Substituted pyridine compounds

Abstract

The invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof described herein; to their use in medicine; to compositions containing them; to processes for their preparation; and to intermediates used in such processes. The compounds of Formula (I) may be useful as therapeutic and / or preventative agents to treat diseases that involve abnormal amino acid metabolism, amino acid transport and / or amino acid level, cardiovascular disorders, renal disorders, or metabolic diseases, such as phenylketonuria, NASH, NAFLD, heart failure, chronic kidney disease, and related disorders.

Description

[0001]PC073174A SUBSTITUTED PYRIDINE COMPOUNDS Field of the Invention The present invention relates to novel substituted pyridine compounds. The invention 5 also relates to the preparation of these novel compounds, intermediates used in the preparation, compositions containing these novel compounds, and uses of these novel compounds for treating or preventing a condition, disease, or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid levels by modulation of SLC6A19 (B0AT1) transporter. 0 Background of the Invention SLC6A19 (B0AT1) is an intestinal and kidney transporter that modulates the absorption / re-absorption of neutral amino acids in the gut / kidney. Therefore, inhibition of SLC6A19 may have therapeutic effect for gut / kidney related diseases or disorders. 5 Desai et al. has disclosed some SLC6A19 inhibitors that may be used to treat metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), phenylketonuria (PKU), urea cycle deficiency and related disorders (see Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19), Bioorg. Med. Chem. Lett.53 (2021), 128421). 0 Although recent studies suggest that SLC6A19 may be a promising target for treating or preventing a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 transporter, very limited SLC6A19 inhibitors have been reported and there is no FDA approved drug as SLC6A19 inhibitor. Accordingly, there remains a need for new and / or improved SLC6A19 inhibitors, for5 example, for developing new and / or improved pharmaceuticals (e.g., more effective, more selective, less toxic, improved patient compliance, and / or having improved biopharmaceutical properties such as physical stability; solubility; oral bioavailability; appropriate metabolic stability; clearance; half-life) to treat or prevent a condition, disease, or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation0 of SLC6A19 transporter, such as those described herein. The present invention is directed to these and other important ends. Summary of the Invention In one embodiment (Embodiment E1), the present invention provides a compound of5 Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1is C1‑C6alkyl, C3‑C6cycloalkyl, a 4- to 8- membered heterocycloalkyl, a 6- to 10- membered aryl, or a 5- to 10- membered heteroaryl, wherein each of said C1‑C6alkyl, C3‑C6cycloalkyl, 4- to 8- membered heterocycloalkyl, 6- to 10- membered aryl, or 5- to 10- membered heteroaryl is optionally substituted with 1 to 6 substituents each independently selected from the group consisting of halogen, -OH, -CN, -N(R8R9), C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C3‑C6halocycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, (C3-C4halocycloalkyl)-C1-C4alkyl-, (C1-C6alkoxy)-C1-C4alkyl-, (C3-C4cycloalkoxy)-C1-C4alkyl-, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, C3‑C6halocycloalkoxy, (C3-C4cycloalkyl)-C1-C4alkoxy-, and (C3-C4halocycloalkyl)-C1-C4alkoxy-; R2is H, halogen, -OH, -CN, -N(R10R11), C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C3‑C6halocycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, or C3‑C6halocycloalkoxy; R3is halogen, -OH, -CN, -N(R12R13), C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C3‑C6halocycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, or C3‑C6halocycloalkoxy; R4is a C3‑C10cycloalkyl, a 4- to 10- membered heterocycloalkyl, a 6- to 10- membered aryl or a 5- to 10- membered heteroaryl, wherein said C3‑C10cycloalkyl, 4- to 10- membered heterocycloalkyl, 6- to 10- membered aryl or 5- to 10- membered heteroaryl is optionally substituted with 1 to 6 substituents with 1 to 6 R4A; each R4Ais independently selected from the group consisting of halogen, -OH, -CN, -SF5, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C3-C6cycloalkyl, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, C3‑C6halocycloalkoxy, (C3-C4cycloalkyl)-C1-C4alkoxy-, (C3-C4halocycloalkyl)-C1-C4alkoxy-, a 4- to 8- membered heterocycloalkyl, phenyl, a 5- to 8- membered heteroaryl, -N(Ra)(Rb), -N(Rc)(C(=O)Rd), -C(=O)-N(Ra)(Rb), Rd-C(=O)-, - C(=O)-OH, -N(Rc)(S(=O)2Rd), N(Ra)(Rb)-S(=O)2-, and -ORd, wherein each of said C1-C6alkyl, C3-C6cycloalkyl, 4- to 8- membered heterocycloalkyl, phenyl, or 5- to 8- membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6 cycloalkyl, C3-C6halocycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkoxy, C3-C6halocycloalkoxy, -N(Ra)(Rb), -N(Rc)(C(=O)Rd), -C(=O)-OH, -C(=O)N(Ra)(Rb), - N(Rc)(S(=O)2Rd), -S(=O)2-N(Ra)(Rb), and –ORd; or two adjacent R4A, together with the two ring atoms to which they are attached, form a fused C3-C6cycloalkyl or a 4- to 8- membered heterocycloalkyl, wherein each of said C3- C6cycloalkyl or 4- to 8- membered heterocycloalkyl is optionally substituted with 1 to 4 independently selected R4B; each R4Bis independently selected from the group consisting of halogen, -OH, -CN, oxo, - SF5, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C3-C6cycloalkyl, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, C3‑C6halocycloalkoxy, (C3-C4cycloalkyl)-C1-C4alkoxy-, (C3-C4halocycloalkyl)-C1-C4alkoxy-, a 4- to 8- membered heterocycloalkyl, phenyl, a 5- to 8- membered heteroaryl, -N(Ra)(Rb), -N(Rc)(C(=O)Rd), -C(=O)-N(Ra)(Rb), Rd-C(=O)-, - C(=O)-OH, -N(Rc)(S(=O)2Rd), N(Ra)(Rb)-S(=O)2-, and -ORd, wherein each of said C1-C6alkyl, C3-C6cycloalkyl, 4- to 8- membered heterocycloalkyl, phenyl, or 5- to 8- membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkoxy, C3-C6halocycloalkoxy, -N(Ra)(Rb), -N(Rc)(C(=O)Rd), -C(=O)-OH, -C(=O)N(Ra)(Rb), - N(Rc)(S(=O)2Rd), -S(=O)2-N(Ra)(Rb), and –ORd; each Rais independently selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, and C3-C6cycloalkyl; each Rbis independently selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, a 4- to 10-membered heterocycloalkyl, a C6-C10aryl, a 5- to 10- membered heteroaryl, (4- to 10-membered heterocycloalkyl)-C1-C4alkyl-, (C6-C10aryl)-C1-C4alkyl-, and (5- to 10-membered heteroaryl)-C1-C4alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-C4alkyl, C3-C6cycloalkyl, C1-C4hydroxylalkyl, HO-C(=O)-, NH2-(C=O)-, N(C1-C4alkyl)2-(C=O)-, C1-C4haloalkyl, C1-C4alkoxy, and C1-C4haloalkoxy; or Raand Rbtogether with the N atom to which they are attached form a 4- to 10- membered heterocycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, -OH, -CN, oxo, HO-C(=O)-, NH2-(C=O)-, N(C1-C4alkyl)2-(C=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4hydroxylalkyl, C1-C4haloalkyl, and C1-C4haloalkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy; each Rcis independently selected from the group consisting of H, C1-C4alkyl, and C3-C6cycloalkyl; each Rdis independently selected from the group consisting of H, C1-C6alkyl, C3-C6cycloalkyl, a 4- to 14-membered heterocycloalkyl, C6-C10aryl, a 5- to 10-membered heteroaryl, (4- to 10-membered heterocycloalkyl)-C1-C4alkyl-, (C6-C10aryl)-C1-C4alkyl-, and (5- to 10-membered heteroaryl)-C1-C4alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, OH, -CN, oxo, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxylalkyl, C3-C6cycloalkyl, C1-C4alkoxy, and C1-C4haloalkoxy; R5is H, halogen, -OH, -N(R14R15), C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C3‑C6halocycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, or C3‑C6halocycloalkoxy; each R6and R7is independently selected from the group consisting of H, halogen, -OH, - CN, C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C3-C6halocycloalkyl, C1‑C6alkoxy, C1‑C6haloalkoxy, C3‑C6cycloalkoxy, and C3‑C6halocycloalkoxy; or R6and R7, together with the carbon atom to which they are attached, form a C3‑C6cycloalkyl or a 4- to 6- membered heterocycloalkyl, each optionally substituted with 1 to 4 substituents each independently selected from the group consisting of -OH, halogen, C1‑C4alkyl, C1‑C4alkoxy, C1‑C4haloalkyl, and C1‑C4haloalkoxy; R8, R9, R10, R11, R12, R13, R14, and R15, are each independently selected from the group consisting of H, C1‑C6alkyl, C3‑C6cycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, (C1-C6alkoxy)-C1-C4alkyl-, (C3-C4cycloalkoxy)-C1-C4alkyl-, and R16-(C=O)-; or R8and R9, together with the N atom to which they are attached, form a 4- to 6- membered heterocycloalkyl; or R10and R11, together with the N atom to which they are attached, form a 4- to 6- membered heterocycloalkyl; or R12and R13, together with the N atom to which they are attached, form a 4- to 6- membered heterocycloalkyl; or R14and R15, together with the N atom to which they are attached, form a 4- to 6- membered heterocycloalkyl; R16is C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, (C1-C6alkoxy)-C1-C4alkyl-, or (C3-C4cycloalkoxy)-C1-C4alkyl-; X is O, -NR17, or absent; Y is -NR18or absent; Z is O, -NR19, or absent; R17, R18and R19are each independently selected from the group consisting of H, C1-C6alkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, and C3-C6cycloalkyl; and n is 1, 2, 3, or 4, provided that: (a) X and Y are not both absent; (b) when Y is absent, then X is not O; (c) when Y is -NR18and R1is an optionally substituted 6- to 10- membered aryl or an optionally substituted 5- to 10- membered heteroaryl, then X is not O; (d) when Y is -NR18, then neither R6nor R7on the same carbon that is directly bonded to Y is halogen, -OH, -CN, C1‑C6alkoxy, C1‑C6haloalkoxy, C3‑C6cycloalkoxy, or C3‑C6halocycloalkoxy; (e) when one of R6and R7is -OH, then the other one on the same carbon is not halogen, - OH, -CN, C1‑C6alkoxy, C1‑C6haloalkoxy, C3‑C6cycloalkoxy, or C3‑C6halocycloalkoxy,; (f) when Z is O or -NR19, then neither R6nor R7on the same carbon that is directly bonded to Z is -OH, -CN, C1‑C6alkoxy, C1‑C6haloalkoxy, C3‑C6cycloalkoxy, or C3‑C6halocycloalkoxy; (g) when n is 1 and Y is -NR18, then Z is not O or -NR19; and (h) when Z is absent and Y is NR18, then n is 2, 3 or 4. The present invention also provides a pharmaceutical composition containing the compound of Formula (I) or a pharmaceutically acceptable salt of the compound and at least one pharmaceutically acceptable excipient. The present invention also provides a method for treating or preventing a condition, disease, or disorder in a subject (e.g., a mammal or a human), which method includes administering to the subject (e.g., the mammal or human) the compound of Formula (I) or a pharmaceutically acceptable salt of the compound, wherein the condition, disease, or disorder is selected from the group consisting of isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle deficiency, urea cycle disorders, hyperammonemia, diabetes, phenylketonuria (PKU), chronic kidney disease (CKD), diabetic kidney disease (DKD), diabetic nephropathy, non-diabetic kidney disease (NDKD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, neurodevelopmental disorders, and autism- spectrum disorders. The present invention also provides the compound of Formula (I) or a pharmaceutically acceptable salt of the compound for use as a medicament. The present invention also provides the compound of Formula (I) or a pharmaceutically acceptable salt of the compound for use in the treatment of a condition, disease, or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B0AT1) transporter. The present invention also provides the compound of Formula (I) or a pharmaceutically acceptable salt of the compound for use in the treatment of a condition, disease, or disorder selected form the group consisting of isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle deficiency, urea cycle disorders, hyperammonemia, diabetes, phenylketonuria (PKU), chronic kidney disease (CKD), diabetic kidney disease (DKD), diabetic nephropathy, non-diabetic kidney disease (NDKD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, neurodevelopmental disorders, and autism- spectrum disorders. The present invention also provides use of the compound of Formula (I) or a pharmaceutically acceptable salt of the compound for manufacturing a medicament in the treatment of a condition, disease, or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B0AT1) transporter. The present invention also provides use of the compound of Formula (I) or a pharmaceutically acceptable salt of the compound for manufacturing a medicament in the treatment of a condition, disease, or disorder selected form the group consisting of isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle deficiency, urea cycle disorders, hyperammonemia, diabetes, phenylketonuria (PKU), chronic kidney disease (CKD), diabetic kidney disease (DKD), diabetic nephropathy, non-diabetic kidney disease (NDKD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, neurodevelopmental disorders, and autism-spectrum disorders. The present invention also provides a method for modulating (e.g. inhibiting) a SLC6A19 (B0AT1) transporter, which method includes contacting the SLC6A19 (B0AT1) transporter with the compound of Formula (I) or a pharmaceutically acceptable salt of the compound. The present invention also provides a pharmaceutical combination including (a) the compound of Formula (I) or a pharmaceutically acceptable salt of the compound and (b) at least one additional therapeutic agent. The present invention also provides a pharmaceutical composition including (a) the compound of Formula (I) or a pharmaceutically acceptable salt of the compound and (b) at least one additional therapeutic agent. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Detailed Description of the Invention The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. E1 A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined above. E2 A compound of embodiment E1, or a pharmaceutically acceptable salt thereof, wherein R1is C1‑C6alkyl, C3‑C6cycloalkyl, a 4- to 8- membered heterocycloalkyl, a 6- to 10- membered aryl, or a 5- to 10- membered heteroaryl, wherein each of said C1‑C6alkyl, C3‑C6cycloalkyl, 4- to 8- membered heterocycloalkyl, 6- to 10- membered aryl, or 5- to 10- membered heteroaryl, is optionally substituted with 1 to 6 substituents each independently selected from the group consisting of halogen, C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C3‑C6halocycloalkyl, C1‑C6alkoxy, and C3‑C6cycloalkoxy. E3 A compound of embodiment E1 or embodiment E2, or a pharmaceutically acceptable salt thereof, wherein R1is C1‑C6 alkyl, C3‑C6 cycloalkyl, or (C3‑C6 cycloalkyl)-C1‑C4 alkyl-,each of which is optionally substituted with 1 to 5 halogens. E4 A compound of embodiment E3, or a pharmaceutically acceptable salt thereof, wherein R1is C1‑C6alkyl, C3‑C6cycloalkyl, or (C3‑C6cycloalkyl)-C1‑C4alkyl-, each of which is optionally substituted with 1 to 5 fluoro. E5 A compound of any one of embodiments E1 to E4, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclobutyl, 1,1- difluoroethyl, and 1,1,1-trifluoroethyl. E6 A compound of any one of embodiments E1 to E5, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of methyl, ethyl, 1,1- difluoroethyl, 1,1,1-trifluoroethyl, and cyclopropyl. E7 A compound of any one of embodiments E1 to E6, or a pharmaceutically acceptable salt thereof, wherein R2is H, halogen, C1‑C6alkyl, or C3‑C6cycloalkyl. E8 A compound of embodiment E7, or a pharmaceutically acceptable salt thereof, wherein R2is H or halogen. E9 A compound of embodiment E8, or a pharmaceutically acceptable salt thereof, wherein R2is H. E10 A compound of any one of embodiments E1 to E9, or a pharmaceutically acceptable salt thereof, wherein R3is halogen, C1‑C6alkyl, C1‑C6haloalkyl, C1-C6alkoxy, C1‑C6haloalkoxy, or C3‑C6cycloalkyl. E11 A compound of embodiment E10, or a pharmaceutically acceptable salt thereof, wherein R3is halogen, C1-C6haloalkyl, or C1-C6haloalkoxy. E12 A compound of embodiment E11, or a pharmaceutically acceptable salt thereof, wherein R3is halogen. E13 A compound of embodiment E12, or a pharmaceutically acceptable salt thereof, wherein R3is Cl. E14 A compound of embodiment E11, or a pharmaceutically acceptable salt thereof, wherein R3is C1-C3haloalkyl. E15 A compound of embodiment E14, or a pharmaceutically acceptable salt thereof, wherein R3is CF3. E16 A compound of embodiment E11, or a pharmaceutically acceptable salt thereof, wherein R3is C1-C6haloalkoxy. E17 A compound of embodiment E16, or a pharmaceutically acceptable salt thereof, wherein R3is OCF2H. E18 A compound of any one of embodiments E1 to E17, or a pharmaceutically acceptable salt thereof, wherein R4is phenyl or 5- to 10- membered heteroaryl, wherein said phenyl or 5- to 10- membered heteroaryl is optionally substituted with 1 to 3 R4A, each R4Ais independently selected from the group consisting of C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, (C3-C4cycloalkyl)-C1-C4alkoxy-, (C1-C6alkoxy)-C1-C4alkyl-, (C1-C6alkoxy)-C3-C6cycloalkyl-, phenyl, and a 4- to 8- membered heterocycloalkyl. E19 A compound of any one of embodiments E1 to E18, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of benzotriazolyl, indazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyradazinyl, pyrimidyl, pyrazolo[1,5-a]pyridinyl, thiadiazolyl, quinolinyl, [1,2,3]triazolo[4,5-b]pyridin-2-yl, and phenyl, each of which is optionally substituted with 1 to 3 R4A, each R4Ais independently selected from the group consisting of C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, (C3-C4cycloalkyl)-C1-C4alkoxy-, (C1-C6alkoxy)-C1-C4alkyl-, (C1-C6alkoxy)-C3-C6cycloalkyl-, phenyl, and a 4- to 8- membered heterocycloalkyl. E20 A compound of embodiment E19, or a pharmaceutically acceptable salt thereof, wherein R4is oxazolyl, pyridinyl, pyrazinyl, or [1,2,3]triazolo[4,5-b]pyridin-2-yl. E21 A compound of embodiment E20, or a pharmaceutically acceptable salt thereof, wherein R4is pyridin-3-yl or pyrazin-2-yl. E22 A compound of any one of embodiments E1 to E21, or a pharmaceutically acceptable salt thereof, wherein the moiety: , wherein t is 0, 1, or 2, and Q1is N, CH, or CR4A. E23 A compound of embodiment E22, or a pharmaceutically acceptable salt thereof, wherein Q1is CH or CR4A. E24 A compound of embodiment E22, or a pharmaceutically acceptable salt thereof, wherein Q1is N. E25 A compound of any one of embodiments E22 to E24, or a pharmaceutically acceptable salt thereof, wherein the moiety: . wherein Q1is N, CH, or CR4A. E26 A compound of embodiment E25, or a pharmaceutically acceptable salt thereof, wherein Q1is CH or CR4A. E27 A compound of embodiment E25, or a pharmaceutically acceptable salt thereof, wherein Q1is N. E28 A compound any one of embodiments E22 to E27, or a pharmaceutically acceptable salt thereof, wherein each R4Aand R4Bis independently selected from the group consisting of C1‑C3alkyl, C1‑C3haloalkyl, C3‑C6cycloalkyl, (C1-C6alkoxy)-C1-C4alkyl-, C1‑C3alkoxy, C1‑C3haloalkoxy, phenyl, and a 5- to 6- membered heterocycloalkyl. E29 A compound of embodiment E28, or a pharmaceutically acceptable salt thereof, wherein each R4Aand R4Bis independently selected from the group consisting of methoxy, ethoxy, cyclopropoxy, cyclopropyl, trifluoromethyl, difluoromethoxy, methoxymethyl, phenyl, and pyrrolidin-1-yl. E30 A compound any one of embodiments E1 to E29, or a pharmaceutically acceptable salt thereof, wherein R5is H, halogen, C1‑C6alkyl, or C3‑C6cycloalkyl. E31 A compound of embodiment E30, or a pharmaceutically acceptable salt thereof, wherein R5is H or halogen. E32 A compound of embodiment E31, or a pharmaceutically acceptable salt thereof, wherein R5is H. E33 A compound any one of embodiments E1 to E32, or a pharmaceutically acceptable salt thereof, wherein each R6and R7is independently H, C1‑C6alkyl, or C3‑C6cycloalkyl. E34 A compound of embodiment E33, or a pharmaceutically acceptable salt thereof, wherein each of R6and R7is H. E35 A compound any one of embodiments E1 to E34, or a pharmaceutically acceptable salt thereof, wherein R8, R9, R10, R11, R12, R13, R14, and R15are each independently H, C1‑C3alkyl, or cyclopropyl. E36 A compound of embodiment E35, or a pharmaceutically acceptable salt thereof, wherein R8, R9, R10, R11, R12, R13, R14, and R15are each H. E37 A compound any one of embodiments E1 to E36, or a pharmaceutically acceptable salt thereof, wherein R16is C1‑C3alkyl or cyclopropyl. E38 A compound any one of embodiments E1 to E37, or a pharmaceutically acceptable salt thereof, wherein R17, R18, and R19are each independently H, C1‑C3alkyl, or cyclopropyl. E39 A compound any one of embodiments E1 to E38, or a pharmaceutically acceptable salt thereof, wherein X is -NR17, and Y is absent. E40 A compound any one of embodiments E1 to E38, or a pharmaceutically acceptable salt thereof, wherein X is absent, and Y is -NR18. E41 A compound any one of embodiments E1 to E40, or a pharmaceutically acceptable salt thereof, wherein Z is O or NH. E42 A compound of embodiment E41, or a pharmaceutically acceptable salt thereof, wherein Z is NH. E43 A compound of embodiment E41, or a pharmaceutically acceptable salt thereof, wherein Z is O. E44 A compound any one of embodiments E1 to E43, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2. E45 A compound of embodiment E44, or a pharmaceutically acceptable salt thereof, wherein n is 1. E46 A compound any one of embodiments E1 to E45, or a pharmaceutically acceptable salt thereof, wherein R1is C1‑C6alkyl, C3‑C6cycloalkyl, or (C3‑C6cycloalkyl)-C1‑C4alkyl-, each of which is optionally substituted with 1 to 5 halogen; R2is H, R3is Cl, CF3, or OCF2H; R4is pyridin-3-yl or pyrazin-2-yl, each optionally substituted with 1 to 3 independently selected R4A; R5is H; R6is H; R7is H; X is NH; Y is absent; n is 1 or 2; and Z is O or NH. E47 A compound of embodiment E46, or a pharmaceutically acceptable salt thereof, wherein R1is C1‑C6alkyl, C3‑C6cycloalkyl, or (C3‑C6cycloalkyl)-C1‑C4alkyl-, each of which is optionally substituted with 1 to 5 fluoro; R2is H, R3is Cl, CF3, or OCF2H; R4is pyridin-3- yl or pyrazin-2-yl, each optionally substituted with 1 to 3 independently selected R4Aselected from the group consisting of methoxy, ethoxy, cyclopropoxy, cyclopropyl, trifluoromethyl, difluoromethoxy, phenyl, 5- to 8- membered heteroaryl, and pyrrolidin-1- yl; R5is H; R6is H; R7is H; X is NH; Y is absent; n is 1; and Z is O or NH. E48 A compound selected from the group consisting of: N2-(5'-Chloro-6-cyclopropyl[3,4'-bipyridin]-2'-yl)-N-ethylglycinamide; N2-[5-Chloro-4-(5-chloro-2H-indazol-2-yl)pyridin-2-yl]-N-ethylglycinamide; N2-[5'-Chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-(5'-chloro-6-ethoxy[3,4'-bipyridin]-2'-yl)-N-ethylglycinamide; N2-[5-chloro-4-(quinolin-3-yl)pyridin-2-yl]-N-ethylglycinamide; N2-[5-chloro-4-(2-phenylpyrimidin-5-yl)pyridin-2-yl]-N-ethylglycinamide; N2-{5-chloro-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-2-yl}-N-ethylglycinamide; 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-(propan-2-yl)acetamide; N2-[5-chloro-4-(5-chloro-2H-pyrazolo[3,4-b]pyridin-2-yl)pyridin-2-yl]-N-ethylglycinamide; 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-methylacetamide; N2-{5-chloro-4-[6-(1H-pyrazol-1-yl)pyridazin-3-yl]pyridin-2-yl}-N-ethylglycinamide; N2-{5-chloro-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-2-yl}-N-methylglycinamide; N2-[5-chloro-4-(5-phenyl-1,2-oxazol-3-yl)pyridin-2-yl]-N-ethylglycinamide; N2-{5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2-yl]pyridin-2-yl}-N-methylglycinamide; 2-({5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2-yl]pyridin-2-yl}oxy)-N-methylacetamide; N2-[5-chloro-4-(6-chloro-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)pyridin-2-yl]-N- ethylglycinamide; N2-{5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2-yl]pyridin-2-yl}-N-ethylglycinamide; N2-[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-methylglycinamide; N2-[5-chloro-4-(5-fluoro-2H-indazol-2-yl)pyridin-2-yl]-N-ethylglycinamide; N2-[5'-chloro-5-(2H-1,2,3-triazol-2-yl)[2,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-{5-chloro-4-[5-(2H-1,2,3-triazol-2-yl)pyrimidin-2-yl]pyridin-2-yl}-N-ethylglycinamide; 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-(2,2,2- trifluoroethyl)acetamide; N2-[5'-chloro-6-(4-fluoro-1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-{5-chloro-4-[4-(1,2-oxazol-3-yl)phenyl]pyridin-2-yl}-N-ethylglycinamide; N2-[5-chloro-4-(5-chloro-2H-1,2,3-benzotriazol-2-yl)pyridin-2-yl]-N-ethylglycinamide; N2-[5'-chloro-6-(1H-pyrazol-3-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-[5'-(difluoromethoxy)-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-[5-amino-5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-(2-hydroxyethyl)acetamide; N2-[5-chloro-4-(5-chloropyrazolo[1,5-a]pyridin-2-yl)pyridin-2-yl]-N-methylglycinamide; N2-[5'-chloro-6-(pyrrolidin-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-[5-chloro-4-(7-chloroquinolin-3-yl)pyridin-2-yl]-N-ethylglycinamide; N2-{5-chloro-4-[1-(pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-ethylglycinamide; and N2-[5-chloro-4-(4-phenyl-1,3-oxazol-2-yl)pyridin-2-yl]-N-ethylglycinamide, or a pharmaceutically acceptable salt thereof. E49 A pharmaceutical composition comprising a compound of any one of embodiments E1 to E48, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. E50 A method for treating or preventing a condition, disease, or disorder in a subject comprising administering to the subject a compound of any one of embodiments E1 to E48, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder is selected from the group consisting of isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle deficiency, urea cycle disorders, hyperammonemia, diabetes, phenylketonuria (PKU), chronic kidney disease (CKD), diabetic kidney disease (DKD), diabetic nephropathy, non-diabetic kidney disease (NDKD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, neurodevelopmental disorders, and autism-spectrum disorders. E51 A method of embodiment E50, wherein said condition, disease, or disorder is urea cycle deficiency, urea cycle disorder, phenylketonuria, or chronic kidney disease. E52 A compound of any one of embodiments E1 to E48, or a pharmaceutically acceptable salt thereof, for use as a medicament. E53 A compound of any one of embodiments E1 to E48, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition, disease, or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B0AT1) transporter. E54 A compound of any one of embodiments E1 to E48, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition, disease, or disorder selected form the group consisting of isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle deficiency, urea cycle disorders, hyperammonemia, diabetes, phenylketonuria (PKU), chronic kidney disease (CKD), diabetic kidney disease (DKD), diabetic nephropathy, non-diabetic kidney disease (NDKD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, neurodevelopmental disorders, and autism-spectrum disorders. E55 Use of a compound of any one of embodiments E1 to E48, or a pharmaceutically acceptable salt thereof, for manufacturing a medicament in the treatment of a condition, disease, or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B0AT1) transporter. E56 Use of a compound of any one of embodiments E1 to E48, or a pharmaceutically acceptable salt thereof, for manufacturing a medicament in the treatment of a condition, disease, or disorder selected from isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle deficiency, urea cycle disorders, hyperammonemia, diabetes, phenylketonuria (PKU), chronic kidney disease (CKD), diabetic kidney disease (DKD), diabetic nephropathy, non-diabetic kidney disease (NDKD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, neurodevelopmental disorders, and autism-spectrum disorders. E57 A method for modulating SLC6A19 (B0AT1) transporter comprising contacting a compound of any one of embodiments E1 to E48, or a pharmaceutically acceptable salt thereof, with the SLC6A19 (B0AT1) transporter. E58 A pharmaceutical combination comprising a compound of any one of embodiments E1 to E48, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent. E59 A pharmaceutical composition comprising a compound of any one of embodiments E1 to E48, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, and at least one excipient. E60 A compound that is 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N- methylacetamide, or a pharmaceutically acceptable salt thereof. E61 A compound that is 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N- methylacetamide. E62 A pharmaceutically acceptable salt of 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'- yl]oxy}-N-methylacetamide. E63 A compound that is N2-[5-chloro-4-(5-phenyl-1,2-oxazol-3-yl)pyridin-2-yl]-N- ethylglycinamide, or a pharmaceutically acceptable salt thereof. E64 A compound that is N2-[5-chloro-4-(5-phenyl-1,2-oxazol-3-yl)pyridin-2-yl]-N- ethylglycinamide. E65 A pharmaceutically acceptable salt of N2-[5-chloro-4-(5-phenyl-1,2-oxazol-3-yl)pyridin-2- yl]-N-ethylglycinamide. E66 A compound that is 2-({5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2-yl]pyridin-2-yl}oxy)-N- methylacetamide, or a pharmaceutically acceptable salt thereof. E67 A compound that is 2-({5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2-yl]pyridin-2-yl}oxy)-N- methylacetamide. E68 A pharmaceutically acceptable salt of 2-({5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2- yl]pyridin-2-yl}oxy)-N-methylacetamide. E69 A compound that is N2-[5-chloro-4-(6-chloro-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)pyridin- 2-yl]-N-ethylglycinamide, or a pharmaceutically acceptable salt thereof. E70 A compound that is N2-[5-chloro-4-(6-chloro-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)pyridin- 2-yl]-N-ethylglycinamide. E71 A pharmaceutically acceptable salt of N2-[5-chloro-4-(6-chloro-2H-[1,2,3]triazolo[4,5- b]pyridin-2-yl)pyridin-2-yl]-N-ethylglycinamide. E72 A compound that is N2-{5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2-yl]pyridin-2-yl}-N- ethylglycinamide, or a pharmaceutically acceptable salt thereof. E73 A compound that is N2-{5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2-yl]pyridin-2-yl}-N- ethylglycinamide. E74 A pharmaceutically acceptable salt of N2-{5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2- yl]pyridin-2-yl}-N-ethylglycinamide. E75 A compound of any embodiments E1 to E48 and E60 to E74, wherein the compound is a solvate, hydrate, tautomer, prodrug, co-crystal, deuterium, chimeric degrader, or degrader thereof. E76 A compound of any embodiments E1 to E48 and E60 to E74, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms of the compound are replaced with deuterium. E77 A compound of embodiment E76, or a pharmaceutically acceptable salt thereof, wherein one, two or three hydrogen atoms of the compound are replaced with deuterium. Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined. In addition, any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of the Examples, or pharmaceutically acceptable salts thereof, for any of the embodiment(s) described herein. Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds described herein. Definitions Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art. The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. “Compounds of the invention” include compounds of Formula I and the novel intermediates used in the preparation thereof. One of ordinary skill in the art will appreciate that compounds of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate that compounds of the invention include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labelled versions thereof (including deuterium substitutions), where they may be formed. As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents. As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of about 5 mg) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5% ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg. As used herein, a wavy ” denotes a point of attachment of a substituentto another group or moiety. If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s). “Optional" or "optionally" means that the subsequently described event or circumstance may, but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not. The terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or the group may have one or more non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Where an optional substituent is attached via a double bond, such as an oxo (=O) substituent, the group occupies two available valences, so the total number of other substituents that are included is reduced by two. In the case where optional substituents are selected independently from a list of alternatives, the selected groups may be the same or different. Throughout the disclosure, it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense to one of ordinary skill in the art. “Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I). “Cyano” refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., -C≡N. "Hydroxy" refers to an -OH group. “Oxo” refers to a double bonded oxygen (=O). "Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups maycontain, but are not limited to, 1 to 6 carbon atoms (“C1‑C6 alkyl”), 1 to 5 carbon atoms (“C1‑C5alkyl”), 1 to 4 carbon atoms (“C1‑C4alkyl”), 1 to 3 carbon atoms (“C1‑C3alkyl”), 1 to 2 carbon atoms (“C1‑C2alkyl”), or 1 carbon atom (“C1alkyl” or methyl). Examples include, but are not limited to, methyl, ethyl, n‑propyl, isopropyl, n‑butyl, sec-butyl, isobutyl, tert‑butyl, n‑pentyl, isopentyl, neopentyl, n‑hexyl, and the like. Alkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example, “haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number. “Haloalkyl” refers to an alkyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen (up to perfluoroalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a fluorine atom). Haloalkyl groups may contain, but are not limited to, 1-6 carbon atoms (“C1-C6haloalkyl”), 1-4 carbon atoms (“C1-C4haloalkyl”), 1-3 carbon atoms (“C1-C3haloalkyl”), 1-2 carbon atoms (“C1-C2haloalkyl”), or 1 carbon atom (“C1haloalkyl”). More specifically, fluorinated alkyl groups may be specifically referred to as “fluoroalkyl.” “Fluoroalkyl” refers to an alkyl group, as defined herein, wherein from one to all of the hydrogen atoms of the alkyl group are replaced by fluoro atoms. For example, the term “C1-3fluoroalkyl” refers to a C1-3alkyl group (e.g., methyl, ethyl, 1-propyl, or 2-propyl) having one or more fluorine substituents (up to perfluoroalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a fluorine atom); and the term “C1fluoroalkyl” refers to methyl having 1, 2, or 3 fluorine substituents. Examples of C1fluoroalkyl include fluoromethyl, difluoromethyl and trifluoromethyl; some examples of C2fluoroalkyl include 1-fluoroethyl, 2-fluoroethyl, 2,2- difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, and the like. “Alkoxy” refers to an alkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of an alkoxy group to a molecule is through the oxygen atom. An alkoxy group may be depicted as alkyl-O-. Alkoxy groups may contain, but are not limited to,1 to 6 carbon atoms (“C1-C6alkoxy”), 1 to 4 carbon atoms (“C1-C4alkoxy”), 1 to 3 carbon atoms (“C1-C3alkoxy”), or 1 carbon atom (“C1alkoxy” or methoxy). Some examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isobutoxy, and the like. As used here, the term “haloalkoxy” refers to an -O-haloalkyl group. For example, the term “C1-4haloalkoxy” refers to an -O-(C1-4haloalkyl) group; and the term “C1-3haloalkoxy” refers to an -O-(C1-3haloalkyl) group. For yet another example, the term “C1 haloalkoxy” refers to a methoxy group having one, two, or three halogen substituents. An example of haloalkoxy is -OCF3or -OCHF2. As used here, the term “fluoroalkoxy” refers to an -O-fluoroalkyl group. For example, theterm “C1-3 fluoroalkoxy” refers to an -O-(C1-3 fluoroalkyl) group; and the term “C1 fluoroalkoxy”refers to an -O-(C1fluoroalkyl) group. Examples of C1fluoroalkoxy include -O-CH2F, -O-CHF2, and -O-CF3. Some examples of C2fluoroalkoxy include -O-CH2CHF2, -O-CH2-CHF2, -O- CH2CF3, -O-CF2CH3, and -O-CF2CF3. “Cycloalkyl” refers to a fully saturated hydrocarbon ring system that has the specified number of carbon atoms, which may be a monocyclic, bridged or fused bicyclic or polycyclic ring system that is connected to the base molecule through a carbon atom of the cycloalkyl ring. Cycloalkyl groups may contain, but are not limited to, 3 to 6 carbon atoms (“C3-C6cycloalkyl”), 3 to 5 carbon atoms (“C3-C5cycloalkyl”) or 3 to 4 carbon atoms (“C3-C4cycloalkyl”). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. As used herein, the term “cycloalkyl-alkyl-” refers to an alkyl group that is substituted by cycloalkyl. For example, the term “(C3-C4cycloalkyl)-C1-C4alkyl-” refers to a C1-C4alkyl group that is substituted with C3-C4cycloalkyl. The point of attachment of “(C3-C4cycloalkyl)-C1-C4alkyl-” occurs at the “C1-C4alkyl” part of the “(C3-C4cycloalkyl)-C1-4alkyl-.” Some examples of (C3-C4cycloalkyl)-C1-C4alkyl- includes cyclopropylmethyl, cyclobutylmethyl, 4-(cyclopropyl)- butan-1-yl, and 3-(cyclopropyl)-butan-1-yl. A cycloalkyl-alkyl- group may be optionally substituted, unsubstituted or substituted, as further defined herein. “Heterocycloalkyl” refers to a fully saturated ring system containing the specified number of ring atoms and containing at least one heteroatom selected from N, O and S as a ring member as far as it makes chemical sense, where ring S atoms are optionally substituted by one or two oxo groups (i.e., S(O)q, where q is 0, 1 or 2) and where the heterocycloalkyl ring is connected to the base molecule via a ring atom, which may be C or N. The heterocycloalkyl group may also optionally contain one or more oxo (i.e., =O) groups to provide compounds such as lactone, lactam, or cyclic carbamate. Heterocycloalkyl rings include rings which are spirocyclic, bridged, or fused to one or more other heterocycloalkyl or carbocyclic rings, where such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated or aromatic to the extent unsaturation or aromaticity makes chemical sense, provided the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system. Heterocycloalkyl rings may contain 1 to 4 heteroatoms selected from N, O, and S(O)qas ring members, or 1 to 2 ring heteroatoms, provided that such heterocycloalkyl rings do not contain two contiguous oxygen or sulfur atoms. Heterocycloalkyl rings may be optionally substituted, unsubstituted or substituted, as further defined herein. Such substituents may be present on the heterocyclic ring attached to the base molecule, or on a spirocyclic, bridged or fused ring attached thereto. Heterocycloalkyl rings may include, but are not limited to, 3-8 membered heterocyclyl groups, for example 4-8, 4-7, or 4-6 membered heterocycloalkyl groups, in accordance with the definition herein. Illustrative examples of heterocycloalkyl rings include, but are not limited to a monovalent radical of: oxepane thiepane azepane 1,4-dioxepane 1,4-oxathiepane (oxepanyl) (thiepanyl) (azepanyl) (1,4-dioxepanyl) (1,4-oxathiepanyl) 1,4-oxaazepane 1,4-thieazepane 1,4-diazepane 1,4-dithiepane (1,4-oxaazepanyl) (1,4-thieazapanyl) (1,-diazepanyl)or(1,4-dithiepanyl)"Aryl" or “aromatic” refers to monocyclic, bicyclic (e.g., biaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms, in which all carbon atoms in the ring are of sp2hybridization and in which the pi electrons are in conjugation. Aryl groups may contain but are not limited to 6 to 10 carbon atoms ("C6-C10aryl"). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. Similarly, "heteroaryl" or “heteroaromatic” refer to monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as a ring member in a ring in which all carbon atoms in the ring are of sp2hybridization and in which the pi electrons are in conjugation. Heteroaryl groups may contain but are not limited to 5 to 10 ring atoms (“5-10 membered heteroaryl”), 5 to 9 ring atoms (“5-9 membered heteroaryl”), or 5 to 6 ring atoms (“5-6 membered heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring. Thus, either 5- or 6-membered heteroaryl rings, alone or in a fused structure, may be attached to the base molecule via a ring C or N atom. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl and carbazolyl. Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl rings. Heteroaryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. Illustrative examples of monocyclic heteroaryl groups include, but are not limited to a monovalent radical of: O N pyrrole furan thiophene pyrazole imidazole isoxazole (pyrrolyl) (furanyl) (thiophenyl) (pyrazolyl)(imidazolyl)(isoxazolyl) oxazole isothiazole thiazolyl 1,2,3-triazole 1,3,4-triazole 1-oxa-2,3-diazole (oxazolyl) (isothiazolyl) (thiazolyl)(1,2,3-triazolyl)(1,3,4-triazolyl)(1-oxa-2,3-diazolyl) 1-oxa-2,4-diazole 1-oxa-2,5-diazole 1-oxa-3,4-diazole 1-thia-2,3-diazole 1-thia-2,4-diazole (1-oxa-2,4-diazolyl)(1-oxa-2,5-diazolyl)(1-oxa-3,4-diazolyl)(1-thia-2,3-diazolyl) (1-thia-2,4-diazolyl) 1-thia-2,5-diazole 1-thia-3,4-diazole tetrazole pyridine pyridazine pyrimidine pyrazine (1-thia-2,5-diazolyl)(1-thia-3,4-diazolyl)(tetrazolyl)(pyridinyl) (pyridazinyl) (pyrimidinyl)(pyrazinyl)Illustrative examples of fused ring heteroaryl groups include, but are not limited to: benzotriazole pyrrolo[2,3-b]pyridine pyrrolo[2,3-c]pyridine pyrrolo[3,2-c]pyridine pyrrolo[3,2-b]pyridine (benzotriazolyl) (pyrrolo[2,3-b]pyridinyl) (pyrrolo[2,3-c]pyridinyl) (pyrrolo[3,2-c]pyridinyl) (pyrrolo[3,2-b]pyridinyl) imidazo[4,5-b]pyridine imidazo[4,5-c]pyridine pyrazolo[4,3-d]pyridine pyrazolo[4,3-c]pyridine (imidazo[4,5-b]pyridinyl) (imidazo[4,5-c]pyridinyl) (pyrazolo[4,3-d]pyidinyl) (pyrazolo[4,3-c]pyidinyl) 2,6-naphthyridine 2,7-naphthyridine pyrido[3,2-d]pyrimidine pyrido[4,3-d]pyrimidine (2,6-naphthyridinyl) (2,7-naphthyridinyl) (pyrido[3,2-d]pyrimidinyl) (pyrido[4,3-d]pyrimidinyl) pyrido[3,4-d]pyrimidine pyrido[2,3-d]pyrimidine pyrido[2,3-b]pyrazine pyrido[3,4-b]pyrazine (pyrido[3,4-d]pyrimidinyl) (pyrido[2,3-d]pyrimidinyl) (pyrido[2,3-b]pyrazinyl) (pyrido[3,4-b]pyrazinyl) pyrimido[5,4-d]pyrimidine pyrazino[2,3-b]pyrazine pyrimido[4,5-d]pyrimidine (pyrimido[5,4-d]pyrimidinyl) (pyrazino[2,3-b]pyrazinyl)or(pyrimido[4,5-d]pyrimidinyl) “Amino” refers to a group -NH2, which is unsubstituted. Where the amino is described as substituted or optionally substituted, the term includes groups of the formula -NRxRy, where each of Rxand Ryis defined as further described herein. For example, “alkylamino” refers to a group having the formula -NRxRy, wherein one of Rxand Ryis an alkyl moiety and the other is H, and “dialkylamino” refers to -NRxRywherein both of Rxand Ryare alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., -NH(C1‑C4alkyl) or -N(C1‑C4alkyl)2). The term “pharmaceutically acceptable” means the substance (e.g., the compounds described herein) and any salt thereof, or composition containing the substance or salt of the invention is suitable for administration to a subject or patient. A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable excipient. “Deuterium enrichment factor” as used herein means the ratio between the deuterium abundance and the natural abundance of deuterium, each relative to hydrogen abundance. An atomic position designated as having deuterium typically has a deuterium enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). "Excipient" as used herein describes any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugar, sodium chloride, or polyalcohol such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof. Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound. The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” SLC6A19 (B0AT1) transporter with a compound of the invention includes the administration of a compound of the present invention to a mammal, such as a human, having the SLC6A19 (B0AT1) transporter, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the SLC6A19 (B0AT1) transporter. As used herein, the term, “subject, “individual” or “patient,” used interchangeably, refers to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development. As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting (or slowing) further development of the pathology or symptomatology or both); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology or symptomatology or both). Salts Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this invention which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compound of the invention that is suitable for administration to a subject or patient. In addition, the compounds of Formula I may also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula I; 2) purifying compounds of Formula I; 3) separating enantiomers of compounds of Formula I; or 4) separating diastereomers of compounds of Formula I. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5- naphathalenedisulfonic acid and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see Paulekun, G. S. et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem.2007; 50(26), 6665-6672. Pharmaceutically acceptable salts of compounds of the invention may be prepared by methods well known to one skilled in the art, including but not limited to the following procedures (i) by reacting a compound of the invention with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of a compound of the invention to another. This may be accomplished by reaction with an appropriate acid or base or by means of a suitable ion exchange procedure. These procedures are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. Solvates The compounds of the invention, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water. In addition, the compounds of Formula I may also include other solvates of such compounds which are not necessarily pharmaceutically acceptable solvates, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula I; 2) purifying compounds of Formula I; 3) separating enantiomers of compounds of Formula I; or 4) separating diastereomers of compounds of Formula I. A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion. When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. Solid form The compounds of the invention may exist in a continuum of solid states ranging from amorphous to crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’). The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) and consists of two dimensional order on the molecular level. Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COO-Na+, -COO-K+, or -SO3-Na+) or non-ionic (such as -N-N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970). Stereoisomers Compounds of the invention may exist as two or more stereoisomers. Stereoisomers of the compounds may include cis and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may also exist for saturated rings. The pharmaceutically acceptable salts of compounds of the invention may also contain a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl- arginine). Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, or by using both of said techniques, and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp.223-249 and references cited therein). When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994). Tautomerism Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) may occur. This may take the form of proton tautomerism in compounds of the invention containing, for example, an imino / amino, keto / enol, or oxime / nitroso group, lactam / lactim or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. It must be emphasized that while, for conciseness, the compounds of the invention have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the invention. Isotopes The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the invention may include isotopes of hydrogen, such as2H (D, deuterium) and3H (T, tritium), carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labelled compounds of the invention, for example those incorporating a radioactive isotope, are useful in one or both of drug or substrate tissue distribution studies. The radioactive isotopes, such as, tritium and14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with positron emitting isotopes, such as,11C,18F,15O and13N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Substitution with deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability. In some embodiments, the disclosure provides deuterium-labeled (or deuterated) compounds and salts, where the formula and variables of such compounds and salts are each and independently as described herein. “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance that is greater than the natural abundance of deuterium (typically approximately 0.015%). A skilled artisan recognized that in chemical compounds with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of the deuterium incorporated into the deuterium-labeled compounds and salt of the invention may be defined by the deuterium enrichment factor. It is understood that one or more deuterium may exchange with hydrogen under physiological conditions. In some embodiments, one or more hydrogen atoms on certain metabolic sites on the compounds of the invention are deuterated. Isotopically-labeled compounds of the invention may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, d6- DMSO. Metabolites Also included within the scope of the invention are active metabolites of compounds of the invention, that is, compounds formed in vivo upon administration of the drug, often by oxidation or dealkylation. Some examples of metabolites in accordance with the invention include, but are not limited to, (i) where the compound of the invention contains an alkyl group, a hydroxyalkyl derivative thereof (-CH > -COH): (ii) where the compound of the invention contains an alkoxy group, a hydroxy derivative thereof (-OR -> -OH); (iii) where the compound of the invention contains a tertiary amino group, a secondary amino derivative thereof (-NRR’-> -NHR or –NHR’); (iv) where the compound of the invention contains a secondary amino group, a primary derivative thereof (-NHR -> -NH2); (v) where the compound of the invention contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); (vi) where the compound of the invention contains an amide group, a carboxylic acid derivative thereof (-CONH2-> COOH); and (vii) where the compound contains a hydroxy or carboxylic acid group, the compound may be metabolized by conjugation, for example with glucuronic acid to form a glucuronide. Other routes of conjugative metabolism exist. These pathways are frequently known as Phase 2 metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, may also be subject to conjugation. Pharmaceutical Compositions In another embodiment, the invention comprises pharmaceutical compositions. For pharmaceutical composition purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention. The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application. Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection. Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dosage form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the invention are ordinarily combined with one or more adjuvants. Such capsules or tablets may comprise a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings. In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as one or more of wetting, emulsifying, suspending, flavoring (e.g., sweetening), or perfuming agents. In another embodiment, the invention comprises a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using one or more of suitable dispersing, wetting agents, or suspending agents. In another embodiment, the invention comprises a topical dosage form. "Topical administration" includes, for example, dermal and transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sci., vol.88, pp.955- 958, 1999. Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable excipient. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. For intranasal administration, the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. In another embodiment, the invention comprises a rectal dosage form. Such rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Other excipients and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well- known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005; Stahl, P. Heinrich and Camilli G. Wermuth, Eds. Handbook of Pharmaceutical Salts: Properties, Selection, and Use. New York: Wiley-VCH, 2011; and Brittain, Harry G., Ed. Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare USA, Inc., 2016. Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counter-ions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG). For oral administration, the compositions may be provided in the form of tablets or capsules containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Dosing regimens may depend on the route of administration, dose scheduling, and use of flat-dose, body surface area or weight-based dosing. For example, for weight-based dosing, intravenously doses may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion. Liposome containing compounds of the invention may be prepared by methods known in the art (See, for example, Chang, H.I.; Yeh, M.K.; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49- 60). Particularly useful liposomes may be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Compounds of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000). Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a compound of the invention, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid. The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. Suitable emulsions may be prepared using commercially available fat emulsions, such as a lipid emulsions comprising soybean oil, a fat emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soya bean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, and have a pH in the range of 5.5 to 8.0. For example, the emulsion compositions may be those prepared by mixing a compound of the invention with a lipid emulsions comprising soybean oil or the components thereof (soybean oil, egg phospholipids, glycerol and water). Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. A drug product intermediate (DPI) is a partly processed material that must undergo further processing steps before it becomes bulk drug product. Compounds of the invention may be formulated into drug product intermediate DPI containing the active ingredient in a higher free energy form than the crystalline form. One reason to use a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, improved mass transport through the mucus layer adjacent to the epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains a compound of the invention isolated and stabilized in the amorphous state (for example, amorphous solid dispersions (ASDs)). There are many techniques known in the art to manufacture ASD’s that produce material suitable for integration into a bulk drug product, for example, spray dried dispersions (SDD’s), melt extrudates (often referred to as HME’s), co-precipitates, amorphous drug nanoparticles, and nano-adsorbates. In one embodiment amorphous solid dispersions comprise a compound of the invention and a polymer excipient. Other excipients as well as concentrations of said excipients and the compound of the invention are well known in the art and are described in standard textbooks. See, for example, “Amorphous Solid Dispersions Theory and Practice” by Navnit Shah et al. Administration and Dosing Typically, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention. The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds of the invention may be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation. The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth. In another embodiment, the compounds of the invention may also be administered parenterally, for example directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques. In another embodiment, the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention may also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, the compounds of the invention may also be administered directly to the eye or ear. The dosage regimen for the compounds of the invention or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. In one embodiment, the total daily dose of a compound of the invention is typically from about 0.01 to about 100 mg / kg (i.e., mg compound of the invention per kg body weight) for the treatment of the indicated conditions discussed herein. In another embodiment, total daily dose of the compound of the invention is from about 0.1 to about 50 mg / kg, and in another embodiment, from about 0.5 to about 30 mg / kg. It is not uncommon that the administration of the compounds of the invention will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired. Therapeutic Methods and Uses The compounds of Formula I of the invention may be useful for treating or preventing a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B0AT1) transporter. See WO2023122267. The compounds of Formula I of the invention may be useful for treating or preventing a disease or disorder such as isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle deficiency, urea cycle disorders, or hyperammonemia. The compounds of Formula I of the invention may also be useful for treating or preventing a disease or disorder such as diabetes, phenylketonuria (PKU), chronic kidney disease (CKD), diabetic kidney disease (DKD), diabetic nephropathy, non-diabetic kidney disease (NDKD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, or neurodevelopmental and autism-spectrum disorders. Preferably, the compounds of Formula I of the invention may also be useful for treating or preventing urea cycle deficiency, urea cycle disorder, phenylketonuria, or chronic kidney disease. Co-administration The compounds of the invention may be used alone, or in combination with one or more other therapeutic agents. The invention provides any of the uses, methods or compositions as defined herein wherein the compound of the invention, or pharmaceutically acceptable salt thereof, is used in combination with one or more other therapeutic agent discussed herein. The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”. A compound of the invention and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients. The term "fixed combination" means a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage. The term "non-fixed combination" means that a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject. These agents and compounds of the invention may be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual’s medical history. Kits Another aspect of the invention provides kits comprising the compound of the invention or pharmaceutical compositions comprising the compound of the invention. A kit may include, in addition to the compound of the invention or pharmaceutical composition thereof, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes the compound or a pharmaceutical composition thereof and a diagnostic agent. In yet another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the invention in quantities sufficient to carry out the methods of the invention. In another embodiment, the kit comprises one or more compounds of the invention in quantities sufficient to carry out the methods of the invention and a container for the dosage and a container for the dosage. Synthetic Methods Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art. Many of the compounds used herein, are related to, or may be derived from compounds in which one or more of the scientific interest or commercial need has occurred. Accordingly, such compounds may be one or more of 1) commercially available; 2) reported in the literature or 3) prepared from other commonly available substances by one skilled in the art using materials which have been reported in the literature. Abbreviations APCI is atmospheric pressure chemical ionization; br is broad; °C is degrees celcius; δ is chemical shift; d is doublet; DMSO is dimethyl sulfoxide; DMSO-d6is deuterodimethylsulfoxide; EI is electron impact ionization; ES is electron scatter; g is gram; GCMS is gas chromatography-mass spectrometry; HPLC is high pressure liquid chromatography; hr(s) is hour(s); L is liter; LCMS is liquid chromatography mass spectrometry; m is multiplet; M is molar; mg is milligram; MHz is mega Hertz; min(s) is minute(s); mL is milliliter; mmol is millimole; mol is mole; MPLC is medium performance liquid chromatography; MS (m / z) is mass spectrum peak; NMR is nuclear magnetic resonance; pH is power of hydrogen; ppm is parts per million; q is quartet; rt is room temperature; RT is retention time; s is singlet; SFC is supercritical fluid chromatography; t is triplet; TLC is thin layer chromatography; UPLC is ultra-performance liquid chromatography; µL is microliter; and µmol is micromole. The Schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present invention. Some of the compounds of the present invention contain a single chiral center. In the following Schemes, the general methods for the preparation of the compounds are shown either in racemic or enantioenriched form. It will be apparent to one skilled in the art that all of the synthetic transformations may be conducted in a precisely similar manner whether the materials are enantioenriched or racemic. Moreover, resolution to the desired optically active material may take place at any desired point in the sequence using well-known methods such as those described herein and in the chemistry literature. In some cases, certain compounds may contain protecting groups, which may be appended or removed by additional steps in the synthetic sequence using conditions known in the art (March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th Edition or Protecting Groups (Thieme Foundations of Organic Chemistry Series), Georg Thieme Verlag, 1994). Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reversed- phase SFC or HPLC. General Methods: Unless stated otherwise, the variables R1, R2, R3, R4, and R5in Schemes I-IV have the same meanings as in Formula (I) or may be precursors of R1, R2, R3, R4, and R5as defined herein. R4M (v) Scheme I Scheme I refers to preparation of substituted pyridines that are represented by Formula (iv). Starting material (i), (iii), and (v) are either commercially available or may be synthesized by those of ordinary skill in the art using literature procedures or preparations described herein. P and Q are herein defined as a suitable halogen atom and may be a choice of Cl, Br and I independently. M is herein defined as a suitable boron species and may be a choice of boronic acid, boronate, and trifluoroborate. Intermediate (ii) may be prepared from starting material (i) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane in the presence of a palladium catalyst (such as Pd(dppf)Cl2) and a suitable base (such as KOAc) in a suitable solvent or a mixed solvent system (such as toluene). Compounds of Formula (iv) may be generated from intermediate (ii) and halide starting material (iii) in the presence of a palladium catalyst (such as cataCXium A Pd G3) and a suitable base (such as K2CO3) in a suitable solvent or a mixed solvent system (such as toluene / 1,4-dioxane / water). Alternatively, compounds of Formula (iv) may be prepared directly from starting material (i) and (v) in the presence of a palladium catalyst (such as Pd(dppf)Cl2) and a suitable base (such as K2CO3) in a suitable solvent or a mixed solvent system (such as 1,4-dioxane / water). Rzhas the same meaning of - Z(CR6R7)nYC(O)XR1as in Formula (I) or may be a precursor of -Z(CR6R7)nYC(O)XR1as defined herein. Scheme II Scheme II refers to preparation of substituted pyridines that are represented by Formula (iv). Starting material (i) and (vi) are either commercially available or may be synthesized by those of ordinary skill in the art using literature procedures or preparations described herein. P is herein defined as a suitable halogen atom and may be a choice of F, Cl, Br and I. Compounds of Formula (iv) may be generated from starting material (i) and (vi) in the presence of a base (such as t-BuOK) in a suitable solvent or a mixed solvent system (such as THF). Alternatively, compounds of Formula (iv) may be prepared from starting material (i) and (vi) in the presence of a suitable copper(I) species (such as Cu2O), a suitable ligand (such as BFMO), and a suitable base (such as K3PO4) in a suitable solvent or a mixed solvent system (such as DMSO). Rzhas the same meaning of -Z(CR6R7)nYC(O)XR1as in Formula (I) or may be a precursor of - Z(CR6R7)nYC(O)XR1as defined herein. Scheme III Scheme III refers to preparation of substituted pyridines that are represented by Formula (ix). Starting material (vii) and (viii) are either commercially available or may be synthesized by those of ordinary skill in the art using literature procedures or preparations described herein. P is herein defined as a suitable halogen atom and may be a choice of F, Cl, and Br. Z has the same meaning as in Formula (I). Compounds of Formula (ix) may be generated from starting material (vii) and (viii) in the presence of a base (such as DIPEA) in a suitable solvent or a mixed solvent system (such as DMSO). Alternatively, compounds of Formula (ix) may be generated from starting material (vii) and (viii) in the presence of a palladium catalyst (such as BrettPhos Pd G3), a suitable ligand (such as BrettPhos), and a suitable base (such as Cs2CO3) in a suitable solvent or a mixed solvent system (such as 1,4-dioxane). Scheme IV refers to preparation of substituted pyridines that are represented by Formula (ix). Starting material (x) and amine (xii) are either commercially available or may be synthesized by those of ordinary skill in the art using literature procedures or preparations described herein. Z has the same meaning as in Formula (I). Intermediate (xi) may be prepared from starting material (x) in the presence of an acid (such as CF3COOH). Compounds of Formula (ix) may be generated from intermediate (xi) and amine (xii) in the presence of a suitable coupling reagent (such as HATU) and a suitable base (such as DIPEA) in a suitable solvent or a mixed solvent system (such as dichloromethane). Experimental Procedures The following illustrate the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art. All starting materials in these Preparations and Examples are either commercially available or can be prepared by methods known in the art or as described herein. Reactions were performed in air or, when oxygen- or moisture-sensitive reagents or intermediates were employed, under an inert atmosphere (nitrogen or argon). When appropriate, reaction apparatuses were dried under dynamic vacuum using a heat gun, and anhydrous solvents (Sure-SealTMproducts from Sigma-Aldrich or DriSolvTMproducts from EMD Chemicals, Gibbstown, NJ) were employed. In some cases, commercial solvents were passed through columns packed with 4Å molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, N,N-dimethylformamide, and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For very sensitive reactions, solvents were further treated with metallic sodium, calcium hydride, or molecular sieves, and distilled just prior to use. Other commercial solvents and reagents were used without further purification. For syntheses referencing procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing. When indicated, reactions were heated by microwave irradiation using Biotage Initiator or Personal Chemistry Emrys Optimizer microwave instruments. Reaction progress was monitored using thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), high-performance liquid chromatography (HPLC), and / or gas chromatography-mass spectrometry (GCMS) analyses. TLC was performed on pre-coated silica gel plates with a fluorescence indicator (254 nm excitation wavelength) and visualized under UV light and / or with I2, KMnO4, CoCl2, phosphomolybdic acid, or ceric ammonium molybdate stains. LCMS data were acquired on an Agilent 1100 Series instrument with a Leap Technologies autosampler, Gemini C18 columns, acetonitrile / water gradients, and either trifluoroacetic acid, formic acid, or ammonium hydroxide modifiers. The column eluent was analyzed using a Waters ZQ mass spectrometer scanning in both positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used. HPLC data were generally acquired on an Agilent 1100 Series instrument using Gemini or XBridge C18 columns, acetonitrile / water gradients, and either trifluoroacetic acid or ammonium hydroxide modifiers. GCMS data were acquired using a Hewlett Packard 6890 oven with an HP 6890 injector, HP-1 column (12 m x 0.2 mm x 0.33 µm), and helium carrier gas. Samples were analyzed on an HP 5973 mass selective detector, scanning from 50 to 550 Da using electron ionization. Purifications were generally performed by medium performance liquid chromatography (MPLC) using Isco CombiFlash Companion, AnaLogix IntelliFlash 280, Biotage SP1, or Biotage Isolera One instruments and pre-packed Isco RediSep or Biotage Snap silica cartridges. Chiral purifications were generally performed by chiral supercritical fluid chromatography (SFC) using Berger or Thar instruments; ChiralPAK- AD, -AS, -IC, Chiralcel-OD, or -OJ columns; and CO2mixtures with methanol, ethanol, propan- 2-ol, or acetonitrile, alone or modified using trifluoroacetic acid or propan-2-amine. UV detection was used to trigger fraction collection. For syntheses referencing procedures in other Examples or Methods, purifications may vary: in general, solvents and the solvent ratios used for eluents / gradients were chosen to provide appropriate Rfs or retention times. Mass spectrometry data are reported from LCMS analyses. Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (EI) or electron scatter (ES) ionization sources. Proton nuclear magnetic spectroscopy (1H NMR) chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on 300, 400, 500, or 600 MHz Varian, Bruker, or Jeol spectrometers. Depending on the NMR settings used, isolated aromatic protons in the compounds characterized below can provide erroneously small integration values, presumably due to their long relaxation times; in these cases, peaks were assigned as 1H, despite their low integrations. Chemical shifts are expressed in parts per million (ppm, δ) referenced to the deuterated solvent residual peaks (chloroform, 7.26 ppm; CD2HOD, 3.31 ppm; acetonitrile-d2, 1.94 ppm; dimethyl sulfoxide-d5, 2.50 ppm; DHO, 4.79 ppm). The peak shapes are described as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br s, broad singlet; app, apparent. Analytical SFC data were acquired on a Berger analytical instrument as described above. Optical rotation data were acquired on a PerkinElmer model 343 polarimeter using a 1 dm cell. Silica gel chromatography was performed primarily using medium-pressure Biotage or ISCO systems using columns pre-packaged by various commercial vendors including Biotage and ISCO. Microanalyses were performed by Quantitative Technologies Inc. and were within 0.4% of the calculated values. Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius). Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature. The terms “concentrated,” “evaporated,” and “concentrated in vacuo” refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath temperature less than 60 °C. The abbreviation “min” and “h” stand for “minutes” and “hours” respectively. The term “TLC” refers to thin-layer chromatography, “room temperature or ambient temperature” means a temperature between 18 and 25 °C, “GCMS” refers to gas chromatography–mass spectrometry, “LCMS” refers to liquid chromatography–mass spectrometry, “UPLC” refers to ultra-performance liquid chromatography and “HPLC” refers to high-performance liquid chromatography, “SFC” refers to supercritical fluid chromatography. Hydrogenation may be performed in a Parr Shaker under pressurized hydrogen gas, or in a Thales-nano H-Cube flow hydrogenation apparatus at full hydrogen and a flow rate between 1 and 2 mL / minute at the specified temperature. HPLC, UPLC, LCMS, GCMS, and SFC retention times were measured using the methods noted in the procedures. In some examples, chiral separations were carried out to separate enantiomers or diastereomers of certain compounds of the invention (in some examples, the separated enantiomers are designated as ENANT-1 and ENANT-2, according to their order of elution; similarly, separated diastereomers are designated as DIAST-1 and DIAST-2, according to their order of elution). In some examples, the optical rotation of an enantiomer was measured using a polarimeter. According to its observed rotation data (or its specific rotation data), an enantiomer with a clockwise rotation was designated as the (+)-enantiomer and an enantiomer with a counter-clockwise rotation was designated as the (-)-enantiomer. Racemic compounds are indicated either by the absence of drawn or described stereochemistry, or by the presence of (+ / -) adjacent to the structure; in this latter case, the indicated stereochemistry represents just one of the two enantiomers that make up the racemic mixture. The synthesized compounds and intermediates described below were named using the naming convention provided with ACD / ChemSketch 2020.2.1.1, File Version C25H41, Build 121153 or ACD / Name 2023.2.0, File Version N25E41, Build 137185 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The naming conventions provided with ACD / ChemSketch 2020.2.1.1 and 2023.2.0 are well known by those skilled in the art and it is believed that the naming conventions provided with ACD / ChemSketch 2020.2.1.1 and 2023.2.0 generally comport with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules. Preparation P1 N2-(4-Bromo-5-chloropyridin-2-yl)-N-ethylglycinamide (P1) P1 Step 1. Synthesis of ethyl N-(4-bromo-5-chloropyridin-2-yl)glycinate (C1) To a 10 °C to 15 °C solution of 4-bromo-5-chloropyridin-2-amine (30.0 g, 1 Eq, 145 mmol) in acetonitrile (1.0 L) was added ethyl oxoacetate (50% solution in toluene; 29.5 g, 1 Eq, 145 mmol), followed by trifluoroacetic acid (32.2 mL, 2.9 Eq, 418 mmol). Triethylsilane (230 mL, 10 Eq, 1.45 mol) was then added dropwise over 3 minutes, whereupon the reaction mixture was stirred at 10 °C to 15 °C for 14 hours before being combined with a similar reaction carried out using 4-bromo-5-chloropyridin-2-amine (5.00 g, 24.1 mmol). The mixture was concentrated in vacuo and subjected to silica gel chromatography (Gradient: 0% to 100% ethyl acetate in petroleum ether); the resulting material was taken up in dichloromethane (50 mL) and petroleum ether (100 mL) and stirred at 70 °C for 30 minutes. After the mixture had been cooled to 20 °C and allowed to stand for 1 hour at 20 °C, the precipitate was collected via filtration to afford C1 as a white solid. Combined yield: 35.0 g, 119 mmol, 70%. LCMS m / z 294.9 (chlorine and bromine isotope pattern observed) [M+H]+.1H NMR (400 MHz, chloroform-d) δ 7.96 (s, 1H), 6.92 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.07 (s, 2H), 1.31 (t, J = 7.2 Hz, 3H). Step 2. Synthesis of N2-(4-bromo-5-chloropyridin-2-yl)-N-ethylglycinamide (P1) Ethylamine (68% solution in water; 56.5 g, 10 Eq, 852 mmol) was slowly added to a 20 °C mixture of C1 (25.0 g, 1 Eq, 85.2 mmol) in methanol (500 mL), whereupon the reaction mixture was stirred at 60 °C for 16 hours. Dichloromethane (50 mL) and petroleum ether (100 mL) were then added, and the mixture was stirred at 60 °C for 30 minutes; after cooling to 20 °C and standing for 1 hour at 20 °C, collection via filtration provided P1 as a white solid. Yield: 20.2 g, 69.0 mmol, 81%. LCMS m / z 293.9 (chlorine and bromine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.91 – 7.84 (m, 1H), 7.18 (t, J = 5.8 Hz, 1H), 6.98 (s, 1H), 3.80 (d, J = 5.8 Hz, 2H), 3.12 – 3.02 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). Preparation P2 2-(2-Bromo-5-chloropyridin-4-yl)-5-chloro-2H-indazole (P2) In a 20 mL dram vial charged with 2-bromo-5-chloro-4-fluoropyridine (131 mg, 1.2 Eq, 855 μmol) and tetrahydrofuran (2.0 mL) was added solid potassium tert-butoxide (96.0 mg, 1.2 Eq, 855 μmol) and stirred for 5 min under nitrogen. The reaction became a dark color mixture. To the reaction mixture was then added 2-bromo-5-chloro-4-fluoropyridine (150 mg, 1.0 Eq, 713 μmol) dissolved in tetrahydrofuran (0.67 mL) dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and brine (1:1 v / v), the aqueous layer was extracted with ethyl acetate (×2). The organic layer was combined and concentrated in vacuo. The1H NMR of the crude material indicated the presence of a mixture of two regioisomers (~2:1). The crude material was purified by silica gel chromatography (Gradient: 0% to 5% ethyl acetate in heptane) to afford 2-(2-bromo-5-chloropyridin-4-yl)-5- chloro-2H-indazole (P2), the minor regioisomer, as a white fluffy solid. Yield: 70 mg, 0.20 mmol, 29%. LCMS m / z 344.1 (chlorine and bromine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.00 (d, J = 0.9 Hz, 1H), 8.83 (s, 1H), 8.22 (s, 1H), 7.97 (dd, J = 0.7, 1.9 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H), 7.38 (dd, J = 2.0, 9.3 Hz, 1H). The structure was further confirmed by 2D NMRs. Preparation P3 3-Bromo-6-(1H-pyrazol-1-yl)pyridazine (P3) A mixture of 3,6-dibromopyridazine (500 mg, 2.10 mmol), 1H-pyrazole (172 mg, 2.53 mmol), and potassium carbonate (871 mg, 6.30 mmol) in N,N-dimethylformamide (15.0 mL) was stirred at 80 °C for 16 hours, whereupon the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3 x 20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 15% ethyl acetate in hexane) provided P3 as a white solid. Yield: 80 mg, 0.36 mmol, 17%. LCMS m / z 227.1 (bromine isotope pattern observed) [M+H]+.1H NMR (400 MHz, chloroform-d) δ 8.72 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.81 (br d, J = 1.6 Hz, 1H), 7.75 (d, J = 9.2 Hz, 1H), 6.55 (dd, J = 2.7, 1.7 Hz, 1H). Preparation P4 2-[(5-Chloro-4-iodopyridin-2-yl)oxy]-N-methylacetamide (P4) Cesium carbonate (19.0 g, 58.3 mmol) was added to a solution of 5-chloro-2-fluoro-4- iodopyridine (6.00 g, 23.3 mmol) and 2-hydroxy-N-methylacetamide (3.32 g, 37.3 mmol) in N,N- dimethylformamide (58 mL), whereupon the reaction mixture was stirred at room temperature for 5 hours. Ice was subsequently added, resulting in precipitation of a solid; the mixture was stirred vigorously and filtered, and the filter cake was washed with water (2 x 150 mL). Silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) provided P4 as a white solid. Yield: 5.23 g, 16.0 mmol, 69%. LCMS m / z 327.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.98 – 7.90 (m, 1H), 7.56 (s, 1H), 4.68 (s, 2H), 2.59 (d, J = 4.6 Hz, 3H). Preparation P5 N2-[5-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]-N-ethylglycinamide A mixture of P1 (400 mg, 1.37 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2- dioxaborolane (486 mg, 1.91 mmol), [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (112 mg, 0.137 mmol), and potassium acetate (268 mg, 2.73 mmol) in toluene (6.0 mL) was stirred at 110 °C for 90 minutes. The reaction mixture, containing crude P5, was used in subsequent chemistry without additional purification. By LCMS analysis, the starting material had been consumed, and the boronic acid of P5 was observed: LCMS m / z 258.2 (chlorine isotope pattern observed) [M+H]+. Preparation P6 2-(2-Bromo-5-chloropyridin-4-yl)-5-fluoro-2H-indazole (P6) 5-Fluoro-1H-indazole (3.5 g, 26 mmol) was added dropwise to a solution of 2-bromo-5- chloro-4-fluoropyridine (6.5 g, 31 mmol) and ethanol (64 mL), whereupon the reaction mixture was stirred at room temperature for 5 minutes before being heated at 80 °C for 2 days. After the reaction mixture had cooled to room temperature, it was filtered, providing a white solid (4.48 g). The filtrate was poured into water and extracted four times with dichloromethane; the combined organic layers were concentrated under reduced pressure and purified using silica gel chromatography (Gradient: 0% to 20% ethyl acetate in heptane) to afford impure P6 (342 mg). The solid (4.48 g) was partitioned between dichloromethane and water, whereupon the aqueous layer was extracted 8 times with dichloromethane. These combined organic layers were concentrated in vacuo; silica gel chromatography (Gradient: 0% to 20% ethyl acetate in heptane) provided P6 as a white solid (3.82 g). Impure fractions were combined with the impure P6 (342 mg) from above and subjected to silica gel chromatography (Gradient: 0% to 20% ethyl acetate in heptane), affording additional P6 as a white solid (0.51 g). Combined yield: 4.33 g, 13.3 mmol, 51%. LCMS m / z 326.1 (bromine chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.98 (br d, J = 1 Hz, 1H), 8.82 (s, 1H), 8.20 (s, 1H), 7.83 (br dd, J = 9.4, 4.8 Hz, 1H), 7.58 (br dd, J = 9.3, 2.6 Hz, 1H), 7.32 (td, J = 9.4, 2.5 Hz, 1H). Preparation P7 N2-(5-Chloro-4-iodopyridin-2-yl)-N-methylglycinamide (P7) To a mixture of 5-chloro-2-fluoro-4-iodopyridine (5.00 g, 19.4 mmol) and N- methylglycinamide (3.42 g, 38.8 mmol) in dimethyl sulfoxide (30 mL) was added N,N- diisopropylethylamine (7.53 g, 10.1 mL, 58.3 mmol). The reaction mixture was heated to 100 °C for 4 hours, whereupon it was cooled to room temperature and treated with ice before being filtered and washed with water (100 mL). The collected solid was oven-dried at 40 °C overnight to afford P7 as a white solid. Yield: 5.14 g, 15.8 mmol, 81%. LCMS m / z 326.2 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.78 (br q, J = 4.8 Hz, 1H), 7.19 (s, 1H), 7.11 (t, J = 6.0 Hz, 1H), 3.79 (d, J = 5.9 Hz, 2H), 2.57 (d, J = 4.6 Hz, 3H). Example 1 N2-(5'-Chloro-6-cyclopropyl[3,4'-bipyridin]-2'-yl)-N-ethylglycinamide (1) This reaction was carried out in two batches. Batch A: To a mixture of P1 (20.0 mg, 68.4 µmol), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (16.8 mg, 68.4 µmol), and potassium carbonate (28.3 mg, 0.205 mmol), in 1,4-dioxane (1.5 mL) and water (0.16 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.00 mg, 6.84 µmol) under N2atmosphere. The reaction mixture was stirred at 90 °C for 3 hours, whereupon LCMS analysis indicated conversion to 1: LCMS m / z 331.3 (chlorine isotope pattern observed) [M+H]+. The reaction mixture was cooled to room temperature to be combined with batch B. Batch B: To a mixture of P1 (40.0 mg, 0.137 mmol), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (33.5 mg, 0.137 mmol), and potassium carbonate (56.7 mg, 0.410 mmol), in 1,4-dioxane (2.0 mL) and water (0.2 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.0 mg, 13.7 µmol) under N2atmosphere. The reaction mixture was stirred at 90 °C for 2 hours, whereupon LCMS analysis indicated conversion to 1: LCMS m / z 331.3 (chlorine isotope pattern observed) [M+H]+. The reaction mixture was cooled to room temperature and combined with batch A, followed by addition of 1,3,5-triazine-2,4,6-trithiol trisodium salt solution (~15% in water, 4.0 mL). The resulting mixture was stirred at room temperature for 30 minutes before it was concentrated in vacuo. Acetonitrile (2.0 mL) was added and the suspension was filtered to afford crude product, which was purified via reversed-phase HPLC (Column: Boston Prime C18, 30 x 150 mm, 5 µm; Mobile phase A: water containing 0.05% ammonium hydroxide and 10 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Gradient: 23% to 43% B; Flow rate: 35 mL / minute) to afford N2-(5'-chloro-6-cyclopropyl[3,4'-bipyridin]-2'-yl)-N-ethylglycinamide (1) as a yellow solid. Yield: 22.3 mg, 67.5 µmol, 33%. LCMS m / z 331.0 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) δ 8.44 (d, J = 2.0 Hz, 1H), 8.09 (s, 1H), 7.80 (dd, J = 8.3, 2.3 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 3.98 (s, 2H), 3.25 (q, J = 7.5 Hz, 2H), 2.21 – 2.14 (m, 1H), 1.14 – 1.02 (m, 7H). Example 2 N2-[5-Chloro-4-(5-chloro-2H-indazol-2-yl)pyridin-2-yl]-N-ethylglycinamide (2) A 2-dram vial charged with 2-(2-bromo-5-chloropyridin-4-yl)-5-chloro-2H-indazole (50 mg, 1 Eq, 0.15 mmol), BrettPhos-Pd-G3 (13 mg, 0.1 Eq, 15 μmol), BrettPhos (7.8 mg, 0.1 Eq, 15 μmol) and cesium carbonate (0.14 g, 3.0 Eq, 0.44 mmol) was degassed and purged with nitrogen three times. To the reaction mixture was added previously degassed 1,4-dioxane (0.73 mL). Then 2-amino-N-ethylacetamide (23 mg, 98% Wt, 1.5 Eq, 0.22 mmol) was added and the resulting reaction mixture was degassed and purged with nitrogen. The reaction mixture was heated to 100 °C and stirred for 1 hour. The reaction mixture was cooled to room temperature before it was quenched with water. The aqueous layer was extracted with ethyl acetate (×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (Gradient: 0% to 10% dichloromethane in methanol). The most polar peak was collected and concentrated in vacuo to give a light-yellow solid. The solid was further purified via reversed-phase HPLC (Column: XBridge C18, 19 x 100 mm, 5 µm; Mobile phase A: water containing 0.05% ammonia hydroxide; Mobile phase B: acetonitrile containing 0.05% ammonia hydroxide; Gradient: 40% to 80% B over 8.5 minutes, then 80% to 95% B over 0.5 minutes, then 95% B for 1.0 minute; Flow rate: 25 mL / minute) to afford N2-[5- chloro-4-(5-chloro-2H-indazol-2-yl)pyridin-2-yl]-N-ethylglycinamide (2) as a white solid. Yield: 37.8 mg, 104 µmol, 71.2%. LCMS m / z 364.2(chlorine isotope pattern observed) [M+H]+.1H NMR (600 MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.26 (s, 1H), 7.98 - 7.89 (m, 2H), 7.79 (d, J = 9.1 Hz, 1H), 7.42 (br t, J = 5.7 Hz, 1H), 7.35 (dd, J = 1.9, 9.2 Hz, 1H), 7.00 (s, 1H), 3.90 (d, J = 5.8 Hz, 2H), 3.18 - 3.02 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). Example 3 N2-[5'-Chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide (3) K2CO3A mixture of 5-bromo-2-(1H-pyrazol-1-yl)pyridine (33.2 mg, 1 Eq, 0.147 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (44.9 mg, 1.2 Eq, 0.177 mmol), [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II), dichloromethane complex (12.0 mg, 0.1 Eq, 14.7 µmol) and potassium acetate (43.4 mg, 3 Eq, 0.441 mmol) in 1,4-dioxane (1.5 mL) was stirred at 80 °C for 6 hours under N2atmosphere, whereupon LCMS analysis indicated formation of 2-(1H-pyrazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (C2): LCMS m / z 272.2 [M+H]+. The reaction mixture was cooled to room temperature and used in the next step without further purification. To the reaction mixture above were added P1 (43.1 mg, 1 Eq, 0.147 mmol), potassium carbonate (61.0 mg, 3 Eq, 0.441 mmol), [1,1'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II), dichloromethane complex (6.0 mg, 0.05 Eq, 7.4 µmol), 1,4- dioxane (0.5 mL), and water (1.0 mL). The mixture was stirred at 80 °C for 12 hours under N2atmosphere, whereupon LCMS analysis indicated formation of N2-[5'-chloro-6-(1H-pyrazol-1- yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide (3): LCMS m / z 357.1 (chlorine isotope pattern observed) [M+H]+. The reaction mixture was cooled to room temperature and diluted with brine (10 mL) before it was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via reversed-phase HPLC (Column: Boston Prime C18, 40 x 150 mm, 5 µm; Mobile phase A: water containing 0.05% ammonium hydroxide and 10 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Gradient: 35% to 55% B; Flow rate: 35 mL / minute) to afford N2-[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide (3) as a white solid. Yield: 20.9 mg, 58.4 µmol, 39.7%. LCMS m / z 357.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) δ 8.65 (d, J = 2.6 Hz, 1H), 8.53 (br s, 1H), 8.10 (s, 1H), 8.09 – 8.00 (m, 2H), 7.80 (d, J = 1.7 Hz, 1H), 6.67 (s, 1H), 6.57 (dd, J = 2.6, 1.8 Hz, 1H), 3.98 (s, 2H), 3.24 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). Example 8 2-{[5'-Chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-(propan-2-yl)acetamide (8) Step 1. Synthesis of tert-butyl [(5-chloro-4-iodopyridin-2-yl)oxy]acetate (C3) To a solution of 5-chloro-2-fluoro-4-iodopyridine (4.70 g, 18.3 mmol) and tert-butyl hydroxyacetate (2.90 g, 21.9 mmol) in dimethyl sulfoxide (50 mL) was added cesium carbonate (11.9 g, 36.5 mmol). After the suspension had been stirred at room temperature overnight and subsequently heated to 45 °C for 2 hours, it was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed twice with water (100 mL). The organic layer was concentrated in vacuo and the residue was purified via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane), affording C3 as a clear oil that solidified into a white solid overnight. Yield: 5.53 g, 15.0 mmol, 82%.1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.41 (s, 1H), 4.73 (s, 2H), 1.46 (s, 9H). Step 2. Synthesis of tert-butyl {[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}acetate (C4) A degassed solution of C2 (100 mg, 0.369 mmol) and C3 (136 mg, 0.368 mmol) in a mixture of 1,4-dioxane (2 mL) and water (0.5 mL) was treated with potassium carbonate (102 mg, 0.738 mmol) and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (30.1 mg, 36.9 µmol). The reaction vessel was evacuated and charged with nitrogen; this evacuation cycle was carried out a total of 3 times, whereupon the reaction mixture was heated at 100 °C overnight. After cooling to room temperature, it was diluted with ethyl acetate (10 mL) and washed with water (5 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded C4 as a clear gum. Yield: 115 mg, 0.297 mmol, 81%. LCMS m / z 387.3 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.61 (br d, J = 2.6 Hz, 1H), 8.51 (br s, 1H), 8.19 (s, 1H), 8.08 (d, half of AB quartet, J = 8.5 Hz, 1H), 7.95 (dd, component of ABX system, J = 8.5, 2.3 Hz, 1H), 7.77 (br s, 1H), 6.90 (s, 1H), 6.49 (br s, 1H), 4.81 (s, 2H), 1.49 (s, 9H). Step 3. Synthesis of {[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}acetic acid (C5) Trifluoroacetic acid (0.5 mL) was added to a solution of C4 (115 mg, 0.297 mmol) in dichloromethane (3 mL). After the reaction mixture had been stirred for 21 hours, additional trifluoroacetic acid (0.5 mL) was added, and stirring was continued for 75 minutes. The reaction mixture was then concentrated in vacuo, and the residue was azeotroped with toluene to provide C5 as a white solid. This material was progressed directly to the following step. LCMS m / z 331.2 (chlorine isotope pattern observed) [M+H]+. Step 4. Synthesis of 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-(propan-2- yl)acetamide (8) To a solution of C5 (from the previous step; ≤0.297 mmol) and propan-2-amine hydrochloride (39 mg, 0.41 mmol) in dichloromethane (2 mL) were added N,N- diisopropylethylamine (0.14 mL, 0.80 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 0.16 g, 0.42 mmol). After the reaction mixture had been stirred for 2 hours and 45 minutes, it was diluted with dichloromethane (10 mL) and washed with saturated sodium bicarbonate solution (10 mL). The organic layer was concentrated in vacuo and purified using reversed-phase HPLC (Column: Waters XBridge C18, 19 x 100 mm, 5 µm; Mobile phase A: water containing 0.03% ammonium hydroxide (v / v); Mobile phase B: acetonitrile containing 0.03% ammonium hydroxide (v / v); Gradient: 35% to 55% B over 8.5 minutes, then 55% to 95% B over 0.5 minutes, then 95% B for 1.0 minute; Flow rate: 25 mL / min) to afford 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'- yl]oxy}-N-(propan-2-yl)acetamide (8). Yield: 8.0 mg, 22 µmol, 7% over 2 steps. LCMS m / z 372.3 (chlorine isotope pattern observed) [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.69 (dd, J = 2.5, 0.7 Hz, 1H), 8.63 (dd, J = 2.4, 0.8 Hz, 1H), 8.35 (s, 1H), 8.19 (dd, J = 8.5, 2.4 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.91 – 7.86 (m, 2H), 7.17 (s, 1H), 6.63 (dd, J = 2.6, 1.7 Hz, 1H), 4.73 (s, 2H), 3.95 – 3.85 (m, 1H), 1.07 (d, J = 6.6 Hz, 6H). Example 9 N2-[5-Chloro-4-(5-chloro-2H-pyrazolo[3,4-b]pyridin-2-yl)pyridin-2-yl]-N-ethylglycinamide (9) A mixture of P1 (150 mg, 0.513 mmol), 5-chloro-2H-pyrazolo[3,4-b]pyridine (118 mg, 0.768 mmol), N1,N2-bis[(furan-2-yl)methyl]ethanediamide (BFMO; 2.55 mg, 10.3 µmol), tripotassium phosphate (218 mg, 1.03 mmol), and copper(I) oxide (1.47 mg, 10.3 µmol) in dimethyl sulfoxide (0.15 mL) was stirred at 120 °C for 16 hours. The reaction mixture was then combined with a similar reaction carried out using P1 (50 mg, 0.17 mmol), diluted with water (5 mL), and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3 x 5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Reversed-phase HPLC (Column: WePure Biotech XP tC18, 40 x 150 mm, 7 µm; Mobile phase A: water containing 0.225% formic acid; Mobile phase B: acetonitrile; Gradient: 24% to 44% B; Flow rate: 60 mL / minute) afforded N2-[5-chloro-4-(5- chloro-2H-pyrazolo[3,4-b]pyridin-2-yl)pyridin-2-yl]-N-ethylglycinamide (9) as a white solid. Combined yield: 32.2 mg, 88.2 µmol, 13%. LCMS m / z 365.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) δ 8.77 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 8.23 (s, 1H), 6.99 (s, 1H), 4.01 (s, 2H), 3.28 – 3.19 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). Example 10 2-{[5'-Chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-methylacetamide (10) A mixture of P4 (556 mg, 1.70 mmol), [6-(1H-pyrazol-1-yl)pyridin-3-yl]boronic acid (643 mg, 3.40 mmol), potassium carbonate (706 mg, 5.11 mmol), and [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (139 mg, 0.170 mmol) in a mixture of degassed 1,4-dioxane (7.1 mL) and water (1.4 mL) was stirred at 90 °C for 80 minutes. After the reaction mixture had cooled, it was partitioned between dichloromethane and water; the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 4% methanol in dichloromethane) provided 2-{[5'-chloro-6- (1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-methylacetamide (10) as a solid. Yield: 500 mg, 1.45 mmol, 85%. LCMS m / z 344.3 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.69 (br d, J = 2.6 Hz, 1H), 8.63 (br d, J = 2.4 Hz, 1H), 8.36 (s, 1H), 8.19 (dd, component of ABX system, J = 8.5, 2.4 Hz, 1H), 8.07 (br d, J = 8.6 Hz, 1H), 8.02 – 7.95 (m, 1H), 7.90 – 7.89 (m, 1H), 7.16 (s, 1H), 6.63 (dd, J = 2.6, 1.7 Hz, 1H), 4.76 (s, 2H), 2.62 (d, J = 4.6 Hz, 3H). Example 11 N2-{5-Chloro-4-[6-(1H-pyrazol-1-yl)pyridazin-3-yl]pyridin-2-yl}-N-ethylglycinamide (11) To a solution of crude P5 (113 mg, ≤0.333 mmol) in toluene (1.5 mL) were added P3 (30.0 mg, 0.133 mmol), potassium carbonate (46.1 mg, 0.334 mmol), mesylate[(di(1- adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) (cataCXium®A Pd G3; 9.71 mg, 13.3 µmol), 1,4-dioxane (1.0 mL), and water (0.2 mL). After the reaction mixture had been stirred at 100 °C for 1 hour, it was cooled, diluted with water (5 mL), and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo; purification via reversed-phase HPLC (Column: Phenomenex Gemini NX-C18, 30 x 150 mm, 5 µm; Mobile phase A: water containing 0.05% ammonium hydroxide and 10 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Gradient: 18% to 58% B; Flow rate: 30 mL / minute) provided N2-{5-chloro-4-[6-(1H-pyrazol-1-yl)pyridazin-3-yl]pyridin-2-yl}-N-ethylglycinamide (11) as a white solid. Yield: 10.3 mg, 28.8 µmol, 22%. LCMS m / z 358.2 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) δ 8.82 (d, J = 2.7 Hz, 1H), 8.39 (d, J = 9.2 Hz, 1H), 8.18 – 8.12 (m, 2H), 7.90 (br s, 1H), 6.90 (s, 1H), 6.67 (br t, J = 2.2 Hz, 1H), 4.00 (s, 2H), 3.24 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H). Example 12 N2-{5-Chloro-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-2-yl}-N-methylglycinamide (12) Step 1. Synthesis of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (C6) A suspension of 2-(4-bromophenyl)-2H-1,2,3-triazole (200 g, 0.89 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (227 g, 0.894 mol) and potassium acetate in 1,4-dioxane (800 mL) was degassed for approximately 15 minutes, whereupon [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (14.6 g, 17.9 mmol) was added and the reaction mixture was heated at 90 °C to 100 °C overnight. After cooling, it was filtered through a pad of diatomaceous earth, and the filter pad was washed with ethyl acetate. The combined filtrates were concentrated in vacuo, and the residue was purified using silica gel chromatography (Eluent: dichloromethane) to afford C6 as a pale-brown solid. Yield: 170 g, 0.627 mol, 70%.1H NMR (400 MHz, CDCl3) δ 8.09 (d, 2H), 7.93 (d, 2H), 7.82 (s, 2H), 1.34 (s, 12H). Step 2. Synthesis of N2-{5-chloro-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-2-yl}-N- methylglycinamide (12) A 0.126 M stock solution of P7 was prepared in a glovebox by combining P7 (518 mg, 1.59 mmol) and 1,4-dioxane (12.6 mL). Concurrently, a catalyst stock solution of 51 mM was prepared by dissolving mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′- biphenyl)]palladium(II) (cataCXium®A Pd G3; 120 mg, 0.165 mmol) in dichloromethane (3.24 mL). The cataCXium®A Pd G3 stock solution (20 µL, 1.0 µmol) was then plated onto a pre- weighed sample of C6 (5.5 mg, 20 µmol) in a 96-well plate and allowed to evaporate. Subsequently, P7 stock solution (80 µL, 10 µmol) was added, followed by aqueous potassium carbonate solution (1.5 M; 20 µL, 30 µmol), whereupon the plate was sealed, removed from the glovebox, and shaken at 70 °C overnight. The reaction mixture was then diluted with ethyl acetate (0.4 mL) and shaken at 30 °C for 20 minutes. Water (0.15 mL) was added, and the layers were separated, whereupon the aqueous layer was again extracted with ethyl acetate (2 x 0.35 mL). The combined organic layers were filtered, concentrated under a stream of nitrogen, and purified via reversed-phase HPLC (Column: Waters Sunfire C18, 7.5 x 50 mm, 5 µm; Mobile phase A: water containing 0.05% formic acid; Mobile phase B: acetonitrile containing 0.05% formic acid; Gradient: 5% to 95% B over 4.25 minutes, followed by 95% B for 0.75 minutes; Flow rate: 4 mL / minute) to afford N2-{5-chloro-4-[4-(2H-1,2,3-triazol-2- yl)phenyl]pyridin-2-yl}-N-methylglycinamide (12). Yield: 1.5 mg, 4.4 µmol, 44%. LCMS m / z 343.1 (chlorine isotope pattern observed) [M+H]+. Retention time: 2.18 minutes. Analytical conditions: Column: Waters Atlantis C18, 4.6 x 50 mm, 5 µm; Mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); Gradient: 5.0% to 95% B over 4.0 minutes, then 95% B for 1.0 minute; Flow rate: 2 mL / minute. Example 13 N2-[5-Chloro-4-(5-phenyl-1,2-oxazol-3-yl)pyridin-2-yl]-N-ethylglycinamide (13) Cs2CO3Step 1. Synthesis of N-[(E)-(2-bromo-5-chloropyridin-4-yl)methylidene]hydroxylamine (C7) A solution of 2-bromo-5-chloropyridine-4-carbaldehyde (500 mg, 2.27 mmol) and hydroxylamine hydrochloride (173 mg, 2.49 mmol) in methanol (5 mL) was heated at 40 °C for 6 hours, whereupon the reaction mixture was concentrated to one-half the original volume using a stream of nitrogen. The residue was diluted with water (25 mL), stirred for 15 minutes, and filtered. The filter cake was rinsed with water (2 x 5 mL) to afford C7 as a white solid. Yield: 463 mg, 1.97 mmol, 87%. LCMS m / z 235.0 (bromine chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.56 (s, 1H), 8.28 (s, 1H), 7.87 (s, 1H). Step 2. Synthesis of 2-bromo-5-chloro-4-(5-phenyl-1,2-oxazol-3-yl)pyridine (C8) A solution of C7 (463 mg, 1.97 mmol) and N-chlorosuccinimide (263 mg, 1.97 mmol) in a mixture of dichloromethane (3.75 mL) and N,N-dimethylformamide (0.18 mL) was stirred at room temperature for 2 hours. The reaction mixture was subsequently concentrated under reduced pressure, and the residue was azeotroped with heptane (20 mL), then diluted with water (6.0 mL). After addition of ethynylbenzene (0.324 mL, 2.94 mmol), the resulting mixture was stirred at room temperature for 1 hour, whereupon dichloromethane (3.75 mL) was added, and stirring was continued for 1 hour. Triethylamine (548 mL, 3.93 mmol) was then added, bringing the pH of the reaction mixture from 4 to 6, and stirring was continued for another hour, whereupon additional triethylamine (274 mL, 1.97 mmol) and ethynylbenzene (0.323 mL, 2.94 mmol) were added. After 2 further hours of stirring, the reaction mixture was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and purified using silica gel chromatography (Gradient: 0% to 5% ethyl acetate in heptane). Mixed fractions were repurified via silica gel chromatography (Gradient: 0% to 0.8% ethyl acetate in heptane), and the product fractions from the two purifications were combined to afford C8 as a light-yellow solid. Yield: 237 mg, 0.706 mmol, 36%. LCMS m / z 335.1 (bromine chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.10 (s, 1H), 8.00 – 7.94 (m, 2H), 7.66 (s, 1H), 7.63 – 7.54 (m, 3H). Step 3. Synthesis of N2-[5-chloro-4-(5-phenyl-1,2-oxazol-3-yl)pyridin-2-yl]-N-ethylglycinamide (13) A reaction vessel containing a mixture of C8 (50 mg, 0.15 mmol), cesium carbonate (150 mg, 0.46 mmol), and XantPhos Pd G4 (14 mg, 15 µmol) was evacuated and charged with nitrogen. This evacuation cycle was carried out a total of 3 times. Degassed 1,4-dioxane (0.74 mL) was added, and the reaction mixture was degassed and purged with nitrogen for 2 additional cycles. N-Ethylglycinamide (98%, 47 mg, 0.45 mmol) was then added; following another cycle of degassing and purging with nitrogen, the reaction mixture was heated at 95 °C for 1 hour. The temperature was then raised to 100 °C, and stirring was continued for an additional 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted 3 times with a 1:4 mixture of methanol and dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and absorbed onto diatomaceous earth. Silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) provided 13 as an off-white solid; further purification via reversed-phase HPLC (Column: Waters XBridge C18, 19 x 100 mm, 5 µm; Mobile phase A: water containing 0.03% ammonium hydroxide (v / v); Mobile phase B: acetonitrile containing 0.03% ammonium hydroxide (v / v); Gradient: 5.0% to 95% B over 8.54 minutes, then 95% B for 1.46 minutes; Flow rate: 25 mL / min) afforded N2-[5- chloro-4-(5-phenyl-1,2-oxazol-3-yl)pyridin-2-yl]-N-ethylglycinamide (13). Yield: 23.9 mg, 67.0 µmol, 45%. LCMS m / z 357.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.98 – 7.95 (m, 2H), 7.90 (br t, J = 5.7 Hz, 1H), 7.60 – 7.53 (m, 3H), 7.45 (s, 1H), 7.29 (br t, J = 5.9 Hz, 1H), 6.95 (s, 1H), 3.87 (d, J = 5.9 Hz, 2H), 3.09 (qd, J = 7.2, 5.5 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H). Table 1. Method of synthesis, structure, and physicochemical data for Examples 4 – 7 and 14 – 34. The examples below were made from analogous processes to the Example(s) identified and from appropriate analogous starting materials. 1H NMR (600 MHz, Method of DMSO-d6) δ; Mass synthesis; spectrum, observed ion Example Non- m / z [M+H]+or HPLC Structure Number commercial retention time; Mass starting spectrum m / z [M+H]+materials (unless otherwise indicated)ClNHN N CH32.16 minutes2; 335.4 P11H H3C O N O (chlorine isotope pattern N2-(5'-chloro-6-ethoxy[3,4'-bipyridin]-2'- observed) yl)-N-ethylglycinamide ClNHN N CH31.82 minutes2; 341.3P13NH O (chlorine isotope pattern N2-[5-chloro-4-(quinolin-3-yl)pyridin-2- observed) yl]-N-ethylglycinamide ClNHN N N CH32.65 m2H inutes ; 368.3 OP14 N(chlorine isotope pattern observed) N2-[5-chloro-4-(2-phenylpyrimidin-5- yl)pyridin-2-yl]-N-ethylglycinamide ClNH NN CH3NN H O2.52 minutes2; 357.2 P15N(chlorine isotope pattern N2-{5-chloro-4-[4-(2H-1,2,3-triazol-2- observed) yl)phenyl]pyridin-2-yl}-N- ethylglycinamide 1H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 1.4 Hz, 1H), 8.84 (d, J = Cl N 1.5 Hz, 1H), 8.70 (dd, J = H N N N CH 2.7, 0.7 Hz, 1H), 8.16 (s, N H3N NO 1H), 7.98 (dd, J = 1.6, P76,70.7 Hz, 1H), 7.86 – 7.77 N2-{5-chloro-4-[5-(1H-pyrazol-1- (m, 1H), 7.27 (t, J = 6.0 yl)pyrazin-2-yl]pyridin-2-yl}-N- Hz, 1H), 6.91 (s, 1H), methylglycinamide 6.70 (dd, J = 2.7, 1.7 Hz, 1H), 3.87 (d, J = 5.8 Hz, 2H), 2.59 (d, J = 4.6 Hz, 3H); 344.2 (chlorine isotope pattern observed) 1H NMR (400 MHz, methanol-d4) δ 9.39 (d, J ClN= 1.5 Hz, 1H), 8.89 (d, J H N ONCH3= 1.4 Hz, 1H), 8.68 (d, J N O = 2.7 Hz, 1H), 8.31 (s mple 11N, Exa N 6,81H), 7.92 – 7.86 (m, 1H), ; P4 2-({5-chloro-4-[5-(1H-pyrazol-1- 7.31 (s, 1H), 6.68 – 6.61 yl)pyrazin-2-yl]pyridin-2-yl}oxy)-N- (m, 1H), 4.61 (br s, 2H), methylacetamide 2.79 (s, 3H); 345.1 (chlorine isotope pattern observed) 8.97 (d, J = 2.3 Hz, 1H), Cl 8.93 (d, J = 2.4 Hz, 1H), N H NNCH 8.34 (s, 1H), 7.96 (br t, J N NN 3N H O = 5.6 Hz, 1H), 7.60 (br t, Example J = 5.4 Hz, 1H), 7.18 (s, 9,1Cl 13021H), 3.92 (d, J = 5.6 Hz, N -[5-chloro-4-(6-chloro-2H- 2H), 3.14 – 3.06 (m, 2H), [1,2,3]triazolo[4,5-b]pyridin-2-yl)pyridin- 1.01 (t, J = 7.2 Hz, 3H); 2-yl]-N-ethylglycinamide 366.0 (dichlorine isotope pattern observed) 1H NMR (400 MHz, methanol-d4) δ 9.34 (d, J = 1.4 Hz, 1H), 8.82 (d, J ClN= 1.5 Hz, 1H), 8.65 (d, J H N NN CH3= 2.7 Hz, 1H), 8.14 (s, N H O 1H), 7.88 (d, J = 1 11 ;NN .6 Hz, Example61H), 6.91 (s, 1H), 6.65 – P5 N2-{5-chloro-4-[5-(1H-pyrazol-1- 6.62 (m, 1H), 3.98 (s, yl)pyrazin-2-yl]pyridin-2-yl}-N- 2H), 3.24 (q, J = 7.2 Hz, ethylglycinamide 2H), 1.10 (t, J = 7.2 Hz, 3H); 358.0 (chlorine isotope pattern observed) 8.68 (dd, J = 2.6, 0.7 Hz, 1H), 8.54 (dd, J = 2.3, 0.8 Hz, 1H), 8.13 (s, 1H), 8.10 (dd, component of ABX system, J = 8.5, 2.3 Hz, 1H), 8.05 (dd, Cl N component of ABX H N N CH3system, J = 8.5, 0.8 Hz, Example 11;NH N N O 1H), 7.88 (dd, J = 1.7, C2, P7 0.7 Hz, 1H), 7.81 (br q, J N2-[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'- = 4.7 Hz, 1H), 7.16 (t, J = bipyridin]-2'-yl]-N-methylglycinamide 5.8 Hz, 1H), 6.70 (s, 1H), 6.63 (dd, J = 2.6, 1.6 Hz, 1H), 3.86 (d, J = 5.9 Hz, 2H), 2.59 (d, J = 4.6 Hz, 3H); 343.2 (chlorine isotope pattern observed) 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 1.0 Hz, 1H), 8.25 (s, 1H), 7.92 (br t, J = 5.7 Hz, Cl 1H), 7.81 (dd, J = 9.4, NHN4.7 Hz, 1H), 7.54 NNNCH3(dd, J = H O 9.4, 2.5 Hz, 1H), 7.40 (br Example 13; t, J = 5.9 Hz, 1H), 7.29 P6F(td, J = 9.4, 2.5 Hz, 1H), N2-[5-chloro-4-(5-fluoro-2H-indazol-2- 6.98 (s, 1H), 3.89 (d, J = yl)pyridin-2-yl]-N-ethylglycinamide 5.9 Hz, 2H), 3.10 (qd, J = 7.2, 5.5 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H); 348.3 (chlorine isotope pattern observed) 1H NMR (400 MHz, Cl N H DMSO-d) δ 9.36 (dd, J e 1011; N NN C 6= ExamplH3H 2.6, 0.8 Hz, 1H), 8.52 P5 N NO (dd, J = 8.6, 2.6 Hz, 1H), N 8.27 (s, 2H), 8.12 (s, 1H), N2-[5'-chloro-5-(2H-1,2,3-triazol-2- 7.91 (dd, J = 8.6, 0.8 Hz, yl)[2,4'-bipyridin]-2'-yl]-N- 1H), 7.87 (br t, J = 5.7 ethylglycinamide Hz, 1H), 7.19 (br t, J = 5 Hz, 1H), 6.87 (s, 1H), 3.86 (d, J = 5.0 Hz, 2H), 3.09 (qd, J = 7.2, 5.6 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H); 358.2 (chlorine isotope pattern observed) 9.54 (s, 2H), 8.30 (s, 2H), 8.10 (s, 1H), 7.85 (t, J = Cl N H 5.7 Hz, 1H), 7.27 – 7.19 N N N CH3(m, 1H) NNNH , 6.99 (s, 1H), O 123.83 (d, J = 4.5 Hz, 2H), P1,13N3.05 (qd, J = 7.2, 5.6 Hz, N2-{5-chloro-4-[5-(2H-1,2,3-triazol-2- 2H), 0.96 (t, J = 7.2 Hz, yl)pyrimidin-2-yl]pyridin-2-yl}-N- 3H); 359.1 (chlorine ethylglycinamide isotope pattern observed) 1H NMR (400 MHz, DMSO-d6) δ 8.76 (br t, J = 6.4 Hz, 1H), 8.69 (dd, J = 2.6, 0.7 Hz, 1H), 8.63 (dd, J = 2.4, 0.8 Hz, 1H), 8.34 (s, 1H), 8.19 (dd, ClNH component of ABX N O CF3system, J = 8.6, 2.4 Hz, NNNO141H), 8.06 (dd, C5 component of ABX 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'- system, J = 8.5, 0.8 Hz, bipyridin]-2'-yl]oxy}-N-(2,2,2- 1H), 7.89 (dd, J = 1.7, trifluoroethyl)acetamide 0.7 Hz, 1H), 7.19 (s, 1H), 6.63 (dd, J = 2.6, 1.6 Hz, 1H), 4.88 (s, 2H), 4.00 – 3.87 (m, 2H); 412.2 (chlorine isotope pattern observed)ClNH N N CH3N H N N O 2.39 minutes2; 375 mple 101.1 Exa5; F (chlorine isotope pattern P1 2 observed) N -[5'-chloro-6-(4-fluoro-1H-pyrazol-1- yl)[3,4'-bipyridin]-2'-yl]-N- ethylglycinamide ClNH NN CH3H O 2.24 minut216N es ; 357.2 Example 21 ; Ol CF3COOH(chlorine isotope pattern P1 N2-{5-chloro-4-[4-(1,2-oxazol-3- observed) yl)phenyl]pyridin-2-yl}-N- ethylglycinamide, trifluoroacetate salt 1H NMR (400 MHz, methanol-d4) δ 8.26 (s, ClN H1H), 8.03 (d, J = 1.9 Hz, NN NNCH31H), 7.99 (d, J = 9.1 Hz, N H O 1H), 7.51 (dd, J = 9.1, Example 9; C 1.9 Hz, 1H), 7.08 (s, 1H), P1lN2-[5-chloro-4-(5-chloro-2H-1,2,3- 4.02 (s, 2H), 3.24 (q, J = benzotriazol-2-yl)pyridin-2-yl]-N- 7.2 Hz, 2H), 1.11 (t, J = ethylglycinamide 7.2 Hz, 3H); 365.1 (dichlorine isotope pattern observed) 8.64 (d, J = 2.6 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.08 (s, 1H), 8.06 (dd, Cl Ncomponent of ABX H N CH system, J = tnotes 1738.5, 2.3 Hz, Foo N N H O 1H), 8.01 (d, half of AB and 18HNNquartet, J = 8.5 Hz, 1H), N2-[5'-chloro-6-(1H-pyrazol-3-yl)[3,4'- 7.87 – 7.82 (m, 2H), 7.08 bipyridin]-2'-yl]-N-ethylglycinamide (t, J = 5.9 Hz, 1H), 6.66 (s, 1H), 6.58 (dd, J = 2.6, 1.7 Hz, 1H), 3.82 (d, J = 5.9 Hz, 2H), 3.05 (qd, J = 7.2, 5.5 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H); 357.2 (chlorine isotope pattern observed) 8.68 (d, J = 2.6 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.10 (dd, component of FFABX system, J = 8.5, 2.3 Hz, 1H), 8.04 (d, half of ONH AB quartet, J = 8.5 Hz, NNCH3H 1H), 8.00 (s, 1H), 7.91 – ExampleN1N NO 7.86 (m, 2H), 7.02 (t, J = 139,2025.9 Hz, 1H), 6.92 (t, J = N -[5'-(difluoromethoxy)-6-(1H-pyrazol- 74.0 Hz, 1H), 6.73 (s, 1-yl)[3,4'-bipyridin]-2'-yl]-N- 1H), 6.62 (dd, J = 2.6, ethylglycinamide 1.6 Hz, 1H), 3.86 (d, J = 5.8 Hz, 2H), 3.13 – 3.06 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H); 389.3 ClNH H2N N N CH3NH N N O 2.19 minutes2; 372.1 Example 24;l CF3COOH(chlorine isotope pattern P1 N2-[5-amino-5'-chloro-6-(1H-pyrazol-1- observed) yl)[3,4'-bipyridin]-2'-yl]-N- ethylglycinamide, trifluoroacetate salt 8.69 (d, J = 2.5 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.36 (s, 1H), 8.19 (dd, J Cl N H = 8.5, 2.4 Hz, 1H), 8.06 N O OH (d, J = 8.6 Hz, 1H), 8.04 NN N O21(t, J = 5.8 Hz, 1H), 7.90 – C2 7.89 (m, 1H), 7.17 (s, 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'- 1H), 6.63 (dd, J = 2.6, bipyridin]-2'-yl]oxy}-N-(2- 1.6 Hz, 1H), 4.77 (s, 2H), hydroxyethyl)acetamide 4.71 (t, J = 5.5 Hz, 1H), 3.41 (apparent q, J = 6.0 Hz, 2H), 3.17 (apparent q, J = 6.1 Hz, 2H); 374.2 (chlorine isotope pattern observed) 8.80 (d, J = 7.3 Hz, 1H), 8.12 (s, 1H), 7.97 (d, J = ClNH 2.4 Hz, 1H), 7.79 (br q, J N N N N CH = 4.7 Hz, 1H), 7.24 – H3O 7.18 (m, 1H), 7.13 (s, P722,23Cl 2H), 7.04 (dd, J = 7.4, N2-[5-chloro-4-(5-chloropyrazolo[1,5- 2.4 Hz, 1H), 3.85 (d, J = a]pyridin-2-yl)pyridin-2-yl]-N- 4.8 Hz, 2H), 2.58 (d, J = methylglycinamide 4.6 Hz, 3H); 350.1 (dichlorine isotope pattern observed) 8.11 (br d, J = 2 Hz, 1H), 8.09 (s, 1H), 7.94 – 7.87 ClNH (m, 2H), 7.02 – 6.92 (m, N N CH3H 1H), 6.65 (s, 1H), 3.86 (s, Example 10; N N O lCF3COOH2H), 3.57 – 3.48 (m, 4H), P1 3.10 (qd, J = 7.2, 5.5 Hz, N2-[5'-chloro-6-(pyrrolidin-1-yl)[3,4'- 2H), 2.05 – 1.99 (m, 4H), bipyridin]-2'-yl]-N-ethylglycinamide, 1.01 (t, J = 7.2 Hz, 3H); trifluoroacetate salt 360.3 (chlorine isotope pattern observed) 1H NMR (400 MHz, methanol-d4) δ 8.97 (d, J = 2.2 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.14 (s, Cl N H 1H), 8.11 (d, J = 2.0 Hz, N N CH31H), 8.05 (d, J = 8.8 Hz, Example 12; H C O 1H), 7.68 (dd, J = 8.8, P1 lNN2-[5-chloro-4-(7-chloroquinolin-3- 2.0 Hz, 1H), 6.74 (s, 1H), yl)pyridin-2-yl]-N-ethylglycinamide 3.99 (s, 2H), 3.25 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H); 374.9 (dichlorine isotope pattern observed)ClNH NCNN H3H N O l 2.04 minutes2; 357.2 Example 12; CF3COOH 33 N (chlorine isotope pattern P1 N2-{5-chloro-4-[1-(pyridin-2-yl)-1H- observed) pyrazol-4-yl]pyridin-2-yl}-N- ethylglycinamide, trifluoroacetate salt ClNH NN N CH3O H O 2.77 minutes2; 357.2 Example 24; 34l CF3COOH(chlorine isotope pattern P1 N2-[5-chloro-4-(4-phenyl-1,3-oxazol-2- observed) yl)pyridin-2-yl]-N-ethylglycinamide, trifluoroacetate salt 1. Reaction of P1 and (6-ethoxypyridin-3-yl)boronic acid, under sp2-sp2Suzuki cross-coupling conditions in the presence of CataCXium A Pd G3 and potassium carbonate, provided Example 4. 2. Analytical conditions. Column: Waters Atlantis C18, 4.6 x 50 mm, 5 µm; Mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); Gradient: 5.0% to 95% B over 4.0 minutes, then 95% B for 1.0 minute; Flow rate: 2 mL / minute. 3. Reaction of P1 and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline, under sp2-sp2Suzuki cross-coupling conditions in the presence of CataCXium A Pd G3 and potassium carbonate, provided Example 5 4. Reaction of P1 and 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine, under sp2-sp2Suzuki cross-coupling conditions in the presence of CataCXium A Pd G3 and potassium carbonate, provided Example 6. 5. Reaction of P1 and [4-(2H-1,2,3-triazol-2-yl)phenyl]boronic acid, under sp2-sp2Suzuki cross-coupling conditions in the presence of CataCXium A Pd G3 and potassium carbonate, provided Example 7. 6. Reaction of 2,5-dibromopyrazine with 1H-pyrazole and potassium carbonate provided the requisite 2-bromo-5-(1H-pyrazol-1-yl)pyrazine. 7. Reaction of P7 with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane, palladium(II) acetate, potassium acetate, and tricyclohexylphosphine provided the corresponding boronate; this was treated with 2-bromo-5-(1H-pyrazol-1-yl)pyrazine (see footnote 6), potassium carbonate, and mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′- biphenyl)]palladium(II) (cataCXium®A Pd G3) to afford Example 14. 8. Reaction of P4 with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane, [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II), and potassium acetate provided the requisite 2-{[5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}-N- methylacetamide. 9. Reaction of 6-chloro-1H-[1,2,3]triazolo[4,5-b]pyridine and 2-bromo-5-chloro-4-fluoropyridine provided the requisite N2-[5-chloro-4-(6-chloro-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)pyridin-2- yl]-N-ethylglycinamide, as well as other regioisomers. The regiochemistry of this material was assigned using one- and two-dimensional1H,13C and15N NMR analysis. 10. In this case, XantPhos Pd G3 was used. 11.2-Chloro-5-iodopyridine and 2H-1,2,3-triazole were reacted with copper(I) iodide in the presence of 1,10-phenanthroline and cesium carbonate, affording the requisite 2-chloro-5- (2H-1,2,3-triazol-2-yl)pyridine. 12.5-Iodopyrimidin-2-amine and 2H-1,2,3-triazole were reacted with copper(I) iodide in the presence of (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine and potassium carbonate. The resulting 5-(2H-1,2,3-triazol-2-yl)pyrimidin-2-amine was subjected to reaction with diiodomethane and tert-butyl nitrite to afford the requisite 2-iodo-5-(2H-1,2,3-triazol-2- yl)pyrimidine. 13. Reaction of P1 with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane, [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II), and potassium acetate provided the corresponding boronate; subsequent reaction with 2-iodo-5-(2H-1,2,3-triazol-2-yl)pyrimidine (see footnote 12), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′- biphenyl)]palladium(II) (cataCXium®A Pd G3), and potassium carbonate afforded Example 21. 14. Condensation of C5 with 2,2,2-trifluoroethan-1-amine, using chloro(dimethylamino)-N,N- dimethylmethaniminium hexafluorophosphate (TCFH) and 1-methyl-1H-imidazole, provided Example 22. 15. The requisite 2-(4-fluoro-1H-pyrazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine was prepared by reaction of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine with 4-fluoro-1H-pyrazole in the presence of potassium carbonate. 16. In this case, 5,5,5',5'-tetramethyl-2,2'-bi-1,3,2-dioxaborinane was used in place of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane. 17. N2-(5-Chloro-4-iodopyridin-2-yl)-N-ethylglycinamide, synthesized in analogous fashion to P7, was reacted with (6-bromopyridin-3-yl)boronic acid, [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II), and tripotassium phosphate to provide the requisite N2-(6-bromo-5'-chloro[3,4'-bipyridin]-2'-yl)-N-ethylglycinamide. 18. Reaction of N2-(6-bromo-5'-chloro[3,4'-bipyridin]-2'-yl)-N-ethylglycinamide (see footnote 17) and sodium 3-methoxy-3-oxopropane-1-sulfinate in the presence of copper(I) iodide provided methyl 3-(5'-chloro-2'-{[2-(ethylamino)-2-oxoethyl]amino}[3,4'-bipyridine]-6- sulfonyl)propanoate. This material was coupled with 3-bromo-1H-pyrazole using palladium(II) acetate, di(1-adamantyl)-n-butylphosphine (cataCXium®A), and potassium carbonate to afford Example 26. 19. Potassium hydroxide-mediated reaction of 6-chloro-4-iodopyridin-3-ol with difluoromethyl trifluoromethanesulfonate provided 2-chloro-5-(difluoromethoxy)-4-iodopyridine. This material was coupled with 2-(1H-pyrazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine using [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and potassium carbonate to afford the requisite 2'-chloro-5'-(difluoromethoxy)-6-(1H-pyrazol-1-yl)-3,4'- bipyridine. 20. In this case, [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2- (2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (BrettPhos-Pd-G3) was also added, partway through the reaction. 21. Cesium carbonate-mediated reaction between 5-chloro-2-fluoro-4-iodopyridine and ethyl hydroxyacetate provided ethyl [(5-chloro-4-iodopyridin-2-yl)oxy]acetate, which was coupled to C2 using [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and potassium carbonate. The resulting ethyl {[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}acetate was reacted with 2-{[tert-butyldi(methyl)silyl]oxy}ethan-1-amine and bis(trimethylaluminum)- 1,4-diazabicyclo[2.2.2]octane adduct to provide N-(2-{[tert-butyldi(methyl)silyl]oxy}ethyl)-2- {[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}acetamide. Subsequent protecting group cleavage with potassium fluoride afforded Example 29. 22.5-Chloropyrazolo[1,5-a]pyridine was reacted with iodine and boron trifluoride diethyl etherate to provide 5-chloro-2-iodopyrazolo[1,5-a]pyridine. 23. Reaction of P7 with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane, [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II), and potassium acetate provided the corresponding boronate; subsequent reaction with 5-chloro-2-iodopyrazolo[1,5-a]pyridine (see footnote 22), [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and potassium carbonate afforded Example 30. SLC6A19 Leucine Uptake Assay MDCK type II cells were transiently transfected with SLC6A19 and collectrin cDNA. Approximately 24 hours post-transfection, cells were lifted from the flasks with 0.25% trypsin. Cell pellets were resuspended in growth media and cell density adjusted to 600,000 viable cells / mL. Twenty-five microliters of cell suspension was added to 384-well CytoStar-T plates (PerkinElmer) for a seeding density of 15,000 viable cells / well. Following an overnight incubation (37 °C-5% CO2humidified incubator), media was removed from the plates by flicking followed by a brief centrifugation (500 rpm for 20 seconds). Growth media was replaced with 20 µL of assay buffer; 136.6 mM NaCl, 5.4 mM KCl, 0.44 mM K2HPO4, 2.7 mM NaH2PO4, 1.26 mM CaCl2, 0.5 mM MgCl2,0.4 mM MgSO4, 10 mM HEPES and 5 mM Glucose pH 7.4, following which plates were returned to the incubator for 10-15 minutes prior to compound addition. Test compounds and the positive control compound were diluted in DMSO followed by the addition of assay buffer to generate a 10x working compound plate. Five microliters of volume from each well of the working plate was added to the corresponding wells in the cell plate. Following compound addition, plates were incubated for approximately 15 minutes at room temperature prior to the addition of Leucine substrate, which was comprised of a mix of cold L-Leucine and14C-labeled L-Leucine. Twenty- five microliters of 300 µM Leucine substrate (150 µM final concentration) was added to each well of the cell plate. Using a Trilux, transporter activity was determined by monitoring the increase in counts over time (2-3 hours) resulting from the transporter-mediated uptake of14C-labeled L- Leucine into the cells. Using control wells, with negative or diluent wells representing uninhibited transporter activity and positive or SLC6A19-selective inhibitor wells representing full transporter inhibition, a % effect for test samples was calculated as follows: % effect = 100 – 100 * ((sample –HPE) / (ZPE-HPE)). The % effect was then plotted versus compound concentration and an IC50determined using a 4-parameter logistic equation. Table 2. Biological activity for Examples 1–34. Example SLC6A19 IC50(nM)1Number 1 101 2 30 3 32 4 91 5 412 6 341 7 24 8 17 9 45 10 12 11 132 12 35 13 16 14 42 15 47 16 53 17 25 18 54 19 34 20 74 21 199 22 12 23 36 24 27 25 14 26 55 27 94 28 130 29 164 30 41 31 122 32 86 33 53 34 93 1. Values represent the geometric mean. Prophetic deuterated analogs (PDAs) of certain compounds of the invention Example X-1: Some Prophetic deuterated analogs (PDA) of Example 10 The compounds provided in Table X-1 are some prophetic deuterated analogs (PDA) of Example 10. The Formula (XA) is a generic formula of deuterated Example 10, wherein Y1a, Y1b, Y1c, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10aand Y10bare each independently H or D (deuterium) and wherein at least one of them is D. The deuterated analogs of Example 10 in Table X-1 can be predicted based on the metabolic profile of Example 10, with MetaSite (moldiscovery.com / software / metasite / ). Y1a, Y1b, Y1c, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10aand Y10bare predicted metabolized positions based on MetaSite predictions. XA Table X-1 PDA # Y1a- Y1cY2Y3Y4Y5Y6Y7Y8Y9Y10a- Y10bXA-1 D H H H H H H H H H XA-2 H D H H H H H H H H XA-3 H H D H H H H H H H XA-4 H H H D H H H H H H XA-5 H H H H D H H H H H XA-6 H H H H H D H H H H XA-7 H H H H H H D H H H XA-8 H H H H H H H D H H XA-9 H H H H H H H H D H XA-10 H H H H H H H H H D XA-11 D D H H H H H H H H XA-12 D H D H H H H H H H XA-13 D H H D H H H H H H XA-14 D H H H D H H H H H XA-15 H D D H H H H H H H XA-16 H D H D H H H H H H XA-17 H D H H D H H H H H XA-18 H H D D H H H H H H XA-19 H H D H D H H H H H XA-20 H H H D D H H H H H Example X-2: Some Prophetic deuterated analogs (PDA) of Example 13 The compounds provided in Table X-2 are some prophetic deuterated analogs (PDA) of Example 13. The Formula (XB) is a generic formula of deuterated Example 13, wherein Y1, Y2a, Y2b, Y3, Y4a, Y4b, Y4c, Y5, Y6a, Y6b, Y7, Y8, and Y9are each independently H or D (deuterium) and wherein at least one of them is D. The deuterated analogs of Example 13 in Table X-2 can be predicted based on the metabolic profile of Example 13, with MetaSite (moldiscovery.com / software / metasite / ). Y1, Y2a, Y2b, Y3, Y4a, Y4b, Y4c, Y5, Y6a, Y6b, Y7, Y8, and Y9are predicted metabolized positions based on MetaSite predictions. Table X-2 PDA # Y1Y2a- Y2bY3Y4a-Y4cY5Y6a-Y6bY7Y8Y9XB-1 D H H H H H H H H XB-2 H D H H H H H H H XB-3 H H D H H H H H H XB-4 H H H D H H H H H XB-5 H H H H D H H H H XB-6 H H H H H D H H H XB-7 H H H H H H D H H XB-8 H H H H H H H D H XB-9 H H H H H H H H D XB-10 D D H H H H H H H XB-11 D H D H H H H H H XB-12 D H H D H H H H H XB-13 D H H H D H H H H XB-14 H D D H H H H H H XB-15 H D H D H H H H H XB-16 H D H H D H H H H XB-17 H H D D H H H H H XB-18 H H D H D H H H H XB-19 H H H D D H H H H Example X-3: Some Prophetic deuterated analogs (PDA) of Example 15 The compounds provided in Table X-3 are some prophetic deuterated analogs (PDA) of Example 15. The Formula (XC) is a generic formula of deuterated Example 15, wherein Y1a, Y1b, Y1c, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9aand Y9bare each independently H or D (deuterium) and wherein at least one of them is D. The deuterated analogs of Example 15 in Table X-3 can be predicted based on the metabolic profile of Example 15, with MetaSite (moldiscovery.com / software / metasite / ). Y1a, Y1b, Y1c, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9aand Y9bare predicted metabolized positions based on MetaSite predictions. XC Table X-3 PDA # Y1a- Y1cY2Y3Y4Y5Y6Y7Y8Y9a- Y9bXC-1 D H H H H H H H H XC-2 H D H H H H H H H XC-3 H H D H H H H H H XC-4 H H H D H H H H H XC-5 H H H H D H H H H XC-6 H H H H H D H H H XC-7 H H H H H H D H H XC-8 H H H H H H H D H XC-9 H H H H H H H H D XC-10 D D H H H H H H H XC-11 D H D H H H H H H XC-12 D H H D H H H H H XC-13 D H H H D H H H H XC-14 H D D H H H H H H XC-15 H D H D H H H H H XC-16 H D H H D H H H H XC-17 H H D D H H H H H XC-18 H H D H D H H H H XC-19 H H H D D H H H H Example X-4: Some Prophetic deuterated analogs (PDA) of Example 16 The compounds provided in Table X-4 are some prophetic deuterated analogs (PDA) of Example 16. The Formula (XD) is a generic formula of deuterated Example 16, wherein Y1a, Y1b, Y2a, Y2b, Y2c, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6, Y7, Y8, and Y9are each independently H or D (deuterium) and wherein at least one of them is D. The deuterated analogs of Example 16 in Table X-4 can be predicted based on the metabolic profile of Example 16, with MetaSite (moldiscovery.com / software / metasite / ). Y1a, Y1b, Y2a, Y2b, Y2c, Y3a, Y3b, Y4a, Y4b, Y5a, Y5b, Y6, Y7, Y8, and Y9are predicted metabolized positions based on MetaSite predictions. XD Table X-4 PDA # Y1a- Y1bY2Y3a- Y3cY4Y5a-Y5bY6Y7XD-1 D H H H H H H XD-2 H D H H H H H XD-3 H H D H H H H XD-4 H H H D H H H XD-5 H H H H D H H XD-6 H H H H H D H XD-7 H H H H H H D XD-8 D D H H H H H XD-9 D H D H H H H XD-10 D H H D H H H XD-11 D H H H D H H XD-12 H D D H H H H XD-13 H D H D H H H XD-14 H D H H D H H XD-15 H H D D H H H XD-16 H H D H D H H XD-17 H H H D D H H Example X-5: Some Prophetic deuterated analogs (PDA) of Example 17 The compounds provided in Table X-5 are some prophetic deuterated analogs (PDA) of Example 17. The Formula (XE) is a generic formula of deuterated Example 17, wherein Y1a, Y1b, Y2, Y3, Y4a, Y4b, Y4c, Y5, Y6a, Y6b, Y7, Y8, Y9, and Y10are each independently H or D (deuterium) and wherein at least one of them is D. The deuterated analogs of Example 17 in Table X-5 can be predicted based on the metabolic profile of Example 17, with MetaSite (moldiscovery.com / software / metasite / ). Y1a, Y1b, Y2, Y3, Y4a, Y4b, Y4c, Y5, Y6a, Y6b, Y7, Y8, Y9, and Y10are predicted metabolized positions based on MetaSite predictions. XE Table X-5 PDA # Y1a- Y1bY2Y3Y4a-Y4cY5Y6a-Y6bY7Y8Y9Y10 XE-1 D H H H H H H H H H XE-2 H D H H H H H H H H XE-3 H H D H H H H H H H XE-4 H H H D H H H H H H XE-5 H H H H D H H H H H XE-6 H H H H H D H H H H XE-7 H H H H H H D H H H XE-8 H H H H H H H D H H XE-9 H H H H H H H H D H XE-10 H H H H H H H H H D XE-11 D D H H H H H H H H XE-12 D H D H H H H H H H XE-13 D H H D H H H H H H XE-14 D H H H D H H H H H XE-15 H D D H H H H H H H XE-16 H D H D H H H H H H XE-17 H D H H D H H H H H XE-18 H H D D H H H H H H XE-19 H H D H D H H H H H XE-20 H H H D D H H H H H General methods / reviews of obtaining metabolite profile and identifying metabolites of a compound are described in: Dalvie, et al., “Assessment of Three Human in Vitro Systems in the Generation of Major Human Excretory and Circulating Metabolites,” Chemical Research in Toxicology, 2009, 22, 2, 357-368, tx8004357 (acs.org); King, R., “Biotransformations in Drug Metabolism,” Ch.3, Drug Metabolism Handbook Introduction, https: / / doi.org / 10.1002 / 9781119851042.ch3; Wu, Y., et al, “Metabolite Identification in the Preclinical and Clinical Phase of Drug Development,” Current Drug Metabolish, 2021, 22, 11, 838-857, 10.2174 / 1389200222666211006104502; Godzien, J., et al, “Chapter Fifteen - Metabolite Annotation and Identification”. Numerous publicly available and commercially available software tools are available to aid in the predictions of metabolic pathways and metabolites of compounds. Examples of such tools include, BioTransformer 3.0 (biotransformer.ca / new) which predicts the metabolic biotransformations of small molecules using a database of known metabolic reactions; MetaSite (moldiscovery.com / software / metasite / ) which predicts metabolic transformations related to cytochrome P450 and flavin-containing monooxygenase mediated reactions in phase I metabolism; and Lhasa Meteor Nexus (lhasalimited.org / products / meteor-nexus.htm) offers prediction of metabolic pathways and metabolite structures using a range of machine learning models, which covers phase I and phase II biotransformations of small molecules. Example X-1 to Example X-5 in Table X-1 to Table X-5 may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability. A person with ordinary skill may make additional deuterated analogs of Example X-1 to Example X-5 in Table X-1 to Table X-5 with different combinations as provided in Table X-1 to Table X-5. Such additional deuterated analogs may provide similar therapeutic advantages that may be achieved by the deuterated analogs It will be apparent to those skilled in the art that various modifications and variations may be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. All references cited herein, including patents, patent applications, papers, textbooks, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entireties. Incorporated by reference herein in the entirety for all purposes is the content of U.S. Provisional Patent Application No.63 / 683,957 (filed August 16, 2024), 63 / 698,130 (filed September 24, 2024), and 63 / 824,403 (filed June 16, 2025). In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

Claims

1. CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is C1‑C6alkyl, C3‑C6cycloalkyl, a 4- to 8- membered heterocycloalkyl, a 6- to 10- membered aryl, or a 5- to 10- membered heteroaryl, wherein each of said C1‑C6alkyl, C3‑C6cycloalkyl, 4- to 8- membered heterocycloalkyl, 6- to 10- membered aryl, or 5- to 10- membered heteroaryl is optionally substituted with 1 to 6 substituents each independently selected from the group consisting of halogen, -OH, -CN, -N(R8R9), C1‑C6 alkyl, C1‑C6 haloalkyl, C3‑C6cycloalkyl, C3‑C6halocycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, (C3-C4halocycloalkyl)-C1-C4alkyl-, (C1-C6alkoxy)-C1-C4alkyl-, (C3-C4cycloalkoxy)-C1-C4alkyl-, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, C3‑C6halocycloalkoxy, (C3-C4cycloalkyl)-C1-C4alkoxy-, and (C3-C4halocycloalkyl)-C1-C4alkoxy-; R2is H, halogen, -OH, -CN, -N(R10R11), C1‑C6 alkyl, C1‑C6 haloalkyl, C3‑C6 cycloalkyl, C3‑C6halocycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, or C3‑C6halocycloalkoxy; R3is halogen, -OH, -CN, -N(R12R13), C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C3‑C6halocycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, or C3‑C6halocycloalkoxy; R4is a C3‑C10cycloalkyl, a 4- to 10- membered heterocycloalkyl, a 6- to 10- membered aryl or a 5- to 10- membered heteroaryl, wherein said C3‑C10cycloalkyl, 4- to 10- membered heterocycloalkyl, 6- to 10- membered aryl or 5- to 10- membered heteroaryl is optionally substituted with 1 to 6 substituents with 1 to 6 R4A; each R4Ais independently selected from the group consisting of halogen, -OH, -CN, -SF5, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C3-C6cycloalkyl, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6 haloalkoxy, C3‑C6 halocycloalkoxy, (C3-C4 cycloalkyl)-C1-C4 alkoxy-, (C3-C4halocycloalkyl)-C1-C4alkoxy-, a 4- to 8- membered heterocycloalkyl, phenyl, a 5- to 8- membered heteroaryl, -N(Ra)(Rb), -N(Rc)(C(=O)Rd), -C(=O)-N(Ra)(Rb), Rd-C(=O)-, -C(=O)-OH, -N(Rc)(S(=O)2Rd), N(Ra)(Rb)-S(=O)2-, and -ORd, wherein each of said C1-C6alkyl, C3-C6cycloalkyl, 4- to 8- membered heterocycloalkyl, phenyl, or 5- to 8- membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkoxy, C3-C6halocycloalkoxy, -N(Ra)(Rb), -N(Rc)(C(=O)Rd), -C(=O)-OH, -C(=O)N(Ra)(Rb), - N(Rc)(S(=O)2Rd), -S(=O)2-N(Ra)(Rb), and –ORd; or two adjacent R4A, together with the two ring atoms to which they are attached, form a fused C3-C6cycloalkyl or a 4- to 8- membered heterocycloalkyl, wherein each of said C3- C6cycloalkyl or 4- to 8- membered heterocycloalkyl is optionally substituted with 1 to 4 independently selected R4B; each R4Bis independently selected from the group consisting of halogen, -OH, -CN, oxo, - SF5, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C3-C6cycloalkyl, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, C3‑C6halocycloalkoxy, (C3-C4cycloalkyl)-C1-C4alkoxy-, (C3-C4halocycloalkyl)-C1-C4alkoxy-, a 4- to 8- membered heterocycloalkyl, phenyl, a 5- to 8- membered heteroaryl, -N(Ra)(Rb), -N(Rc)(C(=O)Rd), -C(=O)-N(Ra)(Rb), Rd-C(=O)-, - C(=O)-OH, -N(Rc)(S(=O)2Rd), N(Ra)(Rb)-S(=O)2-, and -ORd, wherein each of said C1-C6alkyl, C3-C6cycloalkyl, 4- to 8- membered heterocycloalkyl, phenyl, or 5- to 8- membered heteroaryl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkoxy, C3-C6halocycloalkoxy, -N(Ra)(Rb), -N(Rc)(C(=O)Rd), -C(=O)-OH, -C(=O)N(Ra)(Rb), - N(Rc)(S(=O)2Rd), -S(=O)2-N(Ra)(Rb), and –ORd; each Rais independently selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, and C3-C6cycloalkyl; each Rbis independently selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, a 4- to 10-membered heterocycloalkyl, a C6-C10aryl, a 5- to 10- membered heteroaryl, (4- to 10-membered heterocycloalkyl)-C1-C4alkyl-, (C6-C10aryl)-C1-C4alkyl-, and (5- to 10-membered heteroaryl)-C1-C4alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-C4alkyl, C3-C6cycloalkyl, C1-C4hydroxylalkyl, HO-C(=O)-, NH2-(C=O)-, N(C1-C4alkyl)2-(C=O)-, C1-C4haloalkyl, C1-C4alkoxy, and C1-C4haloalkoxy; or Raand Rbtogether with the N atom to which they are attached form a 4- to 10- membered heterocycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, -OH, -CN, oxo, HO-C(=O)-, NH2-(C=O)-, N(C1-C4alkyl)2-(C=O)-, C1-C4alkyl, C1-C4alkoxy, C1-C4hydroxylalkyl, C1-C4haloalkyl, and C1-C4haloalkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy; each Rcis independently selected from the group consisting of H, C1-C4alkyl, and C3-C6cycloalkyl; each Rdis independently selected from the group consisting of H, C1-C6alkyl, C3-C6cycloalkyl, a 4- to 14-membered heterocycloalkyl, C6-C10aryl, a 5- to 10-membered heteroaryl, (4- to 10-membered heterocycloalkyl)-C1-C4alkyl-, (C6-C10aryl)-C1-C4alkyl-, and (5- to 10-membered heteroaryl)-C1-C4alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, OH, -CN, oxo, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxylalkyl, C3-C6cycloalkyl, C1-C4alkoxy, and C1-C4haloalkoxy; R5is H, halogen, -OH, -N(R14R15), C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C3‑C6halocycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, or C3‑C6halocycloalkoxy; each R6and R7is independently selected from the group consisting of H, halogen, -OH, - CN, C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C3-C6halocycloalkyl, C1‑C6alkoxy, C1‑C6haloalkoxy, C3‑C6cycloalkoxy, and C3‑C6halocycloalkoxy; or R6and R7, together with the carbon atom to which they are attached, form a C3‑C6cycloalkyl or a 4- to 6- membered heterocycloalkyl, each optionally substituted with 1 to 4 substituents each independently selected from the group consisting of -OH, halogen, C1‑C4alkyl, C1‑C4alkoxy, C1‑C4haloalkyl, and C1‑C4haloalkoxy; R8, R9, R10, R11, R12, R13, R14, and R15, are each independently selected from the group consisting of H, C1‑C6alkyl, C3‑C6cycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, (C1-C6alkoxy)-C1-C4alkyl-, (C3-C4cycloalkoxy)-C1-C4alkyl-, and R16-(C=O)-; or R8and R9, together with the N atom to which they are attached, form a 4- to 6- membered heterocycloalkyl; or R10and R11, together with the N atom to which they are attached, form a 4- to 6- membered heterocycloalkyl; or R12and R13, together with the N atom to which they are attached, form a 4- to 6- membered heterocycloalkyl; or R14and R15, together with the N atom to which they are attached, form a 4- to 6- membered heterocycloalkyl; R16is C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, (C1-C6alkoxy)-C1-C4alkyl-, or (C3-C4cycloalkoxy)-C1-C4alkyl-; X is O, -NR17, or absent; Y is -NR18or absent; Z is O, -NR19, or absent;R17, R18and R19are each independently selected from the group consisting of H, C1-C6alkyl, (C3-C4cycloalkyl)-C1-C4alkyl-, and C3-C6cycloalkyl; and n is 1, 2, 3, or 4, provided that: (a) X and Y are not both absent; (b) when Y is absent, then X is not O; (c) when Y is -NR18and R1is an optionally substituted 6- to 10- membered aryl or an optionally substituted 5- to 10- membered heteroaryl, then X is not O; (d) when Y is -NR18, then neither R6nor R7on the same carbon that is directly bonded to Y is halogen, -OH, -CN, C1‑C6alkoxy, C1‑C6haloalkoxy, C3‑C6cycloalkoxy, or C3‑C6halocycloalkoxy; (e) when one of R6and R7is -OH, then the other one on the same carbon is not halogen, - OH, -CN, C1‑C6alkoxy, C1‑C6haloalkoxy, C3‑C6cycloalkoxy, or C3‑C6halocycloalkoxy,; (f) when Z is O or -NR19, then neither R6nor R7on the same carbon that is directly bonded to Z is -OH, -CN, C1‑C6alkoxy, C1‑C6haloalkoxy, C3‑C6cycloalkoxy, or C3‑C6halocycloalkoxy; (g) when n is 1 and Y is -NR18, then Z is not O or -NR19; and (h) when Z is absent and Y is NR18, then n is 2, 3 or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is C1‑C6alkyl, C3‑C6cycloalkyl, a 4- to 8- membered heterocycloalkyl, a 6- to 10- membered aryl, or a 5- to 10- membered heteroaryl, wherein each of said C1‑C6alkyl, C3‑C6cycloalkyl, 4- to 8- membered heterocycloalkyl, 6- to 10- membered aryl, or 5- to 10- membered heteroaryl, is optionally substituted with 1 to 6 substituents each independently selected from the group consisting of halogen, C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C3‑C6halocycloalkyl, C1‑C6alkoxy, and C3‑C6cycloalkoxy.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1is C1‑C6alkyl, C3‑C6cycloalkyl, or (C3‑C6cycloalkyl)-C1‑C4alkyl-, each of which is optionally substituted with 1 to 5 halogens.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R1is C1‑C6alkyl, C3‑C6cycloalkyl, or (C3‑C6cycloalkyl)-C1‑C4alkyl-, each of which is optionally substituted with 1 to 5 fluoro.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclobutyl, 1,1-difluoroethyl, and 1,1,1- trifluoroethyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of methyl, ethyl, 1,1-difluoroethyl, 1,1,1- trifluoroethyl, and cyclopropyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2is H, halogen, C1‑C6alkyl, or C3‑C6cycloalkyl. 8 The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R2is H or halogen.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R2is H.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R3is halogen, C1‑C6alkyl, C1‑C6haloalkyl, C1-C6alkoxy, C1‑C6haloalkoxy, or C3‑C6cycloalkyl.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R3is halogen, C1-C6haloalkyl, or C1-C6haloalkoxy.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R3is halogen.

13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R3is C1- C3haloalkyl.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R3is C1- C6haloalkoxy.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R4is phenyl or 5- to 10- membered heteroaryl, wherein said phenyl or 5- to 10- membered heteroaryl is optionally substituted with 1 to 3 R4A, each R4Ais independently selected from the group consisting of C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, (C3-C4cycloalkyl)-C1-C4alkoxy-, (C1-C6alkoxy)-C1- C4alkyl-, (C1-C6alkoxy)-C3-C6cycloalkyl-, phenyl, and a 4- to 8- membered heterocycloalkyl.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of benzotriazolyl, indazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyradazinyl, pyrimidyl, pyrazolo[1,5-a]pyridinyl, thiadiazolyl, quinolinyl, [1,2,3]triazolo[4,5-b]pyridin-2-yl, and phenyl, each of which is optionally substituted with 1 to 3 R4A, each R4Ais independently selected from the group consisting of C1‑C6alkyl, C1‑C6haloalkyl, C3‑C6cycloalkyl, C1‑C6alkoxy, C3‑C6cycloalkoxy, C1‑C6haloalkoxy, (C3-C4cycloalkyl)-C1-C4alkoxy-, (C1-C6alkoxy)-C1-C4alkyl-, (C1-C6alkoxy)-C3-C6cycloalkyl-, phenyl, and a 4- to 8- membered heterocycloalkyl.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R4is oxazolyl, pyridinyl, pyrazinyl, or [1,2,3]triazolo[4,5-b]pyridin-2-yl.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R4is pyridin-3-yl or pyrazin-2-yl.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein each R4Aand R4Bis independently selected from the group consisting of C1‑C3alkyl, C1‑C3haloalkyl, C3‑C6cycloalkyl, (C1-C6alkoxy)-C1-C4alkyl-, C1‑C3alkoxy, C1‑C3haloalkoxy, phenyl, and a 5- to 6- membered heterocycloalkyl.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein each R4Aand R4Bis independently selected from the group consisting of methoxy, ethoxy, cyclopropoxy, cyclopropyl, trifluoromethyl, difluoromethoxy, methoxymethyl, phenyl, and pyrrolidin-1-yl.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R5is H, halogen, C1‑C6alkyl, or C3‑C6cycloalkyl.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R5is H or halogen.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R5is H.

24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein each R6and R7is independently H, C1‑C6alkyl, or C3‑C6cycloalkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein each of R6and R7is H.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R8, R9, R10, R11, R12, R13, R14, and R15are each independently H, C1‑C3alkyl, or cyclopropyl.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R8, R9, R10, R11, R12, R13, R14, and R15are each H.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R16is C1‑C3alkyl or cyclopropyl.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R17, R18, and R19are each independently H, C1‑C3alkyl, or cyclopropyl.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein X is -NR17, and Y is absent.

31. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein X is absent, and Y is -NR18.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Z is O or NH.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein Z is NH.

34. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein Z is O.

35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein n is 1.

37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R1is C1‑C6alkyl, C3‑C6cycloalkyl, or (C3‑C6cycloalkyl)-C1‑C4alkyl-, each of which is optionally substituted with 1 to 5 halogen; R2is H, R3is Cl, CF3, or OCF2H; R4is pyridin-3-yl or pyrazin-2-yl, each optionally substituted with 1 to 3 independently selected R4A; R5is H; R6is H; R7is H; X is NH; Y is absent; n is 1 or 2; and Z is O or NH.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R1is C1‑C6alkyl, C3‑C6cycloalkyl, or (C3‑C6cycloalkyl)-C1‑C4alkyl-, each of which is optionally substituted with 1 to 5 fluoro; R2is H, R3is Cl, CF3, or OCF2H; R4is pyridin-3-yl optionally or pyrazin-2-yl, each substituted with 1 to 3 independently selected R4Aselected from the group consisting of methoxy, ethoxy, cyclopropoxy, cyclopropyl, trifluoromethyl, difluoromethoxy, phenyl, 5-8 membered heteroaryl, and pyrrolidin-1-yl; R5is H; R6is H; R7is H; X is NH; Y is absent; n is 1; and Z is O or NH.

39. A compound selected from the group consisting of: N2-(5'-Chloro-6-cyclopropyl[3,4'-bipyridin]-2'-yl)-N-ethylglycinamide; N2-[5-Chloro-4-(5-chloro-2H-indazol-2-yl)pyridin-2-yl]-N-ethylglycinamide; N2-[5'-Chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-(5'-chloro-6-ethoxy[3,4'-bipyridin]-2'-yl)-N-ethylglycinamide; N2-[5-chloro-4-(quinolin-3-yl)pyridin-2-yl]-N-ethylglycinamide; N2-[5-chloro-4-(2-phenylpyrimidin-5-yl)pyridin-2-yl]-N-ethylglycinamide; N2-{5-chloro-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-2-yl}-N-ethylglycinamide; 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-(propan-2-yl)acetamide; N2-[5-chloro-4-(5-chloro-2H-pyrazolo[3,4-b]pyridin-2-yl)pyridin-2-yl]-N-ethylglycinamide; 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-methylacetamide; N2-{5-chloro-4-[6-(1H-pyrazol-1-yl)pyridazin-3-yl]pyridin-2-yl}-N-ethylglycinamide; N2-{5-chloro-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-2-yl}-N-methylglycinamide; N2-[5-chloro-4-(5-phenyl-1,2-oxazol-3-yl)pyridin-2-yl]-N-ethylglycinamide; N2-{5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2-yl]pyridin-2-yl}-N-methylglycinamide; 2-({5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2-yl]pyridin-2-yl}oxy)-N-methylacetamide; N2-[5-chloro-4-(6-chloro-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)pyridin-2-yl]-N-ethylglycinamide;N2-{5-chloro-4-[5-(1H-pyrazol-1-yl)pyrazin-2-yl]pyridin-2-yl}-N-ethylglycinamide; N2-[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-methylglycinamide; N2-[5-chloro-4-(5-fluoro-2H-indazol-2-yl)pyridin-2-yl]-N-ethylglycinamide; N2-[5'-chloro-5-(2H-1,2,3-triazol-2-yl)[2,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-{5-chloro-4-[5-(2H-1,2,3-triazol-2-yl)pyrimidin-2-yl]pyridin-2-yl}-N-ethylglycinamide; 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-(2,2,2-trifluoroethyl)acetamide; N2-[5'-chloro-6-(4-fluoro-1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-{5-chloro-4-[4-(1,2-oxazol-3-yl)phenyl]pyridin-2-yl}-N-ethylglycinamide; N2-[5-chloro-4-(5-chloro-2H-1,2,3-benzotriazol-2-yl)pyridin-2-yl]-N-ethylglycinamide;N2-[5'-chloro-6-(1H-pyrazol-3-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-[5'-(difluoromethoxy)-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-[5-amino-5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; 2-{[5'-chloro-6-(1H-pyrazol-1-yl)[3,4'-bipyridin]-2'-yl]oxy}-N-(2-hydroxyethyl)acetamide; N2-[5-chloro-4-(5-chloropyrazolo[1,5-a]pyridin-2-yl)pyridin-2-yl]-N-methylglycinamide; N2-[5'-chloro-6-(pyrrolidin-1-yl)[3,4'-bipyridin]-2'-yl]-N-ethylglycinamide; N2-[5-chloro-4-(7-chloroquinolin-3-yl)pyridin-2-yl]-N-ethylglycinamide; N2-{5-chloro-4-[1-(pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-ethylglycinamide; and N2-[5-chloro-4-(4-phenyl-1,3-oxazol-2-yl)pyridin-2-yl]-N-ethylglycinamide, or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

41. A method for treating or preventing a condition, disease, or disorder in a subject comprising administering to the subject a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein the condition, disease, or disorder is selected from the group consisting of isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle deficiency, urea cycle disorders, hyperammonemia, diabetes, phenylketonuria (PKU), chronic kidney disease (CKD), diabetic kidney disease (DKD), diabetic nephropathy, non-diabetic kidney disease (NDKD), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, neurodevelopmental disorders, and autism-spectrum disorders.

42. The method of claim 41, wherein said condition, disease, or disorder is urea cycle deficiency, urea cycle disorder, phenylketonuria, or chronic kidney disease.

43. A pharmaceutical combination comprising a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

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