Substitutive cyclic compounds and methods for treating phenylketonuria and other aminoacidurias.

Abstract

This disclosure relates to compounds that inhibit SLC6A19 and can be used to treat patients with phenylketonuria ("PKU") and other aminoaciduria, as well as compositions containing the same and methods of using the same.

Description

[Technical Field]

[0001] This disclosure relates to compounds that may be used in general for the treatment of patients with phenylketonuria (PKU) and other aminoaciduria, and to methods of using them. [Background technology]

[0002] Phenylalanine hydroxylase (PAH) is an enzyme that converts phenylalanine (Phe), consumed in food, to tyrosine (Tyr), primarily in the liver. Reduced PAH function leads to a toxic accumulation of Phe in the body, which manifests as low levels of Tyr and tryptophan, as well as high levels of Phe (and Phe-derived metabolites such as phenol ketones and phenolpyruvic acid) 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 decreased dopamine and serotonin levels, decreased levels of neutral amino acids, white matter disruption, impaired glucose metabolism, and even amyloid-like fibril formation.

[0003] PKU is caused by an autosomal recessive congenital defect in PAH that results in impaired brain function and accumulation of Phe. Untreated PKU patients develop severe intellectual disability, epilepsy, and behavioral, mental, and / or motor impairments.

[0004] PKU occurs in approximately 1 in 15,000 births in North America and Europe, and approximately 50,000 people currently live with PKU in the United States and Europe. Current treatment for PKU involves the use of a phenylalanine ammonia lyase (PHE) restricted diet, which means that patients must be very careful about the amount of PHE found in their food. However, adhering to an undesirable restricted diet is difficult for many adult and adolescent patients. Therefore, patients who struggle to adhere to a PHE restricted diet need new treatment options. Some physicians have started treating PKU by administering PALYNZIQ®, a recombinant phenylalanine ammonia lyase (PAL) enzyme, to patients. However, some patients are allergic to this product, which can cause life-threatening anaphylaxis in such patients. Therefore, new treatments are needed.

[0005] SLC6A19(B 0 SLC6A19 (sometimes called AT1) is an amino acid transporter expressed only in the kidneys and small intestine. SLC6A19 mediates over 95% of the absorption of free neutral amino acids, including phenylalanine (Phe), from the diet. Therefore, inhibition (and even selective inhibition) of SLC6A19 dramatically reduces the amount of neutral amino acids (including Phe) obtained from food. In this way, the increased amount of Phe and other neutral amino acids will be excreted and eliminated from the body. Such inhibition, especially if it is a small molecule, may be easy for patients to take and would treat PKU and other rare genetic disorders of amino acid and nitrogen metabolism. Furthermore, human gene SLC6A19 deficiency (Hartnapp disease, frequency approximately 1:3000) is typically benign, and the rare symptoms of such a disease are treatable with niacin supplementation.

[0006] Genetic inhibition of SLC6A19 in a PKU mouse model has been shown to reduce plasma and brain Phe levels, normalize neurotransmitter levels, improve neuronal morphological defects, and alleviate behavioral symptoms. (Belanger, Adam M. et al., Inhibiting neutral amino acid transport for the treatment of phenylketonuria, JCI Insight. 2018;3(14);e121762). Therefore, inhibitors of SLC61A19 are an interesting target for the treatment of PKU. International Publication No. 2022 / 192370 pamphlet; Desai, Jigar, et.al., Discovery of novel, potential 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] Therefore, this embodiment provides a compound that inhibits SLC6A19 and can thereby be used to treat PKU and other aminoacidurias. [Overview of the project] [Means for solving the problem]

[0008] This disclosure relates to compounds that inhibit SLC6A19 and can be used to treat patients with phenylketonuria ("PKU") and other aminoaciduria, as well as compositions containing the same and methods of using the same.

[0009] In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] The formula is characterized by (wherein R1, R2, and R3 may be as defined elsewhere in this specification).

[0010] In another embodiment, the compound of formula (II), or a pharmaceutically acceptable salt thereof: [ka] The formula is characterized by (wherein R1, R2, R3, R4, n, R5, and R6 may be as defined elsewhere in this specification).

[0011] In a further embodiment, a compound of formula (III), or a pharmaceutically acceptable salt thereof: [ka] The formula is characterized by (wherein R1, R2, R4, R6, n, m, W1, W2, W3, W4, W5, W6, and X may be as defined elsewhere in this specification).

[0012] In one embodiment, a compound of formula (IV), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R1, R2, R3, R 10 The features include n, two rings, and X (which may be as defined elsewhere in this specification).

[0013] In another embodiment, a compound of formula (V), or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R3, R 10 , R 11 , R 12 , R 13, X1, X2, and n can be as defined anywhere in this specification) and are characterized thereby.

[0014] In another aspect, a compound of formula (VI), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0015] In another aspect, a compound of formula (VII), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0016] In another aspect, a compound of formula (VIII), or a pharmaceutically acceptable salt thereof:

Chemical formula

[0017] In a further aspect, a compound such as the compounds described in Table 1, or a pharmaceutically acceptable salt thereof, is characterized.

[0018]

Table 1

[0019] Table 2

[0020] Table 3

[0021] Table 4

[0022] Table 5

[0023] Table 6

[0024] Table 7

[0025] Table 8

[0026] Table 9

[0027] Table 10

[0028] Table 11

[0029] Table 12

[0030] Table 13

[0031] Table 14

[0032] Table 15

[0033] Table 16

[0034] Table 17

[0035] Table 18

[0036] Table 19

[0037] Table 20

[0038] Table 21

[0039] Table 22

[0040] Table 23

[0041] Table 24

[0042] Table 25

[0043] Table 26

[0044] Table 27

[0045] Table 28

[0046] Table 29

[0047] Table 30

[0048] Table 31

[0049] Table 32

[0050] In one embodiment, the pharmaceutical composition is characterized by comprising a compound described herein (for example, a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing the same) and one or more pharmaceutically acceptable excipients.

[0051] In one embodiment, the present disclosure is characterized by a method for modulating (e.g., inhibiting) SLC6A19 in a subject, comprising administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the inhibition may be in vitro. In some embodiments, the inhibition may be in vivo.

[0052] In one embodiment, a method for treating a condition, disease, or disorder that is improved by modulating (e.g., inhibiting) SLC6A19, for example, a method for treating a condition, disease, or disorder in which altered (e.g., increased or excessive) SLC6A19 expression or activity contributes to the pathology and / or symptoms and / or progression of a condition, disease, or disorder (e.g., cancer) in a subject (e.g., a human). The method comprises administering to a subject in need of such treatment an effective amount of a compound described herein (e.g., a compound described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof).

[0053] In another embodiment, a method for treating aminoaciduria is provided, comprising administering an effective amount of a compound described herein (for example, a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof) to a subject in need of such treatment.

[0054] In a further embodiment, a method for treating phenylketonuria, hyperphenylalaninemia, tyrosinemia, nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, or hyperammonemia is characterized by administering to a subject in need of such treatment an effective amount of a compound described herein (for example, a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing the same).

[0055] In one embodiment, a method for treating a disease or disorder associated with a genetic defect of phenylalanine hydroxylase is provided, comprising administering an effective amount of one of the compounds described herein (for example, one of the compounds described herein in general or specifically, or a pharmaceutically acceptable salt thereof, or a composition containing thereof) to a subject in need of such treatment.

[0056] In one embodiment, a method for treating PKU is provided, comprising administering an effective amount of one of the compounds described herein (for example, one of the compounds described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof) to a subject in need of such treatment.

[0057] In one embodiment, a method for treating hyperphenylalaninemia is provided, comprising administering an effective amount of a compound described herein (for example, a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing thereof) to a subject in need of such treatment.

[0058] In some of the embodiments described above, the compound reduces systemic phenylalanine levels in the subject.

[0059] In one embodiment, a method for treating tyrosinemia (type I, type II, or type III) is provided, comprising administering an effective amount of one of the compounds described herein (e.g., one of the compounds generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition containing the same) to a subject in need of such treatment. In some of the above embodiments, the compound reduces systemic tyrosine levels in the subject.

[0060] In one embodiment, a method for treating nonketotic hyperglycinemia is provided, comprising administering 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 thereof) to a subject in need of such treatment. In some of the above embodiments, the compound lowers the systemic glycine level in the subject.

[0061] In one embodiment, a method for treating isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, or hyperammonemia is provided, comprising administering an effective amount of one of the compounds described herein (for example, one of the compounds described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or a composition containing the same) to a subject in need of such treatment.

[0062] In another embodiment, compounds described herein, or pharmaceutically acceptable salts thereof, are provided for use in the treatment of conditions, diseases, or disorders associated with increased (e.g., excessive) SLC6A19 expression.

[0063] In another embodiment, compounds described herein, or pharmaceutically acceptable salts thereof, are provided for use in the treatment of one or more of the above indications (e.g., PKU).

[0064] In another embodiment, the use of the compounds described herein, or pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical product for the treatment of a condition, disease, or disorder associated with increased (e.g., excessive) SLC6A19 expression is provided.

[0065] In another embodiment, the use of the compounds described herein, or pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical product for the treatment of any one or more of the above indications (e.g., PKU) is provided.

[0066] In another embodiment, the present disclosure is characterized by a method for modulating SLC6A19 in mammalian cells, comprising contacting mammalian cells with an effective amount of the compound described in claim 1, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, contact is performed in vivo.

[0068] In some embodiments, contact is performed in vitro.

[0069] The chemical substance may be administered in combination with one or more additional therapeutic agents and / or regimens. For example, the method may further include administering one or more (e.g., two, three, four, five, six, or more) additional drugs.

[0070] The chemical may be administered in combination with one or more additional therapeutic agents and / or regimens useful for treating other SLC6A19-related conditions (e.g., PKU).

[0071] The method may further include identifying the subject.

[0072] Other embodiments include those described in the detailed description and / or claims.

[0073] Additional definitions To facilitate understanding of the disclosures contained herein, several additional terms are defined below. In general, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications referenced throughout this specification and its appendices are incorporated herein by reference in their entirety.

[0074] As used herein, the term "SLC6A19" is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, antibodies, homologous and / or orthologous SLC6A19 molecules, isoforms, precursors, variants, variants, derivatives, splice variants, alleles, different species, and their active fragments.

[0075] When used in this specification, [ka] The notation indicates that the hydrogen atoms on the ring (in this case, phenyl) are substituted R by the number indicated ("n"). 10 It is intended to mean that it can be substituted with one or more of the following. For example, if n is 0, 1, or 2, then the 0, 1, or 2 hydrogen atoms on the ring can be substituted with 0, 1, or 2 R 10 It can be replaced with.

[0076] The terms “effective dose” or “therapeutic effective dose,” as used herein, refer to a sufficient amount of a chemical substance administered that would, to some extent, alleviate one or more symptoms of the disease or condition being treated. The results include a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired change in the biological system. For example, “effective dose” for therapeutic use is the amount of a composition containing the compounds disclosed herein that is necessary to produce a clinically significant reduction in the symptoms of the disease. The appropriate “effective” dose in any individual case is determined using any preferred technique, such as a dose-escalation study.

[0077] The terms “excipient” or “pharmaceutically acceptable excipient” mean a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of a pharmaceutical formulation, has a reasonable risk-benefit ratio, and is suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications. For example, 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.

[0078] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not destroy the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In some cases, pharmaceutically acceptable salts are obtained by reacting the acidic compounds described herein with a base to form salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, and tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine and lysine, or by other methods previously determined. Pharmacologically acceptable salts are not particularly limited as long as they are usable in pharmaceuticals. Examples of salts formed by the compounds described herein with bases include salts of the compounds with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts of the compounds with organic bases such as methylamine, ethylamine, and ethanolamine; salts of the compounds with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids 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 acidic amino acids such as aspartic acid and glutamic acid.

[0079] The term "pharmaceutical composition" refers to a mixture of the compounds described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspenders, and / or thickeners (collectively referred to herein as "excipients"). Pharmaceutical compositions facilitate the administration of compounds to living organisms. Several techniques for administering compounds exist in the art, but are not limited to, rectal, oral, intravenous, aerosol, parenteral, intraocular, intrapulmonary, and topical administration.

[0080] The term “subject” refers to animals, including but not limited to primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms “subject” and “patient” are used herein synonymously, particularly in relation to mammalian subjects such as humans.

[0081] In the context of treating a disease or disorder, the terms “to treat,” “to treat,” and “treatment” are intended to include reducing or eliminating one or more symptoms of a disorder, disease or condition, or a disorder, disease or condition, or one or more symptoms thereof, or slowing the progression, spread, or worsening of a disease, disorder or condition, or one or more symptoms thereof. [Modes for carrying out the invention]

[0082] This disclosure relates to compounds that inhibit SLC6A19 and can be used to treat patients with phenylketonuria ("PKU") and other aminoaciduria, as well as compositions containing the same and methods of using the same.

[0083] Compound of formula (I) In one embodiment, the present disclosure relates to a compound represented by formula I: [ka] (In the formula, R1 and R2 are selected independently from H or CH3; Each R3 is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, and at least two R3s are H), or is characterized by a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, R1 is CH3 and R2 is H.

[0085] In some embodiments, at least one R3 is F.

[0086] In some embodiments, at least one R3 is Cl.

[0087] In some embodiments, at least one R3 is CH3.

[0088] In some embodiments, both R1 and R2 are H.

[0089] In some embodiments, both R1 and R2 are CH3.

[0090] Compound of formula (II) In one embodiment, the present disclosure relates to a compound represented by formula II: [ka] (In the formula, R1 and R2 are selected independently from H or CH3; Each R3 is independently selected from H, CH2F2, OH, CH3, O-CH3, F, or Cl, and at least two of R3 are H; n is 0, 1, 2, or 3; Each appearance of R4 is independently selected from CH3, CF3, O-CH3, F, Cl, -CN, isopropyl, or cyclopropyl; R6 is H, -CH2CH2OH, or -CH2CH2N(CH3)2; R 5 teeth, [ka] ;-CF2CF3; [ka] C(CH3)3; [ka] (where m is 0, 1, 2, 3, or 4, and X is CH3, OCH3, F, or Cl); [ka] (Here, each X1 is independently either N or CH; however, one X1 is N); [ka] and; However, R5, [ka] If that is the case, then n can never be 0. Or characterized by a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the compound is of formula (II-A): [ka] (In the formula, R 4a , R 4b , R 4c , and R 4d Each appearance of is independently selected from H, CH3, CF3, O-CH3, F, Cl, -CN, isopropyl, or cyclopropyl; however, R 4a , R 4b , R 4c , and R 4d At least one of them is represented as (other than H); or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, R 4a , R 4b , R 4c , and R 4d One of them is Cl, and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4d It can be Cl.

[0093] In some embodiments, R 4a , R 4b , R 4c , and R 4d One of them is CH3, and the others are H, or a pharmaceutically acceptable salt thereof. For example, R 4d This could be CH3.

[0094] In some embodiments, R 4a , R 4b , R 4c , and R 4d One of them is OCH3, and the others are H or a pharmaceutically acceptable salt thereof. For example, R 4c This could be OCH3.

[0095] In some embodiments, R 4a , R 4b , R 4c , and R 4d One of them is F, and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4a It can be F.

[0096] In some embodiments, R 4a , R 4b , R 4c , and R 4d One of them is CF3, and the others are H, or a pharmaceutically acceptable salt thereof. For example, R 4a This could be CF3.

[0097] In some embodiments, R 4a , R 4b , R 4c , and R 4d One of them is CN, and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4b It could be CN.

[0098] In some embodiments, R 4a , R 4b , R 4c , and R 4d One of them is cyclopropyl, and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4b It may be cyclopropyl.

[0099] In some embodiments, R 4a , R 4b , R 4c , and R4d One of them is isopropyl, and the other is H, or a pharmaceutically acceptable salt thereof. For example, R 4b It may be isopropyl.

[0100] In some embodiments, R 4a , R 4b , R 4c , and R 4d Two of these are independently Cl, F, or CH3; the other is H, or a pharmaceutically acceptable salt thereof.

[0101] For example, R 4b and R 4c It can be F.

[0102] As another example, R 4a and R 4b One of them can be F, and R 4a and R 4b The other option could be CH3.

[0103] As another example, R 4a and R 4b One of them can be F, and R 4b and R 4c The other option could be CH3.

[0104] As another example, R 4a and R 4b One of them can be F, and R 4a and R 4d The other option could be CH3.

[0105] In some embodiments, R5 is [ka] That is the case.

[0106] In some embodiments, R5 is [ka] In the equation, each X1 is independently either N or CH; however, one X1 is N.

[0107] In some embodiments, R5 is [ka] The formula is such that m is 0, 1, 2, 3, or 4, and X is CH3, OCH3, F, or Cl, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, R1 is CH3 and R2 is H.

[0109] In some embodiments, R3 is H.

[0110] In some embodiments, R6 is H.

[0111] Compound of formula (III) In one embodiment, the present disclosure relates to a compound represented by formula III: [ka] (In the formula, Each of W1 and W4 is independently selected from N, C, or CH; Each of W2, W3, W5, and W6 is independently selected from N, NH, CH, or CH2; n is 0, 1, 2, or 3; Each appearance of R4 is independently cyclopropyl, Cl, F, CH3, or OCH3; m is 0, 1, 2, or 3; Each occurrence of R6 is independently F, Cl, or CH3; Here, R1 and R2 are selected independently of H or CH3; The dotted line indicates the presence of a single or double bond; X is characterized by H or CF3, or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, W3 is N, W1 and W4 are C, and W2, W5 and W6 are CH, respectively.

[0113] In some embodiments, W2 and W3 are N, W1 and W4 are C, and W5 and W6 are CH, respectively.

[0114] In some embodiments, W3 and W5 are N, W1 and W4 are C, and W2 and W6 are CH.

[0115] In some embodiments, W1 and W4 are each CH, and W2, W3, W5, and W6 are each CH2.

[0116] In some embodiments, W1 is CH, W4 is N, and W2, W3, W5, and W6 are each CH2.

[0117] 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.

[0118] In some embodiments, W2 is N, W1 and W4 are C; W3 and W5 are CH respectively, and W6 is CR6. In certain embodiments, R6 is Cl.

[0119] In some embodiments, W2 is N, W1 and W4 are C, and W3, W5 and W6 are CH, respectively.

[0120] 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.

[0121] In some embodiments, W2 and W6 are N, W1 and W4 are C, W3 is CH, and W5 is CH.

[0122] 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.

[0123] In some embodiments, R1 is CH3 and R2 is H.

[0124] In some embodiments, n is 1 and R4 is F or cyclopropyl.

[0125] Compound of formula (IV) In one aspect, the present disclosure provides a compound represented by formula IV:

Chemical formula

[0126] In some embodiments, the bicyclic ring is

[0127]

Table 33

[0128]

Table 34

[0129] is selected from or its pharmaceutically acceptable salts.

[0130] In some embodiments, R1 is CH3 and R2 is H.

[0131] In some embodiments, each occurrence of R3 is H.

[0132] In some embodiments, X is CF3.

[0133] The compound of formula (V) In one aspect, the present disclosure provides a compound represented by formula V: [Chemical formula] (R 11 is -(CH2) m -A, m is 0, 1, 2 or 3; R 12 is H; R 13 is H, -CH2CH2OH, or -CH2CH2N(CH3)2; A is cyclopropyl, -OH, -OCH3; [Chemical formula] , -CHF2; phenyl, 4-chlorophenyl; [Chemical formula] , or 4-pyridyl; n is 0, 1, 2 or 3; R 10 each occurrence of is independently cyclopropyl, Cl, F, CH3, or OCH3; each R3 is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, and at least two R3s are H; X1 is H or CF3; X2 is H or F; or R 11 and R 12 together with the nitrogen atom to which each is attached,

Chem.

[0134] In some embodiments, R 11 is -(CH2) m -A and R 12 is H.

[0135] In some embodiments, m is 1 or 2.

[0136] In some embodiments, n is 1.

[0137] In some embodiments, R3 is H.

[0138] In some embodiments, X1 is CF3 and X2 is H.

[0139] In some embodiments, X1 is CF3 and X2 is F.

[0140] In some embodiments, X1 is H and X2 is H.

[0141] In some embodiments, R 13 is H. [[ID=,55]]

[0142] The compound of formula (VI) In one aspect, the present disclosure provides a compound represented by formula VI:

Chem.

[0143] In some embodiments, R 61 , R 62 , R 63 , and R 64 One of them is CH3, and the other three are H, or their pharmaceutically acceptable salts.

[0144] In some embodiments, R 61 and R 62 One of them is CH3, and the other is H, or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, R 63 and R 64 One of them is CH3, and the other is H, or a pharmaceutically acceptable salt thereof.

[0146] Compound of formula (VII) In one embodiment, the present disclosure relates to a compound represented by formula VII: [ka] (R 71 and R 72 Each of these is characterized by a (independently selected from H and CH3) or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, R 71 and R 72 One of them is CH3, and the other is H, or a pharmaceutically acceptable salt thereof.

[0148] Compound of formula (VIII) In one embodiment, the present disclosure relates to a compound represented by formula VIII: [ka] (In the formula, Q is (CH2) n The compound is characterized by a ring in which n is 1, 2, or 3, thereby forming a 5, 6, or 7-membered ring, or by a pharmaceutically acceptable salt thereof.

[0149] Pharmaceutical composition and administration Overview In some embodiments, the compound (e.g., a compound that inhibits (e.g., antagonizes) SLC6A19, or a pharmaceutically acceptable salt thereof, and / or hydrate, and / or drug combination thereof) is administered as a pharmaceutical composition comprising the chemical substance and one or more pharmaceutically acceptable excipients, and optionally, one or more additional therapeutic agents as described herein.

[0150] In some embodiments, the chemical may 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), e.g., d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, e.g., Tweens, poloxamer, or other similar polymer delivery matrices, serum proteins, e.g., human serum albumin, buffers, e.g., phosphates, tris, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acids, water, salts, or partial glyceride mixtures of electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives may also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions can be prepared containing 0.005% to 100% of the chemicals described herein, with the remainder consisting of non-toxic excipients. The compositions intended may contain 0.001% to 100% of the chemicals provided herein in one embodiment 0.1% to 95%, in another embodiment 75% to 85%, and in further embodiments 20% to 80%. Actual methods of preparing such dosage forms are known or will be obvious to those skilled in the art; e.g., Remington: The Science and Practice of Pharmacy, 22 nd Please refer to the Edition (Pharmaceutical Press, London, UK, 2012).

[0151] Route of administration and compositional components In some embodiments, the chemical substances or pharmaceutical compositions thereof described herein may be administered to subjects requiring them by any acceptable route of administration. Acceptable routes of administration are not limited to, but include oral cavity, skin, cervix, paranasal sinuses, trachea, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrasacral, intracerebral, cisterna magna, intracoronary artery, intradermal, intratubular, duodenal, intradural, intraepidermal, esophageal, intragastric, intragingival, intraileal, lymphatic vessel, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, nasal cavity, intravertebral, synovial sac, testis, intramedullary, intratubular, intratumoral, intrauterine, intravascular, intravenous, transnasal, transnasogastrostomy, oral, parenteral, transdermal, epidural, rectal, respiratory tract (inhalation), subcutaneous, sublingual, submucosal, local, transdermal, transmucosal, transtracheal, ureter, urethra, and vaginal.

[0152] The composition may be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such a composition can be prepared as either a liquid solution or a suspension for injection, and a solid form suitable for use in preparing a solution or suspension when liquid is added before injection can also be prepared, and the preparation can also be emulsified. The preparation of such formulations will be known to those skilled in the art in consideration of this disclosure.

[0153] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injection solutions or dispersions. In all cases, these forms must be sterile and fluid enough to be easily injected. They must also be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi.

[0154] The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, such as sugars or sodium chloride. Sustained absorption of the injectable composition can be achieved by the use of absorption-delaying agents (e.g., aluminum monostearate and gelatin) in the composition.

[0155] Sterile injectable solutions are prepared by incorporating the required amount of active compound, along with various other components listed above as needed, into a suitable solvent, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary components from those listed above. For sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient + any additional desired components from its previously sterilized filtered solution.

[0156] Pharmacologically acceptable excipients usable in rectal compositions as gels, creams, enemas, or anal suppositories include, but are not limited to, cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointment), glycerin, glycerin gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharate, menthol, sweet almond oil, sorbitol, sodium benzoate, SBN-free, vanilla essential oil, aerosols, and phenoxyethanol. Parabens, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopole, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxymethabites, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins, for example, one or more of vitamins A and E and potassium acetate.

[0157] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical is mixed with one or more pharmaceutically acceptable excipients, e.g., sodium citrate or dicalcium phosphate and / or: a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. Similar types of solid compositions may also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0158] In one embodiment, the composition may take the form of a unit dosage form such as a pill or tablet, and thus the composition may contain, along with the chemicals provided herein, diluents such as lactose, sucrose, and dicalcium phosphate; lubricants such as magnesium stearate; and binders such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, and cellulose derivatives. In other solid dosage forms, powders, pills (marume), solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) are encapsulated in capsules (gelatin or cellulosic capsules). Unit dosage forms in which one or more chemicals or additional activators provided herein are physically separated are also intended, for example, capsules (or tablets in capsules) with granules of each drug, two-layer tablets, two-compartment gel caps, etc. Enteric-coated or delayed-release oral dosage forms are also intended.

[0159] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants, or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known, such as phenol and ascorbic acid.

[0160] In certain embodiments, the excipients are sterilized and generally free of undesirable substances. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for excipients in various oral dosage forms, such as tablets and capsules. USP / NF standards are usually sufficient.

[0161] Topical compositions may include ointments and creams. Ointments are typically semi-solid preparations based on petroleum or other petroleum derivatives. Creams containing selected surfactants are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable and comprise an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes called the “internal” phase, generally consists of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol, while the aqueous phase usually, though not necessarily, exceeds the volume of the oil phase and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0162] Dosage The dosage may vary depending on the patient's needs, the severity of the condition being treated, and the specific compound used. Determining the appropriate dosage for a particular situation may be determined by a person skilled in the medical field. The total daily dose may be divided and administered in several doses throughout the day or by providing continuous delivery.

[0163] In some embodiments, the compounds described herein are administered in doses ranging from about 0.001 mg / kg to about 500 mg / kg (for example, about 0.01 mg / kg to about 100 mg / kg; about 0.01 mg / kg to about 10 mg / kg; about 0.01 mg / kg to about 1 mg / kg; about 0.01 mg / kg to about 0.1 mg / kg; about 0.1 mg / kg to about 100 mg / kg; about 0.1 mg / kg to about 10 mg / kg).

[0164] regimen The above dosages can be administered daily (for example, as a single dose or as two or more divided doses) or not daily (for example, every other day, every two days, every three days, once a week, twice a week, once every two weeks, or once a month).

[0165] In some embodiments, the duration of administration of the compounds described herein is 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 longer. In further embodiments, the period during which administration is stopped is 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 longer. In one embodiment, the therapeutic compound is administered to an individual for a certain period, followed by administration for another period. In another embodiment, the therapeutic compound is administered over a first period and a second period following the first period, with administration stopped during the second period, followed by administration of the therapeutic compound being started in a third period, and then stopped in a fourth period following the third period. In one aspect of this embodiment, the period of administration of the therapeutic compound, followed by the period of administration being stopped, is repeated over a determined or undetermined period. In further embodiments, the duration of administration is 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 longer. In further embodiments, the period during which administration is discontinued is 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 longer.

[0166] Treatment method In some embodiments, methods are provided for treating subjects having a condition, disease, or disorder in which increased (e.g., excessive) SLC6A19 activity contributes to the pathology and / or symptoms and / or progression of the condition, disease, or disorder (e.g., an immune disorder, cancer).

[0167] One aspect of the present invention provides compounds, compositions, and methods useful for treating or preventing diseases or disorders associated with abnormal levels of amino acids by regulating SLC6A19 transport.

[0168] Another aspect of the present invention relates to a method for regulating SLC6A19 transport of a target of interest, comprising administering an effective amount of a compound described herein to the target.

[0169] This disclosure relates to a method for treating a disease or disorder associated with a genetic defect of phenylalanine hydroxylase of a target, comprising administering an effective amount of a compound of formula (I) to the target.

[0170] This disclosure relates to a method for treating phenylketonuria in a subject of interest, comprising administering an effective amount of one of the compounds described herein to the subject.

[0171] This disclosure relates to a method for treating hyperphenylalaninemia in a subject of interest, comprising administering an effective amount of one of the compounds described herein to the subject.

[0172] In some embodiments, the compound reduces systemic phenylalanine levels in the subject.

[0173] This disclosure relates to a method for treating a target of tyrosinemia (type I, type II, or type III) as needed, characterized by a method comprising administering an effective amount of one of the compounds described herein to the target.

[0174] In some embodiments, the compound reduces systemic glycine levels in the subject. In some embodiments, the present invention relates to a method for treating or preventing isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorder, or hyperammonemia in a subject of interest, comprising administering an effective amount of the compound described herein to the subject.

[0175] In some embodiments of any one of the disclosed methods, the compound modulates SLC6A19 in the subject.

[0176] In some embodiments of any one of the disclosed methods, the compound inhibits SLC6A19 in the subject.

[0177] In some embodiments of any one of the disclosed methods, the compound modulates SLC6A19 transport in the subject.

[0178] In some embodiments of any one of the disclosed methods, the compound inhibits SLC6A19 transport in the subject.

[0179] In some embodiments, the compound reduces systemic levels of amino acids in the subject.

[0180] In some embodiments of any one of the disclosed methods, the subject is a mammal. In some embodiments of any one of the disclosed methods, the mammal is a human.

[0181] Combination therapy This disclosure envisions both monotherapy regimens and combination therapy regimens, which may include administering one or more compounds to a patient, followed by administering another drug to the patient.

[0182] In some embodiments, the methods described herein may further include administering one or more additional treatments (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the compounds described herein.

[0183] compound preparation As will be understood by those skilled in the art, the methods for synthesizing the compounds of the formulas herein will be obvious to them. Synthetic chemical 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 described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2nd ed., 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. The starting materials used to prepare the compounds of the present invention are known, prepared by known methods, or commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein can be substituted with alternative equivalents known in the art. For example, in many reactions, triethylamine can be substituted with other bases such as non-nucleophilic bases (e.g., diisopropylamine, 1,8-diazabicycloundeca-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

[0184] Those skilled in the art, for example, 1Those skilled in the art will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including 1H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The above list represents a subset of available characterization methods and is not intended to be limiting.

[0185] To further illustrate the above, the following non-limiting exemplary synthesis schemes are included. Variations of these embodiments within the claims are within the skill of a person skilled in the art and are considered to be within the scope of the invention described herein and claimed. The reader will recognize that a person skilled in the art, provided this disclosure is available, can prepare and use the invention without exhaustive examples.

[0186] Preparation of intermediates General procedure 1: Synthesis of indole-2-carboxylate intermediate Preparation of intermediate 1: Methyl 4-bromo-6-cyclopropyl-1H-indole-2-carboxylate [ka] Step 1: Preparation of methyl 2-amino-4-cyclopropylbenzoate [ka] In a 1 L round-bottom flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet, methyl 2-amino-4-bromo-benzoate (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. The mixture was degassed under reduced pressure and backfilled with N2 (×3). The brown mixture was then heated and refluxed. After 2 hours, LC / MS analysis indicated that the reaction was complete. The mixture was cooled to room temperature and filtered through Celite. 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 obtain a brown oil. Chromatographic purification (CombiFlash, 330 g SiO2 column, 0-20% ethyl acetate / heptane eluate, combined fractions 25-30, racks 1 and 1-11, rack 2) yielded methyl 2-amino-4-cyclopropyl benzoate (18.59 g, 97.2 mmol, 90% yield) as a pale yellow solid; (M+1) = 192.

[0187] Step 2: Preparation of methyl 2-bromo-4-cyclopropylbenzoate [ka] In a 1 L recovery flask equipped with a magnetic stirring bar and a dropping funnel, methyl 2-amino-4-cyclopropyl benzoate (18.64 g, 97.5 mmol), 1,4-dioxane (100 mL), and a 48% hydrobromic acid solution (50 mL) were added. The mixture was cooled to 0°C while adding a solution of sodium nitrite (8.00 g, 116 mmol) in water (30 mL) over 5 minutes via a dropping funnel. The resulting reddish mixture was stirred at 0°C. After 30 minutes, a mixture of copper(I) bromide (34.59 g, 241.1 mmol) in a 48% hydrobromic acid solution (50 mL) was added to the mixture over 15 minutes via a dropping funnel. The ice bath was removed, and the mixture was warmed to room temperature. After 1 hour, LC / MS analysis indicated that the reaction was complete. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic phase was washed with 3N ammonium hydroxide solution (200 mL) and brine (200 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to obtain a brown oil. Chromatographic purification (CombiFlash, 330 g SiO2 column, 5–15% ethyl acetate / heptane eluate, combined fractions 17–30, rack 1) yielded methyl 2-bromo-4-cyclopropyl-benzoate (15.85 g, 62.13 mmol, yield 64%) as a yellow oil; (M+1) = 255.

[0188] Step 3: Preparation of 2-bromo-4-cyclopropylbenzoic acid [ka] In a 500 mL recovery flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet, methyl 2-bromo-4-cyclopropyl benzoate (17.36 g, 68.1 mmol), tetrahydrofuran (100 mL), and water (50 mL) were added. The solution was treated with lithium hydroxide monohydrate (8.50 g, 203 mmol), and the resulting mixture was heated and refluxed. After 2 hours, LC / MS analysis indicated that the reaction was complete. The mixture was cooled 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 (approximately 15 mL). The mixture was then extracted with diethyl ether (2 × 150 mL). The combined organic phases were dried on magnesium sulfate, filtered, and concentrated to obtain 2-bromo-4-cyclopropylbenzoic acid (16.00 g, 66.37 mmol, 98% yield) as a pale yellow solid; (M-1) = 239.

[0189] Step 4: Preparation of (2-bromo-4-cyclopropylphenyl)methanol [ka] 2-bromo-4-cyclopropylbenzoic acid (16.00 g, 66.37 mmol) and tetrahydrofuran (100 mL) were added to a 1 L round-bottom flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet. The solution was treated with boranedimethyl sulfide complex (9.6 mL, 100 mmol) via syringe for 3 minutes (caution: gas generation). The mixture was heated and refluxed. After 30 minutes, LC / MS analysis indicated that the reaction was complete. The mixture was cooled to room temperature. Methanol (15 mL) was slowly added to the reaction mixture (violent gas generation!), and the resulting solution was stirred. After 15 minutes, the mixture was concentrated to obtain a milky white oil. Chromatographic purification (CombiFlash, 220 g SiO2 column, 15-30% ethyl acetate / heptane eluate, combined fractions 1-12, rack 1) yielded (2-bromo-4-cyclopropyl-phenyl)methanol (B, 13.69 g, 60.28 mmol, yield 91%) as a white solid; (M+1) = 227.

[0190] Step 5: Preparation of 2-bromo-4-cyclopropylbenzaldehyde [ka] (2-bromo-4-cyclopropyl-phenyl)methanol (26.10 g, 115 mmol), manganese(IV) oxide (85.00 g, 978 mmol), and chloroform (300 mL) were added to a 1 L round-bottom flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet. The mixture was heated to 70°C and stirred. After 1 hour, LC / MS analysis indicated that the reaction was complete. The mixture was cooled to room temperature and filtered through Celite. The filtered cake was washed with chloroform (3 × 150 mL). The filtrate was concentrated to obtain 2-bromo-4-cyclopropyl-benzaldehyde (25.30 g, 112 mmol, 98% yield) as a pale yellow oil.

[0191] Step 6: Preparation of methyl(Z)-2-azido-3-(2-bromo-4-cyclopropylphenyl)acrylate [ka] Methanol (300 mL) was added to a 1 L three-necked round-bottom flask equipped with a magnetic stirring bar, a dropping funnel, and an N2 inlet. Metallic sodium (5.12 g, 223 mmol) was added to the vessel, and the resulting mixture was stirred as 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 stirred at -40°C for 15 minutes, and then methyl 2-azidoacetate (21.2 mL, 218 mmol) was added dropwise to the reaction mixture over 15 minutes. After the addition was complete, the yellow reaction mixture was slowly warmed to room temperature. After 22 hours, LC / MS analysis of the brown suspension indicated that the reaction was 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 minutes, the mixture was filtered, and the filtered cake was washed with water (150 mL). The wet solid was dissolved in ethyl acetate (250 mL), and the resulting brown solution was dried over magnesium sulfate, filtered, and concentrated to obtain methyl(Z)-2-azido-3-(2-bromo-4-cyclopropyl-phenyl)propa-2-enoate (13.28 g, 41.22 mmol, yield 74%) as a brown oil.

[0192] Step 7: Preparation of methyl 4-bromo-6-cyclopropyl-1H-indole-2-carboxylate Methyl(Z)-2-azido-3-(2-bromo-4-cyclopropyl-phenyl)prop-2-enoate (14.08 g, 43.7 mmol) and p-xylene (300 mL) were added to a 1 L round-bottom flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet. The mixture was heated under reflux. After 1.5 hours, LC / MS analysis indicated that the reaction was complete. The mixture was cooled to room temperature and concentrated to obtain an orange solid. The crude solid was suspended in heptane (150 mL) and ethyl acetate (15 mL). The mixture was heated under reflux. After 20 minutes, most of the solid had dissolved, yielding a reddish-brown solution. The mixture was cooled to room temperature and then refrigerated overnight to form a precipitate. The liquid phase of the mixture was decanted, and the remaining solid was subjected to chromatographic purification (CombiFlash, 220 g SiO2 gold column, 10-40% ethyl acetate / heptane eluate, combined fractions 10-30, rack 1) to obtain a yellow solid. The solid was suspended in heptane (125 mL) and heated under reflux. The mixture was cooled to room temperature and further cooled in a refrigerator for 45 minutes. The cold suspension was filtered, the filter cake was washed with a small amount of heptane (20 mL), and dried to obtain methyl 4-bromo-6-cyclopropyl-1H-indole-2-carboxylate (9.09 g, 30.9 mmol, yield 71%) as an off-white solid; (M+1) = 294.

[0193] The following indole-2-carboxylates were prepared from the corresponding aldehydes as described in steps 6-7 of the general procedure 1:

[0194] [Table 35]

[0195] [Table 36]

[0196] [Table 37]

[0197] [Table 38]

[0198] General Procedure 2: Preparation of Heterocyclic Carboxamides by Amination of Esters Preparation of intermediate 12:4-bromo-N-methyl-1H-indole-2-carboxamide [ka] Methyl 4-bromo-1H-indole-2-carboxylate (11.06 g, 42.66 mmol, CAS 167479-13-2) and a 33% methylamine solution in ethanol (15 mL, 120.49 mmol) were added to a 20 mL microwave reaction vial equipped with a magnetic stirrer. The container was sealed and the contents were heated to 130°C in a microwave reactor. After 1 hour, LC / MS analysis indicated that the reaction was nearly complete. The mixture was allowed to cool to room temperature and a precipitate formed. The mixture was diluted with water (75 mL) and filtered. The filtered cake was washed with water (50 mL) and dried to obtain 4-bromo-N-methyl-1H-indole-2-carboxamide (10.25 g, 40.50 mmol, yield 95%) as a white solid; (M+1)=253.

[0199] The following carboxamides were prepared from the corresponding esters as described in general procedure 2:

[0200] [Table 39]

[0201] [Table 40]

[0202] General Procedure 3: Preparation of Heterocyclic Carboxamides by HATU-mediated Amidation Preparation of intermediate 29: 4-chloro-N,N-dimethylthieno[3,2-c]pyridine-2-carboxamide [ka] 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), and HATU (686.9 mg, 1.7 mmol) in DMF (5 mL) was stirred for 2 hours. An additional HATU (140 mg) was added to complete the reaction. LC / MS showed that all starting materials were consumed. The reaction mixture was partitioned into 1 M NaOH and pharmaceutically acceptable phosphate. The two layers were separated, and the aqueous layer was extracted with HCl (2 ×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel using 100% toluene as an eluent to obtain 4-chloro-N,N-dimethylthieno[3,2-c]pyridine-2-carboxamide (319 mg, 1.3 mmol, 99% yield) as a white solid; (M+1)=241.

[0203] The following carboxamides were prepared from the corresponding acids as described in general procedure 3:

[0204] [Table 41]

[0205] Preparation of intermediate 34: 4-bromo-6-cyclopropyl-N-methyl-1H-benzo[d]imidazole-2-carboxamide [ka] A solution of 4-bromo-6-cyclopropyl-2-(trichloromethyl)-1H-benzimidazole (1.20 g, 3.39 mmol; see International Publication No. 2011097491) in acetonitrile (20 mL) was treated with methylamine hydrochloride (0.45 g, 6.67 mmol), followed by dropwise addition of 4 M potassium carbonate solution (2.30 g, 16.9 mmol). The mixture was stirred overnight at room temperature, then quenched by the 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 over silica gel (MeOH / DCM: 0-5%) to obtain 4-bromo-6-cyclopropyl-N-methyl-1H-benzo[d]imidazole-2-carboxamide as a yellow solid (0.70 g, yield 70%); (M+1)=294.

[0206] Preparation of intermediate 35: 4-bromo-7-fluoro-N-methyl-1H-benzo[d]imidazole-2-carboxamide [ka] Step 1: Preparation of 4-bromo-7-fluoro-2-(trichloromethyl)-1H-benzo[d]imidazole [ka] 2,2,2-Benzyl trichloroacetimate (0.95 mL, 5.12 mmol) was added to a solution of 3-bromo-6-fluorobenzene-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 hour, water (20 mL) was added to the mixture, and the suspension was filtered. The filtered cake was washed with water and dried under reduced pressure to obtain 4-bromo-7-fluoro-2-(trichloromethyl)-1H-benzo[d]imidazole, which was used directly in the next step without further purification.

[0207] Step 2: Preparation of 4-bromo-7-fluoro-N-methyl-1H-benzo[d]imidazole-2-carboxamide The title compound was prepared according to the procedure described for the preparation of intermediate 34; (M+1)=272.

[0208] Preparation of intermediate 36: 4-bromo-6-cyclopropyl-1-(2-hydroxyethyl)-N-methyl-1H-indole-2-carboxamide [ka] (2-bromoethoxy)(tert-butyl)dimethylsilane (49 mol, 0.21 mol) was added to a solution of 4-bromo-6-cyclopropyl-N-methyl-1H-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). The mixture was stirred at room temperature. After 16 hours, LC / MS showed that a 20% desalted product had 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 on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1 elution) to obtain 4-bromo-6-cyclopropyl-1-(2-hydroxyethyl)-N-methyl-indole-2-carboxamide (10 mg, yield 15%); (M+1) = 337.

[0209] Preparation of intermediate 37: 4-bromo-6-cyclopropyl-1-(2-(dimethylamino)ethyl)-N-methyl-1H-indole-2-carboxamide [ka] Sodium hydride (6 mg, 0.26 mmol) was added to a 0°C solution of 4-bromo-6-cyclopropyl-N-methyl-1H-indole-2-carboxamide (50 mg, 0.17 mmol, intermediate 28) in tetrahydrofuran (3 mL). The mixture was warmed to room temperature and stirred. After 1 hour, the mixture was treated with 2-bromo-N,N-dimethyltan-1-amine hydrobromide (44 mg, 0.19 mmol) and stirred at room temperature. After 1 hour, the reaction was quenched by adding water and ethyl acetate, and the resulting mixture was filtered. 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 (PE:EA=4:1) to obtain ethyl 2-[benzyloxycarbonyl-[(4-bromophenyl)methyl]amino]acetate (25 mg, 0.07 mmol, yield 40%); (M+1)=364.

[0210] Preparation of intermediate 38: 4-bromo-3-chloro-N,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide [ka] 4-bromo-N,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (54 mg, 191 μmol; see International Publication No. 2017177955) and DMF (2 mL) were added to a 5 mL microwave reaction vial. The mixture was treated with N-chlorosuccinimide (27 mg, 200 μmol). The mixture was stirred at room temperature for 45 minutes, then heated to 60 °C overnight. The heterogeneous reaction mixture was filtered, and the filtered cake was dried to obtain 4-bromo-3-chloro-N,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (45 mg, 142 μmol, yield 75%) as a white solid; (M+1) = 318.

[0211] Preparation of intermediate 39: 4-bromo-6-cyclopropylbenzo[d]thiazole-2-amine [ka] To a solution of 4-cyclopropylaniline (2.00 g, 15.0 mmol, CAS 3158-71-2) in acetic acid (40 mL), bromine (4.80 g, 30.0 mmol) was added, and the resulting mixture was stirred at room temperature. After 5 minutes, potassium thiocyanate (10.2 g, 10⁵ mol) was added. The mixture was stirred at room temperature. After 2 hours, 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 obtain 4-bromo-6-cyclopropyl-1,3-benzothiazole-2-amine (180 mg, 0.67 mmol, yield 4%); (M+1) = 269.

[0212] Intermediate 40: Preparation of N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxamide [ka] In a 500 mL round-bottom flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet, 4-bromo-N-methyl-1H-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) were added. The mixture was degassed under reduced pressure and backfilled with N2 (×3). The mixture was then heated and refluxed. After 1 hour, LC / MS analysis of the mixture revealed the presence of several new products, including the desired boronic acid ester (major) and the dehalogenated starting material (trace). The mixture was cooled to room temperature and diluted with water (300 mL). The resulting precipitate was isolated by filtration, and the filtration cake was washed with water (50 mL). The wet solid was dissolved in ethyl acetate (150 mL), the solution was dried over magnesium sulfate, filtered, and concentrated to obtain N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxamide (5.72 g, 19.06 mmol, yield 74%) as a yellow solid; (M+1)=301.

[0213] Preparation of intermediate 41: 6-cyclopropyl-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxamide [ka] 4-bromo-6-cyclopropyl-N-methyl-1H-indole-2-carboxamide (1.05 g, 3.58 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.36 g, 5.36 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.15 g, 0.18 mmol), potassium acetate (1.41 g, 14.4 mmol), and 1,4-dioxane (12 mL) were added to a 20 mL microwave reaction vial equipped with a magnetic stirring bar. The contents were degassed under reduced pressure and backfilled with N2 (×3). The mixture was heated to 125°C in a heating block. After 2.5 hours, LC / MS analysis indicated that the reaction was complete. The mixture was cooled to room temperature and diluted with water (100 mL) to form a precipitate. The mixture was filtered, and the filter cake was washed with water (30 mL). The wet 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 filtrate phase was separated, the organic phase was dried over magnesium sulfate, filtered, and concentrated to obtain 6-cyclopropyl-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxamide (794 mg, 2.33 mmol, yield 65%) as a brown solid; (M+1)=341.

[0214] Preparation of intermediate 42: 7-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-2-carboxamide [ka] The title compound was prepared from 4-bromo-7-fluoro-N-methyl-1H-benzo[d]imidazole-2-carboxamide (intermediate 35) as described in the preparation of intermediate 41; (M+1)=320.

[0215] Preparation of intermediate 43: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)benzyl)benzamide [ka] In a 500 mL round-bottom flask equipped with a magnetic stirring bar and an N2 inlet, 4-(4,4,5,5-tetramethyl-1,3,2-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) were added. The resulting suspension was stirred at room temperature for 5 minutes, and then 3-(trifluoromethyl)benzylamine (7.22 g, 41.2 mmol) was added. The mixture was continued to stir at room temperature. After 30 minutes, LC / MS analysis indicated that 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 vigorously stirred. After 30 minutes, a solid was formed. The suspension was filtered, the filter cake was washed with heptane (50 mL), and dried to obtain 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[[3-(trifluoromethyl)phenyl]methyl]benzamide (10.15 g, 25.05 mmol, yield 67%) as a white solid; (M+1)=406.

[0216] Preparation of intermediate 44: 3-fluoro-N-(2-fluoro-5-(trifluoromethyl)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] The title compound was prepared from 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 867256-77-7) and (2-fluoro-5-(trifluoromethyl)phenyl)methaneamine, as described in the preparation of intermediate 43; (M+1)=442.

[0217] Preparation of intermediate 45: 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)benzyl)benzamide [ka] The title compound was prepared from 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and 3-(trifluoromethyl)benzylamine, as described in the preparation of intermediate 43; (M+1)=424.

[0218] Preparation of Intermediate 46: N-benzyl-3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] Step 1: Preparation of N-benzyl-4-bromo-3-methoxybenzamide [ka] A mixture of 4-bromo-3-methoxybenzoic 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 minutes, benzylamine (225 mg, 2.10 mmol) and N,N-diisopropylethylamine (775 mg, 6.00 mmol) were added. The mixture was stirred at room temperature. After 2 hours, 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 on anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (0-30% ethyl acetate / petroleum ether) to obtain N-benzyl-4-bromo-3-methoxybenzamide (550 mg, yield 86%); (M+1)=320.

[0219] Step 2: Preparation of N-benzyl-3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide The title compound was prepared from N-benzyl-4-bromo-3-methoxybenzamide, as described in the preparation of intermediate 41.

[0220] Preparation of intermediate 47: 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)benzyl)benzamide [ka] The title compound was prepared from 4-bromo-3,5-dimethylbenzoic acid (CAS 7697-32-7) and (3-(trifluoromethyl)benzylamine) as described in steps 1-2 for the preparation of intermediate 45; (M+1)=434.

[0221] Preparation of intermediate 48: 6-bromo-2,5-dimethylnicotinic acid [ka] Silver nitrate (988 mg, 5.80 mmol) and water (10 mL) were added to a 100 mL recovery flask equipped with a magnetic stirring bar and an N2 inlet. The solution was cooled to 0°C while adding sodium hydroxide (597 mg, 14.93 mmol) in water (10 mL) all at once. To the resulting brown suspension, 6-bromo-2,5-dimethylnicotinaldehyde (744 mg, 3.48 mmol; see International Publication No. 2022266162) was added, and the mixture was stirred at 0°C. After 45 minutes, LC / MS analysis indicated that 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 approximately 3 by adding 1 N hydrochloric acid solution (approximately 8 mL), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with water (15 mL). The wet solid was dissolved in ethyl acetate (20 mL), the resulting solution was dried over magnesium sulfate, filtered, and concentrated to obtain 6-bromo-2,5-dimethylnicotinic acid (693 mg, 3.01 mmol, yield 87%) as a white solid; (M+1) = 230.

[0222] General Procedure 4: Preparation of Halogen Bonding Partners Preparation of intermediate 49: 2-chloro-4-methyl-N-(3-(trifluoromethyl)benzyl)pyrimidine-5-carboxamide [ka] In a 200 mL recovery flask equipped with a magnetic stirring bar and an N2 inlet, 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 mol, 8.99 mmol) were added. The mixture was stirred at room temperature for 5 minutes, and then 3-(trifluoromethyl)benzylamine (607 mg, 3.30 mmol) was added. The resulting yellow mixture was stirred at room temperature. After 1 hour, LC / MS analysis showed that a portion of the desired material had been formed. The mixture was diluted with water (50 mL) and extracted with diethyl ether (2 × 40 mL). The combined organic phase was washed with 1 N hydrochloric acid solution (75 mL), dried on magnesium sulfate, filtered, and concentrated to obtain a brown oil. Chromatographic purification (CombiFlash, 80g SiO2 gold column, 10-60% 3:1 ethyl acetate:ethanol / heptane eluate, combined fractions 24-27, rack 1) yielded 2-chloro-4-methyl-N-(3-(trifluoromethyl)benzyl)pyrimidine-5-carboxamide (347mg, 1.05 mmol, yield 35%) as a white solid; (M+1)=330.

[0223] The following carboxamides were prepared from the corresponding acids as described in general procedure 4:

[0224] [Table 42]

[0225] [Table 43]

[0226] Example 59: Preparation of 1-(2-(4-iodophenoxy)ethyl)-3-(trifluoromethyl)benzene [ka] In a 100 mL recovery flask equipped with a magnetic stirring bar and an N2 inlet, 4-iodophenol (555 mg, 2.50 mmol), 3-(trifluoromethyl)phenyl alcohol (418 μL, 2.75 mmol), polymer-bound triphenylphosphine (1.15 g, 4.40 mmol), and tetrahydrofuran (25 mL) were added. The mixture was treated with bis(2-methoxyethyl)diazene-1,2-dicarboxylate (819 mg, 3.50 mmol), which produced a slight exothermic reaction after about 3 minutes. The mixture was stirred at room temperature. After 1.75 hours, LC / MS analysis indicated that the reaction was complete. The mixture was filtered to remove the resin-binding material, and the filtrate 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 obtain a yellow oil. Chromatographic purification (CombiFlash, 40g SiO2 gold column, 0-25% ethyl acetate / heptane eluate, combined fractions 14-16, rack 1) yielded 1-(2-(4-iodophenoxy)ethyl)-3-(trifluoromethyl)benzene (488 mg, 1.24 mmol, 50% yield) as a white solid (no M+1 / M-1 peaks were observed).

[0227] Intermediate 60: Preparation of ethyl 4-bromo-7-fluoro-3-methyl-1H-indole-2-carboxylate [ka] In a 500 mL round-bottom flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet, (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) were added. The solution was treated with 2-ketobutyric acid (1.81 g, 17.20 mmol), and the resulting mixture was heated under reflux. As the mixture warmed, a highly viscous yellow precipitate formed in the mixture. The solid gradually dissolved as heating continued, producing a dark brown mixture. After 2 hours, LC / MS analysis indicated that the reaction was complete. The mixture was cooled to room temperature and 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 on magnesium sulfate, filtered, and concentrated to obtain a brown solid. Chromatographic purification (CombiFlash, 220 g SiO2 column, 10-50% ethyl acetate / heptane eluate, combined fractions 3-11, rack 1) yielded ethyl 4-bromo-7-fluoro-3-methyl-1H-indole-2-carboxylate (2.02 g, 6.73 mmol, yield 39.9%) as a pale orange solid; (M-1) = 298.

[0228] Preparation of intermediate 61: 6-bromo-2-(3-(trifluoromethyl)benzyl)-3,4-dihydroisoquinoline-1(2H)-one [ka] A 60% dispersion of sodium hydride in mineral oil (0.350 g, 8.75 mmol, CAS 402-23-3) was added to a stirred and cooled (0°C) solution of 6-bromo-3,4-dihydroisoquinoline-1(2H)-one (1.50 g, 6.64 mmol, CAS 147497-32-3) in DMF (25 mL). 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 1 hour, the reaction was analyzed by LC-MS and found to be complete. The mixture was concentrated and the residue was partitioned into ethyl acetate (approximately 75 mL) and water (approximately 100 mL). The organic layer was combined with the reverse extract of the aqueous layer (ethyl acetate, 1 × approximately 50 mL), dried on sodium sulfate, and concentrated on approximately 8 g of silica. The impregnated medium was subjected to automated flash chromatography (Combiflash Rf instrument; 10-30% ethyl acetate in heptane; 120 g silica column) to obtain a purified product as a waxy, light brown solid (2.53 g, 99% yield); (M+1) = 384.

[0229] Preparation of intermediate 62: 5-bromo-2-(3-(trifluoromethyl)benzyl)isoindorin-1-one [ka] A stirred solution of 5-bromoisoindorin-1-one (2.00 g, 9.43 mmol, CAS 552330-86-6) in DMF (35 mL) was mixed with a 60% dispersion of sodium hydride in mineral oil (0.490 g, 12.3 mmol, 1.30 equivalents). After gas generation ceased, the reaction mixture 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 left stirred at room temperature overnight. The reaction mixture was then concentrated, and the residue was partitioned into water (approx. 125 mL) and ethyl acetate (approx. 100 mL). The organic layer was washed a second time with water (1 × approx. 125 mL), dried on sodium sulfate, and concentrated on approx. 12 g of silica. The impregnated medium was subjected to automated flash chromatography (Combiflash Rf instrument; 20-30% ethyl acetate in heptane; 220 g silica column), and the purified product was obtained as a pale yellow solid (1.30 g, yield 37%); (M+1) = 370.

[0230] Preparation of intermediate 63: 7-bromo-2-(3-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine-1-one [ka] A stirred solution of 7-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine-1-one (0.250 g, 1.04 mmol, CAS 1547064-78-7) in DMF (8 mL) was mixed with a 60% dispersion of sodium hydride in mineral oil (54.1 mg, 1.35 mmol, 1.30 equivalents). After gas generation ceased, the reaction mixture was cooled in an ice bath and treated with 3-(trifluoromethyl)benzyl bromide (200 μL, 0.313 g, 1.31 mmol, 1.26 equivalents). The cooling bath was removed and the reaction mixture was warmed to room temperature. After 2 hours, the mixture was diluted with water (approximately 40 mL). The resulting suspension was sonicated until homogeneous (10-15 minutes) and then filtered by suction. The filtered cake was rinsed with water (3 × approximately 10 mL) and heptane (2 × approximately 10 mL), and then air-dried on frit under house vacuum. The crude product, considered pure enough for use without chromatography, was obtained as a brown solid (0.376 g, 91% yield). (M+1) = 398.

[0231] Preparation of intermediate 64: 6-bromo-N-((rac-(trans)-2-(trifluoromethyl)cyclopropyl)methyl)sinnoline-3-amine [ka] 6-bromo-3-chlorosinnoline (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) were added to a 20 mL microwave reaction vial equipped with a magnetic stirring bar. The container was sealed and the contents were heated to 115°C in a heating block. After 16 hours, LC / MS analysis indicated that the reaction was complete. The mixture was cooled to room temperature and diluted with water (60 mL). The mixture was extracted with ethyl acetate (50 mL). The organic phase was separated, washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to obtain a brown oil. Chromatographic purification (CombiFlash, 40g SiO2 gold column, 20-60% 3:1 ethyl acetate; ethanol / heptane eluate, combined fractions 13-15, rac 1) yielded 6-bromo-N-[[rac-(1R,2R)-2-(trifluoromethyl)cyclopropyl]methyl]sinnoline-3-amine (403 mg, 1.16 mmol, yield 57%) as a brown foamy solid; (M+1)=346.

[0232] Preparation of intermediate 65:rac-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(((trans)-2-(3,3,3-trifluoropropyl)cyclopropyl)methyl)benzamide [ka] Step 1: Preparation of ethyl(E)-6,6,6-trifluorohexa-2-enoate [ka] To a solution of 4,4,4-trifluorobutanal (3.8 mL, 36.5 mmol) in dichloromethane (50 mL), ethyl 2-(triphenylphosphoranylidene) acetate (19.1 g, 54.7 mmol) was added, and the mixture was stirred at room temperature. After 3 hours, the mixture was diluted with ethyl acetate (100 mL) and water (30 mL). The aqueous layer was washed with ethyl acetate (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted at PE / EA = 20 / 1) to obtain ethyl(E)-6,6,6-trifluorohexa-2-enoate (3.70 g, yield 52%); (M+1) = 197.

[0233] Step 2: Preparation of rac-trans-ethyl-2-(3,3,3-trifluoropropyl)cyclopropane-1-carboxylate [ka] A mixture of 1-methyl-3-nitro-1-nitroso-guanidine (750 mg, 5.10 mmol) in diethyl ether (10 mL) at 0°C was mixed with a cold solution of potassium hydroxide (286 mg, 5.10 mmol) in water (2 mL). After stirring for 2 minutes, a portion of the resulting yellow ether solution of diazomethane was added at 0°C to a solution of ethyl(E)-6,6,6-trifluorohexa-2-enoate (1.00 g, 5.10 mmol) in ether (20 mL). Palladium acetate (172 mg, 0.765 mmol) was added, followed by the addition of the diazomethane solution. This process was continued until all of the palladium acetate and diazomethane solution had been added. The mixture was stirred at 0°C for 4 hours, and acetic acid (5 drops) was added. Next, the solvent was removed under reduced pressure to obtain rac-trans-ethyl-2-(3,3,3-trifluoropropyl)cyclopropane-1-carboxylate (852 mg, yield 80%); (M+1)=211.

[0234] Step 3: Preparation of rac-trans-2-(3,3,3-trifluoropropyl)cyclopropane-1-carboxylic acid [ka] A solution of rac-trans-ethyl-2-(3,3,3-trifluoropropyl)cyclopropane-1-carboxylate (852 mg, 4.05 mmol) in THF (10 mL) was mixed with 1 N LiOH aqueous solution (971 mg, 40.5 mmol). The mixture was stirred overnight at room temperature. The mixture was adjusted to pH 3-4 using HCl aqueous solution and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain rac-trans-2-(3,3,3-trifluoropropyl)cyclopropane-1-carboxylic acid (733 mg, yield: 99% yield); (M+1) = 183.

[0235] Step 4: Preparation of rac-trans-2-(3,3,3-trifluoropropyl)cyclopropanecarboxamide [ka] To a solution of rac-trans-2-(3,3,3-trifluoropropyl)cyclopropanecarboxylic acid (1.60 g, 8.78 mmol) in dichloromethane (20 mL), ammonium chloride (940 mg, 17.6 mmol), HATU (5.01 g, 13.2 mmol), and triethylamine (3.6 mL, 26.3 mmol) were added. The mixture was stirred at room temperature. After 3 hours, the reaction mixture was diluted with ethyl acetate and water, and the mixture was filtered. The aqueous layer was washed with ethyl acetate (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain rac-trans-2-(3,3,3-trifluoropropyl)cyclopropanecarboxamide (1.50 g, yield 94%); (M+1) = 182.

[0236] Step 5: Preparation of rac-trans-(2-(3,3,3-trifluoropropyl)cyclopropyl)methaneamine [ka] Lithium aluminum hydride (3.14 g, 82.8 mmol) was added to a solution of rac-trans-2-(3,3,3-trifluoropropyl)cyclopropanecarboxamide (1.50 g, 8.28 mmol) in tetrahydrofuran (30 mL) at 0°C. The mixture was warmed to room temperature and stirred. After 24 hours, the reaction mixture was cooled to 0°C and quenched by adding 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 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain rac-trans-(2-(3,3,3-trifluoropropyl)cyclopropyl)methaneamine (300 mg, yield 22%); (M+1) = 168.

[0237] Step 6: Preparation of rac-trans-4-bromo-N-[[2-(3,3,3-trifluoropropyl)cyclopropyl]methyl]benzamide [ka] To a solution of rac-trans-(2-(3,3,3-trifluoropropyl)cyclopropyl)methaneamine (300 mg, 1.79 mmol) in dichloromethane (5 mL), 4-bromobenzoic acid (541 mg, 2.69 mmol), HATU (1.02 g, 2.69 mmol), and triethylamine (545 mg, 5.38 mmol) were added. The mixture was stirred at room temperature. After 6 hours, the reaction mixture was diluted with ethyl acetate and water. The aqueous layer was washed with ethyl acetate (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain rac-trans-4-bromo-N-[[2-(3,3,3-trifluoropropyl)cyclopropyl]methyl]benzamide (200 mg, yield 32%); (M+1) = 350.

[0238] Step 7: Preparation of rac-trans-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[[2-(3,3,3-trifluoropropyl)cyclopropyl]methyl]benzamide [ka] The title compound was prepared from rac-trans-4-bromo-N-[[2-(3,3,3-trifluoropropyl)cyclopropyl]methyl]benzamide as described in the preparation of intermediate 41; (M+1)=398.

[0239] Preparation of intermediate 66: (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(5,5,5-trifluoropenta-2-en-1-yl)benzamide [ka] Step 1: Preparation of 4-bromo-N-(buta-3-en-1-yl)benzamide [ka] A mixture of 4-bromobenzoic acid (1.0 g) in thionyl chloride (20 mL) was heated under reflux and stirred. After 16 hours, the mixture was concentrated and the residue was dissolved in DCM (10 mL). This solution was added dropwise to a 0°C mixture of buta-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 warmed to room temperature and stirred. After 16 hours, the mixture was concentrated and the residue was purified by flash silica gel column (PE / siRNA 1:1) to obtain 4-bromo-N-buta-3-enyl-benzamide as a white solid (1.00 g, yield 79%); (M+1)=253.

[0240] Step 2: Preparation of (E)-4-bromo-N-(5,5,5-trifluoropenta-2-en-1-yl)benzamide [ka] A mixture of 4-bromo-N-buta-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 filtrate cake was washed with MeOH (2 × 100 mL). The filtrate was concentrated and then purified by C18 gel column (H2O, NH4HCO3 with 0%~80% MeOH) to obtain a crude yellow oil. Next, the oil was purified by flash silica gel column (PE / Â10:1~5:1) to obtain 4-bromo-N-[(E)-5,5,5-trifluoropenta-2-enyl]benzamide as a yellow solid (0.32 g, yield 16%); (M+1)=322.

[0241] Step 3: Preparation of (E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(5,5,5-trifluoropenta-2-en-1-yl)benzamide The title compound was prepared from 4-bromo-N-[(E)-5,5,5-trifluoropenta-2-enyl]benzamide, as described in the preparation of intermediate 41; (M+1)=370.

[0242] Preparation of intermediate 67: 4-(2-(methylcarbamoyl)-1H-indole-4-yl)benzoic acid [ka] Step 1: Preparation of tert-butyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)benzoate [ka] In a 500 mL round-bottom flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet, 4-bromo-N-methyl-1H-indole-2-carboxamide (6.83 g, 27.0 mmol, intermediate 12), (4-tert-butoxycarbonylphenyl)boronic acid (7.10 g, 32.0 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 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) were added. The mixture was degassed under reduced pressure, backfilled with N2 (×3), and then heated to 100°C in an oil bath. After 45 minutes, LC / MS analysis indicated that the reaction was complete. The mixture was cooled 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 obtain a brown oil. The crude oil was suspended in diethyl ether (250 mL) and sonicated briefly to form a precipitate. The mixture was filtered, and the filtration cake was dried to obtain a brown solid. Chromatographic purification (CombiFlash, 330 g SiO2 gold column, 10-55% 3:1 ethyl acetate:ethanol / heptane eluate, combined fractions 12-27, rack 2) yielded a yellow solid. The solid was suspended in diethyl ether (250 mL) and sonicated briefly. The mixture was filtered, and the filtration cake was dried to obtain tert-butyl 4-[2-(methylcarbamoyl)-1H-indole-4-yl]benzoate 7.75 g, 22.1 mmol, yield 82%) as a pale yellow solid; (M+1)=351.

[0243] Step 2: Preparation of 4-(2-(methylcarbamoyl)-1H-indole-4-yl)benzoic acid In a 100 mL recovery flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet, tert-butyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)benzoate (3.80 g, 10.84 mmol) and dichloromethane (50 mL) were added. The mixture was treated with trifluoroacetic acid (30 mL), and the resulting solution was stirred at room temperature. After 30 minutes, LC / MS analysis indicated that the reaction was complete. The mixture was concentrated, and the residue was suspended in diethyl ether (30 mL). The mixture was filtered, the filter cake was washed with diethyl ether (30 mL), and dried to obtain 4-(2-(methylcarbamoyl)-1H-indole-4-yl)benzoic acid (3.05 g, 10.36 mmol, yield 96%) as a brown solid; (M+1) = 295.

[0244] The following carboxylic acids were prepared using the procedure described for the synthesis of intermediate 67:

[0245] [Table 44]

[0246] Preparation of intermediate 71: 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylic acid [ka] Step 1: Preparation of methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylate [ka] The title compound was prepared from methyl 4-bromo-1H-indole-2-carboxylate and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)benzyl)benzamide (intermediate 43) as described in step 1 of the preparation of intermediate 67; (M+1)=453.

[0247] Step 2: Preparation of 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylic acid 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylate (1.40 g, 3.09 mmol) and methanol (60 mL) were added to a 250 mL recovery flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet. The suspension was treated with 1.0 N sodium hydroxide solution (40 mL, 40.00 mmol), and the mixture was heated under reflux. After 30 minutes, LC / MS analysis indicated that the reaction was complete. The mixture was cooled to room temperature and diluted with 1 N hydrochloric acid solution (60 mL) to form a precipitate. The mixture was filtered, and the filter cake was washed with water (30 mL). The wet solid was dissolved in ethyl acetate (50 mL). The solution was dried over magnesium sulfate, filtered, and concentrated to obtain 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylic acid (1.30 g, 3.09 mmol, yield 94%) as a brown solid; (M-1) = 437.

[0248] The following carboxylic acids were prepared using this procedure:

[0249] [Table 45]

[0250] [Table 46]

[0251] Preparation of intermediate 78: 3-chloro-4-(2-(methylcarbamoyl)-1H-indole-4-yl)benzoic acid [ka] A mixture of N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-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 tripotassium phosphate (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 hour. LC / MS showed that all starting materials were consumed. The reaction mixture was filtered through Celite, and the filter cake was washed with HCl and water. The filtrate was partitioned into water and HCl. The two layers were separated, and the aqueous layer was acidified to pH 2 with 1 M HCl. The resulting solid was collected by suction filtration and dried to obtain 3-chloro-4-(2-(methylcarbamoyl)-1H-indole-4-yl)benzoic acid (1.12 g, 3.41 mmol, >100% yield) as a gray solid; (M+1)=329.

[0252] The following carboxylic acids were prepared using the procedure described for the synthesis of intermediate 78:

[0253] [Table 47]

[0254] [Table 48]

[0255] [Table 49]

[0256] Preparation of intermediate 87: (E)-3-(6-cyclopropyl-2-(methylcarbamoyl)-1H-indole-4-yl)-2-methylacrylic acid [ka] Step 1: Preparation of methyl(E)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate [ka] A mixture of methyl(E)-3-bromo-2-methylpropa-2-enoate (0.179 g, 1.00 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (381 mg, 1.50 mmol), potassium acetate (245 mg, 2.50 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride dichloromethane complex (82 mg, 0.10 mmol) in dry DMSO (10 mL) was stirred at 80°C under N2. After 4 hours, the mixture was cooled to room temperature and poured into water (50 mL). The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were dried on sodium sulfate, concentrated, and purified by flash silica gel column (PE / siRNA 95:5) to obtain methyl(E)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate as crude oil (0.188 g, yield 32%); (M+1)=227.

[0257] Step 2: Preparation of (E)-3-(6-cyclopropyl-2-(methylcarbamoyl)-1H-indole-4-yl)-2-methylacrylic acid The title compound was prepared from 4-bromo-6-cyclopropyl-N-methyl-1H-indole-2-carboxamide (intermediate 28) and methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propa-2-enoate, as described in steps 1-2 for the preparation of intermediate 71; (M+1)=299.

[0258] Preparation of intermediate 88: Methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-yl)-1H-indole-2-carboxylate [ka] Step 1: Preparation of tert-butyl 4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate [ka] In a 250 mL recovery flask equipped with a magnetic stirring bar and an N2 inlet, 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) were added. The solution was treated with N,N-diisopropylethylamine (1.53 mL, 8.72 mmol) and stirred at room temperature. After 75 minutes, LC / MS analysis indicated that the reaction was 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 × 50 mL). The combined organic phase was washed with 25 mL of 2N hydrochloric acid solution, 25 mL of 2M sodium carbonate solution, and 25 mL of brine. The organic phase was dried on magnesium sulfate, filtered, and concentrated to obtain 1.57 g of colorless oil. Chromatographic purification (CombiFlash, 80 g SiO2 gold column, 25-75% ethyl acetate / heptane eluate, combined fractions 13-23, rack 2) yielded 4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate (977 mg, 2.53 mmol, yield 58%) as a white solid; (M+1) = 387.

[0259] Step 2: Preparation of N-(3-(trifluoromethyl)benzyl)piperidine-4-carboxamide [ka] To a 100 mL recovery flask equipped with a magnetic stirring bar and an N2 inlet, tert-butyl 4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-carboxylate (3.01 g, 7.79 mmol) and dichloromethane (20 mL) were added. The solution was treated with trifluoroacetic acid (10 mL, 129.80 mmol) and stirred at room temperature. After 30 minutes, LC / MS analysis indicated that the reaction was 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 obtain N-(3-(trifluoromethyl)benzyl)piperidine-4-carboxamide (2.01 g, 7.02 mmol, 90% yield) as a waxy off-white solid; (M+1)=287.

[0260] Step 3: Preparation of methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate [ka] In a 20 mL microwave reaction vial equipped with a magnetic stirring bar, methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate (691 mg, 1.80 mmol, see International Publication No. 2017152076), N-(3-(trifluoromethyl)benzyl)piperidine-4-carboxamide (634 mg, 2.21 mmol), and methanesulfonate (2-di Cyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (168 mg, 191 μmol), dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (94 mg, 198 μmol), cesium carbonate (1.17 g, 3.60 mmol), and tert-butanol (6 mL) were added. The container was sealed and the contents were heated to 85°C in an oil bath. After 19 hours, the reaction mixture was allowed to cool to room temperature. After 65 hours, LC / MS analysis indicated that the reaction was 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 on magnesium sulfate, filtered, and concentrated to obtain 1.24 g of yellow oil. Chromatographic purification (CombiFlash, 40 g SiO2 gold column, 0-90% ethyl acetate / heptane eluate, combined fractions 45-50, rack 1) yielded methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate (138 mg, 234.00 μmol, yield 13.0%) as a yellow solid; (M+1) = 590.

[0261] Step 4: Preparation of methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-yl)-1H-indole-2-carboxylate Methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate (138 mg, 234 μmol) and dichloromethane (5 mL) were added to a 50 mL recovery flask equipped with a magnetic stirring bar and an N2 inlet. The solution was treated with trifluoroacetic acid (3 mL, 38.94 mmol) and stirred at room temperature. After 1 hour and 45 minutes, LC / MS analysis of the reddish-brown solution indicated that the starting material had been consumed. The mixture was concentrated, and the residue was dissolved in dichloromethane (25 mL). The solution was washed with 5N ammonium hydroxide, dried over magnesium sulfate, filtered, and concentrated to obtain 148 mg of a brown solid. 1H NMR analysis showed that the isolated material was N-hydroxymethylindole, not the desired product. The crude solid was dissolved in methanol (5 mL) and treated with potassium carbonate (approximately 100 mg). The mixture was stirred at room temperature. After 20 minutes, LC / MS analysis indicated that the reaction was complete. The mixture was concentrated, and the residue was partitioned into dichloromethane (15 mL) and water (15 mL). The phases were separated, and the aqueous phase was extracted with dichloromethane (3 × 15 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to obtain methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-yl)-1H-indole-2-carboxylate (89 mg, 193.70 μmol, yield 82.8%) as a brown solid; (M+1) = 460.

[0262] Intermediate 89: Preparation of methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-2,3-dihydro-1H-indene-2-carboxylate [ka] The title compound was prepared from methyl 4-bromo-2,3-dihydro-1H-indene-2-carboxylate (see U.S. Patent Application Publication No. 20080255239) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)benzyl)benzamide (intermediate 43), as described in step 1 for the preparation of intermediate 67; (M+1)=454.

[0263] Preparation of intermediate 90: 4-(2-(methylcarbamoyl)-1H-indole-4-yl)cyclohexane-1-carboxylic acid [ka] Step 1: Preparation of ethyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)cyclohexa-3-ene-1-carboxylate [ka] A mixture of 4-bromo-N-methyl-1H-indole-2-carboxamide (500 mg, 2.00 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-enecarboxylate (1.20 g, 4.00 mmol), palladium(II) acetate (22 mg, 99 μmol), tricyclohexylphosphine (57 mg, 198 μmol), and tripotassium phosphate (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 minutes. LC / MS showed that all starting materials were consumed. Both the product and the acid were observed by LC / MS. The reaction mixture was filtered through Celite, and the filter cake was washed with ethyl acetate. The filtrate was partitioned into water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified on silica gel using heptane / siRNA (80 / 20~0 / 100) to obtain ethyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)cyclohexa-3-en-1-carboxylate (520 mg, 1.59 mmol, yield 80.6%) as a brown, sticky solid; (M+1)=327.

[0264] Step 2: Preparation of 4-(2-(methylcarbamoyl)-1H-indole-4-yl)cyclohexa-3-en-1-carboxylic acid [ka] A suspension of ethyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)cyclohexa-3-en-1-carboxylate (520 mg, 1.60 mmol) in 1N sodium hydroxide solution (5.00 mL, 5.00 mmol), THF (5 mL), and methanol (5 mL) was heated at 40°C for 6 hours. LC / MS showed that all starting materials were consumed and the reaction mixture was homogeneous. The reaction mixture was concentrated under reduced pressure to remove the organic solvent. Water was added, and the solution was adjusted to pH 2 with 1M HCl. The turbid solution was extracted with ELISA (twice). The combined organic extracts were washed with brine, dried on magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 4-(2-(methylcarbamoyl)-1H-indole-4-yl)cyclohexa-3-en-1-carboxylic acid (380 mg, 1.30 mmol, yield 80%) as a beige powder; (M+1)=299.

[0265] Step 3: Preparation of 4-(2-(methylcarbamoyl)-1H-indole-4-yl)cyclohexane-1-carboxylic acid A mixture of 4-(2-(methylcarbamoyl)-1H-indole-4-yl)cyclohexa-3-ene-1-carboxylic acid (90 mg, 302 μmol) and 10% palladium-carbon (30 mg, 282 μmol) in ethyl acetate (10 mL) and ethanol (10 mL) was hydrogenated at room temperature for 1 hour. LC / MS showed that all starting materials were consumed. The reaction mixture was filtered through Celite, and the filter cake was washed with ELISA. The filtrate was concentrated under reduced pressure to obtain 4-(2-(methylcarbamoyl)-1H-indole-4-yl)cyclohexane-1-carboxylic acid (78 mg, 260 μmol, yield 86%) as a beige powder; (M+1)=301.

[0266] Preparation of intermediate 91: 4-(4-((2-fluoro-5-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylic acid [ka] Step 1: Preparation of ethyl 4-(4-((2-fluoro-5-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylate [ka] The title compound was prepared from 4-(2-(ethoxycarbonyl)-1H-indole-4-yl)benzoic acid (intermediate 70) and (2-fluoro-5-(trifluoromethyl)phenyl)methaneamine, as described in step 1 for the synthesis of intermediate 88; (M+1)=485.

[0267] Step 2: Preparation of 4-(4-((2-fluoro-5-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylic acid The title compound was prepared from ethyl 4-(4-((2-fluoro-5-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylate as described in step 2 for the synthesis of intermediate 90; (M+1)=457.

[0268] Intermediate 92: Preparation of ethyl 5,6-difluoro-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxylate [ka] The title compound was prepared from ethyl 4-bromo-5,6-difluoro-1H-indole-2-carboxylate (intermediate 5) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(3-(trifluoromethyl)benzyl)benzamide (intermediate 43), as described in step 1 for the synthesis of intermediate 67; (M+1)=503.

[0269] Preparation of intermediate 93: 4-bromo-N-methylisoindoline-2-carboxamide [ka] 4-bromoisoindoline hydrochloride (255 mg, 1.03 mmol, CAS 923590-95-8), N,N-diisopropylethylamine (500 μL, 2.84 mmol), and acetonitrile (5 mL) were added to a 50 mL recovery flask equipped with a magnetic stirring bar and an N2 inlet. The mixture was treated with methyl isocyanate (70 mg, 1.23 mmol). After 5 minutes, a precipitate began to form. After 20 minutes, LC / MS analysis indicated that the reaction was complete. The mixture was diluted with water (30 mL), and the resulting suspension was filtered. The filtered cake was washed with water (15 mL), and the wet solid was dissolved in ethyl acetate (30 mL). The solution was dried over magnesium sulfate, filtered, and concentrated to obtain 4-bromo-N-methylisoindoline-2-carboxamide (213 mg, 835 μmol, yield 81%) as a gray solid; (M+1) = 255.

[0270] Preparation of Intermediate 94: N-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] The title compound was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and benzylamine, as described in the preparation of intermediate 43; (M+1)=338.

[0271] Preparation of intermediate 95: N-benzyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] Step 1: Preparation of N-benzyl-4-bromo-3,5-dimethylbenzamide [ka] To a solution of 4-bromo-3,5-dimethylbenzoic acid (90 mg, 0.39 mmol) in dichloromethane (5 mL), benzylamine (46 mg, 0.43 mmol), HATU (224 mg, 0.59 mmol), and triethylamine (0.137 mL, 0.98 mmol) were added. The resulting mixture was stirred overnight at room temperature. The mixture was then diluted with water, and the organic layer was separated. The aqueous layer was extracted with dichloromethane, and the combined organic phases were washed with brine, dried, and concentrated to obtain N-benzyl-4-bromo-3,5-dimethylbenzamide as a colorless oil (120 mg, 0.37 mmol, yield 96%). LCMS: 318.0, 320.0 (M+1).

[0272] Step 2: Preparation of N-benzyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide 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-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan, as described in the preparation of intermediate 41; (M+1)=366.

[0273] Preparation of intermediate 96: 4-(2-carbamoyl-1H-indole-4-yl)benzoic acid [ka] The title compound was prepared from 4-bromo-1H-indole-2-carboxamide (CAS 955978-73-1) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, as described in the preparation of intermediate 71; (M+1)=281.

[0274] Preparation of intermediate 97: 4-(2,6-dimethyl-4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-7-fluoro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid [ka] The title compound was prepared from methyl 4-chloro-7-fluoro-1H-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 in the preparation of intermediate 71; (M+1)=486. [Examples]

[0275] Preparation of Examples Example 1: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide [ka] In a 500 mL round-bottom flask equipped with a magnetic stirring bar, reflux condenser, and N2 inlet, 4-bromo-N-methyl-1H-indole-2-carboxamide (3.77 g, 14.9 mmol, intermediate 12), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[[3-(trifluoromethyl)phenyl]methyl]benzamide (7.50 g, 19.0 mmol, intermediate 43), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride 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) were added. The mixture was degassed under reduced pressure and backfilled with N2 (×3). Next, the mixture was heated to 100°C in an oil bath. After 1 hour, LC / MS analysis indicated that the reaction was complete. The mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with ethyl acetate (50 mL). The resulting two-phase mixture was filtered through Celite, and the filter cake was washed with ethyl acetate (40 mL). The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated to obtain a brown oil. Chromatographic purification (CombiFlash, 330 g SiO2 gold column, 25-70% 3:1 ethyl acetate:ethanol / heptane eluate, combined fractions 24-30, racks 1 and 1-5, rack 2) yielded N-methyl-4-[4-[[3-(trifluoromethyl)phenyl]methylcarbamoyl]phenyl]-1H-indole-2-carboxamide (4.74 g, 10.5 mmol, yield 71%) as a white solid; 1 H NMR(400MHz,DMSO-d6)δ 11.81(s,1H),9.26(t,J=5.9Hz,1H),8.50(q,J=4.5Hz,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=7.3,1.0Hz,1H),4.63(d,J=5.9Hz,2H),2.81(d,J=4.5Hz,3H)ppm;(M+1)=452.

[0276] The following compounds were prepared as described for the synthesis of Example 1:

[0277] [Table 50]

[0278] [Table 51]

[0279] [Table 52]

[0280] [Table 53]

[0281] [Table 54]

[0282] [Table 55]

[0283] [Table 56]

[0284] [Table 57]

[0285] [Table 58]

[0286] [Table 59]

[0287] Table 60

[0288] Table 61

[0289] Table 62

[0290] Table 63

[0291] Table 64

[0292] Table 65

[0293] Table 66

[0294] Table 67

[0295] Table 68

[0296] Table 69

[0297] [Table 70]

[0298] Example 47: Preparation of 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide [ka] In a 50 mL recovery flask equipped with a magnetic stirring bar and an N2 inlet, 4-(2-carbamoyl-1H-indole-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) were added. The solution was treated with N,N-diisopropylethylamine (122 μL, 699 μmol) and stirred at room temperature. After 30 minutes, LC / MS analysis indicated that the reaction was complete. The yellow solution was diluted with water (25 mL), and the resulting precipitate was isolated by filtration. The filtration cake was washed with water (25 mL), and the wet 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 obtain 154 mg of yellow oil. Chromatographic purification (CombiFlash, 12 g SiO2 gold column, eluate of 50% ethyl acetate / heptane to 100% ethyl acetate, combined fractions 3-8, rack 1) yielded 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide (99 mg, 226 μmol, yield 65%) as a foamy white solid; 1H NMR(400MHz,DMSO-d6)δ 11.74(s,1H),9.23(t,J=5.9Hz,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=5.9Hz,2H)ppm;(M+1)=438.

[0299] The following compounds were prepared as described for the synthesis of Example 47:

[0300] [Table 71]

[0301] [Table 72]

[0302] [Table 73]

[0303] [Table 74]

[0304] [Table 75]

[0305] [Table 76]

[0306] [Table 77]

[0307] [Table 78]

[0308] Table 79

[0309] Table 80

[0310] Table 81

[0311] Table 82

[0312] Table 83

[0313] Table 84

[0314] Table 85

[0315] Table 86

[0316] Table 87

[0317] Table 88

[0318] [Table 89]

[0319] [Table 90]

[0320] [Table 91]

[0321] [Table 92]

[0322] [Table 93]

[0323] [Table 94]

[0324] [Table 95]

[0325] Example 97: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-yl)-1H-indole-2-carboxamide [ka] Methyl 4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-yl)-1H-indole-2-carboxylate (89 mg, 194 μmol, intermediate 88) and a 33% methylamine solution in ethanol (4 mL, 32.13 mmol) were added to a 5 mL microwave reaction vial equipped with a magnetic stirring bar. The container was sealed and the contents were heated to 100°C in a microwave reactor. After 30 minutes, LC / MS analysis indicated that the reaction was not complete. The mixture was subjected to another heating cycle in a microwave reactor (125°C). After 30 minutes, LC / MS analysis indicated that the reaction was nearly complete. The brown mixture was concentrated to obtain a brown oil. Chromatographic purification (CombiFlash, 12g SiO2 gold column, 1-5% methanol / dichloromethane eluate, combined fractions 27-31, rack 1) yielded N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-1-yl)-1H-indole-2-carboxamide (26mg, 57μmol, yield 29%) as a brown solid; 1 H NMR(400MHz,DMSO-d6)δ 11.45(s,1H),8.51(t,J=5.9Hz,1H),8.40(q,J=4.6Hz,1H),7.65-7.56(m,4H),7.16(d,J=2.3Hz,1H),7.08-6.99(m,2H),6.46(dd,J=5.9,2.3Hz ,1H),4.40(d,J=5.9Hz,2H),3.70-3.60(m,2H),2.81(d,J=4.6Hz,3H),2 .76-2.64(m,2H),2.48-2.37(m,1H),2.00-1.85(m,4H)ppm;(M+1)=459.

[0326] The following compounds were prepared as described for the synthesis of Example 97:

[0327] [Table 96]

[0328] Example 100: Preparation of N-methyl-4-((1r,4r)-4-((3-(trifluoromethyl)benzyl)carbamoyl)cyclohexyl)-1H-indole-2-carboxamide [ka] A mixture of 4-(2-(methylcarbamoyl)-1H-indole-4-yl)cyclohexane-1-carboxylic acid (78 mg, 260 μmol, intermediate 90), 3-(trifluoromethyl)benzylamine (46 μL, 312 μmol), HATU (153 mg, 390 μmol), and N,N-diisopropylethylamine (136 μL, 779 μmol) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 3 hours. LC / MS showed that all starting materials were consumed. The reaction mixture was partitioned into water and Et2O. The two layers were separated, and the aqueous layer was extracted once with Et2O. The combined organic layers were washed with water, 1 M HCl, saturated NaHCO3, and brine, dried over MgSO4, filtered, and concentrated. The crude material was purified on silica gel using CH2Cl2 / siRNA (80 / 20~0 / 100) as an eluent to obtain N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)cyclohexyl)-1H-indole-2-carboxamide (69 mg, 150.82 μmol, yield 58.1%) as a white powder (a mixture of cis and trans isomers). The mixture was separated by HPLC to obtain N-methyl-4-((1r,4r)-4-((3-(trifluoromethyl)benzyl)carbamoyl)cyclohexyl)-1H-indole-2-carboxamide (21 mg, 70 μmol, yield 28%); 1H 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=7.7Hz,1H),6.87(d,J=7.2Hz,1H),4.39(d,J (M+1)=458.

[0329] Example 101: Preparation of N-methyl-4-(1-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-4-yl)-1H-indole-2-carboxamide [ka] Step 1: Preparation of tert-butyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] 4-bromo-1H-indole-2-carboxamide (915 mg, 3.83 mmol), N-boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.37 g, 4.21 mmol), palladium(II) acetate (43 mg, 191 μmol), tricyclohexylphosphine (110 mg, 383 μmol), tripotassium phosphate (2.49 g, 11.48 mmol), 1,4-dioxane (10 mL), and water (5 mL) were added to a 20 mL microwave reaction vial equipped with a magnetic stirring bar. The container was sealed and the contents were heated to 125°C in a microwave reactor. After 30 minutes, LC / MS analysis indicated that the reaction was nearly 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 25 mL of 2N hydrochloric acid solution and 25 mL of saturated potassium carbonate solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated to obtain 1.66 g of a yellow solid. Chromatographic purification (CombiFlash, 40 g SiO2 gold column, 50-80% ethyl acetate / heptane eluate, combined fractions 6-15, rack 1) yielded tert-butyl 4-(2-carbamoyl-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.22 g, 3.57 mmol, yield 93.4%) as a white solid; (M-1) = 354.

[0330] Step 2: Preparation of tert-butyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)piperidine-1-carboxylate [ka] In a 200 mL recovery flask equipped with a magnetic stirring bar and a three-way stopcock, tert-butyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.19 g, 3.35 mmol), 10% palladium carbon (1.12 g, 1.05 mmol), and tetrahydrofuran (40 mL) were added. The mixture was degassed under reduced pressure and backfilled with N2 (×3). After final elimination, the atmosphere was replaced with hydrogen (via a balloon), and the mixture was stirred at room temperature. After 45 minutes, LC / MS analysis indicated that the reaction was complete. The atmosphere was replaced with N2, and the mixture was filtered through Celite with ethyl acetate (100 mL). The filtrate was concentrated to obtain tert-butyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)piperidine-1-carboxylate (1.13 g, 3.16 mmol, yield 94%) as an off-white solid; (M-1) = 356.

[0331] Step 3: Preparation of N-methyl-4-(piperidine-4-yl)-1H-indole-2-carboxamide [ka] 1.13 g, 3.16 mmol of tert-butyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)piperidine-1-carboxylate and 20 mL of dichloromethane were added to a 20 mL microwave reaction vial equipped with a magnetic stirring bar. The suspension was treated with 10 mL, 130 mmol of trifluoroacetic acid to form a homogeneous red solution. After 30 minutes, LC / MS analysis indicated that the reaction was complete. The mixture was concentrated, and the residue was dissolved in 30 mL of water. The yellow solution was treated with 10 mL of concentrated ammonium hydroxide solution to form a precipitate. The mixture was filtered, the solid was washed with water (25 mL), and dried to obtain N-methyl-4-(piperidine-4-yl)-1H-indole-2-carboxamide (800 mg, 3.11 mmol, yield 98%) as an off-white solid; (M+1) = 258.

[0332] Step 4: Preparation of N-methyl-4-((1r,4r)-4-((3-(trifluoromethyl)benzyl)carbamoyl)cyclohexyl)-1H-indole-2-carboxamide N-methyl-4-(piperidine-4-yl)-1H-indole-2-carboxamide (150 mg, 582.89 μmol) and acetonitrile (5 mL) were added to a 50 mL recovery flask equipped with a magnetic stirring bar and an N2 inlet. The suspension was treated with 1-(isocyanatomethyl)-3-(trifluoromethyl)benzene (130 mg, 612 μmol). The mixture was heated with a heat gun until a homogeneous solution was obtained (approximately 1 minute), and the resulting solution was stirred. After 45 minutes, a white precipitate formed, and LC / MS analysis indicated that the reaction was complete. The mixture was filtered. The filtered cake was washed with acetonitrile (10 mL) and dried to obtain a white solid. Chromatographic purification (CombiFlash, 12g SiO2 gold column, 0-20% methanol / dichloromethane eluate, combined fractions 1-5, rack 1) yielded N-methyl-4-(1-((3-(trifluoromethyl)benzyl)carbamoyl)piperidine-4-yl)-1H-indole-2-carboxamide (120mg, 262μmol, yield 45%) as a white solid; 1H NMR(400MHz,DMSO-d6)δ 11.53(s,1H),8.44(q,J=4.6Hz,1H),7.68-7.51(m,4H),7.32-7.20(m,3H),7.10(dd,J=8.2,7.1Hz,1H),6.84(d,J=7.1Hz,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=4.6Hz,3H),1.92-1.82(m,2H),1.73-1.59(m,2H)ppm;(M+1)=459.

[0333] Example 102: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperazin-1-yl)-1H-indole-2-carboxamide [ka] Step 1: Preparation of benzyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)piperazine-1-carboxylate [ka] A 20 mL microwave reaction vessel equipped with a stirring bar was filled 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 overnight at 50°C. Subsequently, LC-MS analysis showed that the reaction was incomplete. An additional volume of 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 obtain the crude product as a foamy brown solid (0.969 g, 107%), which was used in the next reaction after purification; (M+1)=393.

[0334] Step 2: Preparation of N-methyl-4-(piperazin-1-yl)-1H-indole-2-carboxamide hydrochloride [ka] 0.735 g, 1.87 mmol of benzyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)piperazine-1-carboxylate (0.735 g, 1.87 mmol) was added to a stirred solution of benzyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)piperazine-1-carboxylate in a mixture of methanol (15 mL) and 1.0 N hydrochloric acid (2.0 mL, 1.07 equivalents). 10% palladium carbon (0.150 g) was added. The suspension was cycled three times between vacuum and a nitrogen atmosphere. The container was finally evacuated and then backfilled with hydrogen. After stirring for 1 hour, the reactants were removed and then opened to air. LC-MS analysis indicated that the reaction was nearly complete. Further amounts of 1.0 N hydrochloric acid (2.0 mL, 1.07 equivalents) and catalyst (0.050 g) were added, and the reaction was restarted as before. After 45 minutes under hydrogen, the reactants were opened to air, and the suspension was filtered by suction through a short Celite column. The reaction flask and filter media were rinsed with methanol, and the combined filtrate was concentrated to obtain N-methyl-4-(piperazin-1-yl)-1H-indole-2-carboxamide hydrochloride as a light brown solid (0.531 g, yield 96%); (M+1)=259.

[0335] Step 3: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperazin-1-yl)-1H-indole-2-carboxamide To a stirred and cooled (0°C) solution of 1,1'-carbonyldiimidazole (0.076 g, 0.469 mmol) in dichloromethane (8 mL), a solution of 3-(trifluoromethyl)benzylamine (0.082 g, 0.47 mmol) in dichloromethane (2 mL) was added. After 15 minutes at 0°C, N-methyl-4-(piperazin-1-yl)-1H-indole-2-carboxamide hydrochloride (0.115 g, 0.39 mmol), followed by N,N-diisopropylethylamine (82 μL, 0.468 mmol) and N-hydroxysuccinimide (0.054 g, 0.47 mmol) were added. The reaction vessel was sealed and heated in a microwave reactor at 60°C for 1 hour. After cooling to room temperature, the mixture was partitioned into chloroform (20 mL) and diluted sodium carbonate aqueous solution (30 mL). The organic layer was combined with an additional extract (chloroform, 1 × 20 mL), dried over sodium sulfate, and concentrated on approximately 4 g of silica. The impregnated medium was subjected to automated flash chromatography (Combiflash Rf instrument; 10-45% 3:1 ethyl acetate / ethanol solution in heptane; 80 g Gold silica column) to obtain a partially purified product as a foamy brown solid. This material was further purified by automated reverse-phase flash chromatography (InterChim PuriFlash XS420 system; 30-100% acetonitrile in water containing 0.1% formic acid; 55 g InterChim C18 column; sample packed as solution in DMSO) to obtain N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)piperazin-1-yl)-1H-indole-2-carboxamide as a white solid (0.081 g, 45%); 1 H NMR(400MHz,CD3OD)δ 7.66-7.46(m,4H),7.21-7.09(m,3H),6.61(dd,J=6.2,2.2Hz,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.

[0336] Example 103: Preparation of 3-chloro-N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide [ka] To a 20 ml vial, a stirring 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) were added. The mixture was sonicated for a short time and then stirred at room temperature. After 20 minutes, the mixture was heated to 55 °C. The reaction was held at this temperature for 3 hours and then heated to 140 °C. After 20 minutes at this temperature, the mixture was cooled to room temperature and diluted with water (30 mL). The mixture was extracted with dichloromethane (3 × 20 mL), the combined organic phase was dried over sodium sulfate, filtered, and concentrated to obtain a brown oil. The crude material was purified by silica gel chromatography (0-40% 3:1 ethyl acetate:ethanol / heptane eluate) to obtain 3-chloro-N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide (0.032 g, 64 μmol, yield 53%) as a white solid; 1 H NMR(400MHz,DMSO-d6)δ 12.16(s,1H),9.24(t,J=5.9Hz,1H),8.01-7.93(m,2H),7.91(q,J=4.6Hz,1H),7.74-7.51(m,7H),7.34(dd, (M+1)=486.

[0337] Example 104: Preparation of N,3-dimethyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide [ka] Step 1: Preparation of 3-bromo-N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide [ka] To a 20 mL vial, a stirring 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) were added. The mixture was sonicated for a short time and then stirred overnight at room temperature. The brown mixture was diluted with water (20 mL), sonicated, and a precipitate was formed. The mixture was filtered, the filter cake was washed with water (20 mL), and dried to obtain 3-bromo-N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide (240 mg, 452 μmol, yield 96%) as a white solid; (M+1) = 530.

[0338] Step 2: Preparation of N,3-dimethyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide 3-bromo-N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide (240 mg, 452 μmol), tripotassium phosphate (288 mg, 1.36 mmol), XPhos Pd G4 (22 mg, 26 μmol), and a 4:1 mixture of 1,4-dioxane / water (2.5 mL) were added to a 5 mL microwave reaction vial equipped with a magnetic stirring bar. The mixture was degassed under reduced pressure and backfilled with 2x N2, then trimethylboroxine (160.10 μL, 1.13 mmol) was added. The resulting dark-colored mixture was heated to 140 °C, and after 25 minutes, the organic layer of the reaction mixture was directly packed into Celite, and the aqueous phase of the reaction mixture was extracted with dichloromethane (5 mL). This solution was also packed into Celite. The Celite pad was dried, and the crude material was purified by silica gel chromatography (0-40% 3:1 ethyl acetate:ethanol / heptane eluate) to obtain N,3-dimethyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-1H-indole-2-carboxamide (15 mg, 25 μmol, yield 6%) as an off-white solid; 1 H NMR(400MHz, 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=8.3,1.0Hz ,1H),7.25(dd,J=8.3,7.1Hz,1H),6.89(dd,J=7.1,1.0Hz,1H),4.68(s,2H),2.93(s,3H),2.04(s,3H)ppm;(M+1)=466.

[0339] Example 105: Preparation of N-methyl-4-(1-((3-(trifluoromethyl)benzyl)amino)isoquinoline-6-yl)-1H-indole-2-carboxamide [ka] Step 1: Preparation of 4-(1-chloroisoquinoline-6-yl)-N-methyl-1H-indole-2-carboxamide [ka] A 20 mL microwave reaction vial filled with 6-bromo-1-chloroisoquinoline (50 mg, 206 μmol, CAS 205055-63-6), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-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) was degassed with nitrogen. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (12 mg, 14 μmol) was added to the reaction mixture. The reaction mixture was heated at 100 °C. LC-MS showed the desired product as the major component. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and 1 M HCl. The two-phase mixture was filtered, and the filtrate was separated. The organic layer was washed with 1 M HCl. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was taken up in MeOH, and the resulting precipitate was isolated by vacuum filtration. The solid was air-dried to obtain 4-(1-chloroisoquinoline-6-yl)-N-methyl-1H-indole-2-carboxamide (20 mg, 60 μmol, yield 29%); (M+1)=336.

[0340] Step 2: Preparation of N-methyl-4-(1-((3-(trifluoromethyl)benzyl)amino)isoquinoline-6-yl)-1H-indole-2-carboxamide A 5 mL microwave reaction vial filled with 4-(1-chloroisoquinoline-6-yl)-N-methyl-1H-indole-2-carboxamide (20 mg, 60 μmol), (3-(trifluoromethyl)phenyl)methaneamine (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 mixture. The reaction mixture was stirred overnight at 100 °C. The reaction mixture was diluted with HCl and 1 M HCl. The phases were separated, and the organic layer was washed with 1 M HCl and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was added to 2 mL of methanol and injected into a C18 RP HPLC. N-methyl-4-(1-((3-(trifluoromethyl)benzyl)amino)isoquinoline-6-yl)-1H-indole-2-carboxamide was obtained as an off-white solid (8 mg, 16 μmol, yield 27%) by elution from 15% to 80% acetonitrile:water (0.1% formic acid modifier). 1 H NMR(400MHz, methanol-d4)δ 8.32(d,J=8.6Hz,1H),8.02(d,J=1.8Hz,1H),7.88(dd,J=8.6,1.8Hz,1H),7.79(d,J=6.0Hz,1H),7.74-7.70(m,1H),7.68(d,J= 7.2Hz,1H),7.57-7.48(m,3H),7.36(dd,J=8.2,7.2Hz,1H),7.31-7.26(m, 2H),7.07(dd,J=6.1,0.8Hz,1H),4.90(s,2H),2.91(s,3H)ppm;(M+1)=475.

[0341] Example 106: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)bicyclo[2.2.2]octan-1-yl)-1H-indole-2-carboxamide [ka] Step 1: Preparation of methyl 4-(2-(methylcarbamoyl)-1H-indole-4-yl)bicyclo[2.2.2]octane-1-carboxylate [ka] 4-bromo-N-methyl-1H-indole-2-carboxamide (500 mg, 1.98 mmol, intermediate 12), methyl 4-bromovicyclo[2.2.2]octane-1-carboxylate (725 mg, 2.79 mmol, CAS 23062-51-3), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (25 mg, 0.022 mmol, CAS 870987-63-6), 2,6-lutidine (0.43 mL, 3.7 mmol), tris(trimethylsilyl)silane (0.66 mL, 2.1 mmol), and DME (10 mL) were added to reaction vial #1. In a separate reaction vial #2, 4,4'-di-tert-butyl-2,2'-dipyridyl (52 mg, 0.19 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (45 mg, 0.20 mmol), and DME (5 mL) were added. The mixture obtained in vial #2 was stirred at room temperature for 15 minutes to obtain a pale green solution. This solution was then added to vial #1. The mixture obtained in vial #1 was aerated with nitrogen for 15 minutes. The reaction mixture was sealed and irradiated in a photoreactor (HepatoChem EvoluChem PhotoRedOx Box device, blue light source - Kessil 35W) for 45 hours. The reaction mixture was diluted with water and ethyl acetate. The resulting mixture was vigorously stirred for 10 minutes. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude material again, which was purified by reverse-phase preparative HPLC (gradient from 30% MeCN in water to 65% MeCN in water, Sunfire C18 30×150 dimension column, Teledyne Isco ACCQPrep HP125 containing 5um). The fractions containing the desired product were combined and concentrated under reduced pressure until the MeCN evaporated. To the residual aqueous layer, siRNA and solid sodium carbonate were added until the aqueous layer became basic. The resulting mixture was stirred for 10 minutes. The organic layer was separated, washed with saturated aqueous NaHCO3 (2×), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain methyl 4-[2-(methylcarbamoyl)-1H-indole-4-yl]bicyclo[2.2.2]octane-1-carboxylate (66 mg, 0.18 mmol, yield 9%) as a yellow solid; (M+1)=341.

[0342] Step 2: Preparation of 4-(2-(methylcarbamoyl)-1H-indole-4-yl)bicyclo[2.2.2]octane-1-carboxylic acid [ka] A suspension of methyl 4-[2-(methylcarbamoyl)-1H-indole-4-yl]bicyclo[2.2.2]octane-1-carboxylate (109 mg, 0.32 mmol) in THF-MeOH (1 mL / 3 mL) was added dropwise to a 2 M aqueous solution of lithium hydroxide (0.32 mL, 0.64 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then heated at 45 °C for 23 hours. A considerable amount of starting material remained. The reaction mixture was heated further at 55 °C for 28 hours. The reaction mixture was cooled to room temperature and acidified to pH 2-3 with a 2 M aqueous solution of hydrochloric acid (0.32 mL, 0.64 mmol). The resulting mixture was diluted with water and then extracted with ELISA (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 4-[2-(methylcarbamoyl)-1H-indole-4-yl]bicyclo[2.2.2]octane-1-carboxylic acid (104 mg, 0.32 mmol, 99% yield) as a yellow solid; (M+1)=327.

[0343] Step 3: Preparation of N-methyl-4-(4-((3-(trifluoromethyl)benzyl)carbamoyl)bicyclo[2.2.2]octan-1-yl)-1H-indole-2-carboxamide At room temperature, EDCI (36 mg, 0.19 mmol) was added to a solution of 4-[2-(methylcarbamoyl)-1H-indole-4-yl]bicyclo[2.2.2]octane-1-carboxylic acid (40 mg, 0.12 mmol) and HOBt (25 mg, 0.18 mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature for 1 hour. 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 hours. The acid starting material still remained. To this mixture, N,N-diisopropylethylamine (0.050 mL, 0.29 mmol), followed by HATU (61 mg, 0.16 mmol), was added. The resulting mixture was stirred at room temperature for a further 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude material was diluted with toluene. The organic layer was washed with saturated aqueous NaHCO3 (2×), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude material, which was purified by reverse-phase preparative HPLC (gradient from 35% MeCN in water to 70% MeCN in water, Sunfire C18 30×150 dimension column, Teledyne Isco ACCQPrep HP125 containing 5 μm). The fractions containing the desired product were combined and concentrated under reduced pressure until the MeCN evaporated. To the residual aqueous layer, toluene and solid sodium carbonate were added until the aqueous layer became basic. The resulting mixture was stirred for 10 minutes. The organic layer was separated, washed with saturated NaHCO3 (2×) aqueous solution, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain N-methyl-4-[4-[[3-(trifluoromethyl)phenyl]methylcarbamoyl]-1-bicyclo[2.2.2]octanyl]-1H-indole-2-carboxamide (50 mg, 0.10 mmol, yield 84%) as a yellow solid; 1HNMR(400MHz,DMSO-d6)δ 11.53(s,1H),8.47-8.36(m,1H),8.18(t,J=6.0Hz,1H),7.64-7.50(m,4H),7.44(dd,J=2.2,0.9Hz,1H),7.27(d,J=8.2Hz,1H),7.06(dd,J=8. (M+1)=484.

[0344] Example 107: Preparation of 4-(4-(benzylcarbamoyl)-1H-pyrazole-1-yl)-6-cyclopropyl-N-methyl-1H-indole-2-carboxamide [ka] Step 1: Preparation of methyl 1-(6-cyclopropyl-2-(methylcarbamoyl)-1H-indole-4-yl)-1H-pyrazole-4-carboxylate [ka] A mixture of 1,4-dioxane (1 mL), 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 copper(I) iodide (0.003 g, 0.017 mmol) was stirred in a sealed tube at 110°C under N2 for 48 hours. The mixture was concentrated and purified by flash silica gel column (DCM / MeOH 50:1~20:1) to obtain methyl 1-[6-cyclopropyl-2-(methylcarbamoyl)-1H-indole-4-yl]pyrazole-4-carboxylate as a brown oil (0.07 g, 0.160 mmol, yield 47%); (M+1)=339.

[0345] Step 2: Preparation of 1-(6-cyclopropyl-2-(methylcarbamoyl)-1H-indole-4-yl)-1H-pyrazole-4-carboxylic acid [ka] A mixture of methyl 1-[6-cyclopropyl-2-(methylcarbamoyl)-1H-indole-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 hours, the mixture was concentrated to obtain a yellow oil; (M+1) = 325.

[0346] Step 3: Preparation of 4-(4-(benzylcarbamoyl)-1H-pyrazole-1-yl)-6-cyclopropyl-N-methyl-1H-indole-2-carboxamide A mixture of 1-[6-cyclopropyl-2-(methylcarbamoyl)-1H-indole-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 hours, the mixture was purified by flash silica gel column (DCM / MeOH 20:1) to obtain crude oil. The oil was purified by flush C18 gel column (H2O, NH4HCO3 with 0%-80% MeOH) to obtain 4-[4-(benzylcarbamoyl)pyrazole-1-yl]-6-cyclopropyl-N-methyl-1H-indole-2-carboxamide as a white solid (0.025 g, 0.060 mmol, yield 29%); 1HNMR (400 MHz, DMSO-d6)δ 11.76(s,1H),8.88(s,1H),8.80(t,J=6.0Hz,1H),8.56(q,J=4.4Hz,1H),8. 24(s,1H),7.42(d,J=1.6Hz,1H),7.40-7.35(m,4H),7.28-7.25(m,1H),7.1 9(s,1H),7.07(d,J=1.2Hz,1H),4.49(d,J=6.0Hz,2H),2.79(d,J=4.4Hz,3H ),2.09-2.06(m,1H),1.01-0.97(m,2H),0.77-0.74(m,2H)ppm;(M+1)=414.

[0347] Determination of in vitro activity compared to human and mouse SLC6A19 Cell Culture: Unless otherwise specified, all cell culture materials were purchased from ThermoFisher Scientific (Waltham, MA, USA). MDCK cells (NBL-2; ATCC, Manassas, VA, USA) stably expressing human SLC6A19+TMEM27 were produced in-house and cultured in DMEM containing 10% fetal bovine serum supplemented with 5 μg / mL blastosidine and puromycin. Similar stable cell lines were created in an MDCK background expressing the mouse version of the transporter, mSLC6a19, and its cofactor mTMEM27. All experiments described herein were performed using cells that had undergone fewer than five passages.

[0348] Test compound recovery: The test compounds were obtained as a 10 mM DMSO stock solution in a source plate. An appropriate amount of stock solution was plated into a 384-well assay plate for testing in an uptake assay using an ECHO 555 Liquid Handler (Labcyte Inc., San Jose, California, USA). Assay buffer was added to dissolve the compounds, achieving a final test concentration of 10 μM and a 0.1% v / v DMSO concentration for each compound.

[0349] Stable Isotope Intake Assay: MDCK cells stably expressing hSLC6A19+hTMEM27 were plated at a density of 2,200 cells / well in a poly-d-lysine coated black transparent bottom 384-well microplate (Corning Life Sciences, Corning, NY, USA) and incubated for 48 hours in a humidified 37°C 95% / 5% air / CO2 incubator. After incubation, the culture medium was aspirated and the cells were washed twice with HBSS. The cells were incubated with 20 μM (2x) of the 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, and then 2 mM of the test compound in assay buffer. 13 C6, 15 NL-isoleucine (Sigma Aldrich, St. Louis, MO, USA) was added and incubated for a further 20 minutes. One column (16 wells) in each plate was dedicated to the positive control for inhibition (2 mM substrate). 13 C6, 15 Two columns (32 wells) were pre-incubated with a saturated concentration of an internally identified specific SLC6a19 reference inhibitor before adding NL-isoleucine (0% transporter activity or 100% inhibition), and were dedicated to negative controls (2 mM for the uptake assay without the reference inhibitor). 13 C6, 15 NL-Isoleucine) (100% transporter activity or 0% inhibition). One column (16 wells) was dedicated to transporting the reference inhibitor in a dose-response manner (8 concentrations in duplicate). The solution was then aspirated, and the cells were washed 6 times with cold assay buffer, with most of the liquid aspirated. The plate was air-dried and subjected to a freeze-thaw cycle to lyse the cells. 30 μL / well of extraction buffer (10% methanol, 1% formic acid, 250 nM L-leucine-1- 13C and cell dissociation buffer were added, the plate was shaken for 5 minutes, incubated at 37°C for 15-20 minutes, and then an additional 60 μL of extraction buffer was added per well. 80 μL of cell extract was clarified by centrifugation through an AcroPrep 384-well, 30K cutoff filtration plate (Pall Corporation, Port Washington, NY, USA). The clarified cell extract was analyzed using a ThermoFisher LX-4 chromatograph coupled to an ABsciex API-4000 triple quadrupole mass spectrometer (Sciex, Framingham, MA, USA). A Waters Acquity UPLC BEH 2.1 × 30 mm C18 chromatography column (Waters Corporation, Milford, MA, USA) was used, with mobile phases A and B being water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid, respectively. The column was kept at room temperature, and the sample injection size was 5 μL. Chromatography was performed at a flow rate of 0.5 mL / min, with the initial condition being 95% mobile phase A. The 95% mobile phase A condition was held for 12 seconds after injection, followed by a 6-second gradient to 50% mobile phase A, and held for 10 seconds before returning to the initial condition. An ABsciex API-4000 mass spectrometer was used with a collision energy of 16 eV to analyze L-leucine-1- 13 Regarding C, the transition from 133 to 86 m / z and 13 C6, 15 NL-isoleucine was manipulated in positive mode to monitor the transition from 139 to 92 m / z. 13 C6, 15 The peak area of ​​NL-isoleucine is used as an internal standard for L-leucine-1- 13 Normalized to C. Z' for each plate was determined using the mean and standard deviation obtained from negative and positive controls, using the standard formula: Z' = 1 - [3(SDNeg + SDPos) / (mean Pos - mean Neg)]. Only plates with Z' > 0.4 were accepted. Dose-response curves and IC of the reference compound obtained from each plate were also analyzed. 50We tracked the assay performance across the entire plate and evaluated its reproducibility. The MDCK cell line was expressed in mSLC6a19+mTMEM27 and at a final concentration of 4 mM. 13 C6, 15 The compounds were evaluated for their activity against mouse transporters using the same protocol as above, except that NL-isoleucine was replaced.

[0350] Data analysis software: Dose-response data were plotted using a 4-parameter variable gradient equation provided by the curve fitting program Prism (GraphPad Software, La Jolla, CA), which does not impose constraints above or below the curve. The equation is of the form: Y = base + (upper - base) / (1 + 10^((LogIC50 - X) × HillSlope)). Screening data were visualized using SpotFire (Tibco Software, Inc., Palo Alto, CA, USA).

[0351] [Table 97]

[0352] [Table 98]

[0353] [Table 99]

[0354] [Table 100]

[0355] [Table 101]

[0356] Other embodiments are within the scope of the following claims.

[0357] Numbered Embodiments 1. Compounds of the formula: [ka] (In the formula, R1 and R2 are selected independently from H or CH3; Each R3 is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, and at least two of the R3s are H. or a pharmaceutically acceptable salt thereof.

[0358] 2. The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R1 is CH3 and R2 is H.

[0359] 3. A compound according to any one of Embodiments 1 to 2, or a pharmaceutically acceptable salt thereof, wherein at least one R3 is F.

[0360] 4. The compound is, formula: [ka] A compound according to any of the embodiments described above, or a pharmaceutically acceptable salt thereof.

[0361] 5. The compound is, formula: [ka] The compound according to Embodiment 3, or a pharmaceutically acceptable salt thereof, represented by [formula].

[0362] 6. The compound is, formula: [ka] The compound according to Embodiment 3, or a pharmaceutically acceptable salt thereof, represented by [formula].

[0363] 7. The compound according to Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein at least one R3 is Cl.

[0364] 8. The compound is, formula: [ka] The compound described in Embodiment 7, or a pharmaceutically acceptable salt thereof, represented by [formula].

[0365] 9. The compound according to Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein at least one R3 is CH3.

[0366] 10. The compound is, formula: [ka] The compound described in Embodiment 2, or a pharmaceutically acceptable salt thereof, represented by [formula].

[0367] 11. The compound is, formula: [ka] The compound described in Embodiment 2, or a pharmaceutically acceptable salt thereof, represented by [formula].

[0368] 12. The compound is, formula: [ka] The compound described in Embodiment 2, or a pharmaceutically acceptable salt thereof, represented by [formula].

[0369] 13. The compound is, formula: [ka] The compound described in Embodiment 2, or a pharmaceutically acceptable salt thereof, represented by [formula].

[0370] 14. The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein both R1 and R2 are H.

[0371] 15. The compound is, formula: [ka] The compound described in Embodiment 2, or a pharmaceutically acceptable salt thereof, represented by [formula].

[0372] 16. The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein both R1 and R2 are CH3.

[0373] 17. The compound is, formula: [ka] The compound described in Embodiment 2, or a pharmaceutically acceptable salt thereof, represented by [formula].

[0374] 18. Compounds of the formula: [ka] (In the formula, R1 and R2 are selected independently from H or CH3; Each R3 is independently selected from H, OH, CH3, O-CH3, CH2F2, F, or Cl, and at least two of R3 are H; n is 0, 1, 2, or 3; Each appearance of R4 is independently selected from CH3, CF3, O-CH3, F, Cl, -CN, isopropyl, or cyclopropyl; R6 is H, -CH2CH2OH, or -CH2CH2N(CH3)2; R 5 teeth, [ka] ;-CF2CF3; [ka] C(CH3)3; [ka] (where m is 0, 1, 2, 3, or 4, and X is CH3, OCH3, F, or Cl); [ka] (Here, each X1 is independently either N or CH; however, one X1 is N); [ka] and; However, R5, [ka] If that is the case, then n can never be 0. or a pharmaceutically acceptable salt thereof.

[0375] 19. The compound is, formula: [ka] It is expressed as, in the formula, R 4a , R 4b , R 4c , and R 4d Each appearance of is independently selected from H, CH3, CF3, O-CH3, F, Cl, -CN, isopropyl, or cyclopropyl; however, R 4a , R 4b , R 4c , and R 4d A compound according to Embodiment 18, wherein at least one of the elements is other than H; or a pharmaceutically acceptable salt thereof.

[0376] 20.R 4a , R 4b , R 4c , and R 4d The compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is Cl and the other is H.

[0377] 21.R 4d The compound according to Embodiment 20, or a pharmaceutically acceptable salt thereof, wherein the compound is Cl.

[0378] 22.R 4a , R 4b , R 4c , and R 4dThe compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein one of the members is CH3 and the other is H.

[0379] 23.R 4d The compound according to Embodiment 22, or a pharmaceutically acceptable salt thereof, wherein the compound is CH3.

[0380] 24.R 4a , R 4b , R 4c , and R 4d The compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein one of the members is OCH3 and the other is H.

[0381] 25.R 4c The compound according to Embodiment 24, or a pharmaceutically acceptable salt thereof, wherein OCH3 is present.

[0382] 26.R 4a , R 4b , R 4c , and R 4d The compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein one of the elements is F and the other is H.

[0383] 27.R 4a The compound according to Embodiment 26, or a pharmaceutically acceptable salt thereof, wherein F is present.

[0384] 28.R 4a , R 4b , R 4c , and R 4d The compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is CF3 and the other is H.

[0385] 29.R 4a The compound according to Embodiment 28, or a pharmaceutically acceptable salt thereof, wherein CF3 is present.

[0386] 30.R 4a , R 4b , R 4c , and R 4dThe compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein one of the elements is CN and the other is H.

[0387] 31.R 4b The compound according to Embodiment 30, or a pharmaceutically acceptable salt thereof, wherein CN is CN.

[0388] 32.R 4a , R 4b , R 4c , and R 4d The compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is cyclopropyl and the other is H.

[0389] 33.R 4b The compound according to Embodiment 32, or a pharmaceutically acceptable salt thereof, wherein is cyclopropyl.

[0390] 34.R 4a , R 4b , R 4c , and R 4d The compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is isopropyl and the other is H.

[0391] 35.R 4b The compound according to Embodiment 34, or a pharmaceutically acceptable salt thereof, wherein isopropyl.

[0392] 36.R 4a , R 4b , R 4c , and R 4d The compound described in Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein two of the elements are independently Cl, F, or CH3, and the other is H.

[0393] 37.R 4b and R 4c The compound according to Embodiment 36, or a pharmaceutically acceptable salt thereof, wherein F is present.

[0394] 38.R 4a and R4b One of them is F, and R 4a and R 4b The other side is CH3; or R 4b and R 4c One of them is F, and R 4b and R 4c The other side is CH3; or R 4a and R 4d One of them is F, and R 4a and R 4d The compound according to Embodiment 36, or a pharmaceutically acceptable salt thereof, wherein the other of the compounds is CH3.

[0395] 39.R5 is, [ka] The compound described in Embodiment 18, or a pharmaceutically acceptable salt thereof.

[0396] 40.R5 is [ka] The compound according to Embodiment 18, or a pharmaceutically acceptable salt thereof, wherein each X1 is independently N or CH; however, one X1 is N.

[0397] 41.R5 is, [ka] The compound according to Embodiment 18, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4, and X is CH3, OCH3, F, or Cl.

[0398] 42. A compound according to any one of Embodiments 18 to 41, or a pharmaceutically acceptable salt thereof, wherein R1 is CH3 and R2 is H.

[0399] 43. A compound according to any one of Embodiments 18 to 42, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R3 is H.

[0400] 44. The compound, [Table 102] [Table 103] [Table 104] [Table 105] [Table 106] [Table 107] [Table 108] [Table 109] A compound selected from the compounds described in Embodiment 18, or a pharmaceutically acceptable salt thereof.

[0401] 45. Compounds of the formula: [ka] (Each of W1 and W4 is independently selected from N, C, or CH; Each of W2, W3, W5, and W6 is independently selected from N, NH, CH, or CH2; n is 0, 1, 2, or 3; Each appearance of R4 is independently cyclopropyl, Cl, F, CH3, isopropyl, CF3, -CN, or OCH3; m is 0, 1, 2, or 3; Each occurrence of R6 is independently F, Cl, or CH3; Here, R1 and R2 are selected independently of H or CH3; The dotted line indicates the presence of a single or double bond; X is H or CF3, or a pharmaceutically acceptable salt thereof.

[0402] 46. ​​The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein W3 is N, W1 and W4 are C, and W2, W5 and W6 are each CH.

[0403] 47. The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein W2 and W3 are N, W1 and W4 are C, and W5 and W6 are each CH.

[0404] 48. The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein W3 and W5 are N, W1 and W4 are C, and W2 and W6 are each CH.

[0405] 49. The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein W1 and W4 are each CH, and W2, W3, W5, and W6 are each CH2.

[0406] 50. The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein each of W1 is CH, W4 is N, and each of W2, W3, W5, and W6 is CH2.

[0407] 51. The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein W3 and W6 are N, W1 and W4 are C, W2 is CR6, and W5 is CH.

[0408] 52. The compound according to Embodiment 51, or a pharmaceutically acceptable salt thereof, wherein R6 is CH3.

[0409] 53. The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein W2 is N, W1 and W4 are C, W3 and W5 are each CH, and W6 is CR6.

[0410] 54. The compound according to Embodiment 53, or a pharmaceutically acceptable salt thereof, wherein R6 is Cl.

[0411] 55. The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein W2 is N, W1 and W4 are C, and W3, W5 and W6 are each CH.

[0412] 56. The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein W2 and W6 are N, W1 and W4 are C, W3 is CR6, and W5 is CH.

[0413] 57. The compound according to Embodiment 56, wherein R6 is CH3, or a pharmaceutically acceptable salt thereof.

[0414] 58. The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein W2 and W6 are N, W1 and W4 are C, W3 is CH, and W5 is CH.

[0415] 59. The compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, wherein W2 is N, W1 and W4 are C, W3 and W6 are each CR6, and W5 is CH.

[0416] 60. The compound according to Embodiment 59, or a pharmaceutically acceptable salt thereof, wherein R6 is CH3.

[0417] 61. A compound according to any one of Embodiments 45 to 60, wherein R1 is CH3 and R2 is H, or a pharmaceutically acceptable salt thereof.

[0418] 62. A compound according to any one of Embodiments 45 to 61, or a pharmaceutically acceptable salt thereof, wherein n is 1 and R4 is F or cyclopropyl.

[0419] 63. The compound, [Table 110] [Table 111] [Table 112] A compound according to Embodiment 45, or a pharmaceutically acceptable salt thereof, selected from the above.

[0420] 64.Formula: [ka] (In the formula, R1 and R2 are selected independently from H or CH3; Each R3 is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, and at least two of the R3s are H; n is 0, 1, or 2; R 10 Each occurrence is independently methyl, F, OH, H, OCH3, CH3, or cyclopropyl; X is either H or CF3; A bicyclic ring is a ring containing 8 to 10 constituent ring atoms, where 1 to 4 of the atoms are heteroatoms independently selected from N, O, or S, and each of the two rings is independently saturated, unsaturated, or aromatic. A compound of or a pharmaceutically acceptable salt thereof.

[0421] 65. The second ring, [Table 113] [Table 114] A compound according to Embodiment 64, or a pharmaceutically acceptable salt thereof, selected from the above.

[0422] 66. The compound according to Embodiment 64 or 65, or a pharmaceutically acceptable salt thereof, wherein R1 is CH3 and R2 is H.

[0423] 67. A compound according to any one of embodiments 64 to 66, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R3 is H.

[0424] 68. A compound according to any one of embodiments 64 to 67, or a pharmaceutically acceptable salt thereof, wherein X is CF3.

[0425] 69. Compounds, [Table 115] [Table 116] [Table 117] [Table 118] A compound according to Embodiment 64, or a pharmaceutically acceptable salt thereof, selected from the above.

[0426] 70.Formula: [ka] (R 11 is, -(CH2) m -A, m is 0, 1, 2, or 3; R 12 H is; R 13 is H, -CH2CH2OH, or -CH2CH2N(CH3)2; A is cyclopropyl, -OH, -OCH3; [ka] ,-CHF2; phenyl, 4-chlorophenyl; [ka] , or 4-pyridyl; n is 0, 1, 2, or 3; R 10 Each occurrence is independently cyclopropyl, Cl, F, CH3, or OCH3; Each R3 is independently selected from H, OH, CH3, O-CH3, CHF2, F, or Cl, and at least two of the R3s are H; X1 is either H or CF3; X2 is either H or F; or R 11 and R 12 Each of them, along with the nitrogen atom to which it is bonded, [ka] A compound represented by (forming) or a pharmaceutically acceptable salt thereof.

[0427] 71. A compound according to Embodiment 70, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

[0428] 72. A compound according to Embodiment 70 or 71, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0429] 73. A compound according to any one of embodiments 70 to 72, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R3 is H.

[0430] 74. A compound according to any one of embodiments 70 to 73, or a pharmaceutically acceptable salt thereof, wherein X1 is CF3 and X2 is H.

[0431] 75. A compound according to any one of embodiments 70 to 73, or a pharmaceutically acceptable salt thereof, wherein X1 is CF3 and X2 is F.

[0432] 76. A compound according to any one of embodiments 70 to 73, or a pharmaceutically acceptable salt thereof, wherein X1 is H and X2 is H.

[0433] 77. Compounds, [Table 119] [Table 120] [Table 121] [Table 122] A compound selected from the compounds described in Embodiment 70, or a pharmaceutically acceptable salt thereof.

[0434] 78.Formula: [ka] (In the formula, R 61 , R 62 , R 63 , and R 64 A compound represented by (each of which is independently selected from H and CH3), or a pharmaceutically acceptable salt thereof.

[0435] 79.R 61 , R 62 , R 63 , and R 64 The compound according to Embodiment 78, or a pharmaceutically acceptable salt thereof, wherein one of the members is CH3 and the other three are H.

[0436] 80.R 61 and R 62 A compound according to Embodiment 78 or 79, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is CH3 and the other is H.

[0437] 81.R 63 and R 64 A compound according to Embodiment 78 or 79, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is CH3 and the other is H.

[0438] 82. Compounds, [Table 123] A compound selected from the compounds described in Embodiment 78, or a pharmaceutically acceptable salt thereof.

[0439] 83.Formula: [ka] (R 71 and R 72 A compound represented by (each of which is independently selected from H and CH3), or a pharmaceutically acceptable salt thereof.

[0440] 84.R 71 and R 72 The compound according to Embodiment 83, or a pharmaceutically acceptable salt thereof, wherein one of the atoms is CH3 and the other is H.

[0441] 85. Compounds, [ka] The compound described in Embodiment 83, or a pharmaceutically acceptable salt thereof.

[0442] 86.Formula: [ka] (In the formula, Q is (CH2) n A compound represented by (where n is 1, 2, or 3 in the ring, thereby forming a 5, 6, or 7-membered ring), or a pharmaceutically acceptable salt thereof.

[0443] 87. Compounds, [Table 124] A compound according to Embodiment 86, or a pharmaceutically acceptable salt thereof, selected from the above.

[0444] 88. [Table 125] [Table 126] A compound selected from, or a pharmaceutically acceptable salt thereof.

[0445] 89. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0446] 90. A method for treating a disease or disorder associated with a genetic defect of phenylalanine hydroxylase, comprising administering to a subject in need an effective amount of a compound described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition described in Embodiment 89.

[0447] 91. A method for treating phenylketonuria, comprising administering to a subject in need thereof an effective amount of a compound described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition described in Embodiment 89.

[0448] 92. A method for treating hyperphenylalaninemia, comprising administering to a subject in need thereof an effective amount of a compound described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition described in Embodiment 89.

[0449] 93. The method according to any one of embodiments 91 to 92, wherein the compound reduces systemic phenylalanine levels in a subject.

[0450] 94. A method for treating or preventing tyrosinemia (type I, type II, or type III), comprising administering to a subject in need of such treatment an effective amount of a compound described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition described in Embodiment 89.

[0451] 95. The method according to Embodiment 94, wherein the compound lowers systemic tyrosine levels in a subject.

[0452] 96. A method for treating or preventing nonketotic hyperglycinemia, comprising administering to a subject in need thereof an effective amount of a compound described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition described in Embodiment 89.

[0453] 97. The method according to Embodiment 96, wherein the compound reduces systemic glycine levels in a subject.

[0454] 98. A method for 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 described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition described in Embodiment 89.

[0455] 99. The method according to any one of embodiments 90 to 98, wherein the compound inhibits SLC6A19 in the target.

[0456] 100. A compound for use in the treatment of a disease or disorder associated with a genetic defect of phenylalanine hydroxylase, wherein the treatment comprises administering to a subject in need of it an effective amount of the compound described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition described in Embodiment 89.

[0457] 101. A compound for use in the treatment of phenylketonuria, wherein the treatment comprises administering to a subject in need of it an effective amount of the compound described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition described in Embodiment 89.

[0458] 102. A compound for use in the treatment of hyperphenylalaninemia, wherein the treatment comprises administering to a subject in need of it an effective amount of the compound described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition described in Embodiment 89.

[0459] 103. A compound for use in the treatment of a disease described in Embodiment 101 or 102, wherein the compound reduces systemic phenylalanine levels in a subject.

[0460] 104. A compound for use in the treatment or prevention of tyrosinemia (type I, type II, or type III), wherein the treatment or prevention comprises administering to a subject in need of it an effective amount of the compound described in any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition described in Embodiment 89.

[0461] 102. A compound for use in the treatment or prevention of tyrosinemia according to Embodiment 101, wherein the compound lowers systemic tyrosine levels in a subject.

[0462] 103. A compound for use in the treatment or prevention of nonketotic hyperglycinemia, wherein the treatment or prevention comprises administering to a subject in need of it an effective amount of the compound described in any one of Embodiments 1 to 85, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition described in Embodiment 86.

[0463] 104. A compound for use in the treatment or prevention of nonketotic hyperglycinemia according to Embodiment 103, wherein the compound reduces systemic glycine levels in a subject.

[0464] 105. Compounds for use in the treatment or prevention of isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, or hyperammonemia, wherein the treatment or prevention comprises administering to a subject in need of it an effective amount of the compound described in any one of Embodiments 1 to 85 or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition described in Embodiment 86.

[0465] 106. A compound for use in the treatment or prevention of the diseases described in Embodiments 97 to 105, wherein the compound inhibits SLC6A19 in the target.

Claims

1. formula: 【Chemistry 1】 (In the formula, R １ and R ２ is H or CH ３ Selected independently of; Each R ３ H, OH, CH ３ O-CH ３ CHF ２ A selection made independently of F or Cl, and at least two R ３ (is H); A compound of or a pharmaceutically acceptable salt thereof.

2. formula: 【Chemistry 2】 (wherein, R １ and R ２ are each independently selected from H or CH ３ ;) Each R ３ H, OH, CH ３ O-CH ３ ,CH ２ F ２ A selection made independently of F or Cl, and at least two R ３ is H; n is 0, 1, 2, or 3; R ４ Each occurrence is CH ３ CF ３ O-CH ３ Independently selected from F, Cl, -CN, isopropyl, or cyclopropyl; R ６ H, -CH ２ CH ２ OH, or -CH ２ CH ２ N(CH ３ ) ２ And; R ５ teeth, 【Transformation 3】 ;-CF ２ CF ３ ; 【Chemistry 4】 C(CH3)3; 【Transformation 5】 (Here, m is 0, 1, 2, 3 or 4, and X is CH) ３ , OCH ３ (It is F or Cl); 【Transformation 6】 (Here, each X １ Independently, is N or CH; however, one X １ (is N); 【Transformation 7】 And; However, R ５ but, 【Transformation 8】 A compound of (where n cannot be 0) or a pharmaceutically acceptable salt thereof.

3. formula: 【Chemistry 9】 (W １ and W ４ Each of these is independently selected from N, C, or CH; W ２ , W ３ , W ５ , and W ６ Each of these is N, NH, CH, or CH ２ Selected independently of; n is 0, 1, 2, or 3; R ４ Each appearance is independently of cyclopropyl, Cl, F, CH ３ Isopropyl, CF ３ , -CN or OCH ３ And; m is 0, 1, 2, or 3; R ６ Each occurrence is independent of F, Cl, or CH ３ And; Here, R １ and R ２ is H or CH ３ Compounds (selected independently from).

4. formula: 【Chemistry 10】 (In the formula, R １ and R ２ is H or CH ３ Selected independently of; Each R ３ H, OH, CH ３ O-CH ３ CHF ２ A selection made independently of F or Cl, and at least two R ３ is H; n is 0, 1, or 2; R １０ Each occurrence is independently methyl, F, OH, H, OCH ３ ,CH ３ , or cyclopropyl; X is H or CF ３ And; Compounds of a bicyclic ring (where the bicyclic ring contains 8 to 10 constituent ring atoms, 1 to 4 of which are heteroatoms independently selected from N, O, or S, and each of the two rings is independently saturated, unsaturated, or aromatic) or pharmaceutically acceptable salts thereof.

5. formula: 【Chemistry 11】 (R １１ is, -(CH ２ ) ｍ -A is, m is 0, 1, 2, or 3; R １２ H is; R １３ H, -CH ２ CH ２ OH, or -CH ２ CH ２ N(CH ３ ) ２ And; A is cyclopropyl, -OH, -OCH ３ ; 【Chemistry 12】 ,-CHF ２ ; Phenylen, 4-chlorophenyl; 【Chemistry 13】 , or 4-pyridyl; n is 0, 1, 2, or 3; R １０ Each appearance is independently of cyclopropyl, Cl, F, CH ３ , or OCH ３ And; Each R ３ H, OH, CH ３ O-CH ３ CHF ２ A selection made independently of F or Cl, and at least two R ３ is H; X １ H or CF ３ And; X ２ is either H or F; or R １１ and R １２ together with the nitrogen atom to which each is attached 【Chemistry 14】 A compound represented by (forming) or a pharmaceutically acceptable salt thereof.

6. formula: 【Chemistry 15】 (In the formula, R ６１ , R ６２ , R ６３ , and R ６４ Each of them is H and CH ３ A compound represented by (independently selected from) or a pharmaceutically acceptable salt thereof.

7. formula: 【Chemistry 16】 (R ７１ and R ７２ each of which is independently selected from H and CH ３ ), or a pharmaceutically acceptable salt thereof.

8. formula: 【Chemistry 17】 (In the formula, Q is (CH ２ ) ｎ A compound represented by (where n is 1, 2, or 3 in the ring, thereby forming a 5, 6, or 7-membered ring), or a pharmaceutically acceptable salt thereof. 【Request Item 9】 【Table 1】 Table 2 A compound selected from, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

11. A compound for use in the treatment of a disease or disorder associated with a genetic defect of phenylalanine hydroxylase, wherein the treatment comprises administering to a subject in need of said treatment an effective amount of the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition according to claim 10.

12. A compound for use in the treatment of phenylketonuria, wherein the treatment comprises administering to a subject in need of said treatment an effective amount of the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition according to claim 10.

13. A compound for use in the treatment of hyperphenylalaninemia, wherein the treatment comprises administering to a subject in need of said treatment an effective amount of the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition according to claim 10.

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

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

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