Compounds and compositions for treating conditions associated with calcitonin receptor and / or amylin receptor activity

Abstract

The present disclosure provides compounds for modulating calcitonin receptor and / or amylin receptor activity, as well as pharmaceutical compositions comprising the compounds disclosed herein. Also provided are methods for treating a calcitonin receptor and / or amylin receptor associated disease or disorder.

Description

[0001] ACCG-0008-WO COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH CALCITONIN RECEPTOR AND / OR AMYLIN RECEPTOR ACTIVITY

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] The application claims the benefit of International Patent Application Numbers PCT / CN2025 / 072416, filed January 15, 2025, PCT / CN2025 / 114412, filed August 13. 2025, and PCT / CN2025 / 145177, tiled December 24, 2025, each of which is incorporated herein by reference in its entirety.

[0004] FIELD

[0005] The present disclosure provides compounds for modulating calcitonin receptor and / or amylin receptor activity, as well as pharmaceutical compositions comprising the compounds disclosed herein. Also provided are methods for treating calcitonin receptor and / or amylin receptor associated diseases, disorders, and conditions.

[0006] BACKGROUND

[0007] Calcitonin and amylin are hormones that interact with receptors within 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. Calcitonin of mammalian origin promotes insulin sensitivity, while the more potent calcitonin extracted from salmon additionally inhibits gastric emptying, promotes gallbladder relaxation, increases energy expenditure and induces satiety as well as weight loss. Studies have also indicated that oral salmon calcitonin (sCT) exerts an insulin-sensitizing effect to improve glucose metabolism in obesity and type 2 diabetes. European Journal of Pharmacology, 2024, 737(7): 91–96.

[0008] Amylin receptors (AMYRs) are G protein-coupled receptors (GPCRs), which respond to the peptide hormones amylin and calcitonin. Amylin receptors are heterodimers comprising the calcitonin receptor, which is a G protein-coupled receptor, and one of three receptor-modifying proteins. Amylin, formed primarily in pancreatic islet P cells, is cosecreted with insulin in response to caloric intake.

[0009] Patients with type 1 diabetes have lower baseline amylin serum concentrations, and amylin response to caloric intake is absent. Patients with type 2 diabetes requiring insulin also have a diminished amylin response to caloric intake, potentially related to the degree of -cell impairment. Key physiologic functions of amylin in maintaining glucose homeostasis include suppressing glucagon release in response to caloric intake, delaying the rate of gastric emptying, and stimulating the satiety center in the brain to limit caloric intake.ACCG-0008-WO The synthetic amylin analogue pramlintide is an approved treatment for diabetes mellitus as an adjunctive therapy to mealtime insulin which promotes better glycemic control and small but significant weight loss. AM833 (cagrilintide), an investigational novel long-acting acylated amylin analogue, acts as a non-selective amylin receptor agonist. This amylin receptor agonist can serve as an attractive novel treatment for obesity, resulting in reduction of food intake and significant weight loss in a dose-dependent manner. J Obes Metab Syndr. 2021; 30(4): 320-325.

[0010] Accordingly, modulators of the amylin and / or calcitonin receptor could be useful in treating various metabolic disorders, as well as inducing weight loss.

[0011] SUMMARY

[0012] The present disclosure provides small molecule calcitonin and / or amylin receptor modulators (e.g., amylin-receptor agonists), as well as pharmaceutical compositions comprising the compounds disclosed herein. Also provided are methods for treating calcitonin receptor and / or amylin receptor associated diseases or disorders.

[0013] This disclosure also provides pharmaceutical compositions comprising one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0014] Also provided herein are pharmaceutical compositions comprising one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0015] Also provided herein are methods for treating or preventing a calcitonin receptor and / or an amylin receptor associated disease or disorder in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or subformula thereof, or a pharmaceulically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof), or a pharmaceutical composition thereof. In some embodiments, the method further comprises administering to the subject, a therapeutically effective amount of one or more additional therapy or therapeutic agent to the patient, such as, but not limited to, an antidiabetic agent, an anti-obesity agent, a weight loss agent, a GLP-1 receptor agonist, an anti-emetic agent, an agent to treat metabolic dysfunction-associated steatohepatitis (MASH), gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

[0016] In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is a bone disorder, a metabolic disorder, pain, a neurodegenerative disease or disorder, a cardiovascular disease, or other disease or disorder.ACCG-0008-WO In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is a bone disorder, including, but not limited to, osteoporosis, Paget’s disease, hypercalcemia, Sudeck’s atrophy, polystatic fibrous dysplasia, intersemocostoclavicular ossification, osteogenesis imperfecta, osteopenia, periodontal disease or defect, osteolytic bone disease, metastatic bone disorder, or bone loss resulting from a malignancy, autoimmune arthritides, a breakage or fracture, or immobility or disuse.

[0017] In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is pain, including, but not limited to, osteopathic pain, phantom limb pain, general pain, hyperalgesia, or pain associated with diabetic neuropathy.

[0018] In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is a ncurodegcncrativc disease or disorder, including, but not limited to, Alzheimer’s disease.

[0019] In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is a metabolic disorder, including, but not limited to, non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), insulin dependent diabetes, non-insulin dependent diabetes, impaired glucose tolerance, obesity, syndrome X, or other diabetic complication.

[0020] In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is include primary or secondary hyperthyroidism, endocrine disorder, conditions associated with inhibiting gastric secretion, gastrointestinal disorders, renal osteodystrophy, or male infertility.

[0021] DETAILED DESCRIPTION

[0022] Definitions

[0023] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0024] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0025] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(0)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurallyACCG-0008-WO required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0026] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “Ci-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0027] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about x” includes description of “x”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0028] “Alkyl” refers to an unbranchcd or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., CM alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2 -pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; 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).

[0029] “Alkenyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 12 carbon atoms (i.e., C2-12 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including

[0030] 1,2-butadienyl, and 1,3-butadienyl).

[0031] “Alkynyl” refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 12 carbon atoms (i.e., C2-12 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.ACCG-0008-WO Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively.

[0032] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec -butoxy, n-pentoxy, n-hexoxy, and

[0033] 1,2-dimethylbutoxy.

[0034] “Alkoxyalkyl” refers to an alkyl group as defined above, wherein a hydrogen atom is replaced by an alkoxy group as defined herein.

[0035] “Haloalkyl” refers to an unbranched 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 an independently selected halo group. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but arc not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0036] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by an independently selected halo group.

[0037] “Haloalkoxy alkyl” refers to an alkyl group as defined above, wherein a hydrogen atom is replaced by a haloalkoxy group as defined herein.

[0038] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0039] “Cyanoalkyl” refers to an alkyl group as defined above, wherein one, or one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by cyano.

[0040] “Alkylthio” refers to the group “alkyl-S-”.

[0041] “Acyl” refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0042] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NRyRzand an “N-amido” group which refers to the group -NRyC(O)Rz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beACCG-0008-WO optionally substituted, as defined herein, or Ryand Rzare taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.

[0043] “Amino” refers to the group -NRyRzwherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0044] “Amidino” refers to -C(NRy)(NRz2), wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0045] “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 has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., Ce n aryl), or 6 to 10 carbon ring atoms (i.e., Ce-io aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with hctcroaryl defined below. If one or more aryl groups arc fused with a heteroaryl, the resulting ring system is heteroaryl regardless of point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of point of attachment. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkyl regardless of point of attachment.

[0046] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0047] “Carboxyl ester” or “ester” refer to both -OC(O)RXand -C(O)ORX, wherein Rxis alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0048] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-14 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e.,

[0049] C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl,ACCG-0008-WO cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule (e.g., 2,3-dihydro- 1 H-indenyl). Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0050] “Cycloalkylalkyl” refers to an alkyl group as defined above, wherein a hydrogen atom is replaced by a cycloalkyl group as defined herein.

[0051] “Imino” refers to a group -C(NRy)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0052] “Imido” refers to a group -C(O)NRyC(O)Rzor -N(C(O)Ry)C(O)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or Ryand Rzare taken together to form a heterocyclyl which may be optionally substituted, as defined herein.

[0053] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0054] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon atoms and heteroatoms. By way of example, 1, 2, or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl, each of which may be optionally 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 be optionally substituted. As used herein, heteroalkyl 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.

[0055] “Heteroalkylene” refers to a divalent heteroalkyl group. “Heteroalkylene” groups must have at least one carbon and at least one heteroatomic group within the chain. The term “heteroalkylene” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2, or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.ACCG-0008-WO Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkylene groups include, e.g., -CH2OCH2-, -CH(CH3)OCH2-, -CH2CH2OCH2-, -0CH2-, -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-, -CH2NRyCH2-, -CH(CH3)NRyCH2-, -CH2CH2NRyCH2-, -CH2CH2NRyCH2CH2NRyCH2-, etc., where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkylene includes 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 present on one or more carbon atoms.

[0056] “Heteroaryl” refers to an aromatic group having a single ring or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3.g heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[l,5-a]pyridinyl, and imidazo[l,5-a]pyridinyl, where the heteroaryl can be bound via either 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 theACCG-0008-WO attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0057] “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=0) (e.g., -C(0)-, -S(0)-, -S(0)2-, or -P(0)-) or N-oxide (-0 ) moieties. Any non-aromatic ring or fused ring system containing at least one heteroatom and one nonaromatic ring is considered a heterocyclyl, regardless of the attachment to the remainder of the molecule. For example, fused ring systems such as 6,7-dihydro-5H-cyclopenta[b]pyridinyl, decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8-tetrahydroquinazolinyl are heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, tliiazolidinyl, tefrahydrofuryl, tetrahydropyranyl, frilliianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and

[0058] 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-l-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-ACCG-0008-WO c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0059] “Sulfonyl” refers to the group -S(O)2Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0060] “Sulfinyl” refers to the group -S(O)Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0061] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more (e.g., 1 to 5, or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0062] As used herein, the term “compound,” is meant to include any or all stereoisomers, geometric isomers, tautomers, and isotopically enriched analogs (e.g., deuterated analogs) of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0063] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0064] Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,170,180,31P,32P,35S,18F,36C1,123I, and125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies,ACCG-0008-WO detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0065] The term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more hydrogens is / are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. 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 employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0066] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and / or an improvement in therapeutic index. An18F,3H,nC labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

[0067] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0068] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0069] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materialsACCG-0008-WO which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0070] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include, e.g., 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-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, 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, tertiary amines, such as salts derived from a N-containing heterocycle, a N-containing heteroaryl, or derived from an amine of formula N(RN)3 (e.g., HN+(RN)3 or (alkyl)N+(RN)s) where each RNis independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy). Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0071] The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, acyl, alkenyl, alkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, amidino, amido, amino, aryl, azido, carbamoyl,ACCG-0008-WO carboxyl, carboxyl ester, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkoxy, haloalkoxy alkyl, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydrazino, hydroxy, hydroxyalkyl, imido, imino, nitro, oxo, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thione, or combinations thereof.

[0072] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxy, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or hctcroaryl, each of which is unsubstituted.

[0073] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0074] A “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0075] The term “pharmaceutically acceptable” as used herein indicates that the compound, or salt or composition thereof is compatible chemically and / or toxicologically with the other ingredients comprising a formulation and / or the subject being treated therewith.ACCG-0008-WO The term “administration” or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian. The method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0076] The terms “effective amount” or “effective dosage” or “pharmaceutically effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, and can include curing the disease. “Curing” means that the symptoms of active disease are eliminated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study. In some embodiments, a “therapeutically effective amount” of a compound as provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.

[0077] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In some embodiments, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0078] The term “pharmaceutical composition” refers to a mixture of a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof as provided herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques ofACCG-0008-WO administering a compound exist in the art including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0079] The term “calcitonin receptor and / or amylin receptor associated disease or disorder” as used herein is meant to include, without limitation, 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 may arise from one or more of a genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, surgical, and / or traumatic etiology.

[0080] The terms “treat,” “treating,” and “treatment,” in the context of treating a disease, disorder, or condition, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.

[0081] The term “preventing,” as used herein, is the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[0082] The terms “subject,” “patient,” or “individual,” as used herein, are used interchangeably and refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the term refers to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired or needed. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease, disorder, or condition to be treated and / or prevented.

[0083] The terms “treatment regimen” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination.

[0084] The term “pharmaceutical combination,” as used herein, refers to a pharmaceutical treatment resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.

[0085] The term “combination therapy” as used herein refers to a dosing regimen of two different therapeutically active agents (i.e., the components or combination partners of the combination), wherein the therapeutically active agents are administered together or separately in a manner prescribed by a medical care taker or according to a regulatory agency as defined herein.ACCG-0008-WO The term “modulate,” “modulating,” or “modulation,” as used herein, refers to a regulation or an adjustment (e.g., increase or decrease) and can include, for example agonism, partial agonism or antagonism.

[0086] Compounds

[0087] Provided herein are compounds that are amylin modulators.

[0088] In some embodiments, provided is a compound of Formula I:

[0089]

[0090] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0091] A is Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, heterocyclylene, arylene, or heteroarylene; wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, heterocyclylene, arylene, or heteroaryl of A is independently optionally substituted with one to five ZA;

[0092] Ring B is a 5- or 6-membered heteroaryl optionally substituted with one to three RB; or a 5-x1

[0093] X3I

[0094] membered heterocyclyl of formula x4y '; wherein:

[0095] X1is O, S, NH, NRA, CH2, or CHRB;

[0096] one of X2and X3is C(O); and the other of X2and X3is 0, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0097] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0098] each RAis independently selected from cyano, C1.3 alkyl, and C1-3 haloalkyl; wherein each C1.3 alkyl of RAis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0099] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1.3 haloalkyl, C1-3 alkoxy, C1.3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1.3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1.3 alkoxy;ACCG-0008-WO L2is a bond, -O-, -S-, -NR2a-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR2a-, -NR2aC(O)-, -OC(O)NR2a-, -NR2aC(O)O-, -NR2aC(O)NR2b-, -S(O)-, -S(O)2-, -S(O)NR2a-, -S(O)2NR2a-, -NR2aS(O)-, -NR2aS(O)2-, -NR2aS(O)NR2b-, -NR2aS(O)2NR2b-, Ci-6 alkylene, C2-6 alkenylene, C2.g alkynylene, Ci-6 heteroalkylene, C3-6 cycloalkylene, 4-6 membered heterocyclylene, or 5 membered heteroarylene; wherein the CM alkylene, C2.3 alkenylene, C2.3 alkynylene, C1-3 heteroalkylene, C3-6 cycloalkylene, 4-6 membered heterocyclylene, or 5 membered heteroarylene of L2is independently optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;

[0100] R1is cyano, -C(O)NRlaRlb, -C(S)NRlaRlb, -S(O)2R2, -S(O)(NR6)R2, or -P(O)R7R2;

[0101] R2is -NRlaRlb, C1-6 alkyl, C2.6alkenyl, CM alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R2is optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C22alkenyl, CM alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy; each Rlaand Rlbis independently hydrogen, C1-3 alkyl, CM alkenyl, CM alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4-6 membered heterocyclyl; wherein each C1-3 alkyl, CM alkenyl. CM alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4-6 membered heterocyclyl of Rlaand Rlbis independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, CM alkyl, CM alkenyl, CM alkynyl, C haloalkyl, C alkoxy, or C haloalkoxy;

[0102] or Rlaand Rlbare taken together with the atoms to which they are attached to form 4-6 membered heterocyclyl independently optionally substituted by one to five substituents independently selected from halo, hydroxy, cyano, C alkyl, CM alkenyl, CM alkynyl, C haloalkyl, C alkoxy, or C haloalkoxy;

[0103] or R2and R6, or R2and R7, together with the atom to which they are attached, form a heterocyclyl optionally substituted with one to five Z2;

[0104] or R1is Y1; R3is Y3; and Y1and Y3, together with Y2and carbon atoms to which R1and R3are

[0105] attached, form a heterocyclyl of formula

[0106]

[0107] ; wherein:

[0108] • Y1is -C(O)-, -C(S)-, -S(O)2-, -S(O)(NR6)-, or -P(O)(R7)-;

[0109] Y2is -O-, -S-, -NR12-, or -C(R12)2-; wherein the bond between Y1and Y2is a single bond; andACCG-0008-WO Y3is -NR8-, -0-, -S-, -C(R9)2-, -NR8-C(R9)2-, -O-C(R9)2-, -S-C(R9)2-, -C(R9a)2-C(R9a)2-, - C(R9a)2-C(R9a)2-C(R9a)2-, or -CR9=CR9-; or

[0110] • Y1is -C(O)-, -C(S)-, -S(O)2-, -S(O)(NR6)-, or -P(O)(R7)-;

[0111] Y2is -N- or -CR12-, and

[0112] Y3is -N- or -CR9-; wherein the bond between Y2and Y3is a double bond; or

[0113] • Y1is -N- or -CR11-;

[0114] Y2is -N- or -CR12-; wherein the bond between Y1and Y2is a double bond; and

[0115] Y3is -NR8-, -O-, or -S-;

[0116] provided that the ring comprising Y1, Y2, and Y3contains at least one heteroatom;

[0117] each R2aand R2bis independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R2aand R2bis independently optionally substituted with one to five Z2a;

[0118] or R2aand R2bare taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Z2a;

[0119] R3is hydrogen, -NR3bR3c, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Ci-e alkoxy, Ci-e haloalkoxy, Ci-e heteroalkyl, Ci-s haloalkyl, Ci-e haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2.g alkynyl, Ci-6 haloalkyl, C1-6 alkoxy, C1-6 heteroalkyl, Ci-e haloalkyl, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R3is independently optionally substituted with one to five Z3;

[0120] R3band R3care each independently hydrogen, C1-6 alkyl, C2-e alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R3band R3cis independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1.3 alkoxy, and C1.3 haloalkoxy;

[0121] or R3band R3care taken together with the nitrogen atom to which they are attached to form a heterocyclyl optionally substituted with one to five Z3b;

[0122] R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;ACCG-0008-WO R5is hydrogen, halo, hydroxy, amino, cyano, Ci-6 alkyl, Ci-6 alkoxy, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R5is independently optionally substituted with one to five Z5;

[0123] R6is hydrogen, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl; wherein the C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1.3 alkoxy, and C1-3 haloalkoxy;

[0124] R7is hydroxy, C1.3 alkoxy, C1.3 haloalkoxy, C1.3 alkyl, or C1.3 haloalkyl;

[0125] R8is hydrogen, -S(O)2-Ci-3 alkyl, -S(O)2-Ci-3 haloalkyl, C1-3 alkyl, C1-3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl; wherein the -S(O)2-Ci-3 alkyl, -S(O)2-Ci-3 haloalkyl, C1.3 alkyl, C1.3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl of R8is optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and Ci -3 haloalkoxy;

[0126] each R9is independently hydrogen, hydroxy, -NR9bR9c, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R9is independently optionally substituted with one to five Z9;

[0127] or two R9, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C310 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z9;

[0128] or two R9, together with the carbon atom to which both are attached, form an oxo;

[0129] each R9ais independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, Ci.g alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C1-6 alkoxy, Ci-e haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R9ais independently optionally substituted with one to five Z9a;

[0130] or two R9a, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z9a;

[0131] or two R9a, together with the carbon atom to which both are attached, form an oxo;ACCG-0008-WO R11is hydrogen, halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;

[0132] each R12is independently hydrogen, C1.3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl; wherein each C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl of R12is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1.3 haloalkoxy;

[0133] or R12and any one or two of R6, R7, R8, R9, R9a, and R11, together with the atoms to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z12;

[0134] each ZA, Z2, Z2a, Z3, Z3b, Z4, Z5, Z9, Z9a, and Z12; is independently halo, cyano, nitro, oxo, =CF2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z2, Z2a, Z3, Z3b, Z4, Z5, Z9, Z9a, and Z12are each independently optionally substituted with one to five Zla;

[0135] each L is independently -O-, -S-, -NR20-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;

[0136] each R20and R21is independently hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0137] each Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C1-6 alkyl, -N(C1-6alkyl)2, -S-C1-6alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-C1-6alkyl, -N(C1-6alkyl)2, -S-C1-6alkyl, C1-6alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;ACCG-0008-WO provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; and

[0138] provided that when A is C1-6 alkylene; then R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted.

[0139] In some embodiments, provided is a compound of Formula I:

[0140]

[0141] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein A, Ring B, L2, R1, R3, R4, and R5, are each independently as defined herein.

[0142] In some embodiments, provided is a compound of Formula I:

[0143] R5

[0144]

[0145] I

[0146] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0147] A is C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, heterocyclylene, arylene, or heteroarylene; wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, heterocyclylene, arylene, or heteroaryl of A is independently optionally substituted with one to five ZA;

[0148] Ring B is a 5- or 6-membered heteroaryl optionally substituted with one to three RB; or a 5- x1

[0149] X3I

[0150] membered heterocyclyl of formula '; wherein:

[0151] X1is O, S, NH, NRA, CH2, or CHRB;ACCG-0008-WO one of X2and X3is C(O); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0152] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0153] each RAis independently selected from cyano, C1-3 alkyl, and C1-3 haloalkyl; wherein each C1-3 alkyl of RAis independently optionally substituted with -NH2, -NHC1.3 alkyl, -N(CM alkyl)2, hydroxy, or C1-3 alkoxy;

[0154] each RBis independently selected from halo, hydroxy, -NH2, cyano, CM alkyl, C haloalkyl, CM alkoxy, CM haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CM alkyl)2, hydroxy, or C1-3 alkoxy;

[0155] L2is a bond, -O-, -S-, -NR2a-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR2a-, -NR2aC(O)-, -OC(O)NR2a-, -NR2aC(O)O-, -NR2aC(O)NR2b-, -S(O)-, -S(O)2-, -S(O)NR2a-, -S(O)2NR2a-, -NR2aS(O)-, -NR2aS(O)2-, -NR2aS(O)NR2b-, -NR2aS(O)2NR2b-, C1-6 alkylene, C2-6 alkenylene, CM alkynylene, C1-6 heteroalkylene, C3-6 cycloalkylene, 4-6 membered heterocyclylene, or 5 membered heteroarylene; wherein the C alkylene, C2.3 alkenylene, C2.3 alkynylene, CM heteroalkylene, C3-6 cycloalkylene, 4-6 membered heterocyclylene, or 5 membered heteroarylene of L2is independently optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, -NH2, -NHC1-3 alkyl, -N(Ci-3 alkyl)2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;

[0156] R1is cyano, -C(O)NRlaRlb, -C(S)NRlaRlb, -S(O)2R2, -S(O)(NR6)R2, or -P(O)R7R2;

[0157] R2is -NRlaRlb, C1-6 alkyl, C2-6 alkenyl, C alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the Ci-e alkyl, CM alkenyl, C2-e alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R2is optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, CM alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy; each Rlaand Rlbis independently hydrogen, C1-3 alkyl, CM alkenyl, CM alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4-6 membered heterocyclyl; wherein each C1-3 alkyl, CM alkenyl, CM alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4-6 membered heterocyclyl of Rlaand Rlbis independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, CM alkyl, C alkenyl, CM alkynyl, C1-3 haloalkyl, CM alkoxy, or C haloalkoxy;

[0158] or Rlaand Rlbare taken together with the atoms to which they are attached to form 4-6 membered heterocyclyl independently optionally substituted by one to five substituents independently selected from halo, hydroxy, cyano, CM alkyl, CM alkenyl, CM alkynyl, C haloalkyl, CM alkoxy, or C haloalkoxy;

[0159] or R2and R6, or R2and R7, together with the atom to which they are attached, form a heterocyclylACCG-0008-WO optionally substituted with one to five Z2;

[0160] or R1is Y1; R3is Y3; and Y1and Y3, together with Y2and carbon atoms to which R1and R3are

[0161] attached, form a heterocyclyl of formula

[0162]

[0163] ; wherein:

[0164] • Y1is -C(0)-, -C(S)-, -S(0)2-, -S(O)(NR6)-, or -P(O)(R7)-;

[0165] Y2is -O-, -S-, -NR12-, or -C(R12)2-; wherein the bond between Y1and Y2is a single bond; and Y3is -NR8-, -O-, -S-, -C(R9)2-, -NR8-C(R9)2-, -O-C(R9)2-, -S-C(R9)2-, -C(R9a)2-Ca(R9a)2-, -C(R9a)2- C(R9a)2-C(R9a)2-, or -CR9=CR9-; or

[0166] • Y1is -C(O)-, -C(S)-, -S(O)2-, -S(O)(NR6)-, or -P(O)(R7)-;

[0167] Y2is -N- or -CR12-, and

[0168] Y3is -N- or -CR9-; wherein the bond between Y2and Y3is a double bond; or

[0169] • Y1is -N- or -CR11-;

[0170] Y2is -N- or -CR12-; wherein the bond between Y1and Y2is a double bond; and

[0171] Y3is -NR8-, -O-, or -S-;

[0172] provided that the ring comprising Y1, Y2, and Y3contains at least one heteroatom;

[0173] each R2aand R2bis independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R2aand R2bis independently optionally substituted with one to five Z2a;

[0174] or R2aand R2bare taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Z2a;

[0175] R3is hydrogen, -NR3bR3c, C1-6 alkyl, C2-e alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, Ci-e alkoxy, Ci-e haloalkoxy, Ci-6 heteroalkyl, Ci-s haloalkyl, Ci-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the Ci-c alkyl, C2-e alkenyl, C2-c alkynyl, Ci-6 haloalkyl, Ci-c alkoxy, Ci-6 heteroalkyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R3is independently optionally substituted with one to five Z3;

[0176] R3band R3care each independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2.& alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R3band R3cis independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;ACCG-0008-WO or R3band R3care taken together with the nitrogen atom to which they are attached to form a heterocyclyl optionally substituted with one to five Z3b;

[0177] R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;

[0178] R5is hydrogen, halo, hydroxy, amino, cyano, C1-6 alkyl, C1-6 alkoxy, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R5is independently optionally substituted with one to five Z3;

[0179] R6is hydrogen, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl; wherein the C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1.3 alkyl, C1-3 haloalkyl, C1.3 alkoxy, and C1-3 haloalkoxy;

[0180] R7is hydroxy, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, or C1-3 haloalkyl;

[0181] R8is hydrogen, -S(O)2-Ci-3 alkyl, -S(O)2-Ci-3 haloalkyl, C1-3 alkyl, C1-3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl; wherein the -S(O)2-Ci-3 alkyl, -S(O)2-Ci-3 haloalkyl, C1-3 alkyl, C1-3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl of R8is optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and Ci -3 haloalkoxy;

[0182] each R9is independently hydrogen, hydroxy, -NR9bR9c, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R9is independently optionally substituted with one to five Z9;

[0183] or two R9, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z9;

[0184] or two R9, together with the carbon atom to which both are attached, form an oxo;

[0185] each R9ais independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, Ci-e haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, Ci-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R9ais independently optionally substituted with one to five Z9a;ACCG-0008-WO or two R9a, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z9a;

[0186] or two R9a, together with the carbon atom to which both are attached, form an oxo;

[0187] R11is hydrogen, halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;

[0188] each R12is independently hydrogen, C1.3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl; wherein each C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl of R12is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1.3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1.3 haloalkyl, C1-3 alkoxy, or C1.3 haloalkoxy;

[0189] or R12and any one or two of R6, R7, R8, R9, R9a, and R11, together with the atoms to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to li ve Z12;

[0190] each ZA, Z2, Z2a, Z3, Z3b, Z4, Z5, Z9, Z9a, and Z12; is independently halo, cyano, nitro, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-II, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z2, Z2a, Z3, Z3b, Z4, Z5, Z9, Z9a, and Z12are each independently optionally substituted with one to five Zla;

[0191] each L is independently -O-, -S-, -NR20-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;

[0192] each R20and R21is independently hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0193] each Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C1-6 alkyl, -N(CI-6 alkylfi, -S-Ci-e alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10ACCG-0008-WO cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-Ci-e alkyl, -N(Ci-e alkyl)2, -S-Ci-e alkyl, Ci-6 alkoxy, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;

[0194] provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0195] In some embodiments, when A is C1-6 alkylene; then R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted.

[0196] In some embodiments, when Ring B is unsubstituted thiophenyl, then -A-L2-R5is not unsubstituted thiophcnyl or unsubstituted phenyl.

[0197] In some embodiments, provided is a compound of Formula II:

[0198]

[0199] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, L2, R3, R4, and R5are each independently as defined herein.

[0200] In some embodiments, R3is isobutyl or cyclopropylmethyl.

[0201] In some embodiments, provided is a compound of Formula III:

[0202] R5

[0203] I

[0204] ( B ) y1

[0205]

[0206] R4jr 'fFO Y3 2In

[0207] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, Y1, Y2, Y3, L2, R4, and R3are each independently as defined herein.In some embodiments, provided is a compound of Formula IIIA or IIIB:

[0208] R5

[0209]

[0210] IIIA

[0211] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, Y2, Y3, L2, R12, R4, and R3are each independently as defined herein.

[0212] In some embodiments, provided is a compound of Formula IIIA:

[0213]

[0214] IIIA

[0215] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, Y3, L2, R12, R4, and R5are each independently as defined herein.

[0216] In some embodiments, provided is a compound of Formula IIIB:

[0217]

[0218] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, Y2, Y\ L2, R4, and R5are each independently as defined herein.

[0219] In some embodiments, Y3is -NR8- or -C(R9)2-.

[0220] In some embodiments, R12is hydrogen; and Y3is -C(R9)2-.

[0221] In some embodiments, R12and R8, or R12and one or two R9, together with the atoms to which they are attached, form a C3-10 cycloalkyl or heterocyclyl; wherein the C3-10 cycloalkyl or heterocyclyl is optionally substituted with one to five Z12.

[0222] In some embodiments, provided is a compound of Formula IIIC:or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, Z12, L2, R4, and R5are each independently as defined herein.

[0223] In some embodiments, provided is a compound of Formula IIID:

[0224]

[0225] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, Z12, L2, R4, and R are each independently as defined herein.

[0226] In some embodiments, provided is a compound of Formula IIIE:

[0227]

[0228] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, L2, R4, and R5are each independently as defined herein.

[0229] In some embodiments, provided is a compound of Formula IIIEa:

[0230] R5

[0231]

[0232] IIIEaACCG-0008-WQ or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, Z12, L2, R4, and R5are each independently as defined herein.

[0233] In some embodiments, provided is a compound of Formula IIIF:

[0234] R5

[0235]

[0236] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, L2, R4, and R5are each independently as defined herein.

[0237] In some embodiments, provided is a compound of Formula ITIG:

[0238] R5

[0239]

[0240] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, L2, R4, and R5are each independently as defined herein.

[0241] In some embodiments, provided is a compound of Formula IIIH:

[0242]

[0243] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B, A, L2, R4, and R5are each independently as defined herein.

[0244] In some embodiments, A is Ci-6 alkylene, C3-10 cycloalkylene, heterocyclylene, arylene, or heteroarylene; wherein the Ci-6 alkylene, C3-10 cycloalkylene, heterocyclylene, arylene, or heteroarylene of A is independently optionally substituted with one to five ZA.ACCG-0008-WO In some embodiments, A is C3-10 cycloalkylene, heterocyclylene, arylene, or heteroarylene; wherein C3-10 cycloalkylene, heterocyclylene, arylene, or heteroarylene of A is independently optionally substituted with one to five ZA.

[0245] In some embodiments, A is C3-10 cycloalkylene or 3 to 10-membered heterocyclylene; wherein the cycloalkylene or heterocyclylene is optionally substituted with one to five ZA.

[0246] In some embodiments, A is arylene or heteroarylene; wherein the arylene or heteroarylene is optionally substituted with one to five ZA.

[0247] In some embodiments, A is heterocyclylene or heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA.

[0248] In some embodiments, A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA.

[0249] In some embodiments, A is arylene optionally substituted with one to five ZA.

[0250] In some embodiments, A is heteroarylene optionally substituted with one to five ZA.

[0251] In some embodiments, A is C3-10 cycloalkylene optionally substituted with one to five ZA.

[0252] In some embodiments, A is 3 to 10-membered heterocyclylene optionally substituted with one to five ZA.

[0253] In some embodiments, each ZAis independently halo or Ci-6 alkyl.

[0254] In some embodiments, A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA; wherein each ZAis independently halo or Ci-6 alkyl.

[0255] NaN

[0256] a

[0257] s

[0258] In some embodiments, Ring A

[0259]

[0260] is; wherein each is independently optionally substituted with one to three substituents independently selected from halo and Ci-6 alkyl; and wherein bond a is bonded to L2.ACCG-0008-WO

[0261] In some embodiments, Ring A

[0262]

[0263] is CH; Y is N or CH; R8aand R8bare each independently selected from hydrogen and ZA; and ZAand Z5are each independently as defined herein.

[0264] In some embodiments, R8aand R8bare each independently selected from hydrogen, halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1.3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1.3 alkoxy.

[0265] In some embodiments, R8aand R8bare each independently selected from hydrogen, halo, and C1.3 alkyl.

[0266] In some embodiments, R8aand R8bare each independently selected from halo and C1-3 alkyl. In some embodiments, R8aand R8bare each independently selected from fluoro and methyl. In some embodiments, L2is -CH2-, -NH-, or -NHCH2-.

[0267] In some embodiments, R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

[0268] In some embodiments, R5is C3-10 cycloalkyl optionally substituted with one to three Z5.

[0269] In some embodiments, R5is heterocyclyl optionally substituted with one to three Z5.

[0270] In some embodiments, R5is aryl optionally substituted with one to three Z5.

[0271] In some embodiments, R5is heteroaryl optionally substituted with one to three Z5.

[0272] In some embodiments, R5is 2,3-dihydro-lH-indenyl, 6,7-dihydro-5H-cyclopenta[blpyridinyl, phenyl, pyridyl, or pyrimidinyl; wherein each is optionally substituted with one to three substituents independently selected from halo, cyano, and -O-Ci-g alkyl.

[0273] In some embodiments, Ring B is a 5-membered heteroaryl optionally substituted with RB.

[0274] In some embodiments, Ring B is 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-oxadiazolyl; wherein each is optionally substituted with C1.3 alkyl or cyclopropyl.In some embodiments, Ring B is 1,3,4-oxadiazolyl optionally substituted with C1.3 alkyl or cyclopropyl.

[0275] In some embodiments, Ring B is

[0276]

[0277] wherein each is optionally substituted with RB.

[0278] optionall

[0279]

[0280] y substituted with RB

[0281] RB

[0282]

[0283] In some embodiments, Ring B is

[0284] In some embodiments, Ring B is a 5-membered heterocyclyl of formula

[0285]

[0286] In some embodiments, Ring

[0287]

[0288] B isIn some embodiments, RBis hydrogen, cyano, C1.3 alkyl, C1-3 haloalkyl, C1.3 alkoxy, C1-3 haloalkoxy, and cyclopropyl.

[0289] In some embodiments, RBis methyl.

[0290] In some embodiments, R4is C7-10 cycloalkyl, 7- to 10-membered heterocyclyl, aryl, or heteroaryl; wherein the C7-10 cycloalkyl, 7- to 10-membered heterocyclyl, aryl, or heteroaryl, aryl, or heteroaryl is optionally substituted with one to five Z4.

[0291]

[0292] five Z4.

[0293]

[0294] ACCG-0008-WO

[0295]

[0296] optionally substituted with one to five Z4.

[0297] In some embodiments, A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA;

[0298] Ring B is a 5-membered heteroaryl optionally substituted with RB; or a 5-membered heterocyclyl Ax1

[0299] I

[0300] of formula

[0301]

[0302] '; wherein:

[0303] X1is O, S, NH, NRA, CH2, or CHRB;

[0304] one of X2and X3is C(O); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0305] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0306] each RAis independently selected from cyano, C1-3 alkyl, and C1-3 haloalkyl; wherein each C1-3 alkyl of RAis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0307] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1.3 alkyl, -N(Ci-3 alkyl)2, hydroxy, or C1.3 alkoxy;L2is -CH2-, -NH-, or -NHCH2-;

[0308] R1is -C(O)NR,aRlb;

[0309] each Rlaand Rlbis independently hydrogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4-6 membered heterocyclyl; wherein each C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4-6 membered heterocyclyl of Rlaand Rlbis independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;

[0310] or Rlaand Rlbare taken together with the atoms to which they are attached to form 4-6 membered heterocyclyl independently optionally substituted by one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1.3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;

[0311] or R1is Y1; R3is Y3; and Y1and Y3, together with Y2and carbon atoms to which R1and R3are

[0312]

[0313] C V 'CY3

[0314] attached, form a heterocyclyl of formulav; wherein:

[0315] Y1is -C(O)- or -S(O)2-;

[0316] Y2is -NR12- or -C(R12)2-; and

[0317] Y3is -NR8- or -C(R9)2-;

[0318] provided that the ring comprising Y1, Y2, and Y3contains at least one heteroatom;

[0319] R3is C1-6 alkyl;

[0320] R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;

[0321] R' is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

[0322] R8is hydrogen, -S(O)2-Ci 3 alkyl, -S(O)2-Ci 3 haloalkyl, C1-3 alkyl, C1-3 haloalkyl C36 cycloalkyl, or 4 to 6-membered heterocyclyl; wherein the -S(O)2-Ci-3 alkyl, -S(O)2-Ci-3 haloalkyl, C1.3 alkyl, C1-3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl of R8is optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and Ci -3 haloalkoxy;

[0323] each R9is independently hydrogen, hydroxy, -NR9bR9c, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e alkoxy, Ci-s heteroalkyl, Ci-e haloalkyl, Ci-s haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R9is independently optionally substitutedACCG-0008-WO with one to five Z9;

[0324] or two R9, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z9;

[0325] or two R9, together with the carbon atom to which both are attached, form an oxo;

[0326] each R9ais independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Ci-s alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R9ais independently optionally substituted with one to five Z9a;

[0327] or two R9a, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z9a;

[0328] or two R9a, together with the carbon atom to which both are attached, form an oxo;

[0329] each R12is independently hydrogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl; wherein each C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl of R12is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1.3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;

[0330] or R12and any one or two of R8, R9, and R9a, together with the atoms to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z12;

[0331] each ZA, Z2, Z3, Z4, Z5, Z9, Z9a, and Z12; is independently halo, cyano, nitro, oxo, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-Ci-s alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z2, Z3, Z4, Z5, Z9, Z9a, and Z12are each independently optionally substituted with one to five Zla;

[0332] each L is independently -O-, -S-, -NR20-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;ACCG-0008-WO each R20and R21is independently hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0333] each Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;

[0334] provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0335] In some embodiments, A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA;

[0336] Ring B is a 5-membered heteroaryl optionally substituted with RB; or a 5-membered heterocyclyl X< 1

[0337] X3, I

[0338] of formula

[0339]

[0340] '; wherein:

[0341] X1is O, S, NH, NRA, CH2, or CHRB;

[0342] one of X2and X3is C(O); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0343] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0344] each RAis independently selected from cyano, C1.3 alkyl, and C1-3 haloalkyl; wherein each C1.3 alkyl of RAis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0345] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1.3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1.3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;L2is -CH2-, -NH-, or -NHCH2-;

[0346] R1is -C(O)NR,aRlb;

[0347] each Rlaand Rlbis independently hydrogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4-6 membered heterocyclyl; wherein each C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4-6 membered heterocyclyl of Rlaand Rlbis independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;

[0348] or Rlaand Rlbare taken together with the atoms to which they are attached to form 4-6 membered heterocyclyl independently optionally substituted by one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1.3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;

[0349] or R1is Y1; R3is Y3; and Y1and Y3, together with Y2and carbon atoms to which R1and R3are

[0350] V 'Y3-'

[0351] attached, form a heterocyclyl of formula; wherein:

[0352] Y1is -C(O)- or -S(O)2-;

[0353] Y2is -NR12- or -C(R12)2-; and

[0354] Y3is -NR8- or -C(R9)2-;

[0355] provided that the ring comprising Y1, Y2, and Y3contains at least one heteroatom;

[0356] R3is C1-6 alkyl;

[0357] R4is C7-10 cycloalkyl, 7- to 10-membered heterocyclyl, aryl, or heteroaryl; wherein the C7-10 cycloalkyl, 7- to 10-membered heterocyclyl, aryl, or heteroaryl, aryl, or heteroaryl is optionally substituted with one to five Z4;

[0358] R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

[0359] R8is hydrogen, -S(O)2-Ci-3 alkyl, -S(O)2-Ci-3 haloalkyl, C1-3 alkyl, C1-3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl; wherein the -S(O)2-Ci-3 alkyl, -S(O)2-Ci-3 haloalkyl, C1-3 alkyl, C1-3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl of R8is optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;

[0360] each R9is independently hydrogen, hydroxy, -NR9bR9c, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, Ci-e heteroalkyl, Ci-e haloalkyl, Ci-e haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-g heteroalkyl, C1-6 haloalkyl, Ci-gACCG-0008-WO haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R9is independently optionally substituted with one to five Z9;

[0361] or two R9, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z9;

[0362] or two R9, together with the carbon atom to which both are attached, form an oxo;

[0363] each R9ais independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, Ci-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R9ais independently optionally substituted with one to five Z9a;

[0364] or two R9a, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z9a;

[0365] or two R9a, together with the carbon atom to which both are attached, form an oxo;

[0366] each R12is independently hydrogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl; wherein each C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl of R12is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;

[0367] or R12and any one or two of R8, R9, and R9a, together with the atoms to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z12;

[0368] each ZA, Z2, Z3, Z4, Z5, Z9, Z9a, and Z12; is independently halo, cyano, nitro, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-Ci-s alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-c haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or hctcroaryl of ZA, Z2, Z3, Z4, Z5, Z9, Z9a, and Z12arc each independently optionally substituted with one to five Zla;ACCG-0008-WO each L is independently -O-, -S-, -NR20-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;

[0369] each R20and R2’ is independently hydrogen, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0370] each Z1ais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C1-6alkyl, -N(C1-6alkyl)2, -S-C1-6 alkyl, C1-6alkoxy, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-C1-6alkyl, -N(C1-6alkyl)2, -S-C1-6alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;

[0371] provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0372] In some embodiments, provided is a compound of Formula IIIC:

[0373] R5

[0374]

[0375] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0376] A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or hctcroarylcnc is optionally substituted with one to five ZA;

[0377] Ring B is a 5-membered heteroaryl optionally substituted with RB; or a 5-membered heterocyclylACCG-0008-WO

[0378] of formula

[0379]

[0380] ; wherein:

[0381] X1is O, S, NH, NRA, CH2, or CHRB;

[0382] one of X2and X3is C(O); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0383] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0384] each RAis independently selected from cyano, C1-3 alkyl, and C1-3 haloalkyl; wherein each C1-3 alkyl of RAis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0385] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1.3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(Ci-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0386] L2is -CH2-, -NH-, or -NHCH2-;

[0387] R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;

[0388] R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

[0389] each ZA, Z4, Z5, and Z12is independently halo, cyano, nitro, oxo, Ci-e alkyl, C2.e alkenyl, C2.e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-Ci-e alkyl,

[0390] -L-C2-6 alkenyl, -L-C2-e alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-hctcrocyclyl, -L-aryl, or -L-heteroaryl; wherein each C1-6 alkyl, C2-e alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z4, Z\ and Z12are each independently optionally substituted with one to five Zla;

[0391] each L is independently -O-, -S-, -NR20-, -CIO)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;

[0392] each R20and R21is independently hydrogen, C1-6alkyl, C2.e alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-e alkenyl, C2.g alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionallyACCG-0008-WO substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Z1a; and

[0393] each Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-Ci-e alkyl, -N(Ci-s alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;

[0394] provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted Ci-g alkyl, unsubsliluled or subsliluled C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or subsliluled aryl, or unsubstituted or substituted heteroaryl.

[0395] In some embodiments, provided is a compound of Formula HID:

[0396]

[0397] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0398] A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA;

[0399] Ring B is a 5-membered heteroaryl optionally substituted with RB; or a 5-membered heterocyclyl

[0400] X=.

[0401] of formula '; wherein:

[0402] X1is O, S, NH, NRA, CH2, or CHRB;

[0403] one of X2and X3is C(O); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0404] provided that at least one of X1, X2, X3, and X4is a heteroatom;ACCG-0008-WO each RAis independently selected from cyano, C1-3 alkyl, and C1-3 haloalkyl; wherein each C1-3 alkyl of RAis independently optionally substituted with -NH2, -NHC1.3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0405] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0406] L2is -CH2-, -NH-, or -NHCH2-;

[0407] R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;

[0408] R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

[0409] each ZA, Z4, Z5, and Z12is independently halo, cyano, nitro, oxo, Ci-c alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-Ci-e alkyl,

[0410] -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z4, Z3, and Z12are each independently optionally substituted with one to five Zla;

[0411] each L is independently -O-, -S-, -NR20-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;

[0412] each R20and R21is independently hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0413] each Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C1-6 alkyl, -N(C1-6alkyl)2, -S-C1-6alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-Ci-e alkyl, -N(Ci-e alkyl)-. -S-Ci-g alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;ACCG-0008-WO provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0414] In some embodiments, provided is a compound of Formula IIIE:

[0415] R5

[0416]

[0417] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0418] A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA;

[0419] Ring B is a 5-membered heteroaryl optionally substituted with RB; or a 5-membered heterocyclyl x1

[0420] X’

[0421] X4^\ /

[0422] of formula '; wherein:

[0423] X1is O, S, NH, NRA, CH2, or CHRB;

[0424] one of X2and X3is C(O); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0425] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0426] each RAis independently selected from cyano, C1.3 alkyl, and C1-3 haloalkyl; wherein each C1.3 alkyl of RAis independently optionally substituted with -NH2, -NHC1.3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0427] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1.3 haloalkyl, C1-3 alkoxy, C1.3 haloalkoxy, and cyclopropyl; wherein each C1.3 alkyl of RBis independently optionally substituted with -NH2, -NHC1.3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0428] L2is -CH2-, -NH-, or -NHCH2-;ACCG-0008-WO R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;

[0429] R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

[0430] each ZA, Z4, Z5, and Z12is independently halo, cyano, nitro, oxo, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-C1-6alkyl,

[0431] -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z4, Z5, and Z12are each independently optionally substituted with one to five Zla;

[0432] each L is independently -O-, -S-, -NR20-, -CIO)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;

[0433] each R20and R21is independently hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0434] each Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;

[0435] provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0436] In some embodiments, provided is a compound of Formula IIIEa:ACCG-0008-WO

[0437]

[0438] IIIEa

[0439] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0440] A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA;

[0441] Ring B is a 5-membered heteroaryl optionally substituted with RB; or a 5-membered heterocyclyl

[0442] of formula

[0443]

[0444] ; wherein:

[0445] X1is O, S, NH, NRA, CH2, or CHRB;

[0446] one of X2and X3is C(O); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0447] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0448] each RAis independently selected from cyano, C1-3 alkyl, and C1-3 haloalkyl; wherein each C1-3 alkyl of RAis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0449] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(Ci-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0450] L2is -CH2-, -NH-, or -NHCH2-;

[0451] R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;

[0452] R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

[0453] each ZA, Z4, and Z5is independently halo, cyano, nitro, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-C1-6 alkyl,ACCG-0008-WO -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z4, and Z5are each independently optionally substituted with one to five Zla;

[0454] each L is independently -O-, -S-, -NR20-, -C(O)-, -C(O)O-, -00(0)-, -00(0)0-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(0)-, -S(0)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;

[0455] each R20and R21is independently hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0456] each Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-Ci-e alkyl, -N(CI-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;

[0457] provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0458] In some embodiments, provided is a compound of Formula IIIEb:

[0459]

[0460] F IIIEbACCG-0008-WO or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0461] n is 0, 1, or 2;

[0462] X is N or CH;

[0463] Y is N or CH;

[0464] Ring B is a 5-membered heteroaryl optionally substituted with RB; or a 5-membered heterocyclyl

[0465] of formula

[0466]

[0467] ; wherein:

[0468] X1is O, S, NH, NRA, CH2, or CHRB;

[0469] one of X2and X3is C(O); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0470] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0471] each RAis independently selected from cyano, C1-3 alkyl, and C1-3 haloalkyl; wherein each C1-3 alkyl of RAis independently optionally substituted with -NH2, -NHC1.3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0472] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0473] R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;

[0474] R8aand R8bare each independently selected from hydrogen and ZA;

[0475] each ZA, Z4, Z5, and Z12is independently halo, cyano, nitro, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-C1-6 alkyl,

[0476] -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each Ci-e alkyl, C2-6 alkenyl, C2-e alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z4, Z5, and Z12are each independently optionally substituted with one to five Zla;ACCG-0008-WO each L is independently -O-, -S-, -NR20-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;

[0477] each R20and R2’ is independently hydrogen, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0478] each Z1ais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C1-6alkyl, -N(C1-6alkyl)2, -S-C1-6 alkyl, C1-6alkoxy, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-C1-6alkyl, -N(C1-6alkyl)2, -S-C1-6alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;

[0479] provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0480] In some embodiments, R8aand R8bare each independently selected from hydrogen, halo, hydroxy, -NH2, cyano, C1.3 alkyl, C1-3 haloalkyl, C1.3 alkoxy, C1.3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy.

[0481] In some embodiments, R8aand R8bare each independently selected from hydrogen, halo, and C1.3 alkyl.

[0482] In some embodiments, R8aand R8bare each independently selected from halo and C1-3 alkyl. In some embodiments, R8aand R8bare each independently selected from fluoro and methyl. In some embodiments, provided is a compound of Formula IV:ACCG-0008-WO

[0483]

[0484] F FIV

[0485] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0486] n is 0, 1, or 2;

[0487] X is N or CH;

[0488] Y is N or CH;

[0489] N., N N

[0490] Ring B

[0491]

[0492] is optionally substituted with RB;

[0493] R4ais hydrogen, halo, C1.3 alkyl, C1.3 haloalkyl, or cyclopropyl;

[0494] each Z5is independently halo or cyano; and

[0495] RBis cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl.

[0496] In some embodiments, provided is a compound of Formula IV:

[0497]

[0498] ACCG-0008-WO or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0499] n is 0, 1, or 2;

[0500] X is N or CH;

[0501] Y is N or CH;

[0502] Ring B is

[0503]

[0504] wherein each is optionally substituted with RB; R41is hydrogen, halo, C1-3 alkyl, C1-3 haloalkyl, or cyclopropyl;

[0505] each Z5is independently halo or cyano; and

[0506] RBis cyano, C1-3 alkyl, C1.3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl.

[0507] In some embodiments, Ring

[0508]

[0509] B is

[0510] In some embodiments, X and Y are N.

[0511] In some embodiments, X and Y are CH.

[0512] In some embodiments, provided is a compound of Formula V:

[0513]

[0514] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0515] R4ais hydrogen, halo, C1.3 alkyl, C1.3 haloalkyl, or cyclopropyl; andRBis hydrogen, cyano, C1.3 alkyl, C1-3 haloalkyl, C1.3 alkoxy, C1-3 haloalkoxy, and cyclopropyl. In some embodiments, RBis methyl.

[0516] In some embodiments, Zlais hydrogen or methyl.

[0517] In some embodiments, provided is a compound of Formula IIIF:

[0518]

[0519] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0520] A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA;

[0521] Ring B is a 5-membered heteroaryl optionally substituted with RB; or a 5-membered heterocyclyl x1

[0522] X’

[0523] of formula '; wherein:

[0524] X1is 0, S, NH, NRA, CH2, or CHRB;

[0525] one of X2and X3is C(0); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0526] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0527] each RAis independently selected from cyano, C1.3 alkyl, and C1-3 haloalkyl; wherein each C1.3 alkyl of RAis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or Ci-3 alkoxy;

[0528] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1.3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0529] L2is -CH2-, -NH-, or -NHCH2-;ACCG-0008-WO R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;

[0530] R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

[0531] each ZA, Z4, and Z3is independently halo, cyano, nitro, oxo, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-Ci-g alkyl,

[0532] -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z4, and Z5are each independently optionally substituted with one to five Zla;

[0533] each L is independently -O-, -S-, -NR20-, -CIO)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;

[0534] each R20and R21is independently hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-e alkenyl, C2-6 alkynyl, C e haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0535] each Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;

[0536] provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0537] In some embodiments, provided is a compound of Formula IIIG:ACCG-0008-WO

[0538] R5

[0539]

[0540] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:

[0541] A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA;

[0542] Ring B is a 5-membered heteroaryl optionally substituted with RB; or a 5-membered heterocyclyl

[0543] X= J.

[0544] of formula

[0545]

[0546] '; wherein:

[0547] X1is O, S, NH, NRA, CH2, or CHRB;

[0548] one of X2and X3is C(O); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0549] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0550] each RAis independently selected from cyano, C1-3 alkyl, and C1-3 haloalkyl; wherein each C1-3 alkyl of RAis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0551] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(Ci-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0552] L2is -CH2-, -NH-, or -NHCH2-;

[0553] R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;

[0554] R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

[0555] each ZA, Z4, and Z5is independently halo, cyano, nitro, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-C1-6 alkyl,ACCG-0008-WO -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z4, and Z5are each independently optionally substituted with one to five Zla;

[0556] each L is independently -O-, -S-, -NR20-, -C(O)-, -C(O)O-, -00(0)-, -00(0)0-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(0)-, -S(0)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;

[0557] each R20and R21is independently hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0558] each Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-Ci-e alkyl, -N(CI-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-C1-6 alkyl, -N(CI-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;

[0559] provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0560] In some embodiments, provided is a compound of Formula IIIH:

[0561] R5

[0562]

[0563] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:ACCG-0008-WO A is bicyclic heterocyclylene or bicyclic heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA;

[0564] Ring B is a 5-membered heteroaryl optionally substituted with RB; or a 5-membered heterocyclyl

[0565] of formula

[0566]

[0567] ; wherein:

[0568] X1is O, S, NH, NRA, CH2, or CHRB;

[0569] one of X2and X3is C(O); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;

[0570] provided that at least one of X1, X2, X3, and X4is a heteroatom;

[0571] each RAis independently selected from cyano, C1-3 alkyl, and C1-3 haloalkyl; wherein each C1-3 alkyl of RAis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0572] each RBis independently selected from halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;

[0573] L2is -CH2-, -NH-, or -NHCH2-;

[0574] R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;

[0575] R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

[0576] each ZA, Z4, and Z5is independently halo, cyano, nitro, oxo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-C1-6 alkyl,

[0577] -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z4, and Z5are each independently optionally substituted with one to five Zla;

[0578] each L is independently -O-, -S-, -NR20-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(O)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;each R20and R21is independently hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; and

[0579] each Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;

[0580] provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

[0581] In some embodiments, provided is compound selected from Table 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof:

[0582] Table 1

[0583]

[0584]

[0585] ACCG-0008-WO

[0586]

[0587]

[0588] No. Structure No. Structure

[0589] 0 V fvA Ck k Jk YjF113*

[0590] 10* ok 7 I / °

[0591] II 1N-iNY

[0592] Cl— \

[0593] first eluting isomer

[0594] Y O. k kk k ¥ jF_ / 'N V0

[0595] 114*

[0596] 11*0YXXK Ct

[0597] third eluting isomer second eluting isomer

[0598] 0. k. k JI Y jF12*

[0599] 115* -Y i i0

[0600] 0

[0601] second eluting isomer CIZ

[0602]

[0603] third eluting isomerACCG-0008-WO No. Structure No. Structure

[0604] y x

[0605] o. Y. Y X Y 's'i Y jF

[0606] 119*

[0607] 16* -Zl i ° X I JJ

[0608] y0y A^NXK Y ° (Yk

[0609] a second eluting isomer first eluting isomer 0

[0610] Y 's' i YfA

[0611] °x

[0612] 0 Yi ^

[0613] 12 * oF17*

[0614] y 'I I 7° A °Y I ' Y NX5,s0XA J / Y^NF^ yo

[0615] first eluting isomer

[0616] 0

[0617] Y ry Yffl °^ANY<CI

[0618] 121* r« I,?

[0619] 18* YY I? A LK

[0620] 0JLXJNY / Y V \ J Y~'YX~N'X'\, F^ yo

[0621] Cl— \ / J

[0622]

[0623] second eluting isomer

[0624]

[0625] first eluting isomerACCG-0008-WO No. Structure No. Structure

[0626] Oyk " A, °rS

[0627] 22* Al 1 / ? 126* A Y

[0628] Ji J L 1

[0629] / A^XN -. 1 / >■ PFpp>-0Cl —

[0630] first eluting isomer second eluting isomer

[0631] 0

[0632] A o. V A Y kA JL P p i °A AFoF

[0633] 23* _ pjf 0 127* JY x / ?

[0634] ''oppA

[0635] _ _ ° JL A X JI P / Nr

[0636] J

[0637] cl^p^ ° \ / y ( p '^ — J '-o first eluting isomer first P( e\= / =l / u)t Z'Z n -i / ng isome 0 — / / \ / . r

[0638] 0 / \ \ \

[0639] P o. AA kA JL P p

[0640] °A

[0641] OFd p °r Ai 24* _ Jr 0

[0642] 12 J'X x / ? / zF8*

[0643] 0 NA^PPYP

[0644] 1 NP X

[0645] . _ ZA ^P JI J

[0646] J / A ci—clpPpv° second eluting isomer

[0647] second eluting isomer 0

[0648] Fp p

[0649] °yK Npp

[0650] 25* PNI T / ? 129

[0651] ^oPPp

[0652] i pp

[0653] ATXN'X^PJ

[0654]

[0655] first eluting isomer

[0656]

[0657] ACCG-0008-WO No. Structure No. StructureN^CIoxANAA V° 0 1 J

[0658] 133

[0659] 30*NA A J * I

[0660] 'N1 JjNH° JLXTAci\ / N^ VFF

[0661] Cl second eluting isomer first eluting isomer 0

[0662] 0

[0663] FAfTNl A Oyrk A N^AC|1 J

[0664] 134*

[0665] Vo y o I Y

[0666] 31* N A A JJ L X

[0667] NJ JNN /

[0668] 'NY L VH-ACl\ / Ffourth eluting isomer

[0669] Cl 0

[0670] second eluting isomer

[0671] 0FAfYNl 1 J

[0672] A oU^x A N^ACI135* I Y

[0673] 1- 0 V 0 ° JVXJA 32*N< A A. A

[0674] Nll TNHCl\ / N^

[0675] FF

[0676]

[0677] first eluting isomer

[0678] Cl

[0679]

[0680] third eluting isomerACCG-0008-WO No. Structure No. Structure

[0681] oyk N^AC|I J

[0682] 36* -P X I? 139* _ o

[0683] y 1

[0684] a

[0685] Cl / JF

[0686] third eluting isomer second eluting isomer

[0687] V 'f'Vi OyL N< Jkc|Oyk N< Jkc|

[0688] 37* _ o 140* T / ?

[0689] 0JCX5S JI JL / s Xy N^y / y " N '" \>yCl\ Jc|—f y^

[0690] — /

[0691] fourth eluting isomer first eluting isomer

[0692] 0 0

[0693] FyN-yN Oyk N^AC|Oyk N^LC|

[0694] 38* _ ^N~N o

[0695] xoAAJ' 141*. _ p VAy

[0696] y ± / n> J A / XN' xJrFCl~\ / — F-( y^ F

[0697]

[0698] third eluting isomer

[0699]

[0700] first eluting isomerACCG-0008-WO No. Structure No. Structure NA^ACI_ o

[0701] 42* 145* Al I P vAY

[0702] L Y / T AAA Y JNM~F AA^NFA Y F FY \=N; A

[0703] second eluting isomer first eluting isomer

[0704] 0

[0705] YN-yk

[0706] Oyk A

[0707] 43*. _ AA P /

[0708] A^AY 146

[0709] L Y / A A

[0710] YjNYF A ArYv AH°C—l\ / ^'

[0711] FA / F

[0712] ^YY AZ z- —

[0713] third eluting isomer W V / / \ / i\ \ _

[0714] dY Y V°AA ° M Z / Y oTyvzA pr o z °A

[0715] 147

[0716] 44* Al I F

[0717] AAA ATN

[0718] Tr

[0719]

[0720] —N

[0721]

[0722] second eluting isomerACCG-0008-WO HEIGHT="541" WIDTH="257" SRC="imgf000065_0001_table.tif" / >

[0723]

[0724] ACCG-0008-WO HEIGHT="484" WIDTH="257" SRC="imgf000066_0002_table.tif" / >

[0725]

[0726] ACCG-0008-WO HEIGHT="485" WIDTH="257" SRC="imgf000067_0001_table.tif" / >

[0727]

[0728] ACCG-0008-WO HEIGHT="615" WIDTH="257" SRC="imgf000068_0001_table.tif" / >

[0729]

[0730] ACCG-0008-WO No. Structure No. Structure

[0731] 0

[0732] A frN^’lC|oX rk JI H y | Cl JHN-N 0 173* o=< X J p

[0733] 70*

[0734] ° i xVci< > —

[0735] Cl— \ / Fsecond eluting isomer first eluting isomer

[0736] -A-rA

[0737] o^ X NX-CI0H ICl174* HN Yp 5 11 } o J1N~N o f

[0738] 71* 'Nd lX| X 1 NH NX

[0739] Cl— J / — Y

[0740] Cl— \ / Fthird eluting isomer second eluting isomer

[0741] O

[0742] N;JL, NXL O YAClYJCL175* Yp 1 o

[0743] 72* ° ™I 1 7 'N1 NH0JL J3N'I

[0744] Cl— \

[0745] Cl— second eluting isomer

[0746]

[0747] first eluting isomer

[0748]

[0749] ACCG-0008-WO HEIGHT="578" WIDTH="257" SRC="imgf000070_0001_table.tif" / >

[0750]

[0751] ACCG-0008-WO No. Structure No. Structure

[0752] 0^ 0

[0753] FY ) °Y — '

[0754] e YNH j(Y zo= SYNX 185 Y X

[0755] 82* U X V>° " j

[0756] ' x

[0757] o Y P YY l j ^Yf^vY0YYLX, o I X / NX

[0758] \ N=< VN" V^F (^X ^N\Y °1 / Ffirst eluting isomer

[0759] (Y

[0760] e XNH 186

[0761] 83* HN~N VSO

[0762] ox X 1 / /

[0763] O^Y iX ^

[0764] l L / Y Y o 7

[0765] vY Xzx ° ——

[0766] ci^ V°

[0767] second eluting isomer

[0768] 0

[0769] Y Y 187z / — Q

[0770] X f

[0771] 184

[0772] Xx Y

[0773] I JL / NX

[0774] N / Y'NV4-F

[0775] — / / F

[0776]

[0777] Oyk N^AC|

[0778] 188 _ P ZY ■’ Y M '^‘xY

[0779]

[0780] F^rvfACCG-0008-WO

[0781]

[0782]

[0783] ACCG-0008-WO

[0784]

[0785]

[0786] ACCG-0008-WO No. Structure No. Structure

[0787] 0

[0788] -A. r"l

[0789] o jNA<C, A ANA-CII J I J

[0790] 200* A! I x 203* A 'o^lAl

[0791] I JL^ 0 AoA / NA NA J A'T ^N X \l / NA

[0792] second eluting isomer

[0793] O second eluting isomer A y

[0794] o. / k A A

[0795] TjCl(A A A 201 _ O N-N T A JF204

[0796] 0— c JI I JOJA0

[0797] NA T i[A

[0798] N^ / A; N A

[0799] CK / A NA^Ffirst eluting isomer A NAA

[0800] °\A^ A A

[0801] YjClAA

[0802] oA AA 202* —Xi? JL / ° T J

[0803] 0N~N AFX A5S 205 A o jf y IA o

[0804] T jA

[0805] A

[0806]

[0807] first eluting isomer cr X Nv

[0808] second eluting isomer

[0809]

[0810] ACCG-0008-WO

[0811]

[0812]

[0813] ACCG-0008-WO No. Structure No. Structure

[0814] 0

[0815] Y on

[0816] °YAN< YY I m

[0817] I J \ I J

[0818] 215 Yo A 0

[0819] 212 AN1 I / ? YAY

[0820] J / I 1 X LNNH AYNV

[0821] 0

[0822] Enantiomer 1 0 F

[0823] 0

[0824] Y fA Y ro oANA\. O'x / YNAACI J "' N I J 216 A l I?

[0825] 213 A O! AY 1^A / ?

[0826] 0Y JXA / OA XN' J^LA / AY

[0827] CIA A

[0828] F^JY°

[0829] Diastereomer 1 Enantiomer 2

[0830] O F

[0831] Y oY oA, AA. I J '" N 214 217 JO u

[0832] 0KCN-I / ANA JClx" / J

[0833]

[0834]

[0835] Diastereomer 2No. Structure

[0836] 219

[0837] Enantiomer 1

[0838] 220

[0839]

[0840]

[0841] ACCG-0008-WO

[0842]

[0843]

[0844] ACCG-0008-WO

[0845]

[0846]

[0847] ACCG-0008-WO

[0848]

[0849]

[0850] No. Structure

[0851] 247

[0852]

[0853] Enantiomeric mixtureACCG-0008-WO

[0854]

[0855]

[0856] ACCG-0008-WO

[0857]

[0858] The compounds of Formula I provided herein encompass stereochemical forms of the compounds, for example, optical isomers, such as enantiomers, diastereomers, as well as mixtures thereof, c.g., mixtures of enantiomers and / or diastereomers, including racemic mixtures, as well as equal or non-equal mixtures of individual enantiomers and / or diastereomers. All stereochemical forms are contemplated in this disclosure. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Representative stereochemical forms are provided throughout the specification, including but not limited to those delineated in Table 2. In some embodiments, provided is compound selected from Table 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof:

[0859]

[0860]

[0861] ACCG-0008-WO

[0862]

[0863]

[0864] ACCG-0008-WO

[0865]

[0866]

[0867] ACCG-0008-WO

[0868]

[0869]

[0870] ACCG-0008-WO

[0871]

[0872]

[0873] ACCG-0008-WO

[0874]

[0875]

[0876] ACCG-0008-WO

[0877]

[0878]

[0879] ACCG-0008-WO

[0880]

[0881]

[0882] ACCG-0008-WO

[0883]

[0884] Cl

[0885]

[0886] ACCG-0008-WO

[0887]

[0888]

[0889] ACCG-0008-WO

[0890]

[0891]

[0892] ACCG-0008-WO

[0893]

[0894]

[0895] ACCG-0008-WO

[0896]

[0897]

[0898] ACCG-0008-WO

[0899]

[0900]

[0901] ACCG-0008-WO

[0902]

[0903]

[0904] ACCG-0008-WO

[0905]

[0906]

[0907] ACCG-0008-WO

[0908]

[0909]

[0910] ACCG-0008-WO

[0911]

[0912]

[0913] ACCG-0008-WO

[0914]

[0915]

[0916] ACCG-0008-WO

[0917]

[0918]

[0919] ACCG-0008-WO

[0920]

[0921]

[0922] ACCG-0008-WO

[0923] Structure

[0924]

[0925]

[0926] ACCG-0008-WO

[0927]

[0928]

[0929] ACCG-0008-WO

[0930]

[0931]

[0932] ACCG-0008-WO

[0933] Structure

[0934]

[0935]

[0936] ACCG-0008-WO

[0937]

[0938]

[0939] ACCG-0008-WO

[0940]

[0941]

[0942] ACCG-0008-WO

[0943]

[0944]

[0945] ACCG-0008-WO Structure Structure

[0946]

[0947]

[0948] ACCG-0008-WO

[0949]

[0950]

[0951] ACCG-0008-WO Structure

[0952]

[0953]

[0954] ACCG-0008-WO

[0955]

[0956]

[0957] ACCG-0008-WO

[0958]

[0959]

[0960] ACCG-0008-WO

[0961] Structure

[0962]

[0963]

[0964] ACCG-0008-WO

[0965]

[0966]

[0967] ACCG-0008-WO

[0968]

[0969]

[0970] ACCG-0008-WO

[0971]

[0972]

[0973] ACCG-0008-WO

[0974]

[0975]

[0976] ACCG-0008-WO

[0977]

[0978]

[0979] ACCG-0008-WO

[0980] Structure

[0981]

[0982]

[0983] ACCG-0008-WO Structure

[0984]

[0985]

[0986] ACCG-0008-WO

[0987]

[0988]

[0989] ACCG-0008-WO

[0990]

[0991]

[0992] ACCG-0008-WO

[0993]

[0994]

[0995] ACCG-0008-WO

[0996]

[0997]

[0998] The compounds of Formula I and subformulas thereof include pharmaceutically acceptable salts thereof. In addition, the compounds of Formula I and subformulas thereof also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and / or purifying compounds of Formula I and subformulas thereof and / or for separating enantiomers of compounds of Formula I and subformulas thereof.

[0999] It will further be appreciated that the compounds of Formula I and subformulas or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present disclosure. For example, compounds of Formula I and subformulas thereof and salts of each thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[1000] Pharmaceutical Compositions and Administration

[1001] When employed as pharmaceuticals, compounds as described herein (e.g., one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof) can be administered in the form of a pharmaceutical compositions. These compositions can be prepared in aACCG-0008-WO manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration can include a dosage form formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[1002] Also provided herein are pharmaceutical compositions which contain, as the active ingredient, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, in combination with one or more pharmaceutically acceptable excipients (carriers). For example, a pharmaceutical composition prepared using one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof.

[1003] In one embodiment, provided is a pharmaceutical composition comprising a compound, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, as disclosed herein, and a pharmaceutically acceptable excipient. In one embodiment, provided is a pharmaceutical composition comprising a compound, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, as disclosed herein, and a pharmaceutically acceptable excipient, wherein a compound, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount greater than about 0.1%, greater than about 1%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 35%, 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%, by weight.

[1004] In some embodiments, the composition is suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by anACCG-0008-WO excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, 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 a tablet or capsule.

[1005] Further provided herein are pharmaceutical compositions containing one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof with a pharmaceutically acceptable excipient. Pharmaceutical compositions containing one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof as the active ingredient can be prepared by intimately mixing one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[1006] 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.

[1007] Methods of formulating 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.

[1008] In some embodiments, the compound or pharmaceutical composition can 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, selfemulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogenACCG-0008-WO phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene -polyoxypropylene -block polymers, and wool fat. Cyclodextrins such as a-, p, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).

[1009] In some embodiments, the compounds and pharmaceutical compositions described herein or a pharmaceutical composition thereof can be administered to patient in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In some embodiments, a route of administration is parenteral (e.g., intratumoral).

[1010] In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof as described herein or pharmaceutical compositions thereof can be formulated for parenteral administration, e.g., formulated for injection via the intraarterial, intrasternal, intracranial, intravenous, intramuscular, sub-cutaneous, or intraperitoneal routes. For example, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure. In some embodiments, devices are used for parenteralACCG-0008-WO administration. For example, such devices may include needle injectors, microneedle injectors, needle-free injectors, and infusion techniques.

[1011] In some embodiments, the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form must be sterile and must be fluid to the extent that it may be easily injected. In some embodiments, the form should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[1012] In some embodiments, the carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. In some embodiments, the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In some embodiments, the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In some embodiments, isotonic agents, for example, sugars or sodium chloride are included. In some embodiments, prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[1013] In some embodiments, sterile injectable solutions are prepared by incorporating one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. In some embodiments, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In some embodiments, sterile powders are used for the preparation of sterile injectable solutions. In some embodiments, the methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[1014] In some embodiments, pharmacologically acceptable excipients usable in a rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, Vaseline, anhydrous lanolin, sharkACCG-0008-WO liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

[1015] In some embodiments, suppositories can be prepared by mixing one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutical compositions as described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In some embodiments, compositions for rectal administration are in the form of an enema.

[1016] In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, as described herein or a pharmaceutical composition thereof is formulated for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms).

[1017] In some embodiments, solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For example, in the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. In some embodiments, solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[1018] In some embodiments, the pharmaceutical compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with one or more compounds asACCG-0008-WO disclosed herein, or a stereoisomer or mixture of stereoisomers thereof as provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, poly vinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In some embodiments, another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’S, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). In some embodiments, unit dosage forms in which one or more compounds and pharmaceutical compositions as provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. In some embodiments, enteric coated or delayed release oral dosage forms are also contemplated.

[1019] In some embodiments, other physiologically acceptable compounds may include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. For example, various preservatives are well known and include, for example, phenol and ascorbic acid.

[1020] In some embodiments, the excipients are sterile and generally free of undesirable matter. For example, these compositions can be sterilized by conventional, well-known sterilization techniques. In some embodiments, for various oral dosage form excipients such as tablets and capsules, sterility is not required. For example, the United States Pharmacopeia / National Formulary (USP / NF) standard can be sufficient.

[1021] In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof as described herein or a pharmaceutical composition thereof is formulated for ocular administration. In some embodiments, ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymers), cyclodextrins); preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.).

[1022] In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof as described herein or a pharmaceutical composition thereof is formulated for topical administration to the skin or mucosa (e.g., dermally or transdermally). In some embodiments, topical compositions can include ointments and creams. In some embodiments, ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. In some embodiments, creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. For example, cream bases are typically water-washable, and contain anACCG-0008-WO oil phase, an emulsifier and an aqueous phase. For example, the oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. In some embodiments, the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. In some embodiments, as with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

[1023] In any of the foregoing embodiments, pharmaceutical compositions as described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D, L-lactic-co-glycolic acid) (PLGA)-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[1024] The amount of the compound in a pharmaceutical composition or formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below.

[1025] Formulation Example 1 - Tablet formulation

[1026] The following ingredients are mixed intimately and pressed into single scored tablets.

[1027] Ingredient Quantity per tablet, mg compound of this disclosure 400

[1028] cornstarch 50

[1029] croscarmellose sodium 25

[1030] lactose 120

[1031] magnesium stearate 5

[1032]

[1033] Formulation Example 2 - Capsule formulation

[1034] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule Ingredient Quantity per capsule, mg compound of this disclosure 200

[1035] lactose, spray-dried 148

[1036] magnesium stearate 2

[1037]

[1038] Formulation Example 3 - Suspension formulation

[1039] The following ingredients are mixed to form a suspension for oral administration.

[1040] Ingredient Amount

[1041] compound of this disclosure 1.0 g

[1042] fumaric acid 0.5 g

[1043] sodium chloride 2.0 g

[1044] methyl paraben 0.15 g

[1045] propyl paraben 0.05 g

[1046] granulated sugar 25.0 g

[1047] sorbitol (70% solution) 13.00 g

[1048] Veegum K (Vanderbilt Co.) 1.0 g

[1049] flavoring 0.035 mL

[1050] coloring 0.5 mg

[1051] distilled water q.s. to 100 mL

[1052]

[1053] Formulation Example 4 - Injectable formulation

[1054] The following ingredients are mixed to form an injectable formulation.

[1055] Ingredient Amount

[1056] compound of this disclosure 0.2 mg-20 mg

[1057] sodium acetate buffer solution, 0.4 M 2.0 mL

[1058] HCl (1N) or NaOH (1N) q.s. to suitable pH

[1059] water (distilled, sterile) q.s. to 20 mL

[1060]

[1061] Formulation Example 5 - Suppository Formulation

[1062] A suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:

[1063] Ingredient Amount

[1064] compound of this disclosure 500 mg

[1065] Witepsol® H-15 balance

[1066]

[1067] ACCG-0008-WO

[1068] In some embodiments, the dosage for one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, is determined based on a multiple factors including, but not limited to, type, age, weight, sex, medical condition of the patient, severity of the medical condition of the patient, route of administration, and activity of the compound or pharmaceutically acceptable s salt, stereoisomer, mixture of stereoisomers, or solvate thereof. In some embodiments, proper dosage for a particular situation can be determined by one skilled in the medical arts. In some embodiments, the total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

[1069] In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, is administered at a dose from about 0.01 to about 1000 mg. For example, from 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.

[1070] In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof as described herein is administered at a dosage of 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 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; 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 a stereoisomer or mixture of stereoisomers thereof as described herein is administered as a dosage of about 100 mg / Kg.

[1071] In some embodiments, the foregoing dosages of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, can be administered on a daily basis (e.g., as a singleACCG-0008-WO dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[1072] In some embodiments, the period of administration of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof as described herein is for 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 more. In some embodiments, a period of during which administration is stopped is for 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 more. In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof is administered to a patient for a period of time followed by a separate period of time where administration of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof is stopped. In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof is started and then a fourth period following the third period where administration is stopped. For example, the period of administration of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In some embodiments, a period of administration is for 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 more. In some embodiments, a period of during which administration is stopped is for 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 more.

[1073] In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, is orally administered to the patient one or more times per day (e.g., one time per day, two times per day, three times per day, four times per day per day or a single daily dose).ACCG-0008-WO In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, is administered by parenteral administration to the patient one or more times per day (e.g., 1 to 4 times, one time per day, two times per day, three times per day, four times per day or a single daily dose).

[1074] In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, is administered by parenteral administration to the patient weekly.

[1075] Methods of Treatment

[1076] In some embodiments, this disclosure provides methods for treating a subject (e.g., a human) having a disease, disorder, or condition in which inhibition of one or more calcitonin receptor and / or amylin receptor is beneficial for the treatment of the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the methods provided herein can include treating one or more conditions associated, co-morbid or sequela with any one or more of the conditions provided herein.

[1077] Provided herein is a method for treating a calcitonin receptor and / or an amylin receptor associated disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein (e.g., a compound of Formula I, or any subformula thereof or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof), or a pharmaceutical composition as disclosed herein. Also provided herein are methods for treating or preventing a calcitonin receptor and / or an amylin receptor associated disease or disorder in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or any subformula thereof, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof), or a pharmaceutical composition thereof.

[1078] In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is a bone disorder, a metabolic disorder, pain, a neurodegenerative disease or disorder, a cardiovascular disease, or other disease or disorder as described herein.

[1079] In some embodiments, the disease or disorder includes, but is not limited to type 1 diabetes mellitus, type 2 diabetes mellitus, early onset type 2 diabetes mellitus, idiopathic type 1 diabetes mellitus (Type lb), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral adipose deposition, eating disorders,ACCG-0008-WO cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, post-prandial 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, cataract, glomerulosclerosis, arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcerations, psoriasis, primary polydipsia, metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn’s disease, short bowel syndrome, Parkinson’s, Alzheimer’s disease, impaired cognition, schizophrenia, and Polycystic Ovary Syndrome (PCOS).

[1080] In some embodiments, the disease or disorder includes, but is not limited to type 2 diabetes mellitus, early onset type 2 diabetes mellitus, obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral adipose deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, hyperglycemia, post-prandial 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, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcerations, psoriasis, primary polydipsia, metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), short bowel syndrome, Parkinson’s disease, Polycystic Ovary Syndrome (PCOS), or any combination thereof.

[1081] In some embodiments, the disease or disorder includes, but is not limited to type 2 diabetes mellitus, early onset type 2 diabetes mellitus, obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral adipose deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemicACCG-0008-WO atacks, hyperglycemia, post-prandial 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 ulcerations, or any combination thereof.

[1082] In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient described herein induce one or more of blood glucose reduction (e.g., reduce blood glucose levels), reduce blood hemoglobin Ale (HbA1c) levels, promote insulin synthesis, stimulate insulin secretion, increase the mass of P-cells, modulate gastric acid secretion, modulate gastric emptying, decrease the body mass index (BMI), and / or decrease glucagon production (e.g., level). In certain embodiments, the compounds and pharmaceutical compositions and methods for treating a patient described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations). Also provided herein are methods for modulating glucose or insulin levels in a patient in need of such modulating, the method comprising administering to the patient an effective amount of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutical composition as disclosed herein.

[1083] In some embodiments, provided herein is a method for reducing the risk (e.g., by about at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%) of major adverse cardiovascular events (MACE) in a patient in need thereof, the method comprising administering to the patient an effective amount of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutical composition as disclosed herein. In certain of these embodiments, the patient is an adult that has been diagnosed with type 2 diabetes (T2D). In certain embodiments, the patient is an adult that has been diagnosed with a heart disease. In certain embodiments, the patient is an adult that has been diagnosed with type 2 diabetes (T2D) and a heart disease. In certain embodiments, the patient is an adult that has type 2 diabetes (T2D). In certain embodiments, the patient is an adult that has a heart disease. In certain embodiments, the patient has type 2 diabetes (T2D) and a heart disease.

[1084] In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is a bone disorder, including, but not limited to, osteoporosis, Paget’s disease, hypercalcemia, Sudeck’s atrophy, polystatic fibrous displasia, intersemocostoclavicular ossification, osteogenesis imperfecta, osteopenia, periodontal disease or defect, osteolytic bone disease, metastatic bone disorder, or bone loss resulting from a malignancy, autoimmune arthritides, a breakage or fracture, or immobility or disuse.ACCG-0008-WO In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is pain, including, but not limited to, osteopathic pain, phantom limb pain, general pain, hyperalgesia, or pain associated with diabetic neuropathy.

[1085] In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is a neurodegenerative disease or disorder, including, but not limited to, Alzheimer’s disease.

[1086] In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is a metabolic disorder, including, but not limited to, non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), insulin dependent diabetes, non-insulin dependent diabetes, impaired glucose tolerance, obesity, syndrome X, or other diabetic complication.

[1087] In some embodiments, the calcitonin receptor and / or amylin receptor associated disease or disorder is include primary or secondary hyperthyroidism, endocrine disorder, conditions associated with inhibiting gastric secretion, gastrointestinal disorders, renal osteodystrophy, or male infertility.

[1088] In some embodiments, 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 is useful to alleviate insulin suppression in pancreatic tissue.

[1089] In some embodiments, 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 is useful to treat alleviate insulin resistance.

[1090] In some embodiments, 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 is useful to treat impaired glucose tolerance.

[1091] In some embodiments, 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 is useful to treat obesity and symptoms thereof.

[1092] In some embodiments, provided is a method for reducing body fat or body fat gain, comprising administering to a subject in need thereof 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.

[1093] In some embodiments, provided is a method of altering a body composition of a subject in need of treatment, wherein body fat is reduced and lean body mass is maintained or increased, comprisingACCG-0008-WO 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.

[1094] In some embodiments, provided is a method for reducing body weight in a subject in need of, 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.

[1095] In some embodiments, provided is a method for reducing caloric intake in a subject in need of reduction thereof, 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.

[1096] In some embodiments, provided is a method for reducing body fat or body fat gain in a subject in need of treatment while maintaining or increasing lean body mass, 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.

[1097] In some embodiments, 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 is useful to treat hypertension.

[1098] In some embodiments, 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 is useful to treat essential hypertension.

[1099] In some embodiments, 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 is useful to treat a subject suffering from hypertension and hyperamylinemia.

[1100] In some embodiments, provided is a method for treating hyperinsulinemia, comprising administering to a subject in need thereof 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.ACCG-0008-WO In some embodiments, provided is a method for treating a hypertensive, insulin-resistant subject suffering from coronary artery disease and having hyperamylinemia or hyperinsulinemia, comprising administering to a subject in need thereof 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.

[1101] In some embodiments, provided is a method for decreasing basal and submaximally stimulated rates of glycogen synthesis in a subject, comprising administering to a subject in need thereof 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.

[1102] In some embodiments, provided is a method for decreasing the rate of incorporation of glucose into glycogen in muscle tissue of a subject, comprising administering to a subject in need thereof 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.

[1103] In some embodiments, provided is a method for treating obesity and hypertension, and the lipid disorders and atherosclerosis associated therewith, in a subject, comprising administering to a subject in need thereof 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.

[1104] In some embodiments, 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 is useful to modulate renin activity in a subject in need thereof.

[1105] In some embodiments, provided is a method for treating or preventing the development of cardiac failure, in a subject, comprising administering to a subject in need thereof 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.

[1106] In some embodiments, 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 is useful to beneficially regulate gastrointestinal motilityACCG-0008-WO in a subject in need thereof. In some embodiments, the beneficial regulation of gastrointestinal motility comprises delaying gastric emptying.

[1107] In some embodiments, 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 is useful to treat postprandial hyperglycemia in a subject in need thereof.

[1108] Obesity

[1109] In some embodiments, the condition, disease or disorder is obesity and conditions, diseases or disorders that are associated with or related to 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 abdominal adiposity). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea agent, or p-blocker-induced obesity).

[1110] In some embodiments, the condition, disease or disorder is associated with obesity. Examples of such conditions, diseases or disorders include, without limitation, glucose tolerance disorders, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism abnormality, hyperlipidemia, hypertension, cardiac failure, hyperuricemia, gout, fatty liver (including metabolic dysfunction-associated steatohepatitis (MASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., brain thrombosis, transient cerebral ischemic attack), bone or articular disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis deformans, lumbago), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorder (e.g., abnormal menstrual cycle, abnormality of menstrual flow and cycle, amenorrhea, abnormal catamenial symptom), visceral obesity syndrome, and metabolic syndrome. In some embodiments, the chemical compound and pharmaceutical compositions described herein can be used to treat patients exhibiting symptoms of both obesity and insulin deficiency.

[1111] Diabetes

[1112] In some embodiments, the condition, disease or disorder is diabetes. Non-limiting examples of diabetes include type 1 diabetes mellitus, type 2 diabetes mellitus (e.g., diet-treated type 2-diabetes, sulfonylurea-treated type 2-diabetes, a far-advanced stage type 2-diabetes, long-term insulin-treated typeACCG-0008-WO 2-diabetes), diabetes mellitus (e.g., non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus), gestational diabetes, obese diabetes, autoimmune diabetes, and borderline type diabetes. In some embodiments, the condition, disease or disorder is type 2 diabetes mellitus (e.g., diet-treated type 2-diabetes, sulfonylurea-treated type 2-diabetes, a far-advanced stage type 2-diabetes, long-term insulin-treated type 2-diabetes).

[1113] Provided herein is a method of treating a diabetes mellitus in a patient, the method comprising (a) determining that the patient has type 2 diabetes mellitus, and (b) administering to the patient a therapeutically effective amount of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutical composition as disclosed herein.

[1114] Provided herein is a method for treating type 2 diabetes mellitus in a patient, the method comprising administering to a patient identified or diagnosed as having type 2 diabetes mellitus a therapeutically effective amount of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutical composition as disclosed herein.

[1115] Also provided herein is a method of treating type 2 diabetes mellitus in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutical composition as disclosed herein.

[1116] In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce non-fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce HbA1c levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce glucagon levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein increase insulin levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce BMI.

[1117] In some embodiments, a reduction in fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in fasting plasmaACCG-0008-WO glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in fasting plasma glucose levels to about or below 126 mg / dL, about or below 110 mg / dL, or about or below 90 mg / dL indicates treatment of the type 2 diabetes mellitus.

[1118] In some embodiments, a reduction in non-fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in non-fasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in non-fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in non-fasting plasma glucose levels to about or below 200 mg / dL, about or below 150 mg / dL, or about or below 130 mg / dL indicates treatment of type 2 diabetes mellitus.

[1119] In some embodiments, a reduction in HbA1c levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in HbA1c levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in HbA1c levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some embodiments, reduction in HbA1c levels to about or below 6.5%, about or below 6.0%, or about or below 5.0% indicates treatment of type 2 diabetes mellitus.

[1120] In some embodiments, a reduction in glucagon levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in glucagon levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in glucagon levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some embodiments, an increase in insulin levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, an increase in insulin levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some embodiments, an increase in insulin levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus.

[1121] In some embodiments, a reduction in BMI of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in BMI of about 15% to about 80% indicates treatment of the type 2 diabetes mellitus. In some embodiments, a reduction in BMI of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in BMI 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 of type 2 diabetes mellitus. In some embodiments, a reduction in BMI toACCG-0008-WO about or below 40, about or below 30, or about or below 20 indicates treatment of type 2 diabetes mellitus.

[1122] In some embodiments, the condition, disease or disorder is associated with diabetes (e.g., a complication of diabetes). Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, inferior limb infection), diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder, diabetic cachexia, delayed wound healing, diabetic dyslipidemia peripheral blood circulation disorder, cardiovascular risk factors, (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors related to unmanaged cholesterol and / or lipid levels, and / or inflammation), metabolic dysfunction-associated steatohepatitis (MASH, bone fracture, and cognitive dysfunction

[1123] Other non-limiting examples of disorders related to diabetes include pre-diabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipemia), metabolic syndrome (e.g., metabolic disorder where activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[1124] In some embodiments, the condition, disease or disorder is diabetes and obesity (diabesity). In some embodiments, the compounds described herein are also useful in improving the therapeutic effectiveness of metformin.

[1125] Disorders of Metabolically Important Tissues

[1126] In some embodiments, the condition, disease or disorder is a disorder of a metabolically important tissue. Non-limiting examples of metabolically important tissues include liver, fat, pancreas, kidney, and gut.

[1127] In some embodiments, the condition, disease or disorder is a fatty liver disease. Fatty liver diseases include, but are not limited to, non-alcoholic fatty acid liver disease (NAFLD), steatohepatitis, metabolic dysfunction-associated steatohepatitis (MASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, Abetalipoproteinemia, glycogen storage diseases, Weber-Christian disease, Wolman’s disease, acute fatty liver of pregnancy, and lipodystrophy.ACCG-0008-WO Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease occurring in the absence of alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver). NAFLD is believed to be linked to a variety of conditions, e.g., metabolic syndrome (including obesity, diabetes and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children and may ultimately 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 the relatively benign isolated predominantly macrovesicular steatosis (i.e., nonalcoholic fatty liver or NAFL) to or metabolic dysfunction-associated steatohepatitis (MASH) (formerly referred to as non-alcoholic steatohepatitis (NASH)) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90). In some embodiments, the patient is a pediatric patient. The term “pediatric patient” as used herein refers to a patient under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W. B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric patient is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric patient is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age. In some embodiments, the patient is an adult patient.

[1128] Other non-limiting examples of disorders in metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g. in the liver); gall stones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorder characterized by altered bone metabolism, such as osteoporosis, including post-menopausal osteoporosis, poor bone strength, osteopenia, Paget’s disease, osteolytic metastasis in cancer patients, osteodistrophy in liver disease and the altered bone metabolism caused by renal failure or hemodialysis, bone fracture, bone surgery, aging, pregnancy, protection against bone fractures, and malnutrition polycystic ovary syndrome;ACCG-0008-WO renal disease (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 syndrome. In some embodiments, the compounds and pharmaceutical compositions described herein can be used for treating surgical trauma by improving recovery after surgery and / or by preventing the catabolic reaction caused by surgical trauma.

[1129] Cardiovascular and Vascular Diseases

[1130] In some embodiments, the disease or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, cardiac failure, cerebrovascular disorder (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher), and prothrombotic state (exemplified by high fibrinogen or plasminogen activator inhibitor in the blood).

[1131] In some embodiments, the disease or disorder is related to a vascular disease. Non-limiting examples of vascular diseases include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular dysfunction, peripheral artery disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorder (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy.

[1132] Neurological Diseases

[1133] In some embodiments, the disease or disorder is a neurological disorder (e.g., neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include brain insulin resistance, mild cognitive impairment (MCI), Alzheimer’s disease (AD), Parkinson’s disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington’s chores, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson, steel-Richard syndrome, Down's syndrome, myasthenia gravis, nerve trauma, brain trauma, vascular amyloidosis, cerebral hemorrhage I with amyloidosis, brain inflammation, Friedrich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeld-Jakob Disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome). See, e.g., US2006 / 0275288A1.

[1134] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics and amphetamines and attention deficit / hyperactivity disorder (ADHD). The compounds and pharmaceuticalACCG-0008-WO compositions described herein can be useful in improving behavioral response to addictive drugs, decreasing drug dependence, prevention drug abuse relapse, and relieving anxiety caused by the absence of a given addictive substance. See, e.g., US2012 / 0021979A1.

[1135] In some embodiments, the compounds and pharmaceutical compositions described herein are useful in improving learning and memory by enhancing neuronal plasticity and facilitation of cellular differentiation, and also in preserving dopamine neurons and motor function in Morbus Parkinson. Insulin-Related Conditions and Disorders

[1136] In some embodiments, the disease or disorder is impaired fasting glucose (IFG), impaired fasting glycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, a hypoglycemic condition, insulin resistant syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesteremia, 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., nighttime hypoglycemia), and concomitant comatose endpoint associated with insulin.

[1137] In some embodiments, the compounds and pharmaceutical compositions described herein can reduce or slow down the progression of borderline type, impaired fasting glucose or impaired fasting glycemia into diabetes.

[1138] Autoimmune Disorders

[1139] In some embodiments, the disease or disorder is an autoimmune disorder. Non-limiting examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorder is associated with immune rejection, graft versus host disease, uveitis, optic neuropathies, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves’ disease. See, e.g., US20120148586A1.

[1140] Stomach and Intestine-Related Disorders

[1141] In some embodiments, the disease or disorder is a stomach or intestine related disorder. Nonlimiting examples of these disorders include ulcers of any etiology (e.g. peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers related to infections or other pathogens), digestion disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel diseases (Crohn’sACCG-0008-WO disease and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy and / or radiation therapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, colitis ulcerosa, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancerous cachexia, tuberculous cachexia, cachexia associated with blood disease, cachexia associated with endocrine disease, cachexia associated with infectious disease, and cachexia caused by acquired immunodeficiency syndrome).

[1142] Body Weight

[1143] In some embodiments, the compounds and pharmaceutical compositions described herein can be used to reduce body weight (e.g., excess body weight), prevent body weight gain, induce weight loss, decrease body fat, or reduce food intake in a patient (e.g., a patient in need thereof). In some embodiments, the weight increase in a patient may be attributed to excessive ingestion of food or unbalanced diets, or may be weight increase derived from a concomitant drug (e.g., insulin sensitizers having a PPARy agonist-like action, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone and the like). In some embodiments, the weight increase may be weight increase before reaching obesity, or may be weight increase in an obese patient. In some embodiments, the weight increase may also be medication-induced weight gain or weight gain subsequent to cessation of smoking.

[1144] In some embodiments, the disease or disorder is an eating disorder, such as hyperphagia, binge eating, bulimia, or compulsive eating.

[1145] Inflammatory Diseases

[1146] In some embodiments, the disease or disorder is an inflammatory disorder. Non-limiting examples of inflammatory disorders include chronic rheumatoid arthritis, spondylitis deformans, arthritis deformans, lumbago, gout, post-operational or post-traumatic inflammation, bloating, neuralgia, laryngopharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory large bowel disease), inflammation in metabolically important tissues including liver, fat, pancreas, kidney and gut, and a proinflammatory state (e.g., elevated levels of proinflammatory cytokines or markers of inflammation-like C-reactive protein in the blood).

[1147] Cancer

[1148] In some embodiments, the disease or disorder is cancer. Suitable examples of cancer include breast cancer (e.g., invasive ductal breast cancer, noninvasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucousACCG-0008-WO adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small-cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), small intestinal cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumor), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharynx cancer, hypopharyngeal cancer), salivary gland cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), neurilemmoma, liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer), renal cancer (e.g., renal cell cancer, transitional cell cancer of the renal pelvis and ureter), bile duct cancer, endometrial cancer, uterine cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor of low malignant potential), 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 cancer), parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumor (e.g., osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, sarcoma of the retina, penis cancer, testicular tumor, pediatric solid tumor (e.g., Wilms’ tumor, childhood kidney tumor), Kaposi’s sarcoma, Kaposi’s sarcoma caused by AIDS, tumor of maxillary sinus, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[1149] Hypothalamic-pituitary disorders

[1150] In some embodiments, the disease or disorder is related to the hypothalamic-pituitary-gonadal axis. For example, the condition, disease or disorder is related to the hypothalamus-pituitary-ovary axis. In another example, the condition, disease or disorder is related to the hypothalamus-pituitary-testis axis. Hypothalamic -pituitary-gonadal axis diseases include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing’s disease.

[1151] In some embodiments, the disease or disorder associated with diabetes is related to the hypothalamic-pituitary-gonadal axis.

[1152] Pulmonary disease

[1153] In some embodiments, the disease or disorder is related to a pulmonary disease. Pulmonary diseases include, but are not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnoea-hypopnoea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (non-reversible) asthma).

[1154] In some embodiments, the disease or disorder associated with diabetes is a pulmonary disease.ACCG-0008-WO Combination Therapy

[1155] In some embodiments, this disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[1156] In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic regimens) in combination with administration of the compounds described herein.

[1157] In some embodiments, the methods described herein include administering a compound described herein in combination with one or more of a diet therapy (e.g., dietary monitoring, diet therapy for diabetes), an exercise therapy (e.g., physical activity), blood sugar monitoring, gastric electrical stimulation (e.g., TANTALUS®), and diet modifications.

[1158] In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof can be administered in combination with one or more additional therapeutic agents.

[1159] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutics, immunotherapeutics, antiinflammatory drugs, antithrombotic agents, anti-oxidants, therapeutic agents for osteoporosis, vitamins, antidementia drugs, erectile dysfunction drugs, therapeutic drugs for urinary frequency or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for metabolic dysfunction-associated steatohepatitis (MASH), therapeutic agents for dysuria and anti -emetic agents.

[1160] In some embodiments, the 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, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulator, GABA modulator (e.g., topiramate), including GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetylCoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturated enzyme inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), sodium-glucose cotransporter 2 (SGLT-2)ACCG-0008-WO 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), glucokinase activators (e.g., piragliatin, 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., metreleptin), leptin resistance improving drugs, CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxyntomodulin (OXM) preparations, appetite suppressants (e.g. ephedrine), FGF21 preparations (e.g., animal FGF21 preparations extracted from the pancreas of bovine or swine; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; fragments or derivatives of FGF21), anorexigenic agents (e.g., P-57), human proislet peptide (HIP), farnesoid X receptor (FXR) agonist, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitor, GDF-15 analog, methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulator, and AMP-activated protein kinase (AMPK) activator.

[1161] In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof can be administered in combination with one or more additional therapeutic agents, wherein the additional therapeutic agent is a GLP-1 agonist or exhibits GLP-1 agonist activity.

[1162] In some embodiments, the additional therapeutic agent is TTP273, LY2944876 (pegapamodutide), HDM1002, K-757, K-833, retatrutide, IBI362 (mazdutide), cotadutide, AMG133, CT-868, HRS9531, HS-20094, dapiglutide, efinopegdutide, efocipegtrutide, pemvidutide, survodutide, AP026, AZD9550, BGM0504, CT-388, DD01, DR10624, G3215, GMA106, 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.

[1163] In some embodiments, the additional therapeutic agent is endogenous GLP-1, endogenous glucagon, oxyntomodulin, exendin-4, exenatide, lixisenatide, albiglutide, beinaglutide, dulaglutide, efpeglenatide, langlenatide, liraglutide, semaglutide, taspoglutide, tirzepatide, pegapamodutide, lithium chloride, PF-06882961 (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),ACCG-0008-WO In some embodiments, one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof can be administered in combination with one or more additional therapeutic agents, wherein the additional therapeutic agent is selected from a compound disclosed in WO2021 / 155841, WO / 2018 / 109607, WO / 2018 / 056453, WO / 2019 / 239319, or WO / 2019 / 239371.

[1164] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as anti-diabetic agents. Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from the pancreas of bovine or swine; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-1), oral insulin preparation, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glucagon analogs (e.g., any of glucagon analogs described, e.g., in WO 2010 / 011439), agents which antagonize the actions of or reduce secretion of glucagon, sulfonylurea agents (e.g., chlorpropamide, tolazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glybuzole, glyburide), thiazolidinedione agents (e.g. rosiglitazone or pioglitazone), a-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), insulin secretagogues, such as prandial glucose regulators (sometimes called “short-acting secretagogues”), e.g., meglitinides (e.g. repaglinide and nateglinide), cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine), NMDA receptor antagonists, dual GLP-l / GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, abiglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[1165] In some embodiments, the one or more additional therapeutic agents include those useful, for example, for treating NAFL and metabolic dysfunction-associated steatohepatitis (MASH). Non-limiting examples include FXR agonists, PF-05221304, a synthetic fatty acid-bile conjugate, an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody, a caspase inhibitor, a MAPK5 inhibitor, a galectin 3 inhibitor, a fibroblast growth factor 21 (FGF21), a niacin analogue, a leukotriene D4 (LTD4) receptor antagonist, an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, an ileal bile acid transporter (IBAT) inhibitor, glycyrrhizin, Schisandra extract, ascorbic acid, glutathione, silymarin, lipoic acid, and d-alpha-tocopherol, ascorbic acid, glutathione, vitamin B-complex, glitazones / thiazolidinediones (e.g., troglitazone, rosiglitazone,ACCG-0008-WO pioglitazone), metformin, cysteamine, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, vitamin E, tetrahydrolipstatin, milk thistle protein, anti-virals, and anti-oxidants.

[1166] In some embodiments, the one or more additional therapeutic agents include those useful, for example, for treating diabetic complications. Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factor and increasing agents thereof (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoting agents described in WOOl / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-l-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in W02004 / 039365), PKG inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridorin, pyridoxamine), serotonin and noradrenalin reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), active oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), and apoptosis signal regulating kinase-1 (ASK-1) inhibitors.

[1167] In some embodiments, the one or more additional therapeutic agents include those useful, for example, for treating hyperlipidemia. Non-limiting examples include HMG-COA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, e.g., N-[[(3R,5S)- l-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo- l,2,3,5-tetrahydro-4, l-benzoxazepin-3-yl]acetyl]piperidin-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resin (e.g., colestyramine), nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), phytosterols (e.g., soysterol, gamma oryzanol (y-oryzanol)), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib) and co-3 fatty acid preparations (e.g., co-3-fatty acid ethyl esters 90).

[1168] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as anti-hypertensive agents. Non-limiting examples include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine) and P-blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol).

[1169] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as diuretics. Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide,ACCG-0008-WO trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide) and chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide).

[1170] In some embodiments, the 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 derivative, picibanil), polysaccharides having immunoenhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering approaches (e.g., interferon, interleukin (IL) such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colonystimulating factor, erythropoietin).

[1171] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as anti-thrombotic agents. Non-limiting examples include heparins (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium) warfarin (e.g., warfarin potassium); antithrombin drugs (e.g., aragatroban, dabigatran) FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, compounds described in W002 / 06234, W02004 / 048363, W02005 / 030740, W02005 / 058823, and W02005 / 113504) ihrombolylic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), and platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, and sarpogrelate hydrochloride).

[1172] In some embodiments, the one or more additional therapeutic agents include those useful, for example, for treating osteoporosis. Non-limiting examples include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium. Suitable examples of vitamins include vitamin B 1 and vitamin B 12. Suitable examples of erectile dysfunction drugs include apomorphine and sildenafil citrate. Suitable examples of therapeutic agents for urinary frequency or urinary incontinence include flavorxate hydrochloride, oxybutynin hydrochloride and propiverine hydrochloride. Suitable examples of therapeutic agents for dysuria include acetylcholine esterase inhibitors (e.g., distigmine). Suitable examples of antiinflammatory agents include nonsteroidal anti-inflammatory drugs such as aspirin, acetaminophen, indomethacin.

[1173] Other exemplary additional therapeutic agents include agents that modulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat the complications of prolonged hyperglycemia, such as aldose reductase inhibitors (e.g. epalrestat and ranirestat), agents usedACCG-0008-WO to treat complications related to micro-angiopathies, 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. plant sterols such as phytosterols), cholesteryl ester transfer protein (CETP) inhibitors, inhibitors of the ileal bile acid transport system (IBAT inhibitors), bile acid binding resins, nicotinic acid (niacin) and analogues thereof, anti-oxidants (e.g., probucol), omega-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. labetalol), adrenergic receptor agonists, including alpha-2 agonists (e.g. clonidine), angiotensin converting enzyme (ACE) inhibitors (e.g. lisinopril), calcium channel blockers, such as dihydropyridines (e.g. nifedipine), phenylalkylamines (e.g. verapamil), and benzothiazepines (e.g. diltiazem), angiotensin II receptor antagonists (e.g. candesartan), aldosterone receptor antagonists (e.g. eplerenone), centrally acting adrenergic drugs, such as central alpha agonists (e.g. clonidine), diuretic agents (e.g. furosemide), haemostasis modulators, including antithrombotics (e.g., activators of fibrinolysis), thrombin antagonists, factor Vila inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), heparin and low molecular weight analogues thereof, factor Xa inhibitors, and direct thrombin inhibitors (e.g. argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g. aspirin)), adenosine diphosphate (ADP) receptor inhibitors (e.g. clopidogrel), phosphodiesterase inhibitors (e.g. cilostazol), glycoprotein IIB / IIA inhibitors (e.g. tirofiban), adenosine reuptake inhibitors (e.g. dipyridamole), noradrenergic agents (e.g. phentermine), serotonergic agents (e.g. sibutramine), diacyl glycerolacyltransferase (DGAT) inhibitors, feeding behavior modifying agents, pyruvate dehydrogenase kinase (PDK) modulators, serotonin receptor modulators, monoamine transmission-modulating agents, such as selective serotonin reuptake inhibitors (SSRI) (e.g. fluoxetine), noradrenaline reuptake inhibitors (NARI), noradrenaline-serotonin reuptake inhibitors (SNRI), and monoamine oxidase inhibitors (MAOI) (e.g. toloxatone and amiflamine), compounds described in W0007 / 013694, W02007 / 018314, W02008 / 093639 and W02008 / 099794, GPR40 agonists (e.g., fasiglifam or a hydrate thereof, compounds described in W02004 / 041266, W02004 / 106276, W02005 / 063729, W02005 / 063725, W02005 / 087710, W02005 / 095338, W02007 / 013689 and W02008 / 001931), SGLT1 inhibitors, adiponectin or agonist thereof, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia-ameliorating agents, such as a cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide agents, tetrahydrocannabinol agents, agents for improving fat metabolism (e.g., eicosapentaenoic acid), growth hormones, IGF-1, antibodies against a cachexia-inducing factor TNF-a, LIF, IL-6, and oncostatin M, metabolism-modifying proteins or peptides such as glucokinase (GK), glucokinase regulatory protein (GKRP), uncoupling proteins 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor ct (PPARa), MC4r agonists, insulinACCG-0008-WO receptor agonist, PDE 5 inhibitors, glycation inhibitors (e.g., ALT-711), nerve regeneration-promoting drugs (e.g., Y-128, VX853, prosapride), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, harkoseride, carbamazepine), antiarrhythmic drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), narcotic analgesics (e.g., morphine), a2 receptor agonists (e.g., clonidine), local analgesics (e.g., capsaicin), antianxiety drugs (e.g., benzothiazepine), phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine), cytotoxic antibodies (e.g., T-cell receptor and IL-2 receptor-specific antibodies), B cell depleting therapies (e.g., anti-CD20 antibody (e.g., rituxan), i-BLyS antibody), drugs affecting T cell migration (e.g., anti-integrin alpha 4 / beta 1 antibody (e.g., tysabri), drugs that act on immunophilins (e.g., cyclosporine, tacrolimus, sirolimus, rapamicin), interferons (e.g., IFN-[3), immunomodulators (e.g., glatiramer), TNF-binding proteins (e.g., circulating receptors), immunosupressants (e.g., my cophenolate), and metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, chiglitazar, lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, exenatide, exendin-4, memantine, midazolam, ketoconazole, ethyl icosapentate, clonidine, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, etoposide, piroxicam, NO donating agents (e.g., organonitrates), and NO promoting agents (e.g., phosphodiesterase inhibitors).

[1174] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as anti-emetic agents. As used herein, an “anti-emetic” agent refers to any agent that counteracts (e.g., reduces or removes) nausea or emesis (vomiting). It is to be understood that when referring to a therapeutically effective amount of an anti-emetic agent, the amount administered is an amount needed to counteract (e.g., reduce or remove) nausea or emesis (vomiting). While not wishing to be bound by theory, it is believed that administering one or more anti-emetic agents in combination with the formula (I) compounds described herein may allow higher dosages of the formula (I) compounds to be administered, e.g., because the patient may be able to have a normal food intake and thereby respond faster to the treatment.

[1175] Non-limiting examples of anti-emetic agents include 5HT3-receptor antagonists (serotonin receptor antagonists), neuroleptics / anti-psychotics, antihistamines, anticholinergic agents, steroids (e.g., corticosteroids), NK1 -receptor antagonists (e.g., Neurokinin 1 substance P receptor antagonists), antidopaminergic agents / dopamine receptor antagonists, benzodiazepines, cannabinoids.

[1176] For example, the antiemetic agent can be selected from the group consisting of; neuroleptics, antihistamines, anti-cholinergic agents, steroids, 5 HT-3 -receptor antagonists, NK1 -receptor antagonists, anti- dopaminergic agents / dopamine receptor antagonists, benzodiazepines and non- psychoactive cannabinoids.ACCG-0008-WO In some embodiments, the anti-emetic agent 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, bemesetron, zatisetron, batanopirde, MDL-73147EF; Metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,l]non-7-yl-l H- indazole-3-carboxamide dihydrochloride), Y-25130 hydrochloride, MDL 72222, Tropanyl-3,5-dimethylbenzoate, 3-(4-Allylpiperazin-1-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride, and mirtazepine. Other non-limiting examples of 5HT3-receptor antagonists (serotonin receptor antagonists) include: cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (+ netupitant), quetiapine, qamosetron, ramosteron, ricasetron, risperidone, ziprasidone, and zatosetron.

[1177] In certain embodiments, the 5 HT-3 -receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopirde, MDL-73147EF, metoclopramide, N-3389, Y- 25130 hydrochloride, MDL 72222, tropanyl-3,5-dimethylbenzoate 3-(4- Allyl- piperazin- l-yl)-2 -quinoxalinecarbonitrile maleate, zacopride hydrochloride and mirtazepine.

[1178] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.

[1179] In certain embodiments, the 5HT-3-receptor antagonist is granisetron, dolasetron and ondansetron.

[1180] In certain embodiments, the 5HT-3-receptor antagonist is granisetron.

[1181] In certain embodiments, the 5HT-3-receptor antagonist is ondansetron.

[1182] In some embodiments, the anti-emetic agent is an antihistamine. Non-limiting examples of antihistamines include: piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.

[1183] In some embodiments, the anti-emetic agent is an anticholinergic agent (inhibitors of the acetylcholine receptors). Non-limiting examples of anticholinergic agents include: atropine, scopolamine, glycopyrron, hyoscine, artane (trihexy-5 trihexyphenidyl hydrochloride), cogentin (benztropine mesylate), akineton (biperiden hydrochloride), disipal (norflex orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and kemadrin (procyclidine hydrochloride).ACCG-0008-WO In some embodiments, the anti-emetic agent is a steroid (e.g., a corticosteroid). Non-limiting examples of steroids include: betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).

[1184] In some embodiments, the anti-emetic agent is an NK1 -receptor antagonists (e.g., Neurokinin 1 substance P receptor antagonists). Non-limiting examples of NK1 -receptor antagonists include: aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.

[1185] 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 (Nolpitantium besilate / chloride), LY 303870 (Lanepitant), MDL-105172A, MDL-103896, MEN-11149, MEN-11467, DNK333A, 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]-8,9,10,1 l-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l,4]diazocino[2,l-g] [1,7]naphthyridine-6, 13-dione], PD 154075, ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)- NHCH(CH3) Ph), FK888, and (D-Pro4, D- Trp7,9,10, Phell)SP4-ll.

[1186] In some embodiments, the anti-emetic agent is an anti- dopaminergic agents / dopamine receptor antagonist (e.g., dopamine receptor antagonist, e.g., D2 or D3 antagonists). Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine,); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.

[1187] In some embodiments, the anti-emetic agent is a non-psychoactive cannabinoids (e.g., Cannabidiol (CBD), Cannabidiol dimethylheptyl (CBD-DMH), Tetra-hydro-cannabinol (THC), Cannabinoid agonists such as WIN 55-212 (a CB1 and CB2 receptor agonist), Dronabinol (Marinol®), and Nabilone (Cesamet)).

[1188] Other exemplary anti-emetic agents include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptics / anti-psychotics (e.g., dixyrazine, haloperidol, and Prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose (Nauzene); orthophosphoric acid; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.

[1189] Still other exemplary anti-emetic agents include those disclosed in US 20120101089A1; US 10,071,088 B2; US 6,673,792 Bl; US 6,197,329 Bl; US 10,828,297 B2; US 10,322,106 B2; USACCG-0008-WO 10,525,033 B2; WO 2009080351 Al; 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 by reference in its entirety.

[1190] In some embodiments, the additional therapeutic agent or regimen is administered to the patient prior to contacting with or administering the compounds and pharmaceutical compositions (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

[1191] In some embodiments, the additional therapeutic agent or regimen is administered to the patient at about the same time as contacting with or administering the compounds and pharmaceutical compositions. By way of example, the additional therapeutic agent or regimen and the compounds and pharmaceutical compositions are provided to the patient simultaneously in the same dosage form. As another example, the additional therapeutic agent or regimen and the compounds and pharmaceutical compositions are provided to the patient concurrently in separate dosage forms.

[1192] Patient Selection

[1193] In some embodiments, the methods described herein further include the step of identifying a patient (e.g., a subject) in need of such treatment (e.g., by way of blood assay, body mass index, or other conventional method known in the art).

[1194] In some embodiments, the methods described herein further include the step of identifying a patient (e.g., patient) that has type 2 diabetes mellitus. In some embodiments, determining if the patient has type 2 diabetes mellitus includes performing an assay to determine the level of hemoglobin Ale (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the level of HbA1c is about 6.5% to about 24.0%. In some embodiments, the level of HbA1c is greater than or about 6.5%. In some embodiments, the level of HbA1c is greater than or about 8.0%. In some embodiments, the level of HbA1c is greater than or about 10.0%. In some embodiments, the level of HbA1c is greater than or about 12.0%. In some embodiments, the level of HbA1c is greater than or about 14.0%. In some embodiments, the level of HbA1c is greater than or about 16.0%. In some embodiments, the level of HbA1c is greater than or about 18.0%. In some embodiments, the level of HbA1c is greater than or about 20.0%. In some embodiments, the level of HbA1c is greater than or about 22.0%. In some embodiments, the level of HbA1c is greater than or about 24.0%.

[1195] In some embodiments, the level of fasting plasma glucose is greater than or about 120 mg / dL to greater than or about 750 mg / dL. In some embodiments, the level of fasting plasma glucose is greaterACCG-0008-WO than or about 200 mg / dL to greater than or about 500 mg / dL. In some embodiments, the level of fasting plasma glucose is greater than or about 300 mg / dL to greater than or about 700 mg / dL.

[1196] In some embodiments, the level of non-fasting plasma glucose is greater than or about 190 mg / dL to greater than or about 750 mg / dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 250 mg / dL to greater than or about 450 mg / dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 400 mg / dL to greater than or about 700 mg / dL.

[1197] In some embodiments, determining if the patient has type 2 diabetes mellitus further includes determining the palieni’s BMI. In some embodiments, the BMI of the patient is greater than or about 22 kg / m2to greater than or about 100 kg / m2. In some embodiments, the BMI of the patient is greater than or about 30 kg / m2to greater than or about 90 kg / m2. In some embodiments, the BMI of the patient is greater than or about 40 kg / m2to greater than or about 80 kg / m2. In some embodiments, the BMI of the patient is greater than or about 50 kg / m2to greater than or about 70 kg / m2.

[1198] In some embodiments, additional factors (c.g. risk factors) used for determining if the patent has type 2 diabetes mellitus further includes age and ethnicity of the patient. In some embodiments, the patient’s age is greater than or about 10 years. In some embodiments, the patent’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 patent’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 padent’s age is greater than or about 42 years. In some embodiments, the padent’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.ACCG-0008-WO 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 padent’s age is greater than or about 95 years. In some embodiments, the ethnicity of the patient may be African American, American Indian or Alaska Native, Asian American, Hispanics or Latinos, or Native Hawaiian or Pacific Islander.

[1199] Synthesis of the Compounds

[1200] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods, and procedures. It will be appreciated that where certain process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[1201] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.

[1202] Furthermore, the compounds of this disclosure may contain one or more chiral centers.

[1203] Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active 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, and the like.

[1204] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance CA USA), EMKA-Chemie Gmbh & Co. KG (Eching Germany), or Millipore Sigma (Burlington MA USA). Others may be prepared by procedures, or obvious modifications thereof, 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, andACCG-0008-WO Suppiementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5thEdition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[1205] Scheme I illustrates a general method which can be employed for the synthesis of compounds described herein, where each wherein each of A, Ring B, L2, R1, R3, R4, and R5, are independently as defined herein, Z is NH or O, and R30is an alkyl or substituted alkyl.

[1206] Scheme I

[1207] R5

[1208] R5

[1209]

[1210] A Hantzsch style pyridine synthesis strategy can be used to synthesize the multi-substituted pyridine-based compound 1-4 or compound 1-7. As shown in Scheme I, coupling compound 1-1 with compounds 1-2 and 1-3 provides 1-4, and coupling compound 1-6 with compounds 1-2 and 1-3 provides I-7. In some embodiments, the coupling reaction is performed under heated conditions in a suitable solvent (e.g., ethanol). Oxidation of 1-4, such as by CAN or DDQ, provides compound 1-5, which can then be further transformed into a heteroaryl using methods known in the art to provide compounds of Formula I. Oxidation of compound 1-7 under similar reaction conditions provides compounds of Formula I.

[1211] Upon reaction completion, compounds of Formula I can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. In certainACCG-0008-WO embodiments, when control of stereochemistry is desired, proper control of reaction conditions and selection of substituents for the reagents can at least partially dictate or preserve the formation of the various stereoisomers.

[1212] For any compound shown in Scheme I, it should be understood that various derivatives can be provided by functional group interconversion at any step. In some embodiments, the various substituents of compounds 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, or 1-7 (e.g., A, Ring B, L2, R1, R3, R4, and R5) are as defined herein. However, derivatization of compounds 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, or 1-7 prior to reacting in any step, and / or further derivatization of the resulting reaction product, provides various compounds of Formula I. Appropriate starting materials and reagents can be purchased or prepared by methods known to one of skill in the art.

[1213] General Synthesis

[1214] Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. In general, compounds described herein are typically stable and isolatable at room temperature and pressure.

[1215] EXAMPLES

[1216] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.ACCG-0008-WO General information: All evaporations or concentrations were carried out in vacuo with a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at rt. Thin layer chromatography (TLC) was performed on silica gel plates, spots were visualized by UV light (214 and 254 nni). Purification by column and flash chromatography was carried out using silica gel (100-200 mesh). Solvent systems were reported as mixtures by volume. NMR spectra were recorded on a Bruker 400 or Varian (400 MHz) spectrometer. H chemical shifts are reported in S values in ppm with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), integration. LCMS spectra were obtained on SHIMADZU LC20-MS2020 or Agilent 1260 series 6125B mass spectrometer or Agilent 1200 series, 6110 or 6120 mass spectrometer with electrospray ionization and excepted as otherwise indicated.

[1217] Unless otherwise indicated in the examples described herein, certain compounds comprise a stereocenter at the carbon atom indicated below (e.g., compounds with stereochemistry at C3 or the C9a fusion), the composition obtained and tested in the assays which follow was a scalemic composition with respect to that stereocenter. It is contemplated that a certain amount of racemization (e.g., less than 50%, or less than 20%) occurs during the Hantzsch style pyridine synthesis. However, the compositions tested favor the stereoisomer indicated in the Examples and Table 1.

[1218]

[1219] For certain compounds which were prepared without a chiral influence, the stereochemistry as indicated in the Examples and Table 1 may have been assigned based on expected potencies (e.g., the compounds labeled with a * in Table 1). Where a compound is referred to by a stereospecific name in the experimentals below, Table 1 will indicate if stereocenters have been assigned based on expected potency. In certain Examples (e.g., Example 47, Compounds 182 and 183), one or more stereocenters may be known based on the synthetic starting material and the other(s) assigned based on potency.

[1220] Separation of the stereoisomers is or can, be, performed using standard techniques (e.g., SFC). For example:

[1221] Column name: ChiralPak IH

[1222] Column size: 250*30 mm 10 μm

[1223] Mobile Phase A: Supercritical CO₂,

[1224]

[1225] Mobile Phase B: EtOH (0.1% NH3H2O )ACCG-0008-WO A: B: 70:30

[1226] Flow: 150 mL / min

[1227]

[1228] Gradient Time 4 min

[1229] INTERMEDIATE 1

[1230] (S)-tetrahydro-lH-pyrrolizine-l,3(2H)-dione

[1231] TMSCI, MeOH t-BuOK, THF

[1232]

[1233] Step A Step B Step A methyl acetyl-L-prolinate

[1234]

[1235] To a solution of acetyl-L-proline (10 g, 63.625 mmol) in methanol (200 mL) were added TMSCI (13.82 g, 127.251 mmol) at 0°C, and the reaction was stirred at room temperature for 18 hr. Then the reaction was concentrated in vacuo to afford the title compound methyl acetyl -L-prolinate (10 g, 58.411 mmol, 91.81%) as a white solid.

[1236] rH NMR (400 MHz, DMSO-d6) 5 ppm 4.36-4.50 (m, 1 H), 3.72-3.76 (m, 3 H), 3.47-3.68 (m, 2 H), 1.90-2.31 (m, 7 H).

[1237] Step B (S)-tetrahydro-lH-pyrrolizine-l,3(2H)-dione

[1238]

[1239] To a solution of methyl acetyl-L-prolinate (1 g, 5.841 mmol) in anhydrous THF (10 mL) was added t-BuOK (11.682 mL) at rt. Then the mixture was stirred at 80°C for 5 h under Ar. Upon completion, the reaction was diluted with EA (50 mL) and water (20 mL). The organic layer wasseparated, washed with further water (20 mL X 2) and saturated NaCl (20 ml). The organic layer was separated, dried with Na2SO4 and then filtered. The organic layer was collected, concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM: MeOH=10:l. The organic layer was collected, concentrated in vacuo, and dried to afford the title compound (S)-tetrahydro-lH-pyrrolizine-l,3(2H)-dione (600 mg, 4.312 mmol, 73.82%) as yellow oil. LC-MS: m / z 140.1 (M+H)+.

[1240] INTERMEDIATE 2

[1241] potassium 5-oxo-2,3-dihydro-lH,5H-2,7a-methanopyrrolizin-7-olate

[1242]

[1243] Step A: 2-(tert-butyl) 1 -methyl 2-az.abicyclo[2.1.1 Jhexane- 1,2-dicarboxylate

[1244] O

[1245]

[1246] Boc

[1247] To a solution of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-l-carboxylic acid (500 mg, 2.20 mmol) in ACN (2 mL) was added potassium carbonate (608 mg, 4.40 mmol) and iodomethane (0.357 mL, 4.40 mmol), and the reaction was stirred at 60°C for 18 hours. The reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 10% ethyl acetate in petroleum ether to afford 2-(tert-butyl) 1-methyl 2-azabicyclo[2.1.1]hexane-l,2-dicarboxylate (450 mg, 84.8 %) as colorless oil. LC-MS: m / z 242.1 (M +H)+.

[1248] Step B: methyl 2-azabicycloJ2.1.1 Jhexane- 1 -carboxylate HCl salt

[1249]

[1250] ACCG-0008-WO To a solution of 2-(tert-butyl) 1 -methyl 2-azabicyclo[2.1.1]hexane-l,2-dicarboxylate (400 mg, 1.66 mmol) in dioxane (4 mL) was added HCl-dioxane (4 M, 4 mL). The reaction was stirred at room temperature for 18 hours. The reaction was concentrated to afford methyl 2-azabicyclo[2.1.1 ]hexane- 1 -carboxylate HC1 salt (300 mg, crude) as a white solid. LC-MS: m / z 142.1 (M +H)+.

[1251] Step C: methyl 2-acetyl-2-azabicyclo[2.l.l]hexane-l-carboxylate

[1252]

[1253] To a solution of methyl 2-azabicyclo[2.1.1]hexane-l -carboxylate HC1 salt (300 mg, crude) in DCM (3 mL) were added TEA (0.87 mL, 6.38 mmol) and acetyl chloride (0.23 mL, 3.20 mmol), and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was quenched with ice water (5 ml), extracted with DCM (20 mL*3). The organic layers were combined, dried over Na₂SO₄, filtered and concentrated under vacuum to dryness. The crude product was purified by column chromatography on silica gel eluted with (CH₂Cl₂ / MeOH 20:1) to give methyl 2-acetyl-2-azabicyclo[2.1.1]hexane-l-carboxylate (300 mg, 77.1%) as brown oil. LC-MS: m / z 184.1 (M +H)+. Step D: potassium 5-oxo-2,3-dihydro- 1 H,5H-2,7a-methanopyrrolizin-7-olate

[1254]

[1255] To a solution of methyl 2-acetyl-2-azabicyclo[2.1.1]hexane-l -carboxylate (50 mg, 0.273 mmol) in THF (2 mL) were added t-BuOK (61 mg, 0.546 mmol), and the reaction was stirred at 80°C for 30 minutes. The reaction was concentrated in vacuo to afford dihydro-lH,5H-2,7a-methanopyrrolizine-5,7(6H)-dione (41 mg, crude) as yellow oil. LC-MS: m / z 208.0 (M +H2O+H)+.

[1256] INTERMEDIATE 3

[1257] methyl (7aS)-6,6-difluoro-l,3-dioxohexahydro-lH-pyrrolizine-2-carboxylate

[1258]

[1259] FACCG-0008-WO

[1260]

[1261] Step A methyl (S)-4,4-difluoro-1-(3-methoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate

[1262]

[1263] To a solution of methyl (2S)-4,4-difluoropyrrolidine-2-carboxylate (1 g, 6.06 mmol) and (3-methoxy-3-oxo-propanoyl)oxypotassium (1.13 g, 7.27 mmol) in THF (10 mL) was added HBTU (2.76 g, 7.27 mmol) and DIPEA (782.0 mg, 6.06 mmol, 1.05 mL). The mixture was stirred at 25 °C for 4 hrs. The reaction mixture was quenched by addition IpO (30 mL), and then extracted with EtOAc (30 mL * 2). The combined organic layers were washed with brine (30 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product methyl (S)-4,4-difluoro-l-(3-methoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate (2 g, crude) was obtained as a yellow oil. LC-MS: m / z 266.0 (M+H)+.

[1264] Step B methyl (7aS)-6,6-difluoro-1,3-dioxohexahydro-1H-pyrrolizine-2-carboxylate

[1265]

[1266] To a solution of methyl (S)-4,4-difluoro-l-(3-methoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate (1 g, 3.77 mmol) in MeOH (10 mL) was added K2CO3 (1.56 g, 11.31 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product methyl (7aS)-6,6-difluoro-l,3-dioxohexahydro-1H-pyrrolizine-2-carboxylate (2.4 g, crude) was obtained as a yellow solid. LC-MS: m / z 233.0 (M+H)+.ACCG-0008-WO INTERMEDIATE 4

[1267] tert-butyl 2-cyclopropyl-3,5-dioxopyrrolidine-l-carboxylate

[1268] EtOAc, 90 °C DMAP, EDCI DCM, 0-20°C

[1269]

[1270] Step A Step B

[1271] Step A tert-butyl (1-cyclopropyl-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxoethyl) carbamate

[1272]

[1273] To a solution of 2-((tert-butoxycarbonyl) amino)-2-cyclopropylacetic acid (5 g, 23.23 mmol) in DCM (70 mL) was added DMAP (3.97 g, 32.52 mmol), 2, 2-dimethyl-l,3-dioxane-4, 6-dione (3.68 g, 25.55 mmol) and EDCI (6.23 g, 32.52 mmol). The mixture was stirred at 0-20 °C for 16 hrs. The mixture was washed with aq. HC1 (0.5 M, 100 mL x 2), H2O (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was used into the next step without further purification. Compound tert-butyl (l-cyclopropyl-2-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-yl)-2-oxoethyl) carbamate (7.93 g, crude) was obtained as a yellow oil.

[1274] Step B tert-butyl 2-cyclopropyl-3,5-dioxopyrrolidine-1-carboxylate

[1275]

[1276] A solution of tert-butyl (l-cyclopropyl-2-(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-yl)-2 -oxoethyl) carbamate (7.93 g, 23.23 mmol) in EtOAc (70 mL) was stirred at 90 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-25% EthylACCG-0008-WO acetate / Petroleum ether gradient at 50 mL / min). Compound tert-butyl 2-cyclopropyl-3,5-dioxopyrrolidine-1 -carboxylate (4.03 g, 72.50% yield) was obtained as a white solid.

[1277] 1H NMR (400 MHz, CDCl3) δ ppm 4.14 (d, J=7.2 Hz, 1H), 3.22 (q, J=7.2 Hz, 2H), 1.59 (s, 9 H), 1.09 - 1.23 (m, 1 H), 0.58 - 0.74 (m, 3 H), 0.44 - 0.54 (m, 1 H).

[1278] INTERMEDIATE 5

[1279] l-(2,3-dihydro-lH-inden-2-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan-l-one

[1280] o AH-NH2N KOH. MeOH / H2O Na2CO3, EtOH, 80 °C Step A Step B

[1281]

[1282] CDI, MgCI2, THF / MeCN,

[1283] 50°C, overnight

[1284] Step C

[1285] Step A ethyl 2-(5-methyl-l,3,4-oxadiazol-2-yl)acetate

[1286]

[1287] A mixture of ethyl 3,3,3-trifluoropropanoate (25 g, 160.154 mmol), acetohydrazide (35.59 g, 480.461 mmol), and Na2CO3(67.90 g, 640.615 mmol) in EtOH (200 mL) were stirred at 80°C for 16 hr. After the reaction was completed, the mixture was filtered and concentrated in vacuum, the residue was purified by column chromatography (PE / EA=1 / 1) to give the ethyl (5-methyl-l,3,4-oxadiazol-2-yl)acetate (20 g, 117.530 mmol, 73.39%) as colorless oil.

[1288] 1H NMR (400 MHz, CDCl3) δ ppm 4.11-4.17 (m, 4H), 2.49 (s, 3H), 1.20 (t, J=7.2 Hz, 3H). Step B potassium 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate

[1289]

[1290] ACCG-0008-WO To a solution of ethyl (5-methyl-1,3,4-oxadiazol-2-yl)acetate (10.68 g, 62.761 mmol) in MeOH (100 mL) and H2O (10 mL) were added KOH (17.61 g, 313.804 mmol). The reaction was stirred at room temperature for 18 hr. The reaction was concentrated in vacuo to afford the title compound potassium 2-(5-methyl-l,3,4-oxadiazol-2-yl)acetate (10 g, 55.494 mmol, 88.42%) as a white solid.

[1291] 1H NMR (400 MHz, DMSO-d6) δ ppm 3.41 (s, 2H), 2.42 (s, 3H).

[1292] Step C l-(2,3-dihydro-lH-inden-2-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan-l-one

[1293] O

[1294] -N

[1295]

[1296] To a solution of 2,3-dihydro-lH-indene-2-carboxylic acid (500 mg, 3.083 mmol) in tetrahydrofuran (2 mL), acetonitrile (2 ml) was added CDI (599.85 mg, 3.699 mmol), and the reaction was stirred at room temperature for 1 hr. Then added potassium 2-(5-methyl-l,3,4-oxadiazol-2-yl)acetate (833.28 mg, 4.624 mmol), magnesium chloride (322.83 mg, 3.391 mmol), and the reaction mixture stirred at 50°C for 18 hr. The mixture was quenched with H2O (40 mL) and extracted with ethyl acetate (30 mL x 2). The organic layer was combined and washed with brine (20 mL x 2), dried over sodium sulfate, filtered and concentrated under vacuum to dryness. The residue was purified by reversed phase column (FA 0.1%) to give l-(2,3-dihydro-lH-inden-2-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan-l-one (450 mg, 1.857 mmol, 60.25%) as colorless oil.

[1297] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.11-7.18 (m, 2H), 7.19-7.26 (m, 2H), 4.39 (s, 2H), 3.60-3.72 (m, 1H), 3.07-3.22 (m, 4H), 2.48 (s, 3H).

[1298] INTERMEDIATE 6

[1299] 3-imino-5-methylhexanamide

[1300] o

[1301] o o

[1302] NH4OH <^NH2

[1303] I MeOH, rt, 72 h I

[1304]

[1305] Step AACCG-0008-WO Step A 3-imino-5-methylhexanamide

[1306] NH2

[1307]

[1308] To a solution of methyl 5-methyl-3-oxohexanoate (10 g, 63.211 mmol) in MeOH (50 mL) were added Ammonium Hydroxide (50 mL), the reaction mixture stirred at room temperature for 3 days. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with (EA) to give 3-azanylidene-5-methylhexanamide (6.5 g, 45.710 mmol, 72.31%) as a white solid. LC-MS: m / z 143.1 (M+H)+.

[1309] INTERMEDIATE 7

[1310] 4-cyclopropyl-3-iminobutanamide

[1311]

[1312] CDI, MgCI2, THF Step B

[1313] Step A

[1314] Step A methyl 4-cyclopropyl-3-oxobutanoate

[1315]

[1316] To a solution of 3-hydroxy-3-methylbutanoic acid (10 g, 84.653 mmol) in THF (200 mL) were added CDI (32.39 g, 199.760 mmol), the reaction was stirred at 25 °C for 16 h under N2. named A. A mixture of [(3-methoxy-l,3-dioxopropyl)oxy]potassium (23.40 g, 149.820 mmol) and magnesium chloride (9.51 g, 99.880 mmol) in THF (200 mL) was stirred at 50 °C for 18 h under N2. named B. After B was cooled to room temperature, A was added. The reaction was stirred at 25°C for 18 h under N2. TLC showed the reaction was completed. The mixture was added to water (800 mL), extracted with EA (300 mL X 2), the combined organic layers were washed with brine (200 mL X 3), dried over sodium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by silica gel chromatographyACCG-0008-WO (eluting PE / EA=1O / 1) to afford methyl 4-cyclopropyL3-oxobutanoate (16.5 g, 105.647 mmol, 105.77%) as a yellow oil. LC-MS: m / z 157.2 (M+H)+.

[1317] Step B 4-cyclopropyl-3-iminobutanamide

[1318]

[1319] To a solution of methyl 4-cyclopropyl-3-oxobutanoate (16.5 g, 105.647 mmol) in Toluene (80 mL) were added DMAP (12.91 g, 105.647 mmol) and ammonium hydroxide (81.383 mL) at 0°C, the reaction was stirred at 25°C for 18 h. The mixture was added to IN HC1 (500 mL), the mixture was extracted with EA (200 mL X 5), the combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuum to afford 4-cyclopropyl-3-oxobutanamide (5.37 g, 38.039 mmol, 36.01%) as a white solid. LC-MS: m / z 141.1 (M+H)+.

[1320] INTERMEDIATE 8

[1321] (Z)-tert-butyl (3-amino-4-cyclopropylbut-2-enoyl)carbamate

[1322] A NH2O

[1323] N H Boc

[1324] A o O NH4OAC A NH2O

[1325]

[1326] L'^'"^^'NHBoc EtOH, 80 °CZ

[1327] Step A

[1328] Step A (Z)-tert-butyl (3-amino-4-cyclopropylbut-2-enoyl)carbamate

[1329] A NH2O

[1330]

[1331] N H Boc

[1332] A mixture of tert-butyl N-(4-cyclopropyl-3-oxo-butanoyl)carbamate (400 mg, 1.66 mmol), NH4OAc (640.00 mg, 8.30 mmol) in EtOH (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The resulting product was dissolved in EtOH (10 mL) and filtered to remove the insoluble. The filter liquor was concentrated in vacuo. Crude compound (Z) -tert-butyl (3-amino-4-cyclopropylbut-2-enoyl)carbamate (411 mg, crude) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 5.10 (s, 1 H), 1.82 - 1.85 (m, 2 H), 1.75 (s, 6 H), 1.26 - 1.28 (m, 9 H), 1.00 - 1.09 (m, 1 H), 0.29 - 0.33 (m, 2 H), -0.03 - 0.05 (m, 2 H).

[1333] INTERMEDIATE 9

[1334] l-(5-fluoro-2,3-dihydrobenzofuran-2-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethanone

[1335]

[1336] step A step B

[1337] Step A 5-fluoro-2,3-dihydrobenzofuran-2-carboxylic acid

[1338] O OH

[1339]

[1340] To a solution of 5-fluorobenzofuran-2-carboxylic acid (2 g, 11.10 mmol) in EtOAc (30 mL) was added Pd / C (2.36 g, 13.32 mmol, 60% purity) under N2atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (77 Psi) at 30 °C for 48 hrs. The resulting product was dissolved in EtOAc (30 mL) and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5um;mobile phase: [water(FA)-ACN];gradient:35%-55% B over 10 min). Compound 5-fluoro-2,3-dihydrobenzofuran-2-carboxylic acid (458 mg, 2.51 mmol, 22.65% yield) was obtained as a white solid.

[1341] 1H NMR (400 MHz, CDCl3) δ ppm 12.61 - 13.59 (m, 1 H), 7.05 - 7.12 (m, 1 H), 6.90 - 6.98 (m, 1 H), 6.78 - 6.85 (m, 1 H), 5.22 - 5.29 (m, 1 H), 3.51 - 3.62 (m, 1 H), 3.23 - 3.30 (m, 1 H).ACCG-0008-WO Step B l-(5-fluoro-2,3-dihydrobenzofuran-2-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethanone

[1342]

[1343] To a solution of potassium 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate (906.22 mg, 5.03 mmol) in THF (20 mL) was added MgCl2(239.40 mg, 2.51 mmol). The mixture was stirred at 25 °C for 30 min and this mixture was marked as Part A. To a mixture of 5-fluoro-2,3-dihydrobenzofuran-2-carboxylic acid (458 mg, 2.51 mmol) in THF (3 mL) was added CDI (448.48 mg, 2.77 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min and this mixture was marked as Part B. Part A solution was added drop-wise to Part B over a period of 2 min at 25 °C and the mixture was stirred at 50 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-10% Dichloromethane / Methanol gradient at 20 mL / min). Compound l-(5-fluoro-2,3-dihydrobenzofuran-2-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan-l-one (500 mg, 1.91 mmol, 75.83% yield) was obtained as a purple solid. 'H NMR (400 MHz, CDCh) 8 ppm 6.67 - 6.89 (m, 3 H), 4.13 - 4.20 (m, 5 H), 2.43 - 2.45 (m, 4 H).

[1344] INTERMEDIATE 10

[1345] l-(5,6-difluoro-2,3-dihydro-lH-inden-2-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan-l-one

[1346]

[1347] ACCG-0008-WO

[1348] Step A Step B

[1349]

[1350] Step A methyl 5,6-difluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate

[1351] O O

[1352]

[1353] F

[1354] To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (5.0 g, 29.74 mmol) in THF (150 mL) was added NaH (3.57 g, 89.21 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 20 min. Dimethyl carbonate (8.04 g, 89.21 mmol) was added slowly at 0 °C. The mixture was stirred at 70 °C for 2 hrs. The solution cooled to 20 °C, then poured into the aqueous of NH4CI solution (250 mL) under stirring. The mixture was extracted with ethyl acetate (200 mL x 2), The combined organic layer was washed with water (150 mL), then brine (100 mL), dried over anhydrous of Na2SO4, filtered and concentrated in vacuum to give a residue. The crude product was triturated with petroleum ether (40 mL), ethyl acetate (10 mL) at 20 °C for 10 min to give methyl 5,6-difluoro-l-oxo-2,3-dihydro-lH-indene-2-carboxylate (3.12 g, 46.39% yield) as a light red solid. LC-MS: m / z 227.0 (M+H)+.

[1355] Step B methyl 5,6-difluoro-2,3-dihydro-lH-indene-2-carboxylate

[1356]

[1357] To a solution of methyl 5,6-difluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (500 mg, 2.21 mmol) in TFA (15 mL) was added triethylsilane (1.29 g, 11.05 mmol). The mixture was stirred at 25 °CACCG-0008-WO for 16 hrs. The solution was poured into water (60 mL), extracted with ethyl acetate (50 mL). The organic layer was washed with the aqueous of NallCCb solution (60 mL), then brine (60 mL), dried over anhydrous of Na2SO4, filtered and concentrated in vacuum to give methyl 5,6-difluoro-2,3-dihydro-lH-indene-2-carboxylate (700 mg, crude) as a brown oil.

[1358] Step C 5,6-difluoro-2,3-dihydro-lH-indene-2-carboxylic acid

[1359]

[1360] A mixture of methyl 5,6-difluoro-2,3-dihydro-lH-indene-2-carboxylate (650 mg, 3.06 mmol) and LiOH (366.80 mg, 15.32 mmol) in THF (5 mL) and H2O (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 2 hrs under N2 atmosphere. The reaction mixture was adjusted pH=2 with 2 M HC1 at 0 °C, and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 5,6-difluoro-2,3-dihydro-lH-indene-2-carboxylic acid (390 mg, 64.25% yield) as a white solid.

[1361] 'H NMR (400 MHz, CDCh) 56.87 - 6.98 (m, 2 H), 3.29 - 3.43 (m, 1 H), 3.05 - 3.24 (m, 4 H). Step D 1-(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethan-1-one

[1362]

[1363] To a solution of 5,6-difluoro-2,3-dihydro-1H-indene-2-carboxylic acid (250 mg, 1.26 mmol) in THF (5 mL) was added CDI (245.47 mg, 1.51 mmol). The mixture was stirred at 25 °C for 30 min and this mixture was marked as Part A. To a mixture of potassium 2-(5-methyl-l,3,4-oxadiazol-2-yl)acetate (454.68 mg, 2.52 mmol) in THF (5 mL) was added MgCl2(120.12 mg, 1.26 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min and this mixture was marked as Part B. Part A solution was added dropwise to Part B over a period of 2 min at 25 °C and the mixture was stirred at 50 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layer was washedwith brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si O2, petroleum ether / ethyl acetate=0 / 1 to1 / 2) to give l-(5,6-difluoro-2,3-dihydro-lH-inden-2-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan-l-one (240 mg, 68.37% yield) as light yellow oil. LC-MS: m / z 279.0 (M+H)+.

[1364] INTERMEDIATE 11

[1365] l-(5-chloro-2,3-dihydro-lH-inden-2-yl)-2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)ethanone

[1366] o KOH, MeOH, H2O Na2CO3, EtOH, 80 °C 20 °C Step B

[1367]

[1368] Step C

[1369] Step A ethyl 2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)acetate

[1370]

[1371] A mixture of ethyl 3,3,3-trifluoropropanoate (5 g, 32.03 mmol), cyclopropanecarbohydrazide (3.21 g, 32.03 mmol) and Na2CO3(4.07 g, 38.44 mmol) in EtOH (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si O2, petroleum ether / ethyl acetate=l / O to 1 / 1) to give ethyl 2-(5 -cyclopropyl- 1, 3, 4-oxadiazol-2-yl)acetate (5.12 g, 81.47% yield) as light yellow oil.ACCG-0008-WO ¹H NMR (400 MHz, CDCl₃) 5 ppm 4.11 - 4.21 (m, 2 H) 3.80 - 3.84 (m, 2 H) 2.03 - 2.14 (m, 1 H) 1.19 - 1.25 (m, 3 H) 1.03 - 1.10 (m, 4 H)

[1372] Step B potassium 2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)acetate

[1373]

[1374] To a solution of ethyl 2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)acetate (5.1 g, 25.99 mmol) in MeOH (50 mL) was added KOH (1.46 g, 25.99 mmol) in H2O (5 mL). The mixture was stirred at 20 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give potassium 2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)acetate (5.4 g, crude) as a light yellow solid.

[1375] 1H NMR (500 MHz, MeOD-d4) δ 3.71 (s, 2 H) 2.16 - 2.23 (m, 1 H) 1.15 - 1.20 (m, 2 H) 1.10 -1.15 (m, 2 H)

[1376] Step C 1 -(5-cMoro-2,3-dihydro-lH-inden-2-yl)-2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)ethanone

[1377]

[1378] To a solution of 5-chloro-2,3-dihydro-lH-indene-2-carboxylic acid (2.00 g, 5.09 mmol) in THF (20 mL) was added CDI (989.57 mg, 6.10 mmol). The reaction mixture was stirred at 25 °C for 30 min and marked as Part A. To a mixture of potassium 2-(5 -cyclopropyl- 1, 3, 4-oxadiazol-2-yl)acetate (2.10 g, 10.17 mmol) in THF (20 mL) was added MgCl₂ (484.21 mg, 5.09 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min and marked as Part B. Part A solution was added drop-wise to Part B over a period of 2 min at 25 °C and the mixture was stirred at 50 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 1 / 2) to give 1-(5-chloro-2,3-dihydro-1H-inden-2-yl)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)ethanone (605 mg, 39.29% yield) as a light yellow solid. LC-MS: m / z 303.1 (M+H)+.ACCG-0008-WO INTERMEDIATE 12

[1379] l-(5-chloro-2,3-dihydro-lH-inden-2-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethanone

[1380] step A

[1381] Step A I-( 5-chloro-2,3-dihydro-lH-inden-2-yl)-2-( 5-methyl-l,3,4-oxadiaz.ol-2-yl)elhanone

[1382]

[1383] To a solution of potassium 2-(5 -methyl- 1, 3,4-oxadiazol-2-yl)acetate (916.46 mg, 5.09 mmol) in THF (2 niL) was added MgCl2(242.11 mg, 2.54 mmol). The mixture was stirred at 25 °C for 30 min. This mixture was marked as Part A. To a mixture of 5-chloroindane-2-carboxylic acid (500 mg, 2.54 mmol) in THF (10 mL) was added CDI (494.78 mg, 3.05 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min and this mixture was marked as Part B. Part A solution was added drop-wise to Part B over a period of 2 min at 25 °C and the mixture was stirred at 50 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient at 40 mL / min). Compound l-(5-chloro-2,3-dihydro-lH-inden-2-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethanone (432 mg, 61.39% yield) was obtained as a white solid. LC-MS: m / z 277.2 (M+H)+.

[1384] 1H NMR (400 MHz, CDCl3) δ ppm 7.10 - 7.15 (m, 1 H), 7.03 - 7.10 (m, 2 H), 4.00 - 4.04 (m, 2 H), 3.46 - 3.60 (m, 1 H), 3.06 - 3.23 (m, 4 H), 2.47 - 2.47 (m, 3 H).The following compounds were synthesized following the similar route to Intermediate 12.

[1385] Structure LC-MS / NMR

[1386] \

[1387] N^.

[1388] LC-MS: m / z 575.3 (2M+Na)+.

[1389] Cl

[1390]

[1391] INTERMEDIATE 13

[1392] l-(3-fluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan-l-one

[1393]

[1394] Step A (5-fIuoropyridine-2,3-diyl)dimethanol

[1395] HO

[1396]

[1397] ACCG-0008-WO To a solution of dimethyl 5-fluoropyridine-2,3-dicarboxylate (1.0 g, 4.69 mmol) in EtOH (15.0 mL) was added NaBIL (0.92 g, 24.32 mmol) portionwise at 0 °C over 2 min. After addition, the mixture was stirred at 25 °C for 2 mins, and then CaCh (523.08 mg, 4.71 mmol) in EtOH (5.0 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched by addition HC1 aqueous solution (1 M) to pH = 3 at 25 °C, stirred for 10 mins and then treated with NaOH aqueous solution to pH = 7. The mixture was diluted with H2O (20 mL) and extracted with EA (50 mL x 3). The combined organic layers were dried over Na2SO4filtered and the filtrate was concentrated under reduced pressure to give (5-fluoropyridine-2,3-diyl)dimethanol (800.0 mg, crude) as a white solid, which was used for the next step without purification. LC-MS: m / z 158.1 (M+H)+.

[1398] 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.8 Hz, 1H), 7.67 (dd, J = 2.8, 10.0 Hz, 1H), 5.44 (t, J = 5.6 Hz, 1H), 5.14 (t, J = 5.6 Hz, 1H), 4.67 (d, J = 5.6 Hz, 2H), 4.55 (d, J = 5.6 Hz, 2H).

[1399] Step B 2,3-bis(chloromethyl)-5-fluoropyridine

[1400]

[1401] To a solution of (5-fhioropyridine-2,3-diyl)dimethanol (800.0 mg, 5.09 mmol) in DCM (5.0 mL) was added dropwise SOCl2(10.0 mL, 137.68 mmol) at 25 °C. After addition, the mixture was stirred at 60 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to give 2,3-bis(chloromethyl)-5-fluoropyridine (950.0 mg, crude) as a yellow oil, which was used for next step without purification. LC-MS: m / z 194.0 (M+H)+.

[1402] Step C dimethyl 3-fluoro-5H-cyclopenta[b]pyridine-6,6(7H)-dicarboxylate

[1403]

[1404] To a solution of 2,3-bis(chloromethyl)-5-fluoropyridine (950.0 mg, 4.90 mmol) and dimethyl malonate (646.84 mg, 4.90 mmol, 561.01 pL) in DMF (70.0 mL) was added K2CO3 (2.03 g, 14.69 mmol) at 25 °C. After addition, the mixture was stirred at 25 °C for 16 hrs. Then Cs₂CO₃ (1.60 g, 4.90 mmol) was added and the reaction mixture was stirred at 65 °C for 3 hrs. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with NaCl aqueous solution (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated underACCG-0008-WO reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-70% Ethyl acetate / Petroleum ether gradient at 35 mL / min) to give dimethyl 3-fluoro-5,7-dihydro-6H-cyclopenta[b]pyridine-6,6-dicarboxylate (580.0 mg, 46.78% yield) as a colorless oil. LC-MS: m / z 254.1 (M+H)+.

[1405] Step D 3-fluoro-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid

[1406] O

[1407]

[1408] To a solution of dimethyl 3-fluoro-5H-cyclopenta[b]pyridine-6,6(7H)-dicarboxylate (560.0 mg, 2.21 mmol) in H2O (5.0 mL) was added dropwise HC1 aqueous solution (11.66 mL, 12 M) at 25 °C. After addition, the mixture was stirred at 100 °C for 3 hrs. The reaction mixture was treated with Nl F*I FC) to pH = 7 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-10% MeOH / DCM gradient at 20 mL / min) to afford 3-fluoro-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid (220.0 mg, 54.91% yield) as a white solid. LC-MS: m / z 182.1 (M+H)+.

[1409] Step E 1-(3-fluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)ethan-1-one

[1410]

[1411] To a solution of potassium 2-(5-methyl-l,3,4-oxadiazol-2-yl)acetate (518.0 mg, 2.87 mmol) in THF (4.0 mL) was added MgCl2(140 mg, 1.47 mmol) and the mixture was stirred at 25 °C for 30 mins to afford reaction mixture A. To a mixture of 3-fluoro-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid (260.0 mg, 1.44 mmol) in THF (4.0 mL) was added CDI (280.0 mg, 1.73 mmol) at 25 °C and the mixture was stirred at 25 °C for 30 mins to afford the mixture B. The mixture A was added drop-wise to the mixture B over a period of 2 mins at 25 °C and the mixture was stirred at 50 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 8 g SepaFlash® Silica Flash Column, Eluent of 0-10% MeOH / DCM gradient at 30 mL / min) to give l-(3-fluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan-l-one (240.0 mg, 64.01% yield) as a purple oil. LC-MS: m / z 262.1 (M+H)+.

[1412] INTERMEDIATE 14

[1413] l-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan-l-one

[1414] / o

[1415]

[1416] Step F

[1417] Step A: diethyl 5-chloropyridine-2,3-dicarboxyIate

[1418]

[1419] A mixture of 2,3-dibromo-5-chloropyridine (20 g, 73.708 mmol), Pd(dppf)C12 (2.70 g, 3.685 mmol) and KOAc (21.70 g, 221.125 mmol) in EtOH (300 ml) was stirred at 75°C overnight under CO atmosphere. After the reaction was completed, the mixture was filtered and the filtrate concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (PE / EA=10 / l) toACCG-0008-WO give diethyl 5-chloropyridine-2,3-dicarboxylate (11 g, 57.92%) as colorless oil. LC-MS: m / z 258.3 (M+H)+.

[1420] Step B: (5-chloropyridine-2,3-diyl)dimethanol

[1421] HO

[1422]

[1423] To a solution of diethyl 5-chloropyridine-2,3-dicarboxylate (8.5 g, 32.988 mmol) in THF (150 mL) was added lithium tris[(2-methylprop-2-yl)oxy]aluminum hydride (19.403 mL, 329.879 mmol), and the reaction was stirred at 70°C for 24 hours. After the reaction was completed, the mixture was quenched with H2O, concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH=20 / l) to give (5-chloropyridine-2,3-diyl)dimethanol (2.92 g, 50.99%) as a white solid. LC-MS: m / z 174.0 (M+H)+.

[1424] Step C: 5-chloro-2,3-bis(chloromethyl)pyridine

[1425] Cl

[1426]

[1427] To a solution of (5-chloropyridine-2,3-diyl)dimethanol (2.92 g, 16.820 mmol) in DCM (50 mL) was added SOCl2(18.301 mL, 252.304 mmol), and the reaction was stirred at rt for 2 hours. After the reaction was completed, the mixture was concentrated under vacuum to dryness. The residue was diluted with DCM (50 mL), adjusted pH to 8 with sat. Na2CO3. The organic layer was washed with water (50 mL), then dried over Na2SO4, filtered and concentrated to give 5-chloro-2,3-bis(chloromethyl)pyridine (3.5 g, 98.86%) as brown oil. LC-MS: m / z 210.1 (M+H)+.

[1428] Step D: dimethyl 3-chloro-5, 7-dihydro-6H-cyclopenla[b]pyridine-6,6-dicarboxylate

[1429] /

[1430] \=o

[1431] / xf / O

[1432] ci — / o

[1433]

[1434] \=N7

[1435] To a solution of 5-chloro-2,3-bis(chloromethyl)pyridine (4.4 g, 20.905 mmol) in DMF (50 mL) were added Cs₂CO₃ (20.43 g, 62.714 mmol), and methyl 3-methoxy-3-oxopropanoate (2.76 g, 20.905ACCG-0008-WO mmol), and the reaction was stirred at 65 °C for 3 hours. After the reaction was completed, the mixture was diluted with EA (100 mL), washed with water (300 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH=20 / l) to give dimethyl 3-chloro-5,7-dihydro-6H-cyclopenta[b]pyridine-6,6- dicarboxylate (2.1 g, 37.25%) as a white solid. LC-MS: m / z 270.0 (M+H)+.

[1436] Step E: 3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid

[1437]

[1438] To a solution of dimethyl 3-chloro-5,7-dihydro-6H-cyclopenta[b]pyridine-6,6-dicarboxylate (1.6 g, 5.933 mmol) in H2O (5 mL) was added HCl (15 mL), and the reaction was stirred at 100°C overnight. After the reaction was completed, the reaction mixture was treated with NH3•H2O to pH = 7 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (DCM / MeOH=20 / l) to give 3-chloro-6,7-dihydro-5H- cyclopenta[b]pyridine-6-carboxylic acid (800 mg, 68.23%) as a white solid. LC-MS: m / z 198.0 (M+H)+. Step F: l-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan- 1-one

[1439]

[1440] A solution of 3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid (810 mg, 4.099 mmol) and CDI (797.54 mg, 4.919 mmol) in THF (10 mL) was stirred at room temperature for 1 hour to afford the active ester solution. A mixture of potassium 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate (2215.80 mg, 12.296 mmol) and MgCl2(428.32 mg, 4.509 mmol) in THF (10 mL) was stirred rt for 1 hour, then was added dropwise with the active ester solution at room temperature. The reaction was stirred at 50 °C overnight. After the reaction was completed, the mixture was concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (DCM / MeOH=20 / l) to give l-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)-2-(5-methyl-l,3,4-oxadiazol-2-yl)ethan-l-one (400 mg, 35.14%) as purple oil. LC-MS: m / z 278.0 (M+H)+.The following compounds were synthesized following the similar route to Intermediate 14.

[1441] Structure LC-MS / NMR

[1442] N~N

[1443] — X1H NMR (400 MHz, CDCl3) δ = 7.38 - 7.26 (m,

[1444] 1H), 6.92 - 6.83 (m, 1H), 4.06 - 4.01 (m, 2H), 3.62 - 3.47 (m, 1H), 3.29 - 3.02 (m, 4H), 2.45 (s, 3H).

[1445] / N

[1446] N'N

[1447] —

[1448] °" l

[1449] LC-MS: m / z 274.2 (M+H)+.

[1450] 0\ / " J

[1451] N= /

[1452] N~N

[1453] — X1H NMR (400 MHz, CDCl3) δ ppm 8.08 - 8.23 (m, 1 H), 7.08 - 7.16 (m, 2 H), 3.87 - 3.97 (m, 2 H),

[1454] 3.33 - 3.42 (m, 1 H), 3.16 - 3.24 (m, 4 H), 2.46 - Ci —

[1455] 2.50 (m, 3 H).

[1456]

[1457] INTERMEDIATE 15

[1458] 4-((5-fluoropyridin-2-yl)methyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde

[1459]

[1460] ACCG-0008-WO

[1461] n-BuLi, i-PrMgCI DMF, THF, -30-25 °C Step B

[1462] Step A7-bromo-2,2-dimethyl-2H-benzo[b][l,4]oxazin-3(4H)-one

[1463]

[1464] Br To a solution of 2-amino-5 -bromophenol (25. g, 132.96 mmol) in acetone (200 mL) was added K2CO3 (55.13 g, 398.89 mmol) and methyl 2-bromo-2-methyl-propanoate (33.70 g, 186.15 mmol, 24.09 mL). The mixture was stirred at 60 °C for 48 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was triturated with PE at 20 °C for 1 hr. Compound 7-bromo-2,2-dimethyl-2H-benzo[b][l,4]oxazin-3(4H)-one (27 g, 105.43 mmol, 79.29% yield) was obtained as a gray solid.

[1465] ¹H NMR (400 MHz, CDCl₃) δ ppm 8.54 - 8.71 (m, 1 H), 7.07 - 7.16 (m, 2 H), 6.68 - 6.73 (m, 1 H), 1.54 - 1.58 (m, 6 H).

[1466] Step B 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][ 1,4 ]oxazine-7-carbaldehyde

[1467] O

[1468] 11 1

[1469]

[1470] %

[1471] To a solution of 7-bromo-2,2-dimethyl-4H-l,4-benzoxazin-3-one (15 g, 58.57 mmol) in THF (200 mL) was added chloro(isopropyl)magnesium (2 M, 32.21 mL) at -10 °C for 30 min and butyllithiumACCG-0008-WO (2.5 M, 93.72 mL) at -30 °C for 30 min. Then DMF (17.12 g, 234.29 mmol, 18.03 mL) was added at -10 °C. The mixture was stirred at 25 °C for 1.5 hrs. The reaction was quenched with 100 mL of water. The solid was filtered out. The filtrate was diluted with H2O (200 mL) and extracted with EtOAc (400 mL * 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;220 g SepaFlash® Silica Flash Column, Eluent of 0-40 % Ethyl acetate / Petroleum ether gradient at 100 mL / min). Compound 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-7-carbaldehyde (10 g, 48.73 mmol, 83.20% yield) was obtained as a yellow oil.

[1472] ¹H NMR (400 MHz, CDCl₃) δ ppm 9.86 - 9.95 (m, 1 H), 9.03 - 9.24 (m, 1 H), 7.47 - 7.62 (m, 2 H), 6.94 - 7.08 (m, 1 H), 1.50 - 1.68 (m, 6 H)

[1473] Step C 4-((5-fluoropyridin-2-yl)methyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][I,4]oxazine-7-carbaldehyde

[1474] o

[1475] YNN\

[1476] I

[1477] T

[1478]

[1479] To a solution of 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-7-carbaldehyde (3 g, 14.62 mmol) in DMF (30 mL) was added K2CO3 (6.06 g, 43.86 mmol) and 2-(chloromethyl)-5-fluoro-pyridine;hydrochloride (3.19 g, 17.54 mmol). The mixture was stirred at 50 °C for 64 hrs. The residue was diluted with H2O (50 mL) and extracted with EtOAc (40 mL * 3). The combined organic layers were washed with brine (60 mL * 4), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetatc / Pctrolcum ether gradient at 100 mL / min).

[1480] Compound 4-[(5-fluoro-2-pyridyl)methyl]-2,2-dimethyl-3-oxo- 1,4-benzoxazine-7-carbaldehyde (2.7 g, 8.59 mmol, 58.76% yield) was obtained as a white solid.

[1481] ¹H NMR (400 MHz, CDCl₃) δ ppm 9.82 - 9.96 (m, 1 H), 8.40 - 8.47 (m, 1 H), 7.50 - 7.52 (m, 1 H), 7.45 - 7.49 (m, 1 H), 7.36 - 7.44 (m, 1 H), 7.25 - 7.31 (m, 1 H), 7.16 - 7.23 (m, 1 H), 5.19 - 5.35 (m, 2 H), 1.56 - 1.62 (m, 6 H).The following compounds were synthesized following the similar route to Intermediate 15.

[1482] O—\

[1483] ) / O== / Structure LC-MS / NMR

[1484] ¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (s, 1H), 8.75 (s, 1H), 8.47 (dd, J = 1.7, 9.9 Hz, 1H), 7.55 (dd, J = 1.8, 8.2 Hz, 1H),amp;

[1485] 7.48 (d, J = 1.8 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 5.43 (s, 2H), 1.48 (s, 6H). LC-MS: m / z 340.1 (M+H)⁺.

[1486]

[1487] INTERMEDIATE 16

[1488] -((5-chloropyrimidin-2-yl)methyl)-2,2-difluoro-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-7- carbaldehyde

[1489] DMF, n-BuLi, i-PrMgCI THF, -30-25 °C

[1490]

[1491] Step C Step DACCG-0008-WO Step A 2-bromo-N-(4-bromo-2-hydroxyphenyl)-2,2-difluoroacetamide

[1492] O

[1493] -Br

[1494]

[1495] Br

[1496] A mixture of ethyl 2-bromo-2,2-difluoro-acetate (78.75 g, 387.97 mmol, 50 mL), TEA (29.81 g, 294.57 mmol, 41 mL), 2-amino-5 -bromo-phenol (50 g, 265.93 mmol) in EtOAc (500 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 2 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was triturated with PE / EA=5 / 1 at 22 °C for 30 min. Compound2-bromo-N-(4-bromo-2-hydroxyphenyl)-2,2-difluoroacetamide (48.2 g, 139.74 mmol, 52.55% yield) was obtained as a yellow solid.

[1497] ¹H NMR (400 MHz, CDCl₃) δ ppm 8.38 - 8.26 (m, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.22 - 7.11 (m, 2H), 6.40 (s, 1H). LC-MS: m / z 345.9 (M+H)⁺.

[1498] Step B 7-bromo-2,2-difluoro-2H-benzo[b][1,4]oxazin-3(4H)-one

[1499]

[1500] Br

[1501] To a solution of 2-bromo-N-(4-bromo-2-hydroxyphenyl)-2,2-difluoroacetamide (48.2 g, 139.74 mmol) in DMF (500 mL) was added K2CO3 (37 g, 267.72 mmol). The mixture was stirred at 60 °C for 2 hrs. The residue was diluted with H2O (1 L) and extracted with EtOAc (I L * 2). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with PE / EA=5 / 1 at 22 °C for 10 min. Compound 7-bromo-2,2-difluoro-2H-benzo[b][l,4]oxazin-3(4H)-one (10.5 g, 39.77 mmol, 28.46% yield) was obtained as a yellow solid.

[1502] ¹H NMR (400 MHz, CDCl₃) δ ppm 7.40 (d, J = 2.0 Hz, 1H), 7.37 - 7.31 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H).ACCG-0008-WO Step C 2,2-difluoro-3-oxo-3,4-dihydro-2H-benzo[b][ 1,4]oxazine-7-carbaldehyde

[1503]

[1504] A solution of 7-bromo-2,2-difluoro-2H-benzo[b][l,4]oxazin-3(4H)-one (10 g, 37.88 mmol) in THF (200 mL) was degassed and purged with N2 for 3 times. Chloro(isopropyl)magnesium (1 M, 40.00 mL) was added at -10 °C for 30 min and then butyllithium (2.5 M, 60.00 mL) was added at -30 °C for 30 min. Then N, N-dimethylformamide (11.88 g, 162.46 mmol, 12.50 mL) was added at -10 °C. The mixture was stirred at 25 °C for 1.5 hrs under N2 atmosphere. The reaction was then quenched by 200 mL of water / ice. The solids were filtered out. The filtrate was diluted with H2O (200 mL) and extracted with EtOAc (500 mL * 2). The combined organic layers were washed with brine (100 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30 % Ethyl acetate / Petroleum ether gradient at 35 mL / min). Compound 2,2-difluoro-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-7-carbaldehyde (4.8 g, 22.52 mmol, 59.46% yield) was obtained as a white solid.

[1505] ¹H NMR (400 MHz, CDCl₃) δ ppm 10.19 - 9.73 (m, 1H), 7.81 - 7.58 (m, 2H), 7.08 (d, J = 8.8 Hz, 1H)

[1506] Step D 2,2-difluoro-3-oxo-3,4-dihydro-2H-benzo[b][ 1,4 Joxazine-7-carbaldehyde

[1507]

[1508] To a solution of 2,2-difluoro-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-7-carbaldehyde and 5-chloro-2-(chloromethyl)pyrimidine (1.10 g, 6.76 mmol) in MeCN (10 mL) was added K2CO3 (2.5 g, 18.09 mmol) and KI (187 mg, 1.13 mmol). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30 % EthylACCG-0008-WO acetate / Petroleum ether gradient at 18 mL / min). Compound 2,2-difluoro-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazine-7-carbaldehyde (1.86 g, 5.48 mmol, 97.26% yield) was obtained as a yellow solid.

[1509] ¹H NMR (400 MHz, CDCl₃) δ ppm 9.85 (s, 1H), 8.58 (s, 2H), 7.68 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 1.6, 8.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.39 (s, 2H).

[1510] INTERMEDIATE 17

[1511] 5-chloro-2-(chloromethyl)-3-methoxypyridine

[1512] ^0

[1513] Step A Step B

[1514]

[1515] Step C

[1516] Step A 5-chloro-2-iodo-3-methoxypyrid.ine

[1517]

[1518] To a solution of 5-chloro-2-iodo-3-methoxy-pyridine (3.7 g, 13.73 mmol) in DMF (15 mL) was added Mel (2.92 g, 20.60 mmol, 1.28 mL) and K2CO3 (2.85 g, 20.60 mmol). The mixture was stirred at 25 °C for 2 hrs. The reaction was quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic was washed with brine (50 mL), dried over Na2SO4, and filtered, concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50 % Ethyl acetate / Petroleum ether gradient at 50 mL / min) to give the product compound 5-chloro-2-iodo-3-methoxy-pyridine (2.7 g, 72.97% yield) as a white solid. LC-MS: m / z 269.8 (M+H)+.ACCG-0008-WO ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.97 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 3.93 (s, 3H). LC-MS: m / z 269.8 (M+H)⁺.

[1519] Step B (5-chloro-3-methoxypyridin-2-yl)methanol

[1520]

[1521] A mixture of 5-chloro-2-iodo-3-methoxy-pyridine (2.7 g, 10.02 mmol), tributylstannylmethanol (4.83 g, 15.03 mmol), XPhos Pd G3 (848 mg, 1.00 mmol) in toluene (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 3 hrs under N2 atmosphere. The reaction was quenched with H2O (30 mL) and saturated aq. KF (30 mL), diluted with EtOAc (70 mL) and filtered. The filtrate was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (70 mL) and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-40% Ethyl acetate / Petroleum ether gradient at 60 mL / min) to give the product Compound (5-chloro-3-methoxy-2-pyridyl) methanol (1.1 g, 44.27% yield, 70% purity) as a yellow solid. LC-MS: m / z 173.7 (M+H)+.

[1522] ¹H NMR (400 MHz, CDCl₃) δ ppm 8.14 (d, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 4.71 (s, 2H), 3.87 (s, 3H). LC-MS: m / z 173.7 (M+H)⁺.

[1523] Step C 5-chloro-2-(chloromethyl)-3-methoxypyridine

[1524]

[1525] To a solution of (5-chloro-3-methoxy-2-pyridyl) methanol (0.3 g, 1.21 mmol) in DCM (5 mL) was added SOCl₂ (1.97 g, 16.52 mmol, 1.2 mL). The mixture was stirred at 25 °C for 2 hrs. The reaction was concentrated under reduced pressure to give the product 5-chloro-2-(chloromethyl)-3-methoxy-pyridine (0.23 g, 69.30% yield, 70% purity) as a yellow oil. The crude was used next step without purification. LC-MS: m / z 192.1 (M+H)+.

[1526] ¹H NMR (400 MHz, CDCl₃) δ ppm 8.17 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 4.70 (s, 2H), 3.92 (s, 3H). LC-MS: m / z 192.1 (M+H)⁺.INTERMEDIATE 18

[1527] (R)-7-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)thieno[2,3-c]pyridine-2-carbaldehyde

[1528] Step A (R)-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)thieno[2,3-c]pyridin-7-amine

[1529]

[1530] A mixture of 7-chlorothieno[2,3-c]pyridine (1.2 g, 7.10 mmol), (R)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine (1.14 g, 8.52 mmol), xantphos (820 mg, 1.42 mmol), Cs₂CO₃ (5.5 g, 17.0 mmol) and Pd₂(dba)₃ (324 mg, 0.71 mmol) in toluene (20 mL) was stirred at 110°C for 16 hours under N2. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=10 / l) to give (R)-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)thieno[2,3-c]pyridin-7-amine (567 mg, yield: 30.0%) as a yellow solid. LC-MS: m / z 268.1 (M+H)+.

[1531] Step B (R)-7-( ( 6, 7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)thieno[2,3-c]pyridine-2-carbaldehyde

[1532]

[1533] To a solution of (R)-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)thieno[2,3-c]pyridin-7-amine (567 mg, 2.12 mmol) in THF (8 mL) was added Lithium diisopropylamide (2 M in THF, 5.3 ml, 10.62 mmol) slowly at -78°C under N2 and stirred for 1 hour. Then DMF (1.4 ml, 16.99 mmol) was added and stirred at -78°C for 2 hour. The mixture was quenched with H2O (50 mL), extracted with EtOAc (50 mL*2). The combined organic layers were washed with aq. NH4C1 (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column (DCM / MeOH = 20 / 1) to give (R)-7-((6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)amino)thieno[2,3-c]pyridine-2-carbaldehyde (376 mg, yield: 60.1%) as a yellow solid. LC-MS: m / z 296.1 (M+H)+.

[1534] INTERMEDIATE 19

[1535] 4-isopropyldihydrothiophen-3(2H)-one 1,1-dioxide

[1536] HCHO, LiHMDS m-CPBA -78 °C to 20 °C phenylmethanamine DCM, rt TEA, EtOH, H2O, rt Step A StepC Step B

[1537] LiHMDS THF, -78 °C

[1538]

[1539] Step D

[1540] Step A ethyl 3-methyl-2-methylenebutanoate

[1541]

[1542] A solution of ethyl 2-acetyl-3-methylbutanoate (12 g, 69.678 mmol) in THF (300 mL) was cooled to -78°C under N2 atmosphere. Lithium bis(trimethylsilyl)amide, IM solution in THF (76.646 mL) was added dropwise, and then dry ice bath was removed for 30 min. The reaction was cooled to -78 °C, and Paraformaldehyde (9.82 g, 327.488 mmol) was added in one portion. After 30 min, the dry ice bath wasACCG-0008-WO removed and the mixture was allowed to warm to 20°C for 16 hrs. The reaction mixture was quenched by addition of aq. NH4CI 150 mL at 20°C. The mixture was extracted with DCM (80 mL x 3). The combined organic layers were washed with brine 200 mL, dried over Na2SO4, filtered and concentrated to give ethyl 3-methyl-2-methylenebutanoate (17 g, 59.775 mmol, 85.79%) yellow oil.

[1543] ¹H NMR (400 MHz, CDCl₃) δ 5.96 (s, 1 H), 5.35 (s, 1 H), 4.06 (q, J = 7.2 Hz, 2 H), 2.53 - 2.72 (m, 1 H), 1.15 (t, J = 7.2 Hz, 3 H), 0.93 (d, J = 6.8 Hz, 6 H),

[1544] Step B ethyl 3-methyl-2-((methylthio)methyl)butanoate

[1545] )

[1546]

[1547] A mixture of ethyl 3-methyl-2-methylenebutanoate (17 g, 59.775 mmol), methyl carbamimidothioate sulfuric acid (11.25 g, 59.775 mmol), TEA (8.309 mL, 59.775 mmol) and phenylmethanamine (6.524 mL, 59.775 mmol) in EtOH (200 mL) and H2O (200 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 16 hrs under N2 atmosphere. After the reaction was completed, the mixture was diluted with DCM (200 mL), washed...

Claims

ACCG-0008-WO CLAIMS:

1. A compound of Formula I:or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:A is Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, heterocyclylene, arylene, or heteroarylene; wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, heterocyclylene, arylene, or heteroaryl of A is independently optionally substituted with one to five ZA;Ring B is a 5- or 6-membered heteroaryl optionally substituted with one to three RB; or a 5- x<x14membered heterocyclyl of formula x4I~ '; wherein:X1is 0, S, NH, NRA, CH2, or CHRB;one of X2and X3is C(0); and the other of X2and X3is O, S, NH, NRA, CH2, or CHRB; and X4is N, CH, or CRB;provided that at least one of X1, X2, X3, and X4is a heteroatom;each RAis independently selected from cyano, C1-3 alkyl, and C1-3 haloalkyl; wherein each C1-3 alkyl of RAis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, hydroxy, or C1-3 alkoxy;each RBis independently selected from halo, hydroxy, -NH2, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl; wherein each C1-3 alkyl of RBis independently optionally substituted with -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)-. hydroxy, or C1-3 alkoxy;L2is a bond, -0-, -S-, -NR2a-, -C(0)-, -C(0)0-, -0C(0)-, -0C(0)0-, -C(0)NR2a-, -NR2aC(0)-, -0C(0)NR2a-, -NR2aC(0)0-, -NR2aC(O)NR2b-, -S(0)-, -S(0)2-, -S(O)NR2a-, -S(O)2NR2a-, -NR2aS(0)-, -NR2aS(O)2-, -NR2aS(O)NR2b-, -NR2aS(O)2NR2b-, C1-6 alkylene, C26 alkenylene, C26 alkynylene, C1-6 heteroalkylene, C3-6 cycloalkylene, 4-6 membered heterocyclylene, or 5 membered heteroarylene; whereinACCG-0008-WO the Ci-3 alkylene, C2-3 alkenylene, C2-3 alkynylene, C1-3 heteroalkylene, C3-6 cycloalkylene, 4-6 membered heterocyclylene, or 5 membered heteroarylene of L2is independently optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, -NH2, -NHC1-3 alkyl, -N(CI-3 alkyl)2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;R1is cyano, -C(O)NRlaRlb, -C(S)NRlaRlb, -S(O)2R2, -S(O)(NR6)R2, or -P(O)R7R2;R2is -NRlaRlb, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R2is optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1.3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1.3 haloalkyl, C1.3 alkoxy, or C1.3 haloalkoxy; each Rlaand Rlbis independently hydrogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4-6 membered heterocyclyl; wherein each C1.3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1.3 haloalkyl, C3-6 cycloalkyl, or 4-6 membered heterocyclyl of Rlaand Rlbis independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;or Rlaand Rlbare taken together with the atoms to which they are attached to form 4-6 membered heterocyclyl independently optionally substituted by one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;or R2and R6, or R2and R7, together with the atom to which they are attached, form a heterocyclyl optionally substituted with one to five Z2;or R1is Y1; R3is Y3; and Y1and Y3, together with Y2and carbon atoms to which R1and R3areattached, form a heterocyclyl of formula; wherein:• Y1is -C(O)-, -C(S)-, -S(O)2-, -S(O)(NR6)-, or -P(O)(R7)-;Y2is -O-, -S-, -NR12-, or -C(R12)2-; wherein the bond between Y1and Y2is a single bond; and Y3is -NR8-, -O-, -S-, -C(R9)2-, -NR8-C(R9)2-, -O-C(R9)2-, -S-C(R9)2-, -C(R9a)2-C(R9a)2-, -C(R9a)2- C(R9a)2-C(R9a)2-, or -CR9=CR9-; or• Y1is -C(O)-, -C(S)-, -S(O)2-, -S(O)(NR6)-, or -P(O)(R7)-;Y2is -N- or -CR12-, andY3is -N- or -CR9-; wherein the bond between Y2and Y3is a double bond; or• Y1is -N- or -CR11-;ACCG-0008-WO Y2is -N- or -CR12-; wherein the bond between Y1and Y2is a double bond; andY3is -NR8-, -O-, or -S-;provided that the ring comprising Y1, Y2, and Y3contains at least one heteroatom;each R2aand R2bis independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R2aand R2bis independently optionally substituted with one to five Z2a;or R2aand R2bare taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Z2a;R3is hydrogen, -NR3bR3c, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-e alkoxy, Ci-e haloalkoxy, Ci-6 heteroalkyl, Ci-s haloalkyl, Ci-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the Ci-c alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-c alkoxy, Ci-6 heteroalkyl, Ci-e haloalkyl, Ci-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or hctcroaryl of R3is independently optionally substituted with one to five Z3;R3band R3care each independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R3band R3cis independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;or R3band R3care taken together with the nitrogen atom to which they are attached to form a heterocyclyl optionally substituted with one to five Z3b;R4is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4is independently optionally substituted with one to five Z4;R5is hydrogen, halo, hydroxy, amino, cyano, Ci-e alkyl, Ci-6 alkoxy, Ci-s haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R5is independently optionally substituted with one to five Z5;R6is hydrogen, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4 to 6-mcmbcred heterocyclyl; wherein the C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;ACCG-0008-WO R7is hydroxy, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, or C1-3 haloalkyl;R8is hydrogen, -S(O)2-Ci-3 alkyl, -S(O)2-Ci-3 haloalkyl, C1.3 alkyl, C1-3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl; wherein the -S(O)2-Ci-3 alkyl, -S(O)2-Ci-3 haloalkyl, C1.3 alkyl, C1-3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl of R8is optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;each R9is independently hydrogen, hydroxy, -NR9bR9c, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, Ci-e haloalkyl, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, Ci-e heteroalkyl, Ci-e haloalkyl, Ci-e haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R9is independently optionally substituted with one to five Z9;or two R9, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, aryl, or hctcroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or hctcroaryl is optionally substituted with one to five Z9;or two R9, together with the carbon atom to which both are attached, form an oxo;each R9ais independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-e alkoxy, Ci-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R9ais independently optionally substituted with one to five Z9a;or two R9a, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z9a;or two R9a, together with the carbon atom to which both are attached, form an oxo;R11is hydrogen, halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;each R12is independently hydrogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl; wherein each C1-3 alkyl, C2-3 alkenyl, C23 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl of R12is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;ACCG-0008-WO or R12and any one or two of R6, R7, R8, R9, R9a, and R11, together with the atoms to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z12;each ZA, Z2, Z2a, Z3, Z3b, Z4, Z5, Z9, Z9a, and Z12; is independently halo, cyano, nitro, oxo, =CF2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, Cue haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z2, Z2a, Z3, Z3b, Z4, Z5, Z9, Z9a, and Z12are each independently optionally substituted with one to five Zla;each L is independently -O-, -S-, -NR20-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)NR20-, -NR20C(O)-, -OC(O)NR20-, -NR20C(O)O-, -NR20C(O)NR21-, -S(O)-, -S(O)2-, -S(O)NR20-, -S(O)2NR20-, -NR20S(O)-, -NR20S(0)2-, -NR20S(O)NR21-, or -NR20S(O)2NR21-;each R20and R21is independently hydrogen, Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20and R21is independently optionally substituted with one to five Zla; or an R20and R21are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Zla; andeach Zlais independently halo, hydroxy, cyano, nitro, oxo, -SH, -NH2, -NH-C1-6 alkyl, -N(Ci s alkyl)2, -S-C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each -NH-Ci-s alkyl, -N(Ci-e alkyl)2, -S-Ci-e alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Zlais independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;provided that when R4is substituted C3-6 cycloalkylene or substituted 4-6 membered heterocyclylene; then Z4is not unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-10 cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; andprovided that when A is Cue alkylene; then R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein the wherein the compound is represented by Formula II:ACCG-0008-WO3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein R3is C1-6 alkyl optionally substituted with C3-10 cycloalkyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein R3is isobutyl or cyclopropylmethyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein the wherein the compound is represented by Formula III:R56. The compound of claim 1 or 5, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein the wherein the compound is represented by Formula IIIA or IIIB:IIIA7. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Y3is -NR8- or -C(R9)2-.

8. The compound of claim 6 or 7, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein R12is hydrogen; and Y3is -C(R9)2-.

9. The compound of claim 6 or 7, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein R12and R8, or R12and one or two R9, together with the atoms to which they are attached, form a C3-10 cycloalkyl or heterocyclyl; wherein the C3-10 cycloalkyl orACCG-0008-WO heterocyclyl is optionally substituted with one to five Z12.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein A is heterocyclylene or heteroarylene; wherein the heterocyclylene or heteroarylene is optionally substituted with one to five ZA.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer,mixture of stereoisomers, or solvate thereof, wherein Ring Ais wherein each is independently optionally substituted with one to three substituents independently selected from halo and Ci-e alkyl; and wherein bond a is bonded to L2.

12. I’he compound of any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein L2is -CH2-, -NH-, or -NHCH2-.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein R5is C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to three Z5.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein R5is 2,3-dihydro-1H-indenyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, phenyl, pyridyl, or pyrimidinyl; wherein each is optionally substituted with one to three substituents independently selected from halo, cyano, and -O-Ci-6 alkyl.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B is a 5 -membered heteroaryl optionally substituted with RB.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B is:; wherein each is optionally substituted with RB.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B is 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4- oxadiazolyl; wherein each is optionally substituted with C1-3 alkyl or cyclopropyl.

17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein Ring B is a 5-membered heterocyclyl of formula18. The compound of any one of claims 1-14 or 17, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers, or solvate thereof, wherein RingB is19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein R4is C7-10 cycloalkyl, 7- to 10-membered heterocyclyl, aryl, or heteroaryl; wherein the C7-10 cycloalkyl, 7- to 10-membered heterocyclyl, aryl, or heteroaryl, aryl, or heteroaryl is optionally substituted with one to five Z4.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein R4is:ACCG-0008-WO 21. The compound of claim 1, 5, or 6, wherein the compound is represented by Formula IV:F FIVor a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:n is 0, 1, or 2;X is N or CH;Y is N or CH;optionally substituted with RB;R4ais hydrogen, halo, C1-3 alkyl, C1-3 haloalkyl, or cyclopropyl;each Z5is independently halo or cyano; andRBis cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and cyclopropyl.

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

23. A pharmaceutical composition comprising a compound of any preceding claim, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, and a pharmaceutically acceptable excipient.

24. A method for treating a calcitonin receptor and / or an amylin receptor associated disease or disorder in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-22, or a pharmaceuticallyACCG-0008-WO acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, or a pharmaceutical composition of claim 23.

25. The method of claim 24, wherein the calcitonin receptor and / or amylin receptor associated disease or disorder is a bone disorder, a metabolic disorder, pain, a neurodegenerative disease or disorder, a cardiovascular disease, or other disease or disorder.

26. The method of claim 24, wherein the calcitonin receptor and / or amylin receptor associated disease or disorder is osteoporosis, Paget’s disease, hypercalcemia, Sudeck’s atrophy, polystatic fibrous displasia, intersemocostoclavicular ossification, osteogenesis imperfecta, osteopenia, periodontal disease or defect, osteolytic bone disease, metastatic bone disorder, bone loss resulting from a malignancy, autoimmune arthritides, a breakage or fracture, or immobility or disuse, osteopathic pain, phantom limb pain, general pain, hyperalgesia, pain associated with diabetic neuropathy, non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), Alzheimer’s disease, insulin dependent diabetes, non-insulin dependent diabetes, impaired glucose tolerance, obesity, syndrome X, a diabetic complication, primary or secondary hyperthyroidism, endocrine disorder, conditions associated with inhibiting gastric secretion, gastrointestinal disorders, renal osteodystrophy, or male infertility.

27. The method of any one of claims 24-26, further comprising administering an additional therapy or therapeutic agent to the patient.

28. The method of claim 27, wherein the additional therapy or therapeutic agent is selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a weight loss agent, a GLP-1 receptor agonist, an anti -emetic agent, an agent to metabolic dysfunction-associated steatohepatitis (MASH), gastric electrical stimulation, dietary monitoring, physical activity, or a combination thereof.

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