Indole analogs

Abstract

The invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof 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] Indole Analogs

[0002] Background of the Invention

[0003] The present invention relates to novel indole analogs. The invention also relates to the preparation of the indole analogs and intermediates used in the preparation, compositions containing the indole analogs, and uses of the indole analogs including treating or preventing a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid levels by modulation of SLC6A19 (B°AT1) transport.

[0004] SLC6A19 (B°AT1) 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.

[0005] 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 B°AT1 (SLC6A19), Bioorg. Med. Chem. Lett. 53 (2021), 128421).

[0006] 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 transport, very limited SLC6A19 inhibitors have been reported. And there is no FDA approved drug as SLC6A19 inhibitor.

[0007] Accordingly, there remains a need for improved SLC6A19 inhibitors. The compounds, combinations and methods of the present invention may have one or more advantages 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 transport.

[0008] Summary of the Invention

[0009] The present invention provides, in part, compounds of Formula (I) and pharmaceutically acceptable salts thereof as SLC6A19 inhibitors. Such compounds may be used 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 transport.

[0010] SLC6A19 inhibitors of the present invention may be used 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 (CKD), Diabetic Kidney Disease (DKD), diabetic nephropathy, Non-Diabetic Kidney Disease (NDKD), and related disorders. Also provided are pharmaceutical compositions, comprising the compounds or salts of the invention, alone or in combination with additional therapeutic agents. The present invention also provides, in part, methods for preparing such compounds, pharmaceutically acceptable salts and compositions of the invention, and methods of using the foregoing. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

[0011] According to an embodiment of the invention there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0012] A is N or CH;

[0013] R1is: wherein if R1comprises one or more methylene group, at least one of said one or more methylene group of R1is optionally substituted 1 to 2 substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and oxo (=0);

[0014] R2is selected from the group consisting of H, halogen, -OH, -CN, -NH2, Ci-Ce alkoxy, C1-C6 alkyl, Ci-Ce haloalkyl, C1-C3 haloalkoxy, and C3-C6 cycloalkyl;

[0015] R3is selected from the group consisting of halogen, -OH, -CN, -NH2, Ci-Ce alkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, C1-C3 haloalkoxy, and C3-C6 cycloalkyl;

[0016] R4is: wherein if R4comprises one or more methylene group, at least one of said one or more methylene group of R4is optionally substituted 1 to 2 substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and oxo (=0), and wherein R4is not -OMe or -(C=O)-OMe;

[0017] R5is selected from the group consisting of Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Cehaloalkyl, C3-C6 halocycloalkyl, Ci-Ce alkoxy, 6-10 membered aryl, and 5-10 membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of O, N and S, wherein said 6-10 membered aryl, 5-10 membered heteroaryl, Ci-Ce alkyl, or C3-C6 cycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C1-C3 haloalkoxy, and Ci-Ce alkoxy;

[0018] R6is selected from the group consisting of Ci-Ce alkyl, Ci-Ce acyl group, C3-C6 cycloalkyl, Ci-Ce haloalkyl, C3-C6 halocycloalkyl, Ci-Ce alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of O, N and S, wherein R6is optionally substituted with one, two, or three substituents independently selected from the group consisting of -OH, -CN, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C1-C3 haloalkoxy, and Ci-Ce alkoxy;

[0019] Q is a bond, -NR7-, O,-(C=O)-, -(C=C)-, or 3-8 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, wherein the 3-8 membered heterocycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and oxo (=0);

[0020] X is -(CH2)-, O, S, or a bond when A is CH, or X is -(CH2)-, O, -NR8-, S, or a bond when A is N;

[0021] Y and Z are each independently -(CH2)-, O, -NR8-, S, or a bond, wherein X and Y are not simultaneously a bond, and wherein Q and Z are not simultaneously a bond;

[0022] P is -(CH2)-, -(C=O)-, O, -NR9-, or S;

[0023] R7, R8and R9are each independently H or C1-C3 alkyl; k is 0, 1 or 2, wherein when k is 0, R6is Ci-Ce acyl group or 5-10 membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of O, N and S, and R6is optionally substituted with one, two, or three substituents independently selected from the group consisting of -OH, -CN, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C1-C3 haloalkoxy, and Ci-Ce alkoxy; m is 0, 1 , 2, 3, or 4; and n is 0, 1 , 2, 3, or 4.

[0024] Described below are embodiments of the invention, where for convenience Embodiment (E1) is identical to the embodiment of Formula (I) provided above. 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.

[0025] Detailed Description of the Invention

[0026] 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.

[0027] E1 A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined above.

[0028] E2 A compound of embodiment E1 or a pharmaceutically acceptable salt thereof, wherein k is 1.

[0029] E3 A compound of any one of embodiments E1 to E2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II)

[0030] E4 A compound of any one of embodiments E1 to E3, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III):

[0031] E5 A compound of any one of embodiments E1 to E3, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IV):

[0032] E6 A compound of any one of embodiments E1 to E5, or a pharmaceutically acceptable salt thereof, wherein R1is:

[0033] E7 A compound of any one of embodiments E1 to E5, or a pharmaceutically acceptable salt thereof, wherein R1is:

[0034] E8 A compound of any one of embodiments E1 to E7, or a pharmaceutically acceptable salt thereof, wherein R2is H or halogen.

[0035] E9 A compound of embodiment E8, or a pharmaceutically acceptable salt thereof, wherein R2is H.

[0036] E10 A compound of any one of embodiments E1 to E9, or a pharmaceutically acceptable salt thereof, wherein R3is halogen, C1-C3 alkyl, or C1-C3 fluoroalkyl.

[0037] E11 A compound of embodiment E10, or a pharmaceutically acceptable salt thereof, wherein R3is Cl.

[0038] E12 A compound of any one of embodiments E1 to E11 , or a pharmaceutically acceptable salt thereof, wherein R4is:

[0039] E13 A compound of any one of embodiments E1 to E11 , or a pharmaceutically acceptable salt thereof, wherein R4is: wherein Z is a bond, and m is 1 , 2, 3, or 4.

[0040] E14 A compound of any one of embodiments E1 to E13, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of:

[0041] E15 A compound of embodiment E14, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of:

[0042] E16 A compound of any one of embodiments E1 to E15, or a pharmaceutically acceptable salt thereof, wherein R5is selected from the group consisting of methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, phenyl,

[0043] E17 A compound of embodiment E16, or a pharmaceutically acceptable salt thereof, wherein R5is selected from the group consisting of methyl, ethyl and cyclopropyl. E18 A compound of any one of embodiments E1 to E17, or a pharmaceutically acceptable salt thereof, wherein R6is selected from the group consisting of oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridinyl, and phenyl, each is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C3 alkoxy.

[0044] E19 A compound of embodiment E18, or a pharmaceutically acceptable salt thereof, wherein

[0045] R6is selected from the group consisting of:

[0046] E20 A compound of any one of embodiments E1 to E19, or a pharmaceutically acceptable salt thereof, wherein R7, R8and R9are each independently H.

[0047] E21 A compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof, wherein X is -(CH2)- or a bond when A is CH.

[0048] E22 A compound of any one of embodiments E1 to E20, or a pharmaceutically acceptable salt thereof, wherein X is-(CH2)-, O, -NH-, or a bond when A is N.

[0049] E23 A compound of any one of embodiments E1 to E22, or a pharmaceutically acceptable salt thereof, wherein Y and Z are each independently -(CH2)-, O, -NH-, or a bond.

[0050] E24 A compound of any one of embodiments E1 to E23, or a pharmaceutically acceptable salt thereof, wherein Q is a bond, -NH-, O, or -(C=O)-.

[0051] E25 A compound of any one of embodiments E1 to E24, or a pharmaceutically acceptable salt thereof, wherein P is -(CH2)-, -(C=O)-, O, or -NH-.

[0052] E26 A compound of embodiment E25, or a pharmaceutically acceptable salt thereof, wherein P is -(C=O)-. E27 A compound of embodiment E25, or a pharmaceutically acceptable salt thereof, wherein P is -(CH2)-.

[0053] E28 A compound of embodiment E25, or a pharmaceutically acceptable salt thereof, wherein P is -NH-.

[0054] E29 A compound of any one of embodiments E1 to E28, or a pharmaceutically acceptable salt thereof, wherein k is 1.

[0055] E30 A compound of any one of embodiments E1 to E29, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 , or 2.

[0056] E31 A compound of any one of embodiments E1 to E30, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

[0057] E32 A compound selected from the group consisting of:

[0058] N-[(5-chloro-6-{[(5-methyl-1,2-oxazol-3-yl)oxy]methyl}-1 H-indol-2- yl)methyl]propanamide;

[0059] N-({5-chloro-3-fluoro-6-[2-(1 ,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)propanamide;

[0060] N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-2,2- difluoroacetamide;

[0061] N-({5-chloro-6-[2-(2-methyl-1,3-oxazol-4-yl)ethyl]-1 H-indol-2-yl}methyl)propanamide;

[0062] N-({5-chloro-6-[2-(1,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)-2-fluoropropanamide;

[0063] N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)propanamide;

[0064] 2-{5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1H-indol-2-yl}-N-cyclopropylacetamide; methyl ({5-chloro-6-[2-(1 , 2-oxazol-3-y I) ethoxy]- 1 H-indol-2-yl}methyl)carbamate;

[0065] N-{[6-(benzyloxy)-5-chloro-1 H-indol-2-yl]methyl}propanamide;

[0066] N-({5-chloro-6-[(3-methyl-1,2-oxazol-5-yl)methoxy]-1 H-indol-2-yl}methyl)propanamide;

[0067] 2-{5-chloro-3-fluoro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}-N- ethylacetamide;

[0068] 2-{5-chloro-6-[2-(1,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}-N-ethylacetamide;

[0069] N-({5-chloro-6-[2-(1,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)propanamide;

[0070] N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)acetamide;

[0071] N-({5-chloro-6-[(5-chloropyridin-2-yl)methoxy]-1 H-indol-2-yl}methyl)propanamide;

[0072] N-({5-chloro-6-[2-(1 H-pyrrol-2-yl)ethyl]-1 H-indol-2-yl}methyl)propanamide; N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-2-fluoro-2- methylpropanamide;

[0073] N-({5-chloro-6-[2-(1 ,2-oxazol-3-yl)ethoxy]-1 H-pyrrolo[2,3-b]pyridin-2- yl}methyl)propanamide;

[0074] N-({5-chloro-3-fluoro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2- yl}methyl)propanamide;

[0075] N-({5-fluoro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)propanamide;

[0076] N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-1- methoxycyclopropane-1 -carboxamide;

[0077] N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-2- methoxyacetamide;

[0078] N-({5-chloro-6-[(5-methyl-1 ,2-oxazol-3-yl)methoxy]-1 H-pyrrolo[2,3-b]pyridin-2- yl}methyl)acetamide;

[0079] N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-N'-methylurea;

[0080] N'-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-N,N- dimethylurea;

[0081] N-({5-ethyl-6-[2-(1 ,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)propanamide;

[0082] 2-{5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}-N-ethylacetamide;

[0083] N-[5-chloro-2-(propanamidomethyl)-1 H-indol-6-yl]-5-methyl-1 ,2-oxazole-3-carboxamide;

[0084] N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-1 ,2-oxazole-3- carboxamide;

[0085] N-({5-chloro-6-[2-(4-fluoro-1 H-pyrazol-1-yl)ethyl]-1 H-indol-2-yl}methyl)propanamide;

[0086] N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)benzamide;

[0087] N-({5-fluoro-6-[2-(1 ,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)propanamide;

[0088] N-[(5-chloro-6-{[(5-methyl-1 ,2-oxazol-3-yl)methyl]amino}-1 H-pyrrolo[2,3-b]pyridin-2- yl)methyl]propanamide;

[0089] N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-pyrrolo[2,3-b]pyridin-2- yl}methyl)propanamide;

[0090] N-[(5-chloro-6-{[(5-methyl-1 ,2-oxazol-3-yl)methyl]amino}-1 H-indol-2- yl)methyl]propanamide;

[0091] N-[(5-chloro-6-{[(5-methyl-1 ,2-oxazol-3-yl)amino]methyl}-1 H-indol-2- yl)methyl]propanamide;

[0092] N-({3-chloro-2-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-6-yl}methyl)propanamide;

[0093] N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-1 ,2-oxazol-3- amine; and

[0094] N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-5-methyl-1 ,2- oxazol-3-amine, or a pharmaceutically acceptable salt thereof.

[0095] E33 A pharmaceutical composition comprising a compound of any one of embodiments E1 to E32, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0096] E34 A method 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 (B°AT1) transport, comprising administering to a subject in need thereof a compound of any one of embodiments E1 to E32, or a pharmaceutically acceptable salt thereof.

[0097] E35 A method of embodiment E34, wherein said disease or disorder is 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), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, or neurodevelopmental and autism-spectrum disorders.

[0098] E36 A method of embodiment E35, wherein said disease or disorder is urea cycle deficiency, urea cycle disorder, phenylketonuria, or chronic kidney disease.

[0099] E37 A compound of any one of embodiments E1 to E32, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0100] E38 A compound of any one of embodiments E1 to E32, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B°AT1) transport.

[0101] E39 A compound for use in the treatment of a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B°AT1) transport according to embodiment E38, wherein said disease or disorder is 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), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, or neurodevelopmental and autism-spectrum disorders.

[0102] E40 Use of a compound of any one of embodiments E1 to E32, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament in the treatment of a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B°AT1) transport.

[0103] E41 Use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament in the treatment of a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B°AT1) transport according to embodiment E40, wherein said disease or disorder is 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), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolic syndrome, obesity related disorders, heart failure, or neurodevelopmental and autism-spectrum disorders.

[0104] E42 A pharmaceutical combination comprising a compound of any one of embodiments E1 to E32, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent or a pharmaceutically acceptable salt thereof.

[0105] E43 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E42 and at least one excipient.

[0106] 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.

[0107] Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds described herein. Definitions

[0108] 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.

[0109] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

[0110] “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.

[0111] 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.

[0112] 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.

[0113] 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).

[0114] “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.

[0115] 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 (=0) 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.

[0116] “Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I).

[0117] “Cyano” refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e. , -C=N.

[0118] "Hydroxy" refers to an -OH group.

[0119] “Oxo” refers to a double bonded oxygen (=0).

[0120] "Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 6 carbon atoms (“Ci-Ce alkyl”), 1 to 5 carbon atoms (“C1-C5 alkyl”), 1 to 4 carbon atoms (“C1-C4 alkyl”), 1 to 3 carbon atoms (“C1-C3 alkyl”), or 1 to 2 carbon atoms (“C1-C2 alkyl”). 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.

[0121] “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. Haloalkyl groups man contain, but are not limited to, 1-6 carbon atoms (“Ci-Ce haloalkyl”), 1-4 carbon atoms (“C1-C4 haloalkyl”), or 1-2 carbon atoms (“C1-C2 haloalkyl”). More specifically, fluorinated alkyl groups may be specifically referred to as “fluoroalkyl.”

[0122] “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. Examples include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of fully substituted fluoroalkyl groups (also referred to as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0123] “Alkoxy” refers to an alkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as alkyl-O-. Alkoxy groups may contain, but are not limited to, 1 to 6 carbon atoms (“Ci-Ce alkoxy”), 1 to 4 carbon atoms (“C1-C4 alkoxy”), or 1 to 3 carbon atoms (“C1-C3 alkoxy”). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, and the like.

[0124] “Haloalkoxy” refers to an alkoxyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen. Haloalkoxy groups may contain, but are not limited to, 1-6 carbon atoms, (“Ci-Ce haloalkoxy”), 1-4 carbon atoms (“C1-C4 haloalkoxy”), or 1-2 carbon atoms (“C1-C2 haloalkoxy”). More specifically, fluorinated alkoxyl groups may be specifically referred to as “fluoroalkoxy.” “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-C6 cycloalkyl”), 3 to 5 carbon atoms (“C3-C5 cycloalkyl”) or 3 to 4 carbon atoms (“C3-C4 cycloalkyl”). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0125] Cycloalkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

[0126] “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, 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. 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.

[0127] 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.

[0128] Heterocycloalkyl rings may include, but are not limited to, 3-8 membered heterocyclyl groups, for example 4-7 or 4-6 membered heterocycloalkyl groups, in accordance with the definition herein.

[0129] 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) (t iepanyl) (azepanyl) (1 ,4-dioxepanyl) (1 ,4-oxathiepanyl)

[0130] 1 ,4-oxaazepane 1 ,4-thieazepane 1 ,4-diazepane 1 ,4-dithiepane (1 ,4-oxaazepanyl) (1 ,4-thieazapanyl) (1 ,-diazepanyl)or(1 ,4-dithiepanyl)

[0131] "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 ("Ce-Cioaryl"). 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.

[0132] 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.

[0133] Illustrative examples of monocyclic heteroaryl groups include, but are not limited to a monovalent radical of: pyrrole furan thiophene pyrazole imidazole isoxazole

[0134] (pyrrolyl) (furanyl) (thiophenyl) (pyrazolyl) (imidazolyl) (isoxazolyl) oxazole isothiazole thiazolyl 1 ,2, 3-triazole 1 ,3,4-triazole (oxazolyl) (isothiazolyl) (thiazolyl) (1 ,2,3-triazolyl) (1 ,3,4-triazolyl) (1-oxa-2,3-diazolyl)

[0135] 1-oxa-2,4-diazole 1-oxa-2,5-diazole 1 -oxa-3,4-diazole 1-thia-2,3-diazole l-thia-2,4-diazole

[0136] (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)

[0137] 1-thia-2,5-diazole 1 -thia-3,4-diazole tetrazole pyridine pyridazine pyrimidine pyrazine

[0138] (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: benzofuran benzothiophene indole benzimidazole indazole

[0139] (benzofuranyl) (benzothiophenyl) (benzimidazolyl) (indazolyl)

[0140]

[0141] “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 form -NRxRy, where each of Rx and Ry is defined as further described herein. For example, “alkylamino” refers to a group -NRxRy, wherein one of Rx and Ry is an alkyl moiety and the other is H, and “dialkylamino” refers to -NRxRy wherein both of Rx and Ry are alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., -NH(CI-C4 alkyl) or -N(CI-C4 alkyl^).

[0142] 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.

[0143] 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.

[0144] “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).

[0145] "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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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:

[0151] (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;

[0152] (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

[0153] (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

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0159] 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.

[0160] 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

[0161] (i) by reacting a compound of the invention with the desired acid or base;

[0162] (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.

[0163] 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.

[0164] Solvates

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] Solid form

[0170] 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’).

[0171] 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 -SOs'Na+) or non-ionic (such as -N'N+(CH3)S) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970).

[0172] Stereoisomers

[0173] Compounds of the invention may exist as two or more stereoisomers. Stereoisomers of the compounds may include c / s 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.

[0174] 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).

[0175] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0176] 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).

[0177] 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).

[0178] Tautomerism

[0179] 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.

[0180] 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.

[0181] Isotopes

[0182] 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.

[0183] 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 as36CI, fluorine, such as18F, iodine, such as123l and125l, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

[0184] 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.

[0185] 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.

[0186] In some embodiments, one or more hydrogen atoms on certain metabolic sites on the compounds of the invention are deuterated.

[0187] 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.

[0188] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, de-acetone, de- DMSO.

[0189] Metabolites

[0190] 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):

[0191] (ii) where the compound of the invention contains an alkoxy group, a hydroxy derivative thereof (-OR -> -OH);

[0192] (iii) where the compound of the invention contains a tertiary amino group, a secondary amino derivative thereof (-NRR’ -> -NHR or -NHR);

[0193] (iv) where the compound of the invention contains a secondary amino group, a primary derivative thereof (-NHR-> -NH2);

[0194] (v) where the compound of the invention contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH);

[0195] (vi) where the compound of the invention contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> COOH); and

[0196] (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.

[0197] Pharmaceutical Compositions

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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. OSS- OSS, 1000.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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).

[0210] 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.

[0211] 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.

[0212] 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).

[0213] 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.

[0214] 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.

[0215] 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 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

[0216] 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).

[0217] 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.

[0218] 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.

[0219] Administration and Dosing

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] Therapeutic Methods and Uses

[0226] 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 (B°AT1) transport. See WO2023122267.

[0227] 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.

[0228] 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 neurodevelopmentai and autism-spectrum disorders.

[0229] 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.

[0230] 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.

[0231] 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”.

[0232] 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.

[0233] 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.

[0234] Kits

[0235] 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.

[0236] Synthetic Methods

[0237] 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.

[0238] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are discussed below, other starting materials and reagents may be substituted to provide one or more of a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below may be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0239] The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of the invention. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

[0240] In the preparation of compounds of the invention it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., a primary amine, secondary amine, carboxyl, etc. in a precursor of a compound of the invention). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition.

[0241] For example, if a compound contains an amine or carboxylic acid functionality, such functionality may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group (PG) which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as / V-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9- fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of the invention.

[0242] Abbreviations

[0243] APCI is atmospheric pressure chemical ionization; br is broad;

[0244] °C is degrees celcius;

[0245] CM BP is (tributyl-A5-phosphanylidene)acetonitrile;

[0246] DCM is dichloromethane;

[0247] 5 is chemical shift; d is doublet;

[0248] DIEPA is / V, / V-diisopropylethylamine;

[0249] DMF is N,N-dimethylformamide;

[0250] DMSO is dimethyl sulfoxide;

[0251] DMSO-de is deuterodimethylsulfoxide;

[0252] El is electron impact ionization;

[0253] ES is electron scatter;

[0254] ESI is electrospray ionization; g is gram;

[0255] GCMS is gas chromatography-mass spectrometry;

[0256] HATLI is 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;

[0257] HPLC is high pressure liquid chromatography; hr(s) is hour(s); L is liter;

[0258] LCMS is liquid chromatography mass spectrometry;

[0259] LG is leaving group; m is multiplet;

[0260] M is molar;

[0261] MeCN is acetonitrile; mg is milligram;

[0262] MHz is mega Hertz; min(s) is minute(s); mL is milliliter; mmol is millimole; mol is mole;

[0263] MPLC is medium performance liquid chromatography;

[0264] MS (m / z) is mass spectrum peak;

[0265] NIS is / V-iodosuccinimide;

[0266] NMR is nuclear magnetic resonance;

[0267] PEG is polyethylene glycol;

[0268] PPhs is triphenylphosphine; pH is power of hydrogen; ppm is parts per million; q is quartet; rt is room temperature;

[0269] RT is retention time; s is singlet;

[0270] SFC is supercritical fluid chromatography; t is triplet; t-Bu XPhos is di-terf-butyl[2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane;

[0271] TEMPO is (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl;

[0272] TFA is trifluoroacetic acid;

[0273] THF is tetrahydrofuran;

[0274] TLC is thin layer chromatography;

[0275] LIPLC is ultra-performance liquid chromatography; pL is microliter; and pmol is micromole.

[0276] 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, the resolution to the desired optically active material may take place at any desired point in the sequence using well known methods such as 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, 10 Georg Thieme Verlag, 1994). Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC.

[0277] General Methods:

[0278] Unless stated otherwise, the variables R1, R3, R4, R5, and A in Schemes l-l V have the same meanings or may be precursors of R1, R3, R4, R5, and A as defined herein.

[0279] Scheme I refers to preparation of substituted indoles and azaindoles that are represented by Formula (vi). Starting materials (i) and (iv) are either commercially available or may be synthesized by those of ordinary skill in the art using literature procedures or preparations described herein.

[0280] Intermediate (ii) may be prepared from starting material (i) using a suitable iodinating agent (such as NIS) and suitable organic or inorganic solvents (such as DMF). Trifluoroacetamide formation from intermediate (ii) may be carried out with trifluoroacetic anhydride in the presence of a suitable base (such as triethylamine) in suitable organic or inorganic solvents (such as THF). Intermediate (v) may be prepared from a Sonogashira coupling between intermediate (iii) and intermediate (iv) in the presence of a palladium catalyst (such as Pd(PPh3)2Ch), a copper catalyst (such as Cui), and a base (such as triethylamine) in a suitable solvent (such as THF). Cyclization of intermediate (v) may be carried out in the presence of a copper catalyst (such as Cui) and a base (such as K2CO3) in a suitable solvent (such as acetonitrile) to generate compounds of Formula (vi). Alternatively, compounds of Formula (vi) may also be obtained directly from a one-pot coupling / cyclization procedure from intermediate (iii) and intermediate (iv) in the presence of a palladium catalyst (such as Pd(PPh3)2Ch), a copper catalyst (such as Cui), and a base (such as triethylamine) in a suitable solvent (such as THF).

[0281] Scheme II

[0282] Alternatively, compounds of Formula (vi) may be prepared from intermediate (vii) as illustrated by Scheme II. Intermediates (vii), (ix), and (x) are either commercially available or may be synthesized by those of ordinary skill in the art using literature procedures or preparations described herein.

[0283] A leaving group (LG) is herein defined as a functional group that assists with a specific reaction and may be a choice of Cl and imidazole.

[0284] Intermediate (viii) may be prepared from intermediate (vii) in the presence of an acid (such as TFA) in suitable organic or inorganic solvents (such as DCM) as the corresponding salt.

[0285] Intermediate (viii) then may be coupled with carboxylic acid intermediate (ix) in the presence of a suitable amide coupling reagent (such as HATLI) and a suitable base (such as DI PEA) in a suitable solvent (such as DMF / acetonitrile) to generate compounds of Formula (vi).

[0286] Alternatively, intermediate (viii) may be coupled with intermediate (x) in the presence of a suitable base (such as triethylamine) in a suitable solvent (such as THF) to generate compounds of Formula (vi). RX-OH

[0287] (xiii)

[0288] (xi) (xii)(xiv)(xv)

[0289] Scheme III

[0290] Scheme III refers to preparation of substituted indoles that are represented by Formula (xv). Intermediates (xi), (xiii), and (xiv) are either commercially available or may be synthesized by those of ordinary skill in the art using literature procedures or preparations described herein. A leaving group (LG) is herein defined as a functional group that assists with a specific reaction and may be a choice of Cl, Br, I, OMs (mesylate), OTs (tosylate), or OTf (triflate).

[0291] Intermediate (xii) may be prepared from intermediate (xi) in the presence of a suitable acid (such as BBrs) in a suitable solvent (such as DCM). Compounds of Formula (xv) may be prepared from intermediate (xii) and alcohol intermediate (xiii) through a Mitsunobu reaction in the presence of a suitable phosphine and a suitable azodicarboxylate (or a suitable phosphorane reagent) such as CMBP in a suitable solvent (such as 1 ,4-dioxane). Alternatively, compounds of Formula (xv) may be prepared from intermediate (xii) and intermediate (xiv) through a nucleophilic substitution reaction in the presence of a suitable base (such as CS2CO3) in a suitable solvent (such as butan-2-one). Rxtogether with O has the same meaning of R4or may be a precursor of R4as defined herein.

[0292] R5-NH2

[0293] Scheme IV

[0294] Scheme IV refers to preparation of substituted indoles that are represented by Formula (xix). Intermediates (xvi) and (xviii) are either commercially available or may be synthesized by those of ordinary skill in the art using literature procedures or preparations described herein. Intermediate (xvii) may be prepared from intermediate (xvi) and methyl bromoacetate in the presence of bicyclo[2.2.1]hept-2-ene, a palladium catalyst (such as Pd(MeCN)2Cl2), and a suitable base (such as NaHCOs) in a suitable solvent (such as DMF / water). Compounds of Formula (xix) may be prepared from intermediate (xvii) and (xviii) through a direct amidation reaction in the presence of a suitable base (such as 1 ,3,4,6,7,8-hexahydro-2 / 7-pyrimido[1,2- a]pyrimidine) in a suitable solvent (such as THF).

[0295] EXAMPLES

[0296] In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

[0297] 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.

[0298] 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-Seal™ products from Sigma-Aldrich or DriSolv™ products from EMD Chemicals, Gibbstown, NJ) were employed. In some cases, commercial solvents were passed through columns packed with 4 molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, / V, / V-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.

[0299] 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, C0CI2, 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 pm), 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; Chiral PAK- AD, -AS, -IC, Chiralcel-OD, or -OJ columns; and CO2 mixtures 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.

[0300] 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 (El) 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. Chemical shifts are expressed in parts per million (ppm, 5) referenced to the deuterated solvent residual peaks (chloroform, 7.26 ppm; CD2HOD, 3.31 ppm; acetonitrile-^, 1.94 ppm; dimethyl sulfoxide-cfc, 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.

[0301] Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius).

[0302] Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0303] 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, “LIPLC” refers to ultra-performance liquid chromatography and “HPLC” refers to high-performance liquid chromatography, “SFC” refers to supercritical fluid chromatography.

[0304] 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.

[0305] HPLC, LIPLC, LCMS, GCMS, and SFC retention times were measured using the methods noted in the procedures.

[0306] 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.

[0307] The compounds and intermediates described below were named using the naming convention provided with ACD / ChemSketch 2020.2.1.1 , File Version C25H41, Build 121153 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The naming convention provided with ACD / ChemSketch 2020.2.1.1 is well known by those skilled in the art and it is believed that the naming convention provided with ACD / ChemSketch 2020.2.1.1 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules.

[0308] Preparation P1 terf-Butyl [(5-chloro-6-hydroxy-1 / 7-indol-2-yl)methyl]carbamate (P1)

[0309] Step 1. Synthesis of 4-chloro-2-iodo-5-methoxyaniline (C1)

[0310] Sodium bicarbonate (93.8 g, 1.12 mol) was added to a 20 °C solution of 4-chloro-3- methoxyaniline (80.0 g, 508 mmol) in a mixture of water (160 mL) and tetrahydrofuran (640 mL). The resulting suspension was cooled to -10 °C, whereupon it was treated with iodine (180 g, 709 mmol) and the reaction mixture was stirred for 12 hours at 20 °C. After addition of saturated aqueous sodium thiosulfate solution (1 L), the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluent: 3:1 ethyl acetate I petroleum ether) provided C1 as a brown solid. Yield: 120 g, 423 mmol, 83%.1H NMR (400 MHz, methanol-cL) 8 7.44 (s, 1H), 6.51 (s, 1H), 3.79 (s, 3H).

[0311] Step 2. Synthesis of / V-(4-chloro-2-iodo-5-methoxyphenyl)-2,2,2-trifluoroacetamide (C2) Triethylamine (44.0 mL, 316 mmol) was added to a 25 °C solution of C1 (53.0 g, 187 mmol) in dichloromethane (530 mL), whereupon the solution was cooled to -10 °C. Trifluoroacetic anhydride (35.6 mL, 252 mmol) was added, and the reaction mixture was stirred at -10 °C for 1 hour before being poured into water (500 mL) and extracted with dichloromethane (3 x 300 mL). The combined organic layers were washed sequentially with saturated aqueous ammonium chloride solution (2 x 300 mL), saturated aqueous sodium bicarbonate solution (3 x 300 mL), and saturated aqueous sodium chloride solution (300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Eluent: 3:1 ethyl acetate I petroleum ether) afforded C2 as a white solid. Yield: 69 g, 180 mmol, 96%.1H NMR (400 MHz, chloroform-d) 8 8.27 (br s, 1 H), 8.00 (s, 1 H), 7.76 (s, 1 H), 3.93 (s, 3H).

[0312] Step 3. Synthesis of ferf-butyl {3-[5-chloro-4-methoxy-2-(2,2,2-trifluoroacetamido)phenyl]prop-2- yn-1-yl}carbamate (C3)

[0313] A mixture of C2 (20.0 g, 52.7 mmol), terf-butyl prop-2-yn-1-ylcarbamate (9.00 g, 58.0 mmol), copper(l) iodide (1.00 g, 5.25 mmol), bis(triphenylphosphine)palladium(ll) dichloride (1.11 g, 1.58 mmol), and triethylamine (21.9 mL, 157 mmol) in tetrahydrofuran (200 mL) was stirred at 20 °C for 16 hours, whereupon it was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo, providing C3 as a grey solid (22 g). A portion of this material was progressed directly to the following step. LCMS m / z 351.1 (chlorine isotope pattern observed) [(M - 2-methylprop-1- ene)+H]+.

[0314] Step 4. Synthesis of terf-butyl [(5-chloro-6-methoxy-1 / 7-indol-2-yl)methyl]carbamate (C4)

[0315] A mixture of C3 (from the previous step; 15.0 g <35.9 mmol), copper(l) iodide (1.40 g, 7.35 mmol), and potassium carbonate (15.3 g, 111 mmol) in acetonitrile (200 mL) was stirred at 70 °C for 9 hours. After the reaction mixture had been diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL), the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo, silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum) provided C4 as a yellow solid. Yield: 9.30 g, 29.9 mmol, 83% over 2 steps.1H NMR (400 MHz, chloroform-d) 8 8.91 (br s, 1 H), 7.52 (s, 1 H), 6.89 (s, 1 H), 6.18 (br s, 1 H), 5.12 - 5.02 (m, 1 H), 4.32 (d, J = Q.2 Hz, 2H), 3.91 (s, 3H), 1.48 (s, 9H).

[0316] Step 5. Synthesis of ferf-butyl [(5-chloro-6-hydroxy-1 / 7-indol-2-yl)methyl]carbamate (P1)

[0317] A suspension of C4 (4.50 g, 14.5 mmol) in dichloromethane (70 mL) was cooled in an ice I ethanol bath, whereupon boron tribromide (4.19 mL, 44.3 mmol) was added drop-wise. The reaction mixture was stirred at 0 °C for 1 hour, slowly warmed to 20 °C, and stirred for 3 days. After the reaction mixture had been cooled to 0 °C, it was treated with methanol (20 mL), stirred for 20 minutes, and concentrated in vacuo. The residue was dissolved in methanol (15 mL) and concentrated under reduced pressure. After the dissolution-concentration procedure had been carried out a total of three times, the phenol intermediate was obtained as a black solid. This material was combined with triethylamine (15.9 mL, 114 mmol) in a mixture of dichloromethane (60 mL) and methanol (15 mL), then cooled in an ice bath. After drop-wise addition of di-terf-butyl dicarbonate (3.73 g, 17.1 mmol), the reaction mixture was stirred at 0 °C for 10 minutes, warmed slowly to 20 °C, and stirred for 16 hours. Removal of volatiles in vacuo was followed first by chromatography on silica gel (Gradient: 0% to 3% methanol in dichloromethane), and then by a second purification via silica gel chromatography (Gradient: 5% to 40% ethyl acetate in petroleum ether), affording P1 as a gray solid. Yield: 2.73 g, 9.20 mmol, 63%.1H NMR (400 MHz, chloroform-d) 5 8.80 (br s, 1 H), 7.47 (s, 1 H), 6.97 (s, 1 H), 6.18 (s, 1 H), 5.44 (br s, 1 H), 5.04 (br s, 1 H), 4.31 (d, J = 5.9 Hz, 2H), 1.47 (s, 9H).

[0318] Preparation P2 terf-Butyl [(6-bromo-5-chloro-1 / 7-indol-2-yl)methyl]carbamate (P2)

[0319] K2CO3

[0320] Step 1 . Synthesis of 5-bromo-4-chloro-2-iodoaniline (C5)

[0321] To a 0 °C suspension of 3-bromo-4-chloroaniline (67.0 g, 324 mmol) in a mixture of methanol (300 mL) and dichloromethane (300 mL) was added, drop-wise over 30 minutes, a solution of iodine monochloride (58.0 g, 357 mmol) in dichloromethane (300 mL). After the reaction mixture had been stirred at 25 °C for 3 days, it was diluted with water (30 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 2% ethyl acetate in petroleum ether) provided C5 as a solid. Yield: 40.0 g, 120 mmol, 37%.1H NMR (400

[0322] MHz, chloroform-d) 5 7.66 (s, 1 H), 6.97 (s, 1 H), 4.13 (br s, 2H).

[0323] Step 2. Synthesis of / V-(5-bromo-4-chloro-2-iodophenyl)-2,2,2-trifluoroacetamide (C6)

[0324] Trifluoroacetic anhydride (5.09 mL, 36.0 mmol) was added drop-wise to a 0 °C solution of C5 (10.0 g, 30.1 mmol) and triethylamine (5.45 mL, 39.1 mmol) in tetrahydrofuran (100 mL). The reaction mixture was slowly warmed to 25 °C and stirred overnight, whereupon it was diluted with ethyl acetate (300 mL), washed sequentially with saturated aqueous ammonium chloride solution (100 mL), aqueous sodium bicarbonate solution (100 mL), and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo, affording C6 as a yellow solid. Yield: 11.0 g, 25.7 mmol, 85%.1H NMR (400 MHz, chloroform-d) 5 8.54 (s, 1 H), 8.21 (br s, 1H), 7.91 (s, 1H).

[0325] Step 3. Synthesis of tert-butyl [(6-bromo-5-chloro-1 / 7-indol-2-yl)methyl]carbamate (P2)

[0326] A mixture of C6 (2.00 g, 4.67 mmol), tert-butyl prop-2-yn-1-ylcarbamate (725 mg, 4.67 mmol), potassium carbonate (1.29 g, 9.33 mmol), copper(l) iodide (35.6 mg, 0.187 mmol), and bis(triphenylphosphine)palladium(ll) dichloride (32.8 mg, 46.7 pmol) in / V, / V-dimethylformamide (30 mL) was sparged with nitrogen for 1 minute, whereupon the reaction mixture was stirred at 60 °C for 3 days. It was then diluted with ethyl acetate (100 mL) and washed with water (3 x 50 mL). The combined aqueous layers were extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (3 x 50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 5% ethyl acetate in dichloromethane) provided P2 as a yellow solid. Yield: 1.25 g, 3.48 mmol, 74%.1H NMR (400 MHz, chloroform-d) 5 9.05 (br s, 1 H), 7.62 (s, 1H), 7.60 (s, 1H), 6.23 (br s, 1 H), 5.15 - 5.03 (m, 1 H), 4.33 (d, J = 6.2 Hz, 2H), 1.48 (s, 9H).

[0327] Preparation P3 tert-Butyl [(6-bromo-5-chloro-1 / 7-pyrrolo[2,3-b]pyridin-2-yl)methyl]carbamate (P3)

[0328] Step 1. Synthesis of 6-bromo-5-chloro-3-iodopyridin-2-amine (C7)

[0329] To a solution of 6-bromo-5-chloropyridin-2-amine (10.0 g, 48.2 mmol) in N,N- dimethylformamide (67 mL) was added trifluoroacetic acid (4.43 mL, 57.5 mmol), followed by N- iodosuccinimide (11.9 g, 52.9 mmol). After the reaction mixture had been stirred at 50 °C for 4 hours, LCMS analysis indicated conversion to C7: LCMS m / z 334.4 (bromo chloro isotope pattern observed) [M+H]+. The reaction mixture was added to water (54 mL), neutralized to a pH of 9 by addition of sodium thiosulfate (5.00 g, 31.6 mmol) and aqueous sodium hydroxide solution (1 M; 80 mL), and filtered, affording C7 as a brown solid. Yield: 15.5 g, 46.5 mmol, 96%.1H NMR (400 MHz, chloroform-d) 8 7.83 (s, 1 H), 5.09 (br s, 2H).

[0330] Step 2. Synthesis of / V-(6-bromo-5-chloro-3-iodopyridin-2-yl)-2,2,2-trifluoroacetamide (C8) Trifluoroacetic anhydride (7.78 mL, 55.1 mmol) was added drop-wise to a 0 °C solution of C7 (15.5 g, 46.5 mmol) and triethylamine (8.45 mL, 60.6 mmol) in tetrahydrofuran (311 mL). The reaction mixture was then slowly warmed to 25 °C and stirred for 10 hours, whereupon it was partitioned between ethyl acetate (70 mL) and aqueous ammonium chloride solution (210 mL) and extracted with ethyl acetate (3 x 140 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (140 mL), dried over sodium sulfate, filtered, and concentrated in vacua, chromatography on silica gel (Gradient: 30% to 60% ethyl acetate in petroleum ether) provided C8 as a brown solid. Yield: 18.8 g, 43.8 mmol, 94%. LCMS m / z 430.6 (bromo chloro isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-cL) 8 8.52 (s, 1 H).

[0331] Step 3. Synthesis of tert-butyl [(6-bromo-5-chloro-1 / 7-pyrrolo[2,3-b]pyridin-2- yl)methyl]carbamate (P3)

[0332] Bis(triphenylphosphine)palladium(ll) dichloride (65.4 mg, 93.2 pmol), copper(l) iodide (26.6 mg, 0.140 mmol), tert-butyl prop-2-yn-1-ylcarbamate (1.08 g, 6.96 mmol), and triethylamine (1.94 mL, 13.9 mmol) were added to a solution of C8 (2.00 g, 4.66 mmol) in tetrahydrofuran (35 mL). After the reaction mixture had been stirred at 25 °C for 16 hours, copper(l) iodide (26.6 mg, 0.140 mmol) and bis(triphenylphosphine)palladium(ll) dichloride (65.4 mg, 93.2 pmol) were again added, and the reaction mixture was stirred at 45 °C for 3 hours. It was then concentrated in vacua, silica gel chromatography (Gradient: 0% to 70% ethyl acetate in petroleum ether) provided P3 as a yellow solid. Yield: 1.32 g, 3.66 mmol, 78%. LCMS m / z 361.7 (bromo chloro isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-^) 8 7.99 (s, 1 H), 6.30 (br s, 1 H), 4.36 (s, 2H), 3.88 (br s, 1 H), 1.46 (s, 9H).

[0333] Preparation P4

[0334] / \ / -[(5-Chloro-6-hydroxy-1 / 7-indol-2-yl)methyl]propanamide (P4)

[0335] Step 1. Synthesis of / V-{3-[5-chloro-4-methoxy-2-(2,2,2-trifluoroacetamido)phenyl]prop-2-yn-1- yljpropanamide (C9)

[0336] After a mixture of C2 (143 g, 377 mmol), / V-(prop-2-yn-1-yl)propanamide (62.8 g, 565 mmol), and triethylamine (157 mL, 1.13 mol) in tetrahydrofuran (1.4 L) was degassed 3 times with nitrogen, copper(l) iodide (2.15 g, 11.3 mmol) and bis(triphenylphosphine)palladium(ll) dichloride (5.29 g, 7.54 mmol) were added. The reaction mixture was again degassed 3 times with nitrogen, whereupon it was stirred at 20 °C for 2 hours and then partitioned between ethyl acetate (1.5 L) and water (2 L). The aqueous layer was extracted with ethyl acetate (3 x 1.5 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution (2 L), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was treated with a mixture of petroleum ether and ethyl acetate (5:1 , 1.3 L), stirred for 15 minutes, and filtered. The filter cake was triturated in the same way to afford C9 as a gray solid. Yield: 130 g, 358 mmol, 95%.1H NMR (400 MHz, DMSO-cfe) 8 11.12 (br s, 1 H), 8.23 (br t, J = 5.5 Hz, 1 H), 7.57 (s, 1H), 7.25 (s, 1H), 4.08 (d, J = 5.4 Hz, 2H), 3.87 (s, 3H), 2.09 (q, J = 7.6 Hz, 2H), 0.99 (t, J = 7.6 Hz, 3H).

[0337] Step 2. Synthesis of / V-[(5-chloro-6-methoxy-1 / 7-indol-2-yl)methyl]propanamide (C10)

[0338] This experiment was carried out in two identical batches. A mixture of C9 (175 g, 482 mmol), copper(l) iodide (9.19 g, 48.2 mmol), and potassium carbonate (133 g, 962 mmol) in acetonitrile (20 L) was degassed 3 times with nitrogen, whereupon it was stirred at 80 °C (inner reaction temperature 70 °C) for 16 hours. The reaction mixture was concentrated in vacuo, and the two batches were combined; this material was partitioned between ethyl acetate (2 L) and water (1 L). After extraction of the aqueous layer with ethyl acetate (2 x 1 L), the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 20% to 80% ethyl acetate in petroleum ether) yielded material (170 g) that was then treated with a mixture of petroleum ether and ethyl acetate (3:1 , 2 L) and stirred for 30 minutes. Collection via filtration afforded C10 as an off-white solid. Combined yield: 132 g, 495 mmol, 51%. LCMS m / z 266.9 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, chloroform-d) 5 9.07 (br s, 1 H), 7.51 (s, 1H), 6.87 (s, 1H), 6.17 (br s, 1H), 6.15 - 6.06 (m, 1 H), 4.43 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.26 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H).

[0339] Step 3. Synthesis of / V-[(5-chloro-6-hydroxy-1 / 7-indol-2-yl)methyl]propanamide (P4)

[0340] Boron tribromide (59.6 mL, 630 mmol) was added slowly, in a drop-wise manner, to a -70 °C solution of C10 (55.0 g, 206 mmol) in dichloromethane (350 mL). After the reaction mixture had been stirred at 25 °C for 16 hours, it was cooled to 0 °C and treated drop-wise with methanol (100 mL). Aqueous ammonium hydroxide solution (130 mL) was then added slowly at 0 °C until the pH reached 9, whereupon the mixture was diluted with water (150 mL) and tetrahydrofuran (500 mL). The aqueous layer was extracted with a mixture of tetrahydrofuran and dichloromethane (1:1, 3 x 400 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting material was treated with dichloromethane (300 mL), stirred for 1 hour, and filtered; the filter cake was mixed with ethyl acetate (500 mL) and methanol (10 mL) and stirred for 1 hour. Filtration afforded P4 as a white solid. Yield: 32.1 g, 127 mmol, 62%. LCMS m / z 253.0 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-cfe) 8 10.65 (br s, 1 H), 9.46 (s, 1H), 8.20 (br t, J = 5.6 Hz, 1H), 7.37 (s, 1H), 6.92 (s, 1H), 6.11 - 6.06 (m, 1 H), 4.31 (d, J = 5.6 Hz, 2H), 2.14 (q, J = 7.6 Hz, 2H), 1.03 (t, J = 7.6 Hz, 3H).

[0341] Preparation P5

[0342] / V-[(6-Bromo-5-chloro-1 / 7-indol-2-yl)methyl]propanamide (P5)

[0343] Cui

[0344] K2CO3

[0345] A mixture of / V-(prop-2-yn-1-yl)propanamide (6.23 g, 56.1 mmol), C6 (15.0 g, 35.0 mmol), triethylamine (14.6 mL, 105 mmol), copper(l) iodide (200 mg, 1.05 mmol), and bis(triphenylphosphine)palladium(ll) dichloride (492 mg, 0.701 mmol) in acetonitrile (200 mL) was sparged with nitrogen for 1 minute. After the reaction mixture had been stirred at 20 °C for 1 hour, copper(l) iodide (1.30 g, 6.83 mmol), and potassium carbonate (9.40 g, 68.0 mmol) were added, and the reaction mixture was sparged with nitrogen for 1 minute and stirred at 80 °C. After 16 hours, LCMS analysis indicated conversion to P5: LCMS m / z 316.7 (bromo chloro isotope pattern observed) [M+H]+. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (250 mL); the aqueous layer was extracted with ethyl acetate (2 x 80 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting material was treated with a mixture of petroleum ether and ethyl acetate (3:1 , 100 mL), stirred for 30 minutes, and filtered, providing P5 as an off-brown solid. Yield: 7.00 g, 22.2 mmol, 63%.1H NMR (400 MHz, chloroform-d) 8 9.20 (br s, 1 H), 7.62 (s, 1 H), 7.59 (s, 1 H), 6.25 - 6.20 (m, 1 H), 6.11 - 6.02 (m, 1 H), 4.45 (d, J = 6.1 Hz, 2H), 2.28 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H).

[0346] Preparation P6

[0347] / V-[(6-Bromo-5-chloro-1 / 7-pyrrolo[2,3-b]pyridin-2-yl)methyl]propanamide (P6) K2CO3

[0348] A mixture of C8 (4.0 g, 9.3 mmol), / V-(prop-2-yn-1-yl)propanamide (1.11 g, 9.99 mmol), potassium carbonate (2.03 g, 14.7 mmol), copper(l) iodide (140 mg, 0.735 mmol), and bis(triphenylphosphine)palladium(ll) dichloride (207 mg, 0.295 mmol) in tetrahydrofuran (58 mL) was sparged with nitrogen for 1 minute, whereupon it was stirred at 60 °C for 4 hours. The reaction mixture was then diluted with aqueous ammonium chloride solution (75 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 x 90 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified using silica gel chromatography (Gradient: 80% to 100% ethyl acetate in dichloromethane) to afford P6 as a white solid. Yield: 1 .30 g, 4.11 mmol, 44%. LCMS m / z 317.9 (bromo chloro isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) 8 7.99 (s, 1 H), 6.32 (s, 1 H), 4.50 (s, 2H), 2.29 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H).

[0349] Preparation P7 tert-Butyl 2-{[(tert-butoxycarbonyl)(propanoyl)amino]methyl}-5-chloro-6-formyl-1 / - / -indole-1 - carboxylate (P7)

[0350]

[0351] Step 1. Synthesis of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-chloroaniline (C11) tert-Butyl(dimethyl)silyl chloride (13.2 g, 87.6 mmol) was added portion-wise over 20 minutes to a 0 °C solution of (5-amino-2-chlorophenyl)methanol (12.5 g, 79.3 mmol) and 1 / 7- imidazole (7.02 g, 103 mmol) in dichloromethane (200 mL). The reaction mixture was stirred at 20 °C for 16 hours, whereupon it was diluted with water (300 mL) and extracted with dichloromethane (2 x 100 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) provided C11 as a yellow oil (23.0 g), the bulk of which was used in the following step. LCMS m / z 272.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, chloroform-d) 5 7.05 (d, J = 8.4 Hz, 1 H), 6.91 - 6.87 (m, 1 H), 6.50 (dd, J = 8.4, 2.9 Hz, 1 H), 4.71 (s, 2H), 3.68 (v br s, 2H), 0.96 (s, 9H), 0.13 (s, 6H).

[0352] Step 2. Synthesis of 5-({[terf-butyl(dimethyl)silyl]oxy}methyl)-4-chloro-2-iodoaniline (C12) / V-lodosuccinimide (20.0 g, 88.9 mmol) was added portion-wise over 20 minutes to a -10 °C suspension of C11 (from the previous step; 22.0 g, <75.8 mmol) and sodium bicarbonate (7.48 g, 89.0 mmol) in acetonitrile (150 mL), whereupon the reaction mixture was stirred at -10 °C for 1 hour. It was then filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded C12 as a brown oil. Yield: 20.4 g, 51.3 mmol, 68% over 2 steps.1H NMR (400 MHz, chloroform-d) 5 7.53 (s, 1 H), 6.95 - 6.91 (m, 1 H), 4.65 (d, J = 1.1 Hz, 2H), 4.10 (br s, 2H), 0.96 (s, 9H), 0.12 (s, 6H).

[0353] Step 3. Synthesis of / V-[5-({[terf-butyl(dimethyl)silyl]oxy}methyl)-4-chloro-2-iodophenyl]-2,2,2- trifluoroacetamide (C13)

[0354] Trifluoroacetic anhydride (3.83 mL, 27.1 mmol) was added drop-wise to a 0 °C solution of C12 (9.00 g, 22.6 mmol) and triethylamine (4.10 mL, 29.4 mmol) in tetrahydrofuran (100 mL), whereupon the reaction mixture was slowly warmed to 25 °C and stirred for 3 hours. It was then combined with a similar reaction carried out using C12 (20.0 g, 50.3 mmol), diluted with ethyl acetate (200 mL), and washed with saturated aqueous ammonium chloride solution (200 mL). The aqueous layer was extracted with ethyl acetate (2 x 200 mL) and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 1% ethyl acetate in petroleum ether) provided C13 as a yellow solid. Combined yield: 17.2 g, 34.8 mmol, 48%.1H NMR (400 MHz, chloroform-d) 5 8.42 (s, 1 H), 8.20 (br s, 1 H), 7.76 (s, 1 H), 4.74 (s, 2H), 0.98 (s, 9H), 0.15 (s, 6H).

[0355] Step 4. Synthesis of / V-{3-[4-({[terf-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-2-(2,2,2- trifluoroacetamido)phenyl]prop-2-yn-1-yl}propanamide (C14) A mixture of C13 (12.4 g, 25.1 mmol), / V-(prop-2-yn-1-yl)propanamide (4.19 g, 37.7 mmol), and triethylamine (10.4 mL, 74.6 mmol) in tetrahydrofuran (200 mL) was degassed three times with nitrogen. After addition of copper(l) iodide (287 mg, 1.51 mmol) and bis(triphenylphosphine)palladium(ll) dichloride (881 mg, 1.26 mmol), the reaction mixture was again degassed three times with nitrogen, whereupon it was stirred at 20 °C for 16 hours. Ethyl acetate (300 mL) was added, and the resulting mixture was washed with water (200 mL). The aqueous layer was extracted with ethyl acetate (2 x 200 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 10% to 25% ethyl acetate in petroleum ether) afforded C14 as a yellow gum. Yield: 10.9 g, 22.9 mmol, 91%. LCMS m / z 477.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, chloroform-d) 5 8.60 (br s, 1 H), 8.53 (s, 1 H), 7.38 (s, 1 H), 5.77 (br s, 1 H), 4.76 (s, 2H), 4.34 (d, J = 5.5 Hz, 2H), 2.27 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H), 0.98 (s, 9H), 0.15 (s, 6H).

[0356] Step 5. Synthesis of / V-{[6-({[terf-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1 / 7-indol-2- yl]methyl}propanamide (C15)

[0357] A mixture of C14 (10.9 g, 22.9 mmol), copper(l) iodide (435 mg, 2.28 mmol), and potassium carbonate (6.32 g, 45.7 mmol) in acetonitrile (200 mL) was degassed three times with nitrogen, whereupon it was stirred at 80 °C for 16 hours, and then at 90 °C for 24 hours. After the reaction mixture had been diluted with ethyl acetate (200 mL) and washed with water (100 mL), the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated in vacuo, and purified via silica gel chromatography (Gradient: 10% to 30% ethyl acetate in petroleum ether), providing C15 as a yellow gum. Yield: 5.40 g, 14.2 mmol, 62%. LCMS m / z 381.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, chloroform-d) 5 9.06 (br s, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 6.22 (s, 1H), 6.10 - 6.01 (m, 1H), 4.86 (s, 2H), 4.46 (d, J = 6.1 Hz, 2H), 2.27 (q, J = 7.5 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H), 0.99 (s, 9H), 0.15 (s, 6H).

[0358] Step 6. Synthesis of / V-{[5-chloro-6-(hydroxymethyl)-1 / 7-indol-2-yl]methyl}propanamide (C16) A solution of C15 (5.20 g, 13.6 mmol) in tetrahydrofuran (50 mL) was treated with a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M; 20.5 mL, 20.5 mmol), whereupon the reaction mixture was stirred at 20 °C for 3 hours. After removal of solvent in vacuo, silica gel chromatography (Gradient: 0% to 3% methanol in ethyl acetate) afforded C16 as an off-white solid. Yield: 3.00 g, 11.2 mmol, 82%. LCMS m / z 249.0 (chlorine isotope pattern observed) [(M - H2O)+H]+.1H NMR (400 MHz, chloroform-d) 5 11.06 (s, 1 H), 8.29 (br t, J = 5.6 Hz, 1 H), 7.48 (s, 1 H), 7.46 (s, 1 H), 6.23 - 6.18 (m, 1 H), 5.27 (t, J = 5.6 Hz, 1 H), 4.59 (d, J = 5.6 Hz, 2H), 4.38 (d, J = 5.6 Hz, 2H), 2.16 (q, J = 7.6 Hz, 2H), 1.03 (t, J = 7.6 Hz, 3H).

[0359] Step 7. Synthesis of / V-[(5-chloro-6-formyl-1 / 7-indol-2-yl)methyl]propanamide (C17)

[0360] Dess-Martin periodinane {[1 ,1 ,1 -tris(acetyloxy)-1 , 1 -dihydro-1 ,2-benziodoxol-3-(1 / 7)-one]; 5.72 g, 13.5 mmol} was added to a 0 °C solution of C16 (3.00 g, 11.2 mmol) in a mixture of dichloromethane (80 mL) and dimethyl sulfoxide (8.0 mL). After the reaction mixture had been stirred at 20 °C for 2 hours, it was treated drop-wise with saturated aqueous sodium bicarbonate solution (40 mL). The aqueous layer was extracted sequentially with ethyl acetate (3 x 50 mL) and a mixture of dichloromethane and methanol (10:1 , 3 x 40 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 30% to 100% ethyl acetate in petroleum ether) provided C17 as an off-white solid. Yield: 2.60 g, 9.82 mmol, 88%. LCMS m / z 264.9 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-cfe) 8 11.65 (br s, 1 H), 10.34 (s, 1 H), 8.40 (br t, J = 5.6 Hz, 1 H), 7.89 (s, 1 H), 7.66 (s, 1 H), 6.40 - 6.35 (m, 1 H), 4.44 (d, J = 5.7 Hz, 2H), 2.18 (q, J = 7.6 Hz, 2H), 1.04 (t, J = 7.6 Hz, 3H).

[0361] Step 8. Synthesis of tert-butyl 2-{[(tert-butoxycarbonyl)(propanoyl)amino]methyl}-5-chloro-6- formyl-1 / - / -indole-1 -carboxylate (P7)

[0362] To a solution of C17 (2.60 g, 9.82 mmol) and 4-(dimethylamino)pyridine (600 mg, 4.91 mmol) in tetra hydrofuran (80 mL) was added di-fert-butyl dicarbonate (6.43 g, 29.5 mmol), whereupon the reaction mixture was stirred at 20 °C for 2 hours. After removal of solvent in vacuo, purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded P7 as a white solid. Yield: 3.60 g, 7.74 mmol, 79%. LCMS m / z 365.1 (chlorine isotope pattern observed) {[M - (2-methylprop-1-ene and CO2)]+H}+.1H NMR (400 MHz, chloroform-d) 8 10.51 (s, 1 H), 8.66 (s, 1 H), 7.46 (s, 1 H), 6.18 - 6.15 (m, 1 H), 5.28 (br s, 2H), 3.00 (q, J = 7.3 Hz, 2H), 1.72 (s, 9H), 1.44 (s, 9H), 1.20 (t, J = 7.3 Hz, 3H).

[0363] Preparation P8

[0364] / V-{4-Chloro-2-iodo-5-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]phenyl}-2,2,2-trifluoroacetamide (P8)

[0365] C18 Step 1. Synthesis of [(5-methyl-1 ,2-oxazol-3-yl)methyl](triphenyl)phosphonium bromide (C18) Triphenylphosphine (21.6 g, 82.4 mmol) was added to a solution of 3-(bromomethyl)-5- methyl-1 ,2-oxazole (10.0 g, 56.8 mmol) in acetonitrile (114 mL), whereupon the reaction mixture was heated at 60 °C (internal reaction temperature) for 20 hours. After addition of methyl tertbutyl ether (150 mL), stirring was continued at room temperature for 15 minutes. Filtration, followed by rinsing of the filter cake with methyl tert-butyl ether (50 mL), afforded C18 as a white solid. Yield: 23.9 g, 54.5 mmol, 96%.1H NMR (400 MHz, DMSO-cfe) 8 7.95 - 7.86 (m, 3H), 7.84 - 7.72 (m, 12H), 5.89 (s, 1 H), 5.38 (d, J = 15.9 Hz, 2H), 2.32 (s, 3H).

[0366] Step 2. Synthesis of tert-butyl [4-chloro-3-(hydroxymethyl)phenyl]carbamate (C19) To a solution of (5-amino-2-chlorophenyl)methanol (14.0 g, 88.8 mmol) in a mixture of tetrahydrofuran (150 mL) and water (50 mL) was added a solution of sodium carbonate (10.4 g, 98.1 mmol) in water (50 mL). After the mixture had been stirred for 5 minutes, di-fert-butyl dicarbonate (22.3 g, 102 mmol) was added in 10 roughly equal portions over approximately 5 minutes, whereupon the reaction mixture was stirred at room temperature overnight. It was then extracted with ethyl acetate (2 x 250 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (150 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was treated with dichloromethane (25 mL), followed by heptane (125 mL), and stirred at room temperature for 15 minutes. Filtration, followed by rinsing of the filter cake with heptane (50 mL) afforded C19 as a solid. Yield: 19.3 g, 74.9 mmol, 84%.1H NMR (400 MHz, DMSO-cfe) 8 9.46 (br s, 1H), 7.74 (d, J = 2.6 Hz, 1H), 7.32 (dd, component of ABX system, J = 8.7, 2.7 Hz, 1 H), 7.24 (d, half of AB quartet, J = 8.6 Hz, 1H), 5.34 (t, J = 5.6 Hz, 1 H), 4.49 (d, J = 5.6 Hz, 2H), 1.47 (s, 9H).

[0367] Step 3. Synthesis of terf-butyl (4-chloro-3-formylphenyl)carbamate (C20)

[0368] To a solution of C19 (19.3 g, 74.9 mmol) in acetonitrile (60 mL) were sequentially added the following: (1) a solution of tetrakis(acetonitrile)copper(l) hexafluorophosphate (1.40 g, 3.76 mmol) in acetonitrile (60 mL); (2) a solution of 2,2'-bipyridine (585 mg, 3.75 mmol) in acetonitrile (60 mL); (3) a solution of (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO; 585 mg, 3.74 mmol) in acetonitrile (60 mL); and (4) 1-methyl-1 / - / -imidazole (0.600 mL, 7.53 mmol). The reaction mixture was rapidly stirred, open to the air, for 3 hours, whereupon a mixture of pentane and diethyl ether (1:1, 500 mL) was added. The resulting mixture was filtered through a plug of silica gel (150 g), and the silica was rinsed with a mixture of pentane and diethyl ether (1 :1 , 200 mL) until the filtrate became colorless. After the filtrate had been concentrated in vacuo at 25 °C, the resulting solid was mixed with heptane (100 mL), granulated via stirring, and filtered; the filter cake was rinsed was heptane (50 mL) to provide C20 as a white solid. The combined filtrates were concentrated under reduced pressure to a volume of approximately 30 mL, and the resulting precipitate was collected via filtration to provide additional C20 as a white solid. Combined yield: 18.2 g, 71.2 mmol, 95%. LCMS m / z 254.1 (chlorine isotope pattern observed) [M-H]-.1H NMR (400 MHz, DMSO-cfe) 8 10.28 (s, 1 H), 9.75 (br s, 1 H), 8.06 (d, J = 2.8 Hz, 1 H), 7.68 (dd, component of ABX system, J = 8.8, 2.8 Hz, 1 H), 7.51 (d, half of AB quartet, J = 8.8 Hz, 1 H), 1.48 (s, 9H).

[0369] Step 4. Synthesis of tert-butyl {4-chloro-3-[2-(5-methyl-1 ,2-oxazol-3- yl)ethenyl]phenyl}carbamate (C21 )

[0370] To a stirred suspension of C18 (35.8 g, 81.7 mmol) in tetrahydrofuran (200 mL) was added a solution of potassium terf-butoxide in tetrahydrofuran (1 M; 80.0 mL, 80.0 mmol) drop- wise, over approximately 10 minutes. After the reaction mixture had been stirred at room temperature for 10 minutes, a solution of C20 (18.2 g, 71.2 mmol) in tetrahydrofuran (100 mL) was added as a steady stream over 4 to 5 minutes, whereupon stirring was continued at room temperature for 25 minutes. Hydrochloric acid (1 M; 40 to 50 drops) was then added, and the resulting mixture was concentrated under reduced pressure (25 °C, 100 mbar) to remove most of the tetrahydrofuran. The residue was partitioned between ethyl acetate (400 mL) and water (120 mL), and the aqueous layer was extracted with ethyl acetate (100 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided C21 as a white solid. The1H NMR spectrum indicated that this material was a mixture of cis and trans double bond isomers. Yield: 21.5 g, 64.2 mmol, 90%. LCMS m / z 335.3 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-cfe), characteristic peaks: 5 [9.54 (br s, major) and 9.51 (br s, minor), total 1 H], 7.97 (d, major, J = 2.4 Hz, <1 H), 7.51 (d, major, J = 16.3 Hz, <1 H), 7.46 - 7.37 (m, 2H), [6.98 (d, major, J = 16.4 Hz) and 6.93 (d, minor, J = 12.1 Hz), total 1 H], [6.75 - 6.71 (m, major) and 5.56 - 5.52 (m, minor), total 1H], 6.69 (d, minor, J = 12.1 Hz, <1 H), [2.43 (br s, major) and 2.28 (d, minor, J = 0.9 Hz), total 3H], [1.49 (s, major) and 1.44 (s, minor), total 9H],

[0371] Step 5. Synthesis of tert-butyl {4-chloro-3-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]phenyl}carbamate (C22)

[0372] Triethylsilane (68.0 mL, 426 mmol) was added drop-wise, over 45 minutes, to a 0 °C mixture of C21 (14.4 g, 43.0 mmol) and palladium on carbon (10%, 2.06 g, 1.94 mmol) in a mixture of tetrahydrofuran (300 mL) and methanol (120 mL). The rate of addition was adjusted to maintain the internal reaction temperature below 8 °C. After the reaction mixture had been stirred for 15 minutes at 0 °C to 8 °C, it was sparged with nitrogen for 10 minutes, diluted with ethyl acetate (150 mL) and methanol (70 mL), stirred for 10 minutes, and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and purified using silica gel chromatography (Gradient: 0% to 40% ethyl acetate in heptane) to afford C22 as a white, waxy solid. Yield: 12.3 g, 36.5 mmol, 85%. LCMS m / z 335.3 (chlorine isotope pattern observed) [M-H]".1H NMR (400 MHz, chloroform-d) 5 7.28 (d, J = 2.6 Hz, 1H), 7.27 - 7.23 (m, 1H, assumed; partially obscured by solvent peak), 7.18 (dd, component of ABC system, J = 8.7, 2.6 Hz, 1 H), 6.46 (br s, 1H), 5.82 (s, 1H), 3.07 - 2.99 (m, 2H), 2.97 - 2.89 (m, 2H), 2.38 (s, 3H), 1.51 (s, 9H). Alternatively, 4-methylbenzene-1 -sulfonohydrazide and potassium tert-butoxide at 90 °C can be used to carry out the reduction; this avoids dechlorination of the substrate during the reaction.

[0373] Step 6. Synthesis of 4-chloro-3-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]aniline (C23) To a 0 °C solution of C22 (3.16 g, 9.38 mmol) in dichloromethane (24 mL) was added trifluoroacetic acid (8.0 mL, 100 mmol); after 2 to 3 minutes, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 75 minutes. Removal of volatiles under reduced pressure (300 to 50 mbar, 25 °C) was followed by partitioning of the residue between dichloromethane (100 mL) and a mixture of saturated aqueous potassium carbonate solution (35 mL) and saturated aqueous sodium chloride solution (10 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. LCMS m / z 237.2 (chlorine isotope pattern observed) [M+H]+. This material was partitioned between dichloromethane (100 mL) and saturated aqueous potassium carbonate solution (35 mL); the organic layer was washed sequentially with saturated aqueous potassium carbonate solution (35 mL) and saturated aqueous sodium chloride solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to provide C23 as a pale-yellow oil. Yield: 2.01 g, 8.49 mmol, 90%.1H NMR (400 MHz, aceton itri I e-cfe) 8 7.05 (d, J = 8.5 Hz, 1 H), 6.56 (d, half of AB quartet, J = 2.8 Hz, 1 H), 6.48 (dd, component of ABX system, J = 8.5, 2.8 Hz, 1 H), 5.98 - 5.96 (m, 1 H), 4.15 (br s, 2H), 2.95 - 2.89 (m, 2H), 2.88 - 2.82 (m, 2H), 2.35 (d, J = 0.9 Hz, 3H).

[0374] Step 7. Synthesis of 4-chloro-2-iodo-5-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]aniline (C24)

[0375] A 15 °C mixture of C23 (2.38 g, 10.0 mmol) and sodium bicarbonate (1.69 g, 20.1 mmol) in a mixture of toluene (3 mL) and water (30 mL) was treated with iodine (3.19 g, 12.6 mmol) in 5 portions over 14 minutes. The reaction mixture was stirred at 1000 rpm to ensure full mixing. After 2.5 hours, saturated aqueous sodium thiosulfate solution (15 mL) was added; the resulting mixture was diluted with aqueous potassium carbonate solution (1 M; 15 mL) and extracted with dichloromethane (2 x 40 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane) afforded C24 as a yellowish-white solid. Yield: 2.75 g, 7.58 mmol, 76%. LCMS m / z 363.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-cL) 8 7.53 (s, 1 H), 6.68 (s, 1 H), 6.00 (s, 1 H), 2.97 - 2.83 (m, 4H), 2.37 (s, 3H). Alternatively, the crude product can be mixed with 4 M hydrochloric acid and 1 ,4-dioxane, stirred, and concentrated in vacuo subsequent slurrying of the residue in tetrahydrofuran, followed by collection via filtration, provides the hydrochloride salt of C24. This work-up removes any byproduct derived from regioisomeric iodination.

[0376] Step 8. Synthesis of / V-{4-chloro-2-iodo-5-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]phenyl}-2,2,2- trifluoroacetamide (P8) Trifluoroacetic anhydride (1.27 mL, 8.99 mmol) was added drop-wise over 5 minutes to a 0 °C solution of C24 (2.75 g, 7.58 mmol) and triethylamine (1.37 mL, 9.83 mmol) in tetrahydrofuran (50 mL). After the reaction mixture had been stirred at 0 °C for 45 minutes, it was partitioned between saturated aqueous sodium bicarbonate solution (40 mL) and diethyl ether (25 mL). The aqueous layer was extracted with ethyl acetate (2 x 40 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo, providing P8 as an off-white solid. Yield: 3.44 g, 7.50 mmol, 99%. LCMS m / z 459.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) 8 7.96 (s, 1H), 7.32 (s, 1H), 6.01 (s, 1 H), 3.07 (t, component of A2B2 system, J = 7.7 Hz, 2H), 2.94 (t, component of A2B2 system, J = 7.7 Hz, 2H), 2.37 (s, 3H).

[0377] Preparation P9

[0378] 2,2,2-Trifluoro- / V-{4-fluoro-2-iodo-5-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]phenyl}acetamide (P9)

[0379] Step 1. Synthesis of tert-butyl [4-fluoro-3-(hydroxymethyl)phenyl]carbamate (C25)

[0380] A solution of sodium carbonate (11.6 g, 109 mmol) in water (30 mL) was added to a solution of (5-amino-2-fluorophenyl)methanol (14.1 g, 99.9 mmol) in a mixture of tetrahydrofuran (200 mL) and water (70 mL). The mixture was stirred for 5 minutes, whereupon di-terf-butyl dicarbonate (26.0 mL, 113 mmol) was added over approximately 5 minutes, in 10 roughly equal portions. After the reaction mixture had been stirred at room temperature for 6 hours, it was extracted with ethyl acetate (2 x 250 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (150 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 100% heptane for 1 column volume, followed by 20% to 50% ethyl acetate in heptane) afforded C25 as an off- white solid. Yield: 18.3 g, 75.8 mmol, 76%. LCMS m / z 240.1 [M-H]-.1H NMR (400 MHz, chloroform-d) 5 7.43 (dd, J = 6.6, 2.8 Hz, 1 H), 7.26 - 7.20 (m, 1 H, assumed; partially obscured by solvent peak), 6.96 (t, J = 9.2 Hz, 1 H), 6.47 (br s, 1 H), 4.72 (s, 2H), 1.51 (s, 9H).

[0381] Step 2. Synthesis of terf-butyl (4-fluoro-3-formylphenyl)carbamate (C26)

[0382] To a solution of C25 (17.5 g, 72.5 mmol) in acetonitrile (50 mL) were sequentially added the following: (1) a solution of tetrakis(acetonitrile)copper(l) hexafluorophosphate (1.36 g, 3.65 mmol) in acetonitrile (50 mL); (2) a solution of 2,2'-bipyridine (566 mg, 3.62 mmol) in acetonitrile (50 mL); (3) a solution of (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO; 567 mg, 3.63 mmol) in acetonitrile (50 mL); and (4) 1-methyl-1 / - / -imidazole (0.580 mL, 7.28 mmol). The reaction mixture was rapidly stirred, open to the air, for 3 hours, whereupon a mixture of pentane and diethyl ether (1:1, 300 mL) was added. The resulting mixture was filtered through a plug of silica gel (150 g), which was then rinsed with a mixture of pentane and diethyl ether (1:1, approximately 300 mL) until the filtrate became colorless. The filtrate was concentrated in vacuo at 25 °C, and the obtained solid was treated with heptane (100 mL), granulated via stirring, and filtered; the filter cake was rinsed with heptane (50 mL) to provide C26 as a white solid. The combined filtrates were concentrated under reduced pressure to a volume of approximately 30 mL, and the resulting precipitate was collected via filtration to provide additional C26 as a white solid. Combined yield: 16.1 g, 67.3 mmol, 93%. LCMS m / z 238.0 [M-H]-.1H NMR (400 MHz, chloroform-d) 5 10.32 (s, 1H), 7.83 - 7.73 (m, 1H), 7.68 (dd, J = 5.8, 2.9 Hz, 1H), 7.12 (t, J = 9.4 Hz, 1 H), 6.56 (br s, 1 H), 1.52 (s, 9H).

[0383] Step 3. Synthesis of tert-butyl {4-fluoro-3-[2-(5-methyl-1 ,2-oxazol-3-yl)ethenyl]phenyl}carbamate (C27)

[0384] A solution of potassium tert-butoxide in tetrahydrofuran (1.0 M; 62.0 mL, 62.0 mmol) was added drop-wise over approximately 10 minutes to a stirring suspension of C18 (27.4 g, 62.5 mmol) in tetrahydrofuran (150 mL). After the reaction mixture had been stirred at room temperature for 10 minutes, a solution of C26 (14.0 g, 58.5 mmol) in tetrahydrofuran (100 mL) was added as a steady stream over 4 to 5 minutes; at the end of this addition, stirring was continued at room temperature for 20 minutes. Addition of hydrochloric acid (1 M; 40 to 50 drops) was followed by concentration under reduced pressure (25 °C, 100 mbar) to remove most of the tetra hydrofuran. After the residue had been partitioned between ethyl acetate (300 mL) and water (100 mL), the aqueous layer was extracted with ethyl acetate (100 mL) and the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded C27 as a white solid. The1H NMR spectrum indicated that this material was a mixture of cis and trans double bond isomers. Yield: 17.0 g, 53.4 mmol, 91%. LCMS m / z 319.2 [M+H]+.1H NMR (400 MHz, aceton itri I e-cfe), peaks attributed to major isomer: 5 7.70 (dd, J = Q.7, 2.8 Hz, 1H), 7.52 (br s, 1H), 7.40 - 7.35 (m, 1H), 7.31 (d, J = 16.7 Hz, 1H), 7.10 (d, J = 16.7 Hz, 1 H), 7.07 (dd, J = 10.5, 8.9 Hz, 1 H), 6.43 (br s, 1 H), 2.41 (d, J = 0.9 Hz, 3H), 1.49 (s, 9H). Characteristic peaks attributed to minor isomer: 5 6.87 (d, J = 12.2 Hz, 1 H), 6.67 (d, J = 12.2 Hz, 1 H), 5.71 (s, 1 H), 2.29 (d, J = 0.9 Hz, 3H), 1.46 (s, 9H).

[0385] Step 4. Synthesis of tert-butyl {4-fluoro-3-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]phenyl}carbamate (C28)

[0386] A 0 °C mixture of C27 (17.0 g, 53.4 mmol) and palladium on carbon (10%, 2.87 g, 2.70 mmol) in a mixture of tetrahydrofuran (300 mL) and methanol (100 mL) was treated drop-wise with triethylsilane (75.0 mL, 470 mmol) over 40 minutes, whereupon the reaction mixture was stirred for 20 minutes at 0 °C. It was then allowed to warm to room temperature, sparged with nitrogen for 10 minutes, and diluted with ethyl acetate (80 mL) and methanol (30 mL). After the resulting mixture had been stirred for 10 minutes, it was filtered through a pad of diatomaceous earth, and the filtrate was concentrated in vacuo. The residue was mixed with heptane (50 mL) and stirred for 30 minutes at room temperature; filtration, followed by rinsing of the filter cake with heptane (20 mL), provided C28 as a white solid. Yield: 16.8 g, 52.4 mmol, 98%. LCMS m / z 319.0 [M-H]".1H NMR (400 MHz, acetonitrile-cfe) 8 8.24 (br s, 1 H), 7.39 (dd, J = 6.8, 2.8 Hz, 1H), 7.32 - 7.25 (m, 1H), 6.88 (dd, J = 9.8, 8.9 Hz, 1H), 5.96 - 5.92 (m, 1H), 2.88 - 2.82 (m, 2H), 2.82 - 2.75 (m, 2H), 2.25 (d, J = 1.0 Hz, 3H), 1.37 (s, 9H).

[0387] Step 5. Synthesis of 4-fluoro-3-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]aniline (C29)

[0388] To a 0 °C solution of C28 (16.8 g, 52.4 mmol) in dichloromethane (120 mL) was added trifluoroacetic acid (40.0 mL, 519 mmol), as a steady stream over approximately 5 minutes. After an additional 5 minutes, the cooling bath was removed. The reaction mixture was stirred at room temperature for 75 minutes, whereupon it was concentrated under reduced pressure, and the resulting oil was partitioned between methyl fert-butyl ether (300 mL) and saturated aqueous potassium carbonate solution (100 mL). The organic layer was washed sequentially with saturated aqueous potassium carbonate solution (2 x 35 mL) and saturated aqueous sodium chloride solution (70 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford C29 as an amber oil. Yield: 11.8 g, 96% purity, 51.4 mmol, 98%. LCMS m / z 221.1 [M+H]+.1H NMR (400 MHz, chloroform-d) 8 6.82 (dd, J = 9.7, 8.4 Hz, 1H), 6.54 - 6.46 (m, 2H), 5.81 - 5.78 (m, 1H), 3.12 (v br s, 2H), 2.90 (s, 4H), 2.38 (d, J = 0.9 Hz, 3H).

[0389] Step 6. Synthesis of 4-fluoro-2-iodo-5-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]aniline (C30)

[0390] To a solution of C29 (from the previous step; 96%, 2.30 g, 10.0 mmol) in toluene (3 mL) was added a solution of sodium bicarbonate (1.68 g, 20.0 mmol) in water (30 mL). This mixture was cooled in an ice bath, stirred at 600 rpm, and treated with iodine (3.18 g, 12.5 mmol) in 8 roughly equal portions over 20 minutes. Stirring at 600 rpm was continued as the ice bath was allowed to melt; after 3 hours, the internal reaction temperature was 19 °C, and the reaction mixture was poured into a stirring aqueous solution of sodium thiosulfate (10%, 150 mL). The reaction flask was rinsed with ethyl acetate (4 x 50 mL), which was used to extract the sodium thiosulfate mixture. The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane) provided material that was slurried in heptane (50 mL) for 12 hours at 50 °C, stirred at room temperature for 1.5 days, and filtered to provide C30 as an off-white solid. Yield: 2.76 g, 7.97 mmol, 80%. LCMS m / z 347.1 [M+H]+.1H NMR (400 MHz, acetonitrile-cfe) 8 7.32 (d, J = 9.3 Hz, 1 H), 6.64 (d, J = 7.0 Hz, 1 H), 5.96 - 5.93 (m, 1 H), 4.27 (br s, 2H), 2.85 (s, 4H), 2.34 (d, J = 1.0 Hz, 3H).

[0391] Step 7. Synthesis of 2,2,2-trifluoro- / V-{4-fluoro-2-iodo-5-[2-(5-methyl-1 ,2-oxazol-3- yl)ethyl]phenyl}acetamide (P9)

[0392] Triethylamine (7.00 mL, 50.2 mmol) was added to a solution of C30 (12.7 g, 36.7 mmol) in methyl terf-butyl ether (170 mL), and the resulting mixture was cooled in an ice bath, whereupon trifluoroacetic anhydride (6.00 mL, 42.5 mmol) was added drop-wise over 3 to 4 minutes. After being stirred at 0 °C for 30 minutes, the reaction mixture was diluted with methyl tert-butyl ether (150 mL) and saturated aqueous sodium bicarbonate solution (90 mL) and stirred for 5 minutes. The organic layer was washed with saturated aqueous sodium chloride solution (90 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in heptane (70 mL), pulverized with a spatula, and stirred for 10 minutes; filtration and rinsing of the filter cake with heptane (approximately 10 to 20 mL) afforded P9 as a fluffy white solid. Yield: 15.8 g, 35.7 mmol, 97%. LCMS m / z 443.0 [M+H]+.1H NMR (400 MHz, chloroform-d) 5 8.11 (br s, 1H), 8.01 (d, J = 7.1 Hz, 1H), 7.51 (s, 1H), 5.84 (br s, 1 H), 3.04 - 2.97 (m, 2H), 2.97 - 2.90 (m, 2H), 2.39 (br s, 3H).

[0393] Preparation P10 tert-Butyl 2-{[(tert-butoxycarbonyl)amino]methyl}-5-chloro-6-[(5-methyl-1 ,2-oxazol-3- yl)methoxy]-1 / 7-pyrrolo[2,3-b]pyridine-1 -carboxylate (P10)

[0394] Step 1. Synthesis of tert-butyl 6-bromo-2-{[(tert-butoxycarbonyl)amino]methyl}-5-chloro-1 / 7- pyrrolo[2,3-b]pyridine-1 -carboxylate (C31)

[0395] To a solution of P3 (1.26 g, 3.49 mmol), triethylamine (1.46 mL, 10.5 mmol), and 4- (dimethylamino)pyridine (42.7 mg, 0.350 mmol) in tetrahydrofuran (30 mL) was added di-tert- butyl dicarbonate (1.53 g, 7.01 mmol). After the reaction mixture had been stirred at 25 °C for 2 hours, it was concentrated in vacua, chromatography on silica gel (Gradient: 0% to 60% ethyl acetate in petroleum ether) afforded C31 as a yellow solid. Yield: 872 mg, 1.89 mmol, 54%. LCMS m / z 483.9 (bromo chloro isotope pattern observed) [M+Na+], Step 2. Synthesis of terf-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}-5-chloro-6-[(5-methyl-1 ,2- oxazol-3-yl)methoxy]-1 / 7-pyrrolo[2,3-b]pyridine-1 -carboxylate (P10)

[0396] To a mixture of C31 (200 mg, 0.434 mmol), (5-methyl-1 ,2-oxazol-3-yl)methanol (93.3 mg, 0.825 mmol), tris(dibenzylideneacetone)dipalladium(0) (24.8 mg, 27.1 pmol), and di-terf- butyl[2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane (t-Bu XPhos; 23.0 mg, 54.2 pmol) in 1,4- dioxane (2.0 mL) was added sodium terf-butoxide (75.1 mg, 0.781 mmol). The reaction mixture was subjected to ultrasound for 30 seconds, then stirred at 90 °C for 16 hours. Concentration in vacuo, followed by silica gel chromatography (Gradient: 0% to 60% ethyl acetate in petroleum ether), provided P10 as a brown gum. Yield: 162 mg, 0.329 mmol, 76%. LCMS m / z 392.9 (chlorine isotope pattern observed) {[M - (2-methylprop-1-ene and CC>2)]+H}+.

[0397] Preparation P11

[0398] 5-Chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 / 7-indole-2-carbaldehyde (P11) Step 1. Synthesis of 6-bromo-2-({[terf-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-1 / 7-indole (C32) A mixture of C6 (30.0 g, 70.0 mmol), terf-butyl(dimethyl)[(prop-2-yn-1-yl)oxy]silane (14.3 g. 84.0 mmol), potassium carbonate (19.4 g, 140 mmol), copper(l) iodide (534 mg, 2.80 mmol), and bis(triphenylphosphine)palladium(ll) dichloride (492 mg, 0.701 mmol) in tetrahydrofuran (500 mL) was stirred at 60 °C for 16 hours. The reaction mixture was concentrated in vacuo and purified using silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) to afford C32 as a black oil. Yield: 18.0 g, 48.0 mmol, 69%. LCMS m / z 376.0 (bromo chloro isotope pattern observed) [M+H]+.1H NMR (400 MHz, chloroform-d) 5 8.30 (br s, 1 H), 7.63 (s, 2H), 6.22 (br s, 1 H), 4.85 (s, 2H), 0.93 (s, 9H), 0.11 (s, 6H).

[0399] Step 2. Synthesis of 2-({[terf-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-6-[(5-methyl-1,2-oxazol-3- yl)ethynyl]-1 / -indole (C33)

[0400] A mixture of C32 (5.00 g, 13.3 mmol), 3-ethynyl-5-methyl-1 ,2-oxazole (2.86 g, 26.7 mmol), potassium carbonate (7.38 g, 53.4 mmol), tri-terf-butylphosphonium tetrafluoroborate (329 mg, 1.13 mmol), and bis(acetonitrile)palladium(ll) dichloride (145 mg, 0.559 mmol) in tetrahydrofuran (150 mL) was stirred at 65 °C for 16 hours, then at 70 °C for 16 hours. 3- Ethynyl-5-methyl-1,2-oxazole (1.43 g, 13.4 mmol) was again added, and stirring was continued at 70 °C for 30 hours, whereupon LCMS analysis indicated conversion to C33: LCMS m / z 401.0 (chlorine isotope pattern observed) [M+H]+. After the reaction mixture had been poured into saturated aqueous sodium chloride solution (100 mL), the aqueous layer was extracted with ethyl acetate (3 x 100 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 15% ethyl acetate in petroleum ether) provided C33 as a yellow solid. Yield: 2.50 g, 6.24 mmol, 47%.1H NMR (400 MHz, chloroform- d) 5 8.42 (br s, 1H), 7.62 (s, 1 H), 7.59 (s, 1 H), 6.28 - 6.24 (m, 1H), 6.20 - 6.16 (m, 1H), 4.88 (s, 2H), 2.46 (d, J = 0.9 Hz, 3H), 0.94 (s, 9H), 0.12 (s, 6H).

[0401] Step 3. Synthesis of 2-({[terf-butyl(dimethyl)silyl]oxy}methyl)-5-chloro-6-[2-(5-methyl-1 ,2-oxazol- 3-yl)ethyl]-1 / - / -indole (C34)

[0402] A solution of C33 (2.50 g, 6.24 mmol), 4-methylbenzene-1 -sulfonohydrazide (11.6 g, 62.3 mmol), and potassium acetate (9.18 g, 93.5 mmol) in a mixture of tetrahydrofuran (30 mL) and water (15 mL) was stirred at 75 °C for 16 hours. 4-Methylbenzene-1-sulfonohydrazide (348 g, 18.7 mmol) was again added, and stirring was continued for 16 hours at 80 °C, at which point LCMS analysis indicated formation of C34: LCMS m / z 404.9 (chlorine isotope pattern observed) [M+H]+. Most of the reaction solution was progressed to the following step. Step 4. Synthesis of {5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methanol (C35)

[0403] To a 20 °C solution of C34 (90% of the reaction mixture from the previous step; <5.62 mmol) in a mixture of tetrahydrofuran (27 mL) and water (13.5 mL) was added potassium hydrogenfluoride (877 mg, 11.2 mmol) in one portion. After the reaction mixture had been stirred at 65 °C for 16 hours, it was combined with a similar reaction carried out using C34 (10% of the reaction mixture from the previous step; <0.624 mmol) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 70% ethyl acetate in petroleum ether) afforded C35 as a yellow solid. Combined yield: 1.00 g, 3.44 mmol, 55% over 2 steps. LCMS m / z 291.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-cL) 8 7.48 (s, 1 H),

[0404] 7.21 (s, 1H), 6.28 (s, 1H), 6.00 (s, 1H), 4.69 (s, 2H), 3.16 - 3.09 (m, 2H), 2.99 - 2.92 (m, 2H), 2.37 (s, 3H).

[0405] Step 5. Synthesis of 5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indole-2-carbaldehyde (P11)

[0406] To a 20 °C mixture of C35 (1.00 g, 3.44 mmol) and silica gel (100-200 mesh; 1.50 g) in dichloromethane (40 mL) was added pyridinium chlorochromate (1.33 g, 6.17 mmol) in portions over 30 minutes, whereupon the reaction mixture was stirred at 20 °C for 16 hours. After removal of solvent in vacuo, the residue was purified via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether), providing P11 as a yellow solid. Yield: 350 mg,

[0407] 1.21 mmol, 35%. LCMS m / z 289.0 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) 8 9.80 (s, 1 H), 7.77 (s, 1 H), 7.36 (s, 1 H), 7.25 (br s, 1 H), 6.04 (s, 1 H), 3.22 - 3.14 (m, 2H), 3.03 - 2.95 (m, 2H), 2.38 (s, 3H).

[0408] Preparation P12

[0409] Methyl {5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}acetate (P12)

[0410] NEt3

[0411] Step 1. Synthesis of tert-butyl 6-bromo-5-chloro-1 / - / -indole-1 -carboxylate (C36)

[0412] Di-tert-butyl dicarbonate (7.53 g, 34.5 mmol) was added drop-wise over 15 minutes to a solution of 6-bromo-5-chloro-1 / - / -indole (5.30 g, 23.0 mmol), 4-(dimethylamino)pyridine (562 mg, 4.60 mmol), and triethylamine (9.61 mL, 68.9 mmol) in tetrahydrofuran (150 mL). The reaction mixture was stirred at 25 °C for 16 hours, whereupon it was concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) to afford C36 as a white solid. Yield: 7.6 g, 23 mmol, quantitative.1H NMR (400 MHz, chloroform-d) 5 8.48 (br s, 1 H), 7.64 (s, 1 H), 7.58 (d, J = 3.8 Hz, 1 H), 6.48 (d, J = 3.8 Hz, 1 H), 1.67 (s, 9H).

[0413] Step 2. Synthesis of tert-butyl 5-chloro-6-[(5-methyl-1 ,2-oxazol-3-yl)ethynyl]-1 / - / -indole-1 - carboxylate (C37)

[0414] A mixture of 3-ethynyl-5-methyl-1 ,2-oxazole (5.51 g, 51.4 mmol), C36 (8.50 g, 25.7 mmol), potassium carbonate (14.2 g, 103 mmol), tri-tert-butylphosphonium tetrafluoroborate (1.49 g, 5.14 mmol), and bis(acetonitrile)palladium(ll) dichloride (667 mg, 2.57 mmol) in tetrahydrofuran (150 mL) was sparged with nitrogen for 1 minute, whereupon the reaction mixture was stirred at 65 °C for 16 hours. After the reaction mixture had been cooled to 25 °C, 3-ethynyl-5-methyl-1 ,2-oxazole (2.75 g, 25.7 mmol) was again added, and stirring was continued at 65 °C for 16 hours. Solvent was removed in vacuo, and the residue was purified using silica gel chromatography (Gradient: 0% to 15% ethyl acetate in petroleum ether) to afford C37 as a pale-yellow solid. Yield: 6.03 g, 16.9 mmol, 66%. LCMS m / z 356.9 (chlorine isotope pattern observed) [M+H]+.

[0415] Step 3. Synthesis of tert-butyl 5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / - / -indole-1 - carboxylate (C38) A solution of C37 (6.03 g, 16.9 mmol), 4-methylbenzene-1 -sulfonohydrazide (18.9 g, 101 mmol), and potassium acetate (16.6 g, 169 mmol) in a mixture of tetrahydrofuran (100 mL) and water (50 mL) was stirred at 70 °C for 16 hours. After addition of saturated aqueous sodium bicarbonate solution (50 mL), the resulting mixture was stirred at 25 °C for 10 minutes and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified via silica gel chromatography (Gradient: 0% to 15% ethyl acetate in petroleum ether) to afford C38 as a pale-yellow gum. Yield: 3.53 g, 9.78 mmol, 58%. LCMS m / z 360.9 (chlorine isotope pattern observed) [M+H]+.

[0416] Step 4. Synthesis of 5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / - / -indole (C39)

[0417] Trifluoroacetic acid (20 mL) and anisole (1.07 mL, 9.84 mmol) were added to a solution of C38 (3.53 g, 9.78 mmol) in dichloromethane (60 mL). After the reaction mixture had been stirred for 3 hours at 25 °C, it was concentrated in vacuo and purified using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in petroleum ether) to afford C39 as an orange solid. Yield: 2.00 g, 7.67 mmol, 78%. LCMS m / z 261.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, chloroform-d) 5 8.16 (br s, 1H), 7.64 (s, 1H), 7.19 (dd, J = 3.2, 2.4 Hz, 1H), 6.49 - 6.44 (m, 1 H), 5.83 (s, 1H), 3.20 - 3.14 (m, 2H), 3.03 - 2.96 (m, 2H), 2.38 (d, J = 0.9 Hz, 3H).

[0418] Step 5. Synthesis of methyl {5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}acetate (P12)

[0419] To a mixture of C39 (1.65 g, 6.33 mmol), sodium bicarbonate (2.13 g, 25.4 mmol), bis(acetonitrile)palladium(ll) dichloride (164 mg, 0.632 mmol), and bicyclo[2.2.1]hept-2-ene (1.19 g, 12.6 mmol) in a mixture of / V, / V-dimethylformamide (60 mL) and water (0.6 mL) was added methyl bromoacetate (0.473 mL, 5.00 mmol). After the reaction mixture had been stirred at 50 °C for 16 hours, it was cooled to 25 °C and methyl bromoacetate (194 mg, 1.27 mmol) was again added; heating was continued at 50 °C for 16 hours, whereupon water (40 mL) was added. The resulting mixture was extracted with ethyl acetate (3 x 50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (3 x 40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether) provided material (1.5 g) that was combined with the products of two similar reactions carried out using C39 (total of 300 mg, 1.15 mmol). Petroleum ether (10 mL) was added and the mixture was stirred at 20 °C for 1 hour, whereupon the solid was isolated via filtration and washed with petroleum ether (10 mL) to provide P12 as a pale-yellow solid. Combined yield: 1.29 g, 3.88 mmol, 52%. LCMS m / z 333.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-^) 8 7.46 (s, 1 H), .19 (s, 1H), 6.23 (s, 1H), 6.00 (s, 1H), 3.81 (s, 2H), 3.72 (s, 3H), 3.16-3.09 (m, 2H), 2.98-.92 (m, 2H), 2.37 (s, 3H).

[0420] Preparation P13 terf-Butyl 6-{[(terf-butoxycarbonyl)amino]methyl}-3-chloro-2-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-

[0421] 1 / 7-indole-1 -carboxylate (P13)

[0422] C44

[0423] Step 1. Synthesis of [(5-methyl-1,2-oxazol-3-yl)methyl](triphenyl)phosphonium chloride (C40) A mixture of 3-(chloromethyl)-5-methyl-1 ,2-oxazole (11.6 g, 88.2 mmol) and triphenylphosphine (34.7 g, 132 mmol) in acetonitrile (300 mL) was stirred at 90 °C for 16 hours. After addition of methyl terf-butyl ether (300 mL), the mixture was stirred at 25 °C for 1 hour, whereupon filtration and rinsing of the filter cake with methyl terf-butyl ether (2 x 100 mL) provided C40 as an off-white solid. Yield: 26.0 g, 66.0 mmol, 75%. LCMS m / z 358.1 [M+],1H NMR (400 MHz, DMSO-c6) 8 7.95 - 7.86 (m, 3H), 7.85 - 7.71 (m, 12H), 5.90 (s, 1 H), 5.42 (d, J = 15.9 Hz, 2H), 2.32 (s, 3H).

[0424] Step 2. Synthesis of 6-bromo-3-chloro-1 / 7-indole-2-carbaldehyde (C41)

[0425] To a mixture of 6-bromo-1 / 7-indole-2-carbaldehyde (500 mg, 2.23 mmol) in methanol (15 mL) was added / V-chlorosuccinimide (381 mg, 2.85 mmol). After the reaction mixture had been stirred at 25 °C for 5 hours, LCMS analysis indicated formation of C41: LCMS m / z 260.0 (bromo chloro isotope pattern observed) [M+H]+. Stirring was continued overnight, whereupon the reaction mixture was concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 25% ethyl acetate in petroleum ether) afforded C41 as a white solid. Yield: 530 mg, 2.05 mmol, 92%.

[0426] Step 3. Synthesis of terf-butyl 6-bromo-3-chloro-2-formyl-1 / - / -indole-1 -carboxylate (C42)

[0427] Di-terf-butyl dicarbonate (671 mg, 3.07 mmol) was added drop-wise to a solution of C41 (530 mg, 2.05 mmol), triethylamine (0.855 mL, 6.13 mmol), and 4-(dimethylamino)pyridine (25.0 mg, 0.205 mmol) in tetrahydrofuran (10 mL). After the reaction mixture had been stirred at 25 °C for 16 hours, LCMS analysis indicated conversion to C42: LCMS m / z 303.8 (bromo chloro isotope pattern observed) [(M - 2-methylprop-1-ene)+H]+. The reaction mixture was concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether), providing C42 as a white solid. Yield: 610 mg, 1.70 mmol, 83%.1H NMR (400 MHz, chloroform-d) 8 10.32 (s, 1H), 8.38 (br d, J = 1.7 Hz, 1H), 7.59 (br d, half of AB quartet, J = 8.5 Hz, 1 H), 7.50 (dd, component of ABX system, J = 8.5, 1.6 Hz, 1 H), 1.69 (s, 9H).

[0428] Step 4. Synthesis of terf-butyl 6-bromo-3-chloro-2-[2-(5-methyl-1 ,2-oxazol-3-yl)ethenyl]-1 / 7- indole-1 -carboxylate (C43) A suspension of C40 (677 mg, 1.72 mmol) and potassium tert-butoxide (210 mg, 1.87 mmol) in / V, / V-dimethylformamide (6.0 mL) was stirred for 10 minutes, whereupon a solution of C42 (560 mg, 1.56 mmol) in tetrahydrofuran (3.0 mL) was added over 2 minutes. After the reaction mixture had been stirred at 25 °C for 2 hours, it was treated with aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3 x 10 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified using silica gel chromatography (Gradient: 0% to 5% ethyl acetate in petroleum ether) to afford C43 as a yellow solid. This material was presumed to comprise a mixture of olefin isomers. Yield: 530 mg, 1.21 mmol, 78%. LCMS m / z 439.0 (bromo chloro isotope pattern observed) [M+H]+.1H NMR (400 MHz, chloroform-d), characteristic peaks, major isomer only: 5 8.34 - 8.32 (m, 1H), 7.41 (AB quartet, AB = 16.8 Hz, AVAB= 61.1 HZ, 2H), 6.24 (br s, 1H), 2.46 (br s, 3H), 1.68 (s, 9H).

[0429] Step 5. Synthesis of tert-butyl 6-bromo-3-chloro-2-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indole- 1 -carboxylate (C44)

[0430] A solution of C43 (530 mg, 1.21 mmol), 4-methylbenzene-1 -sulfonohydrazide (2.25 g, 12.1 mmol), and potassium acetate (1.66 g, 16.9 mmol) in a mixture of tetrahydrofuran (6 mL) and water (3 mL) was stirred at 70 °C for 16 hours, whereupon LCMS analysis indicated the presence of C44: LCMS m / z 441.0 (bromo chloro isotope pattern observed) [M+H]+. After addition of saturated aqueous sodium bicarbonate solution (10 mL), the mixture was stirred at 25 °C for 10 minutes and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in petroleum ether) provided C44 as a yellow gum. Yield: 260 mg, 0.591 mmol, 49%.1H NMR (400 MHz, methanol-d4) 8 8.34 (d, J = 1.7 Hz, 1H), 7.43 (dd, component of ABX system, J = 8.4, 1.6 Hz, 1 H), 7.38 (d, half of AB quartet, J = 8.3 Hz, 1 H), 6.01 (br s, 1 H), 3.48 - 3.40 (m, 2H), 3.01 - 2.93 (m, 2H), 2.37 (br s, 3H), 1.70 (s, 9H).

[0431] Step 6. Synthesis of tert-butyl 6-{[(tert-butoxycarbonyl)amino]methyl}-3-chloro-2-[2-(5-methyl- 1 ,2-oxazol-3-yl)ethyl]-1 / 7-indole-1 -carboxylate (P13)

[0432] A mixture of C44 (250 mg, 0.569 mmol), potassium {[(tert- butoxycarbonyl)amino]methyl}(trifluoro)borate (162 mg, 0.683 mmol), mesylate[(di(1- adamantyl)-n-butylphosphine)-2-(2'-amino-1 ,T-biphenyl)]palladium(ll) (cataCXium® A Pd G3; 20.7 mg, 28.4 pmol), and cesium carbonate (556 mg, 1.71 mmol) in a mixture of 1,4-dioxane (5.0 mL) and water (0.5 mL) was stirred for 5 hours at 80 °C. Water (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (3 x 20 mL); the combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and purified via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) to afford P13 as a yellow solid. Yield: 140 mg, 0.286 mmol, 50%. LCMS m / z 512.2 (chlorine isotope pattern observed) [M+Na+],

[0433] Example 1

[0434] / V-({5-Chloro-6-[2-(2-methyl-1,3-oxazol-4-yl)ethyl]-1 / 7-indol-2-yl}methyl)propanamide (1)

[0435] Step 1. Synthesis of [(2-methyl-1,3-oxazol-4-yl)methyl](triphenyl)phosphonium chloride (C45) A mixture of 4-(chloromethyl)-2-methyl-1 ,3-oxazole (280 mg, 2.13 mmol) and triphenylphosphine (837 mg, 3.23 mmol) in acetonitrile (15 mL) was stirred at 80 °C for 16 hours. After addition of methyl terf-butyl ether (30 mL), the mixture was stirred at 25 °C for 1 hour and filtered; the filter cake was washed with methyl terf-butyl ether (2 x 10 mL) to provide C45 as a brown solid. Yield: 260 mg, 0.660 mmol, 31%. LCMS m / z 358.1 [M+],

[0436] Step 2. Synthesis of terf-butyl 2-{[(terf-butoxycarbonyl)(propanoyl)amino]methyl}-5-chloro-6-[2- (2-methyl-1,3-oxazol-4-yl)ethenyl]-1 / - / -indole-1 -carboxylate (C46)

[0437] While the reaction mixture was maintained at 0 °C to 5 °C, potassium terf-butoxide (57.0 mg, 0.508 mmol) was added in portions over 10 minutes to a stirring mixture of C45 (250 mg, 0.635 mmol) in / V, / V-dimethylformamide (2 mL). Upon completion of the addition, the reaction mixture was warmed to 25 °C and stirred for 10 minutes; a solution of P7 (100 mg, 0.215 mmol) in tetrahydrofuran (1 mL) was then added drop-wise over 10 minutes. After 4 hours, a solution of potassium terf-butoxide (28.5 mg, 0.254 mmol) in tetrahydrofuran (0.5 mL) was again added, and stirring was continued for 2 hours at 25 °C. Addition of saturated aqueous sodium chloride solution (10 mL) was followed by stirring at 25 °C for 5 minutes, whereupon the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and purified using silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) to afford C46 as a yellow solid. Yield: 69.0 mg, 0.127 mmol, 59%. LCMS m / z 544.2 (chlorine isotope pattern observed) [M+H]+.

[0438] Step 3. Synthesis of terf-butyl 2-{[(terf-butoxycarbonyl)(propanoyl)amino]methyl}-5-chloro-6-[2- (2-methyl-1,3-oxazol-4-yl)ethyl]-1 / - / -indole-1 -carboxylate (C47)

[0439] A solution of C46 (64.0 mg, 0.118 mmol), 4-methylbenzene-1 -sulfonohydrazide (219 mg, 1.18 mmol), and potassium acetate (162 mg, 1.65 mmol) in a mixture of tetra hydrofuran (1.2 mL) and water (0.6 mL) was stirred at 70 °C for 16 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added, whereupon the mixture was stirred at 25 °C for 10 minutes and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 15% ethyl acetate in petroleum ether) provided C47 as a yellow gum. Yield: 42.0 mg, 76.9 pmol, 65%. LCMS m / z 546.1 (chlorine isotope pattern observed) [M+H]+.

[0440] Step 4. Synthesis of / \ / -({5-chloro-6-[2-(2-methyl-1 ,3-oxazol-4-yl)ethyl]-1 / 7-indol-2- yl}methyl)propanamide (1)

[0441] Trifluoroacetic acid (0.3 mL, 4 mmol) was added drop-wise to a mixture of C47 (42.0 mg, 76.9 pmol) in dichloromethane (1.0 mL). After the reaction mixture had been stirred at 25 °C for 2 hours, it was concentrated in vacuo and then coevaporated with acetonitrile (15 mL). The residue was dissolved in acetonitrile (15 mL) and triethylamine (1 mL), concentrated under reduced pressure, and purified via reversed-phase HPLC (Column: C18, 40 x 150 mm; Mobile phase A: water containing 0.05% ammonium hydroxide and 10 mM ammonium bicarbonate;

[0442] Mobile phase B: acetonitrile; Gradient: 26% to 66% B; Flow rate: 60 mL / minute) to afford A / -({5- chloro-6-[2-(2-methyl-1,3-oxazol-4-yl)ethyl]-1 / 7-indol-2-yl}methyl)propanamide (1) as a white solid. Yield: 11.3 mg, 32.7 pmol, 43%. LCMS m / z 346.2 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) 8 7.45 (s, 1H), 7.40 (br s, 1H), 7.16 (s, 1H), 6.23 (d, J = 0.9 Hz, 1 H), 4.47 (s, 2H), 3.08 (t, J = 7.7 Hz, 2H), 2.84 - 2.76 (m, 2H), 2.42 (s, 3H), 2.27 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H).

[0443] Example 2 / \ / -({5-Chloro-6-[(3-methyl-1 ,2-oxazol-5-yl)methoxy]-1 / 7-indol-2-yl}methyl)propanamide (2)

[0444] This reaction was carried out in two identical batches. To a mixture of P4 (70.0 mg, 0.277 mmol) and (3-methyl-1,2-oxazol-5-yl)methanol (62.7 mg, 0.554 mmol) in 1,4-dioxane (2.0 mL) was added (tributyl-A5-phosphanylidene)acetonitrile (CMBP; 201 mg, 0.833 mmol), whereupon the reaction mixture was stirred for 16 hours at 100 °C. The two reaction mixtures were combined, concentrated in vacuo, and purified using reversed-phase HPLC (Column: Phenomenex Gemini NX, 30 x 150 mm, 5 pm; Mobile phase A: water containing 0.05% ammonium hydroxide; Mobile phase B: acetonitrile; Gradient: 21% to 61% B; Flow rate: 60 mL / minute). The resulting material was treated with methanol (3 mL) and dichloromethane (1 mL), and concentrated under reduced pressure to remove most of the solvent. Precipitated material was collected via filtration to provide / \ / -({5-chloro-6-[(3-methyl-1 ,2-oxazol-5- yl)methoxy]-1 / 7-indol-2-yl}methyl)propanamide (2) as a white solid. Combined yield: 33.5 mg, 96.3 pmol, 17%. LCMS m / z 348.2 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) 8 7.46 (s, 1 H), 7.07 (s, 1H), 6.36 (s, 1H), 6.23 (br s, 1H), 5.21 (s, 2H), 4.45 (s, 2H), 2.29 (s, 3H), 2.26 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H).

[0445] Example 3 / \ / -({5-Chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methyl)acetamide (3)

[0446] PEG 400

[0447] A reaction vessel containing P8 (1.82 g, 3.97 mmol), / V-(prop-2-yn-1-yl)acetamide (676 mg, 6.96 mmol), potassium carbonate (1.65 g, 11.9 mmol), copper(l) iodide (45.4 mg, 0.238 mmol), and [1 ,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (116 mg, 0.159 mmol) in polyethylene glycol 400 (PEG 400; previously sparged with nitrogen for 15 minutes; 18 mL) was flushed with nitrogen for 2 minutes, whereupon the reaction mixture was heated at 65 °C for 9 hours. After cooling to room temperature, if was partitioned between ethyl acetate (85 mL) and water (85 mL) and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (30 mL) and the aqueous layer of the combined filtrates was extracted with ethyl acetate (60 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 40% to 100% ethyl acetate in heptane) provided material that was slurried in methyl fert-butyl ether (5 mL) for 30 minutes. Filtration provided a filter cake; this was washed with methyl fert-butyl ether (3 mL) to afford N- ({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methyl)acetamide (3) as an off- white (tan-yellow) solid. Yield: 0.909 g, 2.74 mmol, 69%. LCMS m / z 332.3 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) 8 7.46 (s, 1 H), 7.19 (s, 1 H), 6.25 (s, 1 H), 6.00 (s, 1 H), 4.47 (s, 2H), 3.12 (t, component of A2B2system, J = 7.8 Hz, 2H), 2.94 (t, component of A2B2system, J = 7.9 Hz, 2H), 2.37 (s, 3H), 2.00 (s, 3H).

[0448] Example 4

[0449] / \ / -({5-Chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methyl)propanamide (4)

[0450] PEG 400

[0451] A reaction vessel containing P8 (449 mg, 0.979 mmol), / V-(prop-2-yn-1-yl)propanamide

[0452] (200 mg, 1.80 mmol), copper(l) iodide (12.3 mg, 64.6 pmol), [1 ,T- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (28.9 mg, 39.5 pmol), and potassium carbonate (408 mg, 2.95 mmol) was evacuated and charged with nitrogen. This evacuation cycle was repeated once, whereupon polyethylene glycol 400 (PEG 400; previously sparged with nitrogen for 15 minutes; 4.0 mL) was added. After nitrogen had been swept over the suspension for 2 minutes, the reaction vessel was heated at 65 °C for 75 minutes. Upon cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (70 mL). The material between the layers was filtered through diatomaceous earth and the biphasic filtrate (~5 mL) was added to the organic layer, which was then washed sequentially with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 50% acetonitrile in dichloromethane) was followed by slurrying of the derived material in methyl terf-butyl ether (5 mL) at room temperature for 1 hour. Collection via filtration afforded / \ / -({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methyl)propanamide (4) as a white solid. Yield: 210 mg, 0.607 mmol, 62%. LCMS m / z 346.3 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, acetonitrile-cfe) 8 9.35 (br s, 1 H), 7.50 (s, 1 H), 7.27 (s, 1H), 6.81 (br s, 1H), 6.25 - 6.19 (m, 1 H), 5.98 (s, 1H), 4.40 (d, J = 5.9 Hz, 2H), 3.14 - 3.06 (m, 2H), 2.96 - 2.88 (m, 2H), 2.35 (br s, 3H), 2.19 (q, J = 7.6 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H).

[0453] Example 5

[0454] 2-{5-Chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}- / \ / -cyclopropylacetamide (5)

[0455] Cyclopropanamine (0.416 mL, 6.00 mmol) was added to a solution of P12 (200 mg, 601 pmol) and 1,3,4,6,7,8-hexahydro-2 / 7-pyrimido[1 ,2-a]pyrimidine (28.4 mg, 0.204 mmol) in tetrahydrofuran (3.0 mL), whereupon the reaction mixture was transferred to a pre-heated aluminum block and held at 56 °C for 3 hours, followed by 60 °C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed twice with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) afforded 2-{5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7- indol-2-yl}- / V-cyclopropylacetamide (5) as a solid. Yield: 11.2 mg, 31.3 pmol, 5%. LCMS m / z 358.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-cfe) 8 11.00 (s, 1H), 8.12 (s, 1H), 7.48 (s, 1 H), 7.26 (s, 1 H), 6.17 (s, 1 H), 6.13 (s, 1H), 3.50 (s, 2H), 3.11 - 3.00 (m, 2H), 2.93 - 2.83 (m, 2H), 2.39 - 2.30 (m, 4H), 0.68 - 0.56 (m, 2H), 0.45 - 0.36 (m, 2H). Example 6 / \ / -({5-Chloro-6-[2-(1 ,2-oxazol-3-yl)ethoxy]-1 / 7-indol-2-yl}methyl)propanamide (6)

[0456] Step 1. Synthesis of / V-(3-{[terf-butyl(dimethyl)silyl]oxy}propylidene)hydroxylamine (C48)

[0457] A solution of sodium hydroxide (28.7 g, 718 mmol) in water (600 mL) was added dropwise to a 5 °C solution of hydroxylamine hydrochloride (49.8 g, 717 mmol) in water (1.2 L). After the reaction mixture had been stirred for 20 minutes, 3-{[tert-butyl(dimethyl)silyl]oxy}propanal (90.0 g, 478 mmol) was added over 15 minutes, and stirring was continued for 3 days at 20 °C. The reaction mixture was then extracted with ethyl acetate (3 x 300 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo, providing C48 as a colorless oil. This material, by1H NMR analysis, comprised a mixture of oxime isomers. Yield: 96.0 g, 472 mmol, 99%.1H

[0458] NMR (400 MHz, chloroform-d) 5 [7.52 (br s) and 7.17 (br s), total 1H], [7.48 (t, J = 6.1 Hz) and 6.86 (t, J = 5.3 Hz), total 1 H], 3.78 (t, J = 6.3 Hz, 2H), [2.63 - 2.55 (m) and 2.42 (apparent q, J =

[0459] 6.3 Hz), total 2H], [0.89 (s) and 0.89 (s), total 9H], [0.07 (s) and 0.06 (s), total 6H],

[0460] Step 2. Synthesis of 3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-(trimethylsilyl)-1 ,2-oxazole (C49) / V-Chlorosuccinimide (75.6 g, 566 mmol) was added portion-wise over 15 minutes to a 5 °C solution of C48 (96.0 g, 472 mmol) and pyridine (45.6 mL, 564 mmol) in dichloromethane (1.5 L), whereupon the reaction mixture was warmed to room temperature and stirred at 20 °C for 1.5 hours. Ethynyl(trimethyl)silane (69.6 g, 709 mmol) was then added one portion, followed by drop-wise addition of triethylamine (98.7 mL, 708 mmol), and the reaction mixture was stirred overnight. Dilution with water (1 L) was followed by extraction with dichloromethane (3 x 100 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 7% ethyl acetate in petroleum ether) afforded C49 as a lightyellow oil. Yield: 110 g, 367 mmol, 78%. LCMS m / z 300.2 [M+H]+.1H NMR (400 MHz, chloroform-d) 5 6.37 (s, 1 H), 3.88 (t, J = 6.6 Hz, 2H), 2.92 (t, J = 6.6 Hz, 2H), 0.87 (s, 9H), 0.32 (s, 9H), 0.02 (s, 6H).

[0461] Step 3. Synthesis of 2-(1,2-oxazol-3-yl)ethan-1-ol (C50)

[0462] This reaction was carried out in two batches of the same scale. To a mixture of C49 (52.0 g, 174 mmol) in a mixture of methanol (500 mL) and water (50 mL) was added potassium hydrogenfluoride (6.10 g, 78.1 mmol). After the reaction mixture had been stirred at 60 °C for 16 hours, the two batches were combined and concentrated in vacuo. Chromatography on silica gel (Gradient: 5% to 50% ethyl acetate in petroleum ether) provided C50 as a light-yellow oil. Combined yield: 26.0 g, 230 mmol, 66%.1H NMR (400 MHz, chloroform-d) 5 8.35 (d, J = 1.6 Hz, 1 H), 6.28 (d, J = 1.7 Hz, 1 H), 3.97 (apparent q, J = 5.9 Hz, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.20 (br t, J = 5.9 Hz, 1H).

[0463] Step 4. Synthesis of 2-(1,2-oxazol-3-yl)ethyl 4-methylbenzene-1 -sulfonate (C51) Tetrabutylammonium bromide (66.1 mg, 0.205 mmol) and a solution of sodium hydroxide (3.34 g, 83.5 mmol) in water (approximately 8 mL) were added to a 0 °C mixture of C50 (2.32 g, 20.5 mmol) in toluene (20 mL). After portion-wise addition of 4-methylbenzene-1- sulfonyl chloride (4.89 g, 25.6 mmol) over 1 minute, the reaction mixture was warmed to room temperature over 30 minutes and stirred at room temperature for 18 hours. Water (15 mL) was added, and the resulting mixture was stirred for 5 minutes, whereupon the organic layer was washed twice with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo at 40 °C over 1 hour. The resulting oil was seeded with C51 (see below), and the derived solid was triturated with heptane to afford C51 as a straw-colored solid. Yield: 5.00 g, 86% purity, 16.1 mmol, 78%.1H NMR (400 MHz, chloroform-d) 5 8.33 (d, J = 1.7 Hz, 1 H), 7.78 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 6.26 (d, J = 1.7 Hz, 1 H), 4.33 (t, J = 6.6 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H), 2.46 (s, 3H).

[0464] Preparation of C51 seed crystals:

[0465] A closely related preparation of C51 , carried out previously, provided a similar oil; this material solidified upon standing in a freezer for 3 days.

[0466] Step 5. Synthesis of / \ / -({5-chloro-6-[2-(1 ,2-oxazol-3-yl)ethoxy]-1 / 7-indol-2- yl}methyl)propanamide (6)

[0467] A mixture of P4 (1.00 g, 3.96 mmol), C51 (86%, 1.60 g, 5.15 mmol), and cesium carbonate (2.32 g, 7.12 mmol) in butan-2-one (14 mL) was sparged with nitrogen for 5 minutes, whereupon the reaction mixture was heated at an internal reaction temperature of 50 °C to 52 °C for 36 hours. Ethyl acetate (10 mL) was added; after the resulting mixture had been stirred for 5 minutes, solids were removed via filtration, and the filter cake was rinsed with ethyl acetate. The combined filtrates were concentrated in vacuo, and the residue was vigorously stirred in a mixture of ethyl acetate (25 mL) and aqueous sodium hydroxide solution (1 M; 15 mL) for 10 minutes. The organic layer was washed with saturated aqueous sodium chloride solution and adsorbed onto silica gel (10 g). Silica gel chromatography (Gradient: 40% to 100% ethyl acetate in heptane) afforded / \ / -({5-chloro-6-[2-(1 ,2-oxazol-3-yl)ethoxy]-1 / 7-indol-2- yl}methyl)propanamide (6) as a white solid. The reported LCMS data was obtained on the product from a closely related reaction carried out using P4 and C51. Yield: 1.02 g, 2.93 mmol, 74%. LCMS m / z 346.1 (chlorine isotope pattern observed) [M-H]".1H NMR (400 MHz, chloroform-d) 5 9.07 (br s, 1 H), 8.35 (d, J = 1 .7 Hz, 1 H), 7.51 (s, 1 H), 6.87 (s, 1 H), 6.58 (d, J = 1.7 Hz, 1 H), 6.18 (br s, 1 H), 6.13 - 6.04 (m, 1 H), 4.43 (d, J = 5.8 Hz, 2H), 4.28 (t, J = 6.2 Hz, 2H), 3.28 (t, J = 6.2 Hz, 2H), 2.26 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). Alternatively, this reaction can be carried out at 55 °C with potassium carbonate in propan-2-ol.

[0468] Example 7 / V-({5-Fluoro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methyl)propanamide (7)

[0469] A reaction vessel containing P9 (2.21 g, 5.00 mmol), / V-(prop-2-yn-1-yl)propanamide

[0470] (944 mg, 8.49 mmol), copper(l) iodide (57.3 mg, 301 pmol), [1 ,T- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (148 mg, 202 pmol), and potassium carbonate (2.07 g, 15.0 mmol) was evacuated and charged with nitrogen. This evacuation cycle was repeated twice, whereupon polyethylene glycol 400 (PEG 400; previously sparged with nitrogen for 15 minutes; 20 mL) was added. After nitrogen had been bubbled through the stirring suspension for 5 minutes at room temperature, the reaction vessel was placed in a preheated oil bath (65 °C), and the contents were stirred at 65 °C for 90 minutes. Upon cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (175 mL). The aqueous layer and material between the layers were filtered through diatomaceous earth and the filtrate (approximately 20 mL) was added to the organic layer. The organic layer was washed sequentially with water (60 mL) and saturated aqueous sodium chloride solution (60 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 50% acetonitrile in dichloromethane) provided an off-white solid, which was mixed with methyl terf-butyl ether (30 mL) and stirred at 50 °C for 3 hours, then at room temperature for 1 hour. Collection via filtration afforded / \ / -({5-fluoro-6-[2-(5- methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methyl)propanamide (7) as a solid. Yield: 1.39 g, 4.22 mmol, 84%. LCMS m / z 330.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 8 10.88 (s, 1 H), 8.23 (br t, J = 5.6 Hz, 1 H), 7.20 - 7.13 (m, 2H), 6.20 - 6.17 (m, 1 H), 6.14 (br s, 1 H), 4.35 (d, J = 5.5 Hz, 2H), 3.02 - 2.94 (m, 2H), 2.90 - 2.83 (m, 2H), 2.34 (br s, 3H), 2.15 (q, J = 7.6 Hz, 2H), 1.03 (t, J = 7.6 Hz, 3H).

[0471] Example 8

[0472] / V-({5-Chloro-6-[(5-methyl-1 ,2-oxazol-3-yl)methoxy]-1 / 7-pyrrolo[2,3-b]pyridin-2- yl}methyl)acetamide (8)

[0473] Step 1. Synthesis of 1-{5-chloro-6-[(5-methyl-1 ,2-oxazol-3-yl)methoxy]-1 / 7-pyrrolo[2,3-b]pyridin- 2-yl}methanamine, trifluoroacetate salt (C52) To a solution of P10 (162 mg, 0.329 mmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (2.0 mL). After the reaction mixture had been stirred for 1 hour at 25 °C, LCMS analysis indicated the formation of C52: LCMS m / z 275.7 (chlorine isotope pattern observed [(M - NHs)+H]+. The reaction mixture was concentrated in vacuo, whereupon the residue was coevaporated with acetonitrile (3 mL) and triethylamine (2 mL) to provide C52 as a gum. This material was progressed directly to the following step.

[0474] Step 2. Synthesis of / V-({5-chloro-6-[(5-methyl-1 ,2-oxazol-3-yl)methoxy]-1 / 7-pyrrolo[2,3- b]pyridin-2-yl}methyl)acetamide (8)

[0475] Acetic anhydride (33.6 mg, 0.329 mmol) was added to a mixture of C52 (from the previous step; <0.329 mmol) and triethylamine (0.137 mL, 0.983 mmol) in dichloromethane (3.0 mL), and the reaction mixture was stirred at 25 °C for 1 hour. It was then concentrated in vacuo and purified via reversed-phase HPLC (Column: Phenomenex Gemini NX, 30 x 150 mm, 5 pm; Mobile phase A: water containing 0.05% ammonium hydroxide; Mobile phase B: acetonitrile; Gradient: 25% to 65% B; Flow rate: 60 mL / minute) to afford / \ / -({5-chloro-6-[(5-methyl-1 ,2- oxazol-3-yl)methoxy]-1 / 7-pyrrolo[2,3-b]pyridin-2-yl}methyl)acetamide (8) as a white solid. Yield: 28.9 mg, 86.3 pmol, 26% over 2 steps. LCMS m / z 335.3 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-cfe) 8 11.60 (br s, 1 H), 8.29 (br t, J = 5.5 Hz, 1 H), 8.00 (s, 1 H), 6.30 (br s, 1 H), 6.19 (br s, 1 H), 5.44 (s, 2H), 4.33 (d, J = 5.5 Hz, 2H), 2.39 (br s, 3H), 1.88 (s, 3H).

[0476] Example 9

[0477] / V-({5-Chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-pyrrolo[2,3-b]pyridin-2- yl}methyl)propanamide (9)

[0478] Step 1. Synthesis of / V-({5-chloro-6-[(5-methyl-1 ,2-oxazol-3-yl)ethynyl]-1 / 7-pyrrolo[2,3-b]pyridin- 2-yl}methyl)propanamide (C53) A mixture of P6 (150 mg, 0.474 mmol), 3-ethynyl-5-methyl-1 ,2-oxazole (127 mg, 1.19 mmol), potassium carbonate (262 mg, 1.90 mmol), bis(acetonitrile)palladium(ll) dichloride (5.16 mg, 19.9 pmol), and tri-terf-butylphosphonium tetrafluoroborate (11.7 mg, 40.3 pmol) in tetrahydrofuran (3.0 mL) was sparged with nitrogen for 1 minute. After the reaction mixture had been stirred at 65 °C for 16 hours, LCMS analysis indicated conversion to C53: LCMS m / z 343.1 (chlorine isotope pattern observed) [M+H]+. The reaction mixture was cooled to 25 °C and diluted with water (10 mL), whereupon the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 70% ethyl acetate in dichloromethane) afforded C53 as a yellow solid. Yield: 90.0 mg, 0.263 mmol, 55%.

[0479] Step 2. Synthesis of / V-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-pyrrolo[2,3-b]pyridin- 2-yl}methyl)propanamide (9)

[0480] To a 25 °C mixture of C53 (70.0 mg, 0.204 mmol), zinc bromide (9.20 mg, 40.8 pmol), and tris(dibenzylideneacetone)dipalladium(0) (18.7 mg, 20.4 pmol) in a mixture of propan-2-ol (2 mL) and tetrahydrofuran (2 mL) was added triethylsilane (356 mg, 3.06 mmol) drop-wise over 20 minutes. After completion of the addition, the reaction mixture was stirred at 25 °C for 4 hours, whereupon tris(dibenzylideneacetone)dipalladium(0) (18.7 mg, 20.4 pmol) was again added, followed by drop-wise addition of triethylsilane (237 mg, 2.04 mmol) over 10 minutes. Stirring was then continued at 25 °C for 16 hours. At this point, the reaction mixture was combined with a similar reaction carried out using C53 (20.0 mg, 58.3 pmol), and filtered through a pad of diatomaceous earth; the filter cake was washed with ethyl acetate (30 mL) and with methanol (30 mL), and the filtrate was concentrated in vacuo. Purification was carried out using silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane), followed by reversed-phase HPLC (Column: C18, 30 x 150 mm; Mobile phase A: water containing 0.05% ammonium hydroxide and 10 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Gradient: 30% to 60% B; Flow rate: 30 mL / minute), to afford / \ / -({5-chloro-6-[2-(5-methyl-1 ,2- oxazol-3-yl)ethyl]-1 / 7-pyrrolo[2,3-b]pyridin-2-yl}methyl)propanamide (9) as a white solid. Combined yield: 24.0 mg, 69.2 pmol, 26%. LCMS m / z 347.3 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) 8 7.86 (s, 1 H), 6.27 (s, 1 H), 6.02 (br s, 1 H), 4.51 (s, 2H), 3.31 - 3.25 (m, 2H, assumed; partially obscured by solvent peak), 3.11 - 3.05 (m, 2H), 2.37 (br s, 3H), 2.28 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H).

[0481] Example 10

[0482] / \ / -({3-Chloro-2-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-6-yl}methyl)propanamide (10)

[0483] Step 1. Synthesis of 1-{3-chloro-2-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-6- yljmethanamine (C54)

[0484] Trifluoroacetic acid (0.3 mL, 4 mmol) was added drop-wise to a solution of P13 (140 mg, 0.286 mmol) in dichloromethane (1 .0 mL). After the reaction mixture had been stirred at 25 °C for 16 hours, LCMS analysis indicated conversion to C54: LCMS m / z 273.0 (chlorine isotope pattern observed) [(M - NHs)+H]+. The reaction mixture was concentrated in vacuo, and the residue was treated with acetonitrile (10 mL); removal of solvent under reduced pressure provided C54, which was progressed directly to the following step.

[0485] Step 2. Synthesis of / \ / -({3-chloro-2-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-6- yl}methyl)propanamide (10)

[0486] To a solution of C54 (from the previous step; <0.286 mmol) in dichloromethane (2.0 mL) were added triethylamine (0.119 mL, 0.854 mmol) and propanoic anhydride (55.8 mg, 0.429 mmol). After the reaction mixture had been stirred at 25 °C for 16 hours, it was concentrated in vacuo. Purification via reversed-phase HPLC (Column: C18, 40 x 150 mm; Mobile phase A: water containing 0.05% ammonium hydroxide and 10 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Gradient: 33% to 53% B; Flow rate: 60 mL / minute) afforded / \ / -({3-chloro- 2-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-6-yl}methyl)propanamide (10) as a white solid. Yield: 56.9 mg, 0.164 mmol, 57% over 2 steps. LCMS m / z 346.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) 8 7.36 (d, J = 8.2 Hz, 1 H), 7.25 - 7.22 (m, 1 H), 7.01 (dd, J = 8.1 , 1.5 Hz, 1 H), 5.93 - 5.90 (m, 1 H), 4.43 (s, 2H), 3.16 - 3.08 (m, 2H), 3.05 - 2.98 (m, 2H), 2.35 (d, J = 1.0 Hz, 3H), 2.25 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H).

[0487] Example 11 / V-({5-Chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methyl)-1 ,2-oxazol-3-amine (11)

[0488] Acetic acid (8.32 mg, 0.139 mmol) was added to a solution of P11 (40.0 mg, 0.139 mmol) and 1 ,2-oxazol-3-amine (23.3 mg, 0.277 mmol) in methanol (2 mL), and the reaction mixture was stirred at 20 °C. After 4 hours, sodium cyanoborohydride (43.5 mg, 0.692 mmol) was added and stirring was continued for 16 hours at 20 °C. The reaction mixture was combined with a similar reaction carried out using P11 (10 mg, 35 pmol), concentrated in vacuo, and purified via reversed-phase HPLC (Column: C18, 40 x 150 mm; Mobile phase A: water containing 0.05% ammonium hydroxide and 10 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Gradient: 44% to 64% B; Flow rate: 60 mL / minute) to provide A / -({5- chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methyl)-1 ,2-oxazol-3-amine (11) as a white solid. Combined yield: 11.8 mg, 33.1 pmol, 19%. LCMS m / z 357.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) 8 8.20 (d, J = 1.8 Hz, 1H), 7.46 (s, 1H), 7.19 (s, 1H), 6.30 (br s, 1 H), 6.01 - 5.99 (m, 1 H), 5.98 (d, J = 1.8 Hz, 1H), 4.45 (s, 2H), 3.15 - 3.08 (m, 2H), 2.98 - 2.90 (m, 2H), 2.36 (br s, 3H).

[0489] Table 1. Method of synthesis, structure, and physicochemical data for Examples 12 - 40. The examples below were made from analogous processes to the Example(s) identified and from appropriate analogous starting materials.

[0490] 1. Treatment of Example 4 with / V-fluorobenzenesulfonamide and 1 ,4-diazabicyclo[2.2.2]octane afforded Example 12.

[0491] 2. Reaction of P1 with 2-(1 ,2-oxazol-3-yl)ethan-1-ol, using the conditions described in Example 2, was followed by deprotection with trifluoroacetic acid to provide 1-{5-chloro-6-[2-(1 ,2-oxazol-

[0492] 3-yl)ethoxy]-1 / 7-indol-2-yl}methanamine. This material was treated with methyl carbonochloridate and triethylamine to afford Example 13.

[0493] 3. 4-Ethyl-3-methoxyaniline was converted to / V-(4-ethyl-2-iodo-5-methoxyphenyl)-2,2,2- trifluoroacetamide using the method described for synthesis of C13 from C11 in Preparation P7. Subsequent transformation to / V-[(5-ethyl-6-methoxy-1 / 7-indol-2-yl)methyl]propanamide was carried out using the chemistry described in Preparation P6; cleavage of the methyl ether with boron tribromide then afforded the requisite / \ / -[(5-ethyl-6-hydroxy-1 / 7-indol-2- yl)methyl]propanamide.

[0494] 4. Reaction of 5-chloro-6-methoxy-1 / - / -indole and ethyl bromoacetate, using the method described for synthesis of P12 from C39 in Preparation P12, provided ethyl (5-chloro-6- methoxy-1 / 7-indol-2-yl)acetate. The ester was converted to the amide by treatment with ethylamine and 1 ,3,4,6,7,8-hexahydro-2 / 7-pyrimido[1 ,2-a]pyrimidine, whereupon cleavage of the methyl ether with boron tribromide provided the requisite 2-(5-chloro-6-hydroxy-1 / 7-indol-2- yl)- / V-ethylacetamide.

[0495] 5. Using the method described for conversion of C32 to C34 in Preparation P11 , fert-butyl ({5- chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methyl)carbamate was synthesized from P2. Subsequent deprotection with hydrogen chloride and anisole provided the requisite 1- {5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methanamine.

[0496] 6. 1-{5-Chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 / 7-indol-2-yl}methanamine (see footnote 5) was treated with / V-methyl-1 / 7-imidazole-1 -carboxamide in the presence of triethylamine to afford Example 16.

[0497] 7. The requisite / V, / V-dimethyl-1 / 7-imidazole-1 -carboxamide was synthesized by reaction of dimethylamine with 1 ,1’-carbonyldiimidazole.

[0498] 8. Treatment of 4-fluoro-1 / 7-pyrazole with 2-bromoethan-1-ol and sodium hydride provided 2-(4- fluoro-1 / - / -pyrazol-1 -yl)ethan-1 -ol .

[0499] 9. Reaction of P5 with 2-(4-fluoro-1 / - / -pyrazol-1 -yl)ethan-1-ol (see footnote 8), using the deoxygenative arylation methodology of Z. Dong and D.W.C. MacMillan, Nature 2021, 598, 451-456, afforded Example 18.

[0500] 10. Iodination of 3-(benzyloxy)-4-chloroaniline with / V-iodosuccinimide provided 5-(benzyloxy)-4- chloro-2-iodoaniline, which was converted to tert-butyl {[6-(benzyloxy)-5-chloro-1 / 7-indol-2- yl]methyl}carbamate using the method described for synthesis of P2 from C5 in Preparation P2. Cleavage of the benzyl ether with boron tribromide, followed by amide formation with cyclopropanecarboxylic acid using O-(7-azabenzotriazol-1-yl)- / V, / V, / V’, / V-tetramethyluronium hexafluorophosphate and / V, / V-diisopropylethylamine, afforded the requisite / \ / -[(5-chloro-6- hydroxy-1 / 7-indol-2-yl)methyl]cyclopropanecarboxamide.

[0501] 11. Analytical conditions. Column: Waters Atlantis C18, 4.6 x 50 mm, 5 pm; 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.

[0502] 12. Reaction of P4 with (5-chloropyridin-2-yl)methanol, in the presence of diisopropyl azodicarboxylate and resin-bound triphenylphosphine, provided Example 22.

[0503] 13. Protection of P5 by treatment with [2-(chloromethoxy)ethyl](trimethyl)silane and sodium hydride provided / V-[(6-bromo-5-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 / 7-indol-2- yl)methyl]propanamide. This material was reacted with potassium hydroxide in the presence of di-tert-butyl[2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane and tris(dibenzylideneacetone)dipalladium(0) to afford the requisite / V-[(5-chloro-6-hydroxy-1-{[2- (trimethylsilyl)ethoxy]methyl}-1 / 7-indol-2-yl)methyl]propanamide. 14. In this case, the protecting group was removed in a final step, via treatment with tetrabutylammonium fluoride and ethane-1 ,2-diamine, to afford Example 23.

[0504] 15. The final step was an amide coupling, carried out using O-(7-azabenzotriazol-1-yl)- / V, / V, / V’, / V-tetramethyluronium hexafluorophosphate and / V, / V-diisopropylethylamine.

[0505] 16. Hydrolysis of P12 with lithium hydroxide provided the corresponding carboxylic acid, which was reacted with ethylamine and O-(benzotriazol-1-yl)- / V, / V, / V', / V'-tetramethyluronium hexafluorophosphate to afford Example 26.

[0506] 17. Reaction of P6 with potassium hydroxide in the presence of di-ferf-butyl[2',4',6'-tri(propan-2- yl)biphenyl-2-yl]phosphane and tris(dibenzylideneacetone)dipalladium(0) provided the requisite / V-[(5-chloro-6-oxo-6,7-dihydro-1 / 7-pyrrolo[2,3-b]pyridin-2-yl)methyl]propanamide.

[0507] 18. Conversion of P1 to terf-butyl ({5-chloro-6-[2-(1 ,2-oxazol-3-yl)ethoxy]-1 / 7-indol-2- yl}methyl)carbamate was carried out using the chemistry described in Example 2; subsequent deprotection by reaction with trifluoroacetic acid provided the requisite 1-{5-chloro-6-[2-(1 ,2- oxazol-3-yl)ethoxy]-1 / 7-indol-2-yl}methanamine.

[0508] 19. Synthesis of Example 29 from P6 and 1-(5-methyl-1 ,2-oxazol-3-yl)methanamine was carried out via the method described in Preparation P10 for conversion of C31 to P10, except that the reaction was carried out at 110 °C under microwave irradiation.

[0509] 20. Reductive amination of P7 with 5-methyl-1 ,2-oxazol-3-amine, using triethylsilane and trifluoroacetic acid, was followed by deprotection via treatment with trimethylsilyl trifluoromethanesulfonate and pyridine to afford Example 30.

[0510] 21. Protection of P5 by treatment with di-ferf-butyl dicarbonate, triethylamine, and 4- (dimethylamino)pyridine provided terf-butyl 6-bromo-2-{[(terf- butoxycarbonyl)(propanoyl)amino]methyl}-5-chloro-1 / - / -indole-1 -carboxylate, which was coupled with 5-methyl-1 ,2-oxazole-3-carboxamide in the presence of [(4,5-bis(diphenylphosphino)-9,9- dimethylxanthene)-2-(2'-amino-1 ,T-biphenyl)]palladium(ll), methanesulfonate salt, dichloromethane adduct and tripotassium phosphate to afford terf-butyl 2-{[(ferf- butoxycarbonyl)(propanoyl)amino]methyl}-5-chloro-6-[(5-methyl-1 ,2-oxazole-3-carbonyl)amino]- 1 / 7-indole-1 -carboxylate. Protecting group removal with trifluoroacetic acid yielded Example 31.

[0511] 22. ferf-Butyl 6-bromo-2-{[(ferf-butoxycarbonyl)(propanoyl)amino]methyl}-5-chloro-1 / 7-indole-1- carboxylate (see footnote 21) was coupled with 1 ,1-diphenylmethanimine in the presence of ([1 ,1'-binaphthalene]-2,2'-diyl)bis(diphenylphosphane) and tripotassium phosphate, then hydrolyzed with hydroxylamine hydrochloride, to provide terf-butyl 6-amino-2-{[(ferf- butoxycarbonyl)(propanoyl)amino]methyl}-5-chloro-1 / - / -indole-1 -carboxylate. Reaction with 3- (bromomethyl)-5-methyl-1 ,2-oxazole and / V, / V-diisopropylethylamine was followed by treatment with trifluoroacetic acid to remove the protecting groups and afford Example 36.

[0512] 23. Treatment of Example 26 with 1-(chloromethyl)-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) provided Example 37. 24. Reduction of P7 with sodium borohydride, followed by reaction of the derived primary alcohol with 4-methylbenzenesulfonic anhydride and triethylamine, provided tert-butyl 2-{[(tert- butoxycarbonyl)(propanoyl)amino]methyl}-5-chloro-6-{[(4-methylbenzene-1- sulfonyl)oxy]methyl}-1 / - / -indole-1 -carboxylate. Treatment with 5-methyl-1 ,2-oxazol-3(2 / - / )-one and potassium carbonate, and subsequent deprotection with trimethylsilyl trifluoromethanesulfonate, afforded Example 38.

[0513] SLC6A19 Leucine Uptake Assay

[0514] 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% CO2 humidified 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 pL of assay buffer; 136.6 mM NaCI, 5.4 mM KCI, 0.44 mM K2HPO4, 2.7 mM NaH2PO4, 1.26 mM CaCI2, 0.5 mM MgCI2, 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 pM Leucine substrate (150 pM 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 IC50 determined using a 4-parameter logistic equation.

[0515] Table 2. Biological activity for Examples 1 - 40

[0516] 1. Values represent the geometric mean.

[0517] Prophetic deuterated analogs (PDAs) of certain compounds of the invention

[0518] Example X-1 : Some Prophetic deuterated analogs (PDA) of Example 4

[0519] The compounds provided in Table X-1 are some prophetic deuterated analogs (PDA) of Example 4. The Formula (XA) is a generic formula of deuterated Example 4, wherein Y1a, Y1b, independently H or D (deuterium) and wherein at least one of them is D. The deuterated analogs of Example 4 in Table X-1 can be predicted based on the metabolic profile of Example 4, with MetaSite (moldiscovery.com / software / metasite / ). Y1a, Y1b, Y1c, Y2a, Y2b, Y3, Y4a, Y4b, Y5a, Y5b, Y5c, Y6, Y7, Y8, Y9a, Y9b, Y10aand Y10bare predicted metabolized positions based on MetaSite predictions.

[0520] Table X-1

[0521] Example X-2: Some Prophetic deuterated analogs (PDA) of Example 8

[0522] The compounds provided in Table X-2 are some prophetic deuterated analogs (PDA) of Example 8. The Formula (XB) is a generic formula of deuterated Example 8, wherein Y1a, Y1b, Y1c, Y2a, Y2b, Y3a, Y3b, Y3c, Y4, Y5, Y6, Y7a, and Y7bare each independently H or D (deuterium) and wherein at least one of them is D. The deuterated analogs of Example 4 in Table X-2 can be predicted based on the metabolic profile of Example 8, with MetaSite

[0523] (moldiscovery.com / software / metasite / ). Y1a, Y1b, Y1c, Y2a, Y2b, Y3a, Y3b, Y3c, Y4, Y5, Y6, Y7a, and Y7bare predicted metabolized positions based on MetaSite predictions. Table X-2

[0524] Example X-3: Some Prophetic deuterated analogs (PDA) of Example 9

[0525] The compounds provided in Table X-3 are some prophetic deuterated analogs (PDA) of Example 9. The Formula (XC) is a generic formula of deuterated Example 9, wherein Y1a, Y1b, independently H or D (deuterium) and wherein at least one of them is D. The deuterated analogs of Example 9 in

[0526] Table X-3 can be predicted based on the metabolic profile of Example 8, with MetaSite (moldiscovery.com / software / metasite / ). Y1a, Y1b, Y1c, Y2a, Y2b, Y3, Y4a, Y4b, Y5a, Y5b, Y5c, Y6, Y7, Y8a, Y8b, Y9aand Y9bare predicted metabolized positions based on MetaSite predictions. xc

[0527] Table X-3

[0528] Example X-4: Some Prophetic deuterated analogs (PDA) of Example 27 The compounds provided in Table X-4 are some prophetic deuterated analogs (PDA) of Example 27. The Formula (XD) is a generic formula of deuterated Example 27, wherein Y1, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y4c, Y5, Y6, Y7, Y8a, Y8b, Y9aand Y9bare each independently H or D (deuterium) and wherein at least one of them is D. The deuterated analogs of Example 27 in Table X-4 can be predicted based on the metabolic profile of Example 27, with MetaSite (moldiscovery.com / software / metasite / ). Y1, Y2a, Y2b, Y3a, Y3b, Y4a, Y4b, Y4c, Y5, Y6, Y7, Y8a, Y8b, Y9aand Y9bare predicted metabolized positions based on MetaSite predictions. XD

[0529] Table X-4

[0530] Example X-5: Some Prophetic deuterated analogs (PDA) of Example 29

[0531] The compounds provided in Table X-5 are some prophetic deuterated analogs (PDA) of Example 29. The Formula (XE) is a generic formula of deuterated Example 29, wherein Y1a, Y1b, Y1c, Y2a, Y2b, Y3, Y4a, Y4b, Y4c, Y5, Y6, Y7a, Y7b, Y8aand Y8bare each independently H or D (deuterium) and wherein at least one of them is D. The deuterated analogs of Example 29 in Table X-5 can be predicted based on the metabolic profile of Example 29, with MetaSite (moldiscovery.com / software / metasite / ). Y1a, Y1b, Y1c, Y2a, Y2b, Y3, Y4a, Y4b, Y4c, Y5, Y6, Y7a, Y7b, Y8aand Y8bare predicted metabolized positions based on MetaSite predictions.

[0532] XE

[0533] Table X-5

[0534]

[0535] General methods I 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”.

[0536] 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.

[0537] 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.

[0538] 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.

[0539] 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.

[0540] 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 / 568,008 (filed March 21 , 2024). 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

CLAIMSWe claim:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:A is N or CH;R1is:wherein if R1comprises one or more methylene group, at least one of said one or more methylene group of R1is optionally substituted 1 to 2 substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and oxo (=0);R2is selected from the group consisting of H, halogen, -OH, -CN, -NH2, Ci-Ce alkoxy, C1-C6 alkyl, Ci-Ce haloalkyl, C1-C3 haloalkoxy, and C3-C6 cycloalkyl;R3is selected from the group consisting of halogen, -OH, -CN, -NH2, Ci-Ce alkoxy, Ci-Ce alkyl, Ci-Ce haloalkyl, C1-C3 haloalkoxy, and C3-C6 cycloalkyl;R4is:wherein if R4comprises one or more methylene group, at least one of said one or more methylene group of R4is optionally substituted 1 to 2 substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and oxo (=0), and wherein R4is not -OMe or -(C=O)-OMe;R5is selected from the group consisting of Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Cehaloalkyl, C3-C6 halocycloalkyl, Ci-Ce alkoxy, 6-10 membered aryl, and 5-10 membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of O, N and S, wherein said 6-10 membered aryl, 5-10 membered heteroaryl, Ci-Ce alkyl, or C3-C6 cycloalkyl is optionally substituted with one, two or three substituents independentlyselected from the group consisting of -OH, -CN, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C1-C3 haloalkoxy, and Ci-Ce alkoxy;R6is selected from the group consisting of Ci-Ce alkyl, Ci-Ce acyl group, C3-C6 cycloalkyl, Ci-Ce haloalkyl, C3-C6 halocycloalkyl, Ci-Ce alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of O, N and S, wherein R6is optionally substituted with one, two, or three substituents independently selected from the group consisting of -OH, -CN, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C1-C3 haloalkoxy, and Ci-Ce alkoxy;Q is a bond, -NR7-, O,-(C=O)-, -(C=C)-, or 3-8 membered heterocycloalkyl comprising one, two or three heteroatoms selected from the group consisting of N, O, and S, wherein the 3-8 membered heterocycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of -OH, -CN, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and oxo (=0);X is -(CH2)-, O, S, or a bond when A is CH, or X is -(CH2)-, O, -NR8-, S, or a bond when A is N;Y and Z are each independently -(CH2)-, O, -NR8-, S, or a bond, wherein X and Y are not simultaneously a bond, and wherein Q and Z are not simultaneously a bond;P is -(CH2)-, -(C=O)-, O, -NR9-, or S;R7, R8and R9are each independently H or C1-C3 alkyl; k is 0, 1 or 2, wherein when k is 0, R6is Ci-Ce acyl group or 5-10 membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of O, N and S, and R6is optionally substituted with one, two, or three substituents independently selected from the group consisting of -OH, -CN, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, C1-C3 haloalkoxy, and Ci-Ce alkoxy ; m is 0, 1 , 2, 3, or 4; and n is 0, 1 , 2, 3, or 4.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein k is 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II):(II)4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III):

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IV):

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1is:

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1is:

8. The compound according to any one of claims 1 to 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 according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R3is halogen, C1-C3 alkyl, or C1-C3 fluoroalkyl.11 . The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R3is Cl.

12. The compound according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, wherein R4is:

13. The compound according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, wherein R4iswherein Z is a bond, and m is 1 , 2, 3, or 4.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of:

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of:

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R5is selected from the group consisting of methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, phenyl,17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R5is selected from the group consisting of methyl, ethyl and cyclopropyl.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R6is selected from the group consisting of Ci-Ce acyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridinyl, and phenyl, wherein each is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C3 alkoxy.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R6is selected from the group consisting of:

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R7, R8and R9are each independently H.21 . The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein X is -(CH2)- or a bond when A is CH.

22. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein X is-(CH2)-, O, -NH-, or a bond when A is N.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Y and Z are each independently -(CH2)-, O, -NH-, or a bond.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein Q is a bond, -NH-, O, or-(C=O)-.

25. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein P is -(CH2)-, -(C=O)-, O, or -NH-.

26. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein P is -(C=O)-.

27. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein P is -(CH2)-.

28. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, wherein P is -NH-.

29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein k is 1.

30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

31. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

32. A compound selected from the group consisting of:N-[(5-chloro-6-{[(5-methyl-1,2-oxazol-3-yl)oxy]methyl}-1 H-indol-2-yl)methyl]propanamide;N-({5-chloro-3-fluoro-6-[2-(1 ,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)propanamide;N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-2,2-difluoroacetamide;N-({5-chloro-6-[2-(2-methyl-1,3-oxazol-4-yl)ethyl]-1 H-indol-2-yl}methyl)propanamide;N-({5-chloro-6-[2-(1,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)-2-fluoropropanamide;N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)propanamide;2-{5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1H-indol-2-yl}-N-cyclopropylacetamide; methyl ({5-chloro-6-[2-(1 ,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)carbamate;N-{[6-(benzyloxy)-5-chloro-1 H-indol-2-yl]methyl}propanamide;N-({5-chloro-6-[(3-methyl-1,2-oxazol-5-yl)methoxy]-1 H-indol-2-yl}methyl)propanamide;2-{5-chloro-3-fluoro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}-N-ethylacetamide;2-{5-chloro-6-[2-(1,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}-N-ethylacetamide;N-({5-chloro-6-[2-(1,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)propanamide;N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)acetamide;N-({5-chloro-6-[(5-chloropyridin-2-yl)methoxy]-1 H-indol-2-yl}methyl)propanamide;N-({5-chloro-6-[2-(1 H-pyrrol-2-yl)ethyl]-1H-indol-2-yl}methyl)propanamide;N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-2-fluoro-2- methylpropanamide;N-({5-chloro-6-[2-(1,2-oxazol-3-yl)ethoxy]-1 H-pyrrolo[2,3-b]pyridin-2-yl}methyl)propanamide;N-({5-chloro-3-fluoro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)propanamide;N-({5-fluoro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1H-indol-2-yl}methyl)propanamide;N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-1 -methoxycyclopropane-1 -carboxamide;N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-2-methoxyacetamide;N-({5-chloro-6-[(5-methyl-1,2-oxazol-3-yl)methoxy]-1 H-pyrrolo[2,3-b]pyridin-2- yl}methyl)acetamide;N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-N'-methylurea;N'-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-N,N-dimethylurea;N-({5-ethyl-6-[2-(1,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)propanamide;2-{5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1H-indol-2-yl}-N-ethylacetamide;N-[5-chloro-2-(propanamidomethyl)-1 H-indol-6-yl]-5-methyl-1 ,2-oxazole-3-carboxamide;N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-1 ,2-oxazole-3- carboxamide;N-({5-chloro-6-[2-(4-fluoro-1 H-pyrazol-1-yl)ethyl]-1H-indol-2-yl}methyl)propanamide;N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)benzamide;N-({5-fluoro-6-[2-(1,2-oxazol-3-yl)ethoxy]-1 H-indol-2-yl}methyl)propanamide;N-[(5-chloro-6-{[(5-methyl-1,2-oxazol-3-yl)methyl]amino}-1 H-pyrrolo[2,3-b]pyridin-2- yl)methyl]propanamide;N-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-pyrrolo[2,3-b]pyridin-2- yl}methyl)propanamide;N-[(5-chloro-6-{[(5-methyl-1,2-oxazol-3-yl)methyl]amino}-1 H-indol-2-yl)methyl]propanamide;N-[(5-chloro-6-{[(5-methyl-1,2-oxazol-3-yl)amino]methyl}-1 H-indol-2-yl)methyl]propanamide;N-({3-chloro-2-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-6-yl}methyl)propanamide;N-({5-chloro-6-[2-(5-methyl-1 ,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-1 ,2-oxazol-3-amine; andN-({5-chloro-6-[2-(5-methyl-1,2-oxazol-3-yl)ethyl]-1 H-indol-2-yl}methyl)-5-methyl-1 ,2-oxazol-3- amine, or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

34. A method 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 (B°AT1) transport, comprising administering to a subject in need thereof a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

35. The method of claim 34, wherein said disease or disorder is 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, or neurodevelopmental and autis -spectrurn disorders.

36. The method of claim 35, wherein said disease or disorder is urea cycle deficiency, urea cycle disorder, phenylketonuria, or chronic kidney disease.

37. A compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for use as a medicament.

38. A compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B°AT1) transport.

39. The compound for use in the treatment of a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B°AT1) transport according to claim 38, wherein said disease or disorder is 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, or neurodevelopmental and autism-spectrum disorders.

40. Use of a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament in the treatment of a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B°AT1) transport.

41. Use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament in the treatment of a disease or disorder associated with abnormal amino acid metabolism, amino acid transport and / or amino acid level by modulation of SLC6A19 (B°AT1) transport according to claim 40, wherein said disease or disorder is 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, or neurodevelopmental and autism-spectrum disorders.

42. A pharmaceutical combination comprising a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent or a pharmaceutically acceptable salt thereof.

43. The pharmaceutical composition comprising the pharmaceutical combination of claim 42 and at least one excipient.

Images