N-(BENZHYDRIL)CYCLOALKYLCARBOXAMIDE DERIVATIVES AS INHIBITORS OF GLYCOGEN SYNTHASE 1 (GYS1) AND METHODS OF USE THEREOF

Abstract

Provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , X 1 , X 2 , L, and Q 1 is as defined elsewhere herein. Also provided herein are methods of preparing compounds of formula (I). Also provided herein are methods of inhibiting GYS1 and treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 406,684, filed September 14, 2022, the contents of which are incorporated herein by reference. [Background technology]

[0002] Pathological accumulation of glycogen is a hallmark of several serious and chronic human diseases. For some of these disorders, the cellular etiology driving this abnormal accumulation has a clear genetic basis; for others, the mechanical drivers are more complex. Nevertheless, elevated glycogen levels result in altered cellular homeostasis and impaired tissue function over time. The rate-limiting enzyme in the glycogen synthesis pathway is the protein glycogen synthase (GYS). In humans, there are two isoforms: GYS1 and GYS2. The former is ubiquitously expressed but highly abundant in muscle cells, while the latter is expressed exclusively in the liver. Glycogen synthesis ultimately begins with the transport of glucose into cells via the GLUT family of transporters. The conversion of glucose to glycogen follows a well-characterized biochemical pathway, leading to the covalent attachment of glucose molecules via α1,4-glycosidic bonds to long, branched structures by GYS. Glycogen's final globular structure results from the action of glycogen branching enzyme (GBE), which introduces α1,6-linked branch points along the chain. This biochemical chain results in the production of an energy-dense, highly soluble molecule that can be stored in the cellular cytosol for rapid catabolism to glucose energy as needed. An imbalance in the equilibrium of either glycogen synthesis or glycogen degradation can result in abnormal accumulation of cellular glycogen stores. It has long been hypothesized that substrate-reducing therapies targeting inhibition of glycogen synthase could be an effective treatment for disorders of glycogen storage.Indeed, substrate reduction therapeutics have been highly successful in modifying the disease course in patients with other storage disorders, including Gaucher disease and Fabry disease (Platt FM, Butters TD. Substrate Reduction Therapy. Lysosomal Storage Disorders, Springer US chapter 11, pp. 153-168, 2007; Shemesh E, et al. Enzyme replacement and substrate reduction therapy for Gaucher disease. Cochrane Database of Systematic Reviews, Issue 3, 2015). The objective of the present invention is to inhibit glycogen synthase enzyme activity, resulting in a reduction in tissue glycogen stores, with therapeutic benefit to patients suffering from the consequences of abnormal cellular glycogen accumulation.

[0003] Pompe disease is a rare genetic disorder caused by a pathological accumulation of cellular glycogen due to loss-of-function (LOF) mutations in the lysosomal enzyme α-glucosidase (GAA). GAA degrades lysosomal glycogen, and in its absence, glycogen accumulates in lysosomes. This triggers a disease cascade that begins with lysosomal and autophagosome dysfunction, ultimately leading to cell death and muscle atrophy over time (Raben N, et al. Autophagy and mitochondria in Pompe Disease: nothing is so new as what has long been forgotten. American Journal of Medical Genetics, vol. 160, 2012; van der Ploeg AT and Reuser AJJ, Pompe's Disease. Lancet vol. 372, 2008). In humans, the clinical manifestations of the disease range in severity and occur at a prevalence of 1 in 40,000 births (Meena NK, Raben N. Pompe disease: new developments in an old lysosomal storage disorder. Biomolecules, vol. 10, 2020). Infantile-onset patients are born with cellular pathology and rapidly develop severe disorders, including myopathy, cardiac defects, organ enlargement, and hypotension, which, if left untreated, can ultimately claim the child's life within a year. Late-onset children may develop cardiac enlargement but are consistently characterized by progressive loss of motor function, skeletal muscle degeneration, and eventual respiratory failure, leading to early death. Late-onset adult Pompe patients exhibit normal cardiac function but develop progressive muscle weakness and respiratory weakness, followed by respiratory failure. The current standard of care for Pompe patients is enzyme replacement therapy (ERT) with recombinant human GAA.Although ERT treatment has been successful in slowing disease progression, there remains an incredible unmet need in the majority of patients (Schoser B, et al. The humanistic burden of Pompe disease: are there still unmet needs? A systematic review. BMC Neurology, vol. 17, 2017). For over a decade, substrate reduction therapies targeting GYS1 have been hypothesized to be beneficial in the treatment of Pompe disease. Indeed, three separate preclinical studies have demonstrated that genetic LOF of GYS1 in Pompe disease mouse models effectively reduces tissue glycogen and improves disease outcomes in mice (Douillard-Guilloux G, et al. Modulation of glycogen synthesis by RNA interference: toward a new therapeutic approach for glycogenosis type II. Human Molecular Genetics, vol. 17, no. 24, 2008; Douillard-Guilloux G, et al. Restoration of muscle function by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Human Molecular Genetics, vol. 19, no. 4, 2010; Clayton NP, et al. Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe disease. Molecular Therapy - Nucleic Acids, vol. 3, 2014). Small molecule GYS1 inhibitors may be used to address the current unmet needs of Pompe patients, either as monotherapy or in combination with standard of care ERT.

[0004] Pompe disease is only one of more than a dozen diseases caused by inborn errors of metabolism that result in abnormal accumulation of glycogen in various tissues of the body. While specific dietary treatments effectively manage some glycogen storage diseases (GSDs), for others, there are no clinically approved therapeutic interventions to alter the disease course. Therefore, inhibiting glycogen synthesis and the concomitant reduction of tissue glycogen levels may be a viable treatment option for these patients. Cori's disease, GSD III, is caused by mutations in glycogen debranching enzyme (GDE), which leads to pathological glycogen accumulation in the heart, skeletal muscle, and liver (Kishnani P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genetics in Medicine, vol. 12, no. 7, 2010). While dietary management can be effective in ameliorating disease symptoms, there is currently no treatment to prevent progressive myopathy in GSD III. Adult polyglucosan body disease (APBD) is an adult-onset disorder caused by loss of glycogen branching enzyme (GBE1) activity. GBE deficiency leads to the accumulation of long chains of unbranched glycogen that precipitate in the cytosol, generating polyglucosan bodies, ultimately inducing neurological deficits in both the central and peripheral nervous systems. Genetic deletion of GYS1 in an APBD mouse model rescued the deleterious accumulation of glycogen, improved lifespan, and neuromuscular function (Chown EE, et al. GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease. Annals of Clinical and Translational Neurology, vol. 7, no. 11, 2020). Lafora disease (LD) is a highly debilitating early-onset epilepsy disorder similarly characterized by the accumulation of polyglucasone bodies.Genetic crossing of the LD mouse model with GYS1 knockout (KO) mice resulted in rescue of the disease phenotype (Pedersen B, et al. Inhibiting glycogen synthesis prevents Lafora disease in a mouse model. Annals of Neurology, vol. 74, no. 2, 2013; Varea O, et al. Suppression of glycogen synthesis as a treatment for Lafora disease: establishing the window of opportunity. Neurobiology of Disease, 2020).

[0005] Recently, the dependency of clear cell carcinomas on high levels of glycogen has emerged as a novel therapeutic target. Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen-rich clear cell breast cancer (GRCC), acute myeloid leukemia (AML), and non-small cell lung cancer (NSCLC) are all examples of cancers histopathologically defined by abnormally high levels of PAS+ cellular glycogen. Increased GYS1 transcript levels have been significantly correlated with poor disease outcomes in NSCLC (Giatromanolaki A, et al. Expression of enzymes related to glucose metabolism in non-small cell lung cancer and prognosis. Experimental Lung Research, vol. 43, no. 4-5, 2017) and AML (Falantes JF, et al. Overexpression of GYS1, MIF, and MYC is associated with adverse outcome and poor response to azacitidine in myelodysplastic syndromes and acute myeloid leukemia. Clinical Lymphoma, Myeloma & Leukemia, vol. 15, no. 4, 2015). Lentiviral knockdown of GYS1 in cultured myeloid leukemia cells strongly inhibited cancer cell proliferation in vitro and tumor formation in vivo (Bhanot H, et al. Pathological glycogenesis through glycogen synthase I and suppression of excessive AMP kinase activity in myeloid leukemia cells. Leukemia, vol. 29, no. 7, 2015).Genetic knockdown of GYS1 in a ccRCC cell model both inhibits tumor growth in vivo and increases the synthetic lethality of sunitinib (Chen S, et al. GYS1 induces glycogen accumulation and promotes tumor progression via the NF-kB pathway in clear cell renal carcinoma. Theranostics, vol. 10, no. 20, 2020).

[0006] The reduction in GYS1 enzyme activity and reduction in cellular glycogen stores in preclinical models of Pompe disease, APBD, LD, AML, ccRCC, and NSCLC all provide strong evidence of the potential therapeutic benefit of inhibiting glycogen synthesis. The objective of the present invention is to inhibit glycogen synthase activity, resulting in a reduction in tissue glycogen stores, which will provide therapeutic benefit to patients suffering from the consequences of accumulated cellular glycogen. Summary of the Invention

[0007] As used herein, in one aspect, there is provided a compound of formula (I): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y 1 and Y 2 are each CH, or Y 1 and Y 2 One of them is N and Y 1 and Y 2 the other of which is CH, X 1 and X 2 are each independently H or halo; R 3 and R 4 are each —CH3, or R 3 and R 4together with the atom to which they are attached form cyclopropyl or cyclobutyl, (1) L does not exist, and Q 1 but, (I C 6~20 aryl, and Q 1 C 6~20 Aryl is one or more of -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 optionally substituted with -NH-(3- to 15-membered alkyl), -NH-(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 The alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 optionally substituted with cycloalkyl, and -NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6 C optionally substituted with alkyl 6~20 aryl, or (ii) 3- to 15-membered heterocyclyl, where Q 1 wherein the 3- to 15-membered heterocyclyl is optionally substituted by one or more oxo; or (iii) 5- to 20-membered heteroaryl, where Q 1The 5- to 20-membered heteroaryl contains at least one ring N atom and is substituted with one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 a 5- to 20-membered heteroaryl optionally substituted with cycloalkyl; or (2) L is -CH2-, and Q 1 C 3~10 or cycloalkyl; m is 0 or 1, n is 0 or 1, R 1 H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~6 is alkyl, R 1 -C(O)-NH(C 1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~6 Alkyl C 1~6 The alkyl group may be one or more of -NH-C(O)-C 1~6 optionally substituted with alkyl or -C(O)-NH2, and R 2 is H, halo, or —OH.

[0008] As used herein, in one aspect, there is provided a compound of formula (IA): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X4 , X 5 , X 6 , X 7 , X 8 , Y 1 , Y 2 , and R a is as defined elsewhere herein.

[0009] As used herein, in one aspect, there is provided a compound of formula (IB): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , Y 1 , Y 2 , and R a is as defined elsewhere herein.

[0010] As used herein, in one aspect, there is provided a compound of formula (IC): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , Y 1 , Y 2 , R a and Ring A is as defined elsewhere herein.

[0011] As used herein, in one aspect, there is provided a compound of formula (ID): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , Y 1 , Y 2 , R a and Ring A is as defined elsewhere herein.

[0012] In one aspect, the formula (IE): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , R A and Q 1 is as defined elsewhere herein.

[0013] In one aspect, the formula (IF): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n, X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , R A and Q 1 is as defined elsewhere herein.

[0014] As used herein, in one aspect, there is provided a compound of formula (IG): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , R a and Q 1 is as defined elsewhere herein.

[0015] As used herein, in one aspect, there is provided a compound of formula (IH): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 , X 2 , R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , R a and Q 1 is as defined elsewhere herein.

[0016] Provided herein, in one aspect, is a pharmaceutical composition comprising: (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (ii) one or more pharmaceutically acceptable excipients.

[0017] Provided herein, in one aspect, is a method for modulating GYS1 in a cell, the method comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0018] Provided herein, in one aspect, is a method for inhibiting GYS1 in a cell, the method comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0019] Provided herein, in one aspect, is a method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual an effective amount of (i) a composition comprising an effective amount of a compound of Formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of Formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0020] Provided herein, in one aspect, is a method of modulating GYS1 in the cells of an individual in need thereof, comprising administering to the individual an effective amount of (i) a composition comprising an effective amount of a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0021] Provided herein, in one aspect, is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of (i) a composition comprising an effective amount of a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0022] Provided herein, in one aspect, is a method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0023] In one aspect, provided herein is a kit comprising: (i) a composition comprising an effective amount of a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use thereof in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

[0024] In one aspect, provided herein is a kit comprising: (i) a composition comprising a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; or a pharmaceutical composition comprising a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

[0025]

[0013] Provided herein in some aspects are methods for preparing a compound of formula (I), or any embodiment or variation thereof, e.g., a compound of formula (I), (IA), (I-A1), (I-A2), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (IC), (ID), (IE), (I-E1), (I-E2), (IF), (I-F1), (IG), (I-G1), (I-G2), (I-G3), (I-G4), (IH), (I-H1), (I-H2), (I-H3), (I-H4), or (I-H5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. [Brief explanation of the drawings]

[0026] [Figure 1] Figure 1 shows the pathway by which PPP1R3A loss of function (LoF) leads to reduced muscle glycogen.

[0027] [Figure 2A] and [Figure 2B] Figure 1 shows the association between PPP1R3A protein-truncating variants (PTVs) and left ventricular ejection fraction (LVEF) (%) and left ventricular wall thickness (mm) in UK Biobank.

[0028] [Figure 2C] and [Figure 2D] Figure 1 shows the association between PPP1R3A protein-truncating variants (PTV) and exercise power (watts), and maximum heart rate (HR) exercise (bpm) in UK Biobank.

[0029] [Figure 2E] and [Figure 2F] Figure 1 shows the association between PPP1R3A protein-truncating variants (PTVs) and PQ interval (ms) and QRS duration (ms) in UK Biobank.

[0030] [Figure 2G] and [Figure 2H] Figure 1 shows the association between PPP1R3A protein-truncating variants (PTVs) and QT interval (ms) and serum glucose (mmol / L) in UK Biobank. DETAILED DESCRIPTION OF THE INVENTION

[0031] "Individual" refers to mammals, including humans and non-human mammals. Examples of individuals include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, individual refers to a human.

[0032] As used herein, "about" in reference to a parameter or value includes and describes the parameter or value itself. For example, "about X" includes and describes X itself.

[0033] As used herein, an "at risk" individual is an individual at risk of developing a disease or condition. An "at risk" individual may or may not have a detectable disease or condition, and may or may not exhibit detectable disease prior to the treatment methods described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. Individuals who have one or more of these risk factors have a higher likelihood of developing a disease or condition than individuals who do not have these risk factors.

[0034] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired results may include one or more of the following: reducing one or more symptoms resulting from a disease or condition; reducing the severity of a disease or condition; delaying or preventing the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or slowing the worsening or progression of a disease or condition); and alleviating the disease, such as by causing regression of clinical symptoms (e.g., ameliorating a disease state, enhancing the effect of another drug, slowing the progression of a disease, improving quality of life, and / or prolonging survival).

[0035] As used herein, "delaying the onset of a disease or condition" means to postpone, inhibit, slow, decelerate, stabilize, and / or postpone the onset of the disease or condition. This delay can be of varying lengths of time, depending on the disease being treated and / or the medical history of the individual. As will be apparent to one of skill in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.

[0036] As used herein, the term "therapeutically effective amount" or "effective amount" refers to a compound of the present disclosure or a pharmaceutical salt thereof sufficient to provide treatment when administered to an individual. As understood in the art, an effective amount may be one or more administrations, e.g., a single administration or multiple administrations may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents; a single agent may be considered to be administered in an effective amount if, in conjunction with one or more other agents, a desired or beneficial result may be obtained or achieved.

[0037] As used herein, "unit dosage form" refers to physically discrete units suitable as unit dosages, each containing a predetermined amount of active ingredient or compound, which may be in a pharmaceutically acceptable carrier.

[0038] As used herein, "pharmaceutically acceptable" means a substance that is not biologically or otherwise undesirable, e.g., the substance can be incorporated into a pharmaceutical composition administered to an individual without causing significant undesired biological effects.

[0039] The term "alkyl," as used herein, refers to an unbranched or branched monovalent saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbons (i.e., C 1~20 alkyl), 1 to 16 carbons (i.e., C 1~16 alkyl), 1 to 12 carbons (i.e., C 1~12 alkyl), 1 to 10 carbons (i.e., C 1~10 alkyl), 1 to 8 carbons (i.e., C 1~8 alkyl), 1 to 6 carbons (i.e., C 1~6 alkyl), 1 to 4 carbons (i.e., C 1~4 alkyl), or 1 to 3 carbons (i.e., C 1~3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by a chemical name or molecular formula, all positional isomers having that number of carbon atoms are encompassed (e.g., "butyl" includes n-butyl, sec-butyl, isobutyl, and tert-butyl, and "propyl" includes n-propyl and isopropyl). Certain commonly used alternative names may be used and will be understood by those skilled in the art. For example, a divalent group, such as a divalent "alkyl" group, may be referred to as an "alkylene."

[0040] As used herein, the term "alkenyl" refers to a branched or unbranched monovalent hydrocarbon chain containing at least one carbon-carbon double bond. As used herein, alkenyl refers to a hydrocarbon chain having 2 to 20 carbons (i.e., C 2~20 alkenyl), 2 to 16 carbons (i.e., C 2~16 alkenyl), 2 to 12 carbons (i.e., C 2~12 alkenyl), 2 to 10 carbons (i.e., C 2~10 alkenyl), 2 to 8 carbons (i.e., C 2~8 alkenyl), 2 to 6 carbons (i.e., C 2~6 alkenyl), 2 to 4 carbons (i.e., C 2~4 alkenyl), or 2-3 carbons (i.e., C 2~3alkenyl). Examples of alkenyl include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl-1,2-butadienyl, and 1,3-butadienyl. When an alkenyl residue having a specific number of carbon atoms is named by a chemical name or molecular formula, all positional isomers having that number of carbon atoms can be encompassed (e.g., "propenyl" includes prop-1-enyl and prop-2-enyl). Certain commonly used alternative names may be used and will be understood by those skilled in the art. For example, a divalent group such as a divalent "alkenyl" group can be referred to as "alkenylene."

[0041] As used herein, the term "alkynyl" refers to a branched or unbranched monovalent hydrocarbon chain containing at least one carbon-carbon triple bond. As used herein, alkynyl refers to an alkyl group having 2 to 20 carbons (i.e., C 2~20 alkynyl), 2 to 16 carbons (i.e., C 2~16 alkynyl), 2 to 12 carbons (i.e., C 2~12 alkynyl), 2 to 10 carbons (i.e., C 2~10 alkynyl), 2 to 8 carbons (i.e., C 2~8 alkynyl), 2 to 6 carbons (i.e., C 2~6 alkynyl), 2 to 4 carbons (i.e., C 2~4 alkynyl), or 2-3 carbons (i.e., C 2~3 alkynyl). Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl. When an alkynyl residue having a specific number of carbons is named by a chemical name or molecular formula, all positional isomers having that number of carbon atoms can be included (e.g., "propynyl" includes prop-1-ynyl and prop-2-ynyl). Certain commonly used alternative names may be used and will be understood by those skilled in the art. For example, a divalent group such as a divalent "alkynyl" group can be referred to as an "alkynylene."

[0042] The term "alkoxy" as used herein refers to an -O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0043] The term "aryl," as used herein, refers to a fully unsaturated carbocyclic ring moiety. The term "aryl" encompasses monocyclic and polycyclic fused ring moieties. As used herein, aryl refers to, for example, a ring of 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 16 ring carbon atoms (i.e., C 6~16 aryl), 6 to 12 ring carbon atoms (i.e., C 6~12 aryl), or 6 to 10 ring carbon atoms (i.e., C 6~10 Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0044] The term "cycloalkyl," as used herein, refers to a saturated or partially unsaturated carbocyclic ring moiety. The term "cycloalkyl" encompasses monocyclic and polycyclic ring moieties, which may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, where the ring moiety contains at least one cyclic double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety containing at least one non-aromatic ring, regardless of the point of attachment to the rest of the molecule. As used herein, cycloalkyl refers to, for example, a ring having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 16 ring carbon atoms (i.e., C 3~16 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8cycloalkyl), 3 to 6 ring carbon atoms (i.e., C 3~6 cycloalkyl), or 3 to 5 ring carbon atoms (i.e., C 3~5 Cycloalkyl includes rings containing cycloalkyl groups. Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, cycloalkyl also includes spirocycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0045] The term "halo," as used herein, refers to those atoms occupying Group VIIA of the periodic table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

[0046] The term "heteroaryl," as used herein, refers to an aromatic (fully unsaturated) ring moiety containing one or more ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term "heteroaryl" includes both monocyclic and polycyclic fused ring moieties. As used herein, heteroaryl includes, for example, 5 to 20 ring atoms (i.e., 5-20-membered heteroaryl), 5 to 16 ring atoms (i.e., 5-16-membered heteroaryl), 5 to 12 ring atoms (i.e., 5-12-membered heteroaryl), 5 to 10 ring atoms (i.e., 5-10-membered heteroaryl), 5 to 8 ring atoms (i.e., 5-8-membered heteroaryl), or 5 to 6 ring atoms (i.e., 5-6-membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety containing one or more ring heteroatoms is considered heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety can be attached to the remainder of the molecule through any ring carbon or any ring heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, Including, but not limited to, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl.Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, and the heteroaryl may be attached via either ring of the fused system.

[0047] The term "heterocyclyl," as used herein, refers to a saturated or partially unsaturated cyclic moiety containing one or more ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes both monocyclic and polycyclic ring moieties, which may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic aromatic ring moiety containing at least one ring heteroatom is considered to be heterocyclyl, regardless of the point of attachment to the rest of the molecule (i.e., the heterocyclyl moiety can be attached to the rest of the molecule through any ring carbon or any ring heteroatom of the heterocyclyl moiety). Furthermore, the term heterocyclyl is intended to encompass any polycyclic ring moiety containing at least one ring heteroatom, provided that the polycyclic ring moiety contains at least one non-aromatic ring, regardless of the point of attachment to the rest of the molecule. As used herein, heterocyclyl includes, for example, 3 to 20 ring atoms (i.e., 3-20-membered heterocyclyl), 3 to 16 ring atoms (i.e., 3-16-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3-12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3-10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3-8-membered heterocyclyl), 3 to 6 ring atoms (i.e., 3-6-membered heterocyclyl), 3 to 5 ring atoms (i.e., 3-5-membered heterocyclyl), 5 to 8 ring atoms (i.e., 5-8-membered heterocyclyl), or 5 to 6 ring atoms (i.e., 5-6-membered heterocyclyl).Examples of heterocyclyl groups are, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoquinol ... Includes isoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of spiroheterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl may be attached via either ring of the fused system.

[0048] As used herein, the term "oxo" refers to a =O moiety.

[0049] The terms "optional" and "optionally," as used herein, mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. Thus, the term "optionally substituted" infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms at the specified atom, moiety, or group may or may not be replaced by atoms, moieties, or groups other than hydrogen. By way of example, and not limitation, the phrase "methyl optionally substituted with one or more chloro" encompasses the moieties -CH, -CHCl, -CHCl, and -CCl.

[0050] Aspects and embodiments described herein as "comprising" are to be understood to include "consisting of" and "consisting essentially of" embodiments.

[0051] The term "pharmaceutically acceptable salt" of a given compound, as used herein, refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Furthermore, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. See, for example, "Handbook of Pharmaceutical Salts Properties, Selection, and Use," International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), incorporated herein by reference. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines.Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0052] Isotopically labeled forms of the compounds described herein can be prepared. Isotopically labeled compounds have the structures shown herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. In some embodiments, compounds of Formula (A) are provided in which one or more hydrogens are replaced with deuterium or tritium.

[0053] Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with each other. By way of example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, the compounds of this disclosure will be understood by those skilled in the art to include both the amide and imidic acid tautomers. Thus, for example, an amide-containing compound is understood to include its imidic acid tautomer. Similarly, an imidic acid-containing compound is understood to include its amide tautomer.

[0054] Prodrugs of the compounds disclosed herein or pharmaceutically acceptable salts thereof are also provided herein. Prodrugs are compounds that can be administered to an individual and release the compounds disclosed herein as parent drug compounds in vivo. It should be understood that prodrugs can be prepared by modifying functional groups in the parent drug compound so that the modifications are cleaved in vitro or in vivo to release the parent drug compound. See, for example, Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov 7, 255-270 (2008), which is incorporated herein by reference.

[0055] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)- (or, in the case of amino acids, (D)- or (L)-). The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms, and mixtures thereof, in any proportion. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, for example, chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC) and chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers. Similarly, cis and trans are used in their conventional sense to describe relative spatial relationships.

[0056] "Stereoisomers" refer to compounds consisting of the same atoms connected by the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose structures are non-superimposable mirror images of each other. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0057] Where enantiomeric and / or diastereomeric forms of a given structure exist, a planar bond indicates that all stereoisomeric forms of the structure shown may exist, for example: [ka]

[0058] Where enantiomeric and / or diastereomeric forms of a given structure exist, a wedge or hash bond indicates that the composition consists of at least 90% by weight of a single enantiomer or diastereomer of the known stereochemistry, for example, [ka]

[0059] Combinations of the above notations may be used where applicable. Exemplary species may contain stereocenters with known stereochemistry and stereocenters with unknown stereochemistry, such as: [ka]

[0060] compound In one embodiment, a compound of formula (I): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y 1 and Y 2 are each CH, or Y 1 and Y 2 One of them is N and Y 1 and Y 2 the other of which is CH, X 1 and X 2 are each independently H or halo; R 3 and R 4 are each —CH3, or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl, (1) L does not exist, and Q 1 but, (I C 6~20 aryl, and Q 1 C 6~20 Aryl is one or more of -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 optionally substituted with -NH-(3- to 15-membered alkyl), -NH-(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 The alkyl may contain one or more halo, C 1~6Alkoxy or C 3~10 optionally substituted with cycloalkyl, and -NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6 C optionally substituted with alkyl 6~20 aryl, or (ii) 3- to 15-membered heterocyclyl, where Q 1 wherein the 3- to 15-membered heterocyclyl is optionally substituted by one or more oxo; or (iii) 5- to 20-membered heteroaryl, where Q 1 The 5- to 20-membered heteroaryl contains at least one ring N atom and is substituted with one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 a 5- to 20-membered heteroaryl optionally substituted with cycloalkyl; or (2) L is -CH2-, and Q 1 C 3~10 or cycloalkyl; m is 0 or 1, n is 0 or 1, R 1 H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~6 is alkyl, R 1 -C(O)-NH(C 1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~6 Alkyl C 1~6 The alkyl group may be one or more of -NH-C(O)-C 1~6 optionally substituted with alkyl or -C(O)-NH2, and R2 is H, halo, or —OH.

[0061] In some embodiments of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, n is 0, 1, or 2, and m+n is an integer from 1 to 2. In some embodiments, m is 0 and n is 1 or 2. In some embodiments, m is 0 and n is 1. In some embodiments, m is 0 and n is 2. In some embodiments, m is 1 and n is 0 or 1. In some embodiments, m is 1 and n is 0. In some embodiments, m is 1 and n is 1. In some embodiments, m+n is 1. In some embodiments, m+n is 2.

[0062] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 and Y 2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of Y is CH. 1 and Y 2 are each CH. In some embodiments, Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH.

[0063] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 1 is H.

[0064] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 1is halo. In some embodiments, X 1 is fluoro.

[0065] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 2 is H.

[0066] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 2 is halo. In some embodiments, X 2 is fluoro.

[0067] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 1 and X 2 are each independently H or halo. In some embodiments, X 1 and X 2 are each independently H or F. In some embodiments, X 1 and X 2 are each independently H. In some embodiments, X 1 and X 2 are each independently halo. 1 and X 2 are each independently F. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other of X is halo. 1 and X 2 One of them is H and X 1 and X 2 The other of these is F.

[0068] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3 and R 4 are each —CH3. In some embodiments, R 3 and R 4 are taken together with the atom to which they are attached to form a cyclopropyl. In some embodiments, R 3 and R 4 together with the atom to which they are attached form cyclobutyl.

[0069] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 3 and R 4 are -CH3, and X 1 and X 2 are each hydrogen. In some embodiments, R 3 and R 4 are -CH3, and X 1 or X 2 is F. In some embodiments, R 3 and R 4 together with the atom to which they are attached form a cyclopropyl, and X 1 and X 2 are each hydrogen. In some embodiments, R 3 and R 4 together with the atom to which they are attached form a cyclobutyl, and X 1 and X 2 are each hydrogen. In some embodiments, R 3 and R 4 together with the atom to which they are attached form a cyclopropyl, and X 1 or X 2 is F.

[0070] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 and Y 2 are CH, and R 3 and R 4are -CH3, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 are CH, and R 3 and R 4 are -CH3, and X 1 or X 2 is F. In some embodiments, Y 1 and Y 2 are CH, and R 3 and R 4 together with the atom to which they are attached form a cyclopropyl, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 are CH, and R 3 and R 4 together with the atom to which they are attached form a cyclobutyl, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 are CH, and R 3 and R 4 together with the atom to which they are attached form a cyclopropyl, and X 1 or X 2 is F.

[0071] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and R 3 and R 4 are -CH3, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 One of them is N and Y 1 and Y2 The other of these is CH, and R 3 and R 4 are -CH3, and X 1 or X 2 is F. In some embodiments, Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and R 3 and R 4 together with the atom to which they are attached form a cyclopropyl, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and R 3 and R 4 together with the atom to which they are attached form a cyclobutyl, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and R 3 and R 4 together with the atom to which they are attached form a cyclopropyl, and X 1 or X 2 is F.

[0072] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 and Y 2 are CH, respectively.

[0073] In some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound has the structure of Formula (I): [ka] The structure: [ka] In some embodiments, the structure of formula (I) is selected from the group consisting of: [ka] The structure: [ka] In some embodiments, the structure of formula (I) is selected from the group consisting of: [ka] The structure: [ka] In some embodiments, the structure of formula (I) is selected from the group consisting of: [ka] The structure: [ka] is. In some embodiments, the structure of formula (I): [ka] The structure: [ka] In some embodiments, the structure of formula (I): [ka] The structure: [ka] is.

[0074] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH.

[0075] In some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound has the structure of Formula (I): [ka] The structure: [ka] In some embodiments, the structure of formula (I) is selected from the group consisting of: [ka] The structure: [ka] In some embodiments, the structure of formula (I) is selected from the group consisting of: [ka] The structure: [ka] In some embodiments, the structure of formula (I): [ka] The structure: [ka] In some embodiments, the structure of formula (I): [ka] The structure: [ka] is selected from the group consisting of:

[0076] In some embodiments of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent.

[0077] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is C 6~20 aryl, and Q 1 C 6~20 Aryl is a group consisting of one or more of -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 and optionally substituted with -NH-(3- to 15-membered heterocyclyl), -NH-(3- to 15-membered heteroaryl), and the 3- to 15-membered heterocyclyl of -NH-C(O)-(3- to 15-membered heterocyclyl) is optionally substituted with one or more -C(O)-C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 Alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 Optionally substituted with cycloalkyl, wherein the 3- to 15-membered heterocyclyl of -NH-(3- to 15-membered heterocyclyl) is optionally substituted with one or more oxo or C 1~6Optionally substituted with alkyl.

[0078] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is phenyl and Q 1 The phenyl in 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), or -NH-C(=N-CN)-NH2, -NH(C 1~6 alkyl), The 3- to 15-membered heterocyclyl of -NH-C(O)-(3- to 15-membered heterocyclyl) is one or more -C(O)-C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 Alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 optionally substituted with cycloalkyl, and The 3- to 15-membered heterocyclyl of —NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6 Optionally substituted with alkyl.

[0079] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is phenyl and Q 1 The phenyl in 1~3 Alkyl, C 1~3 Alkoxy, C 3~6Cycloalkyl, 5-10 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~3 alkyl), -NH-C(O)-C 1~3 Alkyl, -NH-C(O)-C 3~6 Cycloalkyl, -NH-C(O)-(3- to 6-membered heterocyclyl), or -NH-C(=N-CN)-NH2, -NH(C 1~3 alkyl), The 3- to 6-membered heterocyclyl of -NH-C(O)-(3- to 6-membered heterocyclyl) is one or more -C(O)-C 1~3 Alkyl or C 1~6 optionally substituted with alkyl, C 1~3 Alkyl may contain one or more halo, C 1~3 Alkoxy or C 3~6 optionally substituted with cycloalkyl, and The 3- to 6-membered heterocyclyl of —NH-(3- to 6-membered heterocyclyl) is one or more oxo or C 1~3 Optionally substituted with alkyl.

[0080] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 The structure: [ka] In some embodiments, Q is selected from the group consisting of 1 The structure: [ka] In some embodiments, Q is selected from the group consisting of 1 The structure: [ka] In some embodiments, Q is selected from the group consisting of 1 The structure: [ka] In some embodiments, Q 1 The structure: [ka] is.

[0081] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is a 3- to 15-membered heterocyclyl, and Q 1 In some embodiments, L is absent and Q is optionally substituted with one or more oxo. 1 is a 3- to 6-membered heterocyclyl, and Q 1 In some embodiments, the 3- to 6-membered heterocyclyl of Q is optionally substituted with one or more oxo. 1 is a 6- to 10-membered heterocyclyl, and Q 1 The 6- to 10-membered heterocyclyl may have one or more oxo or C 1~3 In some embodiments, Q is optionally substituted with alkyl. 1 is a 9- to 10-membered heterocyclyl, and Q 1 In some embodiments, the 9- to 10-membered heterocyclyl of Q is optionally substituted with one or more oxo. 1 The structure: [ka] In some embodiments, Q is selected from the group consisting of 1 The structure: [ka] is selected from the group consisting of:

[0082] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is a 5- to 20-membered heteroaryl; Q1 The 5- to 20-membered heteroaryl may be one or more of -NH2, halo, C 1~6 Alkyl, or C 3~10 In some embodiments, Q is optionally substituted with cycloalkyl. 1 is a 5- to 10-membered heteroaryl, and Q 1 The 5- to 10-membered heteroaryl may be one or more of -NH2, halo, C 1~6 Alkyl, or C 3~10 optionally substituted with cycloalkyl, and Q 1 The 5-10 membered heteroaryl of Q contains at least one ring N. In some embodiments, Q 1 is pyridinyl and Q 1 The pyridinyl may be one or more of -NH2, halo, C 1~6 Alkyl, or C 3~10 In some embodiments, Q is optionally substituted with cycloalkyl. 1 is pyridinyl. In some embodiments, Q 1 is pyrazolyl.

[0083] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is a 5- to 20-membered heteroaryl; Q 1 The 5- to 20-membered heteroaryl of the formula (I) contains at least one ring N atom and one or more of -NH2, halo, C 1~6 Alkyl, or C 3~10 In some embodiments, Q is optionally substituted with cycloalkyl. 1 is a 6- to 10-membered heteroaryl, and Q 1 The 6- to 10-membered heteroaryl of the formula (I) contains at least one ring N atom and one or more of -NH2, halo, C 1~6 Alkyl, or C 3~10 In some embodiments, Q is optionally substituted with cycloalkyl. 1 The structure: [ka] In some embodiments, Q is selected from the group consisting of 1 The structure: [ka] In some embodiments, Q is selected from the group consisting of 1 The structure: [ka] is selected from the group consisting of:

[0084] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is -CH2-.

[0085] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is —CH— and Q 1 is C 3~10 In some embodiments, L is -CH- and Q is cycloalkyl. 1 is C 3~6 It is cycloalkyl.

[0086] In some embodiments of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1 and n is 0 or 1. In some embodiments, m is 0 and n is 1. In some embodiments, m is 0 and n is 0. In some embodiments, m is 0 and n is 1 or 0. In some embodiments, m is 1 and n is 0. In some embodiments, m is 1 and n is 1. In some embodiments, m is 1 and n is 0 or 1.

[0087] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~6 alkyl, and R 1 -C(O)-NH(C 1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~6 Alkyl C 1~6 Alkyl is one or more -NH-C(O)-C 1~6 optionally substituted with alkyl or -C(O)-NH; R 2 is H, halo, or —OH. In some embodiments, R 1 is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~3 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~6 alkyl, and R 1 -C(O)-NH(C 1~3 C of alkyl) 1~3 Alkyl is one or more -C(O)-C 1~3 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~3 Alkyl C 1~3 Alkyl is one or more -NH-C(O)-C 1~3 Optionally substituted with alkyl or -C(O)-NH. In some embodiments,

[0088] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is H, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, and -NH-C(O)-C 1~6 is selected from the group consisting of alkyl, -C(O)-NH(C1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; -NH-C(O)-C 1~6 Alkyl C 1~6 Alkyl is one or more -NH-C(O)-C 1~6 Optionally substituted with alkyl or -C(O)-NH2.

[0089] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~6 alkyl, and R 1 -C(O)-NH(C 1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~6 Alkyl C 1~6 Alkyl is one or more -NH-C(O)-C 1~6 Optionally substituted with alkyl or -C(O)-NH2.

[0090] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is H.

[0091] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, and -NH-C(O)-C 1~6is selected from the group consisting of alkyl, -C(O)-NH(C 1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; -NH-C(O)-C 1~6 Alkyl C 1~6 Alkyl is one or more -NH-C(O)-C 1~6 Optionally substituted with alkyl or -C(O)-NH2.

[0092] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is -CN, [ka] is selected from the group consisting of:

[0093] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is H or halo. In some embodiments, R 1 is H or fluoro. In some embodiments, R 1 is H. In some embodiments, R 1 is fluoro.

[0094] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is H, halo, or —OH. In some embodiments, R 2 is H. In some embodiments, R 2 is halo. In some embodiments, R 2 is F. In some embodiments, R 2 is -OH.

[0095] In some embodiments of a compound of Formula (I), or any embodiment or variation thereof, e.g., a compound of Formula (IA), (I-A1), (I-A2), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (IC), (ID), (IE), (I-E1), (I-E2), (IF), (I-F1), (I-F2), (IG), (I-G1), (I-G2), (I-G3), (I-G4), (IH), (I-H1), (I-H2), (I-H3), (I-H4), or (I-H5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, [ka] wherein m, n, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , Y 1 , Y 2 , L and Q 1 is as defined elsewhere herein.

[0096] In some embodiments of a compound of Formula (I), or any embodiment or variation thereof, e.g., a compound of Formula (IA), (I-A1), (I-A2), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (IC), (ID), (IE), (I-E1), (I-E2), (IF), (I-F1), (I-F2), (IG), (I-G1), (I-G2), (I-G3), (I-G4), (IH), (I-H1), (I-H2), (I-H3), (I-H4), or (I-H5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, [ka] wherein m, n, R 1 , R 2 , R3 , R 4 , X 1 , X 2 , Y 1 , Y 2 , and Q 1 is as defined elsewhere herein.

[0097] In some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, n is 0 or 1, and Y 1 and Y 2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are each independently H or halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 is phenyl and Q 1 The phenyl in 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH(C 1~6 and optionally substituted with -NH-(3- to 15-membered heterocyclyl), -NH-(3- to 15-membered heteroaryl), and the 3- to 15-membered heterocyclyl of -NH-C(O)-(3- to 15-membered heterocyclyl) is optionally substituted with one or more -C(O)-C 1~6 Alkyl or C 1~6optionally substituted with alkyl, C 1~6 Alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 Optionally substituted with cycloalkyl, wherein the 3- to 15-membered heterocyclyl of -NH-(3- to 15-membered heterocyclyl) is optionally substituted with one or more oxo or C 1~6 optionally substituted with alkyl, R 1 is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~6 alkyl, and R 1 -C(O)-NH(C 1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~6 Alkyl C 1~6 Alkyl is one or more -NH-C(O)-C 1~6 optionally substituted with alkyl or -C(O)-NH; R 2 is H, halo, or —OH. In some embodiments, m is 0 or 1, n is 0 or 1, and Y 1 and Y 2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are each independently H or halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 is phenyl and Q 1 The phenyl in 1~3 Alkyl, C 1~3 Alkoxy, C6~10 Cycloalkyl, 5-10 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~3 alkyl), -NH-C(O)-C 1~3 Alkyl, -NH-C(O)-C 3~6 Cycloalkyl, -NH-C(O)-(3- to 6-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH(C 1~3 and optionally substituted with -NH-(3- to 10-membered heterocyclyl), -NH-(3- to 10-membered heteroaryl), and the 3- to 10-membered heterocyclyl of -NH-C(O)-(3- to 10-membered heterocyclyl) is optionally substituted with one or more -C(O)-C 1~3 Alkyl or C 1~3 optionally substituted with alkyl, C 1~3 Alkyl may contain one or more halo, C 1~3 Alkoxy or C 6~10 Optionally substituted with cycloalkyl, wherein the 3- to 10-membered heterocyclyl of -NH-(3- to 10-membered heterocyclyl) is optionally substituted with one or more oxo or C 1~3 optionally substituted with alkyl, R 1 is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~3 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~3 alkyl, and R 1 -C(O)-NH(C 1~3 C of alkyl) 1~3 Alkyl is one or more -C(O)-C 1~3 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~3 Alkyl C 1~3 Alkyl is one or more -NH-C(O)-C 1~3 optionally substituted with alkyl or -C(O)-NH; R 2 is H, halo, or —OH.

[0098] In some embodiments, m is 0 or 1, n is 0 or 1, and Y 1 and Y2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are each independently H or halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 is phenyl and Q 1 The phenyl in 6~10 Cycloalkyl, 5-10 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(CH3), -NH-C(O)-CH3, -NH-C(O)-C 3~6 Cycloalkyl, -NH-C(O)-(3- to 6-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH(C 1~3 -C(O)-(3- to 6-membered heterocyclyl) is optionally substituted with one or more -C(O)-CH3 or CH3, and CH3 is optionally substituted with one or more halo, -OCH3, or C 6~10 Optionally substituted with cycloalkyl, wherein the 3- to 6-membered heterocyclyl of -NH-(3- to 6-membered heterocyclyl) is optionally substituted with one or more oxo or C 1~3 optionally substituted with alkyl, R 1 is H, F, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(CH3), -NH-C(O)-NH2, or -NH-C(O)-CH3, and R 1 CH3 of -C(O)-NH(CH3) is optionally substituted with one or more -C(O)-OCH3, and R 1-CH3 of -NH-C(O)-CH3 is optionally substituted with one or more -NH-C(O)-CH3 or -C(O)-NH2, and R 2 is H, halo, or —OH.

[0099] In some embodiments, m is 0, n is 0, and Y 1 and Y 2 are CH, and R 3 and R 4 are -CH3, and X 1 is H and X 2 is H and Q 1 is phenyl and Q 1 The phenyl in the formula (I) is one or more of -OH, -NH2, F, CH3, -OCH3, C 6~10 Cycloalkyl, 5-10 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(CH3), -NH-C(O)-CH3, -NH-C(O)-C 3~6 Cycloalkyl, -NH-C(O)-(3- to 6-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH(C 1~3 -C(O)-(3- to 6-membered heterocyclyl) is optionally substituted with one or more -C(O)-CH3 or CH3, and CH3 is optionally substituted with one or more halo, -OCH3, or C 6~10 Optionally substituted with cycloalkyl, wherein the 3- to 6-membered heterocyclyl of -NH-(3- to 6-membered heterocyclyl) is optionally substituted with one or more oxo or C 1~3 optionally substituted with alkyl, R 1 is H and R 2 is H.

[0100] In some embodiments, m is 0, n is 0, and Y 1 and Y 2 are CH, and R 3 and R 4 are -CH3, and X 1 is H and X 2is F and Q 1 is phenyl and Q 1 is optionally substituted with one or more -NH-C(O)-NH; 1 is H or F, and R 2 is H.

[0101] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, n is 1, and Y 1 is CH and Y 2 is N and R 3 and R 4 are -CH3, and X 1 and X 2 are each independently H, and Q 1 is phenyl and Q 1 The phenyl in 1~3 Alkyl or -NH-C(O)-C 1~3 optionally substituted with alkyl, R 1 is H and R 2 is H. In some embodiments, m is 0, n is 1, and Y 1 is CH and Y 2 is N and R 3 and R 4 are -CH3, and X 1 and X 2 are each independently H, and Q 1 is phenyl and Q 1 The phenyl in R is optionally substituted with one or more -CH or -NH-C(O)-CH; 1 is H and R 2 is H.

[0102] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, n is 1, and Y 1 is CH and Y 2 is N and X 1 is H and X 2 is the halo and R3 and R 4 together with the atoms to which they are attached form a cyclopropyl, and Q 1 is phenyl and Q 1 The phenyl in R is optionally substituted with one or more 5- to 10-membered heteroaryl; 1 is H and R 2 In some embodiments, m is 0, n is 1, and Y 1 is CH and Y 2 is N and X 1 is H and X 2 is the halo and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form a cyclopropyl, and Q 1 is phenyl and Q 1 The phenyl in R is optionally substituted with one or more pyrazolyls; 1 is H and R 2 is F.

[0103] In some embodiments of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, n is 0 or 1, and Y 1 and Y 2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are each independently H or halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 is phenyl and R 1is H, F, -C(O)-NH(CH), -NH-C(O)-NH, or -NH-C(O)-CH; R 1 -CH3 of -NH-C(O)-CH3 is optionally substituted with one or more -NH-C(O)-CH3 or -C(O)-NH2, and R 2 is H or halo.

[0104] In some embodiments of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, n is 0 or 1, and Y 1 and Y 2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are each independently H or halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 is phenyl and R 1 is H, F, -C(O)-NH(CH), -NH-C(O)-NH, or -NH-C(O)-CH; R 1 -CH3 of -NH-C(O)-CH3 is optionally substituted with one or more -NH-C(O)-CH3 or -C(O)-NH2, and R 2 is H, OH, or halo.

[0105] In some embodiments of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, n is 0 or 1, and Y 1 and Y 2 are CH, and X 1 and X 2 are each independently H or halo, and R 3and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 is phenyl and R 1 is H, F, -C(O)-NH(CH), -NH-C(O)-NH, or -NH-C(O)-CH; R 1 -CH3 of -NH-C(O)-CH3 is optionally substituted with one or more -NH-C(O)-CH3 or -C(O)-NH2, and R 2 is H, OH, or halo.

[0106] In some embodiments of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, n is 0 or 1, and Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are each independently H or halo, and R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 is phenyl and R 1 is H or F, and R 2 is H or halo.

[0107] In some embodiments of a compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, n is 0 or 1, and Y 1 and Y 2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2are each independently H or halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 (i) 3- to 15-membered heterocyclyl, and Q 1 wherein Q is a 3- to 15-membered heterocyclyl optionally substituted with one or more oxo; or (ii) a 5- to 20-membered heteroaryl; 1 The 5- to 20-membered heteroaryl contains at least one ring N atom and is substituted with one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 optionally substituted with cycloalkyl; R 1 is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~3 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~3 alkyl, and R 1 -C(O)-NH(C 1~3 C of alkyl) 1~3 Alkyl is one or more -C(O)-C 1~3 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~3 Alkyl C 1~3 Alkyl is one or more -NH-C(O)-C 1~3 optionally substituted with alkyl or -C(O)-NH; R 2 is H, halo, or —OH. In some embodiments, m is 0 or 1, n is 0 or 1, and Y 1 and Y 2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are each independently H or halo, and R 3 and R 4are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 (i) 3- to 10-membered heterocyclyl, and Q 1 wherein Q is a 3- to 10-membered heterocyclyl optionally substituted with one or more oxo; or (ii) a 5- to 10-membered heteroaryl; 1 The 5- to 10-membered heteroaryl contains at least one ring N atom and is substituted with one or more of -NH2, halo, C 1~3 Alkyl or C 3~6 optionally substituted with cycloalkyl; R 1 is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~3 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~3 alkyl, and R 1 -C(O)-NH(C 1~3 C of alkyl) 1~3 Alkyl is one or more -C(O)-C 1~3 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~3 Alkyl C 1~3 Alkyl is one or more -NH-C(O)-C 1~3 optionally substituted with alkyl or -C(O)-NH; R 2 is H, halo, or —OH.

[0108] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, n is 0, and Y 1 and Y 2 are CH, and X 1 and X 2 are each independently H, and R 3 and R 4 are -CH3, and Q 1 is a 3- to 15-membered heterocyclyl, and Q 1is optionally substituted with one or more oxo; and R 1 is H, halo, and R 2 is H, halo, or —OH. In some embodiments, m is 0, n is 0, and Y 1 and Y 2 are CH, and X 1 and X 2 are each independently H, and R 3 and R 4 are -CH3, and Q 1 is a 3- to 10-membered heterocyclyl, and Q 1 is optionally substituted with one or more oxo; and R 1 is H, halo, and R 2 is H, halo, or —OH.

[0109] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, n is 0, and Y 1 is CH and Y 2 is N and X 1 is H and X 2 is the halo and R 3 and R 4 are -CH3, and Q 1 is a 3- to 15-membered heterocyclyl, and Q 1 is optionally substituted with one or more oxo; and R 1 is H, halo, and R 2 is H, halo, or —OH. In some embodiments, m is 0, n is 0, and Y 1 and Y 2 are CH, and X 1 and X 2 are each independently H, and R 3 and R 4 are -CH3, and Q 1 is a 3- to 10-membered heterocyclyl, and Q 1 is optionally substituted with one or more oxo; and R1 is H, halo, and R 2 is H, halo, or —OH.

[0110] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, n is 0, and Y 1 is CH and Y 2 is N and X 1 is H and X 1 and X 2 are each independently H, and R 3 and R 4 are -CH3, and Q 1 is a 3- to 15-membered heterocyclyl, and Q 1 The 3- to 15-membered heterocyclyl is optionally substituted with one or more oxo, and R 1 is H, halo, and R 2 is H, halo, or —OH. In some embodiments, m is 0, n is 0, and Y 1 and Y 2 are CH, and X 1 and X 2 are each independently H, and R 3 and R 4 are -CH3, and Q 1 is a 3- to 10-membered heterocyclyl, and Q 1 is optionally substituted with one or more oxo; and R 1 is H, halo, and R 2 is H, halo, or —OH.

[0111] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, n is 0, and Y 1 and Y 2 are CH, and X 1 and X 2 are each independently H, and R 3 and R 4 are -CH3, and Q 1is a 5- to 20-membered heteroaryl; Q 1 The 5- to 20-membered heteroaryl of the formula (I) contains at least one ring N atom and one or more C 1~6 optionally substituted with alkyl, R 1 is H and R 2 is H. In some embodiments, m is 0, n is 0, and Y 1 and Y 2 are CH, and X 1 and X 2 are each independently H, and R 3 and R 4 are -CH3, and Q 1 is a 5- to 10-membered heteroaryl, and Q 1 The 5- to 10-membered heteroaryl of the formula (I) contains at least one ring N atom and one or more C 1~3 optionally substituted with alkyl, R 1 is H and R 2 is H.

[0112] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, n is 0, and Y 1 and Y 2 are CH, and X 1 is H and X 2 is the halo and R 3 and R 4 are -CH3, and Q 1 is a 5- to 20-membered heteroaryl; Q 1 The 5- to 20-membered heteroaryl of the formula (I) contains at least one ring N atom and one or more C 1~6 optionally substituted with alkyl, R 1 is H or halo, and R 2 is H or halo. In some embodiments, m is 0, n is 0, and Y 1 and Y 2 are CH, and X 1 and X 2 are each independently H, and R 3 and R 4are -CH3, and Q 1 is a 5- to 10-membered heteroaryl, and Q 1 The 5- to 10-membered heteroaryl of the formula (I) contains at least one ring N atom and one or more -C 1~3 optionally substituted with alkyl, R 1 is H, halo, and R 2 is H, halo, or —OH.

[0113] In some embodiments of the compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, n is 0, and Y 1 is CH and Y 2 is N and X 1 is H and X 2 is the halo and R 3 and R 4 are -CH3, and Q 1 is a 5- to 20-membered heteroaryl; Q 1 The 5- to 20-membered heteroaryl of the formula (I) contains at least one ring N atom and one or more -C 1~6 optionally substituted with alkyl, R 1 is H, halo, and R 2 is H or halo. In some embodiments, m is 0, n is 0, and Y 1 and Y 2 are CH, and X 1 and X 2 are each independently H, and R 3 and R 4 are -CH3, and Q 1 is a 5- to 10-membered heteroaryl, and Q 1 The 5- to 10-membered heteroaryl of the formula (I) contains at least one ring N atom and one or more -C 1~3 optionally substituted with alkyl, R 1 is H or halo, and R 2 is H or halo.

[0114] In some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 0, n is 0 or 1, and Y 1 and Y 2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are each independently H or halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 is (i)C 6~20 aryl, and Q 1 C 6~20 Aryl is one or more of -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 and optionally substituted with -NH-(3- to 15-membered heterocyclyl), -NH-(3- to 15-membered heteroaryl), wherein the 3- to 15-membered heterocyclyl of -NH-C(O)-(3- to 15-membered heterocyclyl) is optionally substituted with one or more -C(O)-C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 The alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10Optionally substituted with cycloalkyl, wherein the 3- to 15-membered heterocyclyl of -NH-(3- to 15-membered heterocyclyl) is selected from the group consisting of one or more oxo or C 1~6 or (ii) 3- to 15-membered heterocyclyl, and Q 1 wherein Q is a 3- to 15-membered heterocyclyl optionally substituted with one or more oxo; or (iii) a 5- to 20-membered heteroaryl; 1 The 5- to 20-membered heteroaryl contains at least one ring N atom and is substituted with one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 optionally substituted with cycloalkyl; R 1 is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~6 alkyl, and R 1 -C(O)-NH(C 1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~6 Alkyl C 1~6 Alkyl is one or more -NH-C(O)-C 1~6 optionally substituted with alkyl or -C(O)-NH; R 2 is H, halo, or —OH.

[0115] In some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 1, n is 0 or 1, and Y 1 and Y 2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are each independently H or halo, and R3 and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 is (i)C 6~20 aryl, and Q 1 C 6~20 Aryl is one or more of -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 and optionally substituted with -NH-(3- to 15-membered heterocyclyl), -NH-(3- to 15-membered heteroaryl), wherein the 3- to 15-membered heterocyclyl of -NH-C(O)-(3- to 15-membered heterocyclyl) is optionally substituted with one or more -C(O)-C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 The alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 Optionally substituted with cycloalkyl, wherein the 3- to 15-membered heterocyclyl of -NH-(3- to 15-membered heterocyclyl) is selected from the group consisting of one or more oxo or C 1~6 or (ii) 3- to 15-membered heterocyclyl, and Q 1 wherein Q is a 3- to 15-membered heterocyclyl optionally substituted with one or more oxo; or (iii) a 5- to 20-membered heteroaryl; 1 The 5- to 20-membered heteroaryl contains at least one ring N atom and is substituted with one or more of -NH2, halo, C 1~6 Alkyl or C3~10 optionally substituted with cycloalkyl; R 1 is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~6 alkyl, and R 1 -C(O)-NH(C 1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~6 Alkyl C 1~6 Alkyl is one or more -NH-C(O)-C 1~6 optionally substituted with alkyl or -C(O)-NH; R 2 is H, halo, or —OH. In some embodiments, m is 1, n is 1, Y 1 and Y 2 are each CH or Y 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are each independently H or halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl, and Q 1 is (i)C 6~20 aryl, and Q 1 C 6~20 Aryl is one or more of -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 and optionally substituted with -NH-(3- to 15-membered heterocyclyl), -NH-(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl), and the 3- to 15-membered heterocyclyl of -NH-C(O)-(3- to 15-membered heterocyclyl) is optionally substituted with one or more -C(O)-C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 The alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 cycloalkyl, wherein the 3- to 15-membered heterocyclyl of -NH-(3- to 15-membered heterocyclyl) is optionally substituted with one or more oxo or C 1~6 optionally substituted with alkyl, R 1 is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~6 alkyl, and R 1 -C(O)-NH(C 1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~6 Alkyl C 1~6 Alkyl is one or more -NH-C(O)-C 1~6 optionally substituted with alkyl or -C(O)-NH; R 2 is H, halo, or —OH.

[0116] As used herein, in some embodiments, the compound has the formula (IA): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, of formula (I), wherein: iX 4~8 each independently represents H, —OH, —NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 -(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 The alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 optionally substituted with cycloalkyl, and -NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6 optionally substituted with alkyl; ii.X 6 But X 4 or X 8 and the atoms to which they are attached form ring A, and ring A is 3- to 9-membered heterocyclyl, wherein the 3- to 9-membered heterocyclyl of ring A is optionally substituted with one or more oxo; and X 5 , X 7 , and X 4 or X 8and the other of are, independently at each occurrence, H or oxo; or 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A contains at least one ring N atom and one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 optionally substituted with cycloalkyl; X 5 , X 7 , and X 4 or X 8 and the other of each independently is H, —NH, halo, C 1~6 Alkyl or C 3~10 cycloalkyl, or iii.X 7 But X 5 or X 8 and the atoms to which they are attached form ring A, and ring A is 3- to 9-membered heterocyclyl, wherein the 3- to 9-membered heterocyclyl of ring A is optionally substituted with one or more oxo; and X 4 , X 6 , and X 5 or X 8 and the other of are, independently at each occurrence, H or oxo; or 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A contains at least one ring N atom and one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 optionally substituted with cycloalkyl; X 4 , X 6 , and X 5 or X 8 and the other of each independently is H, —NH, halo, C 1~6 Alkyl or C 3~10 It is cycloalkyl.

[0117] In some embodiments of the compound of formula (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 4~8 are each independently H, —OH, —NH, halo, C1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 -(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of -NH-C(O)-(3- to 15-membered heterocyclyl) is one or more -C(O)-C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 Alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 optionally substituted with cycloalkyl, and The 3- to 15-membered heterocyclyl of —NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6 Optionally substituted with alkyl.

[0118] In some embodiments of the compound of formula (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 4~8 are each independently H.

[0119] In some embodiments of the compound of formula (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 4~8 One of the groups is -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 -(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of -NH-C(O)-(3- to 15-membered heterocyclyl) is one or more -C(O)-C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 Alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 optionally substituted with cycloalkyl, and The 3- to 15-membered heterocyclyl of —NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6 Optionally substituted with alkyl. X 4~8 The others of are each independently H.

[0120] In some embodiments, X 4~8 One of the following is methyl, OH, Cl, -OCH3, NH 2、 -NH(CH3), [ka] and X is selected from the group consisting of 4~8 The others of are each independently H.

[0121] In some embodiments of the compound of formula (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 6 is X 4 or X 8 and the atoms to which they are attached form ring A, and ring A is 3- to 9-membered heterocyclyl, wherein the 3- to 9-membered heterocyclyl of ring A is optionally substituted with one or more oxo; and X 5 , X 7 , and X 4 or X 8 and the other of are, independently at each occurrence, H or oxo; or 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A contains at least one ring N atom and one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 optionally substituted with cycloalkyl; X 5 , X 7 , and X 4 or X 8 and the other of each independently is H, —NH, halo, C 1~6 Alkyl or C 3~10 It is cycloalkyl.

[0122] In some embodiments of the compound of formula (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 6 is X 4 or X 8 and the atoms to which they are attached form ring A, and ring A is 3- to 6-membered heterocyclyl, wherein the 3- to 6-membered heterocyclyl of ring A is optionally substituted with one or more oxo; and X 5 , X 7 , and X 4 or X 8 and the other of are, independently at each occurrence, H or oxo; or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl of ring A contains at least one ring N atom and one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 optionally substituted with cycloalkyl; X 5 , X 7 , and X 4 or X 8 and the other of each independently is H, —NH, halo, C1~6 Alkyl or C 3~10 It is cycloalkyl.

[0123] In some embodiments of the compound of formula (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 6 is X 4 or X 8 and together with the atoms to which they are attached form ring A, wherein ring A is a 3- to 9-membered heterocyclyl, and the 3- to 9-membered heterocyclyl of ring A is optionally substituted with one or more oxo. In some embodiments, ring A is a 3- to 6-membered heterocyclyl, and the 3- to 6-membered heterocyclyl of ring A is optionally substituted with one or more oxo or C 1~3 In some embodiments, ring A is optionally substituted with alkyl. [ka] where # represents the point of attachment to the remainder of the molecule.

[0124] In some embodiments of the compound of Formula (IA), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A is a 5-14 membered heteroaryl, and the 5-14 membered heteroaryl of Ring A contains at least one ring N atom and one or more of -NH, halo, C 1~6 Alkyl, or C 3~10 optionally substituted with cycloalkyl; X 5 , X 7 , and X 4 or X 8 the other of which is independently H, —NH, halo, C 1~6 Alkyl, or C 3~10 In some embodiments, ring A is a 5-8 membered heteroaryl, and the 5-8 membered heteroaryl of ring A is selected from the group consisting of one or more of -NH, halo, C 1~6 Alkyl or C 3~10 optionally substituted with cycloalkyl; X 5 , X7 , and X 4 or X 8 the other of which is independently H, —NH, halo, C 1~6 Alkyl or C 3~10 In some embodiments, ring A is cycloalkyl. [ka] where # represents the point of attachment to the rest of the molecule.

[0125] As used herein, in some embodiments, the compound has the formula (I-A1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 4 H, -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 -(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 Alkyl may contain one or more halo, C 1~6 Alkoxy or C3~10 optionally substituted with cycloalkyl, and -NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6 Optionally substituted with alkyl.

[0126] As used herein, in some embodiments, the compound has the formula (I-A2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 6 H, -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 -(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 Alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 optionally substituted with cycloalkyl, and -NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6Optionally substituted with alkyl.

[0127] As used herein, in some embodiments, the compound has the formula (IB): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 3 H, -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 -(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 Alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 optionally substituted with cycloalkyl, and -NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6 Optionally substituted with alkyl.

[0128] In some embodiments of the compound of formula (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X1 and X 2 are independently H or halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments, X 1 and X 2 are independently H or F, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other is a halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments, X 1 and X 2 One of them is H and X 1 and X 2 The other of these is F and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl.

[0129] In some embodiments of the compound of formula (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 and Y 2 are CH, and X 1 and X 2 are independently H or halo, and R 3 and R 4are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. 1 and Y 2 are CH, and X 1 and X 2 are independently H or F, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. 1 and Y 2 are CH, and X 1 and X 2 One of them is H and X 1 and X 2 The other is a halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. 1 and Y 2 are CH, and X 1 and X 2 One of them is H and X 1 and X 2 The other of these is F and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl.

[0130] In some embodiments of the compound of formula (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 and Y 2 One of them is N and Y 1 and Y2 The other of these is CH, and X 1 and X 2 are independently H or halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 are independently H or F, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 One of them is H and X 1 and X 2 The other is a halo, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. 1 and Y 2 One of them is N and Y 1 and Y 2 The other of these is CH, and X 1 and X 2 One of them is H and X 1 and X 2 The other of these is F and R 3 and R 4 are each -CH3 or R 3and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl.

[0131] In some embodiments of the compound of formula (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 3 H, -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 -(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of -NH-C(O)-(3- to 15-membered heterocyclyl) is one or more -C(O)-C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 Alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 optionally substituted with cycloalkyl, and The 3- to 15-membered heterocyclyl of —NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6 Optionally substituted with alkyl.

[0132] In some embodiments of the compound of formula (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 3 is H.

[0133] In some embodiments of the compound of formula (IB), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 3 -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 -(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of -NH-C(O)-(3- to 15-membered heterocyclyl) is one or more -C(O)-C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 Alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 optionally substituted with cycloalkyl, and The 3- to 15-membered heterocyclyl of —NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6 Optionally substituted with alkyl.

[0134] In some embodiments, X 3 One of the following is methyl, OH, Cl, -OCH3, NH 2、 -NH(CH3), [ka] is selected from the group consisting of:

[0135] As used herein, in some embodiments, the compound is represented by formula (I-B1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0136] In some embodiments of the compound of Formula (I-B1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 1 and X 2 are independently halo and X 3 is C 1~3 Alkyl or C 3~6 is cycloalkyl, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments, X 1 and X 2 are independently F and X 3 is C 1~3 Alkyl or C 3~6 is cycloalkyl, and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl.

[0137] In some embodiments, the compound has formula (I-B2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0138] In some embodiments of the compound of Formula (I-B2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 2 is the halo and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl. In some embodiments, X 2 is F and R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl.

[0139] In some embodiments, the compound has formula (I-B3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0140] In some embodiments of the compound of Formula (I-B3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl.

[0141] As used herein, in some embodiments, the compound is represented by formula (I-B4): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0142] In some embodiments, the compound has formula (I-B5): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0143] In some embodiments of the compound of Formula (I-B5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 2 is the halo, and X 3 is C 1~6 Alkyl, or C 3~10 is cycloalkyl, and X 3 C 3~10 Cycloalkyl is one or more C 1~6 In some embodiments, X is optionally substituted with alkyl. 2 is F and X 3 is C 1~3 Alkyl, or C 3~6 is cycloalkyl, and X 3 C 3~6 Cycloalkyl is one or more C 1~3 Optionally substituted with alkyl.

[0144] In some embodiments, the compound has formula (I-B6): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0145] In some embodiments of the compound of Formula (I-B6), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R 3 and R 4 are each -CH3 or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl.

[0146] As used herein, in some embodiments, the compound has the formula (IC): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is a 3- to 9-membered heterocyclyl, wherein the 3- to 9-membered heterocyclyl of ring A is optionally substituted with one or more oxo; 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A contains at least one ring N atom and one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 Optionally substituted with cycloalkyl.

[0147] As used herein, in some embodiments, the compound has the formula (ID): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is a 3- to 9-membered heterocyclyl, wherein the 3- to 9-membered heterocyclyl of ring A is optionally substituted with one or more oxo; 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl of ring A contains at least one ring N atom and one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 Optionally substituted with cycloalkyl.

[0148] In some embodiments of a compound of Formula (IC), (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A is a 5- to 6-membered heterocyclyl, and the 5- to 6-membered heterocyclyl of Ring A is optionally substituted with one or more oxo. In some embodiments, Ring A is [ka] where # represents the point of attachment to the remainder of the molecule.

[0149] In some embodiments of a compound of Formula (IC), or (ID), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A is a 5-8 membered heteroaryl, and the 5-8 membered heteroaryl of Ring A contains at least one ring N atom and one or more of -NH, halo, C 1~6 Alkyl or C 3~10 In some embodiments, ring A is optionally substituted with cycloalkyl. [ka] where # represents the point of attachment to the rest of the molecule.

[0150] As used herein, in some embodiments, the compound has the formula (IE): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0151] As used herein, in some embodiments, the compound has the formula (I-E1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0152] As used herein, in some embodiments, the compound is represented by formula (I-E2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0153] As used herein, in some embodiments, the compound has the formula (IF): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0154] As used herein, in some embodiments, the compound has the formula (I-F1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0155] As used herein, in some embodiments, the compound has the formula (I-F2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0156] As used herein, in some embodiments, the compound has the formula (IG): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0157] In some embodiments, the compound has the formula (I-G1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0158] In some embodiments, the compound has the formula (I-G2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0159] In some embodiments, the compound has the formula (I-G3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0160] In some embodiments, the compound has the formula (I-G4): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0161] In some embodiments, the compound has the formula (IH): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0162] In some embodiments, the compound has formula (I-H1): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0163] In some embodiments, the compound has formula (I-H2): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0164] In some embodiments, the compound has formula (I-H3): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0165] In some embodiments, the compound has formula (I-H4): [ka] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0166] In some embodiments of a compound of Formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1.

[0167] Compound names contained in Table 1 and for all intermediates and compounds were generated using ChemDraw® Professional software version 17.1.1.0 or Collaborative Drug Discovery Inc. (CDD) CDD Vault update#3.

[0168] A KNIME workflow was created to retrieve structures from the internal ChemAxon Compound Registry, generate canonical smiles using the RDKit Canon SMILES node, remove stereochemistry using the ChemAxon / Infocom MolConverter node, and name the structures using the ChemAxon / Infocom Naming node. The following shows the versions of the KNIME Analytics Platform and extensions used in the workflow: ·Knime Analytics Platform 4.2.2 RDKit KNIME Integration 4.0.1.v202006261025 (This extension includes the RDKit Canon SMILES node) ChemAxon / Infocom Marvin Extensions Feature 4.3.0v202100 (This extension includes the MolConverter node) ChemAxon / Infocom JChem Extensions Feature 4.3.0v202100 (This extension includes the Naming node) [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13]

[0169] Provided herein, in some embodiments, is a compound of Formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of: N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide; N-[(4-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(2-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(3-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(1-methyl-1H-pyrazol-5-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(4-hydroxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(2-hydroxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(3-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(2-acetamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(2-aminophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(3-methoxy-2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(3-hydroxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(2-cyclopropanamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}oxetane-3-carboxamide; N-{[4-(propan-2-yl)phenyl](2-propanamidophenyl)methyl}cyclopropanecarboxamide; N-[(2-chlorophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(2-methanesulfonamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-{[4-(propan-2-yl)phenyl](1H-pyrazol-5-yl)methyl}cyclopropanecarboxamide; 2-Acetamido-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide; N-{[2-(carbamoylamino)phenyl][4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide; N-({2-[(methylcarbamoyl)amino]phenyl}[4-(propan-2-yl)phenyl]methyl)cyclopropanecarboxamide; N-[(2-aminopyridin-3-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-{[3-fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}cyclopropanecarboxamide; N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-2-carboxamide; N-[(2-methylphenyl)[5-(propan-2-yl)pyridin-2-yl]methyl]cyclopropanecarboxamide; N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-3-carboxamide; N-[(4-cyclopropylphenyl)(phenyl)methyl]cyclopropanecarboxamide; N-{phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}cyclopropanecarboxamide; N-[(4-cyclobutylphenyl)(phenyl)methyl]cyclopropanecarboxamide; N-[(2-acetamido-5-fluorophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-[(3-methyl-1H-pyrazol-4-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-{[2-(methylamino)phenyl][4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide; 1-Acetyl-N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-2-carboxamide; 2-(Carbamoylamino)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide; N-[(2-methoxyphenyl)[5-(propan-2-yl)pyridin-2-yl]methyl]cyclopropanecarboxamide; 1-Acetyl-N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-3-carboxamide; 2-Fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopropane-1-carboxamide; 3-Hydroxy-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide; 3-Fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide; N-[(2-oxo-2,3-dihydro-1H-indol-7-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; N-({2-[(1,3-oxazol-2-yl)amino]phenyl}[4-(propan-2-yl)phenyl]methyl)cyclopropanecarboxamide; N1-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1,2-dicarboxamide; N-[(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; 2-acetamido-N-[2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentyl]butanediamide; 2-Fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopropane-1-carboxamide; N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-methylazetidine-3-carboxamide; N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-(cyclopropylmethyl)azetidine-3-carboxamide; N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-(2-methoxyethyl)azetidine-3-carboxamide; N-{2-[(cyclopropylformamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-(2,2,2-trifluoroethyl)azetidine-3-carboxamide; N1-cyano-N2-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1,2-dicarboxamide; 2-(2-acetamidoacetamido)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide; Methyl 3-[(2-{[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentyl)formamido]propanoate; N-{[2-(N”-cyanocarbamimidamido)phenyl][4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide; N-{[2-(carbamoylamino)phenyl](4-cyclobutylphenyl)methyl}cyclopropanecarboxamide; N1-methyl-N2-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1,2-dicarboxamide; N-{[2-(carbamoylamino)phenyl](4-cyclopropylphenyl)methyl}cyclopropanecarboxamide; N-[(2-oxo-2,3-dihydro-1,3-benzoxazol-7-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; 1-(cyclopropylmethyl)-N-(2-{[(2-fluorocyclopropyl)formamido][4-(propan-2-yl)phenyl]methyl}phenyl)piperidine-4-carboxamide; N-(2-{[(2-fluorocyclopropyl)formamide][4-(propan-2-yl)phenyl]methyl}phenyl)-1-(2-methoxyethyl)piperidine-4-carboxamide; N-(2-{[(2-fluorocyclopropyl)formamido][4-(propan-2-yl)phenyl]methyl}phenyl)-1-methylpiperidine-4-carboxamide; 2-Fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](1H-pyrazol-5-yl)methyl}cyclopropane-1-carboxamide; N-{[2-(carbamoylamino)phenyl][3-fluoro-4-(propan-2-yl)phenyl]methyl}-2-fluorocyclopropane-1-carboxamide; N-(2-{[(2-fluorocyclopropyl)formamido][4-(propan-2-yl)phenyl]methyl}phenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carboxamide; N-({2-[(1-methyl-2,5-dioxoimidazolidin-4-yl)amino]phenyl}[4-(propan-2-yl)phenyl]methyl)cyclopropanecarboxamide; 2-cyano-N-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1-carboxamide; N-[(3-acetamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide; 2-Fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)methyl}cyclopropane-1-carboxamide; 2-Fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-5-yl)phenyl]methyl}cyclopropane-1-carboxamide; 2-fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1H-indazol-6-yl)methyl}cyclopropane-1-carboxamide; and N-[(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-2-fluorocyclopropane-1-carboxamide; or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0170] Provided herein, in some embodiments, is a compound of Formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from the group consisting of: (R)-N-((2-acetamidophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; (1R,2S)-N-((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-2-fluoro-N-((S)-(6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methyl)cyclopropane-1-carboxamide; (1R,2S)—N-((S)-(3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-fluorocyclopropane-1-carboxamide; (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4-isopropylphenyl)(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)cyclopropane-1-carboxamide; (R)-N-((3-acetamidophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; (1R,2S)-2-cyano-N-((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1-carboxamide; N-((1R)-(4-isopropylphenyl)(2-((1-methyl-2,5-dioxoimidazolidin-4-yl)amino)phenyl)methyl)cyclopropanecarboxamide; N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamide)(4-isopropylphenyl)methyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carboxamide; (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4-isopropylphenyl)(2-ureidophenyl)methyl)cyclopropane-1-carboxamide; (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4-isopropylphenyl)(1H-pyrazol-5-yl)methyl)cyclopropane-1-carboxamide; N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamide)(4-isopropylphenyl)methyl)phenyl)-1-methylpiperidine-4-carboxamide; N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamide)(4-isopropylphenyl)methyl)phenyl)-1-(2-methoxyethyl)piperidine-4-carboxamide; 1-(cyclopropylmethyl)-N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamide)(4-isopropylphenyl)methyl)phenyl)piperidine-4-carboxamide; (R)-N-((4-isopropylphenyl)(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)methyl)cyclopropanecarboxamide; (1R,2S)-N1-((R)-(4-isopropylphenyl)(o-tolyl)methyl)-N2-methylcyclopentane-1,2-dicarboxamide; (R)-N-((4-cyclopropylphenyl)(2-ureidophenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-cyclobutylphenyl)(2-ureidophenyl)methyl)cyclopropanecarboxamide; (R,E)-N-((2-(2-cyanoguanidino)phenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; Methyl 3-((1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxamido)propanoate; (1R,2S)-2-(2-acetamidoacetamido)-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide; (1S,2R)-N1-cyano-N2-((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide; (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-(2,2,2-trifluoroethyl)azetidine-3-carboxamide; (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-(2-methoxyethyl)azetidine-3-carboxamide; (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-(cyclopropylmethyl)azetidine-3-carboxamide; (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-methylazetidine-3-carboxamide; (1S,2R)-2-fluoro-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopropane-1-carboxamide; (S)-2-acetamido-N1-((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)succinamide; (R)-N-((4-isopropylphenyl)(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)cyclopropanecarboxamide; (1R,2S)-N1-((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide; (R)-N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(2-oxoindolin-7-yl)methyl)cyclopropanecarboxamide; (S)-N-((5-isopropylpyridin-2-yl)(2-methoxyphenyl)methyl)cyclopropanecarboxamide; (1S)-3-Fluoro-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide; (1S)-3-hydroxy-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide; (1R,2S)-2-fluoro-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopropane-1-carboxamide; (R)-1-acetyl-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide; (1R,2S)-N-((S)-(4-isopropylphenyl)(phenyl)methyl)-2-ureidocyclopentane-1-carboxamide; (R)-N-((4-isopropylphenyl)(2-(methylamino)phenyl)methyl)cyclopropanecarboxamide; (S)-N-((4-cyclobutylphenyl)(phenyl)methyl)cyclopropanecarboxamide; (S)-N-((4-cyclopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide; (S)-1-Acetyl-N-(2-((R)-cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide; (R)-N-((4-isopropylphenyl)(3-methyl-1H-pyrazol-4-yl)methyl)cyclopropanecarboxamide; (R)-N-((2-acetamido-5-fluorophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; (S)—N-((5-isopropylpyridin-2-yl)(phenyl)methyl)cyclopropanecarboxamide; (S)—N-((2-acetamidophenyl)(5-isopropylpyridin-2-yl)methyl)cyclopropanecarboxamide; (S)—N-((5-isopropylpyridin-2-yl)(o-tolyl)methyl)cyclopropanecarboxamide; (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide; (S)-N-(2-((R)-cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide; (R)-N-(2-((R)-cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide; (R)-N-((2-aminopyridin-3-yl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; (S)—N-((3-fluoro-4-isopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(2-(3-methylureido)phenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(2-ureidophenyl)methyl)cyclopropanecarboxamide; (1R,2S)-2-acetamido-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide; (R)-N-((4-isopropylphenyl)(1H-pyrazol-5-yl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(2-(methylsulfonamido)phenyl)methyl)cyclopropanecarboxamide; (R)-N-((2-chlorophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(2-propionamidophenyl)methyl)cyclopropanecarboxamide; (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)oxetane-3-carboxamide; (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)cyclopropanecarboxamide; (R)-N-((3-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(3-methoxy-2-methylphenyl)methyl)cyclopropanecarboxamide; (R)-N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(o-tolyl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(m-tolyl)methyl)cyclopropanecarboxamide; (R)-N-((2-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(1-methyl-1H-pyrazol-5-yl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(3-methoxyphenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(2-methoxyphenyl)methyl)cyclopropanecarboxamide; (R)-N-((4-isopropylphenyl)(4-methoxyphenyl)methyl)cyclopropanecarboxamide; (S)—N-((4-isopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide; and or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0171] Treatment method Provided herein are methods for modulating GYS1 in a cell, the methods comprising exposing the cell to (i) a composition comprising an effective amount of a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, is selective for GYS1 over GYS2. In some embodiments, the compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, is 500-fold, 1,000-fold, 1,500-fold, or 1,700-fold selective for GYS1 over GYS2.

[0172] Provided herein are methods for inhibiting GYS1 in a cell, the method comprising exposing the cell to (i) a composition comprising an effective amount of a GYS1 inhibitor, or (ii) a pharmaceutical composition comprising an effective amount of a GYS1 inhibitor and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1 inhibitor is a small molecule. In some embodiments, the GYS1 inhibitor is selective for GYS1 over GYS2. In some embodiments, the GYS1 inhibitor is 500-fold, 1,000-fold, 1,500-fold, or 1,700-fold selective for GYS1 over GYS2.

[0173] Provided herein are methods for inhibiting GYS1 in a cell, the method comprising exposing the cell to (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0174] In some embodiments, the compound of Formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selective for GYS1 over GYS2. In some embodiments, the compound of Formula (I), or any variation or embodiment thereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is 500-fold, 1,000-fold, 1,500-fold, or 1,700-fold selective for GYS1 over GYS2. In some embodiments, the individual has a GYS1-mediated disease, disorder, or condition selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is cancer. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Ewing's sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen-rich clear cell carcinoma (GRCC) breast cancer, non-small cell lung cancer (NSCLC), and acute myeloid leukemia (AML). In some embodiments, the GYS1-mediated disease, disorder, or condition is Pompe disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is late-onset Pompe disease (LOPD).

[0175] Provided herein are methods of reducing tissue glycogen stores in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0176] Provided herein is a method of inhibiting glycogen synthesis in an individual in need thereof, comprising administering to the individual an effective amount of (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0177] Provided herein are methods of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease. In some embodiments, the GYS1-mediated disease, disorder, or condition is cancer. In some embodiments, the GYS1-mediated disease, disorder, or condition is selected from the group consisting of Ewing's sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen-rich clear cell carcinoma (GRCC) breast cancer, non-small cell lung cancer (NSCLC), and acute myeloid leukemia (AML).

[0178] Provided herein are methods of treating a glycogen storage disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, glycogen levels in the individual are reduced during treatment. In some embodiments, glycogen levels in muscle are reduced. In some embodiments, glycogen levels in skeletal muscle are reduced. In some embodiments, glycogen levels are reduced by at least 10%, at least 20%, at least 30%, or at least 50% upon administration of the compound. In some embodiments, the compounds provided herein are effective in treating a lysosomal disorder. In some embodiments, the glycogen storage disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

[0179] Provided herein are methods of treating a glycogen storage disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a composition comprising a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, glycogen levels in the individual are reduced during treatment. In some embodiments, glycogen levels in muscle are reduced. In some embodiments, glycogen levels in skeletal muscle are reduced. In some embodiments, glycogen levels are reduced by at least 10%, at least 20%, at least 30%, or at least 50% upon administration of the compound. In some embodiments, the compounds provided herein are effective in treating a lysosomal disorder. In some embodiments, the glycogen storage disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

[0180] Provided herein are methods of treating Pompe disease in an individual in need thereof, comprising administering to the individual (i) a composition comprising an effective amount of a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the individual has infantile-onset Pompe disease. In some embodiments, the individual has non-classical infantile-onset Pompe disease. In some embodiments, the individual has late-onset Pompe disease. In some embodiments, the individual is deficient in acid alpha-glucosidase (GAA). In some embodiments, the individual has reduced expression of GAA.

[0181] Provided herein are methods of treating Pompe disease in an individual in need thereof, comprising administering to the individual (i) a composition comprising a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the individual has infantile-onset Pompe disease. In some embodiments, the individual has non-classical infantile-onset Pompe disease. In some embodiments, the individual has late-onset Pompe disease. In some embodiments, the individual is deficient in acid alpha-glucosidase (GAA). In some embodiments, the individual has reduced expression of GAA.

[0182] In some embodiments, the compounds provided herein reduce and / or eliminate one or more symptoms associated with Pompe disease. In some embodiments, the compounds reduce and / or eliminate muscle weakness, poor muscle tone, enlarged liver, abnormal growth and weight gain, difficulty breathing, eating disorders, respiratory infections, hearing problems, delayed motor skills, enlarged heart, fatigue, lung infections, frequent falls, or irregular heartbeat. In some embodiments, the compounds provided herein slow the progression of Pompe disease.

[0183] In some embodiments, the compounds provided herein extend the lifespan of an individual, hi some embodiments, the lifespan is extended by at least 5 years, at least 10 years, or at least 20 years after treatment.

[0184] In some embodiments, compounds provided herein prevent, reduce, or delay muscle weakness. In some embodiments, muscle weakness is determined by manual muscle testing, sit-to-stand test, heel-raise test, hand-held dynamometry, or hand grip dynamometry. In some embodiments, strength is graded according to the following scale: 0: no visible muscle contraction; 1: muscle contraction, but no or slight movement; 2: limb movement, but not against gravity; 3: movement against gravity, but not against resistance; 4: movement against at least some resistance is produced by the tester; 5: full strength.

[0185] Also provided herein are methods for inhibiting the GYS1 enzyme in an individual, comprising administering to the individual an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the GYS1 enzyme is human GYS1 (hGYS1). In some embodiments, the compounds provided herein inhibit GYS1 at concentrations less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the compounds provided herein inhibit GYS1 at concentrations between 1 and 10 μM, between 0.01 and 1 μM, or between 0.01 and 10 μM.

[0186] In some embodiments, the compound has an IC of less than 10 nM, less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. 50 In some embodiments, the compounds provided herein have an IC of 1-10 nM, 1-10 μM, 0.01-1 μM, 0.01-10 μM, or 0.001-0.01 μM. 50 It has.

[0187] In some embodiments, glycogen synthesis is inhibited upon administration of a compound provided herein, ie, glycogen synthesis is reduced by at least 10%, at least 20%, at least 40%, or at least 50% upon administration.

[0188] In some embodiments, the individual being treated is a juvenile or infant, hi some embodiments, the individual is under 10 years old, under 9 years old, under 8 years old, under 7 years old, under 6 years old, under 5 years old, under 4 years old, under 3 years old, under 2 years old, or under 1 year old.

[0189] In some embodiments, these methods further comprise enzyme replacement therapy (ERT). Exemplary ERTs include alglucosidase alfa (human recombinant alpha-glucosidase (human GAA)) and those described in Byrne BJ et al (2011). Pompe disease: design, methodology, and early findings from the Pompe Registry. Mol Genet Metab 103:1-11, incorporated herein by reference in its entirety. In some embodiments, the ERT is selected from the group consisting of Myozyme and Lumizyme. In some embodiments, the ERT is Myozyme. In some embodiments, the ERT is Lumizyme. In some embodiments, the individual has an advanced glycogen storage disease. In some embodiments, the individual has late-onset Pompe disease. Accordingly, provided herein are methods of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising: (a) subjecting the individual to glycogen substrate reduction therapy, such as administering to the individual an effective amount of (i) a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of Formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (b) enzyme replacement therapy. In some embodiments, the GYS1-mediated disease, disorder, or condition is Pompe disease, such as late-onset Pompe disease. In some embodiments, the compound of Formula (I) is selective for GYS1 over GYS2. In some embodiments, compounds of formula (I) are 500-fold or 1,000-fold or 1,500-fold or 1,700-fold selective for GYS1 over GYS2.

[0190] In some embodiments, the individual has a mutation in the GAA gene. In some embodiments, the mutation reduces the level of GAA protein. In some embodiments, the mutation is a loss-of-function mutation. In some embodiments, the mutation is a missense mutation. In some embodiments, the mutation is a deletion. In some embodiments, the mutation is a recessive mutation. In some embodiments, the mutation is a splicing variant.

[0191] In some of the foregoing embodiments, the administration is oral.

[0192] kit The present disclosure further provides kits for carrying out the methods of the present invention. The kits may include a compound as described herein or a pharmaceutically acceptable salt thereof and suitable packaging. The kits may include one or more containers containing any of the compounds described herein. In one embodiment, the kits include a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a label and / or instructions for using the compound in the treatment of a disease or disorder described herein. The kits may include a unit dosage form of the compound.

[0193] Provided herein is a kit comprising (i) a composition comprising an effective amount of a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use thereof in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein is a kit comprising (i) a pharmaceutical composition comprising an effective amount of a compound of formula (I), or any variant or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, and (ii) instructions for use thereof in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

[0194] Also provided is an article of manufacture comprising, in a suitable container, a compound of formula (I), or any variation or embodiment thereof as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is an article of manufacture comprising, in a suitable container, a pharmaceutical composition comprising, in a suitable container, a compound of formula (I), or any variation or embodiment thereof as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. The container may be a vial, bottle, ampoule, pre-filled syringe, or intravenous bag.

[0195] Preparation method The present disclosure further provides methods for preparing the compounds of the present invention. Provided herein, in some aspects, are methods for preparing a compound of Formula (I), (IA), (I-A1), (I-A2), (IB), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (IC), (ID), (IE), (I-E1), (I-E2), (IF), (I-F1), (IG), (I-G1), (I-G2), (I-G3), (I-G4), (IH), (I-H1), (I-H2), (I-H3), (I-H4), or (I-H5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0196] In some embodiments, the process for preparing a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises: (a) Formula (I-1): [ka] or a salt thereof (wherein Y 1 and Y 2 are each CH, or Y 1 and Y 2 One of them is N and Y 1 and Y2 the other of which is CH, X 1 and X 2 are each independently H or halo; R 3 and R 4 are each -CH3, or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl, (1) L does not exist, and Q 1 teeth, (I C 6~20 aryl, and Q 1 C 6~20 Aryl is one or more of -OH, -NH2, halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~10 Cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1~6 alkyl), -NH-C(O)-C 1~6 Alkyl, -NH-C(O)-C 3~10 Cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclyl), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1~6 Alkyl, -NH(C 1~6 optionally substituted with -NH-(3- to 15-membered alkyl), -NH-(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C 1~6 Alkyl or C 1~6 optionally substituted with alkyl, C 1~6 The alkyl may contain one or more halo, C 1~6 Alkoxy or C 3~10 optionally substituted with cycloalkyl, and -NH-(3- to 15-membered heterocyclyl) is one or more oxo or C 1~6C optionally substituted with alkyl 6~20 aryl, or (ii) 3- to 15-membered heterocyclyl, where Q 1 wherein the 3- to 15-membered heterocyclyl is optionally substituted by one or more oxo; or (iii) 5- to 20-membered heteroaryl, where Q 1 The 5- to 20-membered heteroaryl contains at least one ring N atom and is substituted with one or more of -NH2, halo, C 1~6 Alkyl or C 3~10 a 5- to 20-membered heteroaryl optionally substituted with cycloalkyl; or (2) L is -CH2-, and Q 1 is C 3~10 or cycloalkyl) in the presence of a coupling reagent to form a compound of formula (I-2): [ka] (In the formula, m is 0 or 1; n is 0 or 1, R 1 is H, halo, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1~6 alkyl), -NH-C(O)-NH2, or -NH-C(O)-C 1~6 is alkyl, R 1 -C(O)-NH(C 1~6 C of alkyl) 1~6 Alkyl is one or more -C(O)-C 1~6 optionally substituted with alkoxy; R 1 -NH-C(O)-C 1~6 Alkyl C 1~6 Alkyl is one or more -NH-C(O)-C 1~6 optionally substituted with alkyl or -C(O)-NH2, and R 2is H, halo, or -OH) to provide a compound of formula (I).

[0197] In some embodiments, the coupling reagent comprises propanephosphonic anhydride (T3P) or N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TFCH). In some embodiments, the method further comprises the presence of a base. In some embodiments, the base comprises an amine. In some embodiments, the base comprises a tertiary amine. In some embodiments, the amine is N-methylmorpholine or N-methylimidazole. [Example]

[0198] The following synthetic reaction schemes, detailed in the schemes and examples, are intended to illustrate only some of the ways in which the compounds of the present disclosure, or embodiments or aspects thereof, may be synthesized. As will be apparent to one of ordinary skill in the art, various modifications to these synthetic reaction schemes can be made.

[0199] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if necessary using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0200] While certain exemplary embodiments are shown and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods generally described herein and / or by methods available to those skilled in the art.

[0201] Synthesis Example As shown in the following schemes and examples, in certain exemplary embodiments, compounds of formula (I), or any variation or embodiment thereof as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared according to general procedures. The following general methods, and others known to synthetic chemists of ordinary skill in the art, may be applied to all formulas, variations, embodiments, and species described herein.

[0202] Scheme Scheme 1 [ka] Compounds of formula S1-3 can be prepared according to general Scheme 1. Reaction of carboxylic acid S1-1 with amine S1-2 using a coupling reagent such as propanephosphonic anhydride (T3P) and a tertiary amine base such as N-methylmorpholine in an aprotic solvent such as DMF provides compounds of formula S1-3.

[0203] Scheme 2 [ka] Compounds of formula S2-3 can be prepared according to the alternative reaction conditions shown in general Scheme 2. Reaction of carboxylic acid S2-1 with amine S2-2 using a coupling reagent such as N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TFCH) and a tertiary amine base such as N-methylimidazole in an aprotic solvent such as acetonitrile provides compounds of formula S2-3.

[0204] Abbreviations used are conventional in the art and are taken from the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. The following examples are intended to be illustrative only and not limiting in any way. [Table 14] Example S-1: [Table 15] [Table 16] [Table 17]

[0205] Intermediate A-1: ​​Synthesis of (6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methanaminium chloride [ka] Step a: To a solution of 6-bromo-1H-indazole (8 g, 40.6 mmol, 1 equiv.) in DMF (50 mL) was added trityl chloride (TrtCl, 12.4 g, 44.6 mmol, 1.1 equiv.) and TEA (7.06 mL, 50.7 mmol, 1.25 equiv.). The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was then diluted with water, and the resulting biphasic mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was triturated with MTBE (30 mL) and filtered to give 6-bromo-1-trityl-1H-indazole, which was carried on to the next step without further purification or characterization.

[0206] Step b: To a mixture of 6-bromo-1-trityl-1H-indazole (16.7 g, 38.0 mmol, 1 equiv.), potassium vinyltrifluoroborate (10.1 g, 76.0 mmol, 2 equiv.), and TEA (15.8 mL, 14.0 mmol, 3 equiv.) in i-PrOH (160 mL) was added Pd(dppf)Cl·CHCl (1.55 g, 1.90 mmol, 0.05 equiv.) under N. The resulting mixture was then degassed and placed under a N atmosphere. The reaction mixture was then warmed to 100 °C and stirred under N for 2 h. After cooling, the mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 100 mL). The combined filtrate was concentrated, and the resulting crude residue was purified by column chromatography to give 1-trityl-6-vinyl-1H-indazole. LC-MS(ESI):m / z:[2M+Na] + C 28 H 22 Calculated for N2: 795.4; measured 795.3.

[0207] Step c: To a solution of 1-trityl-6-vinyl-1H-indazole (14.2 g, 36.7 mmol, 1 equiv) in THF:HO (5:1) (300 mL) at 0 °C, NaIO (31.4 g, 146 mmol, 4 equiv) and KOsO·2HO (676 mg, 1.84 mmol, 0.05 equiv) were added. The resulting mixture was warmed to 50 °C and stirred for 1 h. The reaction mixture was then cooled to 25 °C and quenched with saturated aqueous NaSO (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 100 mL), and the combined extracts were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 1-trityl-1H-indazole-6-carbaldehyde.

[0208] Step d: To a solution of 1-trityl-1H-indazole-6-carbaldehyde (7.3 g, 18.8 mmol, 1 equiv.) in DCM (75 mL) was added CsCO (6.74 g, 20.7 mmol, 1.1 equiv.) and 2-methylpropane-2-sulfinamide (2.51 g, 20.6 mmol, 1.1 equiv.). The mixture was then warmed to 40 °C and stirred for 16 h. The reaction mixture was then filtered, and the filter cake was washed with ethyl acetate (3 × 100 mL). The filtrate was then filtered and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give (E)-2-methyl-N-((1-trityl-1H-indazol-6-yl)methylene)propane-2-sulfinamide.

[0209] Step e: To a solution of 6-bromo-2-fluoro-3-isopropylpyridine (665 mg, 3.05 mmol, 1.5 equiv) in THF (5 mL) at −78° C. was added n-BuLi (1.22 mL, 2.5 M, 1.5 equiv) dropwise under N. The resulting mixture was stirred at −78° C. for 0.5 h. After this time, (E)-2-methyl-N-((1-trityl-1H-indazol-6-yl)methylene)propane-2-sulfinamide (1 g, 2.03 mmol, 1 equiv) in THF (5 mL) cooled to −78° C. under N was added, and the resulting mixture was stirred at −78° C. for 4 h. The reaction was then quenched with saturated aqueous NH.sub.4Cl (20 mL), and the resulting biphasic mixture was extracted with ethyl acetate (3 × 20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give N-((6-fluoro-5-isopropylpyridin-2-yl)(1-trityl-1H-indazol-6-yl)methyl)-2-methylpropane-2-sulfinamide.

[0210] Step f: To a solution of N-((6-fluoro-5-isopropylpyridin-2-yl)(1-trityl-1H-indazol-6-yl)methyl)-2-methylpropane-2-sulfinamide (600 mg, 951 μmol, 1 equiv.) in EtOAc (3 mL) at 0° C. was added HCl / EtOAc (4 M, 3 mL, 12.6 equiv.). The resulting mixture was then warmed to 40° C. and stirred for 16 h. The reaction mixture was then filtered to give (6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methanaminium chloride. LC-MS (ESI): m / z [M-NH3] + C 16 H 17 Calculated for FN4: 268.1; Measured: 268.2.

[0211] Intermediate A-2: Synthesis of (3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methanaminium chloride [ka] Step a: To a solution of 5-(3-bromophenyl)-1H-pyrazole (408 mg, 1.83 mmol, 1.5 equiv) in THF (3 mL) at −60° C. under N2, n-BuLi (2.5 M, 1.22 mL, 2.5 equiv) was added dropwise. Upon completion of the addition, (E)-N-((6-fluoro-5-isopropylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (330 mg, 1.22 mmol, 1 equiv) in THF (2 mL) was added dropwise. The resulting mixture was stirred at −60° C. for 2 hours. The reaction mixture was then poured into ice water (30 mL) and stirred for 2 minutes. The resulting biphasic mixture was then extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give N-((3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m / z: [M+H] + C 22 H 26 Calculated for FN4OS: 415.2; measured 415.2.

[0212] Step b: To a solution of N-((3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (410 mg, 989 umol, 1 equiv.) in dioxane (2 mL) at 15° C., HCl / dioxane (4 mL) was added dropwise. The resulting mixture was stirred at 15° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure to give (3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methanaminium chloride. LC-MS (ESI): m / z: [M+H] + C 18 H 19 Calculated for FN4: 311.2; measured 311.2.

[0213] Intermediate A-3: Synthesis of tert-butyl (2-(amino(4-isopropylphenyl)methyl)phenyl)carbamate [ka] Step a: To a mixture of 4-isopropylbenzaldehyde (10.0 g, 67.4 mmol, 10.2 mL, 1 equiv.) and 2-methylpropane-2-sulfinamide (9.00 g, 74.2 mmol, 1.1 equiv.) in dry THF (75 mL) at 0 °C, Ti(OEt) (30.7 g, 134 mmol, 2 equiv.) was added in one portion under N. The reaction mixture was then degassed and charged with N three times. The reaction mixture was then warmed to 25 °C and stirred under N for 4 h. The reaction was then quenched by cooling to 0 °C, adding HO (150 mL), and stirring for 20 min. The reaction mixture was then filtered, and the filter cake was washed with ethyl acetate (2 × 100 mL). The filtrate was then extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were then washed with saturated aqueous NH4Cl (100 mL), brine (70 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give (E)-N-(4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m / z: [M+H] + C 14 H 21 Calculated for NOS: 252.1; Measured 252.1.

[0214] Step b: To a solution of tert-butyl (2-iodophenyl)carbamate (25.4 g, 79.6 mmol, 2 equiv.) in THF (200 mL) at 0 °C, i-PrMgCl·LiCl (107 mL, 1.3 M, 3.5 equiv.) was added dropwise over 30 min. After the addition was complete, the resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was then cooled to −20 °C, and (E)-N-(4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (10 g, 39.8 mmol, 1 equiv.) in THF (200 mL) was then added dropwise. The resulting mixture was then stirred at −20 °C for 3 h. The reaction mixture was then warmed to 0 °C and quenched by the addition of water (100 mL). The resulting biphasic mixture was extracted with ethyl acetate (2 × 250 mL). The combined organic extracts were washed with brine (2 x 25 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give tert-butyl (2-(((tert-butylsulfinyl)amino)(4-isopropylphenyl)methyl)phenyl)carbamate. LC-MS (ESI): m / z: [M+H] + C 25 H 36 Calculated for N2O3S: 445.2; found 445.4.

[0215] Step c: A mixture of tert-butyl (2-(((tert-butylsulfinyl)amino)(4-isopropylphenyl)methyl)phenyl)carbamate (15 g, 33.7 mmol, 1 equiv.) and I (6.85 g, 26.9 mmol, 0.8 equiv.) in THF (150 mL) and HO (30 mL) was degassed and purged with N. The mixture was then warmed to 50 °C and stirred under a N atmosphere for 2 h. The reaction mixture was then cooled to 0 °C and quenched by the addition of water (100 mL). The resulting biphasic mixture was extracted with ethyl acetate (2 × 250 mL). The combined organic extracts were washed with brine (2 × 25 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give tert-butyl (2-(amino(4-isopropylphenyl)methyl)phenyl)carbamate. LC-MS(ESI):m / z:[M+H] + C 21 H 28 Calculated for N2O2: 341.2; Found 341.4. Intermediate A-4: Synthesis of (S)-(3-fluoro-4-isopropylphenyl)(phenyl)methanaminium chloride [ka]

[0216] Step a: To a mixture of 4-bromo-3-fluoro-benzaldehyde (200 g, 985 mmol, 1.00 equiv.) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (215 g, 1.28 mol, 1.30 equiv.) in toluene (3.70 L) and HO (410 mL) at 25 °C, Pd(dppf)Cl (36.0 g, 49.3 mmol, 0.05 equiv.) and KPO (418 g, 1.97 mol, 2.00 equiv.) were added under N under N. The mixture was warmed to 90 °C and stirred for 12 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 3-fluoro-4-isopropenyl-benzaldehyde. The compound was carried on to the next step without further characterization.

[0217] Step b: To a solution of 3-fluoro-4-isopropenyl-benzaldehyde (124 g, 755 mmol, 1.00 equiv) in EtOAc (1.20 L) was added Pd / C (85.0 g, 10 wt%) under N. The suspension was degassed and purged with H several times. The mixture was stirred under H (15 psi) at 25 °C for 1 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 3-fluoro-4-isopropyl-benzaldehyde. The compound was carried on to the next step without further characterization.

[0218] Step c: To a mixture of 3-fluoro-4-isopropyl-benzaldehyde (80.0 g, 481 mmol, 1.00 equiv.) and (R)-2-methylpropane-2-sulfinamide (64.2 g, 523 mmol, 1.10 equiv.) in DCM (450 mL) at 25 °C, Cs2CO3 (173 g, 530 mmol, 1.10 equiv.) was added. The mixture was warmed to 40 °C and stirred for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give (R,E)-N-(3-fluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m / z: [M+H]+ C 14 H 20 Calculated for FNOS: 270.1; measured value 270.0.

[0219] Step d: To a solution of (R,E)-N-(3-fluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (30.0 g, 111 mmol, 1.00 equiv.) in THF (400 mL) at −65° C., a solution of phenylmagnesium bromide (3 M in EtO, 55.7 mL, 1.50 equiv.) was added dropwise over 30 min under N. The reaction mixture was stirred at −65° C. for 6 h, then warmed to 25° C. and stirred for an additional 6 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with water (3 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give (R)-N-((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide, which was carried on to the next step without further characterization.

[0220] Step e: To a mixture of (R)-N-((S)-(3-fluoro-4-isopropylphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (35.0 g, 101 mmol, 1.00 equiv.) in EtOAc (300 mL) at 25° C., HCl / EtOAc (4 M, 50.4 mL, 2.00 equiv.) was added, and the mixture was stirred for 2 h. The reaction mixture was filtered, and the resulting solid was set aside. The filtrate was concentrated under reduced pressure, and the resulting residue was combined with the previously obtained solid. The mixture was dissolved in MTBE (200 mL), filtered, and the filtrate was concentrated under reduced pressure to give (S)-(3-fluoro-4-isopropylphenyl)(phenyl)methanaminium chloride.

[0221] Intermediate A-5: Synthesis of (S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methanaminium chloride [ka] Step a: In four parallel reactions, 6-fluoropyridin-2-amine (125 g, 1.11 mol, 1 equiv) in MeCN (1.2 L) at 0 °C was treated with NBS (209 g, 1.17 mmol, 1.05 equiv) in MeCN (1.2 L) under N2. The reaction mixture was stirred at 20 °C for 2 h. The four parallel reactions were combined and the resulting mixture was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 5-bromo-6-fluoropyridin-2-amine. LC-MS (ESI): m / z: [M+H] + Calculated for C5H4BrFN2: 190.9; found 191.0.

[0222] Step b: To a mixture of 5-bromo-6-fluoropyridin-2-amine (200 g, 1.04 mol, 1 equiv.) and cyclopropylboronic acid (226 g, 2.63 mol, 2.5 equiv.) in 1,4-dioxane (2 L) and HO (200 mL), KPO (666 g, 3.14 mol, 3 equiv.), PCy (58.6 g, 209 mmol, 0.2 equiv.), and Pd(OAc) (11.7 g, 52.3 mmol, 0.05 equiv.) were added under N. The system was then degassed and flushed with nitrogen three times. The reaction mixture was warmed to 100 °C and stirred for 12 h. The reaction mixture was then cooled to room temperature and filtered through Celite. The resulting filtrate was diluted with HO (2 L) and extracted with EtOAc (3 × 500 mL). The combined organic extracts were washed with brine (2 x 300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-cyclopropyl-6-fluoropyridin-2-amine. LC-MS (ESI): m / z: [M+H] + Calculated for C8H9FN2: 153.1; found 153.0.

[0223] Step c: To a mixture of 5-cyclopropyl-6-fluoropyridin-2-amine (120 g, 788 mmol, 1 equiv.) in dibromomethane (564 mL) was added isopentyl nitrite (110 g, 946 mmol, 127 mL, 1.2 equiv.) under N. To the resulting mixture was added CuBr (211 g, 946 mmol, 44.3 mL, 1.2 equiv.) over 0.5 h. The final mixture was then degassed and flushed with nitrogen three times and then stirred at 20 °C for 16 h. The reaction mixture was then filtered, and the filtrate was diluted with HO (500 mL) and extracted with EtOAc (3 × 300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 6-bromo-3-cyclopropyl-2-fluoropyridine. LC-MS(ESI):m / z:[M+H] + Calculated for C8H7BrFN: 216.0; found 216.1.

[0224] Step d: To a mixture of 6-bromo-3-cyclopropyl-2-fluoropyridine (90 g, 416 mmol, 1 equiv.) and trifluoro(vinyl)-λ-borane, potassium salt (83.7 g, 624 mmol, 1.5 equiv.) in i-PrOH (900 mL) at 20 °C, TEA (126 g, 1.25 mol, 3 equiv.) and Pd(dppf)Cl·DCM (17 g, 20.8 mmol, 0.05 equiv.) were added under N. The resulting mixture was degassed and flushed with nitrogen three times. The reaction mixture was then warmed to 100 °C and stirred for 2 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was diluted with HO (500 mL) and extracted with EtOAc (3 × 300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was then purified by column chromatography to give 3-cyclopropyl-2-fluoro-6-vinylpyridine. LC-MS (ESI): m / z: [M+H] + C 10 H 10 Calculated for FN: 164.1; measured 164.1.

[0225] Step e: To a mixture of 3-cyclopropyl-2-fluoro-6-vinylpyridine (47 g, 288 mmol, 1 equiv.) in THF (800 mL) and HO (160 mL) at 20 °C, NaIO (246 g, 1.15 mol, 4 equiv.) and KOsO·2HO (2.12 g, 5.76 mmol, 0.02 equiv.) were added under N. The resulting mixture was degassed and flushed with nitrogen three times and then stirred for 2 h. The reaction mixture was then filtered, and the filtrate was diluted with HO (500 mL) and extracted with EtOAc (3 × 300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 5-cyclopropyl-6-fluoropicolinaldehyde. LC-MS(ESI):m / z:[M+H] + Calculated for C9H8FNO: 166.1; found 166.2.

[0226] Step f: To a mixture of 5-cyclopropyl-6-fluoropicolinaldehyde (38 g, 230 mmol, 1 equiv.) and (S)-2-methylpropane-2-sulfinamide (30.6 g, 253 mmol, 1.1 equiv.) in DCM (200 mL) at 20 °C, CsCO (82.4 g, 253 mmol, 1.1 equiv.) was added under N. The system was then degassed and filled with nitrogen three times. The resulting mixture was then warmed to 40 °C and stirred for 12 h. The reaction solution was then diluted with HO (300 mL) and extracted with DCM (3 × 200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was then purified by column chromatography to give (S,E)-N-((5-cyclopropyl-6-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m / z: [M+H] + C 13 H 17 Calculated for FN2OS: 269.1; measured 269.2.

[0227] Step g: To a solution of (S,E)—N-((5-cyclopropyl-6-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (58 g, 216 mmol, 1 equiv.) in anhydrous DCM (600 mL) at −70° C. under nitrogen was added PhMgBr (3 M in EtO, 93.6 mL, 281 mmol, 1.3 equiv.). The resulting reaction mixture was stirred at −70° C. for 1 h. The reaction mixture was then quenched with saturated aqueous NH4Cl (500 mL), warmed to room temperature, and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give (S)-N-((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m / z: [M+H] + C 19 H 23 Calculated for FN2OS: 347.2; measured 347.3.

[0228] Step h: To a solution of (S)-N-((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (74 g, 213 mmol, 1 equiv.) in EtOAc (100 mL) at 0 °C was added HCl / EtOAc (4 M, 740 mL, 2940 mmol, 13.8 equiv.) under N2. The resulting mixture was then warmed to 20 °C and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure, and the resulting crude residue was triturated with MTBE (500 mL). The resulting solid was collected by filtration and dried under reduced pressure to give (S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methanaminium chloride. LC-MS (ESI): m / z: [M+H] + C 15 H 15 Calculated for FN2: 243.1; measured 243.2.

[0229] Intermediate A-6: Synthesis of (R)-(4-isopropylphenyl)(2-(1-methylpiperidine-4-carboxamido)phenyl)methanaminium chloride [ka] Step a: To a solution of tert-butyl (2-iodophenyl)carbamate (15 g, 47.0 mmol, 1 equiv.) and (4-isopropylphenyl)boronic acid (9.25 g, 56.4 mmol, 1.2 equiv.) in toluene (100 mL) was added K2CO3 (19.5 g, 141 mmol, 3 equiv.) and Pd(PPh3)2Cl2 (1.65 g, 2.35 mmol, 0.05 equiv.) under N2. The resulting mixture was then degassed and purged with CO2. The resulting mixture was warmed to 120 °C and stirred under CO2 (15 psi) for 10 h. The reaction mixture was then cooled to room temperature and poured into ice-water (100 mL). The resulting biphasic mixture was extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give tert-butyl (2-(4-isopropylbenzoyl)phenyl)carbamate.

[0230] Step b: To a solution of tert-butyl (2-(4-isopropylbenzoyl)phenyl)carbamate (10 g, 29.4 mmol, 1 equiv.) in EtOAc (20 mL) was added HCl / EtOAc (4 M, 100 mL), and the resulting mixture was stirred at 20 °C for 16 h. The reaction mixture was then diluted with water (50 mL), and the pH was adjusted to 8 with saturated aqueous NaHCO. The resulting biphasic mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (2-aminophenyl)(4-isopropylphenyl)methanone. LC-MS (ESI): m / z: [M+H] + C 16 H 17 Calculated for N2O: 240.1; Measured: 240.1.

[0231] Step c: To a solution of (2-aminophenyl)-(4-isopropylphenyl)methanone (7.3 g, 30.5 mmol, 1 equiv.) in THF (120 mL) was added (R)-2-methylpropane-2-sulfinamide (4.07 g, 33.5 mmol, 1.1 equiv.) and Ti(OEt) (13.9 g, 61.0 mmol, 2 equiv.) sequentially. The reaction was warmed to 80 °C and stirred for 16 h. The reaction mixture was then cooled to room temperature and quenched with water (50 mL). The resulting biphasic mixture was then extracted with ethyl acetate (2 × 50 mL), and the combined organic extracts were washed with brine (80 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give (R,E)-N-((2-aminophenyl)(4-isopropylphenyl)methylene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m / z: [M+H] + C 20 H 26 Calculated for N2OS: 343.2; Measured: 343.1.

[0232] Step d: To a solution of (R,E)-N-((2-aminophenyl)(4-isopropylphenyl)methylene)-2-methylpropane-2-sulfinamide (2.5 g, 7.30 mmol, 1 equiv.) in THF (25 mL) at −78° C. was added DIBAL-H (20.4 mL, 1 M, 2.8 equiv.). The resulting mixture was stirred at −78° C. for 2 h. The reaction mixture was then diluted with brine (50 mL), and the resulting biphasic mixture was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give (R)-N-((R)-(2-aminophenyl)(4-isopropylphenyl)methyl)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m / z: [M+Na] + C 20 H 28 Calculated for N2OS: 367.2; Measured: 367.1.

[0233] Step e: To a solution of (R)-N-((R)-(2-aminophenyl)(4-isopropylphenyl)methyl)-2-methylpropane-2-sulfinamide (250 mg, 725 μmol, 1 equiv.) in CHCN (2 mL) at −20° C., N-methylimidazole (148 mg, 1.81 mmol, 2.5 equiv.), 1-methylpiperidine-4-carboxylic acid (114 mg, 798 μmol, 1.1 equiv.), and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (244 mg, 870 μmol, 1.2 equiv.) were added. The resulting mixture was warmed to 0° C. and stirred for 3 h. The reaction mixture was then diluted with water, extracted with 30 mL of EtOAc (3 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give N-(2-((R)-(((R)-tert-butylsulfinyl)amino)(4-isopropylphenyl)methyl)phenyl)-1-methylpiperidine-4-carboxamide. LC-MS (ESI): m / z: [M+H] + C 27 H 39 Calculated for N3O2S: 470.3; Found 470.3.

[0234] Step f: To a solution of N-(2-((R)-(((R)-tert-butylsulfinyl)amino)(4-isopropylphenyl)methyl)phenyl)-1-methylpiperidine-4-carboxamide in EtOAc (2 mL) at 0° C. was added HCl / EtOAc (2 mL). The mixture was then warmed to 15° C. and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure. The resulting crude residue was triturated with MTBE at 15° C. for 30 min to give (R)-(4-isopropylphenyl)(2-(1-methylpiperidine-4-carboxamido)phenyl)methanaminium chloride. LC-MS (ESI): m / z: [M+H] + C 23 H 31 Calculated for N3: 366.3; measured 366.3.

[0235] The following compounds in Table B-1 were synthesized using procedures similar to those for Intermediates A-1 to A-6 using the appropriate starting materials and reagents. [Table 18] [Table 19] [Table 20] [Table 21] [Table 22]

[0236] Example S-1: Synthesis of (1R,2S)-2-fluoro-N-((S or R)-(6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methyl)cyclopropane-1-carboxamide (Compound 3) [ka] Step a: To a solution of (6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methanaminium chloride (150 mg, 468 μmol, 1 equiv.) in DMF (2 mL) at 0° C. was added (1R,2S)-2-fluorocyclopropane-1-carboxylic acid (58 mg, 561 μmol, 1.2 equiv.), NMM (1.87 mmol, 206 μL, 4 equiv.), and T3P (595 mg, 935 μmol, 50% purity, 2 equiv.). The resulting mixture was warmed to 25° C. and stirred for 1 h. The reaction mixture was then diluted with water, and the resulting biphasic mixture was extracted with ethyl acetate (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC to give (1R,2S)-2-fluoro-N-((6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methyl)cyclopropane-1-carboxamide. This mixture of diastereomers was separated by chiral SFC (column: DAICEL CHIRALPAK AD) to give (1R,2S)-2-fluoro-N-((S or R)-(6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methyl)cyclopropane-1-carboxamide as the second eluting isomer. LC-MS (ESI): m / z: [M+H] + C 20 H 20 Calculated for F2N4O: 371.2; found 371.1.

[0237] Example S-2: Synthesis of (R)-N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (Compound 64) and (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-methylazetidine-3-carboxamide (Compound 26) [ka] Step a: To a solution of tert-butyl (2-(amino(4-isopropylphenyl)methyl)phenyl)carbamate (4 g, 7.05 mmol, 60% purity, 1 equiv.) in DCM (100 mL) at 15 °C, NMM (14.1 mmol, 1.55 mL, 2 equiv.) and cyclopropanecarbonyl chloride (884 mg, 8.46 mmol, 1.2 equiv.) were added. The resulting mixture was stirred at 15 °C for 1 h. The reaction mixture was then poured into ice-water (50 mL) and stirred for 3 min. The resulting biphasic mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give tert-butyl (2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)carbamate. LC-MS(ESI):m / z:[M+H] + C 25 H 32 Calculated for N2O3: 409.2; found 409.3.

[0238] Step b: To a solution of tert-butyl (2-(cyclopropanecarboxamide(4-isopropylphenyl)methyl)phenyl)carbamate (3.5 g, 8.57 mmol, 1 equiv.) in EtOAc (30 mL) at 15 °C was added HCl / EtOAc (35 mL). The resulting mixture was stirred at 15 °C for 16 h. The reaction mixture was then concentrated under reduced pressure to give N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide. This mixture of enantiomers was separated by chiral SFC ((s,s)WHELK-O1, first eluting isomer) to give (R)-N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide as the first eluting isomer. LC-MS (ESI): m / z: [M+H] + C 20 H 24 Calculated for N2O: 309.2; measured 309.4.

[0239] Step c: To a solution of (R)-N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (60 mg, 0.194 mmol, 1 equiv.) in MeCN (2 mL) was added 1-methylazetidine-3-carboxylic acid (44 mg, 0.389 mmol, 2 equiv.). The resulting mixture was cooled to 0 °C, and then N-methylimidazole (39.9 mg, 0.486 mmol, 2.5 equiv.) and TCFH (17.5 mg, 0.486 mmol, 2.5 equiv.) were added sequentially. The resulting mixture was warmed to 20 °C and stirred for 2 h. The reaction mixture was then quenched by the addition of ice-water (10 mL), and the resulting biphasic mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC to give (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-methylazetidine-3-carboxamide. LC-MS (ESI): m / z: [M+H] + C 25 H 31 Calculated for N3O2: 406.2; Found 406.2.

[0240] Example S-3: Synthesis of (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide (Compound 48) and (R)-1-acetyl-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide (Compound 37) [ka] Step a: To a mixture of (R)-N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (150 mg, 486 μmol, 1 equiv.), N-methylimidazole (120 mg, 1.46 mmol, 3 equiv.), and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (108 mg, 535 μmol, 1.1 equiv.) in MeCN (5 mL) at 20 °C, TCFH (136 mg, 486 μmol, 1 equiv.) was added under N2. The resulting mixture was then stirred at 20 °C for 1 h. The reaction mixture was then poured into ice-water (10 mL), and the resulting biphasic mixture was extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give tert-butyl (R)-3-((2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)carbamoyl)azetidine-1-carboxylate. LC-MS (ESI): m / z: [M+H] + C 29 H 37 Calculated for N3O4: 492.3; found 492.3.

[0241] Step b: To a mixture of tert-butyl (R)-3-((2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)carbamoyl)azetidine-1-carboxylate (160 mg, 325 μmol, 1 equiv.) in DCM (3 mL) at 25° C., TFA (1.54 g, 13.5 mmol, 1.00 mL, 41.5 equiv.) was added, and the resulting mixture was stirred at 25° C. for 30 min. The reaction mixture was then diluted with HO (10 mL), and the resulting biphasic mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC to give (R)—N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide. LC-MS(ESI):m / z:[M+H] + C24 H 29 Calculated for N3O2: 392.2; Found 392.4.

[0242] Step c: To a mixture of (R)—N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide (10 mg, 25.5 μmol, 1 equiv.) and N-methylmorpholine (5.17 mg, 51.1 μmol, 2 equiv.) in DCM (1 mL) at −20° C., acetyl chloride (2.01 mg, 25.5 μmol, 1 equiv.) was added dropwise under N. The resulting mixture was warmed to 15° C. and stirred for 1 h. The reaction mixture was then cooled to 0° C. and quenched by the addition of HO (5 mL). The resulting biphasic mixture was stirred for 5 min and then extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to give (R)-1-acetyl-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide. LC-MS (ESI): m / z: [M+H] + C 26 H 31 Calculated for N3O3: 434.2; found 434.2.

[0243] Example S-4: Synthesis of (R or S)—N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide (Compound 31) [ka] Step a: To a solution of N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (500 mg, 1.62 mmol, 1.00 equiv) in DCM (30.0 mL) at 0 °C was added phenyl carbonochloridate (305 mg, 1.95 mmol, 1.20 equiv) and triethylamine (820 mg, 8.11 mmol, 5.00 equiv). The resulting mixture was warmed to 25 °C and stirred for 1 h. 2,2-Dimethoxyethan-1-amine (341 mg, 3.24 mmol, 2.00 equiv) was then added to the reaction mixture, and the resulting mixture was placed at 25 °C for 11 h. The reaction mixture was then diluted with HO (30 mL), and the resulting biphasic mixture was extracted with DCM (20 mL). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give N-((2-(3-(2,2-dimethoxyethyl)ureido)phenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide. LC-MS (ESI): m / z: [M+H] + C 25 H 33 Calculated for N3O4: 440.2; found 440.3.

[0244] Step b: To a solution of N-((2-(3-(2,2-dimethoxyethyl)ureido)phenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (250 mg, 569 μmol, 1.00 equiv) in MeOH (0.5 mL) at 0 °C was added HCl / MeOH (0.5 mL). The resulting mixture was warmed to 40 °C and stirred for 12 h. The reaction mixture was then concentrated under reduced pressure. The crude residue was then partitioned between water and DCM (30 mL). The organic layer was collected and washed with saturated aqueous NaHCO (10 mL) and saturated aqueous NaCl (10 mL). The washed organic layer was then dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC to give N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide. This mixture of enantiomers was then separated using chiral SFC (column: DAICEL CHIRALPAK AD) to give (R or S)—N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide as the first eluting isomer. LC-MS (ESI): m / z: [M+H] + C 23 H 25 Calculated for N3O2: 376.2; Found 376.2.

[0245] Example S-5: Synthesis of (R)-N-((3-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (Compound 62) [ka] Step a: To a solution of (R)-N-((4-isopropylphenyl)(3-methoxyphenyl)methyl)cyclopropanecarboxamide (0.35 g, 1.08 mmol, 1 equiv.) in DCM (2 mL) at −78 °C was added BBr (1.36 g, 5.41 mmol, 521 μL, 5 equiv.). The resulting mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was then diluted with saturated aqueous NaHCO to adjust the pH of the solution to 7. The resulting biphasic mixture was then extracted with dichloromethane (2 × 50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC to give (R)-N-((3-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide. LC-MS(ESI):m / z:[M+H] + C 20 H 23 Calculated for NO2: 310.2; measured value 310.1.

[0246] Example S-6: Synthesis of (1R,2S)-2-(2-acetamidoacetamido)-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide (Compound 21) [ka] Step a: To a solution of (S)-(4-isopropylphenyl)(phenyl)methanaminium chloride (0.25 g, 0.95 mmol, 1 equiv.) and (1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (0.44 g, 1.91 mmol, 1 equiv.) in DMF (4.8 mL), EDCI·HCl (0.28 g, 1.4 mmol, 1.5 equiv.), 1-hydroxybenzotriazole hydrate (0.22 g, 1.43 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (0.5 mL, 2.86 mmol, 3 equiv.) were added. The resulting mixture was stirred at 25 °C for 4 h. The reaction mixture was then poured into water (150 mL), and the resulting solution was extracted with EtOAc (3 × 150 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert-butyl ((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)carbamate.

[0247] Step b: To a solution of tert-butyl ((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)carbamate (0.4 g, 0.92 mmol, 1 equiv.) in methanol (4.6 mL) was added hydrochloric acid (1.14 mL, 4 M in dioxane, 4.6 mmol). The resulting reaction mixture was stirred at 25° C. for 2 hours, and then the reaction mixture was concentrated under reduced pressure to give (1R,2S)-2-amino-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide hydrochloride.

[0248] Step c: To a solution of (1R,2S)-2-amino-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide hydrochloride (0.065 g, 0.17 mmol, 1 equiv.) and (tert-butoxycarbonyl)glycine (0.037 g, 0.209 mmol, 1.2 equiv.) in DMF (1 mL), EDCI·HCl (0.05 g, 0.261 mmol, 1.5 equiv.), 1-hydroxybenzotriazole hydrate (0.04 g, 0.261 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (0.091 mL, 0.523 mmol, 3 equiv.) were added. The resulting mixture was stirred at 25 °C for 16 h, and then the reaction mixture was diluted with EtOAc (15 mL) and HO (15 mL). The organic layer was collected and washed successively with HO (15 mL) and brine (15 mL). The washed organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC to give tert-butyl (2-(((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)amino)-2-oxoethyl)carbamate.

[0249] Step d: To a solution of tert-butyl (2-(((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)amino)-2-oxoethyl)carbamate (0.009 g, 0.018 mmol, 1 equiv.) in methanol (1 mL) was added hydrochloric acid (0.5 mL, 4 M in dioxane, 2 mmol, 18 equiv.). The resulting mixture was stirred at 25° C. for 4 hours, and then the reaction mixture was concentrated under reduced pressure to give 2-(((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)amino)-2-oxoethan-1-aminium chloride.

[0250] Step e: To a solution of 2-(((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)amino)-2-oxoethan-1-aminium chloride (0.008 g, 0.019 mmol, 1 equiv.) in DCM (0.5 mL) was added N,N-diisopropylethylamine (0.007 mL, 0.038 mmol, 2 equiv.) and acetic anhydride (0.004 mL, 0.038 mmol, 2 equiv.) sequentially. The resulting mixture was stirred at 25° C. for 30 min. The reaction mixture was then concentrated under reduced pressure, and the resulting crude residue was purified by preparative HPLC to give (1R,2S)-2-(2-acetamidoacetamido)-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide. LC-MS(ESI):m / z:[M+H] + C 26 H 33 Calculated for N3O3: 436.3; found 436.3.

[0251] Example S-7:(1R,2S)-N 1 Synthesis of N-((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide (Compound 30) and (1R,2S)-2-cyano-N-((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1-carboxamide (Compound 7) [ka] Step a: In two parallel reactions, (R)-(4-isopropylphenyl)(o-tolyl)methanaminium chloride (100 mg, 362 μmol, 1 equiv.) was dissolved in dry THF (3 mL). The resulting solution was cooled to 0°C, and then N,N-diisopropylethylamine (93.7 mg, 725 μmol, 2 equiv.) was added. The resulting mixture was stirred at 0°C for 5 minutes, and then rel-(3aR,6aS)-tetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione (76.2 mg, 543 μmol, 1.5 equiv.) was added in one portion. The resulting reaction mixture was warmed to 25°C and stirred for 5 hours. The two reactions were then combined for workup. The combined reactions were cooled to 0°C and quenched by the addition of HO (10 mL). The pH of the resulting biphasic mixture was adjusted to pH = 5 using 2N aqueous HCl, and then the resulting biphasic mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by chiral SFC (column: DAICEL CHIRALPAK AD) to give (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid as the second eluting isomer. LC-MS (ESI): m / z: [M+H] + C 24 H 29 Calculated for NO3: 380.2; Found 380.3.

[0252] Step b: To a solution of (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid (81.5 mg, 0.21 mmol, 1 equiv.) in DMF (1 mL, 0.2 M), N,N-diisopropylethylamine (113 μL, 0.644 mmol, 3 equiv.), HOBt-NH (390 mg, 0.26 mmol, 1.2 equiv.), and TBTU (70 mg, 0.21 mmol, 1 equiv.) were added, and the resulting reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then diluted with EtOAc (30 mL) and HO (30 mL). The organic layer was then collected and washed sequentially with HO (30 mL) and brine (30 mL). The resulting organic solution was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give (1R,2S)-N 1 -((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide was obtained. LC-MS (ESI): m / z: [M+H] + C 24 H 30 Calculated for N2O2: 379.2; Found 379.2.

[0253] Step c: (1R,2S)-N in dichloromethane (1 mL) 1 To -((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide (48 mg, 0.127 mmol, 1 equiv.) was added TFAA (0.027 mL, 0.19 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (0.044 mL, 0.254 mmol, 2 equiv.). The reaction mixture was stirred at 25° C. for 4 hours, then concentrated under reduced pressure and purified by column chromatography to give (1R,2S)-2-cyano-N-((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1-carboxamide. LC-MS (ESI): m / z: [M+H] + C 24 H 28 Calculated for N2O: 361.2; Measured: 361.3. Example S-8:(1S,2R)-N1 -Cyano-N 2 Synthesis of -((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide (compound 22) [ka]

[0254] Step a: To a solution of (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid (25 mg, 0.066 mmol, 1 equiv.) in DCE (1 mL) was added oxalyl chloride (0.05 mL, 2 M, 0.099 mmol, 1.5 equiv.), followed by 1 drop of DMF. The resulting mixture was stirred at 25° C. for 16 h, and then the reaction mixture was concentrated under reduced pressure to give crude (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carbonyl chloride, which was used directly in the next step without further purification or characterization.

[0255] Step b: To a solution of cyanamide (5 mg, 0.131 mmol, 2 equiv.) and triethylamine (28 μL, 0.196 mmol, 3 equiv.) in DCM (1 mL) was added dropwise a solution of (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carbonyl chloride (26 mg, 0.065 mmol, 1 equiv.) in DCM (1 mL) at 25 °C under a N atmosphere. The resulting mixture was stirred at 25 °C for 16 h under a N atmosphere. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC to give (1S,2R)-N 1 -Cyano-N 2 -((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide was obtained. LC-MS (ESI): m / z: [M+H] + C 25 H 29 Calculated for N3O2: 404.2; Found 404.3.

[0256] Example S-9:(1R,2S)-N 1 -((R)-(4-isopropylphenyl)(o-tolyl)methyl)-N 2 Synthesis of 1,2-methylcyclopentane-1,2-dicarboxamide (compound 16) [ka] Step a: To a solution of (1S,2R)-2-(((R)-(4-isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxylic acid (50 mg, 0.132 mmol, 1 equiv.) in DMF (0.5 mL) was added EDCI·HCl (38 mg, 0.198 mmol, 1.5 equiv.), 1-hydroxybenzotriazole hydrate (0.03 g, 0.198 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (0.069 mL, 0.395 mmol, 3 equiv.). The resulting mixture was stirred at 25 °C for 16 h, and then the reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was then collected and washed sequentially with water (20 mL) and brine (20 mL). The organic solution was then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC to give (1R,2S)-N 1 -((R)-(4-isopropylphenyl)(o-tolyl)methyl)-N 2 LC-MS(ESI):m / z:[M+H] + C 25 H 32 Calculated for N2O2: 393.2; Found 393.2.

[0257] The following compounds in Table T-1 were synthesized using procedures similar to those of Examples S-1 to S-9 using the appropriate starting materials and reagents. [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34]

[0258] biological example Example B-1 The GYS1 coupling enzyme assay is a kinetic biochemical assay that indirectly quantifies the rate of glycogen synthesis by coupling the conversion of the GYS1 substrate UDP-glucose to UDP with downstream enzymatic reactions. UDP is released from UDP-glucose when a glucose monomer is attached to a growing glycogen chain by GYS1. The coupling assay then proceeds with pyruvate kinase utilizing UDP and phospho(enol)pyruvate (PEP) to form pyruvate. Lactate dehydrogenase then converts pyruvate and NADH to lactate and NAD+. The oxidation of NADH to NAD+ can be continuously measured using a plate reader by quantifying the decrease in NADH absorbance at 340 nm over time.

[0259] Compounds that inhibit the hGYS1 enzyme and the subsequent downstream conversion of NADH to NAD+ were tested using assay-ready plates (black, clear-bottom 384-well plates) in a final DMSO reaction volume of 2.5% DMSO. The assay buffer contained 50 mM Tris pH 7.5, 2 mM MgCl2, and 100 mM KCl. Fresh stocks of BSA at a final concentration of 0.02% and 1 mM TCEP were added before dividing the buffer into hGYS1 buffer and substrate buffer. Rabbit liver glycogen was added to the hGYS1 buffer to a final concentration of 0.2% glycogen. Glucose-6-phosphate was added to 1 mM, recombinant hGYS1 / GN1 protein was added to the substrate buffer at 50 nM, phosphoenolpyruvate (PEP) was added to 2 mM, UDP-glucose was added to 0.8 mM, NADH was added to 0.6 mM, and pyruvate kinase / lactate dehydrogenase was added to 20 units / mL. The reaction was initiated by mixing the hGYS1 buffer and substrate buffer in a 1:1 ratio. Both buffers were plated using a liquid dispensing device, with the hGYS1 buffer plated first, followed by the substrate buffer. The plate was briefly spun to remove air bubbles and immediately read at 340 nm absorbance in continuous mode at 1-minute intervals for 10 time points, for a total of 10 minutes. The slopes from these 10 time points were normalized to the positive and negative control wells. Duplicate % inhibition values ​​are then averaged and fitted to a Hill equation for dose response according to the Levenberg-Marquardt algorithm, with the maximum value of the Hill equation set to 100 and the minimum value set to 0.

[0260] IC of each compound 50 The results reported are shown in Table 3 below. Unless otherwise stated, IC 50Values ​​are reported as the geometric mean of at least two assay runs on separate days. Each run represents the average of technical replicates, and each compound was assayed twice on the same plate. As shown in the table below, the compounds of the present invention are potent inhibitors of human GYS1.

[0261] Note that in Table 3, these compounds are referenced by the corresponding compound numbers in Table 1, which are also referenced in the synthetic examples. [Table 35]

[0262] Example B-2 The GYS1 cell-based assay is a bioluminescent assay that quantifies glucose resulting from glycogen digestion; the quantified glucose is an indirect measure of GYS1 glycogen synthesis. Newly synthesized glycogen is digested using glucoamylase, and the resulting glucose is quantified using Promega's Glucose-glo assay kit. Glucose-glo functions by coupling glucose oxidation and NADH production with an NADH-activated bioluminescence system. Glucose is oxidized by glucose dehydrogenase, which reduces NAD+ to NADH. NADH activates proluciferin reductase, which reduces the substrate to luciferin. Luciferin is detected in a luciferase reaction using Ultra-Glo rLuciferase and ATP; the luminescence produced is proportional to the glucose in the sample. Luminescence is measured as a single point read on a plate reader.

[0263] Compounds that inhibit the hGYS1 enzyme and subsequently inhibit glycogen synthesis in cells were tested using assay-ready plates (white, clear-bottom 384-well plates) in a final DMSO reaction volume of 1% DMSO. Compounds in the assay-ready plates were mixed with additive-free medium, except for 20 mM glucose, before adding to cells. HeLa cells were starved for 24 hours in additive-free medium, except for 1x Glutamax. Starved HeLa cells were plated at a 1:1 ratio to medium in the assay-ready plates and incubated for 24 hours at 37°C and 5% CO2. Cells were washed with 1x PBS buffer and lysed in lysis buffer containing 50% of the final volume of 1x PBS and 25% 0.3 N HCl in the well or reaction volume. Cells were incubated in lysis buffer for 10 minutes and quenched with the remaining 25% of the reaction volume, consisting of 450 mM Tris pH 8.0. The lysate was mixed with glucoamylase in a 1:1 ratio in 100 mM sodium acetate buffer at pH 5.3, and the mixture was incubated at 37°C for 1 hour. The digested lysate was mixed with Glucose-glo detection mix in a 1:1 ratio based on the vendor's recommendations (luciferase detection buffer, reductase, reductase substrate, glucose dehydrogenase, and NAD) in a readout plate (solid white 384-well plate) and incubated at room temperature for 1 hour. The plate was read using a plate reader with luminescence capabilities. The relative luminescence units (RLU) for each compound concentration were averaged and normalized to the average RLU of the positive and negative controls to obtain percentage inhibition. Normalized data versus concentration was plotted, and the half-maximal concentration (IC 50 To determine ), the Hill equation was fitted to the dose-response data using the Levenberg-Marquardt algorithm.

[0264] IC of each compound 50 The results reported are shown in Table 4 below. Unless otherwise stated, IC 50and values ​​are reported as the geometric mean of at least two assay runs on separate days. As shown in the table below, the compounds of the present invention are potent inhibitors of human GYS1. Unless otherwise specified, IC 50 Values ​​are reported as the geometric mean of at least two assay runs on separate days. Each run represents the average of technical replicates, and each compound was assayed twice on the same plate. [Table 36]

[0265] Example B-3 The GYS2 coupling enzyme assay is a kinetic biochemical assay that indirectly quantifies the rate of glycogen synthesis by coupling the conversion of the GYS2 substrate UDP-glucose to UDP with downstream enzymatic reactions. UDP is released from UDP-glucose when a glucose monomer is attached to the growing glycogen chain by GYS2. The coupling assay then proceeds with pyruvate kinase utilizing UDP and phospho(enol)pyruvate (PEP) to form pyruvate. Lactate dehydrogenase then converts pyruvate and NADH to lactate and NAD+. The oxidation of NADH to NAD+ can be continuously measured using a plate reader by quantifying the decrease in NADH absorbance at 340 nm over time.

[0266] Compounds that inhibit the hGYS2 enzyme and the subsequent downstream conversion of NADH to NAD+ were tested using assay-ready plates (black, clear-bottom 384-well plates) in a final DMSO reaction volume of 2.5% DMSO. The assay buffer contained 50 mM Tris pH 7.5, 2 mM MgCl2, and 100 mM KCl. Fresh stocks of BSA at a final concentration of 0.02% and 1 mM TCEP were added before dividing the buffer into hGYS2 buffer and substrate buffer. Rabbit liver glycogen was added to the hGYS2 buffer to a final concentration of 0.2% glycogen. Glucose-6-phosphate was added at 2 mM, recombinant hGYS2 / GN1 protein was added to the substrate buffer at 200 nM, phosphoenolpyruvate (PEP) was added at 2 mM, UDP-glucose was added at 2 mM, NADH was added at 0.6 mM, and pyruvate kinase / lactate dehydrogenase was added at 20 units / mL. The reaction was initiated by mixing the hGYS2 buffer and substrate buffer in a 1:1 ratio. Both buffers were plated using a liquid dispensing device, with the hGYS2 buffer plated first, followed by the substrate buffer. The plate was briefly spun to remove air bubbles and immediately read at 340 nm absorbance in continuous mode at 1-minute intervals for 10 time points, for a total of 10 minutes. The slopes from these 10 time points were normalized to the positive and negative control wells. Duplicate % inhibition values ​​are then averaged and fitted to a Hill equation for dose response according to the Levenberg-Marquardt algorithm, with the maximum value of the Hill equation set to 100 and the minimum value set to 0.

[0267] IC of each compound 50 The results reported are shown in Table 5 below. Unless otherwise stated, IC 50 and values ​​are reported as the geometric mean of at least two assay runs on separate days. As shown in the table below, the compounds of the present invention are not potent inhibitors of human GYS2. Unless otherwise stated, IC 50Values ​​are reported as the geometric mean of at least two assay runs on separate days. Each run represents the average of technical replicates, and each compound was assayed twice on the same plate. [Table 37]

[0268] Example B-4 Pompe disease is a glycogen storage disorder caused by mutations in the enzyme acid alpha-glucosidase, which leads to the pathological accumulation of glycogen. While glycogen can accumulate in virtually all tissues, the primary pathology affects skeletal and cardiac muscle. Inhibition of muscle glycogen synthesis could reduce pathological glycogen accumulation by acting as a substrate-reducing treatment. Savage et al. identified a predicted protein-truncating variant (PTV) in the PPP1R3A gene (a regulator of glycogen metabolism) in approximately 0.5% of Europeans, resulting in an approximately 65% ​​reduction in muscle glycogen (Savage et al., A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice. PLoS Medicine. 2008, the entire contents of which are incorporated herein by reference). PPP1R3A functions as a major activator of muscle glycogen synthase 1 (GYS1) by dephosphorylating the enzyme and maximizing its activity. Figure 1 shows the pathway by which PPP1R3A (loss-of-function) LoF leads to reduced muscle glycogen.

[0269] Large-scale biobanks allow for the investigation of the consequences of genetic variation on many health-related phenotypes. To assess the consequences of a predicted 65% loss of muscle glycogen, we conducted an association study comparing phenotypes between PPP1R3A PTV carriers and noncarriers in the UK Biobank. Genetic association studies were performed using REGENIE (Mbatchou, J., Barnard, L., Backman, J. et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat Genet 53, 1097-1103, 2021), adjusted for age, sex, and the first 10 principal components of ancestry. Quantitative traits were normalized using an inverse rank normal transformation.

[0270] For Figures 2A-2H, associations between PPP1R3A PTV and quantitative phenotypes are shown: left ventricular ejection fraction (LVEF) (%) (Figure 2A), left ventricular wall thickness (mm) (Figure 2B), exercise power (Watts) (Figure 2C), maximum heart rate (HR) exertion (bpm) (Figure 2D), PQ interval (ms) (Figure 2E), QRS duration (ms) (Figure 2F), QT interval (ms) (Figure 2G), and serum glucose (mmol / L) (Figure 2H). Phenotype values ​​are plotted by PPP1R3A dosage for UK Biobank participants. No associations between PPP1R3A PTV and quantitative phenotypes in UK Biobank were identified.

[0271] Table 6 below lists the P values ​​and number of participants (N) for the results shown in Figures 2A-2H. No associations were identified between PPP1R3A PTV and cardiac parameters, including left ventricular ejection fraction (p=0.871) and wall thickness (p=0.168). There was no evidence of changes in electrocardiographic cardiac conduction intervals or any muscle performance measures (n=49,616), including maximum heart rate (p=0.444) and maximum workload (p=0.100) during exercise testing. Furthermore, no changes were observed in serum glucose (p=0.71) or other members of a panel of approximately 170 serum metabolites. [Table 38]

[0272] No associations were observed between PPP1R3A PTVs and major health outcomes, as shown below in Table 7. In addition to the phenotypes in Table 7, no phenome-wide significant associations were observed between PPP1R3A PTVs and the proportion of any ICD10 code occurring 100 or more times in UK Biobank. [Table 39]

[0273] After conducting an extensive phenome-wide association study in the UK Biobank, no significant associations were found between important outcomes or phenotypes and loss of function of PPP1R3A. The results provided herein demonstrate that loss of function variants in the PPP1R3A gene are not associated with adverse health outcomes in a large biobank population. This suggests that partial reduction of muscle glycogen (approximately 65%) from birth is well tolerated, supporting the potential safety of pharmacological reduction of muscle glycogen.

[0274] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference.

[0275] While the present disclosure has been described in conjunction with the foregoing embodiments, it should be understood that the foregoing descriptions and examples are intended to illustrate, but not limit, the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

Claims

1. Formula (I): 【Chemical 1】 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y １ and Y ２ are each CH, or Y １ and Y ２ One of the two is N, and Y １ and Y ２ the other is CH, X １ and X ２ are each independently H or halo; R ３ and R ４ are each -CH ３ or R ３ and R ４ together with the atom to which they are attached form cyclopropyl or cyclobutyl, (1) L does not exist, and Q １ but, (i) C ６～２０ Aryl, wherein Q １ The above C ６～２０ The aryl is one or more of -OH, -NH ２ , Haro, C １～６ Alkyl, C １～６ Alkoxy, C ３～１０ Cycloalkyl, 5- to 20-membered heteroaryl, —NH—C(O)—NH ２ , -NH-C(O)-NH(C １～６ alkyl), —NH—C(O)—C １～６ Alkyl, —NH—C(O)—C ３～１０ Cycloalkyl, —NH—C(O)-(3- to 15-membered heterocyclyl), —NH—C(═N—CN)—NH ２ , —NH—S(O) ２ -C １～６ Alkyl, —NH(C １～６ optionally substituted with -NH-(3- to 15-membered alkyl), -NH-(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of the —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C １～６ Alkyl or C １～６ Optionally substituted with alkyl, １～６ The alkyl may be one or more halo, C １～６ Alkoxy or C ３～１０ optionally substituted with cycloalkyl, and The 3- to 15-membered heterocyclyl of the —NH-(3- to 15-membered heterocyclyl) is one or more oxo or C １～６ C optionally substituted with alkyl ６～２０ aryl, or (ii) 3- to 15-membered heterocyclyl, wherein Q １ wherein said 3- to 15-membered heterocyclyl is optionally substituted with one or more oxo; or (iii) 5- to 20-membered heteroaryl, wherein Q １ wherein said 5- to 20-membered heteroaryl contains at least one ring N atom and one or more -NH ２ , Haro, C １～６ Alkyl, or C ３～１０ a 5- to 20-membered heteroaryl optionally substituted with cycloalkyl; or (2) L is -CH ２ - and Q １ is C ３～１０ or cycloalkyl; m is 0 or 1; n is 0 or 1; R １ H, halo, -CN, -C(O)-NH ２ , -C(O)-NH(CN), -C(O)-NH(C １～６ alkyl), —NH—C(O)—NH ２ , or —NH—C(O)—C １～６ is alkyl, R １ The above-mentioned -C(O)-NH(C １～６ C of alkyl) １～６ The alkyl is one or more —C(O)—C １～６ optionally substituted with alkoxy; R １ -NH-C(O)-C １～６ Alkyl C １～６ The alkyl is one or more —NH—C(O)—C １～６ Alkyl or —C(O)—NH ２ and R ２ is H, halo, or —OH, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

2. The compound of formula (I) 【Chemistry 2】 2. The compound of claim 1 having the stereochemical configuration: or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

3. X １ is H, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

4. X １ is halo, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

5. X １ 5. The compound of claim 1 or 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein is fluoro.

6. X ２ is H, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

7. X ２ is halo, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

8. X ２ is fluoro, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

9. R ３ and R ４ each independently represents —CH ３ 9. The compound of any one of claims 1 to 8, wherein:

10. R ３ and R ４ are taken together with the atom to which they are attached to form cyclopropyl or cyclobutyl, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

11. R ３ and R ４ are taken together with the atom to which they are attached to form cyclopropyl, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

12. R ３ and R ４ are taken together with the atom to which they are attached to form a cyclobutyl, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

13. 13. The compound of any one of claims 1 to 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is absent.

14. Q １ is C ６～２０ aryl, and Q １ The above C ６～２０ The aryl may be one or more NH ２ , Haro, C １～６ Alkyl, C １～６ Alkoxy, C ３～１０ Cycloalkyl, 5- to 20-membered heteroaryl, —NH—C(O)—NH ２ , -NH-C(O)-NH(C １～６ alkyl), —NH—C(O)—C １～６ Alkyl, —NH—C(O)—C ３～１０ Cycloalkyl, —NH—C(O)-(3- to 15-membered heterocyclyl), —NH—C(═N—CN)—NH ２ , or -NH(C １～６ alkyl), The 3- to 15-membered heterocyclyl of the —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C １～６ Alkyl or C １～６ Optionally substituted with alkyl, １～６ The alkyl may be one or more halo, C １～６ Alkoxy, or C ３～１０ optionally substituted with cycloalkyl, and The 3- to 15-membered heterocyclyl of the —NH-(3- to 15-membered heterocyclyl) is one or more oxo or C １～６ 14. A compound according to any one of claims 1 to 13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally substituted with alkyl.

15. Q １ is phenyl, and Q １ wherein the phenyl is one or more NH ２ , Haro, C １～６ Alkyl, C １～６ Alkoxy, C ３～１０ Cycloalkyl, 5- to 20-membered heteroaryl, —NH—C(O)—NH ２ , -NH-C(O)-NH(C １～６ alkyl), —NH—C(O)—C １～６ Alkyl, —NH—C(O)—C ３～１０ Cycloalkyl, —NH—C(O)—(3- to 15-membered heterocyclyl), or —NH—C(═N—CN)—NH ２ , —NH(C １～６ alkyl), The 3- to 15-membered heterocyclyl of the —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C １～６ Alkyl or C １～６ Optionally substituted with alkyl, １～６ The alkyl may be one or more halo, C １～６ Alkoxy, or C ３～１０ optionally substituted with cycloalkyl, and The 3- to 15-membered heterocyclyl of the —NH-(3- to 15-membered heterocyclyl) is one or more oxo or C １～６ 15. A compound according to any one of claims 1 to 14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally substituted with alkyl.

16. Q １ but, 【Chemistry 3】 16. The compound of any one of claims 1 to 15, selected from the group consisting of: or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

17. Q １ is a 3- to 15-membered heterocyclyl; １ or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

18. Q １ is a 9- to 10-membered heterocyclyl, and Q １ or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

19. Q １ but, 【Chemistry 4】 19. The compound of any one of claims 1 to 13, 17, and 18, selected from the group consisting of: or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

20. Q １ is a 5- to 20-membered heteroaryl; and Q １ wherein said 5- to 20-membered heteroaryl contains at least one ring N atom and one or more -NH ２ , Haro, C １～６ Alkyl, or C ３～１０ 14. A compound according to any one of claims 1 to 13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally substituted with cycloalkyl.

21. Q １ is a 6- to 10-membered heteroaryl; and Q １ wherein said 6- to 10-membered heteroaryl contains at least one ring N atom and one or more -NH ２ , Haro, C １～６ Alkyl, or C ３～１０ 21. A compound according to any one of claims 1 to 13 and 20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally substituted with cycloalkyl.

22. Q １ but, 【Chemistry 5】 22. The compound of any one of claims 1 to 13, 20, and 21, selected from the group consisting of: or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

23. L is -CH ２ - and Q １ is C ３～１０ 13. The compound of any one of claims 1 to 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, which is cycloalkyl.

24. 24. The compound of any one of claims 1 to 23, wherein m and n are each independently 0, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

25. 24. The compound of any one of claims 1 to 23, wherein m and n are each independently 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

26. R １ is H, -CN, -C(O)-NH ２ , -C(O)-NH(CN), -C(O)-NH(C １～６ alkyl), —NH—C(O)—NH ２ and —NH—C(O)—C １～６ is selected from the group consisting of alkyl, The -C(O)-NH(C １～６ C of alkyl) １～６ The alkyl is one or more —C(O)—C １～６ optionally substituted with alkoxy; -NH-C(O)-C １～６ Alkyl C １～６ The alkyl is one or more —NH—C(O)—C １～６ Alkyl or —C(O)—NH ２ 26. The compound of any one of claims 1 to 25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally substituted with

27. R １ is H, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

28. R １ -CN, -C(O)-NH ２ , -C(O)-NH(CN), -C(O)-NH(C １～６ alkyl), —NH—C(O)—NH ２ and —NH—C(O)—C １～６ is selected from the group consisting of alkyl, The -C(O)-NH(C １～６ C of alkyl) １～６ The alkyl is one or more —C(O)—C １～６ optionally substituted with alkoxy; -NH-C(O)-C １～６ Alkyl C １～６ The alkyl is one or more —NH—C(O)—C １～６ Alkyl or —C(O)—NH ２ 27. The compound of any one of claims 1 to 26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally substituted with

29. R １ が、-CN、 【Chemistry 6】 29. The compound of any one of claims 1 to 26 and 28, selected from the group consisting of: or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

30. R １ is H or halo, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

31. R １ is H or fluoro, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

32. R １ 32. The compound of any one of claims 1 to 25, 30, and 31, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein is fluoro.

33. R ２ is H, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

34. R ２ is halo, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

35. R ２ 35. The compound of any one of claims 1 to 32, and 34, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein is fluoro.

36. R ２ is -OH, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

37. The compound has formula (IA): 【Chemistry 7】 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: i.X ４～８ are each independently H, —OH, —NH ２ , Haro, C １～６ Alkyl, C １～６ Alkoxy, C ３～１０ Cycloalkyl, 5- to 20-membered heteroaryl, —NH—C(O)—NH ２ , -NH-C(O)-NH(C １～６ alkyl), —NH—C(O)—C １～６ Alkyl, —NH—C(O)—C ３～１０ Cycloalkyl, —NH—C(O)-(3- to 15-membered heterocyclyl), —NH—C(═N—CN)—NH ２ , —NH—S(O) ２ -C １～６ Alkyl, —NH(C １～６ -(3- to 15-membered alkyl), -NH-(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 9-membered heterocyclyl of the —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C １～６ Alkyl or C １～６ Optionally substituted with alkyl, １～６ The alkyl may be one or more halo, C １～６ Alkoxy, or C ３～１０ optionally substituted with cycloalkyl, and The 3- to 9-membered heterocyclyl of the —NH-(3- to 15-membered heterocyclyl) is one or more oxo or C １～６ optionally substituted with alkyl; ii. X ６ But, X ４ or X ８ and the atoms to which they are attached form ring A, and ring A is 3- to 9-membered heterocyclyl, wherein the 3- to 9-membered heterocyclyl of ring A is optionally substituted with one or more oxo; and X ５ , X ７ , and X ４ or X ８ and the other of are, independently at each occurrence, H or oxo; or 5-14 membered heteroaryl, wherein said 5-14 membered heteroaryl of ring A contains at least one ring N atom and one or more -NH ２ , Haro, C １～６ Alkyl, or C ３～１０ Optionally substituted with cycloalkyl, X ５ , X ７ , and X ４ or X ８ and the other of each independently is H, —NH ２ , Haro, C １～６ Alkyl, or C ３～１０ cycloalkyl, or iii. X ７ But, X ５ or X ８ and the atoms to which they are attached form ring A, and ring A is 3- to 9-membered heterocyclyl, wherein the 3- to 9-membered heterocyclyl of ring A is optionally substituted with one or more oxo; and X ４ , X ６ , and X ５ or X ８ and the other of are, independently at each occurrence, H or oxo; or 5-14 membered heteroaryl, wherein said 5-14 membered heteroaryl of ring A contains at least one ring N atom and one or more -NH ２ , Haro, C １～６ Alkyl, or C ３～１０ Optionally substituted with cycloalkyl, X ４ , X ６ , and X ５ or X ８ and the other of each independently is H, —NH ２ , Haro, C １～６ Alkyl, or C ３～１０ 37. The compound of any one of claims 1 to 21 and 24 to 36, wherein: R is cycloalkyl; ...

38. The compound has formula (IC): 【Chemistry 8】 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is a 3- to 9-membered heterocyclyl, wherein said 3- to 9-membered heterocyclyl of Ring A is optionally substituted with one or more oxo; 5-14 membered heteroaryl, wherein said 5-14 membered heteroaryl of ring A contains at least one ring N atom and one or more -NH ２ , Haro, C １～６ Alkyl, or C ３～１０ 24. The compound of any one of claims 1-10, 13, 15, or 20-23, wherein:

39. 2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1.

40. 40. A process for preparing a compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprising: (a) Formula (I-1): 【Chemistry 9】 or a salt thereof, wherein Y １ and Y ２ are each CH, or Y １ and Y ２ One of the two is N, and Y １ and Y ２ the other of which is CH, X １ and X ２ are each independently H or halo; R ３ and R ４ are each -CH ３ or R ３ and R ４ together with the atom to which they are attached form cyclopropyl or cyclobutyl, (1) L does not exist, and Q １ teeth, (i) C ６～２０ Aryl, wherein Q １ The above C ６～２０ The aryl is one or more of -OH, -NH ２ , Haro, C １～６ Alkyl, C １～６ Alkoxy, C ３～１０ Cycloalkyl, 5- to 20-membered heteroaryl, —NH—C(O)—NH ２ , -NH-C(O)-NH(C １～６ alkyl), —NH—C(O)—C １～６ Alkyl, —NH—C(O)—C ３～１０ Cycloalkyl, —NH—C(O)-(3- to 15-membered heterocyclyl), —NH—C(═N—CN)—NH ２ , —NH—S(O) ２ -C １～６ Alkyl, —NH(C １～６ optionally substituted with -NH-(3- to 15-membered alkyl), -NH-(3- to 15-membered heterocyclyl), or -NH-(5- to 20-membered heteroaryl); The 3- to 15-membered heterocyclyl of the —NH—C(O)-(3- to 15-membered heterocyclyl) is one or more —C(O)—C １～６ Alkyl or C １～６ Optionally substituted with alkyl, １～６ The alkyl may be one or more halo, C １～６ Alkoxy or C ３～１０ optionally substituted with cycloalkyl, and The 3- to 15-membered heterocyclyl of the —NH-(3- to 15-membered heterocyclyl) is one or more oxo or C １～６ C optionally substituted with alkyl ６～２０ aryl, or (ii) 3- to 15-membered heterocyclyl, wherein Q １ wherein said 3- to 15-membered heterocyclyl is optionally substituted with one or more oxo; or (iii) 5- to 20-membered heteroaryl, wherein Q １ wherein said 5- to 20-membered heteroaryl contains at least one ring N atom and one or more -NH ２ , Haro, C １～６ Alkyl, or C ３～１０ a 5- to 20-membered heteroaryl optionally substituted with cycloalkyl; or (2) L is -CH ２ - and Q １ is C ３～１０ or cycloalkyl) in the presence of a coupling reagent to obtain a compound of formula (I-2): 【Chemistry 10】 (In the formula, m is 0 or 1; n is 0 or 1; R １ is H, halo, -CN, -C(O)-NH ２ , -C(O)-NH(CN), -C(O)-NH(C １～６ alkyl), —NH—C(O)—NH ２ , or —NH—C(O)—C １～６ is alkyl, R １ The above-mentioned -C(O)-NH(C １～６ C of alkyl) １～６ Alkyl is one or more —C(O)—C １～６ optionally substituted with alkoxy; R １ -NH-C(O)-C １～６ Alkyl C １～６ Alkyl is one or more -NH-C(O)-C １～６ Alkyl or —C(O)—NH ２ and R ２ is H, halo, or —OH) to provide a compound of formula (I).

41. 40. A pharmaceutical composition comprising: (i) a compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing; and (ii) one or more pharmaceutically acceptable excipients.

42. 42. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to said individual an effective amount of a compound of any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41.

43. 43. The method of claim 42, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

44. 44. The method of claim 42 or 43, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

45. 45. The method of any one of claims 42 to 44, wherein the disease, disorder, or condition is Pompe disease.

46. 43. The method of claim 42, wherein the disease, disorder, or condition is cancer.

47. 47. The method of claim 42 or 46, wherein the disease, disorder, or condition is selected from the group consisting of Ewing's sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen-rich clear cell carcinoma (GRCC), breast cancer, non-small cell lung cancer (NSCLC), and acute myeloid leukemia (AML).

48. 43. The method of claim 42, wherein the individual has a GAA mutation.

49. 49. The method of claim 48, wherein the GAA mutation is a loss-of-function mutation.

50. 42. A kit comprising: (i) a compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41; and (ii) instructions for use thereof in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

51. 51. The kit of claim 50, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

52. 52. The kit of claim 50 or 51, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

53. 53. The kit of any one of claims 50 to 52, wherein the disease, disorder, or condition is Pompe disease.

54. 51. The kit of claim 50, wherein the disease, disorder, or condition is cancer.

55. 55. The kit of claim 50 or 54, wherein the disease, disorder, or condition is selected from the group consisting of Ewing's sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen-rich clear cell carcinoma (GRCC), breast cancer, non-small cell lung cancer (NSCLC), and acute myeloid leukemia (AML).

56. 53. The kit of claim 52, wherein the individual has a GAA mutation.

57. 57. The kit of claim 56, wherein the GAA mutation is a loss-of-function mutation.

58. 42. A method of modulating GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41.

59. 42. A method of inhibiting GYS1 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or to a pharmaceutical composition according to claim 41.

60. 42. A method of reducing tissue glycogen stores in an individual in need thereof, comprising administering to said individual an effective amount of a compound of any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 41.

61. 40. A method of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof, comprising subjecting said individual to glycogen substrate-reducing therapy, said glycogen substrate-reducing therapy comprising administering to said individual an effective amount of a compound of any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 39.

62. 62. The method of claim 61, comprising subjecting the individual to glycogen substrate reduction therapy in combination with enzyme replacement therapy.

63. 63. The method of claim 62, wherein the enzyme replacement therapy is selected from the group consisting of alglucosidase alfa (human recombinant alpha-glucosidase (human GAA)), Myozyme, and Lumizyme.

64. 64. The method of any one of claims 61 to 63, wherein the disease, disorder, or condition is a glycogen storage disorder (GSD).

65. 65. The method of any one of claims 61-64, wherein the disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSD III), adult polyglucosan body disease (APBD), and Lafora disease.

66. 66. The method of any one of claims 61 to 65, wherein the disease, disorder, or condition is Pompe disease.

67. 64. The method of any one of claims 61 to 63, wherein the disease, disorder, or condition is cancer.

68. 68. The method of any one of claims 61-63, or 67, wherein the disease, disorder, or condition is selected from the group consisting of Ewing's sarcoma (ES), clear cell renal cell carcinoma (ccRCC), glycogen-rich clear cell carcinoma (GRCC), breast cancer, non-small cell lung cancer (NSCLC), and acute myeloid leukemia (AML).

69. 64. The method of any one of claims 61 to 63, wherein the individual has a GAA mutation.

70. 70. The method of claim 69, wherein the GAA mutation comprises a loss-of-function mutation.

71. 61. The method of any one of claims 58 to 60, wherein the compound is selective for GYS1 over GYS2.

72. 72. The method of claim 71, wherein the compound is 500-fold or 1,000-fold or 1,500-fold or 1,700-fold selective for GYS1 over GYS2.

73. 73. The method of any one of claims 42-49 or 58-72, comprising reducing glycogen levels in skeletal muscle.

74. 42. A compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41, for use in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

75. 42. A compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41, for use in modulating GYS1 in a cell.

76. 42. A compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41, for use in inhibiting GYS1 in a cell.

77. 42. A compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41, for use in reducing tissue glycogen stores in an individual in need thereof.

78. 42. A compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41, for use in glycogen substrate reduction therapy for the treatment of a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

79. 42. Use of a compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41, in the manufacture of a medicament for use in treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

80. 42. Use of a compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41, in the manufacture of a medicament for use in modulating GYS1 in a cell.

81. 42. Use of a compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41, in the manufacture of a medicament for use in inhibiting GYS1 in a cell.

82. 42. Use of a compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41, in the manufacture of a medicament for use in reducing tissue glycogen stores in an individual in need thereof.

83. 42. Use of a compound according to any one of claims 1 to 39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41, in the manufacture of a medicament for use in glycogen substrate reduction therapy for the treatment of a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

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