Inhibitors of solute carrier family 6a member 19 (SLC6a19) and methods of use thereof

Abstract

Provided herein are compounds of formula (II): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, L, R1, R2, R3, R5, R6, R7, R8, and R9 are as defined elsewhere herein. Also provided herein are methods of preparing compounds of formula (II). 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

Docket No.: 79275-20040.40 INHIBITORS OF SOLUTE CARRIER FAMILY 6A MEMBER 19 (SLC6A19) AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 763,024, filed February 25, 2025, and U. S. Provisional Application No. 63 / 763,058, filed February 25, 2025, the entire contents of each of which are incorporated herein by reference.BACKGROUND OF THE INVENTION

[0002] Solute carrier family 6A member 19 (SLC6A19), also known as B0AT1, is a sodiumdependent 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 etal. 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. RZ / wm. 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. andMetab. (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 etal. JCI Insight (2018) 3, e!21762).Docket No.: 79275-20040.40

[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.l 173+2T> G) (Sveinbjornsson G. etal. Hum. Mol. Genet. (2014) 23, 6935-6943) and missense (D173N) variants in SLC6A19 with protection from CKD has been reported (Sinnott- Amstrong N. etal. 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. Ciirr 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 etal. 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 (II):Docket No.: 79275-20040.40or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:m is an integer from 1 to 4;n is an integer from 0 to 4;R1is -NH-, -O-, or -S-;either:(i) R2and R3are independently H, Ci-ealkyl, Ci-3alkoxy, Cs-iocycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, whereinthe Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x, or(ii) R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, whereinthe 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x; R5is H, halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R6and R9are each independently H or halo;R7is halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, whereinthe Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R8is Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinDocket No.: 79275-20040.40 the Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with one or more R8a;R3aand R8aare each independently -OH, oxo, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-6alkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-locycloalkyl, or -O-Cs-iocycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl of R3ais optionally substituted with one or more R3b, and the Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl of R8ais optionally substituted with one or more R8b;R3Xis -OH, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-ealkoxy, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(Ci-6alkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-C3-locycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b;R3band R8bare each independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy; andR11aR11b*L is absent or isx n“, wherein** denotes the point of attachment to R8and * denotes the point of attachment to the rest of the molecule;X is -O-, -S-, -C(R12a)(R12b)-, -N(H)-, or -N(Ci-6alkyl)-;Rllaand Rllbare independently at each occurrence, H or Ci-ealkyl, orone of Rllaand Rllbis H or Ci-ealkyl, and the other of Rllaand Rllbis taken together with one of R12aor R12bto form a Cs-iocycloalkyl; andR12aand R12bare each independently, H or Ci-ealkyl, orone of R12aand R12bis H or Ci-ealkyl, and the other of R12aand R12bis taken together with one of Rllaor Rllbto form a Cs-iocycloalkyl.

[0009] In one aspect, provided herein is a compound of formula (I'):Docket No.: 79275-20040.40or 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-;either:(i) R2and R3are independently H, Ci-ealkyl, Ci-3alkoxy, Cs-iocycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, whereinthe Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x, or(ii) R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, whereinthe 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x; R5is H, halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R6and R9are each independently H or halo;R7is halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, whereinthe Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R8is Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinDocket No.: 79275-20040.40 the Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with one or more R8a;R3aand R8aare each independently -OH, oxo, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-6alkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-locycloalkyl, or -O-Cs-iocycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b, andthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R8b;R3Xis -OH, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-ealkoxy, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(Ci-6alkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-C3-locycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b; andR3band R8bare each independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy.

[0010] 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;n is an integer from 0-4;X is -O-, -S-, -C(R12a)(R12b)-, -N(H)-, or -N(Ci-6alkyl)-;R1is -NH-, -O-, or -S-;either:(i) R2and R3are independently H, Ci-ealkyl, Ci-3alkoxy, Cs-iocycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, whereinDocket No.: 79275-20040.40 the Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x, or(ii) R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, whereinthe 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x; R5is H, halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R6and R9are each independently H or halo;R7is halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, whereinthe Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R8is Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinthe Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with one or more R8a;R3aand R8aare each independently -OH, oxo, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-6alkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-locycloalkyl, or -O-Cs-iocycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O-C3- locycloalkyl of R3ais optionally substituted with one or more R3b, andthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O-C3- locycloalkyl of R8ais optionally substituted with one or more R8b;R3Xis -OH, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-ealkoxy, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(Ci-6alkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-C3-locycloalkyl, whereinDocket No.: 79275-20040.40 the Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O-C3- locycloalkyl is optionally substituted with one or more R3b;R3band R8bare each independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy;Rllaand Rllbare independently at each occurrence, H or Ci-ealkyl, orone of Rllaand Rllbis H or Ci-ealkyl, and the other of Rllaand Rllbis taken together with one of R12aor R12bto form a Cs-iocycloalkyl; andR12aand R12bare each independently, H or Ci-ealkyl, orone of R12aand R12bis H or Ci-ealkyl, and the other of R12aand R12bis taken together with one of Rllaor Rllbto form a Cs-iocycloalkyl.

[0011] In one aspect, provided herein is a compound of formula (II-A):R9(II-A),or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, m, R2, R3, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0012] In one aspect, provided herein is a compound of formula (I'-A):R9(I'-A),or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R2, R3, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0013] In one aspect, provided herein is a compound of formula (I-A):Docket No.: 79275-20040.40 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, / / , X, R2, R3, R5, R6, R7, R8, R9, Rlla, and Rllbare as defined elsewhere herein.

[0014] In one aspect, provided herein is a compound of formula (II-B):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, m, R2, R3, R5, R6, R7, R9, and ring A are as defined elsewhere herein.

[0015] 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, and R9are as defined for a compound of formula (I); and ring A is 5-10 membered heteroaryl optionally substituted with one or more R8a; and each R8ais as defined elsewhere herein.

[0016] 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, Rlla, Rllb, and ring A are as defined elsewhere herein.

[0017] In one aspect, provided is a compound of formula (II-C):Docket No.: 79275-20040.40(II-C), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, R1, R3, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0018] In one aspect, provided is a compound of formula (I'-C):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.

[0019] In one aspect, provided herein is a compound of formula (I-C):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, s, R2, R3, R5, R6, R7, R9, R8a, Rlla, Rllb, Y1, Y2, Y3, Y4, and Y5are as defined elsewhere herein.

[0020] In one aspect, provided herein is a compound of formula (II-D):(II-D),Docket No.: 79275-20040.40 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, m, R5, R6, R7, R8, and R9are as defined elsewhere herein.

[0021] In one aspect, provided herein is a compound of formula (I'-D):R9(I'-D),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.

[0022] In one aspect, provided herein is a compound of formula (II-E):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, s, R2, R3, R5, R6, R7, R9, and R8aare as defined elsewhere herein; Y1, Y2, Y3, Y4, and Y5are each independently -CH- or -N-; and 5 is an integer from 0-5.

[0023] In one aspect, provided herein is a compound of formula (I'-E):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, s, R2, R3, R5, R6, R7, R9, and R8aare as defined elsewhere herein; Y1, Y2, Y3, Y4, and Y5are each independently -CH- or -N-; and 5 is an integer from 0-5.

[0024] In one aspect, provided herein is a pharmaceutical composition, comprising (i) a compound of formula (II), (P), or (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. This aspect, in someDocket No.: 79275-20040.40 embodiments, may employ a compound of any of formula (II), (P), (I), (II-A), (I'-A), (I-A), (II-B), (P-B), (LB), (II-C), (P-C), (I-C), (II-D), (P-D), (ILE), or (P-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0025] In one aspect, provided herein is a method of modulating SLC6A19 in a cell, comprising contacting the cell with an effective amount of a compound of formula (II), (P), or (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof. This aspect, in some embodiments, may employ a compound of any of formula (II), (P), (I), (II-A), (P-A), (LA), (II-B), (P-B), (I-B), (II-C), (P-C), (LC), (II-D), (P-D), (ILE), or (P-E), or a stereoisomer or tautomer of any of the foregoing.

[0026] In one aspect, provided herein is a method of inhibiting SLC6A19 in a cell, comprising contacting the cell with an effective amount of a compound of formula (II), (P), or (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof. This aspect, in some embodiments, may employ a compound of any of formula (II), (P), (I), (II-A), (P-A), (LA), (II-B), (P-B), (LB), (II-C), (P-C), (LC), (II-D), (P-D), (ILE), or (P-E), or a stereoisomer or tautomer of any of the foregoing.

[0027] 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 (II), (P), or (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 (II), (P), or (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. This aspect, in some embodiments, may employ a compound of any of formula (II), (T), (I), (ILA), (I'-A), (LA), (II-B), (I'-B), (LB), (II-C), (I'-C), (LC), (II-D), (P-D), (ILE), or (P-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0028] In one aspect, provided herein is a method of inhibiting SLC6A19 in a cell of an individual in need thereof, comprising administering to the individual an effective amount of (i) a compound of formula (II), (P), or (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 (II), (P), or (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or aDocket No.: 79275-20040.40 pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. This aspect, in some embodiments, may employ a compound of any of formula (II), (T), (I), (ILA), (I'-A), (LA), (ILB), (I'-B), (I-B), (II-C), (I'-C), (I-C), (II-D), (T-D), (ILE), or (I'-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0029] 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 (II), (I'), or (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 (II), (I'), or (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. This aspect, in some embodiments, may employ a compound of any of formula (II), (T), (I), (ILA), (I'-A), (LA), (ILB), (I'-B), (LB), (II-C), (I'-C), (LC), (II-D), (I'-D), (ILE), or (I'-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0030] 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 (II), (I'), or (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 (II), (I'), or (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. This aspect, in some embodiments, may employ a compound of any of formula (II), (I'), (I), (ILA), (I'-A), (LA), (ILB), (I'-B), (LB), (II-C), (I'-C), (LC), (II-D), (I'-D), (ILE), or (I'-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0031] In one aspect, provided herein is a kit, comprising (i) an effective amount of a compound of formula (II), (I'), or (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 (II), (I'), orDocket No.: 79275-20040.40 (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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. This aspect, in some embodiments, may employ a compound of any of formula (II), (I'), (I), (II-A), (I'-A), (I-A), (II-B), (I'-B), (I-B), (II-C), (I'-C), (I-C), (II-D), (I'-D), (II-E), or (I'-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0032] In another variation, provided herein is a kit, comprising (i) a compound of formula (II), (I'), or (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 (II), (I'), or (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 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. This aspect, in some embodiments, may employ a compound of any of formula (II), (I'), (I), (II-A), (I'-A), (I-A), (II-B), (I'-B), (I-B), (II-C), (I'-C), (I-C), (II-D), (I'-D), (II-E), or (I'-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0033] In some aspects, provided herein are methods of preparing a compound of formula (II), (I'), or (I), or any embodiment or variation thereof, such as a compound of formula (II), (I'), (I), (II-A), (I'-A), (I-A), (II-B), (I'-B), (I-B), (II-C), (I'-C), (I-C), (II-D), (I'-D), (II-E), or (I'-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0034] All compounds, pharmaceutical compositions, methods, kits, uses, or other aspects described herein with reference to formula (II), (I'), or (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are also hereby described and embraced for any one of the other formulas detailed herein, such as formula (II), (I'), (I), (II-A), (I'-A), (I-A), (II-B), (I'-B), (I-B), (II-C), (I'-C), (I-C), (II-D), (I'-D), (II-E), or (I'-E), the same as if each and every embodiment were specifically and individually listed.

[0035] Any embodiments provided herein of a compound of formula (II), (I'), or (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theDocket No.: 79275-20040.40 foregoing, apply where applicable to any other formula detailed herein, the same as if each and every embodiment were specifically and individually listed. Thus, it is understood and described that each embodiment provided herein of a compound of formula (II), (I'), or (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to m, n, s, L, X, R1, R2, R3, R5, R6, R7, R8, R9, R3a, R3X, R8a, R3b, R8b, Rlla, Rllb, R12a, R12b, Y1, Y2, Y3, Y4, Y5, ring A, and ring B apply to formula (II), (T), (I), (II-A), (I'-A), (LA), (II-B), (I'-B), (I-B), (II-C), (I'-C), (I-C), (II-D), (T-D), (ILE), or (I'-E), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the same as if each and every embodiment were specifically and individually listed. It is also understood and described that all such embodiments may be used in any of the pharmaceutical compositions, methods, kits, uses, or other aspects detailed herein.DETAILED DESCRIPTION OF THE INVENTION

[0036] “ 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.

[0037] 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.

[0038] In some embodiments, the term “about,” when used in association with a measurement or to modify a parameter or a value or a range of values, refers to variations of that measurement, parameter, value, or range of values of + / - 10%, + / - 9%, + / - 8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1%. For example, in some embodiments, “about X” includes and describes X + / - 10%, + / - 9%, + / - 8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1% of X. In some embodiments, the term “about” refers to variations of + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1%. In some embodiments, the term “about” refers to variations of + / - 2% or + / - 1%. In some embodiments, the term “about” refers to variations of + / - 2%. In some embodiments, the term “about” refers to variations of + / - 1%.

[0039] “ 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 theDocket No.: 79275-20040.40 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).

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] The term “alkyl”, as used herein, refers to an unbranched or branched saturated univalent hydrocarbon chain. As used herein, alkyl has 1-20 carbons ( / .<., Ci-2oalkyl), 1-16 carbons ( / .<., Ci-iealkyl), 1-12 carbons (i.e., Ci-nalkyl), 1-10 carbons ( / .<., Ci-ioalkyl), 1-8 carbons (i.e., Ci-salkyl), 1-6 carbons i.e., Ci-ealkyl), 1-4 carbons (i.e., Ci-4alkyl), or 1-3Docket No.: 79275-20040.40 carbons (z.e., Ci-3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, / .w-propyl, / / -butyl,.sec-butyl, zso-butyl, tert-butyl, pentyl, 2-pentyl, / .so- 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 positional isomers having that number of carbon atoms may be encompassed — for example, “butyl” includes / / -butyl, ec-butyl, zso-butyl, and tert-butyl; and “propyl” includes / / -propyl and isopropyl. 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”.

[0045] 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 (z.e., C2-2oalkenyl), 2-16 carbons (z.e., C2-iealkenyl), 2-12 carbons (z.e., C2-i2alkenyl), 2-10 carbons (z.e., C2-ioalkenyl), 2-8 carbons (z.e., C2-salkenyl), 2-6 carbons (z.e., C2-ealkenyl), 2-4 carbons (z.e., C2-4alkenyl), or 2-3 carbons (z.e., C2-3alkenyl). Examples of alkenyl include, but are not limited to, ethenyl, prop-l-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-l-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”.

[0046] 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 (z.e., C2-2oalkynyl), 2-16 carbons (z.e., C2-iealkynyl), 2-12 carbons (z.e., C2-i2alkynyl), 2-10 carbons (z.e., C2-ioalkynyl), 2-8 carbons (z.e., C2-salkynyl), 2-6 carbons (z.e., C2-ealkynyl), 2-4 carbons (z.e., C2-4alkynyl), or 2-3 carbons (z.e., C2-3alkynyl). Examples of alkynyl include, but are not limited to, ethynyl, prop-l-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-l-ynyl and prop-2 -ynyl. Certain commonly used alternative names may be used and will beDocket No.: 79275-20040.40 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”.

[0047] The term “alkoxy”, as used herein, refers to an -O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, / / -propoxy, z.w-propoxy, / / -butoxy, Zc / 7-butoxy, ec-butoxy, / / -pentoxy, / / -hexoxy, and 1,2-dimethylbutoxy.

[0048] 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 (z.c., Ce-2oaryl), 6 to 16 annular carbon atoms (z.c., Ce-iearyl), 6 to 12 annular carbon atoms (z.c., Ce-naryl), or 6 to 10 annular carbon atoms (z.c., Ce-ioaryl). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0049] 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 (z.c., a C3-2ocycloalkyl), 3 to 16 annular carbon atoms (i.e., a Cs-iecycloalkyl), 3 to 12 annular carbon atoms (z.c., a Cs-ncycloalkyl), 3 to 10 annular carbon atoms (z.c., a Cs-iocycloalkyl), 3 to 8 annular carbon atoms (z.c., a Cs-scycloalkyl), 3 to 6 annular carbon atoms (z.c., a C3-ecycloalkyl), or 3 to 5 annular carbon atoms (z.c., a Cs-scycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl -bicyclo [2.2.1]heptanyl, and the like. Still further, cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl.

[0050] 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.Docket No.: 79275-20040.40

[0051] 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 ( / .<., a 5-20 membered heteroaryl), 5 to 16 annular atoms ( / .<., a 5-16 membered heteroaryl), 5 to 12 annular atoms ( / .<., a 5-12 membered heteroaryl), 5 to 10 annular atoms ( / .<., a 5-10 membered heteroaryl), 5 to 8 annular atoms ( / .<., 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 ( / .<., 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[l,5-a]pyridinyl, and imidazo[l,5-a]pyridinyl, wherein the heteroaryl can be bound via either ring of the fused system.

[0052] 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 of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached toDocket No.: 79275-20040.40 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 (z.e., a 3-20 membered heterocyclyl), 3 to 16 annular atoms (z.e., a 3-16 membered heterocyclyl), 3 to 12 annular atoms (z.e., a 3-12 membered heterocyclyl), 3 to 10 annular atoms (z.e., a 3-10 membered heterocyclyl), 3 to 8 annular atoms (z.e., a 3-8 membered heterocyclyl), 3 to 6 annular atoms (z.e., a 3-6 membered heterocyclyl), 3 to 5 annular atoms (z.e., a 3-5 membered heterocyclyl), 5 to 8 annular atoms (z.e., a 5-8 membered heterocyclyl), or 5 to 6 annular atoms (z.e., a 5-6 membered heterocyclyl). Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodi oxolyl, 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 (z.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 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-l-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.

[0053] The term “oxo”, as used herein, refers to a =0 moiety.

[0054] The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not.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 replacedDocket No.: 79275-20040.40 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, -CH2CI, -CHCh, and -CCI3 moieties.

[0055] It is understood that aspects and embodiments described herein as “comprising” include “consisting of’ and “consisting essentially of’ embodiments.

[0056] 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 derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(Ao-propyl) amine, tri(w-propyl) amine,Docket No.: 79275-20040.40 ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0057] 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,nC,13C,14C,13N,15N,150,170,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. In some embodiments, a compound of formula (I) is provided wherein one or more hydrogen is replaced by deuterium or tritium.

[0058] 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.

[0059] 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.

[0060] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (5)- (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 (5)-, or (D)- and (L)- isomers may beDocket No.: 79275-20040.40 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.

[0061] 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.COMPOUNDS

[0062] In one aspect, provided herein is a compound of formula (II):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;n is an integer from 0 to 4;R1is -NH-, -O-, or -S-;either:(i) R2and R3are independently H, Ci-ealkyl, Ci-3alkoxy, Cs-iocycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, whereinDocket No.: 79275-20040.40 the Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x, or(ii) R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, whereinthe 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x; R5is H, halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R6and R9are each independently H or halo;R7is halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, whereinthe Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R8is Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinthe Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with one or more R8a;R3aand R8aare each independently -OH, oxo, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-6alkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-locycloalkyl, or -O-Cs-iocycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl of R3ais optionally substituted with one or more R3b, and the Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl of R8ais optionally substituted with one or more R8b;R3Xis -OH, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-ealkoxy, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(Ci-6alkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-C3-locycloalkyl, whereinDocket No.: 79275-20040.40 the Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b;R3band R8bare each independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy; andR11aR11bL is absent or isx n**, wherein** denotes the point of attachment to R8and * denotes the point of attachment to the rest of the molecule;X is -O-, -S-, -C(R12a)(R12b)-, -N(H)-, or -N(Ci-6alkyl)-;Rllaand Rllbare independently at each occurrence, H or Ci-ealkyl, orone of Rllaand Rllbis H or Ci-ealkyl, and the other of Rllaand Rllbis taken together with one of R12aor R12bto form a Cs-iocycloalkyl; andR12aand R12bare each independently, H or Ci-ealkyl, orone of R12aand R12bis H or Ci-ealkyl, and the other of R12aand R12bis taken together with one of Rllaor Rllbto form a Cs-iocycloalkyl.R11aR11b

[0063] In some embodiments, L is absent. In some embodiments, L isx n“, wherein ** denotes the point of attachment to R8and * denotes the point of attachment to the rest of the molecule; X is -O-, -S-, -C(R12a)(R12b)-, -N(H)-, or -N(Ci-6alkyl)-; Rllaand Rllbare independently at each occurrence, H or Ci-ealkyl, or one of Rllaand Rllbis H or Ci-ealkyl, and the other of Rllaand Rllbis taken together with one of R12aor R12bto form a C3-locycloalkyl; and R12aand R12bare each independently, H or Ci-ealkyl, or one of R12aand R12bis H or Ci-ealkyl, and the other of R12aand R12bis taken together with one of Rllaor Rllbto form a Cs-iocycloalkyl.

[0064] In one aspect, provided herein is a compound of formula (I'):r9(I'),or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:Docket No.: 79275-20040.40 m is an integer from 1 to 4;R1is -NH-, -O-, or -S-;either:(i) R2and R3are independently H, Ci-ealkyl, Ci-3alkoxy, Cs-iocycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, whereinthe Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x, or(ii) R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, whereinthe 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x; R5is H, halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R6and R9are each independently H or halo;R7is halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, whereinthe Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R8is Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinthe Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with one or more R8a;R3aand R8aare each independently -OH, oxo, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-6alkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-locycloalkyl, or -O-Cs-iocycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b, andDocket No.: 79275-20040.40 the Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R8b;R3Xis -OH, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-ealkoxy, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(Ci-6alkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-C3-locycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b; andR3band R8bare each independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy.

[0065] 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;n is an integer from 0 to 4;X is -O-, -S-, -C(R12a)(R12b)-, -N(H)-, or -N(Ci-6alkyl)-;R1is -NH-, -O-, or -S-;either:(i) R2and R3are independently H, Ci-ealkyl, Ci-3alkoxy, Cs-iocycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, whereinthe Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x, or(ii) R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, whereinDocket No.: 79275-20040.40 the 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x; R5is H, halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R6and R9are each independently H or halo;R7is halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, whereinthe Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R8is Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinthe Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with one or more R8a;R3aand R8aare each independently -OH, oxo, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-6alkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-locycloalkyl, or -O-Cs-iocycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl of R3ais optionally substituted with one or more R3b, and the Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl of R8ais optionally substituted with one or more R8b;R3Xis -OH, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-ealkoxy, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(Ci-6alkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-C3-locycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b;R3band R8bare each independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy;Rllaand Rllbare independently at each occurrence, H or Ci-ealkyl, orone of Rllaand Rllbis H or Ci-ealkyl, and the other of Rllaand Rllbis taken together with one of R12aor R12bto form a Cs-iocycloalkyl; andDocket No.: 79275-20040.40 R12aand R12bare each independently, H or Ci-ealkyl, orone of R12aand R12bis H or Ci-ealkyl, and the other of R12aand R12bis taken together with one of Rllaor Rllbto form a Cs-iocycloalkyl.

[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 2;n is an integer from 0-2;X is -O-, -S-, -C(R12a)(R12b)-, -N(H)-, or -N(Ci-3alkyl)-;R1is -NH-, -O-, or -S-;either:(i) R2and R3are independently H, Ci-salkyl, Ci-salkoxy, Cs-ecycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocyclyl, whereinthe Ci-salkyl, Ci-3alkoxy, Cs-ecycloalkyl, or 4-6 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-6 membered heteroaryl is optionally substituted with one or more R3x, or (ii) R2and R3are taken together to form 5-6 membered heteroaryl, or 4-6 membered heterocyclyl, whereinthe Ci-3alkyl, Ci-3alkoxy, Cs-ecycloalkyl, or 4-6 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-6 membered heteroaryl is optionally substituted with one or more R3x; R5is H, halo, -CN, Ci-3alkyl, Ci-3alkoxy, Cs-ecycloalkyl or Ci-3haloalkyl, wherein the Ci-3alkyl is optionally substituted with one or more -CN, and the Ci-3alkoxy is optionally substituted with one or more halo;R6and R9are each independently H or halo;R7is halo, -CN, Ci-3alkyl, Ci-3alkoxy, Cs-ecycloalkyl or Ci-3haloalkyl, whereinthe Ci-3alkyl is optionally substituted with one or more -CN, and the Ci-3alkoxy is optionally substituted with one or more halo;R8is Cs-ecycloalkyl, Ce-ioaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinthe Cs-ecycloalkyl, Ce-ioaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl of R8is optionally substituted with one or more R8a;Docket No.: 79275-20040.40 R3aand R8aare each independently -OH, oxo, -CN, halo, Ci-3alkyl, C2-4alkenyl, Ci-3alkoxy, -NH2, -NH(Ci-3alkyl), -N(Ci-3alkyl)2, -C(O)Ci-3alkyl, -C(O)NH2, -C(O)NH(Ci-3alkyl), -C(O)N(Ci-3alkyl)2, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C3. ecycloalkyl, or -O-C3-6cycloalkyl, whereinthe Ci-3alkyl, Ci-3alkoxy, 4-10 membered heterocyclyl, C3-iocycloalkyl or -O- C3-iocycloalkyl of R3ais optionally substituted with one or more R3b, and the Ci-3alkyl, Ci-3alkoxy, 4-10 membered heterocyclyl, C3-iocycloalkyl or -O- C3-iocycloalkyl of R8ais optionally substituted with one or more R8b;R3Xis OH, -CN, halo, Ci-3alkyl, C2-4alkenyl, Ci-3alkoxy, -NH2, -NH(Ci-3alkyl), -N(Ci-3alkyl)2, -C(O)Ci-3alkyl, -C(O)NH2, -C(O)NH(Ci-3alkyl), -C(O)N(Ci-3alkyl)2, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-6cycloalkyl, or -O-C3-6cycloalkyl, wherein the Ci-3alkyl, Ci-3alkoxy, 4-10 membered heterocyclyl, C3-iocycloalkyl or -O- C3-iocycloalkyl is optionally substituted with one or more R3b;R3band R8bare each independently D, -OH, halo, Ci-3alkyl or Ci-3alkoxy;Rllaand Rllbare independently at each occurrence, H or Ci-3alkyl, orone of Rllaand Rllbis H or Ci-3alkyl, and the other of Rllaand Rllbis taken together with one of R12aor R12bto form a C3-6cycloalkyl; andR12aand R12bare each independently, H or Ci-3alkyl, orone of R12aand R12bis H or Ci-3alkyl, and the other of R12aand R12bis taken together with one of Rllaor Rllbto form a C3-6cycloalkyl.

[0067] In some embodiments of a compound of formula (II) or formula (P), 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 Ci-ealkyl;R5is H;R6and R9are each H;R7is halo, or Ci-ealkoxy, whereinthe Ci-ealkoxy is optionally substituted with one or more halo;R8is 5-10 membered heteroaryl optionally substituted with one or more R8a; and R8ais Ci-ealkoxy.Docket No.: 79275-20040.40

[0068] In some embodiments of a compound of formula (II) or formula (P), 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 Ci-3alkyl;R5is H;R6and R9are each H;R7is halo, or Ci-3alkoxy, whereinthe Ci-3alkoxy is optionally substituted with one or more halo;R8is 5-6 membered heteroaryl optionally substituted with one or more R8a; and R8ais Ci-ealkoxy.

[0069] In some embodiments of a compound of formula (II) or 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;n is 1;X is -O-;R1is -NH-;either:(i) R2and R3are independently H or Ci-ealkyl, or(ii) R2and R3are taken together to form 4-10 membered heterocyclyl;R5is H;R6and R9are each H;R7is halo;R8is 5-10 membered heteroaryl optionally substituted with one or more R8a;R8ais Ci-ealkyl; andRllaand Rllbare each H.

[0070] In some embodiments of a compound of formula (II) or 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;n is 1;X is -O-;Docket No.: 79275-20040.40 R1is -NH-;R2is H;R3is Ci-salkyl;R5is H;R6and R9are each H;R7is halo;R8is 5-6 membered heteroaryl optionally substituted with one or more R8a;R8ais Ci-6alkyl; andR1 laand R1 lbare each H.

[0071] In some embodiments, the moiety represented byDocket No.: 79275-20040.40

[0072] In some embodiments, the moiety represented byNHfrom the group consisting of — NH

[0074] In some embodiments, the moiety represented by

[0075] In some embodimentsfrom the group consisting ofDocket No.: 79275-20040.40

[0077] In some embodiments, the moiety represented by R9is selected Cl H Ofrom the group consisting of and oHaR11b

[0078] In some embodiments, the moiety represented byx nRis selected from thegroup consisting ofDocket No.: 79275-20040.40

[0079] In some embodiments, R1is -NH-, -O-, or -S-. In some embodiments, R1is -O-. In some embodiments, R1is -S-. In some embodiments, R1is -NH-.

[0080] In one aspect, provided herein is a compound of formula (II), such as a compound of formula (II- A):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, m, R2, R3, R5, R6, R7, R8, and R9are as defined for a compound of formula (II).

[0081] In one aspect, provided herein is a compound of formula (II) or formula (P), such as a compound of formula (P-A):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R2, R3, R5, R6, R7, R8, and R9are as defined for a compound of formula (II).

[0082] In one aspect, provided herein is a compound of formula (II) or 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, n, X, R2, R3, R5, R6, R7, R8, R9, Rlla, and Rllbare as defined for a compound of formula (I).Docket No.: 79275-20040.40

[0083] In some embodiments, 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.

[0084] In some embodiments, n is an integer from 1-4. In some embodiments, n is an integer from 1-2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0085] In some embodiments, X is -O-, -S-, -C(R12a)(R12b)-, -N(H)-, or -N(Ci-6alkyl)-. In some embodiments, X is -O-.

[0086] In some embodiments, R2and R3are independently H, Ci-ealkyl, Ci-3alkoxy, C3-10-cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, and the 5-10 membered heteroaryl is optionally substituted with one or more R3X.

[0087] In some embodiments, one of R2and R3is H.

[0088] In some embodiments, one ofR2and R3is Ci-ealkyl, Ci-3alkoxy, Cs-iocycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the Ci-ealkyl, Ci-ealkoxy, C3-locycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, and the 5-10 membered heteroaryl is optionally substituted with one or more R3x. In some embodiments, one of R2and R3is Ci-3alkyl, Ci-3alkoxy, Cs-ecycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocyclyl, wherein the Ci-3alkyl, Ci-3alkoxy, Cs-ecycloalkyl, or 4-6 membered heterocyclyl is optionally substituted with one or more R3a, and the 5-6 membered heteroaryl is optionally substituted with one or more R3x.

[0089] In some embodiments, one of R2and R3is Ci-ealkyl, optionally substituted with one or more R3a. In some embodiments, one of R2and R3is Ci-3alkyl. In some embodiments, one of R2and R3is methyl.

[0090] In some embodiments, one of R2and R3is H, and the other of R2and R3is Ci-ealkyl. In some embodiments, one of R2and R3is H, and the other of R2and R3is Ci-3alkyl. In some embodiments, one of R2and R3is H, and the other of R2and R3is methyl.

[0091] In some embodiments, R3ais, independently at each occurrence, -OH, oxo, -CN, halo, Ci-ealkyl, C2-ealkenyl, Ci-ealkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci-ealkyl), - C(O)N(Ci-ealkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-Cs-iocycloalkyl, wherein the Ci-ealkyl, Ci-Docket No.: 79275-20040.40 ealkoxy, 4-10 membered heterocyclyl or Cs-iocylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis, independently at each occurrence, -OH, halo, Ci-ealkyl or Ci-ealkoxy. In some embodiments, R3ais, independently at each occurrence, -OH, oxo, -CN, halo, Ci-3alkyl, C2-4alkenyl, Ci-3alkoxy, -NH2, -NH(Ci-3alkyl), -N(Ci-3alkyl)2, -C(O)Ci-3alkyl, -C(O)NH2, - C(O)NH(Ci-3alkyl), - C(O)N(Ci-3alkyl)2, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, Cs-ecycloalkyl, or -O-Cs-ecycloalkyl, wherein the Ci-3alkyl, Ci-salkoxy, 4-6 membered heterocyclyl, Cs-ecycloalkyl, or -O-Cs-ecylcoalkyl of R3ais optionally substituted with one or more R3b; and each R3bis, independently at each occurrence, D, -OH, halo, Ci-3alkyl or Ci-3alkoxy.

[0092] In some embodiments, R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted with one or more R3a, and the 5-10 membered heteroaryl is optionally substituted with one or more R3x.

[0093] In some embodiments, R5is H, halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more halo, or CN, and the Ci-ealkoxy is optionally substituted with one or more halo. In some embodiments, R5is H, halo, -CN, Ci-3alkyl, Ci-3alkoxy, Cs-ecycloalkyl or Ci-3haloalkyl, wherein the Ci-3alkyl is optionally substituted with one or more halo, or CN, and the Ci-3alkoxy is optionally substituted with one or more halo. In some embodiments, R5is H.

[0094] In some embodiments, R7is halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more halo, or CN, and the Ci-ealkoxy is optionally substituted with one or more halo. In some embodiments, R7is halo, -CN, Ci-3alkyl, Ci-3alkoxy, Cs-ecycloalkyl or Ci-3haloalkyl, wherein the Ci-3alkyl is optionally substituted with one or more halo, or CN, and the Ci-3alkoxy is optionally substituted with one or more halo. In some embodiments, R7is halo.

[0095] In some embodiments, R6and R9are each independently H, or halo. In some embodiments, R6and R9are each H.

[0096] In some embodiments, R8is Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein each R8is optionally substituted with one or more R8a; R8ais, independently at each occurrence, -OH, oxo, -CN, halo, Ci-ealkyl, C2-ealkenyl, Ci-6alkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(Ci-ealkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-Docket No.: 79275-20040.40 wcycloalkyl, or -O-Cs-iocycloalkyl, wherein the Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl or CNiocyl coalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy. In some embodiments, R8is C3-ecycloalkyl, Ce-naryl, 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, Ci-3alkyl, C2-4alkenyl, Ci-3alkoxy, -NH2, -NH(Ci-3alkyl), -N(Ci-3alkyl)2, -C(O)Ci-3alkyl, -C(O)NH2, - C(O)NH(Ci-3alkyl), - C(O)N(Ci-3alkyl)2, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, Cs-ecycloalkyl, or -O-Cs-ecycloalkyl, wherein the Ci-ealkyl, Ci-ealkoxy, 4-6 membered heterocyclyl Cs-ecycloalkyl, or -O-Cs-ecylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, Ci-3alkyl or Ci-salkoxy.

[0097] In some embodiments, R8is 5-10 membered heteroaryl. In some embodiments, R8is 5-10 membered heteroaryl, optionally substituted with one or more R8a, R8ais independently -OH, oxo, -CN, halo, Ci-ealkyl, C2-ealkenyl, Ci-ealkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci-6alkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-Cs-iocycloalkyl, wherein the Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl or Cs-iocylcoalkyl of R8ais optionally substituted with one or more R8b; and each R8bis independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy. In some embodiments, R8is 5-10 membered heteroaryl, optionally substituted with one or more R8a, and each R8ais independently halo, or Ci-ealkoxy. In some embodiments, R8is selected from the group consisting ofand. In some embodiments, R8is 5-10 membered heteroaryl, optionally substituted with one or more R8a, and each R8ais independently Ci-ealkyl. In some embodiments, R8is selected from the groupJ s „consisting ofand N^ / . In some embodiments, R is 5-10 membered heteroaryl, optionally substituted with one or more R8a, and each R8ais independently halo, or Ci-ealkoxy. In some embodiments, R8is selected from the group consisting of°^andN oDocket No.: 79275-20040.40

[0098] In some embodiments, Rllaand Rllbare independently at each occurrence, H or Ci-ealkyl. In some embodiments, Rllaand Rllbare each H.

[0099] In some embodiments, one of Rllaand Rllbis H or Ci-ealkyl, and the other of Rllaand Rllbis taken together with one of R12aor R12bto form a Cs-iocycloalkyl.

[0100] In some embodiments, R12aand R12bare each independently, H or Ci-ealkyl.

[0101] In some embodiments, one of R12aand R12bis H or Ci-ealkyl, and the other of R12aand R12bis taken together with one of Rllaor Rllbto form a Cs-iocycloalkyl.

[0102] In one aspect, provided herein is a compound of formula (II), formula (F), or formula (P-A), such as a compound of (P-Al):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, R2, R3, R7, and R8are as defined for a compound of formula (II) or formula (P).

[0103] In one aspect, provided herein is a compound of formula (II), formula (I), or formula (I-A), such as a compound of formula (I-Al):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, / / , X, R2, R3, R7, R8, Rlla, and Rllbare as defined for a compound of formula (I).

[0104] In some embodiments, R7is halo. In some embodiments, R7is F. In some embodiments, R7is Cl. In some embodiments, R7is halo or Ci-ealkoxy, wherein the Ci-ealkoxy is optionally substituted with one or more halo. In some embodiments, R7is halo or Ci-3alkoxy, wherein the Ci-3alkoxy is optionally substituted with one or more halo. In some embodiments, R7is Ci-ealkoxy optionally substituted with one or more halo. In some embodiments, R7is Ci-3alkoxy optionally substituted with one or more halo. In some embodiments, R7is methoxy optionally substituted with one or more halo. In some embodiments, R7is -OCF3.Docket No.: 79275-20040.40

[0105] In one aspect, provided herein is a compound of formula (II), such as a compound of formula (II-B):R9(II-B),or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, m, R2, R3, R5, R6, R7, R9, and ring A are as defined for a compound of formula (II).

[0106] 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, and R9are as defined for a compound of formula (I); and ring A is 5-10 membered heteroaryl optionally substituted with one or more R8a; and each R8ais as defined for a compound of formula (II) or formula (I').

[0107] In one aspect, provided herein is a compound of formula (II) or 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, Rlla, and Rllbare as defined for a compoundDocket No.: 79275-20040.40 of formula (I); and ring A is 5-10 membered heteroaryl optionally substituted with one or more R8a; and each R8ais as defined for a compound of formula (II) or formula (I).

[0108] In one aspect, provided herein is a compound of formula (II), such as a compound of formula (II-C):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, R1, R3, R5, R6, R7, R8, and R9are as defined for a compound of formula (II).

[0109] 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 R1, R3, R5, R6, R7, R8, and R9are as defined for a compound of formula (II) or formula (P).

[0110] In one aspect, provided herein is a compound of formula (I-C):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, s, R2, R3, R5, R6, R7, R9, R8a, Rlla, and Rllbare as defined for a compound of formula (I); Y1, Y2, Y3, Y4, and Y5are each independently -CH-, -N-, -O-, or -Docket No.: 79275-20040.40 S-; and 5 is an integer from 0-4. In some embodiments, the ring bearing Y1, Y2, Y3, Y4, and Y5, is heteroaryl. In some embodiments, the ring bearing Y1, Y2, Y3, Y4, and Y5, is isoxazolyl or thiazolyl. In some embodiments, the ring bearing Y1, Y2, Y3, Y4, and Y5is isoxazolyl. In some embodiments, the ring bearing Y1, Y2, Y3, Y4, and Y5is thiazolyl.

[0111] In some embodiments, m is an integer from 1 to 2; n is an integer from 1 to 2; R2and R3are independently H or Ci-3alkyl; R5is H; R7is halo; R6and R9are each H; Rllaand Rllbare each H; each R8ais independently Ci-salkyl; Y1, Y2, Y3, Y4, and Y5are each independently -CH-, -N-, -O-, or -S-, wherein at least one of Y1, Y2, Y3, Y4, and Y5is -N-; and.s is an integer from 0-1.

[0112] In some embodiments, the compound is compound of formula:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, s, R2, R3, R7, R8a, Rlla, Rllb, Y1, Y2, Y3, Y4, and Y5are as defined for a compound of formula (I-C).

[0113] In some embodiments, the compound is compound of formula:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, s, R7, R8a, Rlla, Rllb, Y1, Y2, Y3, Y4, and Y5are as defined for a compound of formula (I-C); and ring B is 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl of ring B is optionally substituted with one or more R3a, and the 5-10 membered heteroaryl of ring B is optionally substituted withDocket No.: 79275-20040.40 one or more R3x. In some embodiments, any one of Y1, Y2, Y4, and Y5is -N-, and the others of Y1, Y2, Y4, and Y5are each independently -CH-, -O-, or -S-.

[0114] In one aspect, provided herein is a compound of formula (II), such as a compound of formula (II-D):(II-D),or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, m, R5, R6, R7, R8, and R9are as defined for a compound of formula (II).

[0115] In one aspect, provided herein is a compound of formula (I'-D):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 (II) or formula (P).

[0116] In one aspect, provided herein is a compound of formula (II), such as a compound of formula (II-E):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, s, R2, R3, R5, R6, R7, R9, and R8aare as defined elsewhere herein; Y1, Y2, Y3, Y4, and Y5are each independently -CH- or -N-; and 5 is an integer from 0-5.Docket No.: 79275-20040.40

[0117] In one aspect, provided herein is a compound of formula (P-E):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, s, R2, R3, R5, R6, R7, R9, and R8aare as defined for a compound of formula (II) or formula (P); Y1, Y2, Y3, Y4, and Y5are each independently -CH- or -N-; and 5 is an integer from 0-5. In some embodiments, the ring bearing Y1, Y2, Y3, Y4, and Y5, is heteroaryl. In some embodiments, the ring bearing Y1, Y2, Y3, Y4, and Y5, is pyridyl or pyrazinyl. In some embodiments, the ring bearing Y1, Y2, Y3, Y4, and Y5is pyridyl. In some embodiments, the ring bearing Y1, Y2, Y3, Y4, and Y5is pyrazinyl.

[0118] In some embodiments, m is an integer from 1 to 2; R2and R3are independently H or Ci-3alkyl; R5is H; R7is halo or Ci-3alkoxy, wherein the Ci-3alkoxy is optionally substituted with one or more halo; R6and R9are each H; each R8ais independently halo or Ci-3alkoxy; Y1, Y2, Y3, Y4, and Y5are each independently -CH- or -N-, wherein at least one of Y1, Y2, Y3, Y4, and Y5is -N-; and 5 is an integer from 0-2.

[0119] In some embodiments, the compound is compound of formula (P-E-a-i):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, 5, R2, R3, R7, R8a, Y1, Y2, Y3, Y4, and Y5are as defined for a compound of formula (P-E).

[0120] In some embodiments, the compound is compound of formula (P-E-b-i):Docket No.: 79275-20040.40or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, s, R5, R6, R7, R9, R8a, Y1, Y2, Y3, Y4, and Y5are as defined for a compound of formula (I'-E). In some embodiments, Y3is -CH-. In some embodiments, Y3is -CH-, any one of Y1, Y2, Y4, and Y5is -N-, and the others of Y1, Y2, Y4, and Y5are each independently -CH-. In some embodiments, Y3is -CH-, any two of Y1, Y2, Y4, and Y5is -N-, and the others of Y1, Y2, Y4, and Y5are each -CH-.

[0121] In some embodiments, 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, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-8 of Table 1. In some embodiments, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 1-3 of Table 1. In some embodiments, the compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is selected from compounds 4-8 of Table 1.

[0122] Compound Names included in Table 1 and for all intermediates and compounds were generated using the following procedure. 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 generate a SDFile of structures without stereochemistry. The SDFile is loaded into CDD Vault, which provides the IUPAC name. The following denotes the version of the Knime Analytics Platform and extensions utilized in the workflow:Knime Analytics Platform 4.7.7RDKit Nodes Feature 4.9.1.v202312081930 (this extension includes the RDKit Canon SMILES node )ChemAxon / Infocom JChem Extension Features 4.7.0.v231600 (this extension includes the MolConverter node)Docket No.: 79275-20040.40 CDD Vault https: / / www.collaborativedrug.com / cdd-blog / tag / cdd-vault-updates (February 2025 Update).Table 1Cmpd Structure IUPAC nameNo.1 “e 0 7V-methyl{5-chloro-6-[(3-methyl-5- HN— V z^^ClT isoxazolyl)methoxy]-2- H Me indolyl } acetamideO-N2 1 -( 1 -azetidinyl)-3 - { 5 -chi oro-6-[( 1,3- thiazol -4-yl)methoxy ] -2-indolyl } - 1 - propanone_ po 03 Me-NH N-methy 1 -3 - { 5 -chi oro-6 -[(1,3 -thi azol - \ -. z^ x^CI° JL 4-yl)methoxy] -2-indolyl (propionamide (ZIK H4 3 -(5 -chloro-6-(6-fluoro-5 - p'VU'yY methoxypyridin-2-yl)-U7-indol-2-yl)- / M Xe°Z-^'NHH|l J. MeN-methylpropanamide5 Me O 2-(5-chloro-6-(5-methoxypyrazin-2-yl)- HN— \U7-indol-2-yl)-7V-methylacetamideHT 1U. xk.N OMe6 3-(5-chloro-6-(5-methoxypyrazin-2-yl)- % y— / H NA'^xI^Y N^ U7-indol-2-yl)-7V-methylpropanamide Me-NHH|l J. MeN O'7 3 -(5 -fluoro-6-(5 -methoxypyrazin-2-yl)- w X U7-indol-2-yl)-7V-methylpropanamide Me-NHHU Jk MeN O'Docket No.: 79275-20040.408 3-(6-(5-methoxypyrazin-2-yl)-5- % H AX N (trifluoromethoxy)-l / 7-indol-2-yl)-7V- Me— NHH|l JL MeN O' methylpropanamide

[0123] In some embodiments, provided herein is a compound of formula (II), 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-methyl{5-chloro-6-[(3-methyl-5-isoxazolyl)methoxy]-2-indolyl (acetamide;1-(l-azetidinyl)-3-{5-chloro-6-[(l,3-thiazol-4-yl)methoxy]-2-indolyl(-l-propanone;N-methyl-3-{5-chloro-6-[(l,3-thiazol-4-yl)methoxy]-2-indolyl (propionamide;3-(5-chloro-6-(6-fluoro-5-methoxypyridin-2-yl)-lH-indol-2-yl)-N-methylpropanamide; 2-(5-chloro-6-(5-methoxypyrazin-2-yl)-lH-indol-2-yl)-N-methylacetamide;3-(5-chloro-6-(5-methoxypyrazin-2-yl)-lH-indol-2-yl)-N-methylpropanamide;3-(5-fluoro-6-(5-methoxypyrazin-2-yl)-lH-indol-2-yl)-N-methylpropanamide; and3-(6-(5-methoxypyrazin-2-yl)-5-(tri fluoromethoxy)- lH-indol-2-yl)-N-methylpropanamide, or a pharmaceutically acceptable salt of any of the foregoing.

[0124] In some embodiments, provided herein is a compound of formula (II), 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-methyl{5-chloro-6-[(3-methyl-5-isoxazolyl)methoxy]-2-indolyl (acetamide;1-(l-azetidinyl)-3-{5-chloro-6-[(l,3-thiazol-4-yl)methoxy]-2-indolyl(-l-propanone; and N-methyl-3-{5-chloro-6-[(l,3-thiazol-4-yl)methoxy]-2-indolyl(propionamide, or a pharmaceutically acceptable salt of any of the foregoing.

[0125] 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:3-(5-chloro-6-(6-fluoro-5-methoxypyridin-2-yl)-lH-indol-2-yl)-N-methylpropanamide; 2-(5-chloro-6-(5-methoxypyrazin-2-yl)-lH-indol-2-yl)-N-methylacetamide;Docket No.: 79275-20040.40 3-(5-chloro-6-(5-methoxypyrazin-2-yl)-lH-indol-2-yl)-N-methylpropanamide;3-(5-fluoro-6-(5-methoxypyrazin-2-yl)-lH-indol-2-yl)-N-methylpropanamide; and3-(6-(5-methoxypyrazin-2-yl)-5-(trifluoromethoxy)-lH-indol-2-yl)-N-methylpropanamide, or a pharmaceutically acceptable salt of any of the foregoing.COMPOSITIONS

[0126] All compositions described herein with reference to formula (II), formula (I'), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are also hereby described and embraced for any one of the other formulas detailed herein, such as formula (II-A), (I'-A), (I-A), (I'-Al), (I-Al), (II-B), (I'-B), (I-B), (II-C), (I'-C), (I-C), (I-C-a-i), (I-C-b-i), (I-C-b-ii), (II-D), (I'-D), (II-E), (I'-E), (I'-E-a-i), and (I'-E-b-i), the same as if each and every embodiment were specifically and individually listed. Further, all compositions described herein with reference to a compound of formula (II), formula (I'), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to m, / / , s, L, X, R1, R2, R3, R5, R6, R7, R8, R9, R3a, R3x, R8a, R3b, R8b, Rlla, Rllb, R12a, R12b, Y1, Y2, Y3, Y4, Y5, ring A, and ring B also apply to formula (II-A), (I'-A), (I-A), (I'-Al), (I-Al), (II-B), (I'-B), (I-B), (II-C), (I'-C), (I-C), (I-C-a-i), (I-C-b-i), (I-C-b-ii), (II-D), (I'-D), (II-E), (I'-E), (I'-E-a-i), and (I'-E-b-i), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0127] Provided herein are pharmaceutical compositions comprising a compound of formula (II), formula (I'), or 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 some embodiments, provided herein is a pharmaceutical composition comprising (i) a compound of formula (II), 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, and (ii) one or more pharmaceutically acceptable excipients. In some embodiments, provided herein is a pharmaceutical composition comprising (i) 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, and (ii) one or more pharmaceutically acceptable excipients. In some embodiments, provided herein is aDocket No.: 79275-20040.40 pharmaceutical composition comprising (i) 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, and (ii) one or more pharmaceutically acceptable excipients.

[0128] Suitable pharmaceutically acceptable excipients may include, for example, fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Various substances may be embraced by the term “excipient”, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Examples of suitable excipients are well known to those skilled in the art. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington ’s Pharmaceutical Sciences, Academic Press, 23rded. (2020), which is incorporated herein by reference in its entirety.

[0129] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, oral, rectal, buccal, intranasal, intravitreal, intraocular (e.g. ocular implant), and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, intravitreally, as an ocular implant, or as an inhalant.

[0130] Compounds as described herein may be administered to subjects in a form of generally accepted oral compositions, such as tablets, coated tablets, gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shells are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.METHODS OF TREATMENTDocket No.: 79275-20040.40

[0131] All methods described herein with reference to formula (II), formula (P), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are also hereby described and embraced for any one of the other formulas detailed herein, such as formula (II-A), (I'-A), (I-A), (P-Al), (I-Al), (II-B), (P-B), (I-B), (II-C), (P-C), (I-C), (I-C-a-i), (LC-b-i), (I-C-b-ii), (II-D), (P-D), (II-E), (P-E), (P-E-a-i), and (P-E-b-i), the same as if each and every embodiment were specifically and individually listed. Further, all methods described herein with reference to a compound of formula (II), formula (P), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as embodiments related to m, / / , s, L, X, R1, R2, R3, R5, R6, R7, R8, R9, R3a, R3X, R8a, R3b, R8b, Rlla, Rllb, R12a, R12b, Y1, Y2, Y3, Y4, Y5, ring A, and ring B also apply to formula (II-A), (P-A), (I-A), (P-Al), (LAI), (II-B), (P-B), (I-B), (II-C), (P-C), (I-C), (I-C-a-i), (LC-b-i), (I-C-b-ii), (II-D), (P-D), (II-E), (P-E), (P-E-a-i), and (P-E-b-i), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0132] Provided herein is a method of modulating SLC6A19 in a cell, comprising contacting the cell with an effective amount of a compound of formula (II), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof. Also provided herein is a method of modulating SLC6A19 in a cell, comprising contacting the cell with an effective amount of a compound of formula (P), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof. Also provided herein is a method of modulating SLC6A19 in a cell, comprising contacting the cell with an effective amount of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof.

[0133] Provided herein is a method of inhibiting SLC6A19 in a cell, comprising contacting the cell with a compound of formula (II), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of inhibiting SLC6A19 in a cell, comprising contacting the cell with a compound of formula (P), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is a method of inhibiting SLC6A19 in a cell, comprising contacting the cell with 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.Docket No.: 79275-20040.40

[0134] 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 (II) 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 (II) 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. Also 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. Also 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. In some embodiments, the individual is a human.

[0135] 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 (II) 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 aDocket No.: 79275-20040.40 compound of formula (II) 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. Also 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. Also 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 neurodevel opmental 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 isDocket No.: 79275-20040.40 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. In some embodiments, the individual is a human.

[0136] 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 (II), 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 (II), 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. Also 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. Also 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 neurodevel opmental and autism-spectrum disorders. In some embodiments, the SLC6A19-mediated disease, disorder, or condition is phenylketonuria (PKU), chronic kidney diseaseDocket No.: 79275-20040.40 (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. In some embodiments, the individual is a human.

[0137] Provided herein is a compound of formula (II), 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 (II), 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. Also 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. Also 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.

[0138] Provided herein is a compound of formula (II), 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 (II), 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. Also provided herein is aDocket No.: 79275-20040.40 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. Also 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.

[0139] Provided herein is a compound of formula (II), 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 (II), 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. In some embodiments, the individual is a human. Also 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. In some embodiments, the individual is a human. Also 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, orDocket No.: 79275-20040.40 glycine levels in an individual in need thereof. In some embodiments, the individual is a human.

[0140] Provided herein is a compound of formula (II), 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 (II), 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. In some embodiments, the individual is a human. Also 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. In some embodiments, the individual is a human. Also 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. In some embodiments, the individual is a human.

[0141] Provided herein is a compound of formula (II), 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 (II), 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 modulating SLC6A19 in a cell. Also 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'), orDocket No.: 79275-20040.40 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 modulating SLC6A19 in a cell. Also 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 modulating SLC6A19 in a cell.

[0142] Provided herein is a compound of formula (II), 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 (II), 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 inhibiting SLC6A19 in a cell. Also 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 inhibiting SLC6A19 in a cell. Also 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 inhibiting SLC6A19 in a cell.

[0143] Provided herein is a compound of formula (II), 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 (II), orDocket No.: 79275-20040.40 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 reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof. Also 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 reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof. Also 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 reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof. In some embodiments, the individual is a human.

[0144] Provided herein is a compound of formula (II), 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 (II), 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. Also 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. Provided herein is aDocket No.: 79275-20040.40 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. In some embodiments, the individual is a human.

[0145] In some embodiments, the compounds provided herein inhibit SLC6A19 at a concentration of less than 10 pM, less than 1 pM, less than 0.5 pM, less than 0.1 pM, less than 0.010 pM, or less than 0.001 pM. In some embodiments, the compounds provided herein inhibit SLC6A19 at a concentration of 1-10 pM, 0.01 to 1 pM, or 0.01 to 10 pM.

[0146] In some embodiments, the compounds have an IC50 of less than 10 nM, less than 10 pM, less than 1 pM, less than 0.5 pM, or less than 0.1 pM. In some embodiments, the compounds provided herein have an IC50 of 1 to 10 nM, 1 to 10 pM, 0.01 to 1 pM, 0.01 to 10 pM, 0.001 to 0.01 pM or 0.001 to 0.010 pM.

[0147] 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.

[0148] 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.

[0149] In some embodiments of the foregoing, the administration is oral administration.

[0150] In some embodiments of the foregoing, a compound of formula (II), formula (I'), or 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 (II), formula (I'), or 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, is administered in combination with one or more SGLT2 inhibitors. In some embodiments, theDocket No.: 79275-20040.40 SGLT2 inhibitor is selected from the group consisting of dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, bexagliflozin, sotagliflozin, ipragliflozin, tofogliflozin, luseogliflozin, and remogliflozin etabonate. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the SGLT2 inhibitor is canagliflozin. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the SGLT2 inhibitor is ertugliflozin. In some embodiments, the SGLT2 inhibitor is bexagliflozin. In some embodiments, the SGLT2 inhibitor is sotagliflozin.

[0151] Also provided herein are methods for treating kidney disease, kidney injury, and / or kidney fibrosis, including chronic kidney disease (CKD), diabetic kidney disease, acute kidney injury, and severe kidney fibrosis comprising administration of a combination of (i) a compound of formula (II), formula (I'), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II), formula (I'), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and (ii) an SGLT2 inhibitor or a pharmaceutical composition comprising an SGLT2 inhibitor. Additionally, the disclosed methods may prevent the onset of kidney disease, kidney injury, and / or kidney fibrosis, and / or delay the progression of kidney disease, kidney injury, and / or kidney fibrosis.

[0152] In one aspect, provided herein is a method of treating and / or preventing a disease or condition selected from the group consisting of kidney disease, kidney injury, and kidney fibrosis, wherein the method comprises administering to a subject in need thereof (i) a compound of formula (II), formula (I'), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II), formula (I'), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and (ii) an SGLT2 inhibitor or a pharmaceutical composition comprising an SGLT2 inhibitor.

[0153] In some embodiments, a therapeutically effective amount of the compound of formula (II), formula (I'), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical compositionDocket No.: 79275-20040.40 comprising the compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient, and a therapeutically effective amount of the SGLT2 inhibitor, or the pharmaceutical composition comprising an SGLT2 inhibitor and a pharmaceutically acceptable excipient, is administered. In some embodiments, the compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and the SGLT2 inhibitor are administered in a single pharmaceutical composition. In some embodiments, the compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and the SGLT2 inhibitor are administered individually. In some embodiments, the compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and the SGLT2 inhibitor are administered separately. In some embodiments, the compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and the SGLT2 inhibitor are administered as separate pharmaceutical compositions. In some embodiments, the compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and the SGLT2 inhibitor are administered at the same time. In some embodiments, the compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and the SGLT2 inhibitor are administered at different times relative to each other. In some embodiments, the administration comprises oral administration or intravitreal injection. In some embodiments, the administration comprises oral administration. In some embodiments, the administration comprises intravitreal injection.

[0154] In some embodiments, a combination of (i) a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) an SGLT2 inhibitor is administered.

[0155] In some embodiments of the foregoing, a compound of formula (II), formula (P), or 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 (II), formula (P), or formula (I), or any variation orDocket No.: 79275-20040.40 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, is administered in combination with one or more glucagon-like peptide- 1 receptor agonists (GLP-1 RAs).

[0156] Also provided herein are methods for treating kidney disease, kidney injury, and / or kidney fibrosis, including chronic kidney disease (CKD), diabetic kidney disease, acute kidney injury, and severe kidney fibrosis comprising administration of a combination of (i) a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and (ii) a GLP-1 RA or a pharmaceutical composition comprising a GLP-1 RA. Additionally, the disclosed methods may prevent the onset of kidney disease, kidney injury, and / or kidney fibrosis, and / or delay the progression of kidney disease, kidney injury, and / or kidney fibrosis.

[0157] Combinations of (i) a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and (ii) a GLP-1 RA or a pharmaceutical composition comprising a GLP-1 RA, may be therapeutically beneficial in patients with or at risk of developing kidney disease, kidney injury, and / or kidney fibrosis.

[0158] In one aspect, provided herein is a method of treating and / or preventing a disease or condition selected from the group consisting of kidney disease, kidney injury, and kidney fibrosis, wherein the method comprises administering to a subject in need thereof (i) a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, orDocket No.: 79275-20040.40 a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and (ii) a GLP-1 RA or a pharmaceutical composition comprising a GLP-1 RA.

[0159] In some embodiments of the foregoing, the GLP-1 RA is selected from the group consisting of tirzepatide, semaglutide, dulaglutide, exenatide, liraglutide, lixisenatide, orforglipron, cagrilintide, bimagrumab, survodutide, retatrutide, danuglipron, lotiglipron, mazdutide, maridebart cafraglutide, efinopegdutide, permvidutide, and dapiglutide, or any combination thereof. In some embodiments of the foregoing, the GLP-1 RA is selected from the group consisting of tirzepatide, semaglutide, dulaglutide, exenatide, liraglutide, and lixisenatide, or any combination thereof.

[0160] Also provided herein is a compound of formula (II), formula (P), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in inhibiting SLC6A19 in a cell. Also provided herein is a compound of formula (II), formula (P), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof. Also provided herein is a compound of formula (II), formula (P), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0161] Also provided herein is the use of a compound of formula (II), formula (P), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament, for inhibiting SLC6A19 in a cell. Also provided herein is the use of a compound of formula (II), formula (P), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament, for reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof. Also provided herein is the use of a compound of formula (II), formula (P), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament, for treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, 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,Docket No.: 79275-20040.40 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. In some embodiments, the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, and metabolic diseases. In some embodiments, the disease, disorder, or condition is associated with abnormal levels of amino acids. In some embodiments, the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

[0162] For the combination therapy, the combinations, compositions or combined uses according to this disclosure may envisage the simultaneous, sequential or separate administration of the active components or ingredients. In this context, “combination” or “combined” within the meaning of this invention may include, without being limited, fixed and non-fixed (e.g., free) forms (including kits) and uses, such as e.g. the simultaneous, sequential or separate use of the components or ingredients. The combined administration of this invention may take place by administering the compound of formula (II), formula (I'), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and additional active component of the combination together, such as, e.g., by administering them simultaneously in one single or in two separate formulations or dosage forms. Alternatively, the administration may take place by administering the compound of formula (II), formula (I'), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and additional active component of the combination sequentially, such as e.g. successively in two separate formulations or dosage forms.KITS

[0163] 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 forDocket No.: 79275-20040.40 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.

[0164] Provided herein are kits, comprising (i) an effective amount of a compound of formula (II) 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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. Also 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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. Also 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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0165] Provided herein are kits, comprising (i) a pharmaceutical composition comprising an effective amount of a compound of formula (II) 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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the individual is a human. 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) instructions for treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the individual is a human. 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) instructions for treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the individual is a human.Docket No.: 79275-20040.40

[0166] Provided herein are kits, comprising (i) a compound of formula (II), 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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. Also provided herein are kits, comprising (i) a compound of formula (P), 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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. Also 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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0167] Provided herein are kits, comprising (i) a pharmaceutical composition comprising a compound of formula (II), 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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. Provided herein are kits, comprising (i) a pharmaceutical composition comprising a compound of formula (P), 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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. 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 treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof. In some embodiments, the individual is a human.

[0168] Also provided herein are kits, comprising (i) a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) an SGLT2 inhibitor or aDocket No.: 79275-20040.40 pharmaceutical composition comprising an SGLT2 inhibitor. Also provided herein are kits, comprising (i) a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing; (ii) an SGLT2 inhibitor or a pharmaceutical composition comprising an SGLT2 inhibitor; and (iii) instructions for treating kidney disease, kidney injury, and / or kidney fibrosis, in an individual in need thereof. Also provided herein are kits, comprising (i) a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) a GLP-1 RA or a pharmaceutical composition comprising a GLP-1 RA. Also provided herein are kits, comprising (i) a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a pharmaceutically acceptable salt of any of the foregoing; (ii) a GLP-1 RA or a pharmaceutical composition comprising a GLP-1 RA; and (iii) instructions for treating kidney disease, kidney injury, and / or kidney fibrosis, in an individual in need thereof. In some embodiments, the individual is a human. In some embodiments, the kit comprises a therapeutically effective amount of a compound of formula (II), formula (P), or formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0169] Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (II), 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. Articles of manufacture are also provided, wherein the article of manufacture comprises a compound of formula (P), 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. Articles of manufacture are also provided, wherein the article of manufacture comprises a compound ofDocket No.: 79275-20040.40 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.

[0170] Also provided herein are articles of manufacture, comprising a pharmaceutical composition comprising a compound of formula (II), 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. 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

[0171] 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 formula (II), (I'), (I), (II-A), (I'-A), (I-A), (I'-A1), (I-A1), (II-B), (I'-B), (I-B), (II-C), (I'-C), (I-C), (I-C-a-i), (I-C-b-i), (I-C-b-ii), (II-D), (I'-D), (II-E), (I'-E), (I'-E-a-i), and (I'-E-b-i), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0172] In some embodiments, a process for preparing a compound of formula (II) or 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 (1-1):r9(1-1),Docket No.: 79275-20040.40 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:X1is -O-, -S-, -N(H)-, or -N(Ci-6alkyl)-;m, R1, R2, R3, R5, R6, R7, and R9are as defined for a compound of formula (II) or formula (I); with a compound of formula (1-2):R11aR11bor a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:Q is halo or sulfonic ester; and / / , R8, Rlla, and Rllbare as defined for a compound of formula (II) or formula (I);in the presence of a base,to provide a compound of formula (1-3):

[0173] In some embodiments, Q is a sulfonic ester, and X1is -O-. In some embodiments the sulfonic ester is a tosylate or mesylate. In some embodiments, the sulfonic ester is a mesylate. In some embodiments, Q is halo, and Xhs -O-.

[0174] In some embodiments, the base comprises carbonate or hydroxide. In some embodiments, the base is a carbonate. In some embodiments, the base is cesium carbonate. In some embodiments, the base is LiOH.

[0175] In some embodiments, a process for preparing a compound of formula (II) or formula (P), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, comprises:(a) reacting a compound of formula (I'-l):Docket No.: 79275-20040.40or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:Y is a boronic acid or boronic ester;PG is absent, or a protecting group;R is -N-, -O-, or -S-; andm, R2, R3, R5, R6, R7, and R9are as defined for a compound of formula (II) or formula (P); with a compound of formula (P-2):QR8(I'-2),or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:Q is halo; andR8is as defined for a compound of formula (II) or formula (P);in the presence of a coupling reagent, to provide a compound of formula (P-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;R is -N-, -O-, or -S-;m, R2, R3, R5, R6, R7, R8, and R9are as defined for a compound of formula (II) or formula O');followed by,(b) optionally contacting the compound of formula (P-3) with a deprotecting agent;to provide a compound of formula (II) or formula (P).Docket No.: 79275-20040.40

[0176] In some embodiments, the protecting group is absent.

[0177] In some embodiments, the protecting group is a sulfonyl group. In some embodiments, the protecting group is SChPh.

[0178] In some embodiments, Y is a boronic ester, and Q is halo. 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)C12 CH2Q2.

[0179] In some embodiments, the coupling reagent further comprises a base. In some embodiments, the base is potassium carbonate, cesium carbonate, or sodium carbonate.

[0180] 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.

[0181] In some embodiments, the deprotecting agent comprises a base. In some embodiments the base LiOH.ENUMERATED EMBODIMENTS

[0182] The following embodiments are also contemplated:

[0183] Embodiment Al. 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-;either:(i) R2and R3are independently H, Ci-ealkyl, Ci-3alkoxy, Cs-iocycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, whereinthe Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andDocket No.: 79275-20040.40 the 5-10 membered heteroaryl is optionally substituted with one or more R3x, or(ii) R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, whereinthe 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x; R5is H, halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R6and R9are each independently H or halo;R7is halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, whereinthe Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R8is Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinthe Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with one or more R8a;R3aand R8aare each independently -OH, oxo, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-6alkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-locycloalkyl, or -O-Cs-iocycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b, andthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R8b;R3Xis -OH, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-ealkoxy, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(Ci-6alkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-C3-locycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b; andDocket No.: 79275-20040.40 R3band R8bare each independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy.

[0184] Embodiment A2. The compound of embodiment Al, 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.

[0185] Embodiment A3. The compound of embodiment Al or A2, 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 optionally substituted with one or more R8a.

[0186] Embodiment A4. The compound of any of embodiments A1-A3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1 or 2.

[0187] Embodiment A5. The compound of any of embodiments A1-A4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1.

[0188] Embodiment A6. The compound of any of embodiments A1-A4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 2.

[0189] Embodiment A7. The compound of any of embodiments A1-A6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R2and R3is H, and the other of R2and R3is C 1-3 alkyl.Docket No.: 79275-20040.40

[0190] Embodiment A8. The compound of any of embodiments A1-A7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R2and R3is H, and the other of R2and R3is methyl.

[0191] Embodiment A9. The compound of any of embodiments A1-A8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5is H.

[0192] Embodiment A10. The compound of any of embodiments A1-A9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6and R9are each H.

[0193] Embodiment All. The compound of any of embodiments A1-A10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R7is halo or Ci-ealkoxy, wherein the Ci-ealkoxy is optionally substituted with one or more halo.

[0194] Embodiment A12. The compound of any of embodiments Al-All, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R7is halo.

[0195] Embodiment A13. The compound of embodiment A12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R7is Cl or F.

[0196] Embodiment A14. The compound of any of embodiments Al-All, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R7is Ci-ealkoxy optionally substituted with one or more halo.

[0197] Embodiment A15. The compound of embodiment A14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R7is -OCF3.

[0198] Embodiment Al 6. The compound of any of embodiments Al -Al 5, 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.

[0199] Embodiment Al 7. The compound of any of embodiments Al -Al 6, 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 halo or Ci-ealkoxy.Docket No.: 79275-20040.40

[0200] Embodiment A18. The compound of any of embodiments A1-A17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8F, Nis selected from the group consisting of IT andN /

[0201] Embodiment Al 9. The compound of any of embodiments Al -Al 8, wherein the compound is of formula (I'-E):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, whereinY1, Y2, Y3, Y4, and Y5, are each independently -CH- or -N-; and5 is an integer from 0-5.

[0202] Embodiment A20. The compound of embodiment Al 9, wherein the compound is of formula:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0203] Embodiment A21. The compound of embodiment Al, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from Compounds 4-8 of Table 1.

[0204] Embodiment A22. A pharmaceutical composition comprising (i) a compound of any of embodiments A1-A21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.Docket No.: 79275-20040.40

[0205] Embodiment A23. A method of inhibiting SLC6A19 in a cell, comprising contacting the cell with a compound of any of embodiments A1-A21, or a stereoisomer or tautomer thereof.

[0206] Embodiment A24. 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 A1-A21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of embodiment A22.

[0207] Embodiment A25. 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 A1-A21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of embodiment A22.

[0208] Embodiment A26. The method of embodiment A25, 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.

[0209] Embodiment A27. The method of embodiment A25 or A26, wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, and metabolic diseases.

[0210] Embodiment A28. The method of any of embodiments A25-A27, wherein the disease, disorder, or condition is chronic kidney disease (CKD).

[0211] Embodiment A29. The method of embodiment A25, wherein the disease, disorder, or condition is associated with abnormal levels of amino acids.

[0212] Embodiment A30. The method of embodiment A25 or A26, wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

[0213] Embodiment A31. The method of any of embodiments A25-A30, wherein the individual is human.Docket No.: 79275-20040.40

[0214] Embodiment A32. A kit, comprising (i) a compound of any of embodiments A1-A21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of embodiment A22, and (ii) instructions for treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0215] Embodiment A33. The kit of embodiment A32, wherein the disease, disorder, or condition is associated with abnormal levels of amino acids.

[0216] Embodiment A34. The kit of embodiment A32 or A33, wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

[0217] Embodiment A35. The kit of embodiment A32 or A33, 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.

[0218] Embodiment A36. The kit of any of embodiments A32-A35, wherein the individual has a genetic defect in phenylalanine hydroxylase.

[0219] Embodiment A37. A compound of any one of embodiments A1-A21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in inhibiting SLC6A19 in a cell.

[0220] Embodiment A38. A compound of any one of embodiments A1-A21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment A22, for use in reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof.

[0221] Embodiment A39. A compound of any one of embodiments A1-A21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment A22, for use in treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.Docket No.: 79275-20040.40

[0222] Embodiment A40. Use of a compound of any one of embodiments A1-A21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for inhibiting SLC6A19 in a cell.

[0223] Embodiment A41. Use of a compound of any one of embodiments A1-A21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof.

[0224] Embodiment A42. Use of a compound of any one of embodiments A1-A21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0225] Embodiment B 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;n is an integer from 0-4;X is -O-, -S-, -C(R12a)(R12b)-, -N(H)-, or -N(Ci-6alkyl)-;R1is -NH-, -O-, or -S-;either:(i) R2and R3are independently H, Ci-ealkyl, Ci-3alkoxy, Cs-iocycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, whereinthe Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x, or(ii) R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, whereinDocket No.: 79275-20040.40 the 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x; R5is H, halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R6and R9are each independently H or halo;R7is halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, whereinthe Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R8is Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinthe Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with one or more R8a;R3aand R8aare each independently -OH, oxo, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-6alkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-locycloalkyl, or -O-Cs-iocycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b, and the Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R8b;R3Xis -OH, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-ealkoxy, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(Ci-6alkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-C3-locycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b;R3band R8bare each independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy;Rllaand Rllbare independently at each occurrence, H or Ci-ealkyl, or79MF-366340265Docket No.: 79275-20040.40 one of Rllaand Rllbis H or Ci-ealkyl, and the other of Rllaand Rllbis taken together with one of R12aor R12bto form a Cs-iocycloalkyl; andR12aand R12bare each independently, H or Ci-ealkyl, orone of R12aand R12bis H or Ci-ealkyl, and the other of R12aand R12bis taken together with one of Rllaor Rllbto form a Cs-iocycloalkyl.

[0226] Embodiment B2. The compound of embodiment Bl, wherein the compound is a compound of formula (I-A):R9(I-A),or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0227] Embodiment B3. The compound of embodiment Bl or B2, 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 optionally substituted with one or more R8a.

[0228] Embodiment B4. The compound of any of embodiments B1-B3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1 or 2.

[0229] Embodiment B5. The compound of any of embodiments B1-B4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1.MF-366340265Docket No.: 79275-20040.40

[0230] Embodiment B6. The compound of any of embodiments B1-B4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 2.

[0231] Embodiment B7. The compound of any of embodiments B1-B6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R2and R3is H, and the other of R2and R3is C 1-3 alkyl.

[0232] Embodiment B8. The compound of any of embodiments B1-B7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R2and R3is H, and the other of R2and R3is methyl.

[0233] Embodiment B9. The compound of any of embodiments B1-B6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted with one or more R3a.

[0234] Embodiment B10. The compound of any of embodiments B1-B9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5is H.

[0235] Embodiment B 11. The compound of any of embodiments Bl -B10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6and R9are each H.

[0236] Embodiment B 12. The compound of any of embodiments Bl-Bl 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R7is halo.

[0237] Embodiment B 13. The compound of embodiment Bl 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R7is Cl.

[0238] Embodiment B 14. The compound of any of embodiments B1-B13, 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.

[0239] Embodiment Bl 5. The compound of any of embodiments B1-B14, 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 Ci-ealkyl.81MF-366340265Docket No.: 79275-20040.40

[0240] Embodiment Bl 6. The compound of any of embodiments Bl -Bl 5, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is selected from the group consisting ofand

[0241] Embodiment Bl 7. The compound of any of embodiments Bl -Bl 6, wherein the compound is of formula (I-C):,o R5R6, R7(3 R11aR11bN H O'R9or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, whereinY1, Y2, Y3, Y4, and Y5, are each independently -CH-, -N-, -O-, or -S-; and5 is an integer from 0-4.

[0242] Embodiment Bl 8. The compound of embodiment Bl 7, wherein the compound is of formula:,0p11a p11bN H O'Y~~Y3(I-C-b-i) or,o, R B7Rna R11bN H O'YY* (~~Y3(I-C-b-ii),or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0243] Embodiment Bl 9. The compound of embodiment Bl, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from Compounds 1-3 of Table 1.MF-366340265Docket No.: 79275-20040.40

[0244] Embodiment B20. A pharmaceutical composition comprising (i) a compound of any of embodiments Bl -Bl 9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

[0245] Embodiment B21. A method of inhibiting SLC6A19 in a cell, comprising contacting the cell with a compound of any of embodiments Bl -Bl 9, or a stereoisomer or tautomer thereof.

[0246] Embodiment B22. 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 Bl -Bl 9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of embodiment B20.

[0247] Embodiment B23. 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 Bl -Bl 9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of embodiment B20.

[0248] Embodiment B24. The method of embodiment B23, 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.

[0249] Embodiment B25. The method of embodiment B23 or B24, wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, and metabolic diseases.

[0250] Embodiment B26. The method of any of embodiments B23-B25, wherein the disease, disorder, or condition is chronic kidney disease (CKD).83MF-366340265Docket No.: 79275-20040.40

[0251] Embodiment B27. The method of embodiment B23, wherein the disease, disorder, or condition is associated with abnormal levels of amino acids.

[0252] Embodiment B28. The method of embodiment B23 or B24, wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

[0253] Embodiment B29. The method of any of embodiments B23-B28, wherein the individual is human.

[0254] Embodiment B30. A kit, comprising (i) a compound of any of embodiments B1-B19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of embodiment B20, and (ii) instructions for treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0255] Embodiment B31. The kit of embodiment B30, wherein the disease, disorder, or condition is associated with abnormal levels of amino acids.

[0256] Embodiment B32. The kit of embodiment B30 or B31, wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

[0257] Embodiment B33. The kit of embodiment B30 or B31, 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.

[0258] Embodiment B34. The kit of any of embodiments B30-B33, wherein the individual has a genetic defect in phenylalanine hydroxylase.

[0259] Embodiment B35. A compound of any one of embodiments B1-B19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in inhibiting SLC6A19 in a cell.

[0260] Embodiment B36. A compound of any one of embodiments B1-B19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the84MF-366340265Docket No.: 79275-20040.40 foregoing, or a pharmaceutical composition of embodiment B20, for use in reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof.

[0261] Embodiment B37. A compound of any one of embodiments B1-B19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of embodiment B20, for use in treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

[0262] Embodiment B38. Use of a compound of any one of embodiments Bl -Bl 9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for inhibiting SLC6A19 in a cell.

[0263] Embodiment B39. Use of a compound of any one of embodiments Bl -Bl 9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof.

[0264] Embodiment B40. Use of a compound of any one of embodiments B1-B19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.EXAMPLES

[0265] 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.

[0266] 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.

[0267] Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be85MF-366340265Docket No.: 79275-20040.40 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

[0268] As depicted in the Schemes and Examples below, in certain exemplary embodiments, compounds of formula (II), formula (I'), or 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.

[0269] In some embodiments, provided herein is a process for preparing a compound of formula (II), formula (I'), or formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing according to Scheme 1 - Scheme 3.Scheme 1

[0270] Compounds of the formula Sl-11 can be prepared according to Scheme 1. Oxidation of benzylic alcohol Sl-1 with an oxidizing reagent such as manganese dioxide gives compounds of the formula Sl-2. Homologation of aldehyde Sl-2 with a reagent such as Sl-3, wherein o is an integer from 0 to 2, and a base such as NaH in a solvent such as THF gives 86MF-366340265Docket No.: 79275-20040.40 compounds of the formula Sl-4. Hydrogenation of Sl-4 with a catalyst such as palladium on carbon in a solvent such as acetone gives compounds of the formula Sl-5. Removal of the tert-butyl ester of Sl-5 with an organic acid such as TFA in a solvent such as DCM gives compounds of the formula Sl-6. Amide formation between Sl-6 and an amine such as Sl-7 using a coupling agent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate and an organic base such as diisopropylethylamine in a solvent such as DMF gives compounds of the formula Sl-8.Demethylation of Sl-8 with a reagent such as boron tribromide in a solvent such as DCM gives compounds of the formula Sl-9. Alkylation of Sl-9 with reagents such as Sl-10 using an inorganic base such as cesium carbonate gives compounds of the formula Sl-11.Scheme 2S2-352-4S2-5 S2-6R3O R5R3-NH2(S2-10) HN— V^-k ^R7EDCI, HOBt, DIEA 'AiX jl T DMF p9S2-11

[0271] Compounds of the formula S2-11 can be prepared according to Scheme 1.Sonagashira coupling of compounds such as S2-1, where Xais a leaving group such as bromide or trifluormethansulfonate, with an alkyne such as S2-2 in the presence of a reagent87MF-366340265Docket No.: 79275-20040.40 such as Cui, a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II), and an inorganic base such as potassium acetate in DMF gives compounds of the formula S2-3.Indole formation with copper catalysts such as copper(I)chloride and an inorganic base such as cesium carbonate in a solvent such as acetonitrile gives compounds of the formula S2-4.Palladium catalyzed borylation with a reagent such as B2neop2 in the presence of a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II) and an inorganic base such as potassium acetate in a solvent such as dioxane gives compounds of the formula S2-5.Oxidation of S2-5 using a reagent such as sodium perborate tetrahydrate in a solvent system such as THF and water gives compounds of the formula S2-6. Alkylation of S2-6 with reagents such as S2-7 in the presence of an inorganic base such as cesium carbonate in a solvent system such as acetone gives compounds of the formula S2-8. Saponification of S2-8 with a base such as lithium hydroxide in a solvent system such as water and THF gives compounds of the formula S2-9. Amide bond formation between S2-9 and amine such as S2-10 in the presence of a reagents such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hydroxybenzotriazole and an organic base such as N,N-diisopropylethylamine in a solvent such as DMF gives compounds of the formula S2-11.Scheme 388MF-366340265Docket No.: 79275-20040.40

[0272] Compounds of formula S3-11 can be prepared according to Scheme 3. Sonagashira coupling of compounds such as S3-1, where X is a leaving group such as bromide or trifluormethansulfonate, with alkyne S3-2 in the presence of a reagent such as Cui, a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II), and an inorganic base such as potassium acetate in DMF gives compounds of the formula S3-3. Protection of the aniline nitrogen with a protecting group such as N-sulfonyl can be accomplished by the reaction of N-sulfonyl chloride in the presence of an organic base such as pyridine in a solvent such as DCM to give compounds of the formula S3-4. Indole formation with copper catalysts such as copper(I)chloride and an inorganic base such as cesium carbonate in a solvent such as acetonitrile gives compounds of the formula S3-5. Palladium catalyzed borylation with a reagent such as B2neop2 in the presence of a palladium catalyst such as dichlorobis(triphenylphosphine)palladium(II) and an inorganic base such as potassium carbonate in dioxane gives compounds of the formula S3-6. Suzuki coupling of S3-6 with an aryl or heteroaryl halide such as S3-7 in the presence of a palladium catalyst such as chloro[(di(l-adamantyl)-7V-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) and an inorganic base such as potassium carbonate in aqueous dioxane gives compounds of the formula S3-8. Removal of the methyl ester and the indole 7V-sulfonyl protecting group can be accomplished by heating with LiOH’EhO in a solvent system such as MeOH, H2O, and THF to give compounds of the formula S3-9. Amide bond formation of S3-9 with amine S3-10 in the presence of reagents such as EDCI and DIPEA in a solvent such as DMF gives compounds of the formula S3-11.Example S-l: V-methyl{5-chloro-6-[(3-methyl-5-isoxazolyl)methoxy]-2- indolyljacetamide (Compound 1)89MF-366340265Docket No.: 79275-20040.40

[0273] Step a: Two reactions were carried out in parallel. A mixture of 5-bromo-4-chloro-2-iodoaniline (5.00 g, 15.0 mmol, 1.00 eq) and methyl but-3-ynoate (1.77 g, 18.0 mmol, 1.20 eq) in DMF (50 mL) was degassed and purged with nitrogen three times. To the resulting solution was added Cui (573 mg, 3.01 mmol, 0.20 eq), Pd(PPh3)2C12, (527 mg, 752 pmol, 0.05 eq) and TEA (10.5 mL, 75.2 mmol, 5.00 eq) sequentially under an atmosphere of nitrogen. The resulting mixture was stirred at 23 °C for 16 h. The two reactions were then combined, poured into ice water (70 mL), and extracted with EtOAc (2 x 60 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 4-(2-amino-4-bromo-5-chlorophenyl)but-3-ynoate. LC-MS (ESI) m / z: [M + H]+calcd for CnHioBrClNCh: 302.0; found: 301.9.

[0274] Step b: To a mixture of methyl 4-(2-amino-4-bromo-5-chlorophenyl)but-3-ynoate (3.30 g, 10.9 mmol, 1.00 eq) and pyridine (2.47 mL, 32.7 mmol, 3.00 eq) in DCM (30 mL) at 0 °C was added benzenesulfonyl chloride (2.70 g, 15.2 mmol, 1.40 eq) in portions. The reaction mixture was then warmed to 23 °C and stirred for 16 h. The reaction mixture was then poured into ice water (20 mL) and adjusted to pH = 5 using aqueous HC1 solution (1 N). The resulting biphasic mixture was extracted with DCM (2 x 30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(6-bromo-5-chloro-U / -indol-2-yl)acetate. LC-MS (ESI) m / z: [M + H]+calcd for CnHioBrClNCh: 302.0; found: 301.9.90MF-366340265Docket No.: 79275-20040.40

[0275] Step c: A mixture of methyl 2-(6-bromo-5-chloro-17 / -indol-2-yl)acetate (3.10 g, 10.2 mmol, 1.00 eq) and 5,5,5',5'-tetramethyl-2,2'-bi(l,3,2-dioxaborinane) (2.31 g, 10.2 mmol, 1.00 eq) were dissolved in dioxane (30 mL). The sealed reaction vessel was then evacuated and refilled with nitrogen three times. Potassium acetate (2.21 g, 22.5 mmol, 2.20 eq) and Pd(PPh3)2Cl2(719 mg, 1.0 mmol, 0.10 eq) were then added sequentially. The reaction mixture was then warmed to 120 °C and stirred for 1 h. The reaction mixture was then cooled to room temperature and quenched by addition of H2O (25 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(5-chloro-6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-17 / -indol-2-yl)acetate. LC-MS (ESI) m / z: [M - C5H10 + H]+calcd for C11H11BCINO4: 268.1; found: 268.1.

[0276] Step d: To a solution of methyl 2-(5-chloro-6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-17 / -indol-2-yl)acetate (1.00 g, 2.98 mmol, 1.00 eq) in THF (5 mL) and H2O (5 mL) was added NaBO3·4H2O (1.83 g, 11.9 mmol, 4.00 eq), and the resulting reaction mixture was stirred at 23 °C for 1 h. The reaction mixture was then quenched by the addition of H2O (10 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(5-chloro-6-hydroxy-IT / -indol-2-yl)acetate. LC-MS (ESI) m / z: [M + H]+calcd for C11H11CINO3: 240.0; found: 240.1.

[0277] Step e: To a mixture of methyl 2-(5-chloro-6-hydroxy-17 / -indol-2-yl)acetate (400 mg, 1.34 mmol, 1.00 eq) and (3-methylisoxazol-5-yl)methyl methanesulfonate (255 mg, 1.34 mmol, 1.00 eq) in acetone (5 mL) was added CS2CO3 (870 mg, 2.67 mmol, 2.00 eq). The reaction mixture was then warmed to 70 °C and stirred for 1 h. The reaction was then cooled to room temperature and quenched by the addition of H2O (10 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts 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 methyl 2-(5-chloro-6-((3-methylisoxazol-5-yl)methoxy)-17 / -indol-2-yl)acetate. LC-MS (ESI) m / z: [M + H]+calcd for C16H16CIN2O4: 335.1; found: 335.1.91MF-366340265Docket No.: 79275-20040.40

[0278] Step f: To a solution of methyl 2-(5-chloro-6-((3-methylisoxazol-5-yl)methoxy)-UT-indol-2-yl)acetate (150 mg, 448 pmol, 1.00 eq) in THF (5 mL) was added LiOH (1 M in H2O, 1.4 mL, 3.00 eq) dropwise. The reaction mixture was then warmed to 80 °C and stirred for 1 h. The reaction was then cooled to room temperature, diluted with H2O (10 mL), and adjusted to pH = 2 with aqueous HC1 (1 M). The resulting biphasic mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give 2-(5-chloro-6-((3-methylisoxazol-5-yl)methoxy)-U / -indol-2-yl)acetic acid, which was used directly in the next step without further purification. LC-MS (ESI) m / z: [M + H]+calcd for C15H14CIN2O4: 321.1; found: 321.1.

[0279] Step g: To a mixture of 2-(5-chloro-6-((3-methylisoxazol-5-yl)methoxy)-U / -indol-2-yl)acetic acid (180 mg, 561 pmol, 1.00 eq), EDCI (139 mg, 729 pmol, 1.30 eq), and HOBt (98.5 mg, 729. pmol, 1.30 eq) in DMF (5 mL) was added DIPEA (0.29 mL, 1.68 mmol, 3.00 eq) followed by methylamine hydrochloride (56.8 mg, 841 pmol, 1.50 eq). The resulting reaction mixture was stirred at 23 °C for 1 h. The reaction mixture was then diluted with H2O (10 mL), and the biphasic mixture was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give A-methyl{5-chloro-6-[(3-methyl-5-isoxazolyl)methoxy]-2-indolyl}acetamide. 'H NMR (400 MHz, DMSO-t / 6) 8 ppm 10.97 (s, 1H), 7.89 (d, J= 4.0 Hz, 1H), 7.48 (s, 1H), 7.12 (s, 1H), 6.45 (s, 1H), 6.12 (s, 1H), 5.27 (s, 2H), 3.52 (s, 2H), 2.59 (d, J= 4.4 Hz, 3H), 2.24 (s, 3H). LC-MS (ESI) m / z: [M + H]+calcd for C16H17CIN3O3: 334.1; found: 334.1.Example S-2: l-(l-azetidinyl)-3-{5-chloro-6-[(l,3-thiazol-4-yl)methoxy]-2- indolyl}-l-propanone (Compound 2)92MF-366340265Docket No.: 79275-20040.40

[0280] Step a: To a solution of (5-chloro-6-methoxy-U / -indol-2-yl)methanol (1.12 g, 5.29 mmol, 1.00 eq) in DCM (12 mL) at 0 °C was added MnCh (5.52 g, 63.5 mmol, 12.0 eq). The resulting reaction mixture was warmed to 23 °C and stirred for 4 h. The reaction mixture was then diluted with EtOAc (10 mL) and filtered through a pad of Celite. The filter cake was then washed with EtOAc (2 x 10 mL). The combined organic extracts were washed sequentially with H2O (2 x 10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give 5-chl oro-6-m ethoxy- U / -indole-2-carbaldehy de. LC-MS (ESI) m / z:[M + H]+calcd for C10H9CINO2: 210.0 found: 210.1.

[0281] Step b: To a suspension of NaH (298 mg, 7.44 mmol, 60% purity, 2.00 eq) in THF (7 mL) at 0 °C was added a solution of / c / 7-butyl 2-dimethoxyphosphorylacetate (1.25 g, 5.58 mmol, 1.50 eq) in THF (7 mL). The resulting reaction mixture was stirred at 0 °C for 30 min, followed by the addition of a solution of 5-chloro-6-methoxy-U / -indole-2-carbaldehyde (780 mg, 3.72 mmol, 1.00 eq) in THF (5 mL). The resulting reaction mixture was warmed to 23 °C and stirred for 12 h. The reaction mixture was then cooled to 0 °C and quenched by the addition of saturated aqueous NH4CI (20 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. The crude residue obtained was purified by column chromatography to give tert-butyl-3-(5-chloro-6-methoxy-U / -indol-2-yl)acrylate, which was used directly in the next step without further characterization.93MF-366340265Docket No.: 79275-20040.40

[0282] Step c: To a degassed suspension of Pd / C (750 mg, 10% purity) in acetone (7 mL) was added a solution of tert-butyl-3-(5-chloro-6-methoxy-lJH-indol-2-yl)acrylate (920 mg, 2.99 mmol, 1.00 eq) in acetone (2 mL). The resulting reaction mixture was stirred under H2 (15 psi) at 23 °C for 1 h. The reaction mixture was then diluted with EtOAc (20 mL) and filtered through a pad of Celite. The filtrate was then concentrated under reduced pressure to give tert-butyl 3-(5-chloro-6-methoxy-17 / -indol-2-yl)propanoate, which was used directly in the next step without further purification. LC-MS (ESI) m / z: [M + H]+calcd for C16H21CINO3: 310.1 found: 310.1.

[0283] Step d: To a solution of tert-butyl 3-(5-chloro-6-methoxy-U / -indol-2-yl)propanoate (914 mg, 2.95 mmol, 1.00 eq) in DCM (6 mL) at 0 °C was added TFA (3.05 mL, 41.0 mmol, 13.9 eq). The resulting reaction mixture was then warmed to 23 °C and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to give 3-(5-chloro-6-m ethoxy- U / -indol-2-yl)propanoic acid, which was used directly in the next step without further purification. LC-MS (ESI) m / z: [M + H]+calcd for C12H13CINO3: 254.1 found: 254.2.

[0284] Step e: To a solution of 3-(5-chloro-6-methoxy-17 / -indol-2-yl)propanoic acid (250 mg, 985 pmol, 1.00 eq) in DMF (5 mL) was added HATU (562 mg, 1.48 mmol, 1.50 eq). The resulting reaction mixture was stirred at 23 °C for 30 min. Azetidine (169 mg, 2.96 mmol, 3.00 eq) and DIPEA (514 pL, 2.96 mmol, 3.00 eq) were then added sequentially. The resulting reaction mixture was stirred at 23 °C for 2 h. The reaction mixture was then quenched by the addition of H2O (15 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 8 mL). The combined organic extracts 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 l-(azetidin-l-yl)-3-(5-chloro-6-methoxy-U / -indol-2-yl)propan-l-one. LC-MS (ESI) m / z: [M + H]+calcd for C15H18CIN2O2: 293.1 found: 293.2.

[0285] Step f: To a solution of l-(azetidin-l-yl)-3-(5-chloro-6-methoxy-17 / -indol-2-yl)propan-l-one (200 mg, 683 pmol, 1.00 eq) in DCM (3 mL) at 0 °C was added BBn (684 mg, 2.73 mmol, 4.00 eq). The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was then quenched by the addition of H2O (10 mL), and the resulting biphasic mixture was adjusted to pH = 8 by the addition of saturated aqueous NaHCCL. The biphasic mixture was then extracted with EtOAc (3 x 10 mL). The combined organic extracts 94MF-366340265Docket No.: 79275-20040.40 were washed with brine (2 x 10 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give l-(azetidin-l-yl)-3-(5-chloro-6-hydroxy-l / 7-indol-2-yl)propan-l-one, which was used directly in the next step without further purification. LC-MS (ESI) m / z: [M + H]+calcd for C14H16CIN2O2: 279.1 found: 279.2.

[0286] Step g: To a solution of l-(azetidin-l-yl)-3-(5-chloro-6-hydroxy-l / / -indol-2-yl)propan-l-one (165 mg, 592 pmol, 1.00 eq) in DMF (2 mL) was added 4-(chloromethyl)thiazole hydrochloride (80.5 mg, 473 pmol, 0.80 eq) and CS2CO3 (386 mg, 1.18 mmol, 2.00 eq). The resulting reaction mixture was warmed to 70 °C and stirred for 2 h. After cooling to room temperature, the reaction mixture was quenched by the addition of H2O (10 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give l-(l-azetidinyl)-3-{5-chloro-6-[(l,3-thiazol-4-yl)methoxy]-2-indolyl}-l -propanone. 'H NMR (400 MHz, DMSO-t / 6) 8 ppm 9.46 (s, 1H), 8.84 (d, J= 2.0 Hz, 1H), 7.52 (d, J= 1.2 Hz, 1H), 7.50 (s, 1H), 6.97 (s, 1H), 6.08 (s, 1H), 5.35 (s, 2H), 4.11 -4.05 (m, 4H), 3.01 (t, J= 6.0 Hz, 2H), 2.44 (t, J= 6.0 Hz, 2H), 2.32 - 2.24 (m, 2H). LC-MS (ESI) m / z: [M + H]+calcd for CisH^ClNsChS: 376.1 found: 376.0.

[0287] The additional compounds in Table T-l were synthesized using procedures similar to Examples S-l through S-2 using the appropriate starting materials and intermediates.Table T-lCmpd Structure Exact Mass LCMSNo. Observedm / z [M+H]+1 Me 0 333.1 334.1HN— 4*H °^^Ji\-MeO~NMF-366340265Docket No.: 79275-20040.40 2 375.1 376.13 Me-NH 349.1 350.1\ -. / _^CI° \ JL J.N= / Example S-3: Synthesis of 2-(5-cliloro-6-(5-niethoxypyr:izin-2-yl)-l / / -indol-2-yl)-\- methylacetamide (Compound 5)o cn_ po oMe> / ^O'B-B'O^\<Me4KZIo

[0288] Step a: Two reactions were carried out in parallel. A mixture of 5-bromo-4-chloro-2-iodoaniline (5.00 g, 15.0 mmol, 1.00 eq) and methyl but-3-ynoate (1.77 g, 18.0 mmol, 1.20 eq) in DMF (50 mL) was degassed and purged with nitrogen three times. To the resulting solution was added Cui (573 mg, 3.01 mmol, 0.20 eq), Pd(PPh3)2C12, (527 mg, 752 pmol, 0.05 eq) and TEA (10.5 mL, 75.2 mmol, 5.00 eq) sequentially under an atmosphere of nitrogen. The resulting mixture was stirred at 23 °C for 16 h. The two reactions were then combined, poured into ice water (70 mL), and extracted with EtOAc (2 x 60 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by96MF-366340265Docket No.: 79275-20040.40 column chromatography to give methyl 4-(2-amino-4-bromo-5-chlorophenyl)but-3-ynoate. LC-MS (ESI) m / z: [M + H]+calcd for CnHioBrClNCh: 302.0; found: 301.9.

[0289] Step b: To a mixture of methyl 4-(2-amino-4-bromo-5-chlorophenyl)but-3-ynoate (3.30 g, 10.9 mmol, 1.00 eq) and pyridine (2.47 mL, 32.7 mmol, 3.00 eq) in DCM (30 mL) at 0 °C was added benzenesulfonyl chloride (2.70 g, 15.2 mmol, 1.40 eq) in portions. The reaction mixture was then warmed to 23 °C and stirred for 16 h. The reaction mixture was then poured into ice water (20 mL), adjusted to pH = 5 with aqueous HC1 solution (1 N). The resulting biphasic mixture was extracted with DCM (2 x 30 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(6-bromo-5-chloro-U / -indol-2-yl)acetate. LC-MS (ESI) m / z: [M + H]+calcd for CnHioBrClNCh: 302.0; found: 301.9.

[0290] Step c: A mixture of methyl 2-(6-bromo-5-chloro-U / -indol-2-yl)acetate (3.10 g, 10.2 mmol, 1.00 eq) and 5,5,5',5'-tetramethyl-2,2'-bi(l,3,2-dioxaborinane) (2.31 g, 10.2 mmol, 1.00 eq) were dissolved in dioxane (30 mL). The sealed reaction vessel was then evacuated and refilled with nitrogen three times. Potassium acetate (2.21 g, 22.5 mmol, 2.20 eq) and Pd(PPh3)2Cl2(719 mg, 1.0 mmol, 0.10 eq) were then added sequentially. The reaction mixture was then warmed to 120 °C and stirred for 1 h. The reaction mixture was then cooled to room temperature and quenched by addition of H2O (25 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(5-chloro-6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-U / -indol-2-yl)acetate. LC-MS (ESI) m / z: [M - C5H10 + H]+calcd for C11H11BCINO4: 268.1; found: 268.1.

[0291] Step d: A mixture of methyl 2-(5-chloro-6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-U / -indol-2-yl)acetate (800 mg, 2.4 mmol, 1.00 eq), 2-bromo-5-methoxypyrazine (540 mg, 2.9 mmol, 1.20 eq), and potassium carbonate (988 mg, 7.2 mmol, 3.00 eq) was dissolved in dioxane (10 mL) and H2O (0.2 mL). The sealed reaction vessel was then evacuated and refilled with nitrogen three times. CataCXium A Pd G2(159 mg, 238 pmol, 0.10 eq) was then 97MF-366340265Docket No.: 79275-20040.40 added, and the resulting reaction mixture was warmed to 75 °C and stirred for 1 h under an atmosphere of nitrogen. After cooling to room temperature, the mixture was quenched by addition of H2O (10 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 2-(5-chloro-6-(5-methoxypyrazin-2-yl)-17 / -indol-2-yl)acetate. LC-MS (ESI) m / z: [M +H]+calcd for C16H15CIN3O3: 332.1; found: 332.1.

[0292] Step e: Methyl 2-(5-chloro-6-(5-methoxypyrazin-2-yl)-U / -indol-2-yl)acetate (227 mg, 684 pmol, 1.00 eq) was dissolved in THF (2 mL), H2O (2 mL), and MeOH (2 mL). To the resulting solution was added LiOH H2O (86.1 mg, 2.05 mmol, 3.00 eq). The resulting mixture was warmed to 80 °C and stirred for 1 h. After cooling to room temperature, the reaction was quenched by addition of H2O (10 mL) and adjusted to pH = 5 with aqueous HC1 (1 N). The resulting biphasic mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(5-chloro-6-(5-methoxypyrazin-2-yl)-UT-indol-2-yl)acetic acid, which was used directly in next step without further purification. LC-MS (ESI) m / z: [M +H]+calcd for C15H13CIN3O3: 318.1; found: 318.1.

[0293] Step f: To a solution of 2-(5-chloro-6-(5-methoxypyrazin-2-yl)-U / -indol-2-yl)acetic acid (150 mg, 472 pmol, 1.00 eq), 1 -hydroxybenzotriazole (82.9 mg, 613 pmol, 1.30 eq) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (117 mg, 613 pmol, 1.30 eq) in DMF (4 mL) was added DIPEA (411 pL, 2.36 mmol, 5.00 eq) and methylamine hydrochloride (38.2 mg, 566 pmol, 1.20 eq). The resulting reaction mixture was stirred at 23 °C for 2 h. The reaction mixture was then diluted with H2O (10 mL), and the resulting biphasic mixture was extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 2-(5-chloro-6-(5-methoxypyrazin-2-yl)-U / -indol-2-yl)-A-methylacetamide. 'H NMR (400 MHz, DMSO-tL) 8 ppm 11.28 (s, 1H), 8.44 - 8.41 (m, 2H), 7.98 - 7.97 (m, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 6.2798MF-366340265Docket No.: 79275-20040.40 (s, 1H), 3.97 (s, 3H), 3.61 (s, 2H), 2.61 (d, J = 4.4 Hz, 3H). LC-MS (ESI) m / z: [M + H]+calcd for C16H16CIN4O2: 331.1; found: 331.1.Example S-4: Synthesis of 3-(5-fluoro-6-(5-methoxypyrazin-2-yl)-lH-indol-2-yl)-7V- methylpropanamide (Compound 7)

[0294] Step a: To a solution of 5-bromo-4-fluoro-2-iodoaniline (3.00 g, 9.50 mmol, 1.00 eq) and methyl pent-4-ynoate (1.06 g, 9.50 mmol, 1.00 eq) in DMF (30 mL) was added TEA (6.61 mL, 47.4 mmol, 5.00 eq). The resulting mixture was degassed and purged with nitrogen three times. Cui (180 mg, 949 pmol, 0.1 eq) and Pd(PPh3)2C12 (133 mg, 189 pmol, 0.02 eq) were then added under nitrogen, and the reaction was then stirred at 23 °C for 2 h. The reaction was then quenched by addition of H2O (20 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 5-(2-amino-4-bromo-5-fluorophenyl)pent-4-ynoate (2.71 g). LC-MS (ESI) m / z: [M + H]+calcd for Ci2Hi2BrFNO2: 300.0; found: 300.1.

[0295] Step b. A solution of 5-(2-amino-4-bromo-5-fluorophenyl)pent-4-ynoate (2.66 g, 8.86 mmol, 1.00 eq) and pyridine (1.42 mL, 17.7 mmol, 2.00 eq) in DCM (30 mL) was cooled to 099MF-366340265Docket No.: 79275-20040.40 °C. Benzenesulfonyl chloride (1.57 g, 8.86 mmol, 1.00 eq) was then added in portions. The reaction mixture was then slowly warmed to 23 °C and stirred for 16 h. The reaction was then quenched by addition of H2O (50 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give methyl 5-(4-bromo-5-fluoro-2-(phenylsulfonamido)phenyl)pent-4-ynoate (3.90 g), which was used in the next step directly without further purification. LC-MS (ESI) m / z: [M + H]+calcd for Ci8Hi5BrFNO4S: 440.0; found: 440.0.

[0296] Step c. To a solution of methyl 5-(4-bromo-5-fluoro-2-(phenylsulfonamido)phenyl)pent-4-ynoate (3.90 g, 8.86 mmol, 1.00 eq) in MeCN (40 mL) was added CuCl (131 mg, 1.33 mmol, 0.15 eq) and CS2CO3 (432 mg, 1.33 mmol, 0.15 eq). The resulting mixture was stirred at 23 °C for 12 h. The reaction was then quenched by addition of H2O (100 mL) at 23 °C. The resulting biphasic mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 50 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was triturated with EtOAc:petroleum ether (1:1, 16 mL) at 23 °C for 30 mins. The mixture was then filtered to give methyl 3-(6-bromo-5-fluoro-l-(phenylsulfonyl)-lJ / -indol-2-yl)propanoate. LC-MS (ESI) m / z: [M + H]+calcd for Ci8Hi6BrFNO4S: 440.0; found: 440.0.

[0297] Step d. A mixture of methyl 3-(6-bromo-5-fluoro-l-(phenylsulfonyl)-lJ / -indol-2-yl)propanoate (1.00 g, 2.27 mmol, 1.00 eq), B2neop2 (1.54 g, 6.81 mmol, 3.00 eq) and KOAc (490 mg, 5.00 mmol, 2.20 eq) in dioxane (10 mL) was degassed and purged with nitrogen three times. Pd(PPh3)2Ch (159 mg, 227 pmol, 0.10 eq) was added, and the reaction was warmed to 120 °C and stirred for 30 min under an atmosphere of nitrogen. After cooling to room temperature, the reaction mixture was filtered to give 3 -(6-(5, 5 -dimethyl -1,3, 2-dioxaborinan-2-yl)-5-fluoro-l -(phenyl sulfonyl)- IT / -indol -2 -yl)propanoate, which was used in the next step directly without further purification. LC-MS (ESI) m / z: [M - C5H10 + H]+calcd for C18H17BFNO6S: 406.1; found: 406.1.

[0298] Step e. To a solution of methyl 3-(6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-5-fluoro-l-(phenylsulfonyl)-17 / -indol-2-yl)propanoate (1.00 g, 2.11 mmol, 1.00 eq) in dioxane (10100MF-366340265Docket No.: 79275-20040.40 mL) was added 2-bromo-5-methoxypyrazine (319 mg, 1.69 mmol, 0.80 eq). A solution of K2CO3 (876 mg, 6.34 mmol, 3.00 eq) in H2O (2 mL) was then added dropwise. The resulting reaction mixture was degassed and purged with nitrogen three times. Pd(dppf)C12-DCM (51.7 mg, 63.3 pmol, 0.03 eq) was then added, and the reaction was warmed to 100 °C and stirred for 1 h under an atmosphere of nitrogen. After cooling to room temperature, the reaction was quenched by addition of H2O (20 mL). The resulting biphasic mixture was extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 3-(5-fluoro-6-(5-methoxypyrazin-2-yl)-U / -indol-2-yl)propanoate. LC-MS (ESI) m / z: [M + H]+calcd for C23H21FN3O5S: 470.1; found: 470.1.

[0299] Step f. To a solution of methyl 3-(5-fluoro-6-(5-methoxypyrazin-2-yl)-l-(phenylsulfonyl)-U / -indol-2-yl)propanoate in H2O (1 mL), MeOH (2 mL), and THF (2 mL) was added LiOH H2O (134 mg, 3.19 mmol, 3.00 eq). The resulting reaction mixture was warmed to 80 °C and stirred for 16 h. After cooling to room temperature, the reaction was quenched with H2O (5 mL) and adjusted to pH = 2 with aqueous HC1 (1 N). The resulting biphasic mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 3-(5-fluoro-6-(5-methoxypyrazin-2-yl)-U / -indol-2-yl)propanoic acid, which was used directly in the next step without further purification. LC-MS (ESI) m / z: [M + H]+calcd for C16H15FN3O3: 316.1; found: 316.2.

[0300] Step g. To a solution of 3-(5-fluoro-6-(5-methoxypyrazin-2-yl)-U / -indol-2-yl)propanoic acid (150 mg, 475 pmol, 1.00 eq) in DMF (1.5 mL) was added HATU (271 mg, 713 pmol, 1.50 eq). The resulting reaction mixture was stirred for 1.5 h at 23 °C before MeNH2'HCl (32.1 mg, 475 pmol, 1.00 eq) and DIPEA (253 pL, 1.43 mmol, 3.00 eq) were added. The resulting reaction mixture stirred for 1 h at 23 °C. The reaction mixture was then quenched by 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 (10 mL), filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 3-(5-fluoro-6-(5-methoxypyrazin-2-yl)-U / -indol-2-yl)-A-methylpropanamide. 'HNMR (400 MHz, DMSO-t / 6) 8 ppm 11.17 (s, 1H), 8.56 (s, 1H), 8.43 (d, J= 1.6 Hz, 1H),101MF-366340265Docket No.: 79275-20040.40 7.84 (d, = 4.0 Hz, 1H), 7.75 (d, = 6.8 Hz, 1H), 7.30 (d, J = 12.4 Hz, 1H), 6.17 (s, 1H), 3.96 (s, 3H), 2.96 (t, J= 8.0 Hz, 2H), 2.58 (d, J= 4.4 Hz, 3H), 2.49 - 2.43 (m, 2H). LC-MS (ESI) m / z: [M + H]+calcd for C17H18FN4O2: 329.1; found: 329.2.Example S-5: Synthesis of 3-(5-cliloro-6-(5-niethoxypyr:izin-2-yl)-l / / -indol-2-yl)-\- methylpropanamide (Compound 6)

[0301] Step a: To a mixture of 4-chloro-2-iodo-5-methoxyaniline (5.00 g, 17.6 mmol, 1.00 eq) and methyl pent-4-ynoate (1.98 g, 17.6 mmol, 1.00 eq) in DMF (50 mL) was added TEA (12.3 mL, 88.1 mmol, 5.00 eq), and the resulting mixture was degassed and purged with nitrogen three times. Cui (335 mg, 1.76 mmol, 0.10 eq) and Pd(PPh3)2Ch (247 mg, 352 pmol, 0.02 eq) were then added. The resulting reaction mixture was stirred at 23 °C for 16 h under an atmosphere of nitrogen. The reaction was then quenched with H2O (50 mL). The resulting biphasic mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column102MF-366340265Docket No.: 79275-20040.40 chromatography to give methyl 5-(2-amino-5-chloro-4-methoxyphenyl)pent-4-ynoate. LC-MS (ESI) m / z: [M + H]+calcd for CnHisClNCh: 268.1; found: 268.1.

[0302] Step b. To a solution of methyl 5-(2-amino-5-chloro-4-methoxyphenyl)pent-4-ynoate (4.10 g, 15.3 mmol, 1.00 eq) and pyridine (3.7 mL, 45.9 mmol, 3.00 eq) in DCM (40 mL) at 0 °C was added benzene sulfonyl chloride (2.70 g, 15.3 mmol, 1.00 eq) in portions. The resulting reaction mixture was slowly warmed to room temperature and stirred for 16 h. The reaction was then quenched by addition of H2O (50 mL). The resulting biphasic mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give methyl 5-(5-chloro-4-methoxy-2-(phenylsulfonamido)phenyl)pent-4-ynoate, which was used directly in the next step without further purification. LC-MS (ESI) m / z: [M + H]+calcd for C19H19CINO5S: 408.1; found: 408.1.

[0303] Step c: To a solution of methyl 5-(5-chloro-4-methoxy-2-(phenylsulfonamido)phenyl)pent-4-ynoate (6.00 g, 14.7 mmol, 1.00 eq) in MeCN (60 mL) was added CuCl (218 mg, 2.21 mmol, 0.15 eq) and CS2CO3 (718 mg, 2.21 mmol, 0.15 eq). The resulting reaction mixture was stirred at 23 °C for 12 h. The reaction was then quenched by addition of H2O (50 mL). The resulting biphasic mixture was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was triturated with MBTE: EtOAc (10:1, 40 mL) at 23 °C for 30 minutes and filtered. The filter cake was collected to give methyl 3-(5-chloro-6-methoxy-l-(phenylsulfonyl)-17 / -indol-2-yl)propanoate. LC-MS (ESI) m / z: [M + H]+calcd for C19H19CINO5S: 408.1; found: 408.1.

[0304] Step d: A solution of methyl 3-(5-chloro-6-methoxy-l-(phenylsulfonyl)-lJ / -indol-2-yl)propanoate (1.27 g, 3.11 mmol, 1.00 eq) in DCM (10 mL) at 0 °C was degassed and purged with nitrogen three times. BBr? (1.56 g, 6.23 mmol, 2.00 eq) was then added at 0 °C, and the resulting reaction mixture was stirred at 0 °C for 1 h under an atmosphere of nitrogen. The reaction was then quenched by addition of H2O (10 mL) at 0 °C and stirred for 5 minutes. The resulting biphasic mixture was extracted with EtOAc (3 x 20 mL). The103MF-366340265Docket No.: 79275-20040.40 combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered, and concentrated to give methyl 3-(5-chloro-6-hydroxy-l-(phenylsulfonyl)-l / 7-indol-2-yl)propanoate, which was used directly in the next step without further purification. LC-MS (ESI) m / z: [M + H]+calcd for C18H17ClNO5S: 394.0; found: 394.1.

[0305] Step e: To a solution of methyl 3 -(5-chloro-6-hydroxy- 1 -(phenyl sulfonyl)- 1 / 7-indol-2-yl)propanoate (1.50 g, 3.81 mmol, 1.00 eq) in DCM (10 mL) was added TEA (690 pL, 4.95 mmol, 1.30 eq), and the resulting reaction mixture was cooled to 0 °C.Trifluoromethanesulfonic anhydride (1.50 g, 5.33 mmol, 1.40 eq) was then added dropwise, and the resulting reaction mixture was stirred at 0 °C for 1 h. The reaction was then warmed to 23 °C and quenched by addition of H2O (20 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated. The crude residue obtained was purified by column chromatography to give methyl 3-(5-chloro-l-(phenylsulfonyl)-6-(((trifluoromethyl)sulfonyl)oxy)-l / / -indol-2-yl)propanoate. LC-MS (ESI) m / z: [M + H]+calcd for C19H16CIF3NO7S2: 526.0; found: 526.1.

[0306] Step f: A mixture of methyl 3 -(5 -chi oro-1 -(phenyl sulfonyl)-6-(((trifluoromethyl)sulfonyl)oxy)-l / / -indol-2-yl)propanoate (650 mg, 1.24 mmol, 1.00 eq), 5,5,5',5'-tetramethyl-2,2'-bi(l,3,2-dioxaborinane) (418 mg, 1.85 mmol, 1.50 eq), and KOAc (266 mg, 2.72 mmol, 2.20 eq) was dissolved in dioxane (7 mL). The reaction mixture was then degassed and purged with nitrogen three times. The reaction mixture was then warmed to 120 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was dried under reduced pressure to give methyl 3-(5-chloro-6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-l-(phenylsulfonyl)-l / / -indol-2-yl)propanoate, which was used directly in the next step without further purification. LC-MS (ESI) m / z: [M - C5H10 + H]+calcd for C18H17BClNO6S: 422.1; found: 422.1.

[0307] Step g: A mixture of methyl 3-(5-chloro-6-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-l-(phenylsulfonyl)-lH-indol-2-yl)propanoate (600 mg, 1.23 mmol, 1.00 eq), 2-bromo-5-methoxypyrazine (277 mg, 1.47 mmol, 1.20 eq), and K2CO3 (169 mg, 1.23 mmol, 1.00 eq) was dissolved in dioxane (6 mL) and H2O (1 mL). Pd(dppf)Cl2·DCM (100 mg, 122 pmol,104MF-366340265Docket No.: 79275-20040.40 0.100 eq) was then added, and the resulting reaction mixture was degassed and purged with nitrogen three times. The resulting mixture was then warmed to 100 °C and stirred for 1 h under an atmosphere of nitrogen. After cooling to room temperature, the reaction was quenched by addition of H2O (10 mL). The resulting biphasic mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography to give methyl 3-(5-chloro-6-(5-methoxypyrazin-2-yl)-l-(phenylsulfonyl)-U / -indol-2-yl)propanoate. LC-MS (ESI) m / z: [M + H]+calcd for C23H21CIN3O5S: 486.1; found: 486.1.

[0308] Step h: To a solution of methyl 3-(5-chloro-6-(5-methoxypyrazin-2-yl)-l-(phenylsulfonyl)-U / -indol-2-yl)propanoate (500 mg, 1.03 mmol, 1.00 eq) in THF (3 mL), MeOH (3 mL), H2O (1 mL) was added LiOH H2O (129 mg, 3.09 mmol, 3.00 eq). The resulting reaction mixture was warmed to 80 °C and stirred for 5 h. After cooling to room temperature, the reaction mixture was adjusted to pH = 4 with aqueous HC1 (IN). The resulting biphasic mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were concentrated under reduced pressure to give 3-(5-chloro-6-(5-methoxypyrazin-2-yl)-U / -indol-2-yl)propanoic acid, which was used directly in the next step without further purification. LC-MS (ESI) m / z: [M + H]+calcd for C16H15CIN3O5: 332.1; found: 332.1.

[0309] Step i: To a solution of 3-(5-chloro-6-(5-methoxypyrazin-2-yl)-U / -indol-2-yl)propanoic acid (120 mg, 361 pmol, 1.00 eq) in DMF (1 mL) was added HATU (137 mg, 361 pmol, 1.00 eq). The resulting reaction mixture was stirred for 30 min, followed by the addition of methylamine HCl (29.3 mg, 434 pmol, 1.20 eq) and DIPEA (188 pL, 1.09 mmol, 3.00 eq). The reaction mixture was then stirred at 23 °C for 1 h. The reaction mixture was then quenched by addition of H2O (5 mL). The resulting biphasic mixture was extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give 3-(5-chloro-6-(5-methoxypyrazin-2-yl)-177-indol-2-yl)-7V-methylpropanamide. 'H NMR (400 MHz, DMSO-t / 6) 8 ppm 11.26 (s, 1H), 8.44 (s, 1H), 8.40 (s, 1H), 7.85 (d, J= 4.4 Hz, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 6.18 (s, 1H), 3.96 (s, 3H), 2.96 (t,105MF-366340265Docket No.: 79275-20040.40 J= 7.6 Hz, 2H), 2.57 (d, J= 4.4 Hz, 3H), 2.51 (s, 1H), 2.48 (s, 1H). LC-MS (ESI) m / z: [M + H]+calcd for C17H18ClN4O2: 345.1; found: 345.2.1O / Y I

[0310] The additional compounds in Table T-2 were synthesized using procedures similar to Examples S-3 through S-5 using the appropriate starting materials and intermediates.ZX IZ( n —,zo \Table T-2 3 n>Cmpd Structure Exact Mass LCMSNo. Observedm / z [M+H]+4 361.1 362.1Me— NHHMeO'5 Me O 330.1 331.1HN^HL 16 344.1 345.2 / - / XX NMe-NHHII JL. MeN O'7 328.1 329.28 / _^, OCF3394.1 395.2°A AXX X NMe-NHHII JL. MeN O'Biological Examples106MF-366340265Docket No.: 79275-20040.40 Example B-l

[0311] CHO cells with doxycycline-inducible expression of human SLC6A19 and TMEM27 were maintained in T150 cell culture treated flasks using cell culture media, which consisted of lx DMEM / F12 (Gibco, 11330057), 10% Tet System-Approved FBS (Gibco, A4736401), lOOU / mL Penicillin-Streptomycin (Gibco, 15140122), lx GlutaMAX™ Supplement (Gibco, 35050061), ImM Sodium Pyruvate (Gibco, 11360070), l.lmg / mL Sodium Bicarbonate (Gibco, 25080094), 5pg / mL Blasticidin (InvivoGen, ant-bl-1), 150pg / mL Hygromycin B Gold (InvivoGen, ant-hg-5), and 500pg / mL G418 (Sigma-Aldrich, G8168-100mL). In preparation for the assay, this media was aspirated and 5mL of TrypLE™ Express Enzyme (Gibco, 12605010) was added to each flask to initiate cell dissociation. The flasks were then incubated (humidified, 37°C with 5% CO2) for 2 minutes. After incubation, lOmL of prewarmed cell culture media was added to each flask. The cell suspension was collected and centrifuged for 5 minutes at 200xg. The supernatant was aspirated and the pellet was resuspended in 5mL pre-warmed cell culture media. The resuspended cells were counted using the Countess Cell Counting Chamber (Invitrogen) and the cell concentration of the suspension was readjusted to 1 million live cells / mL using pre-warmed cell culture media. 25uL / well (25,000 cells / well) of readjusted cell suspension was dispensed into Poly-D-Lysine 384-well white / clear plates (Coming, 354660) using a MultiDrop Combi (Thermo Electron Corp). To induce expression of Human SLC6A19 and TMEM27, 25uL / well of cell culture media containing 2pg / mL doxycycline was added to the first 23 columns of each plate resulting in a final concentration of Ipg / mL doxycycline. 25pL / well of cell culture media was added to the last column of each plate, to act as negative control wells for Human SLC6A19 and TMEM27 expression. Assay plates were then incubated (humidified, 37°C with 5% CO2) for 18 hours. After incubation, the media was aspirated and the wells were washed 4 times with pre-warmed HBSS (Sigma-Aldrich, H8264-1L) using an Apricot S-Pipette S2 (Apricot Designs), such that 5uL / well HBSS was remaining at the end of each wash. lOpL / well of test compound, a positive control compound to define 0% activity (i.e., 100% inhibition), or DMSO diluted in HBSS (Sigma-Aldrich, H8264-1L) was then added into each well using the Apricot S-Pipette S2 (Apricot Designs). At this step, the final in-well DMSO concentration in the assay plate is 0.5%. All compounds were plated in a duplicate 8-point dilution series that consisted of 3-fold dilutions. The plates were incubated with 107MF-366340265Docket No.: 79275-20040.40 compound (humidified, 37°C with 5% CO2) for 1 hour. Afterwards, 15uL / well of 3.2mM hotcold leucine solution (1:15000 ratio of L-[3,4,5-3H(N)] Leucine (Perkin Elmer, NET460001MC) to L-Leucine (Sigma-Aldrich, L8912-25G) diluted with HBSS (Sigma-Aldrich, H8264-1L)) was added using the Viaflo 384 (Integra), for a final concentration of 1.6mM hotcold leucine solution. The plates were then incubated (humidified, 37°C with 5% CO2) for 20 minutes to conduct the uptake reaction. Immediately after the incubation, the plates were washed 4 times with HBSS (Sigma-Aldrich, H8264-1L) using the ELx405 Microplate Washer (Biotek) to terminate the uptake reaction. After the washes, 50uL / well Ultima Gold Scintillation Cocktail (Perkin Elmer, 6013326) was added to each well using the Viaflo 384 (Integra). The plates were then incubated (humidified, 37°C with 5% CO2) on a plate shaker at 200rpm for 2 hours. After incubation, the plates were removed from the shaker and kept at room temperature for 15 minutes.

[0312] Liquid scintillation analysis was performed using the MicroBeta2 Microplate Counter (Perkin Elmer). Activity (%) was derived by normalizing the average of positive control compound treated wells to 0% and the average of DMSO (negative control) wells to 100%. Collaborative Drug Discovery software was used for graphing data.Table BlCmpd SLC6A19_ Radioligand Cmpd SLC6A19_ Radioligand # Uptake Assay IC50 (pM) # Uptake Assay IC50 (pM) 1 0.249 5 0.4762 1.66 6 0.3303 0.321 7 0.5224 0.6058 1.81

[0313] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entireties, to the same extent as if each were incorporated by reference individually.

[0314] It is to be understood that, while the disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the108MF-366340265Docket No.: 79275-20040.40 scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.109MF-366340265

Claims

Docket No.: 79275-20040.40CLAIMSWhat is claimed is:

1. A compound of formula (II):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;n is an integer from 0 to 4;R1is -NH-, -O-, or -S-;either:(i) R2and R3are independently H, Ci-ealkyl, Ci-3alkoxy, Cs-iocycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, whereinthe Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x, or(ii) R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, whereinthe 4-10 membered heterocyclyl is optionally substituted with one or more R3a, andthe 5-10 membered heteroaryl is optionally substituted with one or more R3x; R5is H, halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, wherein the Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R6and R9are each independently H or halo;110MF-366340265Docket No.: 79275-20040.40 R7is halo, -CN, Ci-ealkyl, Ci-ealkoxy, Cs-iocycloalkyl or Ci-ehaloalkyl, whereinthe Ci-ealkyl is optionally substituted with one or more -CN, and the Ci-ealkoxy is optionally substituted with one or more halo;R8is Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, whereinthe Cs-iocycloalkyl, Ce-2oaryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted with one or more R8a;R3aand R8aare each independently -OH, oxo, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-6alkoxy, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)Ci-6alkyl, -C(O)NH2, - C(O)NH(Ci- ealkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C3-locycloalkyl, or -O-Cs-iocycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl of R3ais optionally substituted with one or more R3b, and the Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl of R8ais optionally substituted with one or more R8b;R3Xis -OH, -CN, halo, Ci-ealkyl, C2-6alkenyl, Ci-ealkoxy, Ci-ehaloalkyl, -O-Ci-ehaloalkyl, -NH2, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, -C(O)NH2, - C(O)NH(Ci-6alkyl), - C(O)N(Ci-6alkyl)2, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, Cs-iocycloalkyl, or -O-C3-locycloalkyl, whereinthe Ci-ealkyl, Ci-ealkoxy, 4-10 membered heterocyclyl, Cs-iocycloalkyl or -O- Cs-iocycloalkyl is optionally substituted with one or more R3b;R3band R8bare each independently D, -OH, halo, Ci-ealkyl or Ci-ealkoxy; andp11aL is absent or isx n“, wherein** denotes the point of attachment to R8and * denotes the point of attachment to the rest of the molecule;X is -O-, -S-, -C(R12a)(R12b)-, -N(H)-, or -N(Ci-6alkyl)-;Rllaand Rllbare independently at each occurrence, H or Ci-ealkyl, orone of Rllaand Rllbis H or Ci-ealkyl, and the other of Rllaand Rllbis taken together with one of R12aor R12bto form a Cs-iocycloalkyl; and111MF-366340265Docket No.: 79275-20040.40 R12aand R12bare each independently, H or Ci-ealkyl, orone of R12aand R12bis H or Ci-ealkyl, and the other of R12aand R12bis taken together with one of Rllaor Rllbto form a Cs-iocycloalkyl.

2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

3. The compound of claim 1 or claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-A):R2O R5|R3 ]| | R11\ R11bR9(I-A),or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

4. The compound of any of claims 1-3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is a compound of formula (I-B):112MF-366340265Docket No.: 79275-20040.40or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein ring A is 5-10 membered heteroaryl optionally substituted with one or more R8a.

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

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

7. The compound of any of claims 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1.

8. The compound of any of claims 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 2.113MF-366340265Docket No.: 79275-20040.40 9. The compound of any of claims 1-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R2and R3is H, and the other of R2and R3is Ci-3alkyl.

10. The compound of any of claims 1-9, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one of R2and R3is H, and the other of R2and R3is methyl.

11. The compound of any of claims 1 -8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2and R3are taken together to form 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 4-10 membered heterocyclyl is optionally substituted with one or more R3a.

12. The compound of any of claims 1-11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5is H.

13. The compound of any of claims 1-12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6and R9are each H.

14. The compound of any of claims 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R7is halo.

15. The compound of claim 14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R7is Cl.

16. The compound of any of claims 1-15, 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.

17. The compound of any of claims 1-16, 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 Ci-ealkyl.114MF-366340265Docket No.: 79275-20040.40 18. The compound of any of claims 1-17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is selected from thegroup consisting of19. The compound of any of claims 1-16, 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 halo or Ci-ealkoxy.

20. The compound of any of claims 1-16 and claim 19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R8is selectedfrom the group consisting ofand21. The compound of any of claims 1-15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-C):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, whereinY1, Y2, Y3, Y4, and Y5, are each independently -CH-, -N-, -O-, or -S-; and5 is an integer from 0-4.

22. The compound of any of claims 1-15 and claim 21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula:115MF-366340265Docket No.: 79275-20040.40or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

23. The compound of any of claims 1 and 5-15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula (I-E):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, whereinY1, Y2, Y3, Y4, and Y5, are each independently -CH- or -N-; and5 is an integer from 0-5.

24. The compound of claim 23, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula:MF-366340265Docket No.: 79275-20040.40H33C\HNor a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

25. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from Compounds 1-8 of Table 1.

26. A pharmaceutical composition comprising (i) a compound of any of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

27. A method of inhibiting SLC6A19 in a cell, comprising contacting the cell with a compound of any of claims 1-25, or a stereoisomer or tautomer thereof.

28. 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 claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 26.

29. 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 claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 26.

30. The method of claim 29, 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),MF-366340265Docket No.: 79275-20040.40 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.

31. The method of claim 29 or claim 30, wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, and metabolic diseases.

32. The method of any of claims 29-31, wherein the disease, disorder, or condition is chronic kidney disease (CKD).

33. The method of any of claims 29-31, wherein the disease, disorder, or condition is phenylketonuria (PKU).

34. The method of claim 29, wherein the disease, disorder, or condition is associated with abnormal levels of amino acids.

35. The method of claim 29 or claim 30, wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

36. The method of any of claims 29-35, wherein the individual is human.

37. A kit, comprising (i) a compound of any of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 26, and (ii) instructions for treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

38. The kit of claim 37, wherein the disease, disorder, or condition is associated with abnormal levels of amino acids.

39. The kit of claim 37 or claim 38, wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.118MF-366340265Docket No.: 79275-20040.40 40. The kit of claim 37 or claim 38, 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.

41. The kit of any of claims 37-40, wherein the individual has a genetic defect in phenylalanine hydroxylase.

42. A compound of any one of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in inhibiting SLC6A19 in a cell.

43. A compound of any one of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 26, for use in reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof.

44. A compound of any one of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 26, for use in treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

45. Use of a compound of any one of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for inhibiting SLC6A19 in a cell.

46. Use of a compound of any one of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof.119MF-366340265Docket No.: 79275-20040.40 47. Use of a compound of any one of claims 1-25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.120MF-366340265

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