of organic chemistry and specific functional sites and reactivities are defined in accordance with Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0063] The abbreviations used herein have their usual meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0064] When a range of values ​​is expressed, it is intended to include each value and subrange within that range. For example, "C1-C6 alkyl" is intended to include C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C2-C6 alkyl, C2-C5 alkyl, C2-C4 alkyl, C2-C3 alkyl, C3-C6 alkyl, C3-C5 alkyl, C3-C4 alkyl, C4-C6 alkyl, C4-C5, and C5-C6 alkyl.

[0065] The following terms are intended to have the meanings indicated below and are helpful in understanding the description and intended scope of the present invention.

[0066] As used herein, "alkyl" refers to the radical of a straight- or branched-chain saturated hydrocarbon group having from 1 to 24 carbon atoms ("C1-C 24 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C 12 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C2-C6 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each example of an alkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl"), or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C1 to C8 10 Alkyl (e.g., —CH3). In certain embodiments, the alkyl group is a substituted C1-C6 alkyl.

[0067] As used herein, "alkenyl" refers to the radical of a straight or branched chain hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon double bonds and no triple bonds ("C2-C 24 In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C-C10 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., as in 2-butenyl) or terminal (e.g., as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the C2-C6 alkenyl groups described above. 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each example of an alkenyl group independently can be optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C1-C 10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-C6 alkenyl.

[0068] As used herein, the term "alkynyl" refers to a radical of a straight- or branched-chain hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2-C 24 In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C-C 10In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., as in 2-butynyl) or terminal (e.g., as in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Each instance of an alkynyl group independently can be optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~6 It is alkynyl.

[0069] As used herein, the term "haloalkyl" refers to a stable acyclic, straight or branched chain, or combination thereof, containing at least one carbon atom and at least one halogen selected from the group consisting of F, Cl, Br, and I. The halogen(s) F, Cl, Br, and I can be present at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to, -CF, -CCl, -CH-CF, -CH-CCl, -CH-CBr, -CH-CI, -CH-CH-CH(CF)-CH, -CH-CH-CH(Br)-CH, and -CH-CH=CH-CH-CF. Each instance of haloalkyl can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted haloalkyl"), or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted haloalkyl").

[0070] As used herein, the term "heteroalkyl" refers to a stable acyclic straight or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatom(s) O, N, P, S, and Si can be present at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A "heteroalkyl" may be followed by a particular heteroalkyl group, e.g., -CHO, -NR C R D etc., it will be understood that the term heteroalkyl and -CH2O or -NR C R D are neither redundant nor mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" refers to specific heteroalkyl groups, e.g., -CHO, -NR C R D etc. Each example of a heteroalkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted heteroalkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted heteroalkyl").

[0071] As used herein, "cycloalkyl" refers to a group having 3 to 10 ring carbon atoms in a non-aromatic ring system ("C3-C 10 "Cycloalkyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having no heteroatoms. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10 Cycloalkyl groups can be described, for example, as C4-C7 membered cycloalkyl, where the term "member" refers to a non-hydrogen ring atom in the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the aforementioned C3-C6 cycloalkyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. 10 The cycloalkyl group may be any of the above-mentioned C3 to C8 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the foregoing examples illustrate, in certain embodiments, a cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or includes fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused with one or more aryl groups (where the point of attachment is on the cycloalkyl ring). In such instances, the number of carbons still refers to the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group, independently, may be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C6 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0072] As used herein, "heterocyclyl" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, as valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups (where the point of attachment is on either the cycloalkyl ring or the heterocyclyl ring), or ring systems in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocyclyl ring). In such instances, the number of ring members still refers to the number of ring members in the heterocyclyl ring system. A heterocyclyl group can be described, for example, as a 3- to 7-membered heterocyclyl, where the term "member" refers to the non-hydrogen ring atoms in the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of heterocyclyl can independently be optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0073] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin-2-onyl), and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclyl rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,5-bicyclic heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups (also referred to as 4,6-membered heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as 6,7-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as 6,8-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0074] As used herein, the term "cyano" or "-CN" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, eg, C≡N.

[0075] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0076] As used herein, the term "nitro" refers to a substituent having two oxygen atoms attached to a nitrogen atom, e.g., --NO.sub.2.

[0077] As used herein, "oxo" refers to carbonyl, i.e., --C(O)--.

[0078] Symbols used herein for compounds of formula (I) [ka] refers to the point of attachment to another moiety or functional group within the compound.

[0079] Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, and heterocyclyl groups defined herein can be optionally substituted. Generally, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced with a possible substituent (e.g., a substituent that, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction)). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group; when multiple positions in any particular structure are substituted, the substituents are the same or different at each position. The term "substituted" is intended to encompass substitution with all possible substituents of organic compounds (e.g., any of the substituents described herein that result in the formation of a stable compound). The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0080] Two or more substituents may optionally be linked to form a cycloalkyl or heterocyclyl group. Such so-called ring-forming substituents are typically, but not necessarily, attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure form a spiro ring structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0081] The compounds provided herein may exist in one or more specific geometric isomers, optical isomers, enantiomers, diastereomers, epimers, stereoisomers, tautomers, conformers, or anomeric forms, including, but not limited to, cis and trans, E and Z, endo and exo, R, S and meso, D and L, d and l, (+) and (-), keto, enol and enolate, syn and anti, synclinal and anticlinal, α and β, axial and equatorial, boat, chair, twisted, envelope and half-chair forms, and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0082] The compounds described herein may contain one or more asymmetric centers and therefore may exist as various isomers, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, such as racemic mixtures and mixtures enriched in one or more stereoisomers. In one embodiment, the stereochemistry depicted in a compound is relative rather than absolute. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0083] As used herein, an enantiomerically pure compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). That is, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" indicate that a compound contains greater than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% of an enantiomer by weight. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0084] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound may contain, for example, about 90% additives and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may contain, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound may contain, for example, about 90% additives and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may contain, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound.

[0085] In some embodiments, diastereomerically pure compounds may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising a diastereomerically pure exo compound may contain, for example, about 90% additive and about 10% diastereomerically pure exo compound. In certain embodiments, the diastereomerically pure exo compound in such a composition may contain, for example, at least about 95% by weight of the exo compound and at most about 5% by weight of the endo compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising a diastereomerically pure endo compound may contain, for example, about 90% additive and about 10% by weight of the diastereomerically pure endo compound. In certain embodiments, the diastereomerically pure endo compound in such a composition may contain, for example, at least about 95% by weight of the endo compound and at most about 5% by weight of the exo compound, based on the total weight of the compound.

[0086] In some embodiments, isomerically pure compounds may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an isomerically pure exo compound may contain, for example, about 90% additive and about 10% isomerically pure exo compound. In certain embodiments, the isomerically pure exo compound in such a composition may contain, for example, at least about 95% by weight of the exo compound and at most about 5% by weight of the endo compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an isomerically pure endo compound may contain, for example, about 90% additive and about 10% isomerically pure endo compound. In certain embodiments, the isomerically pure endo compound in such a composition may contain, for example, at least about 95% by weight of the endo compound and at most about 5% by weight of the exo compound, based on the total weight of the compound.

[0087] In certain embodiments, the active ingredient can be formulated with little or no excipients or carriers.

[0088] The compounds described herein may contain one or more isotopic substitutions. For example, H is 1 H, 2 H (D or deuterium), and 3 H (T or tritium) and C can be any isotope, 12 C. 13 C, and 14 C can be any isotope, including O 16 O and 18 can be any isotope including O, and N is 14 N and 15 It can be any isotope containing N, and F is 18 F, 19 It can be any isotope, including F.

[0089] As used herein, the term "pharmaceutical composition" has its ordinary meaning and refers to a pharmaceutically acceptable composition.

[0090] As used herein, the term "pharmaceutically acceptable" has its ordinary meaning and refers to compounds, materials, compositions, and / or dosage forms that are within the bounds of safe medical judgment suitable for contact with the tissues of mammals, particularly humans, without undue toxicity, irritation, allergic response, and untoward complications, commensurate with a reasonable benefit / risk ratio.

[0091] The term "pharmaceutically acceptable salt" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents present on the compounds described herein.When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts.When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galactunolonic acid (see, for example, Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present invention contain both basic and acidic functional groups, and such functional groups allow the compounds to be converted into either base or acid addition salts. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those skilled in the art are also suitable for the present invention.

[0092] The term "tautomer" refers to interchangeable forms of a particular compound structure that differ in the arrangement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of a tautomer is the aci and nitro forms of phenylnitromethane, which are also formed by treatment with acid or base. Tautomers may be appropriate to achieve optimal chemical reactivity and biological activity of a compound of interest.

[0093] A "metabolite" of a compound of the invention is an active derivative of a compound according to the invention produced when the compound is metabolized.

[0094] A "prodrug" is a compound that is converted in vivo into a disclosed compound of the present invention or has the same active metabolite as a disclosed compound of the present application.

[0095] Other definitions The following definitions are of more general terms used throughout this disclosure.

[0096] The articles "a" and "an" refer to one or to more than one (e.g., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. The term "and / or" means either "and" or "or" unless otherwise specified.

[0097] The term "about" is used herein to mean within a typical tolerance in the art. For example, "about" can be interpreted as about 2 standard deviations from the mean. In certain embodiments, about means +10%. In certain embodiments, about means +5%. When "about" is present before a series of numbers or ranges, it is understood that "about" can modify each of the numbers in the series or range.

[0098] As used herein, "obtaining" or "obtaining" refers to obtaining a value (e.g., a numerical value) or an image, or a physical entity (e.g., a sample), either by "directly obtaining" or "indirectly obtaining" the value or physical entity. "Directly obtaining" means performing a process (e.g., running an analytical method or protocol) to obtain the value or physical entity. "Indirectly obtaining" refers to receiving the value or physical entity from another party or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Directly obtaining a value or physical entity includes performing a process that involves a physical change of a physical entity or performing a process that involves the use of a machine or device. An example of directly obtaining a value is obtaining a sample from a human subject. Directly obtaining a value includes performing a process that uses a machine or device, for example, performing a process to obtain mass spectrometry data using a mass spectrometer.

[0099] The terms "administer," "administering," or "administration," as used herein, refer to implantation, absorption, ingestion, injection, inhalation, or otherwise introduction of a compound of the present invention or a pharmaceutical composition thereof.

[0100] The terms "disease" and "disorder" are used interchangeably herein.

[0101] The "effective amount" of the compound of formula (I) refers to an amount sufficient to produce a desired biological response, i.e., an amount sufficient to treat a disease. As will be apparent to those skilled in the art, the effective amount of the compound of formula (I) may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the method of administration, and the age and health of the subject. The effective amount includes therapeutic and prophylactic treatments. For example, in the treatment of cancer, an effective amount of the compound of the present invention may reduce tumor burden or stop tumor growth or spread.

[0102] A "therapeutically effective amount" of a compound of Formula (I) is an amount sufficient to provide a therapeutic effect in the treatment of a disease or to delay or minimize one or more symptoms associated with the disease. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic effect in the treatment of a disease or to minimize one or more symptoms associated with the disease. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic effect in the treatment of a disease. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease, or enhances the therapeutic effect of another therapeutic agent.

[0103] "Prevention," "prevent," and "preventing," as used herein, refer to treatment that includes administering a therapy (e.g., administering a compound described herein (e.g., a compound of Formula (I))) prior to the onset of a disease, disorder, or condition to prevent the physical manifestation of the disease, disorder, or condition. In some embodiments, "prevention," "prevent," and "preventing" require that signs or symptoms of the disease, disorder, or condition are not present or observed. In some embodiments, treatment includes prevention, and in other embodiments, does not include prevention.

[0104] "Subjects" to which administration is intended include, but are not limited to, humans (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or elderly adult)) and / or other non-human animals, such as mammals (e.g., commercially important mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially important birds such as chickens, ducks, geese, and / or turkeys). In certain embodiments, the animal is a mammal. The animal may be male or female and at any stage of development. The non-human animal may be a transgenic animal.

[0105] As used herein, the terms "treatment," "treat," and "treating" refer to ameliorating, alleviating, delaying the onset of, or inhibiting the progression of one or more of the symptoms, manifestations, or underlying causes of a disease, disorder, or condition (e.g., as described herein), for example, by administering a therapy (e.g., administering a compound described herein (e.g., a compound of Formula (I))). In one embodiment, treating includes alleviating, alleviating, or relieving a symptom of a disease, disorder, or condition, delaying the onset of a symptom of a disease, disorder, or condition, or inhibiting the progression of a symptom of a disease, disorder, or condition. In one embodiment, treating includes alleviating, alleviating, or relieving a symptom of a disease, disorder, or condition, delaying the onset of a symptom of a disease, disorder, or condition, or inhibiting the progression of a symptom of a disease, disorder, or condition. In one embodiment, treating includes reducing, alleviating, alleviating, reducing, or delaying the onset of a symptom of a disease, disorder, or condition. In some embodiments, "treatment," "treat," and "treating" require that signs or symptoms of a disease or disorder have occurred or are recognized. In other embodiments, treatment can be performed in the absence of signs or symptoms of disease, e.g., in prophylactic treatment. For example, treatment can be performed in an individual who is predisposed to a disease before the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, e.g., to delay or prevent recurrence. Treatment can also be continued after symptoms have resolved, e.g., to delay or prevent recurrence. In some embodiments, treatment includes prevention, while in other embodiments it does not include prevention.

[0106] The term "control" is intended to refer to any process that can slow, interrupt, temporarily halt, or stop the progression of a disease or condition from which a mammal is afflicted. However, "control" does not necessarily indicate the complete elimination of all symptoms of the disease or condition, and is intended to include prophylactic treatment.

[0107] As used herein, the term "carrier" has its ordinary meaning and refers to a pharmaceutically acceptable diluent, adjuvant, excipient, or vehicle with which a pharmaceutically active ingredient is administered.

[0108] As used herein, the term "excipient" has its ordinary meaning and refers to a pharmaceutically acceptable ingredient commonly used in the pharmaceutical arts for preparing granular, solid, or liquid formulations.

[0109] The term "persistent or recurrent congenital hyperinsulinism (CHI)" encompasses forms of hyperinsulinism (HI) that persist despite continuous glucose administration, which may occur in newborns and children due to certain genetic mutations or due to some other metabolic disorder known or unknown to those skilled in the art.

[0110] The term "transient CHI" encompasses forms of HI that can occur during fetal, neonatal, and childhood due to genetic mutations and / or perinatal stress (e.g., preterm birth, intrauterine growth retardation, small for gestational age, or perinatal asphyxia), or due to any other metabolic disorder known or unknown to those skilled in the art.

[0111] How to use Disclosed herein are methods for treating diseases or disorders with a compound, such as a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Exemplary diseases or disorders can include metabolic disorders (e.g., CHI), cancer, neurological disorders, cardiovascular diseases, pulmonary disorders, skin disorders, sexual disorders, urinary disorders, or symptoms thereof.

[0112] In some embodiments, the disease or disorder is a metabolic disorder. In some embodiments, the metabolic disorder is hyperinsulinism (HI), congenital hyperinsulinism (CHI), persistent hyperinsulinism, or transient hyperinsulinism. In some embodiments, the metabolic disorder is a hyperinsulinism-related syndrome, such as Beckwith-Wiedemann syndrome, hyperinsulinism-hyperammonemia (HIHA) syndrome, Sotos syndrome, Turner syndrome, Costello syndrome, or Kabuki syndrome. Glucose is an important energy source for mammals; it is transported from the intestine or liver to body cells via the bloodstream and made available for cellular metabolism through the secretion of the hormone insulin. A precise mechanism, called glucose homeostasis, allows the body of a healthy human subject to maintain glucose concentrations within a desirable range of approximately 3.5 to 5.5 mmol / L. Blood glucose levels outside this normal range can be an indicator of medical disease.

[0113] The primary hormones involved in regulating glucose metabolism on a timescale of several hours are insulin and glucagon, which are secreted by pancreatic islets and both are secreted in response to blood glucose levels, but have opposing actions.

[0114] Insulin is an important peptide hormone involved in nutrient homeostasis and is produced by the beta cells of pancreatic islets. Insulin regulates carbohydrate and fat metabolism by promoting glucose transport from the blood to skeletal muscle and adipose tissue. The general stimulus for insulin secretion is hyperglycemia. Although the level of insulin secreted by the pancreas is always low, the amount secreted into the blood increases as blood glucose levels rise.

[0115] On the other hand, when glucose levels are low, glucagon secretion increases and insulin secretion decreases. The most important effect of increased glucagon is to induce the liver to release glucose stored in its cells (as the polymer glycogen) into the bloodstream. The net effect of this glucose release is an increase in blood glucose concentration. Furthermore, glucagon also induces the liver and other cells to produce glucose from components obtained from other nutrients (e.g., proteins) present in the body.

[0116] Blood glucose levels outside the normal range can be an indicator of medical disease. Persistently high levels are called hyperglycemia, and low levels are called hypoglycemia. One particular disorder associated with dysfunction of glucose homeostasis is hyperinsulinism.

[0117] Hyperinsulinism (HI) is defined as elevated blood insulin levels due to dysregulated insulin release from beta cells, resulting in hypoglycemia. It can be genetic or acquired and can be transient or permanent. Hyperinsulinemic hypoglycemia (HH) is a clinically, genetically, and morphologically heterozygous disorder in which insulin secretion persists despite low blood glucose levels. The most severe and persistent form of HH is due to congenital hyperinsulinism.

[0118] Congenital hyperinsulinism (CHI) is a genetic form of hyperinsulinism-hypoglycemia (HH) caused by mutations in genes involved in regulating insulin secretion. CHI is a persistent form of hypoglycemia in newborns, infants, and children, leading to irreversible brain damage due to the secondary metabolic effects of insulin. Excessive release of insulin leads to the suppression of lipolysis and the depletion of ketones, an alternative energy source for the brain. Elevated insulin levels also inhibit the secretion of glucagon, which prevents the breakdown of fat and causes direct brain damage. Thus, up to 48% of children with recurrent hypoglycemia suffer from brain damage.

[0119] The genetic basis of CHI is associated with 23 mutations in essential genes that control insulin secretion; two of these genes, ABCC8 and KCNJ11, are involved in the K ATP This gene encodes the channel proteins SUR1 and Kir6.2, and among other proteins, regulates the release of insulin from pancreatic beta cells.

[0120] In some embodiments, the metabolic disorder is obesity, e.g., hypothalamic obesity. In some embodiments, the metabolic disorder is diabetes, e.g., type 1 diabetes or type 2 diabetes, or stage 1 diabetes or prediabetic syndrome. In some embodiments, the metabolic disorder is a genetic or epigenetic disorder, e.g., Prader-Willi syndrome, Alström syndrome, Bardet-Biedl syndrome, or Smith-Magenis syndrome. In some embodiments, the metabolic disorder is Prader-Willi syndrome. In some embodiments, the metabolic disorder is Alström syndrome. In some embodiments, the metabolic disorder is Bardet-Biedl syndrome. In some embodiments, the metabolic disorder is Smith-Magenis syndrome. In one embodiment, the disease or disorder is ischemia.

[0121] In some embodiments, the disease or disorder is alopecia or baldness.

[0122] In some embodiments, the methods described herein directly or indirectly reduce or alleviate at least one symptom of a disease or disorder (eg, a disease or disorder described herein).

[0123] In some embodiments, the methods described herein can treat or alleviate at least one symptom of a metabolic disorder, e.g., an increase in waist circumference of at least 2 cm relative to a baseline (e.g., waist circumference in a subject before the onset of a metabolic disorder), increased blood pressure relative to a baseline (e.g., blood pressure in a subject before the onset of a metabolic disorder), hyperglycemia or increased fasting blood glucose relative to a baseline (e.g., fasting blood glucose in a subject before the onset of a metabolic disorder), increased thirst (e.g., increased thirst compared to a baseline (e.g., level of thirst in a subject before the onset of a metabolic disorder)), increased fatigue (e.g., increased fatigue relative to a baseline (e.g., level of fatigue in a subject before the onset of a metabolic disorder)), or increased urination (e.g., increased urination relative to a baseline (e.g., frequency or volume of urination in a subject before the onset of a metabolic disorder)).

[0124] In some embodiments, the methods described herein can prevent or delay the onset of a disease or disorder (eg, a metabolic disorder).

[0125] In some embodiments, the subject may have a comorbid condition, such as obesity, overeating or overeating-related syndrome, unwanted appetite, hypoglycemia, hyperglycemia, hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia. In some embodiments, the metabolic disorder is hyperinsulinemia, such as chronic hyperinsulinemia (CHI). In some embodiments, the metabolic disorder is prediabetes, type I diabetes, or type II diabetes. In some embodiments, the metabolic disorder is diabetic disease.

[0126] In some embodiments, the subject may have undergone a surgical intervention, for example, bariatric surgery.

[0127] In some embodiments, the methods described herein can treat metabolic disorders.In some embodiments, the methods described herein can cause a counterregulatory response to hypoglycemia in subjects with diabetes, for example, type I diabetes or type II diabetes.In some embodiments, the methods described herein can be useful in combination with a second drug (for example, sulfonylurea before rapid administration (bolus administration)) to restore normal insulin levels in subjects, for example, subjects with diabetes, for example, type I diabetes or type II diabetes.

[0128] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a gastrointestinal cancer, such as esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, gallbladder cancer, colorectal cancer, anal cancer, or gastrointestinal carcinoid tumor. In some embodiments, the gastrointestinal cancer is esophageal cancer. In some embodiments, the gastrointestinal cancer is gastric cancer. In some embodiments, the gastrointestinal cancer is pancreatic cancer. In some embodiments, the gastrointestinal cancer is pancreatic cancer, and the pancreatic cancer is insulinoma. In some embodiments, the gastrointestinal cancer is liver cancer. In some embodiments, the gastrointestinal cancer is gallbladder cancer. In some embodiments, the gastrointestinal cancer is colorectal cancer. In some embodiments, the gastrointestinal cancer is anal cancer. In some embodiments, the gastrointestinal cancer is a gastrointestinal cancer.

[0129] In some embodiments, the disease or disorder is a neurological disorder, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, migraine (e.g., chronic migraine), epilepsy, and epilepsy-related syndromes.

[0130] In some embodiments, the methods described herein directly or indirectly reduce or alleviate at least one symptom of a disease or disorder (e.g., a neuropathy or neurological disease described herein). In some embodiments, the methods directly or indirectly reduce or alleviate pain or assist in pain management, i.e., the methods described herein function directly or indirectly in the relief of pain from a disease or disorder (e.g., a neuropathy).

[0131] In some embodiments, the methods described herein directly or indirectly alleviate the symptoms of a disease or disorder (e.g., a neurological disorder). In some embodiments, the methods described herein provide neuroprotection in a subject in need thereof (e.g., a subject with a neurological disorder, e.g., Alzheimer's disease, Parkinson's disease, or multiple sclerosis).

[0132] In some embodiments, the disease or disorder is a cardiovascular disease, such as ischemia, ischemia-reperfusion injury, hypertension, coronary artery spasm, intraocular pressure, peripheral vascular disease, hi some embodiments, the cardiovascular disease is angina pectoris, heart failure, ventricular septal defect, atrial fibrillation, arrhythmia, coronary artery disease, or myocardial stunning.

[0133] In some embodiments, the methods described herein provide cardioprotection in a subject in need thereof (e.g., a subject with a cardiovascular disease, e.g., angina pectoris, heart failure, ventricular septal defect, atrial fibrillation, arrhythmia, coronary artery disease, or myocardial stunning).

[0134] In some embodiments, the disease or disorder is a pulmonary disorder, eg, pulmonary hypertension or asthma.

[0135] In some embodiments, the disease or disorder is a dermatological disorder, particularly a disorder of hair, skin, and nails, hi some embodiments, the disease or disorder is alopecia, baldness, e.g., male pattern baldness, or a disorder of hair follicle growth.

[0136] In some embodiments, the disease or disorder is a sexual disorder, eg, male impotence.

[0137] In some embodiments, the disease or disorder is a urinary disorder, eg, detrusor hypersensitivity.

[0138] In one embodiment, the subject is a mammal, for example, a human. In one embodiment, the subject is an adult (e.g., 18 years of age or older) or a child (e.g., under 18, 12, 10, 8, 6, 4, or 2 years of age). In one embodiment, the subject has previously been treated for a metabolic disorder. For example, the subject may be a bariatric surgery patient.

[0139] Route of administration and dosage The compounds and compositions according to the methods of the present invention may be administered in any amount and using any route of administration effective for treating or reducing the severity of the above-mentioned disorders. The exact amount required may vary from subject to subject, depending on the subject's race, age, and general condition, the severity of the infection, the particular drug, its mode of administration, and the like. The compounds of the present invention are preferably formulated into unit dosage forms for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically discrete pharmaceutical unit appropriate for the patient being treated. However, it will be understood that the total daily dosage of the compounds and compositions of the present invention may be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage for any particular patient or organism will vary depending on a variety of factors, including the disorder and severity of the disorder being treated, the activity of the particular compound employed, the particular composition employed, the patient's age, weight, general health, sex, and diet, the time of administration, route of administration, and excretion rate of the particular compound employed, the duration of treatment, drugs used in combination with or concurrently with the particular compound employed, and similar factors well known in the medical field.

[0140] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., via powder, ointment, or eye drops), bucally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention are administered orally or parenterally, one or more times daily, at a dosage of about 0.01 mg / kg to about 100 mg / kg of subject body weight, preferably about 1 mg / kg to about 50 mg / kg of subject body weight per day, to achieve the desired therapeutic effect.

[0141] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art. Such diluents include, for example, water or other solvents, solubilizers and emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof). In addition to inert diluents, oral compositions may also contain auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0142] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be prepared according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions using non-toxic parenterally acceptable diluents or solvents (e.g., 1,3-butanediol solutions). Usable vehicles and solvents include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any mixed fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid can be used in the preparation of injectable preparations.

[0143] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0144] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound dosage form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot dosage forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer employed. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in tissue-compatible microemulsions or liposomes.

[0145] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a compound of the present invention with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or a suppository wax) that is solid at ordinary temperatures but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0146] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier. For example, such excipients or carriers are sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also optionally contain buffering agents.

[0147] Solid compositions of a similar type are also used as fillers in soft- and hard-filled gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art). They optionally contain opacifying agents and can also be composed so as to release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type are also used as fillers in soft- and hard-filled gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0148] The active compound may also be in microencapsulated form containing one or more of the above-mentioned additives. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (e.g., enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art). In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, starch, etc. Such dosage forms also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms also optionally contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0149] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. The present invention also contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0150] List of embodiments 1. Formula (I) [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein: A is C(R'), each of B and D is independently N; A and B or A and D are connected via a double bond or a single bond; Each of R1, R2, R5, and R6 independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR A , fluorine, chlorine, bromine, iodine, nitro, or cyano, wherein A and B form a double bond, and R x is hydrogen, or A and D form a double bond, and R y is hydrogen, R3 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(RB )(R C wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R4; R' is absent, hydrogen, or C1-C6 alkyl; each R4 is independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, fluorine, chlorine, bromine, or iodine; R A is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; R B and R C each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R7; or R B and R C and together, one or more R 7 forming an optionally substituted heterocyclyl with Each R 7 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR A , fluorine, chlorine, bromine, iodine, nitro, or cyano, or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof.

[0151] 2. Each of R1 and R2 is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR A , fluorine, chlorine, bromine, iodine, nitro, or cyano.

[0152] 3. The compound of any one of the preceding embodiments, wherein each of R1 and R2 is independently hydrogen, fluorine, chlorine, bromine, iodine, or cyano.

[0153] 4. The compound of any one of the preceding embodiments, wherein each of R1 and R2 is independently hydrogen, fluorine, or chlorine.

[0154] 5. A compound of any one of the preceding embodiments, wherein R1 is hydrogen and R2 is fluorine, chlorine, bromine, iodine, nitro, or cyano.

[0155] 6. The compound of any one of the preceding embodiments, wherein R2 is fluorine, chlorine, bromine, iodine, nitro, or cyano; R2 is fluorine, chlorine, bromine, iodine, nitro, or cyano.

[0156] 7. A compound of any one of the preceding embodiments, wherein R1 is hydrogen and R2 is fluorine.

[0157] 8. A compound of any one of the preceding embodiments, wherein R1 is hydrogen and R2 is chlorine.

[0158] 9. The compound of any one of the preceding embodiments, wherein R1 is chlorine and R2 is fluorine.

[0159] 10. The compound of any one of the preceding embodiments, wherein each of R1 and R2 is independently fluorine.

[0160] 11. A compound of any one of the preceding embodiments, wherein R5 is H.

[0161] 12. A compound of any one of the preceding embodiments, wherein R6 is H.

[0162] 13. R3 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(R B )(R C ) each of which is optionally substituted with one or more R7.

[0163] 14. A compound of any one of the preceding embodiments, wherein R3 is C1-C6 heteroalkyl optionally substituted with one or more R7.

[0164] 15. A compound of any one of the preceding embodiments, wherein R3 is C1-C6 haloalkyl optionally substituted with one or more R7.

[0165] 16. A compound of any one of the preceding embodiments, wherein R3 is cycloalkyl optionally substituted with one or more R7.

[0166] 17. A compound of any one of the preceding embodiments, wherein R3 is heterocyclyl optionally substituted with one or more R7.

[0167] 18.R3 is N(R B )(R C )

[0168] 19.R B and R C and together, one or more R 7 19. The compound of embodiment 18, wherein R forms an optionally substituted heterocyclyl (eg, a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, or a bridged heterocyclyl).

[0169] 20.R B 19. The compound of embodiment 18, wherein is hydrogen.

[0170] 21.R C The compound of any one of embodiments 18-20, wherein R is C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, C-C haloalkyl, cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R.

[0171] 22.R C The compound of any one of embodiments 18-21, wherein is C1-C6 alkyl optionally substituted with one or more R7.

[0172] 23.R C The compound of any one of embodiments 18-21, wherein is C1-C6 heteroalkyl optionally substituted with one or more R7.

[0173] 24.R C The compound of any one of embodiments 18-21, wherein is C1-C6 haloalkyl optionally substituted with one or more R7.

[0174] 25.R C The compound of any one of embodiments 18-21, wherein is cycloalkyl (eg, monocyclic cycloalkyl, bicyclic cycloalkyl) optionally substituted with one or more R7.

[0175] 26.R C The compound of any one of embodiments 18-21, wherein is heterocyclyl optionally substituted with one or more R7.

[0176] 27. R7 is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR A 27. The compound of any one of embodiments 21-26, wherein R is fluorine, chlorine, bromine, iodine, nitro, or cyano.

[0177] 28. The compound has the following formula (Ia): [ka] is a compound of the formula A is carbon (C), B and D are nitrogen (N); A and B or A and D are connected via a double bond, R1 and R2 are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine; A and B form a double bond, and R x is H, or A and D form a double bond, and R y is H, R3 is independently [ka] wherein R4 is selected from the group consisting of C1-C3 alkyl optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro and hydroxy, ethynyl, C1-C2 alkoxy, (methoxy)-C1-C2 alkyl, cyano, fluoro, (methylsulfonyl)-C1-C2 alkyl, (dimethylamino)-C1-C2 alkyl, and n-methylcarbamoyl.

[0178] 29. A is carbon (C), B and D are nitrogen (N); A and B or A and D are connected via a double or single bond, R1 and R2 are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine; A and B form a double bond, and R x is H, or A and D form a double bond, and R y is H, R3 is independently [ka] The compound of any one of the preceding embodiments, selected from the group consisting of:

[0179] 30. The compound has the following formula (Ib): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A, B, D, R1, R2, R5, R6, R x , R y , R A , R B , R C , and R 7 is defined as for formula (I).

[0180] 31. The compound has the following formula (Ic): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A, B, D, R1, R2, R5, R6, R x , R y , R A , R B , R C , and R 7 is defined as for formula (I), m is an integer from 0 to 12, and n is an integer from 0 to 4.

[0181] 32. The compound has the following formula (Ie): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R, R, R x , and R 7 is defined as for formula (I), m is an integer from 0 to 12, and n is an integer from 0 to 4.

[0182] 33. The compound has the following formula (If): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R, R, R x , and R 7 is defined as for formula (I), m is an integer from 0 to 12, and n is an integer from 0 to 4.

[0183] 34. The compound is [ka] [ka] The compound of any one of the preceding embodiments, wherein the compound is selected from the group consisting of:

[0184] 35. The compound of any one of the preceding embodiments, wherein said compound is one shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0185] 36. A pharmaceutical composition comprising a compound of any one of the preceding embodiments and a pharmaceutically acceptable excipient.

[0186] 37. A method of treating a disease or disorder in a subject with a compound of any one of embodiments 1 to 35, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 36.

[0187] 38. The method of embodiment 37, wherein the disease or disorder is selected from a metabolic disorder (e.g., CHI), cancer, a neurological disorder, a cardiovascular disease, a pulmonary disorder, a skin disorder, a sexual disorder, a urinary disorder, or a symptom thereof.

[0188] 39. The method of any one of embodiments 37-38, wherein said disease or disorder is a metabolic disorder.

[0189] 40. The method of any one of embodiments 37-38, wherein said metabolic disorder is hyperinsulinism, e.g., congenital hyperinsulinism (CHI).

[0190] 41. The method of any one of embodiments 37-40, wherein said subject has been diagnosed or identified as having said disease or disorder.

[0191] 42. The method of any one of embodiments 37-42, wherein the subject is a mammal (e.g., a human).

[0192] 43. The method of any one of embodiments 37-42, wherein said compound or pharmaceutical composition is formulated for oral or intravenous administration.

[0193] 44. The method of embodiment 43, wherein said compound or pharmaceutical composition is in a solid dosage form, in particular an oral dosage form (e.g., a tablet or capsule).

[0194] 45. A method for preparing a compound according to any one of embodiments 1 to 6, comprising: a) providing a first compound according to formula (X) [ka] (In the formula, A is carbon (C), B and D are nitrogen (N); A and B or A and D are connected via a double or single bond, R1 and R2 are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine; A and B form a double bond, and R x is H, or A and D form a double bond, and R y is H, R4 is independently selected from the group consisting of fluorine, chlorine, bromine, and iodine, and is preferably chlorine; b) providing a second compound according to the formula H-R3, wherein R3 is [ka] wherein R4 is selected from the group consisting of C1-C3 alkyl optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro and hydroxy, ethynyl, C1-C2 alkoxy, (methoxy)-C1-C2 alkyl, cyano, fluoro, (methylsulfonyl)-C1-C2 alkyl, (dimethylamino)-C1-C2 alkyl, and n-methylcarbamoyl; c) reacting the first compound with the second compound under conditions that result in the formation of a compound of any one of embodiments 1 to 35. [Example]

[0195] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: As will be apparent, while the general methods are illustrated for the synthesis of certain specific compounds of the invention, the following general methods, and others known to those of skill in the art, are applicable to all compounds described herein, as well as to the species and subspecies of each such compound.

[0196] 1 H and 1 H{ 19 F}NMR: 1 H NMR and 1 H{ 19 {F} NMR spectra were recorded on a Bruker Ultrashield (400 MHz). Chemical shifts are reported in ppm. The signal multiplicities are indicated by the following abbreviations: br s broad singlet, s singlet, d doublet, t triplet, q quartet, dd doublet of doublet, dt doublet of triplet, m multiplet. All observed coupling constants J are reported in Hertz (Hz). Measurement of exchangeable protons is not always possible.

[0197] LC / MS: Condition 1: LC-MS data was generated using a Waters 2695e system (Waters PDA2998 detector, Waters QDA detector (ESI), Sedere SEDEX80 (light scattering detector)).

[0198] LC-MS method: reversed-phase HPLC analysis, column: Agilent: Poroshell, length: 100 mm, inner diameter: 4.6 mm, particle size: 4 μm, solvent A: water containing formic acid (0.1% V / V), solvent B: acetonitrile, UV detection: 220 nm [Table 6] Condition 2: LC / MS data were generated using a Waters Acquity UPLC Class I (Waters PDA eλ detector, Waters SQD2 MS detector, Sedere SEDEX80 (light scattering detector)). LC / MS method: reversed-phase HPLC analysis; column: Waters Acquity Premier CSH C18, length: 100 mm, internal diameter: 2.1 mm, particle size: 1.7 μm; solvent A: water containing formic acid (0.1% V / V); solvent B: acetonitrile; UV detection: 220 nm. [Table 7]

[0199] Silica gel flash chromatography Condition 1 Mobile phase: cyclohexane / EtOAc, gradient 1:100:0 to 0:100, gradient 2:100:0 to 0:100, then 100% EtOAc, gradient 3:100:0 to 50:50 Condition 2 Mobile phase: EtOAc / MeOH, gradient 1:100:0 to 90:10

[0200] Preparative HPLC: Condition 1: Column: XBridge C18 (30 × 150 (5 μm)), Flow rate: 43 mL / min, Eluent: Water (+0.1% formic acid) / acetonitrile, Gradient 1: 25% to 40% acetonitrile in water (+0.1% formic acid) Condition 2: Column: XBridge C18 (30 × 150 (5 μm)), Flow rate: 43 mL / min, Eluent: Water (+0.1% formic acid) / MeOH, Gradient 1: 40% to 55% MeOH in water (+0.1% formic acid)

[0201] Chiral SFC separation Condition 1 Column: Chiralpak OD-H (20 x 250 mm), mobile phase: CO2 / EtOH, gradient 1:75:25 isocratic, gradient 2:60:40 isocratic Condition 2 Column: Chiralpak OD-H (20 x 250 mm), mobile phase: CO2 / (EtOH+0.3%v / v i-PrNH2), gradient 1:70:30 isocratic Condition 3: Column: Chiralpak OD-H (20 x 250 mm), mobile phase: CO2 / MeOH, gradient 1:75:25 isocratic

[0202] Chiral SFC purity analysis conditions Chiral SFC purity analysis conditions for enantiomer separation Column: ChiralPak AS-3 (4.6 x 100 mm), column temperature: 35°C, flow rate: 3.5 mL / min, detector wavelength: 220-410 nm, injection volume: 2 μL, BPR: 1500 PSI, Condition 1 Mobile phase: CO2 / MeOH, gradient 1:80:20 isocratic, gradient 2:75 / 25 isocratic Condition 2 Mobile phase: CO2 / (EtOH+0.3%c / v i-PrNH2), gradient 1:70 / 30 isocratic Condition 3 Mobile phase: CO2 / EtOH, gradient 1:70:30 isocratic Chiral SFC purity analysis conditions for positional isomer separation Column details: ChiralPak OD-3 (4.6x100mm), column temperature: 35℃, flow rate: 3.5mL / min, detector wavelength: 220~410nm, injection volume: 2μL, BPR: 1500PSI, conditions 1: mobile phase CO2 / EtOH, gradient 1:75:25 isocratic

[0203] Example 1. Synthesis of 3,7-dichloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide [ka] The title compound was obtained by chlorination with phosphorus oxychloride starting from the corresponding 7-chloro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide according to the method previously described by H. Nishimura et al. (U.S. Pat. No. 4,029,780 (1977) Dainippon Pharmaceutical Co.).

[0204] Example 2. Synthesis of 3-chloro-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 2.1. Preparation of 7-fluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide [ka] 2-Amino-5-fluorobenzene-1-sulfonamide (2.5 g, 13.1 mmol) and urea (0.9 g, 14.5 mmol) were thoroughly mixed and heated to 200 °C for 2 h. Ammonia was evolved and the mixture immediately crystallized. The crude solid was dissolved in 1N NaOH (30 mL) solution and stirred for 5 min. The pH was adjusted to 1-2 with 1N HCl (40 mL) solution. The precipitate was collected by filtration, washed with water, and dried under vacuum to give the title compound (2.6 g, 83%) as a white solid. LC-MS (ESI+): m / z 217.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 11.35 (s, 1H), 7.67 (dd, J = 2.8 Hz, J = 7.6 Hz, 1H), 7.57-7.51 (m, 1H), 7.28 (dd, J = 4.4 Hz, J = 9.0 Hz, 1H), one NH missing

[0205] 2.2. Preparation of 3-chloro-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide [ka] A suspension of 7-fluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (2.4 g, 10.1 mmol) in phosphorus oxychloride (14.1 mL, 151.5 mmol) was stirred at 120 °C for 20 h. The mixture was cooled to room temperature, poured into ice water (50 mL), and stirred for 30 min. A 3N NaOH solution (350-400 mL) was added dropwise over 30 min at 0 °C until pH 9 was reached. The mixture was extracted with EtOAc (3 × 200 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound as a white powder (2.1 g, 88%). This product was used without further purification. LC-MS (ESI+): m / z 235.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d): δ 7.38 (dd, J = 2.9 Hz, J = 7.8 Hz, 1H), 7.36-7.30 (m, 1H), 7.19 (dd, J = 5.0 Hz, J = 9.0 Hz, 1H), one NH missing

[0206] Example 3. Synthesis of 3,6-dichloro-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide 3.1. Preparation of 2-amino-4-chloro-5-fluorobenzenesulfonamide [ka] The title compound was obtained starting from the corresponding 3-chloro-4-fluoroaniline according to the method previously described by P. De Tullio et al. (J. Med. Chem. 2005, 48, 4990-5000).

[0207] 3.2. Preparation of 6-chloro-7-fluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide [ka] 2-Amino-4-chloro-5-fluorobenzenesulfonamide (3.0 g, 13.4 mmol) and urea (0.9 g, 14.5 mmol) were thoroughly mixed and heated to 200 °C for 1 h. Ammonia was evolved and the mixture immediately crystallized. The crude solid was dissolved in 1 N NaOH (30 mL) solution and stirred for 5 min. The pH was adjusted to 1-2 with 1 N HCl (40 mL) solution. The precipitate was collected by filtration, washed with water, and dried under vacuum to give the title compound (1.8 g, 53%) as a purple solid. LC-MS (ESI+): m / z 251.1 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 6.1 Hz, 1H), one NH missing

[0208] 3.3. Preparation of 3,6-dichloro-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide [ka] To a solution of 6-chloro-7-fluoro-2H-benzo[e][1,2,4]thiadiazine-3(4H)-one 1,1-dioxide (3.6 g, 14.4 mmol) in phosphorus oxychloride (20.0 mL, 215.4 mmol) was added N,N-diethylaniline (4.3 g, 28.7 mmol, 4.6 mL). The solution was heated at 120 °C for 18 hours, then cooled to 25 °C, poured into ice water (50 mL), and stirred for 1 hour. The precipitate was collected by filtration, washed with water, and dried under vacuum. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc = 100 / 0:0 / 100) to give 2.63 g (68%) of 3,6-dichloro-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide as a light brown solid. LC-MS(ESI+):m / z 269.0[M+H] + . 1 H-NMR (400 MHz, DMSO-d): δ 8.05 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 6.2 Hz, 1H), one NH missing

[0209] Example 4. General procedure for the preparation of 3-(alkylamino)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxides 4.1. Method A: A mixture of the appropriate 3-chlorosubstituted benzothiadiazine 1,1-dioxide (0.5 mmol, 1 equiv.) and the appropriate alkylamine (50 equiv.) was heated in a sealed vessel at 150 °C for 50-60 h (until the reaction was complete as monitored by LC-MS). Excess amine was removed by distillation under reduced pressure. The crude residue was purified by silica gel column chromatography (cyclohexane / EtOAc = 100 / 0:0 / 100, then EtOAc = 100%) to give the title compound (yield: 30-40%) as a white powder.

[0210] 4.2. Method B: A solution of the appropriate 3-chlorosubstituted benzothiadiazine 1,1-dioxide (0.5 mmol, 1 equiv.), the appropriate alkylamine hydrochloride (2 equiv.), and N,N-diisopropylethylamine (3 equiv.) in 2 mL of dioxane was heated in a sealed vessel at 120 °C for 2–20 h (until the reaction was complete, as monitored by LC-MS). The mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc = 100 / 0:0 / 100, then 100% EtOAc) to afford the title compounds (yields: 20–66%) as white powders.

[0211] 4.3. Method C: A solution of the appropriate 3-chlorosubstituted benzothiadiazine 1,1-dioxide (0.5 mmol, 1 equiv.), the appropriate alkylamine hydrochloride (2 equiv.), and N,N-diisopropylethylamine (3 equiv.) in 2 mL of dioxane was heated in a sealed vessel at 60 °C for 2–3 h (until the reaction was complete, as monitored by LC-MS). The mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc = 100 / 0:0 / 100, then 100% EtOAc) to afford the title compounds (yields: 33–65%) as white powders.

[0212] 4.4. Method D: A solution of the appropriate 3-chlorosubstituted benzothiadiazine 1,1-dioxide (0.5 mmol, 1 equiv.), the appropriate alkylamine (2 equiv.), and N,N-diisopropylethylamine (1 equiv.) in 2 mL of dioxane was heated in a sealed vessel at 100 °C for 2–5 h (until the reaction was complete, as monitored by LC-MS). The mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc = 100 / 0:0 / 100, then EtOAc = 100%) to afford the title compounds (yields: 8–45%) as white powders.

[0213] 4.5. Method E: A solution of the appropriate 3-chlorosubstituted benzothiadiazine 1,1-dioxide (0.5 mmol, 1 equiv.), the appropriate alkylamine (2 equiv.), and N,N-diisopropylethylamine (1 equiv.) in 2 mL of dioxane was heated in a sealed vessel at 60 °C for 2–3 h (until the reaction was complete, as monitored by LC-MS). The mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc = 100 / 0:0 / 100, then 100% EtOAc) to afford the title compound (yield: 45–70%) as a white powder.

[0214] 4.6. Method F: A solution of the appropriate 3-chloro-substituted benzothiadiazine 1,1-dioxide (0.5 mmol, 1 equiv.) and the appropriate alkylamine (20 equiv.) in 2 mL of dioxane was heated in a sealed vessel at 120 °C for 18–24 h (until the reaction was complete, as monitored by LC-MS). The mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc = 100 / 0:0 / 100, then 100% EtOAc) to afford the title compound (yield: 40–50%) as a white powder.

[0215] 4.7. Method G: A solution of the appropriate 3-chlorosubstituted benzothiadiazine 1,1-dioxide (0.5 mmol, 1 equiv.) and the appropriate alkylamine (20 equiv.) in 2 mL of dioxane was heated in a sealed vessel at 40 °C for 4–5 days (until the reaction was complete, as monitored by LC-MS). The mixture was diluted with water (25 mL) and extracted with EtOAc (25 mL × 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc = 100 / 0:0 / 100, then EtOAc = 100%) to afford the title compound (yield: 21–27%) as a white powder.

[0216] A list of specific compounds of the present invention and their data is provided in Table 2 below.

[0217] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17]

[0218] Example 5. Synthesis of intermediate A2 [ka]

[0219] Preparation of Intermediate 1 (7-Fluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide) 2-Amino-5-fluorobenzene-1-sulfonamide (2.5 g, 13.1 mmol, 1 equiv.) and urea (0.9 g, 14.5 mmol, 1.1 equiv.) were mixed at 200 °C for 2 h. Ammonia evolved, and the mixture immediately crystallized. The crude solid was dissolved in 1N aqueous NaOH (30 mL) and then stirred for 5 min. The pH was adjusted to 1-2 with 1N aqueous HCl (40 mL). The precipitate was collected by filtration, washed with water, and dried under vacuum to give Intermediate A1 as a white solid (2.6 g, 83%). LC / MS (ESI+): m / z 217.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 11.35 (s, 1H), 7.67 (dd, J = 7.6, 2.8 Hz, 1H), 7.57-7.51 (m, 1H), 7.28 (dd, J = 9.0, 4.4 Hz, 1H), one NH missing

[0220] Preparation of Intermediate 2 (3-chloro-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) A suspension of Intermediate A1 (2.4 g, 10.1 mmol, 1 equiv.) in phosphorus oxychloride (14.1 mL, 151.5 mmol, 15 equiv.) was stirred at 120 °C for 20 h. The mixture was then cooled to room temperature and poured into ice-water (50 mL), followed by stirring for 30 min. 3N aqueous NaOH (350-400 mL) was then added dropwise over 30 min at 0 °C until a pH of 9 was reached. The mixture was extracted with EtOAc (3 × 200 mL), and the organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give Intermediate A2 as a white powder (2.1 g). This product was used without further purification. LC / MS (ESI+): m / z 235.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d): δ 7.38 (dd, J = 7.8, 2.9 Hz, 1H), 7.36-7.30 (m, 1H), 7.19 (dd, J = 9.0, 5.0 Hz, 1H), one NH missing

[0221] Example 6. Synthesis of Intermediate 5 [ka]

[0222] Preparation of Intermediate 3 (2-amino-4-chloro-5-fluorobenzenesulfonamide) Intermediate A3 was obtained starting from the corresponding 3-chloro-4-fluoroaniline according to the method previously shown by P. De Tullio et al. (J. Med. Chem. 2005, 48, 4990-5000).

[0223] Preparation of Intermediate A4 (6-chloro-7-fluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide) Intermediate A3 (3.0 g, 13.4 mmol, 1 equiv.) and urea (0.9 g, 14.5 mmol, 1.1 equiv.) were mixed at 200 °C for 1 h. Ammonia evolved and the mixture immediately crystallized. The crude solid was then dissolved in 1 N aqueous NaOH (30 mL) and stirred for 5 min. The pH was adjusted to 1-2 with 1 N aqueous HCl (40 mL), and the precipitate was collected by filtration, washed with water, and dried under vacuum to give Intermediate A4 as a purple solid (1.8 g). LC / MS (ESI+): m / z 251.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 6.1 Hz, 1H), one NH missing

[0224] Preparation of Intermediate A5 (3,6-Dichloro-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) To a solution of Intermediate A4 (3.6 g, 14.4 mmol, 1 equiv.) in phosphorus oxychloride (20.0 mL, 215 mmol, 15 equiv.) was added N,N-diethylaniline (4.6 mL, 28.7 mmol, 2 equiv.). The solution was heated at 120° C. for 18 hours, then cooled to 25° C., poured into ice water (50 mL), and stirred for 1 hour. The precipitate was collected by filtration, washed with water, and dried under vacuum. The crude residue was then purified by silica gel flash chromatography (Condition 1, Gradient 1) to give Intermediate A5 as a light brown solid (2.63 g). LC / MS (ESI+): m / z 269.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d): δ 8.05 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 6.2 Hz, 1H), one NH missing

[0225] Example 7. Synthesis of intermediate A7 [ka]

[0226] Preparation of Intermediate A6 (6,7-Difluoro-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide) A solution of 3,4-difluoroaniline (0.768 mL, 7.75 mmol, 1 equiv.) in nitromethane (2.3 mL) was added dropwise to a solution of chlorosulfonyl isocyanate (0.809 mL, 9.29 mmol, 1.2 equiv.) in nitromethane (7.4 mL) at −40° C. under an argon atmosphere. The reaction mixture was stirred at −40° C. for 30 minutes and then warmed to room temperature. After that, aluminum chloride (1.34 g, 10.1 mmol, 1.3 equiv.) was added. The reaction mixture was stirred at 110° C. for 1 hour and then cooled to 0° C. Water (25 mL) was added to the reaction mixture, and the resulting precipitate was filtered, washed with water (2×10 mL), and dried under reduced pressure to give Intermediate A6 as a brown solid (0.920 g, 51%). LC / MS (ESI-): m / z 233.0 [M−H] - , 1 H NMR (400 MHz, DMSO-d): δ 11.39 (s, 1H), 8.01 (dd, J = 9.3, 8.0 Hz, 1H), 7.21 (dd, J = 11.2, 6.6 Hz, 1H), one NH missing

[0227] Preparation of Intermediate A7 (3-chloro-6,7-difluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) A solution of Intermediate A6 (920 mg, 3.93 mmol, 1 equiv) in phosphorus oxychloride (9.15 mL, 98.2 mmol, 25 equiv) was stirred in a sealed vessel at 120 °C for 22 h. The mixture was cooled to room temperature, poured into ice water (100 mL), and stirred for 30 min. 10 N aqueous NaOH was added dropwise at 0 °C until the pH was approximately 10. The mixture was saturated with solid NaCl and extracted with EtOAc (2 × 100 mL), and the combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (Condition 1, Gradient 1) to give Intermediate A7 as a pale yellow solid (566 mg). LC / MS (ESI+): m / z 253.0 [M+H] + . 1H NMR (400 MHz, DMSO-d): δ 7.63 (dd, J = 9.6, 8.6 Hz, 1H), 7.15 (dd, J = 12.3, 7.3 Hz, 1H), one NH missing

[0228] Example 8. Synthesis of intermediates A9 and A9' [ka]

[0229] Preparation of Intermediate A9 (3,7-dichloro-6-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) and Intermediate A9' (3,7-dichloro-8-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) A solution of 4-chloro-3-fluoroaniline (1.00 g, 6.87 mmol, 1 equiv.) in nitromethane (2.8 mL) was added dropwise to a solution of chlorosulfonyl isocyanate (0.941 mL, 10.8 mmol, 1.6 equiv.) in nitromethane (9 mL) at −5°C under an argon atmosphere. The reaction mixture was stirred at −5°C to 10°C for 1 h and then warmed to room temperature. Aluminum chloride (1.56 g, 11.7 mmol, 1.7 equiv.) was then added, and the reaction mixture was stirred at 110°C for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (approximately 50 mL), and finally stirred for 30 min. The resulting precipitate was filtered, washed with water (2 × 15 mL), and dried under reduced pressure to give a mixture of intermediates A8 and A8' as a gray solid (1.02 g). The mixture of intermediates A8 and A8' was used directly in the next step without further purification.

[0230] A suspension of Intermediate A8 and A8' (1.00 g, 3.99 mmol, 1 equiv.) in phosphorus oxychloride (7.44 mL, 79.8 mmol, 20 equiv.) was stirred in a sealed vessel at 120 °C for 20 h. The mixture was then cooled to room temperature, poured into ice water (ca. 100 mL), and stirred for 30 min. 3N aqueous NaOH (250 mL) was then added at 0 °C until the pH reached ca. 10, and the resulting mixture was saturated with solid NaCl. The mixture was extracted with EtOAc (3 × 250 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (Condition 1, Gradient 1, then Condition 2, Gradient 1) to afford an inseparable mixture of Intermediate A9 and A9' as a beige solid (525 mg). 1 H NMR ratio A9 / A9'(DMSO-d6)=80:20. LC / MS(ESI-):m / z 266.9[MH] - , a mixture of intermediates A9 and A9' 1 H NMR (400MHz, DMSO-d6): δ7.76(d,J=8.0Hz,0.8H,Intermediate A9),7.58(t,J=8.6Hz,0.2H,Intermediate A 9'),7.12(d,J=11.0Hz,0.8H,intermediate A9),6.99(dd,J=8.9,1.5Hz,0.2H,intermediate A9'), both NH missing

[0231] Example 9. Synthesis of intermediates A11 and A11' [ka]

[0232] Preparation of Intermediate A11 (6-Bromo-3-chloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) and Intermediate A11' (8-Bromo-3-chloro-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) A solution of 3-bromoaniline (0.633 mL, 5.81 mmol, 1 equiv.) in nitromethane (1.8 mL) was added dropwise to a solution of chlorosulfonyl isocyanate (0.607 mL, 6.98 mmol, 1.2 equiv.) in nitromethane (5.8 mL) at −5°C under argon. The reaction mixture was stirred at −5°C to 10°C for 1 h and then warmed to room temperature. Aluminum chloride (1.01 g, 7.56 mmol, 1.3 equiv.) was then added, and the reaction mixture was stirred at 110°C for 1 h. The reaction mixture was then cooled to room temperature, poured into ice water (approximately 50 mL), and stirred for 30 min. The resulting precipitate was filtered, washed with water (2 × 10 mL), and dried under reduced pressure to give a mixture of intermediates A10 and A10' as a gray solid (0.540 g). The mixture of intermediates A10 and A10' was used directly in the next step without purification.

[0233] To a suspension of intermediates A10 and A10' (530 mg, 1.91 mmol, 1 equiv.) in phosphorus oxychloride (4.46 mL, 47.8 mmol, 25 equiv.) was added N,N-diethylaniline (1.01 mL, 6.31 mmol, 3.3 equiv.) at room temperature. The reaction mixture was stirred in a sealed vessel at 100°C for 18 hours, then at 120°C for 3 hours. The reaction mixture was then cooled to room temperature, poured into ice water (approximately 150 mL), and stirred for 30 minutes. 3N aqueous NaOH (100 mL) was added at 0°C to a pH of approximately 8, and the resulting mixture was stirred for 1 hour. The mixture was then reacidified with 1N aqueous HCl (60 mL) to a pH of approximately 2 and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (condition 1, gradient 1) followed by preparative HPLC (condition 1, gradient 1) to give Intermediate A11 (171 mg) and Intermediate A11' (18 mg) as white solids. Analytical data for Intermediate A11: LC / MS (ESI+): m / z 295.1 [M+H] + . 1H NMR (400 MHz, DMSO-d): δ 7.82 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 8.5, 1.9 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H)). Analytical data for one NH missing intermediate A11': LC / MS (ESI+): m / z 295.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d): δ 7.73 (dd, J = 7.9, 1.1 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.38 (dd, J = 8.3, 1.1 Hz, 1H), one NH missing

[0234] Example 10. Synthesis of intermediates A13 and A13' [ka]

[0235] Preparation of Intermediate A13 (3-chloro-6-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) and Intermediate A13' (3-chloro-6-iodo-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide) A solution of 3-iodoaniline (2.75 mL, 22.8 mmol, 1 equiv.) in nitromethane (6.8 mL) was added dropwise to a solution of chlorosulfonyl isocyanate (2.38 mL, 27.4 mmol, 1.2 equiv.) in nitromethane (21.7 mL) at −40° C. under an argon atmosphere. The reaction mixture was stirred at −40° C. for 30 minutes and then warmed to room temperature. After that, aluminum chloride (3.96 g, 29.7 mmol, 1.3 equiv.) was added. The reaction mixture was stirred at 110° C. for 1 hour and then cooled to 0° C. Water (50 mL) was then added, and the reaction mixture was stirred for 30 minutes. The resulting precipitate was filtered, washed with water (2×20 mL), and dried under reduced pressure to give a mixture of intermediates A12 and A12′ as a brown solid (3.64 g). The mixture of intermediates A12 and A12′ was used directly in the next step without purification.

[0236] A suspension of Intermediate A12 and A12' (250 mg, 0.77 mmol, 1 equiv.) in phosphorus oxychloride (1.44 mL, 15.4 mmol, 20 equiv.) was stirred in a sealed vessel at 120 °C for 18 h. The mixture was then cooled to room temperature, poured into ice water (ca. 50 mL), and stirred for 30 min. 3N aqueous NaOH (50 mL) was added at 0 °C until the pH reached ca. 8, and the resulting mixture was stirred for 1 h. The mixture was reacidified with 1N aqueous HCl (30 mL) until the pH reached ca. 2 and then saturated with solid NaCl. The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (Condition 1, Gradient 3) to give Intermediate A13 (75.0 mg) and Intermediate A13' (49 mg) as brown solids. Analytical data for intermediate A13: LC / MS (ESI-): m / z 340.9 [MH] - , 1 H NMR (400 MHz, CD3OD) δ 7.86 (dd, J = 8.4, 1.5 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H). Analytical data for one NH missing intermediate A13': LC / MS (ESI-): m / z 340.9 [MH] - , 1 H NMR (400 MHz, CD3OD): δ 8.07 (dd, J = 7.4, 1.4 Hz, 1H), 7.40 (dd, J = 8.3, 7.4 Hz, 1H), 7.35 (dd, J = 8.3, 1.4 Hz, 1H), one NH missing

[0237] Example 11. Synthesis of Compound 1 from Intermediate A2 A mixture of intermediate A2 (1.00 g, 4.26 mmol, 1 equiv.), bicyclo[1.1.1]pentan-1-amine hydrochloride (0.815 g, 6.82 mmol, 1.6 equiv.), and DIEA (1.93 mL, 11.1 mmol, 2.6 equiv.) in dioxane (36 mL) was heated at 100 °C for 2 h in a sealed vessel. The reaction mixture was concentrated under reduced pressure and then partitioned between EtOAc (100 mL) and a water / brine mixture (2:1, 40 mL). The layers were separated, and the organic layer was washed with a water / brine mixture (2:1, 2 × 40 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Condition 1, Gradient 1) to give compound 1 as a white solid (0.780 g). LC / MS (ESI+): m / z 282.1 [M+H] + ,Rt=6.99 minutes, 1 H NMR(400MHz,DMSO-d6):δ10.44(s,1H),7.80(s,1H),7.50(dd,J=7.6,2.9Hz,1H), 7.45(dt,J=8.8,2.9Hz,1H),7.25(dd,J=8.8,4.4Hz,1H),2.47(s,1H),2.08(s,6H) LC / MS(ESI+):m / z X[M+H] + ,Rt=Y minutes

[0238] The compounds shown in Table 3 below were prepared by a similar procedure from Intermediate A2 as the starting material.

[0239] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0240] Example 12. Synthesis of Compound 14 from Intermediate A5 A mixture of intermediate 5 (0.410 g, 1.52 mmol, 1 equiv.), bicyclo[1.1.1]pentan-1-amine hydrochloride (0.292 g, 2.44 mmol, 1.6 equiv.), and DIEA (0.690 mL, 3.96 mmol, 2.6 equiv.) in dioxane (10 mL) was heated at 100 °C for 2 h in a sealed vessel. The reaction mixture was concentrated under reduced pressure and then partitioned between EtOAc (80 mL) and a water / brine mixture (2:1, 20 mL). The layers were separated, and the organic layer was washed with a water / brine mixture (2:1, 2 × 20 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Condition 1, Gradient 2). The resulting solid was triturated with EtOH (5 mL), filtered, and dried under reduced pressure to give compound 14 as a white solid (0.269 g). LC / MS(ESI+):m / z 316.2[M+H] + ,Rt=5.74 minutes 1 H NMR(400MHz,DMSO-d6):δ10.44(s,1H),8.05(s,1H),7.77(d,J=7.9Hz,1H),7.46(d,J=6.1Hz,1H)),2.48(s,1H),2.09(s,6H)

[0241] The compounds shown in Table 4 below were prepared by similar procedures.

[0242] [Table 6-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13]

[0243] Example 13. Synthesis of Compound 32 from Intermediate A7 A suspension of intermediate 7 (80.0 mg, 0.32 mmol, 1 equiv.), bicyclo[1.1.1]pentan-1-amine hydrochloride (60.6 mg, 0.51 mmol, 1.6 equiv.), and DIEA (143 μL, 0.82 mmol, 2.6 equiv.) in dioxane (2.7 mL) was heated at 100° C. in a sealed vessel for 2 h. The reaction mixture was concentrated under reduced pressure and then partitioned between EtOAc (50 mL) and a 2:1 water / brine mixture (25 mL). The layers were separated, and the organic layer was washed with a 2:1 water / brine mixture (2×25 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (condition 2, gradient 1) to give compound 32 (55.0 mg) as a pale yellow solid. LC / MS (ESI+): m / z 300.3 [M+H] + ,Rt=5.27 minutes, 1H NMR (400MHz, DMSO-d6): δ10.56(br s,1H),7.98(s,1H),7.81(t,J=8.8Hz,1H),7.28(dd,J=11.6,6.5Hz,1H),2.47(s,1H),2.08(s,6H)

[0244] The compounds shown below in Table 5 were prepared by similar procedures.

[0245] [Table 5]

[0246] Example 14. Synthesis of Compounds 35 and 36 from Intermediates A9 and A9' A suspension of a mixture of intermediates 9 and 9' (200 mg, 0.74 mmol, 1 equiv.), bicyclo[1.1.1]pentan-1-amine hydrochloride (142 mg, 1.19 mmol, 1.6 equiv.), and DIEA (0.337 mL, 1.93 mmol, 2.6 equiv.) in dioxane (6.3 mL) was stirred and heated at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure and then partitioned between EtOAc (150 mL) and a 2:1 water / brine mixture (50 mL). The layers were separated, and the organic layer was washed with a 2:1 water / brine mixture (2 × 50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by chiral SFC (condition 1, gradient 1) to give compound 35 (121 mg) and compound 36 (30 mg) as a light brown solid. Chiral SFC analytical data for the separated positional isomers (Column: Chiralpak OD-3 (4.6 × 100 mm), Mobile phase (isocratic conditions): CO2 / EtOH, 75:25) Compound 35: Rt = 1.12 min, Chiral SFC purity: 100% Compound 36: Rt = 2.11 min, Chiral SFC purity: 100% Analytical data for Compound 35: LC / MS (ESI+): m / z 316.1 [M+H] + ,Rt=5.72 minutes, 1 H NMR(400MHz,DMSO-d6):δ10.58(s,1H),8.04(s,1H),7.90(d,J=7.6Hz,1H),7.27(d,J=10.3Hz,1H),2.48(s,1H),2.08(s,6H),1 H{ 19 F}NMR(400MHz,DMSO-d6):δ10.58(s,1H),8.04(s,1H),7.90(s,1H),7.27(s,1H),2.48(s,1H),2.08(s,6H) Analysis data of compound 36:LC / MS(ESI+):m / z 316.1[M+H] + ,Rt=5.56 minutes, 1 H NMR (400MHz, DMSO-d6): δ10.78(s,1H),7.87(br s,1H),7.71(t,J=8.3Hz,1H),7.05(d,J=9.0Hz,1H),2.47(s,1H),2.08(s,6H), 1 H{ 19 F}NMR(400MHz,DMSO-d6):δ10.78(s,1H),7.87(br s,1H),7.71(d,J=9.0Hz,1H),7.05(d,J=9.0Hz,1H),2.47(s,1H),2.08(s,6H)

[0247] Example 15. Synthesis of Compound 37 from Intermediate A11 A suspension of intermediate A11 (550 mg, 1.86 mmol, 1 equiv.), bicyclo[1.1.1]pentan-1-amine hydrochloride (334 mg, 2.79 mmol, 1.5 equiv.), and DIEA (0.810 mL, 4.65 mmol, 2.5 equiv.) in dioxane (15 mL) was stirred and heated at 100 °C for 3 h. The reaction mixture was concentrated under reduced pressure and then partitioned between EtOAc (150 mL) and a water / brine mixture (2:1, 50 mL). The layers were separated, and the organic layer was washed with a water / brine mixture (2:1, 2 × 50 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The crude solid was triturated with EtOAc (2 × 7 mL), filtered, and dried under reduced pressure to give compound 37 as an off-white solid (545 mg). LC / MS(ESI+):m / z 342.2[M+H] + ,Rt=5.41 minutes, 1 H NMR (400MHz, DMSO-d6): δ10.38(s,1H),7.98(s,1H),7.61(d,J=8.8Hz,1H),7.42-7.44(m,2H),2.48(s,1H),2.09(s,6H)

[0248] Example 16. Synthesis of Compound 38 from Intermediate A11' Compound 38 was prepared according to the procedure described for compound 37, starting from intermediate A11' (15.0 mg, 0.051 mmol, 1 eq.), to give compound 38 as an off-white solid (10.0 mg). LC / MS (ESI+): m / z 342.2 [M+H] + ,Rt=5.06 minutes, 1 H NMR(400MHz,DMSO-d6):δ10.48(s,1H),7.63(s,1H),7.45(dd,J=7.9,1.2Hz,1H ),7.40(t,J=7.9Hz,1H),7.15(dd,J=8.0,1.3Hz,1H),2.48(s,1H),2.09(s,6H)

[0249] Example 17. Synthesis of Compound 39 from Intermediate A13 Compound 39 was prepared according to the procedure described for compound 37, starting from intermediate A13 (50.0 mg, 0.15 mmol, 1 eq.), to give compound 39 as a white solid (34.0 mg). LC / MS (ESI+): m / z 390.1 [M+H] + ,Rt=5.51 minutes, 1 H NMR(400MHz,DMSO-d6):δ10.35(s,1H),7.95(s,1H),7.61-7.58(m,2H),7.42(d,J=8.6Hz,1H),2.47(s,1H),2.08(s,6H)

[0250] Example 18. Synthesis of Compound 40 from Compound 37 To a suspension of compound 37 (70.0 mg, 0.21 mmol, 1 equiv.), trimethylboroxine (57.7 μL, 0.41 mmol, 2 equiv.), and CsCO (133 mg, 0.41 mmol, 2 equiv.) in argon-purged anhydrous dioxane (4 mL) was added Pd(dppf)Cl .DCM (16.7 mg, 0.021 mmol, 0.1 equiv) was added. The reaction mixture was degassed by bubbling argon through it for 5 minutes and stirred at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc (30 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (condition 1, gradient 2) followed by preparative HPLC (condition 1, gradient 1) to give compound 40 (28.0 mg) as a white solid. LC / MS (ESI+): m / z 278.3 [M+H] + ,Rt=5.00 minutes, 1 H NMR(400MHz,DMSO-d6):δ10.21(s,1H),7.65(s,1H),7.54(d,J=8.0Hz,1H),7.07(d d,J=8.0,1.7Hz,1H),6.95(d,J=1.7Hz,1H),2.47(s,1H),2.34(s,3H),2.08(s,6H)

[0251] Example 19. Synthesis of Compound 41 from Compound 37 To a solution of compound 37 and zinc cyanide (16.5 mg, 0.14 mmol, 1.6 equiv) in argon-purged anhydrous DMF (0.7 mL) was added Pd(PPh3)4 (12.2 mg, 0.011 mmol, 0.12 equiv). The reaction mixture was degassed by bubbling argon through it for 5 minutes and stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc (15 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (Condition 1, Gradient 2) to give compound 41 (10.0 mg) as a white solid. LC / MS (ESI+): m / z 289.3 [M+H] + ,Rt=5.05 minutes, 1H NMR(400MHz,DMSO-d6):δ10.58(s,1H),8.08(s,1H),7.85(d,J=8.4Hz,1H),7.68-7.65(m,2H),2.48(s,1H),2.09(s,6H)

[0252] [Table 8-1] [Table 8-2]

[0253] [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6]

[0254] [Table 10]

[0255] Example 20. Glucose-stimulated insulin secretion assay (GSIS) INS-1E rat pancreatic tumor (insulinoma) cells were used for the GSIS assay. INS-1E cells were thawed and incubated in culture medium (CM) (RPMI 1640 + glucose qs, HEPES 25 mM, Na-Pyruvate 1 mM, 2-mercaptoethanol 50 μM, fetal calf serum (heat-inactivated (FCS) 10%), penicillin / streptomycin 100 U / ml) at 37°C in a humidified atmosphere with 5% CO2. 96-well plates were coated with Matrigel by incubating the plates with 1 ml of Matrigel pre-diluted 1:10 in 100 μl / well of cold basal medium for 1 hour at 37°C. The Matrigel was then removed and replaced with 100 μl of CM. Cells were then seeded into wells at 70,000 cells / well. CM was refreshed with 200 μl of fresh CM on day 3. On day 6, the CM is refreshed again with 200 μl of fresh CM. The GSIS assay is performed on day 7. The cells in the wells are washed with βKrebs® BSA and incubated with 100 μL / well for 2 hours. The secretion plate is placed in a 37°C, 5% CO2, saturated humidity incubator for 60 minutes. Meanwhile, a lysis solution is prepared by adding 1 tablet of protease inhibitor per 10 mL of TETG solution and kept at 4°C until the end of the experiment. A separate incubation buffer is prepared without the addition of pharmacological compounds, aliquoted, and then placed in a 37°C water bath. Samples are prepared, including a negative control (βKrebs® B0 = 0 mM glucose) and a positive control (βKrebs® B20 = 20 mM glucose), and each compound to be tested is diluted in DMSO to a series of final concentrations including 10.00, 4.00, 1.60, 0.64, 0.26, 0.10, 0.04, 0.02 μM.

[0256] After 2 hours of starvation, glucose stimulation and treatment begins. The KRB buffer is removed from the cells by pipetting. The solution is homogenized and the cells are treated with 90 μL / well. 10 μL of the 10-fold compound dilutions are added to the assay plate (final 100 μL / well) according to the following configuration for each compound to be tested:

[0257] The incubation time is 40 minutes. The plate is placed in an incubator at 37°C, 5% CO2, and saturated humidity. After incubation, 80 μL of supernatant is collected without disrupting the cell layer and stored at 4°C or on ice until centrifugation. The remaining medium is removed from each well, and 100 μL / well of cold lysis solution is added and incubated at room temperature for a minimum of 2 minutes. Cell lysis is observed under a microscope and lysis is allowed to proceed for up to 5 minutes. The cell lysates are collected and all samples, including the supernatants, are centrifuged at 700 x g for 5 minutes at 4°C. 30 μL of each sample is transferred to an aliquot for ELISA. ELISA is performed using an HTRF assay kit, including the insulin high-range kit provided by Cisbio / Perkin Elmer. 5 μL of each insulin standard and 5 μL of either the supernatant or the lysate are transferred to an HTRF plate. 40 μl / well anti-insulin-XL665 and 20 μl / well anti-insulin-EU are added to each well and the plate is read in an HTRF reader (fluorescence at 620 nm and 665 nm).

[0258] GSIS experiments were also performed in other cell lines, such as EndoC-βH1, a standard cell line for screening new therapeutic compounds.

[0259] Figure 1 shows the inhibition of insulin by diazoxide in a GSIS assay. Figure 2 shows the inhibition of insulin by compound 42 in a GSIS assay. Figure 3 shows the inhibition of insulin by compound 54 in a GSIS assay.

[0260] The ability of certain compounds of the invention to inhibit insulin is shown below in Table B. In the table, data are presented according to the following legend: A = 50% or more inhibition, B = 25-50% inhibition, C = 10-25% inhibition, D = 10% or less inhibition.

[0261] [Table B]

[0262] In Table C, the IC50 values ​​are as follows: A is less than 0.5uM, B is 0.5uM to 1uM, C is 1uM to 2uM, and D is 2uM or more.

[0263] [Table C]

[0264] In Table D, the data are presented according to the following legend: A = 50% or more inhibition, B = 25-50% inhibition, C = 10-25% inhibition, D = 10% or less inhibition.

[0265] [Table D]

[0266] [Table E]

[0267] These results demonstrate that the compounds according to the invention are able to reduce insulin secretion.

[0268] Example 2. Selective β-cell K ATP Identification of channel activator compounds In the experiments presented in this example, we used a non-radioactive rubidium efflux assay in conjunction with electrophysiological techniques to selectively induce pancreatic β-cell K ATP Identify and characterize channel activator compounds. SUR1 and Kir6.2 (pancreatic K ATP The K channel isoforms were co-expressed in COSm6 cells, and K channel activation was examined using the Rb efflux assay according to Martin, GM et al., Elife, 2017, 6 and Li, JB et al., J Biol Chem., 2013, 288(32):23038-49, with modifications. Briefly, COSm6 cells (endogenous K ATPcDNAs encoding wild-type SUR1 and Kir6.2 are transiently transfected into a common mammalian cell line (a cell line that does not express a K channel) using Fugene6. The transfected cells are cultured overnight in medium containing 5 mM RbCl. The next day, the cells are quickly washed twice in Ringer's solution without RbCl, and Rb efflux is measured over 30 minutes in the presence or absence of two different concentrations (1 μM and 10 μM) of a candidate compound (e.g., a compound described herein). ATP The activator diazoxide is tested in parallel at 1, 10, and 200 μM and used as a positive control. 0.1% DMSO is used as a vehicle-treated negative control. Untransfected cells are included in the assay to assess background efflux. At the end of the 30-minute incubation, Ringer's solution is collected, and cells are lysed in Ringer's solution + 1% Triton® X-100. Rb concentrations in both the efflux solution and cell lysate are measured using an atomic absorption ion channel reader ICR8100™ (available from Aurora Biomed). For each experiment (i.e., each transfection), replicates (i.e., two identically prepared wells of cells) are performed as duplicates, the average of which represents the data point for a single experiment. To reduce variability that may arise from variations in transfection efficiency, three separate transfections are performed for each test compound, representing three biological replicates. The three data points are averaged and the standard error of the mean is calculated for each compound at each of the two concentrations. ATP To verify that this is due to an increase in channel activity, K ATP The stimulatory effect of the compounds is again tested by including 10 μM of the channel-specific inhibitor glibenclamide. These test compounds are then tested against the K ATP Tested against the channel, K ATP Assess isoform specificity.

[0269] The % efflux was calculated by dividing the Rb in the efflux solution by the total Rb in both the efflux solution and the cell lysate. The efflux from untransfected COSm6 cells was considered background noise and subtracted from the experimental values. Because only two concentrations were tested in the initial experiment, only the % activation of each compound at each concentration (1, 10 μM) was compared with cells treated with diazoxide at the same concentration and at 200 μM (considered maximal stimulation).

[0270] Dose-response electrophysiology experiments are then performed to measure the K concentration using techniques such as inside-out patch clamp. ATP The effective concentration of a compound (e.g., a compound described herein) that activates the channel is determined. At least five concentrations are tested. The concentration to be tested for each compound is determined based on the results of the Rb efflux assay described above. Three biological replicates, each with two replicates, are performed for each compound and concentration. Diazoxide is used as a positive control, and glibenclamide is used as a negative control. If a solvent such as DMSO is used to dissolve the compound, the same concentration of DMSO used to dissolve the compound is used as a vehicle control. Electrophysiological data are used to generate dose-response curves for lead compounds as described above for other pharmacological modulators, and EC50s are calculated using GraphPad.

[0271] Equivalents and Scope This application refers to various published patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference in their entirety. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. Also, any particular embodiment of the present disclosure that falls within the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are deemed known to those of ordinary skill in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present disclosure may be excluded from any claim for any reason, whether related to the existence of prior art or not.

[0272] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not limited to the above specification, drawings, or examples, but is instead set forth in the appended claims. As will be apparent to those skilled in the art, various changes and modifications to the present specification are possible without departing from the scope of the following claims.

Claims

1. Formula (I) below 【Chemistry 44】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein: A is C(R'), each of B and D is independently N; A and B or A and D are connected via a double bond or a single bond; R １ , R ２ , R ５ , and R ６ each independently represents hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR Ａ , fluorine, chlorine, bromine, iodine, nitro, or cyano, wherein A and B form a double bond, and R ｘ is hydrogen, or A and D form a double bond, and R ｙ is hydrogen, R ３ is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(R Ｂ ) (R Ｃ ), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each selected from one or more R ４ and optionally substituted with R' is absent, hydrogen, or C1-C6 alkyl; Each R ４ are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, fluorine, chlorine, bromine, or iodine; R Ａ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, where alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each selected from the group consisting of one or more R ７ and optionally substituted with R Ｂ and R Ｃ are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are each independently selected from one or more R ７ optionally substituted with, or R Ｂ and R Ｃ means, together, one or more R ７ forming an optionally substituted heterocyclyl with Each R ７ is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR Ａ , fluorine, chlorine, bromine, iodine, nitro, or cyano, or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof.

2. R １ and R ２ each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, —OR Ａ , fluorine, chlorine, bromine, iodine, nitro, or cyano.

3. R １ and R ２ 10. The compound of claim 1, wherein each of is independently hydrogen, fluorine, chlorine, bromine, iodine, or cyano.

4. R １ and R ２ 10. The compound of claim 1, wherein each of is independently hydrogen, fluorine, or chlorine.

5. R １ is hydrogen, and R ２ is fluorine, chlorine, bromine, iodine, nitro, or cyano.

6. R ２ is fluorine, chlorine, bromine, iodine, nitro, or cyano; R ２ is fluorine, chlorine, bromine, iodine, nitro, or cyano.

7. R １ is hydrogen, and R ２ The compound of claim 1 , wherein is fluorine.

8. R １ is hydrogen, and R ２ The compound of claim 1 , wherein is chlorine.

9. R １ is chlorine, and R ２ The compound of claim 1 , wherein is fluorine.

10. R １ and R ２ 10. The compound of claim 1, wherein each of is independently fluorine.

11. R ５ The compound of claim 1 , wherein

12. R ６ The compound of claim 1 , wherein

13. R ３ is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, or N(R Ｂ ) (R Ｃ ), each of which is selected from the group consisting of one or more R ７ 2. The compound of claim 1, optionally substituted with

14. R ３ is one or more R ７ 2. The compound of claim 1, wherein the alkyl group is C1-C6 heteroalkyl optionally substituted with

15. R ３ is one or more R ７ 2. The compound of claim 1, wherein the alkyl group is C1-C6 haloalkyl optionally substituted with

16. R ３ is one or more R ７ 10. The compound of claim 1, wherein R is 1 or 2.

11. The compound of claim 1, wherein R is 1 or 2.

17. R ３ is one or more R ７ 10. The compound of claim 1, wherein R is a heterocyclyl optionally substituted with R.

18. R ３ is N(R Ｂ ) (R Ｃ 2. The compound of claim 1, wherein

19. R Ｂ and R Ｃ means, together, one or more R ７ 19. The compound of claim 18, wherein R forms an optionally substituted heterocyclyl (e.g., a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, or a bridged heterocyclyl).

20. R Ｂ 19. The compound of claim 18, wherein is hydrogen.

21. R Ｃ is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, each of which is selected from one or more R ７ 21. The compound of any one of claims 18 to 20, optionally substituted with

22. R Ｃ is one or more R ７ 22. The compound of any one of claims 18 to 21, wherein the alkyl is C1-C6 alkyl optionally substituted with

23. R Ｃ is one or more R ７ The compound of any one of claims 18 to 21, wherein the alkyl is C1-C6 heteroalkyl optionally substituted with

24. R Ｃ is one or more R ７ The compound of any one of claims 18 to 21, wherein the alkyl is C1-C6 haloalkyl optionally substituted with

25. R Ｃ is one or more R ７ The compound of any one of claims 18 to 21, wherein the cycloalkyl is optionally substituted with .

26. R Ｃ is one or more R ７ 22. The compound of any one of claims 18 to 21, wherein R is a heterocyclyl optionally substituted with R.

27. R ７ is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -OR Ａ , fluorine, chlorine, bromine, iodine, nitro, or cyano.

28. The compound has the following formula (Ia): 【Chemistry 45】 is a compound of the formula A is carbon (C), B and D are nitrogen (N); A and B or A and D are connected via a double bond, R １ and R ２ are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine; A and B form a double bond, and R ｘ is H, or A and D form a double bond, and R ｙ is H, R ３ is, independently, 【Chemistry 46】 wherein R ４ is selected from the group consisting of C1-C3 alkyl optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro and hydroxy, ethynyl, C1-C2 alkoxy, (methoxy)-C1-C2 alkyl, cyano, fluoro, (methylsulfonyl)-C1-C2 alkyl, (dimethylamino)-C1-C2 alkyl, and n-methylcarbamoyl.

29. A is carbon (C), B and D are nitrogen (N); A and B or A and D are connected via a double bond or a single bond, R １ and R ２ are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine; A and B form a double bond, and R ｘ is H, or A and D form a double bond, and R ｙ is H, R ３ is, independently, 【Chemistry 47】 2. The compound of claim 1 selected from the group consisting of:

30. The compound has the following formula (I-b): 【Chemistry 48】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A, B, D, R １ , R ２ , R ５ , R ６ , R ｘ R ｙ , R Ａ , R Ｂ , R Ｃ , and R ７ The compound according to claim 1, wherein is defined as for formula (I).

31. The compound has the following formula (I-c): 【Chemistry 49】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein A, B, D, R １ , R ２ , R ５ , R ６ , R ｘ R ｙ , R Ａ , R Ｂ , R Ｃ , and R ７ The compound according to claim 1, wherein: is as defined for formula (I), m is an integer of 0 to 12, and n is an integer of 0 to 4.

32. The compound has the following formula (I-e): [Transformation 50] or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R １ , R ５ , R ｘ , and R ７ The compound according to claim 1, wherein: is as defined for formula (I), m is an integer of 0 to 12, and n is an integer of 0 to 4.

33. The compound has the following formula (If): 【Chemistry 51】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, hydrate, or isotope thereof, wherein R １ , R ５ , R ｘ , and R ７ The compound according to claim 1, wherein: is as defined for formula (I), m is an integer of 0 to 12, and n is an integer of 0 to 4.

34. The compound is 【Chemistry 52-1】 【Chemistry 52-2】 10. The compound of claim 1, which is selected from the group consisting of:

35. 2. The compound of claim 1, wherein the compound is one shown in Table 1 or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

37. 37. A method of treating a disease or disorder in a subject using a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 36.

38. 38. The method of claim 37, wherein the disease or disorder is selected from a metabolic disorder (e.g., CHI), cancer, a neurological disorder, a cardiovascular disease, a pulmonary disorder, a skin disorder, a sexual disorder, a urinary disorder, or a symptom thereof.

39. 38. The method of claim 37, wherein the disease or disorder is a metabolic disorder.

40. 38. The method of claim 37, wherein the metabolic disorder is hyperinsulinism, e.g., congenital hyperinsulinism (CHI).

41. 38. The method of claim 37, wherein the subject has been diagnosed or identified as having the disease or disorder.

42. 38. The method of claim 37, wherein the subject is a mammal (e.g., a human).

43. 38. The method of claim 37, wherein the compound or the pharmaceutical composition is formulated for oral or intravenous administration.

44. 44. The method of claim 43, wherein the compound or the pharmaceutical composition is in a solid dosage form, in particular an oral dosage form (e.g., a tablet or capsule).

45. A process for preparing a compound according to any one of claims 1 to 6, comprising: a) providing a first compound according to formula (X) 【Chemistry 53】 (In the formula, A is carbon (C), B and D are nitrogen (N); A and B or A and D are connected via a double bond or a single bond, R １ and R ２ are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and iodine; A and B form a double bond, and R ｘ is H, or A and D form a double bond, and R ｙ is H, R ４ are independently selected from the group consisting of fluorine, chlorine, bromine, and iodine, and are preferably chlorine; b) Formula HR ３ providing a second compound according to the formula ３ teeth, 【Chemistry 54】 wherein R ４ is selected from the group consisting of C1-C3 alkyl optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro and hydroxy, ethynyl, C1-C2 alkoxy, (methoxy)-C1-C2 alkyl, cyano, fluoro, (methylsulfonyl)-C1-C2 alkyl, (dimethylamino)-C1-C2 alkyl, and n-methylcarbamoyl; c) reacting said first compound with said second compound under conditions that result in the formation of a compound according to any one of claims 1 to 35.

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