Nampt modulators

Abstract

To provide NAMPT modulators.SOLUTION: There are provided compounds of Formula (II) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, and p are as defined herein. There is also provided a pharmaceutically acceptable composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof. There are also provided methods of using a compound of Formula (II), or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the priority and benefit of U.S. Provisional Application No. 62 / 971,838, filed on February 7, 2020, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] Field Provided herein are phenylurea compounds, pharmaceutical compositions containing such compounds, and methods of treating various diseases and conditions mediated by nicotinamide phosphoribosyltransferase (NAMPT) using such compounds.

Background Art

[0003] The present disclosure relates to the use of modulators of nicotinamide phosphoribosyltransferase (NAMPT) and derivatives thereof, and to enhancers or inducers of NAMPT expression, NAMPT activity or NAMPT - mediated signaling for preventing or treating various pathological conditions.

[0004] Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme (enzyme cofactor) involved in both catabolic and anabolic basic biological processes. As a coenzyme, NAD is associated with many oxidases (usually dehydrogenases) involved in energy metabolism and functions as a universal electron carrier. NAD exists in the oxidized state in cells (NAD+ and NADP+), and the reduced state (NADH and NADPH) functions as a chemical means to capture and transfer free energy from the oxidative processes of catabolism or to provide small packets of energy for constructing macromolecules in anabolism. NADH generated from the oxidation of carbohydrates, lipids, and amino acids provides a reduction equivalent to the mitochondrial electron transport system and ultimately promotes the synthesis of ATP in oxidative phosphorylation.

[0005] More than 200 enzymes use either NAD+ or NADP+ as coenzymes, and enzyme functions are not limited to energy metabolism. Currently, it is recognized that NAD+ plays a role in regulating diverse functions such as mitochondrial function, respiratory capacity, and biosynthesis, mitochondrial nuclear signaling. Furthermore, it controls cell signaling, gene expression, DNA repair, hematopoiesis, immune function, endoplasmic reticulum stress (unfolded protein response), and autophagy. Additionally, NAD has anti-inflammatory effects and is a precursor of NADPH, the main source of reducing power to combat oxidative stress. Numerous literatures have shown that increasing NAD levels is an effective strategy for preventing or improving a variety of pathological conditions (Stromland et al., Biochem Soc Trans. 2019, 47(1):119-130; Ralto et al., Nat Rev Nephrol. 2019; Fang et al., Trends Mol Med. 2017, 23(10):899-916; Yoshino et al., Cell Metab. 2011, 14(4):528-36; Yang and Sauve, Biochim Biophys Acta. 2016, 1864:1787-1800; Verdin, Science. 2015, 350(6265):1208-13).

[0006] The levels of NAD+- and NADP+-related enzymes play important roles in normal physiological functions and change under various disease and stress conditions, including aging. Cellular NAD+ levels are associated with aging, metabolic diseases, inflammatory diseases, ischemia / reperfusion injury, and in humans (Massudi et al., PLoS ONE. 2012, 7(7):e42357) as well as in animals (Y It decreases between other states in Ang et al., Cell. 2007, 130(6): 1095-107; Braidy et al., PLoS One. 2011, 26; 6(4): e19194; Peek et al., Science. 2013, 342(6158): 1243417; Ghosh et al., J Neurosci. 2012, 32(17): 5821-32), and it is suggested that the regulation of cellular NAD+ levels affects the rate and severity of the decline and deterioration of body functions. Therefore, an increase in the cellular NAD+ concentration may be beneficial in the context of aging and age-related diseases. The cellular NAD+ pool is regulated by the balance between the activities of NAD+ synthesis and consuming enzymes. In mammals, NAD+ is synthesized from various dietary sources, including one or more of its major precursors, such as tryptophan (Trp), nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nicotinamide (NAM). Based on the bioavailability of its precursors, there are three pathways for synthesizing NAD+ intracellularly: (i) from Trp by the de novo biosynthesis pathway or the kynurenine pathway, (ii) from NA by the Preiss-Handler pathway, and (iii) from NAM, NR, and NMN in the salvage pathway (Verdin et al., Science. 2015, 350(6265):1208-13). Among these, the main NAD+ biosynthesis pathway involves the synthesis step of nicotinamide mononucleotide (NMN) using nicotinamide and 5'-phosphoribosyl pyrophosphate by the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT), which is important for determining lifespan and responses to various stresses (Fulco et al, Dev Cell. 2008, 14(5):661-73; Imai, Curr Pharm Des. 2009, 15(1):20-8; Revollo et al., J Biol Chem. 2004, 279(49):50754-63; Revollo et al., Cell Metab. 2007, Nov; 6(5):363-75; van der Veer et al., J Biol Chem. 2007, 282(15):10841-5; Yang et al., Cell. 2007, 130(6):1095-107). Therefore, increasing the rate of NAMPT catalysis by small molecule activators would be an effective strategy to increase NAD levels and thereby address a wide range of pathological conditions. These include heart disease, tissue damage induced by chemotherapy, kidney disease, metabolic diseases, muscle diseases, neurological diseases and injuries, diseases caused by stem cell dysfunction, as well as DNA damage and primary mitochondrial disorders.

Prior Art Documents

Non-Patent Documents

[0007] [Non-Patent Document 1] Stromland et al., Biochem Soc Trans. 2019, 47(1):119-130 [Non-Patent Document 2] Ralto et al., Nat Rev Nephrol. 2019 [Non-Patent Document 3] Fang et al., Trends Mol Med. 2017, 23(10):899-916 [Non-Patent Document 4] Yoshino et al., Cell Metab. 2011, 14(4):528-36 [Non-Patent Document 5] Yang and Sauve, Biochim Biophys Acta. 2016, 1864:1787-1800 [Non-Patent Document 6] Verdin, Science. 2015, 350(6265):1208-13 [Non-Patent Document 7] Massudi et al., PLoS ONE. 2012, 7(7):e42357 [Non-Patent Document 8] Yang et al., Cell. 2007, 130(6):1095-107 [Non-Patent Document 9] Braidy et al. PLoS One. 2011, 26;6(4):e19194 [Non-Patent Document 10] Peek et al. Science. 2013, 342(6158):1243417 [Non-Patent Document 11] Ghosh et al., J Neurosci. 2012, 32(17):5821-32 [Summary of the Invention] [Means for Solving the Problems]

[0008] In one aspect, provided herein is a compound of formula (II):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0009] In another aspect, provided herein is a compound of formula (I):

Chemical formula

Chemical formula

[0010] In another aspect, provided herein is a compound of formula (I-G):

Chemical formula

[0011] In another aspect, provided herein is a compound of formula (I-A):

Chemical formula

[0012] In another aspect, provided herein is a compound of formula (I-B):

Chemical formula

[0013] In another aspect, provided herein is a compound of formula (I-C):

Chem.

[0014] In another aspect, provided herein is a compound of formula (I-D):

Chem.

[0015] In another aspect, provided herein is a compound of formula (I-E):

Chem.

[0016] In another aspect, provided herein is a compound of formula (I-F): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R f , and R g are as described above for formula (II) or any variation or embodiment thereof.

[0017] In another aspect, provided herein is a compound of formula (II-A): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 4 , and R 6 are as described above for formula (II) or any variation or embodiment thereof.

[0018] In a further aspect, provided herein is a pharmaceutical composition comprising at least one compound of formula (II), (I-G), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), or (II-A), such as a compound of Table 1, or a stereoisomer or tautomer thereof, or optionally further comprising a pharmaceutically acceptable excipient, and a pharmaceutically acceptable salt of any of the foregoing.

[0019] In another aspect, provided herein is a method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an effective amount of at least one compound of formula (II), (I-G), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), or (II-A), such as a compound of Table 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of formula (II), (I-G), (I), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), or (II-A). In some embodiments, the disease or condition is selected from the group consisting of cancer, proliferative disorder or condition, inflammatory disorder or condition, metabolic disorder, heart disease or condition, chemotherapy-induced tissue damage, kidney disease, metabolic disease, neurological disease or injury, neurodegenerative disorder or disease, disease caused by stem cell dysfunction, disease caused by DNA damage, primary mitochondrial disorder, or muscle disease or muscle wasting disorder. In some embodiments, the disease or condition is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury.

[0020] Additional embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and through practice of the present disclosure.

[0021] For the sake of brevity, the disclosures of publications cited herein, including patents, are incorporated herein by reference. DETAILED DESCRIPTION OF THE INVENTION

[0022] DETAILED DESCRIPTION DEFINITIONS As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0023] Throughout this application, unless the context otherwise indicates, references to compounds of formula (II) include all subgroups of formula (II) as defined and / or described herein, such as formula (I), (I-G), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), including, by way of example, all substructures, subgenera, preferences, embodiments, examples, and specific compounds. References to compounds of formula (II) and its subgroups, such as formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes, and / or their protected forms. In some embodiments, references to compounds of formula (II) and its subgroups, such as formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), include polymorphs, solvates, co-crystals, isomers, tautomers, and / or their oxides.In some embodiments, references to the compounds of formula (II) and subgroups thereof, such as formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1) include polymorphs, solvates, and / or their co-crystals. In some embodiments, references to the compounds of formula (II) and subgroups thereof, such as formula (I-G), (I)(I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1) include isomers, tautomers, and / or their oxides. In some embodiments, references to the compounds of formula (II) and subgroups thereof, such as formula (I-G), (I)(I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B。 2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1) include their solvates. Similarly, the term "salt" includes solvates of salts of the compounds.

[0024] "Alkyl" includes straight-chain and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms. For example, C 1-6Alkyl includes both straight-chain and branched-chain alkyls of 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, it is intended to include all branched and straight-chain versions having that number of carbons; thus, for example, "propyl" includes n-propyl and isopropyl. "Butyl" includes n-butyl, sec-butyl, isobutyl, and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0025] When a range of values is specified (e.g., C 1~6 alkyl), each value within that range, and all ranges therebetween are included. For example, "C 1-6 alkyl" includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 alkyl.

[0026] "Alkyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. This group may be in either the cis or trans configuration (Z or E configuration) with respect to the double bond(s). Examples of alkyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).

[0027] "Alkynyl" refers to an unsubstituted branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., buta-1-yn-1-yl, buta-1-yn-3-yl, buta-3-yn-1-yl).

[0028] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. The cycloalkyl group can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cyclopropyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged, caged, and spirocyclic ring groups (e.g., norbornane, bicyclo[2.2.2]octane, spiro[3.3]heptane). Further, when a polycyclic cycloalkyl group is attached to the parent structure via a non-aromatic carbon, one of the rings of the polycyclic cycloalkyl group can be aromatic. For example, 1,2,3,4-tetrahydronaphthalene -1-yl group (part of which is bonded to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, and 1,2,3,4-tetrahydronaphthalen-5-yl (part of which is bonded to the parent structure through an aromatic carbon atom) is not regarded as a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of cycloalkyl groups fused to an aromatic ring are described below.

[0029] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. The aryl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of the polycyclic aryl group are aromatic (e.g., naphthyl). In other examples, the polycyclic aryl group may contain a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is bonded to the parent structure through an atom of the aromatic ring. Accordingly, the 1,2,3,4-tetrahydronaphthalen-5-yl group (wherein a part thereof is bonded to the parent structure through an aromatic carbon atom) is regarded as an aryl group, but 1,2,3,4-tetrahydronaphthalen-1-yl (wherein a part thereof is bonded to the parent structure through a non-aromatic carbon atom) is not regarded as an aryl group. Similarly, the 1,2,3,4-tetrahydroquinolin-8-yl group (wherein a part thereof is bonded to the parent structure through an aromatic carbon atom) is regarded as an aryl group, but the 1,2,3,4-tetrahydroquinolin-1-yl group (wherein a part thereof is bonded to the parent structure through a non-aromatic nitrogen atom) is not regarded as an aryl group. However, the term "aryl" does not include or overlap with "heteroaryl" as defined herein regardless of the bonding point (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In some cases, aryl is phenyl. Additional examples of aryl groups containing an aromatic carbocyclic ring fused to a non-aromatic ring are described below.

[0030] "Heteroaryl" refers to an aromatic ring containing a specified number of atoms (e.g., 5-12, or 5-10 membered heteroaryl) composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon. The heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the heteroaryl group is 1 or less. Unless otherwise indicated, the heteroaryl group can be attached to the parent structure by a carbon or nitrogen atom to the extent permitted by valence. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl groups, and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl groups.

[0031] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazole (e.g., 1,2,4-triazole, 1,3,5-triazine), and tetrazine.

[0032] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H- Imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0033] In other examples, a polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom of an aromatic ring. For example, the 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (where a part of it is attached to the parent structure through an aromatic carbon atom) is regarded as a heteroaryl group, but 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (where a part of it is attached to the parent structure through a non-aromatic carbon atom) is not regarded as a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.

[0034] "Heterocycloalkyl" refers to a non-aromatic fully saturated ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7-membered heterocycloalkyl) composed of one or more heteroatoms (e.g., 1, 2, 3, or 4) selected from N, O, S, and the remaining ring atoms are carbon. The heterocycloalkyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Examples of spirocyclic heterocycloalkyl groups include azaspiro[3.3]heptane, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, and diazaspiro[3.5]nonane. Further, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., may also be (aryl or heteroaryl), provided that this polycyclic heterocycloalkyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (where a part thereof is bonded to the parent structure via a non-aromatic nitrogen atom) is regarded as a heterocycloalkyl group, but a 1,2,3,4-tetrahydroquinolin-8-yl group (where a part thereof is bonded to the parent structure via an aromatic carbon atom) is not regarded as a heterocycloalkyl group. Examples of the polycyclic heterocycloalkyl group composed of a heterocycloalkyl group condensed with an aromatic ring are described below.

[0035] "Heterocycloalkenyl" refers to a non-aromatic ring having a specified number of atoms (e.g., 3-10, or 3-7 membered heterocycloalkyl) composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon, and having at least one double bond obtained by removing one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. The heterocycloalkenyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro)-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydro-pyridinyl (e.g., 1,2,3,4-tetrahydro-pyridinyl, 1,2,3,6-tetrahydro-pyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Further, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkenyl group is bonded to the parent structure through a non-aromatic carbon or nitrogen atom. For example, the 1,2-dihydroquinolin-1-yl group (where a part of this is bonded to the parent structure through a non-aromatic nitrogen atom) is regarded as a heterocycloalkyl group, but the 1,2-tetrahydroquinolin-8-yl group (where a part of this is bonded to the parent structure through an aromatic carbon atom) is not regarded as a heterocycloalkyl group. Examples of polycyclic heterocycloalkenyl groups composed of heterocycloalkenyl groups fused to an aromatic ring are described below.

[0036] Examples of polycyclic rings composed of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[d]imidazol-2 (3H)-One, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-dione, quinoxalin-2(1H)-one, quinoxalin-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyrimidin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one are mentioned. As discussed herein, whether each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group is determined by the atoms to which a part of it is attached to the parent structure.

[0037] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0038] Unless otherwise specified, disclosed compounds and / or compounds described herein include all possible enantiomers, diastereomers, meso isomers, as well as racemic mixtures, optically pure forms, and other stereoisomeric forms including their intermediate mixtures. Enantiomers, diastereomers, meso isomers, and other stereoisomeric forms may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques. Unless otherwise specified, if a compound disclosed and / or described herein contains an olefinic double bond or other geometrically asymmetric center, this compound is intended to include both E and Z isomers. If a compound described herein contains a moiety capable of tautomerization, unless otherwise specified, the compound is intended to include all possible tautomers.

[0039] "Protecting group" has the meaning conventionally associated in organic synthesis, i.e., a group that selectively blocks one or more reaction sites in a polyfunctional compound such that a chemical reaction can be carried out selectively at another unprotected reaction site and such that the group can be readily removed after the selective reaction is complete. A variety of protecting groups are disclosed. For example, T.H. Greene and P.G.M. Wuts, Protective Groups in Organ ic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, "hydroxy protected form" includes at least one hydroxy group protected with a hydroxy protecting group. Similarly, amines and other reactive groups may be protected as well.

[0040] The term "pharmaceutically acceptable salt" refers to salts of any of the compounds of this specification that are known to be non-toxic and are commonly used in the pharmaceutical literature. In some embodiments, a pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compound described herein and is not a salt that is biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 6 6(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Examples of inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0041] When the compounds described in this specification are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the compound is a free base, addition salts, particularly pharmaceutically acceptable addition salts, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds (see Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will be aware of the various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0042] A "solvate" is formed by the interaction of a solvent with a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of the compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0043] The term "substituted" means that a particular group or moiety has one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyl-oxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azide, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy. The term "unsubstituted" means that the specified group bears no substituent. When the term "substituted" is used to describe a structural system, substitution means that substitution occurs at any position where any valence on the system is allowed. It is understood that when a group or moiety has multiple substituents, the substituents may be the same or different from each other. In some embodiments, a substituted group or moiety has from 1 to 5 substituents. In some embodiments, a substituted group or moiety bears 5 substituents. In some embodiments, a substituted group or moiety bears 2 substituents. In some embodiments, a substituted group or moiety bears 3 substituents. In some embodiments, a substituted group or moiety bears 4 substituents. In some embodiments, a substituted group or moiety bears 5 substituents.

[0044] "Optional" or "optionally" means that the event or situation described thereafter may or may not occur, and that the description includes both the case where the event or situation occurs and the case where it does not occur. For example, "alkyl optionally substituted" includes both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, one of ordinary skill in the art will understand that such a group is not intended to introduce any substitution or substitution pattern that is sterically impracticable, synthetically infeasible, and / or inherently unstable. It will also be understood that when a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0045] The compounds disclosed and / or described herein can be, for example, 2 H, 3 H, 11 C, 13 C and / or 14 in an enriched isotopic form rich in the content of C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be prepared, for example, by the procedures described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Such deuterated compounds can improve the effectiveness and increase the duration of action of the compounds disclosed and / or described herein. Deuterium-substituted compounds are described in Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et It can be synthesized using various methods such as those described in al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled Compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0046] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Such media and agents for use with the pharmaceutically active substance are well known in the art. The use thereof in pharmaceutical compositions is contemplated, except insofar as any conventional media or agent is incompatible with the active ingredient. Supplementary active ingredients may also be incorporated into the pharmaceutical compositions.

[0047] The terms "patient", "individual", and "subject" refer to animals such as mammals, birds, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, the patient or subject is a human, for example, a human who has been or will be the subject of treatment, observation, or experiment. The compounds, compositions, and methods described herein can be useful for both human therapeutic and veterinary applications.

[0048] As used herein, the term "therapeutic" refers to the ability to modulate nicotinamide phosphoribosyltransferase (NAMPT). As used herein, "modulate" refers to a change in activity as a direct or indirect response to the presence of a chemical substance described herein, compared to its activity in the absence of the chemical substance. The change may be an increase or a decrease in activity and may be due to a direct interaction of the chemical substance with the target or due to an interaction of the chemical substance with one or more other factors (which in turn affect the activity of the target). For example, the presence of a chemical substance may increase or decrease target activity (directly or indirectly) by, for example, binding directly to the target, increasing or decreasing target activity (directly or indirectly) of another factor, or increasing or decreasing (directly or indirectly) the amount of target present in a cell or organism. Binding to it, (directly or indirectly) increasing or decreasing the target activity of another factor, or (directly or indirectly) increasing or decreasing the amount of target present in a cell or organism can increase or decrease the target activity.

[0049] The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound disclosed and / or described herein that, when administered to a patient in need of such treatment, is sufficient to affect treatment, as defined herein. A therapeutically effective amount of a compound can be an amount sufficient to treat a disease responsive to modulation of nicotinamide phosphoribosyltransferase (NAMPT). The therapeutically effective amount will vary, for example, depending on the subject and condition being treated, the subject's weight and age, the severity of the condition, the particular compound, the dosing regimen to be followed, the timing of administration, the method of administration, all of which can be readily determined by one of ordinary skill in the art. A therapeutically effective amount can be confirmed experimentally, for example, by analyzing the blood concentration of the chemical substance, or theoretically, by calculating bioavailability.

[0050] "Treatment" (and related terms such as "treating", "being treated", "treatment", etc.) includes one or more of the following. Preventing a disease or disorder (i.e., not causing the onset of clinical symptoms of that disease or disorder; inhibiting a disease or disorder; delaying or preventing the onset of clinical symptoms of that disease or disorder; and / or reducing that disease or disorder (i.e., causing reduction or regression of clinical symptoms). This term encompasses situations where a disease or disorder has already been experienced by a patient, as well as situations where that disease or disorder is not currently being experienced but is expected to occur. This term covers both complete and partial reduction or prevention of the condition or disorder, as well as complete or partial reduction of the clinical symptoms of a disease or disorder. Thus, the compounds described and / or disclosed herein may prevent the worsening of an existing disease or disorder, assist in the management of that disease or disorder, or reduce or eliminate that disease or disorder. When used in a prophylactic manner, the compounds disclosed and / or described herein may prevent the onset of a disease or disorder or reduce the extent of a disease or disorder that may occur.

[0051] Compound Compounds and their salts (such as pharmaceutically acceptable salts) are detailed herein, including a brief summary and the appended claims. Also provided are the uses of all compounds described herein, including any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, optical isomers, diastereomers, and mixtures thereof, in any ratio, including racemic mixtures, salts, and solvates of the compounds described herein, as well as methods for making such compounds. Any compound described herein may also be referred to as a drug.

[0052] In one aspect, provided is a compound of formula (II): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R1 is halo or methoxy; R 6 is hydrogen or halo; and p is 0 or 1, where when p is 1, R 2 is hydrogen or C 1 -C 6 alkyl, or together with Z and intervening atoms forms a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; R 4 is hydrogen or C 3 -C 1 -C 6 alkyl; R 4 is a) Z 1 NR a C(O)-, b) Z 2 C(O)NR b -, c) Z 3 (CR c R d ) m NR e -, d) Z 4 S(O) 2 (CH 2 ) n -, e) Z 5 OC(O)-, f) NR f R g C(O)-, g) one or more independently selected C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl-substituted 5- to 10-membered heteroaryl optionally substituted with h) 3- to 10-membered heterocycloalkyl or heterocycloalkenyl which is halo, oxo, -OH, -CN, -C 1 -C 6 alkyl (one or more independently selected R yoptionally substituted with a substituent), -C optionally substituted with one or more independently selected halo substituents 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, -S(O) 2 -C 1 -C 6 alkyl, C optionally substituted with one or more independently selected halo substituents 6 -C 12 aryl, 3-6 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected oxo, one or more independently selected halo, or -C 1 -C 6 5-6 membered heteroaryl optionally substituted with an alkyl substituent, and C 3 - 6 3-10 membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl i) Z 6 S(O) 2 N(R s )-, j) Z 7 N(R t )S(O) 2 -, or k) Z 8 -O-(CH 2 ) q -; wherein R a and R e are each independently hydrogen or C 1 -C 6 alkyl; R b is hydrogen or C 1 -C 6 alkyl, or R 5 and the intervening atoms together form a 5-6 membered heterocycloalkyl or heterocycloalkenyl ring; R c and Rd is each independently hydrogen or C 1 -C 6 -alkyl, or R c and R d together with the carbon to which they are attached form a C 3 -C 6 -cycloalkyl; R f and R g together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl which is optionally substituted with halo, -OH, -CN, oxo, one or more independently selected R x -substituents and is optionally substituted with -C 1 -C 6 -alkyl, -C 3 -C 6 -cycloalkyl, -C 1 -C 6 -alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 -alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and is optionally substituted with one or more independently selected substituents from the group consisting of 5- to 6-membered heteroaryl and forms a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl which is optionally substituted; each R h is independently -C 1 -C 6 -alkyl, -O-C 1 -C 6 -alkyl, or C 6 -C 12 -aryl which is optionally substituted with one or more independently selected halo substituents; each R x is halo, -OH, -C 3 -C 6 -cycloalkyl, -C 1 -C 6 -alkoxy, -NR o R p, independently selected from the group consisting of 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl; each R y is halo, -OH, -CN, -C 1 -C 6 alkoxy, -C(O)NR q R r , C 6 -C 12 , independently selected from the group consisting of aryl, and 5- to 6-membered heteroaryl; each R j , R k , R m , R n , R o , R p , R q , and R r is independently hydrogen or C 1 -C 6 alkyl; R s is hydrogen or -C 1 -C 6 alkyl; R t is hydrogen or -C 1 -C 6 alkyl; m is 0 or 1; n is 0, 1, or 2; and q is 0 or 1; Z 1 and Z 5 are each independently R z ; Z 2 and Z3 are each independently hydrogen or R z ; Z 4 is hydrogen or R z or together with R 2 and the intervening atoms forms a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring; Z 6is selected from the group consisting of 5- to 6-membered heterocycloalkyl or heterocycloalkenyl, 5- to 6-membered heteroaryl, and C 1 -C 6 alkyl; Z 7 is C 6 -C 12 aryl; Z 8 is selected from the group consisting of 5- to 6-membered heteroaryl and C 3 ~C 6 cycloalkyl, and R z is selected from the group consisting of: a) -OH, -CN, C 3 -C 6 cycloalkyl, -NHC 1 -C 6 alkyl, C 6 -C 12 aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl, each independently optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, where C 6 -C 12 aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; b) C 6 -C 12 aryl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, each independently optionally substituted with one or more substituents selected from the group consisting of 5- to 10-membered heteroaryl; 3 -C 6A cycloalkyl, wherein a 5- or 10-membered heteroaryl is optionally further substituted with one or more independently selected C 1 ~C 6 alkyl; c)C 1 -C 6 alkoxy; d) A 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with halo, oxo, -OH, -CN, one or more independently selected R w substituents, of -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents, of -C 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, -S(O) 2 -C 1 -C 6 alkyl, optionally substituted with one or more independently selected halo substituents, of C 6 -C 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 alkyl substituents, of a 5- to 6-membered heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl; wherein each R w is independently selected from the group consisting of halo, -OH, -CN, -C 1 -C 6 alkoxy, -C(O)NR u R v 、C 6 -C 12 aryl, and 5- to 6-membered heteroaryl; wherein R u and R v are each independently hydrogen or C 1 -C 6 alkyl; e)C 6 -C 12 Aryl; and f)One or more independently selected C 1 -C 6 5- to 10-membered heteroaryl optionally substituted with an alkyl substituent; and R 5 is hydrogen, halo, or R b together with the intervening atoms forms a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring, provided that (1) When R 4 is Z 1 NR a C(O)-, Z 1 is methyl, unsubstituted cyclopropyl, -C(CH 3 ) 2 CH 2 OH, and -CH 2 -thiophene other than; (2) When R 4 is 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl,

Chemical formula

[0053] In one aspect, provided is a compound of formula (I-G):

Chemical formula

Chemical formula

[0054] In one aspect, provided is a compound of formula (I):

Chemical formula

[0055] In some embodiments of formula (II), formula (I-G), formula (I-G) or formula (I), (1) when R 4 is Z 1 NR a C(O)-, Z 1 is methyl, unsubstituted cyclopropyl, -C(CH 3 ) 2 CH 2 OH, and -CH 2 - other than thiophene; (2) R 4 is 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-pyridylpiperazinyl, 4-(furanylmethyl)piperazinyl,

Chemical formula

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

[0056] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 1 is halo. For example, in some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is bromo. In other embodiments, R 1 is iodo.

[0057] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 1 is methoxy.

[0058] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 2 is hydrogen. In some embodiments, R 2 is, C 1 -C 6 alkyl. For example, in some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0059] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 3 is hydrogen. In some embodiments, R 3 is, C 1 -C 6 alkyl. For example, in some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0060] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 5 is hydrogen. In some embodiments, R bWhen present, R 5 combines with the intervening atoms to form a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments, R 5 is halo. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is chloro. In some embodiments, R 5 is bromo. In some embodiments, R 5 is iodo.

[0061] In some embodiments of formula (II), formula (I-G), or formula (I), R 6 is hydrogen. In some embodiments of formula (II), formula (I-G), or formula (I), R 6 is halo. In some embodiments of formula (II), formula (I-G), or formula (I), R 6 is fluoro. In some embodiments of formula (II), formula (I-G), or formula (I), R 6 is chloro. In some embodiments of formula (II), formula (I-G), or formula (I), R 6 is bromo. In some embodiments of formula (II), formula (I-G), or formula (I), R 6 is iodo.

[0062] In some embodiments of the compounds of formula (II), p is 1. In some embodiments of the compounds of formula (II), p is 1 and the compound is of formula (I-G). In other embodiments of the compounds of formula (II), p is 1 and the compound is of formula (I).

[0063] In some embodiments of formula (II), formula (I-G) or formula (I), R 4 is Z 1 NR a C(O)-, Z 2 C(O)NR b -, Z 3 (CR c R d ) m NR e -, Z4 S(O) 2 (CH 2 ) n -, Z 5 OC(O)-, and NR f R g is selected from the group consisting of C(O)-. In some embodiments, R 4 is Z 1 NR a C(O)- or NR f R g C(O)-. In some embodiments, R 4 is Z 1 NR a C(O)- or Z 2 C(O)NR b -.

[0064] In another aspect, a compound of formula (II), formula (I-G), or formula (I) is a compound of formula (I-A):

Chemical formula

[0065] In some embodiments, the compound is a compound of formula (I-A1), (I-A2), (I-A3), or (I-A4):

Chemical formula

[0066] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-A), R a is hydrogen. In some embodiments, R a is C 1 -C 6 alkyl. For example, in some embodiments, R a is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0067] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-A), Z 1 is R z . In some embodiments, Z 1 is selected independently from the group consisting of: -OH, C 3 -C 6 cycloalkyl, C 6 -C 12 aryl, a 3- to 10-membered hetero cycloalkyl or heterocycloalkenyl, and a 5- to 10-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, wherein this C 6 -C 12 aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkoxy; C 6 -C 12 aryl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy (optionally substituted with a 5- or 10-membered heteroaryl), each optionally substituted with one or more substituents independently selected from the group consisting of C 3 -C 6A cycloalkyl, wherein the 5- or 10-membered heteroaryl is C 1 -C 6 alkyl, optionally further substituted; and and -C 1 -C 6 alkyl and -C(O)OC 1 -C 6 alkyl, optionally substituted with one or more substituents independently selected from the group consisting of a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, wherein this -C 1 -C 6 alkyl is optionally substituted with C 6 -C 12 aryl.

[0068] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-A), Z 1 is C 1 -C 6 alkyl. In some embodiments, Z 1 is unsubstituted C 1 -C 6 alkyl. In some embodiments, Z 1 is -OH, C 3 -C 6 cycloalkyl, C 6 -C 12 aryl, a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and a C 1 -C 6 alkyl, optionally substituted with one or more substituents independently selected from the group consisting of C 6 -C 12 aryl, a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and a 5- to 10-membered heteroaryl, wherein each of this C 1 -C 6 aryl, a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and a 5- to 10-membered heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl and C

[0069] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-A), Z 1 is C 3 -C 6 cycloalkyl. In some embodiments, Z 1 is unsubstituted C 3 -C 6 cycloalkyl. In some embodiments, Z 1 is C 6 -C 12 aryl, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy (optionally substituted with a 5- or 10-membered heteroaryl), where the 5- or 10-membered heteroaryl is optionally further substituted with C 3 -C 6 cycloalkyl, where the 5- or 10-membered heteroaryl is optionally further substituted with C 1 -C 6 alkyl. In some embodiments, Z 1 is independently C 3 -C 6 cycloalkyl optionally substituted with one or more groups selected from methoxy, ethoxy, and phenyl. In some embodiments, Z 1 is C 1 -C 6 alkoxy optionally substituted with a 5- or 10-membered heteroaryl, where the 5- or 10-membered heteroaryl is optionally further substituted with C 3- C 6 cycloalkyl, where the 5- or 10-membered heteroaryl is optionally further substituted with C 1 -C 6 alkyl (e.g.,

Chemical Formula

[0070] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-A), Z 1 is 3- to 10-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 1 is 3- to 10-membered heterocycloalkyl or heterocycloalkenyl and contains one or more heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, Z 1 is 3- to 6-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 1 is 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl and -C(O)OC 1 -C 6 alkyl, where -C -C 1 -C 6 alkyl is optionally substituted with C 6 -C 12 aryl. In some embodiments, Z 1 is

Chemical Formula

[0071] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-A), Z 1 is C 1 -C 6 alkyl. In certain embodiments, Z 1 is ethyl. In some embodiments, Z 1 is ethyl,

Chemical formula

[0072] In another aspect, a compound of formula (II), formula (I-G), or formula (I) is a compound of formula (I-B):

Chemical formula

[0073] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-B), R b is hydrogen. In some embodiments, R b is C 1 -C 6 alkyl. For example, in some embodiments, R bis methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-B), R 5 is hydrogen. In other embodiments, R b is R 5 which, together with the intervening atoms, forms a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments of Formula (II) or Formula (I-G), R 5 is halo. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is chloro. In some embodiments, R 5 is bromo. In some embodiments, R 5 is iodo.

[0074] In some embodiments, the compound is a compound of Formula (I-B1), (I-B2), or (I-B3):

Chemical formula

[0075] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-B), Z 2 is hydrogen. In some embodiments, Z 2 is R z . In some embodiments, Z 2 is selected from the group consisting of C 3 -C 6 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 5- to 10-membered heteroaryl substituted C 1 -C 6 alkyl; C 1 -C 6 alkyl and C 1 -C 6 independently selected from the group consisting of alkoxy optionally substituted with one or more substituents C 3 -C 6 cycloalkyl; C 1 -C 6 alkoxy; one or more independently selected -C 1 -C 6 optionally substituted with an alkyl substituent 3- to 10-membered heterocycloalkyl or heterocycloalkenyl; C 6 -C 12 aryl; and one or more independently selected C 1 -C 6 optionally substituted with an alkyl substituent 5- to 10-membered heteroaryl.

[0076] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-B), Z 2 is C 3 -C 6 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 5- to 10-membered heteroaryl C 1 -C 6 alkyl. In some embodiments, Z 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, each optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 5- to 10-membered heteroaryl. 3 -C 6 substituted.

[0077] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-B), Z 2 is C 1 -C6 Alkyl and C 1 -C 6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, C 3 -C 6 is cycloalkyl. In some embodiments, Z 2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more substituents independently selected from the group consisting of alkyl, C 1 -C 6 Alkyl and C 1 -C 6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy.

[0078] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-B), Z 2 is C 1 -C 6 alkoxy. In some embodiments, Z 2 is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, or tert-butoxy.

[0079] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-B), Z 2 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with one or more independently selected -C 1 -C 6 alkyl substituents. In some embodiments, Z 2 is a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected -C 1 -C 6 alkyl substituents. In some embodiments, Z 2 is an azetidinyl group optionally substituted with one or more -C 1 -C 6 alkyl substituents, or a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more independently selected -C 1 -C 6It is a tetrahydrofuranyl group optionally substituted with an alkyl substituent. In some embodiments, Z 2 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0080] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-B), Z 2 is C 6 -C 12is aryl. For example, in some embodiments, Z 2 is phenyl or naphthyl.

[0081] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-B), Z 2 is a 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents. In some embodiments, Z 2 is a 5- to 6-membered heteroaryl optionally substituted with one or more independently selected -C 1 -C 6 alkyl substituents. In some embodiments, Z 2 is a pyridyl group optionally substituted with one or more independently selected -C 1 -C 6 alkyl substituents. In some embodiments, Z 2 is a pyridyl group optionally substituted with methyl, ethyl, or isopropyl. In some embodiments, Z 2 is a pyridyl group substituted with methyl. In other embodiments, Z 2 is a pyridyl group substituted with isopropyl. In some embodiments, Z 2 is

Chemical formula

Chemical formula

[0082] In some embodiments, Z 2 is ethyl,

Chemical formula

[0083] In some embodiments, Z is [Chemical formula] .

[0084] In another aspect, the compound of formula (II), formula (I-G), or formula (I) is a compound of formula (I-C): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R c , R d , R e , m, and Z 3 are as defined in formula (I-G) or formula (I), or any variation or embodiment thereof.

[0085] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-C), m is 0. In other embodiments, m is 1. In some embodiments of formula (I-G), formula (I), or formula (I-C), R c is hydrogen. In other embodiments, R c is C 1 -C 6 alkyl. In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-C), R d is hydrogen. In other embodiments, R d is C 1 -C 6 alkyl. In some embodiments, R c and R d , together with the carbon to which they are attached, form C 3 -C 6 cycloalkyl.

[0086] In some embodiments, the compound is a compound of formula (I-C1), (I-C2), (I-C3), or (I-C4): [Chemistry] or a pharmaceutically acceptable salt thereof, wherein R 1 , R e , and Z 3 are as defined in formula (II), formula (I-G), formula (I), or formula (I-C), or any variant or embodiment thereof.

[0087] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-C), R e is hydrogen. In other embodiments, R e is C 1 -C 6 alkyl.

[0088] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-C), Z 3 is hydrogen. In some embodiments, Z 3 is R z . In some embodiments, Z 3 is C 3 -C 6 cycloalkyl; optionally -C 1 -C 6 alkyl or oxo-substituted 3- to 10-membered heterocycloalkyl or heterocycloalkenyl; C 6 -C 12 aryl; 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents. In some embodiments, Z 3 is 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with -C 1 -C 6 alkyl or oxo. In some embodiments, Z 3 is [Chemistry] selected from the group consisting of. In some embodiments, Z3 is [Chem.] as follows.

[0089] In another aspect, a compound of formula (II), formula (I-G), or formula (I) is a compound of formula (ID): [Chem.] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , n, and Z 4 are as defined in formula (II), formula (I-G), or formula (I) or any variation or embodiment thereof.

[0090] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-D), n is 0. In some embodiments, n is 1. In other embodiments, n is 2.

[0091] In some embodiments, the compound is a compound of formula (I-D1) or (I-D2): [Chem.] or a pharmaceutically acceptable salt thereof, wherein R 1 and Z 4 are as defined in formula (I-G), formula (I), or formula (I-D) or any variation or embodiment thereof.

[0092] In some embodiments, the compound is a compound of formula (I-D3), (I-D4), (I-D5), (I-D6) or (I-D7): [Chem.] or a pharmaceutically acceptable salt thereof, wherein R 1is as defined in formula (II), formula (I-G), formula (I) or formula (I-D), or any variation or embodiment thereof.

[0093] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-D), Z 4 is hydrogen. In some embodiments, Z 4 is R z . In other embodiments, Z 4 is C 1 -C 6 alkyl. For example, in some embodiments, Z 4 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, Z 4 is R 2 and the intervening atoms together form a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring. In some embodiments,

Chemical formula

[0094] In another aspect, a compound of formula (II), formula (I-G), or formula (I) is a compound of formula (IE):

Chemical formula

[0095] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-E), Z 5 is C 1 -C 6 alkyl. For example, in some embodiments, Z 5is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, Z 5 is ethyl.

[0096] In another aspect, a compound of formula (II), formula (I-G), or formula (I) is a compound of formula (IF):

Chemical formula

[0097] In some embodiments of formula (II), formula (I-G), formula (I), or formula (I-F), R f and R g together with the nitrogen to which they are attached form a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl which is optionally substituted with one or more substituents independently selected from halo, -OH, -CN, oxo, -C 1 -C 6 alkyl (optionally substituted with one or more independently selected R x substituents), -C 3 -C 6 cycloalkyl, -C 1 -C 6 alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered hetero cycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl, and is optionally substituted with one or more substituents independently selected from the group consisting of 3- to 10-membered heterocycloalkyl or heterocycloalkenyl.

[0098] In some embodiments of Formula (II), Formula (I-G), Formula (I), or Formula (I-F), R f and R g together with the nitrogen to which they are attached form a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl that is optionally substituted with one or more substituents independently selected from halo, -OH, -CN, oxo, -C 1 -C 6 alkyl (optionally substituted with one or more independently selected R x substituents), -C 3 -C 6 cycloalkyl, -C 1 -C 6 alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 alkyl, -NR j R k , -C(O)NR m R n , 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl. In some embodiments, R f and R g together with the nitrogen to which they are attached form a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl selected from the group consisting of azetidyl, pyrrolidinyl, and piperidinyl, each optionally substituted with halo, -OH, -CN, oxo, -C 1 -C 6 alkyl (optionally substituted with one or more independently selected R x substituents), -C 3 -C 6 cycloalkyl, -C 1 -C 6 alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 alkyl, -NR j R k , -C(O)NR m R n, a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 5- to 6-membered heteroaryl. In some embodiments,

Chemical formula

[0099] In embodiments of formula (II), formula (I-G), formula (I), or formula (I-F), R f and R g together with the nitrogen to which they are attached form a 6- to 10-membered heterocycloalkyl or heterocycloalkenyl, which is optionally substituted with one or more independently selected R substituents and is selected from the group consisting of halo, -OH, -CN, oxo, -C 1 -C 6 alkyl (optionally substituted with one or more independently selected R x substituents), -C 3 -C 6 cycloalkyl, -C 1 -C 6 alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 alkyl, -NR j R k , -C(O)NR m R n and is optionally substituted with one or more substituents independently selected from the group consisting of 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl to form a 6- to 10-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, R f and R g together with the nitrogen to which they are attached form a bicyclic 6- to 10-membered heterocycloalkyl or heterocycloalkenyl. For example, in some embodiments, R f and R g together with the nitrogen to which they are attached form [Chemistry] wherein each is independently selected from halo, -OH, -CN, oxo, -C 1 -C 6 alkyl (optionally substituted with one or more independently selected R x substituents), -C 3 -C6 Cycloalkyl, -C 1 -C 6 Alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 Alkyl, -NR j R k , -C(O)NR m R n , optionally substituted with one or more substituents independently selected from the group consisting of 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl. In some embodiments, R f and R g together with the nitrogen to which they are attached form a bridged 6- to 10-membered heterocycloalkyl or heterocycloalkenyl. For example, in some embodiments,

Chemical formula

[0100] In some embodiments, R f and R gTogether with the nitrogen to which they are attached, they form a 6- to 10-membered heterocycloalkyl or heterocycloalkenyl of the spiro ring. For example, in some embodiments,

Chemical formula

[0101] In some embodiments,

Chemical formula

Chemical formula

[0102] In some embodiments of formula (II), formula (I-G), or formula (I), R 4 is a 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents. In some embodiments, R 4is selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzoisoxazolyl, benzoxadiazolyl, benzothiophenyl, benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, tri azolopyridinyl, furopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl, thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl and imidazolothiazolyl, each optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents. In some embodiments, R 4 is one or more independently selected -C 1 -C 6 a 5- to 6-membered heteroaryl optionally substituted with alkyl substituents. In some embodiments, R 4 is pyrazolyl, pyridinyl, or oxadiazole, each optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents. In certain embodiments, R 4 is

Chemical formula

[0103] In some embodiments of formula (II), formula (I-G), or formula (I), R 4is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, which is optionally substituted with halo, oxo, -OH, -CN, one or more independently selected R y -C optionally substituted with substituents 1 -C 6 alkyl, -C optionally substituted with one or more independently selected halo substituents 1 -C 6 alkoxy, -C(O)OC 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, -S(O) 2 -C 1 -C 6 alkyl, C optionally substituted with one or more independently selected halo substituents 6 -C 12 aryl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C 1 -C 6 5- to 6-membered heteroaryl optionally substituted with alkyl substituents, and is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of. In some embodiments, R 4 is -S(O) 2 -C 1 -C 6 alkyl or -C 1 -C 6 4- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with alkyl (optionally substituted with -OH) and is optionally substituted. In some embodiments, R 4 is -S(O) 2 -C 1 -C 6 alkyl or -C 1 -C 6 azetidinyl or piperazinyl optionally substituted with alkyl (optionally substituted with -OH) and is optionally substituted. In some embodiments, R 4 is -S(O) 2 -C 1 -C 6It is azetidinyl optionally substituted with alkyl. In some embodiments, R 4 is azetidinyl substituted with -S(O) 2 CH 3 In some embodiments, R 4 is optionally -C 1 -C 6 piperazinyl substituted with alkyl (optionally substituted with -OH). In certain embodiments, R 4 is -CH 2 C(CH 3 ) 2 piperazinyl optionally substituted with OH.

[0104] In some embodiments of formula (II), formula (I-G), or formula (I), R 4 is

Chemical formula

Chemical formula

Chemical formula

[0105] In some embodiments, R 4 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0106] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 4 is Z 6 S(O) 2 N(R s )-. In some embodiments, Z 6 is a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl. In other embodiments, Z 6 is a 5- to 6-membered heteroaryl. In some embodiments, Z 6 is C 1 -C 6 alkyl. In some embodiments, Z 6 is methyl. In some of the foregoing embodiments, R s is hydrogen. In other embodiments, R s is C 1 -C 6 alkyl. In still other embodiments, R s is methyl. In some embodiments, R 4 is

Chemical formula

[0107] In some embodiments of Formula (II), Formula (I-G), or Formula (I), R 4 is Z 7 N(R t )S(O) 2 -. In some embodiments, Z 7 is C 6 -C 12 aryl. In some embodiments, Z 7 is phenyl. In some embodiments, R t is hydrogen. In other embodiments, R t is C 1 -C 6 alkyl. In still other embodiments, R t is methyl. In some embodiments, R 4 is -S(O) 2 -NH-phenyl.

[0108] In some embodiments of formula (II), formula (I-G), or formula (I), R 4 is Z 8 -O-(CH 2 ) q -. In some embodiments, q is 0, and as a result, R 4 is Z 8 -O-. In other embodiments, q is 1, and as a result, R 4 is Z 8 -O-(CH 2 )-. In some of the foregoing embodiments, Z 8 is a 5- to 6-membered heteroaryl. In some embodiments, Z 8 is pyridinyl. In some of the other foregoing embodiments, Z 8 is C 3 -C 6 cycloalkyl. In one embodiment, Z 8 is cyclopentyl. In some embodiments, R 4 is [Chemical formula] .

[0109] In some embodiments of formula (II), p is 0. In some embodiments of formula (II), p is 0, and the compound is a compound of formula (II-A): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein: R 1 is halo or methoxy; R 4 is l) a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, both of which are nitrogen atoms, and this 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is substituted with one or more independently selected -C 1 -C 6substituted with an alkyl substituent and optionally further substituted with one or more oxo substituents, m) a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly one ring heteroatom which is an oxygen atom, and this 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo or -C 1 -C 6 optionally substituted with an alkyl substituent, n) one or more independently selected -S(O) 2 -C 1 -C 6 substituted with an alkyl substituent and optionally further substituted with one or more independently selected oxo or -C 1 -C 6 3- to 6-membered heterocycloalkyl or heterocycloalkenyl which is substituted with an alkyl substituent, o) a 5-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, and this 5-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C 1 -C 6 alkyl, or -S(O) 2 -(C 1 -C 6 alkyl) substituent, p) a 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, and this 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C 1 -C 6 alkyl, or -S(O) 2 -(C 1 -C 6ア alkyl) substituent, q) A 5-membered heteroaryl containing exactly two cyclic heteroatoms, one being a nitrogen atom and the other being an oxygen atom, wherein the 5-membered heteroaryl is substituted with exactly one methyl substituent, r) A 5-membered heteroaryl containing exactly two cyclic heteroatoms, both being nitrogen atoms, wherein the 5-membered heteroaryl is substituted with one or more methyl substituents, s) A 6-membered heteroaryl containing one or two cyclic heteroatoms, optionally substituted with one or more methyl substituents, wherein the 6-membered heteroaryl is

Chemical formula

Chemical formula

Chemical formula

Chemical Structure

[0110] In some embodiments of formula (II) or formula (II-A), R 4 is selected from the group consisting of: 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms both of which are nitrogen atoms, wherein said 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected -C 1 -C 6 -alkyl substituents and optionally further substituted with one or more oxo substituents, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly one ring heteroatom which is an oxygen atom, wherein said 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally, one or more independently selected oxo or is -C1 -C 6 3- to 6-membered heterocycloalkyl or heterocycloalkenyl substituted with an alkyl substituent 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, wherein one or more independently selected -S(O) 2 -C 1 -C 6 substituted with an alkyl substituent and optionally one or more independently selected oxo or -C 1 -C 6 3- to 6-membered heterocycloalkyl or heterocycloalkenyl further substituted with an alkyl substituent 5-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, and this 5-membered heterocycloalkyl or heterocycloalkenyl is optionally one or more independently selected oxo, -C 1 -C 6 alkyl, or -S(O) 2 -(C 1 -C 6 alkyl) substituted 5-membered heterocycloalkyl or heterocycloalkenyl, and 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two ring heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, wherein this 6-membered heterocycloalkyl or heterocycloalkenyl is optionally one or more independently selected oxo, -C 1 -C 6 alkyl, or -S(O) 2 -(C 1 -C 6 alkyl) substituted 6-membered heterocycloalkyl or heterocycloalkenyl.

[0111] In some embodiments of formula (II) or formula (II-A), R 4is a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly 2 cyclic heteroatoms both of which are nitrogen atoms, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is substituted with one or more independently selected -C 1 -C 6 alkyl substituents and optionally further substituted with one or more oxo substituents. In some embodiments, R 4 is a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly 2 cyclic heteroatoms both of which are nitrogen atoms, wherein the 5- to 6-membered heterocycloalkyl or heterocycloalkenyl is substituted with one or more independently selected -C 1 -C 6 alkyl substituents and optionally further substituted with one or more oxo substituents.

[0112] In some embodiments of formula (II) or formula (II-A), R 4 is a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly 1 cyclic heteroatom which is an oxygen atom, wherein the 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo or -C 1 -C 6 alkyl substituents. In some embodiments, R 4 is a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly 1 cyclic heteroatom which is an oxygen atom, wherein the 5- to 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo or -C 1 -C 6 alkyl substituents.

[0113] In some embodiments of formula (II) or formula (II-A), R 4 is a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing one or more independently selected -S(O) 2 -C 1 -C6 substituted with an alkyl substituent and optionally one or more independently selected oxo or -C 1 -C 6ア and further substituted with an alkyl substituent. In some embodiments, R 4 is a 5- or 6-membered heterocycloalkyl or heterocycloalkenyl, containing one or more independently selected -S(O) 2 -C 1 -C 6 substituted with an alkyl substituent and optionally one or more independently selected oxo or -C 1 -C 6 and further substituted with an alkyl substituent.

[0114] In some embodiments of formula (II) or formula (II-A), R 4 is a 5-membered heterocycloalkyl or heterocycloalkenyl, containing exactly two ring heteroatoms, one of which is a nitrogen atom and the other of which is an oxygen atom, where this 5-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C -C 1 -C 6ア alkyl, or -S(O) 2 -(C 1 -C 6ア alkyl) substituents.

[0115] In some embodiments of formula (II) or formula (II-A), R 4 is a 6-membered heterocycloalkyl or heterocycloalkenyl, containing exactly two ring heteroatoms, one of which is a sulfur atom and the other of which is a nitrogen atom, where this 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C 1 -C 6 alkyl, or -S(O) 2 -(C 1 -C 6 alkyl) substituents.

[0116] In some embodiments of formula (II) or formula (II-A), R 4 is

Chem.

[0117] In some embodiments of formula (II) or formula (II-A), R 4 is a 3- to 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two cyclic heteroatoms, both of which are nitrogen atoms, and this 3- to 6-membered heterocycloalkyl or heterocycloalkenyl is substituted with one or more independently selected -C 1 -C 6 alkyl substituents and optionally further substituted with one or more independently selected oxo substituents, or a 6-membered heterocycloalkyl or heterocycloalkenyl containing exactly two cyclic heteroatoms, one of which is a sulfur atom and the other is a nitrogen atom, and this 6-membered heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more independently selected oxo, -C 1 -C 6 alkyl, or -S(O) 2- (C 1 -C 6 alkyl) substituents. In some embodiments, R 4 is

Chem.

[0118] In some embodiments of formula (II) or formula (II-A), R 4 is selected from the group consisting of: a 5-membered heteroaryl containing exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein this 5-membered heteroaryl is substituted with exactly one methyl substituent, a 5-membered heteroaryl, A 5-membered heteroaryl containing exactly two cyclic heteroatoms both of which are nitrogen atoms, wherein said 5-membered heteroaryl is substituted with one or more methyl substituents, and A 6-membered heteroaryl containing one or two cyclic heteroatoms and optionally substituted with one or more methyl substituents, wherein said 6-membered heteroaryl is

Chemical formula

[0119] In some embodiments of formula (II) or formula (II-A), R 4 is a 5-membered heteroaryl containing exactly two cyclic heteroatoms, one of which is a nitrogen atom and the other is an oxygen atom, wherein said 5-membered heteroaryl is substituted with exactly one methyl substituent. In other embodiments, R 4 is a 5-membered heteroaryl containing exactly two cyclic heteroatoms both of which are nitrogen atoms, wherein said 5-membered heteroaryl is substituted with one or more methyl substituents. In other embodiments, R 4 is a 6-membered heteroaryl containing one or two cyclic heteroatoms and optionally substituted with one or more methyl substituents, wherein said 6-membered heteroaryl is

Chemical formula

Chemical formula

[0120] In some embodiments of formula (II) or formula (II-A), R 4 is Z 9 -S(O) 2 -, Z 10 -S(O) 2 -NH-, Z 11-C(O)-NH-, Z 12 -CH 2 -O-, Z 13 -O-, Z 14 -C(H)(C 1 -C 6 alkyl)-NH-C(O)-,

Chem.

[0121] In some embodiments of formula (II) or formula (II-A), R 4 is Z 9 -S(O) 2 -. In some embodiments, the compound of formula (II) or formula (II-A) is a compound of formula (II-A1):

Chem.

[0122] In some embodiments of formula (II), formula (II-A), or formula (II-A1), Z 9 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted with one or more independently selected R A substituents, provided that Z 9 is

Chem.

Chem.

[0123] In some embodiments, Z 9 is C C optionally substituted with one or more independently selected R 1 -C 6 alkyl, provided that Z 9 is other than unsubstituted methyl or unsubstituted ethyl. In some embodiments, Z 9 is C C optionally substituted with one or more independently selected R 1 -C 3 alkyl, provided that Z 9 is other than unsubstituted methyl or unsubstituted ethyl. In some embodiments, Z 9 is unsubstituted C 3 -C 6 alkyl. In some embodiments, Z 9 is unsubstituted propyl. In some embodiments, Z 9 is C 1 -C 6 alkyl optionally substituted with one or more independently selected 3- to 8-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 9 is C 1 -C 6 alkyl optionally substituted with one or more independently selected 5- to 6-membered heterocycloalkyl or heterocycloalkenyl.

[0124] In some embodiments, Z 9 is -NH(C 1 -C 6 alkyl). In some embodiments, Z 9 is -NH(CH 3 ). In some embodiments, Z 9is -NH substituted with one or more independently selected R B substituents. In some embodiments, Z 2 is -NH 9 and is substituted with one or more independently selected -C 2 -C 1 -alkyl 6 -(5 - to 10 - membered heteroaryl). In some embodiments, Z is -NH substituted with one or more independently selected -C 9 -C 1 -alkyl-(5 - to 6 - membered heteroaryl). In some embodiments, Z 6 is -NH substituted with one or more independently selected -C 2 -C 9 -alkylpyridinyl. In other embodiments, Z 1 -C 6 is 5 - to 10 - membered heteroaryl optionally substituted with one or more independently selected C 2 -C 9 -aryl. In other embodiments, Z 6 -C 12 is 5 - to 6 - membered heteroaryl optionally substituted with one or more phenyls. 9 In one embodiment, Z

[0125] is cyclopropyl. In some embodiments, Z 9 is C 9 -C 6 -aryl. In some embodiments, Z 12 is phenyl. 9 In some embodiments, Z

[0126] is selected from the group consisting of 9

Chemical formula

[0127] is Z 4 ​​10 -S(O)- 2 -NH-. In some embodiments, Z 10 is C substituted with one or more phenyl substituents 1 -C 6 alkyl. In some embodiments, Z 10 is

Chemical formula

[0128] In some embodiments of formula (II) or formula (II-A), R 4 is Z 11 -C(O)-NH-. In some embodiments, when Z 11 is cyclopropyl, on the condition that R 1 is other than methoxy, Z 11 is C 3 -C 10 cycloalkyl. In some embodiments, Z 11 is C substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents 1 -C 6 alkyl. In some embodiments, Z 11 is C substituted with one or more independently selected 5- to 6-membered heterocycloalkyl or heterocycloalkenyl substituents 1 -C 6 alkyl. In some embodiments, Z 11 is

Chemical formula

[0129] In some embodiments of formula (II) or formula (II-A), R 4 is Z 12 -CH 2 -O-. In some embodiments, Z 12 is C 6 -C 12Aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, C 1 -C 6 alkyl (substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 10-membered heteroaryl substituents), and -C(O)-(3- to 10-membered heterocycloalkyl or heterocycloalkenyl), selected from the group consisting of. In some embodiments, Z 12 is C 6 -C 12 aryl. In some embodiments, Z 12 is 5- to 10-membered heteroaryl. In some embodiments, Z 12 is 5- to 6-membered heteroaryl. In some embodiments, Z 12 is 3- to 10-membered heterocycloalkyl or heterocycloalkenyl. In other embodiments, Z 12 is 5- to 6-membered heterocycloalkyl or heterocycloalkenyl. In some embodiments, Z 12 is C 1 -C 6 alkyl (substituted with one or more independently selected 3- to 10-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 10-membered heteroaryl substituents). In some embodiments, Z 12 is C 1 -C 6 alkyl substituted with one or more independently selected 5- to 6-membered heterocycloalkyl or heterocycloalkenyl substituents or 5- to 6-membered heteroaryl substituents. In some embodiments, Z 12 is -C(O)-(3- to 10-membered heterocycloalkyl or heterocycloalkenyl). In other embodiments, Z 12 is -C(O)-(5- to 6-membered heterocycloalkyl or heterocycloalkenyl). In some embodiments, Z 12 is

Chemical formula

[0130] In some embodiments of formula (II) or formula (II-A), R 4 is 13 -O-. In some embodiments, Z 13 is a 5- to 6-membered heteroaryl substituted with one or more independently selected -C(O)-NH(C 1 -C 6 alkyl) substituents. In some embodiments, Z 13 is a pyridinyl substituted with one or more independently selected -C(O)-NH(C 1 -C 6 alkyl) substituents. In some embodiments, Z 13 is

Chemical formula

[0131] In some embodiments of formula (II) or formula (II-A), R 4 is 14 -C(H)(C 1 -C 6 alkyl)-NH-C(O)-. In some embodiments, R 4 is 14 -C(H)(CH 3 )-NH-C(O)-. In some embodiments, Z 14 is a 5- to 6-membered heteroaryl optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents. In some embodiments, Z 14 is a pyridinyl optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents is. In some embodiments of formula (II) or formula (II-A), R 4 is

Chemical formula

[0132] In some embodiments of formula (II) or formula (II-A), R 4 is

Chemical formula

Chemical formula

[0133] In some embodiments of formula (II), or any variant thereof including formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), R 1 is halo. For example, in some embodiments, R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is bromo. In other embodiments, R 1 is iodo. In some embodiments, R 1 is methoxy. In some embodiments of formula (II), or any variant thereof including formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), and (I-F), R 1 is hydrogen. In some embodiments, R 2 is C 1 -C 6is alkyl. For example, in some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments of formula (II), or any variant thereof including formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), and (I-F), R 3 is hydrogen. In some embodiments, R 3 is C 1 -C 6 is alkyl. For example, in some embodiments, R 3 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

[0134] In some embodiments of formula (II), or any variant thereof including formula (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), and (I-F), R 2 and R 3 are each hydrogen. In some embodiments, R 2 is C 1 -C 6 is alkyl and R 3 is hydrogen. For example, in some embodiments, R 2 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl and R 3 is hydrogen. In certain embodiments, R 2 is methyl and R 3is hydrogen. In some embodiments, R 2 is hydrogen and R 3 is C 1 -C 6 alkyl. For example, in some embodiments, R 2 is hydrogen and R 3 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In certain embodiments, R 2 is hydrogen and R 3 is methyl.

[0135] In some embodiments, provided herein are the compounds described in Table 1 and salts thereof.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 2-45

Table 2-46

Table 2-47

Table 2-48

Table 2-49

Table 2-50

Table 2-51

Table 2-52

Table 2-53

Table 2-54

Table 2-55

Table 2-56

Table 2-57

Table 2-58

Table 2-59

Table 2-60

Table 2-61

Table 2-62

Table 2-63

Table 2-64

Table 2-65

Table 2-66

Table 2-67

Table 2-68

Table 2-69

Table 2-70

Table 2-71

Table 2-72

Table 2-73

Table 2-74

Table 2-75

Table 2-76

Table 2-77

Table 2-78

Table 2-79

Table 2-80

Table 2-81

Table 2-82

Table 2-83

Table 2-84

Table 2-85

Table 2-86

Table 2-87

Table 2-88

Table 2-89

Table 2-90

Table 2-91

Table 2-92

Table 2-93

Table 2-94

Table 2-95

Table 2-96

Table 2-97

Table 2-98

Table 2-99

Table 2-100

Table 2-101

Table 2-102

Table 2-103

Table 2-104

Table 2-105

Table 2-106

Table 2-107

Table 2-108

Table 2-109

Table 2-110

Table 2-111

Table 2-112

Table 2-113

Table 2-114

[0136] In some variations, the compounds of formula (II), (I), (I-G), (I)(I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), or any variations thereof, or the compounds of Table 1 may be deuterated (e.g., replacing hydrogen atoms with deuterium atoms). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. The deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. Other methods known in the art may be used to replace hydrogen atoms with deuterium atoms.

[0137] Formula (II), (I-G), (I)(I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I- Any formula described in this specification, such as (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), is intended to represent a structure shown by a structural formula and a compound having a specific modification or form. In particular, a compound of any formula given in this specification may have an asymmetric center and, thus, may exist in the form of different enantiomers or diastereomers. All optical isomers and stereoisomers of a compound of a general formula, as well as mixtures of them in any ratio, are considered to be within the scope of the formula. Accordingly, any formula given in this specification is intended to represent a racemate, one or more enantiomers, one or more diastereomeric forms, one or more atropisomers, and mixtures of them in any ratio. When the compounds in Table 1 are shown in a specific stereochemical constitution, this specification also provides any alternative stereochemical constitution of the compound, as well as mixtures of stereoisomers of the compound in any ratio. For example, when the compound in Table 1 has a stereocenter in the "S" stereochemical configuration, the enantiomer of the compound in which the stereocenter is in the "R" stereochemical configuration is also provided in this specification. Similarly, when the compound in Table 1 has a stereocenter in the "R" configuration, this specification also provides the enantiomer of the compound in the "S" stereochemical configuration. Mixtures of compounds having both "S" and "R" stereochemical configurations are also provided. Further, when the compound in Table 1 has two or more stereocenters, any enantiomer or diastereomer of the compound is also provided. For example, when the compound in Table 1 includes a first stereocenter and a second stereocenter each having an "R" and "R" stereochemical configuration, the stereoisomers of the compound having a first and a second stereocenter each having an "S" and "S" stereochemical configuration, an "S" and "R" stereochemical configuration, and an "R" and "S" stereochemical configuration, respectively, are also provided. When the compound in Table 1 includes a first stereocenter and a second stereocenter each having an "S" and "S" stereochemical configuration, the stereoisomers of the compound having a first and a second stereocenter each having an "R" and "R" stereochemical configuration, an "S" and "R" stereochemical configuration, and an "R" and "S" stereochemical configuration, respectively, are also provided.When the compounds of Table 1 each contain a first stereocenter and a second stereocenter having “S” and “R” stereochemical configurations, respectively, stereoisomers of the compounds having first and second stereocenters with “R” and “S” stereochemical configurations, “R” and “R” stereochemical configurations, and “S” and “S” stereochemical configurations, respectively, are also provided. Similarly, when the compounds of Table 1 each contain a first stereocenter and a second stereocenter having “R” and “S” stereochemical configurations, respectively, stereoisomers of the compounds having first and second stereocenters with “S” and “R” stereochemical configurations, “R” and “R” stereochemical configurations, and “S” and “S” stereochemical configurations, respectively, are also provided. Further, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Further, any formula given herein is intended to refer to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not explicitly described. In some embodiments, the solvent is water and the solvate is a hydrate.

[0138] Representative examples of the compounds detailed herein, including intermediates and final compounds, are shown in any of the tables and elsewhere in this specification. In one aspect, it is understood that any compound can be used in the methods detailed herein, including, where applicable, intermediate compounds that can be isolated and administered to an individual or subject.

[0139] The compounds shown herein may exist as salts even if no salts are shown, and the compositions and methods provided herein are understood to include all salts and solvates of the compounds shown herein, as well as the non-salt and non-solvate forms of the compounds, as is well understood by those skilled in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0140] In one variation, the compounds of this specification are synthetic compounds prepared for administration to an individual or subject. In another variation, a composition is provided that includes the compound in substantially pure form. In another variation, a pharmaceutical composition is provided that includes the compounds detailed herein and a pharmaceutically acceptable carrier. In another variation, a method of administering the compound is provided. The purified form, the pharmaceutical composition, and the method of administering the compound are suitable for any of the compounds or forms thereof detailed herein.

[0141] The R provided herein 1 、R 2 、R 3 、R 4 、R 5 、R 6 、Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 、Z 7 、Z 8 、Z 9 、Z 10 、Z 11 、Z 12 、Z 13 、Z 14 、R a 、R b 、R c 、R d 、R e 、R f 、R g 、R h 、R j 、R k 、R m 、R n 、R o 、R p 、R q 、R r 、R s 、R t 、R x 、R y 、R z 、R A 、R B 、R C 、Any variation or embodiment of m, n, p, and q, for R 1 、R 2 、R 3 、R4 , R 5 , R 6 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , 9 , Z 10 , Z 11 , Z 12 , Z 13 , Z 14 , R a , R b , R c , R d , R e , R f , R g , R h , R j , R k , R m , R n , R o , R p , R q , R r , R s , R t , R x , R y , R z , R A , R B , R C , All other variations or embodiments of m, n, p, and q, and any combination thereof, may be combined as if each and every one were specifically and individually recited.

[0142] Other embodiments will be apparent to those of ordinary skill in the art from the following detailed description.

[0143] As used herein, when a variable in a chemical formula occurs more than once, its definition at each occurrence is independent of its definition at every other occurrence.

[0144] Formula (II) includes all of its sub-formulas. For example, formula (II) includes compounds of formula (I-G), (I)(I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1).

[0145] As shown in Table 1 and Examples 1-16, the names of Compounds 1-552 provided herein are provided by Chem 4d software version 7.5.0.0 of ChemInnovations. The names of Intermediates 1.1-10.0 shown in Examples A-MM are provided by ChemBioDraw Professional 15.0. Those skilled in the art will understand that compounds can be named or identified using various commonly recognized naming systems and symbols. By way of example, compounds can be named or identified by a common name, a systematic name, or a non-systematic name. Systems and symbols of nomenclature commonly recognized in the field of chemistry include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry (IUPAC).

[0146] Composition Also provided are compositions such as compounds disclosed and / or described herein, and pharmaceutical compositions containing one or more additional pharmaceutical agents, agents, adjuvants, carriers, excipients, etc. Suitable pharmaceuticals and agents include those described herein. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant, and at least one chemical substance as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, provided are pharmaceutical compositions comprising one or more of the compounds described herein, or compositions such as pharmaceutically acceptable salts thereof. - sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, provided are pharmaceutical compositions comprising one or more of the compounds described herein, or compositions such as pharmaceutically acceptable salts thereof.

[0147] In some embodiments, provided is a pharmaceutically acceptable composition comprising a compound of formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F) or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some aspects, the composition may comprise a synthetic intermediate that can be used in the preparation of the compounds described herein. The compositions described herein may comprise any other suitable active or inactive agent.

[0148] Any of the compositions described herein may be sterile or may contain sterile components. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more compounds or conjugates that are substantially pure.

[0149] Also provided is a packaged pharmaceutical composition comprising the pharmaceutical composition described herein and instructions for using the composition for treating a patient afflicted with a disease or condition described herein.

[0150] Method of Use The compounds and compositions detailed herein, such as pharmaceutical compositions comprising a compound of any of the formulas provided herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein.

[0151] Without being bound by theory, the compounds and pharmaceutical compositions disclosed herein are thought to act by modulating nicotinamide phosphoribosyltransferase (NAMPT). In some embodiments, the compounds and pharmaceutical compositions disclosed herein are activators of NAMPT. In some embodiments, provided is a method of treating a disease or condition mediated by NAMPT activity in an individual or subject, the method comprising administering to an individual or subject in need thereof a compound of formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating cancer, a proliferative disorder or condition, an inflammatory disorder or condition, a metabolic disorder, a cardiac disorder or condition, chemotherapy-induced tissue damage, a renal disorder, a metabolic disorder, a neurological disorder or injury, a neurodegenerative disorder or disease, a disease caused by stem cell dysfunction, a disease caused by DNA damage, a primary mitochondrial disorder, or a muscle disorder or muscle wasting disorder in an individual or subject is provided, the method comprising administering to an individual or subject in need thereof a compound of formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I- E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0152] The use of a compound of formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition mediated by the NAMPT activity of interest is also provided herein. In some embodiments, a compound or composition described herein is provided for use in a method of treating the human or animal body by therapy. In some embodiments, provided herein is a compound of formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body by therapy. In some embodiments, provided herein is a compound of formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition mediated by NAMPT activity.In some embodiments, the disease or condition is selected from the group consisting of cancer, proliferative disease or condition, inflammatory disease or condition, metabolic disorder, heart disease or condition, chemotherapy-induced tissue damage, kidney disease, metabolic disease, neurological disease or injury, neurodegenerative disorder or disease, disease caused by stem cell dysfunction, disease caused by DNA damage, primary mitochondrial disorder, or muscle disease or muscle wasting disorder.

[0153] Also provided herein are compositions (including pharmaceutical formulations) as described herein for use in treating, preventing, and / or delaying the onset of, and / or the onset of the diseases described herein and in other methods described herein. In certain embodiments, the composition comprises a formulation present in unit dosage form.

[0154] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, rabbit, pig, sheep, horse, cow, or human. In some embodiments, the subject is a human.

[0155] There are many conditions in which small molecule-mediated stimulation of NAMPT activity to boost NAD+ levels may be clinically beneficial (Stromland et al., Biochem Soc Trans. 2019, 47(1):119-130; Ralto et al., Nat Rev Nephrol. 2019; Fang et al., Trends Mol Med. 2017, 23(10):899-916; Yoshino et al., Cell Metab. 2011, 14(4):528-36; Yang and Sauve, Biochim Biophys Acta. 2016, 1864:1787-1800; Verdin, Science. 2015, 350(6265):1208-13). These conditions include, but are not limited to, heart disease, chemotherapy Examples include tissue damage, kidney diseases, metabolic diseases, muscle diseases, neurological diseases and injuries, diseases caused by stem cell dysfunction, as well as DNA damage and primary mitochondrial disorders. In some embodiments, the disease or condition mediated by NAMPT activity is a heart disease, chemotherapy-induced tissue damage, kidney disease, metabolic disease, muscle disease, neurological disease or injury, a disease caused by stem cell dysfunction, or DNA damage and primary mitochondrial disorder.

[0156] Heart disease. In various preclinical models of heart failure, NAD and NAMPT levels are reduced. In these models, cardiac function can be rescued by restoring NAD via oral supplements or overexpression of NAMPT (Diguet et al, Circulation. 2018, 137:2256 - 2273; Zheng et al., Clin Sci (Lond). 2019, 133(13):1505 - 1521; Smyrnias et al., J Am Coll Cardiol. 2019, 73(14):1795 - 1806). Thus, enhancing the catalytic efficiency of NAMPT using small molecule activators to compensate for the reduced protein level is a promising strategy for treating various forms of heart failure.

[0157] Tissue damage induced by chemotherapy. The use of chemotherapy regimens is often limited by toxicity to healthy tissues, and severe oxidative stress is thought to play a major role. NAD boosting has been shown to cause a strong antioxidant response. Therefore, NAMPT activators are thought to be widely useful for preventing reversible and irreversible secondary conditions in various chemotherapy settings. Examples include the cardiotoxicity of anthracyclines and trastuzumab, cisplatin-induced nephropathy, and peripheral neuropathy induced by cisplatin, paclitaxel, vincristine, and other agents. Neuroprotection by NAMPT activation is also useful for treating / preventing chemotherapy-related cognition ("chemobrain") caused by the destruction of healthy nerve tissue during and long after active treatment has been discontinued. For example, see Zheng et al., Clin Sci (Lond). 2019, 133(13):1505-1521.

[0158] Kidney diseases. Kidney diseases are very prevalent and an area of urgent unmet medical need. Approximately 3% of inpatients are diagnosed with acute kidney injury (AKI). A subset of patients may progress to chronic kidney disease, which may require long-term dialysis or kidney transplantation. An important feature of renal dysfunction is the decreased activity of SIRT1 and SIRT3, characterized by a decrease in the sirtuin substrate NAD, mainly due to impairment of de novo NAD+ synthesis. Since NAMPT is strongly expressed during kidney injury, activation of small molecules by NAMPT is thought to be an effective means of preventing AKI. Similarly, mesangial cell hypertrophy in the kidney indicates NAD+ depletion, and restoration of intracellular NAD+ levels is thought to be effective. For example, see Poyan Mehr et al., Nat Med. 2018, Sep;24(9):1351-9.

[0159] Metabolic diseases. NAD+ boosting improves insulin sensitivity, dyslipidemia, and mitochondrial function in metabolic diseases and protects against / improves non-alcoholic and alcoholic steatohepatitis in preclinical models. In the United States alone, over 3 million people are diagnosed with non-alcoholic steatohepatitis annually, which is one of the leading causes of liver transplantation. See Guarino and Dufour, Metabolites. 2019, Sep 10;9(9), pii:E180; Yoshino et al., Cell Metab. 2011,14(4):528-36.

[0160] Muscle diseases. Preclinical data indicate that NAD+ boosting strategies can reduce skeletal muscle dysfunction in many conditions such as Duchenne muscular dystrophy and age-related sarcopenia. See Zhang et al., Clin Sci (Lond). 2019,133(13):1505-1521; Mohamed et al., Aging (Albany NY). 2014,6(10):820-34; Ryu et al., Sci Transl Med. 2016,8(361):361ra139.

[0161] Neurological diseases and injuries. NAD replenishment by NAMPT activation has neuroprotective effects and therapeutic benefits in a wide range of preclinical models of neurological diseases and injuries such as age-related cognitive decline, glaucoma, ischemic stroke, and ALS. See Johnson et al., NPJ Aging Mech Dis. 2018,4:10; Harlan et al., J Biol Chem. 2016,291(20):10836-46; Zhao et

[0162] Diseases caused by stem cell dysfunction. NAD boosting is useful for promoting stem cell activation and hematopoiesis and for promoting the expansion of stem cell populations after stem cell transplantation. See Pi et al., Aging (Albany NY). 2019, 11(11):3505-3522.

[0163] DNA damage disorders and primary mitochondrial disorders. NAMPT activators are also useful for the treatment of DNA damage disorders associated with accelerated aging phenotypes such as xeroderma pigmentosum, Cockayne syndrome, and ataxia telangiectasia. Similarly, there are several primary mitochondrial disorders with common symptoms and signs (where NAD boosting via NAMPT activation may be an appropriate therapeutic intervention). See Fang et al, Cell. 2014, 157(4):882-896; Khan et al, EMBO Mol Med. 2014, Jun;6(6):721-31; Cerutti et al., Cell Metab. 2014, 19(6):1042-9.

[0164] In some embodiments, provided is a method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof, which comprises administering to the individual or subject in need thereof a compound of formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from the group consisting of heart disease, tissue damage induced by chemotherapy, kidney disease, metabolic disease, muscle disease, neurological diseases and injuries, diseases caused by stem cell dysfunction, and DNA damage and primary mitochondrial disorders.

[0165] Additional uses of small molecule NAMPT activators are shown in Table 2. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0166] In some embodiments, the disease or condition mediated by NAMPT activity is cancer and tissue damage induced by chemotherapy, cardiovascular disease, kidney disease, chronic inflammatory and fibrotic diseases, vascular disease, metabolic dysfunction, muscle disease, neurological disease, or injury, or DNA damage disorders or primary mitochondrial disorders. In some embodiments, provided is a method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof, the method comprising administering to the individual or subject in need thereof a compound of formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), or (II-A), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition is cancer or tissue damage induced by chemotherapy, cardiovascular disease, kidney disease, chronic inflammatory or fibrotic disease, vascular disease, metabolic dysfunction, muscle disease, neurological disease, or injury, DNA damage disorder or primary mitochondrial disorder, such as any of the diseases listed in Table 2.

[0167] Permeability Membrane permeability is an important property in small molecule drug design, especially for compounds with intracellular targets, as their effectiveness greatly depends on the ability to cross the membrane. The effectiveness of a drug can depend on the drug's ability to reach the intended site of action. Drug absorption is the movement of the drug into the bloodstream. Many factors, such as the physicochemical properties of the drug, formulation, and route of administration, affect this process. Generally, in the case of oral treatment, the drug needs to be introduced into the blood via the intestinal route. In other routes such as intravenous therapy, intramuscular injection, and enteral nutrition, absorption is easier with respect to the blood. Regardless of the route of administration, the drug needs to be dissolved and absorbed to achieve a therapeutic effect. By adjusting the factors that affect absorption, the pharmacokinetic (PK) profile of the drug may be altered. The permeability of a drug through biological membranes is an important factor that affects absorption and distribution. This is because the drug needs to first cross several semipermeable cell membranes if it wants to reach the systemic circulation. Drugs can cross cell membranes by passive diffusion, facilitated passive diffusion, active transport, and pinocytosis. The physicochemical properties of the drug (such as size and lipophilicity), and membrane-based efflux mechanisms can lead to a decrease in permeability.

[0168] In the case of orally administered drugs, most absorption occurs in the small intestine. Therefore, drugs with insufficient absorption by the small intestine and / or drugs that actively efflux from the small intestine are likely to not actually reach the intended site of action. Due to the low likelihood of reaching the intended site of action, the effectiveness of the drug is significantly reduced, and doses that are significantly higher and potentially unrealistic compared to the doses predicted in in vitro on-target potency assays are required. Conversely, drugs that are easily absorbed and / or have a low amount of active efflux from the small intestine may require a lower dose to be administered compared to similar or even "more potent" drugs with insufficient absorption. Therefore, the ability of a drug to be absorbed and the amount of efflux that occurs in the small intestine due to efflux in the small intestine are important considerations in the development of orally administered drugs.

[0169] To evaluate the permeability of drugs and predict their in vivo absorption, there are various in vitro methods. One such method is the Caco-2 permeability assay. The Caco-2 cell line is derived from human colon cancer and has many characteristics similar to intestinal epithelial cells. The Caco-2 permeability assay is a good method for investigating human intestinal permeability and drug efflux. The monolayer of the Caco-2 cell line is recognized as an accurate in vitro model of human small intestine drug absorption. Even though the cell line is isolated from human colon adenocarcinoma, differentiated Caco-2 cells are similar to intestinal cells (small intestine absorptive cells) in that the Caco-2 cells form functional tight junctions, apical and basolateral domains, and a brush border cytoskeleton. The Caco-2 permeability assay measures the transport rate of compounds passing through Caco-2 cells and evaluates the transport in both directions. The in vitro apparent permeability (P aap ) of drugs across Caco-2 cells from the apical to the basolateral direction has been shown to correlate with human in vivo oral absorption in both respects: drugs with low Caco-2 cell permeability have low in vivo small intestine drug absorption, and drugs with high or complete Caco-2 cell permeability have high in vivo small intestine drug absorption (Artursson, et al., Biochem Biophys Res Comm, 1991, 3(29):880-885). Usually, drugs that are completely absorbed in vivo have a permeability coefficient exceeding 1×10 -6 cm / sec, and the permeability coefficient of drugs with insufficient absorption is less than 1×10-7 cm / sec from the apical to the basolateral direction of Caco-2 cells.

[0170] Furthermore, Caco-2 cells are used to identify and quantify the level of active drug efflux. The active efflux of a drug can be determined by calculating the ratio of P aap from the basolateral to the apical direction to P aap from the apical to the basolateral direction. Usually, the lower the ratio, the higher the ability of the drug to reach the intended site of action, and the greater the potential efficacy of the drug as the ability of the drug to reach the intended site of action increases.

[0171] The compounds provided herein are suitable for oral administration as measured by their permeability characteristics as evaluated by the Caco-2 cell model. The compounds described herein have been demonstrated to have improved permeability as described in Biological Example 2 herein.

[0172] Dosage The dosages of the compounds and compositions disclosed and / or described herein are administered at therapeutically effective dosages, e.g., dosages sufficient to provide treatment of the condition. Human dosages Levels have not yet been optimized for the chemicals described herein, but generally, the daily dose is about 0.01 - 100 mg / kg per kg of body weight; in some embodiments, about 0.05 - 10.0 mg / kg per kg of body weight, and in some embodiments, in the range of about 0.10 - 1.4 mg / kg per kg of body weight. Thus, when administered to a 70 kg person, in some embodiments, the dosage range is from about 0.7 - 7000 mg per day; in some embodiments, from about 3.5 - 700.0 mg per day, and in some embodiments, from about 7 - 100.0 mg per day. The dosage of the compound depends, for example, on the subject being treated and the disease state, the severity of the affliction, the method and schedule of administration, as well as the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day, and an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, depending on the pharmacokinetics of the compound.

[0173] The daily dose is the total amount administered in a day. The daily dose may be administered daily, every other day, weekly, every two weeks, monthly, or at various intervals, but is not limited thereto. In some embodiments, the daily dose is administered over a period ranging from one day to the lifespan of the subject. In some embodiments, the daily dose is administered once a day. In some embodiments, the daily dose is administered in multiple divided doses, such as 2, 3, or 4 divided doses. In some embodiments, the daily dose is administered in two divided doses.

[0174] Administration of the compounds and compositions disclosed and / or described herein may be via any acceptable mode of administration of a therapeutic agent, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and / or described herein are administered orally.

[0175] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms such as tablets, capsules, powders, liquids, suspensions, suppositories, and aerosol forms. The compounds disclosed and / or described herein may be administered in sustained release or controlled release dosage forms (e.g., controlled / sustained release tablets, depot injections, osmotic pumps, or transdermal (including electrotransport) patch platforms) for long-term and / or pulsed administration at a predetermined rate. In some embodiments, the composition is provided in unit dosage form suitable for single administration of an exact dosage.

[0176] The compounds disclosed and / or described in this specification may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). Optionally, the pharmaceutical composition may also contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, depending on the intended mode of administration, the pharmaceutical composition contains from about 0.005% to 95% by weight, or from about 0.5% to 50% by weight, of the compounds disclosed and / or described in this specification. The actual methods for preparing such dosage forms will be known or apparent to those skilled in the art: see, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0177] In some embodiments, the composition takes the form of tablets or pills, and thus the composition, together with the compounds disclosed and / or described in this specification, may contain one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, acacia gum, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powders encapsulated in gelatin capsules, marume, solutions or suspensions (e.g., in propylene carbonate, vegetable oil or triglycerides).

[0178] ​A pharmaceutically administrable composition of a liquid can be prepared, for example, by dissolving, dispersing, or suspending a compound disclosed and / or described herein, and any pharmaceutical additive in a carrier (such as water, physiological saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectables can be in conventional forms, either as a liquid solution or suspension, or as an emulsion, and can be prepared in a solid form suitable for a solution or suspension in a liquid before injection. The proportion of the active compound contained in such a parenteral composition highly depends, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, a percentage of the active ingredient from 0.01% to 10% in solution can be used, and it may be higher if the composition is a solid to be diluted to another concentration later. In some embodiments, this composition contains about 0.2 - 2% of the compound disclosed and / or described herein in solution.

[0179] The pharmaceutical composition of the compound disclosed and / or described herein may be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as an ultrafine powder for insufflation, either alone or in combination with an inert carrier such as lactose. In such cases, the particles of the pharmaceutical composition may have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.

[0180] Furthermore, the pharmaceutical composition may include the compound disclosed and / or described herein and one or more additional agents, drugs, adjuvants, etc. Suitable pharmaceuticals and pharmaceuticals include those described herein.

[0181] Kit Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The article may include a labeled container. Suitable containers include, for example, bottles, vials, and test tubes. The container can be formed from a variety of materials such as glass or plastic. The container can hold the pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or inhibit the conditions described herein, or may indicate directions for use either in vivo or in vitro. In one aspect, provided herein is a kit comprising a compound or composition described herein and instructions for use. The kit may include instructions for use in treating heart disease in an individual or subject in need thereof. The kit may additionally comprise any materials or devices that can be used to administer the compound or composition, such as vials, syringes, or IV bags. The kit may include a sterile package.

[0182] Combination The compounds and compositions described and / or disclosed herein may be administered alone or in combination with other therapies and / or therapeutic agents useful in the treatment of the aforementioned disorders, diseases, or conditions.

[0183] Enumerated embodiments The following enumerated embodiments represent some aspects of the invention.

[0184] 1. A compound of formula (I):

Chemical formula

Chemical formula

[0185] 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is halo.

[0186] 3. The compound of embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl.

[0187] 4. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is methoxy.

[0188] 5. The compound according to any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

[0189] 6.R 2 is C 1 -C 6 alkyl, the compound according to any one of Embodiments 1 to 4 or a pharmaceutically acceptable salt thereof.

[0190] 7.R 3 is hydrogen, the compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof.

[0191] 8.R 3 is C 1 -C 6 alkyl, the compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof.

[0192] 9. The compound of formula (I) is a compound of formula (I-A), the compound according to any one of Embodiments 1 to 6 or a pharmaceutically acceptable salt thereof:

Chemical formula

[0193] 10.R a is hydrogen, the compound according to any one of Embodiments 1 to 9 or a pharmaceutically acceptable salt thereof.

[0194] 11.R a is C 1 -C 6 alkyl, the compound according to any one of Embodiments 1 to 9 or a pharmaceutically acceptable salt thereof.

[0195] 12. The compound according to any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Z 1 is selected from the group consisting of: C 1 -C 6 alkyl which is -OH, C 3 -C 6 cycloalkyl, C 6 -C 12Optionally substituted with one or more substituents independently selected from the group consisting of aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl, wherein said C 6 -C 12 Aryl, 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 10-membered heteroaryl are each independently C 1 -C 6 Optionally substituted with one or more substituents independently selected from the group consisting of alkyl and C 1 -C 6 Alkoxy; C 3 -C 6 Cycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of aryl, C 6 -C 12 Aryl, C 1 -C 6 Alkyl, and C 1 -C 6 Alkoxy (optionally substituted with 5- or 10-membered heteroaryl), wherein said 5- or 10-membered heteroaryl is optionally further substituted with C 1 -C 6 Alkyl; and -C 1 -C 6 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of alkyl and -C(O)OC 1 -C 6 Alkyl, wherein said -C 1 -C 6 Alkyl is optionally substituted with C 6 -C 12 Aryl, said 3- to 10-membered heterocycloalkyl or heterocycloalkenyl.

[0196] 13. A compound according to any one of embodiments 1 to 11 or a pharmaceutically acceptable salt thereof, wherein Z 1 is ethyl,

Chemical formula

[0197] 14. The compound or a pharmaceutically acceptable salt thereof according to embodiment 1, wherein the compound of formula (I) is a compound of formula (I-B): [Chemical formula]

[0198] 15. R b is hydrogen, the compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 8 and 14.

[0199] 16. R b is 1 -C 6 alkyl, the compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 8 and 14.

[0200] 17. R b is 5 and together with the intervening atoms forms a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl ring, the compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 8 and 14.

[0201] 18. Z 2 is hydrogen, the compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 8 and 14 to 17.

[0202] 19. The compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 8 and 14 to 17, wherein Z 2 is C 3 -C 6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and 5- to 10-membered heteroaryl; 1 -C 6 alkyl; C 1 -C 6 Alkyl and C 1 -C 6 Optionally substituted with one or more substituents independently selected from the group consisting of alkoxy, C 3 -C 6 Cycloalkyl; C 1 -C 6 Alkoxy; Optionally one or more -C 1 -C 6 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with alkyl substituents; C 6 -C 12 Aryl; and Optionally one or more independently selected C 1 -C 6 The compound selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with alkyl substituents, or a pharmaceutically acceptable salt thereof.

[0203] 20. Z 2 is one or more -C 1 -C 6 5- to 6-membered heteroaryl optionally substituted with alkyl substituents, the compound according to embodiment 19, or a pharmaceutically acceptable salt thereof.

[0204] 21. Z 2 is one or more -C 1 -C 6 Pyridyl group optionally substituted with alkyl substituents, the compound according to embodiment 20, or a pharmaceutically acceptable salt thereof.

[0205] 22. The compound according to any one of embodiments 1 to 8 and 14 to 17, or a pharmaceutically acceptable salt thereof, wherein Z 2 is ethyl,

Chemical formula

[0206] 23.Z 2 is

Chemical formula

[0207] 24. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-C):

Chemical formula

[0208] 25. The compound according to any one of Embodiments 1 to 8 and 24, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0209] 26. The compound according to any one of Embodiments 1 to 8 and 24, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0210] 27.R c is hydrogen, and the compound is according to any one of Embodiments 1 to 8 and 24 to 25, or a pharmaceutically acceptable salt thereof.

[0211] 28.R c is C 1 -C 6 alkyl, and the compound is according to any one of Embodiments 1 to 8 and 24 to 25, or a pharmaceutically acceptable salt thereof.

[0212] 29.R d is hydrogen, and the compound is according to any one of Embodiments 1 to 8, 24 to 25, and 27 to 28, or a pharmaceutically acceptable salt thereof.

[0213] 30.R d is C 1 -C 6The compound according to any one of Embodiments 1 to 8, 24 to 25, and 27 to 28, which is alkyl, or a pharmaceutically acceptable salt thereof.

[0214] 31.R c and R d together with the carbon to which they are attached form a C 3 -C 6 The compound according to any one of Embodiments 1 to 8 and 24 to 25, which forms cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0215] 32.R e is hydrogen, the compound according to any one of Embodiments 1 to 8 and 24 to 31, or a pharmaceutically acceptable salt thereof.

[0216] 33.R e is C 1 -C 6 The compound according to any one of Embodiments 1 to 8 and 24 to 31, which is alkyl, or a pharmaceutically acceptable salt thereof.

[0217] 34.Z 3 is hydrogen, the compound according to any one of Embodiments 1 to 8 and 24 to 33, or a pharmaceutically acceptable salt thereof.

[0218] 35. The compound according to any one of Embodiments 1 to 8 and 24 to 33, or a pharmaceutically acceptable salt thereof, wherein Z 3 is C 3 -C 6 cycloalkyl; optionally -C 1 -C 6 a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with alkyl; C 6 -C 12 aryl; and one or more independently selected C 1 -C 6The compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with an alkyl substituent.

[0219] 36.Z 3 is

Chemical formula

Chemical formula

[0220] 38. The compound according to any one of Embodiments 1 to 8 and 37, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0221] 39. The compound according to any one of Embodiments 1 to 8 and 37, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0222] 40. The compound according to any one of Embodiments 1 to 8 and 37, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0223] 41.Z 4 is hydrogen or R z The compound according to any one of Embodiments 1 to 8 and 37 to 40, or a pharmaceutically acceptable salt thereof.

[0224] 42.Z 4 is 1 -C 6 alkyl, the compound according to any one of Embodiments 1 to 8 and 37 to 40, or a pharmaceutically acceptable salt thereof.

[0225] 43.Z 4 is R2 The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 8 and 37 to 40, which together with the intervening atom forms a 4- to 6-membered heterocycloalkyl or heterocycloalkenyl ring.

[0226] 44.

Chemical formula

[0227] 45. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein the compound of formula (I) is a compound of formula (I-E):

Chemical formula

[0228] 46. Z 5 is C 1 -C 6 alkyl, the compound according to any one of Embodiments 1 to 8 and 45, or a pharmaceutically acceptable salt thereof.

[0229] 47. Z 5 is ethyl, the compound according to any one of Embodiments 1 to 8 and 45, or a pharmaceutically acceptable salt thereof.

[0230] 48. The compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein the compound of formula (I) is a compound of formula (I-F):

Chemical formula

[0231] 49. The compound according to any one of Claims 1 to 8 and 48, or a pharmaceutically acceptable salt thereof, wherein R f and R g together with the nitrogen to which they are attached are halo, -OH, -CN, oxo, one or more independently selected R x-C optionally substituted with a substituent 1 -C 6 alkyl, -C 3 -C 6 cycloalkyl, -C 1 -C 6 alkoxy, -C(O)R h , -NHC(O)OC 1 -C 6 alkyl, -NR j R k , -C(O)NR m R n forming a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with one or more substituents independently selected from the group consisting of 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and 5- to 6-membered heteroaryl, said compound, or a pharmaceutically acceptable salt thereof.

[0232] 50.R f and R g together with the nitrogen to which they are attached form a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with -C 1 -C 6 wherein said -C 1 -C 6 alkyl is optionally substituted with -OH, the compound or a pharmaceutically acceptable salt thereof according to claim 49.

[0233] 51. A compound according to any one of embodiments 1 to 8 and 48 to 49, or a pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

Chemical formula

[0234] 52. [Chemical formula] The compound according to embodiment 51, or a pharmaceutically acceptable salt thereof.

[0235] 53. R 4 is a 5- to 10-membered heteroaryl optionally substituted with one or more independently selected C 1 -C 6 alkyl substituents. The compound according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof.

[0236] 54. R 4 is [Chemical formula] selected from the group consisting of. The compound according to any one of embodiments 1 to 8 and 53, or a pharmaceutically acceptable salt thereof.

[0237] 55. The compound according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein in the formula R 4 is a 3- to 10-membered heterocycloalkyl or heterocycloalkenyl, which is halo, oxo, -OH, -CN, one or more independently selected R y substituents optionally substituted with -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy optionally substituted with one or more independently selected halo substituents, -C(O)OC 1 -C 6 alkyl, -C(O)C 1 -C 6 alkyl, -S(O) 2 -C 1 -C 6 alkyl, C 6 -C 12 aryl optionally substituted with one or more independently selected halo substituents, 3- to 6-membered heterocycloalkyl or heterocycloalkenyl, and one or more independently selected C1 -C 6 One or more substituents independently selected from the group consisting of 5- to 6-membered heteroaryl optionally substituted with an alkyl substituent, said 3- to 10-membered heterocycloalkyl or heterocycloalkene optionally substituted with one or more substituents, said compound, or a pharmaceutically acceptable salt thereof.

[0238] 56.R 4 is S(O) 2 -C 1 -C 6 alkyl or -C 1 -C 6 4- to 6-membered heterocycloalkyl or heterocycloalkenyl optionally substituted with alkyl (optionally substituted with -OH), the compound according to embodiment 55, or a pharmaceutically acceptable salt thereof.

[0239] 57.R 4 is

Chemical formula

Chemical formula

[0240] 58.R 4 is

Chemical formula

[0241] 59. A compound selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0242] 60. A pharmaceutical composition comprising the compound according to any one of embodiments 1 to 59, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0243] 61. A method of treating a disease or condition mediated by NAMPT activity in a subject in need thereof, the method comprising administering to the subject a compound according to any one of Embodiments 1 to 59, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 60.

[0244] 62. The method according to Embodiment 61, wherein the disease or condition is selected from the group consisting of cancer, proliferative disease or condition, inflammatory disease or condition, metabolic disorder, heart disease or condition, chemotherapy-induced tissue damage, kidney disease, metabolic disease, neurological disease or injury, neurodegenerative disorder or disease, disease caused by stem cell dysfunction, disease caused by DNA damage, primary mitochondrial disorder, or muscle disease or muscle wasting disorder.

[0245] 63. The method according to Embodiment 61, wherein the disease or condition is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliovirus infection), and spinal cord injury.

[0246] General synthetic method The compounds of formula (II), (I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1) are described by reference to the following exemplary synthetic schemes for their general preparation and the following specific examples. One of ordinary skill in the art will recognize that, in order to obtain the various compounds of this specification, the starting materials may be appropriately selected such that the ultimately desired substituents are carried through the reaction scheme, with or without appropriate protection, to produce the desired product. Alternatively, it may be necessary or desirable to use an appropriate group that is carried through the reaction scheme and optionally replaced with the ultimately desired substituent. Further, one of ordinary skill in the art will recognize that protecting groups may be used to protect certain functional groups (amino, carboxy, or side chain groups) from the reaction conditions, and that such groups are removed under standard conditions when appropriate. Unless otherwise specified, the variables are as described above with reference to formula (II), ( I-G), (I), (I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1).

[0247] If it is desired to obtain a particular enantiomer of a compound, this can be achieved from the corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving the enantiomers. Thus, for example, diastereomeric derivatives can be produced by reaction of the enantiomers, such as a racemate, with a suitable chiral compound. The diastereomers can then be separated by any convenient means, such as by crystallization, and the desired enantiomer recovered. In another separation process, chiral high performance liquid chromatography may be used to separate the racemate. Alternatively, if desired, a particular enantiomer may be obtained by using a suitable chiral intermediate in one of the processes described.

[0248] Chromatography, recrystallization and other conventional separation procedures may also be used in obtaining a particular isomer of a compound or, alternatively, in purifying an intermediate or final product when it is desired to obtain the product of the reaction.

[0249] General methods for preparing the compounds described herein are shown in the following exemplary methods. The variable groups in the schemes provided herein are defined as set forth for formulae (II), (I-G), (I)(I-A), (I-A1), (I-A2), (I-A3), (I-A4), (I-B), (I-B1), (I-B2), (I-B3), (I-C), (I-C1), (I-C2), (I-C3), (I-C4), (I-D), (I-D1), (I-D2), (I-D3), (I-D4), (I-D5), (I-D6), (I-D7), (I-E), (I-F), (II-A), and (II-A1), or any variation thereof. Other compounds described herein may be prepared by similar methods.

[0250] In some embodiments, the compounds provided herein can be synthesized according to Scheme A1, A2, or A3. Scheme A1

Chemical formula

[0251] In certain embodiments, the compounds provided herein can be synthesized according to Scheme A1a, A2a, or A3a: Scheme A1a [Chemistry] Scheme A2a [Chemistry] Scheme A3a [Chemistry] Wherein, R 1 , R 2 , R 3 , R 4 , and R 5 are as defined for formula (II) or any of its variations detailed herein.

[0252] In some embodiments, the compounds provided herein can be synthesized according to Scheme B1 or B2: Scheme B1 [Chemistry] Scheme B2 [Chemistry] Wherein, R 1 , R 2 , R3 , R 5 , R a , R g , R f , and Z 1 is as defined in formula (II) or any of its variations described in detail herein.

[0253] In certain embodiments, the compounds provided herein can be synthesized by Scheme B1a or B2a: as follows: Scheme B1a

Chemical formula

Chemical formula

[0254] In some embodiments, the compounds provided herein can be synthesized by Scheme C1 or C2: Scheme C1

Chemical formula

Chemical formula

[0255] In certain embodiments, the compounds provided herein can be synthesized according to Scheme C1a or C2a: Scheme C1a [Chemical formula] Scheme C2a [Chemical formula] wherein R 1 , R 2 , R 3 , R 5 , R b , R c , R e , Z 2 and Z 3 are as defined for formula (II) or any of its variations described in detail herein.

[0256] In some embodiments, the compounds provided herein may be synthesized according to Scheme D1: Scheme D1 [Chemical formula] wherein R 1 , R 5 , R c , R d , m, and Z 3 are as defined for formula (II) or any of its variations described in detail herein, and PG is a suitable protecting group.

[0257] In certain embodiments, the compounds provided herein can be synthesized by Scheme D1a: [Chemical formula] wherein R 1 , R 5 , R c, R d , m, and Z 3 is as defined in formula (II) or any of its variations described in detail herein.

[0258] In some embodiments, the compounds provided herein can be synthesized according to Scheme E1: [Chemical formula] wherein R 1 , R 2 , R 3 , R 5 , n, and Z 4 is as defined in formula (II) or any of its variations described in detail herein.

[0259] In certain embodiments, the compounds provided herein can be synthesized according to Scheme E1a: [Chemical formula] wherein R 1 , R 2 , R 3 , R 5 , n, and Z 4 is as defined in formula (II) or any of its variations described in detail herein.

[0260] In some embodiments, the compounds provided herein can be synthesized by Scheme F1: [Chemical formula] wherein R 1 , R 2 , R 3 , R 5 , n, and Z 4 is as defined in formula (II) or any of its variations described in detail herein.

[0261] In certain embodiments, the compounds provided herein can be synthesized by Scheme F1a: [Chemical formula] In the formula, R 1 , R 2 , R 3 , R 5 , n, and Z 4 are as defined in formula (II) or any variation thereof described in detail herein.

[0262] Specific non-limiting examples are described in the Examples section below. [Examples]

[0263] The following examples are provided to illustrate the compositions, uses, and methods provided herein, but are not intended to be limiting. The compounds are prepared using the general methods described above.

[0264] The following abbreviations are used throughout the examples: TEA (triethylamine), DCM (dichloromethane), (Boc) 2 O (di-tert-butyl dicarbonate), EA (ethyl acetate), PE (petroleum ether), DMF (N,N-dimethylformamide), DIEA (N-ethyl-N-isopropylpropan-2-amine), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HOAt (1-hydroxy-7-azabenzotriazole), HOBt (hydroxybenzotriazole), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), MeOH (methanol), EtOH (ethanol), iPrOH (propan-2-ol), ACN (acetonitrile), TFA (trifluoroacetic acid), DPPA (diphenylphosphoryl azide), DBU (1,8-diazabicyclo(5.4.0)undec-7-ene), THF (tetrahydrofuran), PPh 3(Triphenylphosphine), SM (starting material), Hex (hexane), NCS (N-chlorosuccinimide), r.t. (room temperature), DCE (dichloroethane), FA (formic acid), CHCl 3 (chloroform), BnBr (benzyl bromide), HCl (hydrogen chloride), equivalent, and DSC (bis(2,5-dioxopyrrolyl-yl) carbonate), HBTU (O-(benzotriazol-1-yl)-N,N,N’,N’-tetra methyluronium hexafluorophosphate).

[0265] Example A Synthesis of intermediates 1.1, 1.2, 1.3 and 1.4. Step 1: Preparation of 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (intermediate 1-a):

Chemical formula

[0266] Step 2: Preparation of 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (intermediate 1.1): [Chemical formula] To a 20 °C solution of intermediate 1-a (26.5 g, 77.5 mmol) in 1,4-dioxane (400 mL) was added dropwise 4N LiOH (234.0 mmol). The resulting mixture was stirred at room temperature for 2 hours, and then methanol (50 mL) was added. The pH of the mixture was adjusted to pH 1-2 at 0 °C using 6N aqueous HCl solution. After 1 hour at 0 °C, the slurry was filtered to obtain 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)acetic acid (20.2 g, 64.3 mmol, 82.9% yield) as an off-white solid. LCMS-APCI(POS.) m / z: 315.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.22 (s, 1H), 8.47 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H), 6.50 (t, J = 6.0 Hz, 1H), 4.22 (d, J = 5.7 Hz, 2H), 3.74 (d, J = 1.3 Hz, 3H), 3.46 (s, 2H).

[0267] Intermediates 1.2 and 1.3 were prepared in the same manner as intermediate 1.1 using the reagents shown in the following table instead of 4-methoxybenzyl isocyanate. [Table 4]

[0268] Example B Synthesis of Intermediates 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, and 2.7 Step 1: Preparation of tert-butyl (S)-(1-(4-(3-(4-methoxybenzyl)ureido)phenyl)ethyl)carbamate (intermediate 2-a): [Chemical formula] To a solution of tert-butyl (S)-[1-(4-aminophenyl)ethyl]carbamate (2.0 g, 22.7 mmol) in DCM (20 mL) was added 4-methoxybenzyl isocyanate (14.4 g, 34.0 mmol) dropwise at 20 °C. The resulting mixture was stirred at room temperature for 4 h, then methanol (10 mL) was added and the mixture was cooled to 0 °C. After 1 h at 0 °C, the slurry was filtered to give tert-butyl (S)-(1-(4-(3-(4-methoxybenzyl)ureido)phenyl)ethyl)carbamate (1.2 g, 6.3 mmol, 28% yield) as an off-white solid. LCMS-APCI(POS.) m / z: 400.1 (M+H) + 。 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.43 (s, 1H), 7.36 - 7.19 (m, 4H), 7.14 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.2 Hz, 2H), 6.48 (t, J = 5.9 Hz, 1H), 4.53 (p, J = 7.3 Hz, 1H), 4.21 (d, J = 5.7 Hz, 2H), 3.73 (s, 3H), 1.37 (s, 9H), 1.27 (d, J = 7.0 Hz, 3H).

[0269] Step 2: Preparation of (S)-1-(4-(1-aminoethyl)phenyl)-3-(4-methoxybenzyl)urea hydrochloride (Intermediate 2.1):

Chem.

[0270] Intermediates 2.2, 2.3, 2.4, 2.5, 2.6, and 2.7 were prepared in the same manner as Intermediate 2.1 using the reagents shown in the following table instead of 4-methoxybenzyl isocyanate.

Table 5-1

Table 5-2

[0271] Example C Synthesis of Intermediates 3.1, 3.2, and 3.3 Step 1: Preparation of methyl 4-(3-(4-methoxybenzyl)ureido)benzoate (Intermediate 3-a):

Chemical formula

[0272] Step 2: Preparation of 1-(4-(hydroxymethyl)phenyl)-3-(4-methoxybenzyl)urea (intermediate 3-b):

Chemical formula

[0273] Step 3: Preparation of 1-(4-formylphenyl)-3-(4-methoxybenzyl)urea (Intermediate 3.1):

Chemical Structure

[0274] Intermediates 3.2 and 3.3 were prepared in the same manner as intermediate 2.1 using the reagents shown in the following table instead of (4 - methoxyphenyl)methanamine.

Table 6

[0275] Example D Synthesis of intermediates 4.1 and 4.2 Step 1: Preparation of phenyl(4 - chlorobenzyl)carbamate (intermediate 4.1):

Chemical formula

[0276] Intermediate 4.2 was prepared in the same manner as Intermediate 4.1, using (4-methoxyphenyl)methanamine instead of (4-chlorophenyl)methanamine.

Table 7

[0277] Example E Synthesis of 4-(1-(methylsulfonyl)ethyl)aniline (Intermediate 5.0) Step 1: Preparation of 1-((methylsulfonyl)methyl)-4-nitrobenzene (Intermediate 5-a):

Chem.

[0278] Step 2: Preparation of 1-(1-(methylsulfonyl)ethyl)-4-nitrobenzene (Intermediate 5-b):

Chem.

[0279] Step 3: Preparation of 4-(1-(methylsulfonyl)ethyl)aniline (Intermediate 5.0):

Chem.

[0280] Example F 3-(4-Aminophenyl)thietane 1,1-dioxide trifluoroacetate (Synthesis of Intermediate 6.0) Step 1: Preparation of Diethyl 2-(4-nitrophenyl)malonate (Intermediate 6-a): [Chemical formula] To a solution of 1-bromo-4-nitrobenzene (5 g, 24.752 mmol, 1 eq) in DMSO (50 mL), add diethyl 1,3-propanedioate (12 g, 74.921 mmol, 3.03 eq), CuI (473 mg, 2.484 mmol, 0.10 eq), L-proline (572 mg, 4.968 mmol, 0.20 eq) and K 2 CO 3 (13.7 g, 99.128 mmol, 4.00 eq). The mixture was stirred at 90 °C for 2 days under a nitrogen atmosphere, cooled to room temperature, water (100 mL) was added, and the mixture was extracted twice with EtOAc (100 mL). The combined organic layers were washed twice with brine (100 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure, and purified by silica gel column chromatography, eluting with PE / EtOAc (20:1) to obtain 4.7 g of diethyl 1,3-diethyl 2-(4-nitrophenyl)propanedioate as a yellow oil. LRMS (ES) m / z 282 (M+H).

[0281] Step 2: Preparation of Diethyl 2-(4-aminophenyl)malonate (Intermediate 6-b): [Chemical formula] A solution of diethyl 1,3-diethyl 2-(4-nitrophenyl)propanedioate (2.2 g, 7.822 mmol, 1 equiv) in ethanol (25 mL) was added to Pd / C (1.10 g, 50% w / w). The resulting mixture was stirred at room temperature for 2 h under a hydrogen atmosphere, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to give 1.9 g of diethyl 1,3-diethyl 2-(4-aminophenyl)propanedioate (96.67%) as a yellow oil. LRMS (ES) m / z 252 [M+H].

[0282] Step 3: Preparation of diethyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)malonate (Intermediate 6-c):

Chemical formula

[0283] Step 4: Preparation of tert-butyl (4-(1,3-dihydroxypropan-2-yl)phenyl)carbamate (Intermediate 6-d):

Chemical formula

[0284] Step 5: Preparation of 2-(4-((tert-butoxycarbonyl)amino)phenyl)propane-1,3-diyl dimethanesulfonate (Intermediate 6-e): [Chemical formula] To a solution of tert-butyl N-[4-(1,3-dihydroxypropan-2-yl)phenyl]carbamate (670 mg, 2.506 mmol, 1 equiv) in DCM (10 mL) were added methanesulfonyl chloride (715 mg, 6.242 mmol, 2.49 equiv) and TEA (760 mg, 7.511 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature for 2 h and poured into water (20 mL). The aqueous layer was extracted twice with CH 2 Cl 2 (20 mL). The combined organic layers were washed twice with brine (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to give 1.2 g of tert-butyl N-[4-[2-(methanesulfonyloxy)-1-[(methanesulfonyloxy)methyl]ethyl]phenyl]carbamate as a yellow solid. LRMS (ES) m / z 368 [M+H-56].

[0285] Step 6: Preparation of tert-butyl (4-(thietan-3-yl)phenyl)carbamate (Intermediate 6-f):

Chemical formula

[0286] Step 7: Preparation of tert-butyl (4-(1,1-dioxidothietan-3-yl)phenyl)carbamate (Intermediate 6-g):

Chemical formula

[0287] Step 8: Preparation of 3-(4-aminophenyl)thietane 1,1-dioxide trifluoroacetate (Intermediate 6.0):

Chem.

[0288] Example G Synthesis of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide (Intermediate 7.0) Step 1: Preparation of 2-(4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (Intermediate 7-a):

Chem.

[0289] Step 2: Preparation of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide (Intermediate 7.0): [Chemical formula] To a solution of 2-(4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (1.10 g, 4.559 mmol, 1.00 eq) in methanol (11 mL) was added Pd / C (550.00 mg, 50% w / w). The resulting mixture was stirred at room temperature overnight under a hydrogen atmosphere, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to obtain 800 mg of 2-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide (83.05%) as a yellow solid. LRMS (ES) m / z 212 [M+H].

[0290] Example H Synthesis of 3-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide trifluoroacetate (Intermediate 8.0) Step 1: Preparation of tert-butyl (4-iodophenyl)carbamate (Intermediate 8-a): [Chemical formula] To a solution of 4-iodoaniline (1 g, 4.566 mmol, 1 equiv) in MeOH (20 mL) was added (Boc) 2 O (2 g, 0.009 mmol, 2.01 equiv) and TEA (2 mL). The resulting mixture was stirred at 50 °C overnight, cooled to room temperature, concentrated under vacuum, and water (50 mL) was added. The mixture was extracted twice with EtOAc (50 mL). The combined organic layers were washed twice with brine (50 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure, and purified by silica gel column chromatography, eluting with PE / EtOAc (30:1) to give 650 mg of tert-butyl N-(4-iodophenyl)carbamate (650 mg, 44.61%) as an off-white solid. LRMS (ES) m / z 264 [M+H-56].

[0291] Step 2: Preparation of tert-butyl (4-(1,1-dioxide-2,5-dihydrothiophen-3-yl)phenyl)carbamate (Intermediate 8-b): [Chemical formula] To a solution of tert-butyl N-(4-iodophenyl)carbamate (650 mg, 2.037 mmol, 1 equiv) in toluene (10 mL) was added 2,5-dihydro-1λ6-thiophene-1,1-dione (264 mg, 2.234 mmol, 1.10 equiv), Pd(OAc)2 (91 mg, 0.405 mmol, 0.20 equiv), TBABr (654 mg, 2.029 mmol, 1.00 equiv) and TEA (410 mg, 4.052 mmol, 1.99 equiv). The resulting mixture was stirred at room temperature for 3 days under a nitrogen atmosphere, stirred at 80 °C for 3 hours, cooled to room temperature, and water (20 mL) was added. The mixture was extracted twice with EtOAc (30 mL). The combined organic layers were washed twice with brine (30 mL), dried over anhydrous Na 2 SO4 It was dried, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with PE / EtOAc (3:2) to obtain 430 mg of tert-butyl N-[4-(1,1-dioxido-2,5-dihydro-1λ6-thiophen-3-yl)phenyl]carbamate (68.24%) as a brown solid. LRMS(ES) m / z 254 [M+H-56].

[0292] Step 3: Preparation of tert-butyl (4-(1,1-dioxidotetrahydrothiophen-3-yl)phenyl)carbamate (Intermediate 8-c):

Chemical formula

[0293] Step 4: Preparation of 3-(4-aminophenyl)tetrahydrothiophene 1,1-dioxide trifluoroacetate (Intermediate 8.0):

Chemical formula

[0294] Example I Synthesis of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 9.0) Step 1: Preparation of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (Intermediate 9-a):

Chemical Structure

[0295] Step 2: Preparation of 4-(4-Nitrophenyl)-3,6-dihydro-2H-thiopyran (Intermediate 9-b): [Chemical Formula] To a solution of 3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate (2.4 g, 9.668 mmol, 1 eq) in dioxane (20 mL) and H 2 O (10 mL), (4-Nitrophenyl)boronic acid (1.94 g, 11.602 mmol, 1.20 eq), Pd(dppf)Cl 2 CH 2 Cl 2 (1.58 g, 1.934 mmol, 0.20 eq) and K 2 CO 3 (2.66 g, 19.34 mmol, 2 eq) were added. The resulting mixture was stirred at 85 °C for 3 h under a nitrogen atmosphere, cooled to room temperature, and water (200 mL) was added. The mixture was extracted twice with EtOAc (200 mL). The combined organic layers were washed twice with brine (200 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure, and purified by silica gel column chromatography, eluting with PE / EtOAc (20:1) to give 1 g of 4-(4-Nitrophenyl)-3,6-dihydro-2H-thiopyran (46.74%) as a yellow solid. LRMS (ES) m / z 222 [M+H].

[0296] Step 3: Preparation of 4-(4-Nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (Intermediate 9-c): [Chemical Formula] To a solution of 4-(4-Nitrophenyl)-3,6-dihydro-2H-thiopyran (700 mg, 3.164 mmol, 1 eq) in DCM (15 mL) at -78 °C, m-CPBA (1.6 g, 9.5 mmol, 3 eq) was added. The resulting mixture was stirred at room temperature for 3 h and poured into water (20 mL). The aqueous layer was extracted with CH 2 Cl 2(30 mL) was extracted twice. The combined organic layers were washed with Na 2 SO 3 (10 mL of aqueous solution), NaHCO 3( aq. 10 mL), washed twice with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain 650 mg of 4-(4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide as a yellow solid. LRMS (ES) m / z 254 [M+H].

[0297] Step 4: Preparation of 4-(4-aminophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 9.0):

Chem.

[0298] Example J Synthesis of 4-(4-aminophenyl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 10.0) Step 1: Preparation of ethyl (Z)-2-cyano-3-(4-nitrophenyl)but-2-enoate (Intermediate 10-a):

Chem.

[0299] Step 2: Preparation of 4-methyl-4-(4-nitrophenyl)-2,6-dioxopiperidine-3,5-dicarbonitrile (Intermediate 10-b): [Chemical formula] To a solution of NaOEt in EtOH (30 mL) (2 g, 6.176 mmol, 1.00 equiv, 21%) at 0 °C, 2-cyanoacetamide (517 mg, 6.149 mmol, 1.00 equiv) was added dropwise over 5 minutes. After stirring at room temperature for 15 minutes, ethyl (2Z)-2-cyano-3-(4-nitrophenyl)but-2-enoate (1.6 g, 6.148 mmol, 1 equiv) was added. The resulting reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and the mixture was acidified to pH 1 with HCl (aq. 4 mol / L, ca. 5 mL). The precipitated solid was collected by filtration and dried under reduced pressure to obtain 1.2 g of 4-methyl-4-(4-nitrophenyl)-2,6-dioxopiperidine-3,5-dicarbonitrile (65.44%) as a yellow solid. No LCMS signal. Confirmed by H-NMR. 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.42 - 8.34 (m, 3H), 8.02 - 7.94 (m, 2H), 5.43 (s, 2H), 1.76 (s, 3H).

[0300] Step 3: Preparation of 3 - methyl - 3 - (4 - nitrophenyl) pentanedioic acid (Intermediate 10 - c):

Chemical formula

[0301] Step 4: Preparation of 3 - methyl - 3 - (4 - nitrophenyl) pentane - 1,5 - diol (Intermediate 10 - d):

Chemical formula

[0302] Step 5: Preparation of 3-methyl-3-(4-nitrophenyl)pentane-1,5-diyl dimethanesulfonate (Intermediate 10-e):

Chemical Structure

[0303] Step 6: Preparation of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran (Intermediate 10-f):

Chemical Structure

[0304] Step 7: Preparation of 4-methyl-4-(4-nitrophenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 10-g):

Chemical Structure

[0305] Step 8: Preparation of 4-(4-aminophenyl)-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 10.0):

Chemical Structure

[0306] Example K Synthesis of 3-methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (Intermediate 11.1 - 11.15) Of 3-methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (Intermediate 11-a) Preparation:

Chemical formula

[0307] Intermediates 11.2 to 11.15 were prepared in the same manner as Intermediate 11.1.

Table 8-1

Table 8-2

Table 8-3

[0308] Example L 5-Methyl-1-(4-nitrobenzyl)pyrrolidin-2-one Synthesis of (Intermediate 12.1 - 12.2) Preparation of 5-Methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (Intermediate 12):

Chemical formula

[0309] Intermediate 12.2 was prepared in the same manner as Intermediate 12.1. [Table 9]

[0310] Example M Synthesis of 1-(4-aminobenzyl)-3-methylpyrrolidin-2-one (Intermediates 13.1 - 13.X) Preparation of 1-(4-aminobenzyl)-3-methylpyrrolidin-2-one (Intermediate 13.1): [Chemical formula] 3-Methyl-1-(4-nitrobenzyl)pyrrolidin-2-one (3 g, 12.8 mmol, 1 equivalent) and PtO 2 (0.29 g, 1.28 mmol, 0.1 equivalent) were stirred under H 2 (80 psi) for 1 hour. The reaction mixture was filtered through a pad of celite, and the solvent was removed by rotary evaporation and dried under high vacuum to obtain the product as a reddish solid (2.6 g, 99%). LC / MS (APCI) m / z: 205.2 [M+H]. Intermediates 13.2 - 13.36 were prepared in the same manner as Intermediate 13.1.

[0311] Intermediates 13.2 - 13.36 were prepared in the same manner as Intermediate 13.1. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6]

Table 10-7

[0312] Example N Synthesis of 4-methyl-1-(4-nitrobenzyl)piperazin-2-one (Intermediates 14.1 - 14.6) Step 1: Preparation of 1-(4-nitrobenzyl)piperazin-2-one hydrochloride (Intermediate 14- a):

Chem.

[0313] Step 2: Preparation of 4-methyl-1-(4-nitrobenzyl)piperazin-2-one (Intermediate 14.1):

Chem.

[0314] Intermediates 14.2 - 14.6 were prepared in the same manner as Intermediate 14.1.

Table 11

[0315] Example O Synthesis of 4 - ((azetidin - 1 - ylsulfonyl)methyl)aniline (Intermediates 15.1 - 15.4) Step 1: Preparation of 1 - ((4 - nitrobenzyl)sulfonyl)azetidine (Intermediate 15 - a):

Chem.

[0316] Step 2: Preparation of 4-((azetidin-1-ylsulfonyl)methyl)aniline (Intermediate 15.1):

Chemical Structure

[0317] Intermediates 15.2 - 15.4 were prepared in the same manner as Intermediate 15.1.

Table 12

[0318] Example P Synthesis of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea (Intermediate 16) Step 1: Preparation of phenyl(4-chlorobenzyl)carbamate (Intermediate 16-a):

Chemical formula

[0319] Step 2: Preparation of 1-(4-chlorobenzyl)-3-(4-formylphenyl)urea (Intermediate 16-b):

Chemical formula

[0320] Step 3: Preparation of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (Intermediate 16-c):

Chemical formula

[0321] Step 4: Preparation of 1-(4-chlorobenzyl)-3-(4-(hydroxymethyl)phenyl)urea (Intermediate 16):

Chemical formula

[0322] Example Q Synthesis of 1-(4-chlorobenzyl)-3-(4-(((1,1-dioxidotetrahydrothiophen-3-yl)(methyl)amino)methyl)phenyl)urea (Intermediates 17.1 - 17.6)

Chemical formula

[0323] Intermediates 17.2 - 17.6 were prepared in a similar manner to Intermediate 17.1.

Table 13-1

Table 13-2

[0324] Example R Synthesis of 1-(4-chlorobenzyl)-3-(4-(((1,1-dioxidotetrahydrothiophen-3-yl)(methyl)amino)methyl)phenyl)urea (Intermediates 18.1 - 18.2)

Chemical Structure

[0325] Intermediate 18.2 was prepared in a similar manner to Intermediate 18.1.

Table 14

[0326] Example S Synthesis of tert-butyl (2-(4-nitrophenyl)-2-oxoethyl)carbamate (Intermediate 19) Step 1: Preparation of 2-amino-1-(4-nitrophenyl)ethan-1-one hydrochloride (Intermediate 19-a): [Chemical formula] To a solution of 2-amino-1-(4-bromophenyl)ethanone (100.00 g, 467.154 mmol, 1.00 equivalent) in DCM (1.20 L) was added hexamethylenetetramine (85.00 g, 607.143 mmol, 1.30 equivalents). The resulting mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and washed with CH 2 Cl 2 (500 mL). HCl (200.00 mL, 6 mol / L) and EtOH (1.00 L) were added to the residue. The resulting mixture was stirred at room temperature for 3 hours and left overnight. The precipitated solid was collected by filtration, washed with hexane (500 mL), and concentrated under vacuum to obtain 140 g of 2-amino-1-(4-nitrophenyl)ethanone hydrochloride (crude) as a pale yellow solid. LCMS-APCI(POS.) m / z: 181 (M+H) + .

[0327] Step 2: Preparation of tert-butyl (2-(4-nitrophenyl)-2-oxoethyl)carbamate (Intermediate 19): [Chemical formula] To a solution of 2-amino-1-(4-nitrophenyl)ethanone hydrochloride (140.00 g, 646.293 mmol, 1.00 equivalent) in DCM (1.60 L) was added K 2 O in H 2 CO 3A solution of 2 Cl 2 (1 L) was extracted twice. The combined organic layers were washed twice with brine (1 L) and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give 176 g of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (crude product) as a brown oil. LCMS-APCI(POS.) m / z: 225 (M+H-56) + .

[0328] Example T Synthesis of 5-(4-nitrophenyl)piperazin-2-one (Intermediate 20) Step 1: Preparation of methyl (2-((tert-butoxycarbonyl)amino)-1-(4-nitrophenyl)ethyl)glycinate (Intermediate 20-a): [Chemical formula] A solution of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (14.00 g, 49.950 mmol, 1.00 equivalent) and methyl 2-aminoacetate hydrochloride (12.61 g, 100.400 mmol, 2.01 equivalents) in MeOH (200.00 mL) was stirred at room temperature for 30 minutes. Next, NaBH 3 CN (6.22 g, 98.901 mmol, 1.98 equivalents) was added to the above mixture obtained at 0 °C. The resulting mixture was stirred at 70 °C overnight, cooled to room temperature, adjusted to pH 8 with saturated NH4.H2O (aqueous solution), and extracted twice with EtOAc (200 mL). The combined organic layers were washed twice with water (200 mL) and dried over anhydrous Na 2 SO 4It was dried and concentrated under reduced pressure to obtain 17 g (crude) of methyl 2-([2-[(tert-butoxycarbonyl)amino]-1-(4-nitrophenyl)ethyl]amino)acetate as a brown oil. LCMS-APCI(POS.) m / z: 354 (M+H) + 。

[0329] Step 2: Preparation of 2-((2-methoxy-2-oxoethyl)amino)-2-(4-nitrophenyl)ethan-1-aminium 2,2,2-trifluoroacetate (Intermediate 20-b):

Chem.

[0330] Step 3: Preparation of 5-(4-nitrophenyl)piperazin-2-one (Intermediate 20):

Chem.

[0331] Example U Synthesis of tert-butyl 4-methyl-2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 21) Step 1: Preparation of tert-butyl 2-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 21-a):

Chemical formula

[0332] Step 2: Preparation of tert-Butyl 4-Methyl-2-(4-Nitrophenyl)-5-Oxopiperazine-1-Carboxylate (Intermediate 20):

Chemical Structure

[0333] Example V Synthesis of 4-Methyl-5-(4-Nitrophenyl)Piperazin-2-One (Intermediate 22) Preparation of 4-Methyl-5-(4-Nitrophenyl)Piperazin-2-One (Intermediate 22):

Chemical Structure

[0334] Example W Synthesis of 1,4-dimethyl-5-(4-nitrophenyl)piperazin-2-one (Intermediate 23) Preparation of 1,4-dimethyl-5-(4-nitrophenyl)piperazin-2-one (Intermediate 23):

Chemical formula

[0335] Example X Synthesis of 1,4-dimethyl-6-(4-nitrophenyl)piperazin-2-one (Intermediate 24) Step 1: Preparation of tert-butyl (2-amino-2-(4-nitrophenyl)ethyl)carbamate (Intermediate 24-a): [Chem.] A solution of tert-butyl N-[2-(4-nitrophenyl)-2-oxoethyl]carbamate (20.00 g, 71.357 mmol, 1.00 equiv) in MeOH (400.00 mL) was added with NH 4 OAc (14.00 g, 181.624 mmol, 2.55 equiv) and NaBH 3 CN (110.00 g, 1750.422 mmol, 24.53 equiv) at 0 °C. The resulting mixture was stirred at 70 °C overnight, cooled to room temperature, adjusted to pH 8 with saturated NH 3 H 2 O, and extracted twice with CH 2 Cl 2 (1 L). The combined organic layers were washed twice with brine (1 L), dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, purified by silica gel column chromatography, eluted with MeOH / EtOAc (1:20), and 6.7 g of tert-butyl N-[2-amino-2-(4-nitrophenyl)ethyl]carbamate (33.38%) was obtained as a brown oil, and 2.8 g of tert-butyl (2-hydroxy-2-(4-nitrophenyl)ethyl)carbamate was obtained as a brown solid. LCMS-APCI(POS.) m / z: 226 (M+H-56) + .

[0336] Step 2: Preparation of 1-(4-nitrophenyl)ethane-1,2-diamine (Intermediate 24-b): [Chem.] HCl (gas) in 1,4-dioxane (30.00 mL) was added to a solution of tert-butyl N-[2-amino-2-(4-nitrophenyl)ethyl]carbamate (4.60 g, 16.371 mmol, 1.00 equiv) in DCM (40 mL). The resulting mixture was stirred at room temperature for 3 h, adjusted to pH 13 - 14 with NaOH(aq), and extracted twice with DCM:MeOH (10:1, 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2 SO 4 It was dried with SO, concentrated under reduced pressure, and 2.3 g of 1-(4-nitrophenyl)ethane-1,2-diamine was obtained as a light brown solid. LCMS-APCI(POS.) m / z: 182(M+H) + 。

[0337] Step 3: Preparation of 1-(4-nitrophenyl)ethane-1,2-diamine (Intermediate 24-c):

Chemical formula

[0338] Step 4: Preparation of tert-butyl 3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 24-d):

Chemical formula

[0339] Step 5: Preparation of tert-butyl 4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (Intermediate 24-e): [Chemical formula] To a solution of tert-butyl 3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (1.10 g, 3.423 mmol, 1.00 equiv alent) in DMF (25.00 mL) was added Cs 2 CO 3 (2.20 g, 6.752 mmol, 1.97 equiv) and methyl iodide (534.48 mg, 3.766 mmol, 1.10 equiv). The resulting mixture was stirred at room temperature for 2 h and extracted twice with EtOAc (30 mL). The combined organic layers were washed twice with brine (30 mL) and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EtOAc (1:4) to give 530 mg of tert-butyl-4-methyl-3-(4-nitrophenyl)-5-oxopiperazine-1-carboxylate (46.17%) as a yellow semi-solid. LCMS-APCI(POS.) m / z: 300 (M+H-56) + .

[0340] Step 6: Preparation of 1-methyl-6-(4-nitrophenyl)piperazin-2-one hydrochloride (Intermediate 24-f):

Chemical formula

[0341] Step 7: 1,4-Dimethyl-6-(4-nitrophenyl)piperazin-2-one (Intermediate 24):

Chemical formula

[0342] Example Y Synthesis of 4-(2-fluoro-4-nitrobenzyl)-1-methylpiperazin-2-one (Intermediates 25.1 - 25.2) Preparation of 4-(2-fluoro-4-nitrobenzyl)-1-methylpiperazin-2-one (Intermediate 25.1): [Chemical formula] To a solution of 2-fluoro-4-nitrobenzaldehyde (200.00 mg, 1.183 mmol, 1.00 equiv) in MeOH (5.00 mL) was added 1-methylpiperazin-2-one (202.00 mg, 1.770 mmol, 1.50 equiv). After stirring at room temperature for 30 minutes, AcOH (142.00 mg, 2.365 mmol, 2.00 equiv) and NaBH 3 CN (151.00 mg, 2.403 mmol, 2.03 equiv) were added to the mixture. The resulting mixture was stirred at room temperature overnight, and NH 3 .H 2 O was used to adjust the pH to 8, and the mixture was concentrated under vacuum and then purified by C18 column chromatography, eluting with water (0.05% NH 4 HCO 3 ) / ACN (2:1) to give 80 mg of 4-[(2-fluoro-4-nitrophenyl)methyl]-1-methylpiperazin-2-one (25.31%) as a yellow oil. LCMS-APCI(POS.) m / z: 268 (M+H) + .

[0343] Intermediate 25.2 was prepared in the same manner as Intermediate 25.1.

Table 15

[0344] Example Z Synthesis of 4-methyl-1-(1-(4-nitrophenyl)ethyl)piperazin-2-one (Intermediate 26) Step 1: Preparation of tert-butylmethyl(2-((1-(4-nitrophenyl)ethyl)amino)ethyl)carbamate (Intermediate 26-a): [Chemical formula] PNAP (2.27 g, 13.774 mmol, 1.2 equiv) and tert-butyl N-(2-aminoethyl)-N-methylcarbamate (2.00 g, 11.478 mmol, 1.00 equiv) in a stirred solution of MeOH (30 mL) at 0 °C was added NaBH 3 CN (1.4 4 g, 22.956 mmol, 2 equiv) and AcOH (1.38 g, 22.956 mmol, 2 equiv). The resulting mixture was stirred at room temperature overnight and adjusted to pH 8 with saturated NH 4 .H 2 O (aqueous solution), and extracted twice with EtOAc (50 mL). The combined organic layers were washed twice with water (50 mL), dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, purified by silica gel column chromatography, and 2.8 g (75.43%) of tert-butyl N-methyl-N-(2-[[1-(4-nitrophenyl)ethyl]amino]ethyl)carbamate was obtained as a pale yellow oil. LCMS-APCI (POS.) m / z: 268 (M+H-56) + .

[0345] Step 2: Preparation of tert-butyl (2-(2-chloro-N-(1-(4-nitrophenyl)ethyl)acetamido)ethyl)(methyl)carbamate (Intermediate 24-b):

Chemical formula

[0346] Step 3: Preparation of 2-chloro-N-(2-(methylamino)ethyl)-N-(1-(4-nitrophenyl)ethyl)acetamide hydrochloride (Intermediate 26-c):

Chemical formula

[0347] Step 4: Preparation of 4-methyl-1-(1-(4-nitrophenyl)ethyl)piperazin-2 -one (Intermediate 26):

Chemical formula

[0348] Example AA Synthesis of 1-(4-chlorobenzyl)-3-(4-((methyl(2-oxopyrrolidin-3-yl)amino)methyl)phenyl)urea (Intermediates 27.1 - 27.4) Step 1: Preparation of phenyl(4-formylphenyl)carbamate (Intermediate 27-a): [Chemical formula] To a stirred solution of 4-aminobenzaldehyde (2.00 g, 16.510 mmol, 1.00 equivalent) in THF (40.00 mL) at 0 °C was added a solution of K 2 CO 3 (4.56 g, 32.994 mmol, 2.00 equivalents) in H2O (10.00 mL), and phenyl chloroformate (3.87 g, 24.717 mmol, 1.50 equivalents) was added dropwise over 10 minutes. The resulting mixture was stirred at room temperature for 1 hour and extracted twice with EtOAc (50 mL). The combined organic layers were washed twice with brine (50 mL), dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give 1.9 g of phenyl N-(4-formylphenyl)carbamate (84.41%) as yellow. LCMS-APCI(POS.) m / z: 242 (M+H) + .

[0349] Step 2: Preparation of phenyl(4-(((2-oxopyrrolidin-3-yl)amino)methyl)phenyl)carbamate (Intermediate 27-b): [Chemical formula] To a stirred solution of phenyl N-(4-formylphenyl)carbamate (600.00 mg, 2.487 mmol, 1.00 eq) in DCE (10.00 mL), 3-aminopyrrolidin-2-one (508.00 mg, 5.074 mmol, 2.04 eq), STAB (1056.00 mg, 4.983 mmol, 2.00 eq) and AcOH (299.00 mg, 4.979 mmol, 2.00 eq) were added. The resulting mixture was stirred at room temperature overnight and extracted twice with EtOAc (20 mL). The combined organic layers were washed twice with brine (20 mL), dried over anhydrous MgSO4, concentrated under reduced pressure and purified by silica gel column chromatography, eluting with CH 2 Cl 2 / MeOH (12:1) to afford 415 mg of phenyl N-(4-[[(2-oxopyrrolidin-3-yl)amino]methyl]phenyl)carbamate (46.87%) as an off-white foam. LCMS-APCI(POS.) m / z: 326 (M+H) + .

[0350] Step 3: Preparation of phenyl (4-(((methyl(2-oxopyrrolidin-3-yl)amino)methyl)phenyl)carbamate (Intermediate 27-c):

Chemical Structure

[0351] Step 4: Preparation of 1-(4-chlorobenzyl)-3-(4-((methyl(2-oxopyrrolidin-3-yl)amino)methyl)phenyl)urea (Intermediate 27):

Chem.

[0352] Intermediates 27.2 - 27.4 were prepared in a similar manner to Intermediate 27.1.

Table 16

[0353] Example BB Synthesis of 5-(4-Nitrophenyl)oxazolidin-2-one (Intermediate 28) Step 1: Preparation of tert-Butyl (2-Hydroxy-2-(4-nitrophenyl)ethyl)carbamate (Intermediate 28-a):

Chemical formula

[0354] Step 2: Preparation of 2-Amino-1-(4-nitrophenyl)ethan-1-ol Hydrochloride (Intermediate 28-b):

Chemical formula

[0355] Step 3: Preparation of 5-(4-nitrophenyl)oxazolidin-2-one (Intermediate 28):

Chemical formula

[0356] Example CC 4-(2-Fluoro-4-nitrobenzyl)-1-methylpiperazin-2-one (Synthesis of Intermediate 29) Preparation of 3-methyl-5-(4-nitrophenyl)oxazolidin-2-one (Intermediate 29):

Chemical formula

[0357] Example DD Synthesis of 5-(4-nitrophenyl)oxazolidin-2-one (Intermediates 30.1 - 30.2) Step 1: Preparation of methyl 4-oxo-4-(pyridin-3-yl)butanoate (Intermediate 30-a): [Chemical formula] To a solution of 3-pyridinecarboxaldehyde (5.00 g, 46.7 mmol, 1.00 eq) and methyl chloride (4.80 g, 56.0 mmol, 1.20 eq) in EtOH (50 mL), Et 3 N (9.40 g, 93 mmol, 2.00 eq) and 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride (1.26 g, 4.67 mmol, 0.10 eq) were added under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C overnight under a nitrogen atmosphere, cooled to room temperature, concentrated under reduced pressure, and extracted twice with EtOAc (100 mL). The combined organic layers were washed with brine (100 mL), and anhydrous Na 2 SO 4It was dried, concentrated under reduced pressure, purified by silica gel column chromatography, eluted with PE / EtOAc (4:1), and 2.19 g of methyl 4-oxo-4-(pyridin-3-yl)butanoate was obtained as a yellow solid. LCMS-APCI(POS.) m / z: 194 (M+H) + 。

[0358] Step 2: Preparation of 1-(4-nitrobenzyl)-5-(pyridin-3-yl)pyrrolidin-2-one (Intermediate 30.1):

Chemical formula

[0359] Intermediate 30.2 was prepared in the same manner as Intermediate 30.1.

Table 17

[0360] Example EE Synthesis of 1-(1-(4-nitrophenyl)ethyl)piperidin-2-one (Intermediate 31) [Chemical formula] To a stirred mixture of methyl 5-aminopentanoate hydrochloride (1.00 g, 0.60 mmol, 1.00 eq) and PNAP (1.300 g, 0.79 mmol, 1.32 eq) in DCE (10.00 mL) were added STAB (2.500 g, 1.18 mmol, 1.98 eq) and AcOH (700 mg, 1.17 mmol, 1.95 eq). The resulting mixture was stirred at room temperature for 2 days and adjusted to pH 8 with saturated NaHCO 3 (aqueous solution), and extracted twice with EtOAc (20 mL). The combined organic layers were washed twice with brine (20 mL) and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure, purified by silica gel column chromatography, eluted with PE / EtOAc (1:8) to obtain 1 g of 1-[1-(4-nitrophenyl)ethyl]piperidin-2-one (67.52%) as a yellow solid. LCMS-APCI(POS.) m / z: 249 (M+H) + .

[0361] Example FF Synthesis of 1-(4-(1,1-dioxidothiomorpholin-3-yl)phenyl)-3-(4-methoxybenzyl)urea (Intermediate 32) Step 1: Preparation of tert-butyl (2-((2-(4-nitrophenyl)-2-oxoethyl)thio)ethyl)carbamate (Intermediate 32-a): [Chemical formula] 2-Bromo-1-(4-nitrophenyl)ethanone in ACN (80.00 mL) at 0 °C To a stirred solution of [[[ID=]], 2 SO 4 dried over anhydrous Na + .

[0362] Step 2: Preparation of tert-butyl (2-((2-(4-nitrophenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (Intermediate 32-b):

Chemical formula

[0363] Step 3: Preparation of tert-butyl (2-((2-(4-aminophenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (Intermediate 32-c):

Chemical formula

[0364] Step 4: Preparation of tert-butyl (2-((2-oxo-2-(4-((phenoxycarbonyl)amino)phenyl)ethyl)sulfonyl)ethyl)carbamate (Intermediate 32-d):

Chemical formula

[0365] Step 5: Preparation of tert-butyl (2-((2-(4-(3-(4-methoxybenzyl)ureido)phenyl)-2-oxoethyl)sulfonyl)ethyl)carbamate (Intermediate 32-e):

Chemical Structure

[0366] Step 6: Preparation of 1-(4-(1,1-dioxidothiomorpholin-3-yl)phenyl)-3-(4-methoxybenzyl)urea (Intermediate 32):

Chemical formula

[0367] Example GG Synthesis of 1-(4-(1,1-dioxidothiomorpholin-2-yl)phenyl)-3-(4-methoxybenzyl)urea (Intermediate 33) Step 1: Preparation of methyl 2-bromo-2-(4-nitrophenyl)acetate (Intermediate 33-a): [Chemical Structure] CCl 4 To a stirred solution of methyl 2-(4-nitrophenyl)acetate (5 g, 25.618 mmol, 1.00 equivalent) and AIBN (0.21 g, 1.281 mmol, 0.05 equivalent) in CCl 18 (50 mL), NBS (6.84 g, 38.427 mmol, 1.5 equivalents) was added. The resulting mixture was stirred at 80 °C overnight, cooled to room temperature, water (100 mL) was added, and the mixture was extracted twice with CH2Cl2 (50 mL). The combined organic layers were washed twice with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography, eluting with water (0.05%, NH4HCO3) / ACN (1:1) to obtain 4.1 g (58.39%) of methyl 2-bromo-2-(4-nitrophenyl)acetate as a yellow oil. LCMS-APCI(POS.) m / z: 274 (M + H) + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.34 - 8.19 (m, 2H), 7.89 - 7.78 (m, 2H), 6.17 (s, 1H), 3.76 (s, 3H).

[0368] Step 2: Preparation of 2-(4-nitrophenyl)thiomorpholin-3-one (Intermediate 33-b): [Chemical Structure] To a stirred solution of methyl 2-bromo-2-(4-nitrophenyl)acetate (3 g, 10.946 mmol, 1.00 equivalent) in EtOH (30 mL), cysteamine hydrochloride (1.37 g, 12.041 mmol, 1.1 equivalents) and K 2 CO 3(3.33 g, 24.081 mmol, 2.2 eq) was added. The resulting mixture was stirred at room temperature overnight, water (50 mL) was added, and the mixture was extracted twice with EA (100 mL). The combined organic layers were washed twice with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, purified by silica gel column chromatography, eluted with PE / EA (1:9), and 1.4 g of 53.68% 2-(4-nitrophenyl)thiomorpholin-3-one was obtained as a yellow solid. LCMS-APCI(POS.) m / z: 239 (M+H) + .

[0369] Step 3: Preparation of 2-(4-nitrophenyl)thiomorpholine (Intermediate 33-c): [Chemical formula] To a stirred solution of 2-(4-nitrophenyl)thiomorpholin-3-one (1.4 g, 5.876 mmol, 1.00 eq) in THF (15 mL), BH 3 -Me 2 S (2.94 mL, 29.380 mmol, 5 eq, 2 mol / L) was added. The resulting mixture was stirred at 60 °C for 1 h, concentrated under reduced pressure, HCl (15 mL, 4 N) was added to the residue, and the mixture was stirred at 60 °C for an additional 30 min. The mixture was adjusted to pH 8 with saturated NaHCO 3 (aqueous solution), concentrated under reduced pressure, purified by C 18 column chromatography, eluted with water (0.05% NH 4 HCO 3 ) / ACN (2:1), and 590 mg (44.77%) of 2-(4-nitrophenyl)thiomorpholine was obtained as a red oil. LCMS-APCI(POS.) m / z: 225 (M+H) + .

[0370] Step 4: Preparation of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate (Intermediate 33-d): [Chemical formula] A stirred solution of 2-(4-nitrophenyl)thiomorpholine (590 mg, 2.631 mmol, 1.00 equiv) and TEA (798.58 mg, 7.893 mmol, 3 equiv) in DCM (6 mL) was added to (Boc) 2 O (1148.26 mg, 5.262 mmol, 2 equiv). The resulting mixture was stirred at room temperature overnight, concentrated under reduced pressure, and purified by silica gel column chromatography, eluting with PE / EA (3:1) to give 400 mg (46.87%) of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.33 - 8.17 (m, 2H), 7.77 - 7.66 (m, 2H), 7.71 - 7.54 (m, 1H), 6.92 (s, 1H), 4.34 - 4.09 (m, 3H), 3.20 (ddd, J = 13.6, 10.1, 3.2 Hz, 1H), 2.88 - 2.72 (m, 1H), 2.77 - 2.65 (m, 1H), 2.45 (s, 1H), 1.74 - 1.57 (m, 1H), 1.57 - 1.45 (m, 1H), 1.43 (s, 2H), 1.40 (s, 8H), 1.29 (s, 2H), 1.25 (d, J = 6.4 Hz, 3H), 1.15 (s, 1H), 0.99 - 0.76 (m, 2H).

[0371] Step 5: Preparation of tert-butyl 2-(4-nitrophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (Intermediate 33-e):

Chemical Structure

[0372] Step 6: Preparation of tert-butyl 2-(4-aminophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (Intermediate 33-f): [Chemical formula] To a stirred solution of tert-butyl 2-(4-nitrophenyl)-1,1-dioxo-1λ6-thiomorpholine-4-carboxylate (420 mg, 1.178 mmol, 1.00 equivalent) in i-PrOH (5 mL) was added Pd / C (10% Pd, moistened with 50% water, 210 mg). The resulting mixture was stirred under H2 at room temperature for 2 hours, filtered to remove the solid, and the filtrate was concentrated under reduced pressure to obtain 380 mg of tert-butyl 2-(4-aminophenyl)thiomorpholine-4-carboxylate 1,1-dioxide as a yellow solid. LCMS-APCI(POS.) m / z: 327 (M+H) + .

[0373] Step 7: Preparation of tert-butyl 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)thiomorpholine-4-carboxylate 1,1-dioxide (Intermediate 33-g): [Chemical formula] To a stirred solution of tert-butyl 2-(4-aminophenyl)thiomorpholine-4-carboxylate 1,1-dioxide (420 mg, 1.178 mmol, 1.00 equivalent) in i-PrOH (5 mL) was added Pd / C (10% Pd, moistened with 50% water, 210 mg). The resulting mixture was under H 2Stir at room temperature for 2 hours, filter to remove solids, and concentrate the filtrate under reduced pressure to obtain 380 mg of tert-butyl 2-(4-(3-(4-methoxybenzyl)ureido)phenyl)thiomorpholine-4-carboxylate 1,1-dioxide as a yellow solid. LCMS-APCI(POS.) m / z: 327 (M+H) + 。

[0374] Step 8: Preparation of 1-(4-(1,1-dioxidothiomorpholin-2-yl)phenyl)-3-(4-methoxybenzyl)urea (Intermediate 33):

Chemical Structure

[0375] Example HH Synthesis of N-methyl-N-(4-nitrobenzyl)acetamide (Intermediates 34.1 - 34.2) Preparation of N-methyl-N-(4-nitrobenzyl)acetamide (Intermediate 34):

Chemical Structure

[0376] Intermediate 30.2 was prepared in the same manner as Intermediate 30.1.

Table 18

[0377] Example II Synthesis of 1-(4-chlorobenzyl)-3-(4-(1-(methylsulfonyl)pyrrolidin-3-yl)phenyl)urea (Intermediate 35): Step 1: Preparation of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (Intermediate 35-a):

Chemical formula

[0378] Step 2: Preparation of tert-butyl 3-(4-nitrophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (Intermediate 35-b):

Chemical formula

[0379] Step 3: Preparation of tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (Intermediate 35-c):

Chemical formula

[0380] Step 4: Preparation of tert-butyl 3-(4-(3-(4-chlorobenzyl)ureido)phenyl)pyrrolidine-1-carboxylate (Intermediate 35-d):

Chemical formula

[0381] Step 5: Preparation of 1-(4-chlorobenzyl)-3-(4-(pyrrolidin-3-yl)phenyl)urea (Intermediate 35-e):

Chemical formula

[0382] Step 6: Preparation of 1-(4-chlorobenzyl)-3-(4-(1-(methylsulfonyl)pyrrolidin-3-yl)phenyl)urea (Intermediate 35):

Chemical Structure

[0383] Intermediate 35.2 was prepared in the same manner as Intermediate 35.1.

Table 19

[0384] Example JJ Synthesis of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonyl chloride (Intermediate 36): Step 1: Preparation of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonic acid (Intermediate 36-a):

Chemical formula

[0385] Step 2: Preparation of 4-(3-(4-chlorobenzyl)ureido)benzenesulfonyl chloride (Intermediate 36):

Chemical formula

[0386] Example KK Synthesis of 4-(2-oxaspiro[3.5]nonan-7-yl)aniline (Intermediate 37): Step 1: Preparation of 2-oxaspiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (Intermediate 37-a):​​ [Chemical formula] Diisopropylamine (318 mg, 3.14 mmol, 1.1 eq) and THF (6 mL) were placed in a flame-dried flask. After cooling to -30 °C, an n-BuLi solution (1.32 mL, 3.13 mmol, 1.09 eq) was added dropwise, and the mixture was slowly warmed to -10 °C over 15 minutes. Next, after cooling this to -78 °C, a THF solution of 2-oxaspiro[3.5]nonan-7-one (400 mg, 2.85 mmol, 1.0 eq) was added dropwise. After maintaining deprotonation at -78 °C for 15 minutes, it was further removed from the bath for 15 minutes. Next, the flask was recooled to -78 °C, and a THF solution of PhNTf 2 (1.12 g, 3.14 mmol, 1.1 eq) was slowly added, and the reaction was maintained at -78 °C for 15 minutes and outside the bath for 1 hour again. When completed, a semi-saturated NH 4 Cl solution was added, and the aqueous phase was extracted with EtOAc (50 mL * 3). The combined organic phases were dried (MgSO 4 )), filtered, and concentrated to obtain crude vinyl triflate, which was used directly in the next step. LCMS-ESI(POS.) m / z: 273.1 (M+H) + .

[0387] Step 2: Preparation of 7-(4-nitrophenyl)-2-oxaspiro[3.5]non-6-ene (Intermediate 37-b). [Chemical formula] A solution of 2-oxaspiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (2.85 mmol, 1.0 eq) and (4-nitrophenyl)boronic acid (714 mg, 4.28 mmol, 1.5 eq) in dioxane / H 2 O (10 mL, 3:1) was bubbled with N 2 for 10 minutes, then K 2 CO 3 (794 mg, 5.71 mmol, 2.0 eq) and Pd(dppf)Cl 2(209 mg, 0.285 mmol, 0.1 eq) was added. The mixture was stirred at 75 °C for 15 h. Upon completion, half-saturated NH 4 Cl solution was added and the aqueous phase was extracted with EtOAc (10 mL * 2). The combined organic phases were dried (MgSO 4 ), filtered, concentrated, and purified by flash column chromatography (silica , hexane / EtOAc = 20 / 1 -> 3 / 1) to afford the desired product as a yellowish waxy solid (512 mg, 73%). LCMS-ESI(POS.) m / z: 246.1 (M+H) + . 1 H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 6.24 (tt, J = 3.8, 1.6 Hz, 1H), 4.53 (d, J = 5.8 Hz, 2H), 4.47 (d, J = 5.8 Hz, 2H), 2.61 (dt, J = 4.4, 2.5 Hz, 2H), 2.52 (tq, J = 6.4, 2.1 Hz, 2H), 2.10 (t, J = 6.3 Hz, 2H).

[0388] Step 3: Preparation of 4-(2-oxospiro[3.5]nonan-7-yl)aniline (Intermediate 37):

Chemical Structure

[0389] Example LL Synthesis of 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (Intermediate 38): Step 1: Preparation of 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (Intermediate 38): [Chemical formula] CH 2 Cl 2 To a solution of 2-(4-aminophenyl)ethan-1-ol (1.37 g, 10.0 mmol, 1.0 equivalent) in CH 2 Cl 2 (20 mL) was slowly added p-chlorobenzyl isocyanate (1.70 g, 10.2 mmol, 1.02 equivalents) at 0 °C. The mixture was stirred vigorously at 23 °C for 1 h. Upon completion, the precipitate was filtered and washed with cold CH 2 Cl 2 (10 mL) and Et 2 O (10 mL) to afford 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (2.8 g, 92%) as an off-white solid. LCMS-ESI(POS.) m / z: 305.10 (M+H) 2 Cl 2 and Et 2 O (10 mL) to give 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (2.8 g, 92%) as an off-white solid. LCMS-ESI(POS.) m / z: 305.10 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.59 (t, J = 6.0 Hz, 1H), 4.58 (s, 1H), 4.27 (d, J = 6.0 Hz, 2H), 3.54( t, J = 7.2 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H).

[0390] Example MM Synthesis of 1-(4-(2-bromoethyl)phenyl)-3-(4-chlorobenzyl)urea (Intermediate 39): Preparation of 1-(4-(2-bromoethyl)phenyl)-3-(4-chlorobenzyl)urea (Intermediate 39): [Chemical formula] THF / CH 2 Cl 2 (20 mL, 1:1) of a solution of 1-(4-chlorobenzyl)-3-(4-(2-hydroxyethyl)phenyl)urea (Intermediate 38, 500 mg, 1.64 mmol, 1.0 equiv) was added with PPh 3 (516 mg, 1.97 mmol, 1.2 equiv) and imidazole (167 mg, 2.46 mmol, 2.0 equiv). Next, N-bromosuccinimide (350 mg, 1.97 mmol, 1.2 equiv) was added at 0 °C. The reaction solution was stirred at 23 °C for 1 hour. Upon completion, a mixed solution of NaHCO 3 and Na 2 S 2 O 3 was added to quench the reaction. The aqueous phase was extracted with CH 2 Cl 2 (5 mL). The combined organic phases were washed with brine, dried (MgSO 4 ), filtered, concentrated, and purified by column chromatography (silica, hexane / EtOAc, 20:1 -> 0:1) to obtain 1-(4-(2-bromoethyl)phenyl)-3-(4-chlorobenzyl)urea (200 mg, 33%) as a white solid. LCMS-ESI(POS.) m / z: 367.00 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 5.6 Hz, 2H), 7.31 (d, J = 5.6 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 6.63 (t, J = 6.0 Hz, 1H), 4.28 (d, J = 6.0 Hz, 2H), 3.67 (t, J = 7.3 Hz, 2H), 3.03 (t, J = 7.3 Hz, 2H).

[0391] Example 1 Synthesis of ethyl 2-[4-({[(4-methoxyphenyl)methyl]amino}carbonylamino)phenyl]acetate (Compound 331)

Chemical Structure

Claims

[Claim 1] The invention described in the specification.

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