Prodrug Compounds

Abstract

Formula (I), Formula (II), Formula (III), and Formula (IV): TIFF2022532568000089.tif71165 wherein R1, R2, R3, and R4 are defined herein. Disclosed are compounds of the formula: or salts thereof. Methods of using the compounds as prodrugs of inhibitors of signaling through Toll-like receptors 7, 8, or 9, and pharmaceutical compositions containing such compounds, are also disclosed. These prodrug compounds are useful in the treatment of inflammatory and autoimmune diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 844,439, filed May 7, 2019, the contents of which are specifically incorporated herein by reference. [Background technology]

[0002] The present invention generally relates to substituted indole compounds useful as prodrugs of inhibitors of signaling through Toll-like receptors 7, 8, or 9 (TLR7, TLR8, TLR9), or combinations thereof. Provided herein are prodrug compounds, compositions comprising such compounds, and methods of use thereof. The present invention further relates to pharmaceutical compositions comprising at least one compound described herein, useful for treating conditions associated with TLR modulation, such as inflammatory and autoimmune diseases, and methods of inhibiting TLR activity in a mammal.

[0003] Members of the Toll / IL-1 receptor family are important regulators of inflammation and host resistance. The Toll-like receptor family recognizes molecular patterns derived from infectious organisms such as bacteria, fungi, parasites, and viruses (Kawai, T. et al., Nature Immunol., 11:373-384 (2010)). Ligand binding to the receptor induces dimerization and recruitment of adaptor molecules to a conserved cytoplasmic motif in the receptor called the Toll / IL-1 receptor (TIR) ​​domain; with the exception of TLR3, all TLRs recruit the adaptor molecule MyD88. The IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, JE et al., Nature Rev. Immunol., 10:89-102 (2010)).

[0004] Toll-like receptors (TLRs) are a family of evolutionarily conserved transmembrane innate immune receptors involved in primary defense. As pattern recognition receptors, TLRs protect against foreign molecules and are activated by pathogen-associated molecular patterns (PAMPs) or, from damaged tissue, by damage-associated molecular patterns (DAMPs). A total of 13 TLR family members have been identified, 10 of which are located on the cell surface or in endosomal compartments. TLRs 7-9 are one of a set that are located in endosomes and respond to single-stranded RNA (TLR7 and TLR8) or unmethylated single-stranded DNA containing cytosine-phosphate-guanine (CpG) motifs (TLR9).

[0005] Activation of TLR7 / 8 / 9 can initiate various inflammatory responses (cytokine production, B cell activation, IgG production, and type I interferon response). In autoimmune diseases, abnormal and persistent activation of TLR7 / 8 / 9 leads to exacerbation of the disease state. Overexpression of TLR7 in mice has been shown to exacerbate autoimmune diseases, but knockout of TLR7 in mice has been found to prevent disease in lupus-prone MRL / lpr mice. Double deficiency of TLR7 and 9 has also been shown to improve protection.

[0006] Because many disease states may benefit from treatments involving modulation of cytokines, IFN production, and B cell activity, it is readily apparent that compounds capable of modulating TLR7 and / or TLR8 and / or TLR9, and methods of using those compounds, may provide substantial therapeutic benefit to a wide variety of patients.

[0007] U.S. Patent No. 10,071,079 B2 discloses substituted indole compounds useful in the treatment of inflammatory and autoimmune diseases such as lupus. This patent discloses compounds of formula (A): [ka] The compound, 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide, having the structure: is disclosed as Example 15. This compound has activity as an inhibitor of TLR7 and / or TLR8 and is therefore useful in the treatment of inflammatory and autoimmune diseases. Methods for making and using the compound are also disclosed in U.S. Pat. No. 10,071,079 B2, which is assigned to the present assignee and incorporated herein by reference in its entirety.

[0008] However, the usefulness of oral formulations requires that the active agent is bioavailable and that the degree of bioavailability does not vary significantly.The bioavailability of orally administered drugs is often affected by various factors, such as the solubility of the drug in the gastrointestinal tract, the stability of the drug in the gastrointestinal tract, and the absorption of the drug in the gastrointestinal tract.In addition, these factors may be affected by the co-administration of other drugs and / or the intake of food, which may cause the bioavailability of orally administered drugs to fluctuate.

[0009] The water solubility of Compound A depends on the pH of the aqueous medium. Compound A has a higher solubility at pH 1 than at pH 4 or pH 6. When Compound A is orally administered, its solubility, and therefore its bioavailability, can be affected by the pH of the gastric contents. According to CJ Perigard, Clinical Analysis, Chapter 32, in Remington: The Science and Practice of Pharmacy 20th Edition, AR Gennaro, editor; 2000, Lippinocott Williams & Wilkins, Baltimore, MD, the normal pH of the stomach is 1.2 to 1.8. However, patients often receive other medications to treat conditions related or unrelated to the treatment of inflammatory and autoimmune diseases with Compound A. For example, medications such as antacids or proton pump inhibitors can increase the gastric pH.

[0010] As can be seen, there remains a need for improved delivery of Compound A to patients. Summary of the Invention

[0011] Applicants have discovered that prodrugs of Compound A are useful for delivering Compound A to patients. The prodrugs have been found to have higher solubility than Compound A at pH 4 and / or pH 6.5. By improving solubility over a wider range of pH, the compounds of the present invention will have less variability in solubility at a patient's stomach acid levels. Fluctuations in stomach pH can occur due to other medications or ingested food. Absorption of the prodrugs is less affected by pH fluctuations in the stomach and other parts of the gastrointestinal tract, and is therefore expected to be more uniformly absorbed, independent of stomach pH.

[0012] The present invention fulfills the aforementioned needs by providing prodrug compounds, salts of the prodrug compounds, and the like of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide, which are useful as inhibitors of TLR7 and / or TLR8.

[0013] The present invention provides prodrug compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), or pharmaceutically acceptable salts or solvates thereof, which are useful as inhibitors of signal transduction mediated by Toll-like receptor 7, 8, or 9, and are useful in the treatment of proliferative diseases, allergic diseases, autoimmune diseases, and inflammatory diseases.

[0014] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0015] The present invention also provides methods for inhibiting Toll-like receptors 7, 8, or 9, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0016] The present invention also provides methods for treating proliferative, metabolic, allergic, autoimmune, and inflammatory diseases, comprising administering to a host in need of treatment a therapeutically effective amount of at least one compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.

[0017] The present invention also provides methods for treating a disease or disorder associated with the activity of Toll-like receptor 7, 8, or 9, comprising administering to a mammal in need thereof at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV), or a pharmaceutically acceptable salt or solvate thereof.

[0018] The present invention also provides processes and intermediates for preparing the compounds of formula (I), formula (II), formula (III), and formula (IV), their salts, solvates, and the like.

[0019] The present invention also provides at least one of the compounds of formula (I), formula (II), formula (III), and formula (IV), or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

[0020] The present invention also provides the use of at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment or prevention of a condition, such as an allergic disease, an autoimmune disease, an inflammatory disease, or a proliferative disease, associated with Toll-like receptor 7, 8, or 9.

[0021] Compounds of at least one of Formula (I), Formula (II), Formula (III), and Formula (IV), and compositions comprising compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), may be used to treat, prevent, or cure various conditions associated with Toll-like receptors 7, 8, or 9. Pharmaceutical compositions comprising these compounds are useful for curing, preventing, or inhibiting the progression of diseases or disorders in various therapeutic areas, such as allergic diseases, autoimmune diseases, inflammatory diseases, and proliferative diseases.

[0022] These and other features of the present invention will be expanded upon as the disclosure continues.

[0023] Detailed Description A first aspect of the present invention is a compound represented by formula (I), formula (II), formula (III), and formula (IV): [ka] [In the formula, R1 is -CH2OH, -C(O)O(C 1-4 alkyl), -C(O)CHNR x R x, -C(O)(CH2) 1-3 OP(O)(OH)2, -C(O)CH2NR x C(O)OCH2OP(O)(OH)2, -C(O)OCH2(pyrrolidinyl), -C(O)OCH2(piperidinyl), -C(O)OCHR x OC(O)(aminocyclopropyl), -C(O)OCH(CH3)OC(O)(aminocyclopropyl), -C(O)OCH2OP(O)(OH)2, -P(O)(OH)2, -SCH2CH(NH2)C(O)OH, [ka] and; R2 and R3 are independently -CH2OP(O)(OH)2, -CH2OC(O)NR x CH2CH2NR x R x , -CH2OC(O)NR x CH2CH2OP(O)(OH)2, or [ka] and; R4 is -P(O)(OH)2; R x are each independently hydrogen or -CH3. or a salt thereof.

[0024] In one embodiment, R1 is -CH2OH, -C(O)CH2NH(CH3), -C(O)CH2CH2CH2OP(O)(OH)2, -C(O)CH2N(CH3)C(O)OCH2OP(O)(OH)2, -C(O)OCH2CH3, -C(O)OCH2(pyrrolidinyl), -C(O)OCH2(piperidinyl), -C(O)OCH2OC(O)(aminocyclopropyl), -C(O)OCH(CH3)OC(O)(aminocyclopropyl), -C(O)OCH2OP(O)(OH)2, -P(O)(OH)2, -SCH2CH(NH2)C(O)OH, [ka] and; R2 is -CH2OP(O)(OH)2, -CH2OC(O)N(CH3)CH2CH2NH(CH3), -CH2OC(O)N(CH3)CH2CH2OP(O)(OH)2, [ka] and; R3 is -CH2P(O)(OH)2, -CH2OC(O)N(CH3)CH2CH2OP(O)(OH)2, or [ka] and; R4 is -P(O)(OH)2; At least one compound of formula (I), formula (II), formula (III), and formula (IV), or a salt thereof, is provided.

[0025] In one embodiment, R1 is -CH2OH, -C(O)O(C 1-4 alkyl), -C(O)CHNR x R x , -C(O)(CH2) 1-3 OP(O)(OH)2, -C(O)CH2NR x C(O)OCH2OP(O)(OH)2, -C(O)OCH2(pyrrolidinyl), -C(O)OCH2(piperidinyl), -C(O)OCHR x OC(O)(aminocyclopropyl), -C(O)OCH(CH3)OC(O)(aminocyclopropyl), -C(O)OCH2OP(O)(OH)2, -P(O)(OH)2, -SCH2CH(NH2)C(O)OH, [ka] and; R x are each independently hydrogen or -CH3; Provided is a compound represented by formula (I) or a salt thereof. In this embodiment, R is -CHOH, -C(O)CHNH(CH), -C(O)CHCHCHOP(O)(OH), -C(O)CHN(CH)C(O)OCHOP(O)(OH), -C(O)OCHCH, -C(O)OCH(pyrrolidinyl), -C(O)OCH(piperidinyl), -C(O)OCHOC(O)(aminocyclopropyl), -C(O)OCH(CH)OC(O)(aminocyclopropyl), -C(O)OCHOP(O)(OH), -P(O)(OH), -SCHCH(NH)C(O)OH, [ka] The compounds include compounds in which:

[0026] In one embodiment, R2 and R3 are independently -CH2OP(O)(OH)2, -CH2OC(O)NR x CH2CH2NR x R x , -CH2OC(O)NR x CH2CH2OP(O)(OH)2, or [ka] and; R x are each independently hydrogen or -CH3; At least one compound of formula (II) and formula (III) or a salt thereof is provided. This embodiment includes: R2 is -CH2OP(O)(OH)2, -CH2OC(O)N(CH3)CH2CH2NH(CH3), -CH2OC(O)N(CH3)CH2CH2OP(O)(OH)2, [ka] and; R3 is -CH2P(O)(OH)2, -CH2OC(O)N(CH3)CH2CH2OP(O)(OH)2, or [ka] Compounds are included in which:

[0027] In one embodiment, R2 is -CH2OP(O)(OH)2, -CH2OC(O)NR x CH2CH2NR x R x , -CH2OC(O)NR x CH2CH2OP(O)(OH)2, or [ka] and; R x are each independently hydrogen or -CH3; Provided is a compound of formula (II), or a salt thereof, wherein R is -CH2OP(O)(OH)2, -CH2OC(O)N(CH3)CH2CH2NH(CH3), -CH2OC(O)N(CH3)CH2CH2OP(O)(OH)2, [ka] Compounds are included in which:

[0028] In one embodiment, R3 is -CH2OP(O)(OH)2, -CH2OC(O)NR x CH2CH2NR x R x , -CH2OC(O)NR x CH2CH2OP(O)(OH)2, or [ka] and; R x are each independently hydrogen or -CH3; Compounds of formula (III) or salts thereof are provided, including those in which R is -CHP(O)(OH), -CHOC(O)N(CH)CHCHOP(O)(OH), or [ka] Compounds are included in which:

[0029] One embodiment provides a compound of formula (IV) or a salt thereof, wherein R4 is -P(O)(OH)2.

[0030] In one embodiment, the compound is (S)-Piperidin-2-ylmethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate(1); (S)-(1-(((phosphonooxy)methoxy)carbonyl)piperidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate(2); (S)-Pyrrolidin-2-ylmethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate(3); (S)-(1-(((phosphonooxy)methoxy)carbonyl)pyrrolidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (4); 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1-(methylglycyl)-1H-indol-5-yl)piperidin-1-yl)acetamide ditrifluoroacetate (5); 1-((1-aminocyclopropane-1-carbonyl)oxy)ethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate ditrifluoroacetate (6-7); 4-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-4-oxobutyl dihydrogen phosphate (10);S-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-L-cysteine ​​(11); ((1-aminocyclopropane-1-carbonyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate trifluoroacetate (15); (phosphonooxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (16); (5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)phosphonate (18); (phosphonooxy)methyl (2-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-2-oxoethyl)(methyl)carbamate (19); ((3-methoxy-4-(phosphonooxy)benzoyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (22); Ethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (24); or 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(hydroxymethyl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (25); or a salt thereof.

[0031] In one embodiment, the compound is 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-((phosphonooxy)methyl)piperidin-1-ium trifluoroacetate(8);1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)methyl)piperidin-1-ium Ditrifluoroacetate (12); 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(1-((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl)piperidin-1-ium Ditrifluoroacetate (14); 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(((methyl(2-(phosphonooxy)ethyl)carbamoyl)oxy)methyl)piperidin-1-ium trifluoroacetate (20); or 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(((methyl(2-(methylamino)ethyl)carbamoyl)oxy)methyl)piperidin-1-ium trifluoroacetate (23) or a salt thereof.

[0032] In one embodiment, the compound is 6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-1-((phosphonooxy)methyl)-[1,2,4]triazolo[1,5-a]pyridin-1-ium trifluoroacetate(9);6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-1-(((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridin-1-ium Trifluoroacetate (13); or 6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-1-(((methyl(2-(phosphonooxy)ethyl)carbamoyl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridin-1-ium trifluoroacetate (21) or a salt thereof.

[0033] In one embodiment, the compound is 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)phosphonic acid (17) or a salt thereof.

[0034] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention includes all combinations of the aspects and / or embodiments of the present invention described herein. It is understood that any and all embodiments of the present invention can be taken in combination with any other embodiment to describe further embodiments. It is also understood that each individual element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe further embodiments.

[0035] definition The features and advantages of the present invention will be more readily understood by those skilled in the art upon reading the following detailed description. It should be understood that certain features of the invention that are, for clarity, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be combined to form any subcombination thereof. The embodiments identified in the present invention as exemplary or preferred are intended to be illustrative, not limiting.

[0036] Unless otherwise stated in the specification, references made in the singular may also include the plural, for example, "a" and "an" may refer to one or to one or more.

[0037] As used herein, the phrase "compound" refers to at least one compound. For example, at least one compound of formula (I), formula (II), formula (III), and formula (IV) includes a compound of formula (II). In another example, at least one compound of formula (I), formula (II), formula (III), and formula (IV) includes a compound of formula (I) and a compound of formula (II).

[0038] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have enough hydrogen atoms to satisfy the valences.

[0039] The definitions set forth herein take precedence over definitions set forth in any patents, patent applications, and / or patent application publications incorporated herein by reference.

[0040] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout the specification (unless otherwise limited in specific instances), either individually or as part of a larger group.

[0041] Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0042] According to the practice used in the art, [ka] is used herein in structural formulas to represent the bond that is the point of attachment of a group or substituent to the core or backbone structure.

[0043] As used herein, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number is present in the subscript following the symbol "C," the subscript defines the number of carbon atoms that may be included in a particular group. For example, "C" 1-6 "Alkyl" means straight and branched chain alkyl groups having from 1 to 6 carbon atoms.

[0044] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0045] Compounds of Formula (I), Formula (II), Formula (III), and / or Formula (IV) can form salts that are also within the scope of the present invention. Unless otherwise specified, reference to a compound of the present invention is understood to include reference to one or more salts thereof. The term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Furthermore, the term "salt" includes zwitterions (inner salts), for example, when a compound of Formula (I), Formula (II), Formula (III), and / or Formula (IV) contains both a basic group, such as an amine or pyridine or imidazole ring, and an acidic group, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may be useful, for example, in isolation or purification steps that may be used in synthesis, and are therefore considered within the scope of the present invention. Salts of compounds of Formula (I), Formula (II), Formula (III), and / or Formula (IV) can be formed, for example, by reacting a compound of Formula (I), Formula (II), Formula (III), and / or Formula (IV) with an amount of acid or base, such as an equivalent amount, in a solvent from which the salt precipitates, or in a solvent, such as an aqueous solvent, followed by lyophilization.

[0046] Examples of acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, gluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), Examples include hydroiodide, maleate (formed with maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as formed with sulfuric acid), sulfonate (such as those described herein), tartrate, thiocyanate, toluenesulfonate such as tosylate, undecanoate, and the like.

[0047] Examples of basic salts include alkali metal salts such as ammonium, sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (e.g., organic amines), for example, trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or similar pharmaceutically acceptable amines, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long-chain halides (e.g., decyl chlorides, bromides, and iodides, lauryl, myristyl, and stearyl), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Preferred salts include monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates. Compounds of Formula (I), Formula (II), Formula (III), and / or Formula (IV) can be provided as amorphous or crystalline solids. Lyophilization can be used to provide compounds of Formula (I), Formula (II), Formula (III), and / or Formula (IV) as amorphous solids.

[0048] It should further be understood that solvates (e.g., hydrates) of the compounds of Formula (I), Formula (II), Formula (III), and / or Formula (IV) are also within the scope of the present invention. The term "solvate" refers to a physical association of a compound of Formula (I), Formula (II), Formula (III), and / or Formula (IV) with one or more solvent molecules, either organic or inorganic. This physical association may include hydrogen bonding. In some instances, a solvate may be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolatable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0049] Furthermore, the compounds of Formula (I), Formula (II), Formula (III), and / or Formula (IV), following their synthesis, can be isolated and purified to obtain compositions comprising 99% by weight or greater ("substantially pure") compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), respectively, which can then be used or formulated as described herein. Such "substantially pure" compounds of Formula (I), Formula (II), Formula (III), and / or Formula (IV) are also contemplated herein as part of the present invention.

[0050] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.

[0051] A "therapeutically effective amount" is intended to include the amount of a compound of the invention alone, or of a combination of compounds as claimed, or of a compound of the invention in combination with other active ingredients, that is effective as an inhibitor of TLR7 / 8 / 9, or that is effective in treating or preventing autoimmune and / or inflammatory disease states, such as SLE, IBD, multiple sclerosis (MS), and Sjogren's syndrome, and rheumatoid arthritis.

[0052] As used herein, "treating" or "treating" includes the treatment of a disease state in a mammal, particularly a human, and includes (a) preventing a condition from occurring in a mammal, particularly where such a mammal is predisposed to, but has not yet been diagnosed as having, the condition; (b) inhibiting the condition, i.e., arresting its onset; and / or (c) alleviating the condition, i.e., causing regression of the condition.

[0053] The compounds of the present invention are intended to include all isotopes of atoms present in the compounds of the present invention.Isotopes include atoms having the same atomic number but different mass numbers.By way of general example, and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T).Isotopes of carbon include: 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described herein, substituting an appropriately isotopically labeled reagent for an otherwise unlabeled reagent. For example, methyl (-CH3) also includes deuterated methyl groups such as -CD3.

[0054] usefulness The human immune system evolved to defend the body against microorganisms, viruses, and parasites that can cause infection, disease, or death. Complex regulatory mechanisms ensure that the various cellular components of the immune system target foreign substances or organisms without causing permanent or significant damage to the individual. While the initiating events are not fully understood at present, in autoimmune disease states, the immune system directs an inflammatory response that targets the affected individual's organs. Different autoimmune diseases are generally characterized by the prominent or initial target organ or tissue affected, such as the joints in rheumatoid arthritis, the thyroid gland in Hashimoto's thyroiditis, the central nervous system in multiple sclerosis, the pancreas in type 1 diabetes, and the intestine in inflammatory bowel disease.

[0055] The compounds of the present invention inhibit signaling through Toll-like receptors 7, 8, or 9 (TLR7, TLR8, TLR9), or combinations thereof. Accordingly, the compounds of Formula (I), Formula (II), Formula (III), and Formula (IV) have utility as prodrugs of Compound A, which are useful in treating conditions associated with the inhibition of signaling through one or more of TLR7, TLR8, or TLR9. Such conditions include TLR7, TLR8, or TLR9 receptor-associated diseases in which cytokine levels are modulated as a result of intracellular signaling.

[0056] The term "treating" or "treatment" as used herein includes the treatment of a disease state in a mammal, particularly a human, and includes (a) preventing or delaying the onset of the disease state in a mammal, particularly where the mammal is predisposed to, but has not yet been diagnosed as having, the disease state; (b) inhibiting the disease state, i.e., arresting its progression; and / or (c) achieving complete or partial alleviation of the symptoms or disease state, and / or alleviating, ameliorating, reducing, or curing the disease, disorder, and / or its symptoms.

[0057] In light of their activity as selective inhibitors of TLR7, TLR8, or TLR9, the compounds of formula (I), formula (II), formula (III), and formula (IV), respectively, are useful in the treatment of, but not limited to, inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease, and the like; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus erythematosus, psoriasis, and the like; autoinflammatory diseases such as cryopyrin periodic syndromes (CAPS), TNF receptor-associated periodic syndromes (TRAPS), familial Mediterranean fever (FMF), adult-onset Still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis, and the like; metabolic diseases such as type II diabetes, atherosclerosis, and the like. , myocardial infarction, etc.; destructive bone diseases, such as bone resorption disorders, osteoarthritis, osteoporosis, multiple myeloma-related bone disease, etc.; proliferative disorders, such as acute myeloid leukemia and chronic myeloid leukemia, etc.; angiogenic disorders, such as solid tumors, ocular angiogenesis, and infantile hemangiomas, etc.; infectious diseases, such as sepsis, septic shock, and Shigellosis, etc.; neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, neurodegenerative diseases caused by cerebral ischemia, or trauma, neoplastic diseases and viral diseases, such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and TLR7, TLR8, or TLR9 family receptor-associated diseases, such as HIV infection and CMV retinitis, AIDS, etc.

[0058] More particularly, specific conditions or diseases that may be treated by the compounds of the present invention include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, Ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterized by extensive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, bone resorption disorders, allograft rejection, infection-induced fever and myalgia secondary to infection, cachexia, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and bacillary dysentery; Alzheimer's disease, Parkinson's disease, cerebral ischemia caused by trauma, or neurodegenerative diseases; angiogenesis disorders, such as solid tumors, ocular angiogenesis, and infantile hemangioma; viral diseases Diseases include, for example, acute hepatitis infections (such as hepatitis A, B, and C), HIV infection and CMV retinitis, AIDS, ARC or malignant tumors, and herpes; stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions associated with prostaglandin endoperoxide synthase-2, and pemphigus vulgaris. Included in this embodiment is a method of treatment in which the disease is selected from lupus, e.g., lupus nephritis and systemic lupus erythematosus (SLE), Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris.Also included are methods of treatment in which the condition is selected from ischemia-reperfusion injury, such as cerebral ischemia-reperfusion injury resulting from stroke, and cardiac ischemia-reperfusion injury resulting from myocardial infarction. Another method of treatment is one in which the condition is multiple myeloma.

[0059] In certain embodiments, the compounds of Formula (I), Formula (II), Formula (III), and Formula (IV) are useful as prodrugs of Compound A in the treatment of cancer, such as Waldenstrom's macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneous diffuse large B-cell lymphoma, and primary malignant lymphoma.

[0060] Furthermore, the TLR7, TLR8, or TLR9 inhibitors of the present invention inhibit the expression of inducible proinflammatory proteins such as cyclooxygenase-2 (COX-2), IL-1, IL-6, IL-18, and prostaglandin endoperoxide synthase-2 (PGHS-2), also known as chemokines. Accordingly, additional TLR7 / 8 / 9-related symptoms include edema, analgesia, fever, and pain, such as neuromuscular pain, headache, cancer pain, dental pain, and arthritis pain. The compounds of the present invention can also be used to treat veterinary viral infections, such as lentiviral infections, including, but not limited to, equine infectious anemia virus; or retroviral infections, such as feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.

[0061] Accordingly, the present invention provides methods for treating such conditions, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV), or a salt thereof. A "therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit an autoimmune disease or a chronic inflammatory disease.

[0062] Methods for treating TLR7-, TLR8-, or TLR9-associated diseases may involve administering at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV), alone or in combination with other respective and / or other suitable therapeutic agents useful in treating such conditions. Accordingly, a "therapeutically effective amount" is also intended to include an amount of a combination of the claimed compounds that is effective to inhibit TLR7, TLR8, or TLR9 and / or treat a disease associated with TLR7, TLR8, or TLR9.

[0063] Examples of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear transport inhibitors, such as deoxyspergualin (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib, and rofecoxib; steroids, such as prednisone or dexamethasone; and antiviral drugs. antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®), etc.; antimalarials such as hydroxychloroquine; cytotoxic agents such as azathioprine and cyclophosphamide; TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or RAPAMUNE®) or derivatives thereof.

[0064] When used in combination with the compounds of the present invention, the above-mentioned other therapeutic agents can be used, for example, in amounts indicated in the Physicians' Desk Reference (PDR) or in amounts determined by one skilled in the art. In the methods of the present invention, such other therapeutic agents can be administered before, simultaneously with, or after the administration of the compounds of the present invention. The present invention also provides pharmaceutical compositions capable of treating TLR7 / 8 / 9 receptor-related diseases, such as the above-mentioned IL-1 family receptor-mediated diseases.

[0065] The compositions of the present invention may contain other therapeutic agents, as described above, and may be formulated according to techniques such as those well known in the art of pharmaceutical formulation, for example, by using conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the intended method of administration (e.g., additives, binders, preservatives, stabilizers, flavoring agents, etc.).

[0066] Accordingly, the present invention further includes compositions comprising at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV); and a pharmaceutically acceptable carrier.

[0067] A "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated according to many factors within the skill of those in the art. These include, but are not limited to, the type and nature of the active agent being formulated, the recipient to whom the agent-containing composition will be administered; the intended route of administration of the composition; and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can contain many different components and additives in addition to the active agent, and such additional components are included in the formulation for a variety of reasons well known to those skilled in the art, such as stabilizing the active agent, binding agents, etc. A description of suitable pharmaceutically acceptable carriers and factors related to their selection can be found in a variety of readily available sources, such as Remington's Pharmaceutical Sciences, 17th Edition (1985), the entire contents of which are incorporated herein by reference.

[0068] Compounds according to Formula (I), Formula (II), Formula (III), and / or Formula (IV) can be administered by any means appropriate to the condition to be treated, which may depend on the need for site-specific treatment or the amount of Compound A to be delivered.

[0069] Also within the scope of the present invention are types of pharmaceutical compositions comprising at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV); and one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carrier" substances), and optionally other active ingredients. At least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV) can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such route, and in a dose effective for the intended treatment. The compounds and compositions of the present invention can be administered, for example, orally, mucosally, or parenterally, for example, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally, in unit dosage forms containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier can comprise a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additional ingredients such as lubricants, for example, magnesium stearate, and disintegrants, for example, crospovidone. The carrier mixture may be filled into a gelatin capsule or compressed into a tablet. The pharmaceutical composition may be administered, for example, as an oral dosage form or an injection.

[0070] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably prepared in the form of a unit dosage containing a specific amount of active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing a dose of active ingredient in the range of about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, more preferably about 0.5 to 100 mg. The daily dose suitable for humans or other mammals may vary greatly depending on the patient's condition and other factors, but can be determined using conventional methods.

[0071] Any pharmaceutical composition contemplated herein can be delivered orally, for example, via any acceptable suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions intended for oral administration. To provide a pharmaceutically easy-to-take formulation, the pharmaceutical composition of the present invention can include at least one agent selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0072] Tablets can be prepared, for example, by mixing at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV) with at least one non-toxic pharmaceutically acceptable excipient suitable for tablet manufacture. Exemplary excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone, and acacia; and lubricants such as magnesium stearate, stearic acid, and talc. Furthermore, tablets can be either uncoated or coated by known techniques to mask the unpleasant taste of unpleasant drugs or to delay disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby maintaining the effect of the active ingredient over a prolonged period of time. Exemplary water soluble flavoring materials include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplary time delay materials include, but are not limited to, ethylcellulose and cellulose acetate butyrate.

[0073] Hard gelatin capsules can be prepared, for example, by mixing at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV) with at least one inert solid diluent, such as calcium carbonate; calcium phosphate; and kaolin.

[0074] Soft gelatin capsules can be prepared, for example, by mixing at least the compounds of Formula (I), Formula (II), Formula (III), and Formula (IV) with at least one water-soluble carrier, such as polyethylene glycol; and at least one oil medium, such as peanut oil, liquid paraffin, and olive oil.

[0075] Aqueous suspensions can be prepared, for example, by mixing at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV) with at least one excipient suitable for the manufacture of aqueous suspensions. Exemplary excipients suitable for the manufacture of aqueous suspensions include, but are not limited to, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents such as naturally occurring phosphatides, such as lecithin; condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearates; condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain at least one preservative, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, such as, but not limited to, sucrose, saccharin, and aspartame.

[0076] Oily suspensions can be prepared by suspending at least one compound of formula (I), formula (II), formula (III) and formula (IV) in vegetable oils such as peanut oil, olive oil, sesame oil, and coconut oil; or mineral oils such as liquid paraffin. Oily suspensions can contain at least one thickening agent, such as beeswax, solid paraffin, and cetyl alcohol. To provide a smooth oily suspension, at least one sweetener and / or at least one flavoring agent as described above can be added to the oily suspension. Oily suspensions can also contain at least one preservative, such as, but not limited to, antioxidants, such as butylated hydroxyanisole and alpha-tocopherol.

[0077] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV) with at least one dispersant and / or wetting agent; at least one suspending agent; and / or at least one preservative. Suitable dispersants, wetting agents, and suspending agents have already been described above. Exemplary preservatives include, but are not limited to, antioxidants, such as ascorbic acid. In addition, dispersible powders and granules may also include at least one excipient, such as, but not limited to, sweeteners; flavoring agents; and coloring agents.

[0078] Emulsions of at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV) can be prepared, for example, as oil-in-water emulsions. The oil phase of emulsions containing at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV) can be composed of known ingredients in known manners. The oil phase can be prepared, for example, from vegetable oils, such as olive oil and peanut oil; mineral oils, such as liquid paraffin; and mixtures thereof. The phase can contain only one emulsifier, or a mixture of at least one emulsifier with a fat or oil, or a mixture of both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifiers, with or without a stabilizer, form a so-called emulsifying wax, and the wax, together with the oil and fat, forms the oily dispersed phase of the cream formulation, forming a so-called emulsifying ointment base. The emulsion may also contain sweeteners, flavoring agents, preservatives, and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or with wax, or other materials known in the art.

[0079] At least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV) can also be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable suitable injection. Exemplary injection forms include, but are not limited to, sterile aqueous solutions containing acceptable vehicles and solvents such as water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oily suspensions.

[0080] Preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules using one or more of the carriers or diluents described for use in preparations for oral administration, or other suitable dispersing or wetting agents and suspending agents. The compound can also be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solution, tragacanth gum, and / or various buffers. Other adjuvants and dosage forms are well and widely known in the pharmaceutical field. The active ingredient can also be administered by injection as a composition with a suitable carrier such as saline, dextrose, or water, or with cyclodextrins (i.e., Captisol), cosolvent solubilizers (i.e., propylene glycol), or micelle solubilizers (i.e., Tween 80).

[0081] Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils have traditionally been used as solvents or suspending media. For this purpose, any brand of fixed oil, such as synthetic mono- or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0082] Sterile injectable oil-in-water microemulsions can be prepared, for example, by 1) dissolving at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV) in an oil phase, such as a mixture of soybean oil and lecithin; 2) combining the oil phase containing the compound of Formula (I), Formula (II), Formula (III), and Formula (IV) with a mixture of water and glycerol; and 3) treating the combination to form a microemulsion.

[0083] Sterile aqueous or oily suspension can be prepared according to the method already known in the art.For example, sterile aqueous solution or suspension can be prepared by using non-toxic parenterally acceptable diluent or solvent such as 1,3-butanediol; sterile oily suspension can be prepared by using non-toxic non-acceptable solvent or suspension medium, such as sterile fixed oil, for example, synthetic mono- or diglyceride; and fatty acid such as oleic acid.

[0084] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-alpha-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween, polyethoxylated castor oil, such as Cremophor surfactants (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. Cyclodextrins, such as alpha-, beta-, and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, e.g., 2- and 3-hydroxypropyl-cyclodextrin, or other solubilized derivatives, may also be advantageously used to enhance delivery of the compounds of the formulae described herein.

[0085] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to produce medicaments for administration to patients, such as humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization, and / or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. Tablets and pills may further be prepared with enteric coatings. Such compositions may also contain adjuvants such as wetting agents, sweeteners, flavoring agents, and fragrances.

[0086] The amount of compound administered and the dosage regimen for treating a disease using the compounds and / or compositions of the present invention vary depending on various factors, such as the age, weight, sex, condition of the subject, type of disease, severity of disease, route and frequency of administration, and the particular compound used. Thus, dosage regimens vary widely but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably about 0.0025 to about 50 mg / kg body weight, and most preferably about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. Other dosing schedules include a weekly dose and a cycle of once-every-two-day doses.

[0087] For therapeutic purposes, the active compound of the present invention is usually combined with one or more adjuvants suitable for the applicable administration route.For oral administration, the compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsules or tablets can contain sustained-release preparations, such as can be provided in the dispersion of active compound in hydroxypropylmethylcellulose.

[0088] Pharmaceutical compositions of the present invention comprise at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV), and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Another composition of the present invention comprises at least one compound of Formula (I), Formula (II), Formula (III), and Formula (IV), or a salt thereof, as described herein, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0089] The present invention also includes articles of manufacture. As used herein, articles of manufacture is intended to include, but are not limited to, kits and packages. Articles of manufacture of the present invention include (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof; and (c) a package insert stating that the pharmaceutical composition can be used to treat an inflammatory disorder and / or an autoimmune disease (as defined above). In another embodiment, the package insert states that the pharmaceutical composition can be used to treat an inflammatory disorder and / or an autoimmune disease in combination with a second therapeutic agent (as defined above). The article of manufacture may further include (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside the second container. Located within the first and second containers means that each container holds items within its boundaries.

[0090] The first container is a container used to hold the pharmaceutical composition. This container may be for manufacturing, storing, shipping, and / or individual / bulk sale. First container is intended to include bottles, jars, flasks, syringes, tubes (e.g., for cream formulations), or any other container used to manufacture, hold, store, or dispense pharmaceutical products.

[0091] The second container is used to hold the first container and, if appropriate, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, bins, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container by tape, glue, staples, or another attachment method, and can be placed inside the second container without any physical attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, the package insert is preferably physically attached by tape, glue, staples, or another attachment method. Alternatively, the package insert can be adjacent to or in contact with the outside of the second container without being physically attached.

[0092] The package insert may be a label, tag, marker, etc. It contains information about the pharmaceutical composition located in the first container. The information contained therein will usually be determined by a regulatory agency (e.g., the U.S. Food and Drug Administration) having jurisdiction over the region in which the product will be sold. In some embodiments, the package insert specifically describes the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material that allows a person to read the information contained therein or thereon. For example, the package insert may be a printable material (e.g., paper, plastic, cardboard, foil, single-sided adhesive paper, plastic, etc.) on which the desired information is formed (e.g., printed or attached).

[0093] Manufacturing method The compounds of the present invention can be synthesized by many methods well known to those skilled in the art of organic synthesis.The compounds of the present invention can be synthesized by the methods described below, in combination with synthetic methods known in the field of synthetic organic chemistry, or their variations as understood by those skilled in the art.Preferred methods include, but are not limited to, those described below.All references cited herein are incorporated herein by reference in their entirety.

[0094] The compounds of the present invention can be synthesized using the reactions and techniques described in this section. Reactions are carried out in solvents appropriate to the reagents and materials used and suitable for the transformations affected. It should also be understood that in the description of synthetic methods set forth below, all proposed reaction conditions, such as solvent selection, reaction atmosphere, reaction temperature, experimental time, and workup procedures, are selected as standard conditions for the reactions and would be readily recognized by one of ordinary skill in the art. Those skilled in the art of organic synthesis will understand that the functionality present on various portions of the molecule must be compatible with the proposed reagents and reactions. Restrictions on substituents compatible with such reaction conditions will be readily recognized by those skilled in the art, and alternative methods must be used. This may necessitate the determination of altering the order of synthetic steps or selecting one particular process scheme over another to obtain the desired compounds of the present invention. It should also be understood that another major consideration in the design of any synthetic route in this field is the judicious selection of protecting groups used to protect reactive functional groups present in the compounds described herein. An authoritative account explaining the many options to the skilled artisan is Greene and Wuts (Protective Groups In Organic Synthesis, Third Edition, Wiley and Sons, 1999).

[0095] Example The synthesis of compounds of formula (I), and intermediates used in the synthesis of compounds of formula (I), can be prepared using the procedures set forth in the following examples and related procedures. The methods and conditions used in these examples, and the actual compounds synthesized in these examples, are not meant to be limiting, but rather to demonstrate how compounds of formula (I) can be synthesized. The starting materials and reagents used in these examples, if not synthesized by the procedures described herein, are generally either commercially available, or are reported in the chemical literature, or can be synthesized using procedures described in the chemical literature.

[0096] [Table 1] [Table 2]

[0097] The analytical purity of the compounds was determined by using the following method: Analytical HPLC Method A: Column: SunFire C18 (150 x 4.6 mm) 3.5 micron; Buffer: 0.05% CF3CO2H / H2O; Mobile Phase A = Buffer:CH3CN [95:5]; Mobile Phase B: CH3CN:Buffer [95:5]; 10% B to 100% B; Run Time: 23 min; Flow Rate: 1.0 mL / min. Analytical HPLC Method B: Column: XBridge Phenyl C18 (150 x 4.6 mm) 3.5 micron; Buffer: 0.05% CF3CO2H / H2O; Mobile Phase A = Buffer:CH3CN [95:5]; Mobile Phase B: CH3CN:Buffer [95:5]; 10% B to 100% B; Run Time: 23 min; Flow Rate: 1.0 mL / min. Analytical HPLC Method C: Column: Kinetex EVO C18 (4.6x100) mm, 2.6 micron; Buffer: 0.05% CF3CO2H / H2O; Mobile Phase A = Buffer:CH3CN [95:5]; Mobile Phase B: CH3CN:Buffer [95:5]; 2% B to 100% B; Run Time: 12.5 min; Flow Rate: 1.0 mL / min. Analytical HPLC Method D: Column: XBridge Phenyl C18 (150 x 4.6 mm) 3.5 micron; Buffer: 0.05% CF3CO2H / H2O; Mobile Phase A = Buffer:CH3CN [95:5]; Mobile Phase B: CH3CN:Buffer [95:5]; 0% B to 100% B; Run Time: 12.5 min; Flow Rate: 1.0 mL / min. Analytical HPLC Method E: Column: Kinetex EVO C18 (4.6x100) mm, 2.6 micron; Buffer: 0.05% CF3CO2H / H2O; Mobile Phase A = Buffer:CH3CN [95:5]; Mobile Phase B: CH3CN:Buffer [95:5]; 5% B to 100% B; Run Time: 35 min; Flow Rate: 1.0 mL / min. Analytical HPLC Method F: Column: Kinetex Biphenyl C18 (4.6x100) mm, 2.6 micron; Buffer: 0.05% CF3CO2H / H2O; Mobile Phase A = Buffer:CH3CN [95:5]; Mobile Phase B: CH3CN:Buffer [95:5]; 5% B to 100% B; Run Time: 35 min; Flow Rate: 1.0 mL / min. [Example]

[0098] Example 1 (S)-Piperidin-2-ylmethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] Intermediate 1A: tert-butyl (S)-2-(hydroxymethyl)piperidine-1-carboxylate [ka] (S)-1-Boc-piperidine-2-carboxylic acid (4 g, 17.45 mmol) was dissolved in THF (40 mL) and cooled to 0 °C. Borane dimethyl sulfide complex (2.70 mL, 30.5 mmol) was then added dropwise at 0 °C. The reaction mixture was stirred for 1 h. The reaction mixture was then warmed to 25 °C and stirred for an additional 12 h. The reaction mixture was cooled to 0 °C. Saturated aqueous NaHCO (40 mL) was added slowly to quench the excess reagent. Water (20 mL) was added to dissolve the precipitated salts. The crude reaction contents were then extracted with CHCl (4 x 50 mL), and the combined organic extracts were washed with saturated aqueous NaHCO and HO, dried (MgSO), filtered, and concentrated to give the title compound (3.7 g, 16.33 mmol, 94% yield). 1 H NMR (400 MHz, DMSO-d6) δ 4.63 (t, J = 5.5 Hz, 1H), 4.03 (q, J = 6.5 Hz, 1H), 3.85-3.77 (m, 1H), 3.50 (ddd, J = 10.5, 8.5, 6.0 Hz, 1H), 3.43-3.34 (m, 1H), 2.72 (t, J = 13.1 Hz, 1H), 1.81-1.72 (m, 1H), 1.60-1.52 (m, 1H), 1.52-1.44 (m, 2H), 1.44-1.33 (m, 10H), 1.30-1.19 (m, 1H).

[0099] Intermediate 1B: tert-butyl (S)-2-(((1H-imidazole-1-carbonyl)oxy)methyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl (S)-2-(hydroxymethyl)piperidine-1-carboxylate (3.04 g, 14.12 mmol) in CHCN (40 mL) was added DIPEA (7.40 mL, 42.4 mmol) and 1,1'-carbonyldiimidazole (4.58 g, 28.2 mmol). The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated and the solvent was evaporated. The residue was partitioned between EtOAc and H2O. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a colorless gum. The crude material was purified by CombiFlash (silica gel 60-120 mesh; 50% EtOAc / hexane as eluent) to give the title compound (4.2 g, 12.90 mmol, 91% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.42 (t, J = 1.5 Hz, 1H), 7.05 (s, 1H), 4.76-4.57 (m, 2H), 4.38 (dd, J = 10.8, 5.0 Hz, 1H), 4.15-4.01 (m, 1H), 2.94-2.81 (m, 1H), 1.77-1.64 (m, 4H), 1.55-1.41 (m, 2H), 1.36 (s, 9H). LC-MS (ES): m / z = 308.3 [M+H] + .

[0100] Intermediate 1C: (S)-(1-(tert-butoxycarbonyl)piperidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (1 g, 2.249 mmol) in DMF (10 mL) was added DBU (0.509 mL, 3.37 mmol) and tert-butyl (S)-2-(((1H-imidazole-1-carbonyl)oxy)methyl)piperidine-1-carboxylate (2.088 g, 6.75 mmol). The reaction mixture was stirred at room temperature for 16 hours. Additional portions of tert-butyl (S)-2-(((1H-imidazole-1-carbonyl)oxy)methyl)piperidine-1-carboxylate (1.0 equiv.) and DBU (1.0 equiv.) were added. The reaction mixture was stirred for an additional 8 hours. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a colorless gum. The crude material was purified by CombiFlash (silica gel 60-120 mesh; 50% EtOAc / hexane as eluent) to give the title compound (650 mg, 0.929 mmol, 41.3% yield) as a white solid. LC-MS (ES): m / z = 686.7 [M+H] + .

[0101] Example 1: To a stirred solution of (S)-(1-(tert-butoxycarbonyl)piperidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (650 mg, 0.948 mmol) in CHCl (5 mL) was added CFCOH (1 mL, 12.98 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes and then at room temperature for 30 minutes. The reaction mixture was concentrated to remove the solvent at 30° C. The crude product was purified using RP-HPLC (Column: SunFire C18 (250 x 21.2 mm), 5 microns; Mobile phase A: 0.1% CF3CO2H / HO; Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient (time (min) / %B): 0 / 10, 2 / 10, 10 / 25). The crude product was purified using RP-HPLC (Column: SunFire C18 (250 x 21.2 mm), 5 microns; Mobile phase A: 0.1% CF3CO2H / HO; Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient (time (min) / %B): 0 / 10, 2 / 10, 10 / 25). Fractions were concentrated using high vacuum at 30 °C. The residue was dissolved in a mixture of CH3CN and H2O, frozen, and lyophilized for 12 h to give the title product (650 mg, 0.791 mmol, 83% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.69 (br.s., 1H), 8.97-8.89 (m, 1H), 8.72 (d, J = 3.5 Hz, 1H), 8.59-8.45 (m, 1H), 8.21-8.08 (m, 1H), 8.05 (s, 1H), 7.71-7.75 (m, 2H), 7.35-7.27 (m, 1H), 4.43-4.12 (m, 2H), 3.98 (s, 2H), 3.61 (d, J = 11.5 Hz, 2H), 3.30-3.15 (m, 3H), 3.08 (br.s., 1H), 2.98 (t, J = 12.0 Hz, 1H), 2.76 (dt, J = 14.2, 7.2 Hz, 2H), 2.63-2.55 (m, 3H), 2.23-1.97 (m, 7H), 1.72-1.53 ​​(m, 2H), 1.40-1.20 (m, 8H), 1.19-1.06 (m, 1H), 0.88-0.74 (m, 1H). LC-MS (ES): m / z = 586.4 [M+H] + ; HPLC RT and purity: Method A = 7.597 min and 99.84% and Method B = 7.866 min and 99.85%.

[0102] Example 2 (S)-(1-(((phosphonooxy)methoxy)carbonyl)piperidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] Intermediate 2A: (S)-(1-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)piperidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of (S)-piperidin-2-ylmethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (150 mg, 0.184 mmol) in THF (5 mL) was added DIPEA (0.161 mL, 0.922 mmol). The reaction mixture was cooled to 0 °C, and then ((bis(benzyloxy)phosphoryl)oxy)methyl chloroformate (137 mg, 0.369 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a colorless gum. The crude material was purified using RP-HPLC (column: YMC TRIAT (250 x 20 mm), 5 micron; mobile phase A: 10 mM NH4OAc / HO; mobile phase B: CH3CN; flow rate: 20 mL / min; gradient (time (min) / % B): 0 / 60, 15 / 85). Fractions were concentrated using high vacuum at 30 °C. The residue was dissolved in a mixture of CH3CN and HO, frozen, and lyophilized for 12 h to give the title compound (55 mg, 0.059 mmol, 31.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.75-8.60 (m, 1H), 8.43 (s, 1H), 8.05-7.99 (m, 1H), 7.64 (s, 1H), 7.43-7.21 (m, 13H), 5.61-5.24 (m, 2H), 5.07-4.93 (m, 4H), 4.44-3.74 (m, 4H), 2.99-2.59 (m, 10H), 2.20 (t, J = 9.8 Hz, 2H), 2.11-1.99 (m, 3H), 1.90-1.72 (m, 4H), 1.42-0.99 (m, 12H). LC-MS (ES): m / z = 920.4 [M+H] + .

[0103] Example 2: A stirred solution of (S)-(1-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)piperidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (55 mg, 0.060 mmol) in MeOH (4 mL) was purged with nitrogen. Pd / C (31.8 mg, 0.030 mmol) was then added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere using an air bag for 2 hours. The reaction mixture was filtered through a bed of Celite and washed with MeOH. The organic layer was concentrated under high vacuum at 30° C. to give a colorless gum. The crude product was purified using RP HPLC (Column: SunFire C18 (250 x 21.2 mm), 5 micron; Mobile phase A: 0.1% CFCOH / HO; Mobile phase B: CHCN; Flow rate: 20 mL / min; Gradient (time (min) / %B): 0 / 20, 2 / 20, 9 / 35). Fractions were concentrated under high vacuum at 30 °C. The residue was dissolved in a mixture of CHCN and HO, frozen, and lyophilized for 12 h to give the title compound (35 mg, 0.040 mmol, 67.2% yield) as a mixture of isomers (white solid). 1H NMR (400 MHz, MeOD) δ 8.55-8.49 (m, 1H), 8.41 (d, J = 4.00 Hz, 1H), 8.11-8.03 (m, 1H), 7.61 (s, 1H), 7.26-7.24 (m, 1H), 5.33-5.27 (m, 1H), 5.00-4.85 (m, 1H), 4.50-4.10 (m, 3H), 3.90 (s, 3H), 3.69-3.65 (m, 2H), 3.5-3.3 (m, 1H), 3.20-3.10 (m, 2H), 3.00-2.90 (m, 1H), 2.85-2.76 (m, 1H), 2.56-2.54 (m, 3H), 2.10-2.06 (m, 7H), 1.60-1.15 (m, 12H). LC-MS (ES): m / z = 740.4 [M+H] + ; HPLC RT and purity: Method A = 5.188-5.198 min and 98.24%; Method B = 4.932-4.994 min and 98.67%.

[0104] Example 3 (S)-Pyrrolidin-2-ylmethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] Intermediate 3A: (S)-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl 1H-imidazole-1-carboxylate [ka] To a solution of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (5 g, 24.84 mmol) in CHCN (50 mL) was added DIPEA (13.02 mL, 74.5 mmol) and 1,1'-carbonyldiimidazole (8.06 g, 49.7 mmol). The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated to remove the solvent. The residue was partitioned between EtOAc and H2O. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give a colorless gum. The crude product was purified by CombiFlash (silica gel 60-120 mesh; 40% EtOAc / hexane as eluent) to give the title compound (6.2 g, 19.94 mmol, 80% yield) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 4.51-4.34 (m, 2H), 4.25-4.12 (m, 1H), 3.47 (br.s., 1H), 3.38 (br.s., 1H), 2.13-1.99 (m, 1H), 1.98-1.78 (m, 3H), 1.45 (s, 9H). LC-MS (ES): m / z = 296.4 [M+H] + ;

[0105] Intermediate 3B: (S)-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (527 mg, 1.185 mmol) in DMF (8 mL) was added DBU (0.268 mL, 1.778 mmol) and (S)-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl 1H-imidazole-1-carboxylate (1050 mg, 3.56 mmol). The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was partitioned between EtOAc and HO. The separated organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated to a colorless gum. The crude material was purified by CombiFlash (silica gel 60-120 mesh; 35 to 40% EtOAc / hexanes as eluent) to give the title compound (350 mg, 0.495 mmol, 41.8% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.81 (br.s., 1H), 8.46 (d, J = 2.5 Hz, 1H), 8.18-8.06 (m, 1H), 7.67 (s, 1H), 7.31 (d, J = 9.4 Hz, 2H), 7.16 (br.s., 1H), 4.16-3.96 (m, 1H), 3.92 (br.s., 1H), 3.07 (d, J = 5.9 Hz, 2H), 3.00-2.86 (m, 4H), 2.81-2.62 (m, 3H), 2.57 (s, 3H), 2.31-2.13 (m, 2H), 2.08 (s, 3H), 1.94-1.85 (m, 2H), 1.81 (br.s., 3H), 1.61 (d, J = 6.8 Hz, 1H), 1.51 (d, J = 7.4 Hz, 2H), 1.38-1.18 (m, 15H). LC-MS (ES): m / z = 672.7 [M+H] + .

[0106] Example 3: To a stirred solution of (S)-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (450 mg, 0.670 mmol) in CHCl (5 mL) was added CFCOH (1 mL, 12.98 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, allowed to warm to room temperature, and stirred for 30 minutes. The reaction mixture was concentrated and the solvent was evaporated at 30° C. The crude product was purified using RP HPLC (Column: SunFire C18 (150 x 19 mm), 5 micron; Mobile phase A: 0.1% CF3CO2H / HO; Mobile phase B: CH3CN; Flow rate: 17 mL / min; Gradient (time (min) / %B): 0 / 10, 10 / 30). Fractions were concentrated using high vacuum at 30 °C. The residue was dissolved in a mixture of CH3CN and HO, frozen, and lyophilized for 12 h to give the title compound (320 mg, 0.396 mmol, 59.1% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.64 (br.s., 1H), 9.38 (br.s., 1H), 8.98-8.85 (m, 1H), 8.73 (d, J = 3.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.10-8.15 (d, J = 8.6 Hz, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.74 (s, 1H), 7.28 (d, J = 8.6 Hz, 1H), 4.51-4.31 (m, 3H), 3.98 (br.s., 2H), 3.59-3.18 (m, 5H), 2.98 (t, J = 11.6 Hz, 1H), 2.82-2.68 (m, 1H), 2.58 (s, 3H), 2.24-1.96 (m, 7H), 1.95-1.80 (m, 1H), 1.71 (d, J = 4.6 Hz, 2H), 1.54-1.21 (m, 8H); LC-MS (ES): m / z = 572.4 [M+H] +; HPLC RT and purity: Method A = 7.167 min and 99.54% and Method B = 7.912 min and 99.59%.

[0107] Example 4 (S)-(1-(((phosphonooxy)methoxy)carbonyl)pyrrolidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] Intermediate 4A: (S)-(1-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)pyrrolidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of (S)-pyrrolidin-2-ylmethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate ditrifluoroacetate (125 mg, 0.156 mmol) in THF (5 mL) was added EtN (0.109 mL, 0.781 mmol) and ((bis(benzyloxy)phosphoryl)oxy)methyl chloroformate (116 mg, 0.313 mmol) sequentially. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was partitioned between EtOAc and HO. The organic layer was separated, washed with brine, dried over anhydrous NaSO, filtered, and concentrated to give a colorless gum. The crude material was purified using RP HPLC (Column: X-Bridge Phenyl (250 x 19 mm), 5 micron; Mobile phase A: 10 mM NH4OAc / HO; Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient (time (min) / % B): 0 / 35, 2 / 35, 14 / 65). Fractions were concentrated using high vacuum at 30 °C. The residue was dissolved in a mixture of CH3CN and HO, frozen, and lyophilized for 12 h to give the title product (45 mg, 0.045 mmol, 28.6% yield) as a white solid. 11H NMR (300 MHz, DMSO-d6) δ 8.83 - 8.72 (m, 1H), 8.49 - 8.41 (m, 1H), 8.12 - 8.00 (m, 1H), 7.66 (s, 1H), 7.57 (d, J = 5.0 Hz, 1H), 7.41 - 7.24 (m, 11H), 7.16 (br.s., 1H), 5.63 - 5.43 (m, 2H), 5.02 (d, J = 7.4 Hz, 4H), 4.21 - 3.80 (m, 2H), 3.20 - 3.01 (m, 2H), 3.01 - 2.86 (m, 4H), 2.79 - 2.62 (m, 3H), 2.54 (br.s., 3H), 2.30 - 2.19 (m, 3H), 2.15 (br.s., 1H), 2.00 - 1.81 (m, 4H), 1.52 - 1.31 (m, 2H), 1.35 - 1.19 (m, 8H), 1.01 (d, J = 6.6 Hz, 1H). LC-MS (ES): m / z = 906.8 [M+H] +

[0108] Example 4: A solution of (S)-(1-((((bis(benzyloxy)phosphoryl)oxy)methoxy)carbonyl)pyrrolidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (20 mg, 0.022 mmol) in MeOH (1 mL) was purged with nitrogen. Pd / C (11.75 mg, 0.011 mmol) was then added. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours using an air bag. The reaction mixture was filtered through a bed of Celite and washed with MeOH. The organic layer was concentrated under high vacuum at 30° C. to give a colorless gum. The crude product was purified using RP HPLC (Column: SunFire C18 (150 x 21.2 mm), 5 micron; Mobile phase A: 0.1% CF3CO2H / HO; Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient (time (min) / %B): 0 / 10, 2 / 10, 15 / 40). Fractions were concentrated using high vacuum at 30 °C. The residue was dissolved in a mixture of CH3CN and HO, frozen, and lyophilized for 12 h to give the title compound (20 mg, 0.022 mmol) as a white solid. 1 H NMR (400 MHz, MeOH-d4) δ 8.55-8.52 (m, 1H), 8.43-8.32 (m, 1H), 8.13 (t, J = 8.2 Hz, 1H), 7.62 (br.s., 1H), 7.26 (d, J = 6.8 Hz, 1H), 5.42 (br.s., 1H), 5.36 (br.s., 1H), 4.38-4.27 (m, 1H), 4.12-3.99 (m, 2H), 3.91-3.85 (m, 2H), 3.68-3.66 (m, 4H), 2.97-3.30 (m, 3H), 2.75 (dd, J = 13.9, 7.3 Hz, 1H), 2.55 (br.s., 3H), 2.18-1.96 (m, 7H), 1.71-1.54 (m, 3H), 1.32-1.21 (m, 7H). LC-MS (ES): m / z = 727.2 [M+H] +; HPLC RT and purity: Method A = 4.559 min and 99.40% and Method B = 4.425 min and 99.46%.

[0109] Example 5 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1-(methylglycyl)-1H-indol-5-yl)piperidin-1-yl)acetamide ditrifluoroacetate [ka] Intermediate 5A: Benzyl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate [ka] EtN (0.809 mL, 5.81 mmol) and benzyl chloroformate (1.105 mL, 3.87 mmol) were added to a solution of 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 3.87 mmol) in CHCl (5 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. The resulting suspension was filtered, and the residue after evaporation of the solvent was taken up in EtOAc (50 mL), which was washed with HO and dried over anhydrous NaSO. Evaporation of the solvent gave the crude product, which was purified by Combiflash chromatography (60-120 silica gel; 20-60% EtOAc / petroleum ether as eluent) to give the title compound (0.8 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.01-10.91 (m, 1H), 8.74 (s, 1H), 8.48 (s, 1H), 7.61-7.52 (m, 1H), 7.44-7.24 (m, 6H), 7.08-6.97 (m, 1H), 5.12 (s, 2H), 4.19 (d, J = 13.6 Hz, 2H), 3.06-2.77 (m, 4H), 2.63-2.55 (m, 3H), 2.16 (s, 3H), 2.01-1.91 (m, 1H), 1.84 (d, J = 11.0 Hz, 1H), 1.78-1.53 ​​(m, 2H), 1.38-1.26 (m, 6H). LC-MS (ES): m / z = 522.2 [M+H] + .

[0110] Intermediate 5B: Benzyl 4-(1-(N-(tert-butoxycarbonyl)-N-methylglycyl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate [ka] To a solution of benzyl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (500 mg, 0.958 mmol) in CHCl (10 mL) was added N-(tert-butoxycarbonyl)-N-methylglycine (544 mg, 2.88 mmol), DCC (297 mg, 1.438 mmol), and DMAP (117 mg, 0.958 mmol). The reaction mixture was stirred at 60 °C under N for 16 h, filtered through a Celite bed, and the bed was washed with EtOAc. The filtrate was concentrated under vacuum at 30 °C. The crude product was purified using RP HPLC (Column: Xbridge Phenyl (250 x 4.6 mm) 5 micron; Mobile phase A: 10 mM ammonium bicarbonate - pH 9.5 Mobile phase B: CHCN; Flow rate: 1 mL / min; Gradient (time (min) / % B): 0 / 30, 3 / 60, 15 / 100, 19 / 100, 20 / 30). Fractions were concentrated using high vacuum at 30 °C. The residue was dissolved in a mixture of CHCN and HO, frozen, and lyophilized for 12 h to give the title compound (400 mg, 0.577 mmol, 60.2% yield) as a brownish solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 2.0 Hz, 1H), 8.55-8.48 (m, 1H), 8.29-8.15 (m, 1H), 7.69 (s, 1H), 7.45-7.27 (m, 6H), 5.12 (s, 2H), 4.20 (d, J = 13.1 Hz, 2H), 4.14-3.88 (m, 2H), 3.08-2.83 (m, 3H), 2.75 (s, 1H), 2.70-2.64 (m, 3H), 2.59 (d, J = 8.5 Hz, 3H), 2.57 (s, 3H), 1.85 (d, J = 12.5 Hz, 2H), 1.65 (qd, J = 12.6, 4.3 Hz, 2H), 1.35-1.20 (m, 15H). LC-MS (ES): m / z = 693.4 [M+H] + .

[0111] Intermediate 5C: tert-butyl (2-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(piperidin-4-yl)-1H-indol-1-yl)-2-oxoethyl)(methyl)carbamate [ka] To a solution of benzyl 4-(1-(N-(tert-butoxycarbonyl)-N-methylglycyl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (440 mg, 0.635 mmol) in dry EtOAc (5 mL) was added Pd / C (43.9 mg, 0.041 mmol). The mixture was degassed and then purged with N2 gas. The reaction mixture was stirred under an H2 atmosphere for 5 hours, filtered through a Celite bed, and the bed was washed with EtOAc. The filtrate was concentrated under vacuum at 30 °C to give the title compound (334 mg, 98%). 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.50 (d, J = 7.5 Hz, 1H), 8.27-8.14 (m, 1H), 7.65 (s, 1H), 7.29 (dd, J = 9.3, 3.8 Hz, 1H), 4.14-3.88 (m, 2H), 3.05-3.08 (m, 2H), 2.75 (s, 3H), 2.70-2.58 (m, 7H), 2.14-2.07 (m, 3H), 1.81-1.70 (m, 2H), 1.61 (q, J = 12.4 Hz, 2H), 1.37-1.20 (m, 15H; LC-MS (ES): m / z = 559.2 [M+H] + .

[0112] Intermediate 5D: tert-butyl (2-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-2-oxoethyl)(methyl)carbamate [ka] To a solution of tert-butyl (2-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(piperidin-4-yl)-1H-indol-1-yl)-2-oxoethyl)(methyl)carbamate (300 mg, 0.537 mmol) in DMF (10 mL) was added EtN (0.225 mL, 1.611 mmol) and 2-bromoacetamide (96 mg, 0.698 mmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with HO and extracted with EtOAc. The organic layer was washed with HO and brine, dried over anhydrous NaSO and concentrated under vacuum at 40 °C to give the crude product as a brownish oil, which was purified by RP HPLC (Column: YMC Trait (150 × 20) mm 5 micron; Mobile phase A: 10 mM NH OAc / HO; Mobile phase B: CH CN; Flow rate: 20 mL / min; Gradient (T / % B): 0 / 40, 2 / 40, 12 / 65) to give the title compound (100 mg, 0.161 mmol, 29.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (br.s., 1H), 8.51 (d, J = 7.5 Hz, 1H), 8.27-8.16 (m, 1H), 7.69 (s, 1H), 7.34 (br.s., 1H), 7.26 (br.s., 1H), 7.14 (br.s., 1H), 4.14-3.91 (m, 2H), 2.95 (m, 4H), 2.75-2.58 (m, 8H), 2.26-2.16 (m, 2H), 2.13-2.05 (s, 3H), 1.85-1.59 (m, 4H), 1.34-1.10 (m, 15H). LC-MS (ES): m / z = 616.4 [M+H] + .

[0113] Example 5: To a solution of tert-butyl (2-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-2-oxoethyl)(methyl)carbamate (75 mg, 0.122 mmol) in dry CHCl (2 mL) under a nitrogen atmosphere at 0° C. was added CFCOH (0.3 mL, 3.89 mmol). After stirring for 30 min, the reaction mixture was concentrated in vacuo. The residue was stirred with ether. The solvent was carefully decanted. The solid was dissolved in a mixture of CHCN and HO. The resulting mixture was frozen and lyophilized for 12.0 hours to afford the title compound (46.15 mg, 0.061 mmol, 50.4% yield) as a white solid. 1H NMR (400 MHz, MeOH-d4) δ 8.73 (s, 1H), 8.48 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 4.80 (br.s., 2H), 4.34 (d, J = 16.6 Hz, 1H), 4.04-3.94 (m, 3H), 3.78-3.81 (m, 2H), 3.13 (br.s., 1H), 2.83 (dt, J = 14.2, 7.2 Hz, 1H), 2.69 (s, 6H), 2.25-2.15 (m, 7H), 1.39 (t, J = 6.5 Hz, 6H). LC-MS (ES): m / z = 516.4 [M+H] + HPLC RT and purity: Method A = 5.703 min and 99.96% and Method B = 6.004 min and 99.17%.

[0114] Examples 6 and 7 1-((1-Aminocyclopropane-1-carbonyl)oxy)ethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate ditrifluoroacetate [ka] Intermediate 6A: 1-Chloroethyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of tert-butyl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (2.0 g, 4.10 mmol) in THF (40 mL) was added a 1 M solution of LiHMDS (6.15 mL, 6.15 mmol) in THF. The reaction mixture was stirred at −70° C. under N for 15 minutes. Then, 1-chloroethyl chloroformate (0.888 mL, 8.20 mmol) was added. The reaction mixture was stirred at −70° C. under N for 1 hour. The reaction mixture was partitioned between HO and EtOAc. The organic layer was washed with HO and brine, dried over anhydrous NaSO, and concentrated to give the crude product, which was purified by RP HPLC (SunFire OBD (250x30) mm, 5 micron; mobile phase A: 10 mM NH4OAc / HO; mobile phase B: CH3CN; flow rate: 30 mL / min; gradient (time (min) / % B): 15 / 85) to give two isomers. Isomer 1: The product was obtained as a white solid (1.0 g; 20.5%). 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.47 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.73-7.67 (m, 1H), 7.35 (dd, J = 8.5, 1.5 Hz, 1H), 6.63-6.55 (m, 1H), 4.12 (s, 1H), 4.15 (s, 1H), 2.93-2.74 (m, 4H), 2.58 (s, 3H), 2.10 (s, 3H), 1.82-1.85 (m, 2H), 1.62 (dd, J = 12.3, 3.8 Hz, 2H), 1.44 (s, 9H), 1.34 (d, J = 5.5 Hz, 3H), 1.30 (dd, J = 7.0, 4.0 Hz, 6H). LC-MS (ES): m / z = 594.2 [M+H] + . Isomer 2: The product was obtained as a white solid (0.9 g; 18.5%). 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H), 7.35 (m, 1H), 6.58-6.50 (m, 1H), 4.15 (br.s., 2H), 2.95-2.75 (m, 3H), 2.59 (s, 4H), 2.08 (s, 3H), 1.86-1.83 (m, 2H), 1.68-1.54 (m, 2H), 1.44 (s, 9H), 1.30 (t, J = 7.3 Hz, 6H), 1.14 (d, J = 6.0 Hz, 3H). LC-MS (ES): m / z = 594.2 [M+H] + .

[0115] Intermediate 6B: 1-Chloroethyl 2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(piperidin-4-yl)-1H-indole-1-carboxylate trifluoroacetate [ka] To the solid of 1-chloroethyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (1.1 g, 1.851 mmol), Isomer 1, from the previous step in CHCl (10 mL) was added CFCOH (1.426 mL, 18.51 mmol) at 0 °C under a nitrogen atmosphere. After stirring at 0 °C for 1 h, the reaction mixture was concentrated in vacuo at 30 °C. The residue was stirred with ether. The solvent was carefully stirred. The resulting solid was dried under vacuum to give the crude product as a brown oil (1.1 g, 1.809 mmol, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.59 (br.s., 1H), 8.49 (s, 1H), 8.33 (br.s., 1H), 8.19 (d, J = 9.0 Hz, 1H), 7.69 (d, J = 1.0 Hz, 1H), 7.34 (dd, J = 8.8, 1.8 Hz, 1H), 6.59 (q, J = 5.5 Hz, 1H), 3.42-3.45 (m, 2H), 3.14-2.97 (m, 3H), 2.85-2.75 (m, 1H), 2.58 (s, 3H), 2.10 (s, 3H), 2.07-1.99 (m, 2H), 1.98-1.83 (m, 2H), 1.39-1.25 (m, 9H). LC-MS (ES): m / z = 494.2 [M+H] + .

[0116] Intermediate 6C: 1-Chloroethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of 1-chloroethyl 2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(piperidin-4-yl)-1H-indole-1-carboxylate (1.1 g, 2.227 mmol) in DMF (10 mL) was added EtN (0.931 mL, 6.68 mmol) and 2-bromoacetamide (0.399 g, 2.89 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with HO and extracted with EtOAc. The organic layer was washed with HO and brine, dried over anhydrous NaSO, and concentrated under vacuum at 40 °C to give the crude product as a white solid, which was purified by RP HPLC (Column: SunFire OBD (250 × 30 mm), 5 micron; Mobile phase A: 10 mM NH OAc / HO; Mobile phase B: CH CN; Flow rate: 30 ml / min; Gradient: (Time (min) / % B) 0 / 50, 2 / 50, 13 / 80) to give the title compound (0.8 g, 1.452 mmol, 65.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.47 (s, 1H), 8.13 (d, J = 11.60 Hz, 1H), 7.70 (s, 1H), 7.36 (d, J = 11.20 Hz, 1H), 7.26 (s, 1H), 7.16 (s, 1H), 6.57-6.59 (m, 1H), 2.97-2.80 (m, 4H), 2.78-2.65 (m, 2H), 2.57 (s, 3H), 2.15-2.24 (m, 2H), 2.09 (s, 3H), 1.91-1.81 (m, 4H), 1.20-1.34 (m, 9H). LC-MS (ES): m / z = 551.2 [M+H] + .

[0117] Intermediate 6D: 1-((1-((tert-butoxycarbonyl)amino)cyclopropane-1-carbonyl)oxy)ethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of 1-chloroethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (500 mg, 0.907 mmol) in DMF (5 mL) was added 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid (365 mg, 1.815 mmol), NaI (136 mg, 0.907 mmol), and DIPEA (0.475 mL, 2.72 mmol). After stirring at 75 °C under a nitrogen atmosphere for 12 hours, the reaction mixture was partitioned between EtOAc and HO. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated to give the crude product as a pale yellowish solid. The crude product was purified by RP HPLC (Column: YMC TRIART C18 (250 x 4.6) mm, 5 micron; Mobile phase: A: 10 mM NH4OAc / HO; B: CH3CN; Flow rate: 1.0 mL / min; Gradient (time (min) / % B): 0 / 30, 20 / 70, 21 / 100, 25 / 100, 26 / 30) to give two isomers. Isomer A: The product was obtained as a white solid (135 mg, 0.187 mmol, 20.58% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.46 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.54 (s, 1H), 7.37-7.30 (m, 1H), 7.25 (br.s., 1H), 7.14 (br.s., 1H), 6.65 (d, J = 5.0 Hz, 1H), 2.96 (d, J = 12.0 Hz, 2H), 2.90 (s, 2H), 2.82-2.71 (m, 1H), 2.70-2.63 (m, 1H), 2.60 (s, 3H), 2.21 (t, J = 11.0 Hz, 2H), 2.09 (s, 3H), 1.92-1.75 (m, 4H), 1.36-1.21 (m, 18H), 1.04 (br.s., 2H), 0.98 (d, J = 5.5 Hz, 2H). LC-MS (ES): m / z = 716.4 [M+H] + . Alien B: The product was obtained as a white solid (120 mg, 0.159 mmol, yield 17.55%). 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.46 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.42 (s, 1H), 7.34-7.32 (m, 1H), 7.25 (br.s., 1H), 7.13 (br.s., 1H), 6.70 (d, J = 5.0 Hz, 1H), 2.96 (d, J = 11.0 Hz, 2H), 2.90 (s, 2H), 2.80-2.74 (m, 1H), 2.72-2.61 (m, 1H), 2.57 (s, 3H), 2.28-2.16 (m, 2H), 2.09 (s, 3H), 1.93-1.76 (m, 4H), 1.37-1.05 (m, 18H), 1.04 (br.s., 2H), 0.98 (d, J = 3.0 Hz, 2H). LC-MS (ES): m / z = 716.4 [M+H] + .

[0118] Example 6: To a solution of Isomer A, 1-((1-((tert-butoxycarbonyl)amino)cyclopropane-1-carbonyl)oxy)ethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (10 mg, 0.014 mmol) in CHCl (1 mL), was added CFCOH (10.76 μL, 0.140 mmol). The reaction mixture was stirred in an ice bath for 1 h and at room temperature for 1 h. The reaction mixture was concentrated under high vacuum to give a residue, which was dissolved in a mixture of CHCN and HO. The resulting mixture was frozen and lyophilized for 16 hours to give the title compound (5.05 mg, 6.78 μmol, 48.5% yield) as a colorless solid. 1 H NMR (400 MHz, MeOH-d4) δ 8.64 (s, 1H), 8.46 (s, 1H), 8.22 (d, J = 9.0 Hz, 1H), 7.76 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 6.88 (q, J = 5.4 Hz, 1H), 4.03 (s, 2H), 3.78-3.81 (m, 2H), 3.35-3.30 (m, 2H), 3.11 (d, J = 7.0 Hz, 1H), 2.88 (dt, J = 14.1, 7.0 Hz, 1H), 2.68 (s, 3H), 2.25-2.18 (m, 7H), 1.44-1.35 (m, 8H), 1.32-1.30 (m, 2H), 1.18 (d, J = 5.5 Hz, 3H). LC-MS (ES): m / z = 616.4 [M+H] + HPLC RT and purity: Method A = 7.38 min and 98.78% and Method B = 9.93 min and 98.96%.

[0119] Example 7: To a solution of Isomer B of 1-((1-((tert-butoxycarbonyl)amino)cyclopropane-1-carbonyl)oxy)ethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (120 mg, 0.168 mmol) in dry CHCl (2 mL) under a nitrogen atmosphere at 0° C. was added CFCOH (0.3 mL, 3.89 mmol). After stirring for 30 min, the reaction mixture was concentrated in vacuo. The residue was stirred with ether. The solvent was carefully decanted. The remaining solid was dried under vacuum to give the crude product as an off-white solid. The solid was dissolved in a mixture of CHCN and HO. The resulting mixture was frozen and lyophilized for 12 hours to afford the title compound (70 mg, 0.080 mmol, 48.0% yield) as a white solid. 1 H NMR (400 MHz, MeOH-d4) δ 8.63 (s, 1H), 8.51-8.44 (m, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 6.94-6.84 (m, 1H), 4.03 (s, 2H), 3.81-3.78 (m, 2H), 3.17-3.04 (m, 2H), 2.88 (quin, J = 7.2 Hz, 1H), 2.85-2.82 (m, 1H), 2.67 (s, 3H), 2.26-2.14 (m, 7H), 1.46-1.26 (m, 9H), 1.24 (d, J = 5.5 Hz, 3H), 1.13-1.03 (m, 1H). LC-MS (ES): m / z = 616.4 [M+H] + HPLC RT and purity: Method A = 7.50 min and 97.86% and Method B = 9.03 min and 98.63%.

[0120] Examples 8 and 9 6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-1-((phosphonooxy)methyl)-[1,2,4]triazolo[1,5-a]pyridin-1-ium trifluoroacetate (8) and 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-((phosphonooxy)methyl)piperidin-1-ium trifluoroacetate (9) [ka] Intermediates 8A and 9A: (1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-ium-1-yl)methyl tert-butyl phosphate [ka] To a stirred solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (2.0 g, 4.50 mmol) in CHCl (60.0 mL) was added KCO (0.622 g, 4.50 mmol). The reaction mixture was stirred at room temperature for 10 minutes. To this mixture was added di-tert-butyl (chloromethyl)phosphate (4.07 g, 15.75 mmol) and NaI (2.360 g, 15.75 mmol). The reaction mixture was stirred at 68 °C for 20 hours. The reaction mixture was filtered through a celite bed, washed with excess CHCl, and the filtrate was concentrated in vacuo. The crude product was purified using reverse-phase preparative HPLC (Column: YMC TRIAT (150x20) mm; 5 micron; Mobile phase A: 10 mM NH4OAc / HO; Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient (time (min) / % B): 0 / 30, 15 / 50). Fractions were concentrated using high vacuum at 30°C. The residue was dissolved in a mixture of CH3CN and HO, frozen, and lyophilized for 16 hours to give the title compound as a mixture of isomers (490 mg, 0.626 mmol, 13.91% yield) as an off-white solid. LC-MS (ES): m / z = 611.4 [M+H] + .

[0121] Examples 8 and 9: To a stirred solution of 1-(2-amino-2-oxoethyl)-1-(((tert-butoxy(hydroxy)phosphoryl)oxy)methyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-ium iodide (0.6 g, 0.812 mmol) in CHCl (6.0 mL) was added CFCOH (0.6 mL, 7.79 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 30 minutes and then concentrated under reduced pressure. The crude compound was purified by RP HPLC (Column: X-Bridge C18 (250x30) mm; 5 micron; Mobile phase A: 0.1% CF3CO2H / H2O; Mobile phase B: CH3CN:MeOH (1:1) Flow rate: 30 mL / min; Gradient (time (min) / %B): 70 / 30) to give two isomers. Example 8 (Isomer 1): The compound was obtained as an off-white solid (86 mg, 0.123 mmol, 15.18% yield). 1 H NMR (400 MHz, MeOH-d4) δ 8.70 (s, 1H), 8.60 (s, 1H), 7.72 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 8.5, 1.5 Hz, 1H), 5.33 (d, J = 8.0 Hz, 2H), 4.39 (s, 2H), 4.13-4.10 (m, 2H), 3.68-3.56 (m, 2H), 3.17-2.96 (m, 2H), 2.68 (s, 3H), 2.40-2.27 (m, 5H), 2.26-2.16 (m, 2H), 1.41 (d, J = 7.5 Hz, 6H). LC-MS (ES): m / z = 556.2 [M+H] + HPLC RT and purity: Method A = 4.574 min and 96.36% and Method B = 4.245 min and 96.98%. Example 9 (Isomer 2): The compound was obtained as an off-white solid (300 mg, 0.435 mmol, 53.5% yield). 1H NMR (400 MHz, MeOH-d4) δ 8.71 (s, 1H), 8.62 (s, 1H), 7.70 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 8.5, 1.5 Hz, 1H), 5.53 (d, J = 8.0 Hz, 2H), 4.20-4.10 (m, 4H), 3.90-3.74 (m, 2H), 3.17-2.93 (m, 2H), 2.68 (s, 3H), 2.49-2.33 (m, 2H), 2.30 (s, 3H), 2.15-2.11 (m, 2H), 1.40 (d, J = 7.0 Hz, 6H). LC-MS (ES): m / z = 556.2 [M+H] + ; HPLC RT and purity: Method A = 4.585 min and 97.19% and Method B = 4.265 min and 97.74%.

[0122] Example 10 4-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-4-oxobutyl dihydrogen phosphate [ka] Intermediate 10A: tert-butyl 4-(1-(4-((bis(benzyloxy)phosphoryl)oxy)butanoyl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (1 g, 2.051 mmol) in CHCl (10 mL) was added 4-((bis(benzyloxy)phosphoryl)oxy)butanoic acid (1.494 g, 4.10 mmol), DCC (0.635 g, 3.08 mmol), and DMAP (0.376 g, 3.08 mmol). The reaction mixture was stirred under N for 16 hours and then diluted with CHCl. ​​The precipitated solid was filtered, and the filtrate was concentrated in vacuo to give a residue. The crude compound was purified by reverse-phase HPLC (column: YMC TRIART C18 (150 x 4.6) mm, 5 micron; mobile phase A: 10 mM NH4OAc / HO; B: CH3CN; flow rate: 1.0 mL / min; gradient (time (min) / % B: 0 / 30, 3 / 60, 15 / 100, 20 / 100, 21 / 30). Fractions were concentrated using a high vacuum pump. The final residue was dissolved in CH3CN and HO and lyophilized for 12 h to give the title compound (0.5 g, 0.600 mmol, 29.2% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.42 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H), 7.40-7.19 (m, 11H), 5.02-4.93 (m, 2H), 4.93-4.83 (m, 4H), 4.09 (d, J = 11.2 Hz, 2H), 3.98-3.81 (m, 2H), 3.24-3.09 (m, 2H), 2.83 (t, J = 12.0 Hz, 2H), 2.75-2.59 (m, 3H), 2.01 (s, 3H), 1.87-1.58 (m, 6H), 1.57-1.44 (m, 6H), 1.42 (s, 9H). LC-MS (ES): m / z = 734.2 [M+H] + .

[0123] Intermediate 10B: Dibenzyl (4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(piperidin-4-yl)-1H-indol-1-yl)-4-oxobutyl)phosphate trifluoroacetate [ka] To a solution of tert-butyl 4-(1-(4-((bis(benzyloxy)phosphoryl)oxy)butanoyl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (80 mg, 0.096 mmol) in CHCl (1 mL) at 0 °C was added CFCOH (0.3 mL, 3.89 mmol). The reaction mixture was stirred under N at 0 °C for 1 h and then at room temperature for 1 h. The solvent was removed under high vacuum to give the title compound (80 mg, 0.094 mmol, 98% yield). LC-MS (ES): m / z = 734.2 [M+H] + .

[0124] Intermediate 10C: 4-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-4-oxobutyl dibenzyl phosphate [ka] To a solution of dibenzyl (4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(piperidin-4-yl)-1H-indol-1-yl)-4-oxobutyl)phosphate (80 mg, 0.109 mmol) in anhydrous DMF (1 mL) were added 2-bromoacetamide (19.55 mg, 0.142 mmol) and EtN (0.046 mL, 0.327 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 5 h and partitioned between HO and EtOAc. The organic layer was washed with HO and brine, dried over anhydrous NaSO, and concentrated to give the crude product as a pale yellow oil, which was purified by RP HPLC (Column: SunFire OBD (250x30) mm, 5 micron; Mobile phase A: 10 mM NH4OAc / HO; Mobile phase B: CH3CN; Flow rate: 30 mL / min) to give the title compound (70 mg, 0.089 mmol, 81% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.45 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.36-7.23 (m, 12H), 7.16 (br.s., 1H), 4.94-4.86 (m, 4H), 3.94-3.82 (m, 2H), 3.00-2.86 (m, 4H), 2.76-2.59 (m, 4H), 2.54 (br.s., 3H), 2.30-2.15 (m, 2H), 2.03 (s, 3H), 1.88 (d, J = 11.4 Hz, 2H), 1.79 (br.s., 4H), 1.27 (t, J = 6.5 Hz, 6H). LC-MS (ES): m / z = 791.8 [M+H] + .

[0125] Example 10: To a solution of 4-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-4-oxobutyl dibenzyl phosphate (40 mg, 0.051 mmol) in anhydrous EtOAc (2 mL) was added 10% Pd—C (26.9 mg, 0.025 mmol). The mixture was degassed and then purged with N2 gas. The reaction mixture was stirred under an H2 atmosphere for 1 h, filtered through a Celite bed, and the bed was washed with EtOAc. The filtrate was concentrated under vacuum at 30 °C. The crude product was purified by RP HPLC (YMC Triart C18 (150×4.6) mm, 5 micron; mobile phase A: 10 mM NH4OAc / HO; mobile phase B: CH3CN; flow rate: 1.0 mL / min; gradient: (time (min) / % B) 0 / 10, 20 / 50, 21 / 100, 25 / 100) to give the title compound (5.23 mg, 8.39 μmol, 16.60% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.44 (s, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.66 (s, 1H), 7.37 (br.s., 1H), 7.32-7.19 (m, 2H), 3.64 (br.s., 2H), 3.04 (br.s., 4H), 2.75-2.60 (m, 4H), 2.56 (s, 3H), 2.27-2.33 (m, 2H), 2.06 (s, 3H), 1.89-1.74 (m, 6H), 1.27 (t, J = 6.9 Hz, 6H). LC-MS (ES): m / z = 609.5 [M−H] + ; HPLC RT and purity: Method A = 4.305 min and 99.05% and Method B = 4.494 min and 98.76%.

[0126] Example 11 S-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-L-cysteine [ka] Intermediate 11A: tert-butyl S-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-N-(tert-butoxycarbonyl)-L-cysteinate [ka] To a solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (110 mg, 0.247 mmol) in MeOH (5 mL) was added AgNO (168 mg, 0.990 mmol), EtN (0.138 mL, 0.990 mmol), and di-tert-butyl 3,3′-disulfanediyl(2R,2′R)-bis(2-((tert-butoxycarbonyl)amino)propanoate) (547 mg, 0.990 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solid was filtered, and the filtrate was concentrated under reduced pressure to give an orange colored solid. The crude material was purified by reverse-phase HPLC (column: YMC TRIAT (150x20) mm; 5 micron; mobile phase A: 10 mM NH4OAc / HO; mobile phase B: CH3CN; flow rate: 20 mL / min; gradient (time (min) / % B): 0 / 50, 14 / 80). The purified fractions were concentrated under vacuum to give a residue that was dissolved in a mixture of CH3CN and HO. The resulting mixture was frozen and lyophilized for 12 hours to give the title compound (70 mg, 0.097 mmol, 39.3% yield) as a colorless solid. 1H NMR (400 MHz, MeOH-d4) δ 8.60 (s, 1H), 8.41 (s, 1H), 7.62 (s, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.14-7.09 (m, 1H), 4.29 (dd, J = 8.8, 4.3 Hz, 1H), 3.26-3.19 (m, 3H), 3.06 (br.s., 2H), 3.02-2.91 (m, 1H), 2.83 (dd, J = 14.6, 9.0 Hz, 1H), 2.71-2.61 (m, 4H), 2.46-2.35 (m, 2H), 2.27 (s, 3H), 2.13-2.00 (m, 2H), 1.99-1.88 (m, 2H), 1.55-1.43 (m, 18H), 1.40 (d, J = 7.0 Hz, 6H). LC-MS (ES): m / z = 720.4 [M+H] + HPLC RT and purity: Method A = 9.046 min and 99.42% and Method B = 8.294 min and 99.66%.

[0127] Example 11: To a solution of tert-butyl (5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-N-(tert-butoxycarbonyl)-L-cysteinate (70 mg, 0.097 mmol) in CHCl (1 mL) was added CFCOH (0.075 mL, 0.972 mmol). The reaction mixture was stirred in an ice bath for 1 hour and then at room temperature for 1 hour. The reaction mixture was dried under high vacuum to give a residue, which was dissolved in a mixture of CHCN and HO. The resulting mixture was frozen and lyophilized for 16 hours to give the title compound (52.62 mg, 0.075 mmol, 77% yield) as a colorless solid. 1H NMR (400 MHz, MeOH-d4) δ 8.61 (s, 1H), 8.44 (s, 1H), 7.67 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.12 (d, J = 7.0 Hz, 1H), 4.19-4.10 (m, 3H), 3.80 (t, J = 13.8 Hz, 2H), 3.45-3.20 (m, 4H), 3.06-2.95 (m, 2H), 2.67 (s, 3H), 2.27 (s, 3H), 2.22 (br.s., 4H), 1.41 (d, J = 7.0Hz, 6H). LC-MS (ES): m / z = 564.5 [M+H] + HPLC RT and purity: Method A = 4.13 min and 97.63% and Method B = 4.95 min and 96.63%.

[0128] Examples 12 and 13 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)methyl)piperidin-1-ium ditrifluoroacetate (12) and 6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-1-(((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridin-1-ium tritrifluoroacetate [ka] Intermediates 12A and 13A: 1-(2-amino-2-oxoethyl)-1-((((3-(((N-(tert-butoxycarbonyl)-N-methylglycyl)oxy)methyl)pyridin-2-yl)(methyl)carbamoyl)oxy)methyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-ium chloride (12A) and 6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-((((3-(((N-(tert-butoxycarbonyl)-N-methylglycyl)oxy)methyl)pyridin-2-yl)(methyl)carbamoyl)oxy)methyl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-1-ium chloride (13A). [ka] To a stirred solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (0.1 g, 0.225 mmol) in CHCN (6.0 mL) was added (2-(((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl N-(tert-butoxycarbonyl)-N-methylglycinate (0.271 g, 0.675 mmol) and NaI (0.101 g, 0.675 mmol). The reaction mixture was heated at 68° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase preparative HPLC (Column: SunFire C18 (150x21.2) mm 5 micron; Mobile phase A: 0.1% HCOH / HO; Mobile phase B: CHCN; Flow rate: 20 mL / min; Gradient (Time (min) / %B): 0 / 10, 10 / 35). Fractions were concentrated under high vacuum below 30°C. The residue was dissolved in a mixture of CHCN and HO, frozen, and lyophilized for 16 hours to give 190 mg of product as an off-white solid. The resulting mixture of isomers was separated using (Column / Dimensions: Chiralcel OD-H (250x4.6) mm, 5 micron; % co-solvent: 30% of 0.2% EtN / MeOH:CHCN (1:1); Back pressure: 100 bar; Temperature: 30°C). Fractions were concentrated using high vacuum below 30°C. The residues were dissolved in a mixture of CH3CN and H2O, frozen, and lyophilized for 16 hours to give two products. Intermediate 12A (Isomer A): The product was obtained as an off-white solid (56 mg, 0.062 mmol, 27.4% yield). LC-MS (ES): m / z = 811.4 [M+H] + . Intermediate 13A (Isomer B): The product was obtained as an off-white solid (24 mg, 0.025 mmol, 11.09% yield). LC-MS (ES): m / z = 811.4 [M+H] + ;

[0129] Example 12: To a stirred solution of 1-(2-amino-2-oxoethyl)-1-((((3-(((N-(tert-butoxycarbonyl)-N-methylglycyl)oxy)methyl)pyridin-2-yl)(methyl)carbamoyl)oxy)methyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-ium chloride (50.0 mg, 0.059 mmol) in CHCl (2.0 mL) was added CFCOH (0.5 mL, 6.49 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 30 minutes and then concentrated under reduced pressure. The crude compound was triturated with EtO. The resulting solid was dissolved in a mixture of CH3CN:H2O, frozen, and lyophilized for 16 h to afford the title compound (28 mg, 0.028 mmol, 48.0% yield) as a pale yellow solid. 1 H NMR (400 MHz, MeOH-d4) δ 8.50 (br.s., 2H), 8.33 (s, 1H), 8.00 (br.s., 1H), 7.58 (br.s., 1H), 7.45 (br.s., 1H), 7.32-7.20 (m, J = 8.1 Hz, 1H), 7.12-7.00 (m, J = 8.6 Hz, 1H), 6.30-5.60 (m, 2H), 5.40-5.20 (m, 2H), 4.40-4.10 (m, 4H), 3.99-3.80 (m, 2H), 3.78-3.70 (m, 2H), 3.64-3.45 (m, 3H), 3.20-3.00 (m, 2H), 2.80 (s, 3H), 2.68 (br.s., 3H), 2.37 (br.s., 2H), 2.20-1.93 (m, 5H), 1.35-1.22 (m, 6H). LC-MS (ES): m / z = 711.2 [M+H] + HPLC RT and purity: Method A = 3.901 min and 97.89% and Method B = 6.590 min and 95.44%.

[0130] Example 13: To a stirred solution of 6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-1-((((3-(((N-(tert-butoxycarbonyl)-N-methylglycyl)oxy)methyl)pyridin-2-yl)(methyl)carbamoyl)oxy)methyl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-1-ium (20.0 mg, 0.025 mmol) in CHCl (1.0 mL) was added CFCOH (0.2 mL, 2.60 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 1 hour. The mixture was concentrated under reduced pressure. The crude compound was triturated with EtO, and the solid was dissolved in a mixture of CHCN:HO, then frozen and lyophilized for 16 hours to give the product as a pale yellow solid. The crude compound was purified using reverse-phase preparative HPLC (column: Inersil ODS C18 (250x4.6mm), 5 microns; mobile phase-A: 0.1% CFCOH / HO; mobile phase-B: CHCN; flow rate: 1.0 ml / min; gradient (time (min) / %B): 0 / 20, 2 / 25, 20 / 35, 21 / 20). The fractions were concentrated using high vacuum at 30°C. The residue was dissolved in a mixture of CHCN:HO, then frozen and lyophilized for 16 hours to give the title compound (9.4 mg, 9.51 μmol, 38.6% yield) as a brown solid. 1H NMR (400 MHz, MeOH-d4) δ 8.68-8.54 (m, 2H), 8.45 (s, 1H), 8.11-8.14 (m, 1H), 7.68-7.73 (m, 1H), 7.60 (br.s., 1H), 7.37 (br.s., 1H), 7.20-7.24 (m, 1H), 6.10-5.50 (m, 2H), 5.40-5.25 (m, 2H), 4.55-4.36 (m, 1H), 4.23 (br.s., 1H), 4.11 (br.s., 2H), 3.90 (br.s., 2H), 3.74 (br.s., 1H), 3.63-3.45 (m, 4H), 3.08-2.96 (m, 2H), 2.80 (s, 3H), 2.67 (s, 3H), 2.38-2.15 (m, 7H), 1.41 (d, J=7.0 Hz, 6H). LC-MS (ES): m / z = 711.4 [M+H] + HPLC RT and purity: Method A = 4.822 min and 95.69% and Method B = 5.774 min and 95.25%.

[0131] Example 14 1-(2-Amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(1-((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl)piperidin-1-ium ditrifluoroacetate [ka] Intermediate 14A: 1-(2-amino-2-oxoethyl)-1-(1-(((3-(((N-(tert-butoxycarbonyl)-N-methylglycyl)oxy)methyl)pyridin-2-yl)(methyl)carbamoyl)oxy)ethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-ium chloride [ka] NaI (0.202 g, 1.350 mmol) was added to a stirred solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (0.1 g, 0.225 mmol) and (2-(((1-chloroethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl N-(tert-butoxycarbonyl)-N-methylglycinate (0.561 g, 1.350 mmol) in CHCN (6.0 mL). The reaction mixture was heated to 68 °C and stirred at the same temperature for 18 h. The reaction mixture was concentrated under reduced pressure and purified using reverse-phase preparative HPLC (Xbridge C18 (150x4.6) mm 5 micron; mobile phase A: 0.1% HCOOH / HO; mobile phase B: CHCN; flow rate: 2.0 mL / min; gradient (time (min) / %B): 0 / 10, 20 / 70, 21 / 100, 25 / 100). Fractions were concentrated using high vacuum at 30°C. The residue was dissolved in a mixture of CHCN and HO, frozen, and lyophilized for 16 hours to give the title compound (16 mg, 0.018 mmol, 7.93% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.17-11.09 (br.s., 1H), 10.14-9.73 (s, 1H), 9.36 (br.s., 1H), 8.49 (s, 2H), 7.99-7.91 (m, 1H), 7.60-7.09 (m, 6H), 5.25-5.12 (br.s., 2H), 4.02 (br.s., 2H), 3.16 (br.s., 2H), 2.95-2.85 (m, 10H), 2.38 (br.s., 6H), 2.25-2.11 (m, 2H), 1.93-1.73 (m, 7H), 1.45-1.19 (m, 15H). LC-MS (ES): m / z = 825.4 [M+H] + .

[0132] Example 14: To a stirred solution of 1-(2-amino-2-oxoethyl)-1-(1-(((3-(((N-(tert-butoxycarbonyl)-N-methylglycyl)oxy)methyl)pyridin-2-yl)(methyl)carbamoyl)oxy)ethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-ium chloride (14.0 mg, 0.016 mmol) in CHCl (1.0 mL) was added CFCOH (0.1 mL, 1.298 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 45 min. The reaction mixture was concentrated under reduced pressure. The crude compound was triturated with EtO. The precipitated solid was dissolved in a mixture of CH3CN and H2O, then frozen and lyophilized for 16 h to give the title compound (12 mg, 0.013 mmol, 79% yield) as an off-white solid. 1 H NMR (400 MHz, MeOH-d4) δ 9.89-9.39 (m, 1H), 9.14 (s, 1H), 8.54-8.48 (m, 1H), 8.12-8.04 (m, 1H), 7.70 (s, 1H), 7.60 (br.s., 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.19-7.15 (m, 1H), 5.43 (br.s., 1H), 5.31 (d, J = 12.0 Hz, 1H), 4.18-4.06 (m, 2H), 4.02 (s, 2H), 3.79-3.77 (m, 2H), 3.45 (br.s., 2H), 3.31-3.20 (m, 3H), 3.04-2.88 (m, 5H), 2.79 (br.s., 3H), 2.48 (br.s., 3H), 2.24-2.19 (m, 5H), 1.94 (br.s., 2H), 1.50-1.36 (m, 6H). LC-MS (ES): m / z = 725.4 [M+H] + HPLC RT and purity: Method A = 4.473 min and 94.36% and Method B = 9.070 min and 94.19%.

[0133] Example 15 ((1-Aminocyclopropane-1-carbonyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate trifluoroacetate [ka] Intermediate 15: Chloromethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (200 mg, 0.450 mmol) in DMF (2.0 mL) and sodium hydride (54.0 mg, 1.350 mmol) was added chloromethyl chloroformate (0.060 mL, 0.675 mmol). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was stirred under N at 0° C. for 1 h. The reaction mixture was diluted with EtOAc (30 mL). The solution was washed with HO (2×20 mL) and brine, dried over anhydrous NaSO, filtered, and concentrated (<40° C.) to give a colorless liquid. The crude product was purified by RP HPLC. The HPLC fraction was concentrated in vacuo to give a residue that was dissolved in a mixture of CHCN and HO. The resulting mixture was frozen and lyophilized for 12 hours to give the title compound (150 mg, 0.279 mmol, 62.1% yield) as a colorless solid. 1H NMR (400 MHz, MeOH-d4) δ 8.60 (s, 1H), 8.41 (s, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.72 (s, 1H), 7.37 (dd, J = 8.8, 1.8 Hz, 1H), 5.88 (d, J = 6.0 Hz, 1H), 5.74 (d, J = 6.5 Hz, 1H), 3.16-3.08 (m, 4H), 2.88 (dt, J = 14.1, 7.0 Hz, 1H), 2.73 (d, J = 11.5 Hz, 1H), 2.66 (s, 3H), 2.47-2.36 (m, 2H), 2.20 (s, 3H), 2.03-1.91 (m, 4H), 1.38 (dd, J = 8.5, 7.0 Hz, 6H). LC-MS (ES): m / z = 537.2 [M+H] + .

[0134] Intermediate 15B: ((1-((tert-butoxycarbonyl)amino)cyclopropane-1-carbonyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of chloromethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (70 mg, 0.130 mmol) and 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid (26.2 mg, 0.130 mmol) in DMF was added KI (21.64 mg, 0.130 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water was added to form a homogeneous solution, which was directly purified by RP HPLC (column: YMC TRAIRT (150 x 20 mm), 5 micron; mobile phase A: 10 mM NH4OAc / HO; mobile phase B: CH3CN; flow rate: 20 mL / min; gradient (time (min) / % B): 0 / 20, 2 / 40, 15 / 80, 17 / 100). After purification, the fractions were concentrated under reduced pressure. The residue was dissolved in CH3CN and HO, and the mixture was subjected to lyophilization to give the title compound (30 mg, 0.043 mmol, 32.8% yield) as a white solid. 1 H NMR (400 MHz, MeOH-d4) δ 8.57 (s, 1H), 8.40 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.35 (d, J = 7.0 Hz, 1H), 5.72-5.62 (m, 2H), 3.20-3.11 (m, 4H), 2.88-2.69 (m, 2H), 2.66 (s, 3H), 2.45 (t, J = 11.3 Hz, 2H), 2.18 (s, 3H), 2.06-1.91 (m, 4H), 1.43-1.33 (m, 15H), 1.26 (br.s., 2H), 1.09 (d, J = 3.5 Hz, 2H). LC-MS (ES): m / z = 702.4 [M+H] + .

[0135] Example 15: To a solution of ((1-((tert-butoxycarbonyl)amino)cyclopropane-1-carbonyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (20 mg, 0.028 mmol) in CHCl (1 mL) was added CFCOH (0.2 mL, 0.570 mmol). The reaction mixture was stirred in an ice bath for 1 h and then at room temperature for 1 h. The crude reaction mixture was concentrated under high vacuum to give a residue. The residue was dissolved in a mixture of CHCN and HO. The resulting mixture was frozen and lyophilized for 2 days to give the title compound (15.76 mg, 0.021 mmol, 72.6% yield) as a colorless solid. 1 H NMR (400 MHz, MeOH-d4) δ 8.56 (s, 1H), 8.44 (s, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 5.87 (d, J = 6.0 Hz, 1H), 5.74 (d, J = 6.0 Hz, 1H), 4.03 (s, 2H), 3.81-3.78 (m, 2H), 3.31-3.25 (m, 2H), 3.10 (br.s., 1H), 2.87 (t, J = 7.3 Hz, 1H), 2.67 (s, 3H), 2.27-2.16 (m, 7H), 1.51-1.44 (m, 2H), 1.41-1.33 (m, 8H). LC-MS (ES): m / z = 602.3 [M+H] + HPLC RT and purity: Method A = 5.03 min and 95.04% and Method B = 9.03 min and 94.19%.

[0136] Example 16 (Phosphonooxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] Intermediate 16A: ((Di-tert-butoxyphosphoryl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of chloromethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (120 mg, 0.223 mmol) in DMF (1 mL) was added tetra-n-butylammonium di-tert-butyl phosphate (202 mg, 0.447 mmol) and KI (37.1 mg, 0.223 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture to obtain a homogeneous solution, which was purified by RP HPLC (Column: X-Bridge C18 (150x19) mm; 5 micron; Mobile phase A: 10 mM NH4OAc / HO; Mobile phase B: CH3CN:IPA (70:30); Flow rate: 20 mL / min; Gradient: 0 / 30, 15 / 60). After purification, the fractions were concentrated under reduced pressure, and the residue was dissolved in CH3CN and HO. The mixture was subjected to lyophilization to give the title compound (25 mg, 0.035 mmol, 15.74% yield). 1H NMR (400 MHz, MeOH-d4) δ 8.55-8.52 (m, 1H), 8.42-8.38 (m, 1H), 8.36-8.25 (m, 1H), 7.73-7.69 (m, 1H), 7.36 (t, J = 7.3 Hz, 1H), 5.66 (dd, J = 13.3, 3.3 Hz, 2H), 3.72 (br.s., 1H), 3.50 (br.s., 2H), 2.88 (td, J = 7.0, 4.0 Hz, 4H), 2.75-2.71 (m, 1H), 2.65 (s, 3H), 2.20 (s, 3H), 2.12 (br.s., 2H), 2.06 (br.s., 2H), 1.46-1.30 (m, 24H). LC-MS (ES): m / z = 711.2 [M+H] + .

[0137] Example 16: To a solution of ((di-tert-butoxyphosphoryl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (25 mg, 0.035 mmol) in CHCl (1 mL) was added CFCOH (0.25 mL, 3.24 mmol). The reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated under high vacuum. The residue was dissolved in a mixture of CHCN and HO. The resulting mixture was frozen and lyophilized for 2 days to give the title compound (14.42 mg, 0.019 mmol, 55.2% yield) as a colorless solid. 1H NMR (400 MHz, MeOH-d4) δ 8.62 (s, 1H), 8.55 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 5.64 (ddd, J = 18.7, 13.7, 5.3 Hz, 2H), 4.02 (s, 2H), 3.81-3.78 (m, 2H), 3.30-3.28 (m, 2H), 3.11-3.05 (m, 1H), 2.93-2.82 (m, 1H), 2.66 (s, 3H), 2.31-2.21 (m, 7H), 1.38 (dd, J = 9.0, 7.0 Hz, 6H). LC-MS (ES): m / z = 599.0 [M+H] + HPLC RT and purity: Method A = 7.77 min and 95.94% and Method B = 9.14 min and 95.65%.

[0138] Example 17 (5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)phosphonic acid [ka] Intermediate 17A: Bis(2-(trimethylsilyl)ethyl) (5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)phosphonate [ka] To a stirred solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (0.2 g, 0.450 mmol) in CHCl (2 mL) was added 1H-tetrazole (4% solution in CHCN) (1.300 mL, 0.594 mmol) and bis(2-(trimethylsilyl)ethyl)diisopropylphosphoramidite (0.5 mL, 1.215 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0 °C. Aqueous H0 solution (0.2 mL, 1.940 mmol) was added. The reaction mixture was stirred at the same temperature for 10 minutes. The reaction mixture was partitioned between EtOAc and H0. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a colorless oil. The crude product was purified by RP HPLC (column: X-Bridge C18 (150x19) mm; 5 microns; mobile phase A: 10 mM NH4OAc / HO; mobile phase B: CH3CN; flow rate: 18 mL / min; gradient (time (min) / % B): 0 / 50, 2 / 50, 15 / 80). The fractions were concentrated using high vacuum at 30 °C. The residue was dissolved in a mixture of CH3CN and HO, frozen, and lyophilized for 12 hours to give the title compound (173 mg, 0.234 mmol, 52.0% yield) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ 10.99-10.94 (m, 1H), 8.74 (d, J = 3.5 Hz, 1H), 8.47 (s, 1H), 7.60-7.52 (m, 1H), 7.35-7.23 (m, 1H), 7.03 (d, J = 8.5 Hz, 1H), 4.20-4.07 (m, 3H), 3.86-3.76 (m, 1H), 3.20-3.10 (m, 1H), 3.02-2.83 (m, 3H), 2.64-2.56 (m, 4H), 2.39-2.26 (m, 2H), 2.16 (s, 3H), 2.08 (br.s., 1H), 2.00 (br.s., 1H), 1.81 (br.s., 3H), 1.38-1.28 (m, 6H), 1.26-1.10 (m, 1H), 1.10-0.98 (m, 3H), 0.93 (br.s., 1H), 0.08-0.02 (m, 18H). LC-MS (ES): m / z = 725.5 [M+H] + .

[0139] Example 17: To a stirred solution of bis(2-(trimethylsilyl)ethyl) (5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)phosphonate (100 mg, 0.138 mmol) in CHCl (3 mL) at 0° C. was added CFCOH (0.5 mL, 6.49 mmol). The reaction mixture was stirred at 0° C. for 10 minutes, then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated and the solvent was evaporated at 30° C. The residue was purified using RP HPLC (Column: X-Bridge Phenyl (250x19mm), 5 micron; Mobile phase A: 10 mM NH4HCO3 / HO pH-9.5; Mobile phase B: CH3CN; Flow rate: 16 mL / min; Gradient (time (min) / % B): 0 / 20, 2 / 20, 9 / 35). Fractions were concentrated using high vacuum at 30°C. The residue was dissolved in a mixture of CH3CN and HO, frozen, and lyophilized for 12 hours to give the title compound (45 mg, 0.081 mmol, 59.1% yield) as a white solid. 1 H NMR (400 MHz, MeOH-d4) δ 8.60 (s, 1H), 8.40 (s, 1H), 7.65 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 4.22 (br.s., 1H), 3.65 (br.s., 1H), 3.43 (br.s., 2H), 3.25-3.18 (m, 1H), 3.04-2.93 (m, 2H), 2.76 (br.s., 1H), 2.66 (s, 3H), 2.27 (s, 3H), 2.12 (br.s., 4H), 1.40 (d, J = 7.0 Hz, 6H). LC-MS (ES): m / z = 525.3 [M+H] + HPLC RT and purity: Method A = 6.636 min and 95.01% and Method B = 8.004 min and 95.29%.

[0140] Example 18 (5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)phosphonate [ka] Intermediate 18A: tert-butyl 4-(1-(bis(benzyloxy)phosphoryl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (0.75 g, 1.538 mmol) in THF (20.0 mL) was added sodium hydride (0.154 g, 3.84 mmol). The reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added tetrabenzyl diphosphate (3.31 g, 6.15 mmol) in THF (5.0 mL) at 0 °C. The reaction mixture was stirred at the same temperature for 1 hour, quenched with ice-cold HO, and then partitioned between EtOAc and HO. The organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure to give a residue. The crude product was purified using reverse-phase preparative HPLC (column: YMC TRIART C18 (150 x 4.6) mm, 5 micron; mobile phase A: 10 mM NH4OAc / HO; mobile phase B: CH3CN; flow rate: 1.0 mL / min; gradient (time (min) / % B: 0 / 30, 3 / 60, 15 / 100, 20 / 100, 21 / 30). Fractions were concentrated using high vacuum below 30 °C. The residue was dissolved in CHCl2, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.52 g, 0.667 mmol, 43.4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.44 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.67-7.61 (m, 1H), 7.34-7.15 (m, 9H), 7.10-7.02 (m, 2H), 5.15-4.94 (m, 2H), 4.90 (d, J = 8.0 Hz, 2H), 4.13 (d, J = 12.0 Hz, 2H), 2.95-2.75 (m, 3H), 2.71-2.59 (m, 1H), 2.39 (s, 3H), 1.96 (s, 3H), 1.82-1.85 (m, 2H), 1.69-1.55 (m, 2H), 1.44 (s, 9H), 1.25 (dd, J = 7.0, 2.0 Hz, 6H). LC-MS (ES): m / z = 748.4 [M+H] + .

[0141] Intermediate 18B: Dibenzyl (5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)phosphonate [ka] To a stirred solution of tert-butyl 4-(1-(bis(benzyloxy)phosphoryl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (510 mg, 0.682 mmol) in CHCl (6.0 mL) was added CFCOH (0.6 mL, 7.79 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was stirred at the same temperature for 2.5 hours. The mixture was concentrated under reduced pressure and co-distilled with CHCl and EtO to give the title compound (1.01 g) as a light brown oil. LC-MS (ES): m / z = 648.2 [M+H] +To a stirred solution of the above crude product in DMF (5.0 mL) was added EtN (0.549 mL, 3.94 mmol) and 2-bromoacetamide (0.235 g, 1.707 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.6 g, 0.851 mmol, 64.8% yield) as a light brown oil. LC-MS (ES): m / z = 705.6 [M+H] + .

[0142] Example 18: To a stirred solution of dibenzyl (5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)phosphonate (580.0 mg, 0.823 mmol) in ethanol (5.0 mL) was added Pd / C (150 mg, 0.141 mmol). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through a celite bed and washed with a mixture of MeOH and HO (1:1). The filtrate was concentrated under reduced pressure to give a residue. The crude material was purified using reverse-phase preparative HPLC (Column: YMC TRIAT (150x20) mm, 5 micron; Mobile phase A: 10 mM NH4HCO3 / HO, pH: 9.5 Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient (time (min) / % B): 0 / 10, 13 / 35). Fractions were retained for lyophilization etc. to afford the title compound (6.0 mg, 10.31 μmol, 1.25% yield) as an off-white solid. 1H NMR (400 MHz, MeOH-d4) δ 8.53 (s, 1H), 8.47 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.62 (s, 1H), 7.16 (d, J = 8.5 Hz, 1H), 4.00 (s, 2H), 3.74-3.77 (m, 2H), 3.30-3.20 (m, 2H), 3.00 (br.s., 1H), 2.77 (dt, J = 14.2, 7.2 Hz, 1H), 2.63 (s, 3H), 2.25 (s, 3H), 2.23-2.13 (m, 4H), 1.35 (dd, J = 7.0, 4.5 Hz, 6H). LC-MS (ES): m / z = 525.4 [M+H] + HPLC RT and purity: Method A = 5.901 min and 96.09% and Method B = 5.794 min and 96.02%.

[0143] Example 19 (Phosphonooxy)methyl (2-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-2-oxoethyl)(methyl)carbamate [ka] Intermediate 19A: ((Bis(benzyloxy)phosphoryl)oxy)methyl (2-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-2-oxoethyl)(methyl)carbamate [ka] To a stirred solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1-(methylglycyl)-1H-indol-5-yl)piperidin-1-yl)acetamide (0.275 g, 0.533 mmol) and ((bis(benzyloxy)phosphoryl)oxy)methyl chloroformate (0.723 g, 0.800 mmol) in THF (5 mL) at 0 °C, DIPEA (1.863 mL, 10.67 mmol) was added slowly. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was partitioned between HO and EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product as a pale yellow oil. The crude product was purified using RP HPLC. Fractions were concentrated using high vacuum at 30 °C. The residue was dissolved in a mixture of CH3CN and H2O, frozen, and lyophilized for 12 h to give the title compound (0.060 g, 0.068 mmol, 12.81% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.89-8.85 (m, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.19 (dd, J = 8.5, 7.0 Hz, 1H), 7.69 (s, 1H), 7.37-7.23 (m, 11H), 7.19 (dd, J = 7.8, 1.8 Hz, 2H), 5.61-5.43 (m, 2H), 5.03 (dd, J = 7.8, 5.8 Hz, 2H), 4.98-4.93 (m, 1H), 4.91 (dd, J = 8.0, 4.5 Hz, 1H), 4.16-4.06 (m, 1H), 4.03-3.93 (m, 1H), 2.96 (br.s., 3H), 2.73 (s, 1H), 2.77 (s, 2H), 2.72-2.62 (m, 2H), 2.56 (d, J = 6.5 Hz, 3H), 2.23 (br.s., 2H), 2.14-2.03 (m, 4H), 1.92 (s, 1H), 1.82 (br.s., 3H), 1.36-1.22 (m, 6H). LC-MS (ES): m / z = 850.2 [M+H] + .

[0144] Example 19: To a stirred solution of ((bis(benzyloxy)phosphoryl)oxy)methyl (2-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-2-oxoethyl)(methyl)carbamate (0.050 g, 0.059 mmol) in 1,2-dichloroethane (2 mL) was added CFCOH (0.227 mL, 2.94 mmol) and anisole (0.161 mL, 1.471 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture solvent was concentrated under vacuum at 30 °C to give a brown gum. The residue was triturated with EtO and decanted. The precipitated solid was dried under vacuum. The solid was dissolved in a mixture of CHCN and HO, frozen, and lyophilized for 12 hours to give the crude product as a light brown solid. The crude product was purified using RP HPLC (Column: SunFire C18 (150x19) mm; 5 microns; Mobile phase A: 0.1% CFCOH / HO; Mobile phase B: CHCN; Flow rate: 20 mL / min; Gradient (time (min) / % B): 0 / 10, 2 / 10, 6 / 30). The fractions were concentrated using high vacuum at 30°C. The residue was dissolved in a mixture of CHCN and HO, frozen, and lyophilized for 12 hours to give the title compound (0.028 g, 0.034 mmol, 58.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.52 (br.s., 1H), 8.85-8.89 (m, 1H), 8.54-8.50 (m, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.98 (s, 1H), 7.73-7.71 (m, 1H), 7.31 (d, J = 9.0 Hz, 1H), 5.45-5.28 (m, 2H), 4.22-4.06 (m, 2H), 4.03-3.93 (m, 2H), 3.80-3.60 (m, 2H), 3.30-3.10 (m, 2H), 3.05-2.90 (m, 1H), 2.84-2.79 (m, 3H), 2.70-2.59 (m, 4H), 2.22-1.97 (m, 7H), 1.36-1.23 (m, 6H). LC-MS (ES): m / z = 670.2 [M+H] + HPLC RT and purity: Method C = 4.466 min and 96.47% and Method D = 7.144 min and 98.68%.

[0145] Examples 20 and 21 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(((methyl(2-(phosphonooxy)ethyl)carbamoyl)oxy)methyl)piperidin-1-ium trifluoroacetate (20) and 6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-1-(((methyl(2-(phosphonooxy)ethyl)carbamoyl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridin-1-ium trifluoroacetate (21) [ka] To a solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (500 mg, 1.125 mmol) in CHCl (10 mL) was added chloromethyl (2-((bis(benzyloxy)phosphoryl)oxy)ethyl)(methyl)carbamate (1684 mg, 3.94 mmol) and TBAI (1454 mg, 3.94 mmol). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was filtered through a syringe filter and washed with CHCl. The organic layer was concentrated to give the crude product as a pale yellow oil, which was purified by reverse-phase HPLC (Column: SunFire C18 (150x19) mm; 5 micron; Mobile phase A: 0.1% HC0H / H0 Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient: 0 / 10, 20 / 50) to give 60 mg of a mixture of two compounds [LC-MS (ES): m / z = 746.5 [M+H] + and LC-MS (ES): m / z = 836.6 [M+H] + ].

[0146] To a stirred solution of the compound (60 mg, 0.072 mmol) in 1,2-dichloroethane (2 mL) was added CF3CO2H (5.52 μL, 0.072 mmol) and anisole (7.83 μL, 0.072 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under vacuum at 30 °C to give the crude product as a light brown oil. The crude product was purified by RP HPLC (Kinetex PFP (150 × 21.2) mm; 5 microns; mobile phase A: 0.1% CF3CO2H / HO; mobile phase B: CH3CN:IPA (70:30); flow rate: 18 mL / min; gradient (time (min) / %B): 0 / 10, 10 / 25) to give Isomer 1 and Isomer 2 as off-white solids. Example 20 (Isomer 1): 24.25 mg, 0.031 mmol, 43.0% yield: 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.49 (s, 1H), 7.64 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 5.62 (s, 2H), 4.36 (br.s., 2H), 4.06-3.99 (m, 2H), 3.90-3.87 (m, 2H), 3.59-3.50 (m, 2H), 3.06 (s, 2H), 2.96-2.87 (m, 5H), 2.59 (s, 3H), 2.23-2.13 (m, 5H), 2.08 (br.s., 2H), 1.32 (d, J=7.0 Hz, 6H). LC-MS (ES): m / z = 656.2 [M+H] + ; HPLC RT and purity: Method E = 5.53 min and 98.93% and Method F = 7.02 min and 98.95%. Example 21 (isomer 2): 5.41 mg, 6.88 μmol, 9.60% yield. 1 H NMR (400 MHz, D2O) δ 8.70 (s, 1H), 8.49 (s, 1H), 7.64 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 5.80 (d, J = 6.5 Hz, 2H), 4.12 (d, J = 6.0 Hz, 2H), 4.05-3.91 (m, 4H), 3.61 (br.s., 1H), 3.52 (br.s., 1H), 3.06-2.99 (m, 2H), 2.99-2.85 (m, 4H), 2.60-2.50 (m, 4H), 2.35-2.20 (m, 2H), 2.16 (s, 3H), 2.02-2.06 (m, 2H), 1.33 (d, J = 7.0 Hz, 6H). LC-MS (ES): m / z = 656.2 [M+H] + HPLC RT and purity: Method E = 4.84 min and 98.79% and Method F = 5.39 min and 98.64%.

[0147] Example 22 ((3-Methoxy-4-(phosphonooxy)benzoyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] Intermediate 22A: Chloromethyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of tert-butyl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (1.0 g, 2.051 mmol) in THF (5 mL) was added a 1 M solution of LiHMDS in THF (3.08 mL, 3.08 mmol). The reaction mixture was stirred at −78° C. under N for 1 hour. Then, chloromethyl chloroformate (0.529 g, 4.10 mmol) was added. The reaction mixture was stirred at −78° C. under N for 1 hour. The reaction mixture was partitioned between H O and EtOAc. The organic layer was washed with H O and brine, dried over anhydrous Na SO , and concentrated to give the title compound (0.8 g, 1.379 mmol, 67.2% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.60 (s, 1H), 8.08 (d, J = 11.60 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J = 11.60 Hz, 1H), 5.92-5.83 (m, 2H), 4.12-4.07 (m, 2H), 2.87-2.72 (m, 4H), 2.56 (s, 3H), 2.08 (s, 3H), 1.83-1.75 (m, 2H), 1.59-1.51 (m, 2H), 1.41 (s, 9H), 1.28-1.23 (m, 6H). LC-MS (ES): m / z = 580.5 [M+H] + .

[0148] Intermediate 22B: benzyl (4-((((5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carbonyl)oxy)methoxy)carbonyl)-2-methoxyphenyl)phosphate [ka] To a stirred solution of chloromethyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (0.8 g, 1.379 mmol) in DMF (5.0 mL) was added DIPEA (1.204 mL, 6.90 mmol), TBAI (1.019 g, 2.76 mmol), and 4-((bis(benzyloxy)phosphoryl)oxy)-3-methoxybenzoic acid (1.181 g, 2.76 mmol). The homogeneous reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and HO. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (Column: X-Bridge Phenyl (250x19) mm; 5 micron; Mobile phase A: 10 mM NHHCO pH 9.5; Mobile phase B: CHCN; Flow rate: 20 mL / min; Gradient (time (min) / % B): 0 / 40, 11.5 / 63). Fractions were concentrated using high vacuum at 30°C. The residue was dissolved in a mixture of CHCN and HO, frozen, and lyophilized for 16 hours to give the title compound (180 mg, 0.200 mmol, 14.52% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.37 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.69-7.61 (m, 2H), 7.36-7.30 (m, 2H), 7.30-7.24 (m, 4H), 7.24-7.17 (m, 2H), 5.97 (d, J = 5.5 Hz, 1H), 5.84 (d, J = 6.0 Hz, 1H), 4.79-4.73 (m, 2H), 4.12 (d, J = 11.0 Hz, 1H), 3.79 (s, 3H), 3.22-3.11 (m, 4H), 2.84 (t, J = 11.8 Hz, 1H), 2.31 (s, 3H), 1.97 (s, 3H), 1.82 (d, J = 11.5 Hz, 2H), 1.66-1.51 (m, 2H), 1.43 (s, 9H), 0.97-0.89 (m, 6H). LC-MS (ES): m / z = 881.5 [M+H] + .

[0149] Intermediate 22C: ((4-(((benzyloxy)(hydroxy)phosphoryl)oxy)-3-methoxybenzoyl)oxy) methyl 2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(piperidin-4-yl)-1H-indole-1-carboxylate, trifluoroacetate [ka] To a stirred solution of ((4-(((benzyloxy)(hydroxy)phosphoryl)oxy)-3-methoxybenzoyl)oxy)methyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (0.2 g, 0.227 mmol) in CHCl (2.0 mL) was added CFCOH (0.2 mL, 2.60 mmol) at 0° C. The homogeneous reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was completely concentrated under reduced pressure to give the product (0.19 g, 0.170 mmol, 74.8% yield) as a light brown oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.67 (br.s., 1H), 8.48-8.36 (m, 3H), 8.21 (d, J = 9.0 Hz, 2H), 7.67 (br.s., 2H), 7.44-7.28 (m, 7H), 5.96 (d, J = 6.0 Hz, 1H), 5.89 (d, J = 5.5 Hz, 1H), 5.11-5.03 (m, 2H), 3.86 (s, 3H), 3.42 (d, J = 12.0 Hz, 2H), 3.10-2.97 (m, 2H), 2.74-2.65 (m, 2H), 2.32 (s, 3H), 2.01 (s, 3H), 1.98-1.83 (m, 4H), 1.38-1.20 (m, 6H). LC-MS (ES): m / z = 782.0 [M+H] + .

[0150] Intermediate 22D: ((4-(((benzyloxy)(hydroxy)phosphoryl)oxy)-3-methoxybenzoyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a stirred solution of ((4-(((benzyloxy)(hydroxy)phosphoryl)oxy)-3-methoxybenzoyl)oxy)methyl 2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(piperidin-4-yl)-1H-indole-1-carboxylate (0.18 g, 0.201 mmol) in DMF (5.0 mL) was added EtN (0.084 mL, 0.603 mmol) and 2-bromoacetamide (0.042 g, 0.301 mmol) at 0 °C. The homogeneous reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc and HO. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC (Column: YMC Trait (250x20) mm, 5 micron; Mobile phase A: 10 mM NH4HCO3 pH 9.5 / HO; Mobile phase B: CH3CN; Flow rate: 18 mL / min; Gradient: (Time (min) / % B): 0 / 10, 20 / 70, 21 / 100). Fractions were concentrated using high vacuum at 30°C. The residue was dissolved in a mixture of CH3CN and HO, frozen, and lyophilized for 16 hours to give the title compound (80 mg, 0.093 mmol, 46.5% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.76 (s, 1H), 8.38 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.72-7.59 (m, 3H), 7.42-7.14 (m, 9H), 5.97 (d, J = 5.6 Hz, 1H), 5.85 (d, J = 5.9 Hz, 1H), 4.78 (d, J = 6.6 Hz, 2H), 3.79 (s, 3H), 3.26-3.16 (m, 2H), 2.91 (br.s., 2H), 2.76-2.65 (m, 4H), 2.31 (s, 3H), 2.08 (br.s., 2H), 2.03-1.89 (m, 5H), 1.38-1.19 (m, 6H). LC-MS (ES): m / z = 839.0 [M+H] + .

[0151] Example 22: To a stirred solution of ((4-(((benzyloxy)(hydroxy)phosphoryl)oxy)-3-methoxybenzoyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (120 mg, 0.143 mmol) in dichloroethane (5.0 mL) was added CFCOH (1.0 mL, 12.98 mmol) and anisole (0.1 mL, 0.915 mmol). The reaction mixture was stirred at 55 °C for 1 hour. The reaction mixture was completely concentrated under reduced pressure. The crude compound was stirred with EtO. The precipitated solid was dried under vacuum, dissolved in a mixture of CHCN and HO, frozen, and lyophilized for 16 h to give the title compound (90 mg, 0.115 mmol, 81% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.37 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.00 (br.s., 1H), 7.75-7.65 (m, 2H), 7.51 (d, J = 7.9 Hz, 1H), 7.41-7.25 (m, 3H), 5.96 (d, J = 5.6 Hz, 1H), 5.87 (d, J = 6.3 Hz, 1H), 3.92 (br.s., 2H), 3.53 (br.s., 3H), 3.18 (br.s., 2H), 2.96 (br.s., 2H), 2.67 (dd, J = 14.5, 7.3 Hz, 2H), 2.32 (s, 3H), 2.12-1.93 (m, 7H), 1.36-1.20 (m, 6H). LC-MS (ES): m / z = 749.2 [M+H] + ; HPLC RT and purity: Method A = 8.040 min and 96.08% and Method B = 9.104 min and 97.20%.

[0152] Example 23 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(((methyl(2-(methylamino)ethyl)carbamoyl)oxy)methyl)piperidin-1-ium trifluoroacetate [ka] Intermediate 23A: tert-butyl (chloromethyl)ethane-1,2-diylbis(methylcarbamate) [ka] To a stirred solution of tert-butyl methyl(2-(methylamino)ethyl)carbamate (3.00 g, 15.93 mmol) in CHCl (30 mL) was added pyridine (2.58 mL, 31.9 mmol) and chloromethyl chloroformate (2.84 mL, 31.9 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was partitioned between HO and CHCl. ​​The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo at 0° C. to give the title compound (3.7 g, 13.18 mmol, 83% yield) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 5.86 (d, J = 9.0 Hz, 2H), 3.43-3.29 (m, 4H), 2.88 (s, 3H), 2.77 (br.s., 3H), 1.37 (s, 9H).

[0153] Intermediate 23B: 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(4,7,10,10-tetramethyl-3,8-dioxo-2,9-dioxa-4,7-diazaundecyl)piperidin-1-ium iodide [ka] To a solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (0.500 g, 1.125 mmol) in CHCl3 (15 mL) was added tert-butyl (chloromethyl)ethane-1,2-diylbis(methylcarbamate) (1.105 g, 3.94 mmol) and TBAI (1.454 g, 3.94 mmol). The reaction mixture was heated at 68 °C for 12 h. The reaction mixture was filtered through a celite bed and washed with CHCl3. The filtrate was concentrated under reduced pressure at 30 °C. The crude product was purified using RP HPLC (Column: SunFire OBD (250x30mm), 5 micron; Mobile phase A: 0.1% HCOH / HO; Mobile phase B: CHCN; Flow rate: 30 mL / min; Gradient (T / %B): 0 / 20, 2 / 20, 12 / 40). Fractions were concentrated using high vacuum at 30°C. The residue was dissolved in a mixture of CHCN and HO, frozen, and lyophilized for 12 hours to give a mixture of two isomers (135 mg, 17.4% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.74 (s, 1H), 8.61-8.42 (m, 2H), 8.39 (br.s., 1H), 7.75 (br.s., 1H), 7.68-7.59 (m, 1H), 7.32-7.11 (m, 1H), 5.79-5.64 (m, 2H), 4.48-4.21 (m, 2H), 3.96-3.22 (m, 8H), 2.96-2.74 (m, 8H), 2.59 (s, 3H), 2.38-2.19 (m, 2H), 2.15 (s, 3H), 2.03 (d, J = 13.8 Hz, 2H), 1.44-1.35 (m, 9H), 1.32 (d, J = 7.0 Hz, 6H). LC-MS (ES): m / z = 690.4 [M+H] + .

[0154] Example 23: To a stirred solution of 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(4,7,10,10-tetramethyl-3,8-dioxo-2,9-dioxa-4,7-diazaundecyl)piperidin-1-ium iodide (0.130 g, 0.159 mmol) in dichloromethane (2 mL) was added CFCOH (0.123 mL, 1.592 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under vacuum at 30 °C. The crude product was washed with EtO. The solid was dried under high vacuum at 30 °C. The solid was dissolved in a mixture of CH3CN and H2O, frozen, and lyophilized for 12 h to give the title compound (0.105 g, 0.127 mmol, 80% yield) as an off-white solid. 1 H NMR (400 MHz, MeOH-d4) δ 8.61 (s, 1H), 8.44 (s, 1H), 7.75-7.64 (m, 1H), 7.43-7.34 (m, 1H), 7.26-7.13 (m, 1H), 5.96-5.76 (m, 2H), 4.49-4.27 (m, 2H), 4.24-4.06 (m, 2H), 3.87-3.61 (m, 4H), 3.31-3.27 (m, 2H), 3.18-3.05 (m, 4H), 3.05-2.95 (m, 1H), 2.83-2.74 (m, 3H), 2.67 (s, 3H), 2.52-2.32 (m, 2H), 2.27 (s, 3H), 2.23-2.11 (m, 2H), 1.40 (d, J = 7.0 Hz, 6H). LC-MS (ES): m / z = 590.4 [M+H] + HPLC RT and purity: Method A = 4.183 min and 98.85% and Method B = 4.471 min and 98.85%.

[0155] Example 24 Ethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] Intermediate 24A: Ethyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate [ka] To a solution of tert-butyl 4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidine-1-carboxylate (500 mg, 1.025 mmol) in DMF (5 mL) was added NaH (61.5 mg, 1.538 mmol). The reaction mixture was stirred under N at 0 °C for 30 min. Then, ethyl chloroformate (0.117 mL, 1.230 mmol) was added. The reaction mixture was stirred under N from 0 °C to RT for 16 h and partitioned between H O and EtOAc. The organic layer was washed with H O and brine, dried over anhydrous Na SO and concentrated. The crude material was purified by Combiflash chromatography (60-120 silica gel; 10-50% EtOAc / petroleum ether as eluent) to afford the title compound (290 mg, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.45 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.69-7.64 (m, 1H), 7.30 (dd, J = 8.5, 1.5 Hz, 1H), 4.18-4.02 (m, 4H), 2.91-2.72 (m, 4H), 2.57 (s, 3H), 2.08 (s, 3H), 1.90-1.80 (m, 2H), 1.65-1.55 (m, 2H), 1.44 (s, 9H), 1.29 (t, J = 7.5 Hz, 6H), 0.83 (t, J = 7.0 Hz, 3H). LC-MS (ES): m / z = 560.4 [M+H] + .

[0156] Intermediate 24B: Ethyl 2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(piperidin-4-yl)-1H-indole-1-carboxylate trifluoroacetate [ka] To a solution of ethyl 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (300 mg, 0.536 mmol) in dry CHCl (1 mL) was added CFCOH (0.041 mL, 0.536 mmol) under a nitrogen atmosphere at 0° C. After stirring at 0° C. for 1 h, the reaction mixture was concentrated under reduced pressure at 30° C. The residue was stirred with ether. The solvent was carefully decanted. The resulting solid was dried under vacuum to give the title compound (298 mg, 0.520 mmol, 97% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.61 (br.s., 1H), 8.47 (s, 1H), 8.35-8.37 (m, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.66 (s, 1H), 7.28 (dd, J = 8.5, 1.5 Hz, 1H), 4.18-4.03 (m, 2H), 3.42-3.45 (m, 2H), 3.12-2.96 (m, 3H), 2.77 (dt, J = 14.1, 7.0 Hz, 1H), 2.57 (s, 3H), 2.08 (s, 3H), 2.06-1.98 (m, 2H), 1.97-1.83 (m, 2H), 1.30 (dd, J = 11.0, 7.0 Hz, 6H), 0.83 (t, J = 7.0 Hz, 3H). LC-MS (ES): m / z = 460.4 [M+H] + .

[0157] Example 24: To a solution of ethyl 2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-5-(piperidin-4-yl)-1H-indole-1-carboxylate (298 mg, 0.648 mmol) in DMF (5 mL) was added 2-bromoacetamide (179 mg, 1.297 mmol) and EtN (0.271 mL, 1.945 mmol). The reaction mixture was stirred at room temperature under N for 1 hour. After stirring at room temperature under a nitrogen atmosphere for 1 hour, the reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated. The crude material was purified by reverse-phase preparative HPLC (Column: SunFire C18 (19×150 mm), 5 micron; Mobile phase A: 10 mM NH4OAc / HO; Mobile phase B: CH3CN; Gradient: (Time (min) / % B): 0 / 30, 15 / 80, 16 / 100, 18 / 100; Flow rate: 20 mL / min) to afford the title compound (200 mg, 0.387 mmol, 59.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.45 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.31 (dd, J = 8.5, 1.5 Hz, 1H), 7.25 (br.s., 1H), 7.14 (br.s., 1H), 4.19-4.02 (m, 2H), 2.99-2.90 (m, 2H), 2.90 (s, 2H), 2.77 (quin, J = 7.2 Hz, 1H), 2.70-2.60 (m, 1H), 2.57 (s, 3H), 2.26-2.17 (m, 2H), 2.08 (s, 3H), 1.92-1.75 (m, 4H), 1.30 (dd, J = 8.8, 7.3 Hz, 6H), 0.83 (t, J = 7.3 Hz, 3H). LC-MS (ES): m / z = 517.4 [M+H] + ; HPLC RT and purity: Method E = 5.08 min and 99.13% and Method F = 7.72 min and 99.09%.

[0158] Example 25 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(hydroxymethyl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide [ka] To a solution of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (200 mg, 0.450 mmol) in DMF (2.0 mL) was added sodium hydride (54.0 mg, 1.350 mmol) and chloromethyl chloroformate (0.060 mL, 0.675 mmol). The reaction mixture was stirred at 0° C. under N for 1 h. The reaction mixture was concentrated under high vacuum to give a residue. The crude product was purified by reverse-phase HPLC (Column: YMC TRIAT (150×20) mm; 5 micron; Mobile phase A: 10 mM NH4OAc / HO; Mobile phase B: CH3CN; Flow rate: 20 mL / min; Gradient (T / %B): 0 / 20, 12 / 45). The fractions were concentrated under vacuum. The residue was dissolved in a mixture of CHCN and HO. The resulting mixture was frozen and lyophilized for 16 hours to give the title compound (29.57 mg, 0.061 mmol, 38.9% yield) as a colorless solid. 1 H NMR (400 MHz, MeOH-d4) δ 8.66 (s, 1H), 8.44 (s, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 8.3, 1.8 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H), 5.15 (d, J = 11.5 Hz, 1H), 3.16-3.07 (m, 4H), 2.88 (quin, J = 7.0 Hz, 1H), 2.74-2.64 (m, 4H), 2.39 (td, J = 11.5, 3.0 Hz, 2H), 2.19 (s, 3H), 2.06-1.89 (m, 4H), 1.37 (dd, J = 9.5, 7.0 Hz, 6H). LC-MS (ES): m / z = 475.4 [M+H] + ; HPLC RT and purity: Method A = 8.75 min and 98.27% and Method B = 9.74 min and 98.25%.

[0159] Solubility evaluation in buffered aqueous solution The solid powders of each prodrug were equilibrated in aqueous buffer solutions of pH 1, 4, and 6.5 at 25°C for approximately 24 hours. After equilibration, excess solids were separated by filtration using a 0.45 μm membrane filter, and the filtrates were collected in appropriate glass vials. The filtrates were appropriately diluted with the respective buffers / diluents and analyzed by reversed-phase LC with UV detection. [Table 3] a In the stability test, 15% acetonitrile in buffer was used. The buffers used were 0.1N HCl aqueous solution (pH 1.0), acetate buffer (pH 4.0) at a concentration of 50 μg / mL, and phosphate buffer (pH 6.5). ND = Not determined.

[0160] The compounds of Examples 1-11, 14-15, 19-21, and 23-25 ​​were found to have higher solubility than Compound A at pH 4 and / or pH 6.5. By improving solubility over a wider pH range, the compounds of the present invention will have less solubility variation depending on the patient's gastric acid levels. Fluctuations in gastric pH can occur due to other medications or food intake. The data in Table 1 demonstrate that the test compounds of the present invention are more uniformly absorbed, independent of gastric pH.

[0161] Stability evaluation in buffered aqueous solution Stability studies of individual prodrugs were performed at approximately 50 μg / mL in aqueous buffer solutions of approximately pH 1 (0.1 M HCl), 4 (acetate buffer), and 6.5 (phosphate buffer) over 24 hours at 37°C. Approximately 15% v / v acetonitrile was used as a cosolvent in these pH buffers to obtain clear solutions of the prodrugs. Sample analysis was performed using a standard reverse-phase liquid chromatography (LC) method with UV detection. The area percent (AP) loss of the prodrug peak was quantified as a function of time. The appearance of the parent peak was identified from the chromatographic retention time. The half-life (t 1 / 2, h) were calculated using a pseudo-linear equation for the AP loss versus time plot. [Table 4]

[0162] Recombinant intestinal alkaline phosphatase (rIALP) assay Examples 8 and 9 were evaluated in this assay. To assess the potential for generating parent drug from the phosphate prodrug, 100 μL of rIALP was dissolved in 100 mM Tris-HCl buffer (pH 7.4) and added to 100 μL of freshly prepared prodrug solution (10 mM) prepared in the same buffer. Incubations were performed in triplicate using a 96-well plate (Waters, Milford, MA) in a 37°C shaking bath (Julabo, Allentown, PA). The prodrug and enzyme solutions were preheated to 37°C before the reaction was initiated by the addition of substrate. Incubations were carried out for 120 min, with 100 μL aliquots taken at 0, 5, 10, 15, 30, 60, 90, and 120 min. The assay was terminated at designated time points by the addition of 200 μL of ice-cold acetonitrile containing the internal standard, followed by centrifugation at 4000 g for 4 min. The supernatant was transferred to a new 96-well plate for analysis by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS / MS). 1 / 2 Values ​​were determined from the natural logarithm of the percent remaining versus time plot. [Table 5]

[0163] Pharmacokinetic evaluation of selected prodrugs in rats Under isoflurane anesthesia, SD rats were cannulated into the right jugular vein (JVC) by inserting a silicone-tipped PE50 catheter, and the rats were allowed to recover. The cannulated rats were fasted overnight and allowed free access to water. Food was provided 3 hours after administration.

[0164] Examples 3, 6, 8-10, and 15 (5 mg / kg or parent compound equivalent) were administered as solutions at a dose of 5 mL / kg to SD rats (N=3). The formulation used in these studies was 40% 20 mM citric acid solution, 10% ethanol, 45% PEG 300, and 5% poloxamer 188. Blood samples (150 μL) were collected from the jugular vein catheter at 0.25, 0.5, 1, 3, 5, 7, and 24 hours post-dose. The catheter was flushed with heparinized saline after each sample collection. During sample collection (blood), blood samples were collected into tubes containing 2% K2EDTA, 30 μL of PMSF solution was added, and the samples were immediately centrifuged at 10,000 × g for 5 minutes at 4°C to collect plasma. For the prodrug, an aliquot (30 μL) of the separated plasma was immediately quenched with 150 μL of ACN containing ritonavir (200 nM) as an internal standard. Plasma samples were analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC / MS / MS).

[0165] Sample Preparation for Bioanalysis Separate calibration curves for the parent and prodrug were generated in rat plasma by serial dilution over a concentration range of 0.169 to 10,000 nM. A 30 μL aliquot of plasma standard / research sample (extracted from blood containing PMSF) was quenched online with 150 μL of internal standard (ritonavir: 200 nM) in CH3CN. The quenched sample was filtered through a Millipore Solvinert hydrophilic plate. The sample was then centrifuged at 3700 rpm for 3 minutes at 4°C. The resulting eluate (4 μL) was injected into a mass spectrometer for analysis. UPLC-MS / MS Method: Samples were analyzed using a Waters Acquity UPLC® (ultra-performance liquid chromatography) integrated system (Milford, USA) on a reversed-phase column (Waters: BEH C18, 1.7 micron, 2.1*50 mm) maintained at 40±2°C. Samples were analyzed at a flow rate of 0.5 mL / min over a shallow gradient (solvent A: 0.1% v / v formic acid / 10 mM ammonium formate; solvent B: 0.1% v / v formic acid / CH3CN) for a total run time of 3 min. A linear gradient was used for the separation, where mobile phase B started at 10% and reached 90% at 2.6 min. Over the next 0.2 min, the concentration of mobile phase B returned to 10%.

[0166] Quantitation was achieved by MS / MS detection in positive ion multiple reaction monitoring (MRM) mode using an API4000 Q-Trap mass spectrometer (Applied Biosystems, MDS Sciex, Toronto, Canada) equipped with an electrospray ionization (ESI) source at a capillary voltage of 5.5 kV and a temperature source of 500 °C.

[0167] Quadrupoles Q1 and Q3 were set to unit resolution. Analytical data were acquired and processed by Analyst software (version 1.5.0). Linearity of the calibration standards was determined by the spike concentration and weighted 1 / X. 2The accuracy was assessed by fitting each peak area ratio using linear least-squares regression analysis. If the coefficient of variation of the internal standard was <15%, the batch was accepted. The accuracy of all calibration standards was within 80-120%.

[0168] Data analysis Pharmacokinetic parameters were calculated by non-compartmental analysis using KINETICA® software (version 5.1) ThermoFisher Scientific Corporation, Philadelphia. For the oral administration group, peak concentrations (C max ) and C max Time (T max ) was recorded directly from experimental observations. The last measurable concentration (C last ) drug blood concentration time curve (AUC 0-t ) was calculated using the mixed log-linear trapezoidal rule. [Table 6] a In the case of prodrugs, with the exception of Example 10, equivalent doses of the parent were used.

[0169] Crystal structure determination Crystallization details: Example 7: Single crystals were dissolved as a mixed solvate hydrate or hydrated TFA salt was prepared from a saturated solution of Example 7 in methanol kept at ∼25° C. in an open drum vial. After complete evaporation of the solvent, clear, colorless, block-shaped crystals were obtained. Crystal data of Example 7 (M=789.78g / mol): triclinic system, space group P-1 (No. 2), a = 9.4971(8)Å, b = 13.0969(13)Å, c = 18.0138(16)Å, α = 89.263(6)°, β = 81.145(5)°, γ = 75.206(5)°, V = 2139.7(3)Å 3 , Z = 2, T = 296.15 K, μ(MoKα) = 0.103 mm -1, Dcalc = 1.226 g / cm 3 , 23363 Measured reflection(2.288° < 2θ < 49.998°), 7143 unique (R int = 0.0963, R sigma = 0.1644), which were used in all calculations. The final R1 was 0.2685 (I > 2σ(I)) and wR2 was 0.5907 (all data). Several high-intensity q peaks were observed in the unmodeled structure due to the simplification of the structural model. These q peaks likely correspond to disordered water / solvent molecules that are not assigned in the current model.

[0170] Example 8: Single crystals were prepared from a saturated solution of Example 8 in a mixture of solvents (ethanol:methanol:acetonitrile ∼1:1:1) in an open drum vial at ∼25° C. After complete evaporation of the solvent, clear, pale yellow, block-shaped crystals were obtained. Crystal data of Example 8 (M=592.11g / mol): triclinic system, space group P-1 (No. 2), a = 9.8852(16)Å, b = 11.0560(16)Å, c = 29.357(4)Å, α = 85.118(8)°, β = 85.506(9)°, γ = 84.663(8)°, V = 3174.9(8)Å 3 , Z = 4, T = 296.15 K, μ(MoKα) = 0.231 mm -1 , Dcalc = 1.239 g / cm 3 , 46825 Reflection measurement (2.792° < 2θ < 49.998°), 11169 unique (R int = 0.2467, R sigma = 0.3114), which were used in all calculations. The final R1 was 0.1471 (I > 2σ(I)) and wR2 was 0.4877 (all data).

[0171] Several intense q peaks were observed in the structure, likely corresponding to highly disordered solvent molecules (likely ethyl acetate), and a solvent mask was used during refinement of the structural model for simplification. One of the two API molecules in the asymmetric unit was also observed to be disordered.

[0172] X-ray diffraction single crystal: Single crystals of suitable quality were mounted in a HAMPTON CryoLoop using open paratonol oil. Data were collected at room temperature (~296 K) on a Bruker AXS SMART APEX II CCD diffractometer. Data integration and reduction were performed using SAINT v7.68A (Bruker, 2009), and absorption corrections were performed using SADABS-2008 / 1 (Bruker, 2008) in the Bruker software suite. Structures were solved using intrinsic phasing or direct methods with SHELXS-97 (Sheldrick, 2008) and refined in SHELXTL using SHELXL-97 (version 2014 / 7; Sheldrick, 2014). OLEX2 was used for structure solution, refinement, visualization, and CIF and figure generation. MERCURY was used for intermolecular interaction analysis. All hydrogen atoms were geometrically fixed and refined isotropically. [Claim 1] Formula (I), Formula (II), Formula (III), and Formula (IV): [C1] TIFF0007767151000082.tif71165 [In the formula, R 1 is -CH 2 OH, -C(O)O(C 1-4 alkyl), -C(O)CH 2 NR x R x , -C(O)(CH 2 ) 1-3 OP(O)(OH) 2 , -C(O)CH 2 NR x C(O)OCH 2 OP(O)(OH)2 , -C(O)OCH 2 (pyrrolidinyl), -C(O)OCH 2 (piperidinyl), -C(O)OCHR x OC(O)(aminocyclopropyl), -C(O)OCH(CH 3 )OC(O)(aminocyclopropyl), -C(O)OCH 2 OP(O)(OH) 2 , -P(O)(OH) 2 , -SCH 2 CH(NH 2 )C(O)OH, [Chemistry 2] TIFF0007767151000083.tif37165 and; R 2 and R 3 are independently -CH 2 OP(O)(OH) 2 , -CH 2 OC(O)NR x CH 2 CH 2 NR x R x , -CH 2 OC(O)NR x CH 2 CH 2 OP(O)(OH) 2 ,or [Chemistry 3] TIFF0007767151000084.tif2255 and; R 4 -P(O)(OH) 2 and; R x are each independently hydrogen or -CH 3 ] or a salt thereof. [Claim 2] R 1 But -CH 2 OH, -C(O)CH 2 NH(CH 3 ), -C(O)CH 2 CH 2 CH 2 OP(O)(OH) 2 , -C(O)CH 2 N(CH 3 )C(O)OCH 2 OP(O)(OH) 2 , -C(O)OCH 2 CH 3 , -C(O)OCH 2 (pyrrolidinyl), -C(O)OCH 2 (piperidinyl), -C(O)OCH 2 OC(O)(aminocyclopropyl), -C(O)OCH(CH 3 )OC(O)(aminocyclopropyl), -C(O)OCH 2 OP(O)(OH) 2 , -P(O)(OH) 2 , -SCH 2 CH(NH 2 )C(O)OH, [C4] TIFF0007767151000085.tif37165 and; R 2 But -CH 2 OP(O)(OH) 2 , -CH 2 OC(O)N(CH 3 )CH 2 CH 2 NH(CH 3 ), -CH 2 OC(O)N(CH 3 )CH 2 CH 2 OP(O)(OH) 2 、 [5] TIFF0007767151000086.tif24165 and; R 3 But -CH 2 P(O)(OH) 2 , -CH 2 OC(O)N(CH 3 )CH 2 CH 2 OP(O)(OH) 2 ,or [6] TIFF0007767151000087.tif2257 and; R 4 -P(O)(OH) 2 That is, 2. The compound of claim 1, or a salt thereof. [Claim 3] 3. The compound of claim 1 or 2, having the structure of formula (I), or a salt thereof. [Claim 4] 3. The compound according to claim 1, which is represented by the structure of formula (II), or a salt thereof. [Claim 5] 3. The compound according to claim 1, which is represented by the structure of formula (III), or a salt thereof. [Claim 6] 3. The compound according to claim 1, which is represented by the structure of formula (IV), or a salt thereof. [Claim 7] The compounds are: (S)-piperidin-2-ylmethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (1); (S)-(1-(((phosphonooxy)methoxy)carbonyl)piperidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (2); (S)-pyrrolidin-2-ylmethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (3); (S)-(1-(((phosphonooxy)methoxy)carbonyl)pyrrolidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (4); 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate) Pyridin-6-yl)-3-isopropyl-1-(methylglycyl)-1H-indol-5-yl)piperidin-1-yl)acetamide ditrifluoroacetate(5); 1-((1-aminocyclopropane-1-carbonyl)oxy)ethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate Ditrifluoroacetate (6-7); 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-((phosphonooxy)methyl)piperidin-1-ium trifluoroacetate (8);6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-1-((phosphonooxy)methyl)-[1,2,4]triazolo[1,5-a]pyridin-1-ium trifluoroacetate(9);4-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-4-oxobutyl dihydrogen Phosphate (10); S-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-L-cysteine ​​(11); 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)methyl)piperidin-1-ium Ditrifluoroacetate (12);6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-1-(((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridin-1-ium Tritrifluoroacetate (13); 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(1-((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl)piperidin-1-ium ditrifluoroacetate (14);((1-Aminocyclopropane-1-carbonyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate trifluoroacetate (15); (phosphonooxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (16); 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl); -[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)phosphonic acid (17); (5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)phosphonate (18); (phosphonooxy)methyl (2-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-2-oxoethyl)(methyl)carbamate (19); 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(((methyl(2-(phosphonooxy)ethyl)carbamoyl)oxy)methyl)piperidin-1-ium Trifluoroacetate (20); 6-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-1-(((methyl(2-(phosphonooxy)ethyl)carbamoyl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridin-1-ium trifluoroacetate (21); ((3-methoxy-4-(phosphonooxy)benzoyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (22); 1-(2-amino-2-oxoethyl)-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)-1-(((methyl(2-(methylamino)ethyl)carbamoyl)oxy)methyl)piperidin-1-ium trifluoroacetate (23);2. The compound of claim 1, which is ethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (24); or 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1-(hydroxymethyl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide (25), or a salt thereof. [Claim 8] A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. [Claim 9] 10. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in therapy in the treatment of an autoimmune disease or a chronic inflammatory disease. [Claim 10] 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the autoimmune disease or chronic inflammatory disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), and Sjogren's syndrome.

Claims

1. (S)-Piperidin-2-ylmethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (1); (S)-Pyrrolidin-2-ylmethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (3); (S)-(1-(((phosphonooxy)methoxy)carbonyl)pyrrolidin-2-yl)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (4); 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1-(methylglycyl)-1H-indol-5-yl)piperidin-1-yl)acetamide (5); 1-((1-aminocyclopropane-1-carbonyl)oxy)ethyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (6-7); ((1-aminocyclopropane-1-carbonyl)oxy)methyl 5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indole-1-carboxylate (15); and (phosphonooxy)methyl A compound selected from (2-(5-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-1-yl)-2-oxoethyl)(methyl)carbamate (19), or a salt thereof.

2. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

3. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof for treating an autoimmune disease or a chronic inflammatory disease.

4. 4. The pharmaceutical composition of claim 3, wherein the autoimmune disease or chronic inflammatory disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), and Sjogren's syndrome.

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