Methods of treating inflammatory diseases

Abstract

The present application relates to compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts thereof, and compositions comprising same. Also described are methods of treating the diseases and disorders disclosed herein, with the compounds of Formula (I), and pharmaceutically acceptable salts thereof, and the compositions comprising same.

Description

METHODS OF TREATING INFLAMMATORY DISEASESCLAIM OF PRIORITY

[0001] This application claims priority to U.S. Provisional Application No. 63 / 573,002 filed on April 2, 2024 and U.S. Provisional Application No. 63 / 758,756 filed on February 14, 2025; the entire contents of all of which are hereby incorporated by reference.TECHNICAL FIELD

[0002] The present application relates to the fields of chemistry and biology, in particular to compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts thereof, and compositions comprising same. Also described are methods of treating the diseases and disorders disclosed herein, with the compounds of Formula (I), and pharmaceutically acceptable salts thereof, and the compositions comprising same.BACKGROUND

[0003] Receptor interacting protein kinase 2 (RIPK2) is a serine-threonine protein kinase and is a signaling molecule downstream of nucleotide-binding oligomerization domain 1 (NODI), NOD2, and Toll-like receptors (TLRs). The RIPK2 protein includes a kinase domain (KD), an intermediate domain (INTD), and a caspase activation and recruitment domain (CARD). The CARD domain of RIPK2 mediates interaction with NODI and NOD2. RIPK2 is expressed in the cytoplasm of antigen- presenting cells including dendritic cells and macrophages and is also expressed in T cells and epithelial cells.

[0004] NOD receptors function in the innate immune system, detecting bacterial pathogens by binding to diaminopimelic acid or muramyl dipeptide residues present in bacterial peptidoglycans. Interactions between RIPK2 and NODI, NOD2 and TLRs trigger the release of pro-inflammatory cytokines including TNF-a, IL-6, and IL- 12 / 23p40, and RIPK2-mediated induction of NF-kappa-B-dependent inflammatory responses. Activation of RIPK2 and dysregulation of the RIPK2-NOD signaling pathways may also have a role in the pathogenesis of various inflammatory diseases. RIPK2 has beenreported to be a prognostic indicator and candidate therapeutic target for various cancers.

[0005] It was previously thought that the kinase activity of RIPK2 is an important contributing factor for the pathogenesis of certain diseases. Recent data indicate that the protein-protein interaction (PPI) between RIPK2 and and its interacting partners (such as N0D2 and X-linked inhibitor of apoptosis protein (XIAP)) is also a contributing factor for pathogenesis. As such, there is unmet need for inhibitors that can block both the kinase activity of RIPK2 and the PPI between RIPK2 and RIPK2-binding partners as well as formulations that can deliver such RIPK2 inhibitors.

[0006] Biologies and small molecules targeting pro-inflammatory signaling pathways have been used to successfully treat inflammatory and other diseases in patients, however, a significant fraction of patients are refractory to existing therapies.SUMMARY

[0007] The present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3A, R3B, R6A, R6B, R4, ring A, W, X, Y, Z1, Z2, m, and n are defined herein.

[0008] The present disclosure also provides a compound of Formula (Ila):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3A, R5B, ring A, Z1, Z2, m, and n are defined herein.

[0009] The present disclosure also provides a compound of Formula (lib):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5A, R5B, ring A, Z1, Z2, m, and n are defined herein.

[0010] The present disclosure also provides a compound of Formula (Illa):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5A, R5B, ring A, Z1, Z2, m, and n are defined herein.

[0011] The present disclosure also provides a compound of Formula (Illb):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3A, R5B, ring A, Z1, Z2, m, and n are defined herein.

[0012] The present disclosure also provides a compound of Formula (IVa):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5A, R5B, ring A, Z1, Z2, m, and n are defined herein.

[0013] The present disclosure also provides a compound of Formula (IVb):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3A, R5B, ring A, Z1, Z2, m, and n are defined herein.

[0014] The present disclosure also provides a compound of Formula (Va):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5A, R5B, ring A, Z1, Z2, m, and n are defined herein.

[0015] The present disclosure also provides a compound of Formula (Vb):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3A, R5B, ring A, Z1, Z2, m, and n are defined herein.

[0016] The present disclosure also provides a compound of Formula (Vc):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5A, R3B, ring A, Z1, Z2, m, and n are defined herein.

[0017] The present disclosure also provides a compound of Formula (Vd):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5A, R5B, ring A, Z1, Z2, m, and n are defined herein.

[0018] The present disclosure also provides a compound of Formula (Via):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5A, R5B, Z1, Z2, U, m, and n are defined herein.

[0019] The present disclosure also provides a compound of Formula (VIb):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5A, R5B, Z1, Z2, U, m, and n are defined herein.

[0020] The present disclosure also provides a compound of Formula (Vic):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3A, R5B, Z2, U, and n are defined herein.

[0021] The present disclosure also provides a compound of Formula (Vid):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5A, R3B, Z2, U, and n are defined herein.

[0022] The present disclosure also provides a compound of Formula (Vie):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3A, R5B, U, and n are defined herein.

[0023] The present disclosure also provides a compound of Formula (VIf):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3A, R5B, U, and n are defined herein.

[0024] Also provided herein is a method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (e.g.,a compound of Formula (I), Formula (Ila), Formula (Tib), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Via), Formula (VIb), Formula (Vic), Formula (Vid), Formula (Vie), Formula (VIf), or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety, unless expressly indicated otherwise. In case of conflict, the present specification, including definitions, will control.

[0026] Other features and advantages of the disclosure will be apparent from the following detailed description and figures, and from the claims.DETAILED DESCRIPTION

[0027] The present disclosure describes compounds of Formula (I), and pharmaceutically acceptable salts thereof, for, e.g., the treatment of inflammatory and other diseases in patients, including diseases refractory to existing therapies.Definitions

[0028] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that arementioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. In case of conflict, the present specification, including definitions, will control.

[0029] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.

[0030] The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a disease or disorder as described herein (e.g., inflammatory bowel disease), (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease or disorder, or (iii) delay the onset of one or more symptoms of the particular disease or disorder described herein.

[0031] As used herein, the terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder, diminishment of the extent of a neurological disorder, stabilized (i.e., not worsening) state of a disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease or disorder), and remission (whether partial or total), whether detectable or undetectable and can be determined by various clinical assessments including clinical evaluation and self-reporting. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0032] The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid fdler, diluent, carrier, solvent, or encapsulating material. In one embodiment, 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 areasonable 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 el 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.

[0033] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaricacid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0034] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “pharmaceutically acceptable excipients”), such as stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or other excipients. The pharmaceutical composition facilitates administration of the compound to an organism.

[0035] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.

[0036] The term “halo” or “halogen” refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0037] The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.

[0038] The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, Ao-propyl, / c / 7-butyl, n-hexyl.

[0039] The term “alkenyl” refers to an acyclic hydrocarbon radical that may be a straight chain or branched, containing the indicated number of carbon atoms and one or more carbon-carbon double bonds. Non-limiting examples include ethylenyl and allyl.

[0040] The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0041] The term “hydroxyalkyl” refers to an alkyl group as described herein, in which one or more hydrogen atoms is / are replaced with one or more hydroxyl groups, as described herein.

[0042] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

[0043] The term “thioalkyl” refers to an alkyl group as described herein, whichis attached to a molecule via a sulfur atom (e g., -SCH3).

[0044] The term “haloalkoxy” refers to a haloalkyl group which is attached to a molecule via an oxygen atom (e.g., -OCF3).

[0045] The term “alkoxyalkyl” refers to an alkyl group as described herein, in which one or more hydrogen atoms is / are replaced with one or more alkoxy groups as described herein.

[0046] As used herein, the term “cyano” refers to a -CN radical.

[0047] As used herein, the term “hydroxyl” refers to an -OH radical.

[0048] As used herein, the term “amino” refers to a -NH2 radical.

[0049] As used herein, the term “phosphate” refers to a -P(=O)2(OH)2 radical.

[0050] As used herein, the term “heteroaryl” refers to a 5-14 membered mono-, bi-, or tricyclic group wherein at least one ring in the system is aromatic; and wherein one or more carbon atoms in at least one ring in the system is / are replaced with an heteroatom independently selected from the group consisting of N, O, S, B, Si, and P. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. A heteroaryl may further contain one or more oxo, N-oxide, S-oxide, and / or S, S-di oxide groups, valence permitting. Non-limiting examples of heteroaryl groups include furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4- oxadiazole, thiazole, 1,2, 3 -thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, 2-pyridone, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, triazine, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridine, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazine, r,2'-dihydrospiro[cyclopropane-l,3'-pyrrolo[2,3-b]pyridine], and 3', 4'- dihydrospiro [cyclopropane- 1 ,2'-pyrido[3 ,2-b] [ 1 ,4]oxazine] .

[0051] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated mono-, bi-, or tricyclic carbon group having 3 to 20 carbon atoms. Bicyclic and tricyclic cycloalkyl groups include fused, spiro, and bridged ring systems. Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[l. l.l]pentyl.

[0052] The term “cycloalkoxy” refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl).

[0053] The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10- carbon bicyclic, or 14-carbon tricyclic aromatic ring system. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0054] The term “haloaryl” referes to an aryl as defined herein, in which one or more hydrogen atoms is / are replaced with an independently selected halogen. Examples of haloaryl groups include chlorophenyl, fluoronaphthyl, and the like.

[0055] The term “heterocyclyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic, bicyclic, or tricyclic ring system having from 3 to 20 ring atoms, that is not aromatic, and having at least one heteroatom within the ring system selected from the group consisting of N, O, S, B, Si, and P. Bicyclic and tricyclic heterocyclyl groups include fused, spiro, and bridged ring systems. A heterocyclyl group may be denoted as a “5 to 10 membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. A heterocycle may further contain one or more oxo, thiocarbonyl, N-oxide, S-oxide, and / or S,S-dioxide groups, valence permitting, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. A heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to 1,3-dioxolane, 1,4-dioxolane, maleimide, succinimide, dioxopiperazine, hydantoin, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, oxathiolanyl, isoxazolidinyl, isothiazolidinyl, pyrrolinyl, pyrrolidinonyl, pyrazolidinyl, imidazolinyl, dioxolanyl, sulfolanyl, thiazolidedionyl, succinimidyl, dihydrofuranonyl, pyrazolidinonyl, oxazolidinyl, isoxazolidinonyl, hydantionyl, thiohydantionyl, imidazolidinonyl, oxazolidinonyl, thiazolidinonyl, oxathiolanonyl, dioxolanonyl,dioxazolidinonyl, oxadiazolidinonyl, triazolidinonyl, triazolidinethionyl, oxadiazolidinethionyl, dioxazolidinethionyl, dioxolanethionyl, oxazolidinethionyl, imidazolidinethionyl, isothiazolidinonyl, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, dithianyl, oxazinyl, tetrahydropyranonyl, piperidinonyl, dioxanonyl, oxazinanonyl, morpholinonyl, thiomorpholinonyl, piperazinonyl, tetrahydropyrimidinonyl, piperidinedionyl, oxazinanedionyl, dihydropyrimidindione, tetrahydropyridazinonyl, triazinanonyl, oxadi azinanonyl, dioxazinanonyl, morpholinedionyl, piperazinedionyl, piperazinetrionyl, triazinanedionyl and 2-azaspiro[3.3]heptanyl.

[0056] The term “haloheterocyclyl” refers to heterocyclyl as defined herein, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0057] The term “saturated” as used in this context means only single bonds present between constituent atoms.

[0058] As used herein, when a ring is described as being “partially unsaturated,” it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0059] As used herein, the symbol ' . depicts the point of attachment of an atom or moiety to the indicated atom or group in the remainder of the molecule.

[0060] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. When a group is substituted, that substitution can include the sharing of a carbon atom between the parent group and the substitution to form a spiro ring. For example, an n-butyl group substituted with cyclopropyl includes bothamongst others.

[0061] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e g., carbocycle, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the likedescribed herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which0 represents a zero atom bridge (e.g.,(ii) a single ring atom (spiro-fused ring systems) (e.g.,or (iii) a contiguous array of

[0062] In addition, 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 are referred to as “isotopically enriched.” Isotopically enriched compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.

[0063] 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,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Various isotopically enriched compounds of the present disclosure, for example those into which radioactive isotopes such as13C and14C are incorporated. Such isotopically enriched compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0064] The term “isotopically enriched” compounds includes “deuterated” 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 tometabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. Such compounds are synthesized by means known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. Indeed, isotopically enriched compounds of this disclosure 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 enriched reagent for a non-isotopically enriched reagent.

[0065] Deuterium enriched compounds of the present 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 relative to the corresponding non-enriched compound.

[0066] The concentration of a heavier isotope, such as deuterium, may be defined by an isotopic enrichment factor. In some embodiments, the positions noted as “H” or “hydrogen” in the compounds described herein have hydrogen at its natural abundance isotopic composition. In some embodiments, the positions noted as “H” or “hydrogen” in the compounds described herein have hydrogen enriched in deuterium above its natural abundance isotopic composition, i.e., the compound is a deuterium enriched compound. Examples of deurated groups in the compounds described herein include, but are not limited to deuteromethinemonodeuteromethyleneand dideuteromethylene), trideuteromethyl ^^3), trideuteromethoxy), and the like. Compounds of the present disclosure also include deuterium enriched compounds at the alpha position of an oxo group, such as V D T H , D Dand

[0067] In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:encompasses the tautomeric form containing the moiety:. Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0068] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and / or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.

[0069] The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and from the claims.

[0070] A “RIPK2 inhibitor” as defined herein includes any compound exhibiting RIPK2 inhibition activity. In some embodiments, a RIPK2 inhibitor is selective for RIPK2. Exemplary RIPK2 inhibitors can exhibit inhibition activity (ICso) against a RIPK2 of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as described herein.In some embodiments, a RIPK2 inhibitor can exhibit inhibition activity (IC50) against RIPK2 of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured in an assay as provided herein.Compounds of Formula (I)

[0071] Some embodiments provide a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: each — is a single bond or a double bond;W, X, and Y are independently selected from N, C, and CRX;Rxis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;Ring A is C6-C10 aryl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, S(O), S(O)2, -S(O)2-O-, -O- S(O)2-O-, -S(O)-NH-, -S(O)2-NH-, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl,(iv) C1-C6 alkyl,(v) C1-C6 alkoxy alkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O)2R1A,(xi) -NRARB,(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyl oxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R4is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and NR4AR4B;R3Aand R3Bare independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R3Aand R3Btogether with the atoms to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl;R6Aand R6Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C3-C6 cycloalkyl, and C1-C6 alkoxylalkyl; or R6Aand R6Btogether with the atoms to which they are attached form a C3-C6 cycloalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, R4A, R4D, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C10 haloaryl, and(x) 5-10 membered heteroaryl optionally substituted with 1-2 independently selected halogen; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0072] Some embodiments provide a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: each — is a single bond or a double bond;W, X, and Y are independently selected from N, C, and CRX;Rxis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;Ring A is C6-C10 aryl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRz;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl,(iv) C1-C6 alkyl,(v) C1-C6 alkoxy alkyl,(vi) C1-C6 haloalkoxy,(vii)(viii)(ix)(x)(xi)(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2D,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R4is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and NR4AR4B;R3Aand R3Bare independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R3Aand R3Btogether with the atoms to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(xiv) hydrogen,(xv) C1-C6 alkyl,(xvi) C1-C6 haloalkyl,(xvii) C3-C6 cycloalkyl,(xviii) 3-10 membered heterocyclyl,(xix) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(xx) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xxi) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xxii) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xxiii) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xxiv) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xxv) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xxvi) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, R4A, R4B, RB1, and RB2are each independently selected from:(xi) hydrogen,(xii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionallysubstituted with 1 -2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(xiii) C1-C6 haloalkyl,(xiv) C1-C6 alkoxy,(xv) C1-C6 alkoxy alkyl,(xvi) C3-C8 cycloalkyl,(xvii) 3-8 membered heterocyclyl,(xviii) C6-C10 aryl,(xix) C6-C10 haloaryl, and(xx) 5-10 membered heteroaryl optionally substituted with 1-2 independently selected halogen; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0073] In some embodiments, W, X, and Y are independently selected from N and C.

[0074] In some embodiments, X is N. In some embodiments, X is C.

[0075] In some embodiments, Y is C or N. In some embodiments, Y is C. In some embodiments, Y is N.

[0076] In some embodiments, W is C or N. In some embodiments, W is N. In some embodiments, W is C.

[0077] In some embodiments, Z1is selected from O, S, C(RZ)2, and NRZ. In some embodiments, Z1is selected from S, S(O), S(O)2, -S(O)2-O-, -O-S(O)2-O-, -S(O)- NH-, and -S(O)2-NH-. In some embodiments, Z1is selected from O, S, and NRZ. In some embodiments, Z1is selected from O and S. In some embodiments, Z1is O. In some embodiments, Z1is S. In some embodiments, Z1is selected from C(RZ)2, NRZ, and O. In some embodiments, Z1is selected from C(RZ)2 and NRZ. In some embodiments, NRZis NH

[0078] In some embodiments, Z2is selected from O, S, C(RZ)2, and NRZ. In some embodiments, Z2is selected from O, S, and NRZ. In some embodiments, Z2is selected from O and NRZ. In some embodiments, Z2is O. In some embodiments, Z2is S.In some embodiments, Z2is NRZ. In some embodiments, Z2is C(RZ)2.

[0079] In some embodiments, Rzis selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl. In some embodiments, Rzis selected from hydrogen and C1-C6 alkyl. In some embodiments, Rzis hydrogen. In some embodiments, Rzis C1-C6 alkyl. In some embodiments, Rzis C3-C8 cycloalkyl.

[0080] In some embodiments, m is 1, 2, 3, 4, or 5. In some embodiments, m is1, 2, or 3. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0081] In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 1,2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0082] In some embodiments, R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(vix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or C1-C6 alkoxy, and(xi) -NR2AR2B.

[0083] In some embodiments, R2is selected from:(i) hydrogen,(ii) halogen,(iii)Cl-C6 alkyl,(iv)Cl-C6 haloalkyl,(v) C1-C6 alkoxy, and(vi)Cl-C6 haloalkoxy.

[0084] In some embodiments, R2is selected from: C1-C6 alkyl and C1-C6 alkoxy. In some embodiments, R2is C1-C6 alkyl. In some embodiments, R2is methyl. In some embodiments, R2is C1-C6 alkoxy. In some embodiments, R2is methoxy.

[0085] In some embodiments, R3Aand R3Bare independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R3Aand R3Bare independently selected from C1-C6 alkyl and C1-C6 haloalkyl. In some embodiments, R3Aand R3Bare independently selected from C 1-C6 alkyl. In some embodiments, R3Aand R3Bare methyl.

[0086] In some embodiments, R3Aand R3Btogether with the atoms to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, Cl- C6 alkoxy, and C1-C6 alkoxyalkyl.

[0087] In some embodiments, R3Aand R3Btogether with the atoms to which they are attached form a 5 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. In some embodiments, R3Aand R3Btogether with the atoms to which they are attached form a 5 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, and C1-C6 alkoxy. In some embodiments, R3Aand R3Btogether with the atoms to which they are attached form a 5 membered heterocyclyl substituted with 2 halogens. In some embodiments, R3Aand R3Btogether with the atoms to which they are attached form a 5 membered heterocyclyl substituted with oxo, and C1-C6 alkoxy. In some embodiments, the 5 membered heterocyclyl is selected from:

[0088] In some embodiments, R3Aand R3Btogether with the atoms to which they are attached form a 6 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy. In some embodiments, R3Aand R3Btogether with the atoms to which they are attached form a 6 membered heterocyclyl optionally substituted with oxo. In some embodiments, the 6 membered heterocyclyl is selected from:, and

[0089] In some embodiments, R6Aand R6Bare independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxyl, and C1-C6 haloalkyl. In some embodiments, R6Aand R6Bare independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R6Aand R6Bare independently selected from C1-C6 alkyl and C1-C6 haloalkyl. In some embodiments, R6Aand R6Bare independently selected from C1-C6 alkyl. In some embodiments, R6Aand R6Bare hydrogen. In some embodiments, R6Aand R6Bare methyl.

[0090] In some embodiments, R6Aand R6Btogether with the atoms to which they are attached form a C3-C6 cycloalkyl. In some embodiments, R6Aand R6Btogether with the atoms to which they are attached form a cyclopropyl.

[0091] In some embodiments, R4is selected from hydrogen, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 alkoxy, and NR4AR4B. In some embodiments, R4is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R4is hydrogen. Insome embodiments, R4is C1-C6 alkyl. In some embodiments, R4is C1-C6 haloalkyl.

[0092] In some embodiments, Ring A is C6-C10 aryl. In some embodiments, Ring A is C6-C8 aryl. In some embodiments, Ring A is phenyl. In some embodiments,Ring

[0093] In some embodiments, Ring A is 5-10 membered heteroaryl. In some embodiments, Ring A is 5 or 6 membered heteroaryl. In some embodiments, Ring A is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyridonyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ringsome embodiments, Ring A is pyrazolyl. In some embodiments, Ring

[0094] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0095] In some embodiments, R1is halogen.

[0096] In some embodiments, R1is cyano.

[0097] In some embodiments, R1is hydroxyl.

[0098] In some embodiments, R1is C1-C6 alkyl.

[0099] In some embodiments, R1is C1-C6 alkoxyalkyl.

[0100] In some embodiments, R1is C1-C6 haloalkoxy.

[0101] In some embodiments, R1is -(C=O)R1A.

[0102] In some embodiments, R1is -(C=O)OR1A.

[0103] In some embodiments, R1is -S(O)2R1A.

[0104] In some embodiments, R1is -(C=O)NR1AR1B. In some embodiments, one of R1Aand R1Bis hydrogen, and the other one of R1Aand R1Bis C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl. In some embodiments, the 5-10 membered heteroaryl is a 5-6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, the 5-10 membered heteroaryl is a 9-10 membered heteroaryl selected from the group consisting of indazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzoimidazolyl, and quinazolinyl.

[0105] In some embodiments, R1is selected from the group consisting of

[0106] In some embodiments, R1is selected from the group consisting ofsome embodiments, R1is selected from the group consisting

[0107] In some embodiments, R1is selected from the group consisting of

[0109] In some embodiments, R1is selected from the group consisting of

[0110] In some embodiments, R1is NRARB.

[0111] In some embodiments, RAis hydrogen.

[0112] In some embodiments, RAis C1-C6 alkyl.

[0113] In some embodiments, RBis hydrogen.

[0114] In some embodiments, RBis C1-C6 alkyl.

[0115] In some embodiments, RBis methyl.

[0116] In some embodiments, RBis C1-C6 haloalkyl.

[0117] In some embodiments, RBis C3-C6 cycloalkyl.

[0118] In some embodiments, RBis 3-10 membered heterocyclyl.

[0119] In some embodiments, RBis-(C=O)Cl-C6 alkyl optionally substitutedwith 1 -2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino.

[0114] In some embodiments, RBis -(C=O)C1-C6 alkyl. In some embodiments,

[0115] In some embodiments, RBis -(C=O)C1-C6 alkyl substituted with a halogen. In some embodiments,

[0116] In some embodiments, RBis -(C=O)C1-C6 alkyl substituted with a 6-10 membered aryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino. In some embodiments, RBis

[0117] In some embodiments, RBis -(C=O)C1-C6 alkyl substituted with a 5-10 membered haloaryl. In some embodiments,

[0118] In some embodiments, RBis -(C=O)C1-C6 alkyl substituted with a 5- 10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino. In some embodiments, 5-10 membered heteroaryl of RBis a 5-6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl,thiadiazolyl, oxatriazolyl, and thiatri azolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

[0119] In some embodiments, RBis selected from the group consisting of

[0120] In some embodiments, RBis selected from -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl. In some embodiments, RBis -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl and 5-10 membered heteroaryl. In some embodiments, RBis selected

[0121] In some embodiments, RBis selected from -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl. In some embodiments, RBis -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 independently selected halogen. In some embodiments, RBis selected

[0122] In some embodiments, RBis -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl.

[0123] In some embodiments, RBis -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl.

[0124] In some embodiments, RBis -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl.

[0125] In some embodiments, RBis -(C=O)OC1-C6 alkyl. In some embodiments, RBis selected from

[0126] In some embodiments, RBis -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, and C4-C6 heterocyclyl. In some embodiments,RBis selected from the group consisting

[0127] In some embodiments, RBis -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl. Insome embodiments,

[0128] In some embodiments, RBis -(C=O)NRB1RB2. In some embodiments, one of RB1and RB2is hydrogen, and the other one of RB1and RB2is C1-C6 alkyl. In some embodiments, RB1and RB2are both hydrogen. In some embodiments, RB1and RB2are each independently selected both C1-C6 alkyl. In some embodiments, RB1and RB2are each methyl.

[0129] In some embodiments, RAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl. In some embodiments, RAand RBtogether with the nitrogen atom to which they are attached form a 5 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, Cl- C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl. In some embodiments, the 5 membered heterocyclyl is selected from:and

[0130] RAis independently hydrogen or C1-C6 alkyl; and RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii)C 1 -C6 haloalkyl,(iv)C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi)-(C=O)Cl-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 memberedheteroaryl wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5- 10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix)-(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi)-(C=O)OCl-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl.

[0131] In some embodiments, RAis hydrogen and RBis hydrogen.

[0132] In some embodiments, RAis hydrogen and RBis C1-C6 alkyl.

[0133] In some embodiments, RAis hydrogen and RBis methyl.

[0134] In some embodiments, RAis hydrogen and RBis selected from:(i) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(ii) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(iii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6- C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(iv) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(v) -(C=O)NRB1RB2.

[0135] In some embodiments, RAis hydrogen and RBis selected from the group

[0136] In some embodiments, R1is -NH2.

[0137] In some embodiments, R1is 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl. In some embodiments, R1is selected from the group consisting of

[0138] In some embodiments, R1is -NO2.

[0139] In some embodiments, the disclosure provides for a compound of Formula (Ila) or (lib) :or a pharmaceutically acceptable salt thereof, wherein:Ring A is C6-C10 aryl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl,(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A;(vi) C1-C6 haloalkoxy;(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2D,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or Cl -C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl,C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C10 haloaryl,(x) 5-10 membered heteroaryl, and(xi) 5-10 membered haloheteroaryl; orRD1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0140] In some embodiments, the disclosure provides for a compound of Formula (Illa) or (Illb) :or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R’ is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB,(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A;(vi) C1-C6 haloalkoxy;(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl,C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C10 haloaryl,(x) 5-10 membered heteroaryl, and(xi) 5-10 membered haloheteroaryl; orRD1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0141] In some embodiments, the disclosure provides for a compound of Formula (IVa) or (IVb):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A;(vi) C1-C6 haloalkoxy;(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1 -2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C 10 haloaryl,(x) 5-10 membered heteroaryl, and(xi) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0142] In some embodiments, the disclosure provides for a compound ofFormula (lie), (lid), (IIIc), (Hid), (IVc), and (IVd):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Q is O or NR3A;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A;(vi) C1-C6 haloalkoxy;(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 memb ered heterocy cly 1 ,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl,C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;RIARIB, R2A R2B, R3ARBI,ancj RB2are each indepenc[eritiy selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C10 haloaryl,(x) 5-10 membered heteroaryl, and(xi) 5-10 membered haloheteroaryl; orRD1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0143] In some embodiments, the compound is a compound of Formula (lie). In some embodiments, the compound is a compound of Formula (lid). In some embodiments, the compound is a compound of Formula (IIIc). In some embodiments, the compound is a compound of Formula (Illd). In some embodiments, the compound is acompound of Formula (IVc). In some embodiments, the compound is a compound of Formula (IVd).

[0144] In some embodiments, the disclosure provides for a compound ofFormula (Va), (Vb), (Vc), and (Vd):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxy alkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(Ch)R1 A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A;(vi) C1-C6 haloalkoxy;(vii) 4-10 membered heterocyclyl oxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl; and(xii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0145] In some embodiments, the disclosure provides for a compound of Formula (Ve) and (Vf):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRz;Q is O or NR3A;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(xii) halogen,(xiii) cyano,(xiv) hydroxyl;(xv) C1-C6 alkyl,(xvi) C1-C6 alkoxyalkyl,(xvii) C1-C6 haloalkoxy,(xviii)(xix)(xx)(xxi)(xxii)p is 0, 1, 2, or 3;R2is selected from:(xii) hydrogen,(xiii) halogen,(xiv) C1-C6 alkyl,(xv) C1-C6 haloalkyl,(xvi) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A;(xvii) C1-C6 haloalkoxy;(xviii) 4-10 membered heterocyclyloxy,(xix) -(C=O)NR2AR2B,(xx) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(xxi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xxii) -NR2AR2B;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(xiii) hydrogen,(xiv) C1-C6 alkyl,(xv) C1-C6 haloalkyl,(xvi) C3-C6 cycloalkyl,(xvii) 3-10 membered heterocyclyl,(xviii) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xix) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xx) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xxi) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xxii) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xxiii) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl; and(xxiv) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, R3A, RB1, and RB2are each independently selected from:(xi) hydrogen,(xii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(xiii) C1-C6 haloalkyl,(xiv) C1-C6 alkoxy,(xv) C1-C6 alkoxyalkyl,(xvi) C3-C8 cycloalkyl,(xvii) 3-8 membered heterocyclyl,(xviii) C6-C10 aryl, C6-C10 haloaryl,(xix) 5-10 membered heteroaryl, and(xx) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0146] In some embodiments, the disclosure provides for a compound of Formula (Via) or (VIb):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;U is -C(O)- or -CH2- each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1 A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A;(vi) C1-C6 haloalkoxy;(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R?and R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl; and(xii) -(C=O)NRD1RD2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxy alkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 memb ered hal oheteroary 1 ; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0147] In some embodiments, the disclosure provides for a compound of Formula (Vic) or (Vid):or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3, 4, or 5;Z2is selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;U is -C(O)- or -Cffc- each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxy alkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(Ch)R1 A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A;(vi) C1-C6 haloalkoxy;(vii) 4-10 membered heterocyclyl oxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl; and(xii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0149] In some embodiments, the disclosure provides for a compound of Formula (Vie) or (VIf):or a pharmaceutically acceptable salt thereof, wherein:n is 0, 1, or 2;U is -C(O)- or -Ofc- each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxy alkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A; and(ii) C1-C6 haloalkoxy;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl; and(xii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

[0150] In some embodiments, the disclosure provides for a compound selected from the compounds in Table 1 :Table 1. Exemplary compounds of Formula (I).or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the compounds of Formula (I) include the compounds of Examples 1-146 and pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Examples 1-146 are in the free base form. In some embodiments, the compounds of Examples 1-146 are in salt form, e.g., pharmaceutically acceptable salt form.

[0152] The ability of test compounds to act as RIPK2 inhibitors may be demonstrated by the biological assays described herein. IC50 values are shown in Table A.Pharmaceutical C (impositions

[0153] Some embodiments provide a pharmaceutical composition comprisinga compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.Methods of Treatment

[0154] The compounds and compositions disclosed herein are effective for modulating the activity of RIPK2. In some embodiments, the compounds and compositions disclosed herein are RIPK2 inhibitors.

[0155] An exemplary sequence of human RIPK2 is shown below (UniParc Accession No. UPI00001338F2):MNGEAICSALPTIPYHKLADLRYLSRGASGTVSSARHADWRVQVAVKHLH IHTPLLD SERKD VLREAEILHK ARF S YILPILGICNEPEFLGIVTEYMPNGSL NELLHRKTEYPDVAWPLRFRILHEIALGVNYLHNMTPPLLHHDLKTQNILL DNEFHVKIADFGLSKWRMMSLSQSRSSKSAPEGGTIIYMPPENYEPGQKS RASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVINEESLP YDIPHRARMISLIESGWAQNPDERPSFLKCLIELEPVLRTFEEITFLEAVIQL KKTKLQ S VS S AIHLCDKKKMEL SLNIPVNHGPQEE SCGS SQLHENSGSPET SRSLPAPQDNDFLSRKAQDCYFMKLHHCPGNHSWDSTISGSQRAAFCDH KTTPCSSAIINPLSTAGNSERLQPGIAQQWIQSKREDIVNQMTEACLNQSLD ALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDN KQMGLQPYPEILVVSRSPSLNLLQNKSM

[0156] Some embodiments provide a method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0157] Some embodiments provide a method of treating inflammatory bowel disease in a subject in need thereof, comprising (a) determining that the subject is suffering from inflammatory bowel disease; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0158] Some embodiments provide a method of treating inflammatory bowel disease in a subject previously identified or diagnosed as having inflammatory bowel disease, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the inflammatory bowel disease is Crohn’s disease.

[0160] In some embodiments, the inflammatory bowel disease is ulcerative colitis.

[0161] Some embodiments provide a method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0162] Some embodiments provide a method of treating inflammatory bowel disease in a subject in need thereof, comprising (a) determining that the subject is suffering from inflammatory bowel disease; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0163] Some embodiments provide a method of treating inflammatory bowel disease in a subject previously identified or diagnosed as having inflammatory bowel disease, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0164] Some embodiments provide a method of treating Crohn’s disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0165] Some embodiments provide a method of treating Crohn’s disease in a subject in need thereof, comprising (a) determining that the subject is suffering from Crohn’s disease; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0166] Some embodiments provide a method of treating Crohn’s disease in a subject previously identified or diagnosed as having Crohn’s disease, the method comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the subject is a human.Inhibiting RIPK2 Activity

[0168] Some embodiments provide a method for inhibiting RIPK2 activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the mammalian cell comprises a RIPK2 protein.

[0169] Also provided is a method for inhibiting RIPK2 activity in a mammalian cell comprising a RIPK2 protein, the method comprising contacting the mammalian cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is sufficient to inhibit RIPK2 activity in thecell. Tn some embodiments, the contacting is in vivo, wherein the method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a mammalian cell having RIPK2 activity. In some embodiments, the mammalian cell is a mammalian immune cell. In some embodiments, the mammalian cell is a cancer cell.

[0171] In some embodiments, the RIPK2 activity is inhibited by about 10% to about 99%, for example, about 10% to about 50%, about 25% to about 75%, about 50% to about 99%, 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%, about 95%, about 99%, or any value in between.

[0172] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” RIPK2 (e.g., a RIPK2 protein) with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having a RIPK2 protein, as well as, for example, introducing a compound provided herein into a sample containing a mammalian cellular or purified preparation containing a RIPK2 protein.EXAMPLESMaterials and Methods

[0173] The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

[0174] The reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in onesolvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

[0175] Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry 1stEd., Oxford University Press, 2000; March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thEd., Wiley-Interscience Publication, 2001; and Peturssion, S. et al., “ Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997).IntermediatesIntermediate 1

[0176] tert-butyl (25,4R)-2-(((3-(3-hydroxy-5-nitrophenyl)-6- methoxypyrazolo[l,5-fl]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l- carboxylate: To a solution of 3-nitro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenol (1.13 g, 3.84 mmol, 1.5 eq) and tert-butyl (2 ,4A)-2-(((3-bromo-6- methoxypyrazol o[l ,5-c / ]pyrimi di n-5-yl)oxy (methyl )-4-methoxypyrrolidine- l -carboxylate (1.3 g, 2.56 mmol, 1 eq, prepared as described in WO2021152165, which is incorporated by reference herein in its entirety) in DMF (13 mL) was added Pd(dtbpf)Ch (166.74 mg, 255.84 pmol, 0.1 eq) and K3PO4 (1.63 g, 7.68 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hours under a N2 atmosphere before it was quenched with water (15 mL) at 25 °C and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (45 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to givea residue, which was purified by column chromatography (SiO20-50% EtOAc / petroleum ether) to give the title compound (0.95 g, 1.66 mmol, 64.83% yield, 90% purity) as a yellow solid. ’H NMR (400 MHz, DMSOd6) 5 ppm 10.40 (s, 1H), 8.78 (d, J= 8.0 Hz, 1H), 8.57 (s, 1H), 8.46 (d, J= 12.4 Hz, 1H), 7.85 (d, J= 16.0 Hz, 1H), 7.38 (s, 1H), 4.78-4.44 (m, 2H), 4.30 (s, 1H), 4.07 (s, 1H), 3.89 (s, 3H), 3.57-3.38 (m, 2H), 3.22 (s, 3H), 2.24-2.01 (m, 2H), 1.38-1.23 (m, 9H).

[0177] tert-butyl (25,4R)-2-(((3-(3-(2-bromoethoxy)-5-nitrophenyl)-6- methoxypyrazolo[l,5-a]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l- carboxylate: To a solution of tert-butyl (2S,4R)-2-(((3-(3-hydroxy-5-nitrophenyl)-6- methoxypyrazolo[l,5-a]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l -carboxylate (0.75 g, 1.31 mmol, 1 eq in MeCN (15 mL) was added CS2CO3 (1.28 g, 3.93 mmol, 3 eq) and dibromoethane (4.92 g, 26.19 mmol, 1.98 mL, 20 eq . The mixture was stirred at 80 °C for 1 hour under a N2 atmosphere before it was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO20-70% EtOAc / petroleum ether) to give the title compound (0.7 g, 1.01 mmol, 77.30% yield, 90% purity) as a yellow solid. ’H NMR (400 MHz, DMSOd6) 8 ppm 8.81-8.75 (m, 1H), 8.70 (s, 2H), 8.04 (d, J = 2.8 Hz, 1H), 7.54 (s, 1H), 4.79-4.63 (m, 1H), 4.59-4.42 (m, 3H), 4.32 (s, 1H), 4.10-4.03 (m, 1H), 3.96-3.82 (m, 5H), 3.58-3.40 (m, 2H), 3.22 (s, 3H), 2.22-2.02 (m, 2H), 1.38-1.23 (m, 9H).

[0178] 3-(3-(2-bromoethoxy)-5-nitrophenyl)-6-methoxy-5-(((25,4R)-4- methoxypyrrolidin-2-yl)methoxy)pyrazolo[l,5-a]pyrimidine: To a solution of tertbutyl (2S,4A)-2-(((3-(3-(2-bromoethoxy)-5-nitrophenyl)-6-methoxypyrazolo[l,5- a]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l-carboxylate (0.7 g, 1.01 mmol, 1 eq) in DCM (10 mL) was added HC1 in dioxane (4 M, 9.00 mL, 35.57 eq). The mixture was stirred at 25 °C for 12 hours under a N2 atmosphere before it was neutralized with saturated aqueous NaHCO.3 at 0 °C and then extracted with DCM (3 x 30 mL). The combined organic extracts were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (550 mg, crude) as a yellow solid. [M+H]+= 524.0. ’H NMR (400 MHz, DMSOd6) 8 ppm 8.76 (s, 1H), 8.69 (s, 2H), 8.07 (d, J= 1.6 Hz, 1H), 7.53 (t, J = 2.0 Hz, 1H), 4.54 (t, J= 5.2 Hz, 2H), 4.47-4.34 (tn, 2H), 3.93-3.85 (m, 6H), 3.73-3.65 (m, 1H), 3.19 (s, 3H), 2.98-2.92 (m, 1H), 2.88- 2.83 (tn, 1H), 2.03-1.97 (m, 1H), 1.63-1.56 (m, 1H).

[0179] (23Z,24E,525,54R)-26,54-dimethoxy-l5-nitro-3,8-dioxa-2(3,5)- pyrazolo[l,5-fl]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphane: A mixture of 3-(3-(2-bromoethoxy)-5-nitrophenyl)-6-methoxy-5-(((25,4A)-4- methoxypyrrolidin-2-yl)methoxy)pyrazolo[l,5-a]pyrimidine (525.00 mg, 1.01 mmol, 1 eq), NaHCO3 (844.33 mg, 10.05 mmol, 391.07 pL, 10 eq), CS2CO3 (1.96 g, 6.03 mmol, 6 eq) and KI (500.54 mg, 3.02 mmol, 3 eq) in MeCN (6 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 12 hours under a N2 atmosphere before it was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 0-30% EtOAc / petroleum ether) to give the title compound (45 mg, 91.75 pmol, 9.13% yield, 90% purity) as a yellow solid.JH NMR (400 MHz, CDCI3) 8 ppm 8.88-8.74 (m, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 7.55 (s, 1H), 5.05 (d, J = 10.0 Hz, 1H), 4.52-4.35 (m, 2H), 4.15-4.01 (m, 1H), 3.95 (s, 3H), 3.93-3.85 (m, 2H), 3.52-3.37 (m, 1H), 3.32 (s, 3H), 3.31-3.24 (m, 2H), 2.96-2.83 (m, 1H), 2.26-2.12 (m, 1H), 2.03-1.94 (m, 1H).

[0180] (23Z,24E,525,54R)-26,54-dimethoxy-l5-nitro-3,8-dioxa-2(3,5)- pyrazolo[l,5-o]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacycIooctaphan-55-one:A mixture of (23Z,24E,525',54R)-26,54-dimethoxy-l5-nitro-3,8-dioxa-2(3,5)-pyrazolo[l,5- a]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphane (40 mg, 81.55 pmol, 1 eq) and NaHCO3 (137.02 mg, 1.63 mmol, 63.46 pL, 20 eq) in THF (1 mL) and water (0.4 mL) was stirred at 20 °C for 10 minutes before iodine (310.48 mg, 1.22 mmol, 246.41 pL, 15 eq) was added. The resulting mixture was stirred at 90 °C for 12 hours, and then it was quenched with saturated aqueous Na2SO3 (10 mL) at 25 °C, diluted with water (3 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (40 mg, 79.05 pmol, 96.93% yield, 90% purity) as a yellow solid. ’HNMR (400 MHz, CDCI3) 6 ppm 8.51 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.63 (t, J = 2.0 Hz, 1H), 5.15-5.06 (m, 1H), 4.57-4.47 (m, 2H), 4.22-4.07 (m, 4H), 3.97 (s, 3H), 3.65 (s, 1H), 3.62 (s, 3H), 2.74 (dd, J= 13.2, 8.0 Hz, 1H), 2.21-2.08 (m, 1H).

[0181] The following intermediates were prepared following procedures analogous to that described for Intermediate 1.Intermediate 9

[0182] tert-butyl (25',4R)-2-(((3-(3-amino-5-nitrophenyl)-6- methoxypyrazolo[l,5-fl]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l- carboxylate: To a solution of te / 7-butyl (25,4R)-2-(((3-bromo-6-methoxypyrazolo[l,5- rz]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l-carboxylate (0.75 g, 1.48 mmol, 1 eq) and 3-nitro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (730.85 mg, 2.21 mmol, 1.5 eq) in 1,4-dioxane (16 mL) and water (4 mL) was added Pd(dtbpf)Ch (96.20mg, 147.60 pmol, 0.1 eq) and K3PO4 (939.91 mg, 4.43 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hours under a N2 atmosphere before it was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (45 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO20-90% EtOAc / petroleum ether) to give the title compound (0.7 g, 1.22 mmol, 82.96% yield, 90% purity) as a yellow solid. [M+Na]+= 537.2. 'H NMR (400 MHz, DMSO-d6) 5 ppm 8.74 (d, J= 8.4 Hz, 1H), 8.41 (d, J= 19.6 Hz, 1H), 8.27-8.03 (m, 1H), 7.81-7.45 (m, 1H), 7.23 (s, 1H), 5.80 (d, J= 19.2 Hz, 2H), 4.74-4.70 (m, 1H), 4.57-4.42 (m, 1H), 4.31 (s, 1H), 4.10-4.02 (m, 1H), 3.88 (s, 3H), 3.56-3.44 (m, 1H), 3.34-3.31 (m, 1H), 3.21 (s, 3H), 2.24-2.01 (m, 2H), 1.41-1.21 (m, 9H).

[0183] tert-butyl (25,4^)-4-methoxy-2-(((6-methoxy-3-(3-nitro-5-((4- nitrophenyl)sulfonamido)phenyl)pyrazolo[l,5-a]pyrimidin-5- yl)oxy)inethyl)pyrrolidine-l-carboxylate: To a solution of tert-butyl (25,4R)-2-(((3-(3- amino-5-nitrophenyl)-6-methoxypyrazolo[l,5-rz]pyrimidin-5-yl)oxy)methyl)-4- methoxypyrrolidine- 1 -carboxylate (0.7 g, 1.22 mmol, 1 eq) and pyridine (242.13 mg, 3.06 mmol, 247.07 pL, 2.5 eq) in MeCN (7 mL) was added NsCl (542.71 mg, 2.45 mmol, 2 eq . The mixture was stirred at 60 °C for 12 hours before it was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (45 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, SiO2, 0-80% EtOAc / petroleum ether) to give the title compound (0.92 g, 1.18 mmol, 96.65% yield, 90% purity) as a yellow solid. [M+Na]+= 722.2. 'H NMR (400 MHz, CDCI3) 5 ppm 8.68 (s, 1H), 8.59 (s, 1H), 8.41- 8.32 (m, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 8.00 (d, J= 7.2 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.68-7.55 (m, 2H), 4.96-4.79 (m, 1H), 4.75 (d, J = 10.4 Hz, 1H), 4.64-4.49 (m, 1H), 4.12-4.09 (m, 1H), 3.91 (d, J= 1.6 Hz, 3H), 3.61-3.43 (m, 2H), 3.33 (d, J= 1.2 Hz, 3H), 2.29-2.08 (m, 2H), 1.41 (d, J= 1.6 Hz, 9H).

[0184] tert-butyl (25,4R)-2-(((3-(3-((A-(2-bromoethyl)-4- nitrophenyl)sulfonamido)-5-nitrophenyl)-6-methoxypyrazolo[l,5-a]pyrimidin-5- yl)oxy)methyl)-4-methoxypyrrolidine-l-carboxylate: To a solution of tert-butyl(2S,4R)-4-m eth oxy -2-(((6-meth oxy-3 -(3 -nitro-5 -((4- nitrophenyl)sulfonamido)phenyl)pyrazolo[l,5-cz]pyrimidin-5-yl)oxy)methyl)pyrrolidine- 1-carboxylate (0.90 g, 1.16 mmol, 1 eq) and 1,2-dibromoethane (4.35 g, 23.15 mmol, 1.75 mL, 20 eq) in MeCN (9 mL) was added CS2CO3 (1.13 g, 3.47 mmol, 3 eq). The mixture was stirred at 80 °C for 12 hours before it was diluted with water (3 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO20-4% MeOH / DCM) to give the title compound (1.0 g, 1.12 mmol, 96.38% yield, 90% purity) as a yellow solid. [M+Na]+= 830.1. 'H NMR (400 MHz, CDCI3) 5 ppm 8.89-8.75 (m, 1H), 8.52-8.48 (m, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 8.04- 7.80 (m, 1H), 7.75-7.61 (m, 3H), 7.56-7.45 (m, 1H), 4.77 (dd, J= 11.2, 4.8 Hz, 1H), 4.58- 4.38 (m, 2H), 4.35-4.20 (m, 2H), 4.15-4.13 (m, 1H), 3.91 (s, 3H), 3.59-3.49 (m, 2H), 3.47 (t, J= 6.8 Hz, 2H), 3.33 (s, 3H), 2.27-2.09 (m, 2H), 1.42 (s, 9H).

[0185] N-(2-bronioethyl)-\-(3-(6-methoxy-5-(((2.S.4R)-4- methoxypyrrolidin-2-yl)methoxy)pyrazolo[l,5-a]pyrimidin-3-yl)-5-nitrophenyl)-4- nitrobenzenesulfonamide: To a solution of Zc / 7-butyl (2 ,4R)-2-(((3-(3-((JV-(2- bromoethyl)-4-nitrophenyl)sulfonamido)-5-nitrophenyl)-6-methoxypyrazolo[l,5- rz]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l-carboxylate (0.5 g, 557.87 pmol, 1 eq) in DCM (5 mL) was added HC1 in dioxane (2 M, 2.50 mL, 8.96 eq). The mixture was stirred at 25 °C for 2 hours before it was concentrated under reduced pressure to give the title compound (0.48 g, crude) as a yellow solid. [M+H]+= 708.0. ’H NMR (400 MHz, DMSO-d6) 5 ppm 8.94 (s, 1H), 8.90 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.02-7.97 (m, 1H), 7.95-7.89 (m, 1H), 7.89-7.82 (m, 2H), 7.82-7.76 (m, 1H), 4.87 (dd, J= 11.6, 2.0 Hz, 1H), 4.65 (dd, J= 12.0, 9.2 Hz, 1H), 4.29 (t, J= 5.6 Hz, 2H), 4.20 (s, 2H), 3.92 (s, 3H), 3.57 (s, 4H), 3.26 (s, 3H), 2.44-2.35 (m, 1H), 1.97-1.86 (m, 1H).

[0186] (23Z,24E,525,54R)-26,54-dimethoxy-l5-nitro-8-((4- nitrophenyl)sulfonyl)-3-oxa-8-aza-2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l)- pyrrolidina-l(l,3)-benzenacyclooctaphane: To a solution of N-(2-bromoethyl)-N-(3-(6- methoxy-5-(((2S,4R)-4-methoxypyrrolidin-2-yl)methoxy)pyrazolo[l,5-αz]pyrimidin-3-yl)- 5-nitrophenyl)-4-nitrobenzenesulfonamide (0.73 g, 1.03 mmol, 1 eq) in MeCN (560 mL)was added EtsN (156.83 mg, 1.55 mmol, 215.72 pL, 1.5 eq). The mixture was stirred at 80 °C for 12 hours, and then at 90 °C for another 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (0.4 g, 575.44 pmol, 55.69% yield, 90% purity) as a yellow solid. [M+H]+= 626.2.!H NMR (400 MHz, CDCh) 6 ppm 8.60 (s, 1H), 8.23 (s, 2H), 8.14 (s, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 7.75-7.63 (m, 3H), 5.06-4.91 (m, 1H), 4.36-4.18 (m, 1H), 4.12-3.99 (m, 1H), 3.94-3.92 (s, 5H), 3.85- 3.69 (m, 1H), 3.34 (s, 3H), 3.33-3.16 (m, 3H), 3.02-2.86 (m, 1H), 2.21-2.10 (m, 1H), 2.05- 1.89 (m, 1H).

[0187] (23Z,24E,525,54R)-26,54-dimethoxy-l5-nitro-8-((4- nitrophenyl)sulfonyl)-3-oxa-8-aza-2(3,5)-pyrazolo[l,5-tf]pyrimidina-5(2,l)- pyrrolidina-l(l,3)-benzenacyclooctaphan- 55-one: A mixture of (23Z,24E,525,54A)-26,54- dimethoxy-l5-nitro-8-((4-nitrophenyl)sulfonyl)-3-oxa-8-aza-2(3,5)-pyrazolo[l,5- «]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphane (0.2 g, 287.72 pmol, 1 eq) and NaHCCb (483.41 mg, 5.75 mmol, 223.90 pL, 20 eq) in THF (4 mL) and water (1.6 mL) was stirred at 20 °C for 10 minutes, and then iodine (1.10 g, 4.32 mmol, 869.35 pL, 15 eq) was added. The reaction mixture was stirred at 80 °C for 12 hours before it was quenched with saturated aqueous Na2SCh (10 mL) at 25 °C. The resulting mixture was fdtered, diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to give the title compound (170 mg, 239.21 pmol, 83.14% yield, 90% purity) as a yellow solid. [M+H]+= 640.2. 'H NMR (400 MHz, DMSO-t / 6) 8 ppm 8.85 (s, 1H), 8.68 (s, 2H), 8.35 (s, 1H), 8.08 (d, J= 8.0 Hz, 1H), 7.98- 7.93 (m, 2H), 7.93-7.76 (m, 3H), 4.96 (d, J= 10.8 Hz, 1H), 4.49 (t, J= 9.2 Hz, 1H), 4.36 (t, J= 8.0 Hz, 1H), 4.14-4.05 (m, 3H), 3.90 (s, 3H), 3.89-3.83 (m, 1H), 3.63-3.53 (m, 1H), 3.45 (s, 3H), 2.46-2.39 (m, 1H), 1.96-1.84 (m, 1H).

[0188] (23Z,24E,52,S',54R)-26,54-dim ethoxy- 1=-nitro-3-oxa-8-aza-2(3,5)- pyrazolo[l,5-a]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphan-55-one:A mixture of (23Z,24A’,528',54A)-26,54-dimethoxy-P-nitro-8-((4-nitrophenyl)sulfonyl)-3- oxa-8-aza-2(3,5)-pyrazolo[l,5-rz]pyrimidina-5(2, l)-pyrrolidina- 1(1,3)- benzenacyclooctaphan-55-one (0.14 g, 197.00 pmol, 1 eq), CS2CO3 (128.37 mg, 394.00pmol, 2 eq) and 4-methylbenzenethiol (29.36 mg, 236.40 pmol, 1.2 eq) in DMF (4 mL) was stirred at 25 °C for 12 hours under a N2 atmosphere before it was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (3 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-8% MeOH / DCM) to give the title compound (54 mg, 106.95 pmol, 54.29% yield, 90% purity) as a yellow solid. [M+H]+= 455.1. 'HNMR (400 MHz, DMSO- fc) 8 ppm 8.81 (s, 1H), 8.55 (s, 1H), 8.12 (s, 1H), 7.67 (s, 1H), 7.28 (t, J= 2.0 Hz, 1H), 6.76 (t, J = 5.6 Hz, 1H), 4.96 (d, J = 10.4 Hz, 1H), 4.55-4.45 (m, 1H), 4.33 (t, J= 8.4 Hz, 1H), 4.04 (t, J= 11.2 Hz, 1H), 3.93- 3.86 (m, 4H), 3.62-3.52 (m, 1H), 3.45 (s, 3H), 3.36-3.35 (m, 1H), 2.47-2.40 (m, 1H), 2.03- 1.90 (m, 1H).Intermediate 10

[0189] tert-butyl (25,4R)-2-(((3-(2-chloro-6-fluoropyridin-4-yl)-6- methoxypyrazolo[l,5-fl]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l- carboxylate: A mixture of Zc' / 7-butyl (25,4A)-2-(((3-bromo-6-methoxypyrazolo[l,5- «]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l-carboxylate (1.78 g, 3.50 mmol, 0.9 eq), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1 g, 3.88 mmol, 1 eq), Pd(dppf)Ch (284.16 mg, 388.36 pmol, 0.1 eq) and K2CO3 (1.61 g, 11.65 mmol, 3 eq) in dioxane (0.5 mL) and water (0.1 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 2 hours under a N2 atmosphere before it was diluted with water (40 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO21-51% EtOAc / petroleum ether) to give the title compound (1.6 g, 2.83 mmol,73.00% yield, 90% purity) as a yellow solid. 'H NMR (400 MHz, DMSO-dfi) 8 ppm 8.85 (d, J= 8.4 Hz, 1H), 8.76 (s, 1H), 8.09 (br s, 1H), 7.78 (br s, 1H), 4.78-4.38 (m, 3H), 4.28 (d, J= 5.6 Hz, 1H), 4.10-4.02 (m, 2H), 3.90 (s, 3H), 3.23 (s, 3H), 2.18-2.06 (m, 2H), 1.31 (s 9H).

[0190] 3-(2-chloro-6-fluoropyridin-4-yl)-6-methoxy-5-(((25,4^)-4- methoxypyrrolidin-2-yl)methoxy)pyrazolo[l,5-a]pyrimidine: To a solution of tertbutyl (25',4R)-2-(((3-(2-chloro-6-fluoropyridin-4-yl)-6-methoxypyrazolo[l,5-a]pyrimidin- 5-yl)oxy)methyl)-4-methoxypyrrolidine-l -carboxylate (1.6 g, 2.83 mmol, 1 eq) in DCM (10 mL) was added HC1 in dioxane (4 M, 10 mb). The mixture was stirred at 25 °C for 1 hour before it was concentrated under reduced pressure to give the title compound (1.1 g, crude) as a yellow solid, which was used in the next step without further purification.

[0191] tert-butyl (2-((25,4R)-2-(((3-(2-chlor o-6-fluoropyridin-4-yl)-6- methoxypyrazolo[l,5-a]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidin-l- yl)ethyl)carbamate: To a solution of 3-(2-chloro-6-fluoropyridin-4-yl)-6-methoxy-5- (((2<S',4R)-4-methoxypyrrolidin-2-yl)methoxy)pyrazolo[l,5-a]pyrimidine (1.1 g, 2.43 mmol, 1 eq) and tert-butyl (2-bromoethyl)carbamate (1.63 g, 7.28 mmol, 3 eq) in MeCN (3 mL) was added NaHCO.i (611.80 mg, 7.28 mmol, 283.37 pL, 3 eq), CS2CO3 (4.75 g, 14.57 mmol, 6 eq) and KI (604.45 mg, 3.64 mmol, 1.5 eq . The resulting mixture was stirred at 80 °C for 1 hour before it was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO21-100% EtOAc / petroleum ether) to give the title compound (1.4 g, 2.29 mmol, 94.20% yield, 90% purity) as a yellow solid. 'H NMR (400 MHz, DMSO-dfi) 8 ppm 8.83 (s, 1H), 8.75 (s, 1H), 8.09 (s, 1H), 7.76 (s, 1H), 6.55 (br s, 1H), 4.49 (d, J= 4.8 Hz, 1H), 4.43-4.37 (m, 1H), 3.89 (s, 3H), 3.33-3.29 (m, 2H), 3.20 (s, 3H), 3.17-3.12 (m, 1H), 3.03-2.93 (m, 3H), 2.47-2.40 (m, 1H), 2.35-2.31 (m, 1H), 1.97- 1.92 (m, 1H), 1.88-1.79 (m, 1H), 1.31 (s, 9H).

[0192] 2-((25,4R)-2-(((3-(2-chloro-6-fluoropyridin-4-yl)-6- methoxypyrazolo[l,5-o]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidin-l- yl)ethan-l-amine: To a solution of tert-butyl (2-((25,4R)-2-(((3-(2-chloro-6-fluoropyridin-4-yl)-6-methoxypyrazolo[l ,5-a]pyrimidin-5-yl)oxy)methyl )-4- methoxypyrrolidin-l-yl)ethyl)carbamate (500 mg, 816.68 pmol, 1 eq) in DCM (1 mL) was added HC1 in dioxane (4 M, 1 mL). The resulting mixture was stirred at 25 °C for 1 hour before it was concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 (10 mL) (pH ~ 7) and extracted with DCM (4 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to give the title compound (300 mg, crude) as a white solid.

[0193] (23Z,24E,525,54R)-l6-chloro-26,54-dimethoxy-3-oxa-8-aza-2(3,5)- pyrazolo[l,5-o]pyrimidina-l(4,2)-pyridina-5(2,l)-pyrrolidinacyclooctaphane: To a solution of 2-((25,4R)-2-(((3 -(2-chloro-6-fluoropyridin-4-yl)-6-methoxypyrazolo[ 1,5- aQpyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidin-l-yl)ethan-l-amine (250 mg, 554.45 pmol, 1 eq) in DMSO (8 mL) was added MgCh (52.79 mg, 554.45 pmol, 22.75 pL, 1 eq) and K2CO3 (191.58 mg, 1.39 mmol, 2.5 eq). The mixture was stirred at 80 °C for 12 hours before it was triturated with water (5 mL) at 25 °C for 20 min to give the title compound (200 mg, crude) as a yellow solid after filtration.

[0194] (23Z,24£,525,54R)-l6-chloro-26,54-dimethoxy-3-oxa-8-aza-2(3,5)- pyrazolo[l,5-G]pyrimidina-l(4,2)-pyridina-5(2,l)-pyi'i'olidinacyclooctaphan-5s-one: To a mixture of (23Z,24E,525,54R)-l6-chloro-26,54-dimethoxy-3-oxa-8-aza-2(3,5)- pyrazolo[l,5-cz]pyrimidina-l(4,2)-pyridina-5(2,l)-pyrrolidinacyclooctaphane (20 mg, 46.42 pmol, 1 eq) in THF (2.5 mL) and water (0.5 mL) was added iodine (235.62 mg, 928.32 pmol, 187.00 pL, 20 eq) and NaHCO3 (58.49 mg, 696.24 pmol, 27.09 pL, 15 eq). The mixture was stirred at 25 °C for 1 hour before it was quenched with saturated aqueous Na2SCh (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound (1.50 mg, 3.09 pmol, 6.65% yield, 94.39% purity, 0.3 FA) as a white solid. [M+H]+= 445.0. 'H NMR (400 MHz, DMSO-t / 6) 5 ppm 8.85 (s, 1H), 8.53 (s, 1H), 8.45 (s, 0.3H), 7.64 (s, 1H), 7.06 (t, J= 5.6 Hz, 1H), 6.97 (s, 1H), 4.95 (d, J = 10.4 Hz, 1H), 4.61-4.46 (m, 1H),4.33 (t, J= 8.8 Hz, 1H), 4.06 (t, J= 10.8 Hz, 1H), 3.89 (s, 3H), 3.68-3.55 (m, 1H), 3.43 (s, 3H), 3.29-3.19 (m, 3H), 2.44 (d, J= 4.8 Hz, 1H), 2.00-1.88 (m, 1H).

[0195] The following intermediate was prepared following procedures analogous to those described for Intermediate 10.Intermediate 12

[0196] methyl 2-((4-bromo-6-chloropyridin-2-yl)oxy)acetate: To a solution of methyl 2-hydroxyacetate (2.38 g, 26.44 mmol, 2.04 mb, 2 eq) in THF (60 mL) was added NaH (1.16 g, 29.09 mmol, 60% in oil, 2.2 eq) at 0 °C under a N2 atmosphere. The mixture was stirred at 25 °C for 1 h under a N2 atmosphere, and then it was added dropwiseinto a solution of 4-bromo-2,6-di chloropyridine (3 g, 13.22 mmol, 1 eq) in THF (60 mL) at 60 °C. The resulting mixture was stirred at 60 °C for 1 h under a N2 atmosphere before it was quenched with saturated aqueous NH4CI (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried over Na SO4, filtered and concentrated. The residue was purified by column chromatography (SiO20.5- 10% EtOAc / petroleum ether) to yield the title compound (2.6 g, 69% yield) as colorless oil. [M+H]+= 282.2.NMR (400 MHz, DMSO-tfc) 8 ppm 7.51 (d, J = 1.3 Hz, 1H), 7.34 (d, J= 1.2 Hz, 1H), 4.94 (s, 2H), 3.68 (s, 3H).

[0197] methyl 2-((6-chloro-4-(4,4,5,5-tetramethyl-l,392-dioxaborolan-2- yl)pyridin-2-yl)oxy)acetate: To a solution of methyl 2-((4-bromo-6-chloropyridin-2- yl)oxy)acetate (4.3 g, 15.33 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4.67 g, 18.40 mmol, 1.2 eq) in 1,4-dioxane (50 mL) was added Pd(dppf)C12 (673.00 mg, 919.78 pmol, 0.06 eq) and KOAc (1.81 g, 18.40 mmol, 1.2 eq) under a N2 atmosphere. The mixture was stirred at 100 °C for 12 h under a N2 atmosphere. The mixture was purified by column chromatography (SiO20.5- 10% EtOAc / petroleum ether) to yield the title compound (3.9 g, 76% yield) as a white solid. [M-pinacol+H]+= 246.0. 'H NMR (400 MHz, DMSO-c / e) 8 ppm 7.18 (s, 1H), 7.01 (s, 1H), 4.94 (s, 2H), 3.67 (s, 3H), 1.30 (s, 12H).

[0198] tert-butyl (25,4R)-2-(((3-(2-chloro-6-(2-methoxy-2- oxoethoxy)pyridin-4-yl)-6-methoxypyrazolo[l,5-a]pyrimidin-5-yl)oxy)methyl)-4- methoxypyrrolidine-l-carboxylate: To a solution of tert-butyl (2S,4R)-2-(((3-bromo-6- methoxypyrazolo[l,5-a]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l -carboxylate (4.22 g, 8.31 mmol, 1 eq) and methyl 2-((6-chloro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)oxy)acetate (4.21 g, 12.46 mmol, 1.5 eq) in dioxane (150 mL) and H2O (30 mL) was added K3PO4 (5.29 g, 24.93 mmol, 3 eq) and Pd(dtbpf)Ch (541.56 mg, 830.93 pmol, 0.1 eq). The resulting mixture was stirred at 80 °C for 1 h under N2 before it was quenched with H2O (80 mL) and extracted with EtOAc (3 x 80 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 1-2% EtOAc / petroleum ether) to yield the title compound (3.2 g, 64% yield) as a white solid.[M+H]+= 578.2. ‘H NMR (400 MHz, CDCh) 8 ppm 8.23 (s, 1H), 8.09 (s, 1H), 7.61 (s, 1H), 7.37 (s, 1H), 4.94 (s, 2H), 4.81-4.70 (m, 1H), 4.56-4.45 (m, 1H), 4.66-4.35 (m, 1H), 4.17-4.11 (m, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 3.55 (s, 1H), 3.35 (s, 3H), 2.30-2.15 (m, 2H), 1.61 (s, 9H).

[0199] 2-((4-(5-(((25',4J?)-l-(teH-butoxycarbonyl)-4-methoxypyrrolidin-2- yl)methoxy)-6-methoxypyrazolo[l,5-a]pyriinidin-3-yl)-6-chloropyridin-2- yl)oxy)acetic acid: To a solution of Zc / V-butyl (2S,4R)-2-(((3-(2-chloro-6-(2-methoxy-2- oxoethoxy)pyridin-4-yl)-6-methoxypyrazolo[l,5-<f|pyrimidin-5-yl)oxy)methyl)-4- methoxypyrrolidine- 1 -carboxylate (3 g, 5.19 mmol, 1 eq) in MeOH (90 mL), H2O (90 mL) and THF (90 mL) was added LiOH*H2O (435.56 mg, 10.38 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h before it was acidified to pH 4 with 1 M HC1, and then extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound (3 g, 97% yield) as a white solid, which was used directly in the next step without further purification. [M+Na]+= 586.2. 'H NMR (400 MHz, DMSO-sfc) 8 ppm 13.75-11.86 (m, 1H), 8.82 (d, J = 9.2 Hz, 1H), 8.70 (s, 1H), 7.77 (s, 1H), 7.52 (s, 1H), 4.82 (s, 2H), 4.71-4.48 (m, 2H), 4.30-4.22 (m, 1H), 4.09-4.05 (m, 1H), 3.89 (s, 3H), 3.55-3.42 (m, 2H), 3.22 (s, 3H), 2.20- 2.05 (m, 2H), 1.32 (d, J= 14.4 Hz, 9H).

[0200] 2-((6-chloro-4-(6-methoxy-5-(((25,4R)-4-methoxypyrrolidin-2- yl)methoxy)pyrazolo[l,5-fl]pyrimidin-3-yl)pyridin-2-yl)oxy)acetic acid hydrochloride: To a solution of 2-((4-(5-(((2,S'.4R)- l -( / e77-butoxycarbonyl)-4- methoxypyrrolidin-2-yl)methoxy)-6-methoxypyrazolo[l,5-a]pyrimidin-3-yl)-6- chloropyridin-2-yl)oxy)acetic acid (2.95 g, 4.96 mmol, 1 eq) in DCM (30 mL) was added 6 M HC1 in dioxane (30 mL, 36.26 eq). The mixture was stirred at 25 °C for 1 h before the precipitated solid was isolated by filtration to yield the title compound (3 g, 97% yield) as a white solid, which was used directly in the next step without further purification. [M+H]+= 464.0. ’H NMR (400 MHz, DMSO-Jr,) 8 ppm 9.81 (d, J = 4.4 Hz, 2H), 8.89 (s, 1H), 8.75 (s, 1H), 7.76 (s, 1H), 7.52 (s, 1H), 4.90-4.87 (m, 1H), 4.83 (s, 2H), 4.71-4.55 (m, 1H), 4.18 (s, 2H), 3.91 (s, 3H), 3.40-3.36 (m, 1H), 3.30-3.25 (m, 1H), 3.25 (s, 3H), 2.37-2.31 (m, 1H), 2.00-1.92 (m, 1H).

[0201] (23Z,24E,525,54R)-l6-Chloro-26,54-dimethoxy-3,8-dioxa-2(3,5)- pyrazolo[l,5-tf]pyrimidina-l(4,2)-pyridina-5(2,l)-pyrrolidinacyclooctaphan-6-one: A solution of 2-((6-chloro-4-(6-methoxy-5-(((25,4A)-4-methoxypyrrolidin-2- yl)methoxy)pyrazolo[l,5-a]pyrimidin-3-yl)pyridin-2-yl)oxy)acetic acid hydrochloride (800 mg, 1.28 mmol, 1 eq) in DMF (3 mL) was added into a mixture of DCM (2000 mL) and MeCN (2000 mL). The mixture was adjusted to pH 10 with DIEA, and then a solution of HATU (729.56 mg, 1.92 mmol, 1.5 eq) in DCM (2000 mL) was added into the reaction mixture. The mixture was stirred at 25 °C for 2 h before it was diluted with H2O (3 mL) and concentrated. The residue was added into H2O (20 mL), the solids were isolated by filtration, and the filter cake was washed with H2O. The filter cake was suspended in MeOH (5 mL) and stirred at room temperature for 10 min before the solids were isolated by filtration. The filter cake was washed with MeOH (5 mL) and dried under vacuum to yield the title compound (300 mg, 50% yield) as a white solid. [M+H]+= 446.1.1H NMR (400 MHz, DMSO-c / e) 8 ppm 8.82 (s, 1H), 8.51 (s, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 5.57 (d, J= 12.4 Hz, 1H), 4.90 (d, J= 15.6 Hz, 1H), 4.73 (d, J= 15.6 Hz, 1H), 4.39-4.31 (m, 1H), 4.23-4.15 (m, 1H), 3.99-3.93 (m, 1H), 3.89 (s, 3H), 3.63-3.56 (m, 1H), 3.48-3.42 (m, 1H), 3.24 (s, 3H), 2.27-2.18 (m, 1H), 2.15-2.06 (m, 1H).

[0202] (23Z,24E,525,54R)-l6-chloro-26,54-dimethoxy-3,8-dioxa-2(3,5)- pyrazolo[l,5-a]pyrimidina-l(4,2)-pyridina-5(2,l)-pyrrolidinacyclooctaphane: To a suspension of A1CL (213.08 mg, 1.60 mmol, 1.5 eq) in THF (40 mL) was added LiAlH4 (2.5 M, 1.28 mL, 3 eq) at 0 °C. The resulting mixture was stirred at 0 °C for 20 min, and then a solution of (23Z,24A,52S,54A)-l6-chloro-26,54-dimethoxy-3,8-dioxa-2(3,5)- pyrazolo[l,5-«]pyrimidina-l(4,2)-pyridina-5(2,l)-pyrrolidinacyclooctaphan-6-one (500 mg, 1.07 mmol, 1 eq) in DCM (40 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h before a solution of potassium sodium tartrate tetrahydrate in water was added cautiously into the mixture at 0 °C. After stirring at 0 °C for 1 h, the biphasic mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography (SiO21-30% EtOAc / DCM) to yield the title compound (200 mg, 22% yield) as a white solid. [M+H]+= 432.2. ' H NMR (400 MHz, DMSO-t / 6) 8 ppm 8.83(s, 1H), 8.63 (s, 1H), 8.41-8.31 (m, 1H), 7.46 (s, 1H), 4.93-4.81 (m, 1H), 4.52-4.43 (m, 1H), 4.39-4.33 (m, 1H), 4.04-3.96 (m, 1H), 3.88 (s, 3H), 3.87-3.85 (m, 1H), 3.30-3.25 (m, 2H), 3.22 (s, 3H), 3.17-3.11 (m, 2H), 2.85-2.77 (m, 1H), 2.03-1.96 (m, 1H), 1.89-1.80 (m, 1H).

[0203] (23Z,24E,525,54l?)-l6-chloro-26,54-dimethoxy-3,8-dioxa-2(3,5)- pyrazolo[l,5-fl]pyrimidina-l(4,2)-pyridina-5(2,l)-pyrrolidinacyclooctaphan-55-one: To a solution of (23Z,24£',521S',54R)-l6-chloro-26,54-dimethoxy-3,8-dioxa-2(3,5)- pyrazolo[l,5-a]pyrimidina-l(4,2)-pyridina-5(2,l)-pyrrolidinacyclooctaphane (50 mg, 109.99 pmol, 1 eq) in DCE (10 mL) and H2O (5 mL) was added RuCh (1.46 mg, 11.00 pmol, 0.1 eq) and NaIC>4 (70.57 mg, 329.96 pmol, 3 eq). The resulting mixture was stirred at 80 °C for 1 h before it was cooled, quenched with 10% aqueous Na2S20s (20 mL), and then extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated to give the title compound (50 mg, 92% yield) as a white solid, which was used directly in the next step without further purification. [M+H]+= 446.1. 'H NMR (400 MHz, DMSO-d6) 5 ppm 8.90 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 7.50 (s, 1H), 4.98 (s, 1H), 4.64-4.60 (m, 1H), 4.39-4.37 (m, 1H), 4.27- 4.21 (m, 2H), 4.12 (s, 1H), 3.91 (s, 3H), 3.87 (s, 1H), 3.60-3.58 (m, 1H), 3.45 (s, 3H), 3.26- 3.24 (m, 1H), 1.94-1.88 (m, 1H).Intermediate 13

[0204] tert-butyl (A)-3-(((3-(2-chloro-6-fluoropyridin-4-yl)-6- methoxypyrazolo[l,5-<z]pyrimidin-5-yl)oxy)methyl)morpholine-4-carboxylate: A mixture of tert-butyl ( )-3-(((3-bromo-6-methoxypyrazolo[l,5-r / ]pyrimidin-5- yl)oxy)methyl)morpholine-4-carboxylate (500 mg, 1.02 mmol, 1 eq), 2-chloro-6-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (274.46 mg, 1.07 mmol, 1.05 eq), Pd(dtbpf)C12 (66.16 mg, 101.51 pmol, 0.1 eq) and K3PO4 (646.44 mg, 3.05 mmol, 3 eq) indioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 three times, then the mixture was stirred at 80 °C for 2 hours under a N2 atmosphere. The mixture was fdtered and concentrated to give a residue, which was purified by column chromatography (SiO20-50% EtOAc / petroleum ether) to yield the title compound (550 mg, 99% yield) as a yellow solid. *H NMR (400 MHz, DMSO-t / e) 5 ppm 8.88 (s, 1H), 8.76 (s, 1H), 8.10 (s, 1H), 7.75 (s, 1H), 4.83 (d, J= 5.2 Hz, 2H), 4.50 (s, 1H), 3.91-3.79 (m, 5H), 3.76-3.66 (m, 1H), 3.63-3.58 (m, 1H), 3.43-3.37 (m, 1H), 3.30-3.26 (m, 1H), 1.33-1.10 (m, 9H).

[0205] (A)-3-(((3-(2-chloro-6-fluoropyridin-4-yl)-6-methoxypyrazolo[l,5- a]pyrimidin-5-yl)oxy)methyl)morpholine: To a solution of tert-butyl (S)-3-(((3-(2- chloro-6-fluoropyridin-4-yl)-6-methoxypyrazolo[l,5-a]pyrimidin-5- yl)oxy)methyl)morpholine-4-carboxylate (550 mg, 1.00 mmol, 1 eq) in DCM (5 mL) was added 2 M HC1 in dioxane (4.50 mL, 8.98 eq). The mixture was stirred at 20 °C for 2 hours before it was concentrated. The residue was triturated with H2O (15 mL) and saturated aqueous NaHCO3 (5 mL) at 20 °C for 30 minutes, and then the solids were isolated by filtration and dried under vacuum to give the title compound (460 mg, 93% yield) as a white solid. ’H NMR (400 MHz, DMSO- 4) 8 ppm: 8.83 (s, 1H), 8.76 (s, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 4.45-4.37 (m, 2H), 3.89 (s, 3H), 3.84 (dd, J = 2.4, 10.8 Hz, 1H), 3.70- 3.61 (m, 2H), 3.45-3.40 (m, 2H), 3.24-3.20 (m, 1H), 2.85-2.80 (m, 1H), 2.80-2.74 (m, 1H).

[0206] (A)-2-(3-(((3-(2-chloro-6-fluoropyridin-4-yl)-6- methoxypyrazolo[l,5-fl]pyrimidin-5-yl)oxy)methyl)inorpholino)ethan-l-ol: A mixture of (5)-3-(((3-(2-chloro-6-fluoropyridin-4-yl)-6-methoxypyrazolo[l,5-a]pyrimidin-5- yl)oxy)methyl)morpholine (182.99 mg, 1.52 mmol, 5 eq) in MeOH (2 mL) was stirred at 40 °C for 30 minutes, then l,4-dioxane-2,5-diol (150 mg, 304.72 pmol, 1 eq) was added and stirring was continued at 40 °C for another 30 minutes. The solution was cooled to 20 °C, and then HOAc (91.49 mg, 1.52 mmol, 87.22 pL, 5 eq) and NaBH(OAc)s (484.37 mg, 2.29 mmol, 7.5 eq) were added. The resulting mixture was stirred at 20 °C for 2 hours before it was filtered, and then the filter cake was washed with EtOAc (3 x 10 mL). The solids were diluted with saturated aqueous NH4CI (5 mL), and then the resulting mixture was concentrated. The residue was diluted with water (20 mL) and saturated aqueous NaHCCh (10 mL) before it was extracted with EtOAc (3 x 15 mL). The combined organicextracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO20-5% MeOH / DCM) to give the title compound (120 mg, 81% yield) as a white solid. 'H NMR (400 MHz, DMSO-de) 5 ppm 8.85 (s, 1H), 8.77 (s, 1H), 8.13 (s, 1H), 7.79 (s, 1H), 4.80-4.75 (m, 1H), 4.62-4.57 (m, 1H), 4.40 (t, J= 5.2 Hz, 1H), 3.92-3.87 (m, 3H), 3.81-3.77 (m, 1H), 3.67-3.59 (m, 2H), 3.56-3.48 (m, 3H), 2.97- 2.90 (m, 1H), 2.89-2.82 (m, 2H), 2.63-2.56 (m, 2H).

[0207] (,S',23Z,24£)-l6-chloro-26-methoxy-3,8-dioxa-5(3,4)-morpholina-2(3,5)-pyrazolo[l,5-a]pyrimidina-l(4,2)-pyridinacyclooctaphane: To a solution of (S)- 2-(3-(((3-(2-chloro-6-fluoropyridin-4-yl)-6-methoxypyrazolo[l,5-a]pyrimi din-5- yl)oxy)methyl)morpholino)ethan- 1 -ol (180 mg, 369.99 pmol, 1 eq) in DMSO (20 mL) was added CS2CO3 (361.65 mg, 1.11 mmol, 3 eq). The resulting mixture was stirred at 60 °C for 12 hours before it was diluted with H2O (60 mL) and extracted with EtOAc (3 x 40 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO2, 5% MeOH / DCM) to give the title compound (15 mg, 5% yield) as a white solid. [M+H]+= 418.1. 'H NMR (400 MHz, DMSO-t / e) 8 ppm 8.85 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 7.47 (s, 1H), 4.67 (q, J= 11.2 Hz, 2H), 4.58- 4.48 (m, 1H), 4.29-4.16 (m, 1H), 3.88 (s, 3H), 3.83-3.75 (m, 2H), 3.55-3.46 (m, 2H), 3.29 (d, J= 10.8 Hz, 3H), 3.05-2.98 (m, 1H), 2.78-2.65 (m, 1H).

[0208] (5,23Z,24E')-l6-chloro-26-methoxy-3,8-dioxa-5(3,4)-inorpholina- 2(3,5)-pyrazolo[l,5-a]pyrimidina-l(4,2)-pyridinacyclooctaphan-55-one: A solution of (5, 23Z,24£)-l6-chloro-26-m ethoxy-3 ,8-dioxa-5(3 ,4)-morpholina-2(3 ,5)-pyrazolo[l ,5- tz]pyrimidina-l(4,2)-pyridinacyclooctaphane (140 mg, 291.50 pmol, 1 eq) and NaHCOi (489.77 mg, 5.83 mmol, 20 eq) in THF (20 mL) and H2O (8 mL) was stirred at 25 °C for 10 min under a N2 atmosphere before I2 (2.96 g, 11.66 mmol, 40 eq) was added. The resulting mixture was stirred at 90 °C for 2 h under a N2 atmosphere, and then it was diluted with water (30 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were washed with saturated aqueous Na2SO3 (2 x 30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO21-10% MeOH / DCM) to yield the title compound (40 mg, 28% yield) as a yellow solid. [M+H]+= 432.0.Intermediate 14

[0209] ethyl l-(teti ahydro-2 / / -pyi an-2-yl)-l / / -pvrazole-5-c;irboxvl;ite: To a solution of ethyl 177-pyrazole-5-carboxylate (2 g, 14.27 mmol, 1 eq) in 1,4-dioxane (20 mL) was added p-TsOH’JfcO (271.47 mg, 1.43 mmol, 0.1 eq) and 3,4-dihydro-277-pyran (2.40 g, 28.54 mmol, 2.61 mL, 2 eq). The mixture was stirred at 25 °C for 2 hours before it was concentrated. The residue was purified by column chromatography (SiO20-15% EtOAc / petroleum ether) to give the title compound (2.8 g, 79% yield) as a white solid.!H NMR (400 MHz, DMSO-t / e) 5 ppm 8.00 (d, J= 2.0 Hz, 1H), 6.77 (d, J= 2.4 Hz, 1H), 5.49 (d, J= 9.2 Hz, 1H), 4.27 (q, J= 7.2 Hz, 2H), 3.93 (d, J= 11.2 Hz, 1H), 3.71-3.58 (m, 1H), 2.14-2.02 (m, 1H), 1.92 (d, J= 10.0 Hz, 2H), 1.74-1.60 (m, 1H), 1.59-1.49 (m, 2H), 1.28 (t, J = 6.8 Hz, 3H).

[0210] (5-(ethoxycarbonyl)- 1 -( t et ra hyd ro-2 / / -py ran-2-y I )- LH-pyrazol-3- yl)boronic acid: Amixture of4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.03 g, 8.03 mmol, 1.16 mL, 2 eq), Ir(cod)(OMe)2 (53.20 mg, 80.27 pmol, 0.02 eq) and dtbpy (43.09 mg, 160.53 pmol, 0.04 eq) in pentane (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 0.2 hour under a N2 atmosphere, and then a solution of ethyl l-(tetrahydro-2 / / -pyran-2-yl)-l / / -pyrazole-5-carboxylate (1 g, 4.01 mmol, 1 eq) in THF (4 mL) and pentane (2 mL) was added. The resulting mixture was stirred at 25 °C for 72 hours before it was concentrated. The residue was purified by column chromatography (SiO20-15% EtOAc / petroleum ether) to give the title compound (500 mg, 42% yield) as a colorless solid.JH NMR (400 MHz, DMSOd6) 8 ppm 7.03 (s, 1H), 5.75 (dd, J= 2.4, 10.0 Hz, 1H), 4.35-4.21 (m, 2H), 4.00-3.87 (m, 1H), 3.69-3.52 (m, 1H), 2.31-2.15 (m, 1H), 2.03-1.88 (m, 2H), 1.72-1.49 (m, 3H), 1.30 (s, 3H).

[0211] ethyl 3-(5-(((2>S',4R)-1-(te / 7-butoxycarbonyl)-4-methoxypyrrolidin-2-yl)methoxy)-6-methoxypyrazolo[l,5-a]pyrimidin-3-yl)-l-(tetrahydro-2H-pyran-2- yl)-l / / -pyrazole-5-carboxylate: A mixture of / c / 7-butyl (2S,4R)-2-(((3-bromo-6- methoxypyrazolo[l,5-a]pyrimidin-5-yl)oxy)methyl)-4-methoxypyrrolidine-l -carboxylate (1.51 g, 2.97 mmol, 1 eq), (5-(ethoxycarbonyl)-l-(tetrahydro-277-pyran-2-yl)-177-pyrazol-3-yl)boronic acid (1.34g, 4.51 mmol, 1.52 eq), Pd(dtbpf)Ch (193.68 mg, 297.17 pmol, 0.1 eq) and K3PO4 (1.89 g, 8.92 mmol, 3 eq) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C for 12 hours under a N2 atmosphere before it was concentrated. The residue was purified by column chromatography (Si O2, 0-30% EtOAc / petroleum ether) to give the title compound (1.2 g, 61% yield) as a red oil.JH NMR (400 MHz, CDCI3) 8 ppm 8.16-8.06 (m, 2H), 7.12-7.03 (m, 1H), 5.46 (d, J= 9.2 Hz, 1H), 4.18-4.08 (m, 4H), 3.92 (s, 3H), 3.77-3.60 (m, 2H), 3.59-3.41 (m, 2H), 3.32 (s, 3H), 2.77-2.60 (m, 1H), 2.23-2.11 (m, 3H), 2.02-1.74 (m, 2H), 1.61-1.54 (m, 2H), 1.44-1.40 (m, 9H), 1.38 (d, J= 10.0 Hz, 4H).

[0212] ethyl 3-(6-methoxy-5-(((25,4R)-4-methoxypyrrolidin-2- yl)methoxy)pyrazolo[l,5-«]pyrimidin-3-yl)-lfT-pyrazole-5-carboxylate: To a solution of ethyl 3-(5-(((2<S',4R)-l-(terZ-butoxycarbonyl)-4-methoxypyrrolidin-2-yl)methoxy)-6- methoxypyrazolo[l,5-a]pyrimidin-3-yl)-l-(tetrahydro-2 / / -pyran-2-yl)-l / / -pyrazole-5- carboxylate (1.2 g, 1.80 mmol, 1 eq) in DCM (5 mL) was added 2 M HC1 in dioxane (5 mL). The mixture was stirred at 25 °C for 0.5 hour before it was concentrated to give the title compound (700 mg, 84% yield) as a white solid. 'H NMR (400 MHz, DMSOd6) 8 ppm 8.73 (s, 1H), 8.37 (s, 1H), 7.04 (s, 1H), 4.96-4.90 (m, 1H), 4.55 (t, J= 8.4 Hz, 1H), 4.16-4.11 (m, 1H), 3.95-3.91 (m, 1H), 3.87 (s, 3H), 3.19 (s, 1H), 3.18 (s, 3H), 2.02-1.95 (m, 2H), 1.31 (s, 5H).

[0213] ethyl (l2L.27:.24L.52.S.54R)-2fi.54-diinethoxy-17 / -3-oxa-2(3.5)- pyrazolo[l,5-fi]pyrimidina-l(3,l)-pyi'azola-5(2,l)-pyi'rolidinacyclooctaphane-l5- carboxylate: A mixture of ethyl 3-(6-methoxy-5-(((25,4R)-4-methoxypyrrolidin-2- yl)methoxy)pyrazolo[l,5-a]pyrimidin-3-yl)-l / / -pyrazole-5-carboxylate (200 mg, 432.25 pmol, 1 eq), 1,3 -dibromopropane (261.79 mg, 1.30 mmol, 132.22 pL, 3 eq), CS2CO3 (422.50 mg, 1.30 mmol, 3 eq) and KI (430.52 mg, 2.59 mmol, 6 eq) in MeCN (80 mL) wasstirred at 60 °C for 12 hours under a N2 atmosphere. The reaction mixture was concentrated, and then the residue was purified by column chromatography (SiO20-7% MeOH / DCM) to give the title compound (45 mg, 21% yield) as a yellow solid. [M+H]+= 457.0. ’H NMR (400 MHz, CDCI3) 5 ppm 8.06 (s, 1H), 8.04 (s, 1H), 6.98 (s, 1H), 4.55 (s, 2H), 4.36 (q, J = 6.8 Hz, 2H), 4.13-4.04 (m, 1H), 4.02-3.98 (m, 1H), 3.96-3.93 (m, 1H), 3.91 (s, 3H), 3.86- 3.74 (m, 1H), 3.34 (s, 3H), 3.25-2.96 (m, 3H), 2.87-2.75 (m, 1H), 2.61-2.51 (m, 1H), 2.22- 2.10 (m, 2H), 2.01-1.93 (m, 1H), 1.43-1.36 (m, 3H).

[0214] ethyl (l2 / ;.2, / :.24 / :.52.$'.5tR)-26.54-dimetlioxy-5s-()xo-ll / / -3-oxa- 2(3,5)-pyrazolo[l,5-a]pyrimidina-l(3,l)-pyrazola-5(2,l)-pyrrolidinacyclooctaphane- l5-carboxylate: A solution of ethyl (l2£',23£',24E',525,54R)-26,54-dimethoxy-l1 / f-3-oxa- 2(3,5)-pyrazolo[l,5-tz]pyrimidina-l(3,l)-pyrazola-5(2,l)-pyrrolidinacyclooctaphane-l5- carboxylate (45 mg, 88.72 pmol, 1 eq) and NaHCCh (149.06 mg, 1.77 mmol, 20 eq) in H2O (3 mL) and THF (7.5 mL) was stirred at 25 °C for 0.5 hour under N2, and then I2 (337.77 mg, 1.33 mmol, 15 eq) was added. The resulting mixture was stirred at 80 °C for 12 hours under a N2 atmosphere before it was concentrated. The residue was purified by column chromatography (SiO20-5% MeOH / DCM) and RP-HPLC to give the title compound (8 mg, 17% yield) as a yellow solid. [M+H]+= 471.0. 'H NMR (400 MHz, CDCh) 5 ppm 8.12 (s, 1H), 8.08 (s, 1H), 7.02 (s, 1H), 4.94 (d, J = 11.2 Hz, 1H), 4.70-4.58 (m, 2H), 4.51-4.42 (m, 1H), 4.37 (q, J = 6.8 Hz, 2H), 4.23-4.17 (m, 1H), 4.00-3.92 (m, 4H), 3.91-3.85 (m, 1H), 3.78-3.70 (m, 1H), 3.58 (s, 3H), 2.66 (dd, . / = 12.8, 8.0 Hz, 1H), 2.57-2.46 (m, 1H), 2.41-2.30 (m, 1H), 2.09-2.00 (m, 1H), 1.40 (t, 7.2 Hz, 3H).

[0215] (l2E,23E,24£,525,54R)-26,54-dimethoxy-5s-oxo- 17 / -3-oxa-2(3.5)- pyrazolo[l,5-fl]pyrimidina-l(3,l)-pyi'azola-5(2,l)-pyi'rolidinacyclooctaphane-l5- carboxylic acid: A solution of ethyl (l2£,23E',24E',525',54A)-26,54-dimethoxy-55-oxo-l1 / f- 3-oxa-2(3,5)-pyrazolo[l,5-rz]pyrimidina- 1(3,1 )-pyrazola-5(2,l )- pyrrolidinacyclooctaphane-l5-carboxylate (8 mg, 15.30 pmol, 1 eq) and LiOHHHO (1.28 mg, 30.61 pmol, 2 eq) in H2O (0.3 mL) and MeOH (0.9 mL) was stirred at 25 °C for 12 hours under a N2 atmosphere. The reaction mixture was concentrated to provide the title compound (7 mg, crude) as a yellow solid. [M+H]+= 442.9.

[0216] The following intermediate was prepared following procedures analogous to those described for Intermediate 14.Intermediate 16

[0217] methyl l-(3-(benzyloxy)-3-oxopropyl)-3-bromo-l / 7-pyrazole-5- carboxylate: To a solution of methyl 3-bromo-l / / -pyrazole-5-carboxylate (537.94 mg, 2.99 mmol, 1.02 eq) and benzyl 3-hydroxypropanoate (537.94 mg, 2.99 mmol, 1.02 eq) in THF (10 mb) was added PPhs (1.15 g, 4.39 mmol, 1.5 eq) and DIAD (887.71 mg, 4.39 mmol, 851.11 pL, 1.5 eq) at 0 °C under N2. The mixture was stirred under N2 at 25 °C for 16 hours before it was concentrated. The residue was purified by column chromatography (SiC>2, 1-12% EtOAc / petroleum ether) to yield the title compound (460 mg, 43% yield) as colorless oil. [M+H]+= 366.9.JH NMR (400 MHz, DMSO-t / 6) 5 ppm 7.40-7.29 (m, 5H), 7.00 (s, 1H), 5.08 (s, 2H), 4.74 (t, J= 6.8 Hz, 2H), 3.82 (s, 3H), 2.96 (t, J= 6.8 Hz, 2H).

[0218] methyl l-(3-(benzyloxy)-3-oxopropyl)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole-5-carboxylate: A mixture of methyl l-(3-(benzyloxy)- 3-oxopropyl)-3-bromo-l / f-pyrazole-5-carboxylate (460 mg, 1.25 mmol, 1 eq), IhPim (636.24 mg, 2.51 mmol, 2 eq), KO Ac (368.84 mg, 3.76 mmol, 3 eq) and Pd(dppf)Ch (91.66mg, 125.27 pmol, 0.1 eq) in 1,4-dioxane (8 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 °C for 12 hours under a N2 atmosphere. The reaction mixture was fdtered and concentrated to give a residue, which was purified by column chromatography (SiO21-22% EtOAc / petroleum ether) to yield the title compound (460 mg, 84% yield) as a yellow solid. [M+H]+= 332.9. ’H NMR (400 MHz, DMSO-tA) 6 ppm 7.38-7.25 (m, 5H), 7.05 (s, 1H), 5.06 (s, 2H), 4.79 (t, J= 6.8 Hz, 2H), 3.81 (s, 3H), 2.96 (t, J= 6.8 Hz, 2H), 1.27 (s, 12H).Intermediate 17

[0219] tert-butyl (R)-3-(((3-bromo-6-methoxypyrazolo[l,5-«|pyrimidin-5- yl)amino)methyl)morpholine-4-carboxylate: To a solution of tr / V-bu ty I (A’) -3- (aminomethyl)morpholine-4-carboxylate (4.12 g, 19.05 mmol, 1 eq) and 3-bromo-5- chloro-6-methoxypyrazolo[l,5-a]pyrimidine (5 g, 19.05 mmol, 1 eq) in DMF (100 mL) was added EtsN (5.78 g, 57.14 mmol, 7.95 mL, 3 eq). The mixture was stirred at 80 °C for 1 h before it was diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried overNa2SO4, fdtrated and concentrated. The residue was purified by column chromatography (SiO21-2% EtOAc / DCE) to give the title compound (6 g, 68% yield) as a white solid. [M+H]+= 442.0. 'H NMR (400 MHz, CDCI3) 8 ppm 7.76 (s, 1H), 7.71 (s, 1H), 6.35-5.57 (m, 1H), 4.53-4.12 (m, 2H), 3.90 (d, J= 11.6 Hz, 2H), 3.83 (s, 3H), 3.71-3.66 (m, 2H), 3.59-3.17 (m, 3H), 1.35 (s, 9H).

[0220] tert-butyl (l?)-3-(((3-(l-(3-(benzyloxy)-3-oxopropyl)-5-(methoxycarbonyl)-l / 7-pyrazol-3-yl)-6-methoxypyrazolo[l,5-a]pyrimidin-5- yl)amino)methyl)morpholine-4-carboxylate: To a solution of tert-butyl (R)-3-(((3- bromo-6-methoxypyrazolo[l,5-cz]pyrimidin-5-yl)amino)methyl)morpholine-4- carboxylate (2 g, 4.30 mmol, 1 eq) and methyl l-(3-(benzyloxy)-3-oxopropyl)-3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l / 7-pyrazole-5-carboxylate (2.97 g, 6.44 mmol, 1.5 eq) in dioxane (100 mL) and H2O (20 mL) was added K3PO4 (2.74 g, 12.89 mmol, 3 eq)and Pd(dtbpf)Ch (279.97 mg, 429.57 pmol, 0.1 eq) under N2. The mixture was stirred at 80 °C for 1 h before it was diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, fdtered and concentrated. The residue was purified by column chromatography (SiO21- 100% EtOAc / petroleum ether) to give the title compound (2.8 g, 90% yield) as a white solid. [M+H]+= 651.2. 'H NMR (400 MHz, CDCI3) 8 ppm 8.19 (s, 1H), 7.84 (s, 1H), 7.50-7.43 (m, 1H), 7.37-7.31 (m, 5H), 6.06-5.70 (m, 1H), 5.15 (s, 2H), 4.92 (t, J= 7.2 Hz, 2H), 4.49-4.38 (m, 1H), 3.95 (d, J= 12.0 Hz, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.72-3.68 (m, 1H), 3.54-3.48 (m, 1H), 3.43-3.25 (m, 1H), 3.02 (t, J= 7.2 Hz, 2H), 1.45-1.27 (m, 9H).

[0221] (R)-3-(3-(5-(((4-(tert-butoxycarbonyl)morpholin-3- yl)methyl)amino)-6-methoxypyrazolo[l,5-a]pyrimidin-3-yl)-5-(methoxycarbonyl)- l / Z-pyrazol-l-yl)propanoic acid: A mixture of tert-butyl (R)-3-(((3-(l-(3-(benzyloxy)-3- oxopropyl)-5-(methoxy carbonyl)- CN1H-pyrazol-3-yl)-6-methoxypyrazolo[ l,5-a]pyrimidin-5-yl)amino)methyl)morpholine-4-carboxylate (2.8 g, 3.88 mmol, 1 eq) and 10% Pd / C (4.13 g, 3.88 mmol, 1 eq) in THF (150 mL) and MeOH (150 mL) was degassed and purged with H2 three times, and then the mixture was stirred at 25 °C for 2 h under H2 (30 psi). The solids were removed by filtration, and the filtrate was concentrated to give the title compound (1.8 g, 79% yield) as a white solid, which was used in the next step without purification. [M+H]+= 560.2. ’H NMR (400 MHz, CDCI3) 6 ppm 8.11 (br s, 1H), 7.93- 7.82 (m, 1H), 7.31 (s, 1H), 6.10-5.74 (m, 1H), 4.98-4.86 (m, 2H), 4.42 (s, 1H), 3.98-3.83 (m, 8H), 3.71 (d, J = 10.0 Hz, 1H), 3.55-3.50 (m, 1H), 3.37-3.30 (m, 1H), 2.98 (s, 2H), 1.49-1.31 (m, 9H).

[0222] (J?)-3-(3-(6-methoxy-5-((morpholin-3- ylmethyl)amino)pyrazolo[l,5-a]pyrimidin-3-yl)-5-(methoxycarbonyl)-lH-pyrazol-l- yl)propanoic acid hydrochloride: To a solution of 2 M HC1 in dioxane (45 mL) and DCM (45 mL) was added (R)-3-(3-(5-(((4-(tert-butoxycarbonyl)morpholin-3-yl)methyl)amino)-6-methoxypyrazolo[l, 5-cz]pyrimidin-3-yl)-5-(methoxy carbonyl)- 1 / 7-pyrazol-l- yl)propanoic acid (1.8 g, 2.90 mmol, 1 eq). The mixture was stirred at 30 °C for 1 h before the solids were isolated by filtration, and then dried under reduced pressure to give the titlecompound (2.35 g) as a white solid, which was used directly in the next step without further purification. [M+H]+= 460.1.

[0223] methyl (l2Is,23E,24£',53l?)-26-methoxy-6-oxo-l1H-3-aza-5(3,4)- morpholina-2(3,5)-pyrazolo[l,5-fl]pyrimidina-l(3,l)-pyrazolacyclooctaphane-l5- carboxylate: A solution of (A)-3-(3-(6-methoxy-5-((morpholin-3- ylmethyl)amino)pyrazolo[ 1 ,5-rz]pyrimidin-3 -yl)-5-(m ethoxy carbonyl)- 1 / / -pyrazol- 1 - yl)propanoic acid hydrochloride (750.00 mg, 922.93 pmol, 1 eq) in DCM (2000 mL) was added into a mixture of DMF (9 mL) and MeCN (2000 mL). The mixture was adjusted to pH 10 with DIEA, and then a solution of HATU (526.39 mg, 1.38 mmol, 1.5 eq) in DMF (9 mL) was added. The resulting mixture was stirred at 25 °C for 2 h before it was concentrated. The residue was purified by column chromatography (SiO21-3% MeOH / DCM) to afford the title compound (350 mg, 82% yield) as a white solid. [M+H]+= 442.2.

[0224] methyl (l2E,23E',24E',53l?)-26-methoxy-l1H-3-aza-5(3,4)- morpholina-2(3,5)-pyrazolo[l,5-fl]pyrimidina-l(3,l)-pyrazolacyclooctaphane-l5- carboxylate: A solution of methyl (l2E,23E,24E,53R)-26-methoxy-6-oxo-ll / f-3-aza- 5(3,4)-morpholina-2(3,5)-pyrazolo[l,5-fl']pyrimidina-l(3,l)-pyrazolacyclooctaphane-l5- carboxylate (700 mg, 1.51 mmol, 1 eq) and (Me2HSi)2O (2.02 g, 15.06 mmol, 6 mL, 10 eq) in DCM (300 mL) was degassed and purged with N2 five times, and then IrCl(CO)(PPh3)2 (705.24 mg, 903.86 pmol, 0.6 eq) was added and the solution was again degassed and purged with N2 five times. The resulting mixture was stirred at 25 °C for 1 h before it was diluted H2O (20 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography (SiO21-3% MeOH / DCM) to afford the title compound (240 mg, 35% yield) as a white solid. [M+H]+= 428.2. 'H NMR (400 MHz, CDCI3) 8 ppm 7.93 (s, 1H), 7.83 (s, 1H), 6.91 (s, 1H), 5.63 (s, 1H), 5.31 (s, 1H), 4.95-4.83 (m, 1H), 4.66-4.52 (m, 1H), 4.18-4.03 (m, 1H), 3.95 (s, 1H), 3.89 (d, J = 9.6 Hz, 7H), 3.83 (s, 1H), 3.79-3.72 (m, 1H), 3.69-3.62 (m, 2H), 3.59- 3.52 (m, 2H), 2.76 (s, 1H), 2.65-2.60 (m, 1H), 2.52 (d, J= 9.6 Hz, 1H).

[0225] methyl (l2E,23E,24E,53R)-26-methoxy-55-oxo-l1 / / -3-aza-5(3,4)- morpholina-2(3,5)-pyrazolo[l,5-a]pyrimidina-l(3,l)-pyrazolacyclooctaphane-l5- carboxylate: To a solution of methyl (l2E,23E,24E,53R)-26-methoxy-l17 / -3-aza-5(3,4)- morpholina-2(3 ,5)-pyrazolo[ 1 , 5-c / ]pyri mi dina- 1(3,1 )-pyrazolacyclooctaphane- 15- carboxylate (340 mg, 755.63 pmol, 1 eq) in H2O (40 mL) and THF (40 mL) was added NaHCO3 (952.21 mg, 11.33 mmol, 15 eq) and I2 (1.34 g, 5.29 mmol, 7 eq) at 0 °C. The mixture was stirred at 25 °C for 6 h before it was quenched with saturated aqueous Na2SCh (80 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiC>2, 1-3% MeOH / DCM) to give the title compound (170 mg, 51% yield) as a white solid. [M+H]+= 442.2.!H NMR (400 MHz, CDCI3) 5 ppm 7.99 (s, 1H), 7.89 (s, 1H), 6.98 (s, 1H), 5.76 (t, J= 4.8 Hz, 1H), 4.78-4.68 (m, 1H), 4.49-4.39 (m, 2H), 4.30-4.21 (m, 2H), 4.16 (d, J = 16.4 Hz, 1H), 4.06-3.98 (m, 2H), 3.91 (d, J= 2.0 Hz, 6H), 3.88-3.82 (m, 1H), 3.67 (d, J= 12.0 Hz, 1H), 3.63-3.53 (m, 1H), 2.50-2.40 (m, 2H).

[0226] (l2E,23E,24E,53R)-26-methoxy-55-oxo-l1 / / -3-aza-5(3,4)- morpholina-2(3,5)-pyrazolo[l,5-fl]pyrimidina-l(3,l)-pyrazolacyclooctaphane-l5- carboxylic acid: To a solution of methyl (l2E,23E,24E,53R)-26-methoxy-5:’-oxo-l1 / / -3- aza-5(3 ,4)-morpholina-2(3 ,5)-pyrazolo[ 1 , 5-rz]pyrimidina- 1(3,1 )-pyrazolacyclooctaphane- 15-carb oxy late (150 mg, 339.80 pmol, 1 eq) in MeOH (8 mL), THF (8 mL) and DCM (8 mL) was added a solution of LiOHHhO (14.26 mg, 339.80 pmol, 1 eq) in H2O (8 mL). The mixture was stirred at 25 °C for 16 h before it was acidified with 1 M HC1 and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the title compound (150 mg, 98% yield) as a white solid, which was used directly in the next step without further purification. [M+H]+= 428.0. 'H NMR (400 MHz, DMSO-tfc) 8 ppm 8.36 (s, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 6.92 (s, 1H), 4.69-4.60 (m, 1H), 4.30-4.21 (m, 2H), 4.15 (d, J= 10.4 Hz, 1H), 4.04 (d, J = 11.6 Hz, 2H), 3.91-3.85 (m, 4H), 3.81-3.74 (m, 1H), 3.66-3.54 (m, 3H), 2.27-2.16 (m, 2H).

[0227] The following intermediates were prepared following procedures analogous to those described for Intermediate 17.Intermediate 21

[0228] 3-bromo-l-cyclopropyl-4-methyl-l / / -pyrazole: A mixture of 2,2'- bipyridine (523.85 mg, 3.35 mmol, 2 eq) and Cu(OAc)2 (609.21 mg, 3.35 mmol, 1.2 eq) in DCE (60 mb) was degassed and purged with O2 three times, and then the mixture was stirred at 70 °C for 0.5 h. The mixture was cooled to 25 °C before NaHCO3 (592.49 mg, 5.59 mmol, 2 eq), cyclopropylboronic acid (480.17 mg, 5.59 mmol, 2 eq) and 3-bromo-4- m ethyl- l / / -pyrazole (450 mg, 2.80 mmol, 1 eq) were added into the mixture, and then the mixture was stirred under O2 (15 psi) at 70 °C for 4 h. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography (SiO21-25% EtOAc / petroleum ether) to yield the title compound (500 mg, 80% yield) as a colorless oil.JH NMR (400 MHz, DMSO-d6) 5 ppm 7.63 (s, 1H), 3.67-3.59 (m, 1H), 1.90 (s, 3H), 0.97-0.97 (m, 1H), 0.98-0.94 (m, 2H), 0.94-0.88 (m, 2H).

[0229] 1 -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-LH-pyrazole: A mixture of 3-bromo-l-cyclopropyl-4-methyl-l / / -pyrazole (100 mg, 497.36 pmol, 1 eq), B2Pin2 (252.59 mg, 994.71 pmol, 2 eq) and KO Ac (146.43 mg, 1.49 mmol, 3 eq) in dioxane (5 mL) was degassed and purged with N2 three times. Pd(dppf)Ch (36.39 mg, 49.74 pmol, 0.1 eq) and PCy3 (27.89 mg, 99.47 pmol, 32.25 pL, 0.2 eq) were added into the mixture, and then the mixture was stirred at 110 °C for 12 h under a N2 atmosphere. The solids were removed by filtration, and the filtrate was concentrated to yield the title compound (120 mg, crude) as a white solid. The material was used directly in the next step without further purification.Intermediate 22

[0230] (5-methylisothiazol-3-yl)methanamine hydrochloride: A mixture of3-(chloromethyl)-5-methylisothiazole (150 mg, 1.02 mmol, 1 eq) in ammonium hydroxide (5 mL) was stirred at 100 °C for 1 hour before it was cooled and lyophilized. The residue was purified by RP-HPLC to yield the title compound (57 mg, 34% yield) as a white solid. [M+H]+= 129.1.Intermediate 23

[0231] l-(5-ethylthiazol-2-yl)ethan-l-amine trifluoroacetate: To a solution of l-(5-methylthiazol-2-yl)ethan-l-one (100 mg, 708.26 pmol, 1 eq) and NaBLLCN (178.03 mg, 2.83 mmol, 4 eq) in MeOH (10 mL) was added NLLOAc (655.11 mg, 8.50 mmol, 12 eq). The mixture was stirred at 60 °C for 16 hours before it was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by RP-HPLC to yield the title compound (50 mg, 28% yield) as a white solid.[M+H]+= 143.0. ‘H NMR (400 MHz, DMSO-d6) 5 ppm 8.53 (s, 3H), 7.56 (s, 1H), 4.70- 4.80 (m, 1H), 2.46 (s, 3H), 1.55 (d, J= 6.8 Hz, 3H).

[0232] The following intermediates were prepared following procedures analogous to those described for Intermediate 23.Intermediate 29

[0233] (£)-2-methyl-7V-((l-methyl-l / / -pyrazol-3-yl)methylene)propane-2- sulfinamide: To a solution of 1 -methyl- 17 / -pyrazole-3-carbaldehy de (100 mg, 908.15 pmol, 1 eq) in THF (3 mL) was added 2-methylpropane-2-sulfinamide (132.08 mg, 1.09 mmol, 1.2 eq) and Ti(z-PrO)4 (774.33 mg, 2.72 mmol, 804.08 pL, 3 eq) at 0 °C. The resulting mixture was stirred at 30 °C for 12 h before it was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (3 x 20 mL) and brine (3 x 20 mL), and then dried over Na2SO4, fdtered and concentrated. The residue was purified by column chromatography (SiO20-55% EtOAc / petroleum ether) to give the title compound (120 mg, 62% yield) as a colorless oil. 'H NMR (400 MHz, CDCla) 5 ppm 8.63 (s, 1H), 7.41 (d, J= 2.0 Hz, 1H), 6.78 (d, J= 2.0 Hz, 1H), 4.00 (s, 3H), 1.26 (s, 9H).

[0234] 2-methyl- V-(l-(l-methyl-LH-pyrazol-3-yl)ethyl)propane-2- sulfinamide: To a solution of (E)-2-methyl-A-((l -methyl- IT / -pyrazol-3- yl)methylene)propane-2-sulfmamide (100 mg, 468.82 pmol, 1 eq) in THF (3 mL) was added MeMgBr (3 M, 468.82 pL, 3 eq) at -70 °C under N2. The reaction mixture was stirred under N2 at -70 °C for 0.5 h, and then at 0 °C for 1 h before it was quenched with saturatedaqueous NH4CI (10 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, fdtered and concentrated. The residue was purified by column chromatography (SiO20-50% EtOAc / petroleum ether) to give the title compound (80 mg, 71% yield) as a yellow oil.!H NMR (400 MHz, CDCI3) 8 ppm 7.30-7.20 (m, 1H), 6.21-6.15 (m, 1H), 4.69-4.53 (m, 1H), 3.87-3.86 (m, 3H), 1.63-1.50 (m, 3H), 1.25-1.19 (m, 9H).

[0235] l-(l-methyl-17 / -pyrazol-3-yl)ethan-l-amine hydrochloride: To a solution of 2-methyl-JV-(l-(l -methyl- l / / -pyrazol-3-yl)ethyl)propane-2-sulfinamide (80 mg, 331.38 pmol, 1 eq) in dioxane (2 mL) was added 2 M HC1 in dioxane (1.66 mL, 10 eq). The resulting mixture was stirred at 30 °C for 1 h before it was concentrated to give the title compound (50 mg, 93% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-de) 8 ppm 8.45 (br s, 2H), 7.70 (d, J= 2.0 Hz, 1H), 6.37 (d, J= 2.0 Hz, 1H), 4.36-4.29 (m, 1H), 3.82 (s, 3H), 1.49 (d, J= 6.8 Hz, 3H).

[0236] The following intermediates were prepared following procedures analogous to those described for Intermediate 29.ExamplesExample 1. Preparation of (23Z,24E,525',54R)-l5-amino-26,54-dimethoxy-3,8-dioxa-2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2, 1 )-pyrrolidina-l(l,3)-benzenacyclooctaphan-55-one

[0237] To a solution of (23Z,24E,525,54K)-26,54-dimethoxy-P-nitro-3,8-dioxa- 2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l )-pyrrolidina-l(l,3)-benzenacyclooctaphan-55-one (35 mg, 69.17 pmol, 1 e< / ) in EtOH (5 mL) and water (1 mL) was added iron powder (19.31 mg, 345.83 pmol, 5 eq) and NELCI (18.50 mg, 345.83 pmol, 5 eq). The mixture was stirred at 80 °C for 2 hours under a N2 atmosphere before it was filtered and concentrated under reduced pressure. The residue was diluted with water (3 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (36 mg, crude) as a yellow solid. [M+H]+= 426.1.

[0238] The following compounds were prepared following procedures analogous to that described for Example 1.Example 10. Prepration of tert-butyl ((23Z,24E,52S,54R)-26,54-dimethoxy-55-oxo-3-oxa- 8-aza-2(3,5)-pyrazolo[l,5-a]pyrimidina-l(4,2)-pyridina-5(2,l)- pyrrolidinacyclooctaphane-l6-yl)carbamate

[0239] A mixture of (23Z,24E’,521$',54R)-l6-chloro-26,54-dimethoxy-3-oxa-8- aza-2(3,5)-pyrazolo[l,5-a]pyrimidina-l(4,2)-pyridina-5(2,l )-pyrrolidinacyclooctaphan- 55-one (10 mg, 20.23 pmol, 1 eq), B0CNH2 (4.74 mg, 40.46 pmol, 2 eq), CS2CO3 (19.77 mg, 60.69 pmol, 3 eq) and BrettPhos Pd G3 (3.67 mg, 4.05 pmol, 0.2 eq) in dioxane (4 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 2 hours under a N2 atmosphere before it was filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound (2.36 mg, 4.49 pmol, 22.20% yield, 100% purity) as a white solid. [M+H]+= 526.1.JH NMR (400 MHz, DMSO-d6) 6 ppm 9.06 (s, 1H), 8.81 (s, 1H), 8.29 (s, 1H), 7.43-7.31 (m, 1H), 7.27 (s, 1H), 6.28 (t, J= 6.0 Hz, 1H), 4.95 (d, J= 10.0 Hz, 1H), 4.61-4.43 (m, 1H), 4.33 (t, J= 10.0 Hz, 1H), 4.04 (t, J= 8.8 Hz, 1H), 3.90 (s, 3H), 3.67-3.54 (m, 1H), 3.44 (s, 3H), 3.39-3.35 (m, 1H), 3.28-3.11 (m, 2H), 2.46-2.41 (m, 1H), 2.00-1.89 (m, 1H), 1.47 (s, 9H).

[0240] The following compounds were prepared following procedures analogous to those described for Example 10.Example 23. Preparation of (23Z,24E,525',54R)-l6-amino-26,54-dimethoxy-3-oxa-8-aza-2(3,5)-pyrazolo[l,5-a]pyrimidina-l(4,2)-pyridina-5(2,l )-pyrrolidinacyclooctaphan-55- one

[0241] To a solution of / cvz-butyl ((23Z,24E’,525,54A)-26,54-dimethoxy-5:’-oxo- 3-oxa-8-aza-2(3,5)-pyrazolo[l,5-rz]pyrimidina-l(4,2)-pyridina-5(2,l)- pyrrolidinacyclooctaphane-l6-yl)carbamate (30 mg, 51.37 pmol, 1 eq) in DCM (0.5 mL) was added TFA (0.1 mL). The mixture was stirred at 25 °C for 0.5 hour before it was filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound (2.24 mg, 5.01 pmol, 9.76% yield, 99.33% purity, 0.4FA) as a white solid. [M+H]+= 426.1. 'H NMR (400 MHz, DMSO-t / e) 8 ppm 8.77 (s, 1H), 8.23 (s, 1H), 8.19 (s, 0.4H), 6.91 (br s, 1H), 6.06-5.95 (m, 2H), 5.39 (br s, 2H), 4.92 (d, J= 10.8 Hz, 1H), 4.47 (br s, 1H), 4.32 (t, J = 8.8 Hz, 1H), 4.02 (t, J= 10.8 Hz, 1H), 3.88 (s, 3H), 3.62-3.57 (m, 1H), 3.43 (s, 3H), 3.17-3.00 (m, 3H), 2.46-2.40 (m, 1H), 1.99-1.90 (m, 1H).

[0242] The following compounds were prepared following procedures analogous to those described for Example 23.

[0243] TheExample 26. Preparation of jV-((23Z,24E’,525’,54R)-26,54-dimethoxy-55-oxo-3,8-dioxa- 2(3,5)-pyrazolo[l,5-fl']pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphane-l:’- yl)- 1 -fluorocyclohexane- 1 -carboxamide

[0244] To a solution of 1 -fluorocyclohexane- 1 -carboxylic acid (10.3 mg, 70.52 pmol, 1.5 eq) in DMF (0.5 mL) was added HATU (35.75 mg, 94.02 pmol, 2 eq), DIEA (18.23 mg, 141 .03 pmol, 24.57 pL, 3 eq) and (23Z,24E,52S,54R)-l5-amino-26,54-dimethoxy- 3,8-dioxa-2(3,5)-pyrazolo[l,5-tz]pyrimidina-5(2,l)-pyrrolidina-l(l,3)- benzenacyclooctaphan-55-one (20 mg, 47.01 pmol, 1 eq). The mixture was stirred at 25 °C for 1 hour before it was diluted with water (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over Na?SO4, filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound (7.4 mg, 13.15 pmol, 27.98% yield, 98.41% purity) as a light yellow solid. [M+H]+= 554.2.1H NMR (400 MHz, DMSO-d6) 5 ppm 9.84 (d, J= 3.6 Hz, 1H), 8.79 (s, 1H), 8.23 (s, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 7.17 (s, 1H), 4.94 (d, J = 10.4 Hz, 1H), 4.61-4.50 (m, 1H), 4.35 (t, J = 8.8 Hz, 1H), 4.30-4.21 (m, 1H), 4.19-4.10 (m, 1H), 4.09-4.02 (m, 1H), 3.90 (s, 3H), 3.85-3.75 (m, 1H), 3.63-3.54 (m, 1H), 3.45 (s, 3H), 2.45 (s, 1H), 1.98-1.82 (m, 5H), 1.68 (d, J= 9.6 Hz, 3H), 1.61-1.49 (m, 2H), 1.37-1.27 (m, 1H).

[0245] The following compounds were prepared following procedures analogous to that described for Example 26.Example 60. Preparation of isopropyl ((23Z,24E,525',54R)-26,54-dimethoxy-5:’-oxo-3,8- dioxa-2(3,5)-pyrazolo[l,5-cz]pyrimidina-5(2,l)-pyrrolidina- 1(1,3)- benzenacyclooctaphane-l5-yl)carbamate

[0246] A mixture of (23Z,24E',525',54R)-l:’-amino-26,54-dimethoxy-3,8-dioxa- 2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l )-pyrrolidina-l(l,3)-benzenacyclooctaphan-55-one (10 mg, 21.15 pmol, 1 eq), isopropyl chloroformate (2.59 mg, 21.15 pmol, 2.94 pL, 1 eq) and pyridine (16.73 mg, 211.55 pmol, 17.07 pL, 10 e< / ) in DCM (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 20 °C for 1 hour under a N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by RP-HPLC to give the title compound (2.7 mg, 5.23 pmol, 24.72% yield, 99.06% purity) as a white solid. [M+H]+= 512.1.JH NMR (400 MHz, DMSO-r / r,) 5 ppm 9.53 (s, 1H), 8.79 (s, 1H), 8.19 (s, 1H), 7.86 (s, 1H), 7.36 (s, 1H), 6.87 (s, 1H), 4.98-4.84 (m, 2H), 4.54 (t, J= 9.2 Hz, 1H), 4.35 (t, 8.8 Hz, 1H), 4.28-4.18(m, 1H), 4.15-4.02 (m, 2H), 3.89 (s, 3H), 3.85-3.74 (m, 1H), 3.62-3.54 (m, 1H), 3.44 (s, 3H), 2.45 (dd, J= 12.4, 8.0 Hz, 1H), 1.99-1.88 (m, 1H), 1.26 (d, J= 6.0 Hz, 6H).

[0247] The following compounds were prepared following procedures analogous to that described for Example 60.Example 69. Preparation of 2-hydroxy-2-methylpropyl ((23Z,24E,525,54J?)-26,54- dimethoxy-55-oxo-3,8-dioxa-2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l )-pyrrolidina-l(l,3)- benzenacyclooctaphane-l5-yl)carbamate

[0105] To a solution of (23Z,24 / y52N,54R)- l5-amino-26,54-dimethoxy-3,8- dioxa-2(3,5) pyrazolo[l,5-a]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphan- 55-one (20 mg, 45.13 pmol, 1 eq) in THF (0.5 mL) was added l,l'-carbonyl-di-(l,2,4- triazole) (11.11 mg, 67.70 pmol, 1.5 eq). The mixture was stirred at 40 °C for 2 hours before it was concentrated under reduced pressure to give the activated intermediate (23 mg, crude) as a yellow oil. Separately, to a solution of 2-methylpropane-l,2-diol (2.60 mg, 28.82 pmol, 1.5 eq) in THF (0.5 mL) was added NaH (1.15 mg, 28.82 pmol, 60% in oil, 1.5 eq) at 0 °C under a N2 atmosphere. The resulting mixture was stirred at 0 °C for 0.5 hour, and then a portion of the intermediate from above (10 mg, 19.21 pmol, 1 eq) was added. The mixture was stirred at 25 °C for 12 hours before it was neutralized with saturated aqueous NH4CI at 0 °C, diluted with H2O (60 mL), and then extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (3 x 20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC to give the title compound (2.1 mg, 20% yield) as a white solid. [M+H]+= 542.1. 'H NMR (400 MHz, DMSO-d6) 8 ppm 9.60 (br s, 1H), 8.80 (s, 1H), 8.21 (s, 1H), 7.88 (br s, 1H), 7.37 (s, 1H), 6.90 (br s, 1H), 4.95 (d, J= 10.0 Hz, 1H), 4.59 (s, 1H), 4.57-4.50 (1H), 4.38-4.31 (m, 1H), 4.28-4.19 (m, 1H), 4.15-4.01 (m, 2H), 3.92-3.86 (m, 5H), 3.85-3.74 (m, 1H), 3.63- 3.55 (m, 1H), 3.45 (s, 3H), 2.48-2.40 (m, 1H), 2.02-1.87 (m, 1H), 1.16 (s, 6H).

[0106] The following compound was prepared following procedures analogous to those described for Example 69.Example 71. Preparation of (23Z,24E,525,54R)-26,54-dimethoxy-l5-(2-oxopyrrolidin-l - yl)-3,8-dioxa-2(3,5)-pyrazolo[l,5-tz]pyrimidina-5(2,l)-pyrrolidina-l(l,3)- benzenacyclooctaphan-55-one

[0107] 4-chloro-A-((23Z,24E,52S',54R)-26,54-dimethoxy-5''-oxo-3,8-dioxa-2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphane- l5-yl)butanamide: To a solution of (23Z,24E,525,54A)-P-amino-26,54-dimethoxy-3,8- dioxa-2(3,5)-pyrazolo[l,5-fif]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphan- 55-one (10 mg, 22.57 pmol, 1 eq) in DCM (0.5 mL) was added DIEA (5.83 mg, 45.13 pmol, 7.86 pL, 2 eq) and 4-chlorobutanoyl chloride (2.86 mg, 20.31 pmol, 2.27 pL, 0.9 eq)at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours before it was concentrated under reduced pressure to give the title compound (11 mg, crude) as yellow oil, which was used in the next step without purification. [M+H]+= 530.2.

[0108] (23Z,24E,52S,54R)-26,54-dim ethoxy- 1=-(2-oxopyrrolidin-l-yl)-3,8- dioxa-2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l)-pyrrolidina-l(l,3)- benzenacyclooctaphan-55-one: To a solution of 4-chloro-JV-((23Z,24E,525,54R)-26,54- dimethoxy-55-oxo-3,8-dioxa-2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l)-pyrrolidina- 1(1,3)- benzenacyclooctaphane-l5-yl)butanamide (11 mg, 20.76 pmol, 1 eq) in DMF (0.5 mb) was added CS2CO3 (20.29 mg, 62.27 pmol, 3 eq). The mixture was stirred at 80 °C for 2 hours before it was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was separated, washed with brine (3 x 5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound (2.4 mg, 4.74 pmol, 22.84% yield, 97.48% purity) as a white solid. [M+H]+= 494.1.!H NMR (400 MHz, DMSO-d6) 8 ppm 8.80 (s, 1H), 8.39 (s, 1H), 8.03 (br s, 1H), 7.43 (s, 1H), 7.17 (s, 1H), 4.95 (d, J = 10.4 Hz, 1H), 4.62-4.51 (m, 1H), 4.38-4.23 (m, 2H), 4.18-4.03 (m, 2H), 3.90 (s, 3H), 3.88-3.79 (m, 2H), 3.61 (d, J= 11.2 Hz, 1H), 3.45 (s, 3H), 3.38-3.34 (m, 2H), 3.29 (s, 1H), 2.48-2.40 (m, 1H), 2.13-2.02 (m, 2H), 2.00-1.89 (m, 1H).

[0109] The following compounds were prepared following procedures analogous to that described for Example 71.Example 74. Preparation of (23Z,24£’,525,54R)-l6-(l-cyclopropyl-4-methyl-l / / -pyrazol-3- yl)-26,54-dimethoxy-3-oxa-8-aza-2(3,5)-pyrazolo[l,5-a]pyrimidina-l(4,2)-pyridina- 5(2,l)-pyrrolidinacyclooctaphan-55-one

[0110] To a solution of (23Z,24E,52,54R)-l6-chloro-26,54-dimethoxy-3-oxa-8- aza-2(3 , 5)-pyrazolo[ 1 , 5-c / ]py ri m idi na- 1 (4,2)-pyridina-5(2, 1 )-pyrrolidinacy clooctaphan- 55-one (15 mg, 33.04 pmol, 1 eq) and l-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l / / -pyrazole (81.99 mg, 66.09 pmol, 2 eq) in dioxane (5 mL) and H2O (1 mL) was added BrettPhos Pd G3 (3.00 mg, 3.30 pmol, 0.1 eq) and K3PO4 (21.04 mg, 99.13 pmol, 3 eq) under N2. The mixture was stirred at 80 °C for 1 h before it was diluted with H2O (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by RP-HPLC to yield the title compound (2.2 mg, 13% yield) as a white solid. [M+H]+= 531.3. *H NMR (400 MHz, DMSO-d6) 8 ppm 8.82 (s, 1H), 8.49 (s, 1H), 7.62-7.53 (m, 2H), 7.33 (s, 1H), 6.51 (t, J= 5.6 Hz, 1H), 5.03-4.90 (m, 1H), 4.64- 4.47 (m, 1H), 4.39-4.29 (m, 1H), 4.05 (t, J= 10.4 Hz, 1H), 3.90 (s, 3H), 3.71-3.65 (m, 1H), 3.44 (s, 3H), 3.23-3.11 (m, 3H), 2.45 (s, 1H), 2.30 (s, 3H), 1.99-1.89 (m, 2H), 1.09-1.03 (m, 2H), 0.99-0.94 (m, 2H).

[0111] The following compounds were prepared following procedures analogous to those described for Example 74.Example 78. Preparation of (23Z,24E,525,54A)-26,54-dimethoxy-55-oxo-A-((A)-l-(pyridin-2-yl)ethyl)-3,8-dioxa-2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l)-pyrrolidina-l(l,3)- b enzenacy cl ooctaphane- 15-carb oxami de

[0112] (23Z,24E,525,54R)-26,54-dimethoxy-55-oxo-3,8-dioxa-2(3,5)- pyrazolo[l,5-o]pyrimidina-5(2,l)-pyi'rolidina-l(l,3)-benzenacyclooctaphane-l5- carbonitrile: To a suspension of (23Z,24£’,525,54A)-l5-amino-26,54-dimethoxy-3,8-dioxa- 2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphan-5:’-one (30 mg, 66.99 pmol, 1 eq) in H2O (0.15 mL) and HO Ac (0.15 mL) was added concentratedH2SO4 (13.14 mg, 133.98 pmol, 7.14 pL, 2 eq). The resulting mixture was cooled to 0 °C before a solution of NaNCh (5.08 mg, 73.69 pmol, 1.1 eq) in H2O (0.15 mL) was added dropwise over 2 min. The mixture was stirred at 0 °C for 30 minutes. Meanwhile, in a separate flask, a solution of KCN (21.81 mg, 334.95 pmol, 5 eq) in H2O (0.3 mL) was added to a solution of CuSCU’SLLO (20.07 mg, 80.39 pmol, 1.2 eq) in H2O (0.3 mL), and then the resulting mixture was stirred at 0°C for 30 minutes before saturated aqueous NaHCCh (78 pL, ~30 eq) was added, followed by the NaNCh / LLSCU solution from above (dropwise so that the reaction temperature remained below 5 °C). The reaction mixture was then warmed to room temperature and stirred at 25 °C for 2 h. The mixture was extracted with EtOAc (3 x 10 mL), the combined organic extracts were washed with saturated aqueous NaHCO3, dried over Na2SO4 and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (SiO25-8% MeOH / DCM) to give the title compound (27 mg, 88% yield) as a yellow solid. [M+H]+= 436.2.1H NMR (400 MHz, DMSO-rL) 8 ppm 8.84 (s, 1H), 8.58-8.53 (m, 2H), 7.77 (s, 1H), 7.21-7.17 (m, 1H), 4.97 (d, J= 10.8 Hz, 1H), 4.60-4.54 (m, 1H), 4.38-4.32 (m, 2H), 4.25-4.16 (m, 1H), 4.08 (t, J= 10.8 Hz, 1H), 3.90 (s, 3H), 3.85-3.79 (m, 1H), 3.59-3.54 (m, 1H), 3.45 (s, 3H), 2.03- 1.86 (m, 2H).

[0113] (23Z,24E,525,54R)-26,54-dimethoxy-55-oxo-3,8-dioxa-2(3,5)- pyrazolo[l,5-o]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphane-l5- carboxylic acid: A suspension of (23Z,24E,525,54A)-26,54-dimethoxy-55-oxo-3,8-dioxa- 2(3,5)-pyrazolo[l,5-rz]pyrimidina-5(2,l)-pyrrolidina-l(l,3)-benzenacyclooctaphane-l3- carbonitrile (23 mg, 50.18 pmol, 1 eq) in 4 M HC1 (1 mL, 79.71 eq) was sealed in a tube and stirred under microwave irradiation (2 bar) at 120 °C for 6 hours. The reaction mixture was neutralized with saturated aqueous NaHCCh, and then the mixture was directly purified by RP-HPLC to give the title compound (5.3 mg, 23% yield) as a white solid. [M+H]+= 455.1.

[0114] (23Z,24E,,525,54R)-26,54-dimethoxy-5=-oxo-A-((R)-l-(pyridin-2- yl)ethyl)-3,8-dioxa-2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l)-pyrrolidina-l(l,3)- benzenacyclooctaphane-l5-carboxamide: To a solution of (23Z,24E,525,54R)-26,54- dimethoxy-55-oxo-3,8-dioxa-2(3,5)-pyrazolo[l,5-a]pyrimidina-5(2,l )-pyrrolidina-l(l,3)-benzenacyclooctaphane-1 ’-carboxylic acid (4 mg, 8.75 pmol, 1 eq) and (R)-l-(pyridin-2- yl)ethan- 1 -amine (2.14 mg, 17.50 pmol, 2 eq) in DMF (0.5 mb) was added NMI (2.16 mg, 26.25 pmol, 3 eq) and TCFH (4.91 mg, 17.50 pmol, 2 eq). The resulting mixture was stirred at 25 °C for 3 hours before it was directly purified by RP-HPLC to give the title compound (1.02 mg, 20% yield) as a white solid. [M+H]+= 559.2.rH NMR (400 MHz, DMSO-d6) 5 ppm 8.86-8.77 (m, 2H), 8.55-8.51 (m, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.82- 7.73 (m, 2H), 7.42 (d, J= 7.6 Hz, 1H), 7.29-7.23 (m, 2H), 5.25-5.15 (m, 1H), 4.97 (d, J = 10.8 Hz, 1H), 4.59 (t, J= 8.8 Hz, 1H), 4.40-4.29 (m, 2H), 4.25-4.14 (m, 1H), 4.12-4.03 (m, 1H), 3.90 (s, 3H), 3.88-3.78 (m, 1H), 3.64-3.56 (m, 1H), 3.45 (s, 3H), 2.46-2.44 (m, 1H), 2.01-1.88 (m, 1H), 1.52 (d, J= 7.2 Hz, 3H).

[0115] The following compounds were prepared following procedures analogous to those described for Example 78.Example 81. Preparation of (l2E',23E,24£’,525,54A)-26,54-dimethoxy-55-oxo-A-((A)-l- phenylethyl)-l1Zf-3-oxa-2(3,5)-pyrazolo[l,5-«]pyrimidina-l(3,l)-pyrazola-5(2,l)- pyrrolidinacyclooctaphane- 15-carboxamide

[0116] A solution of (12E,23E,24E,52S,54R)-26,54-dimethoxy-55-oxo-l 1H- 3 -oxa-2(3 , 5)-pyrazolo[ 1 ,5-a]pyrimidina- 1(3,1 )-pyrazola-5(2, 1 )- pyrrolidinacyclooctaphane-15-carboxylic acid (7 mg, 15.82 pmol, 1 eq), (R)-l- phenylethan-1 -amine (34.51 mg, 284.79 pmol, 36.71 pL, 18 eq), DIEA (40.90 mg, 316.44pmol, 55.12 pL, 20 eq) and HATU (60.16 mg, 158.22 pmol, 10 eq) in DMF (1 mL) was stirred at 25 °C for 1 hour under a N2 atmosphere before it was concentrated. The residue was purified by RP-HPLC to give the title compound (2.88 mg, 35% yield) as a white solid. [M+H]+= 546.2. ’H NMR (400 MHz, DMSO-d6) 5 ppm 8.84 (d, J = 8.4 Hz, 1H), 8.74 (s, 1H), 8.21 (s, 1H), 7.42-7.37 (m, 2H), 7.37-7.30 (m, 2H), 7.27-7.21 (m, 1H), 7.19 (s, 1H), 5.20-5.08 (m, 1H), 4.73 (d, J = 10.8 Hz, 1H), 4.59-4.50 (m, 1H), 4.44 (t, J = 8.8 Hz, 1H), 4.33-4.24 (m, 2H), 4.01 (t, J = 10.4 Hz, 1H), 3.87 (s, 4H), 3.54-3.47 (m, 1H), 3.42 (s, 3H), 2.40 (dd, J = 12.4, 8.0 Hz, 1H), 2.32-2.21 (m, 1H), 2.09-2.00 (m, 1H), 1.96-1.86 (m, 1H), 1.47 (d, J = 7.2 Hz, 3H).

[0117] The following compounds were prepared following procedures analogous to those described for Example 81. Detailed chiral analytical data are provided for examples obtained from racemic material by chiral SFC separation.Example 145. Preparation of Zc / 7-butyl ((l2E,23E,24E',521S',54R)-26,54-dimethoxy-55-oxo- l1 / / -3-oxa-2(3,5)-pyrazolo[l,5-a]pyrimidina-l(3,l)-pyrazola-5(2,l)- pyrrolidinacyclooctaphane- 15-yl)carbamate

[0118] A mixture of (l2E,23£,24E,52S',54R)-26,54-dimethoxy-55-oxo-l1 / / -3- oxa-2(3,5)-pyrazolo[l,5-rz]pyrimidina-l(3,l)-pyrazola-5(2,l)-pyrrolidinacyclooctaphane- l5-carboxylic acid (10 mg, 20.34 pmol, 1 eq), DPPA (8.40 mg, 30.51 pmol, 6.59 pL, 1.5 eq) and EtsN (4.12 mg, 40.68 pmol, 5.66 pL, 2 eq) in DMF (0.1 mL) and / -BuOH (2 mL) was degassed and purged with N2 three times before the mixture was stirred at 50 °C for 16 hours under a N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 10 mL), and then the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC to give the title compound (2.0 mg, 19% yield) as a white solid. [M+H]+= 514.1.1HNMR (400 MHz, DMSO-df) 8 ppm 9.41-9.21 (m, 1H), 8.71 (s, 1H), 8.16 (s, 1H), 6.30 (s, 1H), 4.74 (d, J = 10.8 Hz, 1H), 4.47-4.41 (m, 1H), 4.32-4.26 (m, 1H), 4.06-3.95 (m, 3H), 3.86 (s, 3H), 3.84-3.77 (m, 1H), 3.45 (s, 1H), 3.42 (s, 3H), 2.41-2.36 (m, 1H), 2.19-2.06 (m, 2H), 1.94-1.87 (m, 1H), 1.47 (s, 9H).

[0119] The following compound was prepared following procedures analogous to those described for Example 145.Biological DataRIPK2-XIAP binding competition PPI assay

[0120] The ability of selected compounds of Formula (I) to inhibit the binding of an His-XIAP(BIR2)-avi fusion protein to a GST-RIPK2 fusion protein was quantified employing the TR-FRET-based competition assay as described in the following paragraphs.

[0121] Recombinant fusion protein of N-terminal Glutathione-S-Transferase (GST) and a fragment of human RIPK2 (amino acids 1-310 of accession number 043353), expressed in baculovirus infected Sf9 cells, purified via glutathione affinity chromatography, was used as GST-RIPK2 fusion protein. Recombinant fusion protein of N-terminal 6xHistidine (His), a fragment of human XIAP (amino acids 152-231 of accession number P98170), and C-terminal avi tag, expressed in baculovirus infected Sf9 cells, purified via Nickel NTA affinity chromatography, was used as the His-XIAP(BIR2)- avi fusion protein.

[0122] For the assay, a working solution of 1 nM GST-RIPK2, 25nM His- XIAP(BIR2)-avi, 6nM Anti-His-XL665nM (Revvity Catalogue No. 61HISXLB), and 0.5nM Anti-GST-Tb (Revvity Catalogue No. 61GSTTLB) in 25 mM Tris-HCl 7.5, 0.5 mM ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), 10 mMmagnesium chloride (MgC12), 2.5 mM dithiothreitol (DTT), 0.01 % (w / v) bovine serum albumin (BSA), 0.005 % (w / v) Pluronic F-127 (Sigma), 0.5 mM sodium ortho-vanadate, 5 mM P-Glycerophosphate disodium salt hydrate (BGP) was prepared. 50 nL of a 100-fold concentrated solution of each test compound in DMSO was dispensed via acoustic dispensing into a white low volume 384-well microtiter plate (Perkin Elmer Catalogue No. 6008280). Subsequently, 5 pL of the assay working solution were added.

[0123] The resulting mixture was incubated 120 min at 23°C. Subsequently, the amount of complex formed by the GST-RIPK2, XIAP(BIR2)-avi, Anti-His-XL665, and Anti-GST-Tb was evaluated by measurement of the resonance energy transfer from the Tb-cryptate to the XL665. Therefore, the fluorescence emissions at 520 nm and 665 nm after excitation at 337 nm were measured in a TR-FRET reader, e.g. a Pherastar FS (BMG Labtechnologies, Offenburg, Germany) or an Envision (PerkinElmer). The ratio of the emissions at 665 nm and at 520 nm was taken as the measure of the amount of the complex. The data were normalized (assay reaction without inhibitor = 0% activity, 50 nM of GSK583 = -100% activity). Typically the test compounds were tested on the same microtiter plate in 11 different concentrations in the range of 10 pM to 0.04 nM (10 pM, 2.86 pM, 0.82 pM, 0.23 pM, 67 nM, 19 nM, 5.4 nM, 1.6 nM, 0.4 nM, 0.1 nM and 0.04 nM, is the dilution series prepared separately before the assay on the level of the 100- fold concentrated solutions in DMSO by serial dilutions; exact concentrations may vary depending on pipettors used) in duplicate values for each concentration and ICso values were calculated using Collaborative Drug Discovery software.THP-1 Dual cell SEAP and viability assays

[0124] THPl-Dual™ cells (InvivoGen Cat#thpd-nfis) allow simultaneous assessment of the NF-KB pathway, by monitoring the activity of secreted embryonic alkaline phosphatase (SEAP) as well as the IRF pathway, by assessing the activity of a secreted luciferase (Lucia). Cells were cultured according to manufacturers’ recommendations. For the assay, compounds were dispensed into a 384-well plate (Greiner Cat#781090) using an Echo 655 compound dispenser. Compounds were dispensed as ’A log-fold dilutions beginning with a 10 pM top concentration (10 doses, 2 replicates each). 80 pL of assay medium (RPMI 1640, 2 mM L-Glutamine, 25 mMHEPES, 10% heat-inactivated fetal bovine serum) was added to each well of columns 1 and 24 using a Multidrop Combi reagent dispenser. 25,000 cells (in 60 pL assay medium) were seeded into each well of columns 2-23 using the Multidrop Combi. The plate was centrifuged at 800 rpm for 30 seconds. 10 pL of IFN-y in assay medium was added to wells in columns 2-23, to a final concentration of 100 ng / mL. The plate was centrifuged at 800 rpm for 30 seconds and incubated at 37 °C in 5% CO2 for 2 h. 10 pL of L18-MDP in assay medium was added to wells in columns 2-23, to a final concentration of 10 ng / mL. The plate was centrifuged at 800 rpm for 30 seconds and incubated at 37 °C in 5% CO2 for 16-20 h. The plate was centrifuged at 1000 rpm for 2 min and 60 pL supernatant was transferred to a 384-well storage plate using an Agilent Technologies Bravo liquid handler.

[0125] For the SEAP assay: The storage plate was centrifuged at 1000 rpm for 1 min and 15 pL supernatant was transferred to a 384-well SEAP assay plate using the Bravo liquid handler. The SEAP assay plate was centrifuged at 1000 rpm for 1 min. 35 pL QUANTLBlue Solution per well was added using a Multidrop Combi, and the plate was centrifuged at 1000 rpm for 1 min. Following a 2 h incubation in the dark at 37 °C, the optical density (OD) was measured at 620 nm using a Perkin Elmer Envision microplate reader.

[0126] For the viability assay: The cells remaining in the plate were used to assess cell viability. For this, CellTiter-Glo buffer and lyophilized CellTiter-Glo substrate were allowed to equilibrate to room temperature and lyophilized CellTiter-Glo substrate was reconstituted according to the manufacturers’ recommendations. 20 pL of CTG reagent (an equal volume to the remaining cell volume) was added to each well using a Multidrop Combi. The plate was incubated on an orbital shaker for 2 min, followed by centrifugation at 1000 rpm for 1 min. The plate was incubated for 10 min in the dark at room temperature. Luminescence signal was measured using a using the Envision microplate reader.Analysis

[0127] Values of media-only wells were subtracted and % inhibition for each compound concentration relative to the DMSO / IFN-y / L18-MDP -treated controls wascalculated. Inhibition values + / - SD were fitted by non-linear regression using Prism software (GraphPad PRISM Software) to calculate IC50 values.

[0128] Table A below lists IC50 values of selected compounds of Formula (I) measured in the RIPK2 / XIAP binding competition PPI assay and the THP-1 Dual cell SEAP and viability assays.

[0129] For the RIPK2 / XIAP binding competition PPI assay IC50 values, “A” denotes an IC50 of < 1 nM; “B” denotes an IC50 of 1 nM < B < 10; “C” denotes an IC50 of 10 nM < C < 100; and “D” denotes an IC50 of 100 nM < D.

[0130] For the RIPK2 / XIAP binding competition PPI assay Amax values, “A” denotes an Amax of > 80%; “B” denotes an Amax of 80% > B > 55; “C” denotes an Amax of 55% > C > 30; and “D” denotes an Amax of < 30%.

[0131] For the THP-1 assay IC50 values, “A” denotes an IC50 of < 10 nM; “B” denotes an IC50 of 10 nM < B < 100; “C” denotes an IC50 of 100 nM < C < 1,000; and “D” denotes an IC50 of 1,000 nM < D.Table A, IC50 Values

Claims

What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: each = is a single bond or a double bond;W, X, and Y are independently selected from N, C, and CRX;Rxis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;Ring A is C6-C10 aryl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, S(O), S(O)2, -S(O)2-O-, -O- S(O)2-O-, -S(O)-NH-, -S(O)2-NH-, C(RZ)2, and NR7;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl,(iv) C1-C6 alkyl,(v) C1-C6 alkoxy alkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O)2R1A,(xi) -NRARB,(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyl oxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1 -C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R4is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and NR4AR4B;R3Aand R3Bare independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; or R3Aand R3Btogether with the atoms to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl;R6Aand R6Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C3-C6 cycloalkyl, and C1-C6 alkoxylalkyl; or R6Aand R6Btogether with the atoms to which they are attached form a C3-C6 cycloalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, R4A, R4B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxy alkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C10 haloaryl, and(x) 5-10 membered heteroaryl optionally substituted with 1-2 independently selected halogen; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W, X, and Y are independently selected from N and C, .

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is N.The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Y is C or N.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Y is C.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Y is N.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein W is C or N.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein W is N.

9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein W is C.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Z1is selected from C(RZ)2, NRZ, and O.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Z1is selected from C(RZ)2 and NRZ.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein Z1is O.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein Z2is selected from O, S, and NRZ.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Z2is selected from O and NRZ.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein Z2is O.

16. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein Z2is C(RZ)2.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, whereinRzis selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl.

18. The compound of claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein Rzis hydrogen.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein m is 1.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein n is i.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1 -3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or C1-C6 alkoxy, and(xi) -NR2AR2B26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy, and(vi) C1-C6 haloalkoxy.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R2is selected from:(i) C1-C6 alkyl, and(ii) C1-C6 alkoxy.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6 alkyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein R2is methyl.

30. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C6 alkoxy.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R2is methoxy.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Bare independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.

33. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Bare independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

34. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Bare independently selected from C1-C6 alkyl.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Bare methyl.

36. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Btogether with the atoms to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl.

37. The compound of any one of claims 1-31 and 36, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Btogether with the atoms to which they are attached form a 5 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

38. The compound of any one of claims 1-31, 36, and 37, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Btogether with the atoms to which they are attached form a 5 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, and C1-C6 alkoxy.

39. The compound of any one of claims 1-31 and 36-38, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Btogether with the atoms to which they are attached form a 5 membered heterocyclyl substituted with 2 halogens.

40. The compound of any one of claims 1-31 and 36-38, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Btogether with the atoms to which they are attached form a 5 membered heterocyclyl substituted with oxo and C1-C6 alkoxy.

41. The compound of claim 1-31 and 37-38, or a pharmaceutically acceptable salt thereof, wherein the 5 membered heterocyclyl is selected from:

42. The compound of any one of claims 1-31 and 36, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Btogether with the atoms to which they are attached form a 6 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy.

43. The compound of any one of claims 1-31, 36, and 42, or a pharmaceutically acceptable salt thereof, wherein R3Aand R3Btogether with the atoms to which they are attached form a 6 membered heterocyclyl optionally substituted with oxo.

44. The compound of claim 1-31, 36, 42, and 43, or a pharmaceutically acceptable salt thereof, wherein the 6 membered heterocyclyl is selected from:

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and NR4AR4B.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.

47. The compound of any one of claim 1-46, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-C10 aryl.

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-C8 aryl.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

51. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5-10 membered heteroaryl.

52. The compound of any one of claims 1-47 and 51, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5 or 6 membered heteroaryl.

53. The compound of any one of claims 1-47, 51, and 52, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyridonyl.

54. The compound of any one of claims 1-47, and 51-53, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl.

55. The compound of any one of claims 1-47, and 51-53, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl.

56. The compound of any one of claims 1-55, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3.

57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt thereof, wherein p is 1.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is halogen.

60. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is cyano.

61. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is hydroxyl.

62. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is C1-C6 alkyl.

63. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is C1-C6 alkoxy alkyl.

64. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is C1-C6 haloalkoxy.

65. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is -(C=O)R1A.

66. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is -(C=O)OR1A.

67. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, wherein R1is -S(O)2R1A.

68. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is -(C=O)NR1AR1B.

69. The compound of claim 68, or a pharmaceutically acceptable salt thereof, wherein one of R1Aand R1Bis hydrogen, and the other one of R1Aand R1Bis C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl.

70. The compound of claim 69, or a pharmaceutically acceptable salt thereof, wherein the 5-10 membered heteroaryl is a 5-6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein the 5-6 membered heteroaryl is selected from the group consisting of pyrazolyl, isothiazolyl, thiazolyl, pyridinyl, and pyrimidinyl.

72. The compound of claim 69, or a pharmaceutically acceptable salt thereof, wherein the 5-10 membered heteroaryl is a 9-10 membered heteroaryl selected from the group consisting of indazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzoimidazolyl, and quinazolinyl.

73. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is -NRARB.

74. The compound of claim 73, or a pharmaceutically acceptable salt thereof, wherein RAis hydrogen.

75. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis hydrogen.

76. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis C1-C6 alkyl.

77. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis C1-C6 haloalkyl.

78. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis C3-C6 cycloalkyl.

79. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis selected from -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, Cl- C6 alkoxy, hydroxyl, and amino.

80. The compound of claim 79, or a pharmaceutically acceptable salt thereof, wherein RBis -(C=O)C1-C6 alkyl optionally substituted with 1-2 independently selected halogen.

81. The compound of claim 80, or a pharmaceutically acceptable salt thereof,83. The compound of claim 79, or a pharmaceutically acceptable salt thereof, wherein RBis -(C=O)C1-C6 alkyl substituted with a 6-10 membered aryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, Cl- C6 alkoxy, hydroxyl, and amino.

84. The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein85. The compound of claim 79, or a pharmaceutically acceptable salt thereof, wherein RBis -(C=O)C1-C6 alkyl substituted with a 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, Cl- C6 alkoxy, hydroxyl, and amino.

86. The compound of claim 85, or a pharmaceutically acceptable salt thereof, wherein the 5-10 membered heteroaryl of RBis a 5-6 membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, furzanyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, and thiatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

87. The compound of claim 85 or 86, or a pharmaceutically acceptable salt thereof, wherein RBis selected from the group consisting of88. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis selected from -(C=O)C3-C6 cycloalkyl optionally substituted with1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl.

89. The compound of claim 88, or a pharmaceutically acceptable salt thereof, wherein RBis -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl and 5-10 membered heteroaryl.

90. The compound of claim 88 or 89, or a pharmaceutically acceptable salt91. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis selected from -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6- C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl.

92. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein RBis -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 independently selected halogen.

93. The compound of claim 91 or 92 wherein RBis selected from94. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3- C6 cycloalkyl.

95. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl.

96. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis selected from -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl.

97. The compound of claim 96, or a pharmaceutically acceptable salt thereof, wherein RBis -(C=O)OC1-C6 alkyl.

98. The compound of claim 96 or 97, or a pharmaceutically acceptable salt99. The compound of claim 96, or a pharmaceutically acceptable salt thereof, wherein RBis selected from the group consisting of100. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis -(C=O)OC3-C6 cycloalkyl optionally substituted with 1 -2 substituents independently selected from halogen and C1-C6 alkyl.

101. The compound of claim 100, or a pharmaceutically acceptable salt thereof, wherein102. The compound of claim 73 or 74, or a pharmaceutically acceptable salt thereof, wherein RBis -(C=O)NRB1RB2.

103. The compound of claim 102, or a pharmaceutically acceptable salt thereof, wherein one of RB1and RB2is hydrogen, and the other one of RB1and RB2is C1-C6 alkyl.

104. The compound of claim 102, or a pharmaceutically acceptable salt thereof, wherein RB1and RB2are both hydrogen.

105. The compound of claim 102, or a pharmaceutically acceptable salt thereof, wherein RB1and RB2are independently selected C1-C6 alkyl.

106. The compound of claim 105, or a pharmaceutically acceptable salt thereof, wherein RB1and RB2are both methyl.

107. The compound of claim 73, or a pharmaceutically acceptable salt thereof, wherein RAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl.

108. The compound of claim 107, or a pharmaceutically acceptable salt thereof, wherein RAand RBtogether with the nitrogen atom to which they are attached form a 5 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl.

109. The compound of claim 108, or a pharmaceutically acceptable salt thereof, wherein the 5 membered heterocyclyl is selected from:

110. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl.

111. The compound of claim 110, or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of112. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt thereof, wherein R1is -NO2.

113. The compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, wherein R6Aand R6Bare hydrogen.

114. A compound of Formula (I), wherein the compound is a compound of Formula (Ila):or a pharmaceutically acceptable salt thereof, wherein:Ring A is C6-C10 aryl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl,(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A,(xi) -NRARB,(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R?and R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 memb ered heterocy cly 1 ,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(V) C1-C6 alkoxy alkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C10 haloaryl,(x) 5-10 memb ered heteroaryl , and(xi) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

115. A compound of Formula (I), wherein the compound is a compound of Formula (lib):or a pharmaceutically acceptable salt thereof, wherein:Ring A is C6-C10 aryl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A,(xi) -NRARB,(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyl oxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, and 5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1 -2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxy alkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C10 haloaryl, and(x) 5-10 memb ered heteroaryl ; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

116. A compound of Formula (I), wherein the compound is a compound ofFormula (Illa):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A,(xi) -NRARB(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxy alkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C10 haloaryl,(x) 5-10 memb ered heteroaryl , and(xi) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

117. A compound of Formula (I), wherein the compound is a compound ofFormula (Illb):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxy alkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A,(xi) -NRARB,(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R?and R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2;or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C10 haloaryl,(x) 5-10 membered heteroaryl, and(xi) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

118. A compound of Formula (I), wherein the compound is a compound of Formula (IVa):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1 AR1B,(x) -S(O2)R1A,(xi) -NRARB,(xii) 5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, and(xiii) -NO2; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CChH, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyl oxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R?and R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 memb ered heterocy cly 1 ,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl and 5-10 membered heteroaryl, wherein the C6-C10 aryl and 5-10 membered heteroaryl areeach optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, hydroxyl, and amino,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl optionally substituted with C1-C6 alkoxy, C4-C6 heterocyclyl, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(xii) -(C=O)OC3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and C1-C6 alkyl, and(xiii) -(C=O)NRB1RB2; or RAand RDtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl,(ix) C6-C10 haloaryl, and(x) 5-10 membered heteroaryl, and(xi) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

119. A compound of Formula (I), wherein the compound is a compound of Formula (IVb):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1 -2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl,and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl; and(xii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R'ARIB,R2AR2BRBI,and RB2are eachindependentiyselected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxy alkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

120. A compound of Formula (I), wherein the compound is a compound of Formula (Va):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl,(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB;p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R and R3Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(xii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- membered heterocyclyl optionally substituted with 1-2 substituents independentlyselected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxy alkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 memb ered hal oheteroary 1 ; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

121. A compound of Formula (I), wherein the compound is a compound ofFormula (Vb):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5;n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(xii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A,independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 memb ered heteroaryl , and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

122. A compound of Formula (I), wherein the compound is a compound of Formula (Vc):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxy alkyl,(vi) C1-C6 haloalkoxy,(vii)(viii)(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(xii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

123. A compound of Formula (I), wherein the compound is a compound of Formula (Vd):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; each R1is independently selected from:(xxiii) halogen,(xxiv) cyano,(xxv) hydroxyl;(xxvi) C1-C6 alkyl,(xxvii) C1-C6 alkoxy alkyl,(xxviii)Cl-C6 haloalkoxy,(xxix) -(C=O)R1A,(xxx) -(C=O)OR1A,(xxxi) -(C=O)NR1AR1B,(xxxii) -S(Ch)R1 A, and(xxxiii)-NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A;(vi) C1-C6 haloalkoxy;(vii) 4-10 membered heterocyclyl oxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(xii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

124. A compound of Formula (I), wherein the compound is a compound ofFormula (Via):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;U is -C(O)- or -CH2- each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R?and R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 memb ered heterocy cly 1 ,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1 -2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl,and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(xii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R'ARIB,R2AR2BRBI,and RB2are eachindependentiyselected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxy alkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

125. A compound of Formula (I), wherein the compound is a compound of Formula (VIb):or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, 4, or 5;Z1and Z2are independently selected from O, S, C(RZ)2, and NRz;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;U is -C(O)- or -CH2- each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2D,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or Cl -C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(xii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

126. A compound of Formula (I), wherein the compound is a compound ofFormula (Vic):or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3, 4, or 5;Z2is selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;U is -C(O)- or -CH2- each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl,(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1 AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1 -3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R3Aand R3Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(xii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxy alkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 memb ered hal oheteroary 1 ; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

127. A compound of Formula (I), wherein the compound is a compound ofFormula (Vid):or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3, 4, or 5;Z2is selected from O, S, C(RZ)2, and NRZ;Rzis selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl;U is -C(O)- or -CH2- each R’ is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl;(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) hydrogen,(ii) halogen,(iii) C1-C6 alkyl,(iv) C1-C6 haloalkyl,(v) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A,(vi) C1-C6 haloalkoxy,(vii) 4-10 membered heterocyclyloxy,(viii) -(C=O)NR2AR2B,(ix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR2AR2B,(x) 5-6 membered heteroaryl optionally substituted with C1 -C6 alkyl or Cl- C6 alkoxy, and(xi) -NR2AR2B;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1 -2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl,and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(xii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

128. A compound of Formula (I), wherein the compound is a compound of Formula (Vie):or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2;U is -C(O)- or -CH2- each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl,(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A, and(ii) C1-C6 haloalkoxy;R?Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 memb ered heterocy cly 1 ,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl,and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(xii) -(C=O)NRB1RB2; orRAand RBtogether with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R1A, R1B, R2A, R2B, RB1, and RB2are each independently selected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxyalkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

129. A compound of Formula (I), wherein the compound is a compound of Formula (VIf):or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2;U is -C(O)- or -Cffc- each R1is independently selected from:(i) halogen,(ii) cyano,(iii) hydroxyl,(iv) C1-C6 alkyl,(v) C1-C6 alkoxyalkyl,(vi) C1-C6 haloalkoxy,(vii) -(C=O)R1A,(viii) -(C=O)OR1A,(ix) -(C=O)NR1AR1B,(x) -S(O2)R1A, and(xi) -NRARB; p is 0, 1, 2, or 3;R2is selected from:(i) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from:(a) hydroxyl,(b) phosphate,(c) -NR2AR2B,(d) 4-10 membered heterocyclyl optionally substituted with 1 -3 substituents independently selected from hydroxyl, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxy alkyl,(e) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl,(f) C3-C6 cycloalkyl optionally substituted with hydroxyl,(g) CO2H, and(h) C(O)R2A; and(ii) C1-C6 haloalkoxy;R5Aand R5Bare independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and C1-C6 alkoxylalkyl;RAis independently hydrogen or C1-C6 alkyl;RBis selected from:(i) hydrogen,(ii) C1-C6 alkyl,(iii) C1-C6 haloalkyl,(iv) C3-C6 cycloalkyl,(v) 3-10 membered heterocyclyl,(vi) -(C=O)C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(vii) -(C=O)C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(viii) -(C=O)3-6 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C6-C10 aryl, C6-C10 haloaryl, and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl,(ix) -(C=O)C6-C10 aryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(x) -(C=O)5-10 membered heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl,(xi) -(C=O)OC1-C6 alkyl optionally substituted with 1-2 substituents independently selected from halogen, C3-C6 cycloalkyl, C6-C10 aryl, C6- C10 haloaryl,and 5-10 membered heteroaryl, and 5-10 membered haloheteroaryl, and(xii) -(C=O)NRB1RB2; or RAand RBtogether with the nitrogen atom to which they are attached form a 4- 8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, oxo, hydroxy, C1-C6 alkyl, C1-C6 alkoxylalkyl, and C3-C6 cycloalkyl;R'ARIB,R2AR2BRBI,and RB2are eachindependentiyselected from:(i) hydrogen,(ii) C1-C6 alkyl optionally substitituted with phenyl or 5-10 membered heteroaryl, wherein each phenyl or 5-10 membered heteroaryl is optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, and hydroxyl,(iii) C1-C6 haloalkyl,(iv) C1-C6 alkoxy,(v) C1-C6 alkoxy alkyl,(vi) C3-C8 cycloalkyl,(vii) 3-8 membered heterocyclyl,(viii) C6-C10 aryl, C6-C10 haloaryl,(ix) 5-10 membered heteroaryl, and(x) 5-10 membered haloheteroaryl; orRB1and RB2together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl.

130. A compound selected from the compounds disclosed in Table 1, or a pharmaceutically acceptable salt thereof.

131. A pharmaceutical composition comprising a compound of any one of claims 1-130, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

132. A method of treating inflammatory bowel disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of Claims 1-130, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 131.

133. A method of treating inflammatory bowel disease in a subject in need thereof, comprising (a) determining that the subject is suffering from inflammatory bowel disease; and (b) administering to the subject an effective amount of the compound of the compound of any one of Claims 1-130, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 131.

134. A method of treating inflammatory bowel disease in a subject previously identified or diagnosed as having inflammatory bowel disease, the method comprising administering to the subject an effective amount of the compound of the compound of any one of Claims 1-130, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 131.

135. A method of treating Crohn’s disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of thecompound of any one of Claims 1-130, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 131.

136. A method of treating Crohn’s disease in a subject in need thereof, comprising (a) determining that the subject is suffering from Crohn’s disease; and (b) administering to the subject an effective amount of the compound of the compound of any one of Claims 1-130, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 131.

137. A method of treating Crohn’s disease in a subject previously identified or diagnosed as having Crohn’s disease, the method comprising administering to the subject an effective amount of the compound of the compound of any one of Claims 1-130, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 131.

138. The method of any one of claims 132-134, wherein the inflammatory bowel disease is ulcerative colitis.

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