Substituted cyclic compounds and methods of treating phenylketonuria and other amino acid uria

Abstract

The present disclosure relates generally to compounds that inhibit SLC6A19 and are useful in the treatment of patients suffering from phenylketonuria ("PKU") and other amino acid uria, as well as compositions containing these compounds and methods of using these compounds.

Description

TECHNICAL FIELD

[0001] The present disclosure relates generally to compounds useful for treating patients with phenylketonuria (PKU) and other aminoacidurias, and methods of using these compounds. BACKGROUND

[0002] Phenylalanine hydroxylase (PAH) is an enzyme that is primarily present in the liver and is able to convert phenylalanine (Phe) ingested in food to tyrosine (Tyr). Loss of PAH function leads to toxic accumulation of Phe in the body, which is manifested by lower levels of Tyr and tryptophan and high levels of Phe (and Phe-derived metabolites, such as phenolic ketones and phenylpyruvate) in the blood and brain (van Spronsen et al., Phenylketonuria. Nat Rev Dis Primers 7, 35 (2021)). In the brain, such high levels of Phe can lead to reduced levels of dopamine and serotonin, reduced levels of neutral amino acids, white matter damage, reduced glucose metabolism, and even amyloid fibril formation.

[0003] PKU is caused by an autosomal recessive congenital deficiency in PAH that leads to loss of function of the enzyme and accumulation of Phe in the brain. Untreated PKU patients develop severe mental retardation, seizures, and behavioral, psychiatric, and / or motor problems.

[0004] In North America and Europe, PKU occurs in about 1 in 15,000 newborns, and in the United States and Europe, there are currently about 50,000 patients with PKU. Current treatment for PKU primarily employs a dietary therapy that restricts Phe intake, which means that patients must strictly control the amount of Phe derived from food. However, it is challenging for many adult and adolescent patients to adhere to a tasteless, restrictive diet long term. Thus, patients who have difficulty adhering to a Phe-restricted diet long term need new treatment options. Some physicians have begun treating PKU by administering PALYNZIQ® (recombinant phenylalanine ammonia lyase (PAL)) to patients. However, some patients are allergic to this product, which can cause anaphylaxis in such patients, which can be life threatening. Thus, new treatments are needed.

[0005] SLC6A19 (sometimes referred to as B 0AT1) is an amino acid transporter expressed only in the kidney and small intestine. SLC6A19 mediates over 95% of the absorption of free neutral amino acids from the diet, including Phe. Thus, inhibition (even selective inhibition) of SLC6A19 results in a dramatic reduction in the amount of neutral amino acids, including Phe, obtained from food. In this way, excess Phe and other neutral amino acids will be excreted out of the body. Such inhibition, especially if a small molecule inhibitor, can be easier for patients to take and will treat PKU and other rare genetic disorders of amino acid and nitrogen metabolism. Furthermore, human genetic SLC6A19 deficiency (Hartnup Disorder, incidence of about 1 : 3,000) is generally benign and the few symptoms of such a disease can be treated by supplementation with niacin.

[0006] Inhibition of SLC6A19 in a PKU mouse model was shown to reduce plasma and brain Phe levels, normalize neurotransmitter levels, improve neuronal morphological defects, and improve behavioral symptoms. Belanger, Adam M. et al., Inhibiting neutral amino acid transport for the treatment of phenylketonuria, JCI Insight. 2018; 3(14): e121762. Thus, inhibitors of SLC61A19 are interesting targets for the treatment of PKU. See WO2022 / 192370; Desai, Jigar et al., Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19), Bioorg. Med. Chem. Lett. 53 (2021) 128421; Yadav, Aditya et al. (2020) Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter B0AT1 (SLC6A19), a Potential Target to Treat Metabolic Diseases, Front. Pharmacol. 11: 140.

[0007] Accordingly, embodiments of the present application provide compounds useful for inhibiting SLC6A19 and thereby treating PKU and other aminoacidurias. SUMMARY

[0008] The present disclosure is generally directed to compounds that inhibit SLC6A19 and are useful for treating patients with phenylketonuria (“PKU”) and other aminoacidurias, as well as compositions containing these compounds and methods of using these compounds.

[0009] In one aspect, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is featured:

[0010] (I)

[0011] wherein R1, R2and R3may be as defined anywhere herein.

[0012] In another aspect, characterized is a compound of Formula (II), or a pharmaceutically acceptable salt thereof:

[0013] (II)

[0014] wherein R1, R2, R3, R4, n, R5and R6may be as defined anywhere herein.

[0015] In a further aspect, characterized is a compound of Formula (III), or a pharmaceutically acceptable salt thereof:

[0016] (III)

[0017] wherein R1, R2, R4, R6, n, m, W1, W2, W3, W4, W5, W6and X can be as defined anywhere herein.

[0018] In one aspect, characterized is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof:

[0019] (IV)

[0020] wherein R1, R2, R3, R 10 , n, bicyclic and X can be as defined anywhere herein.

[0021] In another aspect, characterized is a compound of Formula (V), or a pharmaceutically acceptable salt thereof:

[0022] (V)

[0023] wherein R3, R 10 , R 11 , R 12 , R 13 , X1, X2and n can be as defined anywhere herein.

[0024] In another aspect, characterized is a compound of Formula (VI), or a pharmaceutically acceptable salt thereof:

[0025] (VI)

[0026] wherein R 61 , R 62 , R 63and R 64 each of which can be as defined anywhere herein, or a pharmaceutically acceptable salt thereof.

[0027] In another aspect, a compound of Formula (VII), or a pharmaceutically acceptable salt thereof, is featured:

[0028] (VII)

[0029] wherein R 71 and R 72 each of which can be as defined anywhere herein, or a pharmaceutically acceptable salt thereof.

[0030] In another aspect, a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof, is featured:

[0031] (VIII)

[0032] wherein Q is (CH2) n herein in the ring, and n is 1, 2, or 3, thereby forming a 5, 6, or 7-membered ring, or a pharmaceutically acceptable salt thereof.

[0033] In further aspects, compounds (e.g., those depicted in Table 1, or a pharmaceutically acceptable salt thereof) are featured.

[0034] Table 1

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062] or a pharmaceutically acceptable salt thereof.

[0063] In one aspect, pharmaceutical compositions are featured that include a compound described herein (e.g., a compound generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition containing the compound) and one or more pharmaceutically acceptable excipients.

[0064] In one aspect, the present disclosure features methods of modulating (e.g., inhibiting) SLC6A19 in a subject, the methods including administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibition can be in vitro. In some embodiments, the inhibition can be in vivo.

[0065] In one aspect, methods of treating a disorder, disease, or condition ameliorated by modulating (e.g., inhibiting) SLC6A19, e.g., methods of treating a disorder, disease, or condition in which altered (e.g., increased or excessive) SLC6A19 expression or activity contributes to the pathological progression and / or symptom manifestation and / or disease progression of the disorder, disease, or condition, such as cancer, are featured. These methods include administering to a subject in need of such treatment an effective amount of a compound described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing such a compound).

[0066] In another aspect, methods of treating an aminoaciduria are featured, these methods including administering to a subject in need of such treatment an effective amount of a compound described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing such a compound).

[0067] In further aspects, methods of treating phenylketonuria, hyperphenylalaninemia, tyrosinemia, non-ketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder, or hyperammonemia are featured, these methods including administering to a subject in need of such treatment an effective amount of a compound described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing such a compound).

[0068] In one aspect, methods of treating a disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase are featured, these methods including administering to a subject in need of such treatment an effective amount of a compound described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing such a compound).

[0069] In one aspect, methods of treating PKU are featured, these methods including administering to a subject in need of such treatment an effective amount of a compound described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing such a compound).

[0070] In one aspect, methods of treating hyperphenylalaninemia are featured, these methods including administering to a subject in need of such treatment an effective amount of a compound described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing such a compound).

[0071] In certain of the foregoing embodiments, the compound reduces the subject's systemic phenylalanine levels.

[0072] In one aspect, methods of treating tyrosinemia (type I, type II, or type III) are featured, including administering to a subject in need of such treatment an effective amount of a compound described herein (e.g., a compound generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition containing the compound). In certain of the foregoing embodiments, the compound reduces the subject’s systemic tyrosine levels.

[0073] In one aspect, methods of treating non-ketotic hyperglycinemia are featured, including administering to a subject in need of such treatment an effective amount of a compound described herein (e.g., a compound generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition containing the compound). In certain of the foregoing embodiments, the compound reduces the subject’s systemic glycine levels.

[0074] In one aspect, methods of treating isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder, or hyperammonemia are featured, including administering to a subject in need of such treatment an effective amount of a compound described herein (e.g., a compound generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition containing the compound).

[0075] In another aspect, a compound as described herein, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of a condition, disease, or disorder associated with increased (e.g., excessive) SLC6A19 expression.

[0076] In another aspect, a compound described herein, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of any one or more of the foregoing indications (e.g., PKU).

[0077] In another aspect, use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition, disease, or disorder associated with increased (e.g., excessive) SLC6A19 expression is provided.

[0078] In another aspect, use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of any one or more of the foregoing indications (e.g., PKU) is provided.

[0079] In another aspect, the present disclosure features methods for modulating SLC6A19 in a mammalian cell, including contacting the mammalian cell with an effective amount of a compound as described in claim 1, or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the contacting occurs in vivo.

[0081] In some embodiments, the contacting occurs in vitro.

[0082] The chemical entity can be administered in combination with one or more additional therapeutic agents and / or regimens. For example, the methods can further comprise administering one or more (e.g., two, three, four, five, six, or more) additional agents.

[0083] The chemical entity can be administered in combination with one or more additional therapeutic agents and / or regimens useful for treating other SLC6A19 -related disorders (e.g., PKU).

[0084] The methods can further comprise identifying the subject.

[0085] Other embodiments include those described in the DETAILED DESCRIPTION and / or claims.

[0086] Further definitions

[0087] To facilitate the understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein, and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein, are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications and other publications mentioned throughout the specification and annexed drawings are hereby incorporated by reference in their entirety for all purposes.

[0088] As used herein, the term “SLC6A19” is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, antibodies, homologous and / or orthologous SLC6A19 molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0089] As used herein, symbols such as:

[0090]

[0091] and the like are intended to mean that any one or more of the indicated number (“n”) of substituents R 10 may replace the hydrogen atoms on the ring (here, phenyl). For example, if n is 0, 1, or 2, then 0, 1, or 2 hydrogen atoms on the ring can be replaced by 0, 1, or 2 R 10 .

[0092] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a chemical entity administered sufficient to relieve to some extent one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a compound as disclosed herein that is needed to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0093] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulation material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a drug formulation for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al. eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0094] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some instances, a pharmaceutically acceptable salt is obtained by reacting a compound described herein that has an acidic group with a base to form a salt (e.g., an ammonium salt; an alkali metal salt, such as a sodium or potassium salt; an alkaline earth metal salt, such as a calcium or magnesium salt; an organic amine salt, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl) methylamine; and a salt with an amino acid such as arginine, lysine, and the like), or by a previously determined method. The pharmacologically acceptable salt is not particularly limited as long as it can be used in a medicine. Examples of the salt of the compound described herein with a base include the following: a salt thereof with an inorganic base such as sodium, potassium, magnesium, calcium, and aluminum; a salt thereof with an organic base such as methylamine, ethylamine, and ethanolamine; a salt thereof with a basic amino acid such as lysine and ornithine; and an ammonium salt. The salt can be an acid addition salt, and specific examples thereof are acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and an acidic amino acid such as aspartic acid and glutamic acid.

[0095] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, which are pharmaceutically acceptable. The pharmaceutical composition promotes the administration of the compound to an organism. There are a variety of techniques for administering a compound in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0096] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, and both refer to, for example, a mammalian subject, such as a human.

[0097] In the context of treating a disease or disorder, the terms "treat," "treating," and "treatment" are intended to include one or more of the reduction or elimination of a disorder, disease, or condition, or a symptom associated with a disorder, disease, or condition; or the slowing, halting, or reversal of the progression, spread, or worsening of a disease, disorder, or condition, or one or more symptoms thereof. DETAILED DESCRIPTION

[0098] The present disclosure generally relates to compounds that inhibit SLC6A19 and are useful for treating patients with phenylketonuria ("PKU") and other aminoacidurias, as well as compositions containing these compounds and methods of using these compounds.

[0099] Compounds of formula (I)

[0100] In one aspect, the present disclosure features a compound of Formula I:

[0101] (I)

[0102] wherein R1and R2are independently selected from H or CH3;

[0103] wherein each R3is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, wherein at least two R3are H; or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, R1is CH3and R2is H.

[0105] In some embodiments, at least one R3is F.

[0106] In some embodiments, at least one R3is Cl.

[0107] In some embodiments, at least one R3is CH3.

[0108] In some embodiments, R1and R2are both H.

[0109] In some embodiments, R1and R2are both CH3.

[0110] Compounds of formula (II)

[0111] In one aspect, the present disclosure features a compound of Formula II:

[0112] (II)

[0113] wherein R1and R2are independently selected from H or CH3;

[0114] wherein each R3is independently selected from H, CH2F2, OH, CH3, O-CH3, F, or Cl, wherein at least two R3are H;

[0115] wherein n is 0, 1, 2, or 3;

[0116] wherein each occurrence of R4is independently selected from CH3, CF3, O-CH3, F, Cl, -CN, isopropyl, or cyclopropyl;

[0117] wherein R6is H, -CH2CH2OH, or -CH2CH2N(CH3)2;

[0118] R5is:

[0119] ; ; -CF2CF3; ; ; ; ; ; ;

[0120] wherein m is 0, 1, 2, 3, or 4, and X is CH3, OCH3, F, or Cl;

[0121] ; ; ; ; ;

[0122] wherein each X1is independently N or CH; provided that one X1is N;

[0123] ; ; or ;

[0124] provided that when R5is the following, n cannot be 0:

[0125] ;

[0126] or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the compound is of Formula (II-A):

[0128] (II-A)

[0129] wherein each occurrence of R 4a , R 4b , R 4c , and R 4d is independently selected from H, CH3, CF3, O-CH3, F, Cl, -CN, isopropyl, or cyclopropyl; provided that at least one of R 4a , R 4b , R 4c , and R 4d is not H; or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, R 4a , R 4b, R 4c and one of R 4d is CI; and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4d may be CI.

[0131] In some embodiments, one of R 4a , R 4b , R 4c , and R 4d is CH3; and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4d may be CH3.

[0132] In some embodiments, one of R 4a , R 4b , R 4c , and R 4d is OCH3; and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4c may be OCH3.

[0133] In some embodiments, one of R 4a , R 4b , R 4c , and R 4d is F; and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4a may be F.

[0134] In some embodiments, one of R 4a , R 4b , R 4c , and R 4d is CF3; and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4a may be CF3.

[0135] In some embodiments, one of R 4a , R 4b , R 4c , and R 4d is CN; and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4b may be CN.

[0136] In some embodiments, one of R 4a , R 4b , R 4c , and R 4d is cyclopropyl; and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4b may be cyclopropyl.

[0137] In some embodiments, one of R 4a , R 4bR 4c and one of R 4d is isopropyl; and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4b may be isopropyl.

[0138] In some embodiments, two of R 4a , R 4b , R 4c , and R 4d are independently Cl, F, or CH3; and the other is H, or a pharmaceutically acceptable salt thereof.

[0139] For example, R 4b and R 4c may be F.

[0140] As another example, one of R 4a and R 4b may be F, and the other of R 4a and R 4b may be CH3.

[0141] As another example, one of R 4a and R 4b may be F, and the other of R 4b and R 4c may be CH3.

[0142] As another example, one of R 4a and R 4b may be F, and the other of R 4a and R 4d may be CH3.

[0143] In some embodiments, R5is:

[0144] .

[0145] In some embodiments, R5is:

[0146] or wherein each X1is independently N or CH; provided that one X1is N.

[0147] In some embodiments, R5is:

[0148] wherein m is 0, 1, 2, 3, or 4, and X is CH3, OCH3, F, or Cl, or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, R1is CH3and R2is H.

[0150] In some embodiments, R3 is H.

[0151] In some embodiments, R6 is H.

[0152] Compounds of formula (III)

[0153] In one aspect, the disclosure features a compound having Formula III:

[0154] (III)

[0155] wherein:

[0156] each of W1 and W4 is independently selected from N, C, or CH;

[0157] each of W2, W3, W5, and W6 is independently selected from N, NH, CH, or CH2;

[0158] n is 0, 1, 2, or 3;

[0159] each occurrence of R4 is independently cyclopropyl, Cl, F, CH3, or OCH3;

[0160] m is 0, 1, 2, or 3;

[0161] each occurrence of R6 is independently F, Cl, or CH3;

[0162] wherein R1 and R2 are independently selected from H or CH3;

[0163] the dashed line indicates the presence of a single or double bond; and

[0164] X is H or CF3, or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, W3 is N, W1 and W4 are C; and each of W2, W5, and W6 is CH.

[0166] In some embodiments, W2 and W3 are N, W1 and W4 are C; and each of W5 and W6 is CH.

[0167] In some embodiments, wherein each of W3 and W5 is N, W1 and W4 are C; and each of W2 and W6 is CH.

[0168] In some embodiments, each of W1 and W4 is CH; and each of W2, W3, W5, and W6 is CH2.

[0169] In some embodiments, W1 is CH, and W4 is N; and each of W2, W3, W5, and W6 is CH2.

[0170] In some embodiments, W3 and W6 are N, W1 and W4 are C; W2 is CR6, and W5 is CH. In certain embodiments, R6 is CH3.

[0171] In some embodiments, W2 is N, W1 and W4 are C; and each of W3 and W5 is CH, and W6 is CR6. In certain embodiments, R6 is Cl.

[0172] In some embodiments, W2 is N, W1 and W4 are C; and each of W3, W5 and W6 is CH.

[0173] In some embodiments, W2 and W6 are N, W1 and W4 are C; W3 is CR6, and W5 is CH. In certain embodiments, R6 is CH3.

[0174] In some embodiments, W2 and W6 are N, W1 and W4 are C; W3 is CH, and W5 is CH.

[0175] In some embodiments, W2 is N, W1 and W4 are C; each of W3 and W6 is CR6, and W5 is CH. In certain embodiments, R6 is CH3.

[0176] In some embodiments, R1 is CH3 and R2 is H.

[0177] In some embodiments, n is 1, and R4 is F or cyclopropyl.

[0178] Compounds of formula (IV)

[0179] In one aspect, the present disclosure features a compound having Formula IV:

[0180] (IV)

[0181] wherein R1 and R2 are independently selected from H or CH3;

[0182] wherein each R3 is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, wherein at least two R3 are H;

[0183] wherein n is 0, 1, or 2;

[0184] wherein each occurrence of R 10 is independently methyl, F, OH, H, OCH3, CH3, or cyclopropyl;

[0185] wherein X is H or CF3; and

[0186] wherein the bicyclic ring is a bicyclic ring comprising 8-10 constituent ring atoms, wherein 1-4 of the atoms are heteroatoms independently selected from N, O, or S, and wherein each of the two rings is independently a saturated, unsaturated, or aromatic ring;

[0187] or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the bicyclic ring is selected from:

[0189]

[0190] or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, R1is CH3and R2is H.

[0192] In some embodiments, each occurrence of R3is H.

[0193] In some embodiments, X is CF3.

[0194] Compounds of formula (V)

[0195] In one aspect, the present disclosure features a compound of Formula V:

[0196] (V)

[0197] R 11 is - (CH2) m -A

[0198] m is 0, 1, 2, or 3;

[0199] R 12 is H;

[0200] R 13 is H, -CH2CH2OH, or -CH2CH2N(CH3)2;

[0201] A is cyclopropyl, -OH, -OCH3; , -CHF2; phenyl, 4-chlorophenyl; or 4-pyridyl;

[0202] n is 0, 1, 2, or 3;

[0203] each occurrence of R 10 is independently cyclopropyl, Cl, F, CH3, or OCH3;

[0204] each R3is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, wherein at least two R3are H; and

[0205] X1is H or CF3;

[0206] X2is H or F;

[0207] or R 11 and R 12 together with the nitrogen atom to which each is attached form:

[0208]

[0209] or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, R 11 is -(CH2) m -A, and R 12 is H.

[0211] In some embodiments, m is 1 or 2.

[0212] In some embodiments, n is 1.

[0213] In some embodiments, R3is H.

[0214] In some embodiments, X1is CF3, and X2is H.

[0215] In some embodiments, X1is CF3, and X2is F.

[0216] In some embodiments, X1is H, and X2is H.

[0217] In some embodiments, R 13 is H.

[0218] Compounds of formula (VI)

[0219] In one aspect, the present disclosure features a compound of Formula VI:

[0220] (VI)

[0221] wherein each of R 61 , R 62 , R 63 , and R 64 is independently selected from H and CH3, or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments, one of R 61 , R 62 , R 63 , and R 64 is CH3, and the other three are H, or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, R61 and R 62 One of them is CH3, and the others are H, or their pharmaceutically acceptable salts.

[0224] In some embodiments, R 63 and R 64 One of them is CH3, and the others are H, or their pharmaceutically acceptable salts.

[0225] Compounds of formula (VII)

[0226] In one respect, this disclosure is characterized by compounds having formula VII:

[0227] (VII)

[0228] R 71 and R 72 Each of them is independently selected from H and CH3, or their pharmaceutically acceptable salts.

[0229] In some embodiments, R 71 and R 72 One of them is CH3, and the others are H, or their pharmaceutically acceptable salts.

[0230] Compounds of formula (VIII)

[0231] In one respect, this disclosure is characterized by compounds having formula VIII:

[0232] (VIII)

[0233] Where Q is (CH2) n Here, it is in a ring, and n is 1, 2, or 3, thus forming a 5, 6, or 7-membered ring, or a pharmaceutically acceptable salt thereof.

[0234] Pharmaceutical compositions and administration

[0235] General description

[0236] In some embodiments, a compound (e.g., a compound that inhibits (e.g., antagonizes) SLC6A19, or a pharmaceutically acceptable salt and / or hydrate, and / or cocrystal, and / or combination of drugs thereof) is administered as a pharmaceutical composition comprising a chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0237] In some embodiments, the chemical entity can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopheryl polyethylene glycol 1000 succinate, surfactants used in manufacturing drug formulations such as Tweens, polox-amer, or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, trisaminomethane, glycine, sorbic acid, potassium sorbate, partially, fatty acid glycerides, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and

[0238] Routes of administration and composition components

[0239] In some embodiments, the chemical entities described herein, or pharmaceutical compositions thereof, can be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, dermal, intracervical, intrasinus, intratracheal, intestinal, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, intracapsular, intracerebral, intracisternal, intracoronary, intradermal, intracatheter, intraduodenal, intradural, intradermal, intragastric, intragastrointestinal, intralumbar, intralymphatic, intramedullary, intramembranous, intramuscular, intranodal, intraperitoneal, intraprostatic, intrapulmonary, intranasal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, and vaginal.

[0240] The compositions can be formulated for parenteral administration, e.g., for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for adding to liquid solutions or suspensions prior to injection can also be prepared; and the preparation can also be emulsified. Preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[0241] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must also be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0242] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0243] A sterile injectable solution can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from the previously sterile-filtered solution thereof.

[0244] Pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g., PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycols, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essence oil, aerosol, parahydroxybenzoic acid esters in phenoxyethanol, methyl sodium p-oxybenzoate, propyl sodium p-oxybenzoate, diethylamine, carbomer, carbopol, methoxybenzoic acid esters, polyoxyl cetylstearyl ether, cocoyl octyl decyl acrylate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grape seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0245] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically-acceptable excipients such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders like, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absoption accelerators such as quaternary ammonium compounds; g) lubricants such as, for example, colloidal silica, and talc; h) absorbents such as kaolin and bentonite clay; and i) lubricating agents such as talc, magnesium stearate, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols.

[0246] In one embodiment, the composition will take the form of a unit dosage form, for example, a pill or tablet, and therefore, in addition to the chemical entity provided herein, the composition can contain a diluent, such as lactose, sucrose, dicalcium phosphate, and the like; a lubricant, such as magnesium stearate and the like; and a binder, such as starch, acacia, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, and the like. In another solid dosage form, powders, marumes, solutions, or suspensions (for example, in propylene carbonate, vegetable oils, PEG, poloxamer 124, or triglycerides) are encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which the chemical entity or entities provided herein or additional active agents are physically separated are also contemplated; for example, capsules containing particles (or tablets within capsules) of each drug; bilayer tablets; bilumen gel capsules, and the like. Enteric-coated or delayed release oral dosage forms are also contemplated.

[0247] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersing agents, or preservatives particularly useful for preventing the growth of microorganisms or for affecting action. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0248] In certain embodiments, the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for various oral dosage forms excipients, such as tablets and capsules. USP / NF standards are generally adequate.

[0249] Topical compositions can include ointments and creams. Ointments are semisolid formulations typically based on petrolatum or other petroleum derivatives. Creams containing a selected active agent are typically viscous liquids or semisolid emulsions, usually oil-in-water or water-in-oil. Cream base is typically water-washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes also referred to as the "internal" phase, is usually composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, though not necessarily, exceeds the oil phase in volume and usually contains a humectant. The emulsifier in cream formulations is usually a nonionic, anionic, cationic, or amphoteric surfactant. As with other carriers or vehicles, ointment bases should be inert, stable, nonirritating, and nonsensitizing.

[0250] Dose

[0251] The dose can vary depending on the requirements of the patient, the severity of the condition being treated, and the particular compound being used. Determination of the proper dosage for a particular situation can be made by those of ordinary skill in the art. The total daily dose can be administered in divided doses throughout the day, or by delivery of sustained release formulations.

[0252] In some embodiments, the compounds described herein are administered at a dose from about 0.001 mg / Kg to about 500 mg / Kg (e.g., from about 0.01 mg / Kg to about 100 mg / Kg; from about 0.01 mg / Kg to about 10 mg / Kg; from about 0.01 mg / Kg to about 1 mg / Kg; from about 0.01 mg / Kg to about 0.1 mg / Kg; from about 0.1 mg / Kg to about 100 mg / Kg; from about 0.1 mg / Kg to about 10 mg / Kg).

[0253] Regimen

[0254] The foregoing doses can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or on a non-daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0255] In some embodiments, the period of administration of a compound described herein lasts for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period of cessation of administration lasts for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In embodiments, a therapeutic compound is administered to an individual for a period of time, followed by a period of separation. In another embodiment, a therapeutic compound is administered for a first period of time and a second period of time following the first period of time, wherein administration is ceased during the second period of time, followed by a third period of time in which administration of the therapeutic compound is resumed, followed by a fourth period of time following the third period of time during which administration is ceased. In an aspect of this embodiment, the following is repeated for a determined or undetermined period of time: a period of administration of a therapeutic compound, followed by a period of cessation of administration. In further embodiments, the period of administration lasts for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period of cessation of administration lasts for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0256] Methods of treatment

[0257] In some embodiments, methods are provided for treating a subject having a condition, disease, or disorder in which increased (e.g., excessive) SLC6A19 activity contributes to the pathological progression and / or symptomatic manifestation and / or disease progression of the condition, disease, or disorder (e.g., an immune disorder, a cancer).

[0258] One aspect of the present application provides compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with abnormal levels of amino acids by modulating SLC6A19 transport.

[0259] Another aspect of the present application relates to methods of modulating SLC6A19 transport in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein.

[0260] The present disclosure features methods of treating a disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I).

[0261] The present disclosure features methods of treating a disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I).

[0262] The present disclosure features methods of treating a disease or disorder associated with a genetic deficiency of phenylalanine hydroxylase in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I).

[0263] In some embodiments, the compound reduces the subject's systemic phenylalanine levels.

[0264] The present disclosure features methods of treating tyrosinemia (type I, type II, or type III) in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein.

[0265] In some embodiments, the compound reduces the subject's systemic glycine levels. In some embodiments, the present application relates to methods of treating or preventing isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder, or hyperammonemia in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein.

[0266] In some embodiments of any of the disclosed methods, the compound modulates SLC6A19 in the subject.

[0267] In some embodiments of any of the disclosed methods, the compound inhibits SLC6A19 in the subject.

[0268] In some embodiments of any of the disclosed methods, the compound modulates SLC6A19 transport in the subject.

[0269] In some embodiments of any of the disclosed methods, the compound inhibits SLC6A19 transport in the subject.

[0270] In some embodiments, the compound reduces systemic amino acid levels in the subject.

[0271] In some embodiments of any of the disclosed methods, the subject is a mammal. In some embodiments of any of the disclosed methods, the mammal is a human.

[0272] Combination therapy

[0273] The present disclosure contemplates both monotherapy regimens and combination therapy regimens. This can involve administering one or more of the compounds to a patient, followed by administering another agent to the patient.

[0274] In some embodiments, the methods described herein can further comprise administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with administering the compounds described herein.

[0275] Preparation of compounds

[0276] As can be appreciated by one skilled in the art, methods of synthesizing compounds having the formulae herein will be readily apparent to one of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful for synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2nded., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. Starting materials used in the preparation of the compounds of the application are known, prepared by known methods, or are commercially available. The skilled artisan will also recognize that the conditions and reagents described herein can be interchanged with alternative art-recognized equivalents. For example, in many reactions, triethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g., diisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphonium phosphate).

[0277] The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including, for example 1 H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of the characterization methods available to the skilled artisan and is not intended to be limiting.

[0278] To further illustrate the foregoing, the following non-limiting exemplary synthetic methods are included. Variations of these examples within the scope of the claims are within the skill of the art and are considered to fall within the scope of the invention as described and claimed herein. The reader will recognize that those skilled in the art, upon receiving this disclosure and their own skills, can prepare and use the invention without exhaustive examples.

[0279] Preparation of intermediates

[0280] General Procedure 1: Synthesis of Indole-2-Carboxylate Intermediates

[0281] Preparation of Intermediate 1: Methyl 4-bromo-6-cyclopropyl-1H-indole-2-carboxylate

[0282]

[0283] Step 1: Preparation of methyl 2-amino-4-cyclopropylbenzoate

[0284]

[0285] Methyl 2-amino-4-bromobenzoate (25.00 g, 109 mmol), cyclopropylboronic acid (11.75 g, 137 mmol), palladium(II) acetate (733 mg, 3.26 mmol), tricyclohexylphosphine (1.85 g, 6.60 mmol), tripotassium phosphate (60.50 g, 285 mmol), toluene (300 mL), and water (50 mL) were added to a 1 L round-bottom flask equipped with a magnetic stir bar, reflux condenser, and N2 inlet. The mixture was degassed under vacuum and backfilled with N2 (x 3). The brown mixture was then heated to reflux. After 2 h, LC / MS analysis showed that the reaction was complete. The mixture was allowed to cool to room temperature and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (200 mL). The filtrate was washed with brine (150 mL), dried over magnesium sulfate, filtered, and concentrated to provide a brown oil. Chromatographic purification (CombiFlash, 330 g SiO2 column, 0-20% ethyl acetate / heptane elution, combined fractions 25-30, scaffold 1 and 1-11, scaffold 2) yielded methyl 2-amino-4-cyclopropylbenzoate as a pale yellow solid (18.59 g, 97.2 mmol, 90% yield); (M+1) = 192.

[0286] Step 2: Preparation of methyl 2-bromo-4-cyclopropylbenzoate

[0287]

[0288] To a 1 L recovery flask equipped with a magnetic stir bar and an addition funnel was added 2-amino-4-cyclopropyl-benzoic acid methyl ester (18.64 g, 97.5 mmol), 1,4-dioxane (100 mL), and a 48% hydrobromic acid solution (50 mL). The mixture was cooled to 0 °C while a solution of sodium nitrite (8.00 g, 116 mmol) in water (30 mL) was added via the addition funnel over 5 min. The resulting pink mixture was allowed to stir at 0 °C. After 30 min, a mixture of copper(I) bromide (34.59 g, 241.1 mmol) in 48% hydrobromic acid solution (50 mL) was added to the mixture via the addition funnel over 15 min. The ice bath was removed and the mixture was allowed to warm to room temperature. After 1 h, LC / MS analysis showed the reaction was complete. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with 3N ammonium hydroxide solution (200 mL) and brine (200 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide a brown oil. Chromatographic purification (CombiFlash, 330 g Si02column, 5%-15% ethyl acetate / heptane elution, fractions 17-30 combined, rack 1) provided 2-bromo-4-cyclopropyl-benzoic acid methyl ester as a yellow oil (15.85 g, 62.13 mmol, 64% yield); (M+1) = 255.

[0289] Step 3: Preparation of 2-bromo-4-cyclopropylbenzoic acid

[0290]

[0291] To a 500 mL recovery flask equipped with a magnetic stir bar, reflux condenser, and N2inlet was added 2-bromo-4-cyclopropyl-benzoic acid methyl ester (17.36 g, 68.1 mmol), tetrahydrofuran (100 mL), and water (50 mL). The solution was treated with lithium hydroxide monohydrate (8.50 g, 203 mmol) and the resulting mixture was heated to reflux. After 2 h, LC / MS analysis showed the reaction was complete. The mixture was allowed to cool to room temperature and diluted with water (250 mL). The mixture was extracted with diethyl ether (150 mL, discarded). The phases were separated and the aqueous phase was acidified with concentrated hydrochloric acid solution (about 15 mL). The mixture was then extracted with diethyl ether (2 x 150 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 2-bromo-4-cyclopropyl-benzoic acid as a light yellow solid (16.00 g, 66.37 mmol, 98% yield); (M-1) = 239.

[0292] Step 4: Preparation of (2-bromo-4-cyclopropylphenyl)methanol

[0293]

[0294] To a 1 L round bottom flask, equipped with a magnetic stir bar, reflux condenser, and N2inlet, was added 2-bromo-4-cyclopropyl-benzoic acid (16.00 g, 66.37 mmol) and tetrahydrofuran (100 mL). The solution was treated with borane dimethyl sulfide complex (9.6 mL, 100 mmol) via syringe over 3 min (note gas evolution). The mixture was heated to reflux. After 30 min, LC / MS analysis showed the reaction to be complete. The mixture was allowed to cool to room temperature. Methanol (15 mL) was slowly added to the reaction mixture (vigorous gas evolution!) and the resulting solution was allowed to stir. After 15 min, the mixture was concentrated to provide a milky white oil. Chromatography purification (CombiFlash, 220 g Si02column, 15%-30% ethyl acetate / heptane elution, fractions 1-12 combined, rack 1) provided (2-bromo-4-cyclopropyl-phenyl)methanol (B, 13.69 g, 60.28 mmol, 91% yield) as a white solid; (M+l) = 227.

[0295] Step 5: Preparation of 2-bromo-4-cyclopropylbenzaldehyde

[0296]

[0297] To a 1 L round bottom flask, equipped with a magnetic stir bar, reflux condenser, and N2inlet, was added (2-bromo-4-cyclopropyl-phenyl)methanol (26.10 g, 115 mmol), manganese(IV) oxide (85.00 g, 978 mmol), and chloroform (300 mL). The mixture was warmed to 70 °C and stirred. After 1 h, LC / MS analysis showed the reaction to be complete. The mixture was allowed to cool to room temperature and filtered through celite. The filter cake was washed with chloroform (3 x 150 mL). The filtrate was concentrated to provide 2-bromo-4-cyclopropyl-benzaldehyde (25.30 g, 112 mmol, 98% yield) as a light yellow oil.

[0298] Step 6: Preparation of (Z)-2-azido-3-(2-bromo-4-cyclopropylphenyl)acrylate

[0299]

[0300] To a 1 L three necked round bottom flask, equipped with a magnetic stir bar, an addition funnel, and a N2inlet, was added methanol (300 mL). Sodium metal (5.12 g, 223 mmol) was added to the vessel and the resulting mixture was allowed to stir while the solid dissolved. The resulting solution was cooled to -40 °C and 2-bromo-4-cyclopropyl-benzaldehyde (12.50 g, 55.5 mmol) was added. The resulting mixture was allowed to stir at -40 °C for 15 min and then methyl 2-azidoacetate (21.2 mL, 218 mmol) was added dropwise to the reaction mixture over 15 min. After the addition was complete, the yellow reaction mixture was allowed to warm slowly to room temperature. LC / MS analysis of the brown suspension after 22 h showed the reaction to be complete. The mixture was diluted with 1.0 N hydrochloric acid solution (350 mL) and the resulting mixture was cooled to 0 °C and stirred. After 15 min, the mixture was filtered and the filter cake was washed with water (150 mL). The damp solid was dissolved in ethyl acetate (250 mL) and the resulting brown solution was dried over magnesium sulfate, filtered and concentrated to provide (Z)-methyl 2-azido-3-(2-bromo-4-cyclopropyl-phenyl)prop-2-enoate (13.28 g, 41.22 mmol, 74% yield) as a brown oil.

[0301] Step 7: Preparation of methyl 4-bromo-6-cyclopropyl-lH-indole-2-carboxylate

[0302] To a 1 L round bottom flask, equipped with a magnetic stir bar, reflux condenser, and N2inlet, was added (Z)-2-azido-3-(2-bromo-4-cyclopropyl-phenyl)prop-2-enoic acid methyl ester (14.08 g, 43.7 mmol) and p-xylene (300 mL). The mixture was heated to reflux. After 1.5 h, LC / MS analysis showed the reaction was complete. The mixture was allowed to cool to room temperature and concentrated to provide an orange solid. The crude solid was suspended in heptane (150 mL) and ethyl acetate (15 mL). The mixture was heated to reflux. After 20 min, most of the solid had dissolved to provide a red-brown solution. The mixture was allowed to cool to room temperature, and then placed in the freezer overnight, resulting in the formation of a precipitate. The liquid phase of the mixture was decanted, and the remaining solid was subjected to chromatographic purification (CombiFlash, 220 g Si02gold cartridge, eluting with 10%-40% ethyl acetate / heptane, fractions 10-30 combined, column 1) to provide a yellow solid. The solid was suspended in heptane (125 mL) and heated to reflux. The mixture was allowed to cool to room temperature and further cooled in the freezer for 45 min. The cold suspension was filtered, and the filter cake was washed with a small amount of heptane (20 mL) and dried to provide 4-bromo-6-cyclopropyl-lH-indole-2-carboxylic acid methyl ester as an off-white solid (9.09 g, 30.9 mmol, 71% yield); (M+l) = 294

[0303] The following indole-2-carboxylates were prepared from the corresponding aldehydes as described in steps 6-7 of General Procedure 1:

[0304]

[0305]

[0306] General Procedure 2: Preparation of heterocyclic carboxamides by amination of esters

[0307] Intermediate 12: Preparation of 4-bromo-N-methyl-lH-indole-2-carboxamide

[0308]

[0309] To a 20 mL microwave reaction vial equipped with a magnetic stir bar was added 4-bromo-lH-indole-2-carboxylic acid methyl ester (11.06 g, 42.66 mmol, CAS 167479-13-2) and a 33% solution of methylamine in ethanol (15 mL, 120.49 mmol). The vessel was sealed and the contents heated to 130 °C in a microwave reactor. After 1 h, LC / MS analysis showed the reaction was near completion. The mixture was allowed to cool to room temperature, resulting in the formation of a precipitate. The mixture was diluted with water (75 mL) and filtered. The filter cake was washed with water (50 mL) and dried to provide 4-bromo-N-methyl-lH-indole-2-carboxamide as a white solid (10.25 g, 40.50 mmol, 95% yield); (M+l) = 253.

[0310] The following carboxamides were prepared from the corresponding esters as described in General Procedure 2:

[0311]

[0312]

[0313] General Procedure 3: Preparation of heterocyclic carboxamides via HATU mediated amidation

[0314] Intermediate 29: Preparation of 4-chloro-N,N-dimethylthieno[3,2-c]pyridine-2- carboxamide

[0315]

[0316] A mixture of 4-chlorothieno[3,2-c]pyridine-2-carboxylic acid (300 mg, 1.3 mmol, CAS 1360891-68-4), dimethylamine (2.7 mL, 5.3 mmol) (2 M in THF), and HATU (686.9 mg, 1.7 mmol) in DMF (5 mL) was stirred for 2 h. More HATU (140 mg) was added to drive the reaction to completion. LC / MS indicated all starting material was consumed. The reaction mixture was partitioned between 1 M NaOH and EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc (2X). The combined organic layers were dried over MgS04, filtered, and concentrated in vacuo. The crude material was purified on silica gel with EtOAc (100%) as eluent to provide 4-chloro-N,N-dimethylthieno[3,2-c]pyridine-2-carboxamide as a white solid (319 mg, 1.3 mmol, 99% yield); (M+l) = 241.

[0317] The following carboxamides were prepared from the corresponding acids as described in General Procedure 3:

[0318]

[0319] Preparation of Intermediate 34: 4-bromo-6-cyclopropyl-N-methyl-1H- benzo[d]imidazole-2-carboxamide

[0320]

[0321] A solution of 4-bromo-6-cyclopropyl-2-(trichloromethyl)-1H-benzimidazole (1.20 g, 3.39 mmol, see WO2011097491) in acetonitrile (20 mL) was treated with methylamine hydrochloride (0.45 g, 6.67 mmol) followed by dropwise addition of a 4M potassium carbonate solution (2.30 g, 16.9 mmol). The mixture was stirred at room temperature overnight and then quenched by addition of brine and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel (MeOH / DCM: 0-5%) to provide 4-bromo-6-cyclopropyl-N-methyl-1H- benzo[d]imidazole-2-carboxamide as a yellow solid (0.70 g, 70% yield); (M+1) = 294.

[0322] Preparation of Intermediate 35: 4-bromo-7-fluoro-N-methyl-1H- benzo[d]imidazole-2-carboxamide

[0323]

[0324] Step 1: Preparation of 4-bromo-7-fluoro-2-(trichloromethyl)-1H- benzo[d]imidazole

[0325]

[0326] Benzyl 2,2,2-trichloro-acetimidate (0.95 mL, 5.12 mmol) was added to a solution of 3-bromo-6-fluoro-benzene-1,2-diamine (1.0 g, 4.88 mmol, CAS 1805502-21-9) in acetic acid (30 mL) and the resulting solution was stirred at room temperature. After 1 h, water (20 mL) was added to the mixture and the suspension was filtered. The filter cake was washed with water and dried under vacuum to provide 4-bromo-7-fluoro-2-(trichloromethyl)-1H- benzo[d]imidazole which was used directly in the next step without further purification.

[0327] Step 2: Preparation of 4-bromo-7-fluoro-N-methyl-1H-benzo[d]imidazole-2- carboxamide

[0328] The title compound was prepared according to the procedure described for the preparation of Intermediate 34; (M+1) = 272.

[0329] Preparation of Intermediate 36: 4-Bromo-6-cyclopropyl-l-(2-hydroxyethyl)-N- methyl-lH-indole-2-carboxamide

[0330]

[0331] To a solution of 4-bromo-6-cyclopropyl-N-methyl-lH-indole-2-carboxamide (60 mg, 0.21 mmol, Intermediate 28), potassium hydroxide (34 mg, 0.61 mmol), and potassium iodide (7 mg, 0.04 mmol) in acetone (3 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (49 mg, 0.21 mmol). The mixture was allowed to stir at room temperature. After 16 h, LC / MS showed 20% desilylation product formed. Water (10 mL) was added and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with water (10 mL x 2) and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with PE : EA = 1 : 1) to give 4-bromo-6-cyclopropyl-l-(2-hydroxyethyl)-N-methyl-indole-2- carboxamide (10 mg, 15% yield); (M+l) = 337.

[0332] Preparation of Intermediate 37: 4-Bromo-6-cyclopropyl-l-(2-(dimethylamino)ethyl)-N- methyl-lH-indole-2-carboxamide

[0333]

[0334] To a solution of 4-bromo-6-cyclopropyl-N-methyl-lH-indole-2-carboxamide (50 mg, 0.17 mmol, Intermediate 28) in tetrahydrofuran (3 mL) at 0 °C was added sodium hydride (6 mg, 0.26 mmol). The mixture was allowed to warm to room temperature and stirred. After 1 h, the mixture was treated with 2-bromo-N,N-dimethylethan-l-amine hydrobromide (44 mg, 0.19 mmol) and allowed to stir at room temperature. After 1 h, the reaction was quenched by the addition of water and ethyl acetate, and the resulting mixture was filtered. The aqueous layer was washed with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE : EA = 4 : 1) to give 2-[benzyloxy carbonyl-[(4-bromophenyl)methyl]amino]ethyl acetate (25 mg, 0.07 mmol, 40% yield); (M+l) = 364.

[0335] Preparation of Intermediate 38: 4-bromo-3-chloro-N,6-dimethyl-7-oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridine-2-carboxamide

[0336]

[0337] To a 5 mL microwave reaction vial was added 4-bromo-N,6-dimethyl-7-oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridine-2-carboxamide (54 mg, 191 µmol, see WO 2017177955) and DMF (2 mL). The mixture was treated with N-chlorosuccinimide (27 mg, 200 µmol). The mixture was allowed to stir at room temperature for 45 min, then heated to 60 °C overnight. The heterogeneous reaction mixture was filtered, and the filter cake was dried to provide 4-bromo-3-chloro-N,6-dimethyl-7-oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridine-2-carboxamide (45 mg, 142 µmol, 75% yield) as a white solid; (M+1) = 318.

[0338] Preparation of Intermediate 39: 4-bromo-6-cyclopropylbenzo[d]thiazol-2-amine

[0339]

[0340] To a solution of 4-cyclopropylaniline (2.00 g, 15.0 mmol, CAS 3158-71-2) in acetic acid (40 mL) was added bromine (4.80 g, 30.0 mmol) and the resulting mixture was allowed to stir at room temperature. After 5 min, potassium thiocyanate (10.2 g, 105 mmol) was added. The mixture was allowed to stir at room temperature. After 2 h, the mixture was diluted with ethyl acetate and water. The aqueous layer was washed twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give 4-bromo-6-cyclopropyl-1,3-benzothiazol-2-amine (180 mg, 0.67 mmol, 4% yield); (M+1) = 269.

[0341] Preparation of Intermediate 40: N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indole-2-carboxamide

[0342]

[0343] To a 500 mL round bottom flask, equipped with a magnetic stir bar, reflux condenser, and N2inlet, was added 4-bromo-N-methyl-lH-indole-2-carboxamide (6.49 g, 25.64 mmol, Intermediate 12), pinacolborane (5.75 ml, 38.46 mmol), bis(acetonitrile)palladium(II) chloride (134 mg, 513 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (859.35 mg, 2.05 mmol), triethylamine (10.78 ml, 76.93 mmol), and 1,4-dioxane (80 ml). The mixture was degassed under vacuum / backfilled with N2(x 3). The mixture was then heated to reflux. After 1 h, LC / MS analysis of the mixture showed the presence of several new products, including the desired boronate (major) and dehalogenated starting material (minor). The mixture was allowed to cool to room temperature and diluted with water (300 mL). The resulting precipitate was isolated by filtration, and the filter cake was washed with water (50 mL). The damp solid was dissolved in ethyl acetate (150 mL), and the solution was dried over magnesium sulfate, filtered, and concentrated to provide N-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole-2-carboxamide as a yellow solid (5.72 g, 19.06 mmol, 74% yield); (M+l) = 301.

[0344] Preparation of Intermediate 41: 6-cyclopropyl-N-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-lH-indole-2-carboxamide

[0345]

[0346] To a 20 mL microwave reaction vial equipped with a magnetic stir bar was added 4-bromo-6-cyclopropyl-N-methyl-lH-indole-2-carboxamide (1.05 g, 3.58 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.36 g, 5.36 mmol), l,l'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (0.15 g, 0.18 mmol), potassium acetate (1.41 g, 14.4 mmol), and 1,4-dioxane (12 mL). The vessel was sealed and the contents were degassed / backfilled with N2(x 3). The mixture was heated to 125 °C in a heating block. After 2.5 h, LC / MS analysis showed the reaction was complete. The mixture was allowed to cool to room temperature and diluted with water (100 mL), resulting in the formation of a precipitate. The mixture was filtered and the filter cake was washed with water (30 mL). The damp solid was dissolved in ethyl acetate (75 mL). The mixture was washed with brine (50 mL) and the resulting emulsion was filtered through Celite. The filter cake was washed with ethyl acetate (25 mL). The filter fractions were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated to provide 6-cyclopropyl-N-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole-2-carboxamide as a brown solid (794 mg, 2.33 mmol, 65% yield); (M+l) = 341.

[0347] Preparation of Intermediate 42: 7-Fluoro-N-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[d]imidazole-2-carboxamide

[0348]

[0349] The title compound was prepared from 4-bromo-7-fluoro-N-methyl-lH-benzo[d]imidazole-2-carboxamide (Intermediate 35) as described for the preparation of Intermediate 41; (M+l) = 320.

[0350] Preparation of Intermediate 43: 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3- (trifluoromethyl)benzyl)benzamide

[0351]

[0352] To a 500 mL round bottom flask equipped with a magnetic stir bar and N2inlet was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (9.3 g, 37 mmol, CAS 180516-87-4), HATU (15.00 g, 39.45 mmol), dichloromethane (200 mL), and N,N-diisopropylethylamine (8.5 mL, 49 mmol). The resulting suspension was allowed to stir at room temperature for 5 min, and then 3-(trifluoromethyl)benzylamine (7.22 g, 41.2 mmol) was added. The mixture was allowed to continue stirring at room temperature. After 30 min, LC / MS analysis showed the reaction was complete. The mixture was diluted with dichloromethane (50 mL) and washed with 1.0 N hydrochloric acid solution (200 mL), 1.0 N sodium hydroxide solution (200 mL), and brine (150 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude product was suspended in heptane (300 mL) and stirred vigorously. After 30 min, a solid formed. The suspension was filtered, and the filter cake was washed with heptane (50 mL) and dried to provide 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-[[3- (trifluoromethyl)phenyl]methyl]benzamide as a white solid (10.15 g, 25.05 mmol, 67% yield); (M+l) = 406.

[0353] Preparation of Intermediate 44: 3-Fluoro-N-(2-fluoro-5-(trifluoromethyl)benzyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide

[0354]

[0355] The title compound was prepared from 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoic acid (CAS 867256-77-7) and (2-fluoro-5- (trifluoromethyl)phenyl)methanamine as described for the preparation of Intermediate 43; (M+l) = 442.

[0356] Preparation of Intermediate 45: 3-Fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)benzyl)benzamide

[0357]

[0358] The title compound was prepared from 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoic acid and 3-(trifluoromethyl)benzylamine as described for the preparation of Intermediate 43; (M+l) = 424.

[0359] Preparation of Intermediate 46: N-benzyl-3-methoxy-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzamide

[0360]

[0361] Step 1: Preparation of N-benzyl-4-bromo-3-methoxybenzamide

[0362]

[0363] A mixture of 4-bromo-3-methoxy-benzoic acid (462 mg, 2.00 mmol, CAS 56256-14-5) and HATU (1.14 g, 3.00 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature. After 15 min, benzylamine (225 mg, 2.10 mmol) and N,N-diisopropylethylamine (775 mg, 6.00 mmol) were added. The mixture was allowed to stir at room temperature. After 2 h, the mixture was diluted with ethyl acetate (60 mL) and water (15 mL). The phases were separated, and the aqueous layer was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (0-30% ethyl acetate / petroleum ether) to afford N-benzyl-4-bromo-3-methoxy-benzamide (550 mg, 86% yield); (M+l) = 320.

[0364] Step 2: Preparation of N-benzyl-3-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzamide

[0365] The title compound was prepared from N-benzyl-4-bromo-3-methoxybenzamide as described for the preparation of Intermediate 41.

[0366] Preparation of Intermediate 47: 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-N-(3-(trifluoromethyl)benzyl)benzamide

[0367]

[0368] The title compound was prepared from 4-bromo-3,5-dimethylbenzoic acid (CAS 7697-32-7) and (3-(trifluoromethyl)benzylamine as described in steps 1 and 2 of the preparation of Intermediate 45; (M+l) = 434.

[0369] Preparation of Intermediate 48: 6-bromo-2,5-dimethyl nicotinic acid

[0370]

[0371] To a 100 mL recovery flask equipped with a magnetic stir bar and N2inlet was added silver nitrate (988 mg, 5.80 mmol) and water (10 mL). The solution was cooled to 0 °C while sodium hydroxide (597 mg, 14.93 mmol) in water (10 mL) was added in one portion. To the resulting brown suspension was added 6-bromo-2,5-dimethyl nicotinaldehyde (744 mg, 3.48 mmol, see WO 2022266162) and the mixture was allowed to stir at 0 °C. After 45 min, LC / MS analysis showed the reaction was complete. The mixture was filtered and the filter cake was washed with water (15 mL). The pH of the filtrate was adjusted to ~3 by the addition of 1 N hydrochloric acid solution (~8 mL), resulting in the formation of a precipitate. The mixture was filtered and the filter cake was washed with water (15 mL). The damp solid was dissolved in ethyl acetate (20 mL) and the resulting solution was dried over magnesium sulfate, filtered and concentrated to provide 6-bromo-2,5-dimethyl nicotinic acid (693 mg, 3.01 mmol, 87% yield) as a white solid; (M+l) = 230.

[0372] General Procedure 4: Preparation of halogenated coupling partners

[0373] Preparation of Intermediate 49: 2-chloro-4-methyl-N-(3-(trifluoromethyl)benzyl)pyrimidine-5- carboxamide

[0374]

[0375] To a 200 mL recovery flask equipped with a magnetic stir bar and N2inlet was added 2-chloro-4-methylpyrimidine-5-carboxylic acid (517 mg, 3.00 mmol, CAS 188781-10-4), HATU (1.49 g, 3.89 mmol), N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (1.58 mL, 8.99 mmol). The mixture was allowed to stir at room temperature for 5 min, and then 3-(trifluoromethyl)benzylamine (607 mg, 3.30 mmol) was added. The resulting yellow mixture was allowed to stir at room temperature. After 1 h, LC / MS analysis showed that some of the desired material had formed. The mixture was diluted with water (50 mL) and extracted with diethyl ether (2 x 40 mL). The combined organic phases were washed with 1 N hydrochloric acid solution (75 mL), dried over magnesium sulfate, filtered, and concentrated to provide a brown oil. Chromatographic purification (CombiFlash, 80 g SiO2cartridge, 10%-60% 3:1 ethyl acetate:ethanol / heptane elution, fractions 24-27 combined, column 1) provided 2-chloro-4-methyl-N-(3-(trifluoromethyl)benzyl)pyrimidine-5- carboxamide as a white solid (347 mg, 1.05 mmol, 35% yield); (M+l) = 330.

[0376] The following carboxamides were prepared from the corresponding acids as described in General Procedure 4:

[0377]

[0378]

[0379] Example 59: Preparation of l-(2-(4-iodophenoxy)ethyl)-3-(trifluoromethyl)benzene

[0380]

[0381] To a 100 mL recovery flask equipped with a magnetic stir bar and N2inlet was added 4-iodophenol (555 mg, 2.50 mmol), 3-(trifluoromethyl)phenethyl alcohol (418 µl, 2.75 mmol), polymer-bound triphenylphosphine (1.15 g, 4.40 mmol), and tetrahydrofuran (25 mL). The mixture was treated with bis(2-methoxyethyl)diazen-1,2-dicarboxylate (819 mg, 3.50 mmol), which produced a slight exotherm after about 3 min. The mixture was allowed to stir at room temperature. After 1.75 h, LC / MS analysis showed the reaction to be complete. The mixture was filtered to remove the resin-bound material, and the filter cake was washed with ethyl acetate (40 mL). The filtrate was washed with 1 N hydrochloric acid solution (30 mL), 1 N sodium hydroxide solution (30 mL), and brine (30 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide a yellow oil. Chromatographic purification (CombiFlash, 40 g SiO2gold cartridge, eluting with 0-25% ethyl acetate / heptane, pooled fractions 14-16, rack 1) provided 1-(2-(4-iodophenoxy)ethyl)-3-(trifluoromethyl)benzene as a white solid (488 mg, 1.24 mmol, 50% yield); (M+1 / M-1 peaks not observed).

[0382] Preparation of Intermediate 60: 4-Bromo-7-fluoro-3-methyl-1H-indole-2-carboxylic acid ethyl ester

[0383]

[0384] To a 500 mL round bottom flask, equipped with a magnetic stir bar, reflux condenser, and N2inlet, was added (5-bromo-2-fluorophenyl)hydrazine hydrochloride (4.16 g, 16.88 mmol, CAS 214916-08-2), ethanol (50 mL), and concentrated hydrochloric acid solution (50 mL). The solution was treated with 2-ketobutyric acid (1.81 g, 17.20 mmol) and the resulting mixture was heated to reflux. As the mixture warmed, a thick yellow precipitate formed in the mixture. As heating continued, the solid gradually dissolved to provide a dark brown mixture. After 2 h, LC / MS analysis showed the reaction to be complete. The mixture was allowed to cool to room temperature and was diluted with water (300 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered, and concentrated to provide a brown solid. Chromatographic purification (CombiFlash, 220 g SiO2column, eluting with 10%-50% ethyl acetate / heptane, fractions 3-11 combined, arm 1) provided 4-bromo-7-fluoro-3-methyl-lH-indole-2-carboxylic acid ethyl ester as a light orange solid (2.02 g, 6.73 mmol, 39.9% yield); (M-l) = 298.

[0385] Preparation of Intermediate 61 : 6-Bromo-2-(3-(trifluoromethyl)benzyl)-3,4- dihydroisoquinolin-l(2H)-one

[0386]

[0387] To a stirred and cooled (0 °C) solution of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (1.50 g, 6.64 mmol, CAS 147497-32-3) in DMF (25 mL) was added sodium hydride 60% dispersion in mineral oil (0.350 g, 8.75 mmol, CAS 402-23-3). The foamy mixture was maintained at 0 °C for 30 minutes and then treated with 3-(trifluoromethyl)benzyl bromide (1.32 mL, 2.07 g, 8.64 mmol). After the addition, the cooling bath was removed. After one hour, the reaction was analyzed by LCMS and found to be complete. The mixture was concentrated and the residue partitioned between ethyl acetate (ca. 75 mL) and water (ca. 100 mL). The organic layer was combined with the aqueous layer anti-extract (ethyl acetate, 1 x ca. 50 mL), dried over sodium sulfate and concentrated onto ca. 8 g of silica. The impregnated media was subjected to automated flash chromatography (Combiflash Rf instrument; 10% to 30% ethyl acetate in heptane; 120 g silica gel column) to provide the purified product as a waxy light amber solid (2.53 g, 99% yield); (M+1) = 384.

[0388] Preparation of Intermediate 62: 5-Bromo-2-(3-(trifluoromethyl)benzyl)isoindolin-1-one

[0389]

[0390] To a stirred solution of 5-bromoisoindolin-1-one (2.00 g, 9.43 mmol, CAS 552330-86-6) in DMF (35 mL) was added sodium hydride 60% dispersion in mineral oil (0.490 g, 12.3 mmol, 1.30 equiv). After gas evolution had ceased, the reaction was cooled in an ice bath and treated with 3-(trifluoromethyl)benzyl bromide (1.87 mL, 2.93 g, 12.2 mmol). The cooling bath was removed and the mixture was stirred at room temperature overnight. After this time, the reaction was concentrated and the residue partitioned between water (ca. 125 mL) and ethyl acetate (ca. 100 mL). The organic layer was washed with water (1 x ca. 125 mL) a second time, dried over sodium sulfate and concentrated onto ca. 12 g of silica. The impregnated media was subjected to automated flash chromatography (Combiflash Rf instrument; 20% to 30% ethyl acetate in heptane; 220 g silica gel column) to provide the purified product as a light yellow solid (1.30 g, 37% yield); (M+1) = 370.

[0391] Preparation of Intermediate 63: 7-Bromo-2-(3-(trifluoromethyl)benzyl)-2,3,4,5- tetrahydro-lH-benzo[c]azepin-l-one

[0392]

[0393] To a stirred solution of 7-bromo-2,3,4,5-tetrahydro-lH-benzo[c]azepin-l-one (0.250 g, 1.04 mmol, CAS 1547064-78-7) in DMF (8 mL) was added a 60% dispersion of sodium hydride in mineral oil (54.1 mg, 1.35 mmol, 1.30 equiv). Once gas evolution had ceased, the reaction was cooled in an ice-bath and treated with 3-(trifluoromethyl)benzyl bromide (200 µL, 0.313 g, 1.31 mmol, 1.26 equiv). The cooling bath was removed and the reaction allowed to warm to room temperature. After two hours, the mixture was diluted with water (ca. 40 mL). The resulting suspension was sonicated until homogeneous (10-15 minutes) and then suction filtered. The filter cake was rinsed with water (3 x ca. 10 mL) and heptane (2 x ca. 10 mL) before being air-dried on a glass frit under room vacuum. The crude product was provided as a tan solid (0.376 g, 91% yield) which was considered sufficiently pure to use without chromatography. (M+l) = 398.

[0394] Preparation of Intermediate 64: 6-Bromo-N-((rac-(trans)-2-(trifluoromethyl)cyclopropyl)methyl)cinnolin-3-amine

[0395]

[0396] To a 20 mL microwave reaction vial equipped with a magnetic stir bar was added 6-bromo-3-chlorocinnoline (500 mg, 2.05 mmol, CAS 2665665-30-3), [rac-(trans)-2-(trifluoromethyl)cyclopropyl]methanamine hydrochloride (583 mg, 3.32 mmol, CAS 2137837-57-9), potassium carbonate (1.70 g, 12.3 mmol), and NMP (10 mL). The vessel was sealed and the contents heated to 115 °C in a heating block. After 16 h, LC / MS analysis showed the reaction to be complete. The mixture was allowed to cool to room temperature and diluted with water (60 mL). The mixture was extracted with ethyl acetate (50 mL). The organic phase was separated and washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to provide a brown oil. Chromatography purification (CombiFlash, 40 g SiO2gold cartridge, 20%-60% 3:1 ethyl acetate:ethanol / heptane elution, fractions 13-15 combined, rack 1) provided 6-bromo-N-[[rac-(lR,2R)-2-(trifluoromethyl)cyclopropyl]methyl]cinnolin-3-amine (403 mg, 1.16 mmol, 57% yield) as a brown foamy solid; (M+l) = 346.

[0397] Preparation of Intermediate 65: rac-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(((trans)-2-(3,3,3-trifluoropropyl)cyclopropyl)methyl)benzamide

[0398]

[0399] Step 1: Preparation of (E)-ethyl 6,6,6-trifluorohex-2-enoate

[0400]

[0401] To a solution of 4,4,4-trifluorobutyraldehyde (3.8 mL, 36.5 mmol) in dichloromethane (50 mL) was added ethyl 2-(triphenylphosphoranylidene)acetate (19.1 g, 54.7 mmol) and the mixture was stirred at room temperature. After 3 h, the mixture was diluted with ethyl acetate (100 mL) and water (30 mL). The aqueous layer was washed with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with PE / EA = 20 / 1) to give (E)-ethyl 6,6,6-trifluorohex-2-enoate (3.70 g, 52% yield); (M+l) = 197.

[0402] Step 2: Preparation of rac-trans-ethyl 2-(3,3,3-trifluoropropyl)cyclopropane-1- carboxylate

[0403]

[0404] To a 0 °C mixture of 1 -methyl-3-nitro-1 -nitroso-guanidine (750 mg, 5.10 mmol) in diethyl ether (10 mL) was added a cold solution of potassium hydroxide (286 mg, 5.10 mmol) in water (2 mL). After stirring for 2 min, a portion of the resulting yellow ether solution of diazomethane was added to a solution of (E)-ethyl 6,6,6-trifluorohex-2-enoate (1.00 g, 5.10 mmol) in ether (20 mL) at 0 °C. Palladium acetate (172 mg, 0.765 mmol) was added followed by additional diazomethane solution. The process was continued until all palladium acetate and diazomethane solution was added. The mixture was stirred at 0 °C for 4 h and acetic acid (5 drops) was added. The solvent was then removed in vacuo to give rac-trans-ethyl 2-(3,3,3-trifluoropropyl)cyclopropane-1 -carboxylate (852 mg, 80% yield); (M+1 ) = 211.

[0405] Step 3: Preparation of rac-trans-2-(3,3,3-trifluoropropyl)cyclopropane-1 -carboxylic acid

[0406]

[0407] To a solution of rac-trans-ethyl 2-(3,3,3-trifluoropropyl)cyclopropane-1 - carboxylate (852 mg, 4.05 mmol) in THF (10 mL) was added 1 N aqueous LiOH (971 mg, 40.5 mmol). The mixture was stirred at room temperature overnight. The mixture was adjusted to pH = 3-4 using aqueous HC1, extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to provide rac-trans-2-(3,3,3-trifluoropropyl)cyclopropane-1 -carboxylic acid (733 mg, yield: 99% yield); (M+1 ) = 183.

[0408] Step 4: Preparation of rac-trans-2-(3,3,3-trifluoropropyl)cyclopropanecarboxamide

[0409]

[0410] To a solution of rac-trans-2-(3,3,3-trifluoropropyl)cyclopropanecarboxylic acid (1.60 g, 8.78 mmol) in dichloromethane (20 mL) was added ammonium chloride (940 mg, 17.6 mmol), HATU (5.01 g, 13.2 mmol), and triethylamine (3.6 mL, 26.3 mmol). The mixture was stirred at room temperature. After 3 h, the reaction mixture was diluted with ethyl acetate and water, and the mixture was filtered. The aqueous layer was washed with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give rac-trans-2-(3,3,3-trifluoropropyl)cyclopropanecarboxamide (1.50 g, 94% yield); (M+l) = 182.

[0411] Step 5: Preparation of rac-trans-(2-(3,3,3-trifluoropropyl)cyclopropyl)methanamine

[0412]

[0413] To a 0 °C solution of rac-trans-2-(3,3,3-trifluoropropyl)cyclopropanecarboxamide (1.50 g, 8.28 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (3.14 g, 82.8 mmol). The mixture was allowed to warm to room temperature and stirred. After 24 h, the reaction mixture was cooled to 0 °C and quenched by the addition of water. The mixture was filtered, and the filter cake was washed with ethyl acetate (30 mL). The aqueous layer was washed with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give rac-trans-(2-(3,3,3-trifluoropropyl)cyclopropyl)methanamine (300 mg, 22% yield); (M+l) = 168.

[0414] Step 6: Preparation of rac-trans-4-bromo-N-[[2-(3,3,3-trifluoropropyl)cyclopropyl]methyl]benzamide

[0415]

[0416] To a solution of rac-trans-(2-(3,3,3-trifluoropropyl)cyclopropyl)methanamine (300 mg, 1.79 mmol) in dichloromethane (5 mL) was added 4-bromobenzoic acid (541 mg, 2.69 mmol), HATU (1.02 g, 2.69 mmol), and triethylamine (545 mg, 5.38 mmol). The mixture was stirred at room temperature. After 6 h, the reaction mixture was diluted with ethyl acetate and water. The aqueous layer was washed with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give rac-trans-4-bromo-N-[[2-(3,3,3-trifluoropropyl)cyclopropyl]methyl]benzamide (200 mg, 32% yield); (M+l) = 350.

[0417] Step 7: Preparation of rac-trans-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-[[2-(3,3,3- trifluoropropyl)cyclopropyl]methyl]benzamide

[0418]

[0419] The title compound was prepared from rac-trans-4-bromo-N-[[2-(3,3,3- trifluoropropyl)cyclopropyl]methyl]benzamide as described for the preparation of Intermediate 41; (M+l) = 398.

[0420] Intermediate 66: Preparation of (E)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(5,5,5- trifluoropent-2-en-l-yl)benzamide

[0421]

[0422] Step 1: Preparation of 4-bromo-N-(but-3-en-l-yl)benzamide

[0423]

[0424] A mixture of 4-bromobenzoic acid (1.0 g) in thionyl chloride (20 mL) was heated to reflux and stirred. After 16 h, the mixture was concentrated and the residue was dissolved in DCM (10 mL). This solution was added dropwise to a 0 °C mixture of but-3-en-1 -amine hydrochloride (0.64 g, 5.97 mmol) and N,N-diisopropylethylamine (2.6 mL, 14.9 mmol) in DCM (20 mL). The mixture was allowed to warm to room temperature and stirred. After 16 h, the mixture was concentrated and the residue was purified by flash silica gel column (PE / EtOAc 1 : 1) to provide 4-bromo-N-but-3-enyl-benzamide as a white solid (1.00 g, 79% yield); (M+1) = 253.

[0425] Step 2: Preparation of (E)-4-bromo-N-(5,5,5-trifluoropent-2-en-1-yl)benzamide

[0426]

[0427] A mixture of 4-bromo-N-but-3-enyl-benzamide (0.60 g, 2.36 mmol), trimethyl(trifluoromethyl)silane (4.03 g, 28.3 mmol), potassium carbonate (3.92 g, 28.3 mmol), (diacetoxyiodo)benzene (4.56 g, 14.2 mmol), and copper(I) thiophene-2-carboxylate (0.45 g, 2.36 mmol) in NMP (30 mL) was heated to 80 °C under N2. After 3 days, the mixture was diluted with DCM / MeOH (20 : 1), filtered through celite, and the filter cake was washed with MeOH (2 x 100 mL). The filtrate was concentrated and then purified by C18 gel column (MeOH in H2O.NH4HCO3, 0% to 80%) to provide a crude yellow oil. The oil was then purified by flash silica gel column (PE / EtOAc 10 : 1 to 5 : 1) to provide 4-bromo-N-[(E)-5,5,5-trifluoropent-2-enyl]benzamide as a yellow solid (0.32 g, 16% yield); (M+1) = 322.

[0428] Step 3: Preparation of (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(5,5,5- trifluoropent-2-en-1-yl)benzamide

[0429] The title compound was prepared from 4-bromo-N-[(E)-5,5,5-trifluoropent-2-enyl]benzamide as described for the preparation of Intermediate 41 ; (M+1) = 370.

[0430] Preparation of Intermediate 67: 4-(2-(methylcarbamoyl)-lH-indol-4- yl)benzoic acid

[0431]

[0432] Step 1: Preparation of tert-butyl 4-(2-(methylcarbamoyl)-lH-indol-4- yl)benzoate

[0433]

[0434] To a 500 mL round bottom flask, equipped with a magnetic stir bar, reflux condenser, and N2inlet, was added 4-bromo-N-methyl-lH-indole-2-carboxamide (6.83 g, 27.0 mmol, Intermediate 12), (4-tert-butoxycarbonylphenyl)boronic acid (7.10 g, 32.0 mmol), (l,l'-bis(diphenylphosphino)ferrocene)dichloropalladium(ll) dichloromethane complex (1.05 g, 1.29 mmol), sodium carbonate (7.15 g, 67.5 mmol), 1,4-dioxane (100 mL), and water (30 mL). The mixture was degassed under vacuum / backfilled with N2(x 3), and then heated to 100 °C in an oil bath. After 45 min, LC / MS analysis showed the reaction was complete. The mixture was allowed to cool to room temperature and diluted with water (30 mL). The mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide a brown oil. The crude oil was suspended in diethyl ether (250 mL) and sonicated briefly, causing the formation of a precipitate. The mixture was filtered, and the filter cake was dried to provide a brown solid. Chromatography purification (CombiFlash, 330 g SiO2gold cartridge, 10%-55% 3: 1 ethyl acetate:ethanol / heptane elution, fractions 12-27 combined, rack 2) provided a yellow solid. The solid was suspended in diethyl ether (250 mL) and sonicated briefly. The mixture was filtered, and the filter cake was dried to provide tert-butyl 4-[2-(methylcarbamoyl)-lH-indol-4-yl]benzoate as a light yellow solid (7.75 g, 22.1 mmol, 82% yield); (M+l) = 351.

[0435] Step 2: Preparation of 4-(2-(methylcarbamoyl)-lH-indol-4- yl)benzoic acid

[0436] To a 100 mL recovery flask equipped with a magnetic stir bar, reflux condenser, and N2inlet was added tert-butyl 4-(2-(methylcarbamoyl)-lH-indol-4-yl)benzoate (3.80 g, 10.84 mmol) and dichloromethane (50 mL). The mixture was treated with trifluoroacetic acid (30 mL) and the resulting solution was allowed to stir at room temperature. After 30 min, LC / MS analysis showed the reaction to be complete. The mixture was concentrated and the residue was suspended in diethyl ether (30 mL). The mixture was filtered and the filter cake was washed with diethyl ether (30 mL) and dried to provide 4-(2-(methylcarbamoyl)-lH-indol-4-yl)benzoic acid as a tan solid (3.05 g, 10.36 mmol, 96% yield); (M+l) = 295.

[0437] The following carboxylic acids were prepared using the procedure described for the synthesis of Intermediate 67:

[0438]

[0439] Preparation of Intermediate 71 : 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-lH- indole-2-carboxylic acid

[0440]

[0441] Step 1 : Preparation of methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-lH- indole-2-carboxylate

[0442]

[0443] The title compound was prepared from methyl 4-bromo-lH-indole-2-carboxylate and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)benzyl)benzamide (Intermediate 43) as described in Step 1 of the preparation of Intermediate 67; (M+l) = 453.

[0444] Step 2: Preparation of 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-lH-indole-2- carboxylic acid

[0445] To a 250 mL recovery flask equipped with a magnetic stir bar, reflux condenser, and N2inlet was added methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylate (1.40 g, 3.09 mmol) and methanol (60 mL). The suspension was treated with 1.0 N sodium hydroxide solution (40 mL, 40.00 mmol) and the mixture heated to reflux. After 30 min, LC / MS analysis showed the reaction to be complete. The mixture was allowed to cool to room temperature and diluted with 1 N hydrochloric acid solution (60 mL), resulting in the formation of a precipitate. The mixture was filtered and the filter cake washed with water (30 mL). The damp solid was dissolved in ethyl acetate (50 mL). The solution was dried over magnesium sulfate, filtered, and concentrated to provide 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylic acid as a tan solid (1.30 g, 3.09 mmol, 94% yield); (M-1) = 437.

[0446] The following carboxylic acids were prepared using this procedure:

[0447]

[0448]

[0449] Intermediate 78: Preparation of 3-chloro-4-(2-(methylcarbamoyl)-1H-indol-4- yl)benzoic acid

[0450]

[0451] A mixture of N-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indole-2-carboxamide (1.00 g, 3.30 mmol, Intermediate 40), 4-bromo-3- chlorobenzoic acid (817 mg, 3.30 mmol, CAS 25118-59-6), palladium(II) acetate (37 mg, 167 µmol), tricyclohexylphosphine (95 mg, 333 µmol), and potassium phosphate tribasic (2.20 g, 10.00 mmol) in 1,4-dioxane (8.0 mL) and water (4.0 mL) was microwaved at 125 °C for 1 h. LC / MS indicated all starting material was consumed. The reaction mixture was filtered through celite and the filter cake was washed with EtOAc and water. The filtrate was partitioned between water and EtOAc. The two layers were separated and the aqueous layer was acidified with 1 M HCl to pH 2. The solid that formed was collected by suction filtration and dried to yield 3-chloro-4-(2-(methylcarbamoyl)-lH-indol-4-yl)benzoic acid as a grey solid (1.12 g, 3.41 mmol, > 100% yield); (M+l) = 329.

[0452] The following carboxylic acids were prepared using the procedure described for the synthesis of Intermediate 78:

[0453]

[0454]

[0455] Preparation of Intermediate 87: (E)-3-(6-cyclopropyl-2-(methylcarbamoyl)-lH- indol-4-yl)-2-methylacrylic acid

[0456]

[0457] Step 1: Preparation of (E)-methyl 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)acrylate

[0458]

[0459] A mixture of (E)-3-bromo-2-methyl-prop-2-enoic acid methyl ester (0.179 g, 1.00 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (381 mg, 1.50 mmol), potassium acetate (245 mg, 2.50 mmol) and (l,l'- bis(diphenylphosphino)ferrocene)dichloropalladium(ll) dichloromethane complex (82 mg, 0.10 mmol) in dry DMSO (10 mL) was stirred at 80 °C under N2. After 4 h, the mixture was allowed to cool to room temperature and poured into water (50 mL). The mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over sodium sulfate, concentrated and purified by flash silica gel column (PE / EtOAc 95 : 5) to afford (E)-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-2-enoic acid methyl ester as a crude oil (0.188 g, 32% yield); (M+l) = 227.

[0460] Step 2: Preparation of (E)-3-(6-cyclopropyl-2-(methylcarbamoyl)-lH-indol-4-yl)-2- methylacrylic acid

[0461] The title compound was prepared from 4-bromo-6-cyclopropyl-N-methyl-lH-indole-2- carboxamide (Intermediate 28) and methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop- 2-enoate as described in Steps 1 and 2 of the preparation of Intermediate 71; (M+l) = 299.

[0462] Intermediate 88: Preparation of methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-l- yl)-lH-indole-2-carboxylate

[0463]

[0464] Step 1: Preparation of tert-butyl 4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-l- carboxylate

[0465]

[0466] To a 250 mL recovery flask equipped with a magnetic stir bar and N2inlet was added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.02 g, 4.36 mmol), 3-(trifluoromethyl)benzylamine (670 µl, 4.58 mmol), HATU (2.14 g, 5.45 mmol), and N,N-dimethylformamide (15 mL). The solution was treated with N,N-diisopropylethylamine (1.53 mL, 8.72 mmol) and allowed to stir at room temperature. After 75 min, LC / MS analysis showed the reaction to be complete. The yellow solution was diluted with water (50 mL) and diethyl ether (50 mL). The phases were separated, and the aqueous phase was extracted with diethyl ether (2 x 50 mL). The combined organic phases were washed with 2N hydrochloric acid solution (25 mL), 2M sodium carbonate solution (25 mL), and brine (25 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 1.57 g of a colorless oil. Chromatographic purification (CombiFlash, 80 g SiO2cartridge, eluting with 25%-75% ethyl acetate / heptane, fractions 13-23 combined, arm 2) provided tert-butyl 4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate (977 mg, 2.53 mmol, 58% yield) as a white solid; (M+1) = 387.

[0467] Step 2: Preparation of N-(3-(trifluoromethyl)benzyl)piperidine-4-carboxamide

[0468]

[0469] To a 100 mL recovery flask equipped with a magnetic stir bar and N2inlet was added tert-butyl 4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate (3.01 g, 7.79 mmol) and dichloromethane (20 mL). The solution was treated with trifluoroacetic acid (10 mL, 129.80 mmol) and allowed to stir at room temperature. After 30 min, LC / MS analysis showed the reaction to be complete. The mixture was concentrated, and the residue was dissolved in dichloromethane (50 mL). The solution was washed with 5N ammonium hydroxide solution (50 mL), dried over magnesium sulfate, filtered, and concentrated to provide N-(3-(trifluoromethyl)benzyl)piperidine-4-carboxamide (2.01 g, 7.02 mmol, 90% yield) as a waxy off-white solid; (M+1) = 287.

[0470] Step 3: Preparation of methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate

[0471]

[0472] To a 20 mL microwave reaction vial equipped with a magnetic stir bar was added methyl 4-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylate (691 mg, 1.80 mmol, see WO 2017152076), N-(3-(trifluoromethyl)benzyl)piperidine-4-carboxamide (634 mg, 2.21 mmol), methane sulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1,1'-biphenyl)(2'-amino-l,1'-biphenyl-2-yl)palladium(II) (168 mg, 191 pmol), dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl (94 mg, 198 pmol), cesium carbonate (1.17 g, 3.60 mmol), and tert-butanol (6 mL). The vessel was sealed and the contents heated to 85 °C in an oil bath. After 19 h, the reaction mixture was allowed to cool to room temperature. After 65 h, LC / MS analysis showed the reaction to be complete. The yellow suspension was diluted with water (75 mL) and extracted with ethyl acetate (75 mL). The organic phase was washed with 2N hydrochloric acid solution (30 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and concentrated to provide 1.24 g of a yellow oil. Chromatographic purification (CombiFlash, 40 g SiO2gold cartridge, eluting with 0-90% ethyl acetate / heptane, pooled fractions 45-50, rack 1) provided methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-l-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylate (138 mg, 234.00 pmol, 13.0% yield) as a yellow solid; (M+l) = 590.

[0473] Step 4: Preparation of methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-l-yl)-lH-indole-2-carboxylate

[0474] To a 50 mL recovery flask equipped with a magnetic stir bar and N2inlet was added 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-l-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylic acid methyl ester (138 mg, 234 pmol) and dichloromethane (5 mL). The solution was treated with trifluoroacetic acid (3 mL, 38.94 mmol) and allowed to stir at room temperature. After 1 h 45 min, LC / MS analysis of the red-brown solution showed that the starting material had been consumed. The mixture was concentrated and the residue dissolved in dichloromethane (25 mL). The solution was washed with 5 N ammonium hydroxide, dried over magnesium sulfate, filtered and concentrated to provide 148 mg of a tan solid.1H NMR analysis revealed that the isolated material was not the desired product, but rather N-hydroxymethyl indole. The crude solid was dissolved in methanol (5 mL) and treated with potassium carbonate (about 100 mg). The mixture was allowed to stir at room temperature. After 20 min, LC / MS analysis showed that the reaction was complete. The mixture was concentrated and the residue partitioned between dichloromethane (15 mL) and water (15 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 15 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to provide 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-l-yl)-lH-indole-2-carboxylic acid methyl ester as a tan solid (89 mg, 193.70 pmol, 82.8% yield); (M+l) = 460.

[0475] Preparation of Intermediate 89: 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)- 2,3-dihydro-lH-indene-2-carboxylic acid methyl ester

[0476]

[0477] The title compound was prepared from 4-bromo-2,3-dihydro-lH-indene-2-carboxylic acid methyl ester (see US20080255239) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N- (3-(trifluoromethyl)benzyl)benzamide (Intermediate 43) as described in Step 1 of the preparation of Intermediate 67; (M+l) = 454.

[0478] Preparation of Intermediate 90: 4-(2-(methylcarbamoyl)-lH-indol-4-yl)cyclohexane-l- carboxylic acid

[0479]

[0480] Step 1: Preparation of 4-(2-(methylcarbamoyl)-lH-indol-4-yl)cyclohex-3- ene- 1 -carboxylic acid ethyl ester

[0481]

[0482] A mixture of 4-bromo-N-methyl-lH-indole-2-carboxamide (500 mg, 2.00 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene carboxylic acid ethyl ester (1.20 g, 4.00 mmol), palladium(II) acetate (22 mg, 99 μmol), tricyclohexylphosphine (57 mg, 198 μmol), and potassium phosphate tribasic (1.28 g, 5.93 mmol) in 1,4-dioxane (8.0 mL) and water (4.0 mL) was microwaved at 125 °C for 30 min. LC / MS indicated all starting material was consumed. Both product and acid were observed from LC / MS. The reaction mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The crude material was purified on silica gel (liquid loading) with heptane / EtOAc (80 / 20 to 0 / 100) to give 4-(2-(methylcarbamoyl)-lH-indol-4-yl)cyclohex-3-ene-l- carboxylic acid ethyl ester (520 mg, 1.59 mmol, 80.6% yield) as an amber sticky solid; (M+l) = 327.

[0483] Step 2: Preparation of 4-(2-(methylcarbamoyl)-lH-indol-4-yl)cyclohex-3- ene- 1 -carboxylic acid

[0484]

[0485] A suspension of 4-(2-(methylcarbamoyl)-lH-indol-4-yl)cyclohex-3-ene-l- carboxylic acid ethyl ester (520 mg, 1.60 mmol) in IN sodium hydroxide solution (5.00 mL, 5.00 mmol), THF (5 mL), and methanol (5 mL) was heated at 40 °C for 6 h. LC / MS indicated all starting material was consumed and the reaction became homogeneous. The reaction mixture was concentrated in vacuo to remove the organic solvents. Water was added and the solution was adjusted to pH 2 with 1 M HC1. The hazy solution was extracted with EtOAc (2X). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 4-(2-(methylcarbamoyl)-lH-indol-4-yl)cyclohex-3-ene-l- carboxylic acid as a beige powder (380 mg, 1.30 mmol, 80% yield); (M+l) = 299.

[0486] Step 3: Preparation of 4-(2-(methylcarbamoyl)-lH-indol-4-yl)cyclohexane-l- carboxylic acid

[0487] A mixture of 4-(2-(methylcarbamoyl)-lH-indol-4-yl)cyclohex-3-ene-l-carboxylic acid (90 mg, 302 µmol) and 10% palladium on carbon (30 mg, 282 µmol) in ethyl acetate (10 mL) and ethanol (10 mL) was hydrogenated at rt for 1 h. LC / MS indicated all starting material was consumed. The reaction mixture was filtered through celite and the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo to give 4-(2-(methylcarbamoyl)-lH-indol-4-yl)cyclohexane-l-carboxylic acid as a beige powder (78 mg, 260 µmol, 86% yield); (M+l) = 301

[0488] Intermediate 91: Preparation of 4-(4-((2-fluoro-5-(trifluoromethyl)benzyl)carbamoyl)phenyl)- lH-indole-2-carboxylic acid

[0489]

[0490] Step 1: Preparation of 4-(4-((2-fluoro-5-(trifluoromethyl)benzyl)carbamoyl)phenyl)-lH- indole-2-carboxylic acid ethyl ester

[0491]

[0492] The title compound was prepared from 4-(2-(ethoxycarbonyl)-lH-indol-4- yl)benzoic acid (Intermediate 70) and (2-fluoro-5-(trifluoromethyl)phenyl)methanamine as described in Step 1 of the synthesis of Intermediate 88; (M+l) = 485.

[0493] Step 2: Preparation of 4-(4-((2-fluoro-5-(trifluoromethyl)benzyl)carbamoyl)phenyl)- lH-indole-2-carboxylic acid

[0494] The title compound was prepared from 4-(4-((2-fluoro-5-(trifluoromethyl)benzyl)carbamoyl)phenyl)-lH-indole-2-carboxylic acid ethyl ester as described in Step 2 of the synthesis of Intermediate 90; (M+l) = 457.

[0495] Intermediate 92: Preparation of 5,6-difluoro-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-lH-indole-2-carboxylic acid ethyl ester

[0496]

[0497] The title compound was prepared from 4-bromo-5,6-difluoro-lH-indole-2-carboxylic acid ethyl ester (Intermediate 5) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(3- (trifluoromethyl)benzyl)benzamide (Intermediate 43) as described in Step 1 of the synthesis of Intermediate 67; (M+l) = 503.

[0498] Intermediate 93: Preparation of 4-bromo-N-methylisoindoline-2-carboxamide

[0499]

[0500] To a 50 mL recovery flask, equipped with a magnetic stir bar and N2inlet, was added 4-bromoisoindoline hydrochloride (255 mg, 1.03 mmol, CAS 923590-95-8), N,N- diisopropylethylamine (500 µL, 2.84 mmol), and acetonitrile (5 mL). The mixture was treated with methyl isocyanate (70 mg, 1.23 mmol). After 5 min, a precipitate began to form. After 20 min, LC / MS analysis showed the reaction was complete. The mixture was diluted with water (30 mL), and the resulting suspension was filtered. The filter cake was washed with water (15 mL), and the damp solid was dissolved in ethyl acetate (30 mL). The solution was dried over magnesium sulfate, filtered, and concentrated to provide 4-bromo-N-methylisoindoline-2-carboxamide as a grey solid (213 mg, 835 µmol, 81% yield); (M+l) = 255.

[0501] Preparation of Intermediate 94: N-benzyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide

[0502]

[0503] The title compound was prepared from 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoic acid and benzylamine as described for the preparation of Intermediate 43; (M+l) = 338.

[0504] Preparation of Intermediate 95: N-benzyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzamide

[0505]

[0506] Step 1: Preparation of N-benzyl-4-bromo-3,5-dimethylbenzamide

[0507]

[0508] To a solution of 4-bromo-3,5-dimethyl-benzoic acid (90 mg, 0.39 mmol) in dichloromethane (5 mL) was added benzylamine (46 mg, 0.43 mmol), HATU (224 mg, 0.59 mmol) and triethylamine (0.137 mL, 0.98 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with water and the organic layer separated. The aqueous layer was extracted with dichloromethane and the combined organic phases washed with brine, dried and concentrated to provide N-benzyl-4-bromo-3,5-dimethylbenzamide (120 mg, 0.37 mmol, 96% yield) as a colourless oil. LCMS: 318.0, 320.0 (M+l).

[0509] Step 2: Preparation of N-benzyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide

[0510] The title compound was prepared from N-benzyl-4-bromo-3,5-dimethylbenzamide and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane as described for the preparation of Intermediate 41; (M+l) = 366.

[0511] Preparation of Intermediate 96: 4-(2-carbamoyl-lH-indol-4-yl)benzoic acid

[0512]

[0513] The title compound was prepared from 4-bromo-lH-indole-2-carboxamide (CAS 955978-73-1) and methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate as described for the preparation of intermediate 71; (M+l) = 281.

[0514] Preparation of intermediate 97: 4-(2,6-dimethyl-4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-7-fluoro-lH-pyrrolo[3,2-c]pyridine-2-carboxylic acid

[0515]

[0516] The title compound was prepared from methyl 4-chloro-7-fluoro-lH-pyrrolo[3,2- c]pyridine-2-carboxylate (intermediate 11) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)benzyl)benzamide (intermediate 47) as described for the preparation of intermediate 71; (M+l) = 486.

[0517] Preparation of examples

[0518] Example 1: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)- lH-indole-2-carboxamide

[0519]

[0520] To a 500 mL round bottom flask, equipped with a magnetic stir bar, reflux condenser, and N2inlet, was added 4-bromo-N-methyl-lH-indole-2-carboxamide (3.77 g, 14.9 mmol, Intermediate 12), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-[[3- (trifluoromethyl)phenyl]methyl]benzamide (7.50 g, 19.0 mmol, Intermediate 43), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (1.00 g, 1.22 mmol), sodium carbonate (4.75 g, 44.8 mmol), 1,4-dioxane (75 mL), and water (20 mL). The mixture was degassed under vacuum / backfilled with N2(x3). The mixture was then heated to 100 °C in an oil bath. After 1 h, LC / MS analysis showed the reaction was complete. The mixture was allowed to cool to room temperature and diluted with water (50 mL). The mixture was extracted with ethyl acetate (50 mL). The resulting biphasic mixture was filtered through celite and the filter cake was washed with ethyl acetate (40 mL). The organic phase was separated and dried over magnesium sulfate, filtered, and concentrated to provide a brown oil. Chromatography (CombiFlash, 330 g SiO2gold cartridge, 25%-70% 3: 1 ethyl acetate:ethanol / heptane elution, fractions 24-30 combined, column 1 and 1-5, column 2) provided N-methyl-4-[4-[[3- (trifluoromethyl)phenyl]methylaminocarbonyl]phenyl]-lH-indole-2-carboxamide as a white solid (4.74 g, 10.5 mmol, 71% yield); 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.26 (t, J = 5.9 Hz, 1H),8.50 (q, J = 4.5 Hz, 1H), 8.13 – 8.03 (m, 2H), 7.86 – 7.75 (m, 2H), 7.75 –7.55 (m, 4H), 7.54 – 7.45 (m, 1H), 7.36 – 7.26 (m, 2H), 7.20 (dd, J = 7.3,1.0 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 2.81 (d, J = 4.5 Hz, 3H) ppm; (M+1) =452.

[0521] As described for the synthesis of Example 1, the following compounds were prepared:

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537] Example 47: Preparation of 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H- indole-2-carboxamide

[0538]

[0539] To a 50 mL recovery flask equipped with a magnetic stir bar and N2inlet was added 4-(2-carbamoyl-lH-indol-4-yl)benzoic acid (98 mg, 350 µmol, Intermediate 96), 3-(trifluoromethyl)benzylamine (54 µl, 367 µmol), HATU (171 mg, 437 µmol), and N,N-dimethylformamide (5 mL). The solution was treated with N,N-diisopropylethylamine (122 µl, 699 µmol) and allowed to stir at room temperature. After 30 min, LC / MS analysis showed the reaction to be complete. The yellow solution was diluted with water (25 mL), and the resulting precipitate was isolated by filtration. The filter cake was washed with water (25 mL), and the damp solid was dissolved in ethyl acetate (50 mL). The solution was washed with 2N hydrochloric acid solution (25 mL), 2M sodium carbonate solution (25 mL), and brine (25 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 154 mg of a yellow oil. Chromatographic purification (CombiFlash, 12 g SiO2gold cartridge, eluting with 50% ethyl acetate / heptane to 100% ethyl acetate, pooled fractions 3-8, arm 1) provided 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-lH-indole-2-carboxamide (99 mg, 226 µmol, 65% yield) as a white solid as a foam; 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 9.23 (t, J = 5.9 Hz, 1H), 8.10 – 8.01 (m, 2H), 7.97 (br s, 1H), 7.84 – 7.75 (m, 2H), 7.74 – 7.54 (m, 4H), 7.49 – 7.45 (m, 1H), 7.41 – 7.24 (m, 3H), 7.12– 7.16 (m, 1H), 4.62 (d, J = 5.9 Hz, 2H) ppm; (M+1) = 438.

[0540] As described for the synthesis of Example 47, the following compounds were prepared:

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558] Example 97: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-l-yl)-lH-indole-2-carboxamide

[0559]

[0560] To a 5 mL microwave reaction vial equipped with a magnetic stir bar was added methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-l-yl)-lH-indole-2-carboxylate (89 mg, 194 µmol, Intermediate 88) and a 33% solution of methylamine in ethanol (4 mL, 32.13 mmol). The vessel was sealed and the contents heated to 100 °C in a microwave reactor. After 30 min, LC / MS analysis showed the reaction was incomplete. The mixture was subjected to another heating cycle in the microwave reactor (125 °C). After 30 min, LC / MS analysis showed the reaction was near completion. The brown mixture was concentrated to provide a brown oil. Chromatographic purification (CombiFlash, 12 g SiO2gold cartridge, 1%-5% methanol / dichloromethane elution, fractions 27-31 combined, rack 1) provided N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-l-yl)-lH-indole-2-carboxamide as a tan solid (26 mg, 57 µmol, 29% yield); 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.51 (t, J = 5.9 Hz, 1H), 8.40 (q, J = 4.6 Hz, 1H), 7.65 - 7.56 (m, 4H), 7.16 (d, J = 2.3 Hz, 1H), 7.08 - 6.99 (m, 2H), 6.46 (dd, J = 5.9, 2.3 Hz, 1H), 4.40 (d, J = 5.9 Hz, 2H), 3.70 - 3.60 (m, 2H), 2.81 (d, J = 4.6 Hz, 3H), 2.76 - 2.64 (m, 2H), 2.48 - 2.37 (m, 1H), 2.00 - 1.85 (m, 4H) ppm; (M+1) = 459.

[0561] As described for the synthesis of Example 97, the following compounds were prepared:

[0562]

[0563] Example 100: Preparation of N-methyl-4-((lr,4r)-4-((3-(trifluoromethyl)benzyl)carbamoyl)cyclohexyl)-lH-indole-2-carboxamide

[0564]

[0565] A mixture of 4-(2-(methylcarbamoyl)-lH-indol-4-yl)cyclohexane-l -carboxylic acid (78 mg, 260 µmol, Intermediate 90), 3-(trifluoromethyl)benzylamine (46 µL, 312 µmol), HATU (153 mg, 390 µmol), and N,N-diisopropyl ethylamine (136 μL, 779 µmol) in N,N-dimethylformamide (5.0 mL) was stirred at rt for 3 h. LC / MS indicated all starting material was consumed. The reaction mixture was partitioned between water and Et20. The two layers were separated and the aqueous layer was extracted once with Et20. The combined organic layers were washed with water, 1 M HC1, saturated NaHC03, and brine, dried over MgS04, filtered, and concentrated. The crude material was purified on silica gel (liquid loading) with CH2CI2 / EtOAc (80 / 20 to 0 / 100) as eluents to give N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)cyclohexyl)-lH-indole-2- carboxamide (69 mg, 150.82 µmol, 58.1% yield) as a white powder (mixture of cis and trans isomers). The mixture was separated by HPLC to give N-methyl-4-((lr,4r)-4-((3-(trifluoromethyl)benzyl)carbamoyl)cyclohexyl)-lH-indole-2-carboxamide (21 mg, 70 µmol, 28% yield); ¾ NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.58 - 8.31 (m, 2H), 7.62 - 7.52 (m, 4H), 7.35 - 7.19 (m, 2H), 7.10 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 4.39 (d, J = 6.0 Hz, 2H), 2.93 - 2.85 (m, 1H), 2.82 (d, J = 4.6 Hz, 3H), 2.40 - 2.32 (m, 1H), 2.01 - 1.93 (m, 4H), 1.69 - 1.61 (m, 4H) ppm; (M+l) = 458.

[0566] Example 101: Preparation of N-methyl-4-(l-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-4-yl)-lH-indole-2-carboxamide

[0567]

[0568] Step 1: Preparation of tert-butyl 4-(2-(methylcarbamoyl)-lH-indol-4-yl)-3,6- dihydropyridine-l(2H)-carboxylate

[0569]

[0570] To a 20 mL microwave reaction vial equipped with a magnetic stir bar was added 4-bromo-lH-indole-2-carboxamide (915 mg, 3.83 mmol), N-boc-l,2,5,6-tetrahydropyridine-4- boronic acid pinacol ester (1.37 g, 4.21 mmol), palladium(II) acetate (43 mg, 191 μmol), tricyclohexylphosphine (110 mg, 383 µmol), potassium phosphate tribasic (2.49 g, 11.48 mmol), 1,4-dioxane (10 mL), and water (5 mL). The vessel was sealed and the contents were heated to 125 °C in a microwave reactor. After 30 min, LC / MS analysis showed that the reaction was almost complete. The mixture was diluted with ethyl acetate (50 mL) and water (30 mL). The phases were separated, and the organic phase was washed with 2N hydrochloric acid solution (25 mL) and saturated potassium carbonate solution (25 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 1.66 g of a yellow solid. Chromatographic purification (CombiFlash, 40 g SiO2gold cartridge, eluting with 50%-80% ethyl acetate / heptane, fractions 6-15 combined, rack 1) provided tert-butyl 4-(2-carbamoyl-lH-indol-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate as a white solid (1.22 g, 3.57 mmol, 93.4% yield); (M-l) = 354.

[0571] Step 2: Preparation of tert-butyl 4-(2-(methylcarbamoyl)-lH-indol-4-yl)piperidine-l- carboxylate

[0572]

[0573] To a 200 mL recovery flask equipped with a magnetic stir bar and a 3 -way stopper was added tert-butyl 4-(2-(methylcarbamoyl)-lH-indol-4-yl)-3,6-dihydropyridine-l(2H)- carboxylate (1.19 g, 3.35 mmol), 10% palladium on carbon (1.12 g, 1.05 mmol), and tetrahydrofuran (40 mL). The mixture was degassed under vacuum / backfilled with N2 (x 3). After the final evacuation, atmospheric air was replaced with hydrogen gas (via a balloon), and the mixture was allowed to stir at room temperature. After 45 min, LC / MS analysis showed the reaction was complete. Atmospheric air was replaced with N2, and the mixture was filtered through celite with the aid of ethyl acetate (100 mL). The filtrate was concentrated to provide tert-butyl 4-(2-(methylcarbamoyl)-lH-indol-4-yl)piperidine-l-carboxylate as an off-white solid (1.13 g, 3.16 mmol, 94% yield); (M-l) = 356.

[0574] Step 3: Preparation of N-methyl-4-(piperidin-4-yl)-lH-indole-2-carboxamide

[0575]

[0576] To a 20 mL microwave reaction vial equipped with a magnetic stir bar was added tert-butyl 4-(2-(methylcarbamoyl)-lH-indol-4-yl)piperidine-l-carboxylate (1.13 g, 3.16 mmol) and dichloromethane (20 mL). The suspension was treated with trifluoroacetic acid (10 mL, 130 mmol), resulting in the formation of a homogeneous red solution. After 30 min, LC / MS analysis showed the reaction was complete. The mixture was concentrated, and the residue was dissolved in water (30 mL). The yellow solution was treated with a concentrated ammonium hydroxide solution (10 mL), resulting in the formation of a precipitate. The mixture was filtered, and the solid was washed with water (25 mL) and dried to provide N-methyl-4-(piperidin-4-yl)-lH-indole-2-carboxamide as an off-white solid (800 mg, 3.11 mmol, 98% yield); (M+l) = 258.

[0577] Step 4: Preparation of N-methyl-4-((lr,4r)-4-((3-(trifluoromethyl)benzyl)carbamoyl)cyclohexyl)-lH-indole-2-carboxamide

[0578] To a 50 mL recovery flask equipped with a magnetic stir bar and N2inlet was added N-methyl-4-(piperidin-4-yl)-1H-indole-2-carboxamide (150 mg, 582.89 µmol) and acetonitrile (5 mL). The suspension was treated with 1-(isocyanatomethyl)-3-(trifluoromethyl)benzene (130 mg, 612 µmol). The mixture was warmed with a heat gun until a homogenous solution was obtained (~1 min) and the resulting solution was allowed to stir. After 45 min, a white precipitate formed and LC / MS analysis showed the reaction was complete. The mixture was filtered. The filter cake was washed with acetonitrile (10 mL) and dried to provide a white solid. Chromatography purification (CombiFlash, 12 g SiO2gold cartridge, 0-20% methanol / dichloromethane elution, fractions 1-5 combined, column 1) provided N-methyl-4-(1-((3-(trifluoromethyl)benzyl)carbamoyl)piperidin-4-yl)-1H-indole-2-carboxamide as a white solid (120 mg, 262 µmol, 45% yield); 1 H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.44 (q, J = 4.6 Hz, 1H),7.68 – 7.51 (m, 4H), 7.32 – 7.20 (m, 3H), 7.10 (dd, J = 8.2, 7.1 Hz, 1H),6.84 (d, J = 7.1 Hz, 1H), 4.35 (d, J = 5.7 Hz, 2H), 4.24 – 4.16 (m, 2H), 3.12– 3.02 (m, 1H), 2.94 – 2.82 (m, 2H), 2.81 (d, J = 4.6 Hz, 3H), 1.92 – 1.82(m, 2H), 1.73 – 1.59 (m, 2H) ppm; (M+1) = 459.

[0579] Example 102: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperazin-1-yl)-1H-indole-2-carboxamide

[0580]

[0581] Step 1: Preparation of 4-(2-(methylcarbamoyl)-1H-indol-4-yl)piperazine-1-carboxylic acid benzyl ester

[0582]

[0583] A 20 mL microwave reaction vessel equipped with a stir bar was charged with methyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-1H-indole-2-carboxylate (0.910 g, 2.31 mmol, Intermediate 3), ethanol (6 mL), and a 33 wt% solution of methylamine in ethanol (6.0 mL, 48 mmol). The vessel was sealed with a septum and stirred at 50 °C overnight. After this time, LCMS analysis showed the reaction was incomplete. An additional portion of the methylamine solution (2.0 mL, 16 mmol) was added, and the reaction was continued at 50 °C for a second night. The mixture was concentrated to yield the crude product as a foamy amber solid (0.969 g, 107%) which was used in the next reaction without purification; (M+1) = 393.

[0584] Step 2: Preparation of N-methyl-4-(piperazin-1-yl)-1H-indole-2-carboxamide hydrochloride

[0585]

[0586] To a stirred solution of benzyl 4-(2-(methylcarbamoyl)-1H-indol-4-yl)piperazine-1- carboxylate (0.735 g, 1.87 mmol) in a mixture of methanol (15 mL) and 1.0 N hydrochloric acid (2.0 mL, 1.07 equivalents) was added 10% palladium on carbon (0.150 g). The suspension was cycled between vacuum and nitrogen atmosphere three times. The vessel was evacuated one last time and then backfilled with hydrogen. After stirring for one hour, the reaction was evacuated and then exposed to air. LCMS analysis showed the reaction was near completion. An additional portion of 1.0 N hydrochloric acid (2.0 mL, 1.07 equivalents) and catalyst (0.050 g) was added, and the reaction was restarted as before. After 45 minutes under hydrogen, the reaction was exposed to air, and the suspension was suction filtered through a short plug of diatomaceous earth. The reaction flask and filter were rinsed with methanol, and the combined filtrates were concentrated to provide N-methyl-4-(piperazin-1-yl)-1H-indole-2-carboxamide hydrochloride as a light amber solid (0.531 g, 96% yield); (M+1) = 259.

[0587] Step 3: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperazin-1-yl)- 1H-indole-2-carboxamide

[0588] To a stirred and cooled (0 °C) solution of 1,1'-carbonyldiimidazole (0.076 g, 0.469 mmol) in dichloromethane (8 mL) was added a solution of 3-(trifluoromethyl)benzylamine (0.082 g, 0.47 mmol) in dichloromethane (2 mL). After 15 min at 0 °C, N-methyl-4-(piperazin-l-yl)-lH-indole-2-carboxamide hydrochloride (0.115 g, 0.39 mmol) was added, followed by N,N-diisopropylethylamine (82 μΐ, 0.468 mmol) and N-hydroxysuccinimide (0.054 g, 0.47 mmol). The reaction vessel was sealed and heated in a microwave reactor at 60 °C for one hour. After cooling to room temperature, the mixture was partitioned between chloroform (20 mL) and dilute aqueous sodium carbonate solution (30 mL). The organic layer was combined with additional extracts (chloroform, 1 x 20 mL), dried over sodium sulfate and concentrated onto ~ 4 g of silica. The impregnated media was subjected to automated flash chromatography (Combiflash Rf instrument; 10% to 45% 3:1 ethyl acetate / ethanol in heptane; 80 g silica gel column) to provide partially purified product as a foamy tan solid. This material was further purified by automated reverse phase flash chromatography (InterChim PuriFlash XS420 system; 30% to 100% acetonitrile in water with 0.1% formic acid; 55 g InterChim C18 column; sample loaded as a solution in DMSO) to provide N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperazin-l-yl)-lH-indole-2-carboxamide as a white solid (0.081 g, 45%); 1 HNMR (400 MHz, CD3OD) δ 7.66 - 7.46 (m, 4H), 7.21 - 7.09 (m, 3H), 6.61 (dd, J = 6.2, 2.2 Hz, 1H), 4.46 (s, 2H), 3.76 - 3.63 (m, 4H), 3.28 - 3.19 (m, 4H), 2.93 (s, 3H) ppm; (M + 1) = 460.

[0589] Example 103: Preparation of 3-chloro-N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-lH-indole-2-carboxamide

[0590]

[0591] To a 20 ml vial was added a stir bar, N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide (54 mg, 120 µmol, Example 1), N-chlorosuccinimide (16 mg, 120 µmol), and N,N-dimethylformamide (2 mL). The mixture was sonicated briefly, and then allowed to stir at room temperature. After 20 min, the mixture was heated to 55 °C. The reaction was kept at this temperature for 3 h, and then it was heated to 140 °C. After 20 min at this temperature, the mixture was allowed to cool to room temperature and diluted with water (30 mL). The mixture was extracted with dichloromethane (3 × 20 mL), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated to provide a brown oil. The crude material was purified via silica gel chromatography (0-40% 3 : 1 ethyl acetate: ethanol / heptane eluting) to provide 3-chloro-N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide as a white solid (0.032 g, 64 µmol, 53% yield); 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 9.24 (t, J = 5.9 Hz, 1H),8.01 – 7.93 (m, 2H), 7.91 (q, J = 4.6 Hz, 1H), 7.74 - 7.51 (m, 7H), 7.34 (dd,J = 8.3, 7.2 Hz, 1H), 7.01 (dd, J = 7.2, 1.0 Hz, 1H), 4.61 (d, J = 5.9 Hz,2H), 2.86 (d, J = 4.6 Hz, 3H) ppm; (M+1) = 486.

[0592] Example 104: Preparation of N,3-dimethyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide

[0593]

[0594] Step 1: Preparation of 3-bromo-N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide

[0595]

[0596] To a 20 mL vial was added a stir bar, N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide (210 mg, 465 µmol, Example 1), N-bromosuccinimide (96 mg, 535 µmol), and N,N-dimethylformamide (2 mL). The mixture was sonicated briefly, and then allowed to stir at room temperature overnight. The brown mixture was diluted with water (20 mL) and sonicated, resulting in the formation of a precipitate. The mixture was filtered, and the filter cake was washed with water (20 mL) and dried to provide 3-bromo-N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide (240 mg, 452 µmol, 96% yield) as a white solid; (M+1) = 530.

[0597] Step 2: Preparation of N,3-dimethyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide

[0598] To a 20 mL vial was added a stir bar, N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide (210 mg, 465 µmol, Example 1), N-bromosuccinimide (96 mg, 535 µmol), and N,N-dimethylformamide (2 mL). The mixture was sonicated briefly, and then allowed to stir at room temperature overnight. The brown mixture was diluted with water (20 mL) and sonicated, resulting in the formation of a precipitate. The mixture was filtered, and the filter cake was washed with water (20 mL) and dried to provide 3-bromo-N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide (240 mg, 452 µmol, 96% yield) as a white solid; (M+1) = 530. 1H NMR (400 MHz, Methanol-d4) δ 7.97 - 7.90 (m, 2H), 7.71 - 7.69 (m, 1H), 7.68 - 7.64 (m, 1H), 7.61 - 7.54 (m, 2H), 7.53 - 7.48 (m, 2H), 7.42 (dd, J = 8.3, 1.0 Hz, 1H), 7.25 (dd, J = 8.3, 7.1 Hz, 1H), 6.89 (dd, J = 7.1, 1.0 Hz, 1H), 4.68 (s, 2H), 2.93 (s, 3H), 2.04 (s, 3H) ppm; (M+1) = 466.

[0599] Example 105: Preparation of N-methyl-4-(l-((3-(trifluoromethyl)benzyl)amino)isoquinolin-6-yl)-lH-indole-2-carboxamide

[0600]

[0601] Step 1: Preparation of 4-(l-chloroisoquinolin-6-yl)-N-methyl-lH-indole-2-carboxamide

[0602]

[0603] A 20 mL microwave reaction vial was charged with 6-bromo-l-chloroisoquinoline (50 mg, 206 µmol, CAS 205055-63-6), N-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole-2-carboxamide (68 mg, 227 µmol, Intermediate 40), potassium carbonate (86 mg, 618 µmol), 1,4-dioxane (3 mL), and water (0.5 mL) and degassed with nitrogen. To the reaction mixture was added l,l'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (12 mg, 14 µmol). The reaction was heated at 100 °C. LCMS showed the desired product as the major component. The reaction was allowed to cool to room temperature and diluted with EtOAc and 1M HCI. The biphasic mixture was filtered and the filtrate separated. The organic layer was washed with 1M HCI. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in MeOH and the resulting precipitate was isolated via vacuum filtration. The solid was air dried to afford 4-(l-chloroisoquinolin-6-yl)-N-methyl-lH-indole-2-carboxamide (20 mg, 60 µmol, 29% yield); (M+1) = 336.

[0604] Step 2: Preparation of N-methyl-4-(l-((3-(trifluoromethyl)benzyl)amino)isoquinolin-6- yl)-lH-indole-2-carboxamide

[0605] A 5 mL microwave reaction vial containing 4-(l-chloroisoquinolin-6-yl)-N-methyl- lH-indole-2-carboxamide (20 mg, 60 µmol), (3-(trifluoromethyl)phenyl)methanamine (13 µl, 89 µmol), cesium carbonate (39 mg, 119 µmol), and N,N-dimethylformamide (1 mL) was degassed with nitrogen. Xantphos Pd G3 (3 mg, 3.0 µmol) was added to the reaction. The reaction was stirred at 100 °C overnight. The reaction was diluted with EtOAc and 1M HCl. The phases were separated and the organic layer was washed with 1M HCl and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in 2 mL of methanol and injected onto a C18 RP HPLC. Elution from 15% to 80% acetonitrile : water (0.1% formic acid modifier) provided N-methyl-4-(l-((3-(trifluoromethyl)benzyl)amino)isoquinolin-6-yl)-lH-indole-2- carboxamide as an off-white solid (8 mg, 16 µmol, 27% yield); 1 H NMR (400 MHz, Methanol-d4) δ 8.32 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.88 (dd, J = 8.6, 1.8 Hz, 1H), 7.79 (d, J = 6.0 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.57 – 7.48 (m, 3H), 7.36 (dd, J = 8.2, 7.2 Hz, 1H), 7.31 – 7.26 (m, 2H), 7.07 (dd, J = 6.1, 0.8 Hz, 1H), 4.90 (s, 2H), 2.91 (s, 3H) ppm; (M+1) = 475.

[0606] Example 106: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)bicyclo[2.2.2]octan- 1-yl)-lH-indole-2-carboxamide

[0607]

[0608] Step 1: Preparation of methyl 4-(2-(methylcarbamoyl)-lH-indol-4-yl)bicyclo[2.2.2]octane- 1-carboxylate

[0609]

[0610] To reaction vial 1 was added 4-bromo-N-methyl-lH-indole-2-carboxamide (500 mg, 1.98 mmol, Intermediate 12), methyl 4-bromobicyclo[2.2.2]octane-1-carboxylate (725 mg, 2.79 mmol, CAS 23062-51-3), (lr[dF(CF3)ppy]2(dtbpy))PF6(25 mg, 0.022 mmol, CAS 870987-63-6), 2,6-dimethylpyridine (0.43 mL, 3.7 mmol), tris(trimethylsilyl)silane (0.66 mL, 2.1 mmol) and DME (10 mL). To another reaction vial 2 was added 4,4'-di-tert-butyl-2,2'-bipyridyl (52 mg, 0.19 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (45 mg, 0.20 mmol) and DME (5 mL). The resulting mixture in vial 2 was stirred at room temperature for 15 min to give a light green solution. This solution was then added to vial 1. The resulting mixture in vial 1 was sparged with nitrogen for 15 min. The reaction mixture was sealed and irradiated in a photoreactor (EvoluChem PhotoRedOx Box device from HepatoChem, blue light source - Kessil 35W) for 45 hours. The reaction mixture was diluted with water and EtOAc. The resulting mixture was stirred vigorously for 10 min. The organic layer was separated, dried over MgS04, filtered and concentrated under reduced pressure to give again crude material which was purified by reverse phase preparative HPLC (30% MeCN in water to 65% MeCN in water, gradient elution, Teledyne Isco ACCQPrep HP125 and Sunfire C18 30 x 150 size column, 5 um). Fractions containing the desired product were combined and concentrated under reduced pressure until MeCN was evaporated. To the residual aqueous layer was added EtOAc and solid sodium carbonate until the aqueous layer became basic. The resulting mixture was stirred for 10 min. The organic layer was separated, washed with saturated aqueous NaHC03(2x), dried over MgS04, filtered and concentrated under reduced pressure to provide methyl 4-[2-(methylcarbamoyl)-lH-indol-4-yl]bicyclo[2.2.2]octane-1-carboxylate (66 mg, 0.18 mmol, 9% yield) as a yellow solid; (M+l) = 341.

[0611] Step 2: Preparation of 4-(2-(methylcarbamoyl)-lH-indol-4-yl)bicyclo[2.2.2]octane- 1 -carboxylic acid

[0612]

[0613] To a suspension of methyl 4-[2-(methylcarbamoyl)-lH-indol-4-yl]bicyclo[2.2.2]octane- 1 - carboxylate (109 mg, 0.32 mmol) in THF-MeOH (1 mL / 3 mL) was added dropwise 2 M aqueous lithium hydroxide (0.32 mL, 0.64 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then heated at 45 °C for 23 hours. A significant amount of starting material remained. The reaction mixture was heated at 55 °C for an additional 28 hours. The reaction mixture was cooled to room temperature and acidified to pH 2-3 with 2 M aqueous hydrochloric acid (0.32 mL, 0.64 mmol). The resulting mixture was diluted with water, and then extracted with EtOAc (2x). The combined organic layers were dried over MgS04, filtered, and concentrated under reduced pressure to provide 4-[2-(methylcarbamoyl)-lH-indol-4-yl]bicyclo[2.2.2]octane- 1 -carboxylic acid as a yellow solid (104 mg, 0.32 mmol, 99% yield); (M+l) = 327.

[0614] Step 3: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)bicyclo[2.2.2]octan- 1 -yl)- 1 H-indole-2-carboxamide

[0615] To a solution of 4-[2-(methylcarbamoyl)-lH-indol-4-yl]bicyclo[2.2.2]octan-l- carboxylic acid (40 mg, 0.12 mmol) and HOBt (25 mg, 0.18 mmol) in DMF (3 mL) was added EDCI (36 mg, 0.19 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Then, 3-(trifluoromethyl)benzylamine (0.020 mL, 0.14 mmol) and TEA (0.050 mL, 0.36 mmol) were added successively. The resulting mixture was stirred at room temperature for 22 h. Acidic starting material was still remaining. To this mixture was added N,N-diisopropylethylamine (0.050 mL, 0.29 mmol) followed by HATU (61 mg, 0.16 mmol). The resulting mixture was stirred at room temperature for another 1 h. The reaction mixture was concentrated under reduced pressure to give crude material which was diluted with EtOAc. The organic layer was washed with saturated aqueous NaHC03(2x), dried over MgS04, filtered, and concentrated under reduced pressure to give crude material which was purified by reverse-phase preparative HPLC (35% MeCN in water to 70% MeCN in water, gradient elution, Teledyne Isco ACCQPrep HP125 and Sunfire CI 8 30 x 150 size column, 5 um). Fractions containing the desired product were combined and concentrated under reduced pressure until MeCN was evaporated. To the residual aqueous layer was added EtOAc and solid sodium carbonate until the aqueous layer became basic. The resulting mixture was stirred for 10 min. The organic layer was separated, washed with saturated aqueous NaHC03(2x), dried over MgS04, filtered, and concentrated under reduced pressure to provide N-methyl-4-[4-[[3- (trifluoromethyl)phenyl]methylcarbamoyl]-l-bicyclo[2.2.2]octyl]-lH-indole-2-carboxamide as a yellow solid (50 mg, 0.10 mmol, 84% yield); 1HNMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.47 - 8.36 (m, 1H), 8.18 (t, J = 6.0 Hz, 1H), 7.64 - 7.50 (m, 4H), 7.44 (dd, J = 2.2, 0.9 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.06 (dd, J = 8.2, 7.3 Hz, 1H), 6.82 (dd, J = 7.3, 1.0 Hz, 1H), 4.37 (d, J = 6.0 Hz, 2H), 2.83 (d, J = 4.6 Hz, 3H), 2.07 - 1.97 (m, 6H), 1.95 - 1.85 (m, 6H) ppm; (M+1) = 484.

[0616] Example 107: Preparation of 4-(4-(benzylcarbamoyl)-1H-pyrazol-1-yl)-6- cyclopropyl-N-methyl-1H-indole-2-carboxamide

[0617]

[0618] Step 1: Preparation of methyl 1-(6-cyclopropyl-2-(methylcarbamoyl)-1H-indol-4-yl)- 1H-pyrazole-4-carboxylate

[0619]

[0620] A mixture of 4-bromo-6-cyclopropyl-N-methyl-1H-indole-2-carboxamide (0.100 g, 0.341 mmol), methyl 1H-pyrazole-4-carboxylate (0.065 g, 0.512 mmol), 1,2- dimethylethylenediamine (0.006 g, 0.068 mmol), potassium carbonate (0.099 g, 0.716 mmol), and iodine(I) (0.003 g, 0.017 mmol) in 1,4-dioxane (1 mL) was stirred at 110 °C in a sealed tube under N2for 48 h. The mixture was concentrated and purified by flash silica gel column (DCM / MeOH 50 : 1 to 20 : 1) to give methyl 1-[6-cyclopropyl-2-(methylcarbamoyl)-1H-indol-4-yl]pyrazole-4- carboxylate (0.07 g, 0.160 mmol, 47% yield) as a brown oil; (M+1) = 339.

[0621] Step 2: Preparation of 1 -(6-cyclopropyl-2-(methylcarbamoyl)- 1 H-indol-4-yl)- 1 H- pyrazole-4-carboxylic acid

[0622]

[0623] A mixture of methyl 1-[6-cyclopropyl-2-(methylcarbamoyl)-1H-indol-4-yl]pyrazole-4- carboxylate (0.070 g, 0.160 mmol, Intermediate 28) and lithium hydroxide monohydrate (0.087 g, 2.07 mmol) in tetrahydrofuran (3 mL) and water (3 mL) was stirred at room temperature. After 16 h, the mixture was concentrated to provide a yellow oil; (M+1) = 325.

[0624] Step 3: Preparation of 4-(4-(benzylcarbamoyl)-1H-pyrazol-1-yl)-6-cyclopropyl-N- methyl-1H-indole-2-carboxamide

[0625] A mixture of 1-[6-cyclopropyl-2-(methylcarbamoyl)-1H-indol-4-yl]pyrazole-4-carboxylic acid (0.067 g, 0.207 mmol), benzylamine (0.044 g, 0.417 mmol), HATU (0.118 g, 0.310 mmol), and N,N-diisopropylethylamine (0.067 g, 0.517 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature. After 16 h, the mixture was purified by flash silica gel column (DCM / MeOH 20:1) to provide a crude oil. The oil was purified by flash C18 gel column (MeOH in H2O.NH4HCO3, 0% to 80%) to provide 4-[4-(benzylcarbamoyl)pyrazol-1-yl]-6-cyclopropyl-N-methyl-1H-indole-2- carboxamide as a white solid (0.025 g, 0.060 mmol, 29% yield); 1HNMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.88 (s, 1H), 8.80 (t, J = 6.0 Hz, 1H), 8.56 (q, J = 4.4 Hz, 1H), 8.24 (s, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.40 - 7.35 (m, 4H), 7.28 - 7.25 (m, 1H), 7.19 (s, 1H), 7.07 (d, J = 1.2 Hz, 1H), 4.49 (d, J = 6.0 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.09 - 2.06 (m, 1H), 1.01 - 0.97 (m, 2H), 0.77 - 0.74 (m, 2H) ppm; (M+1) = 414.

[0626] In vitro activity determination relative to human and mouse SLC6A19

[0627] Cell culture: All cell culture materials were purchased from ThermoFisher Scientific (Waltham, MA, USA) unless otherwise noted. MDCK cells stably expressing human SLC6A19+ TMEM27 (NBL-2; ATCC, Manassas, VA, USA) were generated in-house and cultured in DMEM containing 10% fetal bovine serum supplemented with 5 pg / mL of both blasticidin and puromycin. Similar stable cell lines expressing the mouse version of the transporter mSLC6a19 and its cofactor mTMEM27 were constructed in the MDCK background. All experiments described herein were performed using cells that had undergone fewer than 5 passages.

[0628] Test compound collection: Test compounds were obtained, provided as 10 mM DMSO stock solutions in source plates. Appropriate amounts of stock solutions were plated onto 384-well assay plates for testing in the uptake assay using an ECHO 555 liquid handler (Labcyte, Inc., San Jose, CA, USA). Assay buffer was added to solubilize the compounds and achieve a final test concentration of 10 mM for each compound and a DMSO concentration of 0.1% v / v.

[0629] Stable isotopic uptake assay: MDCK cells stably expressing hSLC6A19 + hTMEM27 are plated in culture medium at a density of 2,200 cells / well in poly-d-lysine coated black clear bottom 384-well microplates (Corning Life Sciences, Corning, NY, USA) and allowed to incubate for 48 hours in a humidified 37 °C, 95% / 5% air / CO2 incubator. Following the incubation period, the culture medium is aspirated and the cells are washed twice with HBSS. The cells are incubated with 20 mM (2X) of test compound in assay buffer (137 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, pH 7.2) at 37 °C for 20 minutes, followed by the addition of 2 mM 13 C6, 15 N-L-isoleucine (Sigma Aldrich, St. Louis, MO, USA) and incubated for an additional 20 minutes. One column (16 wells) per plate is dedicated to the inhibition positive control (2 mM substrate 13 C6, 15 N-L-isoleucine prior to the addition of 2 mM substrate 13 C6, 15 N-L-isoleucine without reference inhibitor) (100% transporter activity or 0% inhibition). One column (16 wells) is dedicated to performing a dose response test of the reference inhibitor (8 concentrations in duplicate). The solution is then aspirated and the cells are washed six times in cold assay buffer and most of the liquid is aspirated. The plates are air dried and subjected to freeze-thaw cycles to lyse the cells. 30 pL / well of extraction buffer (10% methanol, 1% formic acid, 250 nM L-leucine-1- 13C and cell dissociation buffer) and the plates were shaken for 5 minutes and incubated at 37 °C for 15-20 minutes, followed by the addition of an additional 60 μΐ^ of extraction buffer per well. The 80 μΐ^ of cell extract was clarified by centrifugation through an AcroPrep 384-well, 30K cutoff filter plate (Pall Corporation, Port Washington, NY, USA). The clarified cell extracts were analyzed using a ThermoFisher LX-4 chromatograph coupled to an ABsciex API-4000 triple quadrupole mass spectrometer (Sciex Corporation, Framingham, MA, USA). A Waters Acquity UPLC BEH 2.1 x 30 mm C18 column (Waters Corporation, Milford, MA, USA) was used, and the mobile phases A and B were water with 0.1% formic acid and acetonitrile with 0.1% formic acid, respectively. The column was maintained at room temperature, and the sample injection volume was 5 μΐ^. The chromatography was run at a flow rate of 0.5 mL / min, with initial conditions of 95% mobile phase A. After injection, the 95% mobile phase A conditions were maintained for 12 seconds, followed by a 6-second gradient change to 50% mobile phase A, held for 10 seconds, and then back to the initial conditions. The ABsciex API-4000 mass spectrometer was operated in positive ion mode, monitoring the L-leucine-1- 13 C 133→86 m / z transition and 13 C6, 15 N -L-isoleucine 139→92 m / z transition, using 16 eV collision energy. The peak areas for 13 C6, 15 N -L-isoleucine were normalized to L-leucine-1- 13 C as a reference. The Z' for each plate was determined using a standard formula by using the mean and standard deviation obtained from the negative and positive control wells: Z' = 1- [3(SD Neg+SD Pos) / (mean Pos-mean Neg)]. Only plates with Z' > 0.4 were accepted. The dose response curves and IC 50 values obtained from each plate were tracked, and the assay performance reproducibility from plate to plate was evaluated. The same protocol described above was used to evaluate the activity of compounds against the mouse transporter, but the following substitutions were made: the MDCK cell line expressing mSLC6a19+mTMEM27 was used, and the 13 C6, 15 N-L-isoleucine final concentration was adjusted to 4 mM.

[0630] Data analysis software: Dose response data were fit using a four parameter variable slope equation with no constraints on the values of the top and bottom of the curve, and the fitting process was done using the curve fitting program Prism (GraphPad Software, Inc., La Jolla, CA). The form of the equation was: Y = bottom + (top-bottom) / (1 + 10^((LogIC50-X SpotFire (Tibco Software, Inc., Palo Alto, CA, USA) was used to visualize the screening data.

[0631]

[0632]

[0633]

[0634]

[0635] Other embodiments fall within the scope of the following claims. Numbered embodiments

[0636] 1. A compound having the formula:

[0637] (I)

[0638] wherein R1and R2are independently selected from H or CH3;

[0639] wherein each R3is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, wherein at least two R3are H;

[0640] or a pharmaceutically acceptable salt thereof.

[0641] 2. The compound of embodiment 1, wherein R1is CH3and R2is H, or a pharmaceutically acceptable salt thereof.

[0642] 3. The compound of any one of embodiments 1-2, wherein at least one R3is F, or a pharmaceutically acceptable salt thereof.

[0643] 4. The compound of any one of the preceding embodiments, wherein the compound has the formula:

[0644]

[0645] or a pharmaceutically acceptable salt thereof.

[0646] 5. The compound of Example 3, wherein the compound has the formula:

[0647]

[0648] or a pharmaceutically acceptable salt thereof.

[0649] 6. The compound of Example 3, wherein the compound has the formula:

[0650]

[0651] or a pharmaceutically acceptable salt thereof.

[0652] 7. The compound of Example 2, wherein at least one R3 is CI, or a pharmaceutically acceptable salt thereof.

[0653] 8. The compound of Example 7, wherein the compound has the formula:

[0654]

[0655] or a pharmaceutically acceptable salt thereof.

[0656] 9. The compound of Example 2, wherein at least one R3 is CH3, or a pharmaceutically acceptable salt thereof.

[0657] 10. The compound of Example 2, wherein the compound has the formula:

[0658]

[0659] or a pharmaceutically acceptable salt thereof.

[0660] 11. The compound of Example 2, wherein the compound has the formula:

[0661]

[0662] or a pharmaceutically acceptable salt thereof.

[0663] 12. The compound of Example 2, wherein the compound has the formula:

[0664]

[0665] or a pharmaceutically acceptable salt thereof.

[0666] 13. The compound of Example 2, wherein the compound has the formula:

[0667] (Compound 36)

[0668] or a pharmaceutically acceptable salt thereof.

[0669] 14. The compound of Example 1, wherein R1 and R2 are both H, or a pharmaceutically acceptable salt thereof.

[0670] 15. The compound of Example 2, wherein the compound has the formula:

[0671] (Compound 1)

[0672] or a pharmaceutically acceptable salt thereof.

[0673] 16. The compound of Example 1, wherein R1 and R2 are both CH3, or a pharmaceutically acceptable salt thereof.

[0674] 17. The compound of Example 2, wherein the compound has the formula:

[0675] (Compound 2)

[0676] or a pharmaceutically acceptable salt thereof.

[0677] 18. A compound having the formula:

[0678] (II)

[0679] wherein R1 and R2 are independently selected from H or CH3;

[0680] wherein each R3 is independently selected from H, OH, CH3, O-CH3, CH2F2, F, or Cl, wherein at least two R3 are H;

[0681] wherein n is 0, 1, 2, or 3;

[0682] wherein each occurrence of R4 is independently selected from CH3, CF3, O-CH3, F, Cl, -CN, isopropyl, or cyclopropyl;

[0683] wherein R6 is H, -CH2CH2OH, or -CH2CH2N(CH3)2;

[0684] R5 is:

[0685] ; ; -CF2CF3; ; ; ; ; ; ;

[0686] , where m is 0, 1, 2, 3 or 4, and X is CH3, OCH3, F or Cl;

[0687] ; ; ; ; ;

[0688] Each X1 is independently N or CH; provided that an X1 is N;

[0689] ; ;or ;

[0690] The premise is that n cannot be 0 when R5 is below:

[0691] ;

[0692] Or its pharmaceutically acceptable salt.

[0693] 19. The compound as described in Example 18, wherein the compound has the following formula:

[0694]

[0695] R appears each time 4a R 4b R 4c and R 4d Independently selected from H, CH3, CF3, O-CH3, F, Cl, -CN, isopropyl, or cyclopropyl; provided that R 4a R 4b R 4c and R 4d At least one of them is not H;

[0696] Or its pharmaceutically acceptable salt.

[0697] 20. The compound as described in Example 19, wherein R 4a R 4b R 4c and R 4d One of them is Cl; and the others are H, or their pharmaceutically acceptable salts.

[0698] 21. The compound as described in Example 20, wherein R 4d It is Cl, or a pharmaceutically acceptable salt thereof.

[0699] 22. The compound as described in Example 19, wherein R 4a R 4b R4c and R 4d One of them is CH3; and the others are H, or their pharmaceutically acceptable salts.

[0700] 23. The compound as described in Example 22, wherein R 4d It is CH3, or a pharmaceutically acceptable salt thereof.

[0701] 24. The compound as described in Example 19, wherein R 4a R 4b R 4c and R 4d One of them is OCH3; and the others are H, or their pharmaceutically acceptable salts.

[0702] 25. The compound as described in Example 24, wherein R 4c It is OCH3, or a pharmaceutically acceptable salt thereof.

[0703] 26. The compound as described in Example 19, wherein R 4a R 4b R 4c and R 4d One of them is F; and the others are H, or their pharmaceutically acceptable salts.

[0704] 27. The compound as described in Example 26, wherein R 4a It is F, or a pharmaceutically acceptable salt thereof.

[0705] 28. The compound as described in Example 19, wherein R 4a R 4b R 4c and R 4d One of them is CF3; and the others are H, or their pharmaceutically acceptable salts.

[0706] 29. The compound as described in Example 28, wherein R 4a It is CF3, or a pharmaceutically acceptable salt thereof.

[0707] 30. The compound as described in Example 19, wherein R 4a R 4b R 4c and R 4d One of them is CN; and the others are H, or their pharmaceutically acceptable salts.

[0708] 31. The compound as described in Example 30, wherein R 4b It is CN, or a pharmaceutically acceptable salt thereof.

[0709] 32. The compound as described in Example 19, wherein R4a , R 4b , R 4c , and R 4d is cyclopropyl; and the others are H, or a pharmaceutically acceptable salt thereof.

[0710] 33. The compound of embodiment 32, wherein R 4b is cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0711] 34. The compound of embodiment 19, wherein one of R 4a , R 4b , R 4c , and R 4d is isopropyl; and the others are H, or a pharmaceutically acceptable salt thereof.

[0712] 35. The compound of embodiment 34, wherein R 4b is isopropyl, or a pharmaceutically acceptable salt thereof.

[0713] 36. The compound of embodiment 19, wherein two of R 4a , R 4b , R 4c , and R 4d are independently Cl, F, or CH3; and the others are H, or a pharmaceutically acceptable salt thereof.

[0714] 37. The compound of embodiment 36, wherein R 4b and R 4c are F, or a pharmaceutically acceptable salt thereof.

[0715] 38. The compound of embodiment 36, wherein one of R 4a and R 4b is F, and the other of R 4a and R 4b is CH3; or one of R 4b and R 4c is F, and the other of R 4b and R 4c is CH3; or one of R 4a and R 4d is F, and the other of R 4a and R 4d is CH3, or a pharmaceutically acceptable salt thereof.

[0716] 39. The compound of embodiment 18, wherein R5is:

[0717] , or a pharmaceutically acceptable salt thereof.

[0718] 40. The compound of Example 18, wherein R5 is:

[0719] or wherein each X1 is independently N or CH; provided that one X1 is N, or a pharmaceutically acceptable salt thereof.

[0720] 41. The compound of Example 18, wherein R5 is:

[0721] wherein m is 0, 1, 2, 3, or 4, and X is CH3, OCH3, F, or CI, or a pharmaceutically acceptable salt thereof.

[0722] 42. The compound of any one of Examples 18-41, wherein R1 is CH3 and R2 is H, or a pharmaceutically acceptable salt thereof.

[0723] 43. The compound of any one of Examples 18-42, wherein each occurrence of R3 is H, or a pharmaceutically acceptable salt thereof.

[0724] 44. The compound of Example 18, wherein the compound is selected from:

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732] or a pharmaceutically acceptable salt thereof.

[0733] 45. A compound of the formula:

[0734] (III)

[0735] each of W1 and W4 is independently selected from N, C, or CH;

[0736] each of W2, W3, W5, and W6 is independently selected from N, NH, CH, or CH2;

[0737] n is 0, 1, 2, or 3;

[0738] each occurrence of R4is independently cyclopropyl, Cl, F, CH3, isopropyl, CF3, -CN, or OCH3;

[0739] m is 0, 1, 2, or 3;

[0740] each occurrence of R6is independently F, Cl, or CH3;

[0741] wherein R1and R2are independently selected from H or CH3;

[0742] dashed lines indicate the presence of a single or double bond; and

[0743] X is H or CF3, or a pharmaceutically acceptable salt thereof.

[0744] 46. The compound of embodiment 45, wherein W3is N, W1and W4are C; and each of W2, W5, and W6is CH, or a pharmaceutically acceptable salt thereof.

[0745] 47. The compound of embodiment 45, wherein W2and W3are N, W1and W4are C; and each of W5and W6is CH, or a pharmaceutically acceptable salt thereof.

[0746] 48. The compound of embodiment 45, wherein W3and W5are N, W1and W4are C; and each of W2and W6is CH, or a pharmaceutically acceptable salt thereof.

[0747] 49. The compound of embodiment 45, wherein each of W1and W4is CH; and each of W2, W3, W5, and W6is CH2, or a pharmaceutically acceptable salt thereof.

[0748] 50. The compound of embodiment 45, wherein each of W1is CH, and W4is N; and each of W2, W3, W5, and W6is CH2, or a pharmaceutically acceptable salt thereof.

[0749] 51. The compound of embodiment 45, wherein W3and W6are N, W1and W4are C; W2is CR6, and W5is CH, or a pharmaceutically acceptable salt thereof.

[0750] 52. The compound of embodiment 51, wherein R6is CH3, or a pharmaceutically acceptable salt thereof.

[0751] 53. The compound of embodiment 45, wherein W2is N, W1and W4are C; and each of W3and W5is CH, and W6is CR6, or a pharmaceutically acceptable salt thereof.

[0752] 54. The compound of Embodiment 53, wherein R6 is CI, or a pharmaceutically acceptable salt thereof.

[0753] 55. The compound of Embodiment 45, wherein W2 is N, W1 and W4 are C; and each of W3, W5, and W6 is CH, or a pharmaceutically acceptable salt thereof.

[0754] 56. The compound of Embodiment 45, wherein W2 and W6 are N, W1 and W4 are C; W3 is CR6, and W5 is CH, or a pharmaceutically acceptable salt thereof.

[0755] 57. The compound of Embodiment 56, wherein R6 is CH3, or a pharmaceutically acceptable salt thereof.

[0756] 58. The compound of Embodiment 45, wherein W2 and W6 are N, W1 and W4 are C; W3 is CH, and W5 is CH, or a pharmaceutically acceptable salt thereof.

[0757] 59. The compound of Embodiment 45, wherein W2 is N, W1 and W4 are C; each of W3 and W6 is CR6, and W5 is CH, or a pharmaceutically acceptable salt thereof.

[0758] 60. The compound of Embodiment 59, wherein R6 is CH3, or a pharmaceutically acceptable salt thereof.

[0759] 61. The compound of any one of Embodiments 45-60, wherein R1 is CH3 and R2 is H, or a pharmaceutically acceptable salt thereof.

[0760] 62. The compound of any one of Embodiments 45-61, wherein n is 1, and R4 is F or cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0761] 63. The compound of Embodiment 45, wherein the compound is selected from:

[0762]

[0763]

[0764]

[0765] or a pharmaceutically acceptable salt thereof.

[0766] 64. A compound of the formula:

[0767] (IV)

[0768] wherein R1and R2are independently selected from H or CH3;

[0769] wherein each R3is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, wherein at least two R3are H;

[0770] wherein n is 0, 1, or 2;

[0771] wherein each occurrence of R 10 is independently methyl, F, OH, H, OCH3, CH3, or cyclopropyl;

[0772] wherein X is H or CF3; and

[0773] wherein the bicyclic ring is a bicyclic ring comprising 8-10 constituent ring atoms, wherein 1-4 of the atoms are heteroatoms independently selected from N, O, or S, and wherein each of the two rings is independently a saturated, unsaturated, or aromatic ring;

[0774] or a pharmaceutically acceptable salt thereof.

[0775] 65. The compound of any one of embodiments 64, wherein the bicyclic ring is selected from:

[0776]

[0777]

[0778] or a pharmaceutically acceptable salt thereof.

[0779] 66. The compound of any one of embodiments 64 or 65, wherein R1is CH3and R2is H, or a pharmaceutically acceptable salt thereof.

[0780] 67. The compound of any one of embodiments 64-66, wherein each occurrence of R3is H, or a pharmaceutically acceptable salt thereof.

[0781] 68. The compound of any one of embodiments 64-67, wherein X is CF3, or a pharmaceutically acceptable salt thereof.

[0782] 69. The compound of embodiment 64, wherein the compound is selected from:

[0783]

[0784]

[0785]

[0786]

[0787] or a pharmaceutically acceptable salt thereof.

[0788] 70. A compound of the formula:

[0789] (V)

[0790] R 11 is - (CH2) m -A

[0791] m is 0, 1, 2, or 3;

[0792] R 12 is H;

[0793] R 13 is H, -CH2CH2OH, or -CH2CH2N(CH3)2;

[0794] A is cyclopropyl, -OH, -OCH3; , -CHF2; phenyl, 4-chlorophenyl; or 4-pyridyl;

[0795] n is 0, 1, 2, or 3;

[0796] each occurrence of R 10 is independently cyclopropyl, Cl, F, CH3, or OCH3;

[0797] each R3is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, wherein at least two R3are H; and

[0798] X1is H or CF3;

[0799] X2is H or F;

[0800] or R 11 and R 12 together with the nitrogen atom to which each is attached form the following:

[0801]

[0802] or a pharmaceutically acceptable salt thereof.

[0803] 71. The compound of Example 70, wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof.

[0804] 72. The compound of Example 70 or 71, wherein n is 1, or a pharmaceutically acceptable salt thereof.

[0805] 73. The compound of any one of Examples 70-72, wherein each occurrence of R3is H, or a pharmaceutically acceptable salt thereof.

[0806] 74. The compound of any one of embodiments 70-73, wherein X1is CF3and X2is H, or a pharmaceutically acceptable salt thereof.

[0807] 75. The compound of any one of embodiments 70-73, wherein X1is CF3and X2is F, or a pharmaceutically acceptable salt thereof.

[0808] 76. The compound of any one of embodiments 70-73, wherein X1is H and X2is H, or a pharmaceutically acceptable salt thereof.

[0809] 77. The compound of embodiment 70, wherein the compound is selected from:

[0810]

[0811]

[0812]

[0813]

[0814] or a pharmaceutically acceptable salt thereof.

[0815] 78. A compound of the formula:

[0816] (VI)

[0817] wherein each of R 61 , R 62 , R 63 , and R 64 is independently selected from H and CH3, or a pharmaceutically acceptable salt thereof.

[0818] 79. The compound of embodiment 78, wherein one of R 61 , R 62 , R 63 , and R 64 is CH3and the other three are H, or a pharmaceutically acceptable salt thereof.

[0819] 80. The compound of embodiment 78 or 79, wherein one of R 61 and R 62 is CH3and the other is H, or a pharmaceutically acceptable salt thereof.

[0820] 81. The compound of embodiment 78 or 79, wherein one of R 63 and R 64 is CH3and the other is H, or a pharmaceutically acceptable salt thereof.

[0821] 82. The compound of Example 78, wherein the compound is selected from:

[0822]

[0823] or a pharmaceutically acceptable salt thereof.

[0824] 83. A compound having the formula:

[0825] (VII)

[0826] R 71 and R 72 are each independently selected from H and CH3, or a pharmaceutically acceptable salt thereof.

[0827] 84. The compound of Example 83, wherein one of R 71 and R 72 is CH3and the other is H, or a pharmaceutically acceptable salt thereof.

[0828] 85. The compound of Example 83, wherein the compound is:

[0829] or a pharmaceutically acceptable salt thereof.

[0830] 86. A compound having the formula:

[0831] (VIII)

[0832] wherein Q is (CH2) n herein in the ring and n is 1, 2, or 3, thereby forming a 5, 6, or 7-membered ring, or a pharmaceutically acceptable salt thereof.

[0833] 87. The compound of Example 86, wherein the compound is selected from:

[0834]

[0835] or a pharmaceutically acceptable salt thereof.

[0836] 88. A compound selected from the following:

[0837]

[0838]

[0839] or a pharmaceutically acceptable salt thereof.

[0840] 89. A pharmaceutical composition comprising a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0841] 90. A method of treating a disease or disorder associated with a genetic deficiency in phenylalanine hydroxylase, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 89.

[0842] 91. A method of treating phenylketonuria, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 89.

[0843] 92. A method of treating hyperphenylalaninemia, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 89.

[0844] 93. The method of any one of embodiments 91-92, wherein the compound reduces the subject’s systemic phenylalanine levels.

[0845] 94. A method of treating or preventing tyrosinemia (type I, type II, or type III), the method comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 89.

[0846] 95. The method of embodiment 94, wherein the compound reduces the subject’s systemic tyrosine levels.

[0847] 96. A method of treating or preventing non-ketotic hyperglyc inemia, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 89.

[0848] 97. The method of embodiment 96, wherein the compound reduces the subject’s systemic glycine levels.

[0849] 98. A method of treating or preventing isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder, or hyperammonemia, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 89.

[0850] 99. The method of any one of embodiments 90-98, wherein the compound inhibits SLC6A19 in the subject.

[0851] 100. A compound for use in treating a disease or disorder associated with a genetic deficiency in phenylalanine hydroxylase, the treatment comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 89.

[0852] 101. A compound for use in treating phenylketonuria, the treatment comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 89.

[0853] 102. A compound for use in treating hyperphenylalaninemia, the treatment comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 89.

[0854] 103. A compound for use in treating a disease of embodiment 101 or 102, wherein the compound reduces systemic phenylalanine levels in the subject.

[0855] 104. A compound for use in treating or preventing tyrosinemia (type I, type II, or type III), the treatment or prevention comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 89.

[0856] 102. The compound for use in treating or preventing tyrosinemia of embodiment 101, wherein the compound reduces systemic tyrosine levels in the subject.

[0857] 103. A compound for use in treating or preventing non-ketotic hyperglyc inemia, the treatment or prevention comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-85, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 86.

[0858] 104. The compound for use in treating or preventing non-ketotic hyperglyc inemia of embodiment 103, wherein the compound reduces systemic glycine levels in the subject.

[0859] 105. A compound for use in treating or preventing isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder, or hyperammonemia, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-85, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of embodiment 86.

[0860] 106. A compound for use in treating or preventing a disease of embodiments 97-105, wherein the compound inhibits SLC6A19 in the subject.

Claims

1. A compound of formula: wherein R1and R2are independently selected from H or CH3; wherein each R3is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, wherein at least two R3are H; or a pharmaceutically acceptable salt thereof. (I) 2. A compound of formula: wherein R1and R2are independently selected from H or CH3; wherein each R3is independently selected from H, OH, CH3, O-CH3, CH2F2, F, or Cl, wherein at least two R3are H; wherein n is 0, 1, 2, or 3; wherein each occurrence of R4is independently selected from CH3, CF3, O-CH3, F, Cl, -CN, isopropyl, or cyclopropyl; wherein R6is H, -CH2CH2OH, or –CH2CH2N(CH3)2; R5is: provided that when R5is the following, n cannot be 0: or a pharmaceutically acceptable salt thereof.

3. A compound of formula: wherein each of W1and W4is independently selected from N, C, or CH; wherein each of W2, W3, W5, and W6is independently selected from N, NH, CH, or CH2; wherein n is 0, 1, 2, or 3; wherein each occurrence of R4is independently cyclopropyl, Cl, F, CH3, isopropyl, CF3, -CN, or OCH3; wherein m is 0, 1, 2, or 3; wherein each occurrence of R6is independently F, Cl, or CH3; wherein R1and R2are independently selected from H or CH3; or a pharmaceutically acceptable salt thereof.

4. A compound of formula: wherein R1and R2are independently selected from H or CH3; wherein each R3is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, wherein at least two R3are H; wherein n is 0, 1, or 2; wherein X is H or CF3; and wherein the bicyclic ring is a bicyclic ring comprising 8-10 constituent ring atoms, wherein 1-4 of the atoms are heteroatoms independently selected from N, O, or S, and wherein each of the two rings is independently a saturated, unsaturated, or aromatic ring; or a pharmaceutically acceptable salt thereof.

5. A compound of formula: wherein m is 0, 1, 2, or 3; wherein n is 0, 1, 2, or 3; wherein each R3is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, wherein at least two R3are H; and wherein X1is H or CF3; wherein X2is H or F; or a pharmaceutically acceptable salt thereof. (I) 6. A compound of formula:

7. A compound of formula:

8. A compound of formula:

9. A compound selected from the following: or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound as described in any of the preceding claims, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

11. A compound for use in treating a disease or disorder associated with a genetic deficiency in phenylalanine hydroxylase, the treatment comprising administering to a subject in need thereof an effective amount of a compound as described in any of claims 1-9, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as described in claim 10. ; ; -CF2CF3; ; ; ; ; ; ; wherein m is 0, 1, 2, 3, or 4, and X is CH3, OCH3, F, or CI; ； ； ； ； ； wherein each X1is independently N or CH; provided that one X1is N; ; ; or ; ​ ； ​ ​ (III) ​ ​ ​ ​ ​ ​ ​ ​ (IV) ​ ​ ​ wherein each occurrence of R is independently H, F, OH, CH3, or cyclopropyl; and n is 0, 1, 2, 3, or 4. 10 independently is methyl, F, OH, H, OCH3, CH3, or cyclopropyl; ​ ​ ​ ​ (V) R 11 is -(CH2) m -A ​ R 12 is H; R 13 is H, -CH2CH2OH, or -CH2CH2N(CH3)2; A is cyclopropyl, -OH, -OCH3; , -CHF2; phenyl, 4-chlorophenyl; or 4-pyridyl; ​ Each occurrence of R 10 It can be cyclopropyl, Cl, F, CH3 or OCH3 independently; ​ ​ ​ or R 11 and R 12 with the nitrogen atom to which each is attached forms the following: ​ ​ (VI) wherein each of R 61 , R 62 , R 63 , and R 64 is independently selected from H and CH3, or a pharmaceutically acceptable salt thereof. ​ (VII) R 71 and each of R 72 is independently selected from H and CH3, or a pharmaceutically acceptable salt thereof. ​ (VIII) wherein Q is (CH2) n herein is in a ring, and n is 1, 2, or 3, forming a 5, 6, or 7-membered ring, or a pharmaceutically acceptable salt thereof. ​ ​ ​ ​ 12. A compound for use in treating phenylketonuria, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of claim 10.

13. A compound for use in treating hyperphenylalaninemia, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of claim 10.

14. A compound for use in treating a disease of any one of claims 11, 12, or 13, wherein the compound reduces the subject’s systemic phenylalanine levels.

15. A compound for use in treating a disease of any one of claims 11, 12, or 13, wherein the compound inhibits SLC6A19 in the subject.

Images