Modulators of calcitonin receptor and / or amylin receptor activity

Abstract

The present application relates to compounds of Formula I, which modulate calcitonin receptor and / or amylin receptor activity and are useful in the treatment of bone, metabolic, cardiovascular, neurodegenerative and other disorders. I

Description

Cross-reference to related applications

[0001] This application claims priority to international patent application PCT / CN2023 / 107247 filed on July 13, 2023, international patent application PCT / CN2024 / 076848 filed on February 8, 2024, and international patent application PCT / CN2024 / 097845 filed on June 6, 2024, each of which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure provides compounds for modulating the activity of calcitonin receptors and / or amylin receptors, as well as pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating diseases, disorders, and conditions related to calcitonin receptors and / or amylin receptors are also provided. Background Technology

[0003] Calcitonin and amylin are hormones that interact with receptors in the same family to exert their effects on the human organism. Calcitonin, derived from thyroid C cells, is known for its inhibitory effect on osteoclasts. Mammal-derived calcitonin promotes insulin sensitivity, while the more potent salmon-derived calcitonin additionally inhibits gastric emptying, promotes gallbladder relaxation, increases energy expenditure, induces satiety, and results in weight loss. Studies have also shown that oral administration of 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 amylin receptor (AMYR) is a G protein-coupled receptor (GPCR) that responds to the peptide hormones amylin and calcitonin. The amylin receptor is a heterodimer containing the calcitonin receptor (which is a G protein-coupled receptor) and one of three receptor-modifying proteins. Amylin, primarily formed in pancreatic β-cells, is co-secreted with insulin in response to calorie intake. Patients with type 1 diabetes have lower baseline serum amylin concentrations and lack amylin production in response to calorie intake. Patients with type 2 diabetes who require insulin also show reduced amylin production in response to calorie intake, which may be related to the degree of β-cell damage. Key physiological functions of amylin in maintaining glucose homeostasis include inhibiting glucagon release in response to calorie intake, delaying gastric emptying rate, and stimulating the satiety center in the brain to restrict calorie intake.

[0005] The synthetic amylin analog pralintide is an approved diabetes treatment drug used as adjunctive therapy to prandial insulin, promoting better glycemic control and small but significant weight loss. AM833 (cagrilintide) is a novel long-acting acylated amylin analog in investigation that acts as a non-selective amylin receptor agonist. This amylin receptor agonist could serve as an attractive new treatment for obesity, leading to reduced food intake and significant weight loss in a dose-dependent manner. J Obes Metab Syndr. 2021;30(4): 320-325.

[0006] Therefore, modulators of amylin and / or calcitonin receptors can be used to treat various metabolic disorders and induce weight loss. Summary of the Invention

[0007] This disclosure provides small molecule calcitonin and / or amylin receptor modulators (e.g., amylin receptor agonists) and pharmaceutical compositions comprising the compounds disclosed herein. Methods for treating diseases or conditions related to calcitonin receptors and / or amylin receptors are also provided. Calcitonin receptor activation has been shown to be important for glycemic regulation in diabetes; this complements the known metabolically beneficial effects of amylin 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 as disclosed herein, or stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients thereof.

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

[0010] This document also provides methods for treating or preventing calcitonin receptor and / or amylin receptor-related diseases or disorders in subjects of need, the methods comprising administering to the subject of need a therapeutically effective amount of the compounds disclosed herein (e.g., compounds of formula I or a subset thereof, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or solvates thereof) or pharmaceutical compositions thereof. In some embodiments, the methods further comprise administering to the subject a therapeutically effective amount of one or more other therapies or therapeutic agents, such as, but not limited to, antidiabetic agents, antiobesity agents, weight-loss agents, GLP-1 receptor agonists, antiemetics, agents for treating nonalcoholic steatohepatitis (NASH), gastric electrical stimulation, dietary monitoring, physical activity, or combinations thereof.

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

[0012] In some embodiments, the calcitonin receptor and / or amylin receptor-related diseases or disorders are bone disorders, including but not limited to osteoporosis, Paget's disease, hypercalcemia, Zudk atrophy, multiple fibrous dysplasia of bone, costoclavicular ossification, osteogenesis imperfecta, osteopenia, periodontal disease or defects, osteolytic bone disease, metastatic bone disorders, or bone loss caused by malignancy, autoimmune arthritis, bone fissures or fractures, or inactivity or disuse.

[0013] In some embodiments, the calcitonin receptor and / or amylin receptor-related disease or disorder is pain, including but not limited to osteopathic pain, phantom limb pain, generalized pain, hyperalgesia, or pain associated with diabetic neuropathy.

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

[0015] In some embodiments, the calcitonin receptor and / or amylin 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 implementations, the calcitonin receptor and / or amylin receptor-related diseases or disorders include primary or secondary hyperthyroidism, endocrine disorders, conditions associated with gastric secretion inhibition, gastrointestinal disorders, renal osteodystrophy, or male infertility. Attached Figure Description

[0017] Figure 1 The thermodynamic approach for calculating the relative binding free energy is illustrated. Two different transformations are used to calculate the relative binding free energy. First, the free energy for the transformation of ligand 1 to ligand 2 is determined in the solvent; second, the free energy for the transformation of ligand 1 to ligand 2 is determined when bound to a target. The difference between these two values ​​may be related to the difference in binding free energies between ligand 1 and ligand 2.

[0018] Figure 2 The thermodynamic factors involved in ligand-target binding are shown. The left side represents the contribution due to ligand conformation and desolvation; the right side represents the contribution due to target conformation and desolvation.

[0019] Figure 3 The correlation between in vitro amylin receptor cAMP assay I and computer-simulated computational assays is shown for the representative compounds described herein and other compounds with known activity in the corresponding assays.

[0020] Figure 4 The correlation between in vitro calcitonin receptor (CTR) cAMP assays and computer-simulated computational assays is shown for the representative compounds described herein and other compounds with known activity in the corresponding assays. Detailed Implementation definition

[0021] The following description illustrates exemplary embodiments of the present invention. However, it should be understood that this description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

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

[0023] A dash ("-") not located between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH2 is attached via a carbon atom. A dash at the beginning or end of a chemical group is for convenience; a chemical group may be depicted with or without one or more dashes without losing its ordinary meaning. A wavy or dashed line drawn in the structure indicates a designated attachment point of the group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0024] prefix "C" u-v This indicates that the subsequent group has u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0025] This document uses the term "about" to refer to a value or parameter, which includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In some still embodiments, the term "about" includes the indicated amount ± 1%. Furthermore, the term "about X" includes a description of "X". Additionally, unless the context clearly specifies otherwise, the singular forms "an" and "the" include plural indicators. Thus, for example, reference to "the compound" includes multiple such compounds, and reference to "the assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

[0026] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 12 carbon atoms (i.e., C464) 1-12 Alkyl groups, 1 to 8 carbon atoms (i.e., C464-C ... 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C646) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4 Alkyl groups 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 an alkyl residue with a specific number of carbons is named by its chemical name or identified by its molecular formula, all positional isomers having that number of carbons can be included; thus, 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" refers to an alkyl group that contains at least one (e.g., 1-3 or 1) carbon-carbon double bond and has from 2 to 20 carbon atoms (i.e., C36, C46, ​​C56, C6 ... 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl groups. Examples of alkenyl groups include, for example, vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0028] "Alkynyl" refers to an alkyl group that contains at least one (e.g., 1-3 or 1) carbon-carbon triple bond and has 2 to 20 carbon atoms (i.e., C360-C4 ... 2-20 alkynyl group), 2 to 12 carbon atoms (i.e., C 2-12 acetylsyl), 2 to 8 carbon atoms (i.e., C 2-8 acetylsyl), 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 (Alkyne group). The term "alkynyl group" also includes those groups that have one triple bond and one double bond.

[0029] Some commonly used alternative chemical names can be used. For example, divalent groups (such as divalent "alkyl", divalent "aryl", etc.) can also be called "alkylene" groups (or "alkylenyl") and "arylene" groups (or "arylenyl"), respectively.

[0030] "Alkoxy" refers to the "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, wherein the hydrogen atom is replaced by an alkoxy group as defined herein.

[0032] "Haloalkyl" refers to a straight-chain or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by independently selected halogen groups. For example, where a residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted by two ("di") or three ("tri") halogen groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0033] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by independently selected halogen groups.

[0034] "Haloalkoxyalkyl" refers to an alkyl group as defined above, wherein the hydrogen atom is replaced by a haloalkoxy group as defined herein.

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

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

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

[0038] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted, as defined herein. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0039] "Amide group" refers to the substituent group -C(O)NR y R z The "C-amide group" and the substituent group -NR y C(O)R z The two "N-amide groups", of which R y and R z Independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted, as defined herein, or R y and R z Together they form cycloalkyl or heterocyclic groups; each of which may optionally be substituted, as defined herein.

[0040] "Amino" refers to the -NR group. y R z , where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0041] "Amino group" refers to -C(NR) y (NR) z 2), where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0042] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C646-C ... 6-20aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 Aryl groups. Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl groups do not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl group, regardless of the attachment point. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic group, regardless of the attachment point. If one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is a cycloalkyl group, regardless of the attachment point.

[0043] "Carbamoyl" refers to the substituent group -OC(O)NR y R z The "O-carbamoyl" and the substituent group -NR y C(O)OR z The two "N-carbamoyl" groups, of which R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0044] "Carboxylic ester" or "ester" refers to -OC(O)R x and -C(O)OR x Of the two, R x It is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0045] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cycloalkenyl groups having at least one sp... 3 A carbon-cyclic fused ring system (i.e., at least one non-aromatic ring). As used herein, cycloalkyl groups have from 3 to 20 ring carbon atoms (i.e., C164, C2 ... 3-20 cycloalkyl groups), 3 to 14 cyclic carbon atoms (i.e., C1456 ... 3-14 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C146 ... 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6Cycloalkyl. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Furthermore, the term cycloalkyl is intended to include any non-aromatic ring that can fused with an aryl ring, regardless of its attachment to the rest of the molecule (e.g., 2,3-dihydro-1H-indenyl). Still, in the case of two substitution positions on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0046] "Cycloalkylalkyl" refers to an alkyl group as defined above, wherein hydrogen atoms are replaced by cycloalkyl groups as defined herein.

[0047] "Imine" refers to the group -C(NR) y )R z , where R y and R z Each of these groups is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these groups may optionally be substituted, as defined herein.

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

[0049] "Halogen" or "halogen group" refers to an atom that occupies Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0050] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom 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 heterocyclic, each of which may optionally be substituted. 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 optionally be substituted. As used herein, heteroalkyl groups include 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] "Hybrid alkylene" refers to a divalent heteroalkyl group. A "heteroalkylene" must have at least one carbon atom and at least one heteroatom group within the chain. The term "heteroalkylene" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms can be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR. y -, -O-, -S-, -S(O)-, -S(O)2-, etc., among which R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted 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-, -CH2CH2SCH2CH2SCH2-, -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 yCH2-、-CH2CH2NR y CH2CH2NR y CH2- etc., where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted 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 having an oxo group present on one or more carbon atoms.

[0052] "Heteroaryl" refers to an aromatic group having a single ring or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 ring carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-20 (heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl) or 3 to 8 carbon ring atoms (i.e., C 3-8The heteroaryl group comprises 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomium, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. In some cases, the heteroaryl group comprises a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each ring system having independently 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomium, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzooxazolyl, benzothiophenel, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolel, cenolinyl, dibenzofuranyl, dibenzothiaphenel, furanyl, isothiazolyl, imidazolyl, indazolel, indolyl, indazolel, isothiazolyl, imidazolyl, indazolel, and isothiazolyl. Indolyl, isoquinolinyl, isoxazolyl, naphridinyl, oxadiazolyl, oxazolyl, 1-oxopyridyl, 1-oxadiazolyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophene, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, inzolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group can be linked via any ring of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its attachment to the rest of the molecule (i.e., through any one of the fused rings). A heteroaryl does not encompass aryl groups as defined above or overlap with aryl groups as defined above.

[0053] "Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. Heterocyclic groups can be monocyclic or polycyclic, wherein the polycyclic group can be fused, bridged, or spirocyclic, and can contain one or more (e.g., 1 to 3) oxo groups (=O) (e.g., -C(O)-, -S(O)-, -S(O)2-, or -P(O)-) or N-oxides (-O... -The term heterocyclic group refers to any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring, regardless of its attachment to the rest of the molecule. For example, fused ring systems (such as 6,7-dihydro-5H-cyclopentadieno[b]pyridyl, decahydroquinazoline, 1,2,3,4-tetrahydroquinazoline, and 5,6,7,8-tetrahydroquinazoline) are heterocyclic groups regardless of their attachment (i.e., they can be bonded by carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom, which may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of its attachment to the rest of the molecule. As used herein, heterocyclic groups have 2 to 20 ring carbon atoms (i.e., C2, C3, C4, C5, C6, C6, C7 ... 2-20 Heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclic group) or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclic groups); having 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomole independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include, for example, azirrobutyl, azirrobutyl, benzodioxanyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranone, benzofuranone, dioxanyl, dihydropyranyl, hydrogenpyranyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazoalkyl, indololinyl, indolazinyl, isoindololinyl, isothiazolyl, isoxazolyl, Morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolylalkyl, ethylene oxide, oxacyclobutyl, phenothiazinyl, phenothiazinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, tetrahydropyranyl, trithiaalkyl, tetrahydroquinolinyl, thiomorpholinyl, thio-morpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When there are two substitution positions on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spiroheterocyclic rings include, for example, bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindololinyl, wherein the heterocyclic group can be linked via any ring of the fused system.

[0054] "Sulfonyl" refers to the group -S(O)2R y , where R y It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Examples of sulfonyl groups are methanesulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0055] "Sulinate group" refers to the group -S(O)R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0056] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both scenarios in which the event or situation occurs and scenarios in which the event or situation does not occur. Furthermore, the term “optionally substituted” means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a specified atom or group may or may not be substituted with any of the components other than hydrogen.

[0057] As used herein, the term "compound" means any or all stereoisomers, geometric isomers, tautomers, and isotopically enriched analogs (e.g., deuterated analogs) that include the structure described. Unless otherwise stated, compounds identified herein as a particular tautomer form by name or structure are intended to include other tautomer forms.

[0058] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, compounds containing amides can exist in equilibrium with imine tautomers. Regardless of which tautomer is exhibited, and regardless of the equilibrium nature between the tautomers, those skilled in the art will understand that a compound includes both amide and imine tautomers. Therefore, compounds containing amides should be understood to include their imine tautomers. Similarly, compounds containing imines should be understood to include their amide tautomers.

[0059] Any compound or structure described herein is intended to represent both the unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have the structures depicted herein, but one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, as follows: 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. Various isotopically labeled compounds, such as those doped with radioactive isotopes, are disclosed herein. 3 H and 14Compounds containing C. Such isotope-labeled compounds may be useful in: metabolic studies, reaction kinetic studies, detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution), or in the treatment of patients with radiotherapy.

[0060] The term “isotope-enriched analogues” includes “deuterated analogues” of the compounds described herein, wherein one or more hydrogen atoms (such as hydrogen on carbon atoms) are replaced by deuterium. Such compounds exhibit increased metabolic resistance and are therefore used to increase 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 hydrogen atoms have been replaced by deuterium.

[0061] The deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetics) properties, involving distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope such as deuterium may provide certain therapeutic advantages due to its greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18 F, 3 H, 11 C-labeled compounds can be used in PET or SPECT or other imaging studies. The isotopically labeled compounds and their prodrugs of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, by implementing the procedures disclosed in the schemes described below or in the examples and preparations. It should be understood that, in this context, deuterium is considered a substituent in the compounds described herein.

[0062] The concentration of such heavier isotopes (particularly deuterium) can be defined by an isotope 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 said atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen,” said position should be understood as hydrogen having 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 are capable of forming acidic and / or basic salts due to 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" means compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0065] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts formed with inorganic acids and salts formed with organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acidic salt. Conversely, if the product is a free base, the addition salt (particularly pharmaceutically acceptable addition salts) can be produced by dissolving the free base in a suitable organic solvent and treating said solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, 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. For example, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of NH3 or primary, secondary, and tertiary amines, such as those derived from N-containing heterocycles, N-containing heteroaryl groups, or those derived from the formula N(R) N )3 amine salts (e.g., HN) + (R N )3 or (alkyl)N + (R N )3), where each R N Independently, it is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxyl, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines, by way of example only, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0066] The term "substitution" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents that are not hydrogen, provided that the substitution 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, amidyl, amide, amino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, guanidinyl, halogen, haloalkoxy, haloalkoxyalkyl, haloalkyl, heteroalkyl, heteroaryl, heterocyclic, hydrazyl, hydroxy, hydroxyalkyl, imide, imino, nitro, oxo, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thion, or combinations thereof.

[0067] Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of additional substituents (e.g., substituted aryl groups with substituted alkyl groups, said substituted alkyl groups being themselves substituted by substituted aryl groups, said substituted aryl groups being further substituted by substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of an aryl group substituted by two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include disallowed substitution patterns (e.g., methyl groups substituted by five fluorine atoms or heteroaryl groups having two adjacent oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise stated, when a group is described as optionally substituted, any substituted element of said group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halogen, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with a halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with a halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is unsubstituted.

[0068] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition should be considered. Complementary active ingredients may also be incorporated into the composition.

[0069] A "solvent" is formed through the interaction of a solvent with a compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0070] As used herein, the term "pharmaceutically acceptable" means that the compound or its salt or composition is chemically and / or toxicologically compatible with other components constituting the formulation and / or with the subject being treated therein.

[0071] The term "administration" or "administering" refers to the method of administering a given dose of a compound or pharmaceutical composition to a vertebrate or invertebrate (including mammals, birds, fish, or amphibians). The method of administration can 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] As used herein, the terms “effective amount” or “effective dose” or “pharmaceutically effective amount” or “therapeutic effective amount” refer to an adequate amount of a chemical entity (e.g., a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof) that will alleviate one or more symptoms of the disease or condition being treated to a certain extent, and may include curing the disease. “Cure” means the elimination of symptoms of an active disease. Results include a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an “effective amount” for therapeutic use is the amount required for a composition comprising a compound as disclosed herein to provide a clinically significant reduction in the symptoms of a disease. In any individual case, an appropriate “effective” amount is determined using any suitable technique, such as dose escalation studies. In some embodiments, a “therapeutic effective amount” of a compound as provided herein refers to an amount in which the compound is effective as a monotherapy or combination therapy.

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

[0074] The term "pharmaceutical composition" refers to a compound of Formula I as provided herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvation thereof, mixed with other chemical components (collectively referred to herein as "excipients") (such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners). Pharmaceutical compositions facilitate the administration of compounds to a living organism. Various techniques for administering compounds exist in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0075] As used herein, the term "calcitonin receptor and / or amylin receptor-related disease or disorder" means, but is not limited to, those diseases, disorders, or conditions in which activation of at least one calcitonin receptor (CTR) and / or amylin receptor (AMY) by calcitonin and / or amylin contributes to the symptomology or progression of the disease or disorder. These diseases or disorders can be caused by one or more of the following etiologies: genetic, iatrogenic, immunological, infectious, metabolic, neoplastic, toxic, surgical, and / or traumatic.

[0076] In the context of treating a disease, disorder, or symptom, the terms “treat,” “treating,” and “treatment” are intended to include relieving or eradicating a disorder, disease, or symptom, or one or more symptoms associated with said disorder, disease, or symptom; or slowing the progression, spread, or worsening of a disease, disorder, or symptom, or one or more symptoms thereof.

[0077] As used herein, the term “prevention” means the complete or partial prevention of the onset, recurrence, or spread of a disease or condition or its symptoms as described herein.

[0078] As used herein, the terms “subject,” “patient,” or “individual” are used interchangeably 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, the term refers to a subject who expects or needs a diagnosis, prognosis, or therapy, particularly a mammalian subject. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of a disease, disorder, or condition to be treated and / or prevented.

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

[0080] As used herein, the term "drug combination" refers to a pharmaceutical treatment resulting from the mixing or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.

[0081] As used herein, the term “combination therapy” refers to a dosing regimen of two different therapeutic agents (i.e., combined components or combination couples) wherein the therapeutic agents are administered together or separately in a manner prescribed by a healthcare professional or in accordance with a regulatory body as defined herein.

[0082] As used herein, the term “modulate, modulating, or modulation” refers to regulation or adjustment (e.g., increasing or decreasing) and may include, for example, agonistic, partial agonistic, or antagonistic effects. compound

[0083] This article provides compounds that act as regulators of amylin.

[0084] In some implementations, compounds of formula I are provided: I Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein: A is C 1-6Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene; wherein the C of A 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocycloalkylene, arylene or heteroaryl are independently and optionally separated by one to five Z A replace; Ring B is arbitrarily divided by one to three Rs. B Substituted 5- or 6-membered heteroaryl groups; Each R B Independently selected from halogen groups, hydroxyl groups, -NH2 groups, cyano groups, and C groups. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; wherein R B Each C 1-3 Alkyl groups are independently and optionally -NH2, -NHC 1-3 Alkyl, -N(C) 1-3 alkyl)2, hydroxyl or C 1-3 Alkyl substitution; L 1 It is C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 Cycloalkylene or 4-6-membered heterocyclic alkylene groups; wherein L 1 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group or the 4- to 6-membered heterocyclic group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; L 2 It is a key, -O-, -S-, -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 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C 3-6 Cycloalkylene, 4-6-membered heterocyclic cycloidene or 5-membered heteroarylene; wherein L 2 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group, 4-6-membered heterocyclic group, or 5-membered heteroarylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, -NH2, -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 Substituents of haloalkoxy groups; R 1 It 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 ; R 2 Yes -NR 1a R 1b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 2 C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from one to five independently chosen groups: halogen, hydroxyl, cyano, C... 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Substituents of haloalkoxy groups; Or R 2 and R 6 Or R 2 and R 7 Together with the atoms to which they are attached, they form a group optionally bounded by one to five Z. 2 Substituted heterocyclic groups; Each R 1a and R 1b Independently, it is hydrogen and C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups; wherein R 1a and R 1b Each C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 The cycloalkyl or 4- to 6-membered heterocyclic group is independently and optionally composed of one to five independently selected groups: halogen, hydroxyl, cyano, C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Substituents of haloalkoxy groups; Or R 1a and R 1b Together with the atoms to which they are attached, they form 4- to 6-membered heterocyclic groups, wherein the heterocyclic groups are independently and optionally composed of one to five groups independently selected from halogen, hydroxyl, cyano, C, 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Substituents of haloalkoxy groups; Each R 2a and R 2b Independently, it is hydrogen and C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 2a and R 2b Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 2a replace; Or R 2a and R 2b Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 2a Substituted heterocyclic groups; R 3 It is hydrogen, -NR 3b R 3c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 3 replace; R 3b and R 3c Each is independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3b and R 3c Each C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five halogen groups, hydroxyl groups, cyano groups, C6 groups, C7 groups, C8 groups, C9 ... 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; Or R 3b and R 3c Together with the nitrogen atoms to which they are attached, they form optional groups of one to five Zn atoms. 3b Substituted heterocyclic groups; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 4 C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 4 replace; R 5 It is hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 5 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 5 replace; R 6 It is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl or 4- to 6-membered heterocyclic groups; wherein C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 The cycloalkyl or 4- to 6-membered heterocyclic group is optionally surrounded by one to five independently selected groups: halogen, oxo, hydroxyl, cyano, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; R 7 It is hydroxyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; Each Z A Z 2 Z 2a Z 3 Z 3b Z 4 and Z 5 Independently, it is a halogen group, cyano group, nitro group, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; wherein Z A Z 2 Z 2a Z 3 Z 3b Z 4 and Z 5 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally divided by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -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)2NR 20 -、-NR 20 S(O)-、-NR 20 S(O)2-、-NR 20S(O)NR 21 -or-NR 20 S(O)2NR 21 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 20 and R 21 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogen group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-6 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups; The premise is that A is C 1-6 When alkylene, then R 5It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be substituted independently or optionally.

[0085] In some implementations, compounds of formula I are provided: I Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein: A is C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene; wherein the C of A 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is independently and optionally surrounded by one to five Z. A replace; Ring B is arbitrarily divided by one to three Rs. B Substituted 5- or 6-membered heteroaryl groups; Each R B Independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; wherein R B Each C 1-3 Alkyl groups are independently and optionally prefixed with -NH2 or -NHC. 1-3 Alkyl, -N(C) 1-3 alkyl)2, hydroxyl or C 1-3 Alkyl substitution; L 1 It is C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 Cycloalkylene or 4-6-membered heterocyclic alkylene groups; wherein L 1 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group or the 4- to 6-membered heterocyclic group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; L 2 It is a key, -O-, -S-, -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 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C 3-6 Cycloalkylene, 4-6-membered heterocyclic cycloidene or 5-membered heteroarylene; wherein L 2 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group, 4-6-membered heterocyclic group, or 5-membered heteroarylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, -NH2, -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 Substituents of haloalkoxy groups; R 1 It 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)R7 R 2 ; R 2 Yes -NR 1a R 1b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 2 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from one to five independently chosen groups: halogen, hydroxyl, cyano, C... 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Substituents of haloalkoxy groups; Or R 2 and R 6 Or R 2 and R 7 Together with the atoms to which they are attached, they form a group optionally bounded by one to five Z. 2 Substituted heterocyclic groups; Each R 1a and R 1b Independently, it is hydrogen and C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups; wherein R 1a and R 1b Each C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 The cycloalkyl or 4- to 6-membered heterocyclic group is independently and optionally composed of one to five independently selected groups: halogen, hydroxyl, cyano, C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Substituents of haloalkoxy groups; Or R 1a and R 1bTogether with the atoms to which they are attached, they form 4- to 6-membered heterocyclic groups, wherein the heterocyclic groups are independently and optionally composed of one to five groups independently selected from halogen, hydroxyl, cyano, C, 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Substituents of haloalkoxy groups; Each R 2a and R 2b Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 2a and R 2b Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 2a replace; Or R 2a and R 2b Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 2a Substituted heterocyclic groups; R 3 It is hydrogen, -NR 3b R 3c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 3 replace; R 3b and R 3c Each is independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3b and R 3c Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five halogen groups, hydroxyl groups, cyano groups, C6 groups, C7 groups, C8 groups, C9 ... 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; Or R 3b and R 3c Together with the nitrogen atoms to which they are attached, they form optional groups of one to five Zn atoms. 3b Substituted heterocyclic groups; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 4 C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 4 replace; R 5 It is hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 5 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 5 replace; R 6 It is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C3-6 cycloalkyl or 4- to 6-membered heterocyclic groups; wherein C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 The cycloalkyl or 4- to 6-membered heterocyclic group is optionally surrounded by one to five independently selected groups: halogen, oxo, hydroxyl, cyano, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; R 7 It is hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; Each Z A Z 2 Z 2a Z 3 Z 3b Z 4 and Z 5 Independently, it is a halogen group, cyano group, nitro group, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 cycloalkyl, -L-heterocyclic, -L-aryl or -L-heteroaryl; where Z A Z 2 Z 2a Z 3 Z 3b Z 4 and Z 5 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally divided by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -NR 20 -, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20 -、-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 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 20 and R 21 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogen group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -SC 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-6 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups; The premise is that A is C 1-6 When alkylene, then R 5 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be substituted independently or optionally.

[0086] In some implementation schemes, R 1 It is -C(O)NR 1a R 1b -S(O)2R 2 -S(O)(NR) 6 )R 2 or -P(O)R 7 R 2 .

[0087] In some implementation schemes, R 2 Yes -NR 1a R 1b Or C 1-6 alkyl.

[0088] In some implementation schemes, R 1 It is -C(O)NH2, -S(O)2NH2, -S(O)2CH3, , -S(O)(NH)CH3 or -P(O)(CH3)CH3.

[0089] In some implementations, compounds of formula I are provided: I Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein: A is arbitrarily divided by one to five Z. A Replaces 5- to 9-member heteroaryl groups; Ring B is arbitrarily divided by one to three Rs. B Substituted 5- or 6-membered heteroaryl groups; Each R B Independently selected from halogen, hydroxyl, cyano, C1-3 alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C1-3 Halogenated alkoxy groups; wherein R B Each C 1-3 Alkyl groups are independently and optionally -NH2, -NHC 1-3 Alkyl, -N(C) 1-3 alkyl)2, hydroxyl or C 1-3 Alkyl substitution; L 1 It is C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 Cycloalkylene or 4-6-membered heterocyclic alkylene groups; wherein L 1 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group or the 4- to 6-membered heterocyclic group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; L 2 It is a key, -O-, -S-, -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 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C 3-6Cycloalkylene, 4-6-membered heterocyclic cycloidene or 5-membered heteroarylene; wherein L 2 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group, 4-6-membered heterocyclic group, or 5-membered heteroarylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, -NH2, -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 Substituents of haloalkoxy groups; R 1 It is -C(O)NH2; Each R 2a and R 2b Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 2a and R 2b Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 2a replace; Or R 2a and R 2b Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 2a Substituted heterocyclic groups; R 3 It is arbitrarily selected by one to five Z. 3 Replacement C 1-6 alkyl; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 4 C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 4 replace; R 5 It is C3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 5 C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 5 replace; Each Z A Z 2 Z 2a Z 3 Z 3b Z 4 and Z 5 Independently, it is a halogen group, cyano group, nitro group, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 cycloalkyl, -L-heterocyclic, -L-aryl or -L-heteroaryl; where Z A Z 2 Z 2a Z 3 Z 3b Z 4 and Z 5 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally divided by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -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)2NR 20 -、-NR 20S(O)-、-NR 20 S(O)2-、-NR 20 S(O)NR 21 -or-NR 20 S(O)2NR 21 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 20 and R 21 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogen group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-6 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups.

[0090] In some embodiments, a compound of formula IA is provided: IA Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein A, L 1 L 2 R 3 R 4 R 5 Each of rings B is defined independently as described herein; and X is -C(O)- or -S(O)2-. The premise is that A is C 1-6 When alkylene, then R 5 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be substituted independently or optionally.

[0091] In some implementations of formula IA, A is C. 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene; wherein the C of A 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is independently and optionally surrounded by one to five Z. A replace; Ring B is arbitrarily divided by one to three Rs. B Substituted 5- or 6-membered heteroaryl groups; Each R B Independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; wherein R B Each C 1-3 Alkyl groups are independently and optionally prefixed with -NH2 or -NHC. 1-3 Alkyl, -N(C) 1-3 alkyl)2, hydroxyl or C 1-3 Alkyl substitution; L 1 It is C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 Cycloalkylene or 4-6-membered heterocyclic alkylene groups; wherein L1 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group or the 4- to 6-membered heterocyclic group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; L 2 It is a key, -O-, -S-, -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 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C 3-6 Cycloalkylene, 4-6-membered heterocyclic cycloidene or 5-membered heteroarylene; wherein L 2 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group, 4-6-membered heterocyclic group, or 5-membered heteroarylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, -NH2, -NHC. 1-3 Alkyl, -N(C) 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3Substituents of haloalkoxy groups; Each R 2a and R 2b Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 2a and R 2b Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 2a replace; Or R 2a and R 2b Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 2a Substituted heterocyclic groups; R 3 It is hydrogen, -NR 3b R 3c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 3 replace; R 3b and R 3c Each is independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3b and R 3c Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five halogen groups, hydroxyl groups, cyano groups, C6 groups, C7 groups, C8 groups, C9 ... 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; Or R 3b and R 3c Together with the nitrogen atoms to which they are attached, they form optional groups of one to five Zn atoms. 3b Substituted heterocyclic groups; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 4 C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 4 replace; R 5 It is hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 5 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 5 replace; Each Z A Z 2a Z 3 Z 3b Z 4 and Z 5 Independently, it is a halogen group, cyano group, nitro group, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; wherein Z A Z 2a Z 3 Z 3b Z 4 and Z 5 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally divided by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -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)2NR 20 -、-NR 20 S(O)-、-NR 20 S(O)2-、-NR 20 S(O)NR 21 -or-NR 20 S(O)2NR 21 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 20 and R 21 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogen group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-6 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups; The premise is that A is C 1-6 When alkylene, then R 5 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be substituted independently or optionally.

[0092] In some implementations, A is C 1-6 Alkylene, C 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene; wherein the C of A 1-6 Alkylene, C 3-10 Cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is independently and optionally surrounded by one to five Z. A replace.

[0093] In some implementations, A is C 1-6 Alkylene, C 3-10Cycloalkylene, 3- to 10-membered heterocyclic cycloidenes, C 6-10 Aromatic or 5 to 10-unit heteroarylene; each of which is independently and optionally divided by one to five Z. A replace.

[0094] In some implementations, A is methylene, ethylene, or n-propylene. , , , , , , , , , , , , , , , , , , , , , or ;where bond a and L 2 Bonding.

[0095] In some implementations, A is methylene, ethylene, n-propylene, , , , , , , , , , , , , , , , , , , , , or ;where bond a and L 2 Bonding.

[0096] In some implementation schemes, A is , , , , , , , , , , , , , , , , , , , , or ;where bond a and L 2 Bonding.

[0097] In some implementations, a compound of formula IB is provided: IB Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein A, L 1 L 2 R 3 R 4 and R 5 Each is independent as defined in this article; X is -C(O)- or -S(O)2-; and X 1 X 2 X 3 and X 4 Each of them is independently selected from O, S, N, NR B and CR B The premise is X 1 X 2 X 3 and X 4 At least one of them is N; and it contains X 1 X 2 X 3 and X 4 The ring is of the aromatic family; and The premise is that A is C 1-6 When alkylene, then R 5 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be substituted independently or optionally.

[0098] In some implementations of formula IB, A is C. 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene; wherein the C of A1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is independently and optionally surrounded by one to five Z. A replace; Each R B Independently selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; wherein R B Each C 1-3 Alkyl groups are independently and optionally prefixed with -NH2 or -NHC. 1-3 Alkyl, -N(C) 1-3 alkyl)2, hydroxyl or C 1-3 Alkyl substitution; L 1 It is C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 Cycloalkylene or 4-6-membered heterocyclic alkylene groups; wherein L 1 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group or the 4- to 6-membered heterocyclic group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; L 2 It is a key, -O-, -S-, -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)-、-NR2a S(O)2-、-NR 2a S(O)NR 2b -、-NR 2a S(O)2NR 2b -、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C 3-6 Cycloalkylene, 4-6-membered heterocyclic cycloidene or 5-membered heteroarylene; wherein L 2 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group, 4-6-membered heterocyclic group, or 5-membered heteroarylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, -NH2, -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 Substituents of haloalkoxy groups; Each R 2a and R 2b Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 2a and R 2b Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 2a replace; Or R 2a and R 2b Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 2a Substituted heterocyclic groups; R 3 It is hydrogen, -NR 3b R 3c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 3 replace; R 3b and R 3c Each is independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3b and R 3c Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five halogen groups, hydroxyl groups, cyano groups, C6 groups, C7 groups, C8 groups, C9 ... 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; Or R 3b and R 3c Together with the nitrogen atoms to which they are attached, they form optional groups of one to five Zn atoms. 3b Substituted heterocyclic groups; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 4 C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 4 replace; R 5 It is hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 5 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 5 replace; Each Z A Z 2a Z 3 Z 3b Z 4 and Z 5 Independently, it is a halogen group, cyano group, nitro group, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; wherein Z A Z 2a Z 3 Z 3b Z 4 and Z 5 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally divided by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -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-、-NR20 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 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 20 and R 21 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogen group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -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 alkenyl, C 2-6 alkynyl group, C 1-6Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-6 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups; The premise is that A is C 1-6 When alkylene, then R 5 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be substituted independently or optionally.

[0099] In some embodiments, A is an arylene or heteroarylene; wherein the arylene or heteroarylene is independently and optionally surrounded by one to five Z. A replace.

[0100] In some implementations, A is optionally defined by one to five Z. A Substituted aryl groups.

[0101] In some implementations, A is optionally defined by one to five Z. A Substituted heteroaryl groups.

[0102] In some implementations, A is optionally defined by one to five Z. A Substituted heterocyclic groups.

[0103] In some implementations, A is optionally defined by one to five Z. A Substituted cycloalkylene groups.

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

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

[0106] In some implementations, ring B is optionally divided by one to three Rs. B Substituted nitrogen-containing 5- or 6-membered heteroaryl groups. The term "nitrogen-containing" is intended to refer to a heteroaryl group containing at least one cyclic nitrogen atom. The nitrogen-containing ring may contain one or more additional heteroatoms, such as oxygen, sulfur, or nitrogen.

[0107] In some implementations, ring B or part of it It is arbitrarily selected by one to three Rs B Substituted nitrogen-containing 5-membered heteroaryl groups.

[0108] In some implementations, ring B or part of it It is pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl; wherein the pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl group is optionally surrounded by one or two R groups. B replace.

[0109] In some implementations, ring B or part of it yes: , , , , , , , , or Each of them is optionally controlled by one or two Rs. B replace.

[0110] In some implementations, each R B C is independent 1-3 alkyl.

[0111] In some implementations, ring B is optionally divided by one to three Rs. B Substituted 6-membered heteroaryl group.

[0112] In some implementations, ring B is optionally divided by one to three Rs. B Substituted pyridinyl group.

[0113] In some implementations, ring B is optionally replaced by C. 1-3 Alkyl-substituted pyridyl group.

[0114] In some embodiments, ring B is pyridinyl, pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl; wherein the pyridinyl, pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl group is optionally surrounded by one or two R groups. B replace.

[0115] In some implementation schemes, ring B is: , , , , , , , , , , or Each of them is optionally controlled by one or two Rs. B replace.

[0116] In some implementations, L 1 It is C 3-6 Cycloalkylene, C 1-3 Alkylene or C 1-3 Heteroalkylene; wherein each C 3-6 Cycloalkylene, C 1-3Alkylene or C 1-3 The heteroalkylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups.

[0117] In some implementations, L 1 It is optionally decorated with one to three halogen groups, oxo groups, hydroxyl groups, C 1-3 Alkyl or C 1-3 alkoxy-substituted C 1-3 Alkylene.

[0118] In some implementations, L 1 It is C 1-3 Alkylene or C 1-3 Heteroalkylene.

[0119] In some implementation schemes, R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, heterocyclic, or heteroaryl; wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, heterocyclic, or heteroaryl groups are independently and optionally separated by one to five Z groups. 4 replace.

[0120] In some implementation schemes, R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, or aryl, or heteroaryl; wherein C 1-6 Alkyl, C 3-10 cycloalkyl, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 4 replace.

[0121] In some implementation schemes, R 4 It is an aryl, heterocyclic, or heteroaryl group; wherein the aryl, heterocyclic, or heteroaryl group is optionally surrounded by one to five Z groups. 4 replace.

[0122] In some implementation schemes, R 4 It is C 1-3 Alkyl, C 3-9 Cycloalkyl, 4-9 membered heterocyclic or phenyl; wherein C 1-3 Alkyl, C 3-6 The cycloalkyl or phenyl groups are optionally substituted independently with one to three halogen groups.

[0123] In some implementation schemes, R 4 It is C 1-3 Alkyl, C3-6 cycloalkyl or phenyl; wherein C 1-3 Alkyl, C 3-6 The cycloalkyl or phenyl groups are optionally substituted independently with one to three halogen groups.

[0124] In some implementation schemes, R 4 It is C 1-3 Alkyl, C 3-6 cycloalkyl or phenyl; wherein C 1-3 Alkyl, C 3-6 The cycloalkyl or phenyl groups are optionally substituted with halogen groups independently.

[0125] In some implementation schemes, R 3 Yes -NR 3b R 3c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 3 replace.

[0126] In some implementation schemes, R 3 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0127] In some implementation schemes, R 3 It is hydrogen, -NR 3b R 3c C 1-6 Alkyl or C 1-6 Alkyl group.

[0128] In some implementations, L 2 It is a key, -NR 2a -、-C(O)NR 2a-、-NR 2a C(O)-, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, 4-6-membered heterocyclic or 5-membered heteroarylene; wherein C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 The heteroalkylene group, 4-6-membered heterocyclic group, or 5-membered heteroarylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups.

[0129] In some implementations, L 2 It is a key, -NR 2a -、-C(O)NR 2a -、-NR 2a C(O)-, C 1-6 Alkylene, C 1-6 Heteroalkylene, 4-6-membered heterocyclic or 5-membered heteroarylene; wherein C 1-6 Alkylene, C 1-6 The heteroalkylene group, 4-6-membered heterocyclic group, or 5-membered heteroarylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups.

[0130] In some implementations, L 2 It is a bond, -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-triazole dimethyl.

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

[0132] In some implementation schemes, R 5 It is hydrogen, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 5 replace.

[0133] In some implementation schemes, R 5 It is C 1-6 Alkyl, aryl, or heteroaryl; wherein the aryl or heteroaryl group is optionally surrounded by one to five Z-terminal groups. 5 replace.

[0134] In some implementation schemes, R 5 It is arbitrarily C 3-10 C-substituted with cycloalkyl, heterocyclic, aryl or heteroaryl groups 1-6 Alkyl; wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally separated by one to five Z groups. 1a replace.

[0135] In some implementation schemes, R 5 It is an aryl or heteroaryl group; wherein the aryl or heteroaryl group is optionally surrounded by one to five Z groups. 5 replace.

[0136] In some implementation schemes, R 5 It is hydrogen, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, heterocyclic or aryl; wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, heterocyclic, or aryl groups are independently and optionally bound by one to five Z groups. 5 replace.

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

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

[0139] In some implementations, a compound of formula IB is provided: IB Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein A, L 1 and L 2 Each is independent as defined in this article; X is -C(O)- or -S(O)2-; and X 1 X 2 X 3 and X 4 Each of them is independently selected from O, S, N, NR B and CR B The premise is X 1 X 2 X 3 and X 4 At least one of them is N; and it contains X 1 X 2 X 3 and X 4 The ring is from the Aromatic tribe; R 3 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4 It is an aryl or heteroaryl group; wherein each is optionally divided by one to five Z. 4 Replace; and R 5 It is an aryl or heteroaryl group; wherein each is optionally divided by one to five Z. 5 Replace; and The premise is that A is C 1-6 When alkylene, then R 5 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be substituted independently or optionally.

[0140] In some implementations of formula IB, A is C. 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene; wherein the C of A 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocycloalkylene, arylene, or heteroarylene is independently and optionally surrounded by one to five Z. A replace; Each R B Independently selected from halogen, hydroxyl, cyano, C1-3 alkyl, C 1-3Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; wherein R B Each C 1-3 Alkyl groups are independently and optionally -NH2, -NHC 1-3 Alkyl, -N(C) 1-3 alkyl)2, hydroxyl or C 1-3 Alkyl substitution; L 1 It is C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 Cycloalkylene or 4-6-membered heterocyclic alkylene groups; wherein L 1 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group or the 4- to 6-membered heterocyclic group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; L 2 It is a key, -O-, -S-, -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 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C3-6 Cycloalkylene, 4-6-membered heterocyclic cycloidene or 5-membered heteroarylene; wherein L 2 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group, 4-6-membered heterocyclic group, or 5-membered heteroarylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, -NH2, -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 Substituents of haloalkoxy groups; Each R 2a and R 2b Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 2a and R 2b Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 2a replace; Or R 2a and R 2b Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 2a Substituted heterocyclic groups; R 3 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4 It is an aryl or heteroaryl group; wherein each is optionally divided by one to five Z. 5 replace; R 5 It is an aryl or heteroaryl group; wherein each is optionally divided by one to five Z. 4 replace; Each Z A Z 2a Z 4 and Z 5 Independently, it is a halogen group, cyano group, nitro group, oxo group, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; wherein Z A Z 2a Z 4 and Z 5 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally divided by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -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)2NR 20 -、-NR 20 S(O)-、-NR 20 S(O)2-、-NR 20 S(O)NR 21 -or-NR 20 S(O)2NR 21 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 20 and R 21 Each C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogen group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-6 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups; The premise is that A is C 1-6 When alkylene, then R 5 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be substituted independently or optionally.

[0141] In some implementations, a compound of formula IC is provided: IOC Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein A, L 1 and L 2 Each is independent as defined in this article; X is O, and the dashed key does not exist; or X is N, and the dashed bond exists; X 2 It is N or CH; L 2’ It is a bond or -CH2-; R 3 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; L 1 It is C 1-3 Alkylene or C 1-3 Heteroalkylene; wherein L 1 C 1-3 Alkylene or C 1-3 The heteroalkylene group is independently and optionally surrounded by a halogen group, a hydroxyl group, or a C- group. 1-3 Alkyl substitution; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 4 C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one or two halogen groups, C 1-6 Alkyl or C 1-6 Alkyl substitution; R 4 It is an aryl or heteroaryl group; wherein each is optionally divided by one to five Z. 4 Replace; and R 5 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 5 C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally surrounded by one to five halogen groups, hydroxyl groups, or C- groups. 1-6 Alkyl-substituted.

[0142] In some embodiments, compounds selected from Table 1, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or solvates thereof are provided: Table 1

[0143] The compounds of Formula I provided herein cover stereochemical forms of the compounds, such as optical isomers, enantiomers, diastereomers, and mixtures thereof, such as mixtures of enantiomers and / or diastereomers, including racemic mixtures, and homogeneous or heterogeneous mixtures of individual enantiomers and / or diastereomers. All stereochemical forms are considered in this disclosure. Unless otherwise indicated, when a disclosed compound is named or described structurally without specifying a stereochemistry and has one or more chiral centers, it should be understood to represent all possible stereoisomers of the compound. Representative stereochemical forms are provided throughout the specification, including but not limited to those described 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 2

[0144] Compounds of Formula I and its derivatives include pharmaceutically acceptable salts. Furthermore, compounds of Formula I and its derivatives also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for the preparation and / or purification of compounds of Formula I and its derivatives and / or for the isolation of enantiomers of compounds of Formula I and its derivatives.

[0145] It should also be understood that compounds of Formula I and its sub-forms, or their salts, can be isolated as solvates, and therefore any such solvates are included within the scope of this disclosure. For example, compounds of Formula I and its sub-forms and their respective salts can exist in non-solventized forms as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Pharmaceutical composition and administration

[0146] When used as a medicine, compounds as described herein (e.g., one or more compounds disclosed herein, or stereoisomers or mixtures thereof) can be administered in the form of pharmaceutical compositions. These compositions can be prepared in ways well known in the pharmaceutical field and can be administered via a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal or intranasal), oral, or parenteral. Oral administration can include formulations for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, injection, or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or, for example, via a continuous infusion pump. Pharmaceutical compositions and formulations for external application may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, aqueous, powder, or oil-based matrices, thickeners, etc., may be necessary or desired.

[0147] This document also provides pharmaceutical compositions comprising one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, as active ingredients, in combination with one or more pharmaceutically acceptable excipients (carriers). For example, pharmaceutical compositions prepared using one or more compounds as disclosed herein, or stereoisomers or mixtures thereof.

[0148] In one embodiment, a pharmaceutical composition is provided comprising a compound as disclosed herein, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another embodiment, a pharmaceutical composition is provided comprising a compound as 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 the pharmaceutical composition in amounts of: 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 2% by weight. 5%, greater than about 35%, or greater than about 40%, or greater than about 45%, or greater than about 50%, or greater than about 55%, or greater than about 60%, or greater than about 65%, or greater than about 70%, or greater than about 75%, or greater than about 80%, or greater than about 85%, or greater than about 90%, or greater than about 95% purity, or about 40%, or about 45%, or about 50%, or about 55%, or about 60%, or about 65%, or about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 95%.

[0149] In some embodiments, the composition is suitable for external application. In manufacturing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated in a carrier, such as a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material that acts as a medium, carrier, or carrier of the active ingredient. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (containing, for example, up to 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as tablets or capsules.

[0150] This document further provides pharmaceutical compositions comprising one or more compounds as disclosed herein, or stereoisomers thereof, or mixtures thereof, and pharmaceutically acceptable excipients. Pharmaceutical compositions comprising one or more compounds as disclosed herein, or stereoisomers thereof, or mixtures thereof, as active ingredients, can be prepared according to conventional pharmaceutical compounding techniques by closely mixing one or more compounds as disclosed herein, or stereoisomers thereof, with a pharmaceutical carrier. The carrier can take many 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. Descriptions of some 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 preparing pharmaceutical compositions have been described in numerous publications, such as 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 pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tween, poloxamer, or other similar polymer delivery matrices; serum proteins, such as human serum albumin; buffering substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate; mixtures of saturated vegetable fatty acids in the form of glycerides; water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene block copolymers; and lanolin. Cyclodextrins (such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin) or chemically modified derivatives such as hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin) or other soluble derivatives can also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions containing 0.005% to 100% of the chemical entities described herein, with the remainder consisting of non-toxic excipients, can be prepared. The compositions considered may contain 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in yet another embodiment of the chemical entities provided herein. Practical methods for preparing such dosage forms are known to 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 pharmaceutical compositions thereof, may be administered to patients in need via any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, intrasinus, trachea, intestine, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracystic, intracerebral, intracisary, intracoronary, intradermal, intracatheter, duodenal, intradural, intraepithelial, intraepithelial, esophageal, intragastric, intragingival, intraileum, intraileum, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratestinal, intrasheath, intraduct, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, percutaneous, transdural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, tracheal, ureteral, urethral, ​​and vaginal. In some implementations, the route of administration is parenteral (e.g., intratumoral).

[0155] In some embodiments, one or more compounds as disclosed herein, or stereoisomers or mixtures thereof as described herein, 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 injectable preparations, as liquid solutions or suspensions; they may also be prepared in a solid form suitable for preparing solutions or suspensions by adding liquid prior to injection; and the formulation may also be emulsified. The preparation of such formulations will be known to those skilled in the art in light of this disclosure. In some embodiments, parenteral administration is performed using a device. For example, such devices may include needle injectors, microneedle injectors, needle-free injectors, and infusion techniques.

[0156] In some embodiments, suitable pharmaceutical forms for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or propylene glycol; and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid in a manner that facilitates injection. In some embodiments, the form should be stable under manufacturing and storage conditions and must be preserved against contamination by microorganisms such as bacteria and fungi.

[0157] In some embodiments, the carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In some embodiments, suitable flowability can be maintained, for example, by using a coating (e.g., lecithin), in the case of a dispersion, by maintaining a desired particle size, and by using a surfactant. In some embodiments, the antimicrobial effect can be achieved by a variety of antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In some embodiments, isotonic agents, such as sugars or sodium chloride, are included. In some embodiments, the absorption of the injectable composition can be prolonged by using agents that delay absorption (e.g., aluminum monostearate and gelatin) in the composition.

[0158] In some embodiments, a sterile injectable solution is prepared by incorporating a desired amount of one or more compounds as disclosed herein, or stereoisomers thereof, or mixtures thereof, together with various other components listed above (as desired), into a suitable solvent, followed by filtration and sterilization. In some embodiments, a dispersion is prepared by incorporating multiple sterile active ingredients into a sterile medium containing a base dispersion medium and desired other components from those listed above. In some embodiments, sterile powder is used to prepare the sterile injectable solution. In some embodiments, the preparation method is a vacuum drying and freeze-drying technique, which produces a powder of the active ingredient plus any other desired components from its previously sterile filtered solution.

[0159] In some embodiments, pharmacologically acceptable excipients that may be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, but are not limited to, any one or more of the following: glyceryl cocoa butter, synthetic polymers (such as polyvinylpyrrolidone), PEG (such as PEG ointment), glycerin, glycerin-treated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycol and polyethylene glycol fatty acid esters of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxidase, etc. SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methylparaben, polyethylene glycol cetearyl ether, cocoylcaprylocaprate, isopropanol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metasulfite, sodium edetate, sodium benzoate, potassium metasulfite, grapefruit seed extract, methanesulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E), and potassium acetate.

[0160] In some embodiments, the suppository can be prepared by mixing one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, or pharmaceutical compositions as 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, thus melting in the rectum and releasing 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 as disclosed herein, or stereoisomers or mixtures thereof as described herein, or pharmaceutical compositions thereof, are formulated for local delivery to the digestive or gastrointestinal tract via oral administration (e.g., solid or liquid dosage forms).

[0162] In some implementations, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, one or more compounds as disclosed herein, or stereoisomers thereof, or mixtures thereof, are mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as, for example, cetyl alcohol and glyceryl monostearate; h) adsorbents, such as kaolin and bentonite; 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 also contain a buffer. In some embodiments, similar type of solid composition may also be used as a filler in soft and hard filled gelatin capsules using excipients such as lactose or toffee and high molecular weight polyethylene glycol.

[0163] In some embodiments, the pharmaceutical composition will be in the form of a unit dosage form such as a pill or tablet, and therefore, the composition may contain a diluent, such as lactose, sucrose, dicalcium phosphate, etc., together with one or more compounds as disclosed herein, or stereoisomers or mixtures thereof as provided herein; a lubricant, such as magnesium stearate, etc.; and a binder, such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In some embodiments, a powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) as another solid dosage form will be encapsulated in a capsule (gelatin or cellulose matrix capsule). In some embodiments, unit dosage forms in which one or more compounds and pharmaceutical compositions or additional active agents as provided herein are physically separated are also contemplated; for example, capsules (or tablets in capsules) having particles of each drug; two-layer tablets; two-compartment gel caps, etc. In some implementations, enteric-coated or delayed-release oral dosage forms have also been considered.

[0164] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifiers, dispersants, or preservatives specifically designed to prevent microbial growth or activity. For example, a variety of preservatives are well known and include, 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 using conventional, well-known sterilization techniques. In some embodiments, sterilization is not required for excipients used in various oral dosage forms, such as tablets and capsules. For example, United States Pharmacopeia / National Formulary (USP / NF) standards may be sufficient.

[0166] In some embodiments, one or more compounds as disclosed herein, or stereoisomers or mixtures thereof as described herein, or pharmaceutical compositions thereof, are formulated for ocular application. In some embodiments, the ocular composition may include, but is not limited to, any one or more of the following: viscogen (e.g., carboxymethyl cellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizer (e.g., Pluronic (triblock copolymer), cyclodextrin); preservative (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloride complex; Allergan, Inc.)).

[0167] In some embodiments, one or more compounds as disclosed herein, or stereoisomers or mixtures thereof as described herein, or pharmaceutical compositions thereof, are formulated for topical application to the skin or mucous membranes (e.g., transdermal or percutaneous). In some embodiments, the topical composition may include ointments and creams. In some embodiments, ointments are typically semi-solid formulations based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. For example, the cream matrix is ​​typically water-washable and contains an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes referred to as the “internal” phase, typically consists of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol; although not essential, the aqueous phase typically exceeds the volume of the oil phase and typically contains a humectant. In some embodiments, the emulsifier in the cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. In some implementations, like other carriers or media, the ointment base should be inert, stable, non-irritating, and non-sensitizing.

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

[0169] The amount of compounds in a pharmaceutical composition or formulation can vary within the full range used by those skilled in the art. Typically, on a weight percentage (wt%) basis, based on the total formulation, the formulation will contain from about 0.01 wt% to 99.99 wt% of the compounds described in this disclosure, wherein the balance is one or more suitable pharmaceutical excipients. In one embodiment, the compounds are present at a level of about 1 wt% to 80 wt%. Representative pharmaceutical formulations are described below. Formulation Example 1 - Tablet Formulation

[0170] The following ingredients are closely mixed and compressed into a single-score tablet. Example 2 of formulation - capsule formulation

[0171] Mix the following ingredients thoroughly and encapsulate them into hard-shell gelatin capsules. Formulation Example 3 - Suspension Formulation

[0172] Mix the following ingredients to form a suspension for oral administration. Example 4 of the formulation - injectable formulation

[0173] Mix the following ingredients to form an injectable formulation. Example 5 of formulation - Suppository formulation

[0174] A suppository (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) with a total weight of 2.5 g was prepared by mixing the compounds of this disclosure with Wiptsol® H-15, and said suppository has the following composition:

[0175] In some embodiments, the dosage of one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, is determined based on a variety of factors, including but not limited to patient type, age, weight, sex, medical condition, severity of the patient's medical condition, route of administration, and the activity of the compound or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof. In some embodiments, the appropriate dosage for a particular situation can be determined by a person skilled in the medical field. In some embodiments, the total daily dose can be divided into multiple doses and administered in multiple doses throughout the day or by means of a continuous delivery method.

[0176] In some embodiments, one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, are administered in doses of 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 amount.

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

[0178] In some embodiments, the aforementioned dose of one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, may be administered on a daily basis (e.g., as a single dose or as two or more fractional doses) or on a non-daily basis (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[0179] In some embodiments, the administration period of one or more compounds as disclosed herein, or stereoisomers or mixtures thereof as described herein, is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In some embodiments, the discontinuation period 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 as disclosed herein, or stereoisomers or mixtures thereof, are administered to a patient for a period of time, followed by a separate period during which the administration of one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, is discontinued. In some embodiments, one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, are applied for a first time period, followed by a second time period during which application is stopped, then a third time period in which application of one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, is initiated, and then a fourth time period following the third time period in which application is stopped. For example, the time periods for applying one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, and the subsequent time periods for stopping application are defined or undefined periods. In some embodiments, the application time periods are 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 implementation schemes, the period for discontinuing application 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 as disclosed herein, or stereoisomers or mixtures thereof, are administered orally to a patient once or more times (e.g., once daily, twice daily, three times daily, four times daily, or a single daily dose).

[0181] In some embodiments, one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, are administered to a patient via parenteral administration once or more times daily (e.g., 1 to 4 times, once daily, twice daily, three times daily, four times daily, or a single daily dose).

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

[0183] In some embodiments, this disclosure provides methods for treating a subject (e.g., a person) suffering from a disease, disorder, or condition, wherein inhibiting one or more calcitonin receptors and / or amyloid receptors is beneficial for 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 one or more conditions, comorbidities, or sequelae associated with any of the conditions or disorders provided herein.

[0184] This document provides a method for treating calcitonin receptor and / or amylin receptor-related diseases or disorders, the method comprising administering to a subject in need an effective amount of a compound disclosed herein (e.g., a compound of formula I or any of its subforms, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as disclosed herein. This document also provides a method for treating or preventing calcitonin receptor and / or amylin receptor-related diseases or disorders in a subject in need, the method comprising administering to a subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I or any of its subforms, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition thereof.

[0185] In some implementations, calcitonin receptor and / or amylin receptor-related diseases or disorders are bone disorders, metabolic disorders, pain, neurodegenerative diseases or disorders, cardiovascular diseases, or other diseases or disorders as described herein.

[0186] In some implementation schemes, the disease or disorder includes, but is not limited to, type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile atypical diabetes (YOAD), young adult-onset diabetes (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, 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, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, restenosis, thrombosis, hypertension, and pulmonary hypertension. Compression, restenosis after angioplasty, intermittent claudication, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic 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 implementation schemes, the disease or disorder includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, 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 hyperlipidemia, and metabolic acidosis. Ketoacidosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, 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, essential polydipsia, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson's disease, polycystic ovary syndrome (PCOS), or any combination thereof.

[0188] In some implementations, the disease or disorder includes, but is not limited to, type 2 diabetes, early-onset type 2 diabetes, obesity, weight gain due to the use of other medications, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral fat deposition, myocardial infarction, peripheral artery disease, stroke, transient ischemic attack, hyperglycemia, postprandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, 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 and methods described herein for treating a patient induce one or more of the following: lowering blood glucose (e.g., reducing blood glucose levels), lowering blood hemoglobin A1c (HbA1c) levels, promoting insulin synthesis, stimulating insulin secretion, increasing β-cell mass, regulating gastric acid secretion, regulating gastric emptying, reducing body mass index (BMI), and / or reducing glucagon production (e.g., levels). In some embodiments, the compounds and pharmaceutical compositions and methods described herein for treating a patient stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). This document also provides methods for regulating glucose or insulin levels in patients requiring such regulation, the methods comprising administering to the patient an effective amount of one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, or pharmaceutical compositions as disclosed herein.

[0190] In some embodiments, this document provides a method for reducing the risk of major adverse cardiovascular events (MACE) in patients in need (e.g., a reduction of about 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%), said method comprising administering to the patient an effective amount of one or more compounds as disclosed herein, or stereoisomers or mixtures thereof, or pharmaceutical compositions as disclosed herein. In some of these embodiments, the patient is an adult diagnosed with type 2 diabetes (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 (T2D) and heart disease. In some embodiments, the patient is an adult with type 2 diabetes (T2D). In some embodiments, the patient is an adult with heart disease. In some embodiments, the patient has both type 2 diabetes (T2D) and heart disease.

[0191] In some implementations, calcitonin receptor and / or amylin receptor-related diseases or disorders are bone disorders, including but not limited to osteoporosis, Paget's disease, hypercalcemia, Zudk's atrophy, multiple fibrous dysplasia of bone, costoclavicular ossification, osteogenesis imperfecta, osteopenia, periodontal disease or defects, osteolytic bone disease, metastatic bone disorders, or bone loss caused by malignancy, autoimmune arthritis, bone fissures or fractures, or inactivity or disuse.

[0192] In some embodiments, the calcitonin receptor and / or amylin receptor-related disease or disorder is pain, including but not limited to osteopathic pain, phantom limb pain, generalized pain, hyperalgesia, or pain associated with diabetic neuropathy.

[0193] In some embodiments, the calcitonin receptor and / or amylin receptor-related diseases or disorders are neurodegenerative diseases or disorders, including but not limited to Alzheimer's disease.

[0194] In some embodiments, the calcitonin receptor and / or amylin 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 implementations, the calcitonin receptor and / or amylin receptor-related diseases or disorders include primary or secondary hyperthyroidism, endocrine disorders, conditions associated with gastric secretion inhibition, 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, stereoisomers, mixtures of stereoisomers, or solvates thereof) or pharmaceutical compositions as provided herein can be used to alleviate insulin inhibition in pancreatic tissue.

[0197] 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 pharmaceutical compositions as provided herein may be used to treat and reduce insulin resistance.

[0198] 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 pharmaceutical compositions as provided herein may be used to treat impaired glucose tolerance.

[0199] 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 pharmaceutical compositions as provided herein may be used to treat obesity and its symptoms.

[0200] In some embodiments, a method for reducing body fat or increasing body fat is provided, the method 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, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as provided herein.

[0201] In some embodiments, a method is provided to alter the body composition of a subject requiring treatment, wherein body fat is reduced and lean body mass is maintained or increased, the method 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, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as provided herein.

[0202] In some embodiments, a method for reducing the weight of a subject in need is provided, the method 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, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as provided herein.

[0203] In some embodiments, a method is provided for reducing the caloric intake of a subject who requires such reduction, the method 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, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as provided herein.

[0204] In some embodiments, a method is provided for reducing body fat or body fat gain in a subject requiring treatment while maintaining or increasing lean body mass, the method 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, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as provided herein.

[0205] 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 pharmaceutical compositions as provided herein may be used to treat hypertension.

[0206] 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 pharmaceutical compositions as provided herein may be used to treat 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 pharmaceutical compositions as provided herein may be used to treat subjects suffering from hypertension and hyperamylinemia.

[0208] In some embodiments, a method for treating hyperinsulinemia is provided, the method 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, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as provided herein.

[0209] In some embodiments, a method is provided for treating a hypertensive, insulin-resistant subject with coronary artery disease and hyperamylinemia or hyperinsulinemia, the method comprising administering to the subject in need a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as provided herein.

[0210] In some embodiments, a method is provided for reducing the basal and submaximal stimulation rates of glycogen synthesis in a subject, the method 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, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as provided herein.

[0211] In some embodiments, a method is provided for reducing the rate at which glucose is incorporated into glycogen in the muscle tissue of a subject, the method 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, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as provided herein.

[0212] In some embodiments, a method is provided for treating a subject with obesity and hypertension, as well as associated lipid disorders and atherosclerosis, the method 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, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as 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 pharmaceutical compositions as provided herein may be used to modulate renin activity in a subject in need.

[0214] In some embodiments, a method for treating or preventing the development of heart failure in a subject is provided, the method 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, stereoisomer, mixture of stereoisomers, or solvate thereof) or a pharmaceutical composition as 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 pharmaceutical compositions as provided herein may be used to beneficially modulate gastrointestinal motility in a subject of need. In some embodiments, beneficial modulation 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 pharmaceutical compositions as provided herein may be used to treat postprandial hyperglycemia in subjects of need. obesity

[0217] In some implementations, the condition, disease, or disorder is obesity and conditions, diseases, or disorders related to or associated with obesity. Non-limiting examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by excessive abdominal fat). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, type II diabetes mellitus, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., obesity induced by steroids, phenothiazines, insulin, sulfonylureas, or beta-blockers).

[0218] In some implementations, the condition, disease, or disorder is associated with obesity. Examples of such conditions, diseases, or disorders include, but are not limited to, glucose intolerance, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary artery disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), bone or joint disorders (e.g., knee osteoarthritis, hip osteoarthritis, degenerative spondylitis, low back pain), sleep apnea syndrome, obesity-related hypoventilation syndrome (Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycles, abnormal menstrual flow and cycle, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, and metabolic syndrome. In some implementations, the chemical compounds and pharmaceutical compositions described herein can be used to treat patients exhibiting both obesity and insulin deficiency. diabetes

[0219] In some implementations, the condition, disease, or disorder is diabetes. Non-limiting examples of diabetes include type 1 diabetes, type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylureas, very advanced type 2 diabetes, type 2 diabetes treated with long-term insulin therapy), diabetes (e.g., non-insulin-dependent diabetes, insulin-dependent diabetes), gestational diabetes, obese diabetes, autoimmune diabetes, and borderline diabetes. In some implementations, the condition, disease, or disorder is type 2 diabetes (e.g., type 2 diabetes treated with diet, type 2 diabetes treated with sulfonylureas, very advanced type 2 diabetes, type 2 diabetes treated with long-term insulin therapy).

[0220] This document provides a method for treating a patient with diabetes, 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 as disclosed herein, or stereoisomers or mixtures thereof, or pharmaceutical compositions disclosed herein.

[0221] This document provides a method for treating a patient with type 2 diabetes, the method comprising administering to a patient identified or diagnosed with type 2 diabetes a therapeutically effective amount of one or more compounds, stereoisomers thereof, or mixtures thereof, or pharmaceutical compositions disclosed herein.

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

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

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

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

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

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

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

[0229] In some implementations, the condition, disease, or disorder is associated with diabetes (e.g., complications of diabetes). Non-limiting examples of diabetes-related disorders include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macrovascular disease, osteoporosis, hyperosmolar diabetic coma, infectious diseases (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 unmanaged 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, hyperLDL-cholesterolemia, hypoHDL-cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic X syndrome, where activation of GLP-1R is a beneficial metabolic disorder), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0231] In some embodiments, the condition, disease, or disorder is diabetes and obesity (diabetic obesity). In some embodiments, the compounds described herein can also be used to improve the therapeutic efficacy of metformin. Metabolic barriers

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

[0233] In some implementations, the condition, disease, or disorder is fatty liver disease. Fatty liver disease includes, but is not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, abeta-lipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolman disease, acute fatty liver of pregnancy, and lipodystrophy.

[0234] Nonalcoholic fatty liver disease (NAFLD) refers to a range of diseases that occur in the absence of alcohol abuse and are typically characterized by the presence of steatosis (fat in the liver). NAFLD is believed to be associated with a variety of conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children and may 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, predominantly macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90). In some implementations, the patient is a pediatric patient. As used herein, the term “pediatric patient” refers to a patient under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further subdivided into different subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 to 21 years (until, but not including, their twenty-second birthday)). (References: Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th edition Philadelphia: WB Saunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st edition New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd edition Baltimore: Williams & Wilkins; 1994.) In some implementations, pediatric patients are defined as those born within the first 28 days of life, 29 days old to under two years of age, two years old to under 12 years of age, or 12 years old to 21 years of age (up to but not including the twenty-second birthday). In some implementations, pediatric patients are defined as those born within the first 28 days of life, 29 days old to under one year of age, one month old to under four months of age, three months old to under seven months of age, six months old to under one year of age, one year old to under two years of age, two years old to under three years of age, two years old to under seven years of age, three years old to under five years of age, five years old to under ten years of age, six years old to under 13 years of age, ten years old to under 15 years of age, or 15 years old to under 22 years of age. In some implementations, patients are adult patients.

[0235] Other non-limiting examples of disorders affecting 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; skeletal disorders characterized by changes in bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease, and changes in bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection against fractures, and malnutrition due to 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 can be used to treat surgical trauma by improving postoperative recovery and / or by preventing catabolism caused by surgical trauma. Cardiovascular and vascular diseases

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

[0237] In some implementations, the disease or disorder is associated with vascular disease. Non-limiting examples of vascular disease include peripheral vascular disease, large vessel 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. Nervous system diseases

[0238] In some implementations, the disease or disorder is a neurological disorder (e.g., a neurodegenerative disorder) or a mental disorder. Non-limiting examples of neurological disorders include cerebral insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety disorders, dementia (e.g., Alzheimer's disease), traumatic brain injury, Huntington's chores, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down's syndrome, myasthenia gravis, neurological trauma, brain trauma, angioamylindness, intracerebral hemorrhage with amyloidosis, encephalitis, Friedrich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated central nervous system degenerative diseases (e.g., Creutzfeld-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, for example, US 2006 / 0275288A1.

[0239] Non-limiting examples of mental disorders include substance dependence / addiction (narcotics and amphetamines) and attention deficit / hyperactivity disorder (ADHD). The compounds and pharmaceutical compositions described herein can be used to improve behavioral responses to addictive substances, reduce substance dependence, prevent relapse into substance abuse, and alleviate anxiety caused by the absence of a given addictive substance. See, for example, US 2012 / 0021979A1.

[0240] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to improve learning and memory by enhancing neuronal plasticity and promoting cell differentiation, and also to protect dopamine neurons and motor function in Parkinson's disease. Insulin-related conditions and disorders

[0241] In some implementations, the disease or impairment is impaired fasting glucose (IFG), impaired fasting glucose parameters (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, hypoglycemia, insulin resistance syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperprolactinemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related coma endpoints.

[0242] In some embodiments, the compounds and pharmaceutical compositions described herein can reduce or slow the progression of borderline, impaired fasting glucose, or impaired fasting glucose to diabetes. Autoimmune disorders

[0243] In some implementations, the disease or disorder is an autoimmune disorder. Non-limiting 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, US 20120148586A1. Gastrointestinal disorders

[0244] In some implementations, the disease or disorder is a gastrointestinal-related disorder. Non-limiting examples of these disorders include ulcers of any etiology (e.g., gastric ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infection or other pathogens), digestive disorders, malabsorption disorders, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), steatorrhea (celiac sprue), hypogammaglobulinemic sprue, mucositis and diarrhea induced by chemotherapy and / or radiation therapy, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal damage (e.g., gastric mucosal damage caused by aspirin), small intestinal mucosal damage, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with blood disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, and cachexia caused by acquired immunodeficiency syndrome). weight

[0245] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce weight (e.g., excess weight) in patients (e.g., patients in need), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake. In some embodiments, a patient's weight gain may be attributed to excessive food intake or an unbalanced diet, or may be weight gain resulting from accompanying medications (e.g., insulin sensitizers with PPARγ agonist-like effects, such as troglitazone, rosiglitazone, empaglitazone, cycloglitazone, pioglitazone, etc.). In some embodiments, the weight gain may be pre-obesity weight gain or weight gain in obese patients. In some embodiments, the weight gain may also be drug-induced weight gain or weight gain following cessation of smoking.

[0246] In some implementations, the illness or disorder is an eating disorder, such as overeating, binge eating, bulimia, or compulsive eating. Inflammatory diseases

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

[0248] In some implementations, the disease or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal breast cancer, non-invasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), 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), and colorectal cancer (e.g., gastric...). Gastrointestinal stromal tumors (GISTs), colorectal cancers (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, GISTs), small bowel cancers (e.g., non-Hodgkin's lymphoma, GISTs), 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), schwannomas, liver cancers (e.g., Primary liver cancer, extrahepatic bile duct cancer, kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumors, ovarian germ cell tumors, low-potency ovarian tumors), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma). Cancers include: parathyroid carcinoma, nasal cavity carcinoma, sinus carcinoma, 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., nephroblastoma, pediatric kidney tumors), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemias (e.g., acute myeloid leukemia, acute lymphoblastic leukemia). Hypothalamic-pituitary disorders

[0249] In some implementations, the condition or disorder is associated with the hypothalamic-pituitary-gonadal axis. For example, the condition, disease, or disorder is associated with the hypothalamic-pituitary-ovarian axis. In another embodiment, the condition, disease, or disorder is associated with 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 implementations, diabetes-related diseases or disorders are associated with the hypothalamic-pituitary-gonadal axis. pulmonary disease

[0251] In some implementations, the disease or disorder is associated with 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 implementations, the disease or disorder associated with diabetes is lung disease. Combination therapy

[0253] In some implementations, this disclosure considers 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 treatment regimens) in combination with 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., diet monitoring, diet therapy for diabetes), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS®), and dietary modifications.

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

[0257] Other representative therapeutic agents include, but are not limited to, anti-obesity agents, diabetes treatment agents, diabetes complication treatment agents, hyperlipidemia treatment agents, antihypertensive agents, diuretics, chemotherapy drugs, immunotherapy drugs, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis treatment agents, vitamins, anti-dementia drugs, erectile dysfunction drugs, urinary frequency or incontinence treatment agents, NAFLD treatment agents, NASH treatment agents, dysuria treatment agents, and antiemetics.

[0258] In some embodiments, one or more additional therapeutic agents include those useful, for example, as anti-obesity agents. Non-limiting examples include monoamine uptake inhibitors (e.g., tramadol, phenbutylide, sibutramine, mazindol, fluoxetine, tesofensine), 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)), and neuropeptide Y antagonists (e.g., virifibrate). Cannabinoid receptor antagonists (e.g., rimonabant, taranabant), orexin antagonists, orexin receptor antagonists, orexin acylase 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), and pancreatic lipase inhibitors (e.g., orlistat). istat), cetilistat, β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturase 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, trodusquemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucoskinase activators (e.g.,Piraglitin, AZD-1656, AZD6370, TTP-355, compounds described in W0006 / 112549, W0007 / 028135, W0008 / 047821, W0008 / 050821, W0008 / 136428 and W0008 / 156757, leptin, leptin derivatives (e.g., metriptin), leptin resistance modifiers, CNTF (ciliary neurotrophic factor), BDNF ( Brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlinide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oximin (OXM) preparations, appetite suppressants (e.g., ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; using Escherichia coli (Escherichia coli) preparations). Human FGF21 preparations synthesized from genes of *C. coli* or yeast; fragments or derivatives of FGF21; appetite suppressants (e.g., P-57); human propancreatic peptide (HIP); farnesoid X receptor (FXR) agonists; phenbutylamine; zonisamide; norepinephrine / dopamine reuptake inhibitors; GDF-15 analogs; methionine aminopeptidase 2 (MetAP2) inhibitors; diethylamine phenylacetone; benzotriazine; benzylphenamine; fibroblast growth factor receptor (FGFR) modulators; and AMP-activated protein kinase (AMPK) activators.

[0259] In some embodiments, one or more compounds as disclosed herein, or stereoisomers thereof, 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 implementations, additional therapeutic agents include TTP273, LY2944876 (pegapamotide), HDM1002, K-757, K-833, retatrutide, IBI362 (mastautide), cotadutide, AMG133, CT-868, HRS9531, HS-20094, dapiglutide, efinopegdutide, efocipegtrutide, pemvidutide, survodutide, AP026, AZD9550, BGM0504, CT-388, DD01, DR10624, G3215, GMA106, and HEC88473. HZ010, LY3493269, MWN101, NN9487, NN9541, RAY1225, SCO-094, SHR-1816, TB001, VK2735, ZP2929, ecnoglutide, GX-G6, GZR18, HRS-7535, YH14617, avexitide, froniglutide, pegsebrenatide, vurolenatide, JY09, NB1001, Byetalog, GW002, HL08, KN056, SAL0112, SHR2042, VCT220, ZT002, ZYOG1, or utreglutide.

[0261] In some implementations, additional therapeutic agents include endogenous GLP-1, endogenous glucagon, gastrin, salinomycin exotropic peptide-4, exenatide, lixisenatide, abirate, benaglutide, duraglutide, efpeglenatide, langlenatide, liraglutide, semaglutide, taspoglutide, tesipatide, pegapamodutide, lithium chloride, and PF-06882. 961 (danuglipron), LY3502970 (orforglipron), ECC-5004, GSBR-1290, AZD0186, PF-07081532 (lotiglipron), VCT220, TERN-601, RGT-075, CT-996, MDR-001, SAL0112, XW014, AVE-0010, S4P or Boc5.

[0262] In some embodiments, one or more compounds as disclosed herein, or stereoisomers thereof, or mixtures thereof, may be administered in combination with one or more additional therapeutic agents selected from 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 those useful, for example, 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 synthesized using E. coli or yeast genes; 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 their salts (e.g., hydrochloride, fumarate, succinate)), and glucagon analogs (e.g., WO4). Any glucagon analogues described in 2010 / 011439), agents that antagonize the action of glucagon or reduce glucagon secretion, sulfonylurea agents (e.g., chlorpropamide, tolazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, acetohexamide, glipizide, glybuzole, glibenclamide), thiazolidinedione agents (e.g., roxarsone), and thiazolidinediones (e.g., roxarsone). Glitter or pioglitazone), alpha-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), insulin secretagogues such as dietary glucose regulators (sometimes called "short-acting secretagogues"), such as megglitinide (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, abiglutide, duraglutide, abiglutide, tasglutide, lixilatide, smegglutide, AVE-0010, S4P, and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin). (ptin), saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin.

[0264] In some implementations, one or more additional therapeutic agents include those useful for treating NAFL and NASH, for example. 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, galactoglobulin 3 inhibitors, fibroblast growth factor 21 (FGF21), niacin analogs, leukotriene D4 (LTD4) receptor antagonists, acetyl-CoA carboxylase (ACC) inhibitors, hexokinase (KHK) inhibitors, and apoptosis signal-regulated kinase 1 (ASK). 1) Inhibitors, ileal bile acid transporter (IBAT) inhibitors, glycyrrhizin, Schisandra chinensis extract, ascorbic acid, glutathione, silymarin, lipoic acid and d-α-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteine, sulfonylureas, α-glucosidase inhibitors, megglitinide, vitamin E, tetrahydroliprostine, milk thistle protein, antiviral drugs and antioxidants.

[0265] In some embodiments, one or more additional therapeutic agents include those useful for treating, for example, complications of diabetes. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factors and their enhancers (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoters described in WO 01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compounds described in WO 2004 / 039365), and PKC inhibitors (e.g., rubosta mesylate). mesylate), AGE inhibitors (e.g., ALT946, N-benzoylthiazolium bromide (ALT766), EXO-226, pyridorin, pyridoxamine), serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen species scavengers (e.g., lipoic acid), cerebral vasodilators (e.g., tiapuride, 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 those useful for treating, for example, hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (e.g., sodium, calcium salts)) and squalene synthase inhibitors (e.g., those described in WO Compounds in 97 / 10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazon-3-yl]acetyl]piperidine-4-acetic acid), fibrates (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., colestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soy sterol, gamma oryzanol), etc. (oryzanol, γ-oryzanol), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), and ω-3 fatty acid preparations (e.g., ω-3-fatty acid ethyl ester 90).

[0267] In some implementations, one or more additional therapeutic agents include those useful, for example, 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). medoxomil), calcium channel blockers (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 those useful, for example, as diuretics. Non-limiting examples include xanthine derivatives (e.g., sodium theobromine salicylate, calcium theobromine salicylate), thiazide preparations (e.g., ethiothiazide, cyclopentathiazide, trichlorothiazide, hydrochlorothiazide, hydrofluorothiazide, benzyl hydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide)), antialdosterone preparations (e.g., spironolactone, triamterene)), carbonic anhydrase inhibitors (e.g., acetazolamide) and chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruside, indapamide)).

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

[0270] In some implementations, one or more additional therapeutic agents include those useful, for example, as antithrombotic agents. Non-limiting examples include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium); antithrombin agents (e.g., aragatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, described in WO 02 / 06234, WO 2004 / 048363, WO 2005 / 030740, WO... Compounds listed in 2005 / 058823 and WO2005 / 113504), thrombolytic agents (e.g., urokinase, tisokinase, alteplase, allteplase, montelpeplase, pamiplase), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl eicosapentaenoate, beraprost sodium, and sarpogrelate hydrochloride).

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

[0272] Other exemplary therapeutic agents include agents that regulate hepatic glucose balance (e.g., fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucosamine activators); agents designed to treat complications of long-term hyperglycemia, such as aldose reductase inhibitors (e.g., epalrestat and ranisitar); agents for treating complications associated with microvascular complications; anti-dyslipidemia agents, such as HMG-CoA reductase inhibitors (statins, e.g., rosuvastatin), cholesterol-lowering agents, bile acid sequestrants (e.g., cholestyramine), cholesterol absorption inhibitors (e.g., phytosterols, such as phytosterols), cholesterol ester transfer protein (CETP) inhibitors, and ileal bile acids. Transport system inhibitors (IBAT inhibitors), bile acid conjugating resins, nicotinic acid (nicotinic acid) and its analogues, antioxidants (e.g., probucol), ω-3 fatty acids; antihypertensive agents, including adrenergic receptor antagonists such as beta blockers (e.g., atenolol), alpha blockers (e.g., doxazosin), and mixed alpha / beta blockers (e.g., lalobel); adrenergic receptor agonists, including alpha-2 agonists (e.g., clonidine), angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril); calcium channel blockers such as dihydropyridine (e.g., nifedipine), phenylalkylamine (e.g., verapamil), and benzothiazazepine (e.g., diltiazem); angiotensin II receptor agonists... Anticoagulant antagonists (e.g., candesartan); aldosterone receptor antagonists (e.g., eplerenone); centrally acting adrenergic drugs, such as central alpha agonists (e.g., clonidine); diuretics (e.g., furosemide); hemostatic modifiers, including anticoagulants (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., cephalosporins). Lotazobazole); glycoprotein IIB / IIA inhibitors (e.g., tirofiban); adenosine reuptake inhibitors (e.g., dipyridamole); norepinephrine agents (e.g., phentermine); serotonergic agents (e.g., sibutramine); diacylglycerol acyltransferase (DGAT) inhibitors; feeding behavior modifiers; pyruvate dehydrogenase kinase (PDK) modulators; serotonin receptor modulators; monoamine transmission 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., toloxacin and amivamide);Compounds described in WO 007 / 013694, WO 2007 / 018314, WO 2008 / 093639 and WO 2008 / 099794; GPR40 agonists (e.g., fasiglitazone or its hydrate, compounds described in WO 2004 / 041266, WO 2004 / 106276, WO 2005 / 063729, WO 2005 / 063725, WO 2005 / 087710, WO 2005 / 095338, WO 2007 / 013689 and WO Compounds listed in 2008 / 001931); SGLT1 inhibitors; adiponectin or its agonists; IKK inhibitors (e.g., AS-2868); somatostatin receptor agonists; ACC2 inhibitors; cachexia improvers such as cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents; agents for improving lipid metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, antibodies against cachexia-inducing factor TNF-α, LIF, IL-6, and tumor suppressor M; metabolic regulatory proteins or peptides such as glucoskinase (GK), glucoskinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor α (PPARα), MC4r agonists, insulin receptor agonists, PDEs 5. Inhibitors, including glycation inhibitors (e.g., ALT-711); neurotrophic agents (e.g., Y-128, VX853, neurotrophic peptides); antidepressants (e.g., desipramine, amitriptyline, imipramine); antiepileptics (e.g., lamotrigine, oxcarbazepine, levetiracetam, zonisamide, pregabalin, lacosamide, carbamazepine); antiarrhythmics (e.g., mexiletine); acetylcholine receptor ligands (e.g., ABT-594); endothelial angiotensin receptor antagonists (e.g., ABT-627); anesthetic analgesics (e.g., morphine); α2 receptor agonists (e.g., clonidine); local analgesics (e.g., capsaicin); anxiolytics (e.g., benzothiazazepine); phosphorus Esterase 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 therapies (e.g., anti-CD20 antibodies (e.g., rituxan), i-BLyS antibodies); drugs affecting T-cell migration (e.g., anti-integrin α4 / β1 antibodies (e.g., tysabri)); drugs acting on immunoaffinity proteins (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., mycophenolate mofetil).And metaglitazone (metaglidasen), AMG-131, bagliflozin, MBX-2044, letagliflozin, agliflozin, sitagliptin, lobegliflozin, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exenatide-4, memantine hydrochloride, midazolam, ketoconazole, ethyl eicosapentaenoate, clonidine, azosemi, isosorbide, ethacrylic acid, pyrrolitanide, bumetanide, etoposide, piroxicam, NO donors (e.g., organic nitrates) and NO promoters (e.g., phosphodiesterase inhibitors).

[0273] In some implementations, one or more additional therapeutic agents include those useful, for example, as antiemetics. As used herein, an "antiemetic" means any agent that relieves (e.g., reduces or eliminates) nausea or vomiting. It should be understood that when referring to a therapeutically effective amount of an antiemetic, the amount administered is the amount required to relieve (e.g., reduce or eliminate) nausea or vomiting. While not wishing to be bound by theory, it is believed that administration of one or more antiemetics in combination with compounds of formula (I) described herein may allow for the administration of higher doses of compounds of formula (I), for example, because the patient may be able to maintain normal food intake, thereby resulting in a faster response to treatment.

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

[0275] For example, antiemetics can be selected from sedatives, antihistamines, anticholinergics, sterols, 5HT-3 receptor antagonists, NK1 receptor antagonists, antidopaminergics / dopamine receptor antagonists, benzodiazepines, and non-psychoactive cannabinoids.

[0276] In some implementations, the antiemetic is a 5HT3 receptor antagonist (serotonin receptor antagonist). Non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: granisetron (Kytril), dolasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemistron, zatosetron, bartaprazole, MDL-73147EF; metoclopramide, N-3389 (ne-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1H-indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222, scopolamine-3,5-dimethylbenzoate, 3-(4-allylpiperazin-1-yl)-2-quinoxaline carboxylate maleate, zacopride hydrochloride, and mirtazapine. Other non-limiting examples of 5HT3 receptor antagonists (serotonin receptor antagonists) include: celanisetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, miansheline, olanzapine, palonosetron (+netostitan), quetiapine, carmustron (qamosetron), ramosetron, licastron, riperidone, ziprasidone, and zartosetron.

[0277] In some implementations, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemyrosetron, zartosetron, bartaprazole, MDL-73147EF, metoclopramide, N-3389, Y-25130 hydrochloride, MDL 72222, scopolamine-3,5-dimethylbenzoate, 3-(4-allyl-piperazin-1-yl)-2-quinoxaloline carboxylate maleate, zalcopride hydrochloride, and mirtazapine.

[0278] In some implementations, the 5HT-3 receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemyrosetron, and zartosetron.

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

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

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

[0282] In some implementations, the antiemetic is an antihistamine. Non-limiting examples of antihistamines include: piperazine derivatives (e.g., cyproheptadine, meclopramide, and cinnarizine); promirtine; dimethoprim (Gravol); diphenhydramine; hydroxyzine; bucropramide; and meclopramide hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[0283] In some implementations, the antiemetic is an anticholinergic drug (an inhibitor of acetylcholine receptors). Non-limiting examples of anticholinergic drugs include: atropine, scopolamine, glycopyrron, hyoscine, trihexyphenidyl (trihexy-5, trihexyphenidyl hydrochloride), benzalkonium mesylate, bisperidone hydrochloride, disipal (norflex), diphenhydramine, hydroxyzine, scopolamine, and kemadrin (propiconazole hydrochloride).

[0284] In some implementations, the antiemetic is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethoprim (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, cassopitant, elopitant, fosaprepitant, maropitant, netupitant, lorapitant, and vertepitant.

[0286] Other non-limiting 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 (nomipitan ammonium besylate / nomipitan ammonium chloride), LY 303870 (lanepitan), 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]diaza-aranoctano[2,1-g] [1,7]naphthidine-6,13-dione], PD 154075, ([(2-benzofuran)-CH2OCO]-(R)-α-MeTrp-(S)-NHCH(CH3) Ph), FK888 and (D-Pro4, D-Trp7,9,10, Phe11)SP4-11.

[0287] In some embodiments, the antiemetic is an antidopaminer / dopamine receptor antagonist (e.g., a dopamine receptor antagonist, such as a D2 or D3 antagonist). Non-limiting examples include phenothiazines (e.g., propranolol, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiotetracycline, metoprolol); benzamides (e.g., metoclopramide, domperidone); butyric acid ketones (e.g., haloperidol, droperidol); aripiprazole, bromiprazole, clopazole, domperidone, itoprazole, metoclopramide, trimebenzamide, and amisulpride.

[0288] In some implementations, the antiemetic is a non-psychoactive cannabinoid (e.g., cannabidiol (CBD), dimethylheptylcannabidiol (CBD-DMH), tetrahydrocannabinol (THC), cannabinoid agonists such as WIN 55-212 (CB1 and CB2 receptor agonists), dronabinol (Marinol®), and cesamet).

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

[0290] Other exemplary antiemetics include those disclosed in the following documents: US 20120101089A1; US ​​10,071,088 B2; US 6,673,792 B1; US ​​6,197,329 B1; US ​​10,828,297 B2; US 10,322,106 B2; US 10,525,033 B2; WO 2009080351 A1; WO 2019203753 A2; WO 2002020001 A2; US 8,119,697 B2; US 5,039,528; US20090305964A1; and WO 2006 / 111169, each of which is incorporated herein by reference in its entirety.

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

[0292] In some embodiments, an additional therapeutic agent or regimen is administered to the patient at approximately the same time as the contact or application of the compound and pharmaceutical composition. For example, the additional therapeutic agent or regimen is administered to the patient simultaneously with the compound and pharmaceutical composition in the same dosage form. As another example, the additional therapeutic agent or regimen is administered to the patient in parallel with the compound and pharmaceutical composition in a separate dosage form. Patient selection

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

[0294] In some embodiments, the method described herein further includes the step of identifying a patient with type 2 diabetes (e.g., a patient). In some embodiments, determining whether a patient has type 2 diabetes includes performing measurements 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 from about 6.5% to about 24.0%. In some embodiments, the HbA1c level is greater than or about 6.5%. In some embodiments, the HbA1c level is greater than or about 8.0%. In some embodiments, the HbA1c level is greater than or about 10.0%. In some embodiments, the HbA1c level is greater than or about 12.0%. In some embodiments, the HbA1c level is greater than 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 implementations, the HbA1c level is greater than or about 22.0%. In some implementations, the HbA1c level is greater than or about 24.0%.

[0295] In some embodiments, the fasting plasma glucose level is greater than or about 120 mg / dL to greater than or about 750 mg / dL. In some embodiments, the fasting plasma glucose level is greater than or about 200 mg / dL to greater than or about 500 mg / dL. In some embodiments, the fasting plasma glucose level is greater than or about 300 mg / dL to greater than or about 700 mg / dL.

[0296] In some embodiments, the non-fasting plasma glucose level is greater than or about 190 mg / dL to greater than or about 750 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 250 mg / dL to greater than or about 450 mg / dL. In some embodiments, the non-fasting plasma glucose level is greater than or about 400 mg / dL to greater than or about 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 greater than or about 22 kg / m² to greater than or about 100 kg / m². In some embodiments, the patient's BMI is greater than or about 30 kg / m² to greater than or about 90 kg / m². In some embodiments, the patient's BMI is greater than or about 40 kg / m² to greater than or about 80 kg / m². In some embodiments, the patient's BMI is greater than or about 50 kg / m² to greater than or about 70 kg / m².

[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 race. In some embodiments, the patient's age is greater than or about 10 years. In some embodiments, the patient's age is greater than or about 15 years. In some embodiments, the patient's age is greater than or about 20 years. In some embodiments, the patient's age is greater than or about 25 years. In some embodiments, the patient's age is greater than or about 30 years. In some embodiments, the patient's age is greater than or about 35 years. In some embodiments, the patient's age is greater than or about 40 years. In some embodiments, the patient's age is greater than or about 42 years. In some embodiments, the patient's age is greater than or about 44 years. In some embodiments, the patient's age is greater than or about 46 years. In some embodiments, the patient's age is greater than or about 48 years. In some embodiments, the patient's age is greater than or about 50 years. In some embodiments, the patient's age is greater than or about 52 years. In some embodiments, the patient's age is greater than or about 54 years. In some embodiments, the patient's age is greater than or about 56 years. In some embodiments, the patient's age is greater than or about 58 years. In some embodiments, the patient's age is greater than or about 60 years. In some embodiments, the patient's age is greater than or about 62 years. In some embodiments, the patient's age is greater than or about 64 years. In some embodiments, the patient's age is greater than or about 66 years. In some embodiments, the patient's age is greater than or about 68 years. In some embodiments, the patient's age is greater than or about 70 years. In some embodiments, the patient's age is greater than or about 72 years. In some embodiments, the patient's age is greater than or about 74 years. In some embodiments, the patient's age is greater than or about 76 years. In some embodiments, the patient's age is greater than or about 78 years. In some embodiments, the patient's age is greater than or about 80 years. In some embodiments, the patient's age is greater than or about 85 years. In some embodiments, the patient's age is greater than or about 90 years. In some embodiments, the patient's age is greater than or about 95 years. In some implementation schemes, the patient's race can be African American, American Indian or Alaskan Native, Asian American, Hispanic or Latino or Native Hawaiian or Pacific Islander. Compound Synthesis

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

[0300] Furthermore, 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, and suitable conditions for protecting and deprotecting a particular functional group, are well known in the art. For example, many 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, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched with stereoisomers, if desired. Unless otherwise indicated, all such stereoisomers (and mixtures enriched with stereoisomers) are included within the scope of this disclosure. Pure stereoisomers (or mixtures enriched with stereoisomers) can be prepared using, for example, photoactive starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0302] The starting materials used in the following reactions are commonly known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), EMKA-Chemie GmbH & Co. KG (Escherich, Germany), or Millipore Sigma (Burlington, Massachusetts, USA). Other starting materials can be prepared by procedures described in standard reference texts, 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 Supplements (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 (VCH Publishers Inc., 1989).

[0303] Scheme I illustrates a general method that can be used to synthesize the compounds described herein, wherein A, ring B, L 1 L 2 R 1 R 3 R 4 and R 5 Each of them is independently defined as in this paper, and R 50 It is an alkyl or substituted alkyl. Option I

[0304] The Hantzsch-type pyridine synthesis strategy can be used to synthesize polysubstituted pyridine compounds I-4 or I-7. 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 under heating conditions in a suitable solvent (e.g., ethanol). I-4 is oxidized by CAN or DDQ to obtain compound I-5, which can then be further converted to a heteroaryl group using methods known in the art to obtain compounds of formula I. Compound I-7 is oxidized under similar reaction conditions to obtain compounds of formula I.

[0305] For any compound shown in Scheme I, it should be understood that various derivatives can be provided through interconversion of functional groups at 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 1 L 2 R 1 R 3 R 4 and R 5 As defined herein. However, derivatization prior to the reaction of compounds I-1, I-2, I-3, I-4, I-5, I-6, or I-7 in any step and / or further derivatization of the resulting reaction product provides compounds of various formulas I. Suitable starting materials and reagents are commercially available or can be prepared by methods known to those skilled in the art.

[0306] After the reaction is complete, compound I can be recovered using conventional techniques such as neutralization, extraction, precipitation, chromatography, and filtration. In some embodiments, appropriate control of reaction conditions and selection of substituents for reagents can at least partially determine or preserve the formation of various stereoisomers when stereochemistry is desired. Compounds I-1, I-2, and I-3 can be commercially available or synthesized de novo. For example, compounds I-1 and I-6. Compound I-1 can be prepared as shown in Scheme II or Scheme III. Option II

[0307] A-1 reacts with Michaelis acid to give intermediate A-2, which undergoes decarboxylation to yield 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 react with ethane-1,2-diol to give intermediate A-3. Typically, the formate group of A-3 can be converted to various heteroaryl groups to give intermediate A-7, which undergoes deprotection via a mixture of H₂SO₄ and formic acid to give compound I-6. For example, hydrolysis of the ester group of intermediate A-3 yields a carboxylic acid, which can be reacted under conditions suitable for providing intermediate A-7 (e.g., with acetylhydrazine in the presence of HATU and DIEA, the product undergoing cyclization with 4-toluenesulfonyl chloride to give oxadiazole). Deprotection of intermediate A-7 yields compound I-6. Option III

[0309] Carboxylic acid A-1 reacts with potassium carboxylic acid A-8 in the presence of CDI and MgCl2 to give compound I-6.

[0310] Scheme IV below illustrates a general method for synthesizing indenylamine I-7, which can be used to prepare compounds of formula I, wherein R 5 It is an optional substituted cycloalkyl group. Option IV

[0311] Aldehyde A-8 (where v is 0-5 and each Z) 5 Independently (as defined herein), it reacts with Michaelis acid A-9 to give carboxylic acid A-10. It reacts with oxalyl chloride to give its corresponding acyl chloride A-11, the product undergoing intramolecular Friedel-Crafts acylation to generate ketone A-12. This is then reacted with A-13 to give tert-butylsulfinamide A-14. Reduction of the sulfinamide using DIBAL-H yields A-15. Deprotection under acidic conditions gives indanylamine intermediate I-7.

[0312] After each reaction is completed, each of the intermediates or final compounds can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc. Other modified methods for obtaining the compounds of this disclosure are within the scope of the art. General Synthesis

[0313] Typical embodiments of the compounds described herein can be synthesized using the general reaction scheme described below. Given the description herein, it should be clear that the general scheme can be modified by substituting the starting materials with other materials having similar structures to produce correspondingly different products. The following description of the synthesis provides numerous examples of how the starting materials can be varied to provide the corresponding products. Given the desired product that defines the substituents, the necessary starting materials can generally be determined by examination. Starting materials are typically obtained from commercial sources or synthesized using publicly available methods. To synthesize the compounds as embodiments described in this disclosure, examination of the structure of the compound to be synthesized will provide the identity of each substituent. Given the embodiments herein, the identity of the final product will generally make the identity of the necessary starting materials clear through a simple examination process. Generally, the compounds described herein are typically stable and separable at room temperature and pressure. Example

[0314] The following embodiments are included to illustrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and can therefore be considered as specific patterns constituting its practice. However, based on this disclosure, those skilled in the art will understand that many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of this disclosure and still obtaining the same or similar results.

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

[0316] Step A: 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-carboxylic acid ethyl ester

[0317] N-[(1R)-2,3-dihydro-1H-indene]-5-carboxythiophene-2-carboxamide (477.02 mg, 1.758 mmol) and 3-azine-5-methylhexanoamide (300 mg, 2.110 mmol) were added to a solution of ethyl 5-(4-fluorophenyl)-3-oxopentanoate (418.88 mg, 1.758 mmol) in EtOH (10 mL), and the reaction mixture was stirred at 100 °C for 18 hr. The reaction mixture was concentrated to give ethyl 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indene]amino}carbonyl)thiophene-2-yl]-6-(2-methylpropyl)-1,4-dihydropyridine-3-carboxylate (1.1 g, crude). 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

[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 50ºC for 2 hr. The reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed with additional water, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether). The organic layer was collected and concentrated under vacuum to give ethyl 5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophene-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

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

[0322] Step 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

[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-azineylethyl)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 hr. The reaction mixture was diluted with EtOAc (50 mL) and water (20 mL). The organic layer was separated and washed with additional water (20 mL * 2) and a saturated aqueous solution of NaCl (20 mL). The organic layer was separated, dried over Na2SO4, and then filtered. The organic layer was collected and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 1:1). The organic layer was collected, concentrated under vacuum, and dried to give 6-[2-(4-fluorophenyl)ethyl]-4-[5-({[(1R)-2,3-dihydro-1H-indenyl]amino}carbonyl)thiophene-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 EN-[(R)-1-indanyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-4-pyridyl}-2-thiophenecarboxamide (compound 101)

[0325] DBU (37.96 mg, 0.249 mmol) was added 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), and the reaction mixture was stirred at 90ºC for 18 hr. The reaction mixture was filtered and purified by preparative HPLC (FA) to give N-[(R)-1-indanyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-4-pyridyl}-2-thiophene carboxamide (15.53 mg, 0.025 mmol, 39.95%).

[0326] 1 H 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). 19 F 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-oxadiazol-5-yl)-4-pyridyl}-2-thiophenecarboxamide (Compound 102)

[0327] Compound 102 was synthesized using suitable materials and a procedure similar to that described in Example 1 above.

[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, 3H), 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, 2H), 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-oxadiazol-5-yl)-4-pyridyl}-2-thiophenecarboxamide (compound 103)

[0329] Compound 103 was synthesized using suitable materials and a procedure similar to that described in Example 1 above.

[0330] 1H 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=3.6Hz, 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-triazol-4-yl}-2-thienyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)nicotinamide (compound 104)

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

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

[0333] Step B: 5-(1-(3,4-difluorobenzyl)-1H-1,2,3-triazol-4-yl)thiophene-2-carboxaldehyde

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

[0335] Compound 104 was then synthesized using suitable materials and a similar procedure to that described in Example 1 above.

[0336] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1 H), 7.91 (s, 1 H), 7.61 (s, 1H), 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). 19F 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-oxadiazol-5-yl]-4-pyridyl}-2-thiophenecarboxamide (Compound 105)

[0337] Step A: 1H-benzo[d][1,2,3]triazol-1-yl5-carbamoyl-4-(5-((3,4-difluorobenzyl)carbamoyl)thiophen-2-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinate

[0338] To a solution of 5-carbamoyl-4-(5-((3,4-difluorobenzyl)carbamoyl)thiophen-2-yl)-2-(4-fluorophenylethyl)-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 hr. The reaction mixture was diluted with EtOAc (15 mL x 3) and water (10 mL). The organic layer was separated, washed with an additional saturated NaCl solution (10 mL), and concentrated under vacuum. The residue was purified and concentrated by silica gel column chromatography (eluting with 10% methanol in dichloromethane) to give 1H-benzo[d][1,2,3]triazol-1-yl5-carbamoyl-4-(5-((3,4-difluorobenzyl)carbamoyl)thiophene-2-yl)-2-(4-fluorophenylethyl)-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-oxadiazol-5-yl]-4-pyridyl}-2-thiophenecarboxamide (Compound 105)

[0339] Compound 105 was then synthesized using suitable materials and a similar procedure to that described in Example 1 above.

[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, 2H), 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-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (compound 106)

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

[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 hr. The reaction mixture was diluted with EtOAC (50 mL) and water (20 mL). The organic layer was separated and washed with additional water (20 mL * 2) and a saturated aqueous solution of NaCl (20 mL). The organic layer was separated, dried with Na2SO4, and then filtered. The organic layer was collected and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 1:1). The organic layer was collected, concentrated under vacuum, and dried to give 5-(diazylcarbonyl)-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). 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-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (compound 106)

[0344] Add 1-(dimethylamino)-1,1-dimethoxyethane (66.62 mg, 0.500 mmol) to a solution of 5-(diazylcarbonyl)-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), and stir the reaction mixture at 60ºC for 3 hr. Concentrate the reaction mixture and dissolve the residue in toluene (4 mL). Add TsOH (6.37 mg, 0.033 mmol) to the reaction mixture, and stir the reaction mixture again at 120ºC for 2 hr. The reaction mixture was concentrated and the residue was purified by preparative HPLC (FA) to give N-[(R)-1-indanyl]-5-{5-carbamoyl-2-[2-(p-fluorophenyl)ethyl]-6-isobutyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (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 (377MHz, 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-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (Compound 107)

[0346] Compound 107 was synthesized using suitable materials and a procedure similar to that described in Example 4 above.

[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, 5H), 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=6.8Hz, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26, -138.84, -141.33. LC-MS: m / z634.2 (M+H) + . 4-(5-((3,4-difluorobenzyl)carbamoyl)thiophen-2-yl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(4-methylpentyl)nicotinamide (compound 108)

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

[0349] 1H 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=7.67Hz, 2H), 1.43 - 1.52 (m, 1 H), 1.09 - 1.16 (m, 2 H), 0.94 (d, J=6.60 Hz, 6H), 0.81 (d, J=6.60 Hz, 6 H). 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-oxadiazol-2-yl)nicotinamide (Compound 109)

[0350] Compound 109 was synthesized using suitable materials and a procedure similar to that described in Example 4 above.

[0351] 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=3.76 Hz, 1 H), 7.07 - 7.17 (m, 2H), 6.97 - 7.05 (m, 2 H), 6.79 (t, J=6.02 Hz, 1 H), 5.78 (d, J=17.57 Hz, 2H), 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, 2H), 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-oxadiazol-2-yl)nicotinamide (compound 110)

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

[0353] 1 H 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-oxadiazol-2-yl)nicotinamide (compound 111)

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

[0355] 1 H NMR (400 MHz, CD3OD) δ 7.58 (d, J=4.52 Hz, 1 H) 7.19 - 7.28 (m, 2H) 7.12 - 7.18 (m, 1 H) 7.05 - 7.10 (m, 1 H) 4.49 (s, 2 H) 2.83 - 2.89 (m, 2H) 2.62 - 2.68 (m, 2 H) 2.49 (s, 3 H) 2.37 - 2.45 (m, 1 H) 2.05 - 2.18 (m, 1H) 1.02 (d, J=6.60 Hz, 6 H) 0.87 - 0.93 (m, 6 H). 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-oxadiazol-2-yl)pyridine-3-carboxamide (compound 112)

[0356] Compound 112 was synthesized using suitable materials and a procedure similar to that described in Example 4 above.

[0357] 1H NMR (400 MHz, DMSO-d6) δ 9.13 - 9.19 (m, 1 H), 7.88 - 7.95 (m, 1H), 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, 3H), 0.94 (d, J=6.60 Hz, 6H). 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-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (compound 113)

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

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

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

[0361] To a solution of ethyl {2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolane-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 hr. A 1 N aqueous solution of HCl (60 mL) was added to the reaction mixture, and the mixture was diluted with EtOAc (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL x 2) and brine (50 mL), dried over Na₂SO₄, and then filtered. The organic layer was collected and concentrated under vacuum to give {2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolane-2-yl}acetic acid (3 g, 90.03%). LC-MS: m / z 277.1 (M+H) + .

[0362] Step C N'-acetyl-2-(2-(4-fluorophenylethyl)-1,3-dioxolane-2-yl)acetylhydrazine

[0363] Acetylhydrazine (1.75 g, 23.598 mmol), DIEtOAc (4.57 g, 35.397 mmol), and HATU (5.38 g, 14.159 mmol) were added to a solution of {2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolane-2-yl}acetic acid (3 g, 11.799 mmol) in DMF (30 mL). The reaction mixture was stirred at 50ºC for 3 hr. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (20 mL). The organic layer was separated and washed with water (20 mL x 2) and brine (20 mL). The organic layer was separated, dried over Na2SO4, and then filtered. The organic layer was collected and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 1:1). The organic layer was collected, concentrated under vacuum, and dried to give N'-acetyl-2-(2-(4-fluorophenylethyl)-1,3-dioxolane-2-yl)acetylhydrazine (2.8 g, 76.47%). LC-MS: m / z 310.9 (M+H) + .

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

[0365] TEA (1.456 mL, 10.473 mmol) and 4-toluenesulfonyl chloride (1.84 g, 9.667 mmol) were added to a solution of N'-acetyl-2-(2-(4-fluorophenylethyl)-1,3-dioxolane-2-yl)acetylhydrazine (2.5 g, 8.056 mmol) in DCM (30 mL), and the reaction mixture was stirred at 30ºC for 48 hr. The mixture was diluted with DCM (100 mL) and water (50 mL). The organic layer was separated, washed with additional water (50 mL), and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 20:1). The organic layer was collected and concentrated under vacuum to give 2-({2-[2-(4-fluorophenyl)ethyl]-1,3-dioxolane-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-oxadiazol-2-yl)but-2-one

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

[0368] Step F 5-{3-carbamoyl-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)-1,4-dihydropyridin-4-yl}thiophene-2-carboxylic acid benzyl ester

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

[0370] Step G 5-{3-carbamoyl-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)pyridin-4-yl}thiophene-2-carboxylic acid benzyl ester

[0371] Add CAN (821.37 mg, 1.498 mmol) to a solution of 5-{3-carbamoyl-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)-1,4-dihydropyridin-4-yl}thiophene-2-carboxylic acid benzyl ester (600 mg, 0.999 mmol) in EtOH (3 mL), and stir the reaction mixture at room temperature for 2 hr. Dilute the mixture with EtOAc (50 mL) and water (20 mL). Separate the organic layer and wash with water (20 mL x 2) and brine (20 mL). Separate the organic layer, dry it with Na2SO4, and then filter it. Collect the organic layer and concentrate it under vacuum. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 1:1) to give 5-{3-carbamoyl-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)pyridin-4-yl}thiophene-2-carboxylate (500 mg, 83.52%). LC-MS: m / z 599.2 (M+H) + .

[0372] Step H 5-{5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(2-methylpropyl)pyridin-4-yl}thiophene-2-carboxylic acid

[0373] Pd / C (200 mg, 1.879 mmol, 10% Pd, moistened with about 55% water) was added to a solution of 5-{5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(2-methylpropyl)pyridin-4-yl}thiophene-2-carboxylic acid (500 mg, 0.835 mmol) in MeOH (5 mL), and the reaction mixture was stirred at 25ºC under H2 (15 Psi) for 1 hr. The reaction mixture was filtered and concentrated under vacuum to give 5-{5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(2-methylpropyl)pyridin-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-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (Compound 113)

[0375] To a solution of 5-{5-carbamoyl-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(2-methylpropyl)pyridin-4-yl}thiophene-2-carboxylic acid (15 mg, 0.029 mmol) in DMF (1 mL), (3-methoxyphenyl)methylamine (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 hr. The mixture was diluted with EtOAc (10 mL) and washed with water (30 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness under vacuum. 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-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (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, 2H), 3.74 (s, 3 H), 2.93-3.04 (m, 4 H), 2.73 (d, J=6.8 Hz, 2H), 2.38 (s, 3H), 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-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (compound 114)

[0377] Compound 114 was synthesized using suitable materials and a procedure similar to that described in Example 5 above.

[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=6.0Hz, 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-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (Compound 115)

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

[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=6.4Hz, 6H). 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-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (compound 116)

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

[0382] 1 H 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, , 2.25-2.35 (m, 1 H),0.94 (d, J = 6.4 Hz, 6 H). 19F 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-oxadiazol-2-yl)-4-pyridyl}-2-thiophenecarboxamide (compound 117)

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

[0384] 1 H 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, , 2.25-2.34 (m, 1 H),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-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 118)

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

[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, 4H), 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, 1H), 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-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 119)

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

[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, 6H), 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 (377MHz, 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-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 120)

[0389] Compound 120 was synthesized using suitable materials and a procedure similar to that described in Example 5 above.

[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 (377MHz, 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-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 121)

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

[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 (377MHz, 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-fluorophenylethyl)-2-isobutyl-4-(5-((4-methoxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)thiophen-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 122)

[0393] Compound 122 was synthesized using suitable materials and a procedure similar to that described in Example 5 above.

[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 (377MHz, DMSO-d6) δ -117.26. LC-MS: m / z 654.2 (M+H) + . (R)-4-(5-((6,7-dihydro-5H-cyclopentadieno[b]pyridin-5-yl)carbamoyl)thiophen-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 123)

[0395] Compound 123 was synthesized using suitable materials and a procedure similar to that described in Example 5 above.

[0396] 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J=8.0 Hz, 1 H), 8.40 (d, J=4.4Hz, 1 H), 7.90 (s, 1 H), 7.56-7.69 (m, 3 H), 7.00-7.23 (m, 5 H), 6.95 (d, , 0.94 (d, J=6.4 Hz, 6H). 19F NMR (377 MHz, DMSO-d6) δ -117.26. LC-MS: m / z 625.4 (M+H) + . (S)-4-(5-((6,7-dihydro-5H-cyclopentadieno[b]pyridin-5-yl)carbamoyl)thiophen-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 124)

[0397] Compound 124 was synthesized using suitable materials and a procedure similar to that described in Example 5 above.

[0398] 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J=8.0 Hz, 1 H), 8.40 (d, J=4.8Hz, 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, 1H), 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, 1 H),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-oxadiazol-2-yl)-4-pyridyl}-1,3-thiazolyl-5-carboxamide (compound 125)

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

[0400] At room temperature, 5-bromothiazol-2-carboxaldehyde (39 mg, 0.202 mmol) and 3-imino-5-methylhexamethylene (29 mg, 0.202 mmol) were added to a solution of 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)but-2-one (50 mg, 0.202 mmol) in EtOH (2 mL), and the reaction mixture was stirred at 100ºC for 16 hours. The reaction mixture was concentrated under vacuum to give 4-(5-bromothiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide (180 mg, crude). LC-MS: m / z 545.7 (M+H) + .

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

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

[0403] Step C: ethyl 2-(3-carbamoyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)thiazolyl-5-carboxylate

[0404] A mixture of 4-(5-bromothiazol-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-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 70ºC under CO for 16 hr. The reaction mixture was cooled to room temperature, concentrated under vacuum, and purified by silica gel column chromatography (eluting with 25% EtOAc in petroleum ether) to give ethyl 2-(3-carbamoyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)thiazol-5-carboxylate (20 mg, 40.4%). MS: m / z 538.2 (M+H) + .

[0405] Step D: 2-(3-carbamoyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)thiazolyl-5-carboxylic acid

[0406] Ethyl 2-(3-carbamoyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)thiazolyl-5-carboxylic acid (20 mg, 0.0372 mmol) in THF (1 mL) and water (0.1 mL) was added to LiOH·H₂O (8 mg, 0.186 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under vacuum and purified by preparative HPLC (0.03% TFA) to give 2-(3-carbamoyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)thiazolyl-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-oxadiazol-2-yl)-4-pyridyl}-1,3-thiazolyl-5-carboxamide (compound 125)

[0407] Compound 125 was then synthesized using appropriate materials and a similar procedure to that described in Example 5 above.

[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). 19 F 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-oxadiazol-2-yl)nicotinamide (compound 126)

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

[0410] (3,4-difluorophenyl)methylamine (476 mg, 3.33 mmol), HATU (1.52 g, 3.99 mmol), and DIEA (1.29 g, 9.99 mmol) were added to a solution of 4-formylbenzoic acid (500 mg, 3.33 mmol) in DMF (1 mL), and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 mL × 5). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography using 0–10% EtOAc / hexane to give N-(3,4-difluorobenzyl)-4-formylbenzoamide (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] Step B: 4-(4-((3,4-difluorobenzyl)carbamoyl)phenyl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide

[0412] Add 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)but-2-one (40 mg, 0.16 mmol) and (E)-3-amino-5-methylhex-2-enamide (23 mg, 0.16 mmol) to a solution of N-(3,4-difluorobenzyl)-4-carboxybenzoamide (50 mg, 0.18 mmol) in EtOH (1 mL), and stir the reaction mixture at 110ºC for 16 hr. Cool the reaction mixture to room temperature, dilute with water (10 mL), and extract with EtOAc (2 mL × 3). Combine the organic layers, dry over Na2SO4, filter, and concentrate to dryness under vacuum. The crude product was purified by preparative TLC using EtOAc / hexane (1 / 5) to give 4-(4-((3,4-difluorobenzyl)carbamoyl)phenyl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide (50 mg, crude). LC-MS: m / z 630.2 (M+H) + .

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

[0414] To a solution of 4-(4-((3,4-difluorobenzyl)carbamoyl)phenyl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide (50 mg, crude) in EtOH (1 mL), diammonium cerium(IV) nitrate (170 mg, 0.31 mmol) was added, and the reaction mixture was stirred at 50ºC for 2 hr. The reaction mixture was cooled to room temperature, concentrated under vacuum, and analyzed by preparative HPLC (0.03% NH3). . Purification with H2O yielded 4-(p-{[(3,4-difluorophenyl)methyl]carbamoyl}phenyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-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, 3H), 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-Benzothiophene-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 127)

[0416] Compound 127 was synthesized using suitable materials and a procedure similar to that described in Example 7 above.

[0417] 1H 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-oxadiazol-2-yl)-4-pyridyl}-2-furfural (compound 128)

[0418] Compound 128 was synthesized using suitable materials and a procedure similar to that described in Example 7 above.

[0419] 1 H 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=6.4Hz, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -117.30, -138.89, -141.39. LC-MS: m / z618.1 (M+H) + . Example 8 4-(7-bromo-1-benzothiophene-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 129)

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

[0421] A solution of 5-(4-fluorophenyl)-3-oxovalerate (500 mg, 2.099 mmol), 7-bromobenzo[b]thiophene-2-carboxaldehyde (505.96 mg, 2.099 mmol), and 3-imino-5-methylhexanoamide (298.41 mg, 2.099 mmol) in EtOH (10.0 mL) was stirred overnight at 120ºC. The reaction mixture was cooled to room temperature and concentrated under vacuum to give ethyl 4-(7-bromobenzo[b]thiophene-2-yl)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutyl-1,4-dihydropyridine-3-carboxylate (1.23 g, crude). LC-MS: m / z 584.9 (M+H) + .

[0422] Step B: 4-(7-bromobenzo[b]thiophene-2-yl)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid ethyl ester

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

[0424] Step C: 4-(7-bromobenzo[b]thiophene-2-yl)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid

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

[0426] Synthesis of step D: 4-(7-bromobenzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-5-(hydrazine carbonyl)-2-isobutylnicotinamide

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

[0428] Step E: 4-(7-bromo-1-benzothiophene-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 129)

[0429] At room temperature, 1,1-dimethoxy-N,N-dimethylethyl-1-amine (28.07 mg, 0.211 mmol) was added to a solution of 4-(7-bromobenzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-5-(hydrazine carbonyl)-2-isobutylnicotinamide (80 mg, 0.140 mmol) in MeCN (8.0 mL). The solution was stirred at 80ºC for 1 h. HoAc (0.5 mL) was added. The solution was stirred at 100ºC overnight. After the reaction was complete, the reaction was concentrated under vacuum. The reaction was purified by preparative HPLC to give 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, 1H), 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-oxadiazol-2-yl)nicotinamide (compound 130)

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

[0431] Brettphos Pd G3 (99 mg, 0.11 mmol) and Cs2CO3 (1.06 g, 3.27 mmol) were added to a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-7-chlorofurano[2,3-c]pyridine (250 mg, 1.09 mmol) and (3,4-difluorophenyl)methylamine (310 mg, 2.17 mmol) in dioxane (10 mL), and the mixture was stirred in a microwave at 100ºC under N2 for 2 hr. The reaction mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography (EtOAc: PE = 0 to 20%) to give 2-(((tert-butyldimethylsilyl)oxy)methyl)-N-(3,4-difluorobenzyl)furano[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)furano[2,3-c]pyridin-2-yl)methanol

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

[0434] Step 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-oxadiazol-2-yl)nicotinamide

[0435] MnO2 (260 mg, 1.00 mmol) was added to a solution of (7-((3,4-difluorobenzyl)amino)furano[2,3-c]pyridin-2-yl)methanol (100 mg, 0.10 mmol) in DCM (10 mL), and the mixture was stirred at 50ºC for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to give 7-((3,4-difluorobenzyl)amino)furano[2,3-c]pyridin-2-carboxaldehyde (50 mg, crude, 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-oxadiazol-2-yl)nicotinamide (compound 130)

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

[0437] 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.82 (s, 1H), 7.73 (d, J=5.2Hz, 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 FNMR (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-oxadiazol-2-yl)nicotinamide (compound 131)

[0438] Step A (7-bromothiopheno[2,3-c]pyridin-2-yl)methanol

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

[0440] Step B: 7-Bromothiopheno[2,3-c]pyridine-2-carboxaldehyde

[0441] MnO2 (2.85 g, 32.77 mmol) was added to a mixture of (7-bromothieno[2,3-c]pyridin-2-yl)methanol (400 mg, 1.64 mmol) in CHCl3 (10 mL) and MeOH (1 mL), and the reaction mixture was stirred at 70ºC for 6 hr. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc = 2:1, to give 7-bromothieno[2,3-c]pyridin-2-carboxaldehyde (340 mg, 85.71%). LC-MS: m / z 241.9 (M+H) + .

[0442] Step C: 4-(7-bromothiopheno[2,3-c]pyridin-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)-1,4-dihydropyridine-3-carboxamide

[0443] Add 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)but-2-one (329 mg, 1.32 mmol) and (2E)-3-amino-5-methylhex-2-enamide (188 mg, 1.32 mmol) to a mixture of 7-bromothieno[2,3-c]pyridin-2-carboxaldehyde (320 mg, 1.32 mmol) in EtOH (15 mL). Stir the reaction mixture overnight at 120ºC in a sealed tube under N2 protection. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH = 20:1) to give 4-(7-bromothieno[2,3-c]pyridin-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)-1,4-dihydropyridine-3-carboxamide (580 mg, 73.56%). LC-MS: m / z 596.1 (M+H) + .

[0444] Step D: 4-(7-bromothiopheno[2,3-c]pyridin-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)pyridin-3-carboxamide

[0445] Cerium ammonium nitrate (221 mg, 0.402 mmol) was added to a mixture of 4-(7-bromothieno[2,3-c]pyridin-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)-1,4-dihydropyridine-3-carboxamide (80 mg, 0.134 mmol) in DCM (4 mL), and the reaction mixture was stirred in a microwave oven at 70ºC for 30 min. The reaction mixture was cooled to room temperature, filtered, and concentrated under vacuum to give 4-(7-bromothieno[2,3-c]pyridin-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide (50 mg, 62.71%). LC-MS: m / z 594.1 (M+H) + .

[0446] Step 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-oxadiazol-2-yl)nicotinamide (compound 131)

[0447] Add (3,4-difluorophenyl)methylamine (24 mg, 0.17 mmol), Cs₂CO₃ (55 mg, 0.17 mmol), and BrettPhos Pd G₃ (8 mg, 0.008 mmol) to a mixture of 4-(7-bromothiopheno[2,3-c]pyridin-2-yl)-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide (50 mg, 0.084 mmol) in dioxane (4 mL). Stir the reaction mixture in a microwave at 100ºC under N₂ protection for 2 hours. Cool the reaction mixture to room temperature, filter, and concentrate under vacuum. The residue was purified by preparative HPLC with 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-oxadiazol-2-yl)nicotinamide (4.1 mg, 7.42%).

[0448] 1H 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]pyrimidin-6-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 132)

[0450] Compound 132 was synthesized using suitable materials and a procedure similar to that described in Example 10 above.

[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]pyridin-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 133)

[0452] Compound 133 was synthesized using suitable materials and a procedure similar to that described in Example 10 above.

[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-fluorophenylethyl)-2-isobutyl-4-(7-(3-(methoxymethyl)azacyclobutane-1-yl)thieno[2,3-c]pyridin-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 134)

[0454] Compound 134 was synthesized using suitable materials and a procedure similar to that described in Example 10 above.

[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, , 0.94 (d, J=6.8Hz, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -117.26. LC-MS: m / z 615.2 (M+H) + . Example 11 6-(4-fluorophenylethyl)-2-isobutyl-4-(7-(3-methoxypiperidin-1-yl)thieno[2,3-c]pyridin-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 135)

[0456] Step A: 7-(3-methoxypiperidin-1-yl)thiopheno[2,3-c]pyridine

[0457] 3-Methoxyhexahydropyridine (1935.17 mg, 16.80 mmol) was added to a solution of 7-chlorothieno[2,3-c]pyridine (950 mg, 5.60 mmol) in ethylene glycol (10 mL), and the reaction was stirred overnight at 140ºC. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 10:1) to give 7-(3-methoxypiperidin-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-methoxypiperidin-1-yl)thieno[2,3-c]pyridine-2-carboxaldehyde

[0459] At -78ºC, n-BuLi (1.13 mL, 2.819 mmol, 2.5 M in n-hexane) was added dropwise to a solution of 7-(3-methoxyhexahydropyridin-1-yl)thieno[2,3-c]pyridine (500 mg, 2.013 mmol) in tetrahydrofuran (10 mL) and stirred at -78ºC for 30 min, followed by the addition of N,N-dimethylformamide (0.211 mL, 2.617 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with EA and water. The organic layer was separated and washed with additional water. The organic layer was then dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with ethyl acetate in petroleum ether (PE:EtOAc = 9:1)). The organic layer was collected and concentrated under vacuum to give the title compound 7-(3-methoxypiperidin-1-yl)thieno[2,3-c]pyridine-2-carboxaldehyde (395 mg, yield: 70.99%). LC-MS: m / z 277.0 (M+H) + . 6-(4-fluorophenylethyl)-2-isobutyl-4-(7-(3-methoxypiperidin-1-yl)thieno[2,3-c]pyridin-2-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 135)

[0460] Compound 135 was then synthesized using a similar procedure to that described in Example 7 above, by using 7-(3-methoxypiperidin-1-yl)thiopheno[2,3-c]pyridine-2-carboxaldehyde and suitable materials.

[0461] 1H 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-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 136)

[0462] Step A: 7-((3,4-difluorobenzyl)amino)benzo[b]thiophene-2-carboxaldehyde

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

[0464] Step B: 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide

[0465] A mixture of 7-((3,4-difluorobenzyl)amino)benzo[b]thiophene-2-carboxaldehyde (40 mg, 0.132 mmol), 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)but-2-one (36.01 mg, 0.145 mmol), and 3-imino-5-methylhexamamide (20.63 mg, 0.145 mmol) in EtOH (2.0 mL) was stirred overnight at 110ºC. After the reaction was complete, the reaction mixture was concentrated under vacuum. The reaction was purified by preparative TLC (DCM / MeOH = 20 / 1) to give 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide (40 mg, yield: 46.12%). LC-MS: m / z 658.1 (M+H) + .

[0466] Step C: 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 136)

[0467] At room temperature, MnO2 (33.04 mg, 0.380 mmol) was added to a mixture of 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide (25 mg, 0.038 mmol) in dioxane (5 mL). The mixture was stirred overnight at 100ºC. The reaction was filtered and concentrated under vacuum. The reaction was purified by preparative HPLC to give 4-(7-((3,4-difluorobenzyl)amino)benzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-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=1.2Hz, 1 H), 7.31-7.40 (m, 2 H), 7.28 (s, 1 H), 7.17-7.22 (m, 1 H), 0.95 (d, J=6.8 Hz, 6H). 19 F NMR (377MHz, 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]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 137)

[0469] Step A: 2-(7-bromobenzo[b]thiophene-2-yl)-1,3-dioxolane

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

[0471] Step B (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(1,3-dioxolane-2-yl)benzo[b]thiophene-7-amine

[0472] Xantphos (22.30 mg, 0.039 mmol) and Pd2(dba)3 (35.30 mg, 0.039 mmol) were added to a mixture of 2-(7-bromobenzo[b]thiophene-2-yl)-1,3-dioxolane (110 mg, 0.386 mmol), (R)-2,3-dihydro-1H-indene-1-amine (78.53 mg, 0.463 mmol), and Cs2CO3 (377.28 mg, 1.157 mmol) in toluene (3.0 mL) at room temperature. The mixture was stirred overnight at 130ºC. 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 and washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum. The reaction mixture was purified by column chromatography (PE / EA = 10 / 1) to give (R)-N-(2,3-dihydro-1H-inden-1-yl)-2-(1,3-dioxolane-2-yl)benzo[b]thiophene-7-amine (90 mg, 69.14%). LC-MS: m / z 338.1 (M+H) + .

[0473] Step C(R)-7-((2,3-dihydro-1H-inden-1-yl)amino)benzo[b]thiophene-2-carboxaldehyde

[0474] A mixture of (R)-N-(2,3-dihydro-1H-indene-1-yl)-2-(1,3-dioxolane-2-yl)benzo[b]thiophene-7-amine (90 mg, 0.267 mmol), HCOOH (2 mL), and dioxane (1 mL) was stirred at room temperature for 2 hr. The reaction mixture was quenched with H₂O (25 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined and washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum. The reaction mixture was purified by column chromatography (PE / EA = 20 / 1) to give (R)-7-((2,3-dihydro-1H-indene-1-yl)amino)benzo[b]thiophene-2-carboxaldehyde (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]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 137)

[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-indene-1-yl)amino)benzo[b]thiophene-2-carboxaldehyde and suitable materials.

[0476] 1 H 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=8.0Hz, 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=6.8Hz, 6H). 19F NMR (377 MHz, DMSO-d6) δ -117.28. LC-MS: m / z 646.1 (M+H) + . Example 14 4-(7-cyano-1-benzothiophene-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 138)

[0477] Step A: 4-(7-cyano-1-benzothiophene-2-yl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (Compound 138)

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

[0479] 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J=8.0 Hz, 1 H), 7.93-8.02 (m, 2H), 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]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 139)

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

[0481] At 70ºC, 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 70ºC for 16 h. After the reaction was complete, the reaction was quenched with H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed with brine (30 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum. The reaction was purified by column chromatography (PE / EA = 10 / 1) to give (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] Step B: 4-Bromobenzo[b]thiophene-2-carboxaldehyde

[0483] A mixture of (4-bromobenzo[b]thiophene-2-yl)methanol (200 mg, 0.82 mmol) and MnO2 (286.08 mg, 3.291 mmol) in dioxane (2 mL) was added. The reaction mixture was stirred at 100ºC for 16 h. After the reaction was complete, the reaction mixture was filtered and concentrated under vacuum. The reaction mixture was purified by column chromatography (PE / EA = 10 / 1) to give 4-bromobenzo[b]thiophene-2-carboxaldehyde (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, 1H).

[0484] Step C: 4-(4-bromobenzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide

[0485] A mixture of (4-bromobenzo[b]thiophene-2-yl)methanol (130 mg, 0.539 mmol), 4-(4-fluorophenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)but-2-one (134 mg, 0.539 mmol), and (E)-3-amino-5-methylhex-2-enamide (77 mg, 0.539 mmol) in EtOH (2 mL) was stirred at 110ºC for 16 h. After the reaction was complete, the reaction was quenched with H2O (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined and washed with brine (15 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum. The reaction was purified by preparative TLC (PE / EA = 3 / 1) to give 4-(4-bromobenzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydropyridine-3-carboxamide (120 mg, 37.37%). LC-MS: m / z 595.0 (M+H) + .

[0486] Step D: 4-(4-bromobenzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide

[0487] A mixture of 4-(4-bromobenzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-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 50ºC for 16 h. After the reaction was complete, the reaction was quenched with H2O (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined and washed with brine (15 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum. The reaction was purified by preparative TLC (PE / EA = 3 / 1) to give 4-(4-bromobenzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (80 mg, 26.99%). LC-MS: m / z 593.0 (M+H) + .

[0488] Step E (2-(3-carbamoyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)benzo[b]thiophene-4-yl)tert-butyl carbamate

[0489] A mixture of 4-(4-bromobenzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (65 mg, 0.110 mmol) and 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-methylpropyl-2-ylcarbamate (128.30 mg, 1.095 mmol) in dioxane (5 mL) was stirred in a microwave at 100ºC for 2 h. After the reaction was complete, the reaction was quenched with H2O (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined and washed with brine (15 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum. The reaction was purified by preparative TLC (PE / EA = 3 / 1) to give tert-butyl (2-(3-carbamoyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)benzo[b]thiophene-4-yl)carbamate (35 mg, 50.75%). LC-MS: m / z 630.0 (M+H) + .

[0490] Step F 4-(4-aminobenzo[b]thiophen-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 139)

[0491] A mixture of tert-butyl (2-(3-carbamoyl-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-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 h. After the reaction was complete, the reaction was filtered and concentrated under vacuum. The reaction was purified by preparative HPLC (TFA) to give 4-(4-aminobenzo[b]thiophene-2-yl)-6-(4-fluorophenylethyl)-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (2.29 mg, 7.64%).

[0492] 1H 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-oxadiazol-2-yl)nicotinamide (compound 140)

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

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

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

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

[0497] Step C: 4-(5-{[(R)-1-indanylamino]methyl}-2-thienyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 140)

[0498] Add (1R)-2,3-dihydro-1H-indene-1-amine HCl (7.79 mg, 0.058 mmol), K2CO3 (24.24 mg, 0.175 mmol), and KI (0.97 mg, 0.006 mmol) to a solution of 4-[5-(chloromethyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(2-methylpropyl)pyridine-3-carboxamide (30 mg, 0.058 mmol) in DMF (1 mL), and stir the reaction mixture at 70ºC for 18 hr. The reaction mixture was cooled to room temperature, filtered, and purified by preparative HPLC (FA) to give 4-(5-{[(R)-1-indanylamino]methyl}-2-thienyl)-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide. 1H NMR (400MHz, DMSO-d6) δ 7.93 (s, 1 H), 7.52-7.59 (m, 1 H), 7.32-7.38 (m, 1 H), 7.18-7.29 (m, 3 H), 7.00-7.13 (m, 4 H), 6.90-6.98 (m, 2 H), 4.11-4.18 (m, 1 H), 3.99 (s, 2 H), 2.89-3.01 (m, 5 H), 2.68-2.80 (m, 3 H), 2.22-2.34 (m, 5 H), 1.75-1.86 (m, 1 H), 0.93 (d, J=6.4 Hz, 6H). 19 F NMR (377 MHz, DMSO-d6) δ -117.23. LC-MS: m / z 610.2 (M+H) + . Example 17 4-{5-[(3,4-difluorobenzylamino)methyl]-2-thienyl}-6-[2-(p-fluorophenyl)ethyl]-2-isobutyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)nicotinamide (compound 141)

[0499] Step A: 4-(5-(aminomethyl)thiophene-2-yl)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid ethyl ester

[0500] LiAlH4 (28.57 mg, 0.753 mmol) was added to a solution of ethyl 5-carbamoyl-4-(5-cyanothiophene-2-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinate (361 mg, 0.753 mmol, synthesized using a similar procedure to that described in Example 1 with suitable materials) in THF (4 mL), and the reaction mixture was stirred at 0ºC for 20 min. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (25 mL x 3). The organic layers were combined and washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give ethyl 4-(5-(aminomethyl)thiophene-2-yl)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutylnicotinate (190 mg, 52.34%). MS: m / z 484.2 (M+H) + .

[0501] Step B: ethyl 5-carbamoyl-4-(5-((3,4-difluorobenzamido)methyl)thiophene-2-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinate

[0502] To a solution of ethyl 4-(5-(aminomethyl)thiophene-2-yl)-5-carbamoyl-2-(4-fluorophenylethyl)-6-isobutylnicotinate (190 mg, 0.393 mmol) in DMF (2 mL), 3,4-difluorobenzoic acid (62.12 mg, 0.393 mmol), PyBOP (408.91 mg, 0.786 mmol), and DIEA (152.05 mg, 1.179 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The mixture was purified by preparative HPLC to give ethyl 5-carbamoyl-4-(5-((3,4-difluorobenzamido)methyl)thiophene-2-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinate (43 mg, 17.49%). 1H NMR (400 MHz, DMSO-d6) δ 9.35 (t, J=6.0 Hz,1 H), 7.87-7.94 (m, 1 H), 7.74-7.82 (m, 2 H), 7.47-7.61 (m, 2 H), 7.18-7.23(m, 2 H), 7.05-7.10 (m, 2 H), 6.99 (d, J=3.6 Hz, 1 H), 6.93 (d, J=3.6 Hz, 1H), 4.61 (d, J=6.0 Hz, 2 H), 3.99 (q, J=7.2 Hz, 2 H), 2.93-2.99 (m, 4 H), 2.63(d, J=6.8 Hz, 2 H), 2.18-2.28 (m, 1 H), 0.86-0.93 (m, 9 H). 19 F NMR (377 MHz, DMSO-d6) δ -117.37, -134.32, -137.80. MS: m / z 624.3 (M+H) + .

[0503] Step C: 5-Carbamoyl-4-(5-((3,4-difluorobenzamido)methyl)thiophene-2-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid

[0504] LiCl (11.70 mg, 0.27 mmol) was added to a solution of ethyl 5-carbamoyl-4-(5-((3,4-difluorobenzamido)methyl)thiophene-2-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid (43 mg, 0.07 mmol) in DMA (1 mL), and the reaction mixture was stirred at 150ºC for 24 hr. The reaction mixture was cooled to room temperature, filtered, and the filtrate was purified by preparative HPLC (0.1% FA / H2O / CH3CN) to give 5-carbamoyl-4-(5-((3,4-difluorobenzamido)methyl)thiophene-2-yl)-2-(4-fluorophenylethyl)-6-isobutylnicotinic acid (28 mg, 68.29%). LC-MS...

Claims

1. A compound of formula I: I Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein: A is C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene; wherein the C of A 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, heterocycloalkylene, arylene or heteroaryl are independently and optionally separated by one to five Z A replace; Ring B is arbitrarily divided by one to three Rs. B Substituted 5- or 6-membered heteroaryl groups; Each R B Independently selected from halogen groups, hydroxyl groups, -NH2 groups, cyano groups, and C groups. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups; wherein R B Each C 1-3 Alkyl groups are independently and optionally prefixed with -NH2 or -NHC. 1-3 Alkyl, -N(C) 1-3 alkyl)2, hydroxyl or C 1-3 Alkyl substitution; L 1 It is C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 Cycloalkylene or 4-6-membered heterocyclic alkylene groups; wherein L 1 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group or the 4- to 6-membered heterocyclic group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; L 2 It is a key, -O-, -S-, -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 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, C 3-6 Cycloalkylene, 4-6-membered heterocyclic cycloidene or 5-membered heteroarylene; wherein L 2 C 1-3 Alkylene, C 2-3 imidene group, C 2-3 Ethyne group, C 1-3 Heteroalkylene, C 3-6 The cycloalkylene group, 4-6-membered heterocyclic group, or 5-membered heteroarylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, -NH2, -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 Substituents of haloalkoxy groups; R 1 It 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 ; R 2 Yes -NR 1a R 1b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 2 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally selected from one to five independently chosen groups: halogen, hydroxyl, cyano, C... 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Substituents of haloalkoxy groups; Or R 2 and R 6 Or R 2 and R 7 Together with the atoms to which they are attached, they form a group optionally bounded by one to five Z. 2 Substituted heterocyclic groups; Each R 1a and R 1b Independently, it is hydrogen and C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic groups; wherein R 1a and R 1b Each C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 3-6 The cycloalkyl or 4- to 6-membered heterocyclic group is independently and optionally composed of one to five independently selected groups: halogen, hydroxyl, cyano, C. 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Substituents of haloalkoxy groups; Or R 1a and R 1b Together with the atoms to which they are attached, they form 4- to 6-membered heterocyclic groups, wherein the heterocyclic groups are independently and optionally composed of one to five groups independently selected from halogen, hydroxyl, cyano, C, 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Substituents of haloalkoxy groups; Each R 2a and R 2b Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 2a and R 2b Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 2a replace; Or R 2a and R 2b Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 2a Substituted heterocyclic groups; R 3 It is hydrogen, -NR 3b R 3c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 3 replace; R 3b and R 3c Each is independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 3b and R 3c Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five halogen groups, hydroxyl groups, cyano groups, C6 groups, C7 groups, C8 groups, C9 ... 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; Or R 3b and R 3c Together with the nitrogen atoms to which they are attached, they form optional groups of one to five Zn atoms. 3b Substituted heterocyclic groups; R 4 It is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 4 C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 4 replace; R 5 It is hydrogen, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 5 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 5 replace; R 6 It is hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl or 4- to 6-membered heterocyclic groups; wherein the C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 The cycloalkyl or 4- to 6-membered heterocyclic group is optionally surrounded by one to five independently selected groups: halogen, oxo, hydroxyl, cyano, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups; R 7 It is hydroxyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; Each Z A Z 2 Z 2a Z 3 Z 3b Z 4 and Z 5 Independently, it is a halogen group, cyano group, nitro group, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LH, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; wherein Z A Z 2 Z 2a Z 3 Z 3b Z 4 and Z 5 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each independently and optionally divided by one to five Z groups. 1a replace; Each L is independently -O-, -S-, -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)2NR 20 -, -NR 20 S(O)-, -NR 20 S(O)2-, -NR 20 S(O)NR 21 - or -NR 20 S(O)2NR 21 -; Each R 20 and R 21 Independently, it is hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein R 20 and R 21 Each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 1a Replace; or R 20 and R 21 Together with the atoms to which they are attached, they form independently, optionally, one to five Z. 1a Substituted heterocyclic groups; and Each Z 1a Independently, it can be a halogen group, hydroxyl group, cyano group, nitro group, oxo group, -SH, -NH2, or -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein Z 1a Each -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 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally selected from one to five C14 groups. 1-6 Substitution of alkyl, oxo, halogen, hydroxyl and cyano groups; The premise is that A is C 1-6 When alkylene, then R 5 It is C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups may be substituted independently or optionally.

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

3. The compound according to claim 1 or 2, wherein R 1 It is -C(O)NH2, -S(O)2NH2, -S(O)2CH3, , -S(O)(NH)CH3 or -P(O)(CH3)CH3.

4. The compound according to claim 1, wherein the compound is represented by formula IA: IA Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or solvate thereof, wherein X is -C(O)- or -S(O)2-.

5. The compound according to any one of the preceding claims, wherein A is C. 1-6 Alkylene, C 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene; wherein the C of A 1-6 Alkylene, C 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene is independently and optionally surrounded by one to five Z. A replace.

6. The compound according to any one of the preceding claims, wherein A is C. 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene; wherein the C 3-10 Cycloalkylene, heterocyclic, arylene, or heteroarylene is independently and optionally surrounded by one to five Z. A replace.

7. The compound according to any one of claims 1-5, wherein A is methylene, ethylene, or n-propylene. , , , , , , , , , , , , , , , , , , , , , or ;where bond a and L 2 Bonding.

8. The compound according to any one of the preceding claims, wherein the compound is represented by formula IB: ONE Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein: X is -C(O)- or -S(O)2-; and X 1 X 2 X 3 and X 4 Each of them is independently selected from O, S, N, NR B and CR B The premise is X 1 X 2 X 3 and X 4 At least one of them, containing X 1 X 2 X 3 and X 4 The ring is from the Fang ethnic group.

9. The compound according to any one of claims 1-4 or 8, wherein A is an arylene or heteroarylene; wherein the arylene or heteroarylene is independently and optionally composed of one to five Z. A replace.

10. The compound according to any one of claims 1-7 or 9, wherein ring B is pyridinyl, pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl; wherein the pyridinyl, pyrazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl group is optionally surrounded by one or two R groups. B replace.

11. The compound according to any of the preceding claims, wherein ring B or part thereof yes: , , , , , , , , or Each of them is optionally controlled by one or two Rs. B replace.

12. The compound according to any one of the preceding claims, wherein each R B C is independent 1-3 alkyl.

13. The compound according to any one of the preceding claims, wherein L 1 It is C 3-6 Cycloalkylene, C 1-3 Alkylene or C 1-3 Heteroalkylene; wherein each C 3-6 Cycloalkylene, C 1-3 Alkylene or C 1-3 The heteroalkylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups.

14. The compound according to any one of the preceding claims, wherein R 4 It is C 1-6 Alkyl, C 3-10 cycloalkyl, aryl, heterocyclic, or heteroaryl; wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, heterocyclic, or heteroaryl groups are independently and optionally surrounded by one to five Z groups. 4 replace.

15. The compound according to any one of the preceding claims, wherein R 4 It is an aryl, heterocyclic, or heteroaryl group; wherein the aryl, heterocyclic, or heteroaryl group is optionally surrounded by one to five Z groups. 4 replace.

16. The compound according to any one of claims 1-13, wherein R 4 It is C 1-3 Alkyl, C 3-9 Cycloalkyl, 4-9 membered heterocyclic or phenyl; wherein the C 1-3 Alkyl, C 3-6 The cycloalkyl or phenyl groups are optionally substituted independently with one to three halogen groups.

17. The compound according to any one of the preceding claims, wherein R 3 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

18. The compound according to any one of the preceding claims, wherein R 3 It is hydrogen, -NR 3b R 3c C 1-6 Alkyl or C 1-6 Alkyl group.

19. The compound according to any one of the preceding claims, wherein L 2 It is a key, -NR 2a -、-C(O)NR 2a -、-NR 2a C(O)-, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 Heteroalkylene, 4-6-membered heterocyclic alkylene, or 5-membered heteroaryl; wherein the C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 The heteroalkylene group, 4-6-membered heterocyclic group, or 5-membered heteroarylene group is independently and optionally composed of one to five groups independently selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Substituents of haloalkoxy groups.

20. The compound according to any one of the preceding claims, wherein R 5 It is hydrogen, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are independently and optionally separated by one to five Z groups. 5 replace.

21. The compound according to any one of the preceding claims, wherein R 5 It is an aryl or heteroaryl group; wherein the aryl or heteroaryl group is optionally composed of one to five Z groups. 5 replace.

22. The compound according to any one of the preceding claims, wherein R 5 It is hydrogen, halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, heterocyclic, or aryl; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, heterocyclic, or aryl groups are independently and optionally separated by one to five Z groups. 5 replace.

23. A compound as shown in Table 1 or Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof.

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

25. A method for treating a subject in need of calcitonin receptor and / or amylin receptor-related disease or disorder, the method comprising administering to the subject in need a therapeutically effective amount of the compound of any one of claims 1-23, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or solvate thereof, or the pharmaceutical composition of claim 24.

26. The method of claim 25, wherein the calcitonin receptor and / or amylin 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 of claim 25, wherein the calcitonin receptor and / or amylin receptor-related disease or disorder is osteoporosis, Paget's disease, hypercalcemia, Zudecker's atrophy, multiple fibrous dysplasia of bone, costoclavicular ossification, osteogenesis imperfecta, osteopenia, periodontal disease or defects, osteolytic bone disease, metastatic bone disorder, malignancy, autoimmune arthritis, bone fracture or fracture, or bone loss due to immobility or disuse, 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 inhibition, gastrointestinal disorders, renal osteodystrophy, or male infertility.

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

29. The method of claim 28, wherein the additional therapy or treatment agent is selected from antidiabetic agents, antiobesity agents, weight loss agents, GLP-1 receptor agonists, antiemetics, agents for treating nonalcoholic steatohepatitis (NASH), gastric electrical stimulation, diet monitoring, physical activity, or combinations thereof.

Images