N-(benzhydryl) cycloalkyl carboxamide derivatives as glycogen synthase 1 (GYS1) inhibitors 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, R1, R2, R3, R4, Y1, Y2, X1, X2, L, and Q1 are as defined others herein. Also provided herein are methods of making the compounds of formula (I). Also provided herein are methods of inhibiting GYS1 and methods of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof. # imgabs0 #

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the priority of U.S. Provisional Application No. 63 / 406,684, filed on September 14, 2022, the content of which is incorporated herein by reference. Background of the Invention

[0004] Pathological accumulation of glycogen is a hallmark of multiple devastating and chronic human diseases. For some of these conditions, the cellular etiology driving this abnormal accumulation has an obvious genetic basis, while for others, the mechanistic drivers are more complex. Nevertheless, over time, elevated glycogen levels lead to altered cellular homeostasis and impaired tissue function. The rate - limiting enzyme in the glycogen synthesis pathway is the protein glycogen synthase (GYS). Humans have two subtypes: GYS1 and GYS2. The former is ubiquitously expressed and abundant in muscle cells, while the latter is expressed only in the liver. The ultimate starting point for glycogen synthesis is the transport of glucose into the cell via the GLUT family of transporters. The conversion of glucose to glycogen follows a well - characterized biochemical conversion pathway, in which GYS covalently links glucose molecules via α1,4 - glycosidic bonds into long branches. The final spherical structure of glycogen results from the action of glycogen - branching enzyme (GBE), which introduces α1,6 - linked branch points along the chain. The result of this chain of biochemical events is the production of an energy - dense and highly soluble molecule that can be stored in the cytosol of the cell and rapidly broken down into glucose for energy when needed. Imbalances in the equilibrium between glycogen synthesis and glycogenolysis lead to abnormal accumulation of cellular glycogen stores. It has long been hypothesized that substrate - reduction therapies targeting the inhibition of glycogen synthase could be effective in treating glycogen storage diseases. In fact, substrate - reduction therapy drugs have been very successful in modulating the course of 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 object of the present invention is to inhibit glycogen synthase activity, thereby reducing tissue glycogen storage and providing therapeutic benefits to patients suffering from abnormal cellular glycogen accumulation.

[0005] Pompe disease is a rare genetic disorder caused by loss-of-function (LOF) mutations in the lysosomal enzyme α-glucosidase (GAA), leading to pathological accumulation of cellular glycogen. GAA catabolizes lysosomal glycogen, and in its absence, glycogen accumulates in lysosomes. This triggers a disease cascade, starting with lysosomal and autophagosomal dysfunction and ultimately leading to cell death and muscle atrophy (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 vary in severity, with 1 in 40,000 live births affected (Meena NK, Raben N. Pompe disease: new developments in an old lysosomal storage disorder. Biomolecules, Vol. 10, 2020). Patients with infantile-onset disease are born with cellular lesions and rapidly develop severe impairments, including myopathy, heart defects, organomegaly, and hypotonia. Without treatment, the disease will claim the life of the child within a year. Children with later-onset disease may present with cardiac enlargement, but are characterized by a progressive loss of motor function, skeletal muscle degeneration, and ultimately early death due to respiratory failure. Adult patients with late-onset Pompe disease exhibit normal cardiac function but develop progressive muscle weakness and respiratory function decline, eventually leading to failure. The standard treatment for Pompe disease patients currently is enzyme replacement therapy (ERT) with recombinant human GAA. ERT treatment has successfully slowed down the disease progression rate, but for most patients, there are still incredibly unmet needs (Schoser B, et al. The humanistic burden of Pompe disease: are there still unmet needs? A systematic review. BMC Neurology, Vol. 17, 2017). For more than a decade, substrate reduction therapy targeting GYS1 has been thought to be beneficial for the treatment of Pompe disease.In fact, three independent preclinical studies have demonstrated that loss of function (LOF) of the GYS1 gene in Pompe disease model mice can effectively reduce tissue glycogen and improve the disease outcomes in mice (Douillard-Guilloux G, et al. Modulation of glycogen synthesis by RNA interference: towards a new therapeutic approach for glycogenosis type II. Human Molecular Genetics, Vol. 17, No. 24, 2008; Douillard-Guilloux G, et al. Restoration of muscle functionality 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 can be used as monotherapy or in combination with standard of care enzyme replacement therapy (ERT) to address the current unmet needs of Pompe disease patients.

[0006] Pompe disease is just one of more than a dozen diseases caused by inborn errors of metabolism that lead to abnormal accumulation of glycogen in various tissues of the body. For some glycogen storage diseases (GSDs), specific dietary regimens can effectively control the disease, but for others, there are no clinically approved treatment interventions to alter the disease course. Therefore, inhibiting glycogen synthesis while simultaneously reducing tissue glycogen levels may be a viable treatment option for these patients. Cori disease (GSD III) is caused by mutations in glycogen debranching enzyme (GDE), which lead to pathologic 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). Although dietary management can effectively improve some aspects of the disease, there is currently no treatment to prevent the progressive myopathy of GSD III. Adult polyglucosan body disease (APBD) is an adult-onset disorder caused by loss of activity of glycogen branching enzyme (GBE1). GBE deficiency leads to the accumulation of long-chain unbranched glycogen, which precipitates in the cytosol, producing polyglucosan bodies and ultimately causing neurological dysfunction in the central and peripheral nervous systems. Genetic deletion of GYS1 in an APBD mouse model rescued the harmful accumulation of glycogen, extended lifespan, and improved 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 very severe juvenile epilepsy characterized by the accumulation of polyglucosan bodies. Genetic crosses between LD mouse models and GYS1 knockout (KO) mice rescued 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).

[0007] Recently, the dependence of clear cell carcinoma on high levels of glycogen has emerged as a new therapeutic target. Ewing sarcoma (ES), clear cell renal cell carcinoma (ccRCC), and glycogen-rich clear cell carcinoma non-small cell lung cancer (NSCLC) are all examples of cancers that are histopathologically defined by abnormally high levels of cellular glycogen that are PAS+. Elevated GYS1 transcript levels are significantly associated with adverse 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, Nos. 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). In cultured myeloid leukemia cells, lentiviral knockdown of GYS1 effectively inhibits cancer cell growth in vitro and tumorigenesis 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). In a ccRCC cell model, gene knockdown of GYS1 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).

[0008] In preclinical models of Pompe disease, APBD, LD, AML, ccRCC, and NSCLC, both the reduction of GYS1 enzyme activity and the decrease in cellular glycogen storage provide strong evidence of the potential therapeutic benefits of inhibiting glycogen synthesis. The object of the present invention is to inhibit glycogen synthase activity, thereby reducing tissue glycogen storage and providing therapeutic benefits to patients suffering from cellular glycogen accumulation. Summary of the Invention

[0009] In one aspect, the present invention provides a compound of formula (I):

[0010]

[0011] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0012] Y 1 and Y 2 are each CH, or

[0013] Y 1 and Y 2 one of them is N, and Y 1 and Y 2 the other one is CH;

[0014] X 1 and X 2 are each independently H or a halogen group;

[0015] R 3 and R 4 are each -CH3, or

[0016] R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl;

[0017] Or

[0018] (1) L does not exist; and

[0019] Q 1 is:

[0020] (i) C 6-20 aryl, wherein Q 1 of C 6-20 aryl is optionally substituted with one or more -OH, -NH2, halogen, 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)-C3-10 cycloalkyl, -NH-C(O)-(3-15-membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3-15-membered heterocyclic group) or -NH-(5-20-membered heteroaryl), wherein

[0021] the 3-15-membered heterocyclic group of -NH-C(O)-(3-15-membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen atoms, C 1-6 alkoxy or C 3-10 cycloalkyl, and

[0022] the 3-15-membered heterocyclic group of -NH-(3-15-membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 alkyl, or

[0023] (ii) a 3-15-membered heterocyclic group, wherein the 3-15-membered heterocyclic group of Q 1 is optionally substituted by one or more oxo groups, or

[0024] (iii) a 5-20-membered heteroaryl, wherein the 5-20-membered heteroaryl of Q 1 contains at least one ring N atom and is optionally substituted by one or more -NH2, halogen atoms, C 1-6 alkyl or C 3-10 cycloalkyl;

[0025] Or

[0026] (2) L is -CH2-; and

[0027] Q 1 is C 3-10 cycloalkyl;

[0028] m is 0 or 1;

[0029] n is 0 or 1;

[0030] R 1 is H, halogen atom, -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, wherein

[0031] R 1 's -C(O)-NH(C 1-6C of (alkyl) 1-6 The alkyl is optionally substituted by one or more -C(O)-C 1-6 alkoxy groups, and

[0032] R 1 The -NH-C(O)-C of 1-6 C of the alkyl 1-6 The alkyl is optionally substituted by one or more -NH-C(O)-C 1-6 alkyl groups or -C(O)-NH2; and

[0033] R 2 is H, a halogen or -OH.

[0034] In one aspect, the present invention provides compounds of formula (I-A):

[0035]

[0036] 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 4 , X 5 , X 6 , X 7 , X 8 , Y 1 , Y 2 and R a are as defined elsewhere herein.

[0037] In one aspect, the present invention provides compounds of formula (I-B):

[0038]

[0039] 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 are as defined elsewhere herein.

[0040] In one aspect, the present invention provides compounds of formula (I-C):

[0041]

[0042] 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 are as defined elsewhere herein.

[0043] In one aspect, the present disclosure provides compounds of formula (I-D):

[0044]

[0045] 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 are as defined elsewhere herein.

[0046] In one aspect, compounds of formula (I-E) are provided:

[0047]

[0048] 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 Y 1 , Y 2 , R a and Q 1 are as defined elsewhere herein.

[0049] In one aspect, compounds of formula (I-F) are provided:

[0050]

[0051] 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 , R3 、R 4 、Y 1 、Y 2 、R a and Q 1 as defined elsewhere herein.

[0052] In one aspect, the present disclosure provides compounds of formula (I-G):

[0053]

[0054] 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 as defined elsewhere herein.

[0055] In one aspect, the present disclosure provides compounds of formula (I-H):

[0056]

[0057] 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 as defined elsewhere herein.

[0058] In one aspect, the present disclosure provides pharmaceutical compositions comprising (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, and (ii) one or more pharmaceutically acceptable excipients.

[0059] In one aspect, the present disclosure provides methods of modulating GYS1 in a cell, 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.

[0060] In one aspect, the present disclosure provides methods of inhibiting GYS1 in a cell, 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.

[0061] In one aspect, the present disclosure provides methods of reducing tissue glycogen storage 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.

[0062] In one aspect, the present disclosure provides methods 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.

[0063] In one aspect, provided herein are methods 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.

[0064] In one aspect, 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 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.

[0065] 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 treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

[0066] 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 treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.

[0067] In some aspects, provided herein are methods for preparing a compound of formula (I) or any embodiment or variant thereof, such as a compound of formula (I), (I-A), (I-A1), (I-A2), (I-B), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-C), (I-D), (I-E), (I-E1), (I-E2), (I-F), (I-F1), (I-G), (I-G1), (I-G2), (I-G3), (I-G4), (I-H), (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 DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 Depicts the pathway by which loss of function (LoF) of PPP1R3A leads to reduced muscle glycogen.

[0069] Figure 2A and 2B Depicts the association between PPP1R3A protein truncating variants (PTVs) and left ventricular ejection fraction (LVEF) (%) and left ventricular wall thickness (mm) in the UK Biobank.

[0070] Figure 2C and 2D Depicts the association between PPP1R3A protein truncating variants (PTVs) and exercise output (watts) and maximum heart rate (HR) exercise (bpm) in the UK Biobank.

[0071] Figure 2E and 2F Depicts the association between PPP1R3A protein truncating variants (PTVs) and PQ interval (ms) and QRS duration (ms) in the UK Biobank.

[0072] Figure 2G and 2H Depicts the association between PPP1R3A protein truncating variants (PTVs) and QT interval (ms) and serum glucose (mmol / L) in the UK Biobank. DETAILED DESCRIPTION

[0073] "Individual" refers to a mammal and includes human 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, the individual refers to a human.

[0074] As used herein, "about" a parameter or value includes and describes the parameter or value itself. For example, "about X" includes and describes X itself.

[0075] As used herein, an "at-risk" individual is an individual at risk of developing a disease or disorder. An "at-risk" individual may or may not have a detectable disease or disorder and may or may not exhibit a detectable disease prior to the treatment methods described herein. "At risk" means that the individual has one or more so-called risk factors, which are measurable parameters associated with the development of a disease or disorder and are known in the art. An individual having one or more of these risk factors has a higher likelihood of developing a disease or disorder than an individual without these risk factors.

[0076] "Treatment" or "treating" is a method for obtaining a beneficial or desired result, including a clinical result. The beneficial or desired result can include one or more of the following: reducing one or more symptoms caused by a disease or disorder; reducing the extent of the disease or condition; slowing or preventing the development of one or more symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder); and alleviating the disease, e.g., by causing the regression of clinical symptoms (e.g., improving the disease state, enhancing the effect of another drug, delaying the progression of the disease, improving the quality of life, and / or prolonging survival).

[0077] As used herein, "delaying" the development of a disease or disorder means postponing, impeding, slowing, retarding, stabilizing, and / or deferring the development of the disease or disorder. This delay may have different time lengths, depending on the disease history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay may actually encompass prevention, since the individual does not develop the disease or disorder.

[0078] As used herein, the term "therapeutically effective amount" or "effective amount" means an amount sufficient to produce a therapeutic effect when the compounds of the present disclosure or their pharmaceutically acceptable salts are administered to an individual. As understood in the art, the effective amount can be one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. The "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, when combined with one or more other agents, a desired or beneficial result is achieved or realized.

[0079] As used herein, a "unit dosage form" refers to physically discrete units suitable as a unit dose, each unit containing a predetermined amount of the active ingredient or compound in a pharmaceutically acceptable carrier.

[0080] "Pharmaceutically acceptable" as used herein refers to 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 undesirable biological effects.

[0081] As used herein, the term "alkyl" refers to a saturated monovalent hydrocarbon chain, straight or branched. Alkyl as used herein has from 1 to 20 carbons (i.e., C 1-20 alkyl), from 1 to 16 carbons (i.e., C 1-16 alkyl), from 1 to 12 carbons (i.e., C 1-12 alkyl), from 1 to 10 carbons (i.e., C 1-10 alkyl), from 1 to 8 carbons (i.e., C 1-8 alkyl), from 1 to 6 carbons (i.e., C 1-6 alkyl), from 1 to 4 carbons (i.e., C 1-4 alkyl) or from 1 to 3 carbons (i.e., C 1-3 alkyl). Examples of alkyl 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 of a specific number of carbon atoms is named by a chemical name or a molecular formula, it can include all positional isomers having that number of carbon atoms, e.g., "butyl" encompasses n-butyl, sec-butyl, isobutyl and tert-butyl; "propyl" includes n-propyl and isopropyl. Certain common alternative names can be used and those of ordinary skill in the art will understand these names. For example, a divalent group, such as divalent "alkyl", can be referred to as "alkylene".

[0082] As used herein, the term "alkenyl" refers to a monovalent hydrocarbon chain, straight or branched, containing at least one carbon-carbon double bond. Alkenyl as used herein has from 2 to 20 carbons (i.e., C 2-20 alkenyl), from 2 to 16 carbons (i.e., C 2-16 alkenyl), from 2 to 12 carbons (i.e., C 2-12 alkenyl), from 2 to 10 carbons (i.e., C 2-10 alkenyl), from 2 to 8 carbons (i.e., C 2-8 alkenyl), from 2 to 6 carbons (i.e., C 2-6 alkenyl), from 2 to 4 carbons (i.e., C 2-4 alkenyl) or from 2 to 3 carbons (i.e., C 2-3(alkenyl). Examples of alkenyl include, but are not limited to, vinyl, prop-1-enyl, prop-2-enyl, 1,2-butadienyl, and 1,3-butadienyl. When naming an alkenyl residue with a specific number of carbon atoms using a chemical name or molecular formula, all positional isomers having that number of carbon atoms may be included. For example, "propenyl" encompasses prop-1-enyl and prop-2-enyl. Certain commonly used alternative names may be used, and those skilled in the art will understand these names. For example, a divalent group, such as divalent "alkenyl", may be referred to as "alkenylene".

[0083] As used herein, the term "alkynyl" refers to a branched or unbranched monovalent hydrocarbon chain containing at least one carbon-carbon triple bond. The alkynyl used herein has 2 - 20 carbons (i.e., C 2-20 alkynyl), 2 - 16 carbons (i.e., C 2-16 alkynyl), 2 - 12 carbons (i.e., C 2-12 alkynyl), 2 - 10 carbons (i.e., C 2-10 alkynyl), 2 - 8 carbons (i.e., C 2-8 alkynyl), 2 - 6 carbons (i.e., C 2-6 alkynyl), 2 - 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 naming an alkynyl residue with a specific number of carbon atoms using a chemical name or molecular formula, all positional isomers having that number of carbon atoms may be included. For example, "propynyl" includes prop-1-ynyl and prop-2-ynyl. Certain commonly used alternative names may be used, and those skilled in the art will understand these names. For example, a divalent group, such as divalent "alkynyl", may be referred to as "alkynylene".

[0084] As used herein, the term "alkoxy" refers to the -O-alkyl moiety. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0085] As used herein, the term "aryl" refers to a completely unsaturated carbocyclic moiety. The term "aryl" encompasses monocyclic and polycyclic fused-ring moieties. The aryl used herein encompasses ring moieties containing, for example, 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 aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthracenyl.

[0086] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated carbocyclic moiety. The term "cycloalkyl" encompasses monocyclic and polycyclic moieties, where the polycyclic moieties can be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl, where the cyclic moiety contains at least one cyclic double bond. Cycloalkyl includes any polycyclic carbocyclic moiety containing at least one non-aromatic ring, regardless of the point of attachment to the rest of the molecule. The cycloalkyl used herein includes those containing, for example, 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 3-8 cycloalkyl), 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) rings. Monocyclic cycloalkyl moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. In addition, cycloalkyl also includes spiroalkyl cyclic moieties, such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0087] As used herein, the term "halo" refers to an atom occupying Group VIIA of the Periodic Table of the Elements, including fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

[0088] As used herein, the term "heteroaryl" 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 monocyclic and polycyclic fused ring moieties. Heteroaryls as used herein include, for example, 5 to 20 ring atoms (i.e., 5- to 20-membered heteroaryls), 5 to 16 ring atoms (i.e., 5- to 16-membered heteroaryls), 5 to 12 ring atoms (i.e., 5- to 12-membered heteroaryls), 5 to 10 ring atoms (i.e., 5- to 10-membered heteroaryls), 5 to 8 ring atoms (i.e., 5- to 8-membered heteroaryls), or 5 to 6 ring atoms (i.e., 5- to 6-membered heteroaryls). Any monocyclic or polycyclic aromatic ring moiety containing one or more ring heteroatoms is considered a 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 heteroaryls include, but are not limited to, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzobenzenethiolyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolinyl, 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]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be attached through any ring of the fused system.

[0089] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes monocyclic and polycyclic moieties, where the polycyclic moieties can be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic moiety containing at least one ring heteroatom is considered a heterocyclic group, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclic group moiety can be attached to the remainder of the molecule through any ring carbon or any ring heteroatom of the heterocyclic group moiety). Additionally, the term heterocyclic group is intended to encompass any polycyclic moiety containing at least one ring heteroatom, where the polycyclic moiety contains at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. Heterocyclic groups used herein include, for example, 3 to 20 ring atoms (i.e., 3- to 20-membered heterocyclic groups), 3 to 16 ring atoms (i.e., 3- to 16-membered heterocyclic groups), 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclic groups), 3 to 10 ring atoms (i.e., 3- to 10-membered heterocyclic groups), 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclic groups), 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclic groups), 3 to 5 ring atoms (i.e., 3- to 5-membered heterocyclic groups), 5 to 8 ring atoms (i.e., 5- to 8-membered heterocyclic groups), or 5 to 6 ring atoms (i.e., 5- to 6-membered heterocyclic groups). Examples of heterocyclic groups include, for example, azetidinyl, aziridinyl, benzodioxolyl, benz[b][1,4]dioxinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyrone, benzofuranone, dioxolanyl, dihydropyranyl, hydropyranyl, thieno[3,4-c]dithiolanyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinone, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithiolanyl, tetrahydroquinolinyl, thienyl (i.e., thiophenyl), thiomorpholinyl, thioxomorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Examples of spiro heterocyclic rings include, but are not limited to, bicyclic and tricyclic 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 heterocyclic groups 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 heterocyclic group can be attached through any ring of the fused system. yl, benzodioxolyl, benz[b][1,4]dioxinyl, yl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyrone, benzofuranone, dioxolanyl, dihydropyranyl, hydropyranyl, thieno[3,4-c]dithiolanyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinone, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithiolanyl, tetrahydroquinolinyl, thienyl (i.e., thiophenyl), thiomorpholinyl, thioxomorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Examples of spiro heterocyclic rings include, but are not limited to, bicyclic and tricyclic 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 heterocyclic groups 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 heterocyclic group can be attached through any ring of the fused system.

[0090] As used herein, the term "oxo group" refers to the =O moiety.

[0091] As used herein, the term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and this description includes instances where the event or circumstance occurs and instances where it does not occur. Thus, the term "optionally substituted" means that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on a specified atom or moiety or group may or may not be replaced by an atom or moiety or group other than hydrogen. By way of example only and not limitation, the phrase "methyl optionally substituted by one or more chlorine atoms" encompasses the -CH3, -CH2Cl, -CHCl2, and -CCl3 moieties.

[0092] It should be understood that aspects and embodiments described herein as "comprising" include embodiments "consisting of" and "consisting essentially of".

[0093] As used herein, the term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and that are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" include, for example, salts formed with inorganic acids and salts formed with organic acids. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, addition salts, particularly pharmaceutically acceptable addition salts, 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 basic compounds. See, for example, Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is incorporated herein by reference. Those skilled in the art will recognize a variety of 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, aluminum, 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.

[0094] Isotopically labeled forms of the compounds described herein can be prepared. Isotopically labeled compounds have the structures described 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 compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 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, wherein one or more hydrogens are replaced by deuterium or tritium.

[0095] Some of the compounds provided herein can exist in the form of tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound can be in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, one of ordinary skill in the art understands that the compounds of the present disclosure include 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.

[0096] Also provided herein are prodrugs of the compounds described herein, or pharmaceutically acceptable salts thereof. A prodrug is a compound that can be administered to an individual and releases, in vivo, a compound described herein as the parent drug compound. It should be understood that prodrugs can be prepared by modifying a functional group on the parent drug compound such that the modification is 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.

[0097] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may include asymmetric centers and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms, which, in accordance with absolute stereochemistry, may be defined as (R)- or (S)-amino acids (or (D)- or (L)-amino acids). The present disclosure is intended to embrace all such possible isomers, as well as their racemic and optically pure forms and mixtures of any ratio thereof. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or can be resolved using conventional techniques such as chromatography and / or fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC) and chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, the present disclosure is intended to embrace both the E geometric isomers and the Z geometric isomers. Similarly, cis and trans are used in their conventional sense to describe relative spatial relationships.

[0098] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds, but have different three-dimensional structures and are non-interchangeable. The present disclosure contemplates various stereoisomers or mixtures thereof, and includes "enantiomers", which refer to two stereoisomers whose structures are mirror images of each other that do not overlap. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0099] When enantiomers and / or diastereomeric forms of a given structure exist, a flat bond indicates that all stereoisomeric forms of the structure shown may be present, e.g.,

[0100]

[0101] When enantiomers and / or diastereomeric forms of a given structure exist, a wedge or slash bond indicates that the composition consists of at least 90% by weight of a single enantiomer or diastereomer of known stereochemistry, e.g.,

[0102]

[0103] In relevant cases, combinations of the above symbols may be used. An exemplary substance may contain stereocenters of known stereochemistry and stereocenters of unknown stereochemistry, e.g.,

[0104]

[0105] Compound

[0106] In one aspect, there is provided a compound of formula (I):

[0107]

[0108] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0109] Y 1 and Y 2 are each CH, or

[0110] Y 1 and Y 2 one of them is N, and Y 1 and Y 2 the other of them is CH;

[0111] X 1 and X 2 are each independently H or a halogen group;

[0112] R 3 and R 4 are each -CH3, or

[0113] R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl;

[0114] Or

[0115] (1) L is absent; and

[0116] Q 1 is:

[0117] (i) C 6-20 aryl, wherein the C of Q 1 aryl is optionally substituted by one or more -OH, -NH2, halogen, C 6-20 alkyl, C 1-6 alkoxy, C 1-6 cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 3-10 alkyl), -NH-C(O)-C 1-6 alkyl, -NH-C(O)-C 1-6 cycloalkyl, -NH-C(O)-(3-15 membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 3-10 alkyl, -NH(C 1-6 alkyl), -NH-(3-15 membered heterocyclic group) or -NH-(5-20 membered heteroaryl), wherein 1-6 ​

[0118] -NH-C(O)-(3- to 15-membered heterocyclic group), wherein the 3- to 15-membered heterocyclic group is optionally substituted with one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, where the C 1-6 alkyl is optionally substituted with one or more halo groups, C 1-6 alkoxy or C 3-10 cycloalkyl, and

[0119] -NH-(3- to 15-membered heterocyclic group), wherein the 3- to 15-membered heterocyclic group is optionally substituted with one or more oxo groups or C 1-6 alkyl, or

[0120] (ii) a 3- to 15-membered heterocyclic group, wherein the 3- to 15-membered heterocyclic group of Q 1 is optionally substituted with one or more oxo groups, or

[0121] (iii) a 5- to 20-membered heteroaryl, wherein the 5- to 20-membered heteroaryl of Q 1 contains at least one ring N atom and is optionally substituted with one or more -NH2, halo groups, C 1-6 alkyl or C 3-10 cycloalkyl;

[0122] Or

[0123] (2) L is -CH2-; and

[0124] Q 1 is C 3-10 cycloalkyl;

[0125] m is 0 or 1;

[0126] n is 0 or 1;

[0127] R 1 is H, halo group, -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, where

[0128] R 1 of -C(O)-NH(C 1-6 alkyl) of C 1-6 alkyl is optionally substituted with one or more -C(O)-C 1-6 alkoxy, and

[0129] R 1 of -NH-C(O)-C 1-6 alkyl of C 1-6The alkyl group is optionally substituted by one or more -NH-C(O)-C 1-6 alkyl group or -C(O)-NH2; and

[0130] R 2 is H, a halogen group or -OH.

[0131] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, n is 0, 1 or 2, where 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.

[0132] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 and Y 2 are each CH, or one of Y 1 and Y 2 is N and the other of Y 1 and Y 2 is CH. In some embodiments, Y 1 and Y 2 are each CH. In some embodiments, one of Y 1 and Y 2 is N and the other of Y 1 and Y 2 is CH.

[0133] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, X 1 is H.

[0134] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, X 1 is a halogen group. In some embodiments, X 1 is fluorine.

[0135] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, X 2 is H.

[0136] 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, X 2 is a halogen group. In some embodiments, X 2 is fluorine.

[0137] 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, X 1 and X 2 are each independently H or a halogen group. 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 a halogen group. In some embodiments, X 1 and X 2 are each independently F. In some embodiments, one of X 1 and X 2 is H, and the other of X 1 and X 2 is a halogen group. In some embodiments, one of X 1 and X 2 is H, and the other of X 1 and X 2 is F.

[0138] 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, R 3 and R 4 are each -CH3. In some embodiments, R 3 and R 4 together with the atom to which they are attached form cyclopropyl. In some embodiments, R 3 and R 4 together with the atom to which they are attached form cyclobutyl.

[0139] 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, R 3 and R 4 are each -CH3, and X 1 and X 2 are each hydrogen. In some embodiments, R 3 and R 4 are each -CH3, and X 1 or X 2is F. In some embodiments, R 3 and R 4 together with the atoms to which they are attached form cyclopropyl, and X 1 and X 2 are each hydrogen. In some embodiments, R 3 and R 4 together with the atoms to which they are attached form cyclobutyl, X 1 and X 2 are each hydrogen. In some embodiments, R 3 and R 4 together with the atoms to which they are attached form cyclopropyl, X 1 or X 2 is F.

[0140] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 and Y 2 are each CH, R 3 and R 4 are each -CH3, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 are each CH, R 3 and R 4 are each -CH3, and X 1 or X 2 is F. In some embodiments, Y 1 and Y 2 are each CH, R 3 and R 4 together with the atoms to which they are attached form cyclopropyl, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 are each CH, R 3 and R 4 together with the atoms to which they are attached form cyclobutyl, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 are each CH, R 3 and R 4 together with the atoms to which they are attached form cyclopropyl, and X 1 and X 2 are each F.

[0141] 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, Y 1 and Y 2 one of which is N, and Y 1 and Y 2 the other of which is CH, R 3 and R 4 are each -CH3, X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 one of which is N, and Y 1 and Y 2 the other of which is CH, R 3 and R 4 are each -CH3, X 1 or X 2 is F. In some embodiments, Y 1 and Y 2 one of which is N, and Y 1 and Y 2 the other of which is CH, R 3 and R 4 together with the atoms to which they are attached form cyclopropyl, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 one of which is N, and Y 1 and Y 2 the other of which is CH, R 3 and R 4 together with the atoms to which they are attached form cyclobutyl, and X 1 and X 2 are each hydrogen. In some embodiments, Y 1 and Y 2 one of which is N, and Y 1 and Y 2 the other of which is CH, R 3 and R 4 together with the atoms to which they are attached form cyclopropyl, and X 1 or X 2 is F.

[0142] 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, Y 1 and Y 2 are each CH.

[0143] 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 is selected from the group consisting of: In some embodiments, the of formula (I) is selected from consisting of the group. In some embodiments, the of formula (I) is selected from consisting of the group. In some embodiments, the of formula (I) is In some embodiments, the of formula (I) is In some embodiments, the of formula (I) is

[0144] 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, Y 1 and Y 2 one of which is N, and Y 1 and Y 2 the other of which is CH.

[0145] In some embodiments of the compound of formula (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the of formula (I) is selected from consisting of the group. In some embodiments, the of formula (I) is selected from consisting of the group. In some embodiments, the of formula (I) is In some embodiments, the of formula (I) is In some embodiments, the of formula (I) is selected from consisting of the group.

[0146] 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, L is absent.

[0147] 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, L is absent and Q 1 is C 6-20 aryl, wherein the C of Q 1 6-20The aryl is optionally substituted by one or more -OH, -NH2, halogen, 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)-(3-15 membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3-15 membered heterocyclic group) or -NH-(5-20 membered heteroaryl), wherein the 3-15 membered heterocyclic group of -NH-C(O)-(3-15 membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen, C 1-6 alkoxy or C 3-10 cycloalkyl, and the 3-15 membered heterocyclic group of -NH-(3-15 membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 alkyl.

[0148] In some embodiments of the compound of formula (I), or its stereoisomer or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is phenyl, wherein the phenyl of Q 1 is optionally substituted by one or more OH, NH2, halogen, 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)-(3-15 membered heterocyclic group) or -NH-C(=N-CN)-NH2, NH(C 1-6 alkyl) substituted, wherein

[0149] the 3-15 membered heterocyclic group of -NH-C(O)-(3-15 membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen, C1-6 alkoxy or C 3-10 is cycloalkyl-substituted, and

[0150] the 3- to 15-membered heterocyclic group of -NH-(3- to 15-membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 alkyl.

[0151] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is phenyl, wherein Q 1 the phenyl of 1-3 is optionally substituted by one or more OH, NH2, halo, C 1-3 alkyl, C 3-6 alkoxy, C 1-3 cycloalkyl, 5- to 10-membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 1-3 alkyl), -NH-C(O)-C 3-6 alkyl, -NH-C(O)-C 1-3 cycloalkyl, -NH-C(O)-(3- to 6-membered heterocyclic group) or -NH-C(=N-CN)-NH2, NH(C

[0152] the 3- to 6-membered heterocyclic group of -NH-C(O)-(3- to 6-membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-3 alkyl or C 1-6 alkyl, wherein C 1-3 alkyl is optionally substituted by one or more halo, C 1-3 alkoxy or C 3-6 cycloalkyl, and

[0153] the 3- to 6-membered heterocyclic group of -NH-(3- to 6-membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-3 alkyl.

[0154] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is selected from the group consisting of:

[0155]

[0156] In some embodiments, Q 1 is selected from the group consisting of: In some embodiments, Q 1 is selected from a group consisting of. In some embodiments, Q 1 is In some embodiments, Q 1 is

[0157] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is a 3- to 15-membered heterocyclic group, wherein the 3- to 15-membered heterocyclic group of Q 1 is optionally substituted with one or more oxo groups. In some embodiments, L is absent and Q 1 is a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group of Q 1 is optionally substituted with one or more oxo groups. In some embodiments, Q 1 is a 6- to 10-membered heterocyclic group, wherein the 6- to 10-membered heterocyclic group of Q 1 is optionally substituted with one or more oxo groups or C 1-3 alkyl. In some embodiments, Q 1 is a 9- to 10-membered heterocyclic group, wherein the 9- to 10-membered heterocyclic group of Q 1 is optionally substituted with one or more oxo groups. In some embodiments, Q 1 is selected from the group consisting of: In some embodiments, Q 1 is selected from the group consisting of:

[0158] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, L is absent and Q 1 is a 5- to 20-membered heteroaryl group, wherein the 5- to 20-membered heteroaryl group of Q 1 is optionally substituted with one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl. In some embodiments, Q 1 is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group of Q 1 is optionally substituted with one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl, and wherein the 5- to 10-membered heteroaryl group of Q 1 contains at least 1 ring N. In some embodiments, Q 1 is pyridyl, wherein the pyridyl of Q 1 is optionally substituted with one or more -NH2, halo, C 1-6 alkyl or C3-10 Cycloalkyl substitution. In some embodiments, Q 1 is pyridyl. In some embodiments, Q 1 is pyrazolyl.

[0159] 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, L is absent and Q 1 is a 5- to 20-membered heteroaryl, wherein Q 1 of the 5- to 20-membered heteroaryl contains at least one ring N atom and is optionally substituted by one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl substitution. In some embodiments, Q 1 is a 6- to 10-membered heteroaryl, wherein Q 1 of the 6- to 10-membered heteroaryl contains at least one ring N atom and is optionally substituted by one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl substitution. In some embodiments, Q 1 is selected from the group consisting of: In some embodiments, Q 1 is selected from the group consisting of: In some embodiments, Q 1 is selected from the group consisting of:

[0160] 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, L is -CH2-.

[0161] 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, L is -CH2- and Q 1 is C 3-10 cycloalkyl. In some embodiments, L is -CH2- and Q 1 is C 3-6 cycloalkyl.

[0162] 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, 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, 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.

[0163] 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, 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, wherein the C 1 of -C(O)-NH(C 1-6 alkyl) of R 1-6 alkyl is optionally substituted with one or more -C(O)-C 1-6 alkoxy, and the C 1 of -NH-C(O)-C 1-6 alkyl of R 1-6 alkyl is optionally substituted with one or more -NH-C(O)-C 1-6 alkyl or -C(O)-NH2, and 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, wherein the C 1 of -C(O)-NH(C 1-3 alkyl) of R 1-3 alkyl is optionally substituted with one or more -C(O)-C 1-3 alkoxy, and the C 1 of -NH-C(O)-C 1-3 alkyl of R 1-3 alkyl is optionally substituted with one or more -NH-C(O)-C 1-3 alkyl or -C(O)-NH2. In some embodiments,

[0164] 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, R 1 is selected from the group consisting of 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 alkyl, wherein

[0165] the C 1-6 of -C(O)-NH(C 1-6The alkyl group is optionally substituted by one or more -C(O)-C 1-6 alkoxy groups, and

[0166] -NH-C(O)-C 1-6 The C 1-6 The alkyl group is optionally substituted by one or more -NH-C(O)-C 1-6 alkyl groups or -C(O)-NH2.

[0167] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is H, halogen, -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, wherein the C 1 of -C(O)-NH(C 1-6 alkyl) of R 1-6 alkyl group is optionally substituted by one or more -C(O)-C 1-6 alkoxy groups, and the C 1 of -NH-C(O)-C 1-6 alkyl of R 1-6 alkyl group is optionally substituted by one or more -NH-C(O)-C 1-6 alkyl groups or -C(O)-NH2.

[0168] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is H.

[0169] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is selected from the group consisting of -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 alkyl, wherein

[0170] the C 1-6 of -C(O)-NH(C 1-6 alkyl) is optionally substituted by one or more -C(O)-C 1-6 alkoxy groups, and

[0171] the C 1-6 of -NH-C(O)-C 1-6The alkyl group is optionally substituted by one or more -NH-C(O)-C 1-6 alkyl or -C(O)-NH2.

[0172] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is selected from the group consisting of: -CN,

[0173] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, R 1 is H or a halogen group. In some embodiments, R 1 is H or fluorine. In some embodiments, R 1 is H. In some embodiments, R 1 is fluorine.

[0174] In some embodiments of the compound of formula (I-G), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, R 2 is H, a halogen group or -OH. In some embodiments, R 2 is H. In some embodiments, R 2 is a halogen group. In some embodiments, R 2 is F. In some embodiments, R 2 is -OH.

[0175] In some embodiments of the compound of formula (I), or any embodiment or variant thereof, such as the compounds of formula (I-A), (I-A1), (I-A2), (I-B), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-C), (I-D), (I-E), (I-E1), (I-E2), (I-F), (I-F1), (I-F2), (I-G), (I-G1), (I-G2), (I-G3), (I-G4), (I-H), (I-H1), (I-H2), (I-H3), (I-H4) or (I-H5), or their stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, has the stereochemical configuration of formula , wherein m, n, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , Y 1 , Y 2 , L and Q1 As defined elsewhere herein.

[0176] In some embodiments of the compound of formula (I), or any embodiment or variant thereof, such as the compounds of formula (I-A), (I-A1), (I-A2), (I-B), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-C), (I-D), (I-E), (I-E1), (I-E2), (I-F), (I-F1), (I-F2), (I-G), (I-G1), (I-G2), (I-G3), (I-G4), (I-H), (I-H1), (I-H2), (I-H3), (I-H4) or (I-H5), or their stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing, has the formula of the stereochemical configuration, where m, n, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , Y 1 , Y 2 , L and Q 1 As defined elsewhere herein.

[0177] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing, m is 0 or 1; n is 0 or 1; Y 1 and Y 2 are each CH, or one of Y 1 and Y 2 is N, and the other of Y 1 and Y 2 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 atoms to which they are attached form cyclopropyl or cyclobutyl; Q 1 is phenyl, where the phenyl of Q 1 is optionally substituted by one or more 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 heterocyclic group), -NH-C(=N-CN)-NH2, -NH(C 1-6 alkyl), -NH-(3- to 15-membered heterocyclic group) or -NH-(5- to 20-membered heteroaryl), wherein the 3- to 15-membered heterocyclic group of -NH-C(O)-(3- to 15-membered heterocyclic group) is optionally substituted with one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo groups, C 1-6 alkoxy or C 3-10 cycloalkyl, and the 3- to 15-membered heterocyclic group of -NH-(3- to 15-membered heterocyclic group) is optionally substituted with one or more oxo groups or C 1-6 alkyl; R 1 is H, halo group, -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, wherein the C 1 of -C(O)-NH(C 1-6 alkyl) of R 1-6 alkyl is optionally substituted with one or more -C(O)-C 1-6 alkoxy, and the C 1 of -NH-C(O)-C 1-6 alkyl of R 1-6 alkyl is optionally substituted with one or more -NH-C(O)-C 1-6 alkyl or -C(O)-NH2; R 2 is H, halo group or -OH. In some embodiments, m is 0 or 1, and n is 0 or 1; Y 1 and Y 2 are each CH, or one of Y 1 and Y 2 is N, and the other of Y 1 and Y 2 is CH; X 1 and X 2 are each independently H or halo group; 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; Q 1 is phenyl, wherein the phenyl of Q 1 is optionally substituted with one or more OH, NH2, halo groups, C1-3 alkyl, C 1-3 alkoxy, C 6-10 cycloalkyl, 5- to 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 heterocyclic group), -NH-C(=N-CN)-NH2, -NH(C 1-3 alkyl), -NH-(3- to 10-membered heterocyclic group) or -NH-(5- to 10-membered heteroaryl), wherein the 3- to 10-membered heterocyclic group of -NH-C(O)-(3- to 10-membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-3 alkyl or C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted by one or more halo groups, C 1-3 alkoxy or C 6-10 cycloalkyl, and the 3- to 10-membered heterocyclic group of -NH-(3- to 10-membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-3 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, wherein the C 1 in -C(O)-NH(C 1-3 alkyl) of R 1-3 alkyl may be optionally substituted by one or more --C(O)-C 1-3 alkoxy, the C 1 in -NH-C(O)-C 1-3 alkyl of R 1-3 alkyl may be optionally substituted by one or more -NH-C(O)-C 1-3 alkyl or C(O)-NH2; R 2 is H, halo or -OH.

[0178] In some embodiments, m is 0 or 1, and n is 0 or 1; Y 1 and Y 2 are each CH, or one of Y 1 and Y 2 is N, and the other of Y 1 and Y 2 is CH; X 1 and X 2 are each independently H or halo; R 3and R 4 each is -CH3, or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl; Q 1 is phenyl, wherein Q 1 the phenyl of is optionally substituted by one or more 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)-(3-6 membered heterocycle), -NH-C(=N-CN)-NH2, -NH(C 1-3 alkyl), -NH-(3-10 membered heterocycle) or -NH-(5-10 membered heteroaryl), wherein the 3-10 membered heterocycle of -NH-C(O)-(3-6 membered heterocycle) is optionally substituted by one or more -C(O)-CH3 or CH3, wherein CH3 is optionally substituted by one or more halo, -OCH3 or C 6-10 cycloalkyl, and the 3-6 membered heterocycle in -NH-(3-6 membered heterocycle) is optionally substituted by one or more oxo or C 1-3 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, wherein CH3 in -C(O)-NH(CH3) of R 1 is optionally substituted by one or more -C(O)-OCH3, and -CH3 in -NH-C(O)-CH3 of R 1 is optionally substituted by one or more -NH-C(O)-CH3 or -C(O)-NH2; and R 2 is H, halo or -OH.

[0179] In some embodiments, m is 0; n is 0; Y 1 and Y 2 each is CH; R 3 and R 4 each is -CH3; X 1 is H; X 2 is H; Q 1 is phenyl, wherein Q 1 the phenyl of is optionally substituted by one or more -OH, NH2, F, CH3, -OCH3, C 6-10Cycloalkyl, 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)-(3-6 membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH(C 1-3 Alkyl), -NH-(3-10 membered heterocyclic group) or -NH-(5-10 membered heteroaryl) substituted, wherein the 3-10 membered heterocyclic group of -NH-C(O)-(3-6 membered heterocyclic group) is optionally substituted by one or more -C(O)-CH3 or CH3, wherein CH3 is optionally substituted by one or more halo groups, -OCH3 or C 6-10 Cycloalkyl substituted, and the 3-6 membered heterocyclic group of -NH-(3-6 membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-3 Alkyl substituted; R 1 Is H; and R 2 Is H.

[0180] In some embodiments, m is 0; n is 0; Y 1 And Y 2 Each is CH; R 3 And R 4 Each is -CH3; X 1 Is H; X 2 Is F; Q 1 Is phenyl, wherein the phenyl of Q 1 Is optionally substituted by one or more -NH-C(O)-NH2; R 1 Is H or F; and R 2 Is H.

[0181] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; and n is 1; Y 1 Is CH; Y 2 Is N; R 3 And R 4 Each is -CH3; X 1 And X 2 Are each independently H; Q 1 Is phenyl, wherein the phenyl of Q 1 Is optionally substituted by one or more C 1-3 Alkyl or -NH-C(O)-C 1-3 Alkyl substituted; R 1 Is H; and R 2 Is H. In some embodiments, m is 0; and n is 1; Y 1 Is CH; Y 2 Is N; R 3 And R4 Each is -CH3; X 1 and X 2 are each independently H; Q 1 is phenyl, where Q 1 's phenyl is optionally substituted with one or more -CH3 or NH-C(O)--CH3; R 1 is H; and R 2 is H.

[0182] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; and n is 1; Y 1 is CH; Y 2 is N; X 1 is H; X 2 is a halogen group; R 3 and R 4 together with the atom to which they are attached form cyclopropyl; Q 1 is phenyl, where Q 1 's phenyl is optionally substituted with one or more 5- to 10-membered heteroaryl groups; R 1 is H; and R 2 is a halogen group. In some embodiments, m is 0; and n is 1; Y 1 is CH; Y 2 is N; X 1 is H; X 2 is a halogen group; 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; Q 1 is phenyl, where Q 1 's phenyl is optionally substituted with one or more pyrazolyl groups; R 1 is H; and R 2 is F.

[0183] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, and n is 0 or 1; Y 1 and Y 2 are each CH, or one of Y 1 and Y 2 is N, and Y 1 and Y 2 the other of which is CH; X 1 and X 2 are each independently H or a halogen group; R 3 and R 4 are each -CH3, or R 3 and R4 together with the atom(s) to which they are attached form cyclopropyl or cyclobutyl; Q 1 is phenyl; R 1 is H, F, -C(O)-NH(CH3), -NH-C(O)-NH2 or -NH-C(O)-CH3, where the 1 -CH3 in -NH-C(O)-CH3 of R is optionally substituted with one or more -NH-C(O)-CH3 or -C(O)-NH2; and R 2 is H or halo.

[0184] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, and n is 0 or 1; Y 1 and Y 2 are each CH, or one of Y 1 and Y 2 is N, and the other of Y 1 and Y 2 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(s) to which they are attached form cyclopropyl or cyclobutyl; Q 1 is phenyl; R 1 is H, F, -C(O)-NH(CH3), -NH-C(O)-NH2 or -NH-C(O)-CH3, where the 1 -CH3 in -NH-C(O)-CH3 of R is optionally substituted with one or more -NH-C(O)-CH3 or -C(O)-NH2; and R 2 is H, OH or halo.

[0185] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, n is 0 or 1; Y 1 and Y 2 are each 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(s) to which they are attached form cyclopropyl or cyclobutyl; Q 1 is phenyl; R 1is H, F, -C(O)-NH(CH3), -NH-C(O)-NH2 or -NH-C(O)-CH3, where R 1 the -CH3 in -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 a halogen group.

[0186] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1, and n is 0 or 1; Y 1 and Y 2 one of them is N, and Y 1 and Y 2 the other is CH; X 1 and X 2 are each independently H or a halogen group; R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl; Q 1 is phenyl; R 1 is H or F; and R 2 is H or a halogen group.

[0187] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0 or 1; n is 0 or 1; Y 1 and Y 2 are each CH, or one of Y 1 and Y 2 is N, and Y 1 and Y 2 the other is CH; X 1 and X 2 are each independently H or a halogen group; 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; Q 1 is (i) a 3- to 15-membered heterocyclic group, where the 3- to 15-membered heterocyclic group of Q 1 is optionally substituted with one or more oxo groups, or (ii) a 5- to 20-membered heteroaryl group, where the 5- to 20-membered heteroaryl group of Q 1 contains at least one ring N atom and is optionally substituted with one or more -NH2, halogen groups, C 1-6 alkyl or C 3-10 cycloalkyl; R 1is H, a halogen group, -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, where R 1 of -C(O)-NH(C 1-3 alkyl) of the C 1-3 alkyl is optionally substituted by one or more -C(O)-C 1-3 alkoxy, and R 1 of -NH-C(O)-C 1-3 alkyl of the C 1-3 alkyl is optionally substituted by one or more -NH-C(O)-C 1-3 alkyl or -C(O)-NH2; and R 2 is H, a halogen group or -OH. In some embodiments, m is 0 or 1; n is 0 or 1; Y 1 and Y 2 are each CH, or one of Y 1 and Y 2 is N, and the other of Y 1 and Y 2 is CH; X 1 and X 2 are each independently H or a halogen group; 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; Q 1 is (i) a 3- to 10-membered heterocyclic group, where the 3- to 10-membered heterocyclic group of Q 1 is optionally substituted by one or more oxo groups, or (ii) a 5- to 10-membered heteroaryl group, where the 5- to 10-membered heteroaryl group of Q 1 contains at least one ring N atom and is optionally substituted by one or more -NH2, halogen groups, C 1-3 alkyl or C 3-6 cycloalkyl; R 1 is H, a halogen group, -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, where R 1 of -C(O)-NH(C 1-3 alkyl) of the C 1-3 alkyl is optionally substituted by one or more -C(O)-C 1-3 alkoxy, and R 1 of -NH-C(O)-C1-3 The C of the alkyl 1-3 The alkyl is optionally substituted with one or more -NH-C(O)-C 1-3 alkyl or -C(O)-NH2; R 2 is H, halogen or -OH.

[0188] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y 1 and Y 2 are each CH; X 1 and X 2 are each independently H; R 3 and R 4 are each -CH3; Q 1 is a 3- to 15-membered heterocyclic group, wherein the 3- to 15-membered heterocyclic group of Q 1 is optionally substituted with one or more oxo groups; R 1 is H, halogen; and R 2 is H, halogen or -OH. In some embodiments, m is 0; n is 0; Y 1 and Y 2 are each CH; X 1 and X 2 are each independently H; R 3 and R 4 are each -CH3; Q 1 is a 3- to 10-membered heterocyclic group, wherein the 3- to 10-membered heterocyclic group of Q 1 is optionally substituted with one or more oxo groups; R 1 is H, halogen; and R 2 is H, halogen or -OH.

[0189] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y 1 is CH; Y 2 is N; X 1 is H; X 1 is H; X 2 is halogen; R 3 and R 4 are each -CH3; Q 1 is a 3- to 15-membered heterocyclic group, wherein the 3- to 15-membered heterocyclic group of Q 1 is optionally substituted with one or more oxo groups; R 1 is H, halogen; and R 2 is H, halogen or -OH. In some embodiments, m is 0; n is 0; Y 1 and Y 2Each is CH; X 1 and X 2 Each independently is H; R 3 and R 4 Each is -CH3; Q 1 is a 3- to 10-membered heterocyclic group, where Q 1 's 3- to 10-membered heterocyclic group is optionally substituted with one or more oxo groups; R 1 is H, halo; and R 2 is H, halo or -OH.

[0190] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y 1 is CH; Y 2 is N; X 1 is H; X 1 and X 2 Each independently is H; R 3 and R 4 Each is -CH3; Q 1 is a 3- to 15-membered heterocyclic group, where Q 1 's 3- to 15-membered heterocyclic group is optionally substituted with one or more oxo groups; R 1 is H, halo; and R 2 is H, halo or -OH. In some embodiments, m is 0; n is 0; Y 1 and Y 2 Each is CH; X 1 and X 2 Each independently is H; R 3 and R 4 Each is -CH3; Q 1 is a 3- to 10-membered heterocyclic group, where Q 1 's 3- to 10-membered heterocyclic group is optionally substituted with one or more oxo groups; R 1 is H, halo; and R 2 is H, halo or -OH.

[0191] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y 1 and Y 2 Each is CH; X 1 and X 2 Each independently is H; R 3 and R 4 Each is -CH3; Q 1 is a 5- to 20-membered heteroaryl, where Q 1The 5-20 membered heteroaryl contains at least one ring N atom and is optionally substituted by one or more C 1-6 alkyl groups; R 1 is H; and R 2 is H. In some embodiments, m is 0; n is 0; Y 1 and Y 2 are each CH; X 1 and X 2 are each independently H; R 3 and R 4 are each -CH3; Q 1 is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q 1 contains at least one ring N atom and is optionally substituted by one or more C 1-3 alkyl groups; R 1 is H; and R 2 is H.

[0192] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y 1 and Y 2 are each CH; X 1 is H; X 2 is a halogen; R 3 and R 4 are each -CH3; Q 1 is a 5-20 membered heteroaryl, wherein the 5-20 membered heteroaryl of Q 1 contains at least one ring N atom and is optionally substituted by one or more C 1-6 alkyl groups; R 1 is H or a halogen; and R 2 is H or a halogen. In some embodiments, m is 0; n is 0; Y 1 and Y 2 are each CH; X 1 and X 2 are each independently H; R 3 and R 4 are each -CH3; Q 1 is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of Q 1 contains at least one ring N atom and is optionally substituted by one or more -C 1-3 alkyl groups; R 1 is H, a halogen; and R 2 is H, a halogen or -OH.

[0193] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0; Y1 is CH; Y 2 is N; X 1 is H; X 2 is a halogen group; R 3 and R 4 each is -CH3; Q 1 is a 5- to 20-membered heteroaryl group, wherein Q 1 's 5- to 20-membered heteroaryl group contains at least one cyclic N atom and is optionally substituted by one or more C 1-6 alkyl groups; R 1 is H, a halogen group; and R 2 is H or a halogen group. In some embodiments, m is 0; n is 0; Y 1 and Y 2 each is CH; X 1 and X 2 each independently is H; R 3 and R 4 each is -CH3; Q 1 is a 5- to 10-membered heteroaryl group, wherein Q 1 's 5- to 10-membered heteroaryl group contains at least one cyclic N atom and is optionally substituted by one or more -C 1-3 alkyl groups; R 1 is H, a halogen group; and R 2 is H or a halogen group.

[0194] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 0; n is 0 or 1; Y 1 and Y 2 each is CH, or Y 1 and Y 2 one of them is N, and Y 1 and Y 2 the other of them is CH; X 1 and X 2 each independently is H or a halogen group; R 3 and R 4 each is -CH3, or R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl; Q 1 is (i) C 6-20 aryl, wherein Q 1 's C 6-20 aryl is optionally substituted by one or more -OH, -NH2, halogen groups, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5- to 20-membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C1-6 alkyl), -NH-C(O)-C 1-6 alkyl, -NH-C(O)-C 3-10 cycloalkyl, -NH-C(O)-(3- to 15-membered heterocyclic group), NH-C(=N-CN)-NH2, NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3- to 15-membered heterocyclic group) or -NH-(5- to 20-membered heteroaryl), wherein the 3- to 15-membered heterocyclic group of -NH-C(O)-(3- to 15-membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halo groups, C 1-6 alkoxy or C 3-10 cycloalkyl, and the 3- to 15-membered heterocyclic group of -NH-(3- to 15-membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 alkyl, or (ii) a 3- to 15-membered heterocyclic group, wherein the 3- to 15-membered heterocyclic group of Q 1 is optionally substituted by one or more oxo groups, or (iii) a 5- to 20-membered heteroaryl, wherein the 5- to 20-membered heteroaryl of Q 1 contains at least one ring N atom and is optionally substituted by one or more -NH2, halo groups, C 1-6 alkyl or C 3-10 cycloalkyl; R 1 is H, a halo group, -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, wherein the C 1 of -C(O)-NH(C 1-6 alkyl) of R 1-6 alkyl is optionally substituted by one or more -C(O)-C 1-6 alkoxy, the C 1 of -NH-C(O)-C 1-6 alkyl of R 1-6 alkyl is optionally substituted by one or more -NH-C(O)-C 1-6 alkyl or -C(O)-NH2; R 2 is H, a halo group or -OH.

[0195] In some embodiments of the compound of formula (I), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, m is 1; n is 0 or 1; Y 1 and Y 2Each is CH, or Y 1 and Y 2 One of them is N, and Y 1 and Y 2 The other one is CH; X 1 and X 2 Each independently is H or a halogen group; R 3 and R 4 Each is -CH3, or R 3 and R 4 Together with the atoms to which they are attached, form cyclopropyl or cyclobutyl; Q 1 Is (i) C 6-20 Aryl, where Q 1 The C of 6-20 The aryl is optionally substituted by one or more -OH, -NH2, halogen groups, 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)-(3-15 membered heterocyclic group), NH-C(=N-CN)-NH2, NH-S(O)2-C 1-6 Alkyl, -NH(C 1-6 Alkyl), -NH-(3-15 membered heterocyclic group) or -NH-(5-20 membered heteroaryl), where the 3-15 membered heterocyclic group of -NH-C(O)-(3-15 membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 Alkyl or C 1-6 Alkyl, where C 1-6 The alkyl is optionally substituted by one or more halogen groups, C 1-6 Alkoxy or C 3-10 Cycloalkyl, and the 3-15 membered heterocyclic group of -NH-(3-15 membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 Alkyl, or (ii) 3-15 membered heterocyclic group, where the 3-15 membered heterocyclic group of Q 1 Is optionally substituted by one or more oxo groups, or (iii) 5-20 membered heteroaryl, where the 5-20 membered heteroaryl of Q 1 Contains at least one cyclic N atom and is optionally substituted by one or more -NH2, halogen groups, C 1-6 Alkyl or C 3-10 Cycloalkyl; R 1 Is H, halogen group, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C1-6 alkyl), -NH-C(O)-NH2 or -NH-C(O)-C 1-6 alkyl, where R 1 of -C(O)-NH(C 1-6 alkyl) of C 1-6 alkyl is optionally substituted by one or more -C(O)-C 1-6 alkoxy, R 1 of -NH-C(O)-C 1-6 alkyl of C 1-6 alkyl is optionally substituted by one or more -NH-C(O)-C 1-6 alkyl or -C(O)-NH2; R 2 is H, halogen 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 them is CH; X 1 and X 2 are each independently H or halogen; 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; Q 1 is (i) C 6-20 aryl, where Q 1 of C 6-20 aryl is optionally substituted by one or more -OH, -NH2, halogen, 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)-(3-15 membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3-15 membered heterocyclic group) or -NH-(5-20 membered heteroaryl), where the 3-15 membered heterocyclic group of -NH-C(O)-(3-15 membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, where C 1-6The alkyl group is optionally substituted by one or more halogen groups, C 1-6 alkoxy groups or C 3-10 cycloalkyl groups, and the 3- to 15-membered heterocyclic group of the -NH-(3- to 15-membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 alkyl groups; R 1 is H, a halogen group, -CN, -C(O)-NH2, -C(O)-NH(CN), -C(O)-NH(C 1-6 alkyl group), -NH-C(O)-NH2 or -NH-C(O)-C 1-6 alkyl group, wherein the C 1 of -C(O)-NH(C 1-6 alkyl group) of R 1-6 alkyl group is optionally substituted by one or more -C(O)-C 1-6 alkoxy groups, and the C 1 alkyl group of -NH-C(O)-C 1-6 alkyl group of R 1-6 alkyl group is optionally substituted by one or more -NH-C(O)-C 1-6 alkyl groups or -C(O)-NH2; R 2 is H, a halogen group or -OH.

[0196] In some embodiments, provided herein are compounds of formula (I), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts thereof, wherein the compound is a compound of formula (I-A):

[0197]

[0198] or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein, alternatively:

[0199] i. X 4-8 are each independently H, -OH, -NH2, a halogen group, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-10 cycloalkyl group, a 5- to 20-membered heteroaryl group, -NH-C(O)-NH2, -NH-C(O)-NH(C 1-6 alkyl group), -NH-C(O)-C 1-6 alkyl group, -NH-C(O)-C 3-10 cycloalkyl group, -NH-C(O)-(3- to 15-membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl group, -NH(C 1-6 alkyl group), -NH-(3- to 15-membered heterocyclic group) or -NH-(5- to 20-membered heteroaryl group), wherein

[0200] -NH-C(O)-(3- to 15-membered heterocyclic group), the 3- to 9-membered heterocyclic group of which is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halo groups, C 1-6 alkoxy or C 3-10 cycloalkyl, and

[0201] -NH-(3- to 15-membered heterocyclic group), the 3- to 9-membered heterocyclic group of which is optionally substituted by one or more oxo groups or C 1-6 alkyl, or

[0202] ii. X 6 together with X 4 or X 8 and the atoms to which they are attached form ring A, wherein ring A is

[0203] a 3- to 9-membered heterocyclic group, the 3- to 9-membered heterocyclic group of ring A being optionally substituted by one or more oxo groups, wherein X 5 , X 7 and X 4 or X 8 in the other of each is independently H or an oxo group, or

[0204] a 5- to 14-membered heteroaryl group, the 5- to 14-membered heteroaryl group of ring A containing at least one ring N atom and being optionally substituted by one or more -NH2, halo groups, C 1-6 alkyl or C 3-10 cycloalkyl, wherein X 5 , X 7 and X 4 or X 8 in the other of each is independently H, -NH2, halo group, C 1-6 alkyl or C 3-10 cycloalkyl; or

[0205] iii. X 7 together with X 5 or X 8 and the atoms to which they are attached form ring A, wherein ring A is

[0206] a 3- to 9-membered heterocyclic group, the 3- to 9-membered heterocyclic group of ring A being optionally substituted by one or more oxo groups, and wherein X 4 , X 6 and X 5 or X 8 in the other of each is independently H or an oxo group, or

[0207] 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl of ring A contains at least one ring nitrogen atom and is optionally substituted by one or more -NH2, halogen, C 1-6 alkyl or C 3-10 cycloalkyl, and wherein X 4 、X 6 and X 5 or X 8 each independently is H, -NH2, halogen, C 1-6 alkyl or C 3-10 cycloalkyl.

[0208] In some embodiments of the compound of formula (I-A), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, X 4-8 each independently X 4-8 each independently is H, -OH, -NH2, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5- to 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 heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3- to 15-membered heterocyclic group) or -NH-(5- to 20-membered heteroaryl), wherein

[0209] the 3- to 15-membered heterocyclic group of -NH-C(O)-(3- to 15-membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen, C 1-6 alkoxy or C 3-10 cycloalkyl, and

[0210] the 3- to 15-membered heterocyclic group of -NH-(3- to 15-membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 alkyl.

[0211] In some embodiments of the compound of formula (I-A), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, X 4-8 each independently is H.

[0212] In some embodiments of the compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, -OH, -NH2, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, a 5- to 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)-(a 3- to 15-membered heterocyclic group), -NH-C(=N-CN)-NH2, NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(a 3- to 15-membered heterocyclic group) or -NH-(a 5- to 20-membered heteroaryl), wherein

[0213] the 3- to 15-membered heterocyclic group of -NH-C(O)-(a 3- to 15-membered heterocyclic group) is optionally substituted with one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, C 1-6 alkoxy or C 3-10 cycloalkyl, and

[0214] the 3- to 15-membered heterocyclic group of -NH-(a 3- to 15-membered heterocyclic group) is optionally substituted with one or more oxo groups or C 1-6 alkyl.

[0215] And the other groups in X 4-8 are each independently H.

[0216] In some embodiments, one of X 4-8 is selected from the group consisting of methyl, OH, Cl, -OCH3, NH 2、 -NH(CH3),

[0217]

[0218] And the other groups in X 4-8 are each independently H.

[0219] In some embodiments of the compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 6 is linked to X 4 or X8 and together with the atoms to which they are attached form Ring A, wherein Ring A is

[0220] a 3- to 9-membered heterocyclic group, wherein the 3- to 9-membered heterocyclic group of Ring A is optionally substituted with one or more oxo groups, and wherein X 5 、X 7 and X 4 or X 8 each independently is H or an oxo group, or

[0221] a 5- to 14-membered heteroaryl group, wherein the 5- to 14-membered heteroaryl group of Ring A contains at least one ring N atom and is optionally substituted with one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl, and wherein X 5 、X 7 and X 4 or X 8 each independently is H, -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl.

[0222] In some embodiments of the compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 6 together with X 4 or X 8 and the atoms to which they are attached form Ring A, wherein Ring A is

[0223] a 3- to 6-membered heterocyclic group, wherein the 3- to 9-membered heterocyclic group of Ring A is optionally substituted with one or more oxo groups, wherein X 5 、X 7 and X 4 or X 8 each independently is H or an oxo group, or

[0224] a 5- to 6-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group of Ring A contains at least one ring N atom and is optionally substituted with one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl, and wherein X 5 、X 7 and X 4 or X 8 each independently is H, -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl.

[0225] In some embodiments of the compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 6 together with X 4 or X 8 and the atoms to which they are attached form ring A, wherein ring A is a 3- to 9-membered heterocyclic group, and wherein the 3- to 9-membered heterocyclic group of ring A is optionally substituted with one or more oxo groups. In some embodiments, ring A is a 3- to 6-membered heterocyclic group, and the 3- to 6-membered heterocyclic group of ring A is optionally substituted with one or more oxo groups or C 1-3 alkyl. In some embodiments, ring A is selected from the group consisting of where # represents the point of attachment to the remainder of the molecule.

[0226] In some embodiments of the compound of formula (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, a 5- to 14-membered heteroaryl group, wherein the 5- to 14-membered heteroaryl group of ring A contains at least one ring nitrogen atom and is optionally substituted with one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl, and wherein X 5 , X 7 and X 4 or X 8 each independently is H, -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl. In some embodiments, ring A is a 5- to 8-membered heteroaryl group, and the 5- to 8-membered heteroaryl group of ring A is optionally substituted with one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl, and wherein X 5 , X 7 and X 4 or X 8 each independently is H, -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl. In some embodiments, ring A is where # represents the point of attachment to the remainder of the molecule.

[0227] In some embodiments, provided herein is a compound of formula (I) or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-A1):

[0228]

[0229] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 4 is H, -OH, -NH2, halogen, 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)-(3-15 membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3-15 membered heterocyclic group) or -NH-(5-20 membered heteroaryl) substituted, wherein

[0230] the 3-15 membered heterocyclic group of -NH-C(O)-(3-15 membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl substituted, wherein C 1-6 alkyl is optionally substituted by one or more halogen, C 1-6 alkoxy or C 3-10 cycloalkyl substituted, and the 3-15 membered heterocyclic group of -NH-(3-15 membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 alkyl substituted.

[0231] In some embodiments, provided herein are compounds of formula (I) or (I-A), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts thereof, wherein the compound is a compound of formula (I-A2):

[0232]

[0233] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 6 is H, -OH, -NH2, halogen, 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)-(3-15 membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3- to 15-membered heterocyclic group), or -NH-(5- to 20-membered heteroaryl), wherein

[0234] the 3- to 15-membered heterocyclic group of -NH-C(O)-(3- to 15-membered heterocyclic group) is optionally substituted with one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halo groups, C 1-6 alkoxy, or C 3-10 cycloalkyl, and

[0235] the 3- to 15-membered heterocyclic group of -NH-(3- to 15-membered heterocyclic group) is optionally substituted with one or more oxo groups or C 1-6 alkyl.

[0236] In some embodiments, provided herein are compounds of formula (I), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound is a compound of formula (I-B):

[0237]

[0238] or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein X 3 is H, -OH, -NH2, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5- to 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 heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3- to 15-membered heterocyclic group), or -NH-(5- to 20-membered heteroaryl), wherein

[0239] the 3- to 15-membered heterocyclic group of -NH-C(O)-(3- to 15-membered heterocyclic group) is optionally substituted with one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halo groups, C 1-6 alkoxy, or C 3-10 cycloalkyl, and

[0240] The 3- to 15-membered heterocyclic group of -NH-(3- to 15-membered heterocyclic group) is optionally substituted with one or more oxo groups or C 1-6 alkyl groups.

[0241] In some embodiments of the compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 1 and X 2 are independently H or a halogen; 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, one of X 1 and X 2 is H; the other of X 1 and X 2 is a halogen; and 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. In some embodiments, one of X 1 and X 2 is H; the other of X 1 and 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.

[0242] In some embodiments of the compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Y 1 and Y 2 are each CH; X 1 and X 2 are independently H or a halogen; R 3 and R 4 are each -CH3, or R 3 and R 4Together with the atoms to which they are attached, form a cyclopropyl or cyclobutyl group. In some embodiments, Y 1 and Y 2 are each CH; X 1 and X 2 are independently H or F; 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 or cyclobutyl group. In some embodiments, Y 1 and Y 2 are each CH; one of X 1 and X 2 is H; the other of X 1 and X 2 is a halogen; 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 or cyclobutyl group. In some embodiments, Y 1 and Y 2 are each CH; one of X 1 and X 2 is H; the other of X 1 and X 2 is F; 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 or cyclobutyl group.

[0243] In some embodiments of the compounds of formula (I-B), or their stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing, one of Y 1 and Y 2 is N, and the other of Y 1 and Y 2 is CH; X 1 and X 2 are independently H or a halogen; 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 or cyclobutyl group. In some embodiments, one of Y 1 and Y 2 is N, and the other of Y 1 and Y 2 is CH; one of X 1 and X 2is independently H or F; 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, one of Y 1 and Y 2 is N, and the other of Y 1 and Y 2 is CH; one of X 1 and X 2 is H; one of X 1 and X 2 and the other of X 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, one of Y 1 and Y 2 is N, and the other of Y 1 and Y 2 is CH; one of X 1 and X 2 is H; one of X 1 and X 2 and the other of X 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.

[0244] In some embodiments of the compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X 3 is H, -OH, -NH2, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, a 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)-(a 3-15 membered heterocycle), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(a 3-15 membered heterocycle) or -NH-(a 5-20 membered heteroaryl) substituted, wherein

[0245] -NH-C(O)-(3- to 15-membered heterocyclic group), wherein the 3- to 15-membered heterocyclic group is optionally substituted with one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo groups, C 1-6 alkoxy or C 3-10 cycloalkyl, and

[0246] -NH-(3- to 15-membered heterocyclic group), wherein the 3- to 15-membered heterocyclic group is optionally substituted with one or more oxo groups or C 1-6 alkyl.

[0247] In some embodiments of the compound of formula (I-B), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, X 3 is H.

[0248] In some embodiments of the compound of formula (I-B), or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, X 3 is -OH, -NH2, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 5- to 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 heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3- to 15-membered heterocyclic group) or -NH-(5- to 20-membered heteroaryl), wherein

[0249] -NH-C(O)-(3- to 15-membered heterocyclic group), wherein the 3- to 15-membered heterocyclic group is optionally substituted with one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo groups, C 1-6 alkoxy or C 3-10 cycloalkyl, and

[0250] -NH-(3- to 15-membered heterocyclic group), wherein the 3- to 15-membered heterocyclic group is optionally substituted with one or more oxo groups or C 1-6 alkyl.

[0251] In some embodiments, X3 selected from the group consisting of: methyl, OH, Cl, -OCH3, NH 2、 -NH(CH3),

[0252] In some embodiments, provided herein are compounds of formula (I) or formula (I-B), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound has formula (I-B1):

[0253]

[0254] or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing.

[0255] In some embodiments of the compound of formula (I-B1), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, X 1 and X 2 are independently halo; X 3 is C 1-3 alkyl or C 3-6 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; X 3 is C 1-3 alkyl or C 3-6 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.

[0256] In some embodiments, provided herein are compounds of formula (I) or formula (I-B), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound is a compound of formula (I-B2):

[0257]

[0258] or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing.

[0259] In some embodiments of the compound of formula (I-B2), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, X2 is a halogen group; 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.

[0260] In some embodiments, provided herein are compounds of formula (I) or formula (I-B), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound is a compound of formula (I-B3):

[0261]

[0262] or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing.

[0263] In some embodiments of a compound of formula (I-B3), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts 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.

[0264] In some embodiments, provided herein are compounds of formula (I) or formula (I-B), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound has formula (I-B4):

[0265]

[0266] or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing.

[0267] In some embodiments, provided herein are compounds of formula (I) or formula (I-B), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound is a compound of formula (I-B5):

[0268]

[0269] or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing.

[0270] 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 a halogen group; X 3 is C 1-6 alkyl or C 3-10 cycloalkyl, wherein the C 3 of cycloalkyl of X 3-10 is optionally substituted with one or more C 1-6 alkyl. In some embodiments, X 2 is F; and X 3 is C 1-3 alkyl or C 3-6 cycloalkyl, wherein the C 3 of cycloalkyl of X 3-6 is optionally substituted with one or more C 1-3 alkyl.

[0271] In some embodiments, provided herein is a compound of formula (I) or formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B6):

[0272]

[0273] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0274] 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.

[0275] In some embodiments, provided herein is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-C):

[0276]

[0277] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is

[0278] a 3- to 9-membered heterocyclic group, wherein the 3- to 9-membered heterocyclic group of ring A is optionally substituted with one or more oxo groups,

[0279] 5 - 14 - membered heteroaryl, wherein the 5 - 14 - membered heteroaryl of ring A contains at least one ring N atom and is optionally substituted by one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl.

[0280] In some embodiments, provided herein are compounds of formula (I), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound is a compound of formula (I - D):

[0281]

[0282] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is

[0283] a 3 - 9 - membered heterocyclic group, wherein the 3 - 9 - membered heterocyclic group of ring A is optionally substituted by one or more oxo groups,

[0284] 5 - 14 - membered heteroaryl, wherein the 5 - 14 - membered heteroaryl of ring A contains at least one ring N atom and is optionally substituted by one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl.

[0285] In some embodiments of the compounds of formula (I - C), (I - D), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, ring A is a 5 - 6 - membered heterocyclic group, wherein the 5 - 6 - membered heterocyclic group of ring A is optionally substituted by one or more oxo groups. In some embodiments, ring A is selected from the group consisting of where # represents the point of attachment to the remainder of the molecule.

[0286] In some embodiments of the compounds of formula (I - C) or (I - D), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, ring A is a 5 - 8 - membered heteroaryl, wherein the 5 - 8 - membered heteroaryl of ring A contains at least one ring N atom and is optionally substituted by one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl. In some embodiments, ring A is where # represents the point of attachment to the remainder of the molecule.

[0287] In some embodiments, provided herein are compounds of formula (I), or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound is a compound of formula (I - E):

[0288]

[0289] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0290] In some embodiments, provided herein are compounds of formula (I) or (I-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-E1):

[0291]

[0292] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0293] In some embodiments, provided herein are compounds of formula (I) or (I-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-E2):

[0294]

[0295] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0296] In some embodiments, provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-F):

[0297]

[0298] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0299] In some embodiments, provided herein are compounds of formula (I) or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-F1):

[0300]

[0301] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0302] In some embodiments, provided herein are compounds of formula (I) or (I-F), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-F2):

[0303]

[0304] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0305] In some embodiments, provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-G):

[0306]

[0307] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0308] In some embodiments, provided herein are compounds of formula (I) or (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-G1):

[0309]

[0310] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0311] In some embodiments, provided herein are compounds of formula (I), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-G2):

[0312]

[0313] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0314] In some embodiments, provided herein are compounds of formula (I), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-G3):

[0315]

[0316] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0317] In some embodiments, provided herein are compounds of formula (I), (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-G4):

[0318]

[0319] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0320] In some embodiments, provided herein are compounds of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-H):

[0321]

[0322] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0323] In some embodiments, provided herein are compounds of (I) or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-H1):

[0324]

[0325] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0326] In some embodiments, provided herein are compounds of formula (I), (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-H2):

[0327]

[0328] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0329] In some embodiments, provided herein are compounds of (I), (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-H3):

[0330]

[0331] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0332] In some embodiments, provided herein are compounds of formula (I), (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-H4):

[0333]

[0334] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0335] In some embodiments of the 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, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is selected from Table 1.

[0336] The compound names included in Table 1, as well as the names of all intermediates and compounds, were generated using Professional software version 17.1.1.0 or Collaborative Drug Discovery Inc. (CDD) CDD Vault update #3.

[0337] A Knime workflow was created to retrieve structures from the internal ChemAxon compound registry, generate canonical smiles using the RDKitCanon SMILES node, remove stereochemistry using the Chem Axon / Infocom MolConverter node, and name the structures using the ChemAxon / Infocom Naming node. The following represent the versions of the Knime analysis platform and extensions used in the workflow:

[0338] · Knime analysis platform 4.2.2

[0339] · RDKit Knime Integration 4.0.1.v202006261025 (this extension includes the RDKit CanonSMILES node)

[0340] · ChemAxon / Infocom Marvin Extensions Feature 4.3.0v202100 (this extension includes the MolConverter node)

[0341] · ChemAxon / Infocom JChem Extensions Feature 4.3.0v202100 (this extension includes the naming node)

[0342] Table 1

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357] In some embodiments, provided herein are compounds of formula (I), or any variant or embodiment thereof, or stereoisomers or tautomers thereof, or pharmaceutically acceptable salts of any of the foregoing, wherein the compound, or stereoisomer or tautomer thereof, or pharmaceutically acceptable salt of any of the foregoing is selected from the group consisting of:

[0358] N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide;

[0359] N-[(4-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0360] N-[(2-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0361] N-[(3-methoxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0362] N-[(1-methyl-1H-pyrazol-5-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0363] N-[(4-hydroxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0364] N-[(2-hydroxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0365] N-[(3-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0366] N-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0367] N-[(2-acetamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0368] N-[(2-aminophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0369] N-[(3-methoxy-2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0370] N-[(3-hydroxyphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0371] N-[(2-cyclopropanecarboxamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0372] N-{2-[(cyclopropylcarboxamido)[4-(propan-2-yl)phenyl]methyl]phenyl}oxetane-3-carboxamide;

[0373] N-{[4-(propan-2-yl)phenyl](2-propanamidophenyl)methyl}cyclopropanecarboxamide;

[0374] N-[(2-chlorophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0375] N-[(2-methanesulfamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0376] N-{[4-(propan-2-yl)phenyl](1H-pyrazol-5-yl)methyl}cyclopropanecarboxamide;

[0377] 2-acetamido-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide;

[0378] N-{[2-(carbamoylamino)phenyl][4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide;

[0379] N-({2-[(methylcarbamoyl)amino]phenyl}[4-(propan-2-yl)phenyl]methyl)cyclopropanecarboxamide;

[0380] N-[(2-aminopyridin-3-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0381] N-{[3-Fluoro-4-(propan-2-yl)phenyl](phenyl)methyl}cyclopropanecarboxamide;

[0382] N-{2-[(Cyclopropanecarboxamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-2-carboxamide;

[0383] N-[(2-Methylphenyl)[5-(propan-2-yl)pyridin-2-yl]methyl]cyclopropanecarboxamide;

[0384] N-{2-[(Cyclopropanecarboxamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-3-carboxamide;

[0385] N-[(4-Cyclopropylphenyl)(phenyl)methyl]cyclopropanecarboxamide;

[0386] N-{Phenyl[5-(propan-2-yl)pyridin-2-yl]methyl}cyclopropanecarboxamide;

[0387] N-[(4-Cyclobutylphenyl)(phenyl)methyl]cyclopropanecarboxamide;

[0388] N-[(2-Acetamido-5-fluorophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0389] N-[(3-Methyl-1H-pyrazol-4-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0390] N-{[2-(Methylamino)phenyl][4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide;

[0391] 1-Acetyl-N-{2-[(cyclopropanecarboxamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-2-carboxamide;

[0392] 2-(Carbamoylamino)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide;

[0393] N-[(2-Methoxyphenyl)[5-(propan-2-yl)pyridin-2-yl]methyl]cyclopropanecarboxamide;

[0394] 1-Acetyl-N-{2-[(cyclopropanecarboxamido)[4-(propan-2-yl)phenyl]methyl]phenyl}azetidine-3-carboxamide;

[0395] 2-Fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopropane-1-carboxamide;

[0396] 3-Hydroxy-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide;

[0397] 3-Fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide;

[0398] N-[(2-Oxo-2,3-dihydro-1H-indol-7-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0399] N-({2-[(1,3-Oxazol-2-yl)amino]phenyl}[4-(propan-2-yl)phenyl]methyl)cyclopropanecarboxamide;

[0400] N1-[(2-Methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1,2-dicarboxamide;

[0401] N-[(2-Oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0402] 2-Acetamido-N-[2-({phenyl[4-(propan-2-yl)phenyl]methyl}carbamoyl)cyclopentyl]butanediamide;

[0403] 2-Fluoro-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopropane-1-carboxamide;

[0404] N-{2-[(Cyclopropanecarboxamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-methylazetidine-3-carboxamide;

[0405] N-{2-[(Cyclopropanecarboxamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-(cyclopropylmethyl)azetidine-3-carboxamide;

[0406] N-{2-[(Cyclopropanecarboxamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-(2-methoxyethyl)azetidine-3-carboxamide;

[0407] N-{2-[(Cyclopropanecarboxamido)[4-(propan-2-yl)phenyl]methyl]phenyl}-1-(2,2,2-trifluoroethyl)azetidine-3-carboxamide;

[0408] N1-Cyano-N2-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1,2-dicarboxamide;

[0409] 2-(2-Acetamidoacetamido)-N-{phenyl[4-(propan-2-yl)phenyl]methyl}cyclopentane-1-carboxamide;

[0410] Methyl 3-[(2-{[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]carbamoyl}cyclopentyl)carbamoyl]propionate;

[0411] N-{[2-(N”-Cyanoaminoureido)phenyl][4-(propan-2-yl)phenyl]methyl}cyclopropanecarboxamide;

[0412] N-{[2-(Carbamoylamino)phenyl](4-cyclobutylphenyl)methyl}cyclopropanecarboxamide;

[0413] N1-Methyl-N2-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1,2-dicarboxamide;

[0414] N-{[2-(Carbamoylamino)phenyl](4-cyclopropylphenyl)methyl}cyclopropanecarboxamide;

[0415] N-[(2-Oxo-2,3-dihydro-1,3-benzoxazol-7-yl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0416] 1-(Cyclopropylmethyl)-N-(2-{[(2-fluorocyclopropyl)carbamoyl][4-(propan-2-yl)phenyl]methyl}phenyl)piperidine-4-carboxamide;

[0417] N-(2-{[(2-fluorocyclopropyl)carbamoyl][4-(propan-2-yl)phenyl]methyl}phenyl)-1-(2-methoxyethyl)piperidine-4-carboxamide;

[0418] N-(2-{[(2-fluorocyclopropyl)carbamoyl][4-(propan-2-yl)phenyl]methyl}phenyl)-1-methylpiperidine-4-carboxamide;

[0419] 2-Fluoro-N-{[3-fluoro-4-(propan-2-yl)phenyl](1H-pyrazol-5-yl)methyl}cyclopropane-1-carboxamide;

[0420] N-{[2-(Carbamoylamino)phenyl][3-fluoro-4-(propan-2-yl)phenyl]methyl}-2-fluorocyclopropane-1-carboxamide;

[0421] N-(2-{[(2-fluorocyclopropyl)carbamoyl][4-(propan-2-yl)phenyl]methyl}phenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carboxamide;

[0422] N-({2-[(1-Methyl-2,5-dioxoimidazolidin-4-yl)amino]phenyl}[4-(propan-2-yl)phenyl]methyl)cyclopropanecarboxamide;

[0423] 2-Cyano-N-[(2-methylphenyl)[4-(propan-2-yl)phenyl]methyl]cyclopentane-1-carboxamide;

[0424] N-[(3-Acetamidophenyl)[4-(propan-2-yl)phenyl]methyl]cyclopropanecarboxamide;

[0425] 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;

[0426] 2-Fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl][3-(1H-pyrazol-5-yl)phenyl]methyl}cyclopropane-1-carboxamide;

[0427] 2-Fluoro-N-{[6-fluoro-5-(propan-2-yl)pyridin-2-yl](1H-indazol-6-yl)methyl}cyclopropane-1-carboxamide; and

[0428] N-[(5-Cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl]-2-fluorocyclopropane-1-carboxamide;

[0429] or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0430] In some embodiments, provided herein are compounds 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, 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:

[0431] (R)-N-((2-Acetamidophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide;

[0432] (1R,2S)-N-((S)-(5-Cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-2-fluorocyclopropane-1-carboxamide;

[0433] (1R,2S)-2-Fluoro-N-((S)-(6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methyl)cyclopropane-1-carboxamide;

[0434] (1R,2S)-N-((S)-(3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methyl)-2-fluorocyclopropane-1-carboxamide;

[0435] (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;

[0436] (R)-N-((3-acetamidophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide;

[0437] (1R,2S)-2-cyano-N-((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1-carboxamide;

[0438] N-((1R)-(4-isopropylphenyl)(2-((1-methyl-2,5-dioxoimidazolidin-4-yl)amino)phenyl)methyl)cyclopropanecarboxamide;

[0439] N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamido)(4-isopropylphenyl)methyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidine-4-carboxamide;

[0440] (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4-isopropylphenyl)(2-ureidophenyl)methyl)cyclopropane-1-carboxamide;

[0441] (1R,2S)-2-fluoro-N-((R)-(3-fluoro-4-isopropylphenyl)(1H-pyrazol-5-yl)methyl)cyclopropane-1-carboxamide;

[0442] N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamido)(4-isopropylphenyl)methyl)phenyl)-1-methylpiperidine-4-carboxamide;

[0443] N-(2-((R)-((1R,2S)-2-fluorocyclopropane-1-carboxamido)(4-isopropylphenyl)methyl)phenyl)-1-(2-methoxyethyl)piperidine-4-carboxamide;

[0444] 1-(cyclopropylmethyl)-N-(2-((R)-((1R,2S)-2-fluorocyclopropanecarboxamido)(4-isopropylphenyl)methyl)phenyl)piperidine-4-carboxamide;

[0445] (R)-N-((4-isopropylphenyl)(2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)methyl)cyclopropanecarboxamide;

[0446] (1R,2S)-N1-((R)-(4-Isopropylphenyl)(o-tolyl)methyl)-N2-methylcyclopentane-1,2-dicarboxamide;

[0447] (R)-N-((4-Cyclopropylphenyl)(2-ureidophenyl)methyl)cyclopropanecarboxamide;

[0448] (R)-N-((4-Cyclobutylphenyl)(2-ureidophenyl)methyl)cyclopropanecarboxamide;

[0449] (R,E)-N-((2-(2-Cyanoguanidino)phenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide;

[0450] Methyl 3-((1S,2R)-2-(((R)-(4-Isopropylphenyl)(o-tolyl)methyl)carbamoyl)cyclopentane-1-carboxamido)propionate;

[0451] (1R,2S)-2-(2-Acetamidoacetamido)-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide;

[0452] (1S,2R)-N1-Cyano-N2-((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide;

[0453] (R)-N-(2-(Cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-(2,2,2-trifluoroethyl)azetidine-3-carboxamide;

[0454] (R)-N-(2-(Cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-(2-methoxyethyl)azetidine-3-carboxamide;

[0455] (R)-N-(2-(Cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-(cyclopropylmethyl)azetidine-3-carboxamide;

[0456] (R)-N-(2-(Cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)-1-methylazetidine-3-carboxamide;

[0457] (1S,2R)-2-Fluoro-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopropane-1-carboxamide;

[0458] (S)-2-Acetamido-N1-((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)succinamide;

[0459] (R)-N-((4-Isopropylphenyl)(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)cyclopropanecarboxamide;

[0460] (1R,2S)-N1-((R)-(4-Isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide;

[0461] (R)-N-((4-Isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide;

[0462] (R)-N-((4-Isopropylphenyl)(2-oxoindol-7-yl)methyl)cyclopropanecarboxamide;

[0463] (S)-N-((5-Isopropylpyridin-2-yl)(2-methoxyphenyl)methyl)cyclopropanecarboxamide;

[0464] (1S)-3-Fluoro-N-((S)-(4-Isopropylphenyl)phenyl)methyl)cyclopentane-1-carboxamide;

[0465] (1S)-3-Hydroxy-N-((S)-(4-Isopropylphenyl)phenyl)methyl)cyclopentane-1-carboxamide;

[0466] (1R,2S)-2-Fluoro-N-((S)-(4-Isopropylphenyl)phenyl)methyl)cyclopropane-1-carboxamide;

[0467] (R)-1-Acetyl-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide;

[0468] (1R,2S)-N-((S)-(4-Isopropylphenyl)phenyl)methyl)-2-ureidocyclopentane-1-carboxamide;

[0469] (R)-N-((4-Isopropylphenyl)(2-(methylamino)phenyl)methyl)cyclopropanecarboxamide;

[0470] (S)-N-((4-Cyclobutylphenyl)phenyl)methyl)cyclopropanecarboxamide;

[0471] (S)-N-((4-Cyclopropylphenyl)phenyl)methyl)cyclopropanecarboxamide;

[0472] (S)-1-Acetyl-N-(2-((R)-cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide;

[0473] (R)-N-((4-Isopropylphenyl)(3-methyl-1H-pyrazol-4-yl)methyl)cyclopropanecarboxamide;

[0474] (R)-N-((2-Acetamido-5-fluorophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide;

[0475] (S)-N-((5-Isopropylpyridin-2-yl)(phenyl)methyl)cyclopropanecarboxamide;

[0476] (S)-N-((2-Acetamidophenyl)(5-isopropylpyridin-2-yl)methyl)cyclopropanecarboxamide;

[0477] (S)-N-((5-Isopropylpyridin-2-yl)(o-tolyl)methyl)cyclopropanecarboxamide;

[0478] (R)-N-(2-(Cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide;

[0479] (S)-N-(2-((R)-Cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide;

[0480] (R)-N-(2-((R)-Cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-2-carboxamide;

[0481] (R)-N-((2-Aminopyridin-3-yl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide;

[0482] (S)-N-((3-Fluoro-4-isopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide;

[0483] (R)-N-((4-Isopropylphenyl)(2-(3-methylureido)phenyl)methyl)cyclopropanecarboxamide;

[0484] (R)-N-((4-Isopropylphenyl)(2-ureidophenyl)methyl)cyclopropanecarboxamide;

[0485] (1R,2S)-2-Acetamido-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide;

[0486] (R)-N-((4-Isopropylphenyl)(1H-pyrazol-5-yl)methyl)cyclopropanecarboxamide;

[0487] (R)-N-((4-Isopropylphenyl)(2-(methylsulfonamido)phenyl)methyl)cyclopropanecarboxamide;

[0488] (R)-N-((2-chlorophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide;

[0489] (R)-N-((4-isopropylphenyl)(2-propionamidophenyl)methyl)cyclopropanecarboxamide;

[0490] (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)oxetane-3-carboxamide;

[0491] (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)cyclopropanecarboxamide;

[0492] (R)-N-((3-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide;

[0493] (R)-N-((4-isopropylphenyl)(3-methoxy-2-methylphenyl)methyl)cyclopropanecarboxamide;

[0494] (R)-N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide;

[0495] (R)-N-((4-isopropylphenyl)(o-tolyl)methyl)cyclopropanecarboxamide;

[0496] (R)-N-((4-isopropylphenyl)(m-tolyl)methyl)cyclopropanecarboxamide;

[0497] (R)-N-((2-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide;

[0498] (R)-N-((4-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide;

[0499] (R)-N-((4-isopropylphenyl)(1-methyl-1H-pyrazol-5-yl)methyl)cyclopropanecarboxamide;

[0500] (R)-N-((4-isopropylphenyl)(3-methoxyphenyl)methyl)cyclopropanecarboxamide;

[0501] (R)-N-((4-isopropylphenyl)(2-methoxyphenyl)methyl)cyclopropanecarboxamide;

[0502] (R)-N-((4-isopropylphenyl)(4-methoxyphenyl)methyl)cyclopropanecarboxamide;

[0503] (S)-N-((4-isopropylphenyl)(phenyl)methyl)cyclopropanecarboxamide; and

[0504] or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0505] Treatment method

[0506] Methods for modulating GYS1 in cells are provided herein, including exposing the cells 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. In some embodiments, the compound of formula (I) or any variant or embodiment thereof or its stereoisomer or tautomer is more selective for GYS1 than for GYS2. In some embodiments, the compound of formula (I) or any variant or embodiment thereof or its stereoisomer or tautomer is 500 or 1,000 or 1,500 or 1,700 times more selective for GYS1 than for GYS2.

[0507] Methods for inhibiting GYS1 in cells are provided herein, which include exposing the cells 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 more selective for GYS1 than for GYS2. In some embodiments, the GYS1 inhibitor is 500 or 1,000 or 1,500 or 1,700 times more selective for GYS1 than for GYS2.

[0508] Methods for inhibiting GYS1 in cells are provided herein, including exposing the cells 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.

[0509] In some embodiments, the compound of formula (I), or any variant or embodiment thereof, or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, is more selective for GYS1 than for GYS2. In some embodiments, the compound of formula (I), or any variant or embodiment thereof, or its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, is 500 or 1,000 or 1,500 or 1,700 times more selective for GYS1 than for GYS2. In some embodiments, the individual has a GYS1-mediated disease, disorder, or condition selected from the group consisting of Pompe disease, Cori disease (GSDIII), 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).

[0510] Provided herein are methods of reducing tissue glycogen storage in an individual in need thereof, comprising administering to the individual (i) an effective amount of a compound of formula (I), or any variant or embodiment thereof, or its stereoisomers or tautomers, 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 its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing and one or more pharmaceutically acceptable excipients.

[0511] Provided herein are methods 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 variant or embodiment thereof, or its stereoisomers or tautomers, 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 its stereoisomers or tautomers, or a pharmaceutically acceptable salt of any of the foregoing and one or more pharmaceutically acceptable excipients.

[0512] The present disclosure provides 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 (GSDIII), 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 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).

[0513] The present disclosure provides 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, the glycogen levels in the individual are reduced after treatment. In some embodiments, the glycogen levels in muscle are reduced. In some embodiments, the glycogen levels in skeletal muscle are reduced. In some embodiments, after administration of the compound, the glycogen levels are reduced by at least 10%, at least 20%, at least 30%, or at least 50%. In some embodiments, the compounds provided herein are effective in treating lysosomal disorders. In some embodiments, the glycogen storage disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSDIII), adult polyglucosan body disease (APBD), and Lafora disease.

[0514] The present invention provides methods for 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, the glycogen level in the individual is decreased after treatment. In some embodiments, the glycogen level in muscle is decreased. In some embodiments, the glycogen level in skeletal muscle is decreased. In some embodiments, after administering the compound, the glycogen level is decreased by at least 10%, at least 20%, at least 30%, or at least 50%. In some embodiments, the compounds provided herein are effective in treating lysosomal disorders. In some embodiments, the glycogen storage disease, disorder, or condition is selected from the group consisting of Pompe disease, Cori disease (GSDIII), adult polyglucosan body disease (APBD), and Lafora disease.

[0515] The present invention provides methods for 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 atypical infantile-onset Pompe disease. In some embodiments, the individual has late-onset Pompe disease. In some embodiments, the individual lacks acid alpha-glucosidase (GAA). In some embodiments, the individual has decreased GAA expression.

[0516] The present invention provides methods for 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 atypical infantile-onset Pompe disease. In some embodiments, the individual has late-onset Pompe disease. In some embodiments, the individual lacks acid alpha-glucosidase (GAA). In some embodiments, the individual has reduced GAA expression.

[0517] In some embodiments, the compounds provided herein alleviate 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, hepatomegaly, growth arrest and weight gain, dyspnea, feeding problems, respiratory infections, hearing problems, delayed motor skills, cardiac enlargement, fatigue, pulmonary infections, frequent falls, or arrhythmias. In some embodiments, the compounds herein delay the progression of Pompe disease.

[0518] In some embodiments, the compounds provided herein increase the lifespan of the individual. In some embodiments, the lifespan is increased by at least 5 years, at least 10 years, or at least 20 years after treatment.

[0519] In some embodiments, the 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 dynamometer, or grip dynamometer. In some embodiments, the strength is graded according to the following scale: 0: no visible muscle contraction; 1: visible muscle contraction, no or trace movement; 2: limb movement, but not against gravity; 3: movement against gravity but no resistance; 4: movement against at least some resistance provided by the examiner; 5: full strength.

[0520] The present invention also provides a method of 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 a concentration of 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 a concentration of 1-10 μM, 0.01 to 1 μM, or 0.01 to 10 μM.

[0521] In some embodiments, the IC of the compound 50 is less than 10 nM, less than 10 μM, less than 1 μM, less than 0.5 μM, or less than 0.1 μM. In some embodiments, the IC of the compounds provided herein 50 is from 1 to 10 nM, from 1 to 10 μM, from 0.01 to 1 μM, from 0.01 to 10 μM, or from 0.001 to 0.01 μM.

[0522] In some embodiments, after administration of the compounds provided herein, glycogen synthesis is inhibited. In some embodiments, after administration, glycogen synthesis is reduced by at least 10%, at least 20%, at least 40%, or at least 50%.

[0523] In some embodiments, the individual being treated is an adolescent or an infant. In some embodiments, the age of the individual is less than 10 years old, less than 9 years old, less than 8 years old, less than 7 years old, less than 6 years old, less than 5 years old, less than 4 years old, less than 3 years old, less than 2 years old, or less than 1 year old.

[0524] In some embodiments, the method further comprises enzyme replacement therapy (ERT). Exemplary ERTs include glucosidase α (human recombinant α-glucosidase (human GAA)) and those described by Byrne BJ et al. (2011). Pompe disease: design, methodology, and early findings from the Pompe Registry. Mol Genet Metab 103:1-11 (which is 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 a late-onset 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 administering to the individual (a) a glycogen substrate reduction therapy, such as administering to the individual an effective amount of (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, and (b) an 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 more selective for GYS1 than for GYS2. In some embodiments, the selectivity of the compound of formula (I) for GYS1 is 500 or 1,000 or 1,500 or 1,700 times the selectivity for GYS2.

[0525] 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 splice variant.

[0526] In some of the foregoing embodiments, the administration is oral administration.

[0527] Kit

[0528] The present disclosure provides a cartridge for performing the methods of the present invention. The cartridge may include a compound as described herein or a pharmaceutically acceptable salt thereof and a suitable package. The cartridge may include one or more containers containing any of the compounds described herein. In one aspect, the cartridge includes a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a label and / or instructions for treating a disease or disorder described herein using the compound. The cartridge may contain the compound in unit dosage form.

[0529] Also provided herein are cartridges that include (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 treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are cartridges that include (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 treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof

[0530] The present invention also provides an article of manufacture, wherein the article of manufacture comprises a compound of formula (I), or any variant or embodiment thereof (as described elsewhere herein), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. Also provided herein is an article of manufacture that comprises, in a suitable container, a pharmaceutical composition comprising a compound of formula (I) or any variant 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 can be a vial, a bottle, an ampoule, a prefilled syringe, or an intravenous bag.

[0531] Preparation method

[0532] The present disclosure also provides methods for preparing the compounds of the present invention. In some aspects, provided herein are methods for preparing a compound of (I), (I-A), (I-A1), (I-A2), (I-B), (I-B1), (I-B2), (I-B3), (I-B4), (I-B5), (I-B6), (I-C), (I-D), (I-E), (I-E1), (I-E2), (I-F), (I-F1), (I-G), (I-G1), (I-G2), (I-G3), (I-G4), (I-H), (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.

[0533] In some embodiments, a method for preparing a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises: in the presence of a coupling reagent

[0534] (a) a compound of formula (I-1):

[0535]

[0536] or a salt thereof, wherein:

[0537] Y 1 and Y 2 are each CH, or

[0538] Y 1 and Y 2 one of which is N, and Y 1 and Y 2 the other of which is CH;

[0539] X 1 and X 2 are each independently H or a halogen group;

[0540] R 3 and R 4 are each -CH3, or

[0541] R 3 and R 4 together with the atoms to which they are attached form cyclopropyl or cyclobutyl;

[0542] Or

[0543] (1) L is absent; and

[0544] Q 1 is:

[0545] (i) C 6-20 aryl, wherein the C of Q 1 aryl is optionally substituted with one or more -OH, -NH2, halogen, C 6-20 alkyl, C 1-6 alkoxy, C 1-6 cycloalkyl, 5-20 membered heteroaryl, -NH-C(O)-NH2, -NH-C(O)-NH(C 3-10 alkyl), -NH-C(O)-C 1-6 alkyl, -NH-C(O)-C 1-6 alkyl, -NH-C(O)-C 3-10 cycloalkyl, -NH-C(O)-(3-15 membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6substituted with -C(O)-C(alkyl), -NH-(3-15-membered heterocyclic group), or -NH-(5-20-membered heteroaryl), wherein

[0546] the 3-15-membered heterocyclic group of -NH-C(O)-(3-15-membered heterocyclic group) is optionally substituted with one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halo groups, C 1-6 alkoxy, or C 3-10 cycloalkyl, and

[0547] the 3-15-membered heterocyclic group of -NH-(3-15-membered heterocyclic group) is optionally substituted with one or more oxo groups or C 1-6 alkyl, or

[0548] (ii) a 3-15-membered heterocyclic group, wherein the 3-15-membered heterocyclic group of Q 1 is optionally substituted with one or more oxo groups, or

[0549] (iii) a 5-20-membered heteroaryl, wherein the 5-20-membered heteroaryl of Q 1 contains at least one cyclic N atom and is optionally substituted with one or more -NH2, halo groups, C 1-6 alkyl, or C 3-10 cycloalkyl;

[0550] Or

[0551] (2) L is -CH2-; and

[0552] Q 1 is C 3-10 cycloalkyl,

[0553] reacting with the compound of formula (I-2):

[0554]

[0555] wherein,

[0556] m is 0 or 1;

[0557] n is 0 or 1;

[0558] R 1 is H, halo group, -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, wherein

[0559] R 1 of -C(O)-NH(C1-6 C of (alkyl) 1-6 The alkyl is optionally substituted by one or more -C(O)-C 1-6 alkoxy groups, and

[0560] R 1 -NH-C(O)-C of 1-6 C of (alkyl) 1-6 The alkyl is optionally substituted by one or more -NH-C(O)-C 1-6 alkyl or -C(O)-NH2; and

[0561] R 2 is H, halogen or -OH

[0562] to obtain a compound of formula (I).

[0563] In some embodiments, the coupling reagent includes propanephosphonic anhydride (T3P) or N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TFCH). In some embodiments, the method further includes the presence of a base. In some embodiments, the base includes an amine. In some embodiments, the base includes a tertiary amine. In some embodiments, the amine is N-methylmorpholine or N-methylimidazole.

[0564] Examples

[0565] The following synthetic reaction schemes detailed in the schemes and examples illustrate only some of the ways in which the compounds of the present disclosure or their embodiments or aspects can be synthesized. Various modifications can be made to these synthetic reaction schemes, which will be apparent to those of ordinary skill in the art.

[0566] If desired, conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, etc. can be used to separate and purify the starting materials and intermediates of the synthetic reaction schemes. Conventional methods (including physical constants and spectral data) can be used to characterize such materials.

[0567] Although certain exemplary embodiments are described and illustrated herein, the compounds of the present disclosure, or any variants or embodiments thereof, can be prepared using appropriate starting materials according to the methods generally described herein and / or by methods available to those of ordinary skill in the art.

[0568] Synthetic Examples

[0569] As described in the following schemes and examples, in certain exemplary embodiments, the compounds of formula (I), or any variant or embodiment thereof (as described elsewhere herein), or their stereoisomers or tautomers, or pharmaceutically acceptable salts of any of the foregoing are prepared according to general procedures. The following general methods and other methods known to the ordinary synthetic chemist in the art can be applied to all formulas, variants, embodiments, and species described herein.

[0570] Scheme

[0571] Scheme 1

[0572]

[0573] Compounds of formula S1-3 can be prepared according to General Scheme 1. The carboxylic acid S1-1 is reacted with the amine S1-2 using a coupling reagent such as propylphosphonic anhydride (T3P) and a tertiary amine base such as N-methylmorpholine in an aprotic solvent such as DMF to give the compound of formula S1-3.

[0574] Scheme 2

[0575]

[0576] Compounds of formula S2-3 can be prepared according to alternative reaction conditions shown in General Scheme 2. The carboxylic acid S2-1 is reacted with the 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 to give the compound of formula S2-3.

[0577] The abbreviations used are conventional abbreviations in the art and conform to the Periodic Table, CAS version, and the 75th Edition of the Handbook of Chemistry and Physics. The following examples are for illustrative purposes only and are not limiting in any way.

[0578]

[0579]

[0580] Example S-1:

[0581] Table 2

[0582]

[0583]

[0584]

[0585]

[0586]

[0587] Synthesis of Intermediate A-1: (6-Fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methanaminium Chloride

[0588]

[0589] 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. Then the reaction mixture was diluted with water and the resulting two-phase mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained 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.

[0590] Step b: Under N2, 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)Cl2·CH2Cl2 (1.55 g, 1.90 mmol, 0.05 equiv). Then the resulting mixture was degassed and placed under a N2 atmosphere. Then the reaction mixture was heated to 100 °C and stirred under N2 for 2 h. After cooling, the mixture was filtered and the filter cake was washed with ethyl acetate (3 × 100 mL). The combined filtrates were concentrated and the obtained 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 N2 Calculated: 795.4; Found 795.3.

[0591] Step c: At 0 °C, add NaIO4 (31.4 g, 146 mmol, 4 equivalents) and K2OsO4·2H2O (676 mg, 1.84 mmol, 0.05 equivalent) to a solution of 1-trityl-6-vinyl-1H-indazole (14.2 g, 36.7 mmol, 1 equivalent) in THF:H2O (5:1) (300 mL). Warm the resulting mixture to 50 °C and stir for 1 hour. Then cool the reaction mixture to 25 °C and quench with saturated aqueous Na2S2O3 (100 mL). Extract the resulting mixture with ethyl acetate (3 × 100 mL), dry the combined extracts over Na2SO4, filter, and concentrate under reduced pressure. Purify the resulting residue by column chromatography to obtain 1-trityl-1H-indazole-6-carbaldehyde.

[0592] Step d: Add Cs2CO3 (6.74 g, 20.7 mmol, 1.1 equivalents) and 2-methylpropane-2-sulfinamide (2.51 g, 20.6 mmol, 1.1 equivalents) to a solution of 1-trityl-1H-indazole-6-carbaldehyde (7.3 g, 18.8 mmol, 1 equivalent) in DCM (75 mL). Then warm the mixture to 40 °C and stir for 16 hours. Then filter the reaction mixture and wash the filter cake with ethyl acetate (3 × 100 mL). Then filter the filtrate and concentrate under reduced pressure. Purify the obtained crude residue by column chromatography to obtain (E)-2-methyl-N-((1-trityl-1H-indazol-6-yl)methylene)propane-2-sulfinamide.

[0593] Step e: At –78 °C under N2, add n-BuLi (1.22 mL, 2.5 M, 1.5 equivalents) to a solution of 6-bromo-2-fluoro-3-isopropylpyridine (665 mg, 3.05 mmol, 1.5 equivalents) in THF (5 mL). Stir the resulting mixture at -78 °C for 0.5 hour. Thereafter, under N2, add (E)-2-methyl-N-((1-trityl-1H-indazol-6-yl)methylene)propane-2-sulfinamide (1 g, 2.03 mmol, 1 equivalent) in THF (5 mL) cooled to –78 °C and stir the resulting mixture at –78 °C for 4 hours. Then quench the reaction with saturated aqueous NH4Cl (20 mL), extract the resulting two-phase mixture with ethyl acetate (3 × 20 mL), dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the obtained crude residue by column chromatography to obtain N-((6-fluoro-5-isopropylpyridin-2-yl)(1-trityl-1H-indazol-6-yl)methyl)-2-methylpropane-2-sulfinamide.

[0594] Step f: At 0 °C under N₂, HCl / EtOAc (4 M, 3 mL, 12.6 equiv) was added 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). The resulting mixture was then warmed to 40 °C and stirred for 16 h. The reaction mixture was then filtered and concentrated to afford (6-fluoro-5-isopropylpyridin-2-yl)(1H-indazol-6-yl)methanaminium chloride. LC-MS (ESI): m / z: [M–NH₃] + C 16 H 17 FN4 Calcd: 268.1; Found 268.2. Intermediate A-2: Synthesis of (3-(1H-pyrazol-5-yl)phenyl)(6-fluoro-5-isopropylpyridin-2-yl)methanaminium chloride

[0595]

[0596] Step a: At -60 °C under N₂, n-BuLi (2.5 M, 1.22 mL, 2.5 equiv) was added dropwise to a solution of 5-(3-bromophenyl)-1H-pyrazole (408 mg, 1.83 mmol, 1.5 equiv) in THF (3 mL). Once the addition was complete, (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 h. The reaction mixture was then poured into ice water (30 mL) and stirred for 2 min. The resulting two-phase mixture was then extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to afford 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 FN4OS Calcd: 415.2; Found 415.2.

[0597] Step b: At 15 °C, HCl / dioxane (4 mL) was added dropwise 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 μmol, 1 equiv) in dioxane (2 mL). The resulting mixture was stirred at 15 °C for 2 h. Then the reaction mixture was 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 FN4 Calcd: 311.2; Found 311.2.

[0598] Intermediate A-3: Synthesis of tert-butyl (2-(amino((4-isopropylphenyl)methyl)phenyl)carbamate

[0599]

[0600] Step a: Under N2 at 0 °C, Ti(OEt)4 (30.7 g, 134 mmol, 2 equiv) was added in one portion 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 anhydrous THF (75 mL). Then the reaction mixture was degassed and flushed with N2 three times. Then the reaction mixture was warmed to 25 °C and stirred under N2 for 4 h. Then the reaction was cooled to 0 °C, H2O (150 mL) was added and stirred for 20 min to quench. Then the reaction mixture was filtered and the cake was washed with ethyl acetate (2 x 100 mL). Then the filtrate was extracted with ethyl acetate (2 × 100 mL). Then the combined organic extracts were washed with saturated aqueous NH4Cl solution (100 mL), brine (70 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The obtained 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 NOS Calcd: 252.1; Found 252.1.

[0601] Step b: At 0 °C, i-PrMgCl·LiCl (107 mL, 1.3 M, 3.5 equiv) was added dropwise over 30 minutes to a solution of tert-butyl (2-iodophenyl)carbamate (25.4 g, 79.6 mmol, 2 equiv) in THF (200 mL). 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 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 two-phase mixture was extracted with ethyl acetate (2 x 250 mL). The combined organic extracts were washed with brine (2 x 25 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to afford tert-butyl (2-(((tert-butylsulfinyl)amino)(4-isopropylphenyl)methyl)phenyl)carbamate. LC-MS (ESI): m / z: [M+H] + C 25 H 36 Calculated for C24H34N2O3S: 445.2; found 445.4.

[0602] Step c: A mixture of tert-butyl (2-(((tert-butylsulfinyl)amino)(4-isopropylphenyl)methyl)phenyl)carbamate (15 g, 33.7 mmol, 1 equiv) and I2 (6.85 g, 26.9 mmol, 0.8 equiv) in THF (150 mL) and H2O (30 mL) was degassed and purged with N2, then the mixture was warmed to 50 °C and stirred under a N2 atmosphere for 2 h. The reaction mixture was then cooled to 0 °C and quenched by the addition of water (100 mL). The resulting two-phase mixture was extracted with ethyl acetate (2 x 250 mL). The combined organic extracts were washed with brine (2 x 25 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to afford tert-butyl (2-(amino(4-isopropylphenyl)methyl)phenyl)carbamate. LC-MS (ESI): m / z: [M+H] + C 21 H 28 Calculated for C20H26N2O2: 341.2; found 341.4.

[0603] Intermediate A-4: Synthesis of (S)-(3-fluoro-4-isopropylphenyl)(phenyl)methanaminium chloride

[0604]

[0605] Step a: At 25 °C under N2, Pd(dppf)Cl2 (36.0 g, 49.3 mmol, 0.05 eq) and K3PO4 (418 g, 1.97 mol, 2.00 eq) were added to a mixture of 4-bromo-3-fluoro-benzaldehyde (200 g, 985 mmol, 1.00 eq) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (215 g, 1.28 mol, 1.30 eq) in toluene (3.70 L) and H2O (410 mL). The mixture was heated to 90 °C and stirred for 12 h. Then the reaction mixture was 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. This compound was carried on to the next step without further characterization.

[0606] Step b: Under N2, Pd / C (85.0 g, 10 wt%) was added to a solution of 3-fluoro-4-isopropenyl-benzaldehyde (124 g, 755 mmol, 1.00 eq) in EtOAc (1.20 L). The suspension was degassed and purged with H2 several times. The mixture was stirred at 25 °C under H2 (15 psi) for 1 h. Then the reaction mixture was 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. This compound was carried on to the next step without further characterization.

[0607] Step c: At 25 °C, Cs2CO3 (173 g, 530 mmol, 1.10 eq) was added to a mixture of 3-fluoro-4-isopropyl-benzaldehyde (80.0 g, 481 mmol, 1.00 eq) and (R)-2-methylpropane-2-sulfinamide (64.2 g, 523 mmol, 1.10 eq) in DCM (450 mL). The resulting mixture was heated 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 afford (R,E)-N-(3-fluoro-4-isopropylbenzylidene)-2-methylpropane-2-sulfinamide. LC-MS (ESI): m / z: [M+H] + C 14 H 20 Calculated for C13H18FNO2S: 270.1; found 270.0.

[0608] Step d: At -65 °C under N2, 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) was added dropwise with a solution of phenylmagnesium bromide (3 M in Et2O, 55.7 mL, 1.50 equiv) over 30 minutes. The reaction mixture was stirred at -65 °C for 6 hours, then warmed to 25 °C and stirred for an additional 6 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (3 x 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. This compound was carried on to the next step without further characterization.

[0609] Step e: At 25 °C, HCl / EtOAc (4 M, 50.4 mL, 2.00 equiv) was added 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), and the mixture was stirred for 2 hours. 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) and filtered, and the filtrate was concentrated under reduced pressure to give (S)-(3-fluoro-4-isopropylphenyl)(phenyl)methanaminium chloride.

[0610] Intermediate A-5: Synthesis of (S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methanaminium chloride

[0611]

[0612] Step a: In four parallel reactions, 6-fluoropyridin-2-amine (125 g, 1.11 mol, 1 equiv) in MeCN (1.2 L) was treated with NBS (209 g, 1.17 mmol, 1.05 equiv) in MeCN (1.2 L) at 0 °C under N2. The reaction mixture was stirred at 20 °C for 2 hours. 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.

[0613] Step b: Under N2, K3PO4 (666 g, 3.14 mol, 3 equiv), PCy3 (58.6 g, 209 mmol, 0.2 equiv) and Pd(OAc)2 (11.7 g, 52.3 mmol, 0.05 equiv) were added 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 H2O (200 mL). Then the system was degassed and purged with nitrogen three times. The resulting reaction mixture was heated to 100 °C and stirred for 12 h. Then the reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The resulting filtrate was diluted with H2O (2 L) and then extracted with EtOAc (3 × 500 mL). The combined organic extracts were washed with brine (2 x 300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude residue 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.

[0614] Step c: Under N2, isoamyl nitrite (110 g, 946 mmol, 127 mL, 1.2 equiv) was added to a mixture of 5-cyclopropyl-6-fluoropyridin-2-amine (120 g, 788 mmol, 1 equiv) in dibromomethane (564 mL). CuBr2 (211 g, 946 mmol, 44.3 mL, 1.2 equiv) was added to the resulting mixture over 0.5 h. Then the final mixture was degassed and purged with nitrogen three times, and then stirred at 20 °C for 16 h. Then the reaction mixture was filtered, and the filtrate was diluted with H2O (500 mL) and extracted with EtOAc (3 × 300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained 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.

[0615] Step d: At 20 °C under N2, add TEA (126 g, 1.25 mol, 3 equiv) and Pd(dppf)Cl2·DCM (17 g, 20.8 mmol, 0.05 equiv) to a mixture of 6-bromo-3-cyclopropyl-2-fluoropyridine (90 g, 416 mmol, 1 equiv) and potassium trifluoro(vinyl)-λ4-borate (83.7 g, 624 mmol, 1.5 equiv) in i-PrOH (900 mL). Degas the resulting mixture and flush with nitrogen three times. Heat the reaction mixture to 100 °C and stir for 2 h. Then cool the reaction mixture to room temperature and filter. Dilute the filtrate with H2O (500 mL) and extract with EtOAc (3 x 300 mL). Wash the combined organic extracts with brine (300 mL), dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the obtained crude residue by column chromatography to give 3-cyclopropyl-2-fluoro-6-vinylpyridine. LC-MS (ESI): m / z: [M+H] + C 10 H 10 FN Calcd: 164.1; Found 164.1.

[0616] Step e: At 20 °C under N2, add NaIO4 (246 g, 1.15 mol, 4 equiv) and K2OsO4·2H2O (2.12 g, 5.76 mmol, 0.02 equiv) to a mixture of 3-cyclopropyl-2-fluoro-6-vinylpyridine (47 g, 288 mmol, 1 equiv) in THF (800 mL) and H2O (160 mL). Degas the resulting mixture and flush with nitrogen three times, then stir for 2 h. Then filter the reaction mixture, dilute the filtrate with H2O (500 mL), and extract with EtOAc (3 × 300 mL). Wash the combined organic extracts with brine (300 mL), dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the obtained crude residue by column chromatography to give 5-cyclopropyl-6-fluoropicolinaldehyde. LC-MS (ESI): m / z: [M+H] + C9H8FNO Calcd: 166.1; Found 166.2.

[0617] Step f: At 20 °C under N2, Cs2CO3 (82.4 g, 253 mmol, 1.1 eq) was added to a mixture of 5-cyclopropyl-6-fluoropicolinaldehyde (38 g, 230 mmol, 1 eq) and (S)-2-methylpropane-2-sulfinamide (30.6 g, 253 mmol, 1.1 eq) in DCM (200 mL). The system was then degassed and flushed with nitrogen three times. The resulting mixture was then warmed to 40 °C and stirred for 12 h. The reaction solution was diluted with H2O (300 mL) and extracted with DCM (3 x 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 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 C12H15FN2OS: 269.1; Found 269.2.

[0618] Step g: At -70 °C under nitrogen, PhMgBr (3 M in Et2O, 93.6 mL, 281 mmol, 1.3 eq) was added dropwise to a solution of (S,E)-N-((5-cyclopropyl-6-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (58 g, 216 mmol, 1 eq) in anhydrous DCM (600 mL). The resulting reaction mixture was stirred at -70 °C for 1 h. The reaction mixture was then quenched with saturated aqueous NH4Cl solution (500 mL), warmed to room temperature, and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained 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 C18H21FN2OS: 347.2; Found 347.3.

[0619] Step h: At 0 °C under N2, HCl / EtOAc (4 M, 740 mL, 2940 mmol, 13.8 eq) was added to a solution of (S)-N-((S)-(5-cyclopropyl-6-fluoropyridin-2-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (74 g, 213 mmol, 1 eq) in EtOAc (100 mL). 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 obtained 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 FN2 Calcd: 243.1; Found 243.2.

[0620] Intermediate A-6: Synthesis of (R)-(4-isopropylphenyl)(2-(1-methylpiperidine-4-carboxamido)phenyl)methanaminium chloride

[0621]

[0622] Step a: Under N2, K2CO3 (19.5 g, 141 mmol, 3 eq) and Pd(PPh3)2Cl2 (1.65 g, 2.35 mmol, 0.05 eq) were added to a solution of tert-butyl (2-iodophenyl)carbamate (15 g, 47.0 mmol, 1 eq) and (4-isopropylphenyl)boronic acid (9.25 g, 56.4 mmol, 1.2 eq) in toluene (100 mL). The resulting mixture was degassed and purged with CO. The resulting mixture was warmed to 120 °C and stirred under CO (15 psi) for 10 h. The reaction mixture was then cooled to room temperature and poured into ice water (100 mL). The resulting two-phase mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude residue was purified by column chromatography to give tert-butyl (2-(4-isopropylbenzoyl)phenyl)carbamate.

[0623] Step b: HCl / EtOAc (4 M, 100 mL) was added to a solution of tert-butyl (2-(4-isopropylbenzoyl)phenyl)carbamate (10 g, 29.4 mmol, 1 equiv) in EtOAc (20 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 NaHCO3. The resulting two-phase mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, 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 C17H18N2O: 240.1; Found 240.1.

[0624] Step c: (R)-2-methylpropane-2-sulfinamide (4.07 g, 33.5 mmol, 1.1 equiv) and Ti(OEt)4 (13.9 g, 61.0 mmol, 2 equiv) were sequentially added to a solution of (2-aminophenyl)-(4-isopropylphenyl)methanone (7.3 g, 30.5 mmol, 1 equiv) in THF (120 mL). The reaction was heated 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 two-phase mixture was extracted with ethyl acetate (2 x 50 mL), the combined organic extracts were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained 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 C22H28N2OS: 343.2; Found 343.1.

[0625] Step d: At -78 °C, DIBAL-H (20.4 mL, 1 M, 2.8 equiv) was added 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). The resulting mixture was stirred at -78 °C for 2 h. Then the reaction mixture was diluted with brine (50 mL), and the resulting two-phase mixture was extracted with EtOAC (3 × 40 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained 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 C22H31N2OS: 367.2; found 367.1.

[0626] Step e: 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 to a solution of (R)-N-((R)-(2-aminophenyl)(4-isopropylphenyl)methyl)-2-methylpropane-2-sulfinamide (250 mg, 725 μmol, 1 equiv) in CH3CN (2 mL). The resulting mixture was warmed to 0 °C and stirred for 3 h. Then the reaction mixture was diluted with water, extracted with 30 mL (3 × 10 mL) of EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained 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 C28H42N3O2S: 470.3; found 470.3.

[0627] 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 resulting mixture was then warmed to 15 °C and stirred for 1 h. The reaction mixture was then concentrated under reduced pressure. The obtained crude residue was triturated with MTBE at 15 °C for 30 min to afford (R)-(4-isopropylphenyl)(2-(1-methylpiperidine-4-carboxamido)phenyl)methanaminium chloride. LC-MS (ESI): m / z: [M+H] + C 23 H 31 N3 Calcd: 366.3; Found 366.3.

[0628] The following compounds in Table B-1 were synthesized using appropriate starting materials and reagents using procedures similar to those for Intermediates A-1 to A-6.

[0629] Table B-1

[0630]

[0631]

[0632]

[0633]

[0634]

[0635] 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)

[0636]

[0637] Step a: At 0 °C, (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) were added 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). The resulting mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was then diluted with water, and the resulting two-phase mixture was extracted with ethyl acetate (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained 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.

[0638] 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)

[0639]

[0640] Step a: 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 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). The resulting mixture was stirred at 15 °C for 1 h. Then the reaction mixture was poured into ice water (50 mL) and stirred for 3 min. Then the resulting two-phase mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue obtained 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 C22H28N2O3: 409.2; found 409.3.

[0641] Step b: At 15 °C, HCl / EtOAc (35 mL) was added to a solution of tert-butyl (2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)carbamate (3.5 g, 8.57 mmol, 1 equiv) in EtOAc (30 mL). The resulting mixture was stirred at 15 °C for 16 h. Then the reaction mixture was concentrated under reduced pressure to give N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide. This enantiomeric mixture 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 C19H23N2O: 309.2; found 309.4.

[0642] 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. Then the reaction mixture was quenched by adding ice water (10 mL), and the resulting two-phase mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained 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 C22H30N3O2: 406.2; found 406.2.

[0643] 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)

[0644]

[0645] Step a: At 20 °C under N2, add TCFH (136 mg, 486 μmol, 1 equiv) 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). Then stir the resulting mixture at 20 °C for 1 h. Then pour the reaction mixture into ice water (10 mL), and extract the resulting two-phase mixture with EtOAc (2 x 20 mL). Wash the combined organic extracts with brine (100 mL), dry over anhydrous Na2SO4, filter and concentrate under reduced pressure. Purify the obtained crude residue 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 C25H32N3O4: 492.3; found 492.3.

[0646] Step b: At 25 °C, add TFA (1.54 g, 13.5 mmol, 1.00 mL, 41.5 equiv) 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), and stir the resulting mixture at 25 °C for 30 min. Then dilute the reaction mixture with H2O (10 mL), and extract the resulting two-phase mixture with EtOAc (2 x 20 mL). Wash the combined organic extracts with brine (10 mL), dry over anhydrous Na2SO4, filter and concentrate under reduced pressure. Purify the obtained crude residue by preparative HPLC to give (R)-N-(2-(cyclopropanecarboxamido(4-isopropylphenyl)methyl)phenyl)azetidine-3-carboxamide. LC-MS (ESI): m / z: [M+H] + C 24 H 29 Calculated for C20H25N3O2: 392.2; found 392.4.

[0647] Step c: At -20 °C under N2, acetyl chloride (2.01 mg, 25.5 μmol, 1 equiv) was added dropwise 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). The resulting mixture was warmed to 15 °C and stirred for 1 h. Then the reaction mixture was cooled to 0 °C and quenched by the addition of H2O (5 mL). The resulting two-phase mixture was stirred for 5 min and then extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, 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 C24H29N3O3: 434.2; found 434.2.

[0648] Example S-4: Synthesis of (R or S)-N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide (Compound 31)

[0649]

[0650] Step a: At 0 °C, phenyl chloroformate (305 mg, 1.95 mmol, 1.20 equiv) and triethylamine (820 mg, 8.11 mmol, 5.00 equiv) were added to a solution of N-((2-aminophenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide (500 mg, 1.62 mmol, 1.00 equiv) in DCM (30.0 mL). The resulting mixture was warmed to 25 °C and stirred for 1 h. Then 2,2-dimethoxyethan-1-amine (341 mg, 3.24 mmol, 2.00 equiv) was added to the reaction mixture, and the resulting mixture was stirred at 25 °C for 11 h. Then the reaction mixture was diluted with H2O (30 mL), and the resulting two-phase mixture was extracted with DCM (20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained 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 33Calculated value of N3O4: 440.2; measured value 440.3.

[0651] Step b: At 0 °C, HCl / MeOH (0.5 mL) was added 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). 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 NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL). The washed organic layer was then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude residue was purified by preparative HPLC to give N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide. This enantiomeric mixture was then separated by chiral SFC (column: DAICEL CHIRALPAK AD) to give (R or S)-N-((4-isopropylphenyl)(2-(oxazol-2-ylamino)phenyl)methyl)cyclopropanecarboxamide as the first eluted isomer. LC-MS (ESI): m / z: [M+H] + C 23 H 25 Calculated value of N3O2: 376.2; measured value 376.2.

[0652] Example S-5: (R)-N-((3-hydroxyphenyl)(4-isopropylphenyl)methyl)cyclopropanecarboxamide

[0653] Synthesis of (Compound 62)

[0654]

[0655] Step a: At -78 °C, BBr3 (1.36 g, 5.41 mmol, 521 μL, 5 eq) was added to a solution of (R)-N-((4-isopropylphenyl)(3-methoxyphenyl)methyl)cyclopropanecarboxamide (0.35 g, 1.08 mmol, 1 eq) in DCM (2 mL). The resulting mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was then diluted with saturated aqueous NaHCO3 to adjust the solution pH to 7. The resulting two-phase mixture was then extracted with dichloromethane (2 × 50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained 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: 310.2; found 310.1.

[0656] Example S-6: Synthesis of (1R,2S)-2-(2-acetamidoacetamido)-N-((S)-(4-isopropylphenyl)(phenyl)methyl)cyclopentane-1-carboxamide (Compound 21)

[0657]

[0658] Step a: To a solution of (S)-(4-isopropylphenyl)(phenyl)methanaminium chloride (0.25 g, 0.95 mmol, 1 eq) and (1R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (0.44 g, 1.91 mmol, 1 eq) in DMF (4.8 mL) was added EDCI·HCl (0.28 g, 1.4 mmol, 1.5 eq), 1-hydroxybenzotriazole hydrate (0.22 g, 1.43 mmol, 1.5 eq), and N,N-diisopropylethylamine (0.5 mL, 2.86 mmol, 3 eq). 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 x 150 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl ((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)carbamate.

[0659] Step b: Hydrochloric acid (1.14 mL, 4 M in dioxane, 4.6 mmol) was added 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). The resulting reaction mixture was stirred at 25 °C for 2 h, 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.

[0660] Step c: 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 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). The resulting mixture was stirred at 25 °C for 16 h, and then the reaction mixture was diluted with EtOAc (15 mL) and H2O (15 mL). The organic layer was collected and washed successively with H2O (15 mL) and brine (15 mL). The washed organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained 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.

[0661] Step d: Hydrochloric acid (0.5 mL, 4 M in dioxane, 2 mmol, 18 equiv) was added 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). The resulting mixture was stirred at 25 °C for 4 h, 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-oxoethane-1-ammonium chloride.

[0662] Step e: To a solution of 2-(((1S,2R)-2-(((S)-(4-isopropylphenyl)(phenyl)methyl)carbamoyl)cyclopentyl)amino)-2-oxoethan-1-ammonium chloride (0.008 g, 0.019 mmol, 1 equiv) in DCM (0.5 mL) was added successively N,N-diisopropylethylamine (0.007 mL, 0.038 mmol, 2 equiv) and acetic anhydride (0.004 mL, 0.038 mmol, 2 equiv). The resulting mixture was stirred at 25 °C for 30 minutes. Then the reaction mixture was concentrated under reduced pressure and the crude residue obtained 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 C24H33N3O3: 436.3; Found 436.3.

[0663] Example S-7: Synthesis of (1R,2S)-N 1 -((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)

[0664]

[0665] Step a: In two parallel reactions, (R)-(4-isopropylphenyl)(o-tolyl)methanaminium chloride (100 mg, 362 μmol, 1 equiv) was dissolved in anhydrous 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 min, 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 h. Then the two reactions were combined for workup. The combined reaction was cooled to 0 °C and quenched by the addition of H2O (10 mL). The pH of the resulting two-phase mixture was adjusted to pH = 5 using 2N aqueous HCl, and then the resulting two-phase mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained 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 C23H28NO3: 380.2; found 380.3.

[0666] 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) was added N,N-diisopropylethylamine (113 μL, 0.644 mmol, 3 equiv), HOBt-NH3 (390 mg, 0.26 mmol, 1.2 equiv), and TBTU (70 mg, 0.21 mmol, 1 equiv), and the resulting reaction mixture was stirred at 25 °C for 16 h. Then the reaction mixture was diluted with EtOAc (30 mL) and H2O (30 mL). The organic layer was collected and then washed successively with H2O (30 mL) and brine (30 mL). The resulting organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by preparative HPLC to give (1R,2S)-N 1 -((R)-(4-isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide. LC-MS (ESI): m / z: [M+H] + C 24 H30 Calculated value of N2O2: 379.2; measured value 379.2.

[0667] Step c: To (1R,2S)-N 1 -((R)-(4-Isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide (48 mg, 0.127 mmol, 1 equiv) in dichloromethane (1 mL) 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 h, 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 value of N2O: 361.2; measured value 361.3.

[0668] Example S-8: Synthesis of (1S,2R)-N 1 -cyano-N 2 -((R)-(4-Isopropylphenyl)(o-tolyl)methyl)cyclopentane-1,2-dicarboxamide (Compound 22)

[0669]

[0670] 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 a drop of DMF. The resulting mixture was stirred at 25 °C for 16 h, 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.

[0671] Step b: 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) was added dropwise 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) at 25 °C under N2. The resulting mixture was stirred at 25 °C under a N2 atmosphere for 16 h. 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. LC-MS (ESI): m / z: [M+H] + C 25 H 29 N3O2 Calcd: 404.2; Found 404.3.

[0672] Example S-9: Synthesis of (1R,2S)-N 1 -((R)-(4-isopropylphenyl)(o-tolyl)methyl)-N 2 -methylcyclopentane-1,2-dicarboxamide (Compound 16)

[0673]

[0674] 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, then the reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was collected and then washed successively 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 crude residue was purified by preparative HPLC to give (1R,2S)-N 1 -((R)-(4-isopropylphenyl)(o-tolyl)methyl)-N 2 -methylcyclopentane-1,2-dicarboxamide. LC-MS (ESI): m / z: [M+H] + C 25 H32 Calculated value of N2O2: 393.2; measured value 393.2.

[0675] The following compounds in Table T-1 were synthesized using appropriate starting materials and reagents with procedures similar to those of Examples S-1 to S-9.

[0676] Table T-1

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689] Biological Example

[0690] Example B-1

[0691] The GYS1-coupled 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 a downstream enzymatic reaction. When glucose monomers are linked by GYS1 into a growing glycogen chain, UDP is released from UDP-glucose. Then, the coupled assay continues as pyruvate kinase uses UDP and phosphoenolpyruvate (PEP) to form pyruvate. Then, lactate dehydrogenase converts pyruvate and NADH to lactate and NAD+. By quantifying the decrease in NADH absorbance at 340 nm over time, the oxidation of NADH to NAD+ can be continuously measured with a plate reader.

[0692] Compounds that inhibit the hGYS1 enzyme and the subsequent downstream conversion of NADH to NAD+ were tested using an assay preparation plate (a 384-well plate that is black with a transparent bottom) 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 stock solutions of BSA at a final concentration of 0.02% and TCEP at 1 mM were added before dividing the buffer into hGYS1 buffer and substrate buffer. Rabbit liver glycogen at a final concentration of 0.2% was added to the hGYS1 buffer. 1 mM glucose-6-phosphate was added to the substrate buffer, 50 nM recombinant hGYS1 / GN1 protein was added, 2 mM phosphoenolpyruvate (PEP) was added, 0.8 mM UDP-glucose was added, 0.6 mM NADH was added, and 20 units / mL pyruvate kinase / lactate dehydrogenase was added. The reaction was initiated by mixing the hGYS1 buffer and the substrate buffer in a 1:1 ratio. Both buffers were plated using a liquid dispensing device, with the hGYS1 buffer plated first and then the substrate buffer. The plate was briefly rotated to remove air bubbles and immediately read the absorbance at 340 nm in continuous mode, reading 10 time points at one-minute intervals for a total of 10 minutes. The slopes of these 10 time points were normalized to the positive and negative control wells. Then the repeated % inhibition values were averaged according to the Levenberg-Marquardt algorithm and fit to the Hill equation for the dose response, where the maximum value of the Hill equation was set to 100 and the minimum value was set to 0.

[0693] The results are shown in Table 3 below, where the IC 50 of each compound is reported. Unless otherwise stated, the IC 50 values are reported as the geometric mean of at least 2 assays performed on different dates. Each run represents the mean of technical replicates, where each compound was assayed twice in the same plate. As shown in the table below, the compounds of the present invention are potent inhibitors of human GYS1.

[0694] It should be noted that in Table 3, the compounds are referred to by their corresponding compound numbers in Table 1, and the same compound numbers are also used in the synthetic examples.

[0695] Table 3

[0696]

[0697]

[0698] Example B-2

[0699] The GYS1 cell-based assay is a bioluminescence assay that quantifies glucose produced from glycogen digestion; the quantified glucose is an indirect measure of GYS1 glycogen synthesis. Newly synthesized glycogen is digested using glucoamylase; the glucose produced is quantified using Promega's Glucose-glo assay kit. Glucose-glo functions by coupling glucose oxidation and NADH generation to a bioluminescence system activated by NADH. Glucose is oxidized by glucose dehydrogenase, a reaction that reduces NAD+ to NADH; NADH activates reductase, which reduces the luciferin reductase substrate to luciferin. A luciferase reaction using Ultra-Glo rLuciferase and ATP is used to detect luciferin, and the resulting luminescence is proportional to the glucose in the sample. Luminescence is measured by reading a single point in a plate reader.

[0700] Compounds that inhibit the hGYS1 enzyme and subsequently glycogen synthesis in cells are tested using an assay preparation plate (white, clear-bottom 384-well plate) with a final DMSO reaction volume of 1% DMSO. Prior to cell addition, the compounds in the assay preparation plate are mixed with media without any additives (except 20 mM glucose). HeLa cells are starved for 24 hours in media without any additives (except 1X Glutamax). The starved HeLa cells are plated at a 1:1 ratio into the media in the assay preparation plate and incubated at 37 °C and 5% CO2 for 24 hours. The cells are washed in 1X PBS buffer and then lysed in a lysis buffer containing 50% 1X PBS and 25% 0.3 N HCl, which makes up the final volume in the well or reaction volume; the cells are incubated with the lysis buffer for 10 minutes and then quenched with the remaining 25% reaction volume (consisting of 450 mM Tris pH 8.0). The lysate is mixed at a 1:1 ratio with glucoamylase in 100 mM sodium acetate buffer (pH 5.3); the mixture is incubated at 37 °C for 1 hour. The digested lysate is mixed at a 1:1 ratio with the Glucose-glo detection mixture (luciferase detection buffer, reductase, reductase substrate, glucose dehydrogenase, and NAD) in a read plate (solid white 384-well plate) according to the supplier's recommendations and incubated at room temperature for 1 hour. The plate is read using a plate reader with luminescence capabilities. The relative luminescence units (RLU) for each compound concentration are averaged and normalized to the average RLU of the positive and negative controls to obtain the percentage of inhibition. A graph of the normalized data versus concentration is plotted; to determine the half-maximal concentration (IC 50 50), the Hill equation is fit to the dose-response data using the Levenberg-Marquardt algorithm.

[0701] The results are shown in Table 4 below, in which the IC of each compound is reported 50 . Unless otherwise stated, the IC 50 values are reported as the geometric mean of at least 2 determinations performed on different dates. As shown in the table below, the compounds of the present invention are potent inhibitors of human GYS1. Unless otherwise stated, the IC 50 values are reported as the geometric mean of at least two determinations performed on different dates. Each run represents the mean of technical replicates, where each compound is assayed twice in the same plate.

[0702] Table 4

[0703]

[0704] Example B-3

[0705] The GYS2 coupled 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 a downstream enzymatic reaction. When glucose monomers are linked to the growing glycogen chain by GYS2, UDP is released from UDP-glucose. The coupled assay then proceeds with pyruvate kinase using UDP and phosphoenolpyruvate (PEP) to form pyruvate. Lactate dehydrogenase then converts pyruvate and NADH to lactate and NAD+. By quantifying the decrease in NADH absorbance at 340 nm over time, the oxidation of NADH to NAD+ can be continuously measured with a plate reader.

[0706] The inhibition of the hGYS2 enzyme and subsequent downstream conversion of NADH to NAD+ by compounds was tested using a assay preparation plate (a 384-well plate that is black and transparent at the bottom) 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 stock solutions of BSA at a final concentration of 0.02% and TCEP at 1 mM were added before dividing the buffer into hGYS2 buffer and substrate buffer. Rabbit liver glycogen at a final concentration of 0.2% was added to the hGYS2 buffer. 2 mM glucose-6-phosphate was added to the substrate buffer, 200 nM recombinant hGYS2 / GN1 protein was added, 2 mM phosphoenolpyruvate (PEP) was added, 2 mM UDP-glucose was added, 0.6 mM NADH was added, and 20 units / mL pyruvate kinase / lactate dehydrogenase was added. 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 and then the substrate buffer. The plate was briefly rotated to remove air bubbles and immediately read the absorbance at 340 nm in continuous mode, reading 10 time points at one-minute intervals for a total of 10 minutes. The slopes of these 10 time points were normalized to positive and negative control wells. Then the average of the repeated % inhibition values was calculated according to the Levenberg-Marquardt algorithm and fit to the Hill equation for the dose response, where the maximum value of the Hill equation was set to 100 and the minimum value was set to 0.

[0707] The results are shown in Table 5 below, where the IC 50 of each compound is reported. Unless otherwise stated, the IC 50 values are reported as the geometric mean of at least 2 assays performed on different dates. As shown in the table below, the compounds of the present invention are not potent inhibitors of human GYS2. Unless otherwise stated, the IC 50 values are reported as the geometric mean of at least two assays performed on different dates. Each run represents the average of technical replicates, where each compound was assayed twice in the same plate.

[0708] Table 5

[0709]

[0710]

[0711] Example B-4

[0712] Pompe disease is a glycogen storage disease in which pathological accumulation of glycogen results from mutations in acid alpha-glucosidase. Glycogen can accumulate in almost all tissues, but the main pathological effects are on skeletal and cardiac muscle. Inhibiting the synthesis of muscle glycogen can reduce the pathological accumulation of glycogen by substrate reduction therapy. Savage et al. identified a predicted protein truncating variant (PTV) in the PPP1R3A gene (a glycogen metabolism regulator) in approximately 0.5% of Europeans, which results in a reduction of muscle glycogen by approximately 65% (Savage et al., A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice. PLoS Medicine. 2008; which is incorporated herein by reference in its entirety). PPP1R3A acts as a key activator of glycogen synthase 1 (GYS1), functioning by dephosphorylating the enzyme and maximizing its activity. Figure 1 Shows the pathway by which loss of function (LoF) of PPP1R3A results in reduced muscle glycogen.

[0713] Large biobanks enable the study of the effects of genetic variants on many health-related phenotypes. To assess the consequences of the predicted 65% muscle glycogen loss, the UK Biobank conducted an association study comparing phenotypes between PPP1R3A PTV carriers and non-carriers. The genetic association study was 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 the top 10 principal components of age, sex, and ancestry. Inverse rank normal transformation was used to standardize quantitative traits.

[0714] For Figures 2A - 2H , depicts the PPP1R3A PTV versus left ventricular ejection (LVEF) (%) ( Figure 2A ), left ventricular wall thickness (mm) ( Figure 2B ), exercise output (watts) ( Figure 2C ), maximum heart rate (HR) exercise (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 ) between the quantitative phenotypes. The phenotypic values were plotted according to the PPP1R3A dosage of UK Biobank participants. No association was identified between PPP1R3A PTV and the quantitative phenotypes in the UK Biobank.

[0715] Table 6 below lists Figure 2A the P-values and the number of participants (N) for the results shown in -H. No association was 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 EKG cardiac conduction intervals or any muscle performance measurements (n = 49,616), including maximum heart rate (p = 0.444) and maximum workload during exercise testing (p = 0.100). Additionally, no changes were observed in serum glucose (p = 0.71) or any other members of the group of approximately 170 serum metabolites.

[0716] Table 6

[0717] Phenotype P value N LVEF 0.871 27,716 LV wall thickness 0.168 27,579 Motor output 0.100 49,616 Maximum HR during exercise 0.444 49,603 QRS duration 0.527 29,507 PQ interval 0.366 16,694 QT interval 0.222 17,574 Serum glucose 0.477 294,042

[0718] As shown in Table 7 below, no association was also observed between PPP1R3A PTV and key health outcomes. Except for the phenotypes in Table 7, no significant association was observed between PPP1R3A PTV and the phenotypic range of the incidence of any ICD10 code that occurred more than 100 times in the UK Biobank.

[0719] Table 7

[0720] Disease Effect (SE) P value Number of cases Type 2 diabetes -0.094(0.073) 0.200 18,868 Liver cirrhosis -0.041(0.273) 0.880 1,325 Heart failure -0.061(0.127) 0.630 6,117

[0721] After conducting an extensive phenome-wide association study in the UK Biobank, no significant association was found between any key outcomes or phenotypes and loss of PPP1R3A function. The results provided herein indicate that loss-of-function variants of the PPP1R3A gene are not associated with adverse health outcomes in a large biobank population. This suggests that a partial reduction in muscle glycogen (∼65%) from birth is well tolerated and supports the potential safety of drugs that reduce muscle glycogen.

[0722] All publications, patent applications, patents, and other references mentioned herein are hereby expressly incorporated by reference in their entirety to the same extent as if each were individually incorporated by reference.

[0723] It should be understood that although the present disclosure has been described in connection with the above embodiments, the foregoing description and examples are intended to illustrate and 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 the present disclosure pertains.

Claims

1. A compound of formula (I): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y 1 and Y 2 each is CH, or Y 1 and Y 2 one of them is N, and Y 1 and Y 2 the other one is CH; X 1 and X 2 each independently is H or a halogen group; 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; or (1) L does not exist; and Q 1 is: (i) C 6-20 aryl, wherein Q 1 of C 6-20 aryl is optionally substituted by one or more -OH, -NH2, halogen, 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)-(3-15 membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3-15 membered heterocyclic group) or -NH-(5-20 membered heteroaryl), wherein -NH-C(O)-(3- to 15-membered heterocyclic group), wherein the 3- to 15-membered heterocyclic group is optionally substituted with one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo groups, C 1-6 alkoxy groups or C 3-10 cycloalkyl, and -NH-(heterocyclic group having 3 to 15 ring members) of the heterocyclic group having 3 to 15 ring members is optionally substituted with one or more oxo groups or C 1-6 alkyl groups, or (ii) 3- to 15-membered heterocyclic group, wherein Q 1 the 3- to 15-membered heterocyclic group is optionally substituted with one or more oxo groups, or (iii) 5- to 20-membered heteroaryl, wherein Q 1 the 5- to 20-membered heteroaryl contains at least one ring N atom and is optionally substituted by one or more -NH2, halogen, C 1-6 alkyl or C 3-10 cycloalkyl; or (2) L is -CH2-; and Q 1 is C 3-10 cycloalkyl; m is 0 or 1; n is 0 or 1; R 1 is H, a halogen group, -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, wherein R 1 -C(O)-NH(C 1-6 alkyl) of C 1-6 alkyl is optionally substituted with one or more -C(O)-C 1-6 alkoxy, and R 1 -NH-C(O)-C 1-6 of C of alkyl 1-6 The alkyl is optionally substituted by one or more -NH-C(O)-C 1-6 alkyl or -C(O)-NH2; and R 2 is H, a halogen group or -OH.

2. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound of formula (I) has the stereochemical configuration of 3. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is H.

4. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 1 is a halogen group.

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

6. The compound according to any one of claims 1-5, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2 is H.

7. The compound according to any one of claims 1-5, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2 is a halogen group.

8. The compound according to any one of claims 1-5 and 7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 2 is fluorine.

9. The compound according to any one of claims 1-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 are each independently -CH3.

10. The compound according to any one of claims 1-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 together with the atom to which they are attached form cyclopropyl or cyclobutyl.

11. The compound according to any one of claims 1-8 and 10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 together with the atom to which they are attached form cyclopropyl.

12. The compound according to any one of claims 1-8 and 10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 and R 4 together with the atom to which they are attached form cyclobutyl.

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

14. The compound according to any one of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is C 6-20 aryl, wherein the C 1 aryl of Q 6-20 is optionally substituted with one or more NH2, halogen groups, C 1-6 alkyl, C 1-6 alkoxy, C 3-10Cycloalkyl, 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)-(3-15 membered heterocyclic group) or -NH-C(=N-CN)-NH2, -NH(C 1-6 alkyl) substituted, wherein the 3-15 membered heterocyclic group of -NH-C(O)-(3-15 membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen groups, C 1-6 alkoxy or C 3-10 cycloalkyl, and the 3-15 membered heterocyclic group of -NH-(3-15 membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 alkyl.

15. The compound according to any one of claims 1-14, or its stereoisomer or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is phenyl, wherein the phenyl of Q 1 is optionally substituted by one or more NH2, halogen groups, 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)-(3-15 membered heterocyclic group) or -NH-C(=N-CN)-NH2, -NH(C 1-6 alkyl) substituted, wherein the 3-15 membered heterocyclic group of -NH-C(O)-(3-15 membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen groups, C 1-6 alkoxy or C 3-10 cycloalkyl, and the 3-15 membered heterocyclic group of -NH-(3-15 membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 alkyl.

16. The compound according to any one of claims 1-15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is selected from the group consisting of:

17. The compound according to any one of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is a 3- to 15-membered heterocyclic group, wherein Q 1 the 3- to 15-membered heterocyclic group is optionally substituted with one or more oxo groups.

18. The compound according to any one of claims 1-13 and 17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is a 9- to 10-membered heterocyclic group, wherein Q 1 the 9- to 10-membered heterocyclic group is optionally substituted with one or more oxo groups.

19. The compound according to any one of claims 1-13, 17 and 18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is selected from the group consisting of:

20. The compound according to any one of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is a 5- to 20-membered heteroaryl group, wherein Q 1 the 5- to 20-membered heteroaryl group contains at least one ring N atom and is optionally substituted with one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl.

21. The compound according to any one of claims 1-13 and 20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is a 6- to 10-membered heteroaryl group, wherein Q 1 the 6- to 10-membered heteroaryl group contains at least one ring N atom and is optionally substituted with one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl.

22. The compound according to any one of claims 1-13, 20 and 21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Q 1 is selected from the group consisting of:

23. The compound according to any one of claims 1-12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -CH2- and Q 1 is C 3-10 cycloalkyl.

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

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

26. The compound according to any one of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is selected from the group consisting of: 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 alkyl, wherein -C(O)-NH(C 1-6 alkyl)'s C 1-6 alkyl is optionally substituted with one or more -C(O)-C 1-6 alkoxy, and -NH-C(O)-C 1-6 alkyl)'s C 1-6 alkyl is optionally substituted with one or more -NH-C(O)-C 1-6 alkyl or -C(O)-NH2.

27. The compound according to any one of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is H.

28. The compound according to any one of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is selected from the group consisting of: -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 alkyl, wherein -C(O)-NH(C 1-6 alkyl)'s C 1-6 alkyl is optionally substituted with one or more -C(O)-C1-6 alkoxy-substituted, and -NH-C(O)-C 1-6 C of the alkyl 1-6 the alkyl is optionally substituted with one or more -NH-C(O)-C 1-6 alkyl or -C(O)-NH2.

29. The compound according to any one of claims 1-26 and 28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is selected from the group consisting of: -CN, 30. The compound according to any one of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is H or a halogen group.

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

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

33. The compound according to any one of claims 1-32, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is H.

34. The compound according to any one of claims 1-32, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a halogen group.

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

36. The compound according to any one of claims 1-32, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is -OH.

37. The compound according to any one of claims 1-21 and 24-36, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound has the formula (I-A): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Or: i. X 4-8 Each independently is H, -OH, -NH2, a halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, a 5- to 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)-(a 3- to 15-membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(a 3- to 15-membered heterocyclic group) or -NH-(a 5- to 20-membered heteroaryl), wherein the 3- to 9-membered heterocyclic group of -NH-C(O)-(a 3- to 15-membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogens, C 1-6 alkoxy or C 3-10 cycloalkyl, and the 3- to 9-membered heterocyclic group of -NH-(a 3- to 15-membered heterocyclic group) is optionally substituted by one or more oxo groups or C 1-6 alkyl, or ii. X 6 together with X 4 or X 8 and the atoms to which they are attached forms ring A, wherein ring A is a 3- to 9-membered heterocyclic group, wherein the 3- to 9-membered heterocyclic group of ring A is optionally substituted by one or more oxo groups, wherein X 5 , X 7 and X 4 or X 8 in the other of which are each independently H or an oxo group, or a 5- to 14-membered heteroaryl, wherein the 5- to 14-membered heteroaryl of ring A contains at least one ring N atom and is optionally substituted by one or more -NH2, halogens, C 1-6 alkyl or C 3-10 cycloalkyl, wherein X 5 , X 7 and X 4 or X 8 in the other of which are each independently H, -NH2, a halogen, C1-6 alkyl or C 3-10 cycloalkyl; or iii. X 7 together with X 5 or X 8 and the atoms to which they are attached form ring A, wherein ring A is a 3- to 9-membered heterocyclic group, wherein the 3- to 9-membered heterocyclic group of ring A is optionally substituted by one or more oxo groups, and wherein X 4 , X 6 and X 5 or X 8 each independently of the other is H or an oxo group, or a 5- to 14-membered heteroaryl group, wherein the 5- to 14-membered heteroaryl group of ring A contains at least one ring N atom and is optionally substituted by one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl, and wherein X 4 , X 6 and X 5 or X 8 each independently of the other is H, -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl.

38. A compound according to any one of claims 1-10, 13, 15 or 20-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound has formula (I-C): 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 heterocyclic group, wherein the 3- to 9-membered heterocyclic group of ring A is optionally substituted by one or more oxo groups, a 5- to 14-membered heteroaryl group, wherein the 5- to 14-membered heteroaryl group of ring A contains at least one ring N atom, and is optionally substituted by one or more -NH2, halo, C 1-6 alkyl or C 3-10 cycloalkyl.

39. A compound according to 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. A method for preparing a compound according to any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the method comprises: in the presence of a coupling reagent (a) reacting a compound of formula (I-1): or a salt thereof, wherein: Y 1 and Y 2 each is CH, or Y 1 and Y 2 one of them is N, and Y 1 and Y 2 the other one is CH; X 1 and X 2 each independently is H or a halogen group; 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; or (1) L does not exist; and Q 1 is: (i) C 6-20 aryl, wherein Q 1 of C 6-20 the aryl is optionally substituted by one or more -OH, -NH2, halogen, 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)-(3-15 membered heterocyclic group), -NH-C(=N-CN)-NH2, -NH-S(O)2-C 1-6 alkyl, -NH(C 1-6 alkyl), -NH-(3-15 membered heterocyclic group) or -NH-(5-20 membered heteroaryl), wherein The 3- to 15-membered heterocyclic group of -NH-C(O)-(3- to 15-membered heterocyclic group) is optionally substituted by one or more -C(O)-C 1-6 alkyl or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halo groups, C 1-6 alkoxy or C 3-10 cycloalkyl, and -NH-(3- to 15-membered heterocyclic group), the 3- to 15-membered heterocyclic group of which is optionally substituted by one or more oxo groups or C 1-6 alkyl groups, or (ii) 3- to 15-membered heterocyclic group, wherein Q 1 The 3- to 15-membered heterocyclic group is optionally substituted with one or more oxo groups, or (iii) 5- to 20-membered heteroaryl, wherein Q 1 the 5- to 20-membered heteroaryl contains at least one ring N atom and is optionally substituted by one or more -NH2, halogen, C 1-6 alkyl or C 3-10 cycloalkyl; or (2) L is -CH2-; and Q 1 is C 3-10 cycloalkyl with a compound of formula (I-2): wherein, m is 0 or 1; n is 0 or 1; R 1 is H, a halogen group, -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, wherein R 1 -C(O)-NH(C 1-6 alkyl) of C 1-6 alkyl is optionally substituted with one or more -C(O)-C 1-6 alkoxy groups, and R 1 -NH-C(O)-C 1-6 of the C of the alkyl 1-6 The alkyl is optionally substituted with one or more -NH-C(O)-C 1-6 alkyl or -C(O)-NH2; and R 2 is H, a halogen group or -OH to obtain a compound of formula (I).

41. A pharmaceutical composition comprising (i) a compound of any one of claims 1-39, 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. 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 a compound of any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 41.

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

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

46. The method according to claim 42, wherein the disease, disorder or condition is cancer.

47. The method according to claim 42 or claim 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. The method according to claim 42, wherein the individual has a GAA mutation.

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

50. A kit comprising (i) a compound according to any one of claims 1-39, 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 treating a GYS1-mediated disease, disorder or condition in an individual in need thereof.

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

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

54. The kit according to claim 50, wherein the disease, disorder or condition is cancer.

55. The kit according to claim 50 or claim 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. The kit according to claim 52, wherein the individual has a GAA mutation.

57. The medicine box according to claim 56, wherein the GAA mutation is a loss-of-function mutation.

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

60. A method for reducing tissue glycogen storage in an individual in need thereof, which comprises administering to the individual an effective amount of a compound according to any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 41.

61. A method for treating a GYS1-mediated disease, disorder or affliction in an individual in need thereof, which comprises subjecting the individual to glycogen substrate reduction therapy, wherein the glycogen substrate reduction therapy comprises administering to the individual an effective amount of a compound according to any one of claims 1-39, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 39.

62. The method according to claim 61, which comprises subjecting the individual to a combination of glycogen substrate reduction therapy and enzyme replacement therapy.

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

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

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

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

67. The method according to any one of claims 61-63, wherein the disease, disorder or affliction is cancer.

68. The method according to 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. The method according to any one of claims 61 - 63, wherein the individual has a GAA mutation.

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

71. The method according to any one of claims 58 - 60, wherein the compound is more selective for GYS1 than for GYS2.

72. The method according to claim 71, wherein the compound is 500 or 1,000 or 1,500 or 1,700 times more selective for GYS1 than for GYS2.

73. The method according to any one of claims 42 - 49 or 58 - 72, which comprises reducing the glycogen level in skeletal muscle.

74. A compound according to any one of claims 1 - 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. A compound according to any one of claims 1 - 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. A compound according to any one of claims 1 - 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. A compound according to any one of claims 1 - 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 storage in an individual in need thereof.

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

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

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

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

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

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