Inhibitors of solute carrier family 6a member 19 (SLC6a19) 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, R1, R2, R3, R5, R6, R7, R8, R9, and R10 are as defined elsewhere herein. Also provided herein are methods of preparing compounds of formula (I). Also provided herein are methods of inhibiting SLC6A19 and methods of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

Description

INHIBITORS OF SOLUTE CARRIER FAMILY 6A MEMBER 19 (SLC6A19) AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 535,282 filed on August 29, 2023, and U.S. Provisional Application No. 63 / 572,752 filed on April 1, 2024, each of which is hereby incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION

[0002] Solute carrier family 6A member 19 (SLC6A19), also known as B0AT1, is a sodium- dependent neutral amino acid (NAA) transporter that is predominantly expressed on the apical membranes of renal and intestinal epithelial cells (Fairweather et al. J. Biol. Chem (2015) 290, 24308-24325). In the intestines, surface expression of SLC6A19 is dependent on the chaperone protein ACE2, for amino acid uptake (Singer et al Am. J. Physiol. Gastrointest. Liver Physiol (2012) 303, G686-G695). In the kidneys, SLC6A19 requires TMEM27 for surface expression to reabsorb amino acids (Verrey et al. Arch. Eur. J. Physiol. (2009) 458, 53-60).

[0003] Phenylketonuria (PKU) is caused by mutations in the enzyme phenylalanine hydroxylase (PAH), the key enzyme in the metabolism of phenylalanine (Phe) to tyrosine (Tyr), both of which are NAA. PKU patients have toxic buildup of Phe in the blood and other tissues, leading to neurologic alterations (Scriver C.R Hum. Mutat. (2007) 28, 831-843). Treatment options for PKU include severely limiting protein intake, which has poor compliance, and the 2 FDA-approved drugs, Palynziq and Kuvan, both of which are limited to a subset of patients; significant unmet medical need still remain (Strisciuglio et. al. Metabolites (2014) 4, 1007-1017; Gentile et. al. Mol. Genet. and Metab. (2010) 99, S64- S67). Because the symptoms of PKU are a result of systemic buildup of Phe, inhibition of SLC6A19 to limit the intestinal absorption of Phe and its reuptake in the kidneys can be a viable approach to treating PKU. Indeed, loss of SLC6A19 in a mouse model of PKU significantly increased the excretion of Phe in urine and dramatically reduced plasma Phe and normalized neurotransmitter levels (Belanger et al. JCI Insight (2018) 3, e121762).

[0004] The prevalence of chronic kidney disease (CKD) is rapidly increasing and an estimated 15% of the US adult population have CKD (CDC 2021). An association of loss-of- function splice (c.1173+2T>G) (Sveinbjornsson G. et al. Hum. Mol. Genet. (2014) 23, 6935- 6943) and missense (D173N) variants in SLC6A19 with protection from CKD has been reported (Sinnott-Amstrong N. et al. Nat. Genet. (2021) 53, 185-194).

[0005] Metabolic syndrome, and related diseases such as diabetes, is a global epidemic with an estimated one third of US adults having metabolic syndrome (Saklayen M. Curr Hypertens Rep (2018) 20, 12). Mice with deletion of SLC6A19 have a number of improved metabolic outcomes, including resistance to weight gain on a high-fat diet, improved glucose tolerance and insulin sensitivity, and increased energy expenditure (Jiang et al. Mol. Metab. (2015) 4, 406-417). These positive outcomes are likely due to increased secretion of FGF21 and GLP-1, two hormones that play important roles in regulating energy metabolism, (Geng et al. Nat Rev Endo. (2020) 16, 654-667; Baggio et al. Mol Metab (2021) 46). Inhibiting SLC6A19, therefore, may be an effective approach to treat metabolic diseases.

[0006] In humans, SLC6A19 biallelic loss of function results in a rare disease called Hartnup disorder, which is predominantly asymptomatic in patients with adequate nutrition (Seow et al. Nat. Genet. (2004) 36, 1003-1007. Azmanov et al. Hum. Mutat. (2008) 29, 1217-1221). Since the NAA tryptophan is essential for the synthesis of nicotinamide, Harnup patients may develop niacin deficiency and its associated symptoms, which include dermatitis, photosensitivity, and psychosis, but these symptoms are well-controlled with niacin supplementation (Hashmi et al. StatPearls (2021)). Similarly, mice with complete loss of SLC6A19 are viable and fertile (Jiang et al. Mol. Metab. (2015) 4, 406-417). Thus, inhibition of SLC6A19 is believed to be a viable therapeutic approach.

[0007] There remains a need for therapies to treat such diseases / disorders. BRIEF SUMMARY OF THE INVENTION

[0008] In one aspect, 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: m is an integer from 1 to 4; R1is -NH-, -O-, or -S-; R2is H; R3is C1-6alkyl, C1-3alkoxy, C3-10cycloalkyl, -N(R4)2¸ 4-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a, and the 4-10 membered heteroaryl of R3is optionally substituted with one or more R3x, provided that when R3is 4-10 membered heteroaryl, R1is -NH-; each R4is independently H, C1-6alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl, wherein the C1-6alkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a; R5and R7are each independently H, halo, -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN, and the C1-6alkoxy of R5and R7are each independently optionally substituted with one or more halo; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinthe C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; R3xis -OH, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3xis optionally substituted with one or more R3b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0009] In some embodiments of a compound of formula (I):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 4; R1is -NH-, -O-, or -S-;R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1- 6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0010] In one aspect, provided herein is a compound of formula (I-A):foregoing, wherein m, R3, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0011] In one aspect, provided herein is a compound of formula (I-B):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R2, R3, R5, R6, R7, R9, R10and ring A are as defined elsewhere herein.

[0012] In one aspect, provided herein is a compound of formula (I-C):foregoing, wherein m, p, R3a, R1, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0013] In one aspect, provided herein is a compound of formula (I-D):foregoing, wherein m, q, r, R3a, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0014] In one aspect, provided is a compound of formula (I-E):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, R3, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0015] In one aspect, provided herein is a compound of formula (I-F):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0016] In one aspect, provided herein is a compound of formula (I-G):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R4, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0017] In one aspect, provided herein is a compound of formula (I-H):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, s, t, R3, R5, R6, R7, R9, R8a, Y1, Y2, Y3, Y4, and Y5are as defined elsewhere herein.

[0018] In one aspect, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

[0019] In one aspect, provided herein is a method of modulating SLC6A19 in a cell, comprising exposing the cell to (i) an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0020] In one aspect, provided herein is a method of inhibiting SLC6A19 in a cell, comprising exposing the cell to (i) an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0021] In one aspect, provided herein is a method of modulating SLC6A19 in a cell of an individual in need thereof, comprising administering to the individual an effective amount of (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0022] In one aspect, provided herein is a method of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0023] In another variation, provided herein is a method of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, a therapeutically effective amount of the compound or pharmaceutical composition is administered.

[0024] In one aspect, provided herein is a kit, comprising (i) an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, and (ii)instructions for use in treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0025] In another variation, provided herein is a kit, comprising (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, and (ii) instructions for use in treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the kit comprises a therapeutically effective amount of the compound or pharmaceutical composition.

[0026] In some aspects, provided herein are methods of preparing a compound of formula (I), or any embodiment or variation thereof, such as a compound of formula (I), (I-A), (I-A1), (I- A2), (I-A3), (I-A4), (I-A5), (I-A6), (I-B), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. DETAILED DESCRIPTION OF THE INVENTION

[0027] “Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, individual refers to a human.

[0028] As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se.

[0029] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g.,ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[0030] As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and / or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition.

[0031] As used herein, the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.

[0032] As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier.

[0033] As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects.

[0034] The term “alkyl”, as used herein, refers to an unbranched or branched saturated univalent hydrocarbon chain. As used herein, alkyl has 1-20 carbons (i.e., C1-20alkyl), 1-16 carbons (i.e., C1-16alkyl), 1-12 carbons (i.e., C1-12alkyl), 1-10 carbons (i.e., C1-10alkyl), 1-8 carbons (i.e., C1-8alkyl), 1-6 carbons (i.e., C1-6alkyl), 1-4 carbons (i.e., C1-4alkyl), or 1-3 carbons (i.e., C1-3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, iso-pentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positionalisomers having that number of carbon atoms may be encompassed—for example, “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and “propyl” includes n-propyl and iso- propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkyl” group, may be referred to as an “alkylene”.

[0035] The term “alkenyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon double bond. As used herein, alkenyl has 2-20 carbons (i.e., C2-20alkenyl), 2-16 carbons (i.e., C2-16alkenyl), 2-12 carbons (i.e., C2-12alkenyl), 2-10 carbons (i.e., C2-10alkenyl), 2-8 carbons (i.e., C2-8alkenyl), 2-6 carbons (i.e., C2-6alkenyl), 2-4 carbons (i.e., C2-4alkenyl), or 2-3 carbons (i.e., C2-3alkenyl). Examples of alkenyl include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl 1,2- butadienyl, and 1,3-butadienyl. When an alkenyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propenyl” includes prop-1- enyl and prop-2-enyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkenyl” group, may be referred to as an “alkenylene”.

[0036] The term “alkynyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon triple bond. As used herein, alkynyl has 2-20 carbons (i.e., C2-20alkynyl), 2-16 carbons (i.e., C2-16alkynyl), 2-12 carbons (i.e., C2-12alkynyl), 2-10 carbons (i.e., C2-10alkynyl), 2-8 carbons (i.e., C2-8alkynyl), 2-6 carbons (i.e., C2-6alkynyl), 2-4 carbons (i.e., C2-4alkynyl), or 2-3 carbons (i.e., C2-3alkynyl). Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1- ynyl, but-2-ynyl, and but-3-ynyl. When an alkynyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propynyl” includes prop-1- ynyl and prop-2-ynyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkynyl” group, may be referred to as an “alkynylene”.

[0037] The term “alkoxy”, as used herein, refers to an -O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0038] The term “aryl”, as used herein, refers to a fully unsaturated carbocyclic ring moiety. The term “aryl” encompasses monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbon atoms (i.e., C6-20aryl), 6 to 16 annular carbon atoms (i.e., C6-16aryl), 6 to 12 annular carbon atoms (i.e., C6-12aryl), or 6 to 10 annular carbon atoms (i.e., C6-10aryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0039] The term “cycloalkyl”, as used herein, refers to a saturated or partially unsaturated carbocyclic ring moiety. The term “cycloalkyl” encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C3-20cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C3-16cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C3-12cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C3-10cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C3-8cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C3-6cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C3-5cycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbonyl, decalinyl, 7,7-dimethyl -bicyclo [2.2.1]heptanyl, and the like. Still further, cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl.

[0040] The term “halo”, as used herein, refers to atoms occupying groups VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo). Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-C4 haloalkyl” is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.

[0041] The term “heteroaryl”, as used herein, refers to an aromatic (fully unsaturated) ring moiety that comprises one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heteroaryl” includes both monocyclic and polycyclic fused-ring moieties. As used herein, a heteroaryl comprises, for example, 5 to 20 annular atoms (i.e., a 5-20 membered heteroaryl), 5 to 16 annular atoms (i.e., a 5-16 membered heteroaryl), 5 to 12 annular atoms (i.e., a 5-12 membered heteroaryl), 5 to 10 annular atoms (i.e., a 5-10 membered heteroaryl), 5 to 8 annular atoms (i.e., a 5-8 membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5-6 membered heteroaryl). Any monocyclic or polycyclic aromatic ring moiety comprising one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2- a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, 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 the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be bound via either ring of the fused system.

[0042] The term “heterocyclyl”, as used herein, refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety comprising at least one annular heteroatom is considered a heterocyclyl, regardless of the point ofattachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heterocyclyl moiety). Further, the term heterocyclyl is intended to encompass any polycyclic ring moiety comprising at least one annular heteroatom wherein the polycyclic ring moiety comprises at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, a heterocyclyl comprises, for example, 3 to 20 annular atoms (i.e., a 3-20 membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (i.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (i.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of spiro heterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6- oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0043] The term “oxo”, as used herein, refers to a =O moiety.

[0044] The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includesinstances where the event or circumstance occurs and instances where it does not. Accordingly, the term “optionally substituted” infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen. By way of illustration and not limitation, the phrase “methyl optionally substituted with one or more chloro” encompasses -CH3, -CH2Cl, -CHCl2, and -CCl3 moieties.

[0045] It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.

[0046] The term “pharmaceutically acceptable salt”, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. See, e.g., 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 in its entirety. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., 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-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, 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 derivedfrom 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, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N- ethylpiperidine, and the like.

[0047] Isotopically labeled forms of the compounds depicted herein may be prepared. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. In some embodiments, a compound of formula (I) is provided wherein one or more hydrogen is replaced by deuterium or tritium.

[0048] Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with one another. By way of illustration, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers.

[0049] Also provided herein are prodrugs of the compounds depicted herein, or a pharmaceutically acceptable salt thereof. Prodrugs are compounds that may be administered to an individual and release, in vivo, a compound depicted herein as the parent drug compound. It is understood that prodrugs may be prepared by modifying a functional group on a parent drug compound in such a way that the modification is cleaved in vitro or in vivo to release the parent drug compound. See, e.g., 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, in its entirety.

[0050] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids). The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms and mixtures thereof in any ratio. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, for example, chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC), and chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosure includes both E and Z geometric isomers. Likewise, cis- and trans- are used in their conventional sense to describe relative spatial relationships.

[0051] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose structures are non-superimposable mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0052] Where enantiomeric and / or diastereomeric forms exist of a given structure with two stereocenters, wedged and / or dashed bonds indicate the composition is made up of predominantly a single isomer of known relative and absolute stereochemistry, e.g.,.

[0053] Where enantiomeric and / or diastereomeric forms exist of a given structure, flat bonds indicate that all stereoisomeric forms of the depicted structure may be present, e.g.,.

[0054] Where enantiomeric and / or diastereomeric forms exist of a given structure, the composition is made up of at least 90%, by weight, an asterisk indicates a single enantiomer or diastereomer with unknown relative or absolute stereochemistry, e.g.,.

[0055] Where a given structure has potential for cis and trans configuration, and the composition is made up of at least 90%, by weight, astrisks (*) indicate single unknown cis or trans configuration, e.g.,. COMPOUNDS

[0056] In one aspect, 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: m is an integer from 1 to 4; R1is -NH-, -O-, or -S-; R2is H;R3is C1-6alkyl, C1-3alkoxy, C3-10cycloalkyl, -N(R4)2¸ 4-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a, and the 4-10 membered heteroaryl of R3is optionally substituted with one or more R3x, provided that when R3is 4-10 membered heteroaryl, R1is -NH-; each R4is independently H, C1-6alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl, wherein the C1-6alkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a; R5and R7are each independently H, halo, -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN, and the C1-6alkoxy of R5and R7are each independently optionally substituted with one or more halo; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1- 6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, andthe C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; R3xis -OH, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3- 10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3xis optionally substituted with one or more R3b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0057] In some embodiments of a compound of formula (I):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 4; R1is -NH-, -O-, or -S-; R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a;R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0058] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 2; R1is -NH-, -O-, or -S-; R2is H; R3is C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl, -N(R4)2¸ 4-6 membered heteroaryl, or 4-6 membered heterocyclyl, wherein the C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl, or 4-6 membered heterocyclyl of R3is optionally substituted with one or more R3a, andthe 4-6 membered heteroaryl of R3is optionally substituted with one or more R3x; provided that when R3is 4-10 membered heteroaryl, R1is -NH-; each R4is independently H, C1-3alkyl, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, or C3-6cycloalkyl, wherein the C1-3alkyl, or C3-6cycloalkyl of R4is optionally substituted with one or more R4a; R5and R7are each independently H, halo, -CN, C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl or C1-3haloalkyl, wherein the C1-3alkyl of R5and R7are each independently optionally substituted with one or more -CN, and the C1-3alkoxy of R5and R7are each independently optionally substituted with one or more halo; R6and R9are each independently H or halo; R8is C3-6cycloalkyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-6cycloalkyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, -C(O)NH2, -C(O)NH(C1- 3alkyl), -C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-3alkyl, C1-3alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-3alkyl, C1-3alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-3alkyl, C1-3alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b;R3xis OH, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, -C(O)NH2, -C(O)NH(C1-3alkyl), -C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-3alkyl, C1-3alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3xis optionally substituted with one or more R3b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-3alkyl or C1-3alkoxy.

[0059] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 2; R1is -NH-, -O-, or -S-; R2is H; R3is C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, -N(R4)2¸ or 4-6 membered heterocyclyl, wherein the C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, or 4-6 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl, wherein the C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl or C1-3haloalkyl, wherein the C1-3alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is C3-6cycloalkyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-6cycloalkyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H;R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, -O-C1-3haloalkyl, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)NH2, - C(O)NH(C1- 3alkyl), - C(O)N(C1-3alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-3alkyl, C1-3alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-3alkyl, C1-3alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-3alkyl, C1-3alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-3alkyl or C1-3alkoxy.

[0060] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 4; R1is -NH-; R2is H; R3is C1-6alkyl, C1-3alkoxy, C3-10cycloalkyl, -N(R4)2¸ 4-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a, and the 4-10 membered heteroaryl of R3is optionally substituted with one or more R3x;each R4is independently H, C1-6alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl, wherein the C1-6alkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a; R5and R7are each independently H, halo, -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN, and the C1-6alkoxy of R5and R7are each independently optionally substituted with one or more halo; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; R3xis -OH, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, whereinthe C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3xis optionally substituted with one or more R3b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0061] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 4; R1is -NH-; R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, whereinthe C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3a, R4a, and R8aare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0062] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 4; R1is -NH-; R2is H; R3is C1-6alkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H or C1-6alkyl, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, or C1-6alkoxy, or C1-6haloalkyl; R6and R9are each independently H or halo; R8is 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or -O-C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, andthe C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D or halo.

[0063] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 4; R1is -NH-; R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, whereinthe C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0064] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 2; R1is -NH-; R2is H; R3is C1-6alkyl, C1-3alkoxy, C3-10cycloalkyl, -N(R4)2¸ 4-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a, and the 4-10 membered heteroaryl of R3is optionally substituted with one or more R3xprovided that when R3is 4-10 membered heteroaryl, R1is -NH-; each R4is independently H, C1-6alkyl, 4-10 membered heteroaryl, or 4-10 membered heterocyclyl; R5and R7are each independently H, halo, -CN, C1-6alkyl, or C1-6alkoxy, or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN, and the C1-6alkoxy of R5and R7are each independently optionally substituted with one or more halo; R6and R9are each independently H or halo; R8is 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a;R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1- 6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or -O-C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; R3xis C1-6alkyl; and R3b, R4b, and R8bare each independently D, -OH, or halo.

[0065] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 2; R1is -NH-; R2is H; R3is C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, -N(R4)2¸ or 4-6 membered heterocyclyl, wherein the C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, or 4-6 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl, wherein the C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl or C1-3haloalkyl, wherein the C1-3alkyl of R5and R7are each independently optionally substituted with one or more -CN;R6and R9are each independently H or halo; R8is C3-6cycloalkyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-6cycloalkyl, C6-10aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0066] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 4; R1is -NH-; R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a;R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3a, R4a, and R8aare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0067] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 4; R1is -NH-; R2is H; R3is C1-6alkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H or C1-6alkyl, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a;R5and R7are each independently H, halo, C1-6alkyl, or C1-6alkoxy, or C1-6haloalkyl; R6and R9are each independently H or halo; R8is 3-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or -O-C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3a, R4a, and R8aare each independently D or halo.

[0068] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety representedselected from the group consisting of

[0069] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented. In some embodiments, the moiety represented by

[0070] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented.

[0071] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented

[0072] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented

[0073] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented

[0074] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented.

[0075] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented

[0076] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented.

[0077] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented

[0078] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented

[0079] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented

[0080] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety representedselected from the group consisting, , , , , , , , , , ,

[0081] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented

[0082] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented.

[0083] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety representedb

[0084] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety representedthereof, or a pharmaceutically acceptable salt of any of the foregoing, the moiety represented

[0086] In some embodiments of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R1is -NH-, -O-, or -S-. In some embodiments, R1is -O-. In some embodiments, R1is -S-. In some embodiments, R1is -NH-.

[0087] In one aspect, provided herein is a compound of formula (I), such as a compound of formula (I-A):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R3, R5, R6, R7, R8, and R9are as defined for a compound of formula (I).

[0088] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1-4. In some embodiments, m is an integer from 1-2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0089] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is C1- 6alkyl, C1-3alkoxy, C3-10cycloalkyl, -N(R4)2¸ 4-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a, and the 4-10 membered heteroaryl of R3is optionally substituted with one or more R3x, provided that when R3is 4-10 membered heteroaryl, R1is -NH-. In some embodiments, R3is C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl, -N(R4)2¸ 4-6 membered heteroaryl, or 4-6 membered heterocyclyl, wherein the C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl, or 4-6 membered heterocyclyl of R3is optionally substituted with one or more R3a, and the 4-6 membered heteroaryl of R3is optionally substituted with one or more R3x, provided that when R3is 4-6 membered heteroaryl, R1is - NH-.

[0090] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is C1- 6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a. In some embodiments, R3is C1-3alkyl, C1-3haloalkyl, C3-6- cycloalkyl, -N(R4)2¸ or 4-6 membered heterocyclyl, wherein the C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, or 4-6 membered heterocyclyl of R3is optionally substituted with one or more R3a. In some embodiments, R3is C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, -N(R4)2¸ or 4-6 membered heterocyclyl.

[0091] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is C1-6alkyl, optionally substituted with one or more R3a. In some embodiments, R3is C1-3alkyl. In some embodiments, R3is methyl, ethyl, or isopropyl. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is isopropyl.

[0092] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is C1-6alkyl, optionally substituted with one or more R3a; R3ais, independently at each occurrence, - OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis, independently at each occurrence, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R3is C1-3alkyl, optionally substituted with one or more R3a; R3ais, independently at each occurrence, -OH, oxo, -CN, halo, C1- 3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, - C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-3alkyl, C1-3alkoxy, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis, independently at each occurrence, D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R3is C1-3alkyl, optionally substituted with one or more R3a; R3ais -OH, halo, C1-6alkyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl, wherein the C1-6alkoxy or C3-10cycloalkyl of R3ais optionally substituted with one or more R3b; and R3bis -OH, or halo. In some embodiments, R3is selected from the group consisting of ,

[0093] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is C1-6alkyl, optionally substituted with one or more R3a; R3ais, independently at each occurrence, - OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis, independently at each occurrence, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R3is C1-3alkyl, optionally substituted with one or more R3a; R3ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, - O-C1-3haloalkyl, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis, independently at each occurrence, D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R3is C1-3alkyl, optionally substituted with one or more R3a; and R3ais -OH. In some embodiments,

[0094] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is C3-10-cycloalkyl, optionally substituted with one or more R3a; R3ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), - N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis, independently at each occurrence, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R3is C3-6cycloalkyl, optionally substituted with one or more R3a; R3ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, - C(O)C1-3alkyl, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-3alkyl, C1-3alkoxy, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis, independently at each occurrence, D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R3is C3-10-cycloalkyl, optionally substituted with one or more R3a; R3ais -OH, -CN, halo, C1-6alkyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, or 4-10 membered heteroaryl, wherein the C1-6alkoxy of R3ais optionally substituted with one or more R3b; and R3bis halo. In some ,

[0095] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is C3-10cycloalkyl optionally substituted with one or more R3a, R3ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, - NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4- 10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1- 6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R3ais optionally substituted withone or more R3b; and each R3bis, independently at each occurrence, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R3is C3-6cycloalkyl optionally substituted with one or more R3a; R3ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, -O-C1-3haloalkyl, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O- C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis, independently at each occurrence, D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R3is C3-6cycloalkyl optionally substituted with one or more R3a, and R3ais halo or C1-3alkyl. In some embodiments, R3is C3-6cycloalkyl optionally substituted with one or more halo or C1-3alkyl. In some embodiments, R3is cyclopropyl, optionally substituted with one or more C1-3alkyl. In some embodiments, R3is. In some embodiments, R3is C3-6cycloalkyl optionally substituted with one or more R3a, and R3ais halo. In some embodiments, R3is C3-6cycloalkyl optionally substituted with one or more Br, Cl, I, or F. In some embodiments, R3is cyclopropyl, optionally substituted with one or more Br, Cl, I, or F. In some embodiments, R3is. In some embodiments, R3is selected from the group consisting of. In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is -N(R4)2¸ and each R4is independently H, C1-6alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl, wherein the C1-6alkyl, or C3-10-cycloalkyl of R4is optionally substituted with one or more R4a; R4ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), - N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R4ais optionally substituted with one or more R4b; and each R4bis, independently at each occurrence, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R3is -N(R4)2¸ andeach R4is independently H, C1-3alkyl, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, or C3-6cycloalkyl, wherein the C1-3alkyl, or C3-6cycloalkyl of R4is optionally substituted with one or more R4a; R4ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-3alkyl, C1-3alkoxy, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R4ais optionally substituted with one or more R4b; and each R4bis, independently at each occurrence, D, -OH, halo, C1- 3alkyl or C1-3alkoxy. In some embodiments, R3is -N(R4)2¸ and each R4is independently H, C1-6alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl, wherein the C1-6alkyl of R4is optionally substituted with one or more R4a; R4ais, independently at each occurrence, -OH, -CN, halo, C1-6alkyl, or C1-6alkoxy. In some 3embodiments, R is selected from the group consisting of , , ,.

[0096] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is -N(R4)2¸ and each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl. In some embodiments, R3is -N(R4)2¸ and each R4is independently H, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl. In some embodiments, R3is -N(R4)2¸ and each R4is independently H or C1-3-alkyl.

[0097] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is -N(R4)2¸ and both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R4ais independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R4ais optionally substituted with one or more R4b; and each R4bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R3is -N(R4)2¸ and both R4are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl optionally substituted with one or more R4a, R4ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-3alkyl, C1-3alkoxy, C1- 3haloalkyl, -O-C1-3haloalkyl, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R4ais optionally substituted with one or more Rb; and each Rbis, independently at each occurrence, D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R3is -N(R4)2¸ and both R4are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl. In some embodiments, R3is.

[0098] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is 4-10 membered heterocyclyl optionally substituted with one or more R3a; R3ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R3is 4-6 membered heterocyclyl, optionally substituted with one or more R3a, R3ais independently - OH, oxo, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis independently D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R3is 4-10 membered heterocyclyl optionally substituted with one or more R3a; R3ais, independently at each occurrence, -OH, -CN, or C1-6alkyl. In some embodiments, R3is selected from the group consisting of, , ,

[0099] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is 4-10 membered heterocyclyl optionally substituted with one or more R3a; R3ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R3is 4-6 membered heterocyclyl, optionally substituted with one or more R3a, R3ais independently -OH, oxo, -CN, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, -O-C1-3haloalkyl, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis independently D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R3is 4-6 membered heterocyclyl. In some embodiments, R3is 4-6 membered heterocyclyl. In some embodiments, R3is selected from the group consisting of.

[0100] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is C1-3alkoxy, optionally substituted with one or more R3a; R3ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), - N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R3is C1-3alkoxy. In some embodiments, R3is.

[0101] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3is 4-10 membered heteroaryl optionally substituted with one or more R3x; R3xis, independently at each occurrence, -OH, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), - N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R3xis optionally substituted with one or more R3b; and each R3bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R3 is 4-6 membered heteroaryl, optionallysubstituted with one or more R3x, R3xis independently -OH, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, -C(O)NH2, - C(O)NH(C1- 3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R3xis optionally substituted with one or more R3b; and each R3bis independently D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R3is 4-10 membered heteroaryl optionally substituted with one or more R3x; R3xis, independently at each occurrence, C1-6alkyl. In some embodiments, R3is selected from the group consisting.

[0102] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R5and R7are each independently H, halo, -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more halo, or CN, and the C1-6alkoxy of R5and R7are each independently optionally substituted with one or more halo. In some embodiments, R5and R7are each independently H, halo, -CN, C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl or C1-3haloalkyl, wherein the C1-3alkyl of R5and R7are each independently optionally substituted with one or more halo, or CN, and the C1-3alkoxy of R5and R7are each independently optionally substituted with one or more halo. In some embodiments, R5and R7are each independently H, halo, -CN, C1-3alkyl, C1- 3alkoxy, or C1-3haloalkyl, and the C1-3alkoxy of R5and R7are each independently optionally substituted with one or more halo. In some embodiments, R5and R7are each independently H. In some embodiments, one of R5and R7is H, and the other of R5and R7is independently halo, -CN, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl.

[0103] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more halo, or CN. In some embodiments, R5and R7are each independently H, halo, C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl or C1-3haloalkyl, wherein the C1-3alkyl of R5and R7are each independently optionally substituted with one or more halo, or CN. In some embodiments, R5and R7are each independently H, halo, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl. In some embodiments, R5and R7are each independently H. In some embodiments, one of R5and R7is H, and the other of R5and R7is independently halo, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl.

[0104] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R6and R9are each independently H, or halo. In some embodiments, R6and R9are each independently H, F, or Cl. In some embodiments, R6and R9are each independently H. In some embodiments, R6and R9are each independently halo. In some embodiments, R6and R9are each independently F, or Cl. In some embodiments, one of R6and R9is H, and the other of R6and R9is halo. In some embodiments, one of R6and R9is H, and the other of R6and R9is F, or Cl.

[0105] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is C3-10- cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-20 membered heteroaryl, wherein each R8is optionally substituted with one or more R8a; R8ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), - N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R8is C3-6cycloalkyl, C6-12aryl, 3-6 membered heterocyclyl, or 5-10 membered heteroaryl, wherein each R8is optionally substituted with one or more R8a; R8ais independently -OH, oxo, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or - O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-3alkyl or C1-3alkoxy.

[0106] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is C3-10-cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-20 membered heteroaryl, wherein each R8is optionally substituted with one or more R8a; R8ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, - NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4- 10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R8is C3-6cycloalkyl, C6-12aryl, 3-6 membered heterocyclyl, or 5-10 membered heteroaryl, wherein each R8is optionally substituted with one or more R8a; R8ais independently -OH, oxo, -CN, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, -O-C1-3haloalkyl, - NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4- 6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis, independently at each occurrence, D, -OH, halo, C1-3alkyl or C1-3alkoxy.

[0107] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is C3-10cycloalkyl. In some embodiments, R8is C3-10cycloalkyl, optionally substituted with one or more R8a, R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R8is C3-6cycloalkyl, optionally substituted with one or more R8a; R8ais independently -OH, oxo, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-3alkyl or C1-3alkoxy.

[0108] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is C3-10cycloalkyl. In some embodiments, R8is C3-10cycloalkyl, optionally substituted with one or more R8a, R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O- C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), -C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R8ais optionally substituted with one or more R8b; and each Rbis, independently at each occurrence, D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R8is C3-6cycloalkyl.

[0109] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is C6-12aryl. In some embodiments, R8is C6-12aryl, optionally substituted with one or more R8a, R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1- 6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R8is C6-10aryl, optionally substituted with one or more R8a; R8ais independently -OH, oxo, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, - C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-3alkyl or C1- 3alkoxy. In some embodiments, R8is.

[0110] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is C6-12aryl. In some embodiments, R8is C6-12aryl, optionally substituted with one or more R8a, R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R8ais optionally substituted with one or more R8b; and each Rbis, independently at each occurrence, D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R8is C3-6cycloalkyl.

[0111] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is 3-10 membered heterocyclyl. In some embodiments, R8is 3-10 membered heterocyclyl, optionally substituted with one or more R8a, R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R8is 3-10 membered heterocyclyl, optionally substituted with one or more R8a; R8ais independently -OH, oxo, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R8is 3-10 membered heterocyclyl, optionally substituted with one or more R8a, R8ais independently oxo, halo, or C1-6alkyl. In some embodiments, R8is selected from the group consisting of,

[0112] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is 3-10 membered heterocyclyl. In some embodiments, R8is 3-10 membered heterocyclyl, optionally substituted with one or more R8a; R8ais, independently at each occurrence, -OH, oxo, -CN,halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis, independently at each occurrence, D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0113] In some embodiments, R8is 3-6 membered heterocyclyl. In some embodiments, R8is 3-6 membered heterocyclyl, optionally substituted with one or more R8a; R8ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, - O-C1-3haloalkyl, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R8is 3-10 membered heterocyclyl, optionally substituted with one or more R8a; and R8ais, independently at each occurrence, halo or C1-3alkyl. In some embodiments, R8is selected, , . In some embodiments, R8is selected from the group consisting, , .In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is 3-10 membered heteroaryl. In some embodiments, R8is 3-10 membered heteroaryl, optionally substituted with one or more R8a, R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl or C3-10cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R8is 3-10 membered heteroaryl, optionally substituted with one or more R8a; R8ais independently -OH, oxo, -CN, halo, C1-3alkyl, C2-4alkenyl, C1-3alkoxy, -NH2, - NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)C1-3alkyl, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1- 3alkyl)2, 4-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-3alkyl or C1-3alkoxy. In some embodiments, R8is 3-10 membered heteroaryl, optionally substituted with one or more R8a, R8ais independently -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, or C1-6alkoxy, of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, or halo. In some embodiments, R8is selected from the.

[0114] In some embodiments of a compound of formula (I), or (I-A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R8is 5-20 membered heteroaryl. In some embodiments, R8is 5-20 membered heteroaryl, optionally substituted with one or more R8a; R8ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 memberedheterocyclyl or C3-10cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R8is 5-10 membered heteroaryl, optionally substituted with one or more R8a; R8ais, independently at each occurrence, -OH, oxo, -CN, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, -O-C1-3haloalkyl, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -C(O)NH2, - C(O)NH(C1-3alkyl), - C(O)N(C1-3alkyl)2, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-6 membered heterocyclyl C3-6cycloalkyl, or -O-C3-6cylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-3alkyl or C1- 3alkoxy. In some embodiments, R8is 5-10 membered heteroaryl, optionally substituted with one or more R8a; R8ais, independently at each occurrence, -CN, halo, C1-3alkyl, C1-3alkoxy, - C(O)NH2, or C3-6cycloalkyl, wherein the C1-6alkoxy, of R8ais optionally substituted with one or more R8b; and each R8bis, independently at each occurrence, D, or halo. In some

[0115] In one aspect, provided herein is a compound of formula (I), or (I-A), such as a compound of formula (I-A1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R3, R5, R7, and R8, are as defined for a compound of formula (I).

[0116] In one aspect, provided herein is a compound of formula (I), or (I-A), such as a compound of formula (I-A2):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R3, R6, R7, and R8 are as defined for a compound of formula (I).

[0117] In one aspect, provided herein is a compound of formula (I), or (I-A), such as a compound of formula (I-A3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R3, R6, R7, and R8 are as defined for a compound of formula (I).

[0118] In some embodiments of a compound of formula (I), or (I-A), such as a compound of formula (I-A3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R7is H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R7is optionally substituted with one or more halo, or CN; and R9is H, or halo. In some embodiments, R7is H, halo, C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl or C1-3haloalkyl, wherein the C1-3alkyl of R7is optionally substituted with one or more halo, or CN; and R9is H, or halo. In some embodiments R7is H, halo, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl; and R9is H, or halo. In some embodiments, R7is H; and R9is H, or halo. In some embodiments, R7is halo; and R9is halo.

[0119] In one aspect, provided herein is a compound of formula (I), or (I-A), such as a compound of formula (I-A4):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R3, R5, and R8, are as defined for a compound of formula (I).

[0120] In one aspect, provided herein is a compound of formula (I), or (I-A), such as a compound of formula (I-A5):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R3, and R7, are as defined for a compound of formula (I).

[0121] In some embodiments of a compound of formula (I), or (I-A), such as a compound of formula (I-A5), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R7is H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R7is optionally substituted with one or more halo, or CN. In some embodiments, R7is H, halo, C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl or C1-3haloalkyl, wherein the C1-3alkyl of R7is optionally substituted with one or more halo, or CN. In some embodiments, R7is H, halo, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl. In some embodiments, R7is halo, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl. In some embodiments, R7is halo. In some embodiments, R7is F. In some embodiments, R7is Cl. In some embodiments, R7is C1-6alkyl. In some embodiments, R7is C1-3alkyl. In some embodiments, R7is methyl. In some embodiments, R7is ethyl. In some embodiments, R7is isopropyl. In some embodiments, R7is C1-6alkoxy. In some embodiments, R7is C1-3alkoxy. In some embodiments, R7is methoxy. In some embodiments R7is C1-6haloalkyl. In some embodiments, R7is C1-3haloalkyl. In some embodiments, R7is CF3.

[0122] In one aspect, provided herein is a compound of formula (I), or (I-A), such as a compound of formula (I-A6):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R3, and R8are as defined for a compound of formula (I).

[0123] In one aspect, provided herein is a compound of formula (I), such as a compound of formula (I-B):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R2, R3, R5, R6, R7, R9, and R10are as defined for a compound of formula (I); and ring A is 5-10 membered heteroaryl or 5-10 membered heterocyclyl optionally substituted with one or more Ra; each Rais, independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, - C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2 ,4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of Rais optionally substituted with one or more Rb; and each Rbis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy. In some embodiments, R2, R3, R5, R6, R7, R9, and R10are as defined for a compound of formula (I); and ring A is a C6-20aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl optionally substituted with one or more Ra; each Rais, independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, - C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of Rais optionally substituted with one or more Rb; and each Rbis independently D, -OH, halo, C1- 6alkyl or C1-6alkoxy.

[0124] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A isV1, V2, V3, V4, V5, and V6are each independently -N-, -NH-, -S-, -O-, or -CH-; W1, W2, W3, W4, and W5are each independently -N-, or -CH-; X1, X2, X3, X4and X5are each independently -N-, -NH-, -S-, -O-, -CH-, or -CH2-; Z1, Z2, Z3, Z4and Z5are each independently -N-, -S-, -O-, -CH-, or -CH2-; v and v1are each independently an integer from 0-7; w is an integer from 0-6; x is an integer from 0-5; and z and z1are each independently an integer from 0-8.

[0125] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A iswherein V1and V2are each independently -N-, -NH-, -S-, -O-, or -CH-; W1, W2, W3and W4are each independently -N-, or -CH-; X1, X2, X3, X4and X5are each independently -N-, -NH-, -S-, -O-, -CH-, or -CH2-; Z1, Z2, Z3and Z4are each independently -N-, -S-, -O-, or -CH-; v is an integer from 0-7; w is an integer from 0-6; x is an integer from 0-5; and z is an integer from 0-8.

[0126] In some embodiments of a compound of formula (I-B), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring A iswherein V1and V2are each independently -N-, -NH-, -S-, -O-, or -CH-; W1, W2, W3and W4are each independently -N-, or -CH-; X1, X2, X3, X4and X5are each independently -N-, -NH-, -S-, -O-, -CH-, or -CH2-; Z1, Z2, Z3, Z4and Z5are each independently -N-, -S-, -O-, -CH-, or -CH2-; v is an integer from 0-7; w is an integer from 0-6; x is an integer from 0-5; and z is an integer from 0-8.

[0127] In some embodiments of a compound of formula (I), (I-A), or (I-B), or a stereoisomer or tautomer thereof, the compound is a compound of formula:wherein V1, V2, V3, V4, V5, and V6are each independently -N-, -NH-, -S-, -O-, or -CH-; W1, W2, W3, W4, and W5are each independently -N-, or -CH-; X1, X2, X3, X4and X5are each independently -N-, -NH-, -S-, -O-, -CH-, or -CH2-; Z1, Z2, Z3, Z4and Z5are each independently -N-, -S-, -O-, -CH-, or -CH2-; v and v1are each independently an integer from 0-7; w is an integer from 0-6; x is an integer from 0-5; and z and z1are each independently an integer from 0-8. In some embodiments, the compound is a compound of formula (I-B1). In some embodiments, the compound is a compound of formula (I-B2). In some embodiments, the compound is a compound of formula (I-B3). In some embodiments, the compound is a compound of formula (I-B4). In some embodiments, the compound is a compound of formula (I-B5). In some embodiments, the compound is a compound of formula (I-B6).

[0128] In some embodiments of a compound of formula (I), (I-A), or (I-B), or a stereoisomer or tautomer thereof, the compound is a compound of formula:whereinV1and V2are each independently -N-, -NH-, -S-, -O-, or -CH-; W1, W2, W3and W4are each independently -N-, or -CH-; X1, X2, X3, X4and X5are each independently -N-, -NH-, -S-, -O-, -CH-, or -CH2-; Z1, Z2, Z3and Z4are each independently -N-, -S-, -O-, or -CH-; v is an integer from 0-7; w is an integer from 0-6; x is an integer from 0-5; and z is an integer from 0-8. In some embodiments, the compound is a compound of formula (I-B1). In some embodiments, the compound is a compound of formula (I-B2). In some embodiments, the compound is a compound of formula (I-B3). In some embodiments, the compound is a compound of formula (I-B4).

[0129] In some embodiments of a compound of formula (I), (I-A), or (I-B), or a stereoisomer or tautomer thereof, the compound is a compound of formula:(I-B4-i), wherein V1and V2are each independently -N-, -NH-, -S-, -O-, or -CH-; W1, W2, W3and W4are each independently -N-, or -CH-; X1, X2, X3, X4and X5are each independently -N-, -NH-, -S-, -O-, -CH-, or -CH2-; Z1, Z2, Z3and Z4are each independently -N-, -S-, -O-, or -CH-. In some embodiments, the compound is a compound of formula (I-B1-i). In some embodiments, the compound is a compound of formula (I-B2-i). In some embodiments, the compound is a compound of formula (I-B3-i). In some embodiments, the compound is a compound of formula (I-B4-i).

[0130] In one aspect, provided herein is a compound of formula (I), such as a compound of formula (I-C):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, p, R3a, R1, R5, R6, R7, R8, and R9are as defined for a compound of formula (I); and p is an integer from 0 to 5.

[0131] In some embodiments of a compound of formula (I), such as a compound of formula (I-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0132] In one aspect, provided herein is a compound of formula (I), or (I-C), such as a compound of formula (I-C1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R3a, R1, R5, R6, R7, R8, and R9are as defined for a compound of formula (I).

[0133] In some embodiments of a compound of formula (I), or (I-C), such as a compound of formula (I-C1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R1is -NH-.

[0134] In one aspect, provided herein is a compound of formula (I), (I-A), or (I-C), such as a compound of formula (I-C2):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R3a, R5, R6, R7, R8, and R9are as defined for a compound of formula (I).In some embodiments of a compound of formula (I), (I-A), or (I-C), such as a compound of formula (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3ais halo or C1-6alkyl. In some embodiments, R3ais halo or C1-3alkyl. In some embodiments, R3ais C1-3alkyl. In some embodiments, R3ais CH3. In some embodiments, R3ais halo. In some embodiments, R3ais Br, Cl, F, or I. In some embodiments, R3ais F.

[0135] In some embodiments of a compound of formula (I), (I-A), or (I-C), such as a compound of formula (I-C2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, X is -O-, and R3ais C1-6alkyl. In some embodiments, X is -O-, and R3ais C1-3alkyl. In some embodiments, X is -O-, and R3ais methyl.

[0136] In one aspect, provided herein is a compound of formula (I-C3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R5, R6, R7, R8, and R9are as defined for a compound of formula (I).

[0137] In one aspect, provided herein is a compound of formula (I-C4):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R5, R6, R7, R8, and R9are as defined for a compound of formula (I).

[0138] In one aspect, provided herein is a compound of formula (I), or (I-A), such as a compound of formula (I-D):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, q, r, R3a, R5, R6, R7, R8, and R9are as defined for a compound of formula (I); q is an integer from 1-7; and r is an integer from 0-18.

[0139] In some embodiments of a compound of formula (I), such as a compound of formula (I-D), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, q is an integer from 1 to 3. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0140] In one aspect, provided herein is a compound of formula (I), (I-A), or (I-D), such as a compound of formula (I-D1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, r, R3a, R5, R6, R7, R8, and R9are as defined for a compound of formula (I); and r is an integer from 0 to 6.

[0141] In one aspect, provided is a compound of formula (I), such as a compound of formula (I-E):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, R3, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0142] In one aspect, provided herein is a compound of formula (I-F):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R5, R6, R7, R8, and R9are as defined for a compound of formula (I).

[0143] In one aspect, provided herein is a compound of formula (I-G):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R4, R5, R6, R7, R8, and R9are as defined for a compound of formula (I).

[0144] In some embodiments of a compound of formula (I), such as a compound of formula (I-G), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl. In some embodiments, each R4is independently H, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl. In some embodiments, each R4is independently H, or C1-3alkyl. In some embodiments, one R4is H and the other R4is C1-3alkyl. In some embodiments, one R4is H and the other R4is methyl.

[0145] In one aspect, provided herein is a compound of formula (I-H):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, s, t, R3, R5, R6, R7, R9, R8a, Y1, Y2, Y3, Y4, and Y5are as defined for acompound of formula (I); Y1, Y2, Y3, Y4, and Y5, are each independently -C-, -CH-, -CH2-, - N-, -NH-, -S-, or -O-; s is an integer from 0-6; t is 1 or 2; and represents a single or double bond. In some embodiments of formula (I-H), t is 1. In some embodiments of formula (I-H), t is 2. In some embodiments of formula (I-H), the ring bearing Y1through Y5, is aryl or heteroaryl. In some embodiments of formula (I-H), the ring bearing Y1through Y5, is aryl. In some embodiments of formula (I-H), the ring bearing Y1through Y5, is C6aryl. In some embodiments of formula (I-H), the ring bearing Y1through Y5, is heteroaryl. In some embodiments of formula (I-H), the ring bearing Y1through Y5, is 6-membered heteroaryl. In some embodiments of formula (I-H), the ring bearing Y1through Y5, is pyridyl or pyrazinyl. In some embodiments of formula (I-H), the ring bearing Y1through Y5, is pyridyl. In some embodiments of formula (I-H), the ring bearing Y1through Y5, is pyrazinyl.

[0146] In some embodiments of a compound of formula (I), such as a compound of formula (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is an integer from 1 to 2; n is an integer from 0 to 2; X is -O-, -S-, - C(R12a)(R12b)-, -N(H)-, or -N(C1-6alkyl)-; R3is C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, - N(R4)2¸ or 4-6 membered heterocyclyl, wherein each R3is optionally substituted with one or more R3a; each R4is independently H, C1-3alkyl, C1-3haloalkyl, or C3-6cycloalkyl, or both R4are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-3alkyl, C3-6cycloalkyl or C1-3haloalkyl, wherein the C1-3alkyl of R5and R7are each independently optionally substituted with one or more halo or CN; R6and R9are each independently H, or halo; R11aand R11bare each independently H or C1-3alkyl, one of R11aand R11bis H or C1-6alkyl, and the other of R11aand R11bis taken together with one of R12aor R12bto form a C3-10cycloalkyl; R12aand R12bare each independently, H, or C1-3alkyl, or one of R12aand R12bis H, or C1-3alkyl, and the other of R12aand R12bis taken together with R11aor R11bto form a C3-6cycloalkyl; each R8ais independently -OH, oxo, -CN, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, -O-C1-3haloalkyl, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, 4-6 membered heterocyclyl, or C3-6cycloalkyl, wherein the C1-3alkyl, C1-3alkoxy, 4-6 membered heterocyclyl or C3-6cylcoalkyl of Rais optionally substituted with one or more R8b; and each R8bis, independently at each occurrence, -OH, halo, C1-3alkyl or C1-3alkoxy; Y1, Y2, Y3, Y4,and Y5, are each independently -C-, -CH-, -CH2-, -N-, -NH-, -S-, or -O-; s is an integer from 0-6; t is 1 or 2; and represents a single or double bond.

[0147] In some embodiments of a compound of formula (I), such as a compound of formula (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound is compound of formula:embodiments, t is 1.

[0148] In some embodiments of a compound of formula (I), such as a compound of formula (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound is compound of formula:b-iv), wherein q is an integer from 1-7; and r is an integer from 0-18. In some embodiments t is 0. In some embodiments, t is 1. In some embodiments, t is 1, and Y5is -C-. In some embodiments, t is 1, Y5is -C-, any one of Y1, Y2, Y3, and Y4is -N-, -NH-, -S-, or -O- and the others of Y1, Y2, Y3, and Y4are each independently -C-, -CH-, or -CH2-. In some embodiments, t is 1, Y5is -C-, any two of Y1, Y2, Y3, and Y4is -N-, -NH-, -S-, or -O- and the others of Y1, Y2, Y3, and Y4are each independently -C-, -CH-, or -CH2-.

[0149] In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from Table 1. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-83 of Table 1. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-90 of Table 1.

[0150] Compound Names included in Table 1 and for all intermediates and compounds were generated using ChemDraw®Professional software version 17.1.1.0 or Collaborative Drug Discovery Inc. (CDD) CDD Vault update #3.

[0151] A Knime workflow was created to retrieve structures from an internal ChemAxon Compound Registry, generate the canonical smiles using RDKit Canon SMILES node, remove the stereochemistry using ChemAxon / Infocom MolConverter node, and name the structure using ChemAxon / Infocom Naming node. The following denotes the version of the Knime Analytics Platform and extensions utilized in the workflow: Knime Analytics Platform 4.2.2 RDKit Knime Integration 4.0.1.v202006261025 (this extension includes the RDKit Canon SMILES node ) ChemAxon / Infocom Marvin Extensions Feature 4.3.0v202100 (this extension includes the MolConverter node) ChemAxon / Infocom JChem Extensions Feature 4.3.0v202100 (this extension includes the Naming node) Table 15 6 7 8 9 10(dmet yamno)pyrdn-3-y)-1H- indol-2-yl)methyl)acetamide 11 N-((5-chloro-6-(1-methyl-2-oxo-1,2- dihydropyridin-4-yl)-1H-indol-2- yl)methyl)-1-methylcyclopropane-1- carboxamide 12 N-((5-chloro-6-(5- (difluoromethoxy)pyridin-2-yl)-1H- indol-2-yl)methyl)acetamide

[0152] In some embodiments, provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from the group consisting of: N-((5-chloro-6-(6-methoxypyridin-3-yl)-1H-indol-2-yl)methyl)-1-methylcyclopropane-1- carboxamide; N-((5-chloro-6-(1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-indol-2-yl)methyl)-1- methylcyclopropane-1-carboxamide; N-((5'-chloro-1H,1'H-[2,6'-biindol]-2'-yl)methyl)-1-methylcyclopropane-1-carboxamide;N-((5-chloro-6-(5-methoxypyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-methoxypyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyridin-2-yl)-1H-indol-2-yl)methyl)-1-methylcyclopropane-1- carboxamide; N-((5-chloro-6-(6-methoxypyridazin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(2-methoxypyrimidin-5-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-(dimethylamino)pyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1H-indol-2-yl)methyl)-1- methylcyclopropane-1-carboxamide; N-((5-chloro-6-(5-(difluoromethoxy)pyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-(trifluoromethoxy)pyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(pyrazolo[1,5-a]pyridin-5-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(pyrazolo[1,5-a]pyridin-6-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-fluoro-6-(6-methoxypyridazin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-fluoro-6-(5-methoxypyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)-2-hydroxypropanamide; N-((5-fluoro-6-(6-methoxypyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)oxetane-3-carboxamide; N-((5-fluoro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)tetrahydrofuran-2- carboxamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)tetrahydrofuran-3- carboxamide; N-((5-chloro-6-(5-cyclopropylpyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)oxetane-2-carboxamide; N-((5-chloro-6-(3-fluoropyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(1-methyl-1H-pyrazol-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-1H-indol-2- yl)methyl)acetamide; N-((5-chloro-6-(isoindolin-2-yl)-1H-indol-2-yl)methyl)acetamide;N-((5-chloro-6-(4-methoxypyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methylpyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-cyclopropylpyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((6-(5-methoxypyrazin-2-yl)-5-(trifluoromethyl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(2-methoxypyridin-4-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-methoxy-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methylthiazol-2-yl)-1H-indol-2-yl)methyl)acetamide; 5-(2-(acetamidomethyl)-5-chloro-1H-indol-6-yl)pyrazine-2-carboxamide; N-((5-chloro-6-(imidazo[1,2-a]pyrazin-6-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-fluoroisoindolin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-chlorothiazol-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(4-fluoroisoindolin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)-1-methylcyclopropane-1- carboxamide; N-((5-chloro-6-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-1H-indol-2- yl)methyl)acetamide; N-((5-chloro-6-(3-methyl-1H-pyrazol-1-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(imidazo[2,1-b]thiazol-6-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(3-cyclopropyl-1H-pyrazol-1-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxy-6-methylpyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-indol-2-yl)methyl)acetamide; N-((5'-chloro-1-methyl-1H,1'H-[5,6'-biindol]-2'-yl)methyl)acetamide; N-((5-chloro-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-indol-2-yl)methyl)acetamide; N-((6-(benzo[d][1,3]dioxol-5-yl)-5-chloro-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(imidazo[1,2-a]pyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(1-cyclopropyl-1H-imidazol-4-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-ethyl-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-methoxypyrimidin-4-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-(dimethylamino)pyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide;N-((5-chloro-6-(6-cyclopropoxypyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-(trifluoromethoxy)pyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-(difluoromethoxy)pyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-(difluoromethoxy)pyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((6-(5-methoxypyrazin-2-yl)-5-methyl-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(imidazo[1,2-a]pyrimidin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(pyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrimidin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-(methoxy-d3)pyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-cyanopyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-chloroisoindolin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(1-oxoisoindolin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)propionamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)-1-fluorocyclopropane-1- carboxamide; 1-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)-3-methylurea; N-((6-(benzo[b]thiophen-6-yl)-5-chloro-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-7-fluoro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)azetidine-1-carboxamide; N-((5-chloro-6-(2-methylthiazol-4-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(pyridazin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-methylpyridazin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-fluoro-5-methoxypyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-{[6-(3a,5-diaza-2-indenyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,7-diaza-5-indanyl)-2-indolyl]methyl}acetamide; N-{[6-(1,4,7a-triaza-6-indenyl)-5-chloro-2-indolyl]methyl}acetamide; N-({5-chloro-6-[6-(ethylamino)-3-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(2,4-diaza-2H-inden-2-yl)-2-indolyl]methyl}trifluoromethoxyacetamide; N-{[5-chloro-6-(1-methyl-1H-1,2,3-triazol-4-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-fluoro-2-isoindolinyl)-2-indolyl]methyl}trifluoromethoxyacetamide;N-{[5-chloro-6-(5-fluoro-2-isoindolinyl)-2-indolyl]methyl}1- fluorocyclopropanecarboxamide; N-{[6-(2,3a-diaza-5-indenyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[6-(1,3,3a-triaza-5-indenyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(3-fluoro-4-methoxyphenyl)-2-indolyl]methyl}acetamide; 1-{[5-chloro-6-(5-fluoro-2-isoindolinyl)-2-indolyl]methyl}-3-methylurea; N-{[5-chloro-6-(6-indolinyl)-2-indolyl]methyl}acetamide; N-({5-chloro-6-[6-(hydroxymethyl)-3-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(2-methyl-5-pyrimidinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(4-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-indolinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}3,3-difluorolactamide; N-{[5-chloro-6-(1,7-diaza-1H-inden-5-yl)-2-indolyl]methyl}acetamide; N-[(5-chloro-1H,1'H-6,6'-biindolyl-2-yl)methyl]acetamide; N-{[5-chloro-6-(6-cyano-3-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}(2-oxetanyl)acetamide; N-{[5-chloro-6-(6-ethoxy-3-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}2- methoxycyclopropanecarboxamide; 1-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}urea; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-3-hydroxy-3- oxetanecarboxamide; N-{[6-(5-amino-6-fluoro-2-pyridyl)-5-chloro-2-indolyl]methyl}acetamide; 3-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1-cyclopropyl-1- methylurea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}difluoromethoxyacetamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-methyl-1-(1- methylcyclopropyl)urea; N-({6-[5-(1-azetidinyl)-6-fluoro-2-pyridyl]-5-chloro-2-indolyl}methyl)acetamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-cyclopropyl-1-methylurea;N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-2-methyl-2- oxetanecarboxamide; 3-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1-methyl-1-(1- methylcyclopropyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}2-difluoromethoxypropionamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-4- morpholinecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}3-methoxypropionamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- (dimethylamino)cyclopropanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- methoxycyclopropanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2- indolyl]methyl}trifluoromethoxyacetamide; 3-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1-(1- methylcyclopropyl)urea; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}methoxyacetamide; methyl {[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}carbamate; N-{[5-chloro-6-(2-fluoro-4-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-3-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(2-cyclopropyl-5-pyrimidinyl)-2-indolyl]methyl}acetamide; methyl {[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}carbamate; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- (methylamino)cyclopropanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}2-methoxypropionamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}2-methoxybutyramide; N-{[5-cyano-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}acetamide; 3-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1,1-dimethylurea; N-{[5-chloro-6-(5,6-difluoro-3-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-methyl-3-pyridyl)-2-indolyl]methyl}acetamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(1-methylcyclopropyl)urea;3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1,1-dimethylurea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- difluoromethoxycyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1-(2- pyridyl)cyclopropanecarboxamide; N-({5-chloro-6-[6-fluoro-5-(methylamino)-2-pyridyl]-2-indolyl}methyl)1- hydroxycyclopropanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- hydroxycyclopropanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- cyanocyclopropanecarboxamide; N-({5-chloro-6-[5-(ethylamino)-6-fluoro-2-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(5-fluoro-6-methyl-3-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-2-pyridyl)-2-indolyl]methyl}acetamide; N-{[3,5-dichloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}3-hydroxypropionamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-oxa-6-aza-6- spiro[3.3]heptanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- aminocyclopropanecarboxamide; N-({5-chloro-6-[6-chloro-5-(methylamino)-2-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-6-oxa-1-aza-1- spiro[3.3]heptanecarboxamide; N-({5-chloro-6-[6-fluoro-5-(methylamino)-2-pyridyl]-2-indolyl}methyl)-1- azetidinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-oxa-6-aza-6- spiro[3.3]heptanecarboxamide; N-({6-[5-(1-azetidinyl)-2-pyrazinyl]-5-chloro-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-hydroxy-1- azetidinecarboxamide; N-({5-chloro-6-[5-(dimethylamino)-6-fluoro-2-pyridyl]-2-indolyl}methyl)acetamide;N-{[5-chloro-6-(1,4-diaza-5-indanyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}methoxyacetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}3- hydroxycyclobutanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}2- methoxycyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}3-methoxypropionamide; 6-{5-chloro-2-[(3-methylureido)methyl]-6-indolyl}-2-fluoro-3-(methylamino)pyridine; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- methoxycyclopropanecarboxamide; 1-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-3-methylurea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-methyl-4- pyrazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- (dimethylamino)cyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}trifluoromethoxyacetamide; 1-{[5-chloro-6-(6-methoxy-3-pyridyl)-2-indolyl]methyl}-3-methylurea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-4-morpholinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(2-oxetanyl)acetamide; 1-{[5-chloro-6-(5-methoxy-2-pyridyl)-2-indolyl]methyl}-3-methylurea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1,3-oxazole-5-carboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-isoxazolecarboxamide; 3-(3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}ureido)cyclobutanol; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(2,2-difluoroethyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-4-pyridazinecarboxamide; 3-(3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}ureido)propiononitrile; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(3-isoxazolyl)acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}2-hydroxybutyramide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-pyridazinecarboxamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(2-methoxyethyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-azetidinecarboxamide;N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-perhydro-3-furamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1,3-oxazole-4-carboxamide; 1-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-(perhydro-3-furyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-cyano-1- azetidinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}2-hydroxy-3-methylbutyramide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(methylamino)acetamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(4-isoxazolyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-hydroxy-3-methyl-1- azetidinecarboxamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(3-oxetanyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}glycolamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1-cyanocyclobutanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-cyano-3-oxetanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- cyanocyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-5-methyl-3- isoxazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- hydroxycyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-pyrazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-oxabicyclo[2.1.1]hexane-1- carboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-oxabicyclo[2.1.1]hexane-4- carboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}3-fluorolactamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1,3-thiazole-2-carboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- (methylamino)cyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-pyrazinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}2-methoxypropionamide;N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-5-pyrimidinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-4-pyrimidinecarboxamide; N-({5-chloro-6-[6-fluoro-5-(methylamino)-2-pyridyl]-2-indolyl}methyl)acetamide; 1-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-methyl-5- pyrazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}difluoromethoxyacetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(3-oxetanyl)acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-methyl-4- imidazolecarboxamide; N-({5-chloro-6-[6-(methylamino)-3-pyridazinyl]-2-indolyl}methyl)acetamide; N-({5-chloro-6-[5-fluoro-6-(methylamino)-3-pyridyl]-2-indolyl}methyl)acetamide; N-{[6-(5-acetyl-2-pyrazinyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(2,4-diaza-2-indanyl)-2-indolyl]methyl}-1-pyrrolidinecarboxamide; N-{[5-chloro-6-(5-methyl-3-isoxazolyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-perhydro-2-furamide; N-{[5-chloro-6-(5-isopropenyl-2-pyrazinyl)-2-indolyl]methyl}acetamide; N-({5-chloro-6-[6-(methylamino)-3-pyridyl]-2-indolyl}methyl)acetamide; N-({5-chloro-6-[5-(methylamino)-2-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-fluoro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- methylcyclopropanecarboxamide; N-{[5-chloro-6-(5-vinyl-2-pyrazinyl)-2-indolyl]methyl}1-methylcyclopropanecarboxamide; N-{[5-chloro-6-(5-isopropenyl-2-pyrazinyl)-2-indolyl]methyl}1- methylcyclopropanecarboxamide; N-{[5-chloro-6-(2-methyl-1,3-oxazol-4-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-oxazol-5-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,4-dioxa-5,8-diaza-2,3-dihydro-6-naphthyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-quinoxalinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-vinyl-2-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,4-dioxa-5-aza-2,3-dihydro-7-naphthyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-dioxa-4-aza-6-indanyl)-2-indolyl]methyl}acetamide;N-({5-chloro-6-[5-(methylamino)-2-pyrazinyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(1,4-dioxa-5-aza-2,3-dihydro-6-naphthyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-oxazol-2-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(4-methyl-1,3-oxazol-2-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(3-isothiazolyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(3-thia-1,5-diaza-6-indenyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-dioxa-4-aza-5-indanyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1-thia-7-aza-2-indenyl)-2-indolyl]methyl}acetamide; N-{[6-(1,3a-diaza-4,5,6,7-tetrahydro-2-indenyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-dioxa-5-aza-6-indanyl)-2-indolyl]methyl}acetamide; N-{[6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}acetamide; N-({5-chloro-6-[5-(hydroxymethyl)-2-pyrazinyl]-2-indolyl}methyl)acetamide; N-({5-fluoro-6-[5-(trifluoromethyl)-2-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-fluoro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}acetamide; N-({6-[5-(difluoromethyl)-2-pyridyl]-5-fluoro-2-indolyl}methyl)acetamide; N-({5-fluoro-6-[5-(trifluoromethyl)-2-pyrazinyl]-2-indolyl}methyl)acetamide; N-({5-chloro-6-[6-(difluoromethyl)-3-pyridazinyl]-2-indolyl}methyl)acetamide; N-{[6-(1-benzofuran-6-yl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-fluoro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}lactamide; N-{[6-(1-benzothiophen-5-yl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,4-diazabicyclo[3.3.0]octa-2,4-dien-3-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-fluoro-6-methoxy-3-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-ethyl-2-pyrazinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-2- indolyl]methyl}acetamide; N-{[5-chloro-6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-vinyl-2-pyrazinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-2,4-diaza-2-indanyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-ethoxy-2-pyrazinyl)-2-indolyl]methyl}acetamide; N-{[6-(1-benzofuran-5-yl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-thiazol-4-yl)-2-indolyl]methyl}acetamide;N-{[5-chloro-6-(1-methyl-1,4-diaza-1H-inden-5-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1-methyl-1,6-diaza-1H-inden-5-yl)-2-indolyl]methyl}acetamide; N-{[6-(1,3-benzothiazol-2-yl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(4-methyl-1,3-thiazol-2-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(4-thia-1,6-diazabicyclo[3.3.0]octa-2,5,7-trien-3-yl)-2- indolyl]methyl}acetamide; N-{[5-chloro-6-(3-methyl-5-isoxazolyl)-2-indolyl]methyl}acetamide; 2-(3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}ureido)cyclobutanol; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-perhydro-2-furamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-methyl-2- oxetanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}2- cyanocyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-hydroxy-1- pyrrolidinecarboxamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(3,3-difluoropropyl)urea; 2-(3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}ureido)ethanol; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-5-isoxazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-5-pyrazolecarboxamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-cyclopropylurea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-5-methyl-1,3-oxazole-4- carboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-piperazinecarboxamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(3-isoxazolyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-methyl-5- isoxazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-hydroxy-3- oxetanecarboxamide; N-{[5-chloro-6-(3-methyl-1,2-benzisoxazol-5-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(3-methyl-1,2-benzisoxazol-6-yl)-2-indolyl]methyl}acetamide;N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- methylcyclopropanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1- pyrrolidinecarboxamide; and N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1-azetidinecarboxamide; N-{[5-methoxy-6-(6-methoxy-3-pyridazinyl)-2-indolyl]methyl}lactamide; N-{[5-methoxy-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}lactamide; N-{[5-methoxy-6-(6-methoxy-3-pyridazinyl)-2-indolyl]methyl}acetamide; N-{[5-methoxy-6-(6-methoxy-3-pyridazinyl)-2-indolyl]methyl}methoxyacetamide; N-{[5-methoxy-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}3,3-difluoropropionamide; N-{[5-methoxy-6-(6-methoxy-3-pyridazinyl)-2-indolyl]methyl}3,3-difluoropropionamide; N-{[5-methoxy-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}methoxyacetamide; N-{[5-methoxy-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}lactamide; 1-{[5-methoxy-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-methylurea; 3-{[5-methoxy-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1,1-dimethylurea; N-{[5-chloro-6-(5-cyclopropyl-2-pyridyl)-2-indolyl]methyl}acetamide; N-{[6-(5-methoxy-2-pyrazinyl)-5-trifluoromethoxy-2-indolyl]methyl}2- methylpropionamide; and N-{[5-(cyanomethyl)-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}acetamide, or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0153] In some embodiments, provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from the group consisting of: N-((5-chloro-6-(6-methoxypyridin-3-yl)-1H-indol-2-yl)methyl)-1-methylcyclopropane-1- carboxamide; N-((5-chloro-6-(1H-pyrrolo[3,2-b]pyridin-2-yl)-1H-indol-2-yl)methyl)-1- methylcyclopropane-1-carboxamide; N-((5'-chloro-1H,1'H-[2,6'-biindol]-2'-yl)methyl)-1-methylcyclopropane-1-carboxamide; N-((5-chloro-6-(5-methoxypyridin-2-yl)-1H-indol-2-yl)methyl)acetamide;N-((5-chloro-6-(6-methoxypyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyridin-2-yl)-1H-indol-2-yl)methyl)-1-methylcyclopropane-1- carboxamide; N-((5-chloro-6-(6-methoxypyridazin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(2-methoxypyrimidin-5-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-(dimethylamino)pyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1H-indol-2-yl)methyl)-1- methylcyclopropane-1-carboxamide; N-((5-chloro-6-(5-(difluoromethoxy)pyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-(trifluoromethoxy)pyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(pyrazolo[1,5-a]pyridin-5-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(pyrazolo[1,5-a]pyridin-6-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-fluoro-6-(6-methoxypyridazin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-fluoro-6-(5-methoxypyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; (S)-N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)-2-hydroxypropanamide; N-((5-fluoro-6-(6-methoxypyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; (R)-N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)-2-hydroxypropanamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)oxetane-3-carboxamide; N-((5-fluoro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; (S)-N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)tetrahydrofuran-2- carboxamide; (S)-N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)tetrahydrofuran-3- carboxamide; N-((5-chloro-6-(5-cyclopropylpyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; (S)-N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)oxetane-2-carboxamide; (R)-N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)oxetane-2-carboxamide; N-((5-chloro-6-(3-fluoropyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(1-methyl-1H-pyrazol-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-1H-indol-2- yl)methyl)acetamide;N-((5-chloro-6-(isoindolin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(4-methoxypyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methylpyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-cyclopropylpyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((6-(5-methoxypyrazin-2-yl)-5-(trifluoromethyl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(2-methoxypyridin-4-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-methoxy-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methylthiazol-2-yl)-1H-indol-2-yl)methyl)acetamide; 5-(2-(acetamidomethyl)-5-chloro-1H-indol-6-yl)pyrazine-2-carboxamide; N-((5-chloro-6-(imidazo[1,2-a]pyrazin-6-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-fluoroisoindolin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-chlorothiazol-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(4-fluoroisoindolin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)-1-methylcyclopropane-1- carboxamide; N-((5-chloro-6-(1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-1H-indol-2- yl)methyl)acetamide; N-((5-chloro-6-(3-methyl-1H-pyrazol-1-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(imidazo[2,1-b]thiazol-6-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(3-cyclopropyl-1H-pyrazol-1-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxy-6-methylpyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-indol-2-yl)methyl)acetamide; N-((5'-chloro-1-methyl-1H,1'H-[5,6'-biindol]-2'-yl)methyl)acetamide; N-((5-chloro-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-indol-2-yl)methyl)acetamide; N-((6-(benzo[d][1,3]dioxol-5-yl)-5-chloro-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(imidazo[1,2-a]pyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(1-cyclopropyl-1H-imidazol-4-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-ethyl-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-methoxypyrimidin-4-yl)-1H-indol-2-yl)methyl)acetamide;N-((5-chloro-6-(5-(dimethylamino)pyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-cyclopropoxypyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-(trifluoromethoxy)pyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-(difluoromethoxy)pyridin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-(difluoromethoxy)pyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((6-(5-methoxypyrazin-2-yl)-5-methyl-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(imidazo[1,2-a]pyrimidin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(pyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrimidin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-(methoxy-d3)pyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-cyanopyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-chloroisoindolin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(1-oxoisoindolin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)propionamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)-1-fluorocyclopropane-1- carboxamide; 1-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)-3-methylurea; N-((6-(benzo[b]thiophen-6-yl)-5-chloro-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-7-fluoro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)azetidine-1-carboxamide; N-((5-chloro-6-(2-methylthiazol-4-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(pyridazin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-methylpyridazin-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(6-fluoro-5-methoxypyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(oxazol-4-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(isoxazol-3-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(5-methyloxazol-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(2-methyloxazol-5-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(thieno[3,2-b]pyridin-2-yl)-1H-indol-2-yl)methyl)acetamide; N-((5-chloro-6-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-1H-indol-2- yl)methyl)acetamide;N-((5-fluoro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)propionamide; N-{[6-(3a,5-diaza-2-indenyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,7-diaza-5-indanyl)-2-indolyl]methyl}acetamide; N-{[6-(1,4,7a-triaza-6-indenyl)-5-chloro-2-indolyl]methyl}acetamide; N-({5-chloro-6-[6-(ethylamino)-3-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(2,4-diaza-2H-inden-2-yl)-2-indolyl]methyl}trifluoromethoxyacetamide; N-{[5-chloro-6-(1-methyl-1H-1,2,3-triazol-4-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-fluoro-2-isoindolinyl)-2-indolyl]methyl}1- fluorocyclopropanecarboxamide; N-{[5-chloro-6-(5-fluoro-2-isoindolinyl)-2-indolyl]methyl}trifluoromethoxyacetamide; N-{[6-(2,3a-diaza-5-indenyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[6-(1,3,3a-triaza-5-indenyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(3-fluoro-4-methoxyphenyl)-2-indolyl]methyl}acetamide; 1-{[5-chloro-6-(5-fluoro-2-isoindolinyl)-2-indolyl]methyl}-3-methylurea; N-{[5-chloro-6-(6-indolinyl)-2-indolyl]methyl}acetamide; N-({5-chloro-6-[6-(hydroxymethyl)-3-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(2-methyl-5-pyrimidinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(4-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(S)-3,3-difluorolactamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(R)-3,3-difluorolactamide; N-{[5-chloro-6-(5-indolinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3,3-difluorolactamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}[(S)-2-oxetanyl]acetamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}[(R)-2- oxetanyl]acetamide; N-{[5-chloro-6-(1,7-diaza-1H-inden-5-yl)-2-indolyl]methyl}acetamide; N-[(5-chloro-1H,1'H-6,6'-biindolyl-2-yl)methyl]acetamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl} 2-oxetanyl]acetamide; N-{[5-chloro-6-(6-cyano-3-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-ethoxy-3-pyridyl)-2-indolyl]methyl}acetamide;Trans-N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl} 2- methoxycyclopropanecarboxamide; Trans-N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}(1R,2R)-2- methoxycyclopropanecarboxamide; Trans-N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}(1S,2S)-2- methoxycyclopropanecarboxamide; 1-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}urea; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-3-hydroxy-3- oxetanecarboxamide; N-{[6-(5-amino-6-fluoro-2-pyridyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-(R)-2-methyl-2- oxetanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-(S)-2-methyl-2- oxetanecarboxamide; 3-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1-cyclopropyl-1- methylurea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}difluoromethoxyacetamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-methyl-1-(1- methylcyclopropyl)urea; N-({6-[5-(1-azetidinyl)-6-fluoro-2-pyridyl]-5-chloro-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(R)-2- difluoromethoxypropionamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-cyclopropyl-1-methylurea; 3-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1-methyl-1-(1- methylcyclopropyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(S)-2- difluoromethoxypropionamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-4- morpholinecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}3-methoxypropionamide;N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- (dimethylamino)cyclopropanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- methoxycyclopropanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2- indolyl]methyl}trifluoromethoxyacetamide; 3-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1-(1- methylcyclopropyl)urea; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-(S)-perhydro-2-furamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}methoxyacetamide; methyl {[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}carbamate; N-{[5-chloro-6-(2-fluoro-4-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-3-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(2-cyclopropyl-5-pyrimidinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}(R)-2- methoxypropionamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(S)-2-methoxybutyramide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(R )-2-methoxybutyramide; methyl {[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}carbamate; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- (methylamino)cyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(R)-2-methoxybutyramide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(S)-2-methoxybutyramide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}(S)-2- methoxypropionamide; 3-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1,1-dimethylurea; N-{[5-cyano-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5,6-difluoro-3-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-methyl-3-pyridyl)-2-indolyl]methyl}acetamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(1-methylcyclopropyl)urea; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1,1-dimethylurea;N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- difluoromethoxycyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1-(2- pyridyl)cyclopropanecarboxamide; N-({5-chloro-6-[6-fluoro-5-(methylamino)-2-pyridyl]-2-indolyl}methyl)1- hydroxycyclopropanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- hydroxycyclopropanecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- cyanocyclopropanecarboxamide; N-({5-chloro-6-[5-(ethylamino)-6-fluoro-2-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(5-fluoro-6-methyl-3-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-2-pyridyl)-2-indolyl]methyl}acetamide; N-{[3,5-dichloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}3-hydroxypropionamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-oxa-6-aza-6- spiro[3.3]heptanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- aminocyclopropanecarboxamide; N-({5-chloro-6-[6-chloro-5-(methylamino)-2-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-6-oxa-1-aza-1- spiro[3.3]heptanecarboxamide; N-({5-chloro-6-[6-fluoro-5-(methylamino)-2-pyridyl]-2-indolyl}methyl)-1- azetidinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-oxa-6-aza-6- spiro[3.3]heptanecarboxamide; N-({6-[5-(1-azetidinyl)-2-pyrazinyl]-5-chloro-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-hydroxy-1- azetidinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}[(R)-2-oxetanyl]acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}[(S)-2-oxetanyl]acetamide;(1S,2R)-2-(3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}ureido)cyclobutanol; N-({5-chloro-6-[5-(dimethylamino)-6-fluoro-2-pyridyl]-2-indolyl}methyl)acetamide; Trans-N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(1R,2R)-2- methoxycyclopropanecarboxamide; Trans-N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(1S,2S)-2- methoxycyclopropanecarboxamide; N-{[5-chloro-6-(1,4-diaza-5-indanyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(1r,3r)-3- hydroxycyclobutanecarboxamide; (1R,2S)-2-(3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}ureido)cyclobutanol; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}methoxyacetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(1s,3s)-3- hydroxycyclobutanecarboxamide; Trans-N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(-2- methoxycyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}3-methoxypropionamide; cis-N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(1R,2S)-2- methoxycyclopropanecarboxamide; cis-N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(1S,2R)-2- methoxycyclopropanecarboxamide; Trans-N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(1R,2R)-2- cyanocyclopropanecarboxamide; Trans-N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(1S,2S)-2- cyanocyclopropanecarboxamide; 6-{5-chloro-2-[(3-methylureido)methyl]-6-indolyl}-2-fluoro-3-(methylamino)pyridine; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- methoxycyclopropanecarboxamide; 1-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-3-methylurea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(2-oxetanyl)acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-methyl-4- pyrazolecarboxamide;N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- (dimethylamino)cyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}trifluoromethoxyacetamide; 1-{[5-chloro-6-(6-methoxy-3-pyridyl)-2-indolyl]methyl}-3-methylurea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-4-morpholinecarboxamide; 1-{[5-chloro-6-(5-methoxy-2-pyridyl)-2-indolyl]methyl}-3-methylurea; N-{[5-chloro-6-(3-methyl-1,2-benzisoxazol-6-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(3-methyl-1,2-benzisoxazol-5-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-hydroxy-3- oxetanecarboxamide; (1S,2S)-2-(3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}ureido)cyclobutanol; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-methyl-5- isoxazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-methyl-2- oxetanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-(R)-perhydro-2-furamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-(R)-2-methyl-2- oxetanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-(S)-2-methyl-2- oxetanecarboxamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(3-isoxazolyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-piperazinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-5-methyl-1,3-oxazole-4- carboxamide; Trans-N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(-2- cyanocyclopropanecarboxamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-cyclopropylurea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1,3-oxazole-5-carboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-isoxazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-(R)-3-hydroxy-1- pyrrolidinecarboxamide;N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-5-pyrazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-5-isoxazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-(S)-3-hydroxy-1- pyrrolidinecarboxamide; 2-(3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}ureido)ethanol; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(3,3-difluoropropyl)urea; (1s,3s)-3-(3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}ureido)cyclobutanol; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(2,2-difluoroethyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-4-pyridazinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(S)-2-hydroxybutyramide; 3-(3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}ureido)propiononitrile; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(3-isoxazolyl)acetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(R)-2-hydroxybutyramide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-pyridazinecarboxamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(2-methoxyethyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-(R)-2-azetidinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-(R)-perhydro-3-furamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1,3-oxazole-4-carboxamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-[(R)-perhydro-3-furyl]urea; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-[(S)-perhydro-3-furyl]urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-cyano-1- azetidinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(S)-2-hydroxy-3- methylbutyramide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(methylamino)acetamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(4-isoxazolyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-hydroxy-3-methyl-1- azetidinecarboxamide; 3-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-(3-oxetanyl)urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}glycolamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1-cyanocyclobutanecarboxamide;N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-3-cyano-3-oxetanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- cyanocyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-5-methyl-3- isoxazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- hydroxycyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-pyrazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(S)-3-fluorolactamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-oxabicyclo[2.1.1]hexane-1- carboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-oxabicyclo[2.1.1]hexane-4- carboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(R)-3-fluorolactamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1,3-thiazole-2-carboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(S)-2-methoxypropionamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}1- (methylamino)cyclopropanecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-2-pyrazinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(R)-2-methoxypropionamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-5-pyrimidinecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-4-pyrimidinecarboxamide; N-({5-chloro-6-[6-fluoro-5-(methylamino)-2-pyridyl]-2-indolyl}methyl)acetamide; 1-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}urea; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-methyl-5- pyrazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}difluoromethoxyacetamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}-1-methyl-4- imidazolecarboxamide; N-{[5-chloro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(3-oxetanyl)acetamide; N-({5-chloro-6-[6-(methylamino)-3-pyridazinyl]-2-indolyl}methyl)acetamide;N-({5-chloro-6-[5-fluoro-6-(methylamino)-3-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1-azetidinecarboxamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-1- pyrrolidinecarboxamide; N-{[6-(5-acetyl-2-pyrazinyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(2,4-diaza-2-indanyl)-2-indolyl]methyl}-1-pyrrolidinecarboxamide; N-{[5-chloro-6-(5-methyl-3-isoxazolyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}-(R)-perhydro-2-furamide; N-{[5-chloro-6-(5-isopropenyl-2-pyrazinyl)-2-indolyl]methyl}acetamide; N-({5-chloro-6-[6-(methylamino)-3-pyridyl]-2-indolyl}methyl)acetamide; N-({5-chloro-6-[5-(methylamino)-2-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-fluoro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- methylcyclopropanecarboxamide; N-{[5-chloro-6-(5-vinyl-2-pyrazinyl)-2-indolyl]methyl}1-methylcyclopropanecarboxamide; N-{[5-chloro-6-(5-isopropenyl-2-pyrazinyl)-2-indolyl]methyl}1- methylcyclopropanecarboxamide; N-{[5-chloro-6-(2-methyl-1,3-oxazol-4-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-oxazol-5-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,4-dioxa-5,8-diaza-2,3-dihydro-6-naphthyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-vinyl-2-pyridyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-quinoxalinyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(3-methyl-5-isoxazolyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,4-dioxa-5-aza-2,3-dihydro-7-naphthyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-dioxa-4-aza-6-indanyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}1- methylcyclopropanecarboxamide; N-{[5-chloro-6-(1,4-dioxa-5-aza-2,3-dihydro-6-naphthyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-oxazol-2-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(4-methyl-1,3-oxazol-2-yl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(3-isothiazolyl)-2-indolyl]methyl}acetamide; N-({5-chloro-6-[5-(methylamino)-2-pyrazinyl]-2-indolyl}methyl)acetamide;N-{[5-chloro-6-(3-thia-1,5-diaza-6-indenyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-dioxa-4-aza-5-indanyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1-thia-7-aza-2-indenyl)-2-indolyl]methyl}acetamide; N-{[5-chloro-6-(1,3-dioxa-5-aza-6-indanyl)-2-indolyl]methyl}acetamide; N-{[6-(1,3a-diaza-4,5,6,7-tetrahydro-2-indenyl)-5-chloro-2-indolyl]methyl}acetamide; N-{[6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}acetamide; N-({5-chloro-6-[5-(hydroxymethyl)-2-pyrazinyl]-2-indolyl}methyl)acetamide; N-({5-fluoro-6-[5-(trifluoromethyl)-2-pyridyl]-2-indolyl}methyl)acetamide; N-{[5-fluoro-6-(6-fluoro-5-methoxy-2-pyridyl)-2-indolyl]methyl}acetamide; N-({6-[5-(difluoromethyl)-2-pyridyl]-5-fluoro-2-indolyl}methyl)acetamide; N-({5-fluoro-6-[5-(trifluoromethyl)-2-pyrazinyl]-2-indolyl}methyl)acetamide; N-{[5-chloro-6-(5-cyclopropyl-2-pyridyl)-2-indolyl]methyl}acetamide; N-({5-chloro-6-[6-(difluoromethyl)-3-pyridazinyl]-2-indolyl}methyl)acetamide; and N-{[5-fluoro-6-(5-methoxy-2-pyrazinyl)-2-indolyl]methyl}(R)-lactamide; or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. METHODS OF TREATMENT

[0154] Provided herein is a method of modulating SLC6A19 in a cell, comprising exposing the cell to (i) an effective amount of a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

[0155] Provided herein is a method of inhibiting SLC6A19 in a cell, comprising exposing the cell to (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the individual is a human.

[0156] Provided herein is a method of reducing systemic amino acid levels in an individual in need thereof, comprising administering to the individual (i) an effective amount of a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the amino acid is phenylalanine, tyrosine, glutamine, or glycine. In some embodiments, the systemic phenylalanine, tyrosine, glutamine, or glycine level in the individual is reduced upon treatment. In some embodiments, the phenylalanine, tyrosine, glutamine, or glycine level is reduced at least 10%, at least 20%, at least 30% or at least 50% upon administration of the compound.

[0157] Provided herein is a method of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) an effective amount of a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition, comprising an effective amount of a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, metabolic diseases, hyperphenylalaninemia, tyrosinemia (Type I, II, or III), nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, hyperammonemia, diabetes, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity related disorders, and neurodevelopmental and autism-spectrum disorders. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, or metabolic diseases. In some embodiments, the SLC6A19-mediated disease,disorder, or condition is phenylketonuria (PKU). In some embodiments, the SLC6A19- mediated disease, disorder, or condition is chronic kidney disease (CKD). In some embodiments, the SLC6A19-mediated disease, disorder, or condition is a metabolic disease. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is metabolic syndrome. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is associated with abnormal levels of amino acids. In some embodiments, the SLC6A19- mediated disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

[0158] Provided herein is a method of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or (ii) a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, metabolic diseases, hyperphenylalaninemia, tyrosinemia (Type I, II, or III), nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, hyperammonemia, diabetes, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity related disorders, and neurodevelopmental and autism-spectrum disorders. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, or metabolic diseases. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is phenylketonuria (PKU). In some embodiments, the SLC6A19-mediated disease, disorder, or condition is chronic kidney disease (CKD). In some embodiments, the SLC6A19-mediated disease, disorder, or condition is a metabolic disease. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is metabolic syndrome. In some embodiments, the SLC6A19- mediated disease, disorder, or condition is associated with abnormal levels of amino acids. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is associated witha genetic defect in phenylalanine hydroxylase. In some embodiments, the individual is a human.

[0159] Provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in modulating SLC6A19 in a cell.

[0160] Provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in inhibiting SLC6A19 in a cell.

[0161] Provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof.

[0162] Provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0163] Provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), orany variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the manufacture of a medicament, for use in modulating SLC6A19 in a cell.

[0164] Provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the manufacture of a medicament, for use in inhibiting SLC6A19 in a cell.

[0165] Provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in the manufacture of a medicament, for use in reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof.

[0166] Provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for use in treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0167] In some embodiments, the compounds provided herein inhibit SLC6A19 at a concentration of less than 10 μM, less than 1 μM, less than 0.5 μM, less than 0.1 μM, less than 0.010 μM, or less than 0.001 μM. In some embodiments, the compounds provided herein inhibit SLC6A19 at a concentration of 1-10 μM, 0.01 to 1 μM, or 0.01 to 10 μM.

[0168] In some embodiments, the compounds have an IC50of 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 compounds provided herein have an IC50 of 1 to 10 nM, 1 to 10 μM, 0.01 to 1 μM, 0.01 to 10 μM, 0.001 to 0.01 μM or 0.001 to 0.010 μM.

[0169] In some embodiments, the individual receiving treatment is a juvenile human or an infant. In some embodiments, 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 one year old. In some embodiments, the individual is a human.

[0170] In some embodiments, the individual has abnormal levels of amino acids. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase. In some embodiments, the individual is a human.

[0171] In some embodiments of the foregoing, the administration is oral administration. KITS

[0172] The present disclosure further provides kits for carrying out the methods disclosed herein. The kits may comprise a compound or pharmaceutically acceptable salt thereof as described herein and suitable packaging. The kits may comprise one or more containers comprising any compound described herein. In one aspect, a kit includes a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a label and / or instructions for use of the compound in the treatment of a disease or disorder described herein. The kits may comprise a unit dosage form of the compound.

[0173] Provided herein are kits, comprising (i) an effective amount of a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising an effective amount of a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructionsfor use in treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the individual is a human.

[0174] Provided herein are kits, comprising (i) a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) instructions for use in treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a pharmaceutical composition comprising a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions for use in treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the individual is a human.

[0175] Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (I) or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. Also provided herein are articles of manufacture, comprising a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag. METHODS OF PREPARING

[0176] The present disclosure further provides processes for preparing the compounds of present invention. In some aspects, provided herein are processes of preparing a compound of (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-A5), (I-A6), (I-B), (I-B1), (I-B2), (I-B3), (I-B4), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-E), (I-F), (I-G), or (I-H), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0177] In some embodiments, a process for preparing a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises:(a) reacting a compound of formula (I-1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q1is halo; PG is absent, or a protecting group; m is an integer from 1 to 4; R1is -N-, -NH-, -O-, or -S-; R2is H; R3is C1-6alkyl, C1-3alkoxy, C3-10cycloalkyl, -N(R4)2¸ 4-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a, and the 4-10 membered heteroaryl of R3is optionally substituted with one or more R3x, provided that when R3is 4-10 membered heteroaryl, R1is -NH-; each R4is independently H, C1-6alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl, wherein the C1-6alkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a; R5and R7are each independently H, halo, -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN, and the C1-6alkoxy of R5and R7are each independently optionally substituted with one or more halo; R6and R9are each independently H or halo; R10is H;R3aand R4aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and R3xis -OH, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3xis optionally substituted with one or more R3b; and R3band R4bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; with a compound of formula (I-2): (I-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y1is a boronic acid or boronic ester; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; each R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, - NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), -C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; in the presence of a coupling reagent, to provide a compound of formula (I-3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: PG is absent or a protecting group; m is an integer from 1 to 4; R1is -NH-, -O-, or -S-; R2is H; R3is C1-6alkyl, C1-3alkoxy, C3-10cycloalkyl, -N(R4)2¸ 4-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a, and the 4-10 membered heteroaryl of R3is optionally substituted with one or more R3x, provided that when R3is 4-10 membered heteroaryl, R1is -NH-; each R4is independently H, C1-6alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl, wherein the C1-6alkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a; R5and R7are each independently H, halo, -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, whereinthe C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN, and the C1-6alkoxy of R5and R7are each independently optionally substituted with one or more halo; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and R3xis -OH, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3- 10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3xis optionally substituted with one or more R3b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; followed by, (b) optionally contacting the compound of formula (I-3) with a deprotecting agent; to provide a compound of formula (I).

[0178] In some embodiments, a process for preparing a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises: (a) reacting a compound of formula (I-1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q1is halo; PG is absent, or a protecting group; m is an integer from 1 to 4;R1is -N-, -NH-, -O-, or -S-;R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more - CN; R6and R9are each independently H or halo;R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1- 6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; with a compound of formula (I-2): (I-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y1is a boronic acid or boronic ester; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; each R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O- C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy;in the presence of a coupling reagent, to provide a compound of formula (I-3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: PG is absent or a protecting group; m is an integer from 1 to 4; R1is -NH-, -O-, or -S-; R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H;R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; followed by, (b) optionally contacting the compound of formula (I-3) with a deprotecting agent; to provide a compound of formula (I).

[0179] In some embodiments, the protecting group is absent.

[0180] In some embodiments, the protecting group is a sulfonyl group. In some embodiments, the protecting group is SO2Ph. In some embodiments, the protecting group is SO2Ph(CH3).

[0181] In some embodiments, the compound of formula (I-1) is an aryl halide, and the compound of formula (I-2) is a boronic ester or a boronic acid. In some embodiments the boronic ester is a pinacol boronate. In some embodiments the reaction is a Suzuki coupling. In some embodiments, the coupling reagent comprises a catalyst. In some embodiments, the catalyst is Pd(dppf)Cl2.CH2Cl2, Pd(PPh3)4, chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2- aminobiphenyl)]palladium(II), or [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane.

[0182] In some embodiments, the coupling reagent further comprises a base. In some embodiments, the base is potassium carbonate, cesium carbonate, or sodium carbonate.

[0183] In some embodiments, the coupling reagent comprises one or more reagents selected from the group consisting of a palladium catalyst, a phosphine ligand, and a base.

[0184] In some embodiments, the deprotecting agent comprises an acid. In some embodiments the acid is HCl, TFA, or barbituric acid.

[0185] In some embodiments, the deprotecting agent comprises a base. In some embodiments the base is potassium carbonate.

[0186] In some embodiments, a process for preparing a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises: (a) reacting a compound of formula (II-1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q3is H; PG is absent, or a protecting group; m is an integer from 1 to 4; R1ais -N-, -NH-, -O-, or -S-; R2is H; each R4is independently H, C1-6alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl, wherein the C1-6alkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a; R5and R7are each independently H, halo, -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN;R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a;R10is H; R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, - NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; with a compound of formula (II-2):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y3is -C(O)OH, or -C(O)-halo; R3is C1-6alkyl, C1-3alkoxy, C3-10cycloalkyl, -N(R4)2¸ 4-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a, and the 4-10 membered heteroaryl of R3is optionally substituted with one or more R3x, provided that when R3is 4-10 membered heteroaryl, R1is -N- or -NH-; and each R3ais independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, - NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b;R3xis -OH, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3xis optionally substituted with one or more R3b; and each R3bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; in the presence of a coupling reagent, to provide a compound of formula (I-3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: PG is absent or a protecting group; m is an integer from 1 to 4; R1is -NH-, -O-, or -S-; R2is H; R3is C1-6alkyl, C1-3alkoxy, C3-10cycloalkyl, -N(R4)2¸ 4-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a, and the 4-10 membered heteroaryl of R3is optionally substituted with one or more R3x, provided that when R3is 4-10 membered heteroaryl, R1is -NH-; each R4is independently H, C1-6alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-10cycloalkyl, wherein the C1-6alkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a;R5and R7are each independently H, halo, -CN, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)C1-6alkyl, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; R3xis -OH, -CN, halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3xis optionally substituted with one or more R3b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; followed by, (b) optionally contacting the compound of formula (I-3) with a deprotecting agent; to provide a compound of formula (I).

[0187] In some embodiments, a process for preparing a compound of formula (I) or (I’), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises: (a) reacting a compound of formula (II-1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q3is H; PG is absent, or a protecting group; m is an integer from 1 to 4; R1ais -N-, -NH-, -O-, or -S-; R2is H; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more - CN; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H;R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; with a compound of formula (II-2):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y3is -C(O)OH, or -C(O)-halo; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; and each R3ais independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O- C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, each R3bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; in the presence of a coupling reagent, to provide a compound of formula (I-3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: PG is absent or a protecting group; m is an integer from 1 to 4; R1is -NH-, -O-, or -S-; R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H;R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; followed by, (b) optionally contacting the compound of formula (I-3) with a deprotecting agent; to provide a compound of formula (I).

[0188] In some embodiments, the protecting group is absent.

[0189] In some embodiments, the protecting group is a sulfonyl group. In some embodiments, the protecting group is SO2Ph. In some embodiments, the protecting group is SO2Ph(CH3).

[0190] In some embodiments, the deprotecting agent comprises an acid. In some embodiments the acid is HCl, TFA, or barbituric acid.

[0191] In some embodiments, the deprotecting agent comprises a base. In some embodiments the base is potassium carbonate

[0192] In some embodiments, the compound of formula (II-1) is an amine, and the compound of formula (II-2) is a carboxylic acid. In some embodiments, the coupling reagent comprises HATU. In some embodiments, the coupling reagent further comprises a base. In some embodiments, the base is a tertiary amine. In some embodiments the base is DIEA. In some embodiments, the coupling reagent comprises EDCI, HOBt and a tertiary amine base such as DIEA or N-methylimidazole. In some embodiments, the coupling reagent comprises chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate and N-methylimidazole. ENUMERATED EMBODIMENTS

[0193] Embodiment 1. A compound of formula (I):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: m is an integer from 1 to 4; R1is -NH-, -O-, or -S-; R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H;R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy.

[0194] Embodiment 2. The compound of Embodiment 1, wherein the compound is a compound of formula (I-A):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0195] Embodiment 3. The compound of Embodiment 1 or 2, wherein the compound is a compound of formula (I-B):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: ring A is 5-10 membered heteroaryl or 5-10 membered heterocyclyl,wherein the 5-10 membered heteroaryl or 5-10 membered heterocyclyl are each optionally substituted with one or more Ra.

[0196] Embodiment 4. The compound of any of Embodiments 1-3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is an integer from 1-2.

[0197] Embodiment 5. The compound of any of Embodiments 1-4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1.

[0198] Embodiment 6. The compound of any of Embodiments 1-5, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is C1-3alkyl, C1-3haloalkyl, C3-6cycloalkyl, -N(R4)2¸ or 4-6 membered heterocyclyl, wherein each R3is optionally substituted with one or more R3a.

[0199] Embodiment 7. The compound of any of Embodiments 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is C1-3alkyl.

[0200] Embodiment 8. The compound of any of Embodiments 1-7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is methyl.

[0201] Embodiment 9. The compound of any of Embodiments 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is C1-3alkyl, optionally substituted with one or more R3a.

[0202] Embodiment 10. The compound of any of Embodiments 1-6, or 9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3

[0203] Embodiment 11. The compound of any of Embodiments 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is C3-6cycloalkyl optionally substituted with one or more R3a.

[0204] Embodiment 12. The compound of any of Embodiments 1-6, or 11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is C3-6cycloalkyl optionally substituted with one or more halo or C1-3alkyl.

[0205] Embodiment 13. The compound of any of Embodiments 1-6, or 11-12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the

[0206] Embodiment 14. The compound of any of Embodiments 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is -N(R4)2¸ wherein each R4is independently H, or C1-3alkyl.

[0207] Embodiment 15. The compound of any of Embodiments 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is 4-6 membered heterocyclyl, optionally substituted with one or more R3a.

[0208] Embodiment 16. The compound of any of Embodiments 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is -N(R4)2¸ wherein both R4are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl optionally substituted with one or more R3a.

[0209] Embodiment 17. The compound of any of Embodiments 1-6, or 16, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3

[0210] Embodiment 18. The compound of any of Embodiments 1-6 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is 4-6 membered heterocyclyl optionally substituted with one or more R3a.

[0211] Embodiment 19. The compound of any of Embodiments 1-6, or 18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is selected from the group consisting of, , .

[0212] Embodiment 20. The compound of any of Embodiments 1-19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5and R7are each independently H, halo, C1-3alkyl, C1-3alkoxy, C3-6cycloalkyl or C1-3haloalkyl, wherein the C1-3alkyl of R5and R7are each independently optionally substituted with one or more halo, or CN.

[0213] Embodiment 21. The compound of any of Embodiments 1-20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5and R7are each independently H, halo, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl.

[0214] Embodiment 22. The compound of any of Embodiments 1-21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5and R7are each independently H.

[0215] Embodiment 23. The compound of any of Embodiments 1-21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R5and R7is H, and the other of R5and R7is independently halo, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl.

[0216] Embodiment 24. The compound of any of Embodiments 1-23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6and R9are each independently H, or halo.

[0217] Embodiment 25. The compound of any of Embodiments 1-24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6and R9are each independently H, F, or Cl.

[0218] Embodiment 26. The compound of any of Embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6and R9are each independently H.

[0219] Embodiment 27. The compound of any of Embodiments 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R6and R9is H, and the other of R6and R9is F, or Cl.

[0220] Embodiment 28. The compound of any of Embodiments 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is 3-10 membered heterocyclyl, optionally substituted with one or more R8a.

[0221] Embodiment 29. The compound of any of Embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is

[0222] Embodiment 30. The compound of any of Embodiments 1-27, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is 5-10 membered heteroaryl, optionally substituted with one or more R8a.

[0223] Embodiment 31. The compound of any of Embodiments 1-27, or 30, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is 5-10 membered heteroaryl, optionally substituted with one or more R8a, wherein each R8ais independently -CN, halo, C1-3alkyl, C1-3alkoxy, -C(O)NH2, or C3-6cycloalkyl, wherein the C1-6alkoxy, of R8ais optionally substituted with one or more R8b; and each R8bis independently D, or halo.

[0224] Embodiment 32. The compound of any of Embodiments 1-27 ,or 30-31, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the

[0225] Embodiment 33. The compound of any of Embodiments 1-27, or 30-32, wherein the compound is of formula (I-H):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein s is an integer from 0-6; t is 1 or 2; and represents a single or double bond.

[0226] Embodiment 34. The compound of Embodiment 33, wherein the compound is of(I-H-b-iv), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0227] Embodiment 35. The compound of Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from Compounds 1-83 of Table 1.

[0228] Embodiment 36. A process for preparing a compound of formula (I), as defined in any of Embodiments 1-35 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises: (a) reacting a compound of formula (I-1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q1is halo; PG is absent, or a protecting group; m is an integer from 1 to 4;R1is -N-, -NH-, -O-, or -S-;R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more - CN; R6and R9are each independently H or halo;R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1- 6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; with a compound of formula (I-2): (I-2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Y1is a boronic acid or boronic ester; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; each R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O- C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy;in the presence of a coupling reagent, to provide a compound of formula (1-3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:PG is absent or a protecting group; m is an integer from 1 to 4;R1is -NH-, -O-, or -S-;R2is H;R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a;R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN;R6and R9are each independently H or halo;R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a;R10is H;R3aR4aancR8aare each inde pende ntly-OH, oxo, -CN, halo, Ci-6alkyl, C1-6alkoxy, Ci- ehaloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(0)NH2, - C(0)NH(Ci- ealkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3- wcycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; andR3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; followed by,(b) optionally contacting the compound of formula (1-3) with a deprotecting agent; to provide a compound of formula (I).

[0229] Embodiment 37. The process of Embodiment 35, wherein the coupling reagent comprises a palladium catalyst, a phosphine ligand, and / or base.

[0230] Embodiment 38. A process for preparing a compound of formula (I), as defined in any of Embodiments 1-35 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises:(a) reacting a compound of formula (1-1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:Q1is halo;PG is absent, or a protecting group; m is an integer from 1 to 4;R1is -N-, -NH-, -O-, or -S-;R2is H;R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2Jor 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a;R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more - CN;R6and R9are each independently H or halo;R10is H;R3aR4aancR8aoxo, -CN, halo, Ci-6alkyl, C1-6alkoxy, Ci-ehaloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(0)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3- wcycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; andR3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; with a compound of formula (1-2):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:Y1is a boronic acid or boronic ester;R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; each R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O- C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; in the presence of a coupling reagent, to provide a compound of formula (1-3):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:PG is absent or a protecting group; m is an integer from 1 to 4;R1is -NH-, -O-, or -S-;R2is H;R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2, or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a;each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a;R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN;R6and R9are each independently H or halo;R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a;R10is H;R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, Ci- ehaloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3- wcycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-iocycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-iocycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-iocycloalkyl of R8ais optionally substituted with one or more R8b; andR3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; followed by,(b) optionally contacting the compound of formula (1-3) with a deprotecting agent; to provide a compound of formula (I).

[0231] Embodiment 39. The process of any of Embodiments 36-38, wherein the protecting group is a sulfonyl group.

[0232] Embodiment 40. The process of any of Embodiments 36-39, wherein the deprotecting agent comprises a base.

[0233] Embodiment 4E A pharmaceutical composition comprising (i) a compound of any of Embodiments 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

[0234] Embodiment 42. A method of modulating SLC6A19 in a cell, comprising exposing the cell to a composition comprising a compound of any of Embodiments 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of Embodiment 41.

[0235] Embodiment 43. A method of inhibiting SLC6A19 in a cell, comprising exposing the cell to a composition comprising a compound of any of Embodiments 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of Embodiment 41.

[0236] Embodiment 44. A method of reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof, comprising administering to the individual a compound of any of Embodiments 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of Embodiment 41.

[0237] Embodiment 45. A method of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual a compound of any of Embodiments 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of Embodiment 41.

[0238] Embodiment 46. The method of Embodiment 45, wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, metabolic diseases, hyperphenylalaninemia, tyrosinemia (Type I, II, or III), nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, hyperammonemia, diabetes, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity related disorders, and neurodevelopmental and autismspectrum disorders.

[0239] Embodiment 47. The method of Embodiment 45 or 46, wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, and metabolic diseases.

[0240] Embodiment 48. The method of Embodiment 45, wherein the disease, disorder, or condition is associated with abnormal levels of amino acids.

[0241] Embodiment 49. The method of Embodiment 45 or 46, wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

[0242] Embodiment 50. The method of any of Embodiments 45-49, wherein the individual is human.

[0243] Embodiment 51. The method of any one of Embodiments 45-50 wherein a therapeutically effective amount of the compound is administered.

[0244] Embodiment 52. A kit, comprising (i) a compound of any of Embodiments 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of Embodiment 41, and (ii) instructions for use in treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0245] Embodiment 53. The kit of Embodiment 52, wherein the disease, disorder, or condition is associated with abnormal levels of amino acids.

[0246] Embodiment 54. The kit of Embodiment 52 or 53, wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

[0247] Embodiment 55. The kit of Embodiment 52 or 53, wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, metabolic diseases, hyperphenylalaninemia, tyrosinemia (Type I, II, or III), nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, hyperammonemia, diabetes, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity related disorders, and neurodevelopmental and autismspectrum disorders.

[0248] Embodiment 56. The kit of Embodiment any of Embodiments 52-55, wherein the individual has a genetic defect in phenylalanine hydroxylase.

[0249] Embodiment B-l. The compound of any of Embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is

[0250] Embodiment B-2. The compound of any of Embodiments 1-27 ,or 30-31, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the

[0251] Embodiment B-3. The compound of Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from Compounds 1-90 of Table 1.EXAMPLES

[0252] The following synthetic reaction schemes, which are detailed in the Schemes and Examples, are merely illustrative of some of the methods by which the compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art.

[0253] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0254] Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and / or by methods available to one of ordinary skill in the art.Synthetic Examples

[0255] As depicted in the Schemes and Examples below, in certain exemplary embodiments, compounds of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared according to the general procedures. The general methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, variations, embodiments, and species described herein.

[0256] In some embodiments, provided herein is a process for preparing a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing according to any of Scheme 1-Scheme 8.SchemesScheme 1

[0257] Compounds of formula Sl-4 can be prepared according to Scheme 1. Suzuki coupling of Sl-1 with pinacol boronate Sl-2 in the presence of a palladium catalyst such as [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, an inorganic base such as cesium carbonate in hot DMF gives Sl-3. Removal of the indole N- sulfonyl protecting group can be accomplished on heating with a base such as potassium carbonate in aqueous methanol to give compounds of formula Sl-4.Scheme 2

[0258] Compounds of formula S2-5 can be prepared according to Scheme 2. Suzuki coupling of S2-1 with a boronic acid such as S2-2 in the presence of a palladium catalyst such as [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, an inorganic base such as potassium carbonate in hot dioxane gives S2-3.Treatment with a protic acid such as TFA in a solvent such as DCM gives S2-4. Removal of the indole N-sulfonyl protecting group can be accomplished on heating with a base such as potassium carbonate in aqueous methanol to give compounds of formula S2-5.Scheme 3

[0259] Compounds of formula S3-4 can be prepared according to Scheme 3. Suzuki coupling of S3-1 with pinacol boronate S3-2 in the presence of a palladium catalyst such as [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, an inorganic base such as potassium carbonate in hot dioxane gives S3-3. Removal of the indole N-sulfonyl protecting group can be accomplished on heating with a base such as potassium hydroxide in aqueous methanol to give compounds of formula S3-4.Scheme 4

[0260] Compounds of formula S4-7 can be prepared according to Scheme 7. Palladium catalyzed borylation of S4-lwith Bis(pinacolato)diboron with a palladium catalyst such as [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, an inorganic base such as potassium acetate in hot dioxane gives S4-2. Suzuki coupling of S4-2 occurs upon heating an aryl or heteroaryl halide such as S4-3 with a palladium catalyst such as chloro[(di(l-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II), an inorganic base such as potassium carbonate in aqueous dioxane to give S4-4. Removal of the indole N-sulfonyl protecting group can be accomplished on heating with TBAF in THF to give S4-5. Removal of the N-Boc group upon treatment with a protic acid such as HC1 in EtOAc gives S4-6. Coupling of S4-6 with acid S4-7 in the presence of HATU and DIEA in a solvent such as DCM gives compounds of formula S4-8.Scheme 5

[0261] Compounds of formula S5-3 can be prepared according to Scheme 5. Suzuki coupling of S5-1 an aryl or heteroaryl halide such as S5-2 occurs upon heating a palladium catalyst such as chloro[(di(l-adamantyl)-N-butylphosphine)-2-(2- aminobiphenyl)]palladium(II), an inorganic base such as potassium carbonate in hot aqueous dioxane to give S5-3.Scheme 6

[0262] Compounds of formula S6-3 may be prepared according to Scheme 6. Coupling ofS6-1 with carboxylic acid S6-2 occurs in the presence of chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate and N-methylimidazole in a solvent such as acetonitrile to give compounds of formula S6-3.Scheme 7

[0263] Compounds of formula S7-3 may be prepared according to Scheme 7. Coupling of S7-1 with carboxylic acid S7-2 occurs in the presence of EDCI, HOBt, and N- methylimidazole in a solvent such as ethanol to give compounds of formula S7-3.Scheme 8

[0264] Compounds of formula S8-5 may be prepared according to Scheme 8. Stille coupling of S8-1 with an aryl or heteroaryltributyl stannane such as S8-2 with a catalyst such Tetrakis(triphenylphosphine)palladium(0) occurs upon heating in a solvent such as dioxane to give S8-3. Removal of the N-Boc protecting group upon treatment with HC1 in a solvent such as EtOAc gives S8-4. Reaction with acetic anhydride and DIEA in a solvent such as DCM gives compounds of formula S8-5.Scheme 9S9-1 S9-2

[0265] Compounds of formula S9-2 may be prepared according to Scheme 9. Stille coupling of compounds of the formula S9-1 with an aryl or heteroaryltributyl stannane in the presence of a catalyst such tetrakis(triphenylphosphine)palladium(0) occurs upon heating in a solvent such as dioxane to give compounds of the formula S9-2.Scheme 10

[0266] Compounds of formula S10-2 may be prepared according to Scheme 10. Suzuki coupling of a compound of the formula S10-1, in which R12may be hydrogen or a protectinggroup such as phenylsulfonyl, with an aryl or heteroaryl halide in the presence of a catalyst such tetrakis(triphenylphosphine)palladium(0) and a base such as K2CO3 occurs upon heating in a mixed solvent system such as dioxane / water to give compounds of the formula S10-2, which may or may not require additional deprotection or functional group manipulation under standard conditions.Scheme 11

[0267] Compounds of formula SI 1-4 may be prepared according to Scheme 11. Suzuki coupling of a compound of the formula SI 1-1 with an aryl or heteroaryl halide in the presence of a catalyst such Pd(dppf)C12 and a base such as K2CO3 occurs upon heating in a mixed solvent system such as dioxane / water to give compounds of the formula SI 1-2.Deprotection of the amino group using reagents such as HC1 in EtOAc gives compounds of the formula Sll-3. Acylation of the free amino group using an acylating agent such as a carboxylic acid anhydride gives compounds of the formula SI 1-4.Scheme 12

[0268] Compounds of formula S12-2 may be prepared according to Scheme 12. Reaction of compounds of the formula S12-1 using a reagent such as S12-2, in which R3and R13may be individually alkyl or hydrogen or in which R3and R13may be cyclized to form a ring, in thepresence of a base such as DIEA in a solvent such as DCM gives compounds of the formulaS12-3Scheme 13

[0269] Compounds of formula S13-3 may be prepared according to Scheme 13. Reaction of compounds of the formula S13-1 using a reagent such as S13-2, in which R3and R13may be individually alkyl or hydrogen or in which R3and R13may be cyclized to form a ring, in the presence of CDI and a base such as DIEA in a solvent such as DMF gives compounds of the formula SI 3-3.Intermediate A-l: Synthesis of 6-bromo-[l,3]dioxolo[4,5-c]pyridineLDA

[0270] Step a: To a solution of 6-brom opyri din-3 -ol (1.00 g, 5.75 mmol, 1.00 eq) in DMF (4 mL) at 0 °C was added K2CO3 (1.59 g, 11.5 mmol, 2.0 eq) and (chloromethoxy)ethane (815 mg, 8.62 mmol, 1.50 eq) dropwise. The reaction was allowed to warm to room temperature. After 6 h, the reaction mixture was quenched by the addition of H2O (15 mL). The resulting mixture was then extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 2- bromo-5-(ethoxymethoxy)pyridine. LC-MS (ESI) m / z: [M + H]+calcd for CsHioBrNCh: 232.0; found: 232.1.

[0271] Step b: To a solution of 2-bromo-5-(ethoxymethoxy)pyridine (1.00 g, 4.31 mmol, 1.00 eq) in anhydrous THF (10 mL) at -65 °C was added 2 M LDA in THF (2.37 mL, 4.74 mmol, 1.10 eq) dropwise. After 1 h at -65 °C, a THF (5 mL) solution of triisopropyl borate (891 mg, 4.74 mmol, 1.10 eq) was added dropwise. The reaction was warmed to -15 °C. After 3 h, 30 wt% H2O2 (977 mg, 8.62 mmol, 2.00 eq) was added dropwise. The reaction was then warmed to room temperature. After 1.5 h, the reaction was quenched by the addition of H2O (15 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous Na2SOs (2 x 20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-bromo-5- (ethoxymethoxy)pyridin-4-ol. LC-MS (ESI) m / z: [M + H]+calcd for CsHioBrNCh: 248.0; found: 248.1.

[0272] Step c: To a solution of 2-bromo-5-(ethoxymethoxy)pyridin-4-ol (510 mg, 2.1 mmol, 1.00 eq) in MeOH (3.0 mL) was added 4 M HC1 in MeOH (5 mL, 20.0 mmol, 10.0 eq). After 2 h, the reaction mixture was concentrated under reduced pressure to give 6-bromopyridine- 3,4-diol hydrochloride. LC-MS (ESI) m / z: [M + H]+calcd for Cs^BrNCh: 190.0; found: 189.8.

[0273] Step d: To a solution of 6-bromopyridine-3,4-diol hydrochloride (450 mg, 1.99 mmol, 1.00 eq) in DMF (15.0 mL) was added CS2CO3 (971 mg, 2.98 mmol, 1.50 eq) and chloroiodomethane (526 mg, 2.98, 1.50 eq). The reaction mixture was then warmed to 60 °C. After 2 h, the reaction was cooled to room temperature and quenched by the addition of H2O (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 6-bromo-[l,3]dioxolo[4,5-c]pyridine. LC-MS (ESI) m / z: [M + H]+calcd for C6H4BrNO2: 201.9; found: 202.1.Intermediate A-2: Synthesis of 6-chlorothiazolo[5,4-c]pyridine

[0274] Step a: To a solution of 5-bromo-2-chloropyridin-4-amine (4.0 g, 19.3 mmol, 1.00 eq) in acetone (40 mL) was added benzoyl isothiocyanate (9.44 g, 57.8 mmol, 3.0 eq) dropwise. After 16 h, the reaction mixture was then concentrated under reduced pressure. The resultant residue was triturated with n / -heptane (3 mL) for 20 minutes then collected by vacuum filtration to give A-((5-bromo-2-chloropyridin-4-yl)carbamothioyl)benzamide.

[0275] Step b: To a solution of A-((5-bromo-2-chloropyridin-4-yl)carbamothioyl)benzamide (6.00 g, 16.2 mmol, 1.00 eq), in MeOH (60 mL) was added 6 M aqueous sodium hydroxide (5.4 mL, 32.4 mmol, 2.0 eq). The reaction was then warmed to 75 °C. After 4 h, the reaction was cooled to room temperature and quenched by the addition of saturated aqueous NH4CI (20 mL). The resulting precipitate was collected by vacuum filtration. The filter cake was washed with H2O (2 x 20 mL) and DCM (20 mL). The filter cake was then dried under reduced pressure to give l-(5-bromo-2-chloropyridin-4-yl)thiourea. LC-MS (ESI) m / z: [M + H]+calcd for CeHsBrCINsS: 265.9; found: 266.1.

[0276] Step c: To a solution of l-(5-bromo-2-chloropyridin-4-yl)thiourea (1.00 g, 3.75 mmol, 1.00 eq) in DMSO (5.0 mL) was added L-proline (863 mg, 7.50 mmol, 2.0 eq), CS2CO3 (2.44 g, 7.5 mmol, 2.0 eq), and Cui (71.5 mg, 0.38, 0.1 eq). The reaction mixture was then warmed to 70 °C. After 2 h, the reaction was cooled to room temperature and quenched by being poured into H2O (10 mL). The resulting precipitate was collected by vacuum filtration. The filter cake was washed with H2O (10 mL) then dried under reduced pressure to give 6- chlorothiazolo[5,4-c]pyridin-2-amine. LC-MS (ESI) m / z: [M + H]+calcd for C6H4CIN3S: 186.0; found: 185.8.

[0277] Step d: To a solution of 6-chlorothiazolo[5,4-c]pyridin-2-amine (600 mg, 3.23 mmol, 1.00 eq) in THF (6.0 mL) was added isopentyl nitrite (1.89 g, 16.2 mmol, 5.00 eq). The reaction mixture was then warmed to 85 °C. After 4 h, the reaction was cooled to roomtemperature and quenched by being poured into H2O (5 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 6-chlorothiazolo[5,4- c]pyridine. LC-MS (ESI) m / z: [M + H]+calcd for C6H3CIN2S: 171.0; found: 171.2.

[0278] Step a: To a solution of ethane- 1,2-diol (63 mL) at 0 °C was added 60% sodium hydride (3.84 g, 95.9 mmol, 2.00 eq) portionwise. After 30 minutes, 5-bromo-6- chloropyrazin-2-amine (10.0 g, 47.9 mmol, 1.00 eq) was added portionwise. The reaction mixture was then warmed to 140 °C. After 1 h, the reaction mixture was cooled to room temperature and quenched by the addition of ice water (50.0 mL). The resulting mixture was then extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was triturated with EtOAc (12 mL) for 10 minutes. The solid was collected by vacuum filtration and dried under reduced pressure to give 2-((6-bromo-4- iodopyridin-3-yl)oxy)ethan-l-ol. LC-MS (ESI) m / z: [M + H]+calcd for CLHsBrM^: 234.0; found: 234.2.

[0279] Step b: A solution of 2-((6-bromo-4-iodopyridin-3-yl)oxy)ethan-l-ol (4.10 g, 17.5 mmol, 1.00 eq), in (dimethoxymethyl)dimethylamine (12 mL) was warmed to 50 °C. After 1 h, the reaction was cooled to room temperature and quenched by the addition of ice water (25 mL). The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with EtOAc(15 mL) for 10 minutes. The solid was collected by vacuum filtration and dried under reduced pressure to give (E)-A-(5-bromo-6-(2 -hydroxy ethoxy )pyrazin-2-yl)-A,A- dimethylformimidamide. LC-MS (ESI) m / z: [M + H]+calcd for C9Hi3BrN4O2: 289.0; found: 288.8.

[0280] Step c: (E)-A-(5-bromo-6-(2-hydroxyethoxy)pyrazin-2-yl)-A,A- dimethylformimidamide (3.10 g, 10.7 mmol, 1.00 eq) in toluene (310 mL) was added CS2CO3 (10.4 g, 32.1 mmol, 3.00 eq), Pd(OAc)2 (240 mg, 1.1 mmol, 0.1 eq), and BINAP (1.34 g, 2.14, 0.20 eq). The sealed reaction vessel was evacuated and refilled with nitrogen three times and then warmed to 90 °C. After 16 h, the reaction mixture was cooled to room temperature and quenched by being poured into H2O (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers 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 and prep-HPLC to give ( E )- A-(2,3-dihydro-[l,4]dioxino[2,3-b]pyrazin-6-yl)-A,A-dimethylformimidamide. LC-MS (ESI) m / z: [M + 2H]+calcd for C9H12N4O2: 209.1; found: 209.1.

[0281] Step d: (E)-A-(2,3-dihydro-[l,4]dioxino[2,3-b]pyrazin-6-yl)-7V,A- dimethylformimidamide (1.2 g, 2.88 mmol, 1.00 eq) in EtOH (12 mL) was added ethane-1,2- diamine (380 mg, 6.32 mmol, 2.19 eq) dropwise. The reaction was then warmed to 80 °C. After 12 h, the reaction was cooled to room temperature and quenched by being poured into H2O (20 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2,3-dihydro-[l,4]dioxino[2,3-b]pyrazin-6-amine. LC-MS (ESI) m / z: [M + H]+calcd for C6H7N3O2: 154.1; found: 154.0.

[0282] Step e: To a solution of 2,3-dihydro-[l,4]dioxino[2,3-b]pyrazin-6-amine (190 mg, 1.24 mmol, 1.00 eq) in H2O (1 mL) at 0 °C was added 40% aqueous HBr (1 mL, 7.37 mmol, 5.9 eq) and a solution of NaNO2 (128 mg, 1.86 mmol, 1.5 eq) in H2O (0.5 mL). After 5 minutes, CuBr (355 mg, 2.48 mmol, 2.00 eq) was added in one portion. After 1 h, the reaction was warmed to room temperature and quenched by being poured into H2O (2 mL). The resulting mixture was extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentratedunder reduced pressure. The crude residue obtained was purified by prep-HPLC to give 6- bromo-2,3-dihydro-[l,4]dioxino[2,3-b]pyrazine. LC-MS (ESI) m / z: [M + H]+calcd for C6H5BrN2O2: 217.0; found: 217.2.

[0283] Step a: A mixture of A-((6-bromo-5-chl oro-1 -(phenyl sulfonyl)- 1H-indol -2- yl)methyl)acetamide (1.50 g, 3.40 mmol, 1.00 eq) and tributyl(l-ethoxyvinyl)stannane (2.45 g, 6.79 mmol, 2.00 eq) in dioxane (10 mL) was degassed and purged with N2 three times followed by the addition of Pd(PPh3)2Ch (238 mg, 339 pmol, 0.10 eq). The reaction mixture was then warmed to 90 °C and stirred for 16 h. The reaction mixture was then cooled to 23 °C and quenched by addition of aqueous HCI (1 M, 5 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (3 x 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with MTBE (10 mL) at 23 °C for 30 min to give N- ((6-acetyl-5-chloro-l-(phenylsulfonyl)-1H-indol-2-yl)methyl)acetamide. LC-MS (ESI): m / z: [M + H]+calculated for C19H17QN2O4-S: 405.1; found 405.1.

[0284] Step a: Four reactions were carried out in parallel. To a solution of 3-bromo-4- chloroaniline (50.0 g, 242.0 mmol, 1.00 eq) in DCM (270.0 mL) was added acetic acid (41.6 mL, 726.0 mmol, 3.0 eq) in a single portion followed by a solution of NIS (76.3 g, 339.0 mmol, 1.40 eq.) in MeOH (270 mL) dropwise over 1 h. After 5 h, the four reactions were combined for work up. The reaction mixture was quenched by the addition of H2O (2.0 L). The resulting mixture was then extracted with EtOAc (3 x 2.0 L). The combined organic layers were washed with brine (3 x 1.0 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-bromo-4-chloro-2-iodoaniline. LC-MS (ESI) m / z: [M + H]+calcd for C6H4BrClIN: 331.8; found: 331.9.

[0285] Step b: To a solution of 5-bromo-4-chloro-2-iodoaniline (118.0 g, 355.0 mmol, 1.00 eq) in DMF (1.0 L) was added tert-butyl prop-2-yn-l-ylcarbamate (55.1 g, 355 mmol, 1. 0 eq), TEA (247 mL, 1.78 mol, 5.00 eq), Cui (13.5 g, 71.0 mmol, 0.20 eq), and bis(triphenylphosphine)palladium(II) dichloride (7.5 g, 10.7 mmol, 0.03 eq). The sealed reaction vessel was evacuated and refilled with nitrogen three times. After 2 h at room temperature, the reaction was quenched by pouring into ice water (2.0 L). The resulting mixture was extracted with EtOAc (3 x 1.0 L). The combined organic layers were washed with brine (3 x 1.0 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tertbutyl (3-(2-amino-4-bromo-5-chlorophenyl)prop-2-yn-l-yl)carbamate. LC-MS (ESI) m / z: [M - C4H9+ 2H]+calcd for Ci4Hi6BrClN2O2: 303.0; found: 302.8.

[0286] Step c: To a solution of tert-butyl (3-(2-amino-4-bromo-5-chlorophenyl)prop-2-yn-l- yl)carbamate (110.0 g, 305 mmol, 1.00 eq), in DCM (1.0 L) at 0 °C was added pyridine (49.4 mL, 611.0 mmol, 2.0 eq) in a single portion followed by benzenesulfonyl chloride (39.0 mL, 305 mmol, 1.00 eq) dropwise. The reaction was then allowed to warm to room temperature. After 1 h, the reaction mixture was quenched by pouring it into ice water (2.0 L). The resulting biphasic mixture was extracted with EtOAc (3 x 1.0 L). The combined organic layers were washed with brine (3 x 1.0 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl (3-(4-bromo-5-chloro-2- (phenylsulfonamido)phenyl)prop-2-yn-l-yl)carbamate, which was used without further purification. LC-MS (ESI) m / z: [M + Na]+calcd for C2oH2oBrClN204S: 521.0; found: 521.0.

[0287] Step d: To a solution of tert-butyl (3-(4-bromo-5-chloro-2- (phenylsulfonamido)phenyl)prop-2-yn-l-yl)carbamate (150.0 g, 300.0 mmol, 1.00 eq) in MeCN (1.5 L) was added CuCl (4.46 g, 45.0 mmol, 0.15 eq) and Cs2CO3(14.7 g, 45.0 mmol, 0.15 eq.). The sealed reaction vessel was evacuated and refilled with nitrogen three times. After 3 h at room temperature, the reaction was quenched by being poured into ice water (2.0 L). The resulting biphasic mixture was extracted with EtOAc (3 x 1.0 L). The combined organic layers were washed with brine (3 x 1.0 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl ((6-bromo-5-chloro-l- (phenylsulfonyl)-1H-indol-2-yl)methyl)carbamate, which was used without any further purification. LC-MS (ESI) m / z: [M - C4H9+ 2H]+calcd for C2oH2oBrClFN204S: 442.9; found: 443.1.

[0288] Step e: To a solution of tert-butyl ((6-bromo-5-chl oro-1 -(phenyl sulfonyl)- 1H-indol-2- yl)methyl)carbamate (59.0 g, 118.0 mmol, 1.00 eq) in EtOAc (10 mL) at 0 °C was added 4 M HC1 in EtOAc (500 mL, 2.0 mol, 16.9 eq) portionwise. The reaction was then allowed to warm to room temperature. After 1 h, the reaction mixture was concentrated under reduced pressure to give A-((6-bromo-5-chl oro-1 -(phenylsulfonyl)- 1H-indol-2-yl)methyl)-X5- chloranimine, which was used without further purification. LC-MS (ESI) m / z: [M + H]+calcd for Ci5Hi2BrClN2O2S: 398.9; found: 399.1.Example S-l: Synthesis of / V-((5-chloro-7-fluoro-6-(5-methoxypyrazin-2-yl)-lH-indol-2- yl)methyl)acetamide (Compound 78)

[0289] Step a: To a solution of 3-bromo-2-fluoroaniline (14.0 g, 73.7 mmol, 1.00 eq) in DMF (70.0 mL) was added 1 -chloropyrrolidine-2, 5-dione (10.3 g, 77.3 mmol, 1.05 eq). After the addition, the reaction was warmed to 70 °C and stirred for 1 h. The reaction was then cooled to 0 °C and quenched by the addition of H2O (100 mL). The resulting mixture was then extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 3- bromo-4-chloro-2-fluoroaniline, which was used without further purification.

[0290] Step b: To a solution of 3-bromo-4-chloro-2-fluoroaniline (15.0 g, 66.8 mmol, 1.00 eq), in DCM (80 mL) at 0 °C was added 1 -iodopyrrolidine-2, 5-dione (22.5 g, 100.0 mmol, 1.50 eq) and BF3°Et2O (9.48 g, 66.8 mmol, 1.00 eq). After Ih, the reaction mixture was quenched with water (100 mL) and then warmed to room temperature. The resulting biphasic mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 3-bromo-4- chloro-2-fluoro-6-iodoaniline.

[0291] Step c: To a solution of 3-bromo-4-chloro-2-fluoro-6-iodoaniline (6.90 g, 19.6 mmol, 1.00 eq) in DMF (70 mL) was added / c / 7-butyl prop-2-yn-l-ylcarbamate (3.67 g, 23.6 mmol, 1.20 eq), TEA (9.96 g, 98.4 mmol, 5.00 eq), Cui (750 mg, 3.94 mmol, 0.20 eq), and bis(triphenylphosphine)palladium(II) dichloride (1.38 g, 1.97 mmol, 0.10 eq). The sealedreaction vessel was evacuated and refilled with nitrogen 3 times. After 1 h at room temperature, the reaction was quenched with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl (3-(2-amino-4- bromo-5-chloro-3-fluorophenyl)prop-2-yn-l-yl)carbamate. LC-MS (ESI) m / z: [M + H]+calcd for CuHieBrClF^Ch: 377.0; found: 377.1.

[0292] Step d: To a solution of tert-butyl (3-(2-amino-4-bromo-5-chloro-3- fluorophenyl)prop-2-yn-l-yl)carbamate (5.90 g, 15.6 mmol, 1.00 eq) in 1,2-DCE (60 mL) was added Cu(OAc)2*H2O(1.56 mmol, 7.81 mL, 0.50 eq). The reaction mixture was then warmed to 100 °C. After 3 h, the reaction was cooled to room temperature and quenched by being poured into H2O (40 mL). The biphasic solution was then extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl ((6-bromo-5-chloro-7-fluoro- IT / -indol-2- yl)methyl)carbamate. LC-MS (ESI) m / z: [M - C4H9 + 2H]+calcd for Ci4Hi6BrClFN2O2: 320.9; found: 321.0.

[0293] Step e: To a solution of tert-butyl ((6-bromo-5-chloro-7-fluoro-l / / -indol-2- yl)methyl)carbamate (2.00 g, 5.30 mmol, 1.00 eq) in EtOAc (10 mL) at 0 °C was added 4 M HC1 in EtOAc solution (20 mL, 80.00 mmol, 15.10 eq) dropwise. The reaction was then allowed to warm to room temperature. After 1 h, the reaction mixture was concentrated under reduced pressure to give (6-bromo-5-chloro-7-fluoro-l / / -indol-2-yl)methanamine hydrochloride, which was used without further purification. LC-MS (ESI) m / z: [M -NEE]4calcd for C9H8BrClFN2: 259.9; found: 260.0.

[0294] Step f: To a solution of (6-bromo-5-chloro-7-fluoro-l / / -indol-2-yl)methanamine hydrochloride (1.60 g, 5.10 mmol, 1.00 eq) in THF (16 mL) was added DIEA (1.32 g, 10.1 mmol, 2.00 eq) and acetic anhydride (728 mg, 7.13 mmol, 1.40 eq) dropwise. After 1 h, the reaction was quenched by being poured into H2O (10 mL). The reaction mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give A-((6-bromo-5-chloro-7-fluoro- IT / -indol-2-yl)methyl)acetamide. LC-MS (ESI) m / z: [M + H]+calcd for CnHioBrClFN20: 319.0; found: 319.0.

[0295] Step g: Two reactions were carried out in parallel. To a solution of A-((6-bromo-5- chloro-7-fluoro-l / Z-indol-2-yl)methyl)acetamide (640 mg, 1.13 mmol, 1.00 eq) in dioxane (2.0 mL) was added 2-methoxy-5 -(tributyl stannyl)pyrazine (640 mg, 1.25 mmol, 2.00 eq) and Pd(PPh3)4 (145.0 mg, 0.13 mmol, 0.20 eq). The sealed reaction vessel was evacuated and refilled with nitrogen 3 times and then was warmed to 100 °C. After 1 h, the reactions were cooled to room temperature, combined, and poured into H2O (3 mL). The mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (2 x 5mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give A-((5-chloro-7-fluoro-6-(5- methoxypyrazin-2-yl)-17 / -indol-2-yl)methyl)acetamide. 'H NMR (DMS0400 MHz) 5 ppm 11.81 (s, 1H), 8.46 (s, 1H), 8.38 (t, 5.4 Hz, 1H), 8.35 (s, 1H), 7.55 (s, 1H), 6.40 (d, J= 3.2Hz, 1H), 4.42 (d, J= 5.6 Hz, 2H), 3.98 (s, 3H), 1.90 (s, 3H). LC-MS (ESI) m / z: [M + H]+calcd for Ci6Hi5ClFN4O2: 349.1; found: 349.2.Example S-2: Synthesis of 7V-((5-chloro-6-(5,5-dimethyl-l ,3,2-dioxaborinan-2-yl)-lH- indol-2-yl)methyl)acetamide (Compound 88)

[0296] Step a: To a solution of tert-butyl ((5-chloro-6-hydroxy-1H-indol-2- yl)methyl)carbamate (150 g, 505.0 mmol, 1.00 eq) in DCM (1.50 L) at 0 °C was added triethylamine (61.3 g, 606.0 mmol, 1.20 eq) and triflic anhydride (156.0 g, 556 mmol, 1.10 eq). The reaction was then allowed to warm to room temperature. After 1 h, the reaction mixture was quenched by the addition of H2O (1.0 L). The resulting mixture was then extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with MTBE (80 mL) for 30 minutes then collected by vacuum filtration to give 2-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-1 H -indol-6-yl trifluoromethanesulfonate LC-MS (ESI) m / z: [M - C4H9 + 2H]+calcd for C15H17QF3N2O5S: 373.0; found: 373.1.

[0297] Step b: Three reactions were carried out in parallel. To a solution of 2-(((te / 7- butoxycarbonyl)amino)methyl)-5-chloro-1 H -indol-6-yl trifluoromethanesulfonate (75.0 g, 174 mmol, 1.00 eq), in EtOAc (75 mL) at 0 °C was added 4M HC1 in EtOAc (375 mL, 1.5 mol, 8.62 eq) dropwise. The reaction was then allowed to warm to room temperature. After 2 h, the three reactions were combined and concentrated under reduced pressure to give 2-(((X5- chl oraneylidene)amino)methyl)-5-chl oro-1 H -indol-6-yl trifluoromethanesulfonate hydrochloride which was used without further purification. LC-MS (ESI) m / z: [M - NEE]4calcd for C10H8CIF3N2O3S: 312.0; found: 312.2.

[0298] Step c: Three reactions were carried out in parallel. To a solution of 2-(((X5- chl oraneylidene)amino)methyl)-5-chl oro-1 H -indol-6-yl trifluoromethanesulfonate hydrochloride (63.8 g, 174 mmol, 1.00 eq) in THF (575 mL) was added DIEA (45.2 g, 349 mmol, 2.00 eq) and a solution of acetic anhydride (25.0 g, 244 mmol, 1.40 eq) in THF (64 mL) dropwise. After 1 h, the reactions were combined and quenched by the addition of H2O (1.0 L). The solution was then extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1.0 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with petroleum ether / MTBE (1 : 1, 958 mL) for 30 minutes then collected by vacuum filtration to give 2-(acetamidomethyl)-5-chloro-1H-indol-6-yl trifluoromethanesulfonate. LC-MS (ESI) m / z: [M + H]+calcd for C12H10CIF3N2O4S: 371.0; found: 371.1.

[0299] Step d: To a solution of 2-(acetamidomethyl)-5-chloro-1H-indol-6-yl trifluoromethanesulfonate (70 g, 188 mmol, 1.00 eq) in dioxane (700 mL) was added 5,5,5',5'-tetramethyl-2,2'-bi(l,3,2-dioxaborinane) (127 g, 566 mmol, 3.00 eq), potassium acetate (40.7 g, 415 mmol, 2.20 eq), and Pd(PPh3)2Ch (13.2 g, 18.8 mmol, 0.1 eq). The sealed reaction vessel was evacuated and refilled with nitrogen three times and then warmed to 120 °C. After 1 h, the reaction was cooled to room temperature, filtered to remove solids, and concentrated under reduced pressure. The crude residue containing A-((5-chloro-6-(5,5- dimethyl-l,3,2-dioxaborinan-2-yl)-17 / -indol-2-yl)methyl)acetamide was used without further purification.

[0300] Step e: To a solution of A-((5-chloro-6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-UT- indol-2-yl)methyl)acetamide (100 mg, 0.3 mmol, 1.00 eq) in dioxane / fbO (5: 1, 2.4 mL) was added K2CO3 (123 mg, 0.9 mmol, 3.0 eq), 2-bromothieno[3,2-b]pyridine (63.9 mg, 298 pmol, 1.00 eq), and Pd(PPh3)4 (34.5 mg, 29.8 pmol, 0.10 eq). The sealed reaction vessel was evacuated and refilled with nitrogen three times and then warmed to 75 °C. After 1 h, the reaction mixture was cooled to room temperature and quenched by the addition of H2O (5.0 mL). The solution was extracted with EtOAc (3 x 1.0 mL). The combined organic layers were washed with brine (1.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to give A-((5-chloro- 6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-17 / -indol-2-yl)methyl)acetamide.JH NMR (DMSO 400 MHz) 5 ppm 11.30 (s, 1H), 8.67 (d, J= 4.4 Hz, 1H), 8.47 (d, J= 7.6 Hz, 1H), 8.42 (t, J= 5.2 Hz, 1H), 7.72 (d, J= 4.0 Hz, 2H), 7.66 (s, 1H), 7.40 -7.38 (m, 1H), 6.33 (s, 1H), 4.42 (d, J= 5.6 Hz, 2H), 1.91 (s, 3H). LC-MS (ESI) m / z: [M + H]+calcd for C18H14CIN3OS: 356.1; found: 356.1.

[0301] Step a: To a solution of 2-bromo-5-fluoro-4-iodopyridine (10.0 g, 33.1 mmol, 1.00 eq) in NMP (120 mL) at 0 °C was added ethane- 1,2-diol (9.87 g, 159 mmol, 4.8 eq) and t- BuOK (4.09 g, 36.4 mmol, 1.10 eq). The reaction was then warmed to 80 °C. After 1 h, the reaction mixture was cooled to room temperature and quenched by the addition of H2O (50.0 mL). The resulting mixture was then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-((6-bromo-4-iodopyridin-3-yl)oxy)ethan-l-ol. LC-MS (ESI) m / z: [M + H]+calcd for C7H7BrINO2: 343.9; found: 344.0.

[0302] Step b: To a solution of 2-((6-bromo-4-iodopyri din-3 -yl)oxy)ethan-l-ol (4.00 g, 11.6 mmol, 1.00 eq), in z-PrOH (40 mL) at 0 °C was added 3,4,7,8-tetramethyl-l,10- phenanthroline (27.5 mg, 0.12 mmol, 0.01 eq), Cui (22.2 mg, 0.12 mmol, 0.01 eq), and t- BuOK (4.09 g, 36.4 mmol, 1.10 eq) in one portion. The reaction was then warmed to 80 °C. After 1 h, the reaction was cooled to room temperature and quenched by the addition of H2O (20 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 7-bromo-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine. LC-MS (ESI) m / z: [M + H]+calcd for C7H6BrNO: 216.0; found: 215.8.

[0303] Step c: To a solution of A-((5-chloro-6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-UT- indol-2-yl)methyl)acetamide (100 mg, 0.3 mmol, 1.00 eq) in dioxane / ELO (5: 1, 1.2 mL) was added 7-bromo-2,3-dihydro-[l,4]dioxino[2,3-c]pyridine (127 g, 566 mmol, 3.00 eq),potassium carbonate (124 mg, 0.9 mmol, 3.0 eq), and Pd(PPh3)4 (34.5 mg, 0.03 mmol, 0.1 eq). The sealed reaction vessel was then evacuated and refilled with nitrogen three times and then warmed to 75 °C. After 1 h, the reaction was cooled to room temperature and quenched by the addition of H2O (5 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give A-((5-chloro-6-(2,3-dihydro-[l,4]dioxino[2,3-c]pyridin-7-yl)- l / / -indol-2-yl)methyl)acetamide1H NMR (DMSO 400 MHz) 5 ppm 11.16 (s, 1H), 8.39 (t, J = 5.6 Hz, 1H), 8.19 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.11 (s, 1H), 6.28 (s, 1H), 4.40 (d, J= 5.6 Hz, 4H), 4.36 (d, J= 4.8 Hz, 2H), 1.89 (s, 3H). . LC-MS (ESI) m / z: [M + 2H]+calcd for C18H16CIN3O3: 358.1; found: 358.2.Example S-4: Synthesis of 7V-((5-fluoro-6-(5-methoxypyrazin-2-yl)-lH-indol-2- yl)methyl)propionamide (Compound 90)

[0304] Step a: To a solution of tert-butyl ((5-fluoro-6-hydroxy-1H -indol-2- yl)methyl)carbamate (10.0 g, 35.6 mmol, 1.00 eq) in DCM (100 mL) at 0 °C was added TEA (4.33 g, 42.8 mmol, 1.2 eq) and Tf2O (11.0 g, 39.2 mmol, 1.10) dropwise. The reaction was allowed to warm to room temperature. After 1 h, the reaction mixture was quenched by beingpoured into H2O (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with ^-heptane (100 mL) for 30 minutes. The solid was collected by vacuum filtration to give 2-(((tert-butoxycarbonyl)amino)methyl)-5-fluoro-l H-indol-6-yl trifluoromethanesulfonate. LC-MS (ESI) m / z: [M - C4H9 + 2H]+calcd for C15H16F4N2O5S: 357.0; found: 357.2.

[0305] Step b: To a solution of 2-(((tert-butoxycarbonyl)amino)methyl)-5-fluoro-l / / -indol-6- yl trifluoromethanesulfonate (2.00 g, 4.9 mmol, 1.00 eq) in z-PrOAc (10 mL) was added bis(pinacolato)diboron (1.48 g, 5.82 mmol, 1.20 eq), KOPiv (1.50 g, 10.6 mmol, 2.20 eq), XPhos (462 mg, 1.0 mmol, 0.20), and XPhos-Pd G3 (410 mg, 0.49 mmol, 0.10 eq). The sealed reaction vessel was then evacuated and refilled with nitrogen three times and then heated to 85 °C. After 12 h, the reaction was cooled to room temperature and filtered. The filtrate was then concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl ((5-fluoro-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indol-2-yl)methyl)carbamate. LC-MS (ESI) m / z: [M + H]+calcd for C2oH28BrFN204: 391.2; found: 391.4.

[0306] Step c: To a solution of tert-butyl ((5-fluoro-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l / / -indol-2-yl)methyl)carbamate (1.80 g, 3.7 mmol, 1.00 eq) in dioxane / ELO (5: 1, 24 mL) was added 2-bromo-5-methoxypyrazine (697 mg, 3.7 mmol, 1.0 eq), K2CO3 (1.53 g, 11.0 mmol, 3.0 eq), and Pd(dppf)C12*CH2C12 (301 mg, 0.37 mmol, 0.10 eq). The sealed reaction vessel was then evacuated and refilled with nitrogen three times and then warmed to 100 °C. After 2 h, the reaction mixture was cooled to room temperature and quenched by pouring the reaction mixture into H2O (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers 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 give tert-butyl ((5-fluoro- 6-(5-methoxypyrazin-2-yl)-l / / -indol-2-yl)methyl)carbamate. LC-MS (ESI) m / z: [M + H]+calcd for C19H21FN4O3: 373.2; found: 373.2.

[0307] Step d: To a solution of tert-butyl ((5-fluoro-6-(5-methoxypyrazin-2-yl)-l / / -indol-2- yl)methyl)carbamate (800 mg, 2.15 mmol, 1.00 eq) in EtOAc (4 mL) at 0 °C was added 4 M HC1 in EtOAc (10 mL, 40.00 mmol, 18.6 eq) dropwise. The reaction mixture was thenwarmed to 23 °C. After 2 h, the reaction mixture was concentrated under reduced pressure to give (5-fluoro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methanamine hydrochloride, which was used without further purification. LC-MS (ESI) m / z: [M + H]+calcd for C14H13FN4O: 273.1; found: 273.0.

[0308] Step e: To a solution of (5-fluoro-6-(5-methoxypyrazin-2-yl)-1H-indol-2- yl)methanamine hydrochloride (100 mg, 0.32 mmol, 1.00 eq) in THF (2.0 mL) was added DIEA (125 mg, 0.97 mmol, 3.00 eq) and propionic anhydride (50.6 mg, 0.39 mmol, 1.2 eq) dropwise. After 1 h, the reaction was quenched by the addition of H2O (5 mL). The resulting mixture was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give A-((5- chloro-6-(5-methoxypyrazin-2-yl)-1H-indol-2-yl)methyl)propionamide.JH NMR (DMSO 400 MHz) 5 ppm 11.18 (s, 1H), 8.57 (s, 1H), 8.44 (s, 1H), 8.33 (t, J= 5.2 Hz, 1H), 7.82 (d, J = 6.4 Hz, 1H), 7.35 (d, J= 12.4 Hz, 1H), 6.29 (s, 1H), 4.41 (d, J= 5.6 Hz, 2H), 3.96 (s, 3H), 2.20 - 2.14 (m, 2H), 1.03 (t, J= 7.4 Hz, 3H). LC-MS (ESI) m / z: [M + H]+calcd for C17H17FN4O: 329.1; found: 329.2.

[0309] Step a: A mixture of (tert-butyl ((6-bromo-5-chloro-l-(phenylsulfonyl)-1H-indol-2- yl)methyl)carbamate (3.0 g, 6.0 mmol, 1.00 eq), B2Pin2 (4.57 g, 18.0 mmol, 3.0 mmol), and KOAc (1.30 g, 13.2 mmol, 2.20 eq) in dioxane (30 mL) was degassed and purged with N2. Pd(PPh3)2Cl2(490 mg, 600 pmol, 0.1 eq) was then added under N2 and the resulting mixture was warmed to 120 °C. The reaction mixture stirred for 1 h at 120 °C, cooled to 23 °C andfiltered through Celite. The filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert-butyl ((5-chl oro-1 - (phenylsulfonyl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lJH-indol-2- yl)methyl)carbamate. LC-MS (ESI): m / z: [M + Na]+calculated for C26H32BCIN2O6S: 569.2; found 569.3.

[0310] Step b: To a mixture of tert-butyl ((5 -chloro- 1 -(phenyl sulfonyl)-6-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-1 H -indol-2-yl)methyl)carbamate (3.50 g, 5.12 mmol, 1.00 eq), 2-bromo-5 -methoxy-pyrazine (1.02 g, 5.38 mmol, 1.05 eq), and K2COs (2.1 g, 29.8 mmol, 3.00 eq) were added dioxane (2 mL) and H2O (0.4 mL). The reaction mixture was then degassed and purged with N2. CataCXium A Pd G2 (1.71 g, 2.56 mmol, 0.5 eq) was then added under N2, and the resulting mixture was warmed to 80 °C and stirred for 1 h. The reaction was then cooled to room temperature and quenched by addition of H2O (10 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue obtained was purified by column chromatography to give tert-butyl ((5-chloro-6-(5-methoxypyrazin-2-yl)- 1 -(phenyl sulfonyl)- 17 / -indol -2 -yl)methyl)carbamate. LC-MS (ESI): m / z: [M + H]+calculated for C25H25CIN4O5S: 529.2; found 529.3.

[0311] Step c: To a solution of tert-butyl ((5-chl oro-6-(5-methoxypyrazin-2-yl)-l- (phenylsulfonyl)-17 / -indol-2-yl)methyl)carbamate (2.7 g, 5.10 mmol, 1.00 eq) in THF (27 mL) was added TBAF (13.3 g, 51.0 mmol, 10 eq). The resulting mixture was warmed to 50 °C and stirred for 1 h. The reaction was then cooled to 23 °C and quenched by addition of H2O (10 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with saturated aqueous NH4Q (5 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl ((5- chloro-6-(5-methoxypyrazin-2-yl)-17 / -indol-2-yl)methyl)carbamate. LC-MS (ESI): m / z: [M + H]+calculated for C19H21CIN4O3: 389.1; found 389.0.

[0312] Step d: To a solution of tert-butyl ((5-chl oro-6-(5-methoxypyrazin-2-yl)-1H-indol-2- yl)methyl)carbamate (1.8 g, 4.60 mmol, 1.00 eq) in EtOAc (2 mL) was added HC1 (4 M inEtOAc, 20 mL, 80 mmol, 17.3 eq). The resulting mixture was stirred at 23 °C for 1 h. The reaction mixture was then concentrated under reduced pressure to give (5-chloro-6-(5- methoxypyrazin-2-yl)-1H-indol-2-yl)methanaminium chloride. LC-MS (ESI): m / z: [M + H]+calculated for C14H13QN4O: 289.1; found 289.0.

[0313] Step e: To a mixture of (5-chloro-6-(5-methoxypyrazin-2-yl)-1H -indol-2- yl)methanaminium chloride (110 mg, 380 pmol, 1.00 eq) and (35)-tetrahydrofuran-3- carboxylic acid (53.0 mg, 457 pmol, 1.20 eq) in THF (1 mL) was added NMI (156 mg, 1.90 mmol, 5.0 eq). The reaction mixture was then cooled to 0 °C, and TCFH (160 mg, 571 pmol, 1.50 eq) was added. The resulting mixture was warmed to 23 °C and stirred for 1 h. The reaction mixture was then quenched by addition of H2O (5 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give (5)-A-((5-chloro-6-(5- methoxypyrazin-2-yl)- 1H-indol-2-yl)methyl)tetrahydrofuran-3 -carboxamide.JH NMR (400 MHz, DMSO-d6) 5 11.26 (s, 1 H), 8.52 - 8.49 (t, J= 5.6 Hz, 1 H), 8.45 (s, 1 H), 8.41 (d, J= 1.2 Hz, 1 H), 7.65 (s, 1 H), 7.52 (s, 1 H), 6.31 (d, J= 0.8 Hz, 1 H), 4.44 (d, J= 5.6 Hz, 2 H), 3.97 (s, 3 H), 3.93 - 3.85 (m, 1 H), 3.79 - 3.72 (m, 1 H), 3.70 - 3.66 (m, 2 H), 3.03 - 2.99 (m, 1 H), 2.05 - 2.00 (m, 2 H). LC-MS (ESI): m / z: [M + H]+calculated for C19H19CIN4O3: 387.1; found 387.2.Example S-6: Synthesis of N-( ( 5-cIiloro-6-( 5-niel hoxy pyraz in-2-yI )-1H -indol-2- yl)methyl)acetamide (Compound 8)

[0314] Step a: To a solution of (6-bromo-5-chloro-l-(phenylsulfonyl)-1H-indol-2- yl)methanaminium chloride (6.0 g, 15.0 mmol, 1.00 eq) in THF (60 mL) at 0 °C under N2 were added DIEA (3.88 g, 30.0 mmol, 2.00 eq) and AC2O (2.15 g, 21.0 mmol, 1.40 eq). The resulting mixture was warmed to 23 °C and stirred for 1 h. The reaction mixture was then quenched by addition of H2O (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with EtOAc (60 mL) for 30 min at 23 °C. The mixture was then filtered to give A-((6-bromo-5-chloro-l-(phenylsulfonyl)-1 H -indol-2-yl)methyl)acetamide. LC-MS (ESI): m / z: [M + H]+calculated for CnHwBrCMOsS: 440.9; found 441.0.

[0315] Step b: A mixture of A-((6-bromo-5-chl oro-1 -(phenyl sulfonyl)- UT-indol -2- yl)methyl)acetamide (6.00g, 13.5 mmol, 1.00 eq), B2neop2 (30.6 g, 135 mmol, 10.0 eq), and KOAc (2.9 g, 29.8 mmol, 2.20 eq) in dioxane (60 mL) was degassed and purged with N2. Pd(PPh3)2C12 (1.43 g, 2.04 mmol, 0.15 eq) was added, and the resulting mixture was warmed to 120 °C and stirred for 1 h. The reaction was then cooled to room temperature and filtered through Celite. The filter cake was washed with EtOAc (50 mL), and the filtrate was concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give A-((5-chloro-6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-l- (phenylsulfonyl)-1H-indol-2-yl)methyl)acetamide. LC-MS (ESI): m / z: [M + Na]+calculated for C22H24BCIN2O5S: 497.1; found 497.2.

[0316] Step c: In two parallel reactions, separate mixtures of A-((5-chloro-6-(5,5-dimethyl- l,3,2-dioxaborinan-2-yl)-l-(phenylsulfonyl)-17 / -indol-2-yl)methyl)acetamide (2.60 g, 5.48 mmol, 1.00 eq), 2-bromo-5-methoxypyrazine (108 mg, 1.27 mmol, 5.00 eq), and K2CO3 (2.27 g, 16.4 mmol, 3.00 eq) in dioxane (26 mL) and H2O (5 mL) were degassed and purged with N2. Pd(PPh3)4 (1.27 g, 1.10 mmol, 0.20 eq) was then added in one portion. The reaction mixtures were further degassed and purged with N2. The resulting mixture was warmed to 100 °C and stirred for 1 h. The reactions were then cooled to room temperature, and the two reactions were combined. The resulting mixture was quenched by addition of H2O (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude residue obtained wastriturated with MTBE (10 mL) at 23 °C for 30 min. The resulting solid was then filtered to give 7V-((5-chloro-6-(5-methoxypyrazin-2-yl)-l -(phenyl sulfonyl)- 1H-indol-2- yl)methyl)acetamide. LC-MS (ESI): m / z: [M + H]+calculated for C22H19QN4O4S: 471.1; found 471.1.

[0317] Step d: To a solution of N-((5-chloro-6-(5-methoxypyrazin-2-yl)-l-(phenylsulfonyl)- 1H-indol-2-yl)methyl)acetamide (2.9 g, 6.16 mmol, 1.00 eq) in THF (20 mL) and MeOH (20 mL) was added CS2CO3 (6.0 g, 18.4 mmol, 3.0 eq). The resulting mixture was warmed to 80 °C and stirred for 1 h. The reaction was then cooled to room temperature and quenched by addition of H2O (30 mL). The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was recrystallized from EtOH (20 mL) to give N -((5-chloro-6-(5-methoxypyrazin-2-yl)-1H -indol- 2-yl)methyl)acetamide.1HNMR (400 MHz, DMSO4) 5 11.25 (s, 1 H), 8.45 (s, 1 H), 8.41 - 8.40 (m, 2H), 7.65 (s, 1 H), 7.52 (s, 1 H), 6.31 (s, 1 H), 4.41 (d, J= 5.6 Hz, 2 H), 3.97 (s, 3 H), 1.90 (m, 3 H). LC-MS (ESI): m / z: [M + H]+calculated for C16H15CIN4O2: 331.1; found 331.1.

[0318] Step a: To a solution of N -((6-acetyl-5-chl oro-1 -(phenyl sulfonyl)- 1H-indol-2- yl)methyl)acetamide (500 mg, 1.23 mmol, 1.00 eq) in THF (5 mL) under N2 was addedphenyltrimethylammonium tribromide (511 mg, 1.36 mmol, 1.10 eq). The resulting mixture was warmed to 70 °C and stirred for 1 h. The reaction mixture was then cooled to 23 °C and quenched by addition of H2O (15 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give A-((6-(2-bromoacetyl)-5-chloro-l- (phenylsulfonyl)-1H-indol-2-yl)methyl)acetamide. LC-MS (ESI): m / z: [M + H]+calculated for Ci9Hi6BrClN2O4-S: 483.0; found 483.2.

[0319] Step b: A mixture of A-((6-(2-bromoacetyl)-5-chl oro-1 -(phenyl sulfonyl)- UT-indol -2- yl)methyl)acetamide (200 mg, 413 pmol, 1.00 eq), AgOTf (159 mg, 620 pmol, 1.50 eq), and formamide (27.0 mg, 620 pmol, 1.50 eq) in EtOAc (3 mL) was sealed in a microwave vial. The mixture was warmed to 70 °C under microwave for 30 min. The reaction was then cooled to room temperature and quenched with the addition of H2O (5 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (3 x 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-TLC to give A-((5-chloro- 6-(oxazol-4-yl)-l-(phenylsulfonyl)-1H-indol-2-yl)methyl)acetamide. LC-MS (ESI): m / z: [M + H]+calculated for C20H16CIN3O4S: 430.0; found 430.0.

[0320] Step c: To a solution of A-((5-chloro-6-(oxazol-4-yl)-l-(phenylsulfonyl)-1H-indol-2- yl)methyl)acetamide (160 mg, 372 pmol, 1.00 eq) in MeOH (2 mL) was added K2CO3 (103 mg, 744 pmol, 2.0 eq). The resulting mixture was warmed to 80 °C and stirred for 2 h. The reaction was then cooled to 23 °C and quenched by addition of H2O (5 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by prep-HPLC to give A-((5- chloro-6-(oxazol-4-yl)-1H-indol-2-yl)methyl)acetamide. 'H NMR (400 MHz, DMSO-tA) 5 11.25 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 8.41 (t, J= 4.4 Hz, 1H), 8.03 (s, 1H), 7.62 (s, 1 H), 6.27 (s, 1H), 4.40 (d, J= 5.6 Hz, 2H), 1.91 (s, 3H). LC-MS (ESI): m / z: [M + H]+calculated for C14H12CIN3O2: 290.1; found 290.1.

[0321] Step a: To a solution of A-((6-bromo-5-chloro-l-(phenylsulfonyl)-1H-indol-2- yl)methyl)acetamide (3.00 g, 6.79 mmol, 1.00 eq) in THF (9 mL) at 0 °C was added z'PrMgCELiCl (1.3 M in THF, 20.9 mL, 27.2 mmol, 4.0 eq). The resulting mixture was warmed to 23 °C and stirred for 1 h. The reaction mixture was cooled to 0 °C, and DMF (4.96 g, 67.9 mmol, 10.0 eq) was added dropwise. The reaction mixture was warmed to 23 °C and stirred for 1 h. The reaction mixture was then quenched by addition of saturated aqueous NH4Q (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 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 triturated with petroleum ether (10 mL) and EtOAc (2 mL) at 23 °C for 20 min to give A-((5-chloro-6- formyl- 1 -(phenyl sulfonyl)- 1 J / -indol-2-yl)methyl)acetamide.

[0322] Step b: To a solution of A-((5-chloro-6-formyl-l-(phenylsulfonyl)-1H-indol-2- yl)methyl)acetamide (1.80 g, 4.61 mmol, 1.00 eq) in EtOH (4 mL), H2O (4 mL) and THF (10 mL) were added hydroxylamine hydrochloride (480 mg, 6.91 mmol, 1.50 eq) and NaOAc (755 mg, 9.21 mmol, 2.00 eq). The resulting mixture was stirred at 23 °C for 3 h. The reaction mixture was then quenched by the addition of H2O (10 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (A-((5- chloro-6-((hydroxyimino)methyl)-l -(phenyl sulfonyl)- 1H-indol-2-yl)methyl)acetamide. LC- MS (ESI): m / z: [M + H]+calculated for C18H16CIN3O4S: 406.0; found 406.0.

[0323] Step c: To a solution of A-((5-chloro-6-formyl-l-(phenylsulfonyl)-1H-indol-2- yl)methyl)acetamide (300 mg, 739 pmol, 1.00 eq) in DMF (5 mL) at 0 °C were added NCS (118 mg, 887 pmol, 1.20 eq) and pyridine (3.63 mg, 45.8 pmol, 0.06 eq). The resulting mixture was warmed to 23 °C and stirred for 12 h The reaction mixture was then cooled to 0°C. Trimethylsilylacetylene (123 mg, 1.26 mmol, 1.70 eq) and triethylamine (78.5 mg, 776 pmol, 1.05 eq) were then added, and the reaction was warmed to 23 °C for 3 h. The reaction was then quenched by addition of H2O (5 mL). The resulting 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 resulting crude residue was purified by column chromatography to give A-((5-chloro-l- (phenylsulfonyl)-6-(5-(trimethylsilyl)isoxazol-3-yl)-1H-indol-2-yl)methyl)acetamide. LC-MS (ESI): m / z: [M + H]+calculated for C23H24ClN3O4SSi: 502.1; found 502.2.

[0324] Step d: To a solution of A-((5-chloro-l-(phenylsulfonyl)-6-(5-(trimethylsilyl)isoxazol- 3-yl)-1H-indol-2-yl)methyl)acetamide (200 mg, 398 pmol, 1.00 eq) in MeOH (2 mL) was added K2CO3 (110 mg, 796 pmol, 2.0 eq). The resulting mixture was warmed to 80 °C and stirred for 1 h. The reaction was then cooled to 23 °C and quenched by addition of H2O (5 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by prep-HPLC to give A-((5-chloro-6- (oxazol-4-yl)-1H-indol-2-yl)methyl)acetamide. ’H NMR (400 MHz, DMSO-tA) 5 11.32 (s, 1H), 9.01 (d, J= 2.0 Hz, 1H), 8.42 (t, J= 5.6 Hz, 1H), 7.69 (s, 1H), 7.62 (s, 1H), 6.94 (s, 1H), 6.33 (s, 1H), 4.42 (d, J= 5.6 Hz, 2H), 1.90 (s, 3H). LC-MS (ESI): m / z: [M + H]+calculated for C14H12CIN3O2: 290.1; found 290.1.Example S-9: Synthesis of \-((5-chloro-6-(2-methyloxazol-5-yl)-l / / -indol-2- yl)methyl)acetamide (Compound 87)

[0325] Step a: A mixture of A-((6-acetyl-5-chloro-l-(phenylsulfonyl)-1H-indol-2- yl)methyl)acetamide (3.00 g, 6.79 mmol, 1.00 eq) and 12 (501 mg, 1.98 mmol, 2.00 eq) in DMSO (4 mL) was degassed and purged with N2. The reaction mixture was then warmed to 110 °C and stirred for 1 h, followed by addition of 2-aminopropanioic acid (176 mg, 1.98 mmol, 2.0 eq) at 110 °C. The resulting mixture was stirred at 110 °C for 1 h. The reactionmixture was cooled to 23 °C and quenched by addition of H2O (5 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained triturated with MTBE (1 mL) at 23 °C for 30 min to give A-((5-chloro-6-(2-methyloxazol-5-yl)-l -(phenyl sulfonyl)- 1H-indol-2- yl)methyl)acetamide. LC-MS (ESI): m / z: [M + H]+calculated for C21H18CIN3O4-S: 444.1; found 444.2.

[0326] Step b: To a solution of A-((5-chloro-6-(2-methyloxazol-5-yl)-l-(phenylsulfonyl)-1H- indol-2-yl)methyl)acetamide (200 mg, 450 pmol, 1.00 eq) in MeOH (0.5 mL) and THF (0.5 mL) was added CS2CO3 (440 mg, 1.35 mmol, 3.0 eq). The resulting mixture was warmed to 80 °C and stirred for 2 h. The reaction was then cooled to 23 °C and quenched by addition of H2O (2 mL). The resulting mixture was extracted with EtOAc (3 x 2 mL). The combined organic extracts were washed with brine (2 x 2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by prep- HPLC to give A-((5-chloro-6-(2-methyloxazol-5-yl)-1H-indol-2-yl)methyl)acetamide. 'H NMR (400 MHz, DMSO-d6)11.25 (s, 1H), 8.41 (t, J= 5.6 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.48 (s, 1H), 6.28 (s, 1H), 4.41 (d, J= 5.6 Hz, 2H), 2.50 (s, 3H), 1.89 (s, 3H). LC-MS (ESI): m / z: [M + H]+calculated for C15H14CIN3O2: 304.0; found 304.0.Example S-10: Synthesis of N-( ( 5-c hloro-6-( 5-ni el Iiy loxazol-2-y 1 )- 1 H -indol-2- yl)methyl)acetamide (Compound 86)

[0327] Step a: To a solution of A-((6-bromo-5-chloro-l-(phenylsulfonyl)-1H-indol-2- yl)methyl)acetamide (2.3 g, 5.21 mmol, 1.00 eq) in MeOH (30 mL) and DMF (6 mL) was added TEA (737 mg, 7.29 mmol, 1.40 eq). The reaction mixture was then degassed and purged with CO three times.(425 mg, 520 pmol, 0.1 eq) was then added,and the resulting reaction mixture was warmed to 80 °C and stirred for 16 h under CO (50 psi). The reaction mixture was then cooled to 23 °C and quenched by addition of H2O (5 mL). The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with MTBE (30 mL) at 23 °C for 10 min. The mixture was then filtered to give methyl 2- (acetamidomethyl)-5-chl oro-1 -(phenyl sulfonyl)- lH -indole-6-carboxylate. LC-MS (ESI): m / z: [M + H]+calculated for C19H17CIN2O5S: 421.1; found 421.0.

[0328] Step b: To a solution of methyl 2-(acetamidomethyl)-5-chloro-l-(phenylsulfonyl)-UT- indole-6-carboxylate (2.1 g, 3.74 mmol, 1.00 eq) in THF (20 mL) and H2O (10 mL) was added LiOEEELO (314 mg, 7.48 mmol, 2.0 mmol). The resulting mixture was warmed to 50 °C and stirred for 5 h. The reaction was then cooled to 23 °C and quenched with H2O (2 mL). The resulting mixture was washed with EtOAc (2 x 10 mL). The aqueous layer was adjusted to pH = 1 with aqueous HC1 (1 M, 2 mL). The aqueous layer was then extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2- (acetamidomethyl)-5-chloro-l-(phenylsulfonyl)-1H-indole-6-carboxylic acid. LC-MS (ESI): m / z: [M + H]+calculated for C18H15QN2O5S: 407.1; found 407.2.

[0329] Step c: To a solution of 2-(acetamidomethyl)-5-chloro-l-(phenylsulfonyl)-1H-indole- 6-carboxylic acid (1.20 g, 1.47 mmol, 1.00 eq) in DMA (15 mL) was added CDI (358 mg, 2.21 m...

Claims

in the presence of a coupling reagent, to provide a compound of formula (I-3): ), or a stereoisomer or tautom able salt of any of the foregoing, wherein: PG is absent or a protecm is an integer from 1 to 4; R1is -NH-, -O-, or -S-; R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more -CN; R6and R9are each independently H or halo; R8is C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; R10is H;R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; followed by, (b) optionally contacting the compound of formula (I-3) with a deprotecting agent; to provide a compound of formula (I). [0229] Embodiment 37. The process of Embodiment 35, wherein the coupling reagent comprises a palladium catalyst, a phosphine ligand, and / or base. [0230] Embodiment 38. A process for preparing a compound of formula (I), as defined in any of Embodiments 1-35 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises: (a) reacting a compound of formula (I-1): (I-1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q1is halo; PG is absent, or a protecting group; m is an integer from 1 to 4; R1is -N-, -NH-, -O-, or -S-;R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a; each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independently optionally substituted with one or more - CN; R6and R9are each independently H or halo; R10is H; R3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1- 6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O-C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; with a compound of formula (I-2): (I-2),or a stereoisomer or tautome table salt of any of the foregoing, wherein: Y1is a boronic acid or b R8is C3-10cycloalkyl, C6or 5-10 memberedheteroaryl, wherein the C3-10cycloalkyl, C6-20aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a; each R8ais independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O- C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 me r -O-C3-10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4- lkyl or -O-C3-10cycloalkyl of R8ais optionally substitu 8each Rbis independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; in the presence of a coupling reagent, to provide a compound of formula (I-3): (I-3), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: PG is absent or a protecting group; m is an integer from 1 to 4; R1is -NH-, -O-, or -S-; R2is H; R3is C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, -N(R4)2¸ or 4-10 membered heterocyclyl, wherein the C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, or 4-10 membered heterocyclyl of R3is optionally substituted with one or more R3a;each R4is independently H, C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl, wherein the C1-6alkyl, C1-6haloalkyl, or C3-10cycloalkyl of R4is optionally substituted with one or more R4a, or both R4are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R4a; R5and R7are each independently H, halo, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl or C1-6haloalkyl, wherein the C1-6alkyl of R5and R7are each independentlyR3a, R4a, and R8aare each independently -OH, oxo, -CN, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, -O-C1-6haloalkyl, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -C(O)NH2, - C(O)NH(C1-6alkyl), - C(O)N(C1-6alkyl)2, 4-10 membered heterocyclyl, C3-10cycloalkyl, or -O-C3- 10cycloalkyl, wherein the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R3ais optionally substituted with one or more R3b, the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R4ais optionally substituted with one or more R4b, and the C1-6alkyl, C1-6alkoxy, 4-10 membered heterocyclyl, C3-10cycloalkyl or -O- C3-10cycloalkyl of R8ais optionally substituted with one or more R8b; and R3b, R4b, and R8bare each independently D, -OH, halo, C1-6alkyl or C1-6alkoxy; followed by, (b) optionally contacting the compound of formula (I-3) with a deprotecting agent; to provide a compound of formula (I). [0231] Embodiment 39. The process of any of Embodiments 36-38, wherein the protecting group is a sulfonyl group.[0234] Embodiment 42. A method of modulating SLC6A19 in a cell, comprising exposing the cell to a composition comprising a compound of any of Embodiments 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of Embodiment 41. [0235] Embodiment 43. A method of inhibiting SLC6A19 in a cell, comprising exposing the cell to a composition comprising a compound of any of Embodiments 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of Embodiment 41. [0236] Embodiment 44. A method of reducing systemic phenylalanine, tyrosine, glutamine, lpharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of Embodiment 41. [0238] Embodiment 46. The method of Embodiment 45, wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, metabolic diseases, hyperphenylalaninemia, tyrosinemia (Type I, II, or III), nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, hyperammonemia, diabetes, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity related disorders, and neurodevelopmental and autism- spectrum disorders.[0239] Embodiment 47. The method of Embodiment 45 or 46, wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney r rder, ual is[0244] Embodiment 52. A kit, comprising (i) a compound of any of Embodiments 1-35, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of Embodiment 41, and (ii) instructions for use in treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. [0245] Embodiment 53. The kit of Embodiment 52, wherein the disease, disorder, or condition is associated with abnormal levels of amino acids. [0246] Embodiment 54. The kit of Embodiment 52 or 53, wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase. [0247] Embodiment 55. The kit of Embodiment 52 or 53, wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, metabolic diseases, hyperphenylalaninemia, tyrosinemia (Type I, II, or III), nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12[0249] Embodiment B-1. The compound of any of Embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is selected from the group consisting of , , , , , , , , , , and . [0250] Embodiment B-2. The compound of any of Embodiments 1-27 ,or 30-31, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . [0251] Embodiment B-3. The compound of Embodiment 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from Compounds 1-90 of Table 1.EXAMPLES [0252] The following synthetic reaction schemes, which are detailed in the Schemes and e se of n be to, be co pou s o e p ese sc osu e, o a y va a o o e o e e eo , ay e prepared using appropriate starting materials according to the methods described generally herein and / or by methods available to one of ordinary skill in the art. Synthetic Examples [0255] As depicted in the Schemes and Examples below, in certain exemplary embodiments, compounds of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared according to the general procedures. The general methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, variations, embodiments, and species described herein. [0256] In some embodiments, provided herein is a process for preparing a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing according to any of Scheme 1-Scheme 8. Schemes Scheme 1[ [ i stScheme 3[0259] Compounds of formula S3-4 can be prepared according to Scheme 3. Suzuki coupling of S3-1 with pinacol boronate S3-2 in the presence of a palladium catalyst such as [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, an inorganic base such as potassium carbonate in hot dioxane gives S3-3. Removal of the indole N-sulfonyl protecting group can be accomplished on heating with a base such as potassium[0260] Compounds of formula S4-7 can be prepared according to Scheme 7. Palladium catalyzed borylation of S4-1with Bis(pinacolato)diboron with a palladium catalyst such as [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, an inorganic base such as potassiu uzuki coupling of S4-2 occurs upon heating an aryl or h alladium catalyst such as chloro[(di(1-adamantyl)-N-b alladium(II), an inorganic base such as potassiu e S4-4. Removal of theindole N-sulfonyl protecting group can be accomplished on heating with TBAF in THF to give S4-5. Removal of the N-Boc group upon treatment with a protic acid such as HCl in EtOAc gives S4-6. Coupling of S4-6 with acid S4-7 in the presence of HATU and DIEA in a solvent such as DCM gives compounds of formula S4-8. Scheme 5[0261] Compounds of formula S5-3 can be prepared according to Scheme 5. Suzuki coupling of S5-1 an aryl or heteroaryl halide such as S5-2 occurs upon heating a palladium catalyst such as chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2- aminobiphenyl)]palladium(II), an inorganic base such as potassium carbonate in hot aqueous dioxane to give S5-3. Scheme 6 [0262] Compounds of formula S6-3 may be prepared according to Scheme 6. Coupling of S6-1 with carboxylic acid S6-2 occurs in the presence of chloro-N,N,N′,N′- tetramethylformamidinium hexafluorophosphate and N-methylimidazole in a solvent such as acetonitrile to give compounds of formula S6-3. Scheme 7 [0263] Compounds of formula S7-3 may be prepared according to Scheme 7. Coupling of S7-1 with carboxylic acid S7-2 occurs in the presence of EDCI, HOBt, and N- methylimidazole in a solvent such as ethanol to give compounds of formula S7-3. Scheme 8[0264] Compounds of formula S8-5 may be prepared according to Scheme 8. Stille coupling of S8-1 with an aryl or heteroaryltributyl stannane such as S8-2 with a catalyst such Tetrakis(triphenylphosphine)palladium(0) occurs upon heating in a solvent such as dioxane to give S8-3. Removal of the N-Boc protecting group upon treatment with HCl in a solvent such as EtOAc gives S8-4. Reaction with acetic anhydride and DIEA in a solvent such as DCM gives compounds of formula S8-5. Scheme 9 R5 R6 R8SnBu3 R5 R6 R7Pd(PPh3)4R7O O NHNHBr dioxane, 110 ºCNHN 8HR R3R9R3R9S9-1 S9-2 [0265] Compounds of formula S9-2 may be prepared according to Scheme 9. Stille coupling of compounds of the formula S9-1 with an aryl or heteroaryltributyl stannane in the presence of a catalyst such tetrakis(triphen pon heating in a solvent such as dioxane to give compoun R5 R6 R5 R6 R7R7O NHNO O Bdioxane / H2O, 75 ºC N831MeNH RRR 2R9OR3R12R9Me S10-1 S10-2 [0266] Compounds of formula S10-2 may be prepared according to Scheme 10. Suzuki coupling of a compound of the formula S10-1, in which R12may be hydrogen or a protectinggroup such as phenylsulfonyl, with an aryl or heteroaryl halide in the presence of a catalyst such tetrakis(triphenylphosphine)palladium(0) and a base such as K2CO3 occurs upon heating in a mixed solvent system such as dioxane / water to give compounds of the formula S10-2, which may or may not require additional deprotection or functional group manipulation under standard conditions. Scheme 11 R5 R6R8 Xdppf)Cl2, K2CO3,R6 6 R7Pd(R5R5 RDIEA R7HCl / EtOAc R7BocN N O Me Cl H Bdioxane / H O, 75 ºC Et92 BocNNHR8OAC H3N NR8R O MeHMe R9R9Me S11-1 S11-2 S11-3 O O R3 OR3R5 R6 DIEA R7O THFNH N HR8R3R9S11-4 [0267] Compounds of formula S11-4 may be prepared according to Scheme 11. Suzuki coupling of a compound of the formula S11-1 with an aryl or heteroaryl halide in the presence of a catalyst such Pd(dppf)Cl2and a base such as K2CO3occurs upon heating in a mixed solvent system such as dioxane / water to give compounds of the formula S11-2. Deprotection of the amino group using reagents such as HCl in EtOAc gives compounds of the formula S11-3. Acylation of the free amino group using an acylating agent such as a carboxylic acid anhydride gives compounds of the formula S11-4. Scheme 12 O S12-2 R3N Cl R5 R6 R3R5 R6 1 R7R7DIEA Cl O H3N N 8DCMNHNR8H R3N H 9 R R R9R13S12-1 S12-3 [0268] Compounds of formula S12-2 may be prepared according to Scheme 12. Reaction of compounds of the formula S12-1 using a reagent such as S12-2, in which R3and R13may be individually alkyl or hydrogen or in which R3and R13may be cyclized to form a ring, in thepresence of a base such as DIEA in a solvent such as DCM gives compounds of the formula S12-3. Scheme 13 [0269] Compounds of formula S13-3 may be prepared according to Scheme 13. Reaction of compounds of the formula S13-1 using a reagent such as S13-2, in which R3and R13may be individually alkyl or hydrogen or in which R3and R13may be cyclized to form a ring, in the presence of CDI and a base such as DIEA in a solvent such as DMF gives compounds of the formula S13-3. Intermediate A-1: Synthesis of 6-bromo-[1,3]dioxolo[4,5-c]pyridine [0270] Step a: To a solution of 6-bromopyridin-3-ol (1.00 g, 5.75 mmol, 1.00 eq) in DMF (4 mL) at 0 °C was added K2CO3(1.5 loromethoxy)ethane (815 mg, 8.62 mmol, 1.50 eq) dropwise. arm to room temperature. After 6 h, the reaction mixture was O (15 mL). The resulting mixture was then extracted with Et d organic layers werewashed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 2- bromo-5-(ethoxymethoxy)pyridine. LC-MS (ESI) m / z: [M + H]+calcd for C8H10BrNO2: 232.0; found: 232.1.[0271] Step b: To a solution of 2-bromo-5-(ethoxymethoxy)pyridine (1.00 g, 4.31 mmol, 1.00 eq) in anhydrous THF (10 mL) at –65 °C was added 2 M LDA in THF (2.37 mL, 4.74 mmol, 1.10 eq) dropwise. After 1 h at –65 °C, a THF (5 mL) solution of triisopropyl borate (891 mg, 4.74 mmol, 1.10 eq) was added dropwise. The reaction was warmed to –15 °C. After 3 h, 30 wt% H2O2 (977 mg, 8.62 mmol, 2.00 eq) was added dropwise. The reaction was then warmed to room temperature. After 1.5 h, the reaction was quenched by the addition of H2O (15 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous Na2SO3 (2 x 20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 2-bromo-5- (ethoxymethoxy)pyridin-4-ol. LC-MS (ESI) m / z: [M + H]+calcd for C8H10BrNO3: 248.0; found: 248.

1. [0272] Step c: To a solution of 2-bromo-5-(ethoxymethoxy)pyridin-4-ol (510 mg, 2.1 mmol, 1.00 eq) in MeOH (3.0 mL) was added 4 M HCl in MeOH (5 mL, 20.0 mmol, 10.0 eq). After 2 h, the reaction mixture was concentrated under reduced pressure to give 6-bromopyridine- 3,4-diol hydrochloride. LC-MS (ESI) m / z: [M + H]+calcd for C5H4BrNO2: 190.0; found: 189.

8. [0273] Step d: To a solution of 6-bromopyridine-3,4-diol hydrochloride (450 mg, 1.99 mmol, 1.00 eq) in DMF (15.0 mL) was added Cs2CO3 (971 mg, 2.98 mmol, 1.50 eq) and chloroiodomethane (526 mg, 2.98, 1.50 eq). The reaction mixture was then warmed to 60 °C. After 2 h, the reaction was cooled to room temperature and quenched by the addition of H2O (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 6-bromo-[1,3]dioxolo[4,5-c]pyridine. LC-MS (ESI) m / z: [M + H]+calcd for C6H4BrNO2: 201.9; found: 202.

1. Intermediate A-2: Synthesis of 6-chlorothiazolo[5,4-c]pyridineS CNCl NH2O H H H Cl N N NaOH Cl N NH2NBracetone, 23 °CN MeOH, 75 °C NS BrS OBrCuI Cs2CO3MeONOL-proline Cl N Me Cl N NH DMSO, 70 °C N2S THF, 85 °C N S [0274] Step a: To a solution of 5-bromo-2-chloropyridin-4-amine (4.0 g, 19.3 mmol, 1.00 eq) in acetone (40 mL) was added benzoyl isothiocyanate (9.44 g, 57.8 mmol, 3.0 eq) dropwise. After 16 h, the reaction mixture was then concentrated under reduced pressure. The resultant residue was triturated with n-heptane (3 mL) for 20 minutes then collected by vacuum filtration to give N-((5-bromo-2-chloropyridin-4-yl)carbamothioyl)benzamide. [0275] Step b: To a solution of N-((5-bromo-2-chloropyridin-4-yl)carbamothioyl)benzamide (6.00 g, 16.2 mmol, 1.00 eq), in MeOH (60 mL) was added 6 M aqueous sodium hydroxide (5.4 mL, 32.4 mmol, 2.0 eq). The reaction was then warmed to 75 °C. After 4 h, the reaction was cooled to room temperature and quenched by the addition of saturated aqueous NH4Cl (20 mL). The resulting precipitate was collected by vacuum filtration. The filter cake was washed with H2O (2 x 20 mL) and DCM (20 mL). The filter cake was then dried under reduced pressure to give 1-(5-bromo-2-chloropyridin-4-yl)thiourea. LC-MS (ESI) m / z: [M + H]+calcd for C6H5BrClN3S: 265.9; found: 266.

1. [0276] Step c: To a solution of 1-(5-bromo-2-chloropyridin-4-yl)thiourea (1.00 g, 3.75 mmol, 1.00 eq) in DMSO (5.0 mL) was added L-proline (863 mg, 7.50 mmol, 2.0 eq), Cs2CO3 (2.44 g, 7.5 mmol, 2.0 eq), and CuI (71.5 mg, 0.38, 0.1 eq). The reaction mixture was then warmed to 70 °C. After 2 h, the reaction was cooled to room temperature and quenched by being poured into H2O (10 mL). The re l i i i ll d b vacuum filtration. The filter cake was washed with H2O ressure to give 6- chlorothiazolo[5,4-c]pyridin-2-a alcd for C6H4ClN3S: 186.0; found: 185.

8. [0277] Step d: To a solution of 6ne (600 mg, 3.23 mmol, 1.00 eq) in THF (6.0 mL) was added isopentyl nitrite (1.89 g, 16.2 mmol, 5.00 eq). The reaction mixture was then warmed to 85 °C. After 4 h, the reaction was cooled to roomtemperature and quenched by being poured into H2O (5 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 6-chlorothiazolo[5,4- c]pyridine. LC-MS (ESI) m / z: [M + H]+calcd for C6H3ClN2S: 171.0; found: 171.

2. Intermediate A-3: Synthesis of 6-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazine HOOHN Br N Br NaH N Br DMF-DMA OHMeOHH2NNCl 0 → 140 °C H2N NO50 °CN NNOMe Pd(OAc)2NaNO BINAP22 3N O CuBr Cs CO ethane-1,2-diamine N O HBr N O Me PhMe, 90 °C N N N OEtOH, 80 °CH NNO H O, 0 °C Br N O Me2 2[0278] Step a: To a solution of ethane-1,2-diol (63 mL) at 0 °C was added 60% sodium hydride (3.84 g, 95.9 mmol, 2.00 eq) portionwise. After 30 minutes, 5-bromo-6- chloropyrazin-2-amine (10.0 g, 47.9 mmol, 1.00 eq) was added portionwise. The reaction mixture was then warmed to 140 °C. After 1 h, the reaction mixture was cooled to room temperature and quenched by the addition of ice water (50.0 mL). The resulting mixture was then extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was triturated with EtOAc (12 mL) for 10 minutes. The solid was collected by vacuum filtration and dried under reduced pressure to give 2-((6-bromo-4- iodopyridin-3-yl)oxy)ethan-1-ol. LC-MS (ESI) m / z: [M + H]+calcd for C6H8BrN3O2: 234.0; found: 234.

2. [0279] Step b: A solution of 2-((6-bromo-4-iodopyridin-3-yl)oxy)ethan-1-ol (4.10 g, 17.5 mmol, 1.00 eq), in (dimethoxymethyl)dimethylamine (12 mL) was warmed to 50 °C. After 1 h, the reaction was cooled to room temperature and quenched by the addition of ice water (25 mL). The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with EtOAc(15 mL) for 10 minutes. The solid was collected by vacuum filtration and dried under reduced pressure to give (E)-N-(5-bromo-6-(2-hydroxyethoxy)pyrazin-2-yl)-N,N- dimethylformimidamide. LC-MS (ESI) m / z: [M + H]+calcd for C9H13BrN4O2: 289.0; found: 288.

8. [0280] Step c: (E)-N-(5-bromo-6-(2-hydroxyethoxy)pyrazin-2-yl)-N,N- dimethylformimidamide (3.10 g, 10.7 mmol, 1.00 eq) in toluene (310 mL) was added Cs2CO3 (10.4 g, 32.1 mmol, 3.00 eq), Pd(OAc)2(240 mg, 1.1 mmol, 0.1 eq), and BINAP (1.34 g, 2.14, 0.20 eq). The sealed reaction vessel was evacuated and refilled with nitrogen three times and then warmed to 90 °C. After 16 h, the reaction mixture was cooled to room temperature and quenched by being poured into H2O (30 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers 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 and prep-HPLC to give (E)- N-(2,3-dihydro-[1,4]dioxino[2,3-b]pyrazin-6-yl)-N,N-dimethylformimidamide. LC-MS (ESI) m / z: [M + 2H]+calcd for C9H12N4O2: 209.1; found: 209.

1. [0281] Step d: (E)-N-(2,3-dihydro-[1,4]dioxino[2,3-b]pyrazin-6-yl)-N,N- dimethylformimidamide (1.2 g, 2.88 mmol, 1.00 eq) in EtOH (12 mL) was added ethane-1,2- diamine (380 mg, 6.32 mmol, 2.19 eq) dropwise. The reaction was then warmed to 80 °C. After 12 h, the reaction was cooled to room temperature and quenched by being poured into H2O (20 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2,3-dihydro-[1,4]dioxino[2,3-b]pyrazin-6-amine. LC-MS (ESI) m / z: [M + H]+calcd for C6H7N3O2: 154.1; found: 154.

0. [0282] Step e: To a solution of 2,3-dihydro-[1,4]dioxino[2,3-b]pyrazin-6-amine (190 mg, 1.24 mmol, 1.00 eq) in H2O (1 mL) at 0 °C was added 40% aqueous HBr (1 mL, 7.37 mmol, 5.9 eq) and a solution of NaNO2(128 mg, 1.86 mmol, 1.5 eq) in H2O (0.5 mL). After 5 minutes, CuBr (355 mg, 2.48 mmol, 2.00 eq) was added in one portion. After 1 h, the reaction was warmed to room temperature and quenched by being poured into H2O (2 mL). The resulting mixture was extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentratedunder reduced pressure. The crude residue obtained was purified by prep-HPLC to give 6- bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazine. LC-MS (ESI) m / z: [M + H]+calcd for C6H5BrN2O2: 217.0; found: 217.

2. Intermediate A-4: Synthesis of N-((6-acetyl-5-chloro-1-(phenylsulfonyl)-1H-indol-2- yl)methyl)acetamide [0283] Step a: A mixture of N-((6-bromo-5-chloro-1-(phenylsulfonyl)-1H-indol-2- yl)methyl)acetamide (1.50 g, 3.40 mmol, 1.00 eq) and tributyl(1-ethoxyvinyl)stannane (2.45 g, 6.79 mmol, 2.00 eq) in dioxane (10 mL) was degassed and purged with N2three times followed by the addition of Pd(PPh3)2Cl2 (238 mg, 339 μmol, 0.10 eq). The reaction mixture was then warmed to 90 °C and stirred for 16 h. The reaction mixture was then cooled to 23 °C and quenched by addition of aqueous HCl (1 M, 5 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (3 x 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with MTBE (10 mL) at 23 °C for 30 min to give N- ((6-acetyl-5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)acetamide. LC-MS (ESI): m / z: [M + H]+calculated for C19H17ClN2O4-S: 405.1; found 405.

1. Intermediate A-5: Synthesis of N-((6-bromo-5-chloro-1-(phenylsulfonyl)-1H-indol-2- yl)methyl)-λ5-chloranimineMeMeO O O Me O N HSMMeOClCl N I CleIS, AcOH Pd(PPh3)2Cl2, CuI Me O N H Cl H2N BrDCM / MeOH, 23 °CH2N BrTEA, DMF, 23 °Cpyridine H2N Br DCM, 0–23 °CMeMeO Cl Cl Me O N H Cl O CuCl, Cs2CO3MeNH N BrHCl / EtOAc ClH3N NBrHN Br Me O O2S EtOA O2S MeC Me c, 0–23 °C SO2N, 23 °C [0284] Step a: Four reactions were carried out in parallel. To a solution of 3-bromo-4- chloroaniline (50.0 g, 242.0 mmol, 1.00 eq) in DCM (270.0 mL) was added acetic acid (41.6 mL, 726.0 mmol, 3.0 eq) in a single portion followed by a solution of NIS (76.3 g, 339.0 mmol, 1.40 eq.) in MeOH (270 mL) dropwise over 1 h. After 5 h, the four reactions were combined for work up. The reaction mixture was quenched by the addition of H2O (2.0 L). The resulting mixture was then extracted with EtOAc (3 x 2.0 L). The combined organic layers were washed with brine (3 x 1.0 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-bromo-4-chloro-2-iodoaniline. LC-MS (ESI) m / z: [M + H]+calcd for C6H4BrClIN: 331.8; found: 331.

9. [0285] Step b: To a solution of 5-bromo-4-chloro-2-iodoaniline (118.0 g, 355.0 mmol, 1.00 eq) in DMF (1.0 L) was added tert-butyl prop-2-yn-1-ylcarbamate (55.1 g, 355 mmol, 1. 0 eq), TEA (247 mL, 1.78 mol, 5.00 eq), CuI (13.5 g, 71.0 mmol, 0.20 eq), and bis(triphenylphosphine)palladium(II) dichloride (7.5 g, 10.7 mmol, 0.03 eq). The sealed reaction vessel was evacuated and refilled with nitrogen three times. After 2 h at room temperature, the reaction was quenched by pouring into ice water (2.0 L). The resulting mixture was extracted with EtOAc (3 x 1.0 L). The combined organic layers were washed with brine (3 x 1.0 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give tert- butyl (3-(2-amino-4-bromo-5-chlorophenyl)prop-2-yn-1-yl)carbamate. LC-MS (ESI) m / z: [M – C4H9 + 2H]+calcd for C14H16BrClN2O2: 303.0; found: 302.8.[0286] Step c: To a solution of tert-butyl (3-(2-amino-4-bromo-5-chlorophenyl)prop-2-yn-1- yl)carbamate (110.0 g, 305 mmol, 1.00 eq), in DCM (1.0 L) at 0 °C was added pyridine (49.4 mL, 611.0 mmol, 2.0 eq) in a single portion followed by benzenesulfonyl chloride (39.0 mL, 305 mmol, 1.00 eq) dropwise. The reaction was then allowed to warm to room temperature. After 1 h, the reaction mixture was quenched by pouring it into ice water (2.0 L). The resulting biphasic mixture was extracted with EtOAc (3 x 1.0 L). The combined organic layers were washed with brine (3 x 1.0 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl (3-(4-bromo-5-chloro-2- (phenylsulfonamido)phenyl)prop-2-yn-1-yl)carbamate, which was used without further purification. LC-MS (ESI) m / z: [M + Na]+calcd for C20H20BrClN2O4S: 521.0; found: 521.

0. [0287] Step d: To a solution of tert-butyl (3-(4-bromo-5-chloro-2- (phenylsulfonamido)phenyl)prop-2-yn-1-yl)carbamate (150.0 g, 300.0 mmol, 1.00 eq) in MeCN (1.5 L) was added CuCl (4.46 g, 45.0 mmol, 0.15 eq) and Cs2CO3(14.7 g, 45.0 mmol, 0.15 eq.). The sealed reaction vessel was evacuated and refilled with nitrogen three times. After 3 h at room temperature, the reaction was quenched by being poured into ice water (2.0 L). The resulting biphasic mixture was extracted with EtOAc (3 x 1.0 L). The combined organic layers were washed with brine (3 x 1.0 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl ((6-bromo-5-chloro-1- (phenylsulfonyl)-1H-indol-2-yl)methyl)carbamate, which was used without any further purification. LC-MS (ESI) m / z: [M – C4H9+ 2H]+calcd for C20H20BrClFN2O4S: 442.9; found: 443.

1. [0288] Step e: To a solution of tert-butyl ((6-bromo-5-chloro-1-(phenylsulfonyl)-1H-indol-2- yl)methyl)carbamate (59.0 g, 118.0 mmol, 1.00 eq) in EtOAc (10 mL) at 0 °C was added 4 M HCl in EtOAc (500 mL, 2.0 mol, 16.9 eq) portionwise. The reaction was then allowed to warm to room temperature. After 1 h, the reaction mixture was concentrated under reduced pressure to give N-((6-bromo-5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)-λ5- chloranimine, which was used without further purification. LC-MS (ESI) m / z: [M + H]+calcd for C15H12BrClN2O2S: 398.9; found: 399.

1. Example S-1: Synthesis of N-((5-chloro-7-fluoro-6-(5-methoxypyrazin-2-yl)-1H-indol-2- yl)methyl)acetamide (Compound 78)

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