Compounds, compositions, and methods

Abstract

This disclosure provides compounds for modulating calcitonin receptor and / or amyrin receptor activity, as well as pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating calcitonin receptor and / or amyrin receptor-related diseases or disorders are also provided. TIFF2026525766000421.tif38170

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to international patent applications PCT / CN2023 / 107247 filed on 13 July 2023, international patent applications PCT / CN2024 / 076848 filed on 8 February 2024, and international patent applications PCT / CN2024 / 097845 filed on 6 June 2024, each of which is incorporated in whole by reference.

[0002] This disclosure provides compounds for modulating calcitonin receptor and / or amyrin receptor activity, as well as pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating calcitonin receptor and / or amyrin receptor-related diseases, disorders, and conditions are also provided. [Background technology]

[0003] Calcitonin and amylin are hormones that exert effects on the human body by interacting with receptors within the same family. Calcitonin derived from thyroid C cells is known for its inhibitory effect on osteoclasts. Mammalian calcitonin promotes insulin sensitivity, while the more potent calcitonin extracted from salmon further suppresses gastric emptying, promotes gallbladder relaxation, increases energy expenditure, and induces satiety and weight loss. Studies have also shown that oral salmon calcitonin (sCT) exerts an insulin-sensitizing effect to improve glucose metabolism in obesity and type 2 diabetes. European Journal of Pharmacology, 2024, 737(7): 91-96.

[0004] The amyrin receptor (AMYR) is a G protein-coupled receptor (GPCR) that responds to the peptide hormones amyrin and calcitonin. The amyrin receptor is a heterodimer containing the calcitonin receptor, a G protein-coupled receptor, and one of three receptor-modified proteins. Amyrin, primarily formed in pancreatic islet β-cells, is co-secreted with insulin in response to calorie intake. Patients with type 1 diabetes have lower baseline amyrin blood levels and a lack of amyrin response to calorie intake. Patients with type 2 diabetes who require insulin also have a reduced amyrin response to calorie intake, which may be related to the degree of β-cell damage. Key physiological functions of amyrin in maintaining glucose homeostasis include suppression of glucagon release in response to calorie intake, delay of gastric emptying rate, and stimulation of the satiety center in the brain to limit calorie intake.

[0005] Pramulintide, a synthetic amyrin analog, is an approved treatment for diabetes as an adjunct to mealtime insulin, promoting better glycemic control and a small but significant weight loss. AM833 (caglilintide), a novel long-acting acylated amyrin analog currently in clinical trials, acts as a non-selective amyrin receptor agonist. This amyrin receptor agonist may serve as an attractive new treatment for obesity, resulting in dose-dependent reduction in food intake and significant weight loss. J Obes Metab Syndr. 2021; 30(4): 320-325.

[0006] Therefore, amylin and / or calcitonin receptor modulators may be useful in treating various metabolic disorders, as well as in inducing weight loss. [Overview of the project]

[0007] This disclosure provides low-molecular-weight calcitonin and / or amyrin receptor modulators (e.g., amyrin receptor agonists), as well as pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating calcitonin receptor and / or amyrin receptor-related diseases or disorders are also provided. Activation of the calcitonin receptor has been shown to be important for blood glucose regulation in diabetes. This adds to the known metabolically beneficial roles of amyrin receptor activation. Journal of Pharmacology and Experimental Therapeutics, 2020, 374 (1)74-83.

[0008] This disclosure also provides pharmaceutical compositions comprising one or more compounds disclosed herein, or stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0009] This specification also provides pharmaceutical compositions comprising one or more compounds disclosed herein, or stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0010] Also provided herein are methods for treating or preventing calcitonin receptor and / or amyrin receptor-related diseases or disorders in subjects requiring such treatment, comprising administering to subjects requiring such treatment a therapeutically effective amount of one of the compounds disclosed herein (e.g., a compound of formula I or a subformula thereof, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition thereof. In some embodiments, the method further comprises administering to a patient a therapeutically effective amount of one or more additional therapies or therapeutic agents, including, but not limited to, antidiabetic agents, anti-obesity agents, weight-loss agents, GLP-1 receptor agonists, antiemetics, agents for treating non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or combinations thereof.

[0011] In some embodiments, calcitonin receptor and / or amyrin receptor-related diseases or disorders include bone disorders, metabolic disorders, pain, neurodegenerative diseases or disorders, cardiovascular diseases, or other diseases or disorders.

[0012] In some embodiments, calcitonin receptor and / or amyrin receptor-related diseases or disorders are bone disorders, including, but not limited to, osteoporosis, Paget's disease, hypercalcemia, Sudeck's atrophy, multiple fibrous dysplasia, intersemocostoclavicular ossification, osteogenesis imperfecta, osteopenia, periodontal disease or defects, osteolytic bone disease, metastatic bone disorders, or bone defects resulting from malignant tumors, autoimmune arthritis, fracture or breakage, or immobility or non-use.

[0013] In some embodiments, the calcitonin receptor and / or amyrin receptor-related disorder or impairment is pain, including, but not limited to, bone-related pain, phantom limb pain, general pain, hyperalgesia, or pain associated with diabetic neuropathy.

[0014] In some embodiments, calcitonin receptor and / or amyrin receptor-related diseases or disorders are neurodegenerative diseases or disorders, including but not limited to Alzheimer's disease.

[0015] In some embodiments, calcitonin receptor and / or amyrin receptor-related diseases or disorders are metabolic disorders, including but not limited to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, impaired glucose tolerance, obesity, syndrome X, or other diabetic complications.

[0016] In some embodiments, calcitonin receptor and / or amyrin receptor-related diseases or disorders include primary or secondary hyperthyroidism, endocrine disorders, conditions associated with gastric secretion suppression, gastrointestinal disorders, renal osteodystrophy, or male infertility. [Brief explanation of the drawing]

[0017] [Figure 1] Figure 1 illustrates the thermodynamic pathway used to calculate the relative binding free energies. The relative binding free energies were calculated using two different transformations. First, the free energy for converting ligand 1 to ligand 2 was determined in the solvent. Second, the free energy for converting ligand 1 to ligand 2 was determined while bound to the target. The difference between these two values ​​can be associated with the difference in the binding free energies of ligands 1 and 2.

[0018] [Figure 2] Figure 2 illustrates the thermodynamic factors involved in ligand binding to the target. The left side shows the contributions of ligand conformation and desolvation, while the right side shows the contributions of target conformation and desolvation.

[0019] [Figure 3] Figure 3 illustrates the relationship between the in vitro amyrin receptor cAMP assay I and the in silico computation assay for representative compounds described herein and other compounds with known activity in each of the assays described herein.

[0020] [Figure 4] Figure 4 illustrates the relationship between the in vitro calcitonin receptor (CTR) cAMP assay and the in silico computation assay for representative compounds described herein, as well as other compounds with known activity in each of the assays described herein. [Modes for carrying out the invention]

[0021] definition The following description provides exemplary embodiments of the technology. However, it should be recognized that such description is provided as an example of the embodiments and is not intended to limit the scope of the disclosure.

[0022] As used herein, the following words, phrases, and symbols are intended to have the meanings set forth below, unless otherwise indicated in the context in which they are used.

[0023] A dash ("-") that is not between two letters or symbols is used to indicate the bonding point of a substituent. For example, -C(O)NH2 is bonded via a carbon atom. Dashes at the beginning or end of a chemical group are a matter of convenience. Chemical groups may be drawn with or without one or more dashes without losing their usual meaning. Dashed or dashed lines drawn through lines in a structure indicate specific bonding points of a group. Unless chemically or structurally required, the order in which chemical groups are listed or named neither indicates nor implies directionality or stereochemistry.

[0024] Prefix “C” u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 The term "alkyl" indicates that an alkyl group has one to six carbon atoms.

[0025] References to values ​​or parameters in this specification that use the term "about" include (and describe) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In certain other embodiments, the term "about" includes ±1% of the indicated amount. The term "about X" also includes the description of "X". The singular forms "a" and "the" also include references to the plural form unless otherwise explicitly indicated in the context. Thus, for example, a reference to "the compound" includes multiple such compounds, and a reference to "the assay" includes one or more assays and their equivalents known to those skilled in the art.

[0026] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C 1-20 Alkyl), 1 to 12 carbon atoms (i.e., C 1-12 Alkyl), 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), 1 to 6 carbon atoms (i.e., C 1-6 Alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 Alkyl compounds include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When alkyl residues having a specific number of carbon atoms are named by their chemical name or specified by their molecular formula, all positional isomers having that number of carbon atoms may be included. For example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., (CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0027] "Alkenyl" contains at least one (e.g., 1 to 3, or 1) carbon-carbon double bond and has 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl), and refers to an alkyl group having such. Examples of alkenyl groups include, for example, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0028] "Alkynyl" contains at least one (e.g., 1 to 3, or 1) carbon-carbon triple bond and has 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl), and refers to an alkyl group having such. The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0029] Some commonly used alternative chemical names may be used. For example, divalent groups such as a divalent "alkyl" group and a divalent "aryl" group may be referred to as an "alkylene" group or an "alkylenyl" group, an "arylene" group or an "arylenyl" group, respectively.

[0030] "Alkoxy" refers to an "alkyl-O-" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0031] "Alkoxyalkyl" refers to an alkyl group as defined above, in which a hydrogen atom is substituted with an alkoxy group as defined herein.

[0032] "Haloalkyl" refers to an alkyl group, either unbranched or branched, as defined above, in which one or more hydrogen atoms (e.g., 1-6 or 1-3) are replaced by independently selected halo groups. For example, if a residue is substituted with two or more halogens, it may be referred to using a prefix corresponding to the number of halogenated moieties. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, which may or may not be the same halogen. Examples of haloalkyls include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0033] A "haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms (for example, 1 to 6, or 1 to 3) are replaced by independently selected halo groups.

[0034] "Haloalkoxyalkyl" refers to an alkyl group as defined above, in which a hydrogen atom is replaced with a haloalkoxy group as defined herein.

[0035] "Hydroxyalkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms (for example, 1 to 6, or 1 to 3) are replaced by hydroxyl groups.

[0036] "Cyanoalkyl" refers to an alkyl group as defined above, in which one or more (for example, 1 to 6 or 1 to 3) hydrogen atoms are replaced by cyano atoms.

[0037] "Alkylthio" refers to the "alkyl-S-" group.

[0038] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be substituted as appropriate as defined herein. Examples of acyls include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0039] "Amide" is the group -C(O)NR y R z The "C-amide" group and the group -NR refer to the "C-amide" group. y C(O)R z This refers to both of the "N-amide" groups, and here R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be appropriately substituted as defined herein, or R y and R z These together form cycloalkyl or heterocyclines, which may be substituted as appropriate, as defined herein.

[0040] "Amino" is the base -NR y R z This refers to R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be appropriately substituted as defined herein.

[0041] "Amidino" is -C(NR y )(NR z 2) refers to, and here R y and R zThese are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be appropriately substituted as defined herein.

[0042] "Aryl" refers to an aromatic carbocyclic group having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) system including a condensed system. As used herein, aryl refers to a ring carbon atom (i.e., C) with 6 to 20 carbon atoms. 6-20 aryl), 6-12 carbocyclic atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 They have an aryl group. Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthuryl. However, aryls do not include, or overlap in any way with, heteroaryls as defined below. When one or more aryl groups are condensed with a heteroaryl, the resulting ring system is heteroaryl regardless of the bonding site. When one or more aryl groups are condensed with a heterocyclyl, the resulting ring system is heterocyclyl regardless of the bonding site. When one or more aryl groups are condensed with a cycloalkyl, the resulting ring system is cycloalkyl regardless of the bonding site.

[0043] "Carbamoyl" is based on the base -OC(O)NR y R z The "O-carbamoyl" group and the group -NR refer to these. y C(O)OR z This refers to both of the "N-carbamoyl" groups, where R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be appropriately substituted as defined herein.

[0044] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR xThis refers to both, where Rx is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be substituted as appropriate as defined herein.

[0045] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having monocyclic or polycyclic structures including condensed, crosslinked, and spirocyclic systems. The term "cycloalkyl" refers to a cycloalkenyl group (i.e., a cyclic group having at least one double bond) and at least one sp 3 It comprises a carbon-carbon fused ring system (i.e., at least one non-aromatic ring) having carbon atoms. As used herein, cycloalkyl refers to a ring with 3 to 20 carbon atoms (i.e., C 3-20 Cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl, or a ring of 3-6 carbon atoms (i.e., C 3-6 They have cycloalkyl groups. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, dekalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, etc. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring regardless of its bond to the rest of the molecule (e.g., 2,3-dihydro-1H-indenyl). In addition, cycloalkyl also includes "spirocycloalkyl" when there are two positions for substitution on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0046] "Cycloalkylalkyl" refers to an alkyl group as defined above, in which a hydrogen atom is replaced with a cycloalkyl group as defined herein.

[0047] "Imino" is base-C(NR y )R z This refers to R y and R z Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, which may be substituted as appropriate as defined herein.

[0048] "Imide" is the group -C(O)NR y C(O)R z or -N(C(O)R y )C(O)R z This refers to R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, which may each be appropriately substituted as defined herein, or R y and R z Together, they form a heterocycline, which may be appropriately substituted as defined herein.

[0049] "Halogen" or "halo" refers to atoms that occupy Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodine.

[0050] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatomic groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatomic groups. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be substituted as appropriate. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be substituted as appropriate. As used herein, a heteroalkyl group comprises 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0051] "Heteroalkylene" refers to a divalent heteroalkyl group. A "heteroalkylene" group must have at least one carbon and at least one heteroatomic group in its chain. The term "heteroalkylene" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatomic groups. Heteroatomic groups include -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc. are included, but are not limited to these, and here R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be substituted as appropriate as defined herein. Examples of heteroalkylene groups include, for example, -CH2OCH2, -CH(CH3)OCH2, -CH2CH2OCH2, -OCH2, -CH(CH3)O, -CH2CH2O, -CH2CH2OCH2CH2OCH2, -CH2CH2OCH2CH2O, -CH2SCH2, -CH(CH3)SCH2, -CH2CH2SCH2, -CH2CH2SCH2CH2CH2, -SCH2, -CH(CH3)S, -CH2CH2S, -CH2CH2SCH2CH2S, -CH2S(O)2CH2, -CH(CH3)S(O)2CH2, -CH2CH2S(O)2CH2, -CH2CH2S(O)2CH2CH2OCH2, -CH2NR y CH2, -CH(CH3)NR y CH2, -CH2CH2NR y CH2, -CH2CH2NR y CH2 CH2NR y CH2, etc. (R here) y (These are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be substituted as appropriate as defined herein). As used herein, a heteroalkylene comprises 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. As used herein, the term "heteroalkylene" does not include groups such as amides or other functional groups where an oxo exists on one or more carbon atoms.

[0052] "Heteroaryl" refers to an aromatic group having a monocyclic or multiple fused rings and having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl has 1 to 20 ring carbon atoms (i.e., C 1-20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12Heteroaryls), or 3 to 8 carbon ring atoms (i.e., C 3-8The heteroaryl comprises a heteroaryl and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. In some examples, the heteroaryl comprises a 5 to 10-membered ring system, a 5 to 7-membered ring system, or a 5 to 6-membered ring system, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, sinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, This includes isoxazolyl, naphthilidinyl, oxadiazolyl, oxazolyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl may be bonded via any of the rings in the fused system. Any aromatic ring having a monocyclic or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its bond to the rest of the molecule (i.e., bond via any one of the fused rings). Heteroaryls do not encompass or overlap in any way with the aryls defined above.

[0053] A "heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, condensed heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyls may be monocyclic or polycyclic, where the polycyclic may be condensed, bridged, or spirocyclic, and may also contain one or more (e.g., 1 to 3) oxo(=O)(e.g., -C(O)-, -S(O)-, -S(O)2-, or -P(O)-) or N-oxide(-O-) moieties. Any non-aromatic ring or condensed ring system containing at least one heteroatom and one non-aromatic ring is considered a heterocyclyl, regardless of its bonding to the rest of the molecule. For example, condensed ring systems such as 6,7-dihydro-5H-cyclopenta[b]pyridinyl, decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8-tetrahydroquinazolinyl are heterocyclyls regardless of the bonding (i.e., they may be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be condensed into a cycloalkyl, aryl, or heteroaryl ring regardless of bonding to the rest of the molecule. As used herein, a heterocyclyl is a ring containing 2 to 20 carbon atoms (i.e., C 2-20 Heterocyclines), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocycline), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclyl), 2-8 ring carbon atoms (i.e., C 2-8 Heterocyclines), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclyl), 3-8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3-6 ring carbon atoms (i.e., C 3-6A heterocyclyl group has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b]13 dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxynyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl-34 dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolidinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, This includes octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxylanil, oxetanyl, phenothiazinyl, phenoxadinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianil, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" when there are two positions for substitution on the same carbon atom. Examples of spiroheterocyclyl rings include, for example, bicyclo and tricyclo ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be linked via any of the rings in the condensation system.

[0054] "Sulfonyl" is the group -S(O)2R y This refers to R yThe elements are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be substituted as appropriate as defined herein. Examples of sulfonyls include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0055] "Sulfinyl" is the group S(O)R y This refers to Ry, where Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be substituted as appropriate as defined herein.

[0056] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and that the description includes both cases in which such event or situation occurs and cases in which it does not occur. The term "may be substituted as appropriate" means that one or more hydrogen atoms (e.g., 1-5 or 1-3) on the specified atom or group may or may not be replaced with non-hydrogen parts.

[0057] As used herein, the term “compound” is intended to include any or all stereoisomers, geometric isomers, tautomers, and isotopic-enriched analogs (e.g., deuterated analogs) of the structure depicted. Unless otherwise specified, any compound identified herein by name or structure as a particular tautomer is intended to include other tautomers.

[0058] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with its imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between tautomers, it is understood by those skilled in the art that the compound includes both tautomers of the amide and imidic acid. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0059] Any compound or structure provided herein is intended to represent both the unlabeled form and the isotopically labeled form of the compound. Compounds of these forms may also be referred to as "isotopically enriched analogs." An isotopically labeled compound has the structure depicted herein except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, namely, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I respectively. Various isotopically labeled compounds of the present disclosure incorporate radioactive isotopes such as 3 H and 14 C. Such isotopically labeled compounds may be useful in metabolic studies, kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) (including tissue distribution assays of drugs or substrates), or in the radiotherapy of patients.

[0060] The term “isotope-enriched analog” includes “deuterated analogs” of the compounds described herein, in which one or more hydrogens are replaced by deuterium (e.g., hydrogen on a carbon atom). Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens are replaced by deuterium.

[0061] The deuterium-labeled or substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties relating to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in specific therapeutic benefits arising from higher metabolic stability, e.g., increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F, 3 H, 11 14C-labeled compounds may be useful in PET or SPECT or other imaging studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the procedures disclosed in the following schemes or examples and preparations, by substituting readily available isotope-labeling reagents with non-isotope-labeling reagents. In this context, deuterium is understood to be a substituent of the compounds described herein.

[0062] The concentrations of such heavier isotopes, particularly deuterium, may be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, where a position is specifically designated as "H" or "hydrogen," it is understood that the position has hydrogen in its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0063] In many cases, the compounds of this disclosure may form salts of acids and / or bases in the presence of amino and / or carboxyl groups, or similar groups.

[0064] pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. “pharmaceutically acceptable” or “physiologically acceptable” refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0065] The term "pharmaceutically acceptable salt" of a compound refers to a salt that retains the biological efficacy and properties of the compound and is not biologically or otherwise undesirable. "pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Furthermore, when obtaining the compounds described herein as acid addition salts, a free base can be obtained by making a solution of the acid acid basic. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, may be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable addition salts. pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvate, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, for illustrative purposes only, salts of sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium. Salts derived from organic bases include, but are not limited to, salts of NH3 or salts of primary, secondary, and tertiary amines, such as salts derived from N-containing heterocycles, N-containing heteroaryls, or salts of the formula N(R N )3 amines (for example, HN + (R N )3 or (alkyl)N + (R N )3) is a salt derived from, where each R NThese are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be appropriately substituted with one or more substituents (e.g., 1-5 or 1-3) (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, for illustrative purposes only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0066] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group have been replaced with one or more non-hydrogen substituents, provided that the valence of the specified atom does not exceed the normal valence of the specified atom. One or more substituents include, but are not limited to, acyl, alkenyl, alkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, amidino, amide, amino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkoxy, haloalkoxyalkyl, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydrazino, hydroxy, hydroxyalkyl, imide, imino, nitro, oxo, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thion, or combinations thereof.

[0067] Polymers or similar non-tertiary structures obtained by defining substituents indefinitely with further substituents (e.g., a substituted aryl having a substituted alkyl, which itself is substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms, or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may also refer to other chemical groups as defined herein. Unless otherwise specified, when a group is described as optionally substituted, any substituent of that group is itself unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to alkyl groups having one or more substituents, including hydroxy, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each being substituted. In other embodiments, substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each being unsubstituted.

[0068] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and agents with pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is assumed unless any conventional media or agent is incompatible with the active ingredient. Auxiliary active ingredients may also be incorporated into compositions.

[0069] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0070] When used herein, the term "pharmaceutically acceptable" means that a compound, or a salt or composition thereof, is chemically and / or toxicologically compatible with the other components of the formulation and / or the subject being treated thereby.

[0071] The terms "administration" or "administering" refer to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including mammals, birds, fish, or amphibians. The method of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0072] The terms “effective dose,” “effective dosage,” “pharmaceutically effective amount,” or “therapeutic effective dose,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvate) administered, which may include alleviating one or more symptoms of the disease or condition being treated, and may include curing the disease. “Cure” means eliminating the symptoms of an active disease. Results may include a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desirable changes in the biological system. For example, “effective dose” for therapeutic use is the amount of a composition containing the compound disclosed herein required to provide a clinically significant reduction in disease symptoms. The appropriate “effective” dose in individual cases is determined using any suitable method, such as a dose-escalation study. In some embodiments, “therapeutic effective dose” of a compound provided herein refers to an amount of the compound effective as monotherapy or in combination therapy.

[0073] The terms “excipient” or “pharmaceutically acceptable excipient” mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid extender, diluent, carrier, solvent, or encapsulating material. In some embodiments, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of a pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0074] The term “pharmaceutical composition” means a mixture of a compound of Formula I provided herein, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvate thereof, with other chemical components such as carriers, stabilizers, diluents, dispersants, suspenders, and / or concentrators (collectively referred to herein as “excipients”). Pharmaceutical compositions facilitate the administration of compounds to living organisms. Several methods of administering compounds exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0075] The term “calcitonin receptor and / or amyrin receptor-related disease or disorder” is intended, as used herein, to include, but is not limited to, diseases, disorders, or conditions in which activation of at least one calcitonin receptor (CTR) and / or amyrin receptor (AMY) by calcitonin and / or amyrin contributes to the symptoms or progression of the disease or disorder. These diseases or disorders may arise from one or more genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, surgical, and / or traumatic etiologies.

[0076] The terms “treat,” “treating,” and “treatment” are intended to include, in the context of treating a disease, disorder, or condition, alleviating or eliminating one or more symptoms of a disorder, disorder, or condition, or a disorder, disorder, or condition, or one or more symptoms thereof, or slowing the progression, spread, or worsening of a disease, disorder, or condition or one or more of its symptoms.

[0077] As used herein, the term “preventing” means preventing, in whole or in part, the onset, recurrence, or spread of any disease or condition or symptom described herein.

[0078] The terms “subject,” “patient,” or “individual,” as used herein, are interchangeable and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, this term refers to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or treatment is desired or required. In some embodiments, the subject is human. In some embodiments, the subject has experienced and / or presented with at least one symptom of a disease, disorder, or condition to be treated and / or prevented.

[0079] The terms "treatment regimen" and "administration regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in a combination therapy.

[0080] As used herein, the term "combination of pharmaceuticals" refers to a pharmaceutical treatment resulting from the mixing or combination of two or more active ingredients, including both immobilized and unimmobilized combinations of active ingredients.

[0081] The term "combination therapy," as used herein, refers to a regimen of administration of two different therapeutically effective agents (i.e., combination components or combination partners) administered together or separately in the manner prescribed by a healthcare professional or in accordance with the regulatory authorities as defined herein.

[0082] The terms “modulate,” “modulating,” or “modulation,” as used herein, mean regulation or adjustment (e.g., increase or decrease), and may include, for example, agonism, partial agonism, or antagonism. compound

[0083] This specification provides compounds that are amylin modulators.

[0084] In some embodiments, formula I: [ka] Compounds thereof, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof are provided. [In formula: A is C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, C 3-10A is a cycloalkylene, heterocyclylene, arylene, or heteroarylene; where A is C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, C 3-10 Cycloalkylenes, heterocyclylenes, arylenes, or heteroaryls independently contain 1 to 5 Z A It may be replaced as appropriate; Ring B contains 1 to 3 R B It is a 5-membered or 6-membered heteroaryl that may be appropriately substituted with; R B These are independently halo, hydroxy, -NH2, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 Selected from haloalkoxys; where R B C is 1-3 Alkyl groups are independently -NH2 and -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, hydroxy, or C 1-3 They may be substituted with alkoxy as appropriate; L 1 C 1-3 Alkilen, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 A cycloalkylene, or a 4- to 6-membered heterocyclene; where L 1 The aforementioned C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 Cycloalkylenes, or 4- to 6-membered heterocyclenes, are independently classified as halo, oxo, hydroxy, cyano, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; L 2 These are bonded, -O-, -S-, and -NR 2a -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 2a -, -NR 2a C(O)-, -OC(O)NR 2a -, -NR 2a C(O)O-, -NR 2a C(O)NR 2b -, -S(O)-, -S(O)2-, -S(O)NR 2a -, -S(O)2NR 2a -, -NR 2a S(O)-, -NR 2a S(O)2-, -NR 2a S(O)NR 2b -, -NR 2a S(O)2NR 2b -, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 3-6 The cycloalkylene is a 4-6 member heterocyclylene, or a 5 member heteroarylene; where L 2 The aforementioned C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 Cycloalkylenes, 4- to 6-membered heterocyclylenes, or 5-membered heteroarylenes are independently classified as halo, oxo, hydroxy, cyano, -NH2, or -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; R 1 This is cyano, -C(O)NR 1a R 1b -C(S)NR 1a R 1b -S(O)2R2 -S(O)(NR 6 )R 2 , or -P(O)R 7 R 2 and; R 2 -NR 1a R 1b , C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 2 The aforementioned C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are halo, hydroxy, cyano, C 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, or C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; Alternatively, R 2 and R 6 , or R 2 and R 7 Together with the atoms they are bonded to, they form 1 to 5 Z 2 It forms a heterocycline which may be appropriately substituted; R 1a and R 1b Each of them is independently of hydrogen and C 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 1-3 Haloalkyl, C 3-6 It is a cycloalkyl or a 4- to 6-membered heterocycline; where R 1a and R 1b C is 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 1-3Haloalkyl, C 3-6 Cycloalkyls, or 4-6 membered heterocyclines, are each independently classified as halo, hydroxy, cyano, or C. 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, or C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; Alternatively, R 1a and R 1b These, together with the atoms they are bonded to, form halo, hydroxy, cyano, and C 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, or C 1-3 It forms a 4-6 member heterocycline which may be independently and appropriately substituted with 1-5 substituents independently selected from the haloalkoxy; R 2a and R 2b Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 2a and R 2b C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 2a It may be replaced as appropriate; Alternatively, R 2a and R 2b Together with the atoms they are bonded to, they form 1 to 5 Z 2a They independently form heterocyclines which may be substituted as appropriate; R 3 is hydrogen, -NR 3b R 3c , C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3 The aforementioned C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 3 It may be replaced as appropriate; R 3b and R 3c Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3b and R 3c C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently halo, hydroxy, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; Alternatively, R 3b and R 3c Together with the nitrogen atoms to which they are bonded, they form 1 to 5 Z 3b It forms a heterocycline which may be appropriately substituted; R 4 C 1-6 Alkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 4 The aforementioned C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 4 It may be replaced as appropriate; R 5 is hydrogen, halo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 5 The aforementioned C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 5 It may be replaced as appropriate; R 6 is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 A cycloalkyl or a 4-6 membered heterocycline; where C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyls, or 4-6 member heterocyclines, are classified as halo, oxo, hydroxy, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; R 7 is hydroxy, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Alkyl, or C 1-3 It is a haloalkyl; Z A , Z 2 , Z 2a , Z 3 , Z 3b , Z 4 , and Z 5 These are independently known as halo, cyano, nitro, oxo, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkinyl, -LC 1-6 Haloalkyl, -LC 3-10 It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; where Z A , Z 2 , Z 2a , Z 3 , Z 3b , Z 4 , and Z 5 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; L stands for -O-, -S-, -NR, and L respectively, independently. 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -, or -NR 20 S(O)2NR 21 -and;R 20 and R 21 Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 and R 21 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; or, R 20 and R 21 Together with the atoms they are bonded to, they form 1 to 5 Z 1a They independently form heterocyclines which may be substituted as appropriate; Z 1a These are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, and -NH-C. 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where Z 1a -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently C 1-6 The molecule may be appropriately substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano; However, A is C 1-6 If it is an alkylene, R 5 C 3-10 A cycloalkyl, heterocyclyl, aryl, or heteroaryl; where C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted independently as appropriate.

[0085] In some embodiments, formula I: [ka] Compounds thereof, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof are provided. [In formula: A is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 3-10 A is a cycloalkylene, heterocyclylene, arylene, or heteroarylene; where A is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 3-10Cycloalkylenes, heterocyclylenes, arylenes, or heteroarylenes independently contain 1 to 5 Z A It may be replaced as appropriate; Ring B contains 1 to 3 R B It is a 5-membered or 6-membered heteroaryl that may be appropriately substituted with; R B These are independently halo, hydroxy, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 Selected from haloalkoxys; where R B C is 1-3 Alkyl groups are independently -NH2 and -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, hydroxy, or C 1-3 They may be substituted with alkoxy as appropriate; L 1 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 A cycloalkylene, or a 4- to 6-membered heterocyclene; where L 1 The aforementioned C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 Cycloalkylenes, or 4- to 6-membered heterocyclenes, are independently classified as halo, oxo, hydroxy, cyano, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; L 2 These are bonded, -O-, -S-, and -NR 2a -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 2a -, -NR 2aC(O)-, -OC(O)NR 2a -, -NR 2a C(O)O-, -NR 2a C(O)NR 2b -, -S(O)-, -S(O)2-, -S(O)NR 2a -, -S(O)2NR 2a -, -NR 2a S(O)-, -NR 2a S(O)2-, -NR 2a S(O)NR 2b -, -NR 2a S(O)2NR 2b -, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 3-6 The cycloalkylene is a 4-6 member heterocyclylene, or a 5 member heteroarylene; where L 2 The aforementioned C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 Cycloalkylenes, 4- to 6-membered heterocyclylenes, or 5-membered heteroarylenes are independently classified as halo, oxo, hydroxy, cyano, -NH2, or -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; R 1 This is cyano, -C(O)NR 1a R 1b -C(S)NR 1a R 1b -S(O)2R 2 -S(O)(NR 6 )R 2 , or -P(O)R 7 R 2 and; R 2 -NR 1aR 1b , C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 2 The aforementioned C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are halo, hydroxy, cyano, C 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, or C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; Alternatively, R 2 and R 6 , or R 2 and R 7 Together with the atoms they are bonded to, they form 1 to 5 Z 2 It forms a heterocycline which may be appropriately substituted; R 1a and R 1b Each of them is independently of hydrogen and C 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 1-3 Haloalkyl, C 3-6 It is a cycloalkyl or a 4- to 6-membered heterocycline; where R 1a and R 1b C is 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyls, or 4-6 membered heterocyclines, are each independently classified as halo, hydroxy, cyano, or C. 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 1-3Haloalkyl, C 1-3 Alkoxy, or C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; Alternatively, R 1a and R 1b These, together with the atoms they are bonded to, form halo, hydroxy, cyano, and C 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, or C 1-3 It forms a 4-6 member heterocycline which may be independently and appropriately substituted with 1-5 substituents independently selected from the haloalkoxy; R 2a and R 2b Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 2a and R 2b C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 2a It may be replaced as appropriate; Alternatively, R 2a and R 2b Together with the atoms they are bonded to, they form 1 to 5 Z 2a They independently form heterocyclines which may be substituted as appropriate; R 3 is hydrogen, -NR 3b R 3c , C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3 The aforementioned C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 3 It may be replaced as appropriate; R 3b and R 3c Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3b and R 3c C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently halo, hydroxy, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; Alternatively, R 3b and R 3c Together with the nitrogen atoms to which they are bonded, they form 1 to 5 Z3b It forms a heterocycline which may be appropriately substituted; R 4 C 1-6 Alkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 4 The aforementioned C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 4 It may be replaced as appropriate; R 5 is hydrogen, halo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 5 The aforementioned C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 5 It may be replaced as appropriate; R 6 is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 A cycloalkyl or a 4-6 membered heterocycline; where C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyls, or 4-6 member heterocyclines, are classified as halo, oxo, hydroxy, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; R 7 is hydroxy, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C1-3 Alkyl, or C 1-3 It is a haloalkyl; Z A , Z 2 , Z 2a , Z 3 , Z 3b , Z 4 , and Z 5 These are independently known as halo, cyano, nitro, oxo, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkinyl, -LC 1-6 Haloalkyl, -LC 3-10 It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; where Z A , Z 2 , Z 2a , Z 3 , Z 3b , Z 4 , and Z 5 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; L stands for -O-, -S-, -NR, and L respectively, independently. 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20-, -S(O)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -, or -NR 20 S(O)2NR 21 -and;R 20 and R 21 Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 and R 21 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; or, R 20 and R 21 Together with the atoms they are bonded to, they form 1 to 5 Z 1a They independently form heterocyclines which may be substituted as appropriate; Z 1a These are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, and -NH-C. 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where Z 1a -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently C 1-6 The molecule may be appropriately substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano; However, A is C 1-6 If it is an alkylene, R 5 C 3-10 A cycloalkyl, heterocyclyl, aryl, or heteroaryl; where C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted independently as appropriate.

[0086] In some embodiments, R 1 is -C(O)NR 1a R 1b -S(O)2R 2 -S(O)(NR 6 )R 2 , or -P(O)R 7 R 2 That is the case.

[0087] In some embodiments, R 2 -NR 1a R 1b or C 1-6 It is alkyl.

[0088] In some embodiments, R 1 The structures are -C(O)NH2, -S(O)2NH2, -S(O)2CH3, and the following structure: [ka] It is either -S(O)(NH)CH3 or -P(O)(CH3)CH3.

[0089] In some embodiments, formula I: [ka] Compounds thereof, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof are provided. [In formula: A is 1 to 5 Z A It is a 5- to 9 member heteroarylene which may be substituted as appropriate; Ring B contains 1 to 3 R B It is a 5-membered or 6-membered heteroaryl that may be appropriately substituted with; R B These are independently halo, hydroxy, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 Selected from haloalkoxys; where R B C is 1-3 Alkyl groups are independently -NH2 and -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, hydroxy, or C 1-3 They may be substituted with alkoxy as appropriate; L 1 C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 A cycloalkylene, or a 4- to 6-membered heterocyclene; where L 1 The aforementioned C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 Cycloalkylenes, or 4- to 6-membered heterocyclenes, are independently classified as halo, oxo, hydroxy, cyano, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; L 2 These are bonded, -O-, -S-, and -NR 2a -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 2a -, -NR 2a C(O)-, -OC(O)NR 2a -, -NR 2a C(O)O-, -NR 2a C(O)NR 2b -, -S(O)-, -S(O)2-, -S(O)NR 2a -, -S(O)2NR 2a -, -NR 2a S(O)-, -NR 2a S(O)2-, -NR 2a S(O)NR 2b -, -NR 2a S(O)2NR 2b -, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 3-6 The cycloalkylene is a 4-6 member heterocyclylene, or a 5 member heteroarylene; where L 2 The aforementioned C 1-3 Alkylene, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 Cycloalkylenes, 4- to 6-membered heterocyclylenes, or 5-membered heteroarylenes are independently classified as halo, oxo, hydroxy, cyano, -NH2, or -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; R 1 is -C(O)NH2; R 2a and R2b Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 2a and R 2b C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 2a It may be replaced as appropriate; Alternatively, R 2a and R 2b Together with the atoms they are bonded to, they form 1 to 5 Z 2a They independently form heterocyclines which may be substituted as appropriate; R 3 This is 1 to 5 Z 3 C may be replaced as appropriate. 1-6 It is alkyl; R 4 C 1-6 Alkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 4 The aforementioned C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 4 It may be replaced as appropriate; R 5 C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 5 The aforementioned C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 5 It may be replaced as appropriate; Z A , Z2 , Z 2a , Z 3 , Z 3b , Z 4 , and Z 5 These are independently known as halo, cyano, nitro, oxo, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkinyl, -LC 1-6 Haloalkyl, -LC 3-10 It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; where Z A , Z 2 , Z 2a , Z 3 , Z 3b , Z 4 , and Z 5 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; L stands for -O-, -S-, -NR, and L respectively, independently. 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR20 S(O)NR 21 - or -NR 20 S(O)2NR 21 -; R 20 and R 21 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 and R 21 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently optionally substituted with 1 to 5 Z 3-10 ; or R 1a and R 20 together with the atom to which they are attached form a heterocyclyl that is independently optionally substituted with 1 to 5 Z 21 ; 1a Z 1a are each independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, -S-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; where Z 1a -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, -S-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently C 1-6 [The molecule may be appropriately substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano atoms.]

[0090] In some embodiments, formula IA: [ka] Compounds thereof, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof are provided. [In the formula, A, L 1 , L 2 , R 3 , R 4 , R 5 Ring B and ring B are each independently as defined herein; X is -C(O)- or -S(O)2-; However, A is C 1-6 If it is alkylene; R 5 C 3-10 A cycloalkyl, heterocyclyl, aryl, or heteroaryl; where C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted independently as appropriate.

[0091] In some embodiments of formula IA, A is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 3-10 A is a cycloalkylene, heterocyclylene, arylene, or heteroarylene; where A is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkinylene, C 3-10 Cycloalkylenes, heterocyclylenes, arylenes, or heteroarylenes independently contain 1 to 5 Z Amay be appropriately substituted; Ring B is a 5- or 6-membered heteroaryl which may be appropriately substituted with 1 to 3 Rs; B where R is each independently selected from halo, hydroxy, cyano, C R B alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy; wherein C 1-3 alkyl is each independently optionally substituted with -NH2, -NHC B alkyl, -N(C 1-3 alkyl)2, hydroxy, or C 1-3 alkoxy; 1-3 L 1-3 is C 1 alkylene, C 1-3 alkenylene, C 2-3 alkynylene, C 2-3 heteroalkylene, C<opposite 1-3 cycloalkylene, or a 4- to 6-membered heterocyclylene; wherein the C 3-6 alkylene, C 1 alkenylene, C 1-3 alkynylene, C 2-3 heteroalkylene, C 2-3 cycloalkylene, or a 4- to 6-membered heterocyclylene is each independently optionally substituted with 1 to 5 substituents independently selected from halo, oxo, hydroxy, cyano, C 1-3 alkyl, C 3-6 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy; 1-3 1-3 2 2a L is a bond, -O-, -S-, -NR L 2 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 2a -, -NR 2a C(O)-, -OC(O)NR 2a -, -NR 2a C(O)O-, -NR 2a C(O)O-; 2aC(O)NR 2b -, -S(O)-, -S(O)2-, -S(O)NR 2a -, -S(O)2NR 2a -, -NR 2a S(O)-, -NR 2a S(O)2-, -NR 2a S(O)NR 2b -, -NR 2a S(O)2NR 2b -, C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 3-6 The cycloalkylene is a 4-6 member heterocyclylene, or a 5 member heteroarylene; where L 2 The aforementioned C 1-3 Alkilen, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 Cycloalkylenes, 4- to 6-membered heterocyclylenes, or 5-membered heteroarylenes are independently classified as halo, oxo, hydroxy, cyano, -NH2, or -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; R 2a and R 2b Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 2a and R 2b C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 2a It may be replaced as appropriate; Alternatively, R 2a and R 2b These, together with the atoms they are bonded to, form 1 to 5 Z 2a They independently form heterocyclines which may be substituted as appropriate; R 3 is hydrogen, -NR 3b R 3c , C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3 The aforementioned C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 3 It may be replaced as appropriate; R 3b and R 3c Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3b and R 3c C is1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently halo, hydroxy, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; Alternatively, R 3b and R 3c Together with the nitrogen atoms to which they are bonded, they form 1 to 5 Z 3b It forms a heterocycline which may be appropriately substituted; R 4 C 1-6 Alkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 4 The aforementioned C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 4 It may be replaced as appropriate; R 5 is hydrogen, halo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 5 The aforementioned C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 5 It may be replaced as appropriate; Z A , Z 2a , Z 3 , Z 3b , Z4 , and Z 5 These are independently known as halo, cyano, nitro, oxo, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkinyl, -LC 1-6 Haloalkyl, -LC 3-10 It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; where Z A , Z 2a , Z 3 , Z 3b , Z 4 , and Z 5 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; L stands for -O-, -S-, -NR, and L respectively, independently. 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -, or -NR 20 S(O)2NR 21 -and; R 20 and R 21 Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 and R 21 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; or, R 20 and R 21 Together with the atoms they are bonded to, they form 1 to 5 Z 1a It forms a heterocycline which may be appropriately substituted; Z 1a These are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, and -NH-C. 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where Z 1a -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently C 1-6 The molecule may be appropriately substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano; However, A is C 1-6 If it is alkylene; R 5 C 3-10 A cycloalkyl, heterocyclyl, aryl, or heteroaryl; where C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted independently as appropriate.

[0092] In some embodiments, A is C 1-6 Alkilen, C 3-10 A is a cycloalkylene, heterocyclylene, arylene, or heteroarylene; where A is C 1-6 Alkilen, C 3-10 Cycloalkylenes, heterocyclylenes, arylenes, or heteroarylenes independently contain 1 to 5 Z A It may be replaced as appropriate.

[0093] In some embodiments, A is C 1-6 Alkilen, C 3-10 Cycloalkylene, 3-10 membered heterocyclylene, C 6-10 Arylene, or 5-10 member heteroarylene; where each independently comprises 1-5 Z A It may be replaced as appropriate.

[0094] In some embodiments, A is methylene, ethylene, n-propylene, or the following structure: [ka] And; here, the combination a is L 2 It is connected.

[0095] In some embodiments, A is methylene, ethylene, n-propylene, or the following structure: [ka] And; here, the combination a is L 2 It is connected.

[0096] In some embodiments, A has the following structure: [ka] And; here, the combination a is L 2 It is connected.

[0097] In some embodiments, formula IB: [ka] Compounds thereof, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof are provided. [In the formula, A, L 1 , L 2 , R 3 , R 4 , and R 5 Each of these is independent and as defined herein; X is -C(O)- or -S(O)2-; X 1 , X 2 , X 3 , and X 4 These are O, S, N, and NR, respectively, and are independent of each other. B , and CR B Selected from; however, X 1 , X 2 , X 3 , and X 4 At least one of them is N; X 1 , X 2 , X 3 , and X 4 The ring containing the aromatic compound is aromatic; However, A is C 1-6 If it is alkylene; R 5 C 3-10A cycloalkyl, heterocyclyl, aryl, or heteroaryl; where C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted independently as appropriate.

[0098] In some embodiments of formula IB, A is C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, C 3-10 A is a cycloalkylene, heterocyclylene, arylene, or heteroarylene; where A is C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, C 3-10 Cycloalkylenes, heterocyclylenes, arylenes, or heteroarylenes independently contain 1 to 5 Z A It may be replaced as appropriate; R B These are independently halo, hydroxy, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 Selected from haloalkoxys; where R B C is 1-3 Alkyl groups are independently -NH2 and -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, hydroxy, or C 1-3 They may be substituted with alkoxy as appropriate; L 1 C 1-3 Alkilen, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 A cycloalkylene, or a 4- to 6-membered heterocyclene; where L 1 The aforementioned C 1-3 Alkilen, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6Cycloalkylenes, or 4- to 6-membered heterocyclenes, are independently classified as halo, oxo, hydroxy, cyano, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; L 2 These are bonded, -O-, -S-, and -NR 2a -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 2a -, -NR 2a C(O)-, -OC(O)NR 2a -, -NR 2a C(O)O-, -NR 2a C(O)NR 2b -, -S(O)-, -S(O)2-, -S(O)NR 2a -, -S(O)2NR 2a -, -NR 2a S(O)-, -NR 2a S(O)2-, -NR 2a S(O)NR 2b -, -NR 2a S(O)2NR 2b -, C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 3-6 The cycloalkylene is a 4-6 member heterocyclylene, or a 5 member heteroarylene; where L 2 The aforementioned C 1-3 Alkilen, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 Cycloalkylenes, 4- to 6-membered heterocyclylenes, or 5-membered heteroarylenes are independently classified as halo, oxo, hydroxy, cyano, -NH2, or -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; R 2a and R 2b Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 2a and R 2b C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 2a It may be replaced as appropriate; Alternatively, R 2a and R 2b These, together with the atoms they are bonded to, form 1 to 5 Z 2a They independently form heterocyclines which may be substituted as appropriate; R 3 is hydrogen, -NR 3b R 3c , C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3 The aforementioned C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 3 It may be replaced as appropriate; R 3b and R 3c Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3b and R 3c C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently halo, hydroxy, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; Alternatively, R 3b and R 3c Together with the nitrogen atoms to which they are bonded, they form 1 to 5 Z 3b It forms a heterocycline which may be appropriately substituted; R 4 C 1-6 Alkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 4 The aforementioned C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 4 It may be replaced as appropriate; R 5is hydrogen, halo, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 5 The aforementioned C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 5 It may be replaced as appropriate; Z A , Z 2a , Z 3 , Z 3b , Z 4 , and Z 5 These are independently known as halo, cyano, nitro, oxo, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkinyl, -LC 1-6 Haloalkyl, -LC 3-10 It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; where Z A , Z 2a , Z 3 , Z 3b , Z 4 , and Z 5 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; L stands for -O-, -S-, -NR, and L respectively, independently. 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 -, or -NR 20 S(O)2NR 21 -and; R 20 and R 21 Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 and R 21 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; or, R 20 and R 21 Together with the atoms they are bonded to, they form 1 to 5 Z 1a They independently form heterocyclines which may be substituted as appropriate; Z 1a These are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, and -NH-C. 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where Z 1a -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently C 1-6 The molecule may be appropriately substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano; However, A is C 1-6 If it is alkylene; R 5 C 3-10 A cycloalkyl, heterocyclyl, aryl, or heteroaryl; where C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted independently as appropriate.

[0099] In some embodiments, A is an arylene or heteroarylene; where the arylene or heteroarylene is independently 1 to 5 Z A It may be replaced as appropriate.

[0100] In some embodiments, A is 1 to 5 Z A These are arylenes that may be substituted as appropriate.

[0101] In some embodiments, A is 1 to 5 Z A It is a heteroarylene which may be substituted as appropriate.

[0102] In some embodiments, A is 1 to 5 Z A It is a heterocyclylene that may be substituted as appropriate.

[0103] In some embodiments, A is 1 to 5 Z A These are cycloalkylenes that may be substituted as appropriate.

[0104] In some embodiments, X is -C(O)-.

[0105] In some embodiments, X is -S(O)2-.

[0106] In some embodiments, ring B has 1 to 3 R B These are nitrogen-containing five- or six-membered heteroaryls, which may be appropriately substituted. The term "nitrogen-containing" is intended to refer to heteroaryls containing at least one ring nitrogen. The nitrogen-containing ring may contain one or more additional heteroatoms (e.g., oxygen, sulfur, or nitrogen).

[0107] In some embodiments, ring B or the following portion: [ka] This is 1 to 3 R B It is a nitrogen-containing 5-membered heteroaryl that may be appropriately substituted with other compounds.

[0108] In some embodiments, ring B or the following portion: [ka] is pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl; where the pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl is one or two R B It may be replaced as appropriate.

[0109] In some embodiments, ring B or the following portion: [ka] The structure is as follows: [ka] And here, each is one or two R B It may be replaced as appropriate.

[0110] In some embodiments, R B Each is independent of C 1-3 It is alkyl.

[0111] In some embodiments, ring B has 1 to 3 R B It is a 6-membered heteroaryl that may be substituted as appropriate.

[0112] In some embodiments, ring B has 1 to 3 R B This is pyridyl, which may be substituted as appropriate.

[0113] In some embodiments, ring B is C 1-3 This is a pyridyl that may be appropriately substituted with alkyl groups.

[0114] In some embodiments, ring B is pyridyl, pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl; where the pyridyl, pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl is one or two R B It may be replaced as appropriate.

[0115] In some embodiments, ring B has the following structure: [ka] And here, each is one or two R B It may be replaced as appropriate.

[0116] In some embodiments, L 1C 3-6 Cycloalkylene, C 1-3 Alkylene or C 1-3 It is a heteroalkylene; here, C 3-6 Cycloalkylene, C 1-3 Alkylene or C 1-3 Heteroalkylenes are each independently classified as halo, oxo, hydroxy, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it.

[0117] In some embodiments, L 1 It contains 1-3 halo, oxo, hydroxy, and C atoms. 1-3 Alkyl, or C 1-3 C may be appropriately substituted with alkoxy. 1-3 It is alkylene.

[0118] In some embodiments, L 1 C 1-3 Alkylene or C 1-3 It is a heteroalkylene.

[0119] In some embodiments, R 4 C 1-6 Alkyl, C 3-10 The C is a cycloalkyl, aryl, heterocyclyl, or heteroaryl; where C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, heterocyclyl, or heteroaryl compounds independently contain 1 to 5 Z 4 It may be replaced as appropriate.

[0120] In some embodiments, R 4 C 1-6 Alkyl, C 3-10 It is a cycloalkyl, or aryl, or heteroaryl; where C 1-6 Alkyl, C 3-10Cycloalkyl, aryl, or heteroaryl groups independently contain 1 to 5 Z 4 It may be replaced as appropriate.

[0121] In some embodiments, R 4 is an aryl, heterocyclyl, or heteroaryl; where the aryl, heterocyclyl, or heteroaryl is 1 to 5 Z 4 It may be replaced as appropriate.

[0122] In some embodiments, R 4 C 1-3 Alkyl, C 3-9 The C is a cycloalkyl, a 4- to 9-membered heterocycline, or a phenyl; where C 1-3 Alkyl, C 3-6 The cycloalkyl or phenyl group may be independently substituted with 1 to 3 halos as appropriate.

[0123] In some embodiments, R 4 C 1-3 Alkyl, C 3-6 It is a cycloalkyl or phenyl; where C 1-3 Alkyl, C 3-6 The cycloalkyl or phenyl group may be independently substituted with 1 to 3 halos as appropriate.

[0124] In some embodiments, R 4 C 1-3 Alkyl, C 3-6 It is a cycloalkyl or phenyl; where C 1-3 Alkyl, C 3-6 The cycloalkyl or phenyl group may be independently substituted with a halo as appropriate.

[0125] In some embodiments, R 3 -NR 3b R 3c , C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 3 The aforementioned C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 3 It may be replaced as appropriate.

[0126] In some embodiments, R 3 C 1-6 Alkyl or C 1-6 It is a haloalkyl group.

[0127] In some embodiments, R 3 is hydrogen, -NR 3b R 3c , C 1-6 Alkyl, or C 1-6 It is an alkoxy.

[0128] In some embodiments, L 2 is a combination, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 The C is a heteroalkylene, a 4-6 membered heterocyclene, or a 5 membered heteroarylene; where C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6Alkinylene, C 1-6 Heteroalkylenes, 4-6 member heterocyclylenes, or 5 member heteroarylenes are independently classified as halo, oxo, hydroxy, cyano, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it.

[0129] In some embodiments, L 2 is a combination, -NR 2a -, -C(O)NR 2a -, -NR 2a C(O)-, C 1-6 Alkilen, C 1-6 The C is a heteroalkylene, a 4-6 membered heterocyclene, or a 5 membered heteroarylene; where C 1-6 Alkilen, C 1-6 Heteroalkylenes, 4-6 member heterocyclylenes, or 5 member heteroarylenes are independently classified as halo, oxo, hydroxy, cyano, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it.

[0130] In some embodiments, L 2 These are the bonds -C(O)-, -NH-, -NHCH2-, -CH2NH-, -OCH2-, -CH2O-, -C(O)NH-, -NHC(O)-, -C(O)NHCH2-, -NHCH2C(O)-, -OC(O)NHCH2-, -CH2NH(CO)O-, -CH2CH2-, or 1,2,3-triazolidiyl.

[0131] In some embodiments, R 2a It is hydrogen.

[0132] In some embodiments, R 5 is hydrogen, halo, amino, cyano, C 1-6 Alkyl, C1-6 Alkoxy, C 3-10 A cycloalkyl, heterocyclyl, aryl, or heteroaryl; where C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain 1 to 5 Z 5 It may be replaced as appropriate.

[0133] In some embodiments, R 5 C 1-6 The alkyl, aryl, or heteroaryl group is an alkyl or heteroaryl group, where the aryl or heteroaryl group has 1 to 5 Z groups. 5 It may be replaced as appropriate.

[0134] In some embodiments, R 5 C 3-10 C may be appropriately substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl. 1-6 It is alkyl; here, the C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may have 1 to 5 Z 1a It may be replaced as appropriate.

[0135] In some embodiments, R 5 is an aryl or heteroaryl; where the aryl or heteroaryl is 1 to 5 Z 5 It may be replaced as appropriate.

[0136] In some embodiments, R 5 is hydrogen, halo, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 It is a cycloalkyl, heterocyclyl, or aryl; where C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, heterocyclyl, or aryl compounds independently contain 1 to 5 Z 5It may be replaced as appropriate.

[0137] In some embodiments, R 6 C 1-3 It is alkyl or cyclopropyl. In some embodiments, R 6 C 1-3 It is alkyl.

[0138] In some embodiments, R 7 C 1-3 It is alkyl or cyclopropyl. In some embodiments, R 7 C 1-3 It is alkyl.

[0139] In some embodiments, formula IB: [ka] Compounds thereof, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof are provided. [In the formula, A, L 1 , and L 2 Each of these is independent and as defined herein; X is -C(O)- or -S(O)2-; X 1 , X 2 , X 3 , and X 4 These are O, S, N, and NR, respectively, and are independent of each other. B , and CR B Selected from; however, X 1 , X 2 , X 3 , and X 4 At least one of them is N; X 1 , X 2 , X 3 , and X 4 The ring containing the aromatic compound is aromatic; R 3 C 1-6 Alkyl or C 1-6 It is a haloalkyl; R 4is an aryl or heteroaryl compound; where each is 1 to 5 Z 4 It may be replaced as appropriate; R 5 is an aryl or heteroaryl compound; where each is 1 to 5 Z 5 It may be replaced as appropriate; However, A is C 1-6 If it is alkylene; R 5 C 3-10 A cycloalkyl, heterocyclyl, aryl, or heteroaryl; where C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted independently as appropriate.

[0140] In some embodiments of formula IB, A is C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, C 3-10 A is a cycloalkylene, heterocyclylene, arylene, or heteroarylene; where A is C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, C 3-10 Cycloalkylenes, heterocyclylenes, arylenes, or heteroarylenes independently contain 1 to 5 Z A It may be replaced as appropriate; R B These are independently halo, hydroxy, cyano, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 Selected from haloalkoxys; where R B C is 1-3 Alkyl groups are independently -NH2 and -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, hydroxy, or C 1-3 They may be substituted with alkoxy as appropriate; L 1 C 1-3 Alkilen, C2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 A cycloalkylene, or a 4- to 6-membered heterocyclene; where L 1 The aforementioned C 1-3 Alkilen, C 2-3 Alkenylene, C 2-3 Alkinylene, C 1-3 Heteroalkylene, C 3-6 Cycloalkylenes, or 4- to 6-membered heterocyclenes, are independently classified as halo, oxo, hydroxy, cyano, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; L 2 These are bonded, -O-, -S-, and -NR 2a -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 2a -, -NR 2a C(O)-, -OC(O)NR 2a -, -NR 2a C(O)O-, -NR 2a C(O)NR 2b -, -S(O)-, -S(O)2-, -S(O)NR 2a -, -S(O)2NR 2a -, -NR 2a S(O)-, -NR 2a S(O)2-, -NR 2a S(O)NR 2b -, -NR 2a S(O)2NR 2b -, C 1-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkinylene, C 1-6 Heteroalkylene, C 3-6 The cycloalkylene is a 4-6 member heterocyclylene, or a 5 member heteroarylene; where L 2 The aforementioned C 1-3 Alkilen, C 2-3 Alkenylene, C 2-3Alkinylene, C 1-3 Heteroalkylene, C 3-6 Cycloalkylenes, 4- to 6-membered heterocyclylenes, or 5-membered heteroarylenes are independently classified as halo, oxo, hydroxy, cyano, -NH2, or -NHC. 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 The haloalkoxy may be appropriately substituted with 1 to 5 substituents selected independently of it; R 2a and R 2b Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 2a and R 2b C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 2a It may be replaced as appropriate; Alternatively, R 2a and R 2b Together with the atoms they are bonded to, they form 1 to 5 Z 2a They independently form heterocyclines which may be substituted as appropriate; R 3 C 1-6 Alkyl or C 1-6 It is a haloalkyl; R 4 is an aryl or heteroaryl compound; where each is 1 to 5 Z 5 It may be replaced as appropriate; R 5is an aryl or heteroaryl compound; where each is 1 to 5 Z 4 It may be replaced as appropriate; Z A , Z 2a , Z 4 , and Z 5 These are independently known as halo, cyano, nitro, oxo, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkinyl, -LC 1-6 Haloalkyl, -LC 3-10 It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; where Z A , Z 2a , Z 4 , and Z 5 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; L stands for -O-, -S-, -NR, and L respectively, independently. 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR 20 -, -NR 20 C(O)-, -OC(O)NR 20 -, -NR 20 C(O)O-, -NR 20 C(O)NR 21 -, -S(O)-, -S(O)2-, -S(O)NR 20 -, -S(O)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR20 S(O)NR 21 -, or -NR 20 S(O)2NR 21 -; R 20 and R 21 Each of them is independently of hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 20 and R 21 C is 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contains 1 to 5 Z 1a It may be replaced as appropriate; or, R 20 and R 21 Together with the atoms they are bonded to, they form 1 to 5 Z 1a It forms a heterocycline which may be appropriately substituted; Z 1a These are independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, and -NH-C. 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where Z 1a -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -SC 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently C 1-6 The molecule may be appropriately substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano; However, A is C 1-6 If it is alkylene; R 5 C 3-10 A cycloalkyl, heterocyclyl, aryl, or heteroaryl; where C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted independently as appropriate.

[0141] In some embodiments, formula IC: [ka] Compounds thereof, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof are provided. [In the formula, A, L 1 , and L 2 Each of these is independent and as defined herein; X is O, and the dashed connection does not exist; or X is N, and the dashed connection exists; X 2 is N or CH; L 2 ' is a bond or -CH2-; R 3 C 1-6 Alkyl or C 1-6 It is a haloalkyl; L 1 C 1-3 Alkylene or C 1-3 It is a heteroalkylene; here, L 1 The aforementioned C 1-3 Alkylene or C 1-3 Heteroalkylenes are independently classified as halo, hydroxy, or C.1-3 It may be appropriately substituted with alkyl groups; R 4 C 1-6 Alkyl, C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 4 The aforementioned C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl can independently contain one or two halos, C 1-6 Alkyl, or C 1-6 They may be substituted with alkoxy as appropriate; R 4 is an aryl or heteroaryl compound; where each is 1 to 5 Z 4 It may be replaced as appropriate; R 5 C 3-10 It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R 5 The aforementioned C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently contain 1 to 5 halo, hydroxy, or C atoms. 1-6 [These may be substituted with alkoxy as appropriate.]

[0142] In some embodiments, compounds selected from Table 1, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof are provided. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37

[0143] The compounds of formula I provided herein include stereochemical forms of the compounds, such as optical isomers including enantiomers and diastereomers, as well as mixtures thereof, such as mixtures of enantiomers and / or diastereomers including racemic mixtures, and equimolar or unequal mixtures of individual enantiomers and / or diastereomers. All stereochemical forms are intended in this disclosure. Unless otherwise noted, if a disclosed compound is described by name or structure without specifying its stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Representative stereochemical forms are provided throughout the specification, including but not limited to those listed in Table 2. In some embodiments, compounds selected from Table 2, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or solvates thereof are provided. [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44] [Table 45] [Table 46] [Table 47] [Table 48] [Table 49] [Table 50] [Table 51] [Table 52] [Table 53]

[0144] Compounds of formula I and their subformulas include pharmaceutically acceptable salts thereof. In addition, compounds of formula I and their subformulas also include other salts of such compounds, which do not necessarily have to be pharmaceutically acceptable salts, and these may be useful as intermediates for preparing and / or purifying compounds of formula I and their subformulas, and / or for purifying enantiomers of compounds of formula I and their subformulas.

[0145] It will be further understood that the compounds of formula I and its subformulas, or salts thereof, may be isolated in solvated form, and therefore any such solvated form is included within the scope of this disclosure. For example, the compounds of formula I and its subformulas, as well as each of their salts, may exist in unsolvated form and in solvated form with a pharmaceutically acceptable solvent such as water or ethanol.

[0146] Pharmaceutical composition and administration When used as a pharmaceutical, the compounds described herein (e.g., one or more of the compounds disclosed herein, or their stereoisomers or mixtures thereof) may be administered in the form of pharmaceutical compositions. These compositions may be prepared by methods well known in the pharmaceutical field and may be administered by various routes depending on whether they are intended for topical or systemic treatment and the area to be treated. Administration may be topical (including delivery to mucous membranes, including transdermal, epithelial, ocular, and intranasal, intravaginal, and rectal delivery), pulmonary (e.g., by inhalation or infusion (insufflation) of powder or aerosol, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powdery, or oily bases, thickeners, etc., may be required or desirable.

[0147] Pharmaceutical compositions are also provided herein that, as active ingredients, include one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, in combination with one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition was prepared using one or more compounds disclosed herein, or their stereoisomers or mixtures thereof.

[0148] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In one embodiment, a pharmaceutical composition comprising a compound disclosed herein, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof is present in an amount greater than about 0.1%, greater than about 1%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 35%, greater than about 40%, or greater than about 45%, and A pharmaceutical composition is provided in which the substance is present in the pharmaceutical composition with a purity of approximately 50%, or approximately 55%, or approximately 60%, or approximately 65%, or approximately 70%, or approximately 75%, or approximately 80%, or approximately 85%, or approximately 90%, or approximately 95%, or in an amount of approximately 40% by weight, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95% by weight.

[0149] In some embodiments, the compositions are suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or encapsulated in a carrier, such as a capsule, sachet, paper, or other container. Where the excipient functions as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, caches, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments containing up to 10% by weight of the active compound, for example, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders. In some embodiments, the compositions are formulated for oral administration. In some embodiments, the compositions are solid oral formulations. In some embodiments, the compositions are formulated as tablets or capsules.

[0150] Furthermore, pharmaceutical compositions comprising one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, together with pharmaceutically acceptable excipients are provided herein. Pharmaceutical compositions comprising one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, as active ingredients may be prepared by densely mixing one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, with a pharmaceutically acceptable carrier according to conventional formulation techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0151] Suitable pharmaceutically acceptable carriers are well known in the art. Some descriptions of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0152] Methods for formulating pharmaceutical compositions are described in numerous publications, including Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al. (published by Marcel Dekker, Inc.).

[0153] In some embodiments, the compound or pharmaceutical composition may be administered in combination with one or more conventional pharmaceutically acceptable excipients. Pharmacopoecitable excipients include, but are not limited to, ion exchangers, self-emulsifying drug delivery systems (SEDDS) such as alumina, aluminum stearate, lecithin, d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical administration forms such as Tweens, poloxamers or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, electrolytes such as water, salts, or protamine sulfates, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and lanolin fat. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives may also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions may be prepared containing the chemical entities described herein in an amount ranging from 0.005% to 100%, with the remainder being non-toxic excipients. The hypothetical compositions may contain 0.001% to 100% of the chemical entities provided herein, and in some embodiments, 0.1% to 95%, in other embodiments, 75% to 85%, and in further embodiments, 20% to 80%. Practical methods for preparing such dosage forms are known or will be apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).

[0154] In some embodiments, the compounds and pharmaceutical compositions described herein, or the pharmaceutical compositions thereof, may be administered to a patient in need by any approved route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, intracervical, sinus, tracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, bursal, intracerebral, intracisional, intravascular, intradermal, intraductal, duodenal, intradural, intraepithelial, intraesophageal, intragastric, intragingival, intraileal, lymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, sinusal, spinal cord, synovial, testicular, intramedullary, intraductal, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal cavity), nasogastrostomy, oral, parenteral, percutaneous, peridural, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, percutaneous, transmucosal, intratracheal, ureter, urethra, and vaginal. In some embodiments, the route of administration is parenteral (e.g., intratumoral).

[0155] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, or pharmaceutical compositions thereof, may be formulated for parenteral administration, for example, for injection via intra-arterial, intrasternal, intracranial, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. For example, such compositions may be prepared as either liquid solutions or suspensions for injection, as solid forms suitable for use in preparing solutions or suspensions when liquid is added before injection, and the preparations may be emulsified. In light of this disclosure, the preparation of such formulations is known to those skilled in the art. In some embodiments, devices are used for parenteral administration. For example, such devices may include needle syringes, microneedle syringes, needleless syringes, and injection techniques.

[0156] In some embodiments, pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and fluid enough to be easily injected. In some embodiments, the form must be stable under manufacturing and storage conditions and be protected against contamination by microorganisms such as bacteria and fungi.

[0157] In some embodiments, the carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In some embodiments, adequate fluidity may be maintained by, for example, the use of a coating such as lecithin, maintaining the required particle size in the case of dispersion, and the use of a surfactant. In some embodiments, prevention of microbial action may be provided by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In some embodiments, isotonic agents, such as sugars or sodium chloride, may be included. In some embodiments, sustained absorption of the injectable composition may be provided by using absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0158] In some embodiments, a sterile injection solution is prepared by compounding, as needed, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, in a suitable solvent with various other components as described above, and subsequently by sterile filtration. In some embodiments, a dispersion is prepared by compounding various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other components as needed from those described above. In some embodiments, a sterile powder is used for the preparation of a sterile injection solution. In some embodiments, the preparation method is vacuum drying and freeze-drying techniques, which yield the active ingredient powder plus any additional desired components from the pre-sterile filtered solution thereof.

[0159] In some embodiments, pharmacokinetically acceptable excipients usable in rectal compositions as gels, creams, enemas, or rectal suppositories are, without limitation, synthetic polymers such as cocoa butter glycerides and polyvinylpyrrolidone, PEG (such as PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oil, poloxamer, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, and anoxide. Contains SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopole, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxymethabites, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate (one or more of these).

[0160] In some embodiments, suppositories can be prepared by mixing one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, or the pharmaceutical compositions described herein, with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In some embodiments, the composition for rectal administration is in the form of an enema.

[0161] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, or pharmaceutical compositions thereof, are formulated for topical delivery to the gastrointestinal tract or GI tract by oral administration (e.g., in solid or liquid dosage forms).

[0162] In some embodiments, the solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, are mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or the following: a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) glycerol, etc. d) wetting agents, a) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) adsorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets, and pills, the dosage form may include buffers. In some embodiments, similar types of solid compositions may be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0163] In some embodiments, the pharmaceutical composition takes the form of a unit dosage form such as a pill or tablet, and the composition may therefore contain, along with one or more compounds disclosed herein, or stereoisomers or mixtures thereof provided herein, diluents such as lactose, sucrose, and dicalcium phosphate; lubricants such as magnesium stearate; and binders such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, and cellulose derivatives. In some embodiments, another solid dosage form, such as a powder, marme, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides), is encapsulated in a capsule (gelatin or cellulose-based capsule). In some embodiments, unit dosage forms in which one or more compounds and pharmaceutical compositions provided herein, or additional active ingredients, are physically separated are also envisioned, such as capsules containing granules (or tablets in capsules) of each drug; two-layer tablets; two-compartment gel caps, etc. In some embodiments, enteric coating or delayed-release oral dosage forms are also envisioned.

[0164] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants, or preservatives that are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known, including, for instance, phenol and ascorbic acid.

[0165] In some embodiments, the excipients are sterile and generally free of undesirable substances. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, sterilization is not required for excipients of various oral dosage forms, such as tablets and capsules. For example, the United States Pharmacopeia / National Pharmacopoeia (USP / NF) standards may suffice.

[0166] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, or pharmaceutical compositions thereof, are formulated for ophthalmic administration. In some embodiments, the ophthalmic composition may, but is not limited to, one or more of the following: viscosity modifiers (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0167] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, or pharmaceutical compositions thereof, are formulated for topical administration to the skin or mucous membranes (e.g., transdermally). In some embodiments, topical compositions may include ointments and creams. In some embodiments, ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing the selected active ingredient are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. For example, cream bases are typically washable and comprise an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase (sometimes called the “internal phase”) generally consists of petrolatum and aliphatic alcohols such as cetyl alcohol or stearyl alcohol; the aqueous phase usually, but not necessarily, exceeds the oil phase by volume and generally contains a wetting agent. In some embodiments, the emulsifier in the cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. In some embodiments, the ointment base, like other carriers or vehicles, should be inactive, stable, non-irritating, and non-sensitizing.

[0168] In any of the embodiments described herein, the pharmaceutical composition may comprise one or more of the following: lipids, interlayer crosslinked multilayer vesicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) (PLGA)-based or polyanhydride-based nanoparticles or microparticles, and lipid bilayers supported by nanoporous particles.

[0169] The amount of compound in a pharmaceutical composition or formulation can vary within the range adopted by those skilled in the art. Typically, a formulation contains, based on the total formulation, about 0.01 to 99.99% by weight of the compound disclosed, with the remainder being one or more preferred pharmaceutical excipients. In some embodiments, the compound is present at a level of about 1 to 80% by weight. Representative pharmaceutical formulations are described below.

[0170] Formulation Example 1 - Tablet Formulation The following ingredients are densely mixed and compressed into tablets with a single score line. [Table 54]

[0171] Formulation Example 2 - Capsule Formulation The following ingredients are densely mixed and filled into hard-shell gelatin capsules. [Table 55]

[0172] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration. [Table 56]

[0173] Formulation Example 4 - Injectable Formulation The following ingredients are mixed to form an injectable preparation. [Table 57]

[0174] Formulation Example 5 - Suppository Formulation By mixing the compound of this disclosure with Witepsol® H-15 (saturated plant fatty acid triglyceride; Riches-Nelson, Inc., New York), a suppository weighing 2.5 g was prepared, having the following composition: [Table 58]

[0175] In some embodiments, the dosage of one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, is determined based on several factors, but are not limited to, the patient's type, age, weight, sex, medical condition, severity of the patient's condition, route of administration, and the activity of the compound or its pharmaceutically acceptable salts, stereoisomers, mixtures thereof, or solvates. In some embodiments, the appropriate dosage for a particular situation may be determined by those skilled in the medical art. In some embodiments, the total daily dose may be divided and administered in divided doses throughout the day, or by means of providing continuous delivery.

[0176] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, are administered in doses ranging from about 0.01 to about 1000 mg. For example, about 0.1 to about 30 mg, about 10 to about 80 mg, about 0.5 to about 15 mg, about 50 mg to about 200 mg, about 100 mg to about 300 mg, about 200 to about 400 mg, about 300 mg to about 500 mg, about 400 mg to about 600 mg, about 500 mg to about 800 mg, about 600 mg to about 900 mg, or about 700 mg to about 1000 mg. In some embodiments, the dose is a therapeutically effective dose.

[0177] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures of stereoisomers described herein, are administered in doses of about 0.0002 mg / kg to about 100 mg / kg (e.g., about 0.0002 mg / kg to about 50 mg / kg; about 0.0002 mg / kg to about 25 mg / kg; about 0.0002 mg / kg to about 10 mg / kg; about 0.0002 mg / kg to about 5 mg / kg; about 0.0002 mg / kg to about 1 mg / kg; about 0.0002 mg / kg to about 0.5 mg / kg; about 0.0002 mg / kg to about 0.1 mg / kg; about 0.001 mg / kg to about 50 mg / kg; about 0.001 mg / kg to about 25 mg / kg; about 0.001 mg / kg to about 10 mg / kg; about 0.001 mg / kg kg~about 5mg / kg;about 0.001mg / kg~about 1mg / kg;about 0.001mg / kg~about 0.5mg / kg;about 0.001mg / kg~about 0.1mg / kg;about 0.01mg / kg~about 50mg / kg;about 0.01mg / kg~about 25mg / kg;about 0.01mg / kg~about 10mg / kg;about 0.01mg / kg~about 5mg / kg;about 0.01mg / kg (~approximately 1 mg / kg; approximately 0.01 mg / kg to approximately 0.5 mg / kg; approximately 0.01 mg / kg to approximately 0.1 mg / kg; approximately 0.1 mg / kg to approximately 50 mg / kg; approximately 0.1 mg / kg to approximately 25 mg / kg; approximately 0.1 mg / kg to approximately 10 mg / kg; approximately 0.1 mg / kg to approximately 5 mg / kg; approximately 0.1 mg / kg to approximately 1 mg / kg; approximately 0.1 mg / kg to approximately 0.5 mg / kg). In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures of stereoisomers described herein, are administered at a dose of approximately 100 mg / kg.

[0178] In some embodiments, the aforementioned doses of one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, may be administered daily (e.g., as a single dose or as two or more divided doses) or not daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0179] In some embodiments, the duration of administration of one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, the period of discontinuation of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, are administered to a patient for a period of time, followed by another period of discontinuation of administration of one or more compounds disclosed herein, or their stereoisomers or mixtures thereof. In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, are administered for a first period, followed by a second period during which administration is discontinued, and then a third period during which administration of one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, is initiated, followed by a fourth period during which administration is discontinued. For example, the period of administration followed by the period of discontinuation of administration of one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, is repeated for a determined or undetermined period. In some embodiments, the duration of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.In some embodiments, the period of discontinuation of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0180] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, are administered orally to a patient at least once a day (for example, once a day, twice a day, three times a day, four times a day, or as a single daily dose).

[0181] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, are administered to a patient by parenteral administration at least once a day (for example, 1 to 4 times a day, once a day, twice a day, three times a day, four times a day, or as a single daily dose).

[0182] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, are administered to a patient weekly by parenteral administration.

[0183] Treatment method In some embodiments, the Disclosure provides methods for treating subjects (e.g., humans) having a disease, disorder, or condition in which inhibition of one or more calcitonin receptors and / or amyrin receptors is beneficial in treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods provided herein may include treating conditions related to, coexisting with, or secondary to any one or more conditions provided herein.

[0184] Methods for treating calcitonin receptor and / or amyrin receptor-related diseases or disorders are provided herein, comprising administering to a subject in need an effective amount of a compound disclosed herein (e.g., the compound of formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvates thereof) or a pharmaceutical composition disclosed herein. Methods for treating or preventing calcitonin receptor and / or amyrin receptor-related diseases or disorders in a subject in need are also provided herein, comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., the compound of formula I, or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvates thereof) or a pharmaceutical composition thereof.

[0185] In some embodiments, the calcitonin receptor and / or amyrin receptor-related disease or disorder is a bone disorder, metabolic disorder, pain, neurodegenerative disease or disorder, cardiovascular disease, or other disease or disorder as described herein.

[0186] In some embodiments, the disease or disorder includes type 1 diabetes, type 2 diabetes, juvenile-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile-onset atypical diabetes (YOAD), juvenile-onset adult-onset diabetes (MODY), adult latent autoimmune diabetes (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, and left ventricle. Hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, decreased vascular compliance, restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorder, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation This includes, but is not limited to, premenstrual syndrome (cessation), premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine addiction, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, and polycystic ovary syndrome (PCOS).

[0187] In some embodiments, the disease or disorder includes type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, renal disease, adipocyte dysfunction, sleep apnea, visceral fat accumulation, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, hyperglycemia, postprandial dyslipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, and smoking cessation. This includes, but is not limited to, diabetes mellitus, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0188] In some embodiments, the disease or disorder includes, but is not limited to, type 2 diabetes, juvenile-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat accumulation, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial dyslipidemia, metabolic acidosis, ketosis, hyperinsulinemia, glucose metabolism disorders, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcers, or any combination thereof.

[0189] In some embodiments, the compounds and pharmaceutical compositions described herein, as well as methods for treating a patient, induce one or more of the following: a decrease in blood glucose (e.g., a decrease in blood glucose levels), a decrease in blood hemoglobin A1c (HbA1c) levels, an increase in insulin synthesis, an increase in β-cell mass, a regulation of gastric acid secretion, a regulation of gastric emptying, a decrease in body mass index (BMI), and / or a decrease in glucagon production (e.g., a decrease in levels). In some embodiments, the compounds and pharmaceutical compositions described herein, as well as methods for treating a patient, stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Methods for regulating glucose or insulin levels in a patient requiring such regulation are also provided herein, and such methods include administering to the patient an effective amount of one or more of the compounds disclosed herein, or their stereoisomers or mixtures thereof, or the pharmaceutical compositions disclosed herein.

[0190] In some embodiments, methods are provided herein for reducing the risk of major cardiovascular events (MACE) in patients in need thereof (e.g., by about 20%, 30%, 40%, 50%, 60%, 70%, or 80%), the methods comprising administering to the patient an effective amount of one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, or a pharmaceutical composition disclosed herein. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes mellitus (T2D). In some embodiments, the patient is an adult diagnosed with heart disease. In some embodiments, the patient is an adult diagnosed with both type 2 diabetes mellitus (T2D) and heart disease. In some embodiments, the patient is an adult with type 2 diabetes mellitus (T2D). In some embodiments, the patient is an adult with heart disease. In some embodiments, the patient has both type 2 diabetes mellitus (T2D) and heart disease.

[0191] In some embodiments, calcitonin receptor and / or amyrin receptor-related diseases or disorders are bone disorders, including, but not limited to, osteoporosis, Paget's disease, hypercalcemia, Sudeck's atrophy, multiple fibrous dysplasia, intercostal ossification, osteogenesis imperfecta, osteopenia, periodontal disease or defects, osteolytic bone disease, metastatic bone disorders, or bone defects resulting from malignant tumors, autoimmune arthritis, fracture or fracture, or immobility or non-use.

[0192] In some embodiments, calcitonin receptor and / or amyrin receptor-related disorders or impairments are pain, including, but not limited to, osteopathic pain, phantom limb pain, general pain, hyperalgesia, or pain associated with diabetic neuropathy.

[0193] In some embodiments, the calcitonin receptor and / or amyrin receptor-related disease or disorder is a neurodegenerative disease or disorder, which includes, but is not limited to, Alzheimer's disease.

[0194] In some embodiments, calcitonin receptor and / or amyrin receptor-related diseases or disorders are metabolic disorders, including, but not limited to, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, impaired glucose tolerance, obesity, syndrome X, or other diabetic complications.

[0195] In some embodiments, calcitonin receptor and / or amyrin receptor-related diseases or disorders include primary or secondary hyperthyroidism, endocrine disorders, conditions associated with gastric secretion suppression, gastrointestinal disorders, renal osteodystrophy, or male infertility.

[0196] In some embodiments, the compounds disclosed herein (e.g., compounds of formula I, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof), or the pharmaceutical compositions provided herein, are useful for alleviating insulin suppression in pancreatic tissue.

[0197] In some embodiments, the compounds disclosed herein (e.g., compounds of formula I, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof), or the pharmaceutical compositions provided herein, are useful for alleviating insulin resistance.

[0198] In some embodiments, the compounds disclosed herein (e.g., compounds of formula I, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof), or the pharmaceutical compositions provided herein, are useful for treating impaired glucose tolerance.

[0199] In some embodiments, the compounds disclosed herein (e.g., compounds of formula I, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof), or the pharmaceutical compositions provided herein, are useful for treating obesity and its symptoms.

[0200] In some embodiments, methods for reducing body fat or body fat gain are provided herein, the methods comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof) or a pharmaceutical composition provided herein.

[0201] In some embodiments, methods are provided herein for altering the body composition of a subject requiring treatment, wherein the method involves administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof) or a pharmaceutical composition provided herein.

[0202] In some embodiments, methods are provided herein for reducing body weight in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof) or a pharmaceutical composition provided herein.

[0203] In some embodiments, methods are provided herein for reducing the calorie intake of subjects requiring a reduction in calorie intake, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, or a solvate thereof) or a pharmaceutical composition provided herein.

[0204] In some embodiments, methods are provided herein for reducing body fat or body fat gain in a subject requiring treatment while maintaining or increasing lean body mass, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof) or a pharmaceutical composition provided herein.

[0205] In some embodiments, the compounds disclosed herein (e.g., compounds of formula I, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof), or the pharmaceutical compositions provided herein, are useful for treating hypertension.

[0206] In some embodiments, the compounds disclosed herein (e.g., compounds of formula I, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof), or the pharmaceutical compositions provided herein, are useful for treating essential hypertension.

[0207] In some embodiments, the compounds disclosed herein (e.g., compounds of formula I, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or solvates thereof), or the pharmaceutical compositions provided herein, are useful for treating subjects suffering from hypertension and hyperamylinemia.

[0208] In some embodiments, methods for treating hyperinsulinemia are provided herein, comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof) or a pharmaceutical composition provided herein.

[0209] In some embodiments, methods are provided herein for treating hypertensive and insulin-resistant subjects suffering from coronary artery disease and having hyperamylinemia or hyperinsulinemia, the methods comprising administering to subjects in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof) or a pharmaceutical composition provided herein.

[0210] In some embodiments, methods are provided herein for reducing the basis and submaximal stimulation rate of glycogen synthesis in a subject, the methods comprising administering to a subject requiring such reduction a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof) or a pharmaceutical composition provided herein.

[0211] In some embodiments, methods are provided herein for reducing the rate of glucose uptake into glycogen in muscle tissue of interest, the methods comprising administering to an interest subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, or a solvate thereof) or a pharmaceutical composition provided herein.

[0212] In some embodiments, methods are provided herein for treating obesity and hypertension, as well as associated dyslipidemia and atherosclerosis, the methods comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof) or a pharmaceutical composition provided herein.

[0213] In some embodiments, the compounds disclosed herein (e.g., compounds of formula I, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or solvates thereof), or the pharmaceutical compositions provided herein, are useful for modulating renin activity in subjects requiring it.

[0214] In some embodiments, methods are provided herein for treating or preventing the onset of heart failure in a subject, the methods comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, or a solvate thereof) or a pharmaceutical composition provided herein.

[0215] In some embodiments, the compounds disclosed herein (e.g., compounds of formula I, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or solvates thereof), or the pharmaceutical compositions provided herein, are useful for beneficially regulating gastrointestinal motility in subjects requiring it. In some embodiments, beneficial regulation of gastrointestinal motility includes delaying gastric emptying.

[0216] In some embodiments, the compounds disclosed herein (e.g., compounds of formula I, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or solvates thereof), or the pharmaceutical compositions provided herein, are useful for treating postprandial hyperglycemia in subjects requiring it.

[0217] obesity In some embodiments, a condition, disease, or disorder is obesity and any condition, disease, or disorder associated with or related to obesity. Non-limiting examples of conditions associated with obesity include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal fat). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obese type II diabetes mellitus, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence Moon-Beadle syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea, or beta-blocker-induced obesity).

[0218] In some embodiments, the pathology, disease, or disorder is related to obesity. Examples of such pathology, disease, or disorder include, but are not limited to, impaired glucose tolerance, diabetes mellitus (e.g., type 2 diabetes, obese diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), stroke (e.g., cerebral thrombosis, transient ischemic attack), bone or joint diseases (e.g., osteoarthritis of the knee, osteoarthritis of the hip, degenerative spondylosis, lower back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwick's syndrome), menstrual disorders (e.g., abnormal menstrual cycle, abnormal menstrual flow and cycle, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, and metabolic syndrome. In some embodiments, the chemical compounds and pharmaceutical compositions described herein may be used to treat patients exhibiting symptoms of both obesity and insulin deficiency.

[0219] diabetes In some embodiments, the condition, disease, or disorder is diabetes mellitus. Non-limiting examples of diabetes mellitus include type 1 diabetes mellitus, type 2 diabetes mellitus (e.g., type 2 diabetes treated with diet, type 2 diabetes mellitus treated with sulfonylureas, type 2 diabetes mellitus in a highly advanced stage, type 2 diabetes mellitus treated with long-term insulin), diabetes mellitus (e.g., non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus), gestational diabetes mellitus, obesity diabetes mellitus, autoimmune diabetes mellitus, and prediabetes. In some embodiments, the condition, disease, or disorder is type 2 diabetes mellitus (e.g., type 2 diabetes mellitus treated with diet, type 2 diabetes mellitus treated with sulfonylureas, type 2 diabetes mellitus in a highly advanced stage, type 2 diabetes mellitus treated with long-term insulin).

[0220] This specification provides a method for treating diabetes in a patient, the method comprising (a) determining that the patient has type 2 diabetes, and (b) administering to the patient a therapeutically effective amount of one or more compounds disclosed herein, or stereoisomers or mixtures thereof, or a pharmaceutical composition disclosed herein.

[0221] This specification provides a method for treating type 2 diabetes in a patient, the method comprising administering to a patient identified or diagnosed with type 2 diabetes one or more compounds disclosed herein, or a stereoisomer thereof or a mixture thereof, or a pharmaceutical composition disclosed herein, a therapeutically effective amount thereof.

[0222] This specification also provides a method for treating type 2 diabetes in patients in need thereof, the method comprising administering to the patient a therapeutically effective amount of one or more compounds disclosed herein, or stereoisomers or mixtures thereof, or a pharmaceutical composition disclosed herein.

[0223] In some embodiments, compounds, pharmaceutical compositions, and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) described herein reduce fasting plasma glucose levels. In some embodiments, compounds, pharmaceutical compositions, and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) described herein reduce non-fasting plasma glucose levels. In some embodiments, compounds, pharmaceutical compositions, and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) described herein reduce HbA1c levels. In some embodiments, compounds, pharmaceutical compositions, and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) described herein reduce glucagon levels. In some embodiments, compounds, pharmaceutical compositions, and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) described herein increase insulin levels. In some embodiments, compounds, pharmaceutical compositions, and methods for treating patients with a condition, disease, or disorder (e.g., type 2 diabetes) described herein reduce BMI.

[0224] In some embodiments, a reduction of approximately 5% to approximately 95% in fasting plasma glucose levels indicates treatment for type 2 diabetes. In some embodiments, a reduction of approximately 15% to approximately 80% in fasting plasma glucose levels indicates treatment for type 2 diabetes. In some embodiments, a reduction of approximately 25% to approximately 60% in fasting plasma glucose levels indicates treatment for type 2 diabetes. In some embodiments, a reduction of fasting plasma glucose levels to approximately 126 mg / dL or less, approximately 110 mg / dL or less, or approximately 90 mg / dL or less indicates treatment for type 2 diabetes.

[0225] In some embodiments, a reduction of approximately 5% to approximately 95% in non-fasting plasma glucose levels indicates treatment of type 2 diabetes. In some embodiments, a reduction of approximately 15% to approximately 80% in non-fasting plasma glucose levels indicates treatment of type 2 diabetes. In some embodiments, a reduction of approximately 25% to approximately 60% in non-fasting plasma glucose levels indicates treatment of type 2 diabetes. In some embodiments, a reduction of approximately 200 mg / dL or less, approximately 150 mg / dL or less, or approximately 130 mg / dL or less indicates treatment of type 2 diabetes.

[0226] In some embodiments, a reduction in HbA1c levels of approximately 5% to approximately 95% indicates treatment of type 2 diabetes. In some embodiments, a reduction in HbA1c levels of approximately 15% to approximately 80% indicates treatment of type 2 diabetes. In some embodiments, a reduction in HbA1c levels of approximately 25% to approximately 60% indicates treatment of type 2 diabetes. In some embodiments, a reduction in HbA1c levels to approximately 6.5% or less than 6.5%, approximately 6.0% or less than 6.0%, or approximately 5.0% or less than 5.0% indicates treatment of type 2 diabetes.

[0227] In some embodiments, a reduction in glucagon levels of approximately 5% to approximately 95% indicates treatment for type 2 diabetes. In some embodiments, a reduction in glucagon levels of approximately 15% to approximately 80% indicates treatment for type 2 diabetes. In some embodiments, a reduction in glucagon levels of approximately 25% to approximately 60% indicates treatment for type 2 diabetes. In some embodiments, an increase in insulin levels of approximately 5% to approximately 95% indicates treatment for type 2 diabetes. In some embodiments, an increase in insulin levels of approximately 15% to approximately 80% indicates treatment for type 2 diabetes. In some embodiments, an increase in insulin levels of approximately 25% to approximately 60% indicates treatment for type 2 diabetes.

[0228] In some embodiments, a BMI reduction of approximately 5% to approximately 95% indicates treatment of type 2 diabetes. In some embodiments, a BMI reduction of approximately 15% to approximately 80% indicates treatment of type 2 diabetes. In some embodiments, a BMI reduction of approximately 25% to approximately 60% indicates treatment of type 2 diabetes. In some embodiments, a BMI reduction of approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or approximately 95% indicates treatment of type 2 diabetes. In some embodiments, a BMI reduction to approximately 40 or less, approximately 30 or less, or approximately 20 or less indicates treatment of type 2 diabetes.

[0229] In some embodiments, the pathology, disease, or disorder is related to diabetes (e.g., complications of diabetes). Non-limiting examples of disorders related to diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macrovascular complications, osteopenia, hyperosmolar diabetic coma, infections (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral circulatory disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors associated with uncontrolled cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive impairment.

[0230] Other non-limiting examples of diabetes-related disorders include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-HDL cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic disorders in which GLP-1R activation is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0231] In some embodiments, the pathological condition, disease, or disorder is diabetes and obesity (diabetic obesity). In some embodiments, the compounds described herein are also useful in improving the therapeutic efficacy of metformin.

[0232] Damage to metabolically important tissues In some embodiments, the pathology, disease, or disorder is a disorder of metabolically important tissues. Non-limiting examples of metabolically important tissues include the liver, fat, pancreas, kidneys, and intestines.

[0233] In some embodiments, the condition, disease, or disorder is a fatty liver disease. Fatty liver diseases include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease due to hepatitis, fatty liver disease due to obesity, fatty liver disease due to diabetes, fatty liver disease due to insulin resistance, fatty liver disease due to hypertriglyceridemia, abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolmann disease, acute fatty liver of pregnancy, and lipodystrophy.

[0234] Non-alcoholic fatty liver disease (NAFLD) represents a range of conditions that occur in the absence of alcohol abuse and are typically characterized by the presence of fatty degeneration (fat in the liver). NAFLD is thought to be associated with various conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children and can eventually lead to cirrhosis (Skelly et al., J Hepatol 2001;35:195-9; Chitturi et al., Hepatology 2002;35(2):373-9). The severity of NAFLD ranges from relatively benign, isolated, and primarily macrodroplet fatty degeneration (i.e., non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002;17 Suppl:S186-90). In some embodiments, the patients are pediatric. As used herein, the term “pediatric patient” refers to a patient under 21 years of age at the time of diagnosis or treatment. The term “pediatric” can be further divided into various subgroups, including: neonates (from birth to 1 month of age); infants (1 month to 2 years of age); children (2 years to 12 years of age); and adolescents (12 years to 21 years of age (excluding the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, pediatric patients are defined as those from birth to 28 days old, from 29 days old to under 2 years old, from 2 years old to under 12 years old, or from 12 years old to 21 years old (excluding their 22nd birthday, but up to that point).In some embodiments, pediatric patients are from birth to 28 days old, from 29 days old to under 1 year old, from 1 month to under 4 months old, from 3 months to under 7 months old, from 6 months to under 1 year old, from 1 year to under 2 years old, from 2 years to under 3 years old, from 2 years to under 7 years old, from 3 years to under 5 years old, from 5 years to under 10 years old, from 6 years to under 13 years old, from 10 years to under 15 years old, or from 15 years to under 22 years old. In some embodiments, the patient is an adult patient.

[0235] Other non-limiting examples of disorders in metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), fatty degeneration (e.g., in the liver); gallstones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorders characterized by changes in bone metabolism (e.g., osteoporosis (including postmenopausal osteoporosis), decreased bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, bone dystrophy in liver disease, and changes in bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection against fractures, and malnutrition, polycystic ovary syndrome); kidney diseases (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In some embodiments, the compounds and pharmaceutical compositions described herein may be used to treat surgical trauma by improving postoperative recovery and / or by preventing catabolic reactions caused by surgical trauma.

[0236] Cardiovascular and vascular diseases In some embodiments, the disease or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular diseases include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., ≥130 / 85 mmHg), and prethrombotic conditions (exemplified by high fibrinogen or plasminogen activator inhibitor levels in the blood).

[0237] In some embodiments, the disease or disorder is related to vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular dysfunction, peripheral artery disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorders (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, severe limb ischemia, retinopathy, nephropathy, and neuropathy.

[0238] Neurological diseases In some embodiments, the disease or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include cerebral insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperactivity, mania, Parkinson's disease (Morbus Parkinson), Steele-Richardson syndrome, Down syndrome, myasthenia gravis, neurotrauma, traumatic brain injury, vascular amyloidosis, cerebral hemorrhage with amyloidosis I, encephalitis, Friedrich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting diseases). For example, see US2006 / 0275288A1.

[0239] Non-limiting examples of mental disorders include drug addiction / indulgence (narcotics and amphetamines, as well as attention deficit hyperactivity disorder (ADHD)). The compounds and pharmaceutical compositions described herein may be useful in improving behavioral responses to addictive substances, reducing drug dependence, preventing drug relapse, and alleviating anxiety caused by the absence of certain addictive substances. See, for example, US2012 / 0021979A1.

[0240] In some embodiments, the compounds and pharmaceutical compositions described herein are useful in improving learning and memory by enhancing neuroplasticity and promoting cell differentiation, as well as in preserving dopamine neurons and motor function in Morbus Parkinson's disease.

[0241] Insulin-related conditions and disorders In some embodiments, the disease or disorder is poor fasting blood glucose (IFG), abnormal fasting blood glucose levels (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hypoglycemic state, insulin resistance syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, impaired glucose tolerance, increased fasting blood glucose, dyslipidemia (e.g., atherosclerotic dyslipidemia characterized by hyperlipidemia, high triglycerides and low HDL cholesterol), glucagonoma, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concomitant coma endpoints.

[0242] In some embodiments, the compounds and pharmaceutical compositions described herein may reduce or delay the progression of prediabetes, poor fasting blood glucose, or abnormal fasting blood glucose levels to diabetes.

[0243] autoimmune disorders In some embodiments, the disease or disorder is an autoimmune disorder. Non-exclusive examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves' disease. See, for example, US20120148586A1.

[0244] Stomach and intestinal disorders In some embodiments, the disease or disorder is a gastrointestinal or intestinal disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infection or other pathogens), digestive disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac sprue, hypogammaglobulinemia sprue, chemotherapy and / or radiotherapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexies (e.g., cancerous cachexies, tuberculous cachexies, cachexies associated with hematological disorders, cachexies associated with endocrine disorders, cachexies associated with infectious diseases, and cachexies caused by acquired immunodeficiency syndromes).

[0245] body weight In some embodiments, the compounds and pharmaceutical compositions described herein may be used to reduce body weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a patient (e.g., a patient in need of it). In some embodiments, weight gain in a patient may be due to excessive food intake or an unbalanced diet, or to weight gain due to concomitant medications (e.g., insulin sensitizers having PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, siglitazone, pioglitazone, etc.). In some embodiments, weight gain may be weight gain before becoming obese, or weight gain in an obese patient. In some embodiments, weight gain may be drug-induced weight gain or weight gain after quitting smoking.

[0246] In some embodiments, the disease or disorder is an eating disorder such as bulimia, binge eating, bulimia nervosa, or compulsive eating.

[0247] inflammatory diseases In some embodiments, the disease or disorder is an inflammatory disorder. Non-limiting examples of inflammatory disorders include chronic rheumatoid arthritis, spondylitis degenerative, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, laryngitis, cystitis, pneumonia, pancreatitis, colitis, inflammatory bowel disease (including inflammatory bowel disease), inflammation in metabolically important tissues including the liver, fat, pancreas, kidneys and intestines, and pro-inflammatory conditions (e.g., elevated levels of pro-inflammatory cytokines or markers of inflammation such as C-reactive protein in the blood).

[0248] cancer In some embodiments, the disease or disorder is cancer. Preferred examples of cancer include breast cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., ductal adenocarcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor) Tumors), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (e.g., non-Hodgkin lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., primary Liver cancer, extrahepatic cholangiocarcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), cholangiocarcinoma, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid cancer), parathyroid cancer, This includes nasal cavity cancer, paranasal sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, pediatric solid tumors (e.g., Wilms' tumor, pediatric renal tumors), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0249] Hypothalamic-pituitary dysfunction In some embodiments, the disease or disorder is related to the hypothalamic-pituitary-gonadal axis. For example, the pathology, disease, or disorder is related to the hypothalamic-pituitary-ovarian axis. In another example, the pathology, disease, or disorder is related to the hypothalamic-pituitary-testicular axis. Hypothalamic-pituitary-gonadal axis disorders include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

[0250] In some embodiments, diabetes-related diseases or disorders are associated with the hypothalamic-pituitary-gonadal axis.

[0251] Lung disease In some embodiments, the disease or disorder is related to a lung disease. Lung diseases include, but are not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hypopnea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (irreversible) asthma).

[0252] In some embodiments, the diabetes-related disease or disorder is a lung disease.

[0253] Combination therapy In some embodiments, this disclosure envisions both monotherapy regimens and combination therapy regimens.

[0254] In some embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the compounds described herein.

[0255] In some embodiments, the methods described herein include administering the compounds described herein in combination with one or more of the following: diet therapy (e.g., dietary monitoring, diabetes diet therapy), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modification.

[0256] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, may be administered in combination with one or more additional therapeutic agents.

[0257] Typical additional therapeutic agents include, but are not limited to, anti-obesity agents, diabetic agents, diabetic complications agents, hyperlipidemia agents, antihypertensive agents, diuretics, chemotherapeutic agents, immunotherapies, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis agents, vitamins, anti-dementia drugs, erectile dysfunction drugs, medications for frequent urination or urinary incontinence, NAFLD agents, NASH agents, dysuria agents, and antiemetics.

[0258] In some embodiments, one or more additional therapeutic agents include, for example, those useful as anti-obesity agents. Non-limiting examples include monoamine reuptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensin), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulators, GABA modulators (e.g., topiramate) (including GABA receptor agonists (e.g., gabapentin, pregabalin)), neuropeptide Y antagonists (e.g., berneperit), cannabinoid receptor antagonists Gonists (e.g., limonabant, taranaban), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylates inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), dia Silglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturates inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose cotransporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin), NFK inhibitors (e.g., HE-3286), PPAR Agonists (e.g., GFT-505, DRF-11605, gemfibrozil and fenofibrate), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodoskemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucokinase activators (e.g., pyragliatin, AZD-1656, AZD6370, TTP-355, W0006 / 112549, W0007 / 028135, W0008 / 047821, W0008 / 050821,Compounds described in W0008 / 136428 and W0008 / 156757), leptin, leptin derivatives (e.g., metreleptin), leptin resistance improvers, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., plumlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obinate, TM-30339, TM-30335), oxintomodulin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal extract from bovine or porcine pancreas) This includes FGF21 preparations (genetically synthesized human FGF21 preparations using E. coli or yeast; fragments or derivatives of FGF21), appetite suppressants (e.g., P-57), human proislet peptides (HIP), farnesoid X receptor (FXR) agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, fendimethrazine, benzfetamine, fibroblast growth factor receptor (FGFR) modulators, and AMP-activated protein kinase (AMPK) activators.

[0259] In some embodiments, one or more compounds disclosed herein, or their stereoisomers or mixtures thereof, may be administered in combination with one or more additional therapeutic agents, wherein the additional therapeutic agents are GLP-1 agonists or exhibit GLP-1 agonist activity.

[0260] In some embodiments, additional therapeutic agents include TTP273, LY2944876 (pegapamozutide), HDM1002, K-757, K-833, letatorutide, IBI362 (mazuzutide), cotazutide, AMG133, CT-868, HRS9531, HS-20094, dapiglutide, efinopegzutide, efosipegtorutide, pembizutide, sulvozutide, AP026, AZD9550, BGM0504, CT-388, DD01, DR10624, G3215, GMA106, HEC88473, HZ0 10, LY3493269, MWN101, NN9487, NN9541, RAY1225, SCO-094, SHR-1816, TB001, VK2735, ZP2929, echnoglutide, GX-G6, GZR18, HRS-7535, YH14617, abexitide, floniglutide, pegcebrenatide, brorenatide, JY09, NB1001, Byetalog, GW002, HL08, KN056, SAL0112, SHR2042, VCT220, ZT002, ZYOG1, or utreglutide.

[0261] In some embodiments, additional therapeutic agents include endogenous GLP-1, endogenous glucagon, oxytomodulin, exendin-4, exenatide, lixisenatide, albiglutide, veinaglutide, dulaglutide, efpeglenatide, lamglenatide, liraglutide, semaglutide, taspoglutide, tilzepatide, pegapamozutide, lithium chloride, and PF-06. These are 882961 (Danuglypron), LY3502970 (Olfolglypron), ECC-5004, GSBR-1290, AZD0186, PF-07081532 (Rotiglycropron), VCT220, TERN-601, RGT-075, CT-996, MDR-001, SAL0112, XW014, AVE-0010, S4P, or Boc5.

[0262] In some embodiments, one or more compounds disclosed herein, or stereoisomers thereof, or mixtures thereof may be administered in combination with one or more additional therapeutic agents, the additional therapeutic agents being selected from the compounds disclosed in WO2021 / 155841, WO / 2018 / 109607, WO / 2018 / 056453, WO / 2019 / 239319, or WO / 2019 / 239371.

[0263] In some embodiments, one or more additional therapeutic agents include, for example, those useful as antidiabetic agents.Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or its salts), biguanides (e.g., metformin, buformin or its salts (e.g., hydrochloride, fumarate, succinate)), glucagon analogs (e.g., WO Any of the glucagon analogs listed in 2010 / 011439, etc., agents that antagonize the action of glucagon or reduce glucagon secretion, sulfonylureas (e.g., chlorpropamide, trazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glibzol, glibride), thiazolidinediones (e.g., rosiglitazone or pioglitazone), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, e.g., mealtime glucose regulators (sometimes called "rapid-acting secretagogues"), e.g., meglitinides (e.g., repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, Tacrine), NMDA receptor antagonists, dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, aviglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P, and Boc5), and dipeptidyl peptidase IV (DPP). -4) Inhibitors (e.g., vildagliptin, zutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adgliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin) are included.

[0264] In some embodiments, one or more additional therapeutic agents include, for example, those useful for treating NAFL and NASH. Non-limiting examples include FXR agonists, PF-05221304, synthetic fatty acid-bile conjugates, anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies, caspase inhibitors, MAPK5 inhibitors, galectin 3 inhibitors, fibroblast growth factor 21 (FGF21), niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, apoptosis signal-regulated kinase 1 (ASK1) inhibitors, and ileal bile acid trans This includes porter (IBAT) inhibitors, glycyrrhizin, schisandra extract, ascorbic acid, glutathione, silymarin, lipoic acid, and d-α-tocopherol, ascorbic acid, glutathione, B vitamins, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteamine, sulfonylureas, α-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipustatin, milk thistle protein, antiviral agents, and antioxidants.

[0265] In some embodiments, one or more additional therapeutic agents include, for example, those useful for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., torrestat, epalrestat, zoporerestat, fidarestat, CT-112, ranirestat, lidrestat), neurotrophic factors and their enhancers (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion enhancers described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in WO2004 / 039365), PKC inhibitors (e.g., ruboxy These include staurine mesylate, AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridrine, pyridoxamine), serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen species scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal-regulated kinase-1 (ASK-1) inhibitors.

[0266] In some embodiments, one or more additional therapeutic agents include, for example, those useful for treating hyperlipidemia. Non-limiting examples include HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl]acetyl This includes [L]piperidine-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, symfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), nicotinic acid derivatives (e.g., nicomole, niceritrol, niaspan), phytosterols (e.g., soysterol, gamma-oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., zethia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and ω-3 fatty acid preparations (e.g., ω-3 fatty acid ethyl ester 90).

[0267] In some embodiments, one or more additional therapeutic agents include, for example, those useful as antihypertensive agents. Non-limiting examples include angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, delapril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine), and beta-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[0268] In some embodiments, one or more additional therapeutic agents include, for example, those useful as diuretics. Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., etiazide, cyclopentiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, meticlothiazide), anti-aldosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide), and chlorobenzenesulfonamide preparations (e.g., chlorthalidone, mefluside, indapamide).

[0269] In some embodiments, one or more additional therapeutic agents include, for example, those useful as immunotherapeutic agents. Non-limiting examples include microbial or bacterial compounds (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunoenhancing activity (e.g., lentinan, schizophyllan, krestin), cytokines obtained by genetic engineering techniques (e.g., interferons, interleukins (IL) such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).

[0270] In some embodiments, one or more additional therapeutic agents include, for example, those useful as antithrombotic agents. Non-limiting examples include heparins (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin agents (e.g., argatroban, dabigatran); FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740). This includes compounds described in WO2005 / 058823 and WO2005 / 113504; thrombolytic agents (e.g., urokinase, tysokinase, alteplase, nateplase, monteplase, pamiteplase); and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl eicosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[0271] In some embodiments, one or more additional therapeutic agents include, for example, those useful for treating osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcatonin, salmoncalcitonin, estriol, ipriflavone, disodium pamidronate, sodium alendronate hydrate, disodium incadronate, and disodium risedronate. Preferred examples of vitamins include vitamin B1 and vitamin B12. Preferred examples of erectile dysfunction drugs include apomorphine and sildenafil citrate. Preferred examples of therapeutic agents for frequent urination or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, and propiverine hydrochloride. Preferred examples of therapeutic agents for dysuria include acetylcholinesterase inhibitors (e.g., distigmine). Preferred examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs such as aspirin, acetaminophen, and indomethacin.

[0272] Other exemplary additional therapeutic agents include agents designed to treat complications of long-term hyperglycemia, such as those that regulate hepatic glucose balance (e.g., fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), aldose reductase inhibitors (e.g., epalrestat and ranilestat), agents used to treat complications associated with microangiopathy, and dyslipidemia treatments, such as HMG-CoA reductase inhibitors (statins, e.g., ros). These include vastatin, cholesterol-lowering agents, bile acid adsorbents (e.g., cholestyramine), cholesterol absorption inhibitors (e.g., plant sterols such as phytosterols), cholesterol ester transfer protein (CETP) inhibitors, ileal bile acid transport system inhibitors (IBAT inhibitors), bile acid binding resins, nicotinic acid (niacin) and its analogues, antioxidants (e.g., probucol), omega-3 fatty acids, and antihypertensive agents, which include adrenergic receptor antagonists, such as beta-blockers (e.g., atenolol), and alpha-blockers (e.g., (e.g., doxazosin), and mixed α / β blockers (e.g., labetalol), adrenergic receptor agonists, including α-2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril), calcium channel blockers, such as dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazepines (e.g., diltiazem), angiotensin II receptor antagonists (e.g., candesartan), aldosterone receptor antagonists (e.g., For example, eplerenone, centrally acting adrenergic agonists, such as central α-agonists (e.g., clonidine), diuretics (e.g., furosemide), hemostatic modulators, including antithrombotic agents (e.g., fibrinolytic activators), thrombin antagonists, factor VIIa inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), heparin and its low molecular weight analogs, factor Xa inhibitors, and direct thrombin inhibitors (e.g., argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g., aspirin)),Adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tyrofiban), adenosine reuptake inhibitors (e.g., dipyridamole), norepinephrine agents (e.g., phentermine), serotonin agents (e.g., sibutramine), diacylglycerol acyltransferase (DGAT) inhibitors, feeding behavior modifiers, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamylase Electrotransmission modulators, such as selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine), norepinephrine reuptake inhibitors (NARIs), norepinephrine-serotonin reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) (e.g., troxatone and amyflamin), compounds described in WO0007 / 013694, WO2007 / 018314, WO2008 / 093639 and WO2008 / 099794, GPR40 agonists (e.g., faciglifam or its hydrate), WO200 Compounds described in 4 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 and WO2008 / 001931), SGLT1 inhibitors, adiponectin or its agonists, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexy improving agents, e.g., cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., mexomethacin acetate) Gestrol), glucocorticoids (e.g., dexamethasone), metoclopramide, tetrahydrocannabinol, lipid metabolism enhancers (e.g., eicosapentaenoic acid), growth hormone, IGF-1, cachexy inducer TNF-α, LIF, IL-6, and antibodies against oncostatin M, glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDE5 inhibitors,Glycation inhibitors (e.g., ALT-711), nerve regeneration promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trireptal, Keppra, Zonegran, pregabalin, harcoceride, carbamazepine), antiarrhythmic drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT) -627), narcotic analgesics (e.g., morphine), α2 receptor agonists (e.g., clonidine), topical analgesics (e.g., capsaicin), anxiolytics (e.g., benzothiazepine), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T cell receptor and IL-2 receptor specific antibodies), B cell depletion therapy (e.g., anti-CD20 antibodies (e.g., lithuxane), i-BLyS antibodies), T cells Drugs that affect migration (e.g., anti-integrin α4 / β1 antibodies (e.g., Tysabri)), drugs that act on immunophyllines (e.g., cyclosporine, tacrolimus, sirolimus, rapamycin), interferons (e.g., IFN-β), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosuppressants (e.g., mycophenolic acids), as well as metaglidacen, AMG-131, paraglitazone, MBX-2044, This includes riboglitazone, alleglitazar, tiglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl eicosapentate, clonidine, azosemide, isosorbide, ethacrine, pyretanide, bumetanide, etoposide, piroxicam, NO donors (e.g., organic nitrates), and NO promoters (e.g., phosphodiesterase inhibitors).

[0273] In some embodiments, one or more additional therapeutic agents include, for example, those useful as antiemetics. As used herein, “antiemetic” means any agent that counteracts (e.g., reduces or eliminates) nausea or vomiting (nausea). When referring to a therapeutically effective dose of an antiemetic, it should be understood that the amount administered is the amount required to counteract (e.g., reduce or eliminate) nausea or vomiting (nausea). While we do not wish to be bound by theory, it is thought that administering one or more antiemetics in combination with a compound of formula (I) described herein may allow for the administration of higher doses of the compound of formula (I), for example, because the patient may be able to maintain normal food intake and thereby respond more quickly to treatment.

[0274] Non-exclusive examples of antiemetics include 5HT3 receptor antagonists (serotonin receptor antagonists), neuroleptics / antipsychotics, antihistamines, anticholinergics, steroids (e.g., corticosteroids), NK1 receptor antagonists (e.g., neurokinin 1 substance P receptor antagonists), antidopaminergics / dopamine receptor antagonists, benzodiazepines, and cannabinoids.

[0275] For example, antiemetics may be selected from a group consisting of neuroleptics, antihistamines, anticholinergics, steroids, 5HT-3 receptor antagonists, NK1 receptor antagonists, anti-dopaminergic agents / dopamine receptor antagonists, benzodiazepines, and non-psychoactive cannabinoids.

[0276] In some embodiments, the antiemetic is a 5HT3 receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: granisetron (Kytril), drasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, allosetron, azasetron, bemethetron, zatisetron, batanopirde, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]nonan-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222 includes tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazine-1-yl)-2-quinoxaline carbonnitrile maleate, zacoprid hydrochloride, and mirtazapine. Other non-exclusive examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: silancetron, clozapine, cyproheptadine, dazoprid, hydroxyzine, rerisetron, metoclopramide, mianserin, olanzapine, palonosetron (+netupitant), quetiapine, qamosetron, lamosterone, ricasetron, risperidone, ziprasidone, and zatosetron.

[0277] In some embodiments, the 5HT-3 receptor antagonist is granisetron, drasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemethetron, zatisetron, batanopirde, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL-72222, tropanyl-3,5-dimethylbenzoate, 3-(4-allylpiperazine-1-yl)-2-quinoxaline carbonnitrile maleate, zacoprid hydrochloride, and mirtazapine.

[0278] In some embodiments, the 5HT-3 receptor antagonist is granisetron, drasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, allosetron, bemethetron, and zatisetron.

[0279] In some embodiments, the 5HT-3 receptor antagonist is granisetron, drasetron, or ondansetron.

[0280] In some embodiments, the 5HT-3 receptor antagonist is granisetron.

[0281] In some embodiments, the 5HT-3 receptor antagonist is ondansetron.

[0282] In some embodiments, the antiemetic is an antihistamine. Non-limiting examples of antihistamines include: piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinates (dramanin, gravol); diphenhydramine; hydroxyzine; buclidine; and meclizine hydrochloride (bonin, antibart), doxylamine, and mirtazapine.

[0283] In some embodiments, antiemetics are anticholinergics (inhibitors of acetylcholine receptors). Non-limiting examples of anticholinergics include: atropine, scopolamine, glycopyrone, hyostine, altan (trihexy-5-trihexyphenidyl hydrochloride), cogentine (benztropine mesylate), akineton (biperiden hydrochloride), disipal (norflex orphenadyl hydrate), diphenhydramine, hydroxyzine, hyoscyamine, and kemadrin (procyclidine hydrochloride).

[0284] In some embodiments, the antiemetic is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include: betamethasone, dexamethasone, methylprednisolone, prednisone®, and trimethobenzamide (Tigan).

[0285] In some embodiments, the antiemetic is an NK1 receptor antagonist (e.g., a neurokinin 1 substance P receptor antagonist). Non-limiting examples of NK1 receptor antagonists include: aprepitant, casopitant, ezropitant, fosaprepitant, maropitant, netsupitant, lorapitant, and vestipitant.

[0286] Other non-exclusive examples of NK1 receptor antagonists include: MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (norpitantium besylate / chloride), LY 303870 (ranepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK 333A, YM-49244, YM-44778, ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK-33A, 6b-l, CJ-11974 j. Benserazide and carbidopa k TAK-637[(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazosino[2,1-g][1,7]naphthyridine-6,13-dione], PD This includes 154075, ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)Ph), FK888, and (D-Pro4,D-Trp7,9,10,Phe11)SP4-11.

[0287] In some embodiments, the antiemetic is an anti-dopamine agent / dopamine receptor antagonist (e.g., dopamine receptor antagonists, e.g., D2 or D3 antagonists). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine); benzamides (e.g., metoclopramide, domperidone); butyrophenones (e.g., haloperidol, droperidol); arizaprid, bromoprid, clevopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[0288] In some embodiments, the antiemetic is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), cannabidiol dimethylheptyl (CBD-DMH), tetrahydrocannabinol (THC), cannabinoid agonists, e.g., WIN 55-212 (CB1 and CB2 receptor agonist), dronabinol (Marinol®), and nabilone (Cesamet)).

[0289] Other exemplary antiemetics include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptics / antipsychotics (e.g., dixylazine, haloperidol, and prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphate; fructose; glucose (Emetrol); bismuth subsalicylate (PeptoBismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[0290] Further exemplary antiemetics include those disclosed in US20120101089A1;US10,071,088B2;US6,673,792B1;US6,197,329B1;US10,828,297B2;US10,322,106B2;US10,525,033B2;WO2009080351A1;WO2019203753A2;WO2002020001A2;US8,119,697B2;US5,039,528;US20090305964A1; and WO2006 / 111169, each of which is incorporated in whole by reference.

[0291] In some embodiments, additional therapeutic agents or treatment regimens are administered to the patient before contact with or administration of the compound and pharmaceutical composition (e.g., about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month prior).

[0292] In some embodiments, additional therapeutic agents or treatment regimens are administered to the patient almost simultaneously with contact with or administration of the compound and pharmaceutical composition. For example, the additional therapeutic agents or treatment regimens, as well as the compound and pharmaceutical composition, are provided to the patient simultaneously in the same dosage form. In another example, the additional therapeutic agents or treatment regimens, as well as the compound and pharmaceutical composition, are provided to the patient in parallel in separate dosage forms.

[0293] Patient selection In some embodiments, the methods described herein further include the step of identifying patients (e.g., subjects) who require such treatment (e.g., by blood assays, body mass index, or other conventional methods known in the art).

[0294] In some embodiments, the methods described herein further include the step of identifying a patient (e.g., a patient) who has type 2 diabetes. In some embodiments, determining whether a patient has type 2 diabetes involves performing an assay to determine the levels of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the HbA1c level is between about 6.5% and about 24.0%. In some embodiments, the HbA1c level is 6.5% or greater or about 6.5%. In some embodiments, the HbA1c level is 8.0% or greater or about 8.0%. In some embodiments, the HbA1c level is greater than 10.0% or about 10.0%. In some embodiments, the HbA1c level is greater than 12.0% or about 12.0%. In some embodiments, the HbA1c level is greater than 14.0% or about 14.0%. In some embodiments, the HbA1c level is greater than or about 16.0%. In some embodiments, the HbA1c level is greater than or about 18.0%. In some embodiments, the HbA1c level is greater than or about 20.0%. In some embodiments, the HbA1c level is greater than or about 22.0%. In some embodiments, the HbA1c level is greater than or about 24.0%.

[0295] In some embodiments, fasting plasma glucose levels range from over 120 mg / dL or about 120 mg / dL to over 750 mg / dL or about 750 mg / dL. In some embodiments, fasting plasma glucose levels range from over 200 mg / dL or about 200 mg / dL to over 500 mg / dL or about 500 mg / dL. In some embodiments, fasting plasma glucose levels range from over 300 mg / dL or about 300 mg / dL to over 700 mg / dL or about 700 mg / dL.

[0296] In some embodiments, non-fasting plasma glucose levels range from greater than or approximately 190 mg / dL to greater than or approximately 750 mg / dL. In some embodiments, non-fasting plasma glucose levels range from greater than or approximately 250 mg / dL to greater than or approximately 450 mg / dL. In some embodiments, non-fasting plasma glucose levels range from greater than or approximately 400 mg / dL to greater than or approximately 700 mg / dL.

[0297] In some embodiments, determining whether a patient has type 2 diabetes further includes determining the patient's BMI. In some embodiments, the patient's BMI is 22 kg / m². 2 Over or approximately 22 kg / m 2 From 100 kg / m 2 Over or approximately 100 kg / m 2 Up to this point. In some embodiments, the patient's BMI is 30 kg / m². 2 Over or approximately 30 kg / m 2 From 90 kg / m 2 Over or approximately 90 kg / m 2 Up to this point. In some embodiments, the patient's BMI is 40 kg / m². 2 Over or approximately 40 kg / m 2 From, 80 kg / m 2 Over or approximately 80 kg / m 2 Up to that point. In some embodiments, the patient's BMI is 50 kg / m². 2 Over or approximately 50 kg / m 2 From, 70 kg / m 2 Over or approximately 70 kg / m 2 That is the end.

[0298] In some embodiments, additional factors (e.g., risk factors) used to determine whether a patient has type 2 diabetes further include the patient's age and ethnicity. In some embodiments, the patient's age is over 10 years or about 10 years. In some embodiments, the patient's age is over 15 years or about 15 years. In some embodiments, the patient's age is over 20 years or about 20 years. In some embodiments, the patient's age is over 25 years or about 25 years. In some embodiments, the patient's age is over 30 years or about 30 years. In some embodiments, the patient's age is over 35 years or about 35 years. In some embodiments, the patient's age is over 40 years or about 40 years. In some embodiments, the patient's age is over 42 years or about 42 years. In some embodiments, the patient's age is over 44 years or about 44 years. In some embodiments, the patient's age is over 46 years or about 46 years. In some embodiments, the patient's age is over 48 years or about 48 years. In some embodiments, the patient's age is over 50 or approximately 50 years old. In some embodiments, the patient's age is over 52 or approximately 52 years old. In some embodiments, the patient's age is over 54 or approximately 54 years old. In some embodiments, the patient's age is over 56 or approximately 56 years old. In some embodiments, the patient's age is over 58 or approximately 58 years old. In some embodiments, the patient's age is over 60 or approximately 60 years old. In some embodiments, the patient's age is over 62 or approximately 62 years old. In some embodiments, the patient's age is over 64 or approximately 64 years old. In some embodiments, the patient's age is over 66 or approximately 66 years old. In some embodiments, the patient's age is over 68 or approximately 68 years old. In some embodiments, the patient's age is over 70 or approximately 70 years old. In some embodiments, the patient's age is over 72 or approximately 72 years old. In some embodiments, the patient's age is over 74 years or approximately 74 years. In some embodiments, the patient's age is over 76 years or approximately 76 years. In some embodiments, the patient's age is over 78 years or approximately 78 years. In some embodiments, the patient's age is over 80 years or approximately 80 years.In some embodiments, the patient's age is over 85 years or approximately 85 years. In some embodiments, the patient's age is over 90 years or approximately 90 years. In some embodiments, the patient's age is over 95 years or approximately 95 years. In some embodiments, the patient's ethnicity may be African American, Native American or Alaskan Native, Asian American, Hispanic or Latino, or Native Hawaiian or Pacific Islander.

[0299] Compound Synthesis The compounds of this disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where specific process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the reactants or solvent used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0300] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as preferred conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in TW Greene and GMWuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0301] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Therefore, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as concentrated mixtures of stereoisomers. Unless otherwise indicated, all such stereoisomers (and concentrated mixtures) are included within the scope of this disclosure. Pure stereoisomers (or concentrated mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds may be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0302] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, USA), EMKA-Chemie GmbH & Co. KG (Eching, Germany), or MilliporeSigma (Burlington, USA). Other preparations may be made by procedures or obvious modifications thereof described in standard references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

[0303] Scheme I illustrates a general method that may be selected for the synthesis of the compounds described herein, where A, ring B, L 1 , L 2 , R 1 , R 3 , Y 3 , R 4 , and R 5 Each of these is independently defined as herein, and R 50 It is an alkyl or substituted alkyl group. Scheme I [ka]

[0304] Polysubstituted pyridine compounds I-4 or I-7 can be synthesized using the Hantsch pyridine synthesis strategy. As shown in Scheme I, compound I-1 is coupled with compounds I-2 and I-3 to obtain I-4, and compound I-6 is coupled with compounds I-2 and I-3 to obtain I-7. In some embodiments, the coupling reaction is carried out in a suitable solvent (e.g., ethanol) under heating conditions. Compound I-5 is obtained by oxidation of I-4 with CAN or DDQ, etc., which is then further converted to a heteroaryl using methods known in the art to obtain the compound of formula I. Compound I-7 is obtained by oxidation of compound I-7 under similar reaction conditions to obtain the compound of formula I.

[0305] It should be understood that for any compound shown in Scheme I, various derivatives can be obtained by functional group interconversion in any step. In some embodiments, various substituents (e.g., A, ring B, L) of compounds I-1, I-2, I-3, I-4, I-5, I-6, or I-7 are used. 1 , L 2 , R 1 , R 3 , Y 3 , R 4 , and R 5 ) is as defined herein. However, derivatization of compounds I-1, I-2, I-3, I-4, I-5, I-6, or I-7 before reaction in any step, and / or further derivatization of the resulting reaction product, provides a variety of compounds of formula I. Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art.

[0306] After the reaction is complete, the compounds of formula I can be recovered by conventional methods such as neutralization, extraction, precipitation, chromatography, and filtration. In some embodiments, where stereochemical control is desired, appropriate control of reaction conditions and selection of substituents on the reagents can at least partially specify or maintain the formation of various stereoisomers. Compounds I-1, I-2, and I-3 may be commercially available or newly synthesized. For example, compounds I-1 and I-6 may be prepared as shown in scheme II or scheme III. Scheme II [ka]

[0307] A-1 is reacted with meldrumic acid to obtain intermediate A-2, which is then decarboxylated to obtain β-keto acid compound I-1. Compound I-1 can also be synthesized directly by reacting A-1 with alkyl potassium malonate in the presence of CDI and MgCl2.

[0308] Compound I-1 can also be reacted with ethane-1,2-diol to obtain intermediate A-3. Generally, the carboxylate group of A-3 is converted to various heteroaryl groups to obtain intermediate A-7, which is then deprotected with a mixture of H2SO4 and formic acid to obtain compound I-6. For example, hydrolysis of the ester group of intermediate A-3 yields a carboxylic acid, which can be reacted under appropriate conditions to obtain intermediate A-7 (for example, by reacting it with acetohydrazide using HATU and DIEA, and then cyclizing it with 4-toluenesulfonic acid chloride to obtain oxadiazole). Deprotection of intermediate A-7 yields compound I-6. Scheme III [ka]

[0309] Compound I-6 is obtained by reacting carboxylic acid A-1 with potassium carboxylic acid salt A-8 in the presence of CDI and MgCl2.

[0310] The following scheme IV shows a general scheme for synthesizing indanylamine I-7, which is R 5 It can be used to prepare compounds of formula I, which are cycloalkyl groups that may be appropriately substituted. Scheme IV [ka]

[0311] Aldehyde A-8 (v is 0-5, each Z 5 (which is independently defined herein) is reacted with meldrum acid A-9 to obtain carboxylic acid A-10. This is reacted with oxalyl chloride to obtain the corresponding acyl chloride A-11, which undergoes intramolecular Friedel-Crafts acylation to produce ketone A-12. This is then reacted with A-13 to obtain tert-butylsulfinamide A-14. Reduction of the sulfinamide using DIBAL-H yields A-15. Deprotection under acidic conditions yields indanylamine intermediate I-7.

[0312] After each reaction is complete, each intermediate or final compound can be recovered and purified as appropriate by conventional methods such as neutralization, extraction, precipitation, chromatography, and filtration. Other modifications to obtain the compounds of this disclosure are within the scope of the art.

[0313] General synthesis Typical embodiments of the compounds described herein may be synthesized using the general reaction scheme described below. Given the descriptions herein, it will be apparent that the general scheme can be modified by substituting the starting materials with other materials having similar structures, and correspondingly different products can be obtained. To provide numerous examples of how to modify the starting materials to obtain the corresponding products, the synthesis is described below. Given the desired products with defined substituents, the required starting materials may generally be determined by scrutiny. Starting materials are typically obtained from commercial suppliers or synthesized using published methods. To synthesize the compounds in the embodiments described herein, each substituent will be identified by scrutinizing the structure of the compound to be synthesized. Given the examples herein, the required starting materials will be easily identified by a simple scrutiny process by identifying the final product. Generally, the compounds described herein are typically stable at room temperature and atmospheric pressure and are isolateable. [Examples]

[0314] The following embodiments are included to illustrate specific embodiments of the Disclosure. Those skilled in the art will understand that the methods disclosed in the following embodiments represent methods that function well in the implementation of the Disclosure and may therefore be considered to constitute a particular mode for its implementation. However, those skilled in the art will understand that many modifications to the specific embodiments disclosed in light of the Disclosure may still yield similar or similar results without departing from the spirit and scope of the Disclosure.

[0315] General Information: All evaporation or concentration was performed under reduced pressure using a rotary evaporator. Analytical samples were dried under vacuum (1–5 mmHg) at room temperature. Thin-layer chromatography (TLC) was performed on silica gel plates, and spots were visualized by UV light (214 and 254 nm). Purification by column and flash chromatography was performed using silica gel (100–200 mesh). Solvent systems were reported by volume as mixtures. NMR spectra were recorded using a Bruker 400 or Varian (400 MHz) spectrometer. 1H chemical shifts were reported as δ values ​​in ppm, with deuterated solvent as the internal standard. Data were reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quadruplet, br=broad, m=multilet), coupling constant (Hz), and integral value. LC-MS spectra were obtained using a SHIMADZU LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer with electrospray ionization, or an Agilent 1200 series, 6110, or 6120 mass spectrometer, unless otherwise specified. Example 1 N-[(R)-1-indanyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(3-methyl-1,2,4-oxadiazole-5-yl)-4-pyridyl}-2-thenamide (compound 101) [ka] compound 1 [ka]

[0316] Step A: Ethyl 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-6-(2-methylpropyl)-1,4-dihydropyridine-3-carboxylate [ka]

[0317] To a solution of ethyl 5-(4-fluorophenyl)-3-oxopentanoate (418.88 mg, 1.758 mmol) in EtOH (10 mL), N-[(1R)-2,3-dihydro-1H-indenyl]-5-formylthiophene-2-carboxamide (477.02 mg, 1.758 mmol) and 3-azanylidene-5-methylhexanamide (300 mg, 2.110 mmol) were added, and the reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was concentrated to obtain ethyl 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-6-(2-methylpropyl)-1,4-dihydropyridine-3-carboxylate (1.1 g, crude product). LC-MS: m / z 615.8 (M+H) + .

[0318] Step B: Ethyl 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-6-(2-methylpropyl)pyridine-3-carboxylate [ka]

[0319] To a solution of ethyl 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-6-(2-methylpropyl)-1,4-dihydropyridine-3-carboxylate (1.1 g, 1.786 mmol) in DCM (15 mL), cerium ammonium nitrate (1.47 g, 2.680 mmol) was added, and the reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with water, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate in petroleum ether. The organic layer was collected and concentrated under reduced pressure to obtain ethyl 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-6-(2-methylpropyl)pyridine-3-carboxylate (420 mg, 38.31%). LC-MS: m / z 614.0 (M+H) + .

[0320] Step C: 5-Carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-6-(2-methylpropyl)pyridine-3-carboxylic acid [ka]

[0321] Ethyl 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-6-(2-methylpropyl)pyridine-3-carboxylate (400 mg, 0.652 mmol) was dissolved in DMA (1 mL) and LiCl (138.13 mg, 3.259 mmol) was added. The reaction mixture was stirred under microwave at 150°C for 5 hours. The reaction mixture was purified by column chromatography eluting with FA / H2O / ACN. The organic layer was collected, concentrated under reduced pressure, and dried to obtain 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-6-(2-methylpropyl)pyridine-3-carboxylic acid (100 mg, 26.20%). LC-MS: m / z 586.3 (M+H) + .

[0322] Process D: 6-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-5-({[(1Z)-1-(hydroxyamino)ethylidene]amino}carbonyl)-2-(2-methylpropyl)pyridine-3-carboxamide [ka]

[0323] To a solution of 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-6-(2-methylpropyl)pyridine-3-carboxylic acid (50 mg, 0.085 mmol) in DMF (1 mL), N-(1-azanylideneethyl)hydroxylamine (7.59 mg, 0.102 mmol), DIEA (33.10 mg, 0.256 mmol), and PyBOP (53.31 mg, 0.102 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with  (50 mL) and water (20 mL). The organic layer was separated and further diluted with water (20 mL). * 2) The mixture was washed with saturated NaCl aqueous solution (20 mL). The organic layer was separated, dried over Na2SO4, and then filtered. The organic layer was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:siRNA = 1:1. The organic layer was collected, concentrated under reduced pressure, and dried to obtain 6-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-5-({[(1Z)-1-(hydroxyamino)ethylidene]amino}carbonyl)-2-(2-methylpropyl)pyridine-3-carboxamide (50 mg, 91.26%). LC-MS: m / z 642.2 (M+H) + .

[0324] Step E: N-[(R)-1-indanyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(3-methyl-1,2,4-oxadiazole-5-yl)-4-pyridyl}-2-thenamide (compound 101) [ka]

[0325] To a solution of 6-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-5-({[(1Z)-1-(hydroxyamino)ethylidene]amino}carbonyl)-2-(2-methylpropyl)pyridine-3-carboxamide (40 mg, 0.062 mmol) in DMF (2 mL), DBU (37.96 mg, 0.249 mmol) was added, and the reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was filtered and purified by preparative HPLC (FA) to obtain N-[(R)-1-indanyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(3-methyl-1,2,4-oxadiazole-5-yl)-4-pyridyl}2-tenamide (15.53 mg, 0.025 mmol, 39.95%).

[0326] 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J=8.4 Hz, 1 H), 7.91 (s, 1 H), 7.68 (d, J=3.6 Hz, 1 H), 7.60-7.64 (m, 1 H), 7.16-7.30 (m, 4 H), 7.08-7.15 (m, 2 H), 7.03-7.06 (m, 2 H), 6.94 (d, J=3.6 Hz, 1 H), 5.43-5.51 (m, 1 H), 2.93-3.08 (m, 5 H), 2.79-2.89 (m, 1 H), 2.73 (d, J=3.6 Hz, 2 H), 2.43-2.48 (m, 1 H), 2.38 (s, 3 H), 2.25-2.34 (m, 1 H), 1.88-1.99 (m, 1 H), 0.94 (d, J=6.4 Hz, 6 H). 19F NMR (377 MHz, DMSO-d6) δ -117.22. LC-MS: m / z 624.3 (M+H) + . N-(3,4-difluorophenyl)methyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(3-methyl-1,2,4-oxadiazole-5-yl)-4-pyridyl}2-thenamide (compound 102) [ka] Compound 102

[0327] Compound 102 was synthesized using a similar procedure to that described in Example 1 above, with the use of appropriate materials.

[0328] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (t, J=6.0 Hz, 1 H), 7.89 (s, 1 H), 7.64 (d, J=3.6 Hz, 1 H), 7.60 (s, 1 H), 7.30-7.44 (m, 2 H), 7.09-7.18 (m, 3 H), 7.05 (t, J=8.8 Hz, 2 H), 6.97 (d, J=4.0 Hz, 1 H), 4.40 (d, J=5.6 Hz, 2 H), 2.94-2.99 (m, 4 H), 2.73 (d, J=6.8 Hz, 2 H), 2.36 (s, 3 H), 2.24-2.35 (m, 1 H), 0.93 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.24, -138.84, -141.32. LC-MS: m / z 634.2 (M+H) + . N-(3,4-difluorophenyl)methyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(3-isopropyl-1,2,4-oxadiazole-5-yl)-4-pyridyl}2-thenamide (compound 103) [ka] Compound 103

[0329] Compound 103 was synthesized using a similar procedure to that described in Example 1 above, with the use of appropriate materials.

[0330] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (t, J=6.0 Hz, 1 H), 7.90 (s, 1 H), 7.58-7.67 (m, 2 H), 7.19-7.45 (m, 2 H), 7.00-7.07 (m, 5 H), 6.97 (d, J=3.6 Hz, 1 H), 4.40 (d, J=6.0 Hz, 2 H), 3.01-3.12 (m, 1 H), 2.91-2.98 (m, 4 H), 2.74 (d, J=7.2 Hz, 2 H), 2.23-2.36 (m, 1 H), 1.18 (d, J=6.8 Hz, 6 H), 0.94 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.18, -138.88, -141.36. LC-MS: m / z 662.2 (M+H) + . Example 2 4-(5-{1-[(3,4-difluorophenyl)methyl]-1H-1,2,3-triazole-4-yl}-2-thienyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(3-methyl-1,2,4-oxadiazole-5-yl)nicotinamide (compound 104) [ka] Compound 104 [ka]

[0331] Step A: 4-(azidomethyl)-1,2-difluorobenzene [ka]

[0332] NaN3 (669.25 mg, 5.809 mmol) was added to a mixture of 4-(bromomethyl)-1,2-difluorobenzene (500 mg, 3.873 mmol) in DMSO (10 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous NaHCO3 solution (25 mL) and extracted with RINKAN (25 mL x 3). The organic layers were combined, washed with brine (25 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-(azidomethyl)-1,2-difluorobenzene (370 mg, crude product).

[0333] Process B: 5-(1-(3,4-difluorobenzyl)-1H-1,2,3-triazole-4-yl)thiophene-2-carboaldehyde [ka]

[0334] To a mixture of 4-(azidomethyl)-1,2-difluorobenzene (370 mg, crude product) and 5-ethynylthiophene-2-carboaldehyde (307.26 mg, 2.26 mmol) in EtOH (4.0 mL) and H2O (4.0 mL), copper sulfate pentahydrate (28.17 mg, 0.113 mmol) and sodium ascorbate (44.70 mg, 0.226 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with H2O (20 mL) and extracted with siRNA (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â5=3 / 1) to obtain 5-(1-(3,4-difluorobenzyl)-1H-1,2,3-triazole-4-yl)thiophene-2-carboaldehyde (148 mg, 22.19%). LC-MS: m / z 306.1 (M+H) + . 4-(5-{1-[(3,4-difluorophenyl)methyl]-1H-1,2,3-triazole-4-yl}-2-thienyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(3-methyl-1,2,4-oxadiazole-5-yl)nicotinamide (compound 104) [ka]

[0335] Compound 104 was synthesized using a similar procedure to that described in Example 1 above, with the use of appropriate materials.

[0336] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1 H), 7.91 (s, 1 H), 7.61 (s, 1 H), 7.43-7.53 (m, 2 H), 7.30 (d, J=3.6 Hz, 1 H), 7.03-7.23 (m, 5 H), 6.95 (d, J=4.0 Hz, 1 H), 5.64 (s, 2 H), 2.91-2.97 (m, 4 H), 2.73 (d, J=7.2 Hz, 2 H), 2.26-2.36 (m, 4 H), 0.94 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.24, 137.87, 139.14. LC-MS: m / z 658.0 (M+H) + . Example 3 N-(3,4-difluorophenyl)methyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]-4-pyridyl}2-thenamide (compound 105) [ka] [ka]

[0337] Process A: 1H-benzo[d][1,2,3]triazole-1-yl 5-carbamoyl-4-(5-((3,4-difluorobenzyl)carbamoyl)thiophen-2-yl)-2-(4-fluorophenethyl)-6-isobutylnicotinate [ka]

[0338] To a solution of 5-carbamoyl-4-(5-((3,4-difluorobenzyl)carbamoyl)thiophen-2-yl)-2-(4-fluorophenethyl)-6-isobutylnicotinic acid (50 mg, 0.084 mmol) in DMF (1.5 mL), DIEA (33 mg, 0.252 mmol) and PyBOP (66 mg, 0.126 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then mixed with 15 mL of butyl (15 mL). * 3) was diluted with water (10 mL). The organic layer was separated, washed with saturated NaCl solution (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 10% methanol in dichloroform, concentrated, and obtained 1H-benzo[d][1,2,3]triazole-1-yl5-carbamoyl-4-(5-((3,4-difluorobenzyl)carbamoyl)thiophen-2-yl)-2-(4-fluorophenethyl)-6-isobutylnicotinate (45 mg, 75.2%). LC-MS: m / z 713.2 (M+H) + . N-(3,4-difluorophenyl)methyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]-4-pyridyl}2-thenamide (compound 105) [ka]

[0339] Compound 105 was synthesized using a similar procedure to that described in Example 1 above, with the use of appropriate materials.

[0340] 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (t, J=6.4 Hz, 1 H), 7.93 (s, 1 H), 7.66 (d, J=3.6 Hz, 2 H), 7.28-7.44 (m, 2 H), 7.11-7.17 (m, 3 H), 6.98-7.06 (m, 3 H), 4.40 (d, J=6.0 Hz, 2 H), 2.96-3.14 (m, 4 H), 2.76 (d, J=9.2 Hz, 2 H), 2.25-2.39 (m, 1 H), 0.95 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -65.33, -117.16, 138.90, 141.33. LC-MS: m / z 688.1 (M+H) + . Example 4 N-[(R)-1-indanyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}2-thenamide (compound 106) [ka] compound 106 [ka]

[0341] Process A: 5-(diazanylcarbonyl)-6-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-2-(2-methylpropyl)pyridine-3-carboxamide [ka]

[0342] To a solution of 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-6-(2-methylpropyl)pyridine-3-carboxylic acid (200 mg, 0.341 mmol) in DMF (2 mL), hydrazine hydrochloride (0.011 mL, 0.341 mmol), DIEA (132.41 mg, 1.024 mmol), and PyBOP (213.25 mg, 0.410 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAC (50 mL) and water (20 mL). The organic layer was separated and further diluted with water (20 mL). * 2) The mixture was washed with saturated NaCl aqueous solution (20 mL). The organic layer was separated, dried over Na2SO4, and then filtered. The organic layer was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:siRNA = 1:1. The organic layer was collected, concentrated under reduced pressure, and dried to obtain 5-(diazanylcarbonyl)-6-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-2-(2-methylpropyl)pyridine-3-carboxamide (250 mg, crude product). LC-MS: m / z 599.8 (M+H) + .

[0343] Step B: N-[(R)-1-indanyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}-2-thenamide (compound 106) [ka]

[0344] To a solution of 5-(diazanylcarbonyl)-6-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophen-2-yl]-2-(2-methylpropyl)pyridine-3-carboxamide (200 mg, 0.333 mmol) in DMF (2 mL), 1-(dimethylamino)-1,1-dimethoxyethane (66.62 mg, 0.500 mmol) was added, and the reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was concentrated, and the residue was dissolved in toluene (4 mL). TsOH was added to the reaction mixture, and the reaction mixture was stirred for a further 2 hours at 120°C. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (FA) to obtain N-[(R)-1-indanyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}2-tenamide (27.97 mg, 0.045 mmol, 13.45%).

[0345] 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=8.4 Hz, 1 H), 7.88 (br s, 1 H), 7.67 (d, J=4.0 Hz, 1 H), 7.58 (br s, 1 H), 7.16-7.30 (m, 4 H), 7.02-7.14 (m, 4 H), 6.94 (d, J=4.0 Hz, 1 H), 5.42-5.51 (m, 1 H), 2.93-3.03 (m, 5 H), 2.79-2.89 (m, 1 H), 2.73 (d, J=7.2 Hz, 2 H), 2.42-2.46 (m, 1 H), 2.40 (s, 3 H), 2.25-2.35 (m, 1 H), 1.88-1.99 (m, 1 H), 0.94 (d, J=6.4 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.28. LC-MS: m / z 624.4 (M+H) + . N-(3,4-difluorophenyl)methyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}2-thenamide (compound 107) [ka] compound 107

[0346] Compound 107 was synthesized using a similar procedure to that described in Example 4 above, with the use of appropriate materials.

[0347] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (t, J=6.0 Hz, 1 H), 7.89 (s, 1 H), 7.64 (d, J=3.6 Hz, 1 H), 7.59 (s, 1 H), 7.30-7.45 (m, 2 H), 7.01-7.18 (m, 5 H), 6.97 (d, J=4.0 Hz, 1 H), 4.40 (d, J=6.0 Hz, 2 H), 2.94-3.01 (m, 4 H), 2.73 (d, J=6.8 Hz, 2 H), 2.38 (s, 3 H), 2.25-2.35 (m, 1 H), 0.93 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26, -138.84, -141.33. LC-MS: m / z 634.2 (M+H) + . 4-(5-((3,4-difluorobenzyl)carbamoyl)thiophen-2-yl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-6-(4-methylpentyl)nicotinamide (compound 108) [ka] compound 108

[0348] Compound 108 was synthesized using a similar procedure to that described in Example 4 above, with appropriate materials.

[0349] 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (t, J=5.99 Hz, 1 H), 7.91 (s, 1 H), 7.64 (d, J=3.91 Hz, 1 H), 7.60 (s, 1 H), 7.30 - 7.44 (m, 2 H), 7.15 (s, 1 H), 6.99 (d, J=3.79 Hz, 1 H), 4.40 (d, J=5.87 Hz, 2 H), 2.72 (d, J=7.09 Hz, 2 H), 2.56 - 2.63 (m, 2 H), 2.43 (s, 3 H), 2.29 - 2.34 (m, 1 H), 1.62 (q, J=7.67 Hz, 2 LC-MS: m / z 596.2 (M+H) + . 6-(2-cyclohexylethyl)-4-(5-((3,4-difluorobenzyl)carbamoyl)thiophen-2-yl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 109) [ka] Compound 109

[0350] Compound 109 was synthesized using a similar procedure to that described in Example 4 above, with the use of appropriate materials.

[0351] 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=3.76 Hz, 1 H), 7.07 - 7.17 (m, 2 H), 6.97 - 7.05 (m, 2 H), 6.79 (t, J=6.02 Hz, 1 H), 5.78 (d, J=17.57 Hz, 2 H), 4.48 (d, J=6.02 Hz, 2 H), 2.82 (d, J=7.28 Hz, 2 H), 2.66 - 2.74 (m, 2 H), 2.47 (s, 3 H), 2.36 (d, J=6.78 Hz, 1 H), 1.64 (s, 7 H), 1.52 (d, J=9.03 Hz, 2 H), 1.08 - 1.21 (m, 4 H), 0.98 (d, J=6.53 Hz, 6 H), 0.81 - 0.84 (m, 2 H). LC-MS: m / z 622.3 (M+H) + . 4-(5-((3,4-difluorobenzyl)carbamoyl)thiophen-2-yl)-6-(4-fluorobenzyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 110) [ka]

[0352] Compound 110 was synthesized using a similar procedure to that described in Example 4 above, with appropriate materials.

[0353] 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=3.91 Hz, 1H), 7.08-7.19 (m, 2H), 6.97-7.07 (m, 4H), 6.85-6.93 (m, 2H), 6.37 (t, J=5.87 Hz, 1H), 5.51-5.70 (m, 2H), 4.51 (d, J=5.87 Hz, 2H), 4.20 (s, 2H), 2.86 (d, J=7.21 Hz, 2H), 2.35-2.44 (m, 1H), 2.32 (s, 3H), 0.99 (d, J=6.60 Hz, 6H). LC-MS: m / z 620.2 (M+H) + . 4-(5-((3,4-difluorobenzyl)carbamoyl)thiophen-2-yl)-2,6-diisobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 111) [ka] Compound 111

[0354] Compound 111 was synthesized using a similar procedure to that described in Example 4 above, with appropriate materials.

[0355] 1 H NMR (400 MHz, CD3OD) δ 7.58 (d, J=4.52 Hz, 1 H) 7.19 - 7.28 (m, 2 H) 7.12 - 7.18 (m, 1 H) 7.05 - 7.10 (m, 1 H) 4.49 (s, 2 H) 2.83 - 2.89 (m, LC-MS: m / z 568.2 (M+H) + . 4-[5-[(3,4-difluorophenyl)methylcarbamoyl]-2-thienyl]-6-ethyl-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-3-carboxamide (compound 112) [ka] compound 112

[0356] Compound 112 was synthesized using a similar procedure to that described in Example 4 above, with the use of appropriate materials.

[0357] 1 H NMR (400 MHz, DMSO-d6) δ 9.13 - 9.19 (m, 1 H), 7.88 - 7.95 (m, 1 H), 7.64 (d, J=3.79 Hz, 1 H), 7.62 (s, 1 H), 7.39 (d, J=10.76 Hz, 2 H), 7.11 - 7.17 (m, 1 H), 6.96 - 7.00 (m, 1 H), 4.36 - 4.43 (m, 2 H), 2.71 (s, 2 H), 2.60 - 2.67 (m, 2 H), 2.43 (s, 3 H), 2.23 - 2.34 (m, 1 H), 1.12 - 1.20 (m, 3 H), 0.94 (d, J=6.60 Hz, 6 H). LC-MS: m / z 540.2 (M+H) + . Example 5 N-(m-methoxyphenyl)methyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}2-thenamide (compound 113) [ka] compound 113 [ka] [ka]

[0358] Step A: Ethyl {2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolan-2-yl}acetate [ka]

[0359] To a solution of ethyl 5-(4-fluorophenyl)-3-oxopentanoate (14 g, 58.759 mmol) in toluene (2 mL), ethylene glycol (32.769 mL, 587.593 mmol) and TsOH·H2O (0.08 g, 0.420 mmol) were added, and the reaction mixture was stirred at 140 °C for 24 hours. The reaction mixture was diluted with HCl (300 ml) and water (300 ml). The organic layer was separated, washed with saline solution (300 ml), and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate (PE:HCl = 10:1) in petroleum ether. The organic layer was concentrated under reduced pressure to obtain ethyl {2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolan-2-yl]acetate (3.7 g, 22.30%). LC-MS: m / z 305.1 (M+Na) + .

[0360] Step B: {2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolan-2-yl}acetic acid [ka]

[0361] To a solution of ethyl {2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolan-2-yl}acetate (3.7 g, 13.106 mmol) in MeOH (40 mL) and H2O (15 mL), NaOH (2.10 g, 52.424 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. 1N aqueous HCl (60 mL) was added to the reaction mixture, and the mixture was diluted with HCl (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL x 2) and saline solution (50 mL), dried over Na2SO4, and then filtered. The organic layer was collected and concentrated under reduced pressure to obtain {2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolan-2-yl}acetic acid (3 g, 90.03%). LC-MS: m / z 277.1 (M+H) + .

[0362] Step C: N'-Acetyl-2-(2-(4-fluorophenethyl)-1,3-dioxolan-2-yl)acetohydrazide [ka]

[0363] To a solution of {2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolan-2-yl}acetic acid (3 g, 11.799 mmol) in DMF (30 mL), acetohydrazide (1.75 g, 23.598 mmol), DI Depositphotos (4.57 g, 35.397 mmol), and HATU (5.38 g, 14.159 mmol) were added, and the reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature and diluted with Depositphotos (50 mL) and water (20 mL). The organic layer was separated and washed with water (20 mL x 2) and saline solution (20 mL). The organic layer was separated, dried over Na₂SO₄, and then filtered. The organic layer was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE: Depositphotos = 1:1. The organic layer was collected, concentrated under reduced pressure, and dried to obtain N'-acetyl-2-(2-(4-fluorophenethyl)-1,3-dioxolan-2-yl)acetohydrazide (2.8 g, 76.47%). LC-MS: m / z 310.9 (M+H) + .

[0364] Step D: 2-({2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolan-2-yl}methyl)-5-methyl-1,3,4-oxadiazole [ka]

[0365] To a solution of N'-acetyl-2-(2-(4-fluorophenethyl)-1,3-dioxolan-2-yl)acetohydrazide (2.5 g, 8.056 mmol) in DCM (30 mL), TEA (1.456 mL, 10.473 mmol) and 4-toluenesulfonyl chloride (1.84 g, 9.667 mmol) were added, and the reaction mixture was stirred at 30°C for 48 hours. The mixture was diluted with DCM (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM:MeOH = 20:1. The organic layer was collected and concentrated under reduced pressure to obtain 2-({2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolan-2-yl}methyl)-5-methyl-1,3,4-oxadiazole (1.8 g, 76.44%). LC-MS: m / z 293.1 (M+H) + .

[0366] Step E: 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazole-2-yl)butan-2-one [ka]

[0367] To a solution of 2-({2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolan-2-yl}methyl)-5-methyl-1,3,4-oxadiazole (1.8 g, 6.158 mmol) in HCOOH (5 mL), H2SO4 (0.02 mL) was added, and the reaction mixture was stirred at 45°C for 2 hours. The reaction mixture was cooled to room temperature and diluted with HCl (100 mL) and water (50 mL). The organic layer was separated and further washed with water (50 mL x 2). The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate (PE:HCl = 3:1) in petroleum ether. The organic layer was collected and concentrated under reduced pressure to obtain 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazole-2-yl)butan-2-one (1.2 g, 78.50%). LC-MS: m / z 249.1 (M+H) + .

[0368] Process F: Benzyl 5-{3-carbamoyl-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)-1,4-dihydropyridine-4-yl}thiophene-2-carboxylate [ka]

[0369] To a solution of benzyl 5-formylthiophene-2-carboxylate (238.09 mg, 0.967 mmol) in EtOH (3 mL), 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazole-2-yl)butan-2-one (240 mg, 0.967 mmol) and 3-azanylidene-5-methylhexanamide (151.22 mg, 1.063 mmol) were added, and the reaction mixture was stirred at 110°C for 18 hours. The reaction mixture was cooled to room temperature, concentrated, and used directly without further workup (600 mg, crude product). LC-MS: m / z 601.2 (M+H) + .

[0370] Process G: Benzyl 5-{3-carbamoyl-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)pyridine-4-yl}thiophene-2-carboxylate [ka]

[0371] To a solution of benzyl 5-{3-carbamoyl-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)-1,4-dihydropyridine-4-yl}thiophene-2-carboxylate (600 mg, 0.999 mmol) in EtOH (3 mL), CAN (821.37 mg, 1.498 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ELISA (50 mL) and water (20 mL). The organic layer was separated and washed with water (20 mL x 2) and saline solution (20 mL). The organic layer was separated, dried over Na2SO4, and then filtered. The organic layer was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE:Â=1:1 elution to obtain benzyl 5-{3-carbamoyl-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)pyridine-4-yl}thiophene-2-carboxylate (500 mg, 83.52%). LC-MS: m / z 599.2 (M+H) + .

[0372] Process H: 5-{5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazole-2-yl)-6-(2-methylpropyl)pyridine-4-yl}thiophene-2-carboxylic acid [ka]

[0373] To a solution of benzyl 5-{5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazole-2-yl)-6-(2-methylpropyl)pyridine-4-yl}thiophene-2-carboxylate (500 mg, 0.835 mmol) in MeOH (5 mL), Pd / C (200 mg, 1.879 mmol, 10% Pd, moistened with approximately 55% water) was added, and the reaction mixture was stirred under H2 (15 Psi) at 25°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain 5-{5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazole-2-yl)-6-(2-methylpropyl)pyridine-4-yl}thiophene-2-carboxylic acid (390 mg, 91.82%). LC-MS: m / z 509.1 (M+H) + .

[0374] Step I: N-(m-methoxyphenyl)methyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}2-thenamide (compound 113) [ka]

[0375] To a solution of 5-{5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazole-2-yl)-6-(2-methylpropyl)pyridine-4-yl}thiophene-2-carboxylic acid (15 mg, 0.029 mmol) in DMF (1 mL), (3-methoxyphenyl)methanamine (6.07 mg, 0.044 mmol), DIEA (11.44 mg, 0.088 mmol), and PyBOP (23.02 mg, 0.044 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with  (10 mL) and water (30 mL) *The mixture was washed in step 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by preparative HPLC to obtain N-(m-methoxyphenyl)methyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}2-thenamide (2.03 mg, 10.96%).

[0376] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (t, J=6.0 Hz, 1 H), 7.88 (s, 1 H), 7.65 (d, J=3.6 Hz, 1 H), 7.58 (s, 1 H), 7.25 (t, J=8.0 Hz, 1 H), 7.02-7.14 (m, 4 H), 6.97 (d, J=4.0 Hz, 1 H), 6.78-6.90 (m, 3 H), 4.40 (d, J=5.6 Hz, 2 H), 3.74 (s, 3 H), 2.93-3.04 (m, 4 H), 2.73 (d, J=6.8 Hz, 2 H), 2.38 (s, 3 H), 2.26-2.35 (m, 1 H), 0.94 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.27. LC-MS: m / z 628.1 (M+H) + . N-(p-methoxyphenyl)methyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}2-thenamide (compound 114) [ka] compound 114

[0377] Compound 114 was synthesized using a similar procedure to that described in Example 5 above, with the use of appropriate materials.

[0378] 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (t, J=5.6 Hz, 1 H), 7.89 (s, 1 H), 7.63 (d, J=3.6 Hz, 1 H), 7.59 (s, 1 H), 7.23 (d, J=8.0 Hz, 2 H), 7.01-7.15 (m, 4 H), 6.96 (d, J=3.6 Hz, 1 H), 6.90 (d, J=8.4 Hz, 2 H), 4.35 (d, J=6.0 Hz, 2 H), 3.73 (s, 3 H), 2.91-3.03 (m, 4 H), 2.73 (d, J=6.8 Hz, 2 H), 2.38 (s, 3 H), 2.23-2.35 (m, 1 H), 0.94 (d, J=6.4 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26. LC-MS: m / z 628.2 (M+H) + . N-benzyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}2-thenamide (compound 115) [ka] compound 115

[0379] Compound 115 was synthesized using a similar procedure to that described in Example 5 above, with appropriate materials.

[0380] 1H NMR (400 MHz, DMSO-d6) δ 9.09 (t, J=5.6 Hz, 1 H), 7.88 (s, 1 H), 7.65 (d, J=4.0 Hz, 1 H), 7.59 (br s, 1 H), 7.22-7.37 (m, 5 H), 7.01-7.14 (m, 4 H), 6.96 (d, J=4.0 Hz, 1 H), 4.43 (d, J=6.0 Hz, 2 H), 2.92-3.01 (m, 4 H), 2.73 (d, J=7.2 Hz, 2 H), 2.38 (s, 3 H), 2.23-2.35 (m, 1 H), 0.94 (d, J=6.4 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.27. LC-MS: m / z 598.2 (M+H) + . N-[(3-fluoro-5-methoxyphenyl)methyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}-2-thenamide (compound 116) [ka] compound 116

[0381] Compound 116 was synthesized using a similar procedure to that described in Example 5 above, with appropriate materials.

[0382] 1H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J=6.0 Hz, 1 H), 7.89 (br s, 1 H), 7.66 (d, J=3.6 Hz, 1 H), 7.59 (br s, 1 H), 7.01-7.16 (m, 4 H), 6.97 (d, J=4.0 Hz, 1 H), 6.63-6.76 (m, 3 H), 4.39 (d, J=6.0 Hz, 2 H), 3.75 (s, 3 H), 2.90-3.05 (m, 4 H), 2.73 (d, J=7.2 Hz, 2 H), 2.37 (s, 3 H), 2.25-2.35 (m, 1H), 0.94 (d, J=6.4 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -111.85, -117.26. LC-MS: m / z 646.1 (M+H) + . N-[(4-fluoro-3-methoxyphenyl)methyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}2-thenamide (compound 117) [ka] compound 117

[0383] Compound 117 was synthesized using a similar procedure to that described in Example 5 above, with appropriate materials.

[0384] 1H NMR (400 MHz, DMSO-d6) δ 9.07 (t, J=6.0 Hz, 1 H), 7.89 (br s, 1 H), 7.65 (d, J=4.0 Hz, 1 H), 7.59 (br s, 1 H), 7.00-7.20 (m, 6 H), 6.96 (d, J=3.6 Hz, 1 H), 6.81-6.87 (m, 1 H), 4.39 (d, J=6.0 Hz, 2 H), 3.82 (s, 3 H), 2.90-3.02 (m, 4 H), 2.73 (d, J=7.2 Hz, 2 H), 2.38 (s, 3 H), 2.25-2.34 (m, 1H), 0.91 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.27, -137.96. LC-MS: m / z 646.2 (M+H) + . (S)-4-(5-((2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 118) [ka] compound 118

[0385] Compound 118 was synthesized using a similar procedure to that described in Example 5 above, with appropriate materials.

[0386] 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J=8.4 Hz, 1 H), 7.89 (s, 1 H), 7.67 (d, J=3.6 Hz, 1 H), 7.60 (s, 1 H), 7.15-7.33 (m, 4 H), 7.00-7.15 (m, 4 H), 6.94 (d, J=4.0 Hz, 1 H), 5.42-5.52 (m, 1 H), 2.93-3.06 (m, 5 H), 2.78-2.90 (m, 1 H), 2.73 (d, J=7.2 Hz, 2 H), 2.37-2.46 (m, 4 H), 2.22-2.35 (m, 1 H), 1.85-2.01 (m, 1 H), 0.94 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26. LC-MS: m / z 624.2 (M+H) + . (R)-4-(5-((4-fluoro-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 119) [ka] Compound 119

[0387] Compound 119 was synthesized using a similar procedure to that described in Example 5 above, with appropriate materials.

[0388] 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J=8.4 Hz, 1 H), 7.89 (s, 1 H), 7.66 (d, J=4.0 Hz, 1 H), 7.60 (s, 1 H), 7.20-7.32 (m, 1 H), 7.01-7.15 (m, 6 H), 6.95 (d, J=4.0 Hz, 1 H), 5.45-5.55 (m, 1 H), 2.92-3.11 (m, 5 H), 2.79-2.90 (m, 1 H), 2.73 (d, J=6.8 Hz, 2 H), 2.45-2.48 (m, 1 H), 2.40 (s, 3 H), 2.23-2.35 (m, 1 H), 1.93-2.07 (m, 1 H), 0.94 (d, J=6.4 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26, -118.80. LC-MS: m / z 642.3 (M+H) + . (R)-4-(5-((5-fluoro-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 120) [ka] compound 120

[0389] Compound 120 was synthesized using a similar procedure to that described in Example 5 above, with the use of appropriate materials.

[0390] 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=8.0 Hz, 1 H), 7.89 (br s, 1 H), 7.66 (d, J=4.0 Hz, 1 H), 7.59 (br s, 1 H), 7.19-7.27 (m, 1 H), 6.97-7.15 (m, 6 H), 6.94 (d, J=3.6 Hz, 1 H), 5.39-5.45 (m, 1 H), 2.93-3.05 (m, 5 H), 2.80-2.90 (m, 1 H), 2.73 (d, J=7.2 Hz, 2 H), 2.43-2.48 (m, 1 H), 2.40 (s, 3 H), 2.22-2.36 (m, 1 H), 1.91-2.04 (m, 1 H), 0.94 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -115.77, -117.27. LC-MS: m / z 642.2 (M+H) + . (R)-4-(5-((6-fluoro-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 121) [ka] compound 121

[0391] Compound 121 was synthesized using a similar procedure to that described in Example 5 above, with appropriate materials.

[0392] 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=8.4 Hz, 1 H), 7.89 (br s, 1 H), 7.67 (d, J=4.0 Hz, 1 H), 7.59 (br s, 1 H), 7.25-7.32 (m, 1 H), 6.98-7.15 (m, 6 H), 6.95 (d, J=4.0 Hz, 1 H),5.41-5.45 (m, 1 H), 2.90-3.03 (m, 5 H), 2.77-2.86 (m, 1 H), 2.73 (d, J=7.2 Hz, 2 H), 2.43-2.48 (m, 1 H), 2.40 (s, 3 H), 2.23-2.35 (m, 1 H), 1.91-2.02 (m, 1 H), 0.94 (d, J=6.4 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -116.96, -117.27. 19 F NMR (377 MHz, DMSO-d6) δ -116.96, -117.27. LC-MS: m / z 642.4 (M+H) + . (R)-6-(4-fluorophenethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 122) [ka] compound 122

[0393] Compound 122 was synthesized using a similar procedure to that described in Example 5 above, with the use of appropriate materials.

[0394] 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J=8.4 Hz, 1 H), 7.90 (s, 1 H), 7.67 (d, J=4.0 Hz, 1 H), 7.60 (s, 1 H), 7.19 (t, J=8.0 Hz, 1 H), 7.01-7.15 (m, 4 H), 6.95 (d, J=3.6 Hz, 1 H), 6.79-6.90 (m, 2 H), 5.40-5.50 (m, 1 H), 3.80 (s, 3 H), 2.88-3.01 (m, 5 H), 2.64-2.78 (m, 3 H), 2.37-2.48 (m, 4 H), 2.24-2.36 (m, 1 H), 1.86-1.99 (m, 1 H), 0.94 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26. LC-MS: m / z 654.2 (M+H) + . (R)-4-(5-((6,7-dihydro-5H-cyclopenta[b]pyridine-5-yl)carbamoyl)thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 123) [ka] compound 123

[0395] Compound 123 was synthesized using a similar procedure to that described in Example 5 above, with the use of appropriate materials.

[0396] 1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J=8.0 Hz, 1 H), 8.40 (d, J=4.4 Hz, 1 H), 7.90 (s, 1 H), 7.56-7.69 (m, 3 H), 7.00-7.23 (m, 5 H), 6.95 (d, J=4.0 Hz, 1 H), 5.43-5.57 (m, 1 H),2.86-3.09 (m, 7 H), 2.73 (d, J=6.8 Hz, 2 H), 2.40 (s, 3 H), 2.24-2.35 (m, 1 H), 1.91-2.05 (m, 1 H), 0.94 (d, J=6.4 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26. LC-MS: m / z 625.4 (M+H) + . (S)-4-(5-((6,7-dihydro-5H-cyclopenta[b]pyridine-5-yl)carbamoyl)thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 124) [ka] compound 124

[0397] Compound 124 was synthesized using a similar procedure to that described in Example 5 above, with the use of appropriate materials.

[0398] 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J=8.0 Hz, 1 H), 8.40 (d, J=4.8 Hz, 1 H), 7.89 (s, 1 H), 7.56-7.67 (m, 3 H),7.19 (dd, J=5.2 Hz, J=7.6 Hz, 1 H), 7.02-7.13 (m, 4 H), 6.95 (d, J=3.6 Hz, 1 H), 5.43-5.55 (m, 1 H), 2.91-3.00 (m, 7 H), 2.73 (d, J=7.2 Hz, 2 H), 2.40 (s, 3 H), 2.25-2.35 (m, 1H), 1.94-2.01 (m, 1 H), 0.94 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26. LC-MS: m / z 625.2 (M+H) + . Example 6 N-(3,4-difluorophenyl)methyl-2-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}-1,3-thiazole-5-carboxamide (compound 125) [ka] compound 125 [ka]

[0399] Step A: Synthesis of 4-(5-bromothiazol-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide [ka]

[0400] To a solution of 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazole-2-yl)butan-2-one (50 mg, 0.202 mmol) in EtOH (2 mL), 5-bromothiazole-2-carboaldehyde (39 mg, 0.202 mmol) and 3-imino-5-methylhexanamide (29 mg, 0.202 mmol) were added at room temperature, and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain 4-(5-bromothiazole-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide (180 mg, crude product). LC-MS: m / z 545.7 (M+H) + .

[0401] Step B: Synthesis of 4-(5-bromothiazol-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide [ka]

[0402] To a solution of 4-(5-bromothiazol-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide (180 mg, crude product) in EtOH (3 mL), cerium(IV) diammonium nitrate (221 mg, 0.404 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 30% ethyl acetate in petroleum ether to obtain 4-(5-bromothiazol-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (50 mg, yield 45.9%). LC-MS: m / z 544.0 (M+H) + .

[0403] Step C: Ethyl 2-(3-carbamoyl-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-4-yl)thiazole-5-carboxylate [ka]

[0404] A mixture of 4-(5-bromothiazol-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (50 mg, 0.0921 mmol), KOAc (27 mg, 0.276 mmol), and Pd(dppf)Cl2 (7 mg, 0.00921 mmol) in EtOH (3 mL) was stirred at 70°C for 16 hours under CO. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography eluted with 25% ethyl ether in petroleum ether to obtain ethyl 2-(3-carbamoyl-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-4-yl)thiazole-5-carboxylate (20 mg, 40.4%). MS: m / z 538.2 (M+H) + .

[0405] Step D: 2-(3-carbamoyl-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-4-yl)thiazole-5-carboxylic acid [ka]

[0406] To a solution of ethyl 2-(3-carbamoyl-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-4-yl)thiazole-5-carboxylate (20 mg, 0.0372 mmol) in THF (1 mL) and water (0.1 mL), LiOH·H2O (8 mg, 0.186 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (0.03% TFA) to obtain 2-(3-carbamoyl-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-4-yl)thiazole-5-carboxylic acid (14 mg, 74.1%). MS: m / z 510.2 (M+H) + . N-(3,4-difluorophenyl)methyl-2-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}-1,3-thiazole-5-carboxamide (compound 125) [ka]

[0407] Compound 125 was synthesized using a similar procedure to that described in Example 5 above, with the use of appropriate materials.

[0408] 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (t, J=5.6 Hz, 1 H), 8.30 (s, 1 H), 8.12 (br s, 1 H), 7.78 (br s, 1 H), 7.34-7.45 (m, 2 H), 7.01-7.20 (m, 5 H), 4.44 (d, J=6.0 Hz, 2 H), 2.93-3.12 (m, 4 H), 2.77 (d, J=7.2 Hz, 2 H), 2.39 (s, 3 H), 2.26-2.33 (m, 1 H), 0.93 (d, J=6.4 Hz, 6 H). 19F NMR (377 MHz, DMSO-d6) δ -117.26, -138.76, -141.17. MS: m / z 635.2 (M+H) + . Example 7 4-(p-{[(3,4-difluorophenyl)methyl]carbamoyl}phenyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 126) [ka] compound 126 [ka]

[0409] Process A: N-(3,4-difluorobenzyl)-4-formylbenzamide [ka]

[0410] To a solution of 4-formylbenzoic acid (500 mg, 3.33 mmol) in DMF (1 mL), (3,4-difluorophenyl)methaneamine (476 mg, 3.33 mmol), HATU (1.52 g, 3.99 mmol), and DIEA (1.29 g, 9.99 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with toluene (2 mL x 5). The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The crude product was purified by silica gel column chromatography using 0-10% toluene / hexane to obtain N-(3,4-difluorobenzyl)-4-formylbenzamide (650 mg, 70.91%). 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1 H), 7.95 (m, 4 H), 6.99-7.26 (m, 3 H), 6.57-6.74(m, 1 H), 4.61 (d, J=5.6 Hz, 2 H).

[0411] Process B: 4-(4-((3,4-difluorobenzyl)carbamoyl)phenyl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide [ka]

[0412] To a solution of N-(3,4-difluorobenzyl)-4-formylbenzamide (50 mg, 0.18 mmol) in EtOH (1 mL), 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazole-2-yl)butan-2-one (40 mg, 0.16 mmol) and (E)-3-amino-5-methylhexa-2-enamide (23 mg, 0.16 mmol) were added, and the reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ELISA (2 mL x 3). The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to dryness. The crude product was purified by preparative TLC using siRNA / hexane (1 / 5) to obtain 4-(4-((3,4-difluorobenzyl)carbamoyl)phenyl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide (50 mg, crude product). LC-MS: m / z 630.2 (M+H) + .

[0413] Process C: 4-(p-{[(3,4-difluorophenyl)methyl]carbamoyl}phenyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 126) [ka]

[0414] To a solution of 4-(4-((3,4-difluorobenzyl)carbamoyl)phenyl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide (50 mg, crude product) in EtOH (1 mL), cerium(IV) diammonium nitrate (170 mg, 0.31 mmol) was added, and the reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by preparative HPLC (0.03% NH3·H2O) to obtain 4-(p-{[(3,4-difluorophenyl)methyl]carbamoyl}phenyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (19.84 mg, 39.81%).

[0415] 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J=4.8 Hz, 1 H), 7.74-7.79 (m, 3 H), 7.30-7.50 (m, 3 H), 6.97-7.24 (m, 7 H), 4.43 (d, J=5.2 Hz, 2 H), 2.91-3.02 (m, 4 H), 2.74 (d, J=6.8 Hz, 2H), 2.24-2.30 (m, 4 H), 0.95 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.30, -138.96, -141.56. LC-MS: m / z 628.1 (M+H) + . 4-(1-benzothiophen-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 127) [ka] compound 127

[0416] Compound 127 was synthesized using a similar procedure to that described in Example 7 above, with the use of appropriate materials.

[0417] 1 H NMR (400 MHz, DMSO-d6) δ 7.91-7.93 (m, 2H), 7.84-7.86 (m, 1H), 7.56 (s, 1H),7.36-7.39 (m, 3H), 7.10-7.14 (m, 2H), 7.03-7.08 (m, 2H), 2.95-3.03 (m, 4H), 2.75 (d, J=7.2 Hz, 2H), 3.32-3.35 (m, 1H), 2.29 (s, 3H), 0.95 (d, J=6.8 Hz, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -117.27. LC-MS: m / z 514.9 (M+H) + . N-(3,4-difluorophenyl)methyl-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazole-2-yl)-4-pyridyl}-2-flamid (compound 128) [ka] compound 128

[0418] Compound 128 was synthesized using a similar procedure to that described in Example 7 above, with the use of appropriate materials.

[0419] 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J=6.4 Hz, 1 H), 8.05 (br s, 1 H), 7.78 (br s, 1 H), 7.27-7.44 (m, 2 H), 7.19 (d, J=3.6 Hz, 1 H), 7.01-7.15 (m, 5 H), 6.82 (d, J=3.6 Hz, 1 H), 4.35 (d, J=6.0 Hz, 2 H), 2.92-3.05 (m, 4 H), 2.73 (d, J=7.2 Hz, 2 H), 2.39 (s, 3 H), 2.25-2.33 (m, 1 H), 0.91 (d, J=6.4 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.30, -138.89, -141.39. LC-MS: m / z 618.1 (M+H) + . Example 8 4-(7-bromo-1-benzothiophen-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 129) [ka] compound 129 [ka]

[0420] Step A: Ethyl 4-(7-bromobenzo[b]thiophen-2-yl)-5-carbamoyl-2-(4-fluorophenethyl)-6-isobutyl-1,4-dihydropyridine-3-carboxylate [ka]

[0421] A solution of ethyl 5-(4-fluorophenyl)-3-oxopentanoate (500 mg, 2.099 mmol), 7-bromobenzo[b]thiophene-2-carboaldehyde (505.96 mg, 2.099 mmol), and 3-imino-5-methylhexanamide (298.41 mg, 2.099 mmol) in EtOH (10.0 mL) was stirred overnight at 120 °C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain ethyl 4-(7-bromobenzo[b]thiophene-2-yl)-5-carbamoyl-2-(4-fluorophenethyl)-6-isobutyl-1,4-dihydropyridine-3-carboxylate (1.23 g, crude product). LC-MS: m / z 584.9 (M+H) + .

[0422] Step B: Ethyl 4-(7-bromobenzo[b]thiophen-2-yl)-5-carbamoyl-2-(4-fluorophenethyl)-6-isobutylnicotinate [ka]

[0423] At room temperature, a mixture of ethyl 4-(7-bromobenzo[b]thiophen-2-yl)-5-carbamoyl-2-(4-fluorophenethyl)-6-isobutyl-1,4-dihydropyridine-3-carboxylate (1.23 g, crude product) in EtOH (10.0 mL) was mixed with diammonium cerium(IV) nitrate (1.73 g, 3.151 mmol). The mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature, quenched with H2O (200 mL), and extracted with ELISA (100 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA=3 / 1) to obtain ethyl 4-(7-bromobenzo[b]thiophen-2-yl)-5-carbamoyl-2-(4-fluorophenethyl)-6-isobutylnicotinate (800 mg, 65.26%). LC-MS: m / z 582.9 (M+H) + .

[0424] Process C: 4-(7-bromobenzo[b]thiophen-2-yl)-5-carbamoyl-2-(4-fluorophenethyl)-6-isobutylnicotinic acid [ka]

[0425] At room temperature, a solution of ethyl 4-(7-bromobenzo[b]thiophen-2-yl)-5-carbamoyl-2-(4-fluorophenethyl)-6-isobutylnicotinate (540 mg, 0.925 mmol) in DMA (10.0 mL) was mixed with LiCl (392.28 mg, 9.25 mmol). The mixture was stirred overnight at 130 °C. The reaction mixture was cooled to room temperature, concentrated, and purified by reverse-phase column chromatography (HCOOH, 0.1%) to obtain 4-(7-bromobenzo[b]thiophen-2-yl)-5-carbamoyl-2-(4-fluorophenethyl)-6-isobutylnicotinic acid (140 mg, 27.24%). LC-MS: m / z 554.8 (M+H) + .

[0426] Step D: Synthesis of 4-(7-bromobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-5-(hydrazinecarbonyl)-2-isobutylnicotinamide [ka]

[0427] At room temperature, a mixture of 4-(7-bromobenzo[b]thiophen-2-yl)-5-carbamoyl-2-(4-fluorophenethyl)-6-isobutylnicotinic acid (140 mg, 0.252 mmol) and hydrazine hydrochloride (25.90 mg, 0.378 mmol) in DMF (5.0 mL) was mixed with PyBOP (393.19 mg, 0.756 mmol) and DIEA (0.3 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction product was quenched with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saline solution (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction product was purified by column chromatography (DCM / MeOH=20 / 1) to obtain 4-(7-bromobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-5-(hydrazinecarbonyl)-2-isobutylnicotinamide (90 mg, yield: 62.70%). LC-MS: m / z 569.1 (M+H) + .

[0428] Process E: 4-(7-bromo-1-benzothiophen-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 129) [ka]

[0429] At room temperature, 1,1-dimethoxy-N,N-dimethylethane-1-amine (28.07 mg, 0.211 mmol) was added to a solution of 4-(7-bromobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-5-(hydrazinecarbonyl)-2-isobutylnicotinamide (80 mg, 0.140 mmol) in MeCN (8.0 mL). The solution was stirred at 80 °C for 1 hour. HoAc (0.5 mL) was added. The solution was stirred overnight at 100 °C. After the reaction was complete, the reaction product was concentrated under reduced pressure. The reaction product was purified by preparative HPLC to obtain compound 129 (44.84 mg, yield: 53.78%). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1 H), 7.90 (d, J=24.8 Hz, 1 H), 7.64 (d, J=21.2 Hz, 1 H), 7.58 (s, 1 H), 7.50 (s, 1 H), 7.36 (t, J=7.6 Hz, 1 H), 7.01-7.16 (m, 4 H), 2.93-3.06 (m, 4 H), 2.76 (d, J=7.6 Hz, 2 H), 2.27-2.35 (m, 4 H), 0.95 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26. LC-MS: m / z 593.0 (M+H) + . Example 9 4-(7-{[(3,4-difluorophenyl)methyl]amino}-1-oxa-6-aza-2-indenyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 130) [ka] compound 130 [ka]

[0430] Step A: 2-(((tert-butyldimethylsilyl)oxy)methyl)-N-(3,4-difluorobenzyl)fl[2,3-c]pyridine-7-amine [ka]

[0431] To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-chlorofl[2,3-c]pyridine (250 mg, 1.09 mmol) and (3,4-difluorophenyl)methaneamine (310 mg, 2.17 mmol) in dioxane (10 mL), Brettphos Pd G3 (99 mg, 0.11 mmol) and Cs2CO3 (1.06 g, 3.27 mmol) were added, and the mixture was stirred in a microwave under N2 at 100°C for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and purified by column chromatography (ÂPE = 0-20%) on silica gel to obtain 2-(((tert-butyldimethylsilyl)oxy)methyl)-N-(3,4-difluorobenzyl)fl[2,3-c]pyridine-7-amine (175 mg, 40.0%). LC-MS: m / z 405.1 (M+H) + .

[0432] Step B: (7-((3,4-difluorobenzyl)amino)fluoro[2,3-c]pyridine-2-yl)methanol [ka]

[0433] To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-N-(3,4-difluorobenzyl)fl[2,3-c]pyridine-7-amine (175 mg, 0.43 mmol) in MeOH (15 mL), TsOH (164 mg, 0.87 mmol) was added, and the mixture was stirred at 40°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated, and purified by reverse-phase flush (0.1 FA / H2O:ACN=0~10%) to obtain (7-((3,4-difluorobenzyl)amino)fl[2,3-c]pyridine-2-yl)methanol (100 mg, 79.4%). LC-MS: m / z 290.9 (M+H) + .

[0434] Process C: 4-(7-{[(3,4-difluorophenyl)methyl]amino}-1-oxa-6-aza-2-indenyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide [ka]

[0435] To a solution of (7-((3,4-difluorobenzyl)amino)fl[2,3-c]pyridine-2-yl)methanol (100 mg, 0.10 mmol) in DCM (10 mL), MnO2 (260 mg, 1.00 mmol) was added, and the mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain 7-((3,4-difluorobenzyl)amino)fl[2,3-c]pyridine-2-carboaldehyde (50 mg, crude product, 50.5%). LC-MS: m / z 289.1 (M+H) + . 4-(7-{[(3,4-difluorophenyl)methyl]amino}-1-oxa-6-aza-2-indenyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 130) [ka]

[0436] Compound 130 was synthesized using a similar procedure to that described in Example 7 above, with appropriate materials.

[0437] 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.82 (s, 1H), 7.73 (d, J=5.2 Hz, 1H), 7.29-7.39 (m, 2H), 7.13-7.17 (m, 3H), 7.04-7.08 ( m, 3H), 6.87-6.93 (m, 2H), 4.57 (d, J=5.6 Hz, 2H), 3.08-3.11 (m, 2H), 2.98-3.02 (m, 2H), 2.77 (d, J=6.8 Hz, 2H), 2.46-2.48 (m, 1H), 2.30 (s, 3H), 0.93 (d, J = 6.8 Hz, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -117.25, -139.27, -142.07. LC-MS: m / z 641.3 (M+H) + . Example 10 4-(7-{[(3,4-difluorophenyl)methyl]amino}-1-thia-6-aza-2-indenyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 131) [ka] Compound 131 [ka]

[0438] Step A: (7-bromothieno[2,3-c]pyridine-2-yl)methanol [ka]

[0439] At 0°C, LiBH4 (288.14 mg, 13.23 mmol) was added to a mixture of methyl 7-bromothieno[2,3-c]pyridine-2-carboxylate (900 mg, 3.31 mmol) in THF (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with RINKAN and saline solution. The organic layer was separated, washed with saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (7-bromothieno[2,3-c]pyridine-2-yl)methanol (440 mg, 54.50%). LC-MS: m / z 243.9 (M+H) + .

[0440] Process B: 7-bromothieno[2,3-c]pyridine-2-carbaldehyde [ka]

[0441] A mixture of (7-bromothieno[2,3-c]pyridine-2-yl)methanol (400 mg, 1.64 mmol) in CHCl3 (10 mL) and MeOH (1 mL) was mixed with MnO2 (2.85 g, 32.77 mmol), and the reaction mixture was stirred at 70°C for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE:siRNA=2:1 elution to obtain 7-bromothieno[2,3-c]pyridine-2-carbaldehyde (340 mg, 85.71%). LC-MS: m / z 241.9 (M+H) + .

[0442] Process C: 4-(7-bromothieno[2,3-c]pyridine-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)-1,4-dihydropyridine-3-carboxamide [ka]

[0443] To a mixture of 7-bromothieno[2,3-c]pyridine-2-carboaldehyde (320 mg, 1.32 mmol) in EtOH (15 mL), 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazole-2-yl)butan-2-one (329 mg, 1.32 mmol) and (2E)-3-amino-5-methylhexa-2-enamide (188 mg, 1.32 mmol) were added. The reaction mixture was stirred overnight at 120°C in a sealed tube under N2 protection. The residue was purified by silica gel column chromatography using DCM:MeOH = 20:1 elution to obtain 4-(7-bromothieno[2,3-c]pyridine-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)-1,4-dihydropyridine-3-carboxamide (580 mg, 73.56%). LC-MS: m / z 596.1 (M+H) + .

[0444] Process D: 4-(7-bromothieno[2,3-c]pyridine-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide [ka]

[0445] To a mixture of 4-(7-bromothieno[2,3-c]pyridine-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)-1,4-dihydropyridine-3-carboxamide (80 mg, 0.134 mmol) in DCM (4 mL), cerium(IV) ammonium nitrate (221 mg, 0.402 mmol) was added, and the reaction mixture was stirred under microwave at 70°C for 30 minutes. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain 4-(7-bromothieno[2,3-c]pyridine-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide (50 mg, 62.71%). LC-MS: m / z 594.1 (M+H) + .

[0446] Process E: 4-(7-{[(3,4-difluorophenyl)methyl]amino}-1-thia-6-aza-2-indenyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 131) [ka]

[0447] A mixture of 4-(7-bromothieno[2,3-c]pyridine-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide (50 mg, 0.084 mmol) in dioxane (4 mL) was mixed with (3,4-difluorophenyl)methaneamine (24 mg, 0.17 mmol), Cs2CO3 (55 mg, 0.17 mmol), and BrettPhos Pd G3 (8 mg, 0.008 mmol). The reaction mixture was stirred at 100 °C for 2 hours under N2 protection and microwave. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC using 0.1% FA to obtain 4-(7-{[(3,4-difluorophenyl)methyl]amino}-1-oxa-6-aza-2-indenyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (4.1 mg, 7.42%).

[0448] 1 H NMR (400 MHz, CD3OD) δ 7.87 (d, J=6.0 Hz, 1H), 7.30 (s, 1H), 7.13-7.25 (m, 3H), 7.02-7.06 (m, 3H), 6.92-6.96 (m, 2H), 4.69 (s, 2H), 3.15-3.19 (m, 2H), 3.02-3.07 (m, 2H), 2.90 (d, J=7.2 Hz, 2H), 2.38-2.45 (m, 1H), 2.29 (s, 3H), 1.04 (d, J=6.8 Hz, 6H). 19 F NMR (377 MHz, CD3OD) δ -119.31, -141.11, -143.93. LC-MS: m / z 651.3 (M+H) + .

[0449] 4-(4-((3,4-difluorobenzyl)amino)thieno[3,2-d]pyrimidine-6-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 132) [ka] compound 132

[0450] Compound 132 was synthesized using a similar procedure to that described in Example 10 above, with the use of appropriate materials.

[0451] 1 H NMR (400 MHz, CD3OD) δ 8.44 (s,1H),7.30 (s, 1H), 7.19-7.28 (m, 3H), 7.03-7.07 (m, 2H), 6.92-6.97 (m, 2H), 4.76 (s, 2H), 3.14-3.18 (m, 2H), 3.04-3.08 (m, 2H), 2.90 (d, J=7.2 Hz, 2H), 2.38-2.45 (m, 1H), 2.33(s,3H), 1.04 (d, J=6.8 Hz, 6H). 19 F NMR (377 MHz, CD3OD) δ -119.30, -140.66, -140.71, -143.12, -143.18. LC-MS: m / z 658.3 (M+H) + . 4-(4-((3,4-difluorobenzyl)amino)thieno[3,2-c]pyridine-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 133) [ka] compound 133

[0452] Compound 133 was synthesized using a similar procedure to that described in Example 10 above, with the use of appropriate materials.

[0453] 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.79-7.83 (m, 2H), 7.59 (s, 1H), 7.56 (s, 1H), 7.32-7.37 (m, 2H), 7.03-7.14 (m, 6H), 4.62 (d, J=5.6 Hz, 2H), 2.99-3.00 (m, 4H), 2.75 (d, J=7.6 Hz, 2H), 2.32-2.33 (m, 1H), 2.31 (s, 3H), 0.93 (d, J=6.8 Hz, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26, -139.21, -139.27, -141.98, -142.04. LC-MS: m / z 657.0 (M+H) + . 6-(4-fluorophenethyl)-2-isobutyl-4-(7-(3-(methoxymethyl)azetidine-1-yl)thieno[2,3-c]pyridine-2-yl)-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 134) [ka] compound 134

[0454] Compound 134 was synthesized using a similar procedure to that described in Example 10 above, with the use of appropriate materials.

[0455] 1H NMR (400 MHz, DMSO-d6): δ 7.89-7.96 (m, 2 H), 7.60 (br s, 1 H), 7.31 (s, 1 H), 7.01-7.17 (m, 5 H), 4.17 (t, J=8.0 Hz, 2 H), 3.87 (dd, J=6.0 Hz, J=7.6 Hz, 2 H), 3.53 (d, J=6.0 Hz, 2 H), 3.30 (s, 2 H), 3.28 (s, 3 H), 2.95-3.02 (m, 4 H), 2.75 (d, J=7.2 Hz, 2 H), 2.33 (s, 3 H), 0.94 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26. LC-MS: m / z 615.2 (M+H) + . Example 11 6-(4-fluorophenethyl)-2-isobutyl-4-(7-(3-methoxypiperidine-1-yl)thieno[2,3-c]pyridine-2-yl)-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 135) [ka] compound 135 [ka]

[0456] Step A: 7-(3-methoxypiperidine-1-yl)thieno[2,3-c]pyridine [ka]

[0457] To a solution of 7-chlorothieno[2,3-c]pyridine (950 mg, 5.60 mmol) in ethylene glycol (10 mL), 3-methoxyhexahydropyridine (1935.17 mg, 16.80 mmol) was added, and the reaction mixture was stirred overnight at 140°C. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE / Â=10:1) on silica gel to obtain 7-(3-methoxypiperidine-1-yl)thieno[2,3-c]pyridine (1.3 g mg, yield: 93.47%). LC-MS: m / z 249.1 (M+H) + .

[0458] Step B: 7-(3-methoxypiperidine-1-yl)thieno[2,3-c]pyridine-2-carbaldehyde [ka]

[0459] To a solution of 7-(3-methoxyhexahydropyridine-1-yl)thieno[2,3-c]pyridine (500 mg, 2.013 mmol) in tetrahydrofuran (10 mL), n-BuLi (1.13 mL, 2.819 mmol, 2.5 M in n-hexane) was added dropwise at -78°C and stirred for 30 minutes at -78°C, then N,N-dimethylmethaneamide (0.211 mL, 2.617 mmol) was added. The reaction mixture was gradually heated to room temperature and stirred for a further 1 hour. The reaction mixture was diluted with EA and water. The organic layer was separated and washed with water. The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate (PE:Â=9:1) in petroleum ether. The organic layer was collected and concentrated under reduced pressure to obtain the title compound 7-(3-methoxypiperidine-1-yl)thieno[2,3-c]pyridine-2-carboaldehyde (395 mg, yield: 70.99%). LC-MS: m / z 277.0 (M+H) + . 6-(4-fluorophenethyl)-2-isobutyl-4-(7-(3-methoxypiperidine-1-yl)thieno[2,3-c]pyridine-2-yl)-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 135) [ka]

[0460] Compound 135 was synthesized using a similar procedure to that described in Example 7 above, by using 7-(3-methoxypiperidine-1-yl)thieno[2,3-c]pyridine-2-carboaldehyde and appropriate materials.

[0461] 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=5.6 Hz, 1 H), 7.92 (br s, 1 H), 7.60 (br s, 1 H), 7.35 (s, 1 H), 7.25 (d, J=5.6 Hz, 1 H), 7.02-7.15 (m, 4 H), 3.96-4.05 (m, 1 H), 3.70-3.79 (m, 1 H), 3.26 (s, 3 H), 2.94-3.22 (m, 7 H), 2.75 (d, J=7.2 Hz, 2 H), 2.27-2.35 (m, 4 H), 1.96-2.04 (m, 1H), 1.75-1.85 (m, 1H), 1.41-1.56 (m, 2 H), 0.94 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.27. LC-MS: m / z 629.1 (M+H) + . Example 12 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 136) [ka] [ka]

[0462] Process A: 7-((3,4-difluorobenzyl)amino)benzo[b]thiophene-2-carboaldehyde [ka]

[0463] A mixture of 7-bromobenzo[b]thiophene-2-carboaldehyde (70 mg, 0.290 mmol), (3,4-difluorophenyl)methaneamine (49.87 mg, 0.348 mmol), and Cs2CO3 (283.95 mg, 0.871 mmol) in toluene (3 mL) was mixed with Xantphos (16.75 mg, 0.029 mmol) and Pd2(dba)3 (26.57 mg, 0.029 mmol) at room temperature. The mixture was stirred under microwave at 130 °C for 1 hour. After the reaction was complete, the reaction product was quenched with H2O (25 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography (PE / EA = 10 / 1) to obtain 7-((3,4-difluorobenzyl)amino)benzo[b]thiophene-2-carboaldehyde (40 mg, 0.132 mmol, 45.42%). LC-MS: m / z 304.1 (M+H) + .

[0464] Process B: 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide [ka]

[0465] A mixture of 7-((3,4-difluorobenzyl)amino)benzo[b]thiophene-2-carboaldehyde (40 mg, 0.132 mmol), 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazole-2-yl)butan-2-one (36.01 mg, 0.145 mmol), and 3-imino-5-methylhexanamide (20.63 mg, 0.145 mmol) in EtOH (2.0 mL) was stirred overnight at 110°C. After the reaction was complete, the reaction product was concentrated under reduced pressure. The reaction product was purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide (40 mg, yield: 46.12%). LC-MS: m / z 658.1 (M+H) + .

[0466] Process C: 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 136) [ka]

[0467] At room temperature, a mixture of 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide (25 mg, 0.038 mmol) in dioxane (5 mL) was mixed with MnO2 (33.04 mg, 0.380 mmol), and the mixture was stirred overnight at 100 °C. The reaction product was filtered and concentrated under reduced pressure. The reaction product was purified by preparative HPLC to obtain 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (5.89 mg, yield: 23.6%).

[0468] 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J=1.2 Hz, 1 H), 7.57 (d, J=1.2 Hz, 1 H), 7.31-7.40 (m, 2 H), 7.28 (s, 1 H), 7.17-7.22 (m, 1 H), 7.03-7.16 (m, 6 H), 6.31-6.39 (m, 2 H), 4.39-4.44 (m, 2 H), 2.95-3.05 (m, 4 H), 2.76 (d, J=7.2 Hz, 2 H), 2.30-2.38 (m, 4 H), 0.95 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -141.74, -139.01, -117.26. LC-MS: m / z 656.1 (M+H) + . Example 13 (R)-4-(7-((2,3-dihydro-1H-inden-1-yl)amino)benzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 137) [ka] compound 137 [ka]

[0469] Process A: 2-(7-bromobenzo[b]thiophen-2-yl)-1,3-dioxolane [ka]

[0470] At room temperature, a mixture of 7-bromobenzo[b]thiophene-2-carboaldehyde (650 mg, 2.696 mmol) and ethylene glycol (0.451 mL, 8.088 mmol) in toluene (25 mL) was mixed with TsOH (51.28 mg, 0.270 mmol). The mixture was stirred overnight at 130 °C. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA = 1 / 10) to obtain 2-(7-bromobenzo[b]thiophene-2-yl)-1,3-dioxolane (360 mg, 46.83%). LC-MS: m / z 285.0 (M+H) + .

[0471] Process B: (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(1,3-dioxolan-2-yl)benzo[b]thiophene-7-amine [ka]

[0472] At room temperature, a mixture of 2-(7-bromobenzo[b]thiophen-2-yl)-1,3-dioxolane (110 mg, 0.386 mmol), (R)-2,3-dihydro-1H-idden-1-amine (78.53 mg, 0.463 mmol), and Cs2CO3 (377.28 mg, 1.157 mmol) in toluene (3.0 mL) was mixed with Xantphos (22.30 mg, 0.039 mmol) and Pd2(dba)3 (35.30 mg, 0.039 mmol). The mixture was stirred overnight at 130 °C. The reaction mixture was cooled to room temperature, quenched with H2O (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was purified by column chromatography (PE / EA = 10 / 1) to obtain (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(1,3-dioxolan-2-yl)benzo[b]thiophene-7-amine (90 mg, 69.14%). LC-MS: m / z 338.1 (M+H) + .

[0473] Process C: (R)-7-((2,3-dihydro-1H-inden-1-yl)amino)benzo[b]thiophen-2-carboaldehyde [ka]

[0474] A mixture of (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(1,3-dioxolan-2-yl)benzo[b]thiophene-7-amine (90 mg, 0.267 mmol) and HCOOH (2 mL) in dioxane (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was quenched with H2O (25 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saline solution (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction product was purified by column chromatography (PE / EA = 20 / 1) to obtain (R)-7-((2,3-dihydro-1H-inden-1-yl)amino)benzo[b]thiophene-2-carboaldehyde (30 mg, 38.34%). LC-MS: m / z 294.2 (M+H) + . (R)-4-(7-((2,3-dihydro-1H-inden-1-yl)amino)benzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 137) [ka]

[0475] Compound 137 was then synthesized using a similar procedure to that described in Example 12 above, by using (R)-7-((2,3-dihydro-1H-inden-1-yl)amino)benzo[b]thiophene-2-carboaldehyde and appropriate materials.

[0476] 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1 H), 7.56 (s, 1 H), 7.01-7.30 (m, 12 H), 6.78 (d, J=7.6 Hz, 1 H), 5.77 (d, J=8.8 Hz, 1 H), 5.18 (dd, J=8.0 Hz, J=15.6 Hz, 1 H), 3.30 (s, 2 H), 2.94-3.00 (m, 4 H), 2.80-2.91(m, 1 H), 2.75 (d, J=7.2 Hz, 2 H), 2.31 (s, 3 H), 1.92-2.06 (m, 1 H), 0.94 (d, J=6.8 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.28. LC-MS: m / z 646.1 (M+H) + . Example 14 4-(7-cyano-1-benzothiophen-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 138) [ka] compound 138 [ka]

[0477] Process A: 4-(7-cyano-1-benzothiophen-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 138) [ka]

[0478] At room temperature, a mixture of 4-(7-bromobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (60 mg, 0.101 mmol) and Zn(CN)2 (118.7 mg, 1.011 mmol) in DMF (4 mL) was mixed with bis(cyclopentyldiphenylphosphan)iron(0) (5.7 mg, 0.010 mmol) and Pd2(dba)3 (9.3 mg, 0.010 mmol), and the mixture was stirred overnight at 125 °C. The reaction mixture was cooled to room temperature, quenched with H2O (25 mL), and extracted with siRNA (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 4-(7-cyano-1-benzothiophen-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (31.30 mg, 57.38%).

[0479] 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=8.0 Hz, 1 H), 7.93-8.02 (m, 2 H), 7.56-7.67 (m, 2 H), 7.50 (s, 1 H), 7.11-7.16 (m, 2 H), 7.06 (t, J=8.8 Hz, 2 H), 2.94-3.09 (m, 4 H), 2.76 (d, J=7.2 Hz, 2 H), 2.25-2.38 (m, 4 H), 0.95 (d, J=6.4 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.24. LC-MS: m / z 540.2 (M+H) + . Example 15 4-(4-aminobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 139) [ka] compound 139 [ka] [ka]

[0480] Step A: (4-bromobenzo[b]thiophene-2-yl)methanol [ka]

[0481] At 70°C, LiBH4 (2.17 g, 54.292 mmol) was added to a mixture of methyl 4-bromobenzo[b]thiophene-2-carboxylate (800 mg, 36.195 mmol) in THF (10 mL). The mixture was stirred at 70°C for 16 hours. After the reaction was complete, the reaction product was quenched with H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction product was purified by column chromatography (PE / EA = 10 / 1) to obtain (4-bromobenzo[b]thiophene-2-yl)methanol (320 mg, 44.61%). 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J=8.0 Hz, 1 H), 7.57-7.59 (m, 1 H), 7.22-7.30 (m, 2 H), 5.75(br s, 1 H), 4.78 (s, 2 H).

[0482] Process B: 4-bromobenzo[b]thiophene-2-carboaldehyde [ka]

[0483] A mixture of (4-bromobenzo[b]thiophen-2-yl)methanol (200 mg, 0.82 mmol) and MnO2 (286.08 mg, 3.291 mmol) in dioxane (2 mL). The reaction mixture was stirred at 100°C for 16 hours. After the reaction was complete, the reaction product was filtered and concentrated under reduced pressure. The reaction product was purified by column chromatography (PE / EA = 10 / 1) to obtain 4-bromobenzo[b]thiophen-2-carboaldehyde (130 mg, 65.54%). 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1 H), 8.44 (s, 1 H), 8.16 (d, J=8.0 Hz, 1 H), 7.77 (d, J=8.0 Hz, 1 H), 7.51(t, J=8.0 Hz, 1 H).

[0484] Process C: 4-(4-bromobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide [ka]

[0485] A mixture of (4-bromobenzo[b]thiophen-2-yl)methanol (130 mg, 0.539 mmol), 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazole-2-yl)butan-2-one (134 mg, 0.539 mmol), and (E)-3-amino-5-methylhexa-2-enamide (77 mg, 0.539 mmol) in EtOH (2 mL) was stirred at 110 °C for 16 hours. After the reaction was complete, the reaction product was quenched with H2O (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with saline solution (15 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction product was purified by preparative TLC (PE / EA = 3 / 1) to obtain 4-(4-bromobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide (120 mg, 37.37%). LC-MS: m / z 595.0 (M+H) + .

[0486] Process D: 4-(4-bromobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide [ka]

[0487] A mixture of 4-(4-bromobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)-1,4-dihydropyridine-3-carboxamide (120 mg, 0.498 mmol) and CAN (1 g, 1.991 mmol) in EtOH (2 mL) was stirred at 50°C for 16 hours. After the reaction was complete, the reaction product was quenched with H2O (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with saline solution (15 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction product was purified by preparative TLC (PE / EA = 3 / 1) to obtain 4-(4-bromobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (80 mg, 26.99%). LC-MS: m / z 593.0 (M+H) + .

[0488] Step E: tert-butyl(2-(3-carbamoyl-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-4-yl)benzo[b]thiophene-4-yl)carbamate [ka]

[0489] A mixture of 4-(4-bromobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (65 mg, 0.110 mmol), Pd2(dba)3 (10.03 mg, 0.011 mmol), Cs2CO3 (107.05 mg, 0.329 mmol), Xantphos (12.67 mg, 0.022 mmol), and 2-methylpropane-2-ylaminomethanoate (128.30 mg, 1.095 mmol) in dioxane (5 mL) was stirred in a microwave at 100°C for 2 hours. After the reaction was complete, the reaction product was quenched with H2O (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with saline solution (15 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The reaction product was purified by preparative TLC (PE / EA = 3 / 1) to obtain tert-butyl(2-(3-carbamoyl-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-4-yl)benzo[b]thiophene-4-yl)carbamate (35 mg, 50.75%). LC-MS: m / z 630.0 (M+H) + .

[0490] Process F: 4-(4-aminobenzo[b]thiophen-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 139) [ka]

[0491] A mixture of tert-butyl(2-(3-carbamoyl-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)pyridine-4-yl)benzo[b]thiophene-4-yl)carbamate (35 mg, 0.056 mmol) in DCM (3 mL) and TFA (0.5 mL) was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction product was filtered and concentrated under reduced pressure. The reaction product was purified by preparative HPLC (TFA) to obtain 4-(4-aminobenzo[b]thiophene-2-yl)-6-(4-fluorophenethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (2.29 mg, 7.64%).

[0492] 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (br s, 1 H), 7.51 (br s, 1 H), 7.43 (s, 1 H), 6.98-7.15 (m, 6 H), 6.48-6.53 (m,1 H), 2.97 (s, 4 H), 2.75 (d, J=7.2 Hz, 2 H), 2.27-2.36 (m, 4 H), 0.94 (d, J=6.4 Hz, 6 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.28. LC-MS: m / z 530.2 (M+H) + . Example 16 4-(5-{[(R)-1-indanylamino]methyl}-2-thienyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazole-2-yl)nicotinamide (compound 140) [ka] compound 140 [ka]

[0493] Process A: 6-[2-(4-fluorophenyl)ethyl]-4-[5-(hydroxymethyl)thiophen-2-yl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide [ka]

[0494] To a solution of 5-{5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazole-2-yl)-6-(2-methylpropyl)pyridine-4-yl}thiophene-2-carboxylic acid (390 mg, 0.767 mmol) in THF (3 mL), 1 M BH3 (7.669 mL) in THF was added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with MeOH (10 mL) and diluted with siRNA (50 mL) and water (20 mL). The organic layer was separated, washed with water (20 mL x 2), separated again, dried over Na2SO4, and then filtered. The organic layer was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with methanol in dichloroform (DCM:MeOH = 30:1). The organic layer was collected and concentrated under reduced pressure to obtain 6-[2-(4-fluorophenyl)ethyl]-4-[5-(hydroxymethyl)thiophen-2-yl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide (330 mg, 87.01%). LC-MS: m / z 495.2 (M+H) + .

[0495] Process B: 4-[5-(chloromethyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide [ka]

[0496] At 0°C, a solution of 6-[2-(4-fluorophenyl)ethyl]-4-[5-(hydroxymethyl)thiophen-2-yl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide (330 mg, 0.667 mmol) in DCM (5 mL) was mixed with SOCl2 (158.74 mg, 1.334 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ELISA (50 mL) and water (30 mL). The organic layer was separated, washed with water (30 mL x 2), separated again, dried over Na2SO4, and then filtered. The organic layer was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with methanol in dichloroform (DCM:MeOH = 30:1). The organic layer was collected and concentrated under reduced pressure to obtain 4-[5-(chloromethyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazole-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide (160 mg, 46.74%). LC-MS: m / z 513.2 (M+H) + . ...

Claims

1. Formula I: 【Chemistry 1】 Compounds thereof, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or solvates thereof. [In the formula: A is C １－６ alkylene, C ２－６ alkenylene, C ２－６ alkynylene, C ３－１０ cycloalkylene, heterocyclylene, arylene, or heteroarylene; wherein the C １－６ alkylene, C ２－６ alkenylene, C ２－６ alkynylene, C ３－１０ cycloalkylene, heterocyclylene, arylene, or heteroaryl is independently optionally substituted with 1 to 5 Z Ａ and may be substituted as appropriate; Ring B has 1 to 3 R Ｂ It is a five-membered or six-membered heteroaryl which may be appropriately substituted; R Ｂ These are independently halo, hydroxy, and -NH ２ , cyano, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, and C １－３ Selected from haloalkoxys; where R Ｂ C is １－３ Each alkyl group is independently -NH ２ , - NHC １－３ Alkyl, -N(C) １－３ Alkyl) ２ , hydroxy, or C １－３ It may also be substituted with alkoxy as appropriate; L １ C １－３ Alkylene, C ２－３ Alkenylene, C ２－３ Alkinylene, C １－３ Heteroalkylene, C ３－６ A cycloalkylene, or a 4- to 6-membered heterocyclene; where L １ The above C １－３ Alkylene, C ２－３ Alkenylene, C ２－３ Alkinylene, C １－３ Heteroalkylene, C ３－６ Cycloalkylenes, or 4- to 6-membered heterocyclenes, are independently classified as halo, oxo, hydroxy, cyano, or C. １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, and C １－３ The haloalkoxy may be appropriately substituted with 1 to 5 substituents independently selected; L ２ The bonds are -O-, -S-, and -NR. ２ａ -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR ２ａ -, -NR ２ａ C(O)-, -OC(O)NR ２ａ -, -NR ２ａ C(O)O-, -NR ２ａ C(O)NR ２ｂ -, -S(O)-, -S(O) ２ -, -S(O)NR ２ａ -, -S(O) ２ NR ２ａ -, -NR ２ａ S(O)-, -NR ２ａ S(O) ２ -, -NR ２ａ S(O)NR ２ｂ -, -NR ２ａ S(O) ２ NR ２ｂ -, C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkinylene, C １－６ Heteroalkylene, C ３－６ The cycloalkylene is a 4- to 6-membered heterocyclylene, or a 5-membered heteroarylene; where L ２ The above C １－３ Alkylene, C ２－３ Alkenylene, C ２－３ Alkinylene, C １－３ Heteroalkylene, C ３－６ Cycloalkylenes, 4- to 6-membered heterocyclylenes, or 5-membered heteroarylenes are independently classified as halo, oxo, hydroxy, cyano, or -NH ２ , - NHC １－３ Alkyl, -N(C) １－３ Alkyl) ２ , C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, and C １－３ The haloalkoxy may be appropriately substituted with 1 to 5 substituents independently selected; R １ is cyano, -C(O)NR １ａ R １ｂ , -C(S)NR １ａ R １ｂ , -S(O) ２ R ２ , -S(O)(NR ６ ) R ２ , or -P(O)R ７ R ２ And; R ２ is -NR １ａ R １ｂ 、C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C ２ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, or heteroaryl as defined by R may be optionally substituted with 1 to 5 substituents independently selected from halo, hydroxy, cyano, C １－３ alkyl, C ２－３ alkenyl, C ２－３ alkynyl, C １－３ haloalkyl, C １－３ alkoxy, or C １－３ haloalkoxy; Alternatively, R ２ and R ６ , or R ２ and R ７ Together with the atoms to which they are bonded, they form 1 to 5 Z ２ It forms a heterocycline which may be appropriately substituted; R １ａ and R １ｂ Each of them is independently of hydrogen and C １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C １－３ Haloalkyl, C ３－６ It is a cycloalkyl or a 4- to 6-membered heterocycline; where R １ａ and R １ｂ C is １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C １－３ Haloalkyl, C ３－６ Cycloalkyls, or 4- to 6-membered heterocyclines, are each independently classified as halo, hydroxy, cyano, or C. １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C １－３ Haloalkyl, C １－３ Alkoxy, or C １－３ The haloalkoxy may be appropriately substituted with 1 to 5 substituents independently selected; Alternatively, R １ａ and R １ｂ These, together with the atoms they are bonded to, form halo, hydroxy, cyano, and C １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl, C １－３ Haloalkyl, C １－３ Alkoxy, or C １－３ It forms a 4-6 membered heterocycline which may be independently and appropriately substituted with 1-5 substituents independently selected from the haloalkoxy; R ２ａ and R ２ｂ Each of them is independently of hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ２ａ and R ２ｂ C is １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Each cycloalkyl, heterocyclyl, aryl, or heteroaryl group independently contains 1 to 5 Z groups. ２ａ It may be replaced as appropriate; Alternatively, R ２ａ and R ２ｂ Together with the atoms to which they are bonded, they form 1 to 5 Z ２ａ They independently form heterocyclines which may be substituted as appropriate; R ３ is hydrogen, -NR ３ｂ R ３ｃ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C １－６ Heteroalkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－１０ It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ３ The above C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Heteroalkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently have 1 to 5 Z ３ It may be replaced as appropriate; R ３ｂ and R ３ｃ Each of them is independently of hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ３ｂ and R ３ｃ C is １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently halo, hydroxy, cyano, and C. １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, and C １－３ The haloalkoxy may be appropriately substituted with 1 to 5 substituents independently selected; Alternatively, R ３ｂ and R ３ｃ Together with the nitrogen atoms to which they are bonded, they form 1 to 5 Z ３ｂ It forms a heterocycline which may be appropriately substituted; R ４ C １－６ Alkyl, C ３－１０ It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ４ The above C １－６ Alkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently have 1 to 5 Z ４ It may be replaced as appropriate; R ５ is hydrogen, halo, hydroxy, amino, cyano, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C ３－１０ It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ５ The above C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl independently have 1 to 5 Z ５ It may be replaced as appropriate; R ６ is hydrogen, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ A cycloalkyl or a 4-6 membered heterocycline; where C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ Cycloalkyls, or 4- to 6-membered heterocyclines, are classified as halo, oxo, hydroxy, cyano, or C. １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, and C １－３ The haloalkoxy may be appropriately substituted with 1 to 5 substituents independently selected; R ７ is hydroxy, C １－３ Alkoxy, C １－３ Haloalkoxy, C １－３ Alkyl, or C １－３ It is a haloalkyl; Z Ａ Z ２ Z ２ａ Z ３ Z ３ｂ Z ４ , and Z ５ These are independently known as halo, cyano, nitro, oxo, and C. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-C １－６ Alkyl, -L-C ２－６ Alkenyl, -L-C ２－６ Alkinyl, -L-C １－６ Haloalkyl, -L-C ３－１０ It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; where Z Ａ Z ２ Z ２ａ Z ３ Z ３ｂ Z ４ , and Z ５ C is １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Each cycloalkyl, heterocyclyl, aryl, or heteroaryl group independently contains 1 to 5 Z groups. １ａ It may be replaced as appropriate; L is independent of -O-, -S-, and -NR ２０ -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR ２０ -, -NR ２０ C(O)-, -OC(O)NR ２０ -, -NR ２０ C(O)O-, -NR ２０ C(O)NR ２１ -, -S(O)-, -S(O) ２ -, -S(O)NR ２０ -, -S(O) ２ NR ２０ -, -NR ２０ S(O)-, -NR ２０ S(O) ２ -, -NR ２０ S(O)NR ２１ -, or -NR ２０ S(O) ２ NR ２１ - and; R ２０ and R ２１ Each of them is independently of hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where R ２０ and R ２１ C is １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Each cycloalkyl, heterocyclyl, aryl, or heteroaryl group independently contains 1 to 5 Z groups. １ａ It may be replaced as appropriate; or, R ２０ and R ２１ Together with the atoms to which they are bonded, they form 1 to 5 Z １ａ They independently form heterocyclines which may be substituted as appropriate; Z １ａ Each of these is independently: halo, hydroxy, cyano, nitro, oxo, -SH, -NH ２ , -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , -S-C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; where Z １ａ NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , -S-C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently C １－６ The molecule may be appropriately substituted with 1 to 5 substituents independently selected from alkyl, oxo, halo, hydroxy, and cyano; However, A is C １－６ If it is alkylene, R ５ C ３－１０ The C is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound; where C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted independently as appropriate.

2. R １ However, -C(O)NR １ａ R １ｂ , -S(O) ２ R ２ , -S(O)(NR ６ ) R ２ , or -P(O)R ７ R ２ The compound according to claim 1.

3. R １ However, -C(O)NH ２ , -S(O) ２ NH ２ , -S(O) ２ CH ３ The following structure: 【Chemistry 2】 -S(O)(NH)CH ３ , or -P(O)(CH ３ )CH ３ The compound according to claim 1 or 2.

4. The aforementioned compound is of formula IA: 【Transformation 3】 The compound described in claim 1, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof, represented by [the specified formula]. [In the formula, X is -C(O)- or -S(O)] ２ - is.

5. A is C １－６ Alkylene, C ３－１０ A is a cycloalkylene, heterocyclylene, arylene, or heteroarylene; where A is C １－６ Alkylene, C ３－１０ Cycloalkylene, heterocyclylene, arylene, or heteroarylene independently contain 1 to 5 Z Ａ The compound according to any of the preceding claims, which may be appropriately substituted with the compound.

6. A is C ３－１０ Cycloalkylene, heterocyclylene, arylene, or heteroarylene; where C ３－１０ Cycloalkylene, heterocyclylene, arylene, or heteroarylene independently contain 1 to 5 Z Ａ The compound according to any of the preceding claims, which may be appropriately substituted with the compound.

7. A is methylene, ethylene, n-propylene, or one of the following structures: 【Chemistry 4】 And; here, bond a is L ２ A compound according to any one of claims 1 to 5, which is bonded to the compound.

8. The aforementioned compound is of formula IB: 【Transformation 5】 A compound as described in any of the preceding claims, represented by, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof. [In the formula: X is -C(O)- or -S(O) ２ - and; X １ , X ２ , X ３ , and X ４ These are O, S, N, and NR, respectively, independently. Ｂ , and CR Ｂ Selected from; however, X １ , X ２ , X ３ , and X ４ at least one of X １ , X ２ , X ３ , and X ４ The ring containing [the element] is aromatic.

9. A is an arylene or heteroarylene; here, the arylene or heteroarylene independently comprises 1 to 5 Z Ａ The compound according to any one of claims 1 to 4 or claim 8, which may be appropriately substituted with the compound.

10. Ring B is pyridyl, pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl; where the pyridyl, pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl is one or two R Ｂ The compound according to any one of claims 1 to 7 or claim 9, which may be appropriately substituted with the compound.

11. Ring B or the following portion: 【Transformation 6】 However, the structure is as follows: 【Transformation 7】 And here each is one or two R Ｂ The compound according to any of the preceding claims, which may be appropriately substituted with the compound.

12. R Ｂ Each of them operates independently, C １－３ A compound according to any of the preceding claims, wherein it is alkyl.

13. L １ However, C ３－６ Cycloalkylene, C １－３ Alkylene, or C １－３ It is a heteroalkylene; here, C ３－６ Cycloalkylene, C １－３ Alkylene or C １－３ Each heteroalkylene is independently classified as halo, oxo, hydroxy, cyano, or C. １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, and C １－３ The compound according to any of the preceding claims, which may be optionally substituted with 1 to 5 substituents independently selected from the haloalkoxy.

14. R ４ However, C １－６ Alkyl, C ３－１０ The C is a cycloalkyl, aryl, heterocyclyl, or heteroaryl; where C １－６ Alkyl, C ３－１０ Cycloalkyl, aryl, heterocyclyl, or heteroaryl groups independently have 1 to 5 Z groups. ４ The compound according to any of the preceding claims, which may be appropriately substituted with the compound.

15. R ４ However, the aryl, heterocyclyl, or heteroaryl is an aryl, heterocyclyl, or heteroaryl. ４ The compound according to any of the preceding claims, which may be appropriately substituted with the compound.

16. R ４ However, C １－３ Alkyl, C ３－９ The C is a cycloalkyl, a 4- to 9-membered heterocycline, or a phenyl; where C １－３ Alkyl, C ３－６ The compound according to any one of claims 1 to 13, wherein the cycloalkyl or phenyl group may be independently substituted with 1 to 3 halos as appropriate.

17. R ３ However, C １－６ Alkyl or C １－６ A compound according to any of the preceding claims, which is a haloalkyl compound.

18. R ３ However, hydrogen, -NR ３ｂ R ３ｃ , C １－６ Alkyl, or C １－６ A compound according to any of the preceding claims, which is an alkoxy.

19. L ２ However, binding, -NR ２ａ -, -C(O)NR ２ａ -, -NR ２ａ C(O)-, C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkinylene, C １－６ The heteroalkylene, 4-6 membered heterocyclene, or 5 membered heteroarylene; where C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkinylene, C １－６ Heteroalkylenes, 4-6 member heterocyclenes, or 5 member heteroarylenes can independently be classified as halo, oxo, hydroxy, cyano, or C. １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, and C １－３ The compound according to any of the preceding claims, which may be optionally substituted with 1 to 5 substituents independently selected from the haloalkoxy.

20. R ５ However, hydrogen, halo, amino, cyano, C １－６ Alkyl, C １－６ Alkoxy, C ３－１０ The C is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound; where C １－６ Alkyl, C １－６ Alkoxy, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 5 Z groups. ５ The compound according to any of the preceding claims, which may be appropriately substituted with the compound.

21. R ５ However, the aryl or heteroaryl is an aryl or heteroaryl, where the aryl or heteroaryl is a group of 1 to 5 Z ５ The compound according to any of the preceding claims, which may be appropriately substituted with the compound.

22. R ５ However, hydrogen, halo, amino, cyano, C １－６ Alkyl, C １－６ Alkoxy, C ３－１０ The C is a cycloalkyl, heterocyclyl, or aryl; where C １－６ Alkyl, C １－６ Alkoxy, C ３－１０ Cycloalkyl, heterocyclyl, or aryl groups independently have 1 to 5 Z groups. ５ The compound according to any of the preceding claims, which may be appropriately substituted with the compound.

23. Compounds shown in Table 1 or Table 2, or their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or solvates thereof.

24. A pharmaceutical composition comprising a compound described in any of the preceding claims, or a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, or a prodrug, and a pharmaceutically acceptable additive.

25. A method for treating a disease or disorder related to calcitonin receptors and / or amyrin receptors in a subject requiring treatment, the method comprising administering to the subject requiring treatment a therapeutically effective amount of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, stereoisomer, mixture of stereoisomers, or solvates thereof, or a pharmaceutical composition according to claim 24.

26. The method according to claim 25, wherein the calcitonin receptor and / or amyrin receptor-related disease or disorder is a bone disorder, metabolic disorder, pain, neurodegenerative disease or disorder, cardiovascular disease, or other disease or disorder.

27. The method according to claim 25, wherein the calcitonin receptor and / or amyrin receptor-related disease or disorder is osteoporosis, Paget's disease, hypercalcemia, Sudeck's atrophy, multiple fibrous dysplasia, ossification of the sternoclavicular bones, osteogenesis imperfecta, osteopenia, periodontal disease or defects, osteolytic bone disease, metastatic bone disorder, osteopenia due to malignant tumor, autoimmune arthritis, fracture or fracture, or immobility or non-use, osteopathic pain, phantom limb pain, general pain, hyperalgesia, pain associated with diabetic neuropathy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Alzheimer's disease, insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, impaired glucose tolerance, obesity, syndrome X, diabetic complications, primary or secondary hyperthyroidism, endocrine disorders, conditions associated with gastric secretion suppression, gastrointestinal disorders, renal osteodystrophy, or male infertility.

28. The method according to any one of claims 25 to 27, further comprising administering an additional therapy or therapeutic agent to the patient.

29. The method according to claim 28, wherein the additional therapy or therapeutic agent is selected from the group consisting of antidiabetic agents, anti-obesity agents, weight-loss agents, GLP-1 receptor agonists, antiemetic agents, agents for treating non-alcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

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