Salicylamides and methods of use thereof

Abstract

Salicylamide compounds and methods of their use are provided, as well as pharmaceutical compositions including the salicylamide compounds and methods of using the pharmaceutical compounds.

Description

SALICYLAMIDES AND METHODS OF USE THEREOF CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Application No. 63 / 679,561, filed on August 5, 2024, the disclosure of which is hereby incorporated by reference in its entirety. STATEMENT OF GOVERNMENT LICENSE RIGHTS

[0002] This invention was made with Government support under Grant No. U44NS119284 awarded by the NATIONAL INSTITUTES OF HEALTH (“NIH”). The government has certain rights in the invention. BACKGROUND

[0003] Pain is the most common reason Americans access the health care system. Chronic pain affects ~116 million people in the United States. Pain can be classified into 3 broad categories: 1) Nociceptive pain arising from actual or threatened damage to non- neural tissue; 2) Neuropathic pain caused by a lesion or disease of the nervous system; and 3) Nociplastic pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage. Nociplastic pain can arise from nociceptive injury or neuropathic injury. Nociplastic pain is therefore a maladaptive response of the nervous system. Pain may also be referred to as acute (fast injury and repair) or chronic (lasting months to years). Chronic pain states arising from diseases include diabetic peripheral neuropathy (DPN), post-herpetic neuralgia (PHN), cancer or tumor induced pain, spinal cord injury (SCI), chemotherapy-induced peripheral neuropathy (CIPN), multiple sclerosis, stroke-induced pain, and others.

[0004] The three main classes of approved treatments of chronic or neuropathic pain are: (1) anti-epileptics (e.g. pregabalin (DPN), gabapentin (for PHN), lamotrigine (for PHN)); (2) serotonin / norepinephrine reuptake inhibitors (SNRI; Duloxetine (for DPN), Fluoxetine (for DPN)) and (3) opioids (Tapentadol (for DPN)). Current pain medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, opioids and anti-epileptics (gabapentin, pregabalin) have significant side effects, exhibit limited efficacy for neuropathic pain and / or work only in subsets of patients. These inadequacies are partly responsible for the growing opioid epidemic wherein subjects become addicted to the therapeutic agent, and indicate the critical need for analgesics that do not cause addiction.

[0005] Therefore, a need exists for therapeutic agents which act as effective analgesics and lack unwanted side effects. The present disclosure fulfills this need and provides further related advantages. DESCRIPTION OF THE DRAWINGS

[0006] The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same become better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein:

[0007] FIG.1 shows a schematic of the protein complex localized at the N-methyl- D-aspartate (NMDA) receptor, and the general target for the claimed composition. DETAILED DESCRIPTION

[0008] An underlying cause of neuropathic pain, nociplastic pain or chronic pain is the sustained or excessive activation of N-methyl-D-aspartate receptors (NMDAR) by the excitatory neurotransmitter glutamate. Activation of these receptors can mediate plastic changes in the central nervous system (CNS) that underlie chronic pain as well as other pathological states such as post-traumatic stress disorder (PTSD).

[0009] NMDA-induced neuronal excitotoxicity depends on recruitment and formation of a multiprotein cascade complex at the receptor (FIG.1). NMDAR recruits post-synaptic density 95 protein (PSD95) which then recruits neuronal nitric oxide synthase (nNOS, NOS1), forming a NMDAR-PSD95-nNOS complex. Activated nNOS synthesizes nitric oxide (NO), a cell permeant molecule responsible for activating multiple signaling cascades leading to excitotoxic injury and neuroplastic changes. PSD95 is thus a keyprotein linking NMDAR to multiple downstream pathways involved in the development of neuropathic pain, or development and maintenance of nociplastic pain.

[0010] Neuropathic pain is defined as pain caused by injury to the nervous system. Damage to the nervous system may arise due to many different types of injuries or diseases. These may include, but are not limited to, spinal cord injury, brain injury, stroke, cancer, tumors, drug injury or toxicity, surgical injury, diabetes induced neuropathy, autoimmune disease, or neurodegenerative diseases.

[0011] In preclinical studies, neuropathic pain is induced through a variety of treatments that induce injury (e.g. formalin, complete Freund's adjuvant, surgical ligation or axotomy of the sciatic nerve, paclitaxel and other treatments or methods). Hypersensitivity is assessed most commonly using methods that measure evoked responses in the paw such as responses to mechanical pressure, cold or heat. Other behavioral measures may be used to measure painful responses such as gait or grimace analysis. In patients, neuropathic pain is evaluated based on history and physical exam including symptoms reported by the subject and type of pain reported (e.g. burning, aching, etc.), frequency of pain, duration of pain, etc. Additional tests may be performed such as imaging, neurofunctional tests, and pain scoring with or without evoked responses.

[0012] Nociplastic pain is a newly classified pain state. Nociplastic pain may overlap with, or be distinct from, neuropathic pain. Nociplastic pain is an altered pain perception likely due to remodeling of the nervous system in the absence of actual injury or after full recovery from the initial injury. Other terms associated with nociplastic pain include "centralized pain" or "central sensitization." While often arising from acute injury, nociplastic pain is distinct and may be present after the initial injury is fully healed. An example is phantom limb pain where patients continue to experience sensations, including pain or discomfort from a limb that is no longer present. This can occur months after healing. Because the compounds disclosed herein act in the pathway that promotes nervous system remodeling ("neuroplasticity"), they are effective in treating nociplastic pain independent of the initial injury.

[0013] Many of the same preclinical models used to assess neuropathic injury may also be used to demonstrate central sensitization and thus may represent nociplastic pain. Electrophysiological observation of effects on central sensitization may be used to reveal nociplastic (like) pain. Nociplastic pain may be diagnosed through the same methods as neuropathic pain. Additionally, imaging (for example function MRI, fMRI) may be particularly useful for diagnosing nociplastic pain. Additional methods may include resting state electroencephalography, magnetoencephaolography and positron emission tomography (PET).

[0014] Compounds that target PSD95-nNOS are effective analgesics useful for treating multiple types of pain (neuropathic, nociplastic, chronic) but with improved safety profiles compared to approved drugs since they have a different mechanism of action than current FDA approved drugs and act narrowly on mechanisms underlying pathological pain. Since the compositions disclosed herein do NOT target opioid receptors, they provide an alternative to opioids for the treatment of pain and thus provide an option for pain treatment without the drawbacks, addiction, and tolerance issues associated with current opioid therapies.

[0015] 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. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the subject matter of the present disclosure, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Definitions

[0016] In certain embodiments herein, reference is made to features and aspects of the disclosure, including method steps. All possible combinations of such features and aspects within the embodiments of the disclosure are included, at least to the extent that such combinations are non-contradictory. For example, if an embodiment presents aspects A, B, and C, it is understood that this also discloses embodiments including both aspects Aand B, both aspects B and C, and both aspects A and C, as well as an embodiment with aspects A, B, and C.

[0017] The terms "a," "an," or "the" not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0018] The term "about" refers to an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Typical exemplary degrees of error are within ± 20 percent (%), within ± 10%, or within ± 5% of a given value or range of values. Any reference to "about X" specifically indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach and provide written support for a claim limitation of, e.g., "0.98X." Alternatively, in biological systems, the term "about" means values that are within an order of magnitude, within 5-fold, or within 2-fold of a given value. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term "about" can be inferred when not expressly stated. When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "from about 5 to 20%" is equivalent to "from about 5% to about 20%." When "about" is applied to the first value of a set of values, it applies to all values in that set. Thus, "about 7, 9, or 11 mg / kg" is equivalent to "about 7, about 9, or about 11 mg / kg."

[0019] The term "or" refers to an alternative and should in general be construed non-exclusively. For example, a claim to "a composition comprising A or B" would typically present an aspect with a composition comprising both A and B. "Or" should, however, be construed to exclude those aspects presented that cannot be combined without contradiction (e.g., a composition having a pH that is between 9 and 10 or between 7 and 8).

[0020] The group "A or B" is equivalent to the group "selected from the group consisting of A and B."

[0021] The linking term "comprising" or "comprise" is not closed. For example, "a composition comprising A" must include at least the component A, but it may also include one or more other components (e.g., B; B and C; B, C, and D; and the like). The term "comprising" therefore should in general be construed as not excluding additional ingredients. For example, a claim to "a composition comprising A" would cover compositions that include A and B; A, B, and C; A, B, C, and D; A, B, C, D, and E; and the like.

[0022] The term "NMDA" refers to N-methyl-D-aspartate. NMDA is a small amino acid analog neurotransmitter that binds to NMDA receptors activating downstream signaling pathways.

[0023] The term "NMDAR" refers to the N-methyl-D-aspartate receptors. Glutamate receptors are distinguished by their ability to bind to different agonists as well as their response to agonist stimulation. Pharmacologically, NMDA binds to NMDA receptors activating the receptor and leading to changes in downstream signaling.

[0024] The term "PSD95" refers to postsynaptic density protein 95. PSD95 is also known as PSD-95, synapse-associated protein 90 (SAP-90, SAP90). PSD95 is encoded by the DLG4 gene. The protein, PSD95, is comprised of 5 binding domains: three PDZ domains, an SH3 domain and a guanylate kinase-like domain. PSD95 is a scaffolding protein whose function is to bring together other proteins into a large multimeric complex via the PDZ, SH3 or guanylate kinase-like domains. See Uniprot P78352.

[0025] The term "nNOS" refers to neuronal nitric oxide synthase. Nitric oxide synthase enzymes convert arginine to nitric oxide, a small cell permeant neurotransmitter. nNOS is also known as NOS1 and brain specific NOS. See Uniprot P29475.

[0026] The term "a subject" includes all mammals, including without limitation, humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs, and rodents.

[0027] "Mammal" includes humans; domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits); and non- domestic animals such as wildlife, and the like.

[0028] As used herein, the terms "disease," "condition," and "disorder" may be used interchangeably or may be different in that the particular malady, condition, disorder, or syndrome may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition, disorder, or syndrome, or is a disruption of normal processes or functions, wherein a more or less specific set of symptoms has been identified by a clinician or researcher. In some embodiments, a disease is a pathological condition of an organ, a body part, or a system, resulting from various causes such as infection, genetic defect, or environmental stress that is characterized by an identifiable group of symptoms.

[0029] "Therapeutically effective amount" or "effective amount" refers to the amount of a compound of the disclosure that, when administered to a mammal (e.g., a human), is sufficient to effect treatment as defined herein, reduction in symptoms, or cure, of a disease or condition in the mammal, preferably a human. The amount of a compound of the disclosure which constitutes a "therapeutically effective amount" will vary depending on the compound; the condition and its severity; the manner of administration; and the age, weight, and genetics of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

[0030] The term "agent" refers to a compound or mixture of compounds that, when added to a composition, tends to produce an effect on the composition's properties. For example, a composition comprising a thickening agent is likely to be more viscous than an otherwise identical comparative composition that lacks the thickening agent.

[0031] The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reactiontemperature, that is about the temperature of the room in which the reaction is carried out,e.g.

[0032] At various places in the present specification, certain features of the compounds are disclosed in groups or in ranges. It is specifically intended that such a disclosure include each and every individual sub-combination of the members of such groups and ranges. For example, the terms "C1-6 alkyl" and "C1-C6alkyl" are specifically intended to individually disclose (without limitation) methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl, including all linear and branched compositions (e.g., n-butyl, sec-butyl, iso-butyl, and tert-butyl for C4alkyl).

[0033] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen substituent. Additionally, a compound can be substituted with a hydrogen, and hydrogen can be a substituent. The term "substituted," unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra-, penta-, or higher substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0034] The terms "Cn-m" and "Cn-Cm," where n and m are integers, indicates a group that contains from n to m carbon atoms, includes both linear and branched configurations, and does not exclude substituents. Examples include C1-4, C1-6, and the like. The term is intended to expressly disclose every member in the range, i.e., Cn, Cn+1, Cn+2 … Cm-2, Cm-1, Cm. For example, C1-6is intended to disclose C1, C2, C3, C4, C5, and C6. As used herein, "Cn-m" means the same as "Cn-Cm."

[0035] The term "n-membered," where n is an integer (e.g., 6-membered), typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. The term "n-m membered" wherein n and m are integers (e.g., 6- to 10-membered) describes a range wherein the number of ring forming atoms is from n to m. For example, piperidinyl is an example of a 6-membered heterocyclyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0036] "Alkyl" refers to a straight or branched hydrocarbon group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms, more preferably one to six carbon atoms, and which is attached to the molecule by a single bond. An alkyl group is an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the molecule. Alkyl groups can be linear or branched. For example, representative alkyl groups can be methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1,1- dimethylethyl (t-butyl), sec-butyl, isobutyl, n-pentyl, 3-methylhexyl, 2-methylhexyl, and the like. In another example, C1-C3alkyl means methyl, ethyl, n-propyl, and isopropyl. In certain specific embodiments, an alkyl group may be optionally substituted. The alkyl group may optionally contain one or more heteroatoms, wherein a carbon atom of the alkyl group is replaced with a heteroatom selected from oxygen, nitrogen or sulfur.

[0037] "Cycloalkyl" refers to a non-aromatic monocyclic hydrocarbon consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, or having from three to ten carbon atoms, which is saturated or unsaturated, and which is attached to the rest of the molecule by a covalent bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. In some embodiments, a cycloalkyl group may be optionally substituted by one or more substituents, wherein the one or more substituents are the same or are different.

[0038] "Bicycloalkyl" refers to a non-aromatic polycyclic hydrocarbon consisting solely of carbon and hydrogen atoms, which may include fused, bridged, or spiro ring systems, having from five to fifteen carbon atoms, or having from five to ten carbon atoms,which is saturated or unsaturated, and which is attached to the rest of the molecule by one or more covalent bond. Examples of bicycloalkyl groups include, but are not limited to, bicyclo[2.2.2]octanyl, bicyclo[2.2.1]heptanyl, and bicyclo[1.1.1]pentanyl. In some embodiments, a bicycloalkyl group may be optionally substituted by one or more substituents, wherein the one or more substituents are the same or are different.

[0039] "Heterocyclyl" refers to a 3- to 18-membered non-aromatic ring which comprises two to twelve carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atoms in the heterocyclyl group may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl group may be saturated or unsaturated (e.g., the heterocyclyl comprises one or more double bond). Examples of heterocyclyl groups include, but are not limited to, azepanyl, decahydro-isoquinolyl, morpholinyl, thiomorpholinyl, octahydroindolyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuryl¸ and the like. In certain embodiments, a heterocyclyl group may be optionally substituted with one or more substituents, wherein the one or more substituents can independently be the same or different.

[0040] "Bicycloheterocyclyl" refers to a 5- to 18-membered non-aromatic ring which comprises two to twelve carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise, the bicycloheterocyclyl is a bicyclic, tricyclic, or tetracyclic ring system, which includes fused, bridged, and spiro ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl group may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl group may be saturated or unsaturated. Examples of bicycloheterocyclyl groups include, but are not limited to, octahydropyrrolo[3,4-c]pyrrole, octahydrocyclopenta[c]pyrrole, octahydro-1H-pyrrolo[3,2-b]pyridine, 5- azaspiro[2.5]octanyl, 5-azaspiro[2.3]hexanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 3- azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2- azaspiro[3.3]heptanyl, 2-azabicyclo[2.2.2]octanyl, 2-azabicyclo[2.2.1]heptanyl, 2,8-diazaspiro[4.5]decanyl, azetidinyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1-azaspiro[3.3]heptan- 1-yl, 5-azaspiro[2.3]hexan-5-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 1-oxa-6- azaspiro[3.4]octan-6-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro-[3.3]heptan- 1-yl, 6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 2,6- diazaspiro[3.3]heptan-2-yl, In certain embodiments, the bicycloheterocyclyl group may be optionally substituted with one or more substituents, wherein the one or more substituents can independently be the same or different.

[0041] In some embodiments, the heterocyclyl group or bicycloheterocyclyl group can be fused with an aryl group. Examples of bicycloheterocyclyl groups fused with an aryl group include, but are not limited to, 2,3-dihydro-1H-1,3-benzodiazol-2-one, 3,4- dihydro-2H-1,4-benzoxazine, 1,2,3,4-tetrahydroquinoline, and 1,2,3,4- tetrahydroisoquinoline.

[0042] "Aryl" refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For example, "aryl" can be C6-C10. For purposes of this disclosure, the aryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from phenyl, benzene, naphthalene, anthracene, aceanthrylene, acenaphthylene, acephenanthrylene, azulene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, an aryl group may be unsubstituted or substituted. In embodiments wherein the aryl can be substituted, the aryl is substituted with one or more substituents, one substituent, two substituents, three substituents, 4 substituents, or five substituents, each substituent of which can be the same or can be different. In some embodiments, the term "aryl," when substituted, can include a fused ring substituent, e.g., a 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydronaphthalene, or 2,3-dihydro-1H-1,3-benzodiazol-2-one, 3,4-dihydro- 2H-1,4-benzoxazine.

[0043] "Heteroaryl" refers to a 5- to 14-membered ring system comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of this disclosure, the heteroaryl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl may be optionally oxidized; and the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, 1H-1,2,3- benzotriazolyl, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2- a]pyridinyl, benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1- oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2- d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). In some embodiments, the heteroaryl group can be unsubstituted or substituted. In embodiments wherein the heteroaryl is substituted, the heteroaryl is substituted with one or more substituents, each of which can be the same or can be different. In some embodiments, the term "heteroaryl" can include, e.g., structures such as the following:

[0044] "Substituted" refers to a group in which one or more hydrogens are optionally replaced by a non-hydrogen group to the extent that such substitution is chemically possible. Typical substituents include, but are not limited to, halogens (F, Cl, Br, I), =O, =N-CN, =N-OR, =NR, OR, NR2, SiR3, SR, SO2R, SO2NR2, NRSO2R, NRCONR2, NRC(O)OR, NRC(O)R, CN, C(O)OR, C(O)NR2, OC(O)R, C(O)R, and NO2, wherein each R is independently H, C1-C6alkyl, C2-C8heteroalkyl, C1-C6acyl, C2- C8heteroacyl, C2-C8alkenyl, C2-C8heteroalkenyl, C2-C8alkynyl, C2-C8heteroalkynyl, C6-C10 aryl, or C5-C10 heteroaryl, and each R is optionally substituted with halogens (F, Cl, Br, I), =O, =N-CN, =N-OR', =NR', OR', NR'2, SiR'3, SR', SO2R', SO2NR'2, NR'SO2R', NR'CONR'2, NR'C(O)OR', NR'C(O)R', CN, C(O)OR', C(O)NR'2, OC(O)R', C(O)R', and NO2, wherein each R' is independently H, C1-C6alkyl, C2-C8heteroalkyl, C1-C8acyl, C2- C8heteroacyl, C6-C10aryl, or C5-C10heteroaryl. Alkyl, alkenyl, and alkynyl groups can also be substituted by C1-C6acyl, C2-C8heteroacyl, C6-C10aryl, or C5-C10heteroaryl, each of which can be substituted by substituents appropriate for the particular group.

[0045] The compounds and methods of the present disclosure are intended to encompass compounds of Structures (I) and (II) having one or more hydrogen atoms replaced by deuterium, i.e.,2H. Substitution of one or more hydrogen with deuterium may afford certain therapeutic advantages such as modified pharmacokinetic properties. For example, when substituted with deuterium, the compounds may have increased in vivo half- life or reduced dosage requirements, and hence may be preferred in some circumstances. In some embodiments, the compounds of the disclosure are enriched with deuterium. Such deuterated compounds can be achieved by methods known to one skilled in the art, such as exchanging protons with deuterium, or by synthesizing the molecule with deuterium- enriched starting materials.

[0046] "Pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," or "pharmaceutically acceptable carrier or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, pH adjusting agent, hydrogel, salt, inert solid, printed solid, or emulsifier, which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0047] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0048] A pharmaceutically acceptable acid addition salt refers to salts which retain the biological effectiveness and properties of the free bases, which are not biologically, or otherwise, undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0049] A pharmaceutically acceptable base addition salt refers to salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0050] A "pharmaceutical composition" refers to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of the compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0051] A "stereoisomer" refers to a compound comprising the same atoms bonded by the same bonds, but having different three-dimensional structures which are not interchangeable. The present disclosure includes various stereoisomers and mixtures thereof. The present disclosure includes enantiomers, which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. See, e.g., Smith, M. B. and J. March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007), for a detailed description of the structure andproperties of enantiomers and stereoisomers. The present disclosure includes diastereomers, which refers to two stereoisomers whose molecules are non-superimposable non-mirror images of one another.

[0052] The compounds of the disclosure, or their pharmaceutically acceptable salts, may contain one or more stereocenter and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present disclosure is meant to include all such possible isomers, all combinations of such isomers, a racemic mixture, a mixture of unequal combinations of stereoisomers, or (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers, diastereomers, or stereoisomers include chiral synthesis from a suitable optically pure precursor, or resolution of the mixture (e.g., racemate or the racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC).

[0053] The present disclosure includes an essentially pure enantiomer, diastereomer, (R)-stereoisomer, or (S)-stereoisomer. The present disclosure includes mixtures of enantiomers, diastereomers, stereoisomers, or a combination thereof. The mixture can be a racemic mixture, as known to one having skill in the art, as a 50 / 50 mixture of enantiomers. The mixture can also include a mixture of any other ratio or relative composition of enantiomers, diastereomers, stereoisomers, or a combination thereof. As disclosed herein, all stereoisomers are to be included for any given chemical structure or substituent when a chiral center in the chemical structure or substituent is present, unless otherwise indicated. For example, the following structure:is intended to include each and every one of the following structures:, and the following structure:is intended to include each and every one of the following structures:,

[0054] When the compounds described herein contain olefinic double bonds or other centers giving rise to geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both the E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0055] A "tautomer" refers to a constitutional isomer wherein a proton can shift from one atom of a molecule to another atom of the same molecule (e.g., keto-enol). The present disclosure includes tautomers of any said compounds.

[0056] The use of parentheses and brackets in substituent groups is used herein to conserve space. Accordingly, the use of parentheses in a substituent group indicates that the group enclosed within the parentheses is attached directly to the atom preceding the parenthesis (e.g., -C(O)- represents a carbonyl). The use of brackets in a substituent group indicates that the group enclosed within the brackets is also attached directly to the atom preceding the brackets.

[0057] The chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using ChemDraw®Professional Version 22.2.0.3300 software program. For complex chemical names employed herein, a substituent group is named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. In chemical structure diagrams, all bonds are identified, except for some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.

[0058] At certain places, the definitions or embodiments may refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member, provided that the valency of the atom is not exceeded.

[0059] When any two groups or two instances of the same substituent group are "independently" selected from a list of alternatives, the groups may be the same, or the groups may be different. For example, if Raand Rbare independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, then a molecule with two Ragroups and two Rbgroups could have all groups be an alkyl group (e.g., four different alkyl groups, or four of the same alkyl groups). Alternatively, the first Racould be alkyl, the second Racould be fluoro, the first Rbcould be hydroxyalkyl, and the second Rbcould be amino (or any other substituents taken from the group). Alternatively, both Raand the first Rbcould be fluoro, while the second Rbcould be alkyl (i.e., some pairs of substituent groups may be the same, while other pairs may be different). Unless otherwise indicated, if two or more groups having the same definition are present, but the definition provides for alternatives, it should be understood that each occurrence of the same group isindependently selected from the possible alternatives. For example, if two or more Ragroups are present in a compound, and the definition of Raprovides that Racan be A, B, or C, then it should be understood that each Ragroup present in the compound is independently chosen from A, B, and C, so that the Ragroups present in the compound can be the same or different.

[0060] Compounds, and salts thereof, including pharmaceutically acceptable salts, can be found together with other substances such as water and solvents (e.g., hydrates and solvates), or can be isolated.

[0061] Compounds, and salts thereof, can additionally include more than one salt form. For example, the salt of a compound having two basic groups can include e.g., two trifluoroacetic acid salts, or one trifluoroacetic acid salt and one hydrochloride salt. Compounds

[0062] In some aspects, the present disclosure provides a compound having Structure (I):or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, C1-C6alkyl, or C3-C6cycloalkyl;R2 is hydrogen, C1-6alkyl, substituted or unsubstituted C3-C6cycloalkyl,substituted or unsubstituted bicycloalkyl, substituted or unsubstituted C5-C7heterocyclyl,substituted or unsubstituted bicycloheterocyclyl, substituted or unsubstituted C6-C10aryl,substituted or unsubstituted C6-C10aryl fused with substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted C3-C6cycloalkyl fused with substituted orunsubstituted C6-C10aryl, substituted or unsubstituted C6-C10heteroaryl, or -SO2CH3,or R1and R2, together with the N atom to which they are attached, form a substitutedor unsubstituted C4-C10heterocyclyl, a substituted or unsubstituted C5-C10bicycloheterocyclyl, or a substituted or unsubstituted heterocyclyl fused with C6-C10aryl,and wherein L is absent; Ais a substituted or unsubstituted C6-C10aryl or a substituted or unsubstituted C5-C10heteroaryl; andL is a C1-C6alkyl or absent.

[0063] In some embodiments, A is a substituted or unsubstituted C6-C10aryl. Insome embodiments, A is a substituted or unsubstituted phenyl.

[0064] In some embodiments, A is selected from the group consisting of:

[0065] In some embodiments, A is selected from the group consisting of:

[0066] In some embodiments, A is

[0067] In some embodiments, A is a substituted or unsubstituted C5-C10heteroaryl.

[0068] In some embodiments, A is selected from the group consisting of:

[0069] In some embodiments, R1is hydrogen. In some embodiments, R1is C1-C6alkyl. In some embodiments, R1 is C3-C6cycloalkyl. In some embodiments, R1 isselected from the group consisting of methyl, ethyl, and isopropyl. In some embodiments, R1is cyclopropyl.

[0070] In some embodiments, R2 is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstitutedbicycloalkyl, substituted or unsubstituted 5- to 8-membered heterocyclyl, substituted or unsubstituted bicycloheterocyclyl, substituted or unsubstituted C6-C10aryl, substituted orunsubstituted C6-C10aryl fused with substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted C3-C6cycloalkyl fused with substituted or unsubstituted C6-C10aryl, substituted or unsubstituted C6-C10heteroaryl, or -SO2CH3.

[0071] In some embodiments, R2is hydrogen.

[0072] In some embodiments, R2 is substituted or unsubstituted C1-6alkyl. Insome embodiments, R2is selected from the group consisting of:

[0073] In some embodiments, R2 is substituted or unsubstituted C3-C6cycloalkyl.In some embodiments, R2ais selected from the group consisting of:

[0074] In some embodiments, R2is substituted or unsubstituted bicycloalkyl. Insome embodiments, R2ais selected from the groupaconsisting of:R R Ra

[0075] In some embodiments, R2is substituted or unsubstituted 3- to 8-memberedheterocyclyl. In some embodiments, R2is selected from the group consisting of:

[0076] In some embodiments, R2is substituted or unsubstitutedbicycloheterocyclyl. In some embodiments, the bicycloheterocyclyl comprises between 1- 3 bridging atoms, wherein the bridging atoms comprise atoms of carbon, nitrogen, oxygen, sulfur, or a combination thereof. In some embodiments, R2is selected from the group

[0077] In some embodiments, the bicycloheterocyclyl comprises a spiro fused ring system, wherein each ring of the spiro fused ring is a 3- to 8-membered ring, wherein at least one ring comprises one or more heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein the spiro fused ring system comprises between 1-3 rings. In some embodiments, R2is:

[0078] In some embodiments, R2 is a substituted or unsubstituted C6-C10aryl. Insome embodiments, R2is a substituted or unsubstituted phenyl. In some embodiments, R2is selected from the group consisting of:.

[0079] In some embodiments, R2 is a substituted or unsubstituted C6-C10arylfused with substituted or unsubstituted heterocycloalkyl. In some embodiments, the substituted or unsubstituted C6-C10aryl is a substituted or unsubstituted phenyl. In someembodiments, the substituted or unsubstituted heterocycloalkyl is a 3- to 8-membered ring comprising at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, R2is:.

[0080] In some embodiments, R2 is a substituted or unsubstituted C3-C6cycloalkyl fused with substituted or unsubstituted C6-C10aryl. In some embodiments, R2is a substituted or unsubstituted C3-C6cycloalkyl fused with substituted or unsubstitutedphenyl. In some embodiments, R2is selected from the group consisting of:

[0081] In some embodiments, R2is a substituted or unsubstituted 5- to 10- membered heteroaryl. In some embodiments, R2is a substituted or unsubstituted pyridinyl.In some embodiments, R2is selected from the group consisting of:

[0082] In some embodiments, R2is selected from the group consisting of:.In some embodiments, R2isIn some embodiments, R2isIn some embodiments, R2is

[0083] In some embodiments, R2 is -SO2CH3.

[0084] In some embodiments, R1and R2, together with the N atom to which theyare attached, form a substituted or unsubstituted 4- to 10-membered heterocyclyl. In someembodiments, the R1and R2, together with the N atom to which they are attached, areselected from the group consisting of:

[0085] In some embodiments, R1and R2, together with the N atom to which theyare attached, form a substituted or unsubstituted 5- to 10-membered bicycloheterocyclyl. In some embodiments, the bicycloheterocyclyl is a heterocyclyl fused with another heterocyclyl. In some embodiments, the bicycloheterocyclyl is a heterocyclyl fused with a cycloalkyl. For example, the heterocyclyl can comprise 3- to 9 atoms, at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl is fused with a ring formed by at least one additional atom. In some embodiments, the heterocyclyl is fused with a ring formed by 1-3 additional atoms. In some embodiments, the heterocyclyl is fused with a ring formed by 1-4 additional atoms.In some embodiments, the R1and R2, together with the N atom to which they are attached,are selected from the group consisting of:.

[0086] In some embodiments, R1and R2, together with the N atom to which theyare attached, form a substituted or unsubstituted 4- to 10-membered heterocyclyl fused with C6-C10aryl. In some embodiments, R1 and R2, together with the N atom to which theyare attached, form a substituted or unsubstituted 4- to 10-membered heterocyclyl fused with phenyl. For example, the heterocyclyl can comprise 4- to 10 atoms. In some embodiments, the heterocyclyl comprises 5 atoms. In some embodiments, the heterocyclyl comprises 6 atoms. In some embodiments, the heterocyclyl comprises at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and is fused with an aromatic ring. In some embodiments, the R1and R2, together with the N atom to which they areattached, are selected from the group consisting of:

[0087] In some embodiments, R1and R2, together with the N atom to which theyare attached, form a substituted or unsubstituted bicycloheterocyclyl wherein the bicycloheterocyclyl is a spiro-fused heterocyclyl ring. In some embodiments, theheterocyclyl comprises 3- to 10 atoms. In some embodiments, the heterocyclyl comprises at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl comprises 1-3 spiro fused rings. For example, the spiro-fused heterocyclyl can comprise two rings wherein one ring is a heterocyclyl and the second ring is a heterocyclyl. In another example, the spiro-fused heterocyclyl can comprise two rings wherein one ring is a heterocyclyl and the second ring is a cycloalkyl. In some embodiments, each ring comprises between 3- to 7 atoms. In some embodiments, the R1and R2, together with the N atom to which they are attached, are selected from thegroup consisting of:

[0088] In some aspects, the present disclosure provides a compound having Structure (II):R4awherein: B is nitrogen or CH; Cis absent or -CH2-;D is absent or -CH2-;E is absent or -CH2-;F is absent, -CH2-, or -CH2-CH2-;R3ais selected from the group consisting of hydrogen and hydroxy;R4ais selected from the group consisting of hydrogen, halogen, cyano, and nitro;and R5a is selected from the group consisting of hydrogen, halogen, phenyl, and C1-6alkyl.

[0089] In some embodiments, of Structure (II), B is nitrogen. In some embodiments, of Structure (II), B is CH.

[0090] In some embodiments, of Structure (II), C is absent and D is -CH2-. In someembodiments, of Structure (II), D is absent and C is -CH2-. In some embodiments, ofStructure (II), C is absent and D is absent. In some embodiments, of Structure (II), C is -CH2- and D is -CH2-.

[0091] In some embodiments of Structure (II), E is absent. In some embodimentsof Structure (II), E is -CH2-. In some embodiments of Structure (II), F is absent. In someembodiments of Structure (II), F is -CH2-. In some embodiments of Structure (II), F is -CH2-CH2-. In some embodiments of Structure (II), the ring comprising B, F, and E is a4-membered ring. In some embodiments of Structure (II), the ring comprising B, F, and E is a 5-membered ring. In some embodiments of Structure (II), the ring comprising B, F, and E is a 6-membered ring. In some embodiments of Structure (II), the ring comprising B, F, and E is a 7-membered ring.

[0092] In some embodiments of Structure (II), B is nitrogen; C is absent; D isabsent; E is -CH2-; and F is -CH2-, and the structure is:a.

[0093] In some embodiments of Structure (II), B is CH; C is -CH2-; D is -CH2-; Eis -CH2-; and F is -CH2-, and the structure is:

[0094] In some embodiments of Structure (II), B is CH; C is -CH2- and D is absent,or D is -CH2- and C is absent; E is -CH2-; and F is -CH2-, and the structure is:.

[0095] In some embodiments of Structure (II), B is nitrogen; C is absent; D isabsent; E is -CH2-; and F is -CH2-CH2-, and the structure is:

[0096] In some embodiments of Structure (II), R3ais hydroxy. In someembodiments of Structure (II), R3ais hydrogen.

[0097] In some embodiments of Structure (II), R4ais hydrogen. In someembodiments of Structure (II), R4ais halogen. In some embodiments of Structure (II), R4ais chloro. In some embodiments of Structure (II), R4ais bromo. In some embodiments ofStructure (II), R4ais fluoro. In some embodiments of Structure (II), R4ais cyano. In someembodiments of Structure (II), R4ais nitro.

[0098] In some embodiments of Structure (II), R5ais hydrogen. In someembodiments of Structure (II), R5ais halogen. In some embodiments of Structure (II), R5ais chloro. In some embodiments of Structure (II), R5ais bromo. In some embodiments ofStructure (II), R5ais fluoro. In some embodiments of Structure (II), R5ais phenyl. Insome embodiments of Structure (II), R5a is C1-6alkyl.

[0099] In some embodiments of Structure (II), R3ais hydroxy, R4ais halogen, andR5ais halogen. In some embodiments of Structure (II), the structure of the phenylcomprising R3a, R4a, and R5ais

[0100] In some embodiments, of Structure (I) or Structure (II), Rais selected fromthe group consisting of:-H, -CH3, -NH2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -COOH, -C(O)OtBu,- C(O)OCH3, -NHC(O)CH3, -NHC(O)CH2CF3, -C(O)CH3, -C(O)NHCH2CF3, -SO2CH3, - CH2C(O)NH2, -CH2COOH, -C(O)CH2CH(CH3)2, -C(O)CH(CH3)2, -SO2CH(CH3)2, - SO2CH2CH3, -C(O)CH2CF3, -OCH3, -C(O)NH(CH2)3SO2CH3, -CH2CH3, - C(O)CH2N(CH3)2, -SO2CF3, -C(O)CH2CH2N(CH3)2, -C(O)NHtBu, -C(O)CH2tBu, - C(O)NHCH(CH3)2, -C(O)CH2CH3, -SO2CH2CH(CH3)2, -SO2NH2, -NHC(O)OtBu, -OH, - C(O)OCH2CH3, -C(O)C(CH3)2CH2CH3,

[0101] In some embodiments of Structure (I) or Structure (II), Rais selected fromthe group consisting of:-H, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -COOH, -C(O)OtBu, - NHC(O)CH2CF3,-C(O)CH3, -SO2CH3, - CH2C(O)NH2, -CH2COOH, -C(O)CH2CH(CH3)2, -C(O)CH(CH3)2, -SO2CH(CH3)2, - SO2CH2CH3, -C(O)CH2CF3, -CH2CH3,- C(O)CH2N(CH3)2, -SO2CF3, -C(O)CH2CH2N(CH3)2, -C(O)NHtBu, -C(O)CH2tBu,- C(O)NHCH(CH3)2, -C(O)CH2CH3, -SO2CH2CH(CH3)2, -SO2NH2,5

[0102] In some embodiments of Structure (I) or Structure (II), Rais selected fromthe group consisting of: -C(O)NH2, -CO2H, -SO2CH(CH3)2, -SO2CH3, -SO2NH2,,

[0103] In some embodiments of Structure (I) or Structure (II), Rais selected from the group consisting of:-C(O)NH2, -CO2H,

[0104] In some embodiments of Structure (I) or Structure (II), Rais selected fromthe group consisting of:.

[0105] In some embodiments of Structure (I) or Structure (II), Rais hydrogen.

[0106] In some embodiments of Structure (I) or Structure (II), Rais selected from the group consisting of -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -COOH, -C(O)OtBu, -C(O)OCH3, -C(O)CH3, -C(O)NHCH2CF3, -C(O)CH2CH(CH3)2, -C(O)CH(CH3)2, -C(O)CH2CF3, -C(O)NH(CH2)3SO2CH3, -C(O)CH2N(CH3)2, -C(O)CH2CH2N(CH3)2,-C(O)NHtBu, -C(O)CH2tBu, -C(O)NHCH(CH3)2, -C(O)CH2CH3, -C(O)OCH2CH3, -C(O)C(CH3)2CH2CH3,,

[0107] In some embodiments of Structure (I) or Structure (II), Rais selected fromthe group consisting of -NH2, -NHC(O)CH3, -NHC(O)CH2CF3, -NHC(O)OtBu,

[0108] In some embodiments of Structure (I) or Structure (II), Rais selected from5 the group consisting of:

[0109] In some embodiments of Structure (I) or Structure (II), Rais selected from the group consisting of:5 -SO2CH3, -SO2CH(CH3)2, -SO2CH2CH3, -SO2CF3, -SO2CH2CH(CH3)2, -SO2NH2,OO O O

[0110] In some embodiments, Rbis selected from the group consisting ofhydrogen, halogen, -OCH3, and -OH. In some embodiments, Rbis hydrogen.

[0111] In some embodiments, L is absent.

[0112] In some embodiments, L is -CH2-. In some embodiments, L is -CH2CH2-.In some embodiments, L is -CH(CH3)-. In some embodiments, L is -CH2CH2CH2-.

[0113] In some embodiments,L is absent; R1is H;Ra is selected from the group consisting of: -C(O)NH2, -CO2H, -SO2CH(CH3)2,-SO2CH3, -SO2NH2,

[0114] In some embodiments,A is ; L is absent; R1is H; R2is selected from the gr aoup consisting of: aaRa is selected from the group consisting of: -C(O)NH2, -CO2H,

[0115] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Structure (I) or Structure (II) as disclosed herein,or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Methods of Use

[0116] In some embodiments, the compounds of Structures (I) and (II), or a stereoisomer, tautomer, or pharmaceutically acceptable salt, and embodiments thereof, are useful for disrupting formation of a multi-protein complex and for therapeutic use.

[0117] In some aspects, the present disclosure provides a method of disrupting formation of a multi-protein complex in a subject, the method comprising administering to the subject an amount of a compound of Structure (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, effective to disrupt the multi-protein complex formation, wherein the compound of Structure (I) is as described herein.

[0118] In some aspects, the present disclosure provides a method of disrupting formation of a multi-protein complex in a subject, the method comprising administering to the subject an amount of a compound of Structure (II), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, effective to disrupt the multi-protein complex formation, wherein the compound of Structure (II) is as described herein.

[0119] In some embodiments, the multi-protein complex comprises an NMDA receptor, a scaffolding protein, a postsynaptic density protein 95 (PSD95), a neuronal nitric oxide synthase (nNOS), or a combination thereof.

[0120] The NMDA receptor, (e.g., NMDA receptor subtype 2 B), upon activation by glutamate and glycine, a co-agonist, concurrent with depolarization, unblocks its ion pore and can also bind to PSD95. PSD95 then binds to nNOS. The proteins form this complex via specific binding domains. The C-terminal end of the NMDA receptor binds to PDZ 1 domain of PSD95 (PDZ1) likely introducing a conformational change in both proteins. The second PDZ domain of PSD95 (PDZ2) binds to the N-terminal domain of nNOS. Thus, nNOS is brought close to the NMDA receptor. The N-terminal domain ofnNOS is also able to bind to other proteins as are the other PSD95 domains. Binding events may be regulated by various post-translational modifications, or may vary due to alternative splicing of PSD95 isoforms. The assays disclosed herein consist of measuring the interaction of 2 protein fragments: PSD95, PDZ domains 1 through 3 and nNOS, amino acids 1-299. PDZ1 through 3 may bind to NMDA receptor C-terminal tails and nNOS. nNOS (1-299) is unique to this nitric oxide synthase isoform. This sequence is not found in the other two forms of nitric oxide synthase (endothelial NOS (eNOS) or inflammatory NOS (iNOS)). The assay as described herein was designed to specifically identify and characterize molecules that inhibit the PSD95 (PDZ1 through 3) interactions with nNOS (1-299) since these binding domains are important for complex formation. This provides specificity for blocking these domain interactions and avoiding undesirable activities, such as inhibiting nitric oxide synthase catalytic activity. Other studies demonstrate that compounds do NOT inhibit nitric oxide synthase catalysis, do not bind glutamate receptors (including NMDA receptors) and block the formation of the PSD95-nNOS complex in neurons. Thus, the compounds appear to act specifically by blocking the PSD95-nNOS complex.

[0121] In some embodiments, the disrupting the formation of the multi-protein complex comprises inhibiting a protein-protein interaction. For example, the disrupting the formation of the multi-protein complex can include inhibiting binding of the compound to nNOS, inhibiting binding of PSD95 to NMDA, inhibiting binding of nNOS to PSD95, inhibiting binding of NOS1AP to nNOS, inhibiting nitric oxide production, inhibiting cGMP synthesis, inhibiting p38 MAPK activity, or a combination thereof.

[0122] In some embodiments, the present disclosure provides a method for disrupting the formation of the multi-protein complex in a subject, comprising administering to the subject a compound having a structure in Tables 1-27.

[0123] In some embodiments, the present disclosure provides a method for disrupting the formation of the multi-protein complex in a subject, comprising administering as a pharmaceutical composition a compound of Structure (I) or Structure(II) as disclosed herein, its stereoisomer, tautomer, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

[0124] In some embodiments, the compound of Formula (I) or Formula (II) acts in a neuron.

[0125] In some embodiments, the subject is a human. EXAMPLES

[0126] The following examples are provided by way of illustration only and not by way of limitation. Those of skill in the art will readily recognize a variety of noncritical parameters which could be changed or modified to yield essentially similar results. General Methods

[0127] Compounds described herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those illustrated in the Examples.

[0128] The reactions for preparing compounds described 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 or reactants, the intermediates, or the 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 one solvent 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. Preparation of compounds of the disclosure 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 is described in, e.g., Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry,"J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006). Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H or13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC). The particular synthetic methods used in the Examples provide general guidance in connection with preparing the compounds of the disclosure. One skilled in the art would understand that the preparations can be modified or optimized using general knowledge of organic chemistry to prepare various compounds within the scope of the present disclosure. Starting materials, reagents, and intermediates whose synthesis is not described herein are either commercially available, known in the literature, or may be prepared by methods known to one skilled in the art. It will be appreciated by one skilled in the art that the processes described herein are not the exclusive means by which compounds of the disclosure may be synthesized, and that a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds of the disclosure. The person skilled in the art knows how to select and implement appropriate synthetic routes. Suitable synthetic methods of starting materials, intermediates, and products may be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry, Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols.1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001- 2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2nd Edition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II (Pergamon Press, 1996); Smith et al., March's AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

[0129] If not otherwise stated, chromatography refers to flash chromatography conducted on silica gel. Example 1 Scheme 1: ANA-100 ClPreparation of N-(1-Acetylpiperidin-4-yl)-3,5-dichloro-2-hydroxybenzamide OH Cl Cl

[0130] Diisopropylethylamine (1.75 mL, 10.0 mmol) was added to a solution of 3,5-dichloro-2-hydroxybenzoic acid (1.03 g, 5.00 mmol) in N,N-dimethylformamide (12.5 mL). After stirring for 5 min, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU) (2.09 g, 5.50 mmol) was added to the reaction mixture. After stirring for an additional 5 min, 1-(4-aminopiperidin-1-yl)ethan-1- one (714 mg, 5.02 mmol) was added to the reaction mixture. The mixture was stirred for 1 h, then quenched with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was triturated with methanol and collected by vacuum filtration, then rinsed with methanol and dried under vacuum to provide N-(1- acetylpiperidin-4-yl)-3,5-dichloro-2-hydroxybenzamide (322 mg, 19%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6J = 7.3, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 4.36 (d, J = 13.3 Hz, 1H), 4.12–4.03 (m, 1H), 3.85 (d, J = 13.9 Hz, 1H), 3.18–3.10 (m, 1H), 2.67 (td, J = 12.9, 2.5 Hz, 1H), 2.02 (s, 3H), 1.88 (d, J = 11.6 Hz, 1H), 1.82 (d, J = 12.7 Hz, 1H), 1.50 (qd, J = 12.0, 4.1 Hz, 1H), 1.39 (qd, J= 12.0, 4.1 Hz, 1H); ESI MS m / z 331 [C14H16Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 97.3% (AUC), tR= 4.48 min. Example 2 Scheme 2: ANA-101Preparation of tert-Butyl (1-(Isopropylsulfonyl)piperidin-4-yl)carbamate

[0131] Triethylamine (138.0 mL, 988.7 mmol) was added dropwise to a solution of tert-butyl piperidin-4-ylcarbamate (188.2 g, 939.8 mmol) in dichloromethane (1.8 L) under inert atmosphere, followed by a dropwise addition of isopropylsulfonyl chloride (100.0 mL, 981.6 mmol). The mixture was allowed to stir at room temperature overnight, then quenched with saturated ammonium chloride (1 L), diluted with water (500 mL) and extracted with dichloromethane (500 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to provide tert-butyl (1- (isopropylsulfonyl)piperidin-4-yl)carbamate (218.5 g, 713.1 mmol, 76%) as a yellow solid: ESI MS m / z 307 [C13H26N2O4S + H]+. Preparation of 1-(Isopropylsulfonyl)piperidin-4-amine Hydrochloride

[0132] 4M Hydrogen chloride in 1,4-dioxane (715 mL, 2860 mmol) was added dropwise to a suspension of tert-butyl (1-(isopropylsulfonyl)piperidin-4-yl)carbamate (218.5 g, 713.1 mmol) in 1,4-dioxane (430 mL). The mixture was allowed to stir overnight, then the precipitates were collected by vacuum filtration, rinsed with diethyl ether (1 L), and dried under vacuum to provide 1-(isopropylsulfonyl)piperidin-4-amine hydrochloride (160.2 g, 659.8 mmol, 93%) as an off-white solid: ESI MS m / z 207 [C8H18N2O2S + H]+. Example 3Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(isopropylsulfonyl)piperidin-4- yl)benzamide [ANA-101] OH Cl Cl

[0133] Diisopropylethylamine (345 mL, 1980 mmol) was added dropwise over 30 minutes to a solution of 3,5-dichloro-2-hydroxybenzoic acid (136.8 g, 660.8 mmol) in N,N- dimethylformamide (1.2 L). Then, 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (253.2 g, 666.0 mmol) was added portion wise to the reaction mixture in 10 g portions. Then, the reaction mixture was added slowly to a suspension of 1-(isopropylsulfonyl)piperidin-4-amine hydrochloride (154.6 g, 636.9 mmol) in N,N-dimethylformamide (450 mL). The mixture was stirred for 1 h, then quenched by dropping 165 mL × 10 portions of the reaction mixture dropwise to water (3.3 L × 10). The precipitates were collected by vacuum filtration, rinsed with water (500 mL), and dried under vacuum. The combined precipitates were triturated with methanol (500 mL × 3) and collected by vacuum filtration, then rinsed with methanol (500 mL) and dried under vacuum to provide 3,5-dichloro-2-hydroxy-N-(1- (isopropylsulfonyl)piperidin-4-yl)benzamide (136.0 g, 344.1 mmol, 54%) as an off-white solid:1H NMR (500 MHz, DMSO-d6J = 6.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.09–3.99 (m, 1H), 3.68 (d, J = 12.9 Hz, 2H), 3.37– 3.31 (m, 1H), 3.03 (t, J = 11.5 Hz, 2H), 1.87 (d, J = 10.0 Hz, 2H), 1.57 (qd, J = 12.0, 4.0 Hz, 2H), 1.23 (d, J = 6.8 Hz, 6H); ESI MS m / z 395 [C15H20Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 98.2% (AUC), tR= 4.82 min. Example 4Scheme 3: ANA-102 B CPreparation of tert-Butyl (1-(piperidine-1-carbonyl)piperidin-4-yl)carbamate

[0134] Diisopropylethylamine (0.96 mL, 5.5 mmol) was added dropwise to a solution of tert-butyl piperidin-4-ylcarbamate (1.00 g, 5.02 mmol) in dichloromethane (50 mL) under inert atmosphere, followed by a dropwise addition of piperidine-1-carbonyl chloride (0.68 mL, 5.5 mmol). The mixture was allowed to stir at room temperature overnight, then quenched with saturated ammonium chloride (100 mL), diluted with water (100 mL) and extracted with dichloromethane (100 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl (1-(piperidine-1-carbonyl)piperidin-4-yl)carbamate (4.48 g) as an orange oil that was used without further purification: ESI MS m / z 312 [C16H29N3O3+ H]+. Preparation of (4-Aminopiperidin-1-yl)(piperidin-1-yl)methanone Hydrochloride

[0135] 4M Hydrogen chloride in 1,4-dioxane (5 mL, 20 mmol) was added dropwise to tert-butyl (1-(piperidine-1-carbonyl)piperidin-4-yl)carbamate (4.48 g). The mixture was allowed to stir overnight, then the precipitates were collected by vacuum filtration, rinsed with diethyl ether (10 mL), and dried under vacuum to provide (4-aminopiperidin-1- yl)(piperidin-1-yl)methanone hydrochloride (1.73 g) as an off-white solid that was used without further purification: ESI MS m / z 212 [C11H21N3O + H]+. Example 5Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(piperidine-1-carbonyl)piperidin-4- yl)benzamide [ANA-102] OH Cl Cl

[0136] Diisopropylethylamine (3.5 mL, 20 mmol) was added dropwise to a solution of 3,5-dichloro-2-hydroxybenzoic acid (1.04 g, 5.03 mmol) in N,N-dimethylformamide (12.5 mL). Then, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (2.10 g, 5.51 mmol) was added slowly to the reaction mixture. (4-Aminopiperidin-1-yl)(piperidin-1-yl)methanone hydrochloride (1.73 g) was then added to the reaction mixture. The mixture was stirred for 1 h, then quenched by dropping the mixture into water (250 mL) with vigorous stirring. The precipitates were collected by vacuum filtration and rinsed with water (50 mL). The combined precipitates were triturated with acetonitrile (20 mL) then methanol (20 mL) and collected by vacuum filtration, then rinsed with methanol (10 mL) and dried under vacuum to provide 3,5- dichloro-2-hydroxy-N-(1-(piperidine-1-carbonyl)piperidin-4-yl)benzamide (1.02 g, 2.56 mmol, 51%) as a white solid:1H NMR (500 MHz, DMSO-d61H), 8.04 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 4.06–3.97 (m, 1H), 3.57 (d, J = 13.3 Hz, 2H), 3.13–3.09 (m, 4H), 2.82 (t, J = 11.5 Hz, 2H), 1.79 (dd, J = 12.0, 2.6 Hz, 2H), 1.58–1.52 (m, 4H), 1.52–1.45 (m, 4H); ESI MS m / z 400 [C18H23Cl2N3O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 5.16 min. Example 6SchemPreparation of tert-Butyl 4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxylate

[0137] Diisopropylethylamine (3.5 mL, 20 mmol) was added to a solution of 3,5- dichloro-2-hydroxybenzoic acid (2.07 g, 10.0 mmol) in N,N-dimethylformamide (20 mL). After stirring for 5 min, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU) (4.00 g, 10.5 mmol) was added to the reaction mixture. After stirring for an additional 5 min, tert-butyl 4-aminopiperidine-1- carboxylate (2.00 g, 10.0 mmol) was added to the reaction mixture. The mixture was stirred for 1 h, then quenched by dropping slowly into water (100 mL) with vigorous stirring. The precipitates were collected by vacuum filtration, rinsed with water, and dried under vacuum to provide tert-butyl 4-(3,5-dichloro-2-hydroxybenzamido) piperidine-1-carboxylate (3.16 g, 8.14 mmol, 81%) as an off-white solid: ESI MS m / z 389 [C17H22Cl2N2O4+ H]+. Preparation of 3,5-Dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide Hydrochloride

[0138] 4M Hydrogen chloride in 1,4-dioxane (8.0 mL, 32.0 mmol) was added dropwise to tert-butyl 4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1-carboxylate (3.15 g, 8.09 mmol). The mixture was allowed to stir overnight, then the precipitates were collected by vacuum filtration and rinsed with diethyl ether (20 mL), and dried under vacuum to provide 3,5-dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride (2.64 g, 8.09 mmol, >99%) as an off-white solid: ESI MS m / z 289 [C12H14Cl2N2O2+ H]+. Example 7Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(pyrimidin-2-yl)piperidin-4- yl)benzamide [ANA-103] OH Cl Cl

[0139] Diisopropylethylamine (4.2 mL, 24.1 mmol) was added to a suspension of 3,5- dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride (2.64 g, 8.09 mmol) and 2-chloropyrimidine (1.01 g, 8.80 mmol) in 200 proof ethanol (40 mL). The reaction mixture was heated to 120 °C in a sealed vessel for 6 h, then cooled to room temperature. The reaction mixture was filtered, then the filtrate was concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (C18 silica gel, 5-100% acetonitrile / water). The fractions were collected and concentrated under reduced pressure, then triturated with dilute hydrochloric acid. The solids were collected by vacuum filtration, rinsed with water, and dried under vacuum to provide 3,5-dichloro-2- hydroxy-N-(1-(pyrimidin-2-yl)piperidin-4-yl)benzamide (600 mg, 1.63 mmol, 20%) as a light orange solid:1H NMR (500 MHz, DMSO-d6J = 7.5 Hz, 1H), 8.37 (d, J = 4.5 Hz, 2H), 8.02 (d, J = 2.5 Hz, 2H), 7.77 (d, J = 2.5 Hz, 1H), 6.63 (t, J = 5.0 Hz, 1H), 4.66 (d, J = 13.5 Hz 1H), 4.20-4.13 (m, 1H), 3.02 (td, J = 12.8, 2.1 Hz, 2H), 1.88 (d, J = 10.0 Hz, 2H), 1.57 (qd, J = 12.0, 3.9 Hz, 2H); ESI MS m / z 367 [C16H16Cl2N4O2+ H]+; UPLC (BEH C18, Method A) 96.1% (AUC), tR= 4.17 min. Example 8Scheme 5: ANA-104Preparation of N-Cyclobutyl-1H-imidazole-1-carboxamide

[0140] Cyclobutylamine (0.34 mL, 4.0 mmol) was added dropwise to a suspension of 1,1'-carbonyldiimidazole (664 mg, 4.01 mmol) in acetonitrile (2.4 mL). N,N- dimethylformamide (0.8 mL) was added to the mixture, which was allowed to stir at room temperature overnight. The mixture was concentrated under reduced pressure, and the crude residue was purified by column chromatography (silica gel, 0-20% methanol / dichloromethane) to provide N-cyclobutyl-1H-imidazole-1-carboxamide (631 mg, 3.82 mmol, 93%) as a yellow oil: ESI MS m / z 166 [C8H11N3O + H]+. Preparation of tert-Butyl 4-(3,5-Dichloro-2-hydroxybenzamido)azepane-1- carboxylate

[0141] Diisopropylethylamine (0.35 mL, 2.0 mmol) was added dropwise a solution of 3,5-dichloro-2-hydroxybenzoic acid (207 mg, 1.00 mmol) in N,N-dimethylformamide (2.5 mL). Then, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU) (389 mg, 1.02 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then tert-butyl 4-aminoazepane-1- carboxylate (0.21 mL, 1.0 mmol) was added, and the mixture was allowed to stir for 1 h. The mixture was quenched by adding the reaction mixture dropwise to water (50 mL) with 20 vigorous stirring. The precipitates were collected by vacuum filtration and rinsed withwater (5 mL), then dried under vacuum to provide tert-butyl 4-(3,5-dichloro-2- hydroxybenzamido)azepane-1-carboxylate (255 mg, 0.632 mmol, 63%) as an off-white solid: ESI MS m / z 403 [C11H22N2O2+ H]+. Preparation of N-(Azepan-4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride

[0142] 4 M Hydrogen chloride in 1,4-dioxane (1.25 mL, 5.00 mmol) was added dropwise to tert-butyl 4-(3,5-dichloro-2-hydroxybenzamido)azepane-1-carboxylate (255 mg, 0.632 mmol). The mixture was allowed to stir overnight, then the precipitates were collected by vacuum filtration and rinsed with diethyl ether (5 mL) to provide N-(azepan- 4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (201 mg, 0.592 mmol, 93%) as an off-white solid: ESI MS m / z 303 [C13H16Cl2N2O2+ H]+. Example 9 Preparation of N-Cyclobutyl-4-(3,5-dichloro-2-hydroxybenzamido)azepane-1- carboxamide [ANA-104] O Cl Cl

[0143] Diisopropylethylamine (0.31 mL, 1.8 mmol) was added to a suspension of N-(azepan-4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (201 mg, 0.592 mmol) and N-cyclobutyl-1H-imidazole-1-carboxamide (197 mg, 1.19 mmol) in dichloromethane (3 mL). The reaction mixture was heated to 100 °C in a sealed microwave vessel for 1 h under microwave irradiation, then cooled to room temperature and concentrated under vacuum. The crude residue was purified by reverse phase chromatography (C18 silica gel, 5-100% acetonitrile / water). The fractions were collected and concentrated under reduced pressure, then triturated with dilute hydrochloric acid. The solids were collected by vacuum filtration, rinsed with water, and dried under vacuum to provide N-cyclobutyl-4- (3,5-dichloro-2-hydroxybenzamido)azepane-1-carboxamide (102 mg, 0.255 mmol, 43%) as a white solid: 1H NMR (500 MHz, DMSO-d61H), 7.75 (s, 1H), 6.36 (d, J = 7.6 Hz, 1H), 4.14 (sx, J = 8.0 Hz 1H), 3.96–3.85 (m, 1H),3.58 (d, J = 15.5, 1H), 3.39–3.30 (m, 2H), 3.14–3.08 (m, 1H), 2.13–2.07 (m, 2H), 1.98– 1.87 (m, 3H) 1.81 (d, J = 8.4 Hz, 2H), 1.75–1.64 (m, 1H) 1.64–1.49 (m, 4H); ESI MS m / z 400 [C18H23Cl2N3O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.67 min. Example 10 Scheme 6: ANA-105Preparation of 2,5-Dioxopyrrolidin-1-yl Oxetan-3-yl Carbonate

[0144] Cyclobutanol (0.16 mL, 2.0 mmol) was added dropwise to a suspension of N,N-disuccinimidyl carbonate (1.04 g, 4.08 mmol) in acetonitrile (2.2 mL). Triethylamine (0.85 mL, 6.1 mmol) was added to the mixture, which was allowed to stir at room temperature overnight. The mixture was quenched with saturated sodium bicarbonate (20 mL), then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, then filtered and concentrated under reduced pressure to provide cyclobutyl (2,5-dioxopyrrolidin-1-yl) carbonate as a clear oil that was used without further purification. Preparation of tert-Butyl 4-(3,5-Dichloro-2-hydroxybenzamido)azepane-1- carboxylate

[0145] Diisopropylethylamine (3.5 mL, 20 mmol) was added dropwise a solution of 3,5-dichloro-2-hydroxybenzoic acid (2.07 g, 10.0 mmol) in N,N-dimethylformamide (20mL). Then, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU) (4.00 g, 10.5 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then tert-butyl 4-aminoazepane-1- carboxylate (2.00 g, 10.0 mmol) was added, and the mixture was allowed to stir for 1 h. The mixture was quenched by adding the reaction mixture dropwise to water (400 mL) with vigorous stirring. The precipitates were collected by vacuum filtration and rinsed with water (40 mL), then dried under vacuum to provide tert-butyl 4-(3,5-dichloro-2- hydroxybenzamido)azepane-1-carboxylate (3.12 g, 8.03 mmol, 80%) as an off-white solid: ESI MS m / z 403 [C11H22N2O2+ H]+. Preparation of N-(Azepan-4-yl)-3,5-dichloro-2-hydroxybenzamide Hydrochloride 4 M Hydrogen chloride in 1,4-dioxane (8.0 mL, 32 mmol) was added dropwise to tert-butyl 4-(3,5-dichloro-2-hydroxybenzamido)azepane-1-carboxylate (3.07 g, 7.88 mmol). The mixture was allowed to stir overnight, then the precipitates were collected by vacuum filtration and rinsed with diethyl ether (20 mL) to provide N-(azepan-4-yl)-3,5- dichloro-2-hydroxybenzamide hydrochloride (2.52 g, 7.75 mmol, 98%) as an off-white solid: ESI MS m / z 303 [C13H16Cl2N2O2+ H]+. Example 11 Preparation of Oxetan-3-yl 4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxylate [ANA-105] OH Cl Cl

[0146] Triethylamine (0.14 mL, 1.0 mmol) was added to a suspension of N- (azepan-4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (81 mg, 0.25 mmol) and 2,5-dioxopyrrolidin-1-yl oxetan-3-yl carbonate (78 mg, 0.36 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred overnight, then quenched with saturated ammonium chloride (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organiclayers were dried over sodium sulfate, then filtered and concentrated under reduced pressure. The crude residue was triturated with dilute hydrochloric acid, and the solids were collected by vacuum filtration, rinsed with water, and dried under vacuum to provide oxetan-3-yl 4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1-carboxylate (66 mg, 0.17 mmol, 68%) as a white solid: 1H NMR (500 MHz, DMSO-d61H), 8.03 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 5.32–5.26 (m, 1H), 4.77 (t, J = 7.0 Hz, 2H), 4.49 (ddd, J = 7.5, 5.0, 1.0 Hz, 2H), 4.12–3.92 (m, 3H), 3.10–2.85 (m, 2H), 1.86 (d, J = 11.5 Hz, 2H), 1.58–1.44 (m, 2H); ESI MS m / z 389 [C16H18Cl2N2O5+ H]+; UPLC (BEH C18, Method A) 95.1% (AUC), tR= 4.51 min. Example 12 Scheme 7: ANA-106Preparation of tert-Butyl 4-(3,5-Dichloro-2-hydroxybenzamido)azepane-1- carboxylate

[0147] Diisopropylethylamine (3.5 mL, 20 mmol) was added dropwise to a solution of 3,5-dichloro-2-hydroxybenzoic acid (2.07 g, 10.0 mmol) in N,N-dimethylformamide (20 mL). Then, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU) (4.00 g, 10.5 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then tert-butyl 4-aminoazepane-1- carboxylate (2.00 g, 10.0 mmol) was added, and the mixture was allowed to stir for 1 h. The mixture was quenched by adding the reaction mixture dropwise to water (400 mL) with vigorous stirring. The precipitates were collected by vacuum filtration and rinsed withwater (40 mL), then dried under vacuum to provide tert-butyl 4-(3,5-dichloro-2- hydroxybenzamido)azepane-1-carboxylate (3.12 g, 8.03 mmol, 80%) as an off-white solid: ESI MS m / z 403 [C11H22N2O2+ H]+. Preparation of N-(Azepan-4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride

[0148] 4 M Hydrogen chloride in 1,4-dioxane (8.0 mL, 32 mmol) was added dropwise to tert-butyl 4-(3,5-dichloro-2-hydroxybenzamido)azepane-1-carboxylate (3.07 g, 7.88 mmol). The mixture was allowed to stir overnight, then the precipitates were collected by vacuum filtration and rinsed with diethyl ether (20 mL) to provide N-(azepan- 4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (2.52 g, 7.75 mmol, 98%) as an off- white solid: ESI MS m / z 303 [C13H16Cl2N2O2+ H]+. Example 13Preparation of tert-Butyl 4-(3,5-Dichloro-2-hydroxybenzamido)azepane-1- carboxylate

[0149] Diisopropylethylamine (3.5 mL, 20 mmol) was added dropwise to a solution of 3,5-dichloro-2-hydroxybenzoic acid (2.07 g, 10.0 mmol) in N,N-dimethylformamide (20 mL). Then, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU) (4.00 g, 10.5 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then tert-butyl 4-aminoazepane-1- carboxylate (2.00 g, 10.0 mmol) was added, and the mixture was allowed to stir for 1 h. The mixture was quenched by adding the reaction mixture dropwise to water (400 mL)with vigorous stirring. The precipitates were collected by vacuum filtration and rinsed with water (40 mL), then dried under vacuum to provide tert-butyl 4-(3,5-dichloro-2- hydroxybenzamido)azepane-1-carboxylate (3.12 g, 8.03 mmol, 80%) as an off-white solid: ESI MS m / z 403 [C11H22N2O2+ H]+. Preparation of N-(Azepan-4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride

[0150] 4 M Hydrogen chloride in 1,4-dioxane (8.0 mL, 32 mmol) was added dropwise to tert-butyl 4-(3,5-dichloro-2-hydroxybenzamido)azepane-1-carboxylate (3.07 g, 7.88 mmol). The mixture was allowed to stir overnight, then the precipitates were collected by vacuum filtration and rinsed with diethyl ether (20 mL) to provide N-(azepan- 4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (2.52 g, 7.75 mmol, 98%) as an off- white solid: ESI MS m / z 303 [C13H16Cl2N2O2 + H]+. Example 14 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-isobutyrylpiperidin-4-yl)benzamide [ANA 106]

[0151] Diisopropylethylamine (2.4 mL, 14 mmol) was added dropwise to a solution of isobutyric acid (0.42 mL, 4.6 mmol) in N,N-dimethylformamide (11.5 mL). Then, 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (1.75 g, 4.60 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then N-(azepan-4-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride (1.49 g, 5.17 mmol) was added, and the mixture was allowed to stir for 1 h. The mixture was quenched by adding the reaction mixture dropwise to water (250 mL) with vigorous stirring. The precipitates were collected by vacuum filtration and rinsed with water (20 mL), then dried under vacuum. The crude solids were triturated with methanol (5 mL), then filtered and dissolved in 2 M sodium hydroxide (5 mL). The solution was filtered, then acidified with 2 M hydrochloric acid. The precipitateswere collected by vacuum filtration, rinsed with water, then dried under vacuum to provide 3,5-dichloro-2-hydroxy-N-(1-isobutyrylpiperidin-4-yl)benzamide (1.28 g, 3.56 mmol, 77%) as a white solid:1H NMR (500 MHz, DMSO-d6(d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 4.40 (d, J = 12.1 Hz, 1H), 4.15–4.04 (m, 1H), 3.98 (d, J = 14.3 Hz, 1H), 3.14 (t, J = 12.6 Hz, 1H), 2.90 (quint, J = 6.8 Hz, 1H), 2.66 (t, J = 12.6 Hz, 1H), 1.89 (d, J = 9.7 Hz, 1H), 1.83 (d, J = 11.2 Hz, 1H), 1.52–1.30 (m, 2H), 1.00 (dd, J = 9.7, 6.8 Hz, 6H); ESI MS m / z 359 [C16H20Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 98.8% (AUC), tR= 4.67 min. Example 15 Scheme 8: ANA-107Preparation of tert-Butyl 4-(3,5-Dichloro-2-hydroxybenzamido)azepane-1- carboxylate

[0152] Diisopropylethylamine (0.35 mL, 2.0 mmol) was added dropwise a solution of 3,5-dichloro-2-hydroxybenzoic acid (207 mg, 1.00 mmol) in N,N-dimethylformamide (2.5 mL) . Then, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU) (381 mg, 1.00 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then tert-butyl 4-aminoazepane-1- carboxylate (0.21 mL, 1.0 mmol) was added, and the mixture was allowed to stir for 1 h.The mixture was quenched by adding the reaction mixture dropwise to water (50 mL) with vigorous stirring. The precipitates were collected by vacuum filtration and rinsed with water (5 mL), then dried under vacuum to provide tert-butyl 4-(3,5-dichloro-2- hydroxybenzamido)azepane-1-carboxylate (217 mg, 0.538 mmol, 54%) as an off-white solid: ESI MS m / z 403 [C11H22N2O2+ H]+. Preparation of N-(Azepan-4-yl)-3,5-dichloro-2-hydroxybenzamide Hydrochloride

[0153] 4 M Hydrogen chloride in 1,4-dioxane (1.0 mL, 4.00 mmol) was added dropwise to tert-butyl 4-(3,5-dichloro-2-hydroxybenzamido)azepane-1-carboxylate (217 mg, 0.538 mmol). The mixture was allowed to stir overnight, then the precipitates were collected by vacuum filtration and rinsed with diethyl ether (5 mL) to provide N-(azepan- 4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (179 mg, 0.527 mmol, 98%) as an off-white solid: ESI MS m / z 303 [C13H16Cl2N2O2+ H]+. Preparation of 2-((1-Acetylazepan-4-yl)carbamoyl)-4,6-dichlorophenyl acetate

[0154] Triethylamine (1.05 mL, 0.75 mmol) was added to a solution of N-(azepan- 4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (83 mg, 0.25 mmol). Then acetyl chloride (35 μL, 0.49 mmol) was added to the reaction mixture, and the mixture was allowed to stir overnight at room temperature. The reaction mixture was quenched with a saturated ammonium chloride solution (20 mL), then extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, then concentrated under reduced pressure to provide 2-((1-acetylazepan-4-yl)carbamoyl)-4,6- dichlorophenyl acetate (105 mg) as an orange oil that was used without further purification: ESI MS m / z 387 [C17H20Cl2N2O4+ H]+. Example 16 Preparation of N-(1-Acetylazepan-4-yl)-3,5-dichloro-2-hydroxybenzamide [ANA- 107]

[0155] A 2M aqueous solution of lithium hydroxide (2.0 mL, 4.0 mmol) was added to 2-((1-acetylazepan-4-yl)carbamoyl)-4,6-dichlorophenyl acetate (105 mg), and the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was then concentrated under reduced pressure, and the crude residue was purified by reverse phase chromatography (C18 silica gel, 0-100% acetonitrile / water) to provide N-(1- acetylazepan-4-yl)-3,5-dichloro-2-hydroxybenzamide (31 mg, 0.090 mmol, 36%) as an off-white solid:1H NMR (500 MHz, DMSO-d6J = 10.3, 8.0 Hz, 1H), 7.48 (dd, J = 3.0, 1.8 Hz, 1H), 7.06 (dd, J = 3.0, 1.2 Hz, 1H), 4.00–3.88 (m, 1H), 3.55–3.46 (m, 1H), 3.46–3.35 (m, 3H), 2.00 (d, J = 10.4 Hz, 3H), 1.98–1.91 (m, 1H), 1.89–1.79 (m, 1H), 1.79–1.68 (m, 2H), 1.68–1.59 (m, 1H), 1.59–1.48 (m, 1H), amide NH not observed; ESI MS m / z 345 [C15H18Cl2N2O3 + H]+; UPLC (BEH C18, Method A) 97.6% (AUC), tR = 4.04 min. Example 17Preparation of tert-Butyl 4-(3,5-Dichloro-2-hydroxybenzamido)azepane-1- carboxylate

[0156] Diisopropylethylamine (0.35 mL, 2.0 mmol) was added dropwise a solution of 3,5-dichloro-2-hydroxybenzoic acid (207 mg, 1.00 mmol) in N,N-dimethylformamide(2.5 mL). Then, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU) (381 mg, 1.00 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then tert-butyl 4-aminoazepane-1- carboxylate (0.21 mL, 1.0 mmol) was added, and the mixture was allowed to stir for 1 h. The mixture was quenched by adding the reaction mixture dropwise to water (50 mL) with vigorous stirring. The precipitates were collected by vacuum filtration and rinsed with water (5 mL), then dried under vacuum to provide tert-butyl 4-(3,5-dichloro-2- hydroxybenzamido)azepane-1-carboxylate (217 mg, 0.538 mmol, 54%) as an off-white solid: ESI MS m / z 403 [C11H22N2O2+ H]+. Preparation of N-(Azepan-4-yl)-3,5-dichloro-2-hydroxybenzamide Hydrochloride

[0157] 4 M Hydrogen chloride in 1,4-dioxane (1.0 mL, 4.00 mmol) was added dropwise to tert-butyl 4-(3,5-dichloro-2-hydroxybenzamido)azepane-1-carboxylate (217 mg, 0.538 mmol). The mixture was allowed to stir overnight, then the precipitates were collected by vacuum filtration and rinsed with diethyl ether (5 mL) to provide N-(azepan- 4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (179 mg, 0.527 mmol, 98%) as an off-white solid: ESI MS m / z 303 [C13H16Cl2N2O2+ H]+. Preparation of 2,4-Dichloro-6-((1-(cyclopropylsulfonyl)azepan-4- yl)carbamoyl)phenyl cyclopropanesulfonate

[0158] Triethylamine (1.05 mL, 0.75 mmol) was added to a solution of N-(azepan- 4-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (84 mg, 0.25 mmol). Then cyclopropanesulfonyl chloride (50 μL, 0.49 mmol) was added to the reaction mixture dropwise, and the mixture was allowed to stir overnight at room temperature. The reaction mixture was quenched with a saturated ammonium chloride solution (20 mL), then extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, then concentrated under reduced pressure to provide 2-((1- acetylazepan-4-yl)carbamoyl)-4,6-dichlorophenyl acetate (166 mg) as an orange oil that was used without further purification: ESI MS m / z 511 [C19H24Cl2N2O6S2+ H]+. Example 18Preparation of 3,5-Dichloro-N-(1-(cyclopropylsulfonyl)azepan-4-yl)-2- hydroxybenzamide [ANA-108]

[0159] A 2M aqueous solution of sodium hydroxide (1.5 mL, 3.0 mmol) was added to a solution of 2,4-dichloro-6-((1-(cyclopropylsulfonyl)azepan-4-yl)carbamoyl)phenyl cyclopropanesulfonate (166 mg) in methanol (1.5 mL), and the reaction mixture was heated to 80 °C for 1h. The reaction mixture was cooled to room temperature and quenched with a saturated ammonium chloride solution (20 mL), then extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, then concentrated under reduced pressure. The crude residue was triturated in methanol (5 mL), filtered, rinsed with methanol (5 mL), then dried under vacuum to provide 3,5-dichloro-N- (1-(cyclopropylsulfonyl)azepan-4-yl)-2-hydroxybenzamide (38 mg, 0.093 mmol, 37%) as light yellow solid:1H NMR (500 MHz, DMSO-d6J = 1.9 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 4.19–4.00 (m, 1H), 3.53 (ddd, J = 14.5, 5.3, 3.7 Hz, 1H), 3.43–3.36 (m, 1H), 3.35–3.15 (m, 2H), 2.67–2.60 (m, 1H), 2.02–1.95 (m, 1H), 1.93–1.84 (m, 2H), 1.84–1.73 (m, 1H), 1.73–1.62 (m, 2H), 0.99–0.50 (m, 4H); ESI MS m / z 407 [C16H20Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 96.5% (AUC), tR= 4.87 min. Example 19 Scheme 10: ANA-109Preparation of Methyl trans-4-(3,5-Dichloro-2-hydroxybenzamido)cyclohexane-1- carboxylate

[0160] Diisopropylethylamine (0.52 mL, 3.0 mmol) was added dropwise to a solution of 3,5-dichloro-2-hydroxybenzoic acid (208 mg, 1.00 mmol) in N,N- dimethylformamide (2.5 mL). Then, 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (396 mg, 1.04 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then methyl trans-4-aminocyclohexane-1-carboxylate (200 mg, 1.03 mmol) was added, and the mixture was allowed to stir for 1 h. The reaction mixture was quenched by dropping into water (50 mL) with vigorous stirring. The precipitates were collected by vacuum filtration, rinsed with water (10 mL), then dried under vacuum to provide methyl trans-4-(3,5-dichloro-2- hydroxybenzamido)cyclohexane-1-carboxylate (297 mg, 0.858 mmol, 86%) as a white solid: ESI MS m / z 346 [C15H17Cl2NO4+ H]+. Preparation of trans-4-(3,5-Dichloro-2-hydroxybenzamido)cyclohexane-1-carboxylic acid

[0161] 2 M aqueous sodium hydroxide (1.75 mL, 3.50 mmol) was added dropwise to a solution of methyl trans-4-(3,5-dichloro-2-hydroxybenzamido)cyclohexane-1- carboxylate (297 mg, 0.858 mmol) in methanol (1.75 mL). The mixture was allowed to stir overnight, then the reaction mixture was concentrated under reduced pressure, and the crude residue was purified by reverse phase chromatography (C18 silica gel, water / acetonitrile 5-100%) to provide trans-4-(3,5-dichloro-2- hydroxybenzamido)cyclohexane-1-carboxylic acid (249 mg, 0.750 mmol, 82%) as a white solid: ESI MS m / z 332 [C14H15Cl2NO4 + H]+. Example 20 Preparation of 3,5-Dichloro-N-(trans-4-(cyclobutylcarbamoyl)cyclohexyl)-2- hydroxybenzamide [ANA-109]O Cl Cl

[0162] Diisopropylethylamine (0.13 mL, 0.75 mmol) was added dropwise to a solution of trans-4-(3,5-dichloro-2-hydroxybenzamido)cyclohexane-1-carboxylic acid (88 mg, 0.25 mmol) in N,N-dimethylformamide (1.25 mL) . Then, 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (100 mg, 0.26 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then cyclobutylamine (20 μL, 0.24 mmol) was added, and the mixture was allowed to stir for 1 h. The mixture was quenched by adding the reaction mixture dropwise to water (25 mL) with vigorous stirring, and then acidified by dropwise addition of 2M hydrochloric acid. The precipitates were collected by vacuum filtration and rinsed with water (5 mL), then dried under vacuum. The crude solids were triturated with acetonitrile (5 mL) , then collected by vacuum filtration, rinsed with acetonitrile (1 mL), then dried under vacuum to provide 3,5-dichloro-N-(trans-4- (cyclobutylcarbamoyl)cyclohexyl)-2-hydroxybenzamide (56 mg, 0.15 mmol, 59%) as a white solid:1H NMR (500 MHz, DMSO-d67.95 (d, J = 7.7 Hz, 1H), 7.75 (s, 1H), 4.16 (sx, J = 8.5 Hz, 1H), 3.82–3.73 (m, 1H), 2.13 (qt, J = 7.7, 2.9 Hz, 2H), 3.14 (tt, J = 11.5, 3.6 Hz, 1H), 1.92–1.80 (m, 4H), 1.76 (d, J = 12.3 Hz, 2H), 1.68–1.54 (m, 2H), 1.48–1.31 (m, 4H); ESI MS m / z 385 [C18H22Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 98.9% (AUC), tR= 4.79 min. Example 21 Scheme 11: ANA-110Preparation of 3,5-Dichloro-2-hydroxy-N-(pyrrolidin-3-ylmethyl)benzamide hydrochloride

[0163] 3,5-Dichloro-2-hydroxy-N-(pyrrolidin-3-ylmethyl)benzamide hydrochloride was prepared as an intermediate according to Synthetic Scheme 7: ESI MS m / z 289 [C12H14Cl2N2O2+ H]+. Preparation of Ethyl 2-(3-((3,5-dichloro-2-(2-ethoxy-2- oxoethoxy)benzamido)methyl)pyrrolidin-1-yl)acetate

[0164] Triethylamine (0.26 mL, 1.9 mmol) was added dropwise to a solution of 3,5-dichloro-2-hydroxy-N-(pyrrolidin-3-ylmethyl)benzamide hydrochloride (163 mg, 0.501 mmol) in N,N-dimethylformamide (2.5 mL). Ethyl bromoacetate (0.06 mL, 0.5 mmol) was added to the reaction mixture, which was allowed to stir overnight. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3 x 25 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide ethyl 2-(3-((3,5-dichloro-2-(2-ethoxy-2- oxoethoxy)benzamido)methyl)pyrrolidin-1-yl)acetate (502 mg) which was used without further purification: ESI MS m / z 461 [C20H26Cl2N2O6 + H]+. Preparation of 2-(3-((3,5-Dichloro-2-hydroxybenzamido)methyl)pyrrolidin-1- yl)acetic acid

[0165] A 2M sodium hydroxide solution (3.0 mL, 6.0 mmol) was added to ethyl 2- (3-((3,5-dichloro-2-(2-ethoxy-2-oxoethoxy)benzamido)methyl)pyrrolidin-1-yl)acetate(503 mg) and the mixture was allowed to stir overnight. The reaction mixture was quenched with hydrochloric acid (5 mL) and concentrated under reduced pressure. The crude solids were dissolved in methanol, filtered, then concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (C18 silica, acetonitrile / water, 5-100%) to provide 2-(3-((3,5-dichloro-2- hydroxybenzamido)methyl)pyrrolidin-1-yl)acetic acid (57 mg, 0.17 mmol, 34%): ESI MS m / z 333 [C14H16Cl2N2O4+ H]+. Example 22 Preparation of N-((1-(2-Amino-2-oxoethyl)pyrrolidin-3-yl)methyl)-3,5-dichloro-2- hydroxybenzamide [ANA-110]

[0166] Diisopropylethylamine (30 μL, 0.17 mmol) was added dropwise a solution of 2-(3-((3,5-dichloro-2-hydroxybenzamido)methyl)pyrrolidin-1-yl)acetic acid (29 mg, 0.084 mmol) in N,N-dimethylformamide (0.4 mL) . Then, 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (36 mg, 0.095 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then ammonium chloride (6.0 mg, 0.11 mmol) was added, and the mixture was allowed to stir for 1 h. The mixture was quenched with water (10 mL), then extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (C18 silica, acetonitrile / water, 5-100%), then lyophilized to provide N-((1-(2-amino-2-oxoethyl)pyrrolidin-3-yl)methyl)- 3,5-dichloro-2-hydroxybenzamide (9 mg, 0.03 mmol, 30%) as a white solid:1H NMR (500 MHz, DMSO-d6–3.68 (m, 2H), 3.43–3.32 (m, 3H), 3.22–3.04 (m, 3H), 3.00–2.85 (m, 1H), 2.61–2.55 (m, 1H), 2.10– 2.00 (m, 1H), 1.73–1.61 (m, 1H); ESI MS m / z 346 [C14H17Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 97.5% (AUC), tR= 3.59 min.Example 23 Scheme 12: ANA-111Preparation of Phenyl Isocyanate

[0167] A solution of aniline (0.09 mL, 1 mmol) in dichloromethane (2.0 mL) was added dropwise to a solution of triphosgene (297 mg, 1.00 mmol) in dichloromethane (2.0 mL). Then, a solution of triethylamine (0.30 mL, 2.2 mmol) in dichloromethane (1.0 mL) was added dropwise to the reaction mixture, and the mixture was allowed to stir for 5 min. The mixture was concentrated under reduced pressure to provide phenyl isocyanate (756 mg) as a yellow oil, which was used without further purification. Preparation of 3,5-Dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide Hydrochloride

[0168] 3,5-Dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride was prepared as an off-white solid according to Synthetic Scheme 7, as an intermediate: ESI MS m / z 289 [C12H14Cl2N2O2+ H]+. Example 24 Preparation of 4-(3,5-Dichloro-2-hydroxybenzamido)-N-phenylpiperidine-1- carboxamide [ANA-111] OH Cl Cl

[0169] Triethylamine (0.14 mL, 1.0 mmol) was added to a solution of phenyl isocyanate (755 mg) in dichloromethane (2.5 mL). Then 3,5-dichloro-2-hydroxy-N- (piperidin-4-yl)benzamide hydrochloride (162 mg, 0.498 mmol) was added to the reactionmixture, and the mixture was allowed to stir for 1 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by reverse phase chromatography (C18 silica gel, acetonitrile / water, 5-100%) to provide 4-(3,5-dichloro-2- hydroxybenzamido)-N-phenylpiperidine-1-carboxamide (54 mg, 0.13 mmol, 27%) as a white solid:1H NMR (500 MHz, DMSO-d68.04 (s, 1H), 7.77 (s, 1H), 7.46 (dd, J = 8.7, 1.1 Hz, 2H), 7.23 (t, J = 7.4 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1H), 4.15 (d, J = 14.2 Hz, 2H), 4.12–4.05 (m, 1H), 2.92 (t, J = 12.7 Hz, 2H), 1.85 (dd, J = 12.9, 2.9 Hz, 2H), 1.53 (qd, J = 12.2, 3.9 Hz, 2H); ESI MS m / z 408 [C19H19Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 98.4% (AUC), tR= 4.75 min. Example 25 Scheme 13: ANA-112 OPreparation of 3,5-Dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide Hydrochloride

[0170] 3,5-Dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride was prepared as an off-white solid according to Synthetic Scheme 7, as an intermediate: ESI MS m / z 289 [C12H14Cl2N2O2+ H]+. Example 26 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(4-methylpiperazine-1- carbonyl)piperidin-4-yl)benzamide [ANA-112]

[0171] Diisopropylethylamine (0.13 mL, 0.75 mmol) was added to a suspension of 3,5-dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride (83 mg, 0.25 mmol) in dichloromethane (2.5 mL). Then 4-methylpiperazine-1-carbonyl chloride (51 mg, 0.31 mmol) was added to the reaction mixture, and the mixture was allowed to stir for 48 h. Thereaction mixture was concentrated under reduced pressure, and the crude residue was triturated in acetonitrile / water (1.0 mL, 1:1). The solids were removed by vacuum filtration, and the filtrate was purified by reverse phase chromatography (C18 silica gel, acetonitrile / water, 5-100%) to provide 3,5-dichloro-2-hydroxy-N-(1-(4-methylpiperazine- 1-carbonyl)piperidin-4-yl)benzamide (28 mg, 0.067 mmol, 26%) as an off-white solid:1H NMR (500 MHz, CD3 J = 2.6 Hz, 1H), 7.44 (d, J = 2.6 Hz, 1H), 4.09 (tt, J = 10.6, 4.0 Hz, 1H), 3.72 (dt, J = 13.5, 3.3 Hz, 2H), 3.40–3.32 (m, 3H), 3.04 (ddd, J = 13.6, 11.2, 2.4 Hz, 2H), 2.71–2.62 (m, 3H), 2.46 (s, 2H), 2.02 (s, 3H), 1.96 (dd, J = 13.0, 2.7 Hz, 2H), 1.59 (qd, J = 11.3, 4.0 Hz, 2H); ESI MS m / z 415 [C18H24Cl2N4O3+ H]+; UPLC (BEH C18, Method A) 95.2% (AUC), tR= 3.55 min. Example 27 Scheme 14: ANA-113Preparation of N-(1-Acetylpiperidin-4-yl)-2-hydroxy-5-methylbenzenesulfonamide [ANA-113]

[0172] Bis(trimethylsilyl)acetamide (30 μL, 0.12 mmol) was added to a solution of 2-hydroxy-5-methylbenzenesulfonyl chloride (25 mg, 0.12 mmol) in chloroform (0.25 mL) under a nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for 1h, then triethylamine (30 μL, 0.22 mmol) and 1-(4-aminopiperidin-1-yl)ethan-1-one (17 mg, 0.12 mmol) were added to the reaction mixture, and the mixture was allowed to stir at room temperature overnight. Methanol (0.5 mL) was added to the reaction mixture, and the mixture was heated to 65 °C in a sealed vessel under nitrogen atmosphere, and allowed to stir for 1 h. The reaction mixture was cooled to room temperature, thenconcentrated under reduced pressure. The crude residue was dissolved in dichloromethane (5 mL), quenched with 2M hydrochloric acid (20 mL), and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-20% methanol / dichloromethane) to provide N-(1- acetylpiperidin-4-yl)-2-hydroxy-5-methylbenzenesulfonamide (7 mg, 0.02 mmol, 20%) as a white solid:1H NMR (500 MHz, DMSO-d6J = 1.7 Hz, 1H), 7.23 (dd, J = 8.5, 2.0 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.04 (d, J = 13.1 Hz, 1H), 3.64 (d, J = 13 Hz, 1H), 3.26–3.18 (m, 1H), 3.00 (ddd, J = 14.1, 11.1, 3.0 Hz, 1H), 2.69–2.60 (m, 1H), 2.24 (s, 3H), 1.93 (s, 3H), 1.64–1.51 (m, 2H), 1.34 (qd, J = 11.5, 4.0 Hz, 1H), 1.24 (qd, J = 11.5, 4.0 Hz, 1H); ESI MS m / z 313 [C14H20N2O4S + H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 2.83 min. Example 28 Scheme 15: ANA-114Preparation of 3,5-Dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride

[0173] 3,5-dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide was prepared as an intermediate according to Synthetic Scheme 7: ESI MS m / z 289 [C12H14Cl2N2O2+ H]+. Example 29 Preparation of 3,5-Dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide [ANA-114]

[0174] Saturated aqueous sodium bicarbonate (4.0 mL) was added to a suspension of 3,5-dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride (2.17 g, 6.66 mmol) in dichloromethane (4.0 mL), and the mixture was allowed to stir overnight. The solids were collected by vacuum filtration, rinsed with dichloromethane (1 mL), then driedunder vacuum to provide 3,5-dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide (818 mg, 2.83 mmol, 42%) as an off-white solid:1H NMR (500 MHz, DMSO-d68.43 (br s, 2H), 7.53 (s, 1H), 7.14 (s, 1H), 4.05–3.97 (m, 1H), 3.29–3.21 (m, 2H), 3.01 (t, J = 11.8 Hz, 2H), 2.01 (d, J = 13.4 Hz, 2H), 1.59 (q, J = 10.1 Hz, 2H); ESI MS m / z 289 [C12H14Cl2N2O2+ H]+; UPLC (BEH C18, Method A) 95.3% (AUC), tR= 3.19 min. Example 30 Scheme 16: ANA-115Preparation of 3-Chloro-2-hydroxy-5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5- yl)benzoic Acid

[0175] A degassed aqueous solution of 2M potassium carbonate (1.45 mL, 2.90 mmol) was added to a suspension of 5-bromo-3-chloro-2-hydroxybenzoic acid (482 mg, 1.92 mmol), 2-hydroxybenzimidazole-5-boronic acid, pinacol ester (502 mg, 1.93 mmol), and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) in degassed N,N- dimethylformamide (6.5 mL) under a nitrogen atmosphere. The reaction mixture was heated to 80 °C in a sealed vessel, and allowed to stir overnight. The mixture was cooled to room temperature, then concentrated under reduced pressure. The crude residue was dissolved in 2M sodium hydroxide (50 mL), then washed with ethyl acetate (50 mL). The aqueous layer was acidified with 2M hydrochloric acid, and the precipitates were collectedvia vacuum filtration, rinsed with water (20 mL), and dried under vacuum to provide 3- chloro-2-hydroxy-5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzoic acid (224 mg, 0.735 mmol, 38%) as a brown solid: ESI MS m / z 305 [C14H9ClN2O4+ H]+. Example 31 Preparation of N-(1-Acetylpiperidin-4-yl)-3-chloro-2-hydroxy-5-(2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)benzamide [ANA-115]

[0176] Diisopropylethylamine (0.26 mL, 1.5 mmol) was added dropwise to a solution of 3-chloro-2-hydroxy-5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzoic acid (214 mg, 0.702 mmol) in N,N-dimethylformamide (4.0 mL). Then, 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (277 mg, 0.728 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then 1-(4-aminopiperidin-1-yl)ethan-1-one (106 mg, 0.745 mmol) was added, and the mixture was allowed to stir for 1 h. The mixture was quenched by adding the reaction mixture dropwise to water (80 mL) with vigorous stirring. The mixture was acidified with 2M hydrochloric acid, and the precipitates were collected by vacuum filtration, rinsed with water (20 mL), then dried under vacuum. The crude solids were triturated with acetonitrile / water (1 mL, 1:1) and filtered. The filtrate was purified by reverse phase chromatography (C18 silica gel, acetonitrile / water, 5-100%) to provide N-(1-acetylpiperidin-4-yl)-3-chloro-2-hydroxy-5-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)benzamide (5 mg, 0.01 mmol, 2%) as a light brown solid:1H NMR (500 MHz, DMSO-d6–10.58 (m, 3H), 8.06 (s, 1H), 7.76 (br s, 1H), 7.26–7.18 (m, 1H), 7.18–7.10 (m, 1H), 7.00–6.93 (m, 2H), 4.44–4.27 (m, 1H), 4.15–4.05 (m, 1H), 3.89– 3.79 (m, 1H), 3.22–3.11 (m, 1H), 2.75–2.65 (m, 1H), 2.02 (s, 3H), 1.90 (d, J = 10.3 Hz,1H), 1.84 (d, J = 10.3 Hz, 1H), 1.57–1.46 (m, 1H), 1.46–1.35 (m, 1H); ESI MS m / z 429 [C21H21ClN4O4+ H]+; UPLC (BEH C18, Method A) 95.2% (AUC), tR= 3.33 min. Example 32 Scheme 17: ANA-116Preparation of 3,5-Dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide Hydrochloride

[0177] 3,5-Dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride was prepared as an off-white solid according to Synthetic Scheme 7, as an intermediate: ESI MS m / z 289 [C12H14Cl2N2O2+ H]+. Example 33 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-sulfamoylpiperidin-4-yl)benzamide [ANA-116]

[0178] Diisopropylethylamine (0.09 mL, 0.5 mmol) was added to a suspension of 3,5-dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride (82 mg, 0.25 mmol) in 1,4-dioxane (2.5 mL). Then sulfamide (99 mg, 1.03 mmol) was added to the reaction mixture, and the mixture was heated to 100 °C and allowed to stir for 24 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the crude residue was purified by reverse phase chromatography (C18 silica gel, acetonitrile / water, 5-100%) to provide 3,5-dichloro-2-hydroxy-N-(1- sulfamoylpiperidin-4-yl)benzamide (5 mg, 0.02 mmol, 6%) as a white solid:1H NMR (500 MHz, DMSO-d63.92–3.83 (m, 1H), 3.50 (d, J = 11.4 Hz, 2H), 2.63 (t, J = 11.1 Hz, 2H), 1.92 (d, J = 10.0Hz, 2H), 1.63 (q, J = 12.0 Hz, 2H); ESI MS m / z 368 [C12H15Cl2N3O4S + H]+; UPLC (BEH C18, Method A) 98.8% (AUC), tR= 4.38 min. Example 34Preparation of tert-Butyl (1-(Chlorosulfonyl)piperidin-4-yl)carbamate

[0179] Triethylamine (0.17 mL, 1.2 mmol) was added to a solution of tert-butyl piperidin-4-ylcarbamate (205 mg, 1.02 mmol) in dichloromethane (5.0 mL). The mixture was added dropwise to a solution of sulfuryl chloride (1.1 mL, 1M in dichloromethane, 1.1 mmol) in dichloromethane (5 mL) at -78 °C under a nitrogen atmosphere. The reaction mixture was allowed to slowly warm to room temperature and allowed to stir overnight. The reaction mixture was quenched with 1M hydrochloric acid (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl (1- (chlorosulfonyl)piperidin-4-yl)carbamate (282 mg, 0.944 mmol, 92%): ESI MS m / z 299 [C10H19ClN2O4S + H]+. Preparation of tert-Butyl (1-(N-Cyclobutylsulfamoyl)piperidin-4-yl)carbamate

[0180] Triethylamine (0.16 mL, 1.15 mmol) was added to a solution of tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate (282 mg, 0.944 mmol) in dichloromethane (6.5 mL). Cyclobutylamine (0.12 mL, 1.4 mmol) was added to the reaction mixture, and the mixture was allowed to stir at room temperature overnight. The reaction mixture wasquenched with 1M hydrochloric acid (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl (1-(chlorosulfonyl)piperidin-4- yl)carbamate (296 mg, 0.888 mmol, 94%): ESI MS m / z 334 [C14H27N3O4S + H]+. Preparation of 4-Amino-N-cyclobutylpiperidine-1-sulfonamide Hydrochloride

[0181] 4M hydrochloric acid in 1,4-dioxane (0.90 mL, 3.6 mmol) was added to tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate (296 mg, 0.888 mmol). The mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with diethyl ether (5 mL), and the precipitates were collected by vacuum filtration, rinsed with diethyl ether (5 mL), and dried under vacuum to provide 4-amino-N- cyclobutylpiperidine-1-sulfonamide hydrochloride (239 mg, 0.886 mmol, 99%): ESI MS m / z 234 [C9H19N3O2S + H]+. Example 35 Preparation of 3,5-Dichloro-N-(1-(N-cyclobutylsulfamoyl)piperidin-4-yl)-2- hydroxybenzamide [ANA-117]

[0182] Diisopropylethylamine (0.13 mL, 0.75 mmol) was added to a solution of 3,5-dichloro-2-hydroxybenzoic acid (52 mg, 0.25 mmol) in N,N-dimethylformamide (0.6 mL). Then, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU) (100 mg, 0.26 mmol) was added to the reaction mixture. The mixture was allowed to stir for 5 min, then 4-amino-N-cyclobutylpiperidine- 1-sulfonamide hydrochloride (68 mg, 0.25 mmol) was added, and the mixture was allowed to stir for 1 h. The mixture was quenched by adding the reaction mixture dropwise to water (20 mL) with vigorous stirring, then acidified with 2M hydrochloric acid (1.0 mL). The precipitates were collected by vacuum filtration and rinsed with water (20 mL), then dried under vacuum. The crude solids were triturated with acetonitrile (5 mL), collected byvacuum filtration, rinsed with acetonitrile (1.0 mL), and dried under vacuum to provide 3,5-dichloro-N-(1-(N-cyclobutylsulfamoyl)piperidin-4-yl)-2-hydroxybenzamide (19 mg, 0.045 mmol, 18%) as a white solid:1H NMR (500 MHz, DMSO-d6(d, J = 7.2 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 3.97–3.89 (m, 1H), 3.65 (sx, J = 8.5 Hz, 1H), 3.53 (d, J = 12.7 Hz, 2H), 2.70 (td, J = 12.5, 2.2 Hz, 2H), 2.17 (qt, J = 7.6, 2.4 Hz, 2H), 1.98–1.85 (m, 4H), 1.65–1.48 (m, 4H); ESI MS m / z 422 [C16H21Cl2N3O4S + H]+; UPLC (BEH C18, Method A) 98.2% (AUC), tR= 5.02 min. Example 36 Scheme 19: ANA-118Preparation of Ethyl trans-2-(((Methylsulfonyl)oxy)methyl)cyclopropane-1- carboxylate

[0183] To a mixture of ethyl trans-2-(hydroxymethyl)cyclopropane-1-carboxylate (700 mg, 4.86 mmol), triethylamine (1.48 g, 14.6 mmol) and dichloromethane (7 mL) was added mesyl chloride (891 mg, 7.78 mmol) slowly at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction mixture was purified by column chromatography (silica gel, 0-100% ethyl acetate / hexanes) to provide ethyl trans-2- (((methylsulfonyl)oxy)methyl)cyclopropane-1-carboxylate as thick oil (880 mg, 81%).1HNMR (500 MHz, CDCl3) 4.21–4.05 (m, 4H), 3.04 (s, 3H), 1.89–1.84 (m, 1H), 1.72–1.68 (m, 1H), 1.34–1.31 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H), 0.99–0.95 (m, 1H); ESI MS m / z 223 [C8H14O5S + H]+. Preparation of Ethyl trans-2-(Azidomethyl)cyclopropane-1-carboxylate

[0184] A mixture of ethyl trans-2-(((methylsulfonyl)oxy)methyl)cyclopropane-1- carboxylate (880 g, 3.96 mmol), sodium azide (386 mg, 5.94 mmol) and N,N- dimethylformamide (12 mL) was heated at 60 °C for 3 h. The reaction was diluted with ethyl acetate, washed with brine (3 × 10 mL), filtered and concentrated under reduced pressure to 15 mL as a solution of ethyl trans-2-(azidomethyl)cyclopropane-1-carboxylate that was used without further purification. Preparation of Ethyl trans-2-(Aminomethyl)cyclopropane-1-carboxylate Hydrochloride

[0185] To the solution of ethyl trans-2-(azidomethyl)cyclopropane-1-carboxylate obtained above was added palladium on carbon (10% , 60 mg) under nitrogen. The mixture was hydrogenated with a hydrogen balloon for 16 h, then diluted with ethyl acetate. The mixture was filtered and the filtrate concentrated under reduced pressure to small volume (20 mL). Hydrochloric acid (4 M in dioxane, 1.5 mL) was added. The solid was filtered, washed with ethyl acetate and dried to provide ethyl trans-2-(aminomethyl)cyclopropane- 1-carboxylate hydrochloride (480 mg, 68% over two steps).1H NMR (500 MHz, DMSO- d6) 8.08 (br s, 3H), 4.11–4.01 (m, 2H), 2.83–2.72 (m, 1H), 1.77–1.74 (m, 1H), 1.62–1.55 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H), 1.05–0.98 (m, 2H); ESI MS m / z 144 [C7H13NO2+ H]+. Preparation of 2-Acetoxy-3,5-dichlorobenzoic Acid

[0186] A mixture of 3,5-dichloro-2-hydroxybenzoic acid (500 mg, 2.42 mmol), acetic anhydride (741 mg, 7.26 mmol) and sodium acetate (40 mg, 0.48 mmol) was heated at 50 °C for 2 h. After cooling to room temperature, water was added. The solid was filtered and washed with water. The crude product was purified by reverse phase column chromatography (C18 silica gel, 0-100% acetonitrile / water) to provide 2-acetoxy-3,5- dichlorobenzoic acid as a white solid (500 mg, 83%).1H NMR (500 MHz, DMSO-d6)13.79 (br s, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.87 (d, J = 2.6 Hz, 1H), 2.32 (s, 3H); ESI MS m / z 247 [C9H6Cl2O4– H]-. Preparation of Ethyl trans-2-((3,5-Dichloro-2- hydroxybenzamido)methyl)cyclopropane-1-carboxylate

[0187] To a solution of 2-acetoxy-3,5-dichlorobenzoic acid (258 mg, 1.04 mmol) in dichloromethane (8 mL) was added oxalyl chloride (158 mg, 1.25 mmol), followed by one drop of N,N-dimethylformamide. After 30 min., the reaction was cooled to 0 °C. Ethyl trans-2-(aminomethyl)cyclopropane-1-carboxylate hydrochloride (206 mg, 1.14 mmol) was added, followed by triethylamine (316 mg, 3.12 mmol). The reaction was warmed to rt. After 30 min., dichloromethane was added and the mixture was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate / hexanes) to provide ethyl trans-2-((3,5-dichloro-2-hydroxybenzamido)methyl)cyclopropane-1-carboxylate as a white solid (358 mg, 92%).1H NMR (500 MHz, DMSO-d6) 8.68 (t, J = 5.5 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 4.08–4.02 (m, 2H), 3.29–2.25 (m, 1H), 3.14–308 (m, 1H), 2.27 (s, 3H), 1.62–1.59 (m, 1H), 1.56–1.50 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H), 1.09–0.98 (m, 1H), 0.93–0.89 (m, 1H). ESI MS m / z 372 [C16H17Cl2NO5– H]-. Preparation of trans-2-((3,5-Dichloro-2-hydroxybenzamido)methyl)cyclopropane-1- carboxylic Acid

[0188] To a solution of ethyl trans-2-((3,5-dichloro-2- hydroxybenzamido)methyl)cyclopropane-1-carboxylate (258 mg, 0.689 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL) was added lithium hydroxide solution (2 M, 2 mL), followed by water (2 mL). After 2 h, the reaction was acidified with 1 N hydrochloric acid to pH 5 then concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with brine, dried over sodium sulfate and concentrated under reduced pressure to provide trans-2-((3,5-dichloro-2- hydroxybenzamido)methyl)cyclopropane-1-carboxylic acid as an off-white solid (190 mg, 91%). ESI MS m / z 302 [C11H12Cl2NO4– H]-.Example 37 Preparation of N-((trans-2-Carbamoylcyclopropyl)methyl)-3,5-dichloro-2- hydroxybenzamide [ANA-118]

[0189] To a solution of trans-2-((3,5-dichloro-2- hydroxybenzamido)methyl)cyclopropane-1-carboxylic acid (30 mg, 0.099 mmol) in dichloromethane (2 mL) was added ammonium chloride (26 mg, 0.49 mmol), followed by propanephosphonic acid anhydride (47 mg, 0.15 mmol) and diisopropylethylamine (89 mg, 0.69 mmol). The reaction was stirred at room temperature overnight. Acetonitrile (5 mL) was added, followed by water (3 mL). The mixture was acidified with 1 N hydrochloric acid to pH 5 and concentrated under reduced pressure. The product was purified by reverse phase column chromatography (C18 silica gel, 0-100% acetonitrile / water) and lyophilized to provide N-((trans-2-carbamoylcyclopropyl)methyl)-3,5-dichloro-2-hydroxybenzamide (15 mg, 49%) as a white solid:1H NMR (500 MHz, DMSO-d61H), 8.02 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.48 (s, 1H), 6.77 (s, 1H), 3.32– 3.27 (m, 1H), 3.24–3.18 (m, 1H), 1.52–1.42 (m, 2H), 0.88–0.85 (m, 1H), 0.74–0.70 (m, 1H); ESI MS m / z 301 [C12H12Cl2N2O3– H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 3.86 min. Example 38 Scheme 20: ANA-119Preparation of Methyl 4-(3,5-Dichloro-2-hydroxybenzamido)bicyclo[2.2.2]octane-1- carboxylate OH Cl Cl

[0190] Methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (50.0 g, 273 mmol), N,N-diisopropylethylamine (79 mL, 450 mmol), and N-[(dimethylamino)-1H-1,2,3- triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N- oxide (103.8 g, 273.0 mmol) were added to a solution of 3,5-dichloro-2-hydroxybenzoic acid (47.0 g, 227 mmol) in N,N-dimethylformamide (470 mL) at 5 °C. The resulting mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was added dropwise to water (800 mL) with vigorous stirring, resulting in the formation of solid precipitate. The solids were collected by vacuum filtration, washed with water, and dried under reduced pressure to provide 4-(3,5-dichloro-2- hydroxybenzamido)bicyclo[2.2.2]octane-1-carboxylate (52.3 g, 61%) as an off white solid: 1H NMR (500 MHz, DMSO-d6J = 2.4 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 3.58 (s, 3H), 2.00–1.97 (m, 6H), 1.84–1.81 (m, 6H); ESI MS m / z 370 [C17H19Cl2NO4- H]-. Preparation of 4-(3,5-Dichloro-2-hydroxybenzamido)bicyclo[2.2.2]octane-1- carboxylic Acid [ANA-120]OH Cl Cl

[0191] A solution of sodium hydroxide (140 mL, 2 M, 281 mmol) was added to a solution of 4-(3,5-dichloro-2-hydroxybenzamido)bicyclo[2.2.2]octane-1-carboxylate (should be methyl 4-(3,5-dichloro-2-hydroxybenzamido)bicyclo[2.2.2]octane-1- carboxylate) (52.3 g, 140 mmol) in tetrahydrofuran (260 mL) and water (260 mL) and stirred at room temperature for 18 h. After this time, another portion of a sodium hydroxide solution (140 mL, 2 M, 281 mmol) was added to the reaction mixture and stirred at room temperature for 4 h. After this time, the reaction mixture was cooled to 5 °C, vigorously stirred, and acidified dropwise with 2 M hydrochloric acid to pH 2 resulting in the formation of solid precipitate. The resulting precipitate was collected by vacuum filtration and dried under reduced pressure to provide 4-(3,5-dichloro-2- hydroxybenzamido)bicyclo[2.2.2]octane-1-carboxylic acid (41.7 g, 83%) as an off white solid:1H NMR (500 MHz, DMSO-d6J = 2.5 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 1.99–1.96 (m, 6H), 1.82–1.78 (m, 6H); ESI MS m / z 356 [C16H17Cl2NO4- H]-; UPLC (BEH C18, Method A) 98.0% (AUC), tR= 4.83 min. Preparation of 4-(3,5-Dichloro-2-hydroxybenzamido)bicyclo[2.2.2]octane-1- carboxamide [ANA-119] OH Cl Cl

[0192] Ammonium chloride (7.5 g, 140 mmol), N,N-diisopropylethylamine (40 mL, 230 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (53.2 g, 140 mmol) were added to a solution of 4-(3,5-dichloro-2-hydroxybenzamido)bicyclo[2.2.2]octane-1- carboxylic acid (41.7 g, 116 mmol) in N,N-dimethylformamide (420 mL) at 5 °C. The resulting mixture was allowed to warm to room temperature and stirred for 18 h. After thistime, the reaction mixture was added dropwise to water (700 mL) with vigorous stirring, resulting in the formation of solid precipitate. The solids were collected by vacuum filtration and washed with water and crystallized from hot ethanol. The crystals were collected by vacuum filtration, washed with cold ethanol, and dried under reduced pressure to provide 4-(3,5-dichloro-2-hydroxybenzamido)bicyclo[2.2.2]octane-1-carboxamide (20.3 g, 48%) as a white crystalline solid:1H NMR (500 MHz, DMSO-d6 8.25 (s, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 6.95 (s, 1H), 6.72 (s, 1H), 1.97–1.94 (m, 6H), 1.78–1.74 (m, 6H); ESI MS m / z 355 [C16H18Cl2N2O3- H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.29 min. Example 39 Scheme 21: ANA-121Preparation of Methyl (1s,4s)-4-(3,5-Dichloro-2- hydroxybenzamido)bicyclo[2.2.1]heptane-1-carboxylate OH Cl Cl

[0193] Methyl (1s,4s)-4-aminobicyclo[2.2.1]heptane-1-carboxylate (1.0 g, 5.9 mmol), N,N-diisopropylethylamine (1.7 mL, 9.8 mmol), and N-[(dimethylamino)-1H- 1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (2.2 g, 5.9 mmol) were added to a solution of 3,5-dichloro-2-hydroxybenzoic acid (1.0 g, 4.9 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred for 18 h. The reaction mixture was concentrated onto silica and purified by normal phase chromatography (silica gel, 0-80% ethyl acetate / hexanes) to provide methyl (1s,4s)-4-(3,5-dichloro-2-hydroxybenzamido)bicyclo[2.2.1]heptane-1- 5 carboxylate (828 mg, 47%) as a white solid:1H NMR (500 MHz, DMSO-d61H), 9.11 (s, 1H), 8.10 (d, J = 2.5 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 3.63 (s, 3H), 2.04– 1.92 (m, 6H), 1.71–1.67 (m, 4H); ESI MS m / z 358 [C16H17Cl2NO4+ H]+. Preparation of (1s,4s)-4-(3,5-Dichloro-2-hydroxybenzamido)bicyclo[2.2.1]heptane-1- carboxylic Acid 10

[0194] A solution of sodium hydroxide (2.3 mL, 2 M, 4.6 mmol) was added to a solution of methyl (1s,4s)-4-(3,5-dichloro-2-hydroxybenzamido)bicyclo[2.2.1]heptane-1- carboxylate (828 mg, 2.31 mmol) in tetrahydrofuran (8 mL) and water (8 mL) and stirred at room temperature for 18 h. The reaction mixture was acidified dropwise with 2 M hydrochloric acid to pH 2 and extracted with ethyl acetate (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to provide (1s,4s)-4-(3,5-dichloro-2- hydroxybenzamido)bicyclo[2.2.1]heptane-1-carboxylic acid (729 mg, crude) as a white solid:1H NMR (500 MHz, DMSO-d620 (d, J = 2.4 Hz, 1H), 7.749–7.745 (m, 1H), 2.00–1.91 (m, 8H), 1.67–1.63 (m, 2H); ESI MS m / z 344 [C15H15Cl2NO4+ H]+. Preparation of (1s,4s)-4-(3,5-Dichloro-2-hydroxybenzamido)bicyclo[2.2.1]heptane-1- carboxamide [ANA-121]

[0195] Ammonium chloride (30 mg, 0.52 mmol), N,N-diisopropylethylamine (150 μL, 0.872 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (200 mg, 0.523 mmol) were added to a solution of (1s,4s)-4-(3,5-dichloro-2- hydroxybenzamido)bicyclo[2.2.1]heptane-1-carboxylic acid (150 mg, 0.436 mmol) in N,N-dimethylformamide (3 mL) at 5 °C and then allowed to warm to room temperature and stirred for 18 h. The reaction mixture was purified by reverse phase chromatography (C18 silica gel, 0-100% acetonitrile / water) and lyophilized from water / acetonitrile to provide (1s,4s)-4-(3,5-dichloro-2-hydroxybenzamido)bicyclo[2.2.1]heptane-1- carboxamide (99.3 mg, 66%) as a white solid:1H NMR (500 MHz, DMSO-d61H), 9.11 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.09 (s, 1H), 6.82 (s, 1H), 1.96–1.90 (m, 8H), 1.67–1.61 (m, 2H); ESI MS m / z 343 [C15H16Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 97.8% (AUC), tR= 4.15 min. Example 40 Scheme 22: ANA-122 N

[0196] Cyclobutanamine (1.0 g, 14 mmol) was added to a solution of - carbonyldiimidazole (2.46 g, 15.2 mmol) in N,N-dimethylformamide (2 mL) and acetonitrile (4 mL) and stirred at room temperature for 18 h. The crude reaction mixture was purified by chromatography (silica gel, 0–10% methanol / methylene chloride) to provide N-cyclobutyl-1H-imidazole-1-carboxamide (1.83 g, 78%) as a clear, colorless oil: ESI MS m / z 166 [C8H11N3O + H]+. Preparation of tert-Butyl (1R,5S,7s)-7-(3,5-Dichloro-2-hydroxybenzamido)-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate

[0197] tert-Butyl (1R,5S,7s)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonane-9- carboxylate (592 mg, 2.44 mmol), N,N-diisopropylethylamine (709 μL, 4.07 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (930 mg, 2.44 mmol) was added to a solution of 3,5-dichloro-2-hydroxybenzoic acid (422 mg, 2.04 mmol) in N,N- dimethylformamide (9 mL) and stirred for 18 h at room temperature. After this time, the reaction mixture was concentrated onto silica and purified by normal phase chromatography (silica gel, 0-80% ethyl acetate / hexanes) to provide tert-butyl (1R,5S,7s)- 7-(3,5-dichloro-2-hydroxybenzamido)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (318 mg, 36%) as a white solid:1H NMR (500 MHz, DMSO-d6J = 8.7 Hz, 1H), 7.77 (dd, J = 11.5, 2.4 Hz, 1H), 4.16–4.09 (m, 1H), 4.05–3.99 (m, 2H), 3.82 (t, J = 11.9 Hz, 2H), 3.54 (dd, J = 11.3, 2.3 Hz, 2H), 2.19–2.12 (m, 2H), 1.75–1.71 (m, 2H), 1.43 (s, 9H); ESI MS m / z 431 [C19H24Cl2N2O5+ H]+. Preparation of N-((1R,5S,7s)-3-Oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0198] A solution of 2M hydrochloric acid in ether (3.6 mL, 7.4 mmol) was added to a solution of tert-butyl (1R,5S,7s)-7-(3,5-dichloro-2-hydroxybenzamido)-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (318 mg, 0.738 mmol) in methylene chloride (6.3 mL) and stirred at room temperature for 18 h. After this time, the reaction mixture was concentrated under reduced pressure to provide N-((1R,5S,7s)-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (274 mg, crude) as a white solid:1H NMR (500 MHz, DMSO-d6J = 9.3 Hz, 1H), 9.08 (s, 1H), 8.96 (d, J = 8.1 Hz, 1H), 7.77 (dd, J = 14.4, 2.5 Hz, 2H), 4.44–4.40 (m, 1H), 4.03 (d, J = 12.4 Hz, 2H), 3.91 (d, J = 12.0 Hz, 2H), 3.60–3.59 (m, 2H), 2.46– 2.40 (m, 2H), 1.98 (d, J = 15.1 Hz, 2H); ESI MS m / z 331 [C14H16Cl2N2O3+ H]+. Preparation of (1R,5S,7s)-N-Cyclobutyl-7-(3,5-dichloro-2-hydroxybenzamido)-3- oxa-9-azabicyclo[3.3.1]nonane-9-carboxamide [ANA-122]

[0199] In a sealed microwave vial, N-cyclobutyl-1H-imidazole-1-carboxamide (248 mg, 1.50 mmol) and triethylamine (420 μL, 3.00 mmol) was added to a solution of N- ((1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (276 mg, 0.752 mmol) in methylene chloride (5.5 mL), heated to 100 °C for 1 h under microwave irradiation, then cooled to room temperature and purified by normal phase chromatography (silica gel, 0–10% methanol / methylene chloride). The fractions were concentrated under reduced pressure and purified by reverse phase chromatography (silica gel, 0-100% acetonitrile / water) to provide (1R,5S,7s)-N-cyclobutyl-7-(3,5-dichloro- 2-hydroxybenzamido)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxamide (176 mg, 54%) as a white solid:1H NMR (500 MHz, DMSO-d6J = 8.7 Hz, 1H), 7.76 (q, J = 7.5, 2.4 Hz, 2H), 6.69 (d, J = 7.5 Hz, 1H), 4.16–4.07 (m, 4H), 3.82 (d, J = 11.1 Hz, 2H), 3.55–3.52 (m, 2H), 2.16–2.09 (m, 4H), 1.94–1.86 (m, 2H), 1.70–1.66 (m, 2H),1.63–1.50 (m, 2H); ESI MS m / z 428 [C19H23Cl2N2O4+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.76 min. Example 41 Scheme 23: ANA-123Preparation of tert-Butyl (4-(3,5-Dichloro-2-hydroxybenzamido)bicyclo[2.2.2]octan- 1-yl)carbamate OH Cl Cl

[0200] tert-Butyl (4-aminobicyclo[2.2.2]octan-1-yl)carbamate (1.0 g, 4.2 mmol), N,N-diisopropylethylamine (1.2 mL, 6.9 mmol), and N-[(dimethylamino)-1H-1,2,3- triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N- oxide (1.6 g, 4.2 mmol) was added to a solution of 3,5-dichloro-2-hydroxybenzoic acid (717 mg, 3.47 mmol) in N,N-dimethylformamide (14 mL) and allowed to stir overnight at room temperature. The reaction mixture was purified by normal phase chromatography (silica gel, 0-80% ethyl acetate / hexanes) to provide tert-butyl (4-(3,5-dichloro-2- hydroxybenzamido)bicyclo[2.2.2]octan-1-yl)carbamate (1.14 g, 76%) as a white solid:1H NMR (500 MHz, DMSO-d6J = 2.4 Hz, 1H), 7.70(d, J = 2.4 Hz, 1H), 6.42 (s, 1H), 2.02–1.99 (m, 6H), 1.86–1.83 (m, 6H), 1.36 (s, 9H); ESI MS m / z 429 [C20H26Cl2N2O4+ H]+. Preparation of N-(4-Aminobicyclo[2.2.2]octan-1-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0201] A solution of hydrochloric acid in ether (13 mL, 2 M, 26 mmol) was added to a solution of tert-butyl (4-(3,5-dichloro-2-hydroxybenzamido)bicyclo[2.2.2]octan-1- yl)carbamate (1.14 g, 2.66 mmol) in methylene chloride (20 mL) and allowed to stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure to provide N-(4-aminobicyclo[2.2.2]octan-1-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride (826 mg, crude) as a white solid:1H NMR (500 MHz, DMSO-d6J = 2.5 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 2.10–2.07 (m, 6H), 1.85–1.82 (m, 6H); ESI MS m / z 329 [C15H18Cl2N2O2+ H]+. Preparation of 2,4-Dichloro-6-((4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1- yl)carbamoyl)phenyl Cyclopropanesulfonate

[0202] Cyclopropanesulfonyl chloride (83 μL, 0.82 mmol) and triethylamine (171 μL, 1.23 mmol) was added to a solution of N-(4-aminobicyclo[2.2.2]octan-1-yl)-3,5- dichloro-2-hydroxybenzamide hydrochloride (150 mg, 0.410 mmol) in methylene chloride (3 mL) and allowed to stir overnight at room temperature. The reaction mixture was quenched with a saturated solution of ammonium chloride (2 mL) and extracted with methylene chloride (3 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered under vacuum, and concentrated under reduced pressure to provide 2,4-dichloro-6-((4-(cyclopropanesulfonamido) bicyclo[2.2.2]octan-1-yl)carbamoyl)phenyl cyclopropanesulfonate (300 mg) as a white solid which was used without further purification: ESI MS m / z 537 [C21H26Cl2N2O6S2+ H]+. Preparation of 3,5-Dichloro-N-(4-(cyclopropanesulfonamido)bicyclo[2.2.2]octan-1- yl)-2-hydroxybenzamide [ANA-123]

[0203] A solution of sodium hydroxide (800 μL, 1.6 mmol) was added to a solution of 2,4-dichloro-6-((4-(cyclopropanesulfonamido) bicyclo[2.2.2]octan-1- yl)carbamoyl)phenyl cyclopropanesulfonate (300 mg, 0.558) in methanol (8 mL), heated to 80 °C, and allowed to stir for 2 h. The reaction mixture purified by reverse phase chromatography (C18 silica gel, 10-100% acetonitrile / water) to provide 3,5-dichloro-N-(4- (cyclopropanesulfonamido)bicyclo[2.2.2]octan-1-yl)-2-hydroxybenzamide (31.8 mg, 17%) as an off white solid:1H NMR (500 MHz, DMSO-d68.06 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 6.85 (s, 1H), 2.55–2.51 (m, 1H), 2.05– 2.02 (m, 6H), 1.92–1.89 (m, 6H), 0.96–0.89 (m, 4H); ESI MS m / z 433 [C18H22Cl2N2O4S + H]+; UPLC (BEH C18, Method A) >99% (AUC), tR = 5.14 min. Example 42 Scheme 24: ANA-124Preparation of N-(4-Aminobicyclo[2.2.2]octan-1-yl)-3-chloro-5-fluoro-2- hydroxybenzamide hydrochloride

[0204] N-(4-aminobicyclo[2.2.2]octan-1-yl)-3-chloro-5-fluoro-2- hydroxybenzamide hydrochloride (1.16 g, crude) was synthesized as a white solid according to the procedure outlined in Scheme 23:1H NMR (500 MHz, DMSO-d6(s, 1H), 8.26 (s, 1H), 8.03 (s, 3H), 7.89 (dd, J = 9.6, 3.0 Hz, 1H), 7.64 (dd, J = 8.1, 3.0 Hz, 1H), 2.10–2.07 (m, 6H), 1.84–1.81 (m, 6H); ESI MS m / z 313 [C15H18ClFN2O2+ H]+. Preparation of 3-Chloro-N-(4-(2-cyclobutylacetamido)bicyclo[2.2.2]octan-1-yl)-5- fluoro-2-hydroxybenzamide [ANA-124]

[0205] 2-Cyclobutylacetic acid (98 mg, 0.86 mmol), N,N-diisopropylethylamine (250 μL, 1.43 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (326 mg, 0.859 mmol) was added to a solution of N-(4-aminobicyclo[2.2.2]octan-1-yl)-3-chloro-5-fluoro- 2-hydroxybenzamide hydrochloride (250 mg, 0.716 mmol) in N,N-dimethylformamide (2.5 mL) and allowed to stir at room temperature for 18 h. The reaction mixture was added dropwise to water (10 mL) with vigorous stirring to form solid precipitate. The solids were collected by vacuum filtration and washed with water and dried under reduced pressure to provide 3-chloro-N-(4-(2-cyclobutylacetamido)bicyclo[2.2.2]octan-1-yl)-5-fluoro-2- hydroxybenzamide (207 mg, 70%) as a white solid:1H NMR (500 MHz, DMSO-d613.21 (s, 1H), 8.13 (s, 1H), 7.87 (q, J = 9.7, 3.1 Hz, 1H), 7.62 (dd, J = 8.1, 3.0 Hz, 1H), 7.64 (dd, J = 8.1, 3.0 Hz, 1H), 7.23 (s, 1H), 2.09 (d, J = 7.5 Hz, 2H), 2.02–1.93 (m, 8H),1.90–1.87 (m, 6H), 1.84–1.73 (m, 2H), 1.67–1.59 (m, 2H); ESI MS m / z 407 [C21H26ClFN2O3- H]-; UPLC (BEH C18, Method A) 95.3% (AUC), tR= 4.99 min. Scheme 25: ANA-125Preparation of N-((1s,4s)-4-Aminobicyclo[2.2.1]heptan-1-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride OH Cl Cl

[0206] N-((1s,4s)-4-Aminobicyclo[2.2.1]heptan-1-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride (2.56 g) was synthesized as a white solid according to the procedure outlined in Scheme 23:1H NMR (500 MHz, DMSO-d69.22 (s, 1H), 8.62 (s, 3H), 8.15 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 3.17 (s, 1H), 2.11 (s, 2H), 2.05–1.90 (m, 6H), 1.76–1.72 (m, 2H); ESI MS m / z 315 [C14H16Cl2N2O2+ H]+. Preparation of 3,5-Dichloro-N-((1s,4s)-4-(2- cyclobutylacetamido)bicyclo[2.2.1]heptan-1-yl)-2-hydroxybenzamide [ANA-125] H OH Cl Cl

[0207] 2-Cyclobutylacetic acid (78 mg, 0.68 mmol), N,N-diisopropylethylamine (200 μL, 2.27 mmol), and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (259 mg, 0.683 mmol) was added to a solution of N-((1s,4s)-4-aminobicyclo[2.2.1]heptan-1-yl)-3,5- dichloro-2-hydroxybenzamide hydrochloride (200 mg, 0.569 mmol) in N,N- dimethylformamide (4 mL) and allowed to stir at room temperature for 18 h. The reaction mixture was purified by normal phase chromatography (C18 silica gel, 10–70% acetonitrile / water) to provide 3,5-dichloro-N-((1s,4s)-4-(2- cyclobutylacetamido)bicyclo[2.2.1]heptan-1-yl)-2-hydroxybenzamide (174 mg, 74%) as a white solid:1H NMR (500 MHz, DMSO-d6J = 2.5 Hz, 1H), 7.85 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 2.58–2.52 (m, 1H), 2.14 (d, J = 7.6 Hz, 2H), 2.09 (s, 2H), 2.01–1.85 (m, 8H), 1.83–1.61 (m, 6H); ESI MS m / z 409 [C20H24Cl2N2O3- H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 5.30 min. Example 43 Scheme 26: ANA-126Preparation of N-(4-Aminobicyclo[2.2.2]octan-1-yl)-3,5-dichloro-2- hydroxybenzamide HydrochlorideOH Cl Cl

[0208] N-(4-Aminobicyclo[2.2.2]octan-1-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (1.7 g, 94%) was synthesized as a white solid according to the procedure outlined in Scheme 23:1H NMR (500 MHz, DMSO-d6(s, 3H), 8.07 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 2.10–2.07 (m, 6H), 1.85–1.82 (m, 6H); ESI MS m / z 329 [C15H18Cl2N2O2+ H]+. Preparation of 2,4-Dichloro-6-((4-(cyclobutanecarboxamido)bicyclo[2.2.2]octan-1- yl)carbamoyl)phenyl Cyclobutanecarboxylate O O Cl Cl

[0209] Cyclobutanecarbonyl chloride (777 mg, 6.56 mmol), and N,N- diisopropylethylamine (1.1 mL, 6.6 mmol) was added to a solution of N-(4- aminobicyclo[2.2.2]octan-1-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (1.2 g, 3.3 mmol) in N,N-dimethylformamide (24 mL) and allowed to stir at room temperature for 18 h. The resulting mixture was concentrated under reduced pressure to provide 2,4- dichloro-6-((4-(cyclobutanecarboxamido)bicyclo[2.2.2]octan-1-yl)carbamoyl)phenyl cyclobutanecarboxylate (1.2 g) as a white solid that was used without further purification: ESI MS m / z 493 [C25H30Cl2N2O4+ H]+. Preparation of 3,5-Dichloro-N-(4-(cyclobutanecarboxamido)bicyclo[2.2.2]octan-1- yl)-2-hydroxybenzamide [ANA-1 Cl

[0210] A solution of sodium hydroxide (5.0 mL, 2.0 M, 9.7 mmol) was added to a solution of 2,4-dichloro-6-((4-(cyclobutanecarboxamido)bicyclo[2.2.2]octan-1- yl)carbamoyl)phenyl cyclobutanecarboxylate (1.2 g, 2.4 mmol) in methanol (24 mL), heated to 80 °C, and allowed to stir for 1 h. The reaction mixture was purified by normal phase chromatography (silica gel, 0–10% methanol / methylene chloride) to provide 3,5- dichloro-N-(4-(cyclobutanecarboxamido)bicyclo[2.2.2]octan-1-yl)-2-hydroxybenzamide (485 mg, 48%) as a white solid:1H NMR (500 MHz, DMSO-d61H), 8.06 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.10 (s, 1H), 2.98–2.92 (m, 1H), 2.09–2.00 (m, 8H), 1.96–1.78 (m, 9H), 1.74–1.67 (m, 1H); ESI MS m / z 411 [C20H24Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 97.2% (AUC), tR= 5.29 min. Example 44 Scheme 27: ANA-127Preparation of N-((1R,5S,7r)-3-Oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride OH Cl Cl

[0211] N-((1R,5S,7r)-3-Oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride (546 mg) was synthesized as a white solid according to the procedure outlined in Scheme 22:1H NMR (500 MHz, DMSO-d69.02 (d, J = 7.5 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 2.6 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 2.7 Hz, 1H), 5.15–5.06 (m, 1H), 3.97 (s, 4H), 3.61 (s, 2H), 2.24–2.21 (m, 2H), 2.12–2.06 (m, 2H); ESI MS m / z 331 [C14H16Cl2N2O3 + H]+. Preparation of 2-(((1R,5S,7r)-9-Acetyl-3-oxa-9-azabicyclo[3.3.1]nonan-7- yl)carbamoyl)-4,6-dichlorophenyl Acetate

[0212] Acetic anhydride (53 μL, 0.56 mmol) and triethylamine (283 μL, 2.03 mmol) were added to a solution of N-((1R,5S,7r)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)- 3,5-dichloro-2-hydroxybenzamide hydrochloride (186 mg, 0.510 mmol) in tetrahydrofuran (4 mL) and allowed to stir overnight at room temperature. After this time, the reaction mixture was concentrated onto silica and purified by normal phase chromatography (silica gel, 0–10% methanol / methylene chloride) to provide 2-(((1R,5S,7r)-9-acetyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)carbamoyl)-4,6-dichlorophenyl acetate (228 mg) as a white solid: ESI MS m / z 415 [C18H20Cl2N2O5+ H]+. Preparation of N-((1R,5S,7r)-9-Acetyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3,5- dichloro-2-hydroxybenzamide [ANA-127]

[0213] A solution of sodium hydroxide (550 μL, 1.10 mmol) was added to a solution of 2-(((1R,5S,7r)-9-acetyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)carbamoyl)-4,6- dichlorophenyl acetate (228 mg, 0.549 mmol) in methanol (5 mL), heated to 80 °C, and allowed to stir for 2 h. The reaction mixture was purified by reverse phase chromatography(C18 silica gel, 10–100% acetonitrile / water). From the resulting solids, product was extracted with acetonitrile and concentrated under reduced pressure to provide N- ((1R,5S,7r)-9-acetyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3,5-dichloro-2- hydroxybenzamide (4.8 mg, 2%) as a white solid:1H NMR (500 MHz, DMSO-d6(s, 1H), 7.50 (s, 1H), 7.07 (s, 1H), 5.00–4.97 (m, 1H), 4.38 (s, 1H), 3.94 (s, 1H), 3.86 (d, J = 11.5 Hz, 2H), 3.63–3.61 (m, 1H), 3.52–3.49 (m, 1H), 2.12 (d, J = 19.3 Hz, 1H), 2.06– 2.01 (m, 4H), 1.55–1.38 (m, 2H), amide NH not observed; ESI MS m / z 371 [C16H18Cl2N2O4- H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.14 min. Example 45 Scheme 28: ANA-128Preparation of Sodium 2-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-4,6- dichlorophenolateC

[0214] A solution of 4-(3,5-dichloro-2-hydroxybenzamido)bicyclo[2.2.2]octane-1- carboxamide (30.1 mg, 0.0843 mmol) in sodium hydroxide (63 μL, 2 M, 1.5 eq.) was allowed to stir for 3 h. After this time, the reaction mixture was lyophilized from acetonitrile / water to provide sodium 2-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)- 4,6-dichlorophenolate (20.3 g, 48%) as a white crystalline solid:1H NMR (500 MHz, DMSO-d6J = 3.1 Hz, 1H), 7.03 (d, J = 3.1 Hz, 1H), 6.91 (s, 1H), 6.65 (s, 1H), 1.87–1.71 (m, 12H); ESI MS m / z 355 [C16H18Cl2N2O3- H]-; UPLC (BEH C18, Method A) 97.9% (AUC), tR = 4.48 min. Example 46Scheme 29: ANA-129Preparation of tert-Butyl (1R,4R,5R)-5-(3,5-Dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.2]octane-2-carboxylate OH Cl Cl

[0215] To a chilled (2–8 °C) solution of 3,5-dichloro-2-hydroxybenzoic acid (0.402 g, 1.94 mmol) in N,N-dimethylformamide (4.00 mL) was charged N,N- diisopropylethylamine (1.05 mL, 6.02 mmol) and N-[(dimethylamino)-1H-1,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.780 g, 2.04 mmol). The ice bath was removed and the resulting solution was held under nitrogen for 20 min. After this time, the activated acid slurry was transferred to a second round bottom flask containing a chilled (2–8 °C) solution of tert-butyl (1R,4R,5R)-5- amino-2-azabicyclo[2.2.2]octane-2-carboxylate (0.470 g, 2.08 mmol) in N,N- dimethylformamide (3.20 mL) under a nitrogen atmosphere. N,N-dimethylformamide (0.800 mL) was used to aid in the transfer. The ice bath was removed and the resulting mixture was held with gradual warming to ambient temperature for 20 h. After this time, the reaction mixture was poured into stirring 5% LiCl solution (80 mL) at ambient temperature and extracted into ethyl acetate (80 mL). The organic layer was separated and the aqueous layer back extracted with ethyl acetate (40 mL). The combined organic layerwas dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude viscous oil was dissolved in methanol / dichloromethane (1:5), adsorbed onto silica gel and purified by silica gel chromatography (0–40% hexanes / ethyl acetate) to afford tert-butyl (1R,4R,5R)-5-(3,5-dichloro-2-hydroxybenzamido)-2-azabicyclo[2.2.2]octane-2- carboxylate (0.613 g, 75%) as a light yellow solid: ESI MS m / z 413 [C19H24Cl2N2O4– H]- . Preparation of N-((1R,4R,5R)-2-Azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0216] To a round bottom flask containing tert-butyl (1R,4R,5R)-5-(3,5-dichloro- 2-hydroxybenzamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (0.610 g, 1.47 mmol) was charged 4 M hydrochloric acid in 1,4-dioxane (2.9 mL, 12 mmol) at ambient temperature and under a nitrogen atmosphere. The resulting slurry was held with stirring for 20 h. After this time, the slurry was collected by filtration rinsing portion-wise with dichloromethane (20 mL total volume) to afford N-((1R,4R,5R)-2-azabicyclo[2.2.2]octan-5-yl)-3,5- dichloro-2-hydroxybenzamide hydrochloride (0.492 g, 95%) as a yellow solid: ESI MS m / z 313 [C14H16Cl2N2O2– H]- . Preparation of 3,5-Dichloro-N-((1R,4R,5R)-2-(2-cyclobutylacetyl)-2- azabicyclo[2.2.2]octan-5-yl)-2-hydroxybenzamide [ANA-129]

[0217] To a chilled (1–8 °C) solution of 2-cyclobutylacetic acid (0.026 g, 0.23 mmol) in N,N-dimethylformamide (0.75 mL) was charged N,N-diisopropylethylamine (0.120 mL, 0.660 mmol) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (0.087 g, 0.23 mmol). The ice bath was removed and the resulting solution was held under nitrogen for20 min. After this time, the activated acid slurry was transferred to a second round bottom flask containing a chilled (1–8 °C) solution of N-((1R,4R,5R)-2-azabicyclo[2.2.2]octan-5- yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (0.075 g, 0.21 mmol) in N,N- dimethylformamide (0.75 mL) under a nitrogen atmosphere. N,N-Dimethylformamide (0.15 mL) was used to aid in the transfer. The ice bath was removed and the resulting mixture was held with gradual warming to ambient temperature for 16 h. After this time, the reaction was charged dropwise into stirring 0.1 N hydrochloric acid (20 mL) chilled in an ice bath. The resulting precipitate was collected by filtration. The solid was rinsed with water in portions (total of 25 mL) and then dried under high vacuum at 50 °C to afford 3,5- dichloro-N-((1R,4R,5R)-2-(2-cyclobutylacetyl)-2-azabicyclo[2.2.2]octan-5-yl)-2- hydroxybenzamide (0.059 g, 67%) as a white solid:1H NMR (500 MHz, DMSO-d6 (s, 1H), 8.90 (br s, 1H), 8.14–8.13 (m, 1H), 7.77–7.75 (m, 1H), 4.45–4.37 (m, 0.5H), 4.19– 4.12 (m, 1H), 3.92–3.89 (0.5H), 3.64 (d, J = 11.0 Hz, 0.5H), 3.44 (d, J = 12.7 Hz, 0.5H), 3.36–3.32 (m, 0.5H), 3.25 (d, J = 12.3 Hz, 0.5H), 2.61–2.53 (m, 1H), 2.43–2.36 (m, 1.5H), 2.31–2.25 (m, 0.5H), 2.20–2.02 (m, 4H), 1.91–1.54 (m, 9 H); ESI MS m / z 409 [C20H24Cl2N2O3– H]-; UPLC (BEH C18, Method A) 96.2% (AUC), tR= 5.37 min. Example 47 Scheme 30: ANA-130Preparation of cyclobutyl 2,5-dioxopyrrolidine-1-carboxylate

[0218] To a slurry of bis(2,5-dioxopyrrolidin-1-yl) carbonate (0.200 g, 0.781 mmol) and acetonitrile (0.50 mL) was charged cyclobutanol (0.024 g, 0.36 mmol) and triethylamine (0.163 mL, 1.17 mmol). The resulting solution was stirred at ambient temperature for 19 h. After this time, the reaction was quenched by addition of saturated sodium bicarbonate solution (3 mL) and extracted into ethyl acetate (10 mL). The aqueous layer was back extracted twice with ethyl acetate (10 mL each). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford cyclobutyl 2,5-dioxopyrrolidine-1-carboxylate (0.047 g, 57%) as a pale-yellow oil that was used without further purification or analysis. Preparation of N-((1R,4R,5R)-2-Azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0219] N-((1R,4R,5R)-2-azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride was prepared according to Synthetic Scheme 29. Example 48 Preparation of Cyclobutyl (1R,4R,5R)-5-(3,5-dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.2]octane-2-carboxylate [ANA-130]

[0220] A round bottom flask was charged with N-((1R,4R,5R)-2- azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (0.060 g, 0.17 mmol), tetrahydrofuran (2.40 mL) and triethylamine (0.095 mL, 0.68 mmol). To the resulting mixture was charged a solution of cyclobutyl 2,5-dioxopyrrolidine-1-carboxylate (0.047 g, 0.22 mmol) in tetrahydrofuran (1.5 mL). The reaction was held at ambient temperature for 22 h. After this time, the mixture was diluted in dichloromethane (10 mL)and washed with a saturated sodium chloride solution (10 mL). The aqueous layer was back extracted with dichloromethane (10 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) and then precipitation from water to provide cyclobutyl (1R,4R,5R)-5- (3,5-dichloro-2-hydroxybenzamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (0.029 g, 41%) as a white solid:1H NMR (500 MHz, DMSO-d6– 8.14 (m, 1H), 7.76 (s, 1H), 4.89–4.83 (m, 1H), 4.20–4.10 (m, 1H), 3.96 (br s, 1H), 3.50 (dd, J = 38.8, 11.4 Hz, 1H), 3.20 (dd, J = 34.5, 11.4 Hz, 1H), 2.28–2.20 (m, 2H), 2.17–2.09 (m, 1H), 2.03–1.86 (m, 4H), 1.78–1.61 (m 4H), 1.60–1.49 (m, 2H); ESI MS m / z 411 [C19H22Cl2N2O4 – H]-; UPLC (BEH C18, Method A) >99% (area%), tR = 5.57 min. Example 49 Scheme 31: ANA-131Preparation of N-Cyclobutyl-1H-imidazole-1-carboxamide

[0221] To a suspension of di(1H-imidazol-1-yl)methanone (0.200 g, 1.23 mmol) in acetonitrile (0.75 mL) under a nitrogen atmosphere was charged cyclobutanamine (0.081g, 1.1 mmol) followed by N,N-dimethylformamide (0.25 mL). The resulting solution was held at ambient temperature for 19 h. After this time, the reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (silica gel, 0– 10% methanol / dichloromethane) to afford N-cyclobutyl-1H-imidazole-1-carboxamide (0.126 g, 62%) as a cloudy film: ESI MS m / z 166 [C8H11N3O + H]+. Preparation of tert-Butyl (1R,4R,5S)-5-(3,5-Dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.2]octane-2-carboxylate

[0222] 3,5-dichloro-2-hydroxybenzoic acid (0.430 g, 2.08 mmol) was reacted with tert-butyl (1R,4R,5S)-5-amino-2-azabicyclo[2.2.2]octane-2-carboxylate (0.517 g, 2.28 mmol) according to Synthetic Scheme 1. The crude reaction mixture was added dropwise into stirring DI water (65 mL) and cooled to 15–20 °C. After a 15 min hold, the resulting precipitate was removed by filtration. The filtrate was extracted into ethyl acetate (100 mL) with 5% lithium chloride solution (20 mL) added to aid in separation of the layers. The organic layer was removed and the aqueous phase back extracted with ethyl acetate (100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was adsorbed onto a plug of silica gel and purified by column chromatography (silica gel, 0–2% methanol / dichloromethane) to provide tert-butyl (1R,4R,5S)-5-(3,5-dichloro-2- hydroxybenzamido)-2-azabicyclo[2.2.2]octane-2-carboxylate (0.489 g, 57%) as a yellow crushable foam: ESI MS m / z 413 [C19H24Cl2N2O4– H]- . Preparation of N-((1R,4R,5S)-2-Azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0223] tert-Butyl (1R,4R,5S)-5-(3,5-dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.2]octane-2-carboxylate (0.489 g, 1.18 mmol) was combined with 1,4- dioxane (1 mL) and 4 M hydrochloric acid in 1,4-dioxane (2 mL) according to Synthetic Scheme 1. After the overnight hold, diethyl ether (20 mL) was added to the reaction slurry and held with stirring for 15 min. After this time, the slurry was filtered rinsing with diethyl ether (50 mL total in portions) and then dried under high vacuum at 50 °C overnight to provide N-((1R,4R,5S)-2-azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (0.411 g, 99%) as a white solid: ESI MS m / z 313 [C14H16Cl2N2O2– H]- . Example 50 Preparation of (1R,4R,5S)-N-Cyclobutyl-5-(3,5-dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.2]octane-2-carboxamide [ANA-131]

[0224] To a solution of N-cyclobutyl-1H-imidazole-1-carboxamide (0.051 g, 0.31 mmol) in dichloromethane (1.00 mL) was added N-((1R,4R,5S)-2-azabicyclo[2.2.2]octan- 5-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (0.054 g, 0.15 mmol) and triethylamine (64.0 mL, 0.460 mmol). The resulting slurry was heated to 100 °C in a sealed microwave vessel for 30 min under microwave irradiation, then cooled to room temperature and concentrated under reduced pressure. The crude residue was dissolved in acetonitrile / water (0.2 / 0.4 mL) and purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water). Desired fractions were concentrated under reduced pressure and dried under high vacuum at 50 °C to provide (1R,4R,5S)-N-cyclobutyl-5-(3,5- dichloro-2-hydroxybenzamido)-2-azabicyclo[2.2.2]octane-2-carboxamide (0.009 g, 14%) as a light brown solid:1H NMR (500 MHz, DMSO-d6(s, 1H), 7.76 (s, 1H), 6.22 (d, J = 7.8 Hz, 1H), 4.18–4.09 (m, 2H), 4.04 (br s, 1H), 3.35 (d, J = 10.5 Hz, 1H), 3.26 (dd, J = 10.5, 2.4 Hz, 1H), 2.19–2.04 (m, 4H), 1.98-1.80 (m, 3H),1.79–1.60 (m, 3H), 1.59–1.42 (m, 3H); ESI MS m / z 410 [C19H23Cl2N2O3– H]-; UPLC (BEH C18, Method A) 97.5% (area%), tR= 4.75 min. Example 51 Scheme 32: ANA-132Preparation of N-((1R,4R,5R)-2-Azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0225] N-((1R,4R,5R)-2-azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride was prepared according to Synthetic Scheme 29. Preparation of 2-(((1R,4R,5R)-2-Acetyl-2-azabicyclo[2.2.2]octan-5-yl)carbamoyl)- 4,6-dichlorophenyl Acetate

[0226] In a vial under nitrogen atmosphere was charged N-((1R,4R,5R)-2- azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (0.075 g, 0.21 mmol) and tetrahydrofuran (1.5 mL). The resulting white slurry was cooled in an ice bath. Triethylamine (0.15 mL, 1.1 mmol) was charged followed by acetic anhydride(0.065 g, 0.64 mmol). The reaction was held with gradual warming to room temperature for 16 h. After this time, the slurry was added dropwise into chilled 0.1 N hydrochloric acid (10 mL) and extracted into ethyl acetate (20 mL). The aqueous phase was back extracted with ethyl acetate (20 mL) and the combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was further dried under high vacuum at ambient temperature overnight to afford 2-(((1R,4R,5R)-2-acetyl-2- azabicyclo[2.2.2]octan-5-yl)carbamoyl)-4,6-dichlorophenyl acetate (0.090 g, >99%) as a clear, colorless film which was used without further purification: ESI MS m / z 397 [C18H20Cl2N2O4– H]-; Example 52 Preparation of N-((1R,4R,5R)-2-Acetyl-2-azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide [ANA-132]

[0227] A 2 N aqueous solution of lithium hydroxide (1.13 mL, 2.25 mmol) was added to a solution of 2-(((1R,4R,5R)-2-acetyl-2-azabicyclo[2.2.2]octan-5-yl)carbamoyl)- 4,6-dichlorophenyl acetate (0.090 g, 0.23 mmol) in methanol (1.0 ml), and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was cooled in an ice bath and adjusted to pH 3 with 2 N aqueous solution of hydrochloric acid resulting in a thick slurry. The slurry was thinned with water (1 mL) and the solids collected by filtration rinsing portion-wise with water (20 mL total). The solid was dried under high vacuum at 50 °C to provide N-((1R,4R,5R)-2-acetyl-2-azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide (0.066 g, 87%) as a white solid:1H NMR (500 MHz, DMSO-d6) 13.63 (s, 1H), 8.94 (br s, 1H), 8.14–8.12 (m, 1H), 7.75 (t, J = 2.5 Hz, 1H), 4.40–4.39 (m, 0.5H), 4.19–4.14 (m, 1H), 3.87–3.84 (m, 0.5H), 3.66–3.64 (m, 0.5H), 3.46–3.44 (m, 0.5H), 3.34–3.32 (m, 0.5H), 3.25–3.23 (m, 0.5H), 2.21–2.09 (m, 1H), 2.07–2.03 (m, 1H), 1.91 (s,1.5H), 1.95–1.89 (m, 2H), 1.85–1.78 (m, 1H), 1.74–1.55 (m, 3.5H); ESI MS m / z 355 [C16H18Cl2N2O3– H]-; UPLC (BEH C18, Method A) 96.8% (AUC), tR= 4.55 min. Example 53 Scheme 33: AN-133Preparation of N-((1R,4R,5R)-2-Azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0228] N-((1R,4R,5R)-2-azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride was prepared according to Synthetic Scheme 29: ESI MS m / z 313 [C14H16Cl2N2O2– H]-. Preparation of 2,4-Dichloro-6-(((1R,4R,5R)-2-(cyclopropylsulfonyl)-2- azabicyclo[2.2.2]octan-5-yl)carbamoyl)phenyl Cyclopropanesulfonate

[0229] In a flask under nitrogen atmosphere was charged N-((1R,4R,5R)-2- azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (0.075 g, 0.21 mmol) and dichloromethane (1.5 mL). The resulting slurry was cooled in an ice bath. Triethylamine (0.14 mL, 0.98 mmol) was charged followed by cyclopropanesulfonylchloride (0.075 g, 0.53 mmol). The reaction was held with gradual warming to room temperature for 16 h. After this time, the thin slurry was added dropwise into chilled 0.1 N hydrochloric acid (10 mL) and extracted into dichloromethane (20 mL). The aqueous phase was back extracted with dichloromethane (20 mL) and the combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was further dried under high vacuum at ambient temperature overnight to afford 2,4-dichloro-6-(((1R,4R,5R)-2-(cyclopropylsulfonyl)-2-azabicyclo[2.2.2]octan-5- yl)carbamoyl)phenyl cyclopropanesulfonate (0.115 g, >99%) as a light yellow foam which was used without further purification. Preparation of 3,5-Dichloro-N-((1R,4R,5R)-2-(cyclopropylsulfonyl)-2- azabicyclo[2.2.2]octan-5-yl)-2-hydroxybenzamide [ANA-133]

[0230] A 2 N aqueous solution of sodium hydroxide (1.50 mL, 3.00 mmol) was added to a solution of 2,4-dichloro-6-(((1R,4R,5R)-2-(cyclopropylsulfonyl)-2- azabicyclo[2.2.2]octan-5-yl)carbamoyl)phenyl cyclopropanesulfonate (0.115 g, 0.220 mmol) in methanol (1.0 mL), and the reaction mixture was stirred at 80 °C for 3.5 h. The reaction mixture was adjusted to pH 3 with a 2 N aqueous solution of hydrochloric acid. The resulting solids were collected by filtration, rinsing with water (20 mL total) in portions. The solid was dried under high vacuum at 50 °C and then purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water), followed by trituration in acetonitrile (0.4 mL). The solid was then suspended in diethyl ether (1 mL) and vigorously stirred for 5 h. After this time, it was collected by filtration and rinsed with diethyl ether (2 mL). The material was dried under high vacuum at 50 °C to provide 3,5- dichloro-N-((1R,4R,5R)-2-(cyclopropylsulfonyl)-2-azabicyclo[2.2.2]octan-5-yl)-2- hydroxybenzamide (0.015 g, 17%) as a white solid:1H NMR (500 MHz, DMSO-d6 13.51 (s, 1H), 8.96 (br s, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 4.15–4.10(m, 1H), 3.66 (d, J = 2.9 Hz, 1H), 3.60 (d, J = 10.4 Hz, 1H), 3.29–3.28 (m, 1H), 2.73–2.68 (m, 1H), 2.23–2.17 (m, 1H), 2.09 (d, J = 2.0 Hz, 1H), 2.05–1.94 (m, 2H), 1.75–1.72 (m, 2H), 1.60–1.56 (m, 1H), 0.99–0.90 (m, 4H); ESI MS m / z 417 [C17H20Cl2N2O4S – H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 5.36 min. Example 54 Scheme 34: ANA-134Preparation of N-((1R,4R,5R)-2-Azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0231] N-((1R,4R,5R)-2-azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride was prepared according to Synthetic Scheme 29. Example 55 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(pyrimidin-2-yl)-2- azabicyclo[2.2.2]octan-5-yl)benzamide [ANA-134]

[0232] To a slurry of N-((1R,4R,5R)-2-azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro- 2-hydroxybenzamide hydrochloride (0.041 g, 0.12 mmol) in ethanol (1.00 mL) was added 2-chloropyrimidine (0.014 g, 0.13 mmol) and N,N-diisopropylethylamine (0.063 mL). The resulting solution was heated to 120 °C in a sealed microwave vessel for 3h under microwave irradiation, then cooled to room temperature and concentrated under reducedpressure. The crude reaction mixture was filtered rinsing with ethyl acetate (20 mL). The filtrate was washed with saturated sodium chloride solution (10 mL), and the organic was dried over sodium sulfate, filtered and concentrated under reduced pressure to dryness. The crude film was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford 3,5-dichloro-2-hydroxy-N-((1R,4R,5R)-2-(pyrimidin-2-yl)-2- azabicyclo[2.2.2]octan-5-yl)benzamide (0.007 g, 15%) as a white solid:1H NMR (500 MHz, DMSO-d6J = 25.1 Hz, 2H), 8.11 (br s, 1H), 7.72 (br s, 1H), 6.55 (t, J = 4.7 Hz, 1H), 4.76 (s, 1H), 4.28–4.20 (m, 1H), 3.65 (d, J = 12.2 Hz, 1H), 3.42 (d, J = 11.1 Hz, 1H), 2.26–2.19 (m, 1H), 2.14–2.10 (m, 1H), 1.96–1.86 (m, 1H), 1.82–1.73 (m, 2H), 1.72–1.63 (m, 2H); ESI MS m / z 391 [C18H18Cl2N4O2– H]-; UPLC (BEH C18, Method A) >99% (area%), tR = 3.91 min. Example 56 Scheme 35: ANA-135Preparation of N-((1R,5S,6r)-3-Azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0233] N-((1R,5S,6r)-3-azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride was prepared according to Synthetic Scheme 29. Example 57 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,5S,6r)-3-(pyridazin-3-yl)-3- azabicyclo[3.1.1]heptan-6-yl)benzamide [ANA-135]

[0234] In a sealable reaction vessel was charged N-((1R,5S,6r)-3- azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (0.050 g, 0.15 mmol), 3-bromopyridazine (0.028 g, 0.18 mmol), ethanol (1.25 mL) and N,N- diisopropylethylamine (0.080 mL, 0.46 mmol). The reaction vessel was sealed and the solution was heated to 120 °C and held for 21 h. After this time, the reaction was cooled to room temperature and concentrated under reduced pressure. The crude residue was dissolved in dichloromethane (20 mL) and washed with a saturated aqueous solution of ammonium chloride (10 mL). The aqueous phase was back extracted three times with dichloromethane (10 mL each). The combined organic phase was washed with a saturated solution of sodium chloride (10 mL), then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was adsorbed onto a plug of silica gel and purified by column chromatography (silica gel, 0–90% 84:15:1 dichloromethane / methanol / ammonium hydroxide / dichloromethane). Desired fractions were concentrated under reduced pressure and then taken up in acetonitrile (0.3 mL) / 0.5 N hydrochloric acid (0.3 mL), frozen and lyophilized to afford 3,5-dichloro-2-hydroxy-N- ((1R,5S,6r)-3-(pyridazin-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl)benzamide (0.012 g, 6%) as a brown solid:1H NMR (500 MHz, DMSO-d6J = 3.3 Hz, 1H), 8.68 (d, J = 3.5 Hz, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.92–7.90 (m, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 4.20–4.17 (m, 1H), 3.81 (s, 4H), 2.92 (t, J = 5.8 Hz, 2H), 2.11–2.07 (m, 1H), 1.59 (d, J = 9.8 Hz, 1H); ESI MS m / z 377 [C17H16Cl2N4O2– H]-; UPLC (BEH C18, Method A) 95.2% (area%), tR= 3.26 min. Example 58 Scheme 36: ANA-136Preparation of N-((1R,5S,6r)-3-Azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0235] N-((1R,5S,6r)-3-azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride was prepared according to Synthetic Scheme 29. Example 59 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,5S,6r)-3-(pyridin-2-yl)-3- azabicyclo[3.1.1]heptan-6-yl)benzamide [ANA-136]

[0236] A microwave tube was charged with N-((1R,5S,6r)-3- azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (0.050 g, 0.15 mmol), 2-fluoropyridine (0.017 g, 0.18 mmol), ethanol (1.50 mL) and N,N- diisopropylethylamine (0.080 mL, 0.46 mmol). The tube was sealed and the solution was heated to 120 °C and held for 4 d. After this time, the reaction was cooled to room temperature and concentrated under reduced pressure. The crude residue was dissolved in dichloromethane (30 mL) and washed with a saturated solution of sodium chloride (20 mL). The aqueous phase was back extracted with dichloromethane (10 mL). The combined organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was adsorbed onto a plug of silica gel and purifiedby column chromatography (silica gel, 0–10% methanol / dichloromethane) to afford 3,5- dichloro-2-hydroxy-N-((1R,5S,6r)-3-(pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-6- yl)benzamide (0.013 g, 23%) as a light yellow solid:1H NMR (500 MHz, DMSO-d613.2 (br s, 1H), 8.95 (br s, 1H), 8.08–8.07 (m, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.68 (s, 1H), 7.51–7.48 (m, 1H), 6.58 (q, J = 12.1, 5.4 Hz, 2H), 4.12 (q, J = 5.6, 2.3 Hz, 1H), 3.62 (q, J = 19.4, 11.6 Hz, 4H), 2.86 (t, J = 5.6 Hz, 2H), 2.04–1.99 (m, 1H), 1.48 (d, J = 9.4 Hz, 1H); ESI MS m / z 378 [C18H17Cl2N3O2+ H]+; UPLC (BEH C18, Method A) 97.7% (area%), tR= 3.59 min. Example 60 Scheme 37: ANA-137Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,5S,6r)-3-(pyrimidin-2-yl)-3- azabicyclo[3.1.1]heptan-6-yl)benzamide

[0237] 3,5-dichloro-2-hydroxy-N-((1R,5S,6r)-3-(pyrimidin-2-yl)-3- azabicyclo[3.1.1]heptan-6-yl)benzamide was prepared according to Synthetic Scheme 34. Example 61 Preparation of Sodium 2,4-Dichloro-6-(((1R,5S,6r)-3-(pyrimidin-2-yl)-3- azabicyclo[3.1.1]heptan-6-yl)carbamoyl)phenolate [ANA-137]4357-P1WO -132-

[0238] To a slurry of 3,5-dichloro-2-hydroxy-N-((1R,5S,6r)-3-(pyrimidin-2-yl)-3- azabicyclo[3.1.1]heptan-6-yl)benzamide (0.030 g, 0.079 mmol) in acetonitrile (0.40 mL) and water (0.45 mL) was added a 2 N aqueous solution of sodium hydroxide (0.050 mL, 0.10 mmol). The resulting solution was frozen and lyophilized to provide sodium 2,4- dichloro-6-(((1R,5S,6r)-3-(pyrimidin-2-yl)-3-azabicyclo[3.1.1]heptan-6- yl)carbamoyl)phenolate (0.035 g, >99%) as a white solid:1H NMR (500 MHz, DMSO-d6) 8.36 (d, J = 4.7 Hz, 2H), 7.48 (d, J = 3.1 Hz, 1H), 7.03 (d, J = 3.1 Hz, 1H), 6.64 (t, J = 4.7 Hz, 1H), 4.34 (t, J = 6.0 Hz, 1H), 3.86 (d, J = 12.6 Hz, 2H), 3.53 (d, J = 12.4 Hz, 2H), 2.65 (t, J = 5.7 Hz, 2H), 1.93–1.88 (m, 1H), 1.36 (d, J = 9.5 Hz, 1H); ESI MS m / z 377 [C17H15Cl2N4O2– H]-; UPLC (BEH C18, Method A) >99% (area%), tR= 3.71 min. Example 62 Scheme 38: ANA-138Preparation of N-((1R,5S,6r)-3-Azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0239] N-((1R,5S,6r)-3-Azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride was prepared according to Synthetic Scheme 29. Example 63 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,5S,6r)-3-(1-methyl-1H-1,2,4-triazol-3- yl)-3-azabicyclo[3.1.1]heptan-6-yl)benzamide [ANA-138]OH Cl Cl

[0240] Under a nitrogen atmosphere, sodium trimethylsilanolate (0.042 g, 0.38 mmol), N-((1R,5S,6r)-3-azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (0.050 g, 0.15 mmol) and 3-bromo-1-methyl-1H-1,2,4-triazole (0.020 g, 0.12 mmol) were charged to a microwave tube. Tetrahydrofuran (degassed with nitrogen prior to addition, 0.5mL) was then added, followed by GPhos palladium G6 bromide (0.004 g, 0.006 mmol). The resulting slurry was degassed with nitrogen for 1 min, the tube was sealed and placed into an oil bath pre-heated to 80 °C for 19 h. After this time, the reaction was filtered, rinsing with tetrahydrofuran (5 mL). The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (10 mL). The solution was washed with saturated aqueous ammonium chloride (10 mL), and the organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to provide 3,5-dichloro-2-hydroxy-N-((1R,5S,6r)-3-(1- methyl-1H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.1]heptan-6-yl)benzamide (0.005 g, 11%) as a white solid:1H NMR (500 MHz, DMSO-d6(s, 1H), 7.87 (br s, 1H), 7.69 (br s, 1H), 4.09 (br s, 1H), 3.64 (s, 3H), 3.58–3.51 (m, 4H), 2.76 (br s, 2H), 2.00–1.95 (m, 1H), 1.48 (d, J = 9.4 Hz, 1H); ESI MS m / z 382 [C16H17Cl2N5O2+ H]+; UPLC (BEH C18, Method A) 97.6% (area%), tR= 3.91 min. Example 64 Scheme 39: ANA-139Preparation of N-((1R,5S,6r)-3-Azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0241] N-((1R,5S,6r)-3-Azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride was prepared according to Synthetic Scheme 29. Example 65 Preparation of 3,5-Dichloro-N-((1R,5S,6r)-3-(4-(cyclobutylamino)pyrimidin-2-yl)-3- azabicyclo[3.1.1]heptan-6-yl)-2-hydroxybenzamide [ANA-139]

[0242] A sealable reaction vessel was charged with N-((1R,5S,6r)-3- azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2-hydroxybenzamide hydrochloride (0.050 g, 0.15 mmol), 2-chloro-N-cyclobutylpyrimidin-4-amine (0.029 g, 0.16 mmol), dimethyl sulfoxide (0.5 mL) and N,N-diisopropylethylamine (0.130 mL, 0.742 mmol). The reaction vessel was sealed and the solution was heated to 120 °C and held for 21 h. After this time, the reaction slurry was cooled to room temperature and diluted in methanol. The resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The crude residue was purified by a second trituration in methanol followed by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford 3,5-dichloro-N-((1R,5S,6r)-3-(4-(cyclobutylamino)pyrimidin-2-yl)-3- azabicyclo[3.1.1]heptan-6-yl)-2-hydroxybenzamide (0.03 g, 5%) as a yellow solid:1HNMR (500 MHz, DMSO-d6 + 4 drops d- J = 2.5 Hz, 1H), 7.75 (d, J = 2.5Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 6.08 (d, J = 7.2 Hz, 1H), 4.43 (quint, J = 8.0 Hz, 1H), 4.14 (t, J = 6.0 Hz, 1H), 3.87 (dd, J = 13.1, 2.7 Hz, 1H), 3.76 (d, J = 12.7 Hz, 1H), 3.70– 3.65 (m, 2H), 2.90–2.87 (m, 2H), 2.34–2.24 (m, 2H), 2.08–2.03 (m, 1H), 2.01–1.91 (m,2H), 1.77–1.69 (m, 2H), 1.54 (d, J = 9.7 Hz, 1H); ESI MS m / z 448 [C21H23Cl2N5O2+ H]+; UPLC (BEH C18, Method A) 90.7% (area%), tR= 4.36 min. Example 66 Scheme 40: ANA-140Preparation of (3,5-Dichloro-2-hydroxyphenyl)(piperazin-1-yl)methanone Hydrochloride

[0243] (3,5-Dichloro-2-hydroxyphenyl)(piperazin-1-yl)methanone hydrochloride was prepared according to Synthetic Scheme 29. Preparation of N-Cyclobutyl-1H-imidazole-1-carboxamide

[0244] N-Cyclobutyl-1H-imidazole-1-carboxamide was prepared according to Synthetic Scheme 31. Example 67 Preparation of N-Cyclobutyl-4-(3,5-dichloro-2-hydroxybenzoyl)piperazine-1- carboxamide [ANA-140]

[0245] A sealable reaction vessel was charged with (3,5-dichloro-2- hydroxyphenyl)(piperazin-1-yl)methanone hydrochloride (0.080 g, 0.26 mmol), N- cyclobutyl-1H-imidazole-1-carboxamide (0.085 g, 0.51 mmol), dimethyl sulfoxide (0.8 mL) and N,N-diisopropylethylamine (0.175 mL, 1.03 mmol). The reaction vessel wassealed and the solution was heated to 120 °C and held for 19 h. After this time, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography (C18 silica gel, 10– 100% acetonitrile / water) to afford N-cyclobutyl-4-(3,5-dichloro-2- hydroxybenzoyl)piperazine-1-carboxamide (0.053 g, 55%) as a white solid:1H NMR (500 MHz, DMSO-d6 J = 2.5 Hz, 1H), 7.22 (d, J = 2.5 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 4.13–4.04 (m, 1H), 3.54 (br s, 2H), 3.28 (br s, 4H), 3.13 (br s, 2H), 2.13–2.07 (m, 2H), 1.93–1.85 (m, 2H), 1.61–1.50 (m, 2H); ESI MS m / z 370 [C16H19Cl2N3O3– H]-; UPLC (BEH C18, Method A) 98.1% (area%), tR= 3.42 min. Example 68 Scheme 41: ANA-141Preparation of tert-Butyl (S)-2-(3-Hydroxy-3-methylpyrrolidin-1-yl)acetate

[0246] To a sealable reaction vessel under a nitrogen atmosphere was charged (S)- 3-methylpyrrolidin-3-ol hydrochloride (0.100 g, 0.727 mmol), potassium carbonate (0.251 g, 1.82 mmol) and acetonitrile (1.9 mL). The resulting suspension was cooled in an ice bath and tert-butyl 2-bromoacetate (0.170 g, 0.872 mmol) was added. The vessel was sealed and held at 80 °C for 3 h. After this time, the mixture was diluted in ethyl acetate (10 mL) and washed with water (10 mL). The organic phase was separated and the aqueous phase was back extract with ethyl acetate (10 mL). The combined organic phase was thenwashed with a saturated solution of sodium carbonate (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl (S)-2-(3-hydroxy-3- methylpyrrolidin-1-yl)acetate (0.066 g, 42%) as a colorless film:1H NMR (500 MHz, DMSO-d6J = 2.6 Hz, 2H), 2.17–2.67 (m, 1H), 2.64–2.60 (m, 1H), 2.57–2.53 (m, 2H), 1.72–1.64 (m, 2H), 1.41–1.40 (m, 9H), 1.22 (s, 3H). Preparation of (S)-2-(3-Hydroxy-3-methylpyrrolidin-1-yl)acetic Acid

[0247] To a solution of tert-butyl (S)-2-(3-hydroxy-3-methylpyrrolidin-1- yl)acetate (0.064 g, 0.30 mmol) in dichloromethane (2.2 mL) was charged trifluoroacetic acid (0.960 mL). The vessel was sealed and held at ambient temperature for 3.5 h. After this time, the mixture was concentrated under reduced pressure. The residue was then taken up in diethyl ether (~ 2 mL) and concentrated under reduced pressure. This operation was repeated for a total of five times and then placed under high vacuum at ambient temperature to afford (S)-2-(3-hydroxy-3-methylpyrrolidin-1-yl)acetic acid (0.081 g, >99%) which was used without further purification or analysis. Preparation of N-((1R,4R,5R)-2-Azabicyclo[2.2.1]heptan-5-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride

[0248] N-((1R,4R,5R)-2-azabicyclo[2.2.1]heptan-5-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride was prepared as a light brown solid according to Synthetic Scheme 1; ESI MS m / z 299 [C13H14Cl2N2O2– H]-. Example 69 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(2-((S)-3-hydroxy-3- methylpyrrolidin-1-yl)acetyl)-2-azabicyclo[2.2.1]heptan-5-yl)benzamide [ANA-141]

[0249] 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(2-((S)-3-hydroxy-3- methylpyrrolidin-1-yl)acetyl)-2-azabicyclo[2.2.1]heptan-5-yl)benzamide was prepared according to Synthetic Scheme 1. With completion of the reaction, the solution was charged dropwise into stirring water (19 mL) chilled in an ice-bath. The reaction was extracted into ethyl acetate (20 mL). The organic phase was separated and washed with an aqueous solution of 5% lithium chloride (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to provide the title compound as a white solid:1H NMR (500 MHz, DMSO-d6s, 1H), 9.01 (br s, 1H), 8.04 (d, J = 13.1 Hz, 1H), 7.75 (s, 1H), 5.31–5.28 (m, 1H), 4.46– 4.27 (m, 2H), 4.18–4.11 (m, 2H), 3.77–3.43 (m, 2H), 3.40 (d, J = 11.5 Hz, 1H), 3.21 (d, J = 11.0 Hz, 1H), 3.11–2.87 (m, 2H), 2.20–2.09 (m, 1H), 1.96 (br s, 2H), 1.77–1.64 (m, 3H), 1.34 (s, 3H); ESI MS m / z 440 [C20H25Cl2N3O4– H]-; UPLC (BEH C18, Method A) 97.3% (AUC), tR= 3.59min. Example 70 Scheme 42: ANA-142 OPreparation of N-((1R,3r,5S)-8-Azabicyclo[3.2.1]octan-3-yl)-3,5-dichloro-2- hydroxybenzamide Hydrochloride4357-P1WO -139-

[0250] N-((1R,3r,5S)-8-Azabicyclo[3.2.1]octan-3-yl)-3,5-dichloro-2- hydroxybenzamide hydrochloride was prepared as a white solid according to Synthetic Scheme 29; ESI MS m / z 313 [C14H16Cl2N2O2– H]-. Example 71 Preparation of Sodium 2-(((1R,3r,5S)-8-acetyl-8-azabicyclo[3.2.1]octan-3- yl)carbamoyl)-4,6-dichlorophenolate [ANA-142] O

[0251] To an ice-cold mixture of N-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)- 3,5-dichloro-2-hydroxybenzamide hydrochloride (0.053 g, 0.15 mmol) was charged triethylamine (0.065 mL, 0.47 mmol) and acetic anhydride (0.015 g, 0.15 mmol). The heterogeneous mixture was allowed to gradually warm to ambient temperature and was held for 19 h. After this time, the reaction was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted into ethyl acetate (30 mL). The aqueous phase was back extracted with ethyl acetate (20 mL) and the combined organic phase was dried over sodium sulfate, filtered and concentrated under reduce pressure. The crude residue was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to provide sodium 2-(((1R,3r,5S)-8-acetyl-8-azabicyclo[3.2.1]octan-3- yl)carbamoyl)-4,6-dichlorophenolate:1H NMR (500 MHz, DMSO-d6J = 4.7 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 4.40–4.39 (m, 1H), 4.16 (br s, 1H), 3.90–3.89 (m, 1H), 2.26 (s, 3H), 2.08–1.92 (m, 5H), 1.98–1.75 (m, 3H); ESI MS m / z 355 [C16H17Cl2N2NaO3– H]-; UPLC (BEH C18, Method A) 97.6% (AUC), tR= 3.81 min. Example 72 Scheme 43: ANA-143Preparation of Ethyl 5-(3,5-dichloro-2-hydroxybenzoyl)-5-azaspiro[2.5]octane-1- carboxylate

[0252] Ethyl 5-(3,5-dichloro-2-hydroxybenzoyl)-5-azaspiro[2.5]octane-1- carboxylate was prepared as a viscous, brown oil according to Synthetic Scheme 29 with the following modification: the crude oil was purified by column chromatography (silica gel, 0-2% methanol / dichloromethane): ESI MS m / z 370 [C17H19Cl2NO4– H]-. Preparation of 5-(3,5-Dichloro-2-hydroxybenzoyl)-5-azaspiro[2.5]octane-1- carboxylic Acid

[0253] To a solution of ethyl 5-(3,5-dichloro-2-hydroxybenzoyl)-5- azaspiro[2.5]octane-1-carboxylate (0.519 g, 1.40 mmol) in tetrahydrofuran (3.1 mL) and water (3.1 mL) was charged a 2 N aqueous solution of sodium hydroxide (1.4 mL). The resulting solution was held at ambient temperature overnight. After this time, the reaction was acidified to pH 3 with a 2 N aqueous solution of hydrochloric acid and extracted into ethyl acetate (30 mL). The organic phase was isolated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting yellow foam was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford 5-(3,5-dichloro-2-hydroxybenzoyl)-5-azaspiro[2.5]octane-1-carboxylic acid (0.15 g, 31%) as a white foam: ESI MS m / z 342 [C15H15Cl2NO4– H]-.Example 73 Preparation of N-(Cyclobutylmethyl)-5-(3,5-dichloro-2-hydroxybenzoyl)-5- azaspiro[2.5]octane-1-carboxamide [ANA-143]

[0254] N-(Cyclobutylmethyl)-5-(3,5-dichloro-2-hydroxybenzoyl)-5- azaspiro[2.5]octane-1-carboxamide was prepared as a light brown solid according to Synthetic Scheme 29 with the following modifications: The isolated solid was then purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water):1H NMR (500 MHz,DMSO-d6(d, J = 2.1 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 3.50 (br s, 1H), 3.27–3.07 (m, 3H), 2.98 (br s, 1H), 2.38–2.35 (m, 1H), 1.96–1.92 (m, 2H), 1.84–1.23 (m, 10.5H), 0.91–0.80 (m, 1.5H); ESI MS m / z 409 [C20H24Cl2N2O3– H]-; UPLC (BEH C18, Method A) 95.9% (AUC), tR= 4.26 min. Example 74 Scheme 44: ANA-144Preparation of Benzyl (2-(Methylamino)-2-oxoethyl)carbamate

[0255] Benzyloxycarbonylglycine (2.41 g, 11.5 mmol) was dissolved in methylene chloride (50 mL) and methylamine hydrochloride (930 mg, 13.8 mmol) was added. To this solution was added diisopropylethylamine (8.02 mL, 46.1 mmol) followed by dropwise addition of propylphosphonic anhydride (10.20 mL, 17.28 mmol). The reaction was thenstirred overnight at room temperature. The mixture was quenched with saturated sodium bicarbonate (50 mL), then extracted with methylene chloride (3 × 50 mL). The combined organic layers were dried over sodium sulfate, then filtered and concentrated under reduced pressure. Purified by column chromatography (silica gel, 0–6% methanol / methylene chloride) to provide benzyl (2-(methylamino)-2-oxoethyl)carbamate as a white solid (2.20 g, 89%): ESI MS m / z 223 [C11H14N2O3 + H]+. Preparation of 2-Amino-N-methylacetamide

[0256] To the benzyl (2-(methylamino)-2-oxoethyl)carbamate (2.17 g, 9.77 mmol) in methanol (40 mL) under an argon atmosphere was added palladium on carbon (10 wt%). The flask was evacuated and purged with hydrogen three times and then left to stir overnight under a hydrogen balloon. The mixture was evacuated and purged with argon three times and then filtered through celite and the celite washed with methanol x 3. The solvents were removed in vacuo and the residue taken up in acetonitrile (10 mL) and concentrated under reduced pressure to give 2-amino-N-methylacetamide (0.86 g, 100%) as clear oil. Preparation of 2-Amino-N-methylacetamide Hydrochloride H

[0257] 2 M Hydrogen chloride in diethyl ether (2.30 mL, 4.45 mmol) was added dropwise to 2-amino-N-methylacetamide (200 g, 2.27 mmol) in diethyl ether (2 mL). The mixture was allowed to stir for 1 hour, then the mixture was concentrated under reduced pressure and used crude in the next step. Preparation of N-(2-(Methylamino)-2-oxoethyl)-1H-imidazole-1-carboxamide

[0258] To the 2-amino-N-methylacetamide hydrochloride (283 mg, 2.27 mmol) in N,N-dimethylformamide (2 mL) was added the carbonyl diimidazole (480 mg, 2.95 mmol)and the reaction allowed to stir for 2 hours at room temperature. This solution was then used crude in the next step. Example 75 Preparation of 4-(3,5-Dichloro-2-hydroxybenzamido)-N-(2-(methylamino)-2- oxoethyl)piperidine-1-carboxamide [ANA-144]

[0259] To the solution of N-(2-(methylamino)-2-oxoethyl)-1H-imidazole-1- carboxamide (431 mg, 2.27 mmol) formed in the previous step, was added 3,5-dichloro-2- hydroxy-N-(piperidin-4-yl)benzamide hydrochloride (740 mg, 2.27 mmol, synthesized via scheme 6) followed by diisopropylethylamine (1.20 mL, 6.80 mmol). The reaction was then stirred overnight at room temperature. In the morning, the reaction was concentrated under reduced pressure and purified by reverse phase column chromatography (C18 silica gel, 5–95% acetonitrile / water with 0.05% trifluoroacetic acid). Product fractions were combined, concentrated under reduced pressure and lyophilized overnight to give 4-(3,5- dichloro-2-hydroxybenzamido)-N-(2-(methylamino)-2-oxoethyl)piperidine-1- carboxamide J = 7.5 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 4.17–4.04 (m, 3H), 3.76 (s, 2H), 2.96 (m, 2H), 2.74 (s, 3H), 1.95 (m, 2H), 1.58 (qd, J = 4.0, 12.0 Hz, 2H); ESI MS m / z 403 [C16H20Cl2N4O4+ H]+; UPLC (BEH C18, Method A) 98.9% (AUC). Example 76 Scheme 45: ANA-145Preparation of (9H-Fluoren-9-yl)methyl (S)-(4-Methyl-1-(methylamino)-1- oxopentan-2-yl)carbamate

[0260] Fmoc-L-leucine (2.05 g, 5.80 mmol) was dissolved in methylene chloride (40 mL) and methylamine hydrochloride (430 mg, 6.38 mmol) was added. To this solution was added diisopropylethylamine (4.00 mL, 23.2 mmol) followed by dropwise addition of propylphosphonic anhydride (5.20 mL, 8.70 mmol). The reaction was then stirred overnight at room temperature. The mixture was quenched with saturated sodium bicarbonate (50 mL), then extracted with methylene chloride (3 × 50 mL). The combined organic layers were dried over sodium sulfate, then filtered and concentrated under reduced pressure. Purified by column chromatography (silica gel, 0–4% methanol / methylene chloride) to provide (9H-fluoren-9-yl)methyl (S)-(4-methyl-1-(methylamino)-1- oxopentan-2-yl)carbamate (1.80 g, 85%): ESI MS m / z 367 [C22H26N2O3+ H]+. Preparation of (S)-2-Amino-N,4-dimethylpentanamide

[0261] To the (9H-fluoren-9-yl)methyl (S)-(4-methyl-1-(methylamino)-1- oxopentan-2-yl)carbamate (367 mg, 1.00 mmol) in tetrahydrofuran (5 mL) was added the 1,8-diazabicyclo(5.4.0)undec-7-ene (15 μL, 0.1 mmol) followed by the 3-mercaptopropyl functionalized silica gel (2.00 g, 2.40 mmol) and the reaction stirred overnight at room temperature. The reaction mixture was then filtered, concentrated under reduced pressureand purified by column chromatography (silica gel, 0–50% CMA (80% chloroform, 18% methanol, 2% ammonium hydroxide) / methylene chloride) to give (S)-2-amino-N,4- dimethylpentanamide (120 mg, 83%) as a clear oil: ESI MS m / z 145 [C7H16N2O + H]+. Preparation of (S)-2-Amino-N,4-dimethylpentanamide Hydrochloride

[0262] 2 M Hydrogen chloride in diethyl ether (0.79 mL, 1.6 mmol) was added dropwise to (S)-2-amino-N,4-dimethylpentanamide (0.14 g, 0.79 mmol) in diethyl ether (3 mL) and acetonitrile (1 mL). The mixture was allowed to stir for 2 hours, then the mixture was concentrated under reduced pressure and used crude in the next step. Preparation of (S)-N-(4-Methyl-1-(methylamino)-1-oxopentan-2-yl)-1H-imidazole-1- carboxamide

[0263] To the (S)-2-amino-N,4-dimethylpentanamide hydrochloride (142 mg, 0.786 mmol) in N,N-dimethylformamide (3 mL) was added the carbonyl diimidazole (153 mg, 0.944 mmol) and the reaction allowed to stir for 2 hours at room temperature. This solution was then used crude in the next step. Example 77 Preparation of (S)-4-(3,5-Dichloro-2-hydroxybenzamido)-N-(4-methyl-1- (methylamino)-1-oxopentan-2-yl)piperidine-1-carboxamide [ANA-145] C

[0264] To the solution of (S)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)- 1H-imidazole-1-carboxamide (187 mg, 0.785 mmol) formed in the previous step, wasadded 3,5-dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride (215 mg, 0.660 mmol, synthesized via scheme 6) followed by diisopropylethylamine (0.35 mL, 2.0 mmol). The reaction was then stirred overnight at room temperature. In the morning, the reaction was concentrated under reduced pressure and purified by reverse phase column chromatography (C18 silica gel, 5–95% acetonitrile / water with 0.05% trifluoroacetic acid). Product fractions were combined, concentrated under reduced pressure and lyophilized overnight to give (S)-4-(3,5-dichloro-2-hydroxybenzamido)-N-(4-methyl-1- (methylamino)-1-oxopentan-2-yl)piperidine-1-carboxamide (164 mg, 54%) as an off- J = 7.5 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 4.25 (dd, J = 5.0, 10.0 Hz, 1H), 4.17–4.05 (m, 3H), 3.00– 2.89 (m, 2H), 2.73 (s, 3H), 1.94 (d, J = 12.0 Hz, 2H), 1.73–1.49 (m, 5H), 0.96 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H); ESI MS m / z 459 [C20H28Cl2N4O4+ H]+; UPLC (BEH C18, Method A) >99% (AUC) Example 78 Scheme 46: ANA-146Preparation of 2-Methylpropan-2-amine Hydrochloride H2N

[0265] 1 M Hydrogen chloride in diethyl ether (2.70 mL, 1.73 mmol) was added dropwise to 2-methylpropan-2-amine (100 mg, 1.36 mmol) in diethyl ether (5 mL). The mixture was allowed to stir for 1 hour, then the mixture was concentrated under reduced pressure and used crude in the next step. Preparation of N-(tert-Butyl)-1H-imidazole-1-carboxamide

[0266] To the 2-methylpropan-2-amine hydrochloride (150 mg, 1.36 mmol) in N,N-dimethylformamide (3 mL) was added the carbonyl diimidazole (222 mg, 1.36 mmol) and the reaction allowed to stir for 2 hours at room temperature. This solution was then used crude in the next step. Example 79 Preparation of N-(tert-Butyl)-4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxamide [ANA-146]

[0267] To the solution of N-(tert-butyl)-1H-imidazole-1-carboxamide (220 mg, 1.31 mmol) formed in the previous step, was added 3,5-dichloro-2-hydroxy-N-(piperidin- 4-yl)benzamide hydrochloride (200 mg, 0.66 mmol, synthesized via scheme 6) followed by diisopropylethylamine (0.32 mL, 2.0 mmol). The reaction was then stirred overnight at room temperature. In the morning, the reaction was concentrated under reduced pressure and purified by reverse phase column chromatography (C18 silica gel, 5–95% acetonitrile / water with 0.05% trifluoroacetic acid). Product fractions were combined, concentrated under reduced pressure and lyophilized overnight to give N-(tert-butyl)-4- (3,5-dichloro-2-hydroxybenzamido)piperidine-1-carboxamide (170 mg, 71%) as a white J = 7.5 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 4.13–4.04 (m, 1H), 4.02 (d, J = 13.5 Hz, 2H), 2.86 (m, 2H), 1.95– 1.88 (m, 2H), 1.53 (qd, J = 4.0, 12.0 Hz, 2H), 1.33 (s, 9H); ESI MS m / z 388 [C17H23Cl2N3O3 + H]+; UPLC (BEH C18, Method A) >99% (AUC). Scheme 47: ANA-147Preparation of tert-Butyl (R)-3-(Cyclobutylcarbamoyl)pyrrolidine-1-carboxylate

[0268] (R)-L-N-Boc-betaproline (800 mg, 3.71 mmol) was dissolved in methylene chloride (20 mL) and cyclobutanamine (290 mg, 4.09 mmol) was added. To this solution was added diisopropylethylamine (1.30 mL, 7.43 mmol) followed by dropwise addition of propylphosphonic anhydride (3.32 mL, 5.57 mmol). The reaction was then stirred overnight at room temperature. The mixture was quenched with saturated sodium bicarbonate (50 mL), then extracted with methylene chloride (3 × 50 mL). The combined organic layers were dried over sodium sulfate, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 0-6% methanol / methylene chloride) to provide tert-butyl (R)-3- (cyclobutylcarbamoyl)pyrrolidine-1-carboxylate (830 mg, 83%) as a clear oil: ESI MS m / z 269 [C14H24N2O3+ H]+. Preparation of (R)-N-Cyclobutylpyrrolidine-3-carboxamide Hydrochloride H

[0269] 1 M Hydrogen chloride in diethyl ether (4.92 mL, 4.92 mmol) was added dropwise to tert-butyl (R)-3-(cyclobutylcarbamoyl)pyrrolidine-1-carboxylate (220 mg, 0.82 mmol) in diethyl ether (3 mL) and methanol (1 mL). The mixture was allowed to stir overnight at room temperature. In the morning, the reaction concentrated under reducedpressure and placed on a high-vac line for 2 hours to give (R)-N-cyclobutylpyrrolidine-3- carboxamide hydrochloride (120 mg, 87%) as a white solid: ESI MS m / z 169 [C9H16N2O + H]+. Preparation of (R)-N-Cyclobutyl-1-(1H-imidazole-1-carbonyl)pyrrolidine-3- carboxamide

[0270] To the (R)-N-cyclobutylpyrrolidine-3-carboxamide hydrochloride (120 mg, 0.58 mmol) in N,N-dimethylformamide (1 mL) and acetonitrile (5 mL) was added the carbonyl diimidazole (114 mg, 0.703 mmol) and the reaction allowed to stir for 2 hours at room temperature. The mixture was then concentrated under reduced pressure and used crude in the next step. Preparation of (R)-N-Cyclobutyl-1-(4-(3,5-dichloro-2-hydroxybenzamido)piperidine- 1-carbonyl)pyrrolidine-3-carboxamide [ANA-147]

[0271] To the (R)-N-cyclobutyl-1-(1H-imidazole-1-carbonyl)pyrrolidine-3- carboxamide (153 mg, 0.583 mmol) in dimethyl sulfoxide was added 3,5-dichloro-2- hydroxy-N-(piperidin-4-yl)benzamide hydrochloride (158 mg, 0.485 mmol, synthesized via scheme 6) followed by diisopropylethylamine (0.25 mL, 1.5 mmol). The reaction was then stirred for 2 days at 130 °C. After this time, the reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (C18 silica gel, 5–95% acetonitrile / water with 0.05% trifluoroacetic acid). Product fractions were combined, concentrated under reduced pressure and lyophilized overnight. The solid was then re-purified by column chromatography (silica gel, 10–60% CMA (80% chloroform, 18% methanol, 2% ammonium hydroxide) / dichloromethane). Product fractions were combined, concentrated under reduced pressure and lyophilized overnight to give (R)-N-cyclobutyl-1-(4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1-carbonyl)pyrrolidine-3- carboxamide J = 7.5 Hz, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 4.33–4.23 (m, 1H), 4.15–4.06 (m, 1H), 3.87–3.76 (m, 2H), 3.58–3.42 (m, 4H), 3.00–2.84 (m, 3H), 2.32–2.23 (m, 2H), 2.12–1.89 (m, 6H), 1.78–1.52 (m, 4H); ESI MS m / z 483 [C22H28Cl2N4O4+ H]+; UPLC (BEH C18, Method A) 96.4% (AUC). Example 80

[0272] 1 M Hydrogen chloride in diethyl ether (4.40 mL, 4.40 mmol) was added dropwise to dimethylamine (2 M in tetrahydrofuran, 1.10 mL, 2.20 mmol) in diethyl ether (2 mL). The mixture was allowed to stir for 2 hours, then the mixture was concentrated under reduced pressure and used crude in the next step. Preparation of N,N-Dimethyl-1H-imidazole-1-carboxamide N

[0273] To the dimethylamine hydrochloride (180 mg, 2.20 mmol) in acetonitrile (6 mL) and N,N-dimethylformamide (1 mL) was added the carbonyl diimidazole (360 mg, 2.20 mmol) and the reaction allowed to stir for 18 hours at room temperature. This solution was then concentrated under reduced pressure and used crude in the next step. Example 81 Preparation of 4-(3,5-Dichloro-2-hydroxybenzamido)-N,N-dimethylpiperidine-1- carboxamide [ANA-148]

[0274] To the N,N-dimethyl-1H-imidazole-1-carboxamide (306 mg, 2.20 mmol) formed in the previous step, was added dimethyl sulfoxide (6 mL) and 3,5-dichloro-2- hydroxy-N-(piperidin-4-yl)benzamide hydrochloride (200 mg, 0.63 mmol, synthesized via scheme 6) followed by diisopropylethylamine (0.43 mL, 2.5 mmol). The reaction was then stirred for 2 days at 130 °C. After this time, the reaction was concentrated under reduced pressure and purified by reverse phase column chromatography (C18 silica gel, 5–95% acetonitrile / water with 0.05% trifluoroacetic acid). Product fractions were combined, concentrated under reduced pressure and lyophilized overnight. The solid was then re- purified by column chromatography (silica gel, 5-40% CMA (80% chloroform, 18% methanol, 2% ammonium hydroxide) / dichloromethane). Product fractions were combined, concentrated under reduced pressure and lyophilized overnight to give 4-(3,5-dichloro-2- hydroxybenzamido)-N,N-dimethylpiperidine-1-carboxamide (48 mg, 22%) as a white J = 2.5 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 4.13–4.05 (m, 1H), 3.71 (d, J = 13.5 Hz, 2H), 2.97–2.89 (m, 2H), 2.85 (s, 6H), 1.98–1.91 (m, 2H), 1.61 (qd, J = 4.0, 12.0 Hz, 2H); ESI MS m / z 360 [C15H19Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 99.0% (AUC). Example 82 Scheme 49: ANA-149Preparation of tert-Butyl (R)-(1-(Methylamino)-1-oxopropan-2-yl)carbamate

[0275] Boc-D-alanine-OH (1.30 g, 6.88 mmol) was dissolved in methylene chloride (25 mL) and methylamine hydrochloride (560 mg, 8.25 mmol) was added. To this solution was added diisopropylethylamine (4.80 mL, 27.5 mmol) followed by dropwise addition of propylphosphonic anhydride (6.20 mL, 10.3 mmol). The reaction was then stirred overnight at room temperature. The mixture was quenched with saturated sodium bicarbonate (100 mL), then extracted with methylene chloride (3 × 50 mL). The combined organic layers were dried over sodium sulfate, then filtered and concentrated under reduced pressure. Purified by column chromatography (silica gel, 0–8% methanol / methylene chloride) to provide tert-butyl (R)-(1-(methylamino)-1-oxopropan-2-yl)carbamate (1.17 g, 85%) as a white solid: ESI MS m / z 203 [C9H18N2O3+ H]+. Preparation of (R)-2-Amino-N-methylpropanamide Hydrochloride

[0276] 4 M Hydrogen chloride in 1,4-dioxane (0.96 mL, 3.8 mmol) was added dropwise to tert-butyl (R)-(1-(methylamino)-1-oxopropan-2-yl)carbamate (194 mg, 0.959 mmol) in 1,4-dioxane (3 mL). The mixture was allowed to stir overnight at room temperature. In the morning, the reaction concentrated under reduced pressure and placed on a high-vac line for 2 hours to give (R)-2-amino-N-methylpropanamide hydrochloride as a white solid which was used crude in the next step. Preparation of (R)-N-(1-(Methylamino)-1-oxopropan-2-yl)-1H-imidazole-1- carboxamide

[0277] To the (R)-2-amino-N-methylpropanamide hydrochloride (70 mg, 0.50 mmol) in N,N-dimethylformamide (5 mL) was added the carbonyl diimidazole (90 mg,0.55 mmol) and the reaction allowed to stir overnight at room temperature. The mixture was then used crude in the next step. Example 83 Preparation of (R)-4-(3,5-Dichloro-2-hydroxybenzamido)-N-(1-(methylamino)-1- oxopropan-2-yl)piperidine-1-carboxamide [ANA-149]

[0278] To the solution of (R)-N-(1-(methylamino)-1-oxopropan-2-yl)-1H- imidazole-1-carboxamide (91 mg, 0.38 mmol) formed in the previous step, was added 3,5- dichloro-2-hydroxy-N-(piperidin-4-yl)benzamide hydrochloride (63 mg, 0.19 mmol, synthesized via scheme 6) followed by diisopropylethylamine (0.10 mL, 0.58 mmol). The reaction was then stirred overnight at room temperature. In the morning, the reaction was concentrated under reduced pressure and purified by reverse phase column chromatography (C18 silica gel, 5-95% acetonitrile / water with 0.05% trifluoroacetic acid). Product fractions were combined, concentrated under reduced pressure and lyophilized to give (R)-4-(3,5-dichloro-2-hydroxybenzamido)-N-(1-(methylamino)-1-oxopropan-2- yl)piperidine-1-carboxamide (85 mg, 40%) as a white solid: 1H NMR (500 MHz, MeOD) J = 2.5 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 4.21 (q, J = 7.5 Hz, 1H), 4.17–4.05 (m, 3H), 3.00–2.89 (m, 2H), 2.73 (s, 3H), 1.95 (m, 2H), 1.64–1.50 (m, 2H), 1.33 (d, J = 7.0 Hz, 3H); ESI MS m / z 417 [C17H22Cl2N4O4+ H]+; UPLC (BEH C18, Method A) >99% (AUC). Scheme 50: ANA-150Example 84Preparation of 2-(4-(3,5-Dichloro-2-hydroxybenzamido)piperidin-1-yl)pyrimidine-5- carboxylic Acid [ANA-150]

[0279] To the methyl 2-(4-(3,5-dichloro-2-hydroxybenzamido)piperidin-1- yl)pyrimidine-5-carboxylate (41 mg, 0.096 mmol, synthesized via scheme 7) was added tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL). Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was then added and the reaction stirred for 4 hours at room temperature. After this time, the reaction was acidified with 2 N aqueous hydrogen chloride to pH 4 and concentrated under reduced pressure. The resulting solids were taken up in water and filtered and washed with water and diethyl ether to give 2-(4-(3,5-dichloro- 2-hydroxybenzamido)piperidin-1-yl)pyrimidine-5-carboxylic acid (35 mg, 90%) as a white solid: 1H NMR (500 MHz, DMSO-d6J = 6.0 Hz, 1H), 8.78 (s, 2H), 8.03 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H), 4.75 (d, J = 13.0 Hz, 2H), 4.26–4.16 (m, 1H), 3.22–3.13 (m, 2H), 1.95 (dd, J = 2.5, 12.0 Hz, 2H), 1.53 (qd, J = 3.5, 12.0 Hz, 2H); ESI MS m / z 411 [C17H16Cl2N4O4+ H]+; UPLC (BEH C18, Method A) 97.0% (AUC). Example 85 Scheme 51: ANA-151Preparation of N-Cyclobutyl-2-(4-(3,5-dichloro-2-hydroxybenzamido)piperidin-1- yl)pyrimidine-5-carboxamide [ANA-151]

[0280] To the 2-(4-(3,5-dichloro-2-hydroxybenzamido)piperidin-1-yl)pyrimidine- 5-carboxylic acid (31 mg, 0.075 mmol, synthesized via scheme 8) was added methylene chloride (1 mL) and N,N-dimethylformamide (1 mL).1-[Bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (43 mg, 0.11 mmol) was then added followed by diisopropylethylamine (0.04 mL, 0.2 mmol) and the reaction stirred overnight at room temperature. In the morning, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, 5–40% ethyl acetate / methylene chloride). The product fractions were combined, concentrated under reduced pressure and lyophilized to give N-cyclobutyl-2-(4-(3,5- dichloro-2-hydroxybenzamido)piperidin-1-yl)pyrimidine-5-carboxamide (17 mg, 50%) as J = 7.5 Hz, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 4.89 (d, J = 13.5 Hz, 2H), 4.47 (m, 1H), 4.25 (m, 1H), 3.18–3.10 (m, 2H), 2.39–2.29 (m, 2H), 2.14–2.00 (m, 4H), 1.82–1.72 (m, 2H), 1.59 (qd, J = 4.0, 12.0 Hz, 2H); ESI MS m / z 464 [C21H23Cl2N5O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC). Example 86 Scheme 52: ANA-152Preparation of N-(Azetidin-3-yl)-4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxamide [ANA-152]

[0281] To the tert-butyl 3-(4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxamido)azetidine-1-carboxylate (126 mg, 0.258 mmol, synthesized via scheme 5) in 1,4-dioxane (5 mL) was added 4 N hydrochloric acid in 1,4-dioxane (0.26 mL, 1.0 mmol) and the reaction stirred overnight at room temperature. In the morning, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, 20–90% CMA (80% chloroform, 18% methanol, 2% ammonium hydroxide) / methylene chloride). The product fractions were combined, concentrated under reduced pressure and lyophilized to give N-(azetidin-3-yl)-4-(3,5-dichloro-2- hydroxybenzamido)piperidine-1-carboxamide (57 mg, 57%) as a white solid: 1H NMR J = 3.0 Hz, 1H), 7.27 (d, J = 3.0 Hz, 1H), 4.50 (t, J = 8.0 Hz, 1H), 4.25–4.15 (m, 2H), 4.13–4.06 (m, 1H), 3.87–3.78 (m, 2H), 3.30–3.22 (m, 2H), 3.02 (dd, J = 4.5, 13.0 Hz, 1H), 2.85 (dd, J = 7.0, 13.0 Hz, 1H), 2.04–1.95 (m, 2H), 1.68–1.56 (m, 2H); ESI MS m / z 387 [C16H20Cl2N4O3+ H]+; UPLC (BEH C18, Method A) 96.0% (AUC). Example 87 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(methylsulfonyl)piperidin-4- yl)benzamide [ANA-153]

[0282] 3,5-Dichloro-2-hydroxy-N-(1-(methylsulfonyl)piperidin-4-yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d6J = 5.0 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 4.00–3.91 (m, 1H), 3.60 (d, J = 12.3 Hz, 2H), 2.86 (td, J = 12.2, 2.4 Hz, 2H),2.50 (s, 3H), 1.94 (dd, J = 12.6, 2.7 Hz, 2H), 1.57 (qd, J = 12.2, 4.2 Hz, 2H); ESI MS m / z 367 [C13H16Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 96.6% (AUC), tR= 4.26 min. Example 88 Preparation of N-(1-Acetylpiperidin-4-yl)-2-hydroxy-5-methylbenzamide [ANA-154] O

[0283] N-(1-Acetylpiperidin-4-yl)-2-hydroxy-5-methylbenzamide was prepared as an off-white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d613.29 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.20 (dd, J = 8.3, 1.9 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 4.34 (d, J = 13.9 Hz, 1H), 4.11–4.01 (m, 1H), 3.83 (d, J = 14.6 Hz, 1H), 3.14 (td, J = 13.0, 2.8 Hz, 1H), 2.67 (td, J = 12.5, 2.8 Hz, 1H), 2.24 (s, 3H), 2.02 (s, 3H), 1.86 (d, J = 10.7 Hz, 1H), 1.80 (d, J = 12.4 Hz, 1H), 1.50 (qd, J = 12.1, 4.2 Hz, 1H), 1.39 (qd, J = 12.5, 4.6 Hz, 1H); ESI MS m / z 277 [C15H20N2O3+ H]+; UPLC (BEH C18, Method A) 97.0% (AUC), tR= 3.10 min. Example 89 Preparation of N-(1-Acetylpiperidin-4-yl)-3-chloro-2-hydroxybenzamide [AN-155] O

[0284] N-(1-Acetylpiperidin-4-yl)-3-chloro-2-hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d613.67 (s, 1H), 8.83 (d, J = 5.8 Hz, 1H), 7.68 (dd, J = 8.1, 1.5 Hz, 1H), 7.60 (dd, J = 7.9, 1.4 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 4.37 (d, J = 13.3 Hz, 1H), 4.12–4.01 (m, 1H), 3.85 (d, J = 13.8 Hz, 1H), 3.14 (td, J = 13.0, 2.7 Hz, 1H), 2.65 (td, J = 13.0, 2.7 Hz, 1H), 2.01 (s, 3H), 1.87 (dd, J = 12.5, 1.9 Hz, 1H), 1.82 (dd, J = 12.8, 2.3 Hz, 1H), 1.52 (qd, J = 12.4, 4.4 Hz, 1H), 1.41 (qd, J = 12.4, 4.4 Hz, 1H); ESI MS m / z 297 [C14H17ClN2O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR = 3.37 min.Example 90 Preparation of N-(1-Acetylpiperidin-4-yl)-2-hydroxybenzamide [ANA-156]

[0285] N-(1-Acetylpiperidin-4-yl)-2-hydroxybenzamide was prepared as an off- white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d6J = 5.0 Hz, 1H), 8.57 (d, J = 7.7 Hz, 1H), 7.87 (dd, J = 8.4, 1.5 Hz, 1H), 7.39 (td, J = 7.8, 1.6 Hz, 1H), 6.91–6.86 (m, 2H), 4.34 (d, J = 13.6 Hz, 1H), 4.11–4.021 (m, 1H), 3.83 (d, J = 14.4 Hz, 1H), 3.14 (td, J = 13.0, 2.7 Hz, 1H), 2.67 (td, J = 12.7, 2.8 Hz, 1H), 2.02 (s, 3H), 1.87 (dd, J = 12.2, 2.3 Hz, 1H), 1.82 (dd, J = 12.7, 2.3 Hz, 1H), 1.50 (qd, J = 12.2, 4.3 Hz, 1H), 1.40 (qd, J = 12.3, 4.4 Hz, 1H); ESI MS m / z 263 [C14H18N2O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 2.74 min. Example 91 Preparation of N-(1-Acetylpiperidin-4-yl)-4-bromo-2-hydroxybenzamide [ANA-157]

[0286] N-(1-Acetylpiperidin-4-yl)-4-bromo-2-hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d612.82 (br s, 1H), 8.63 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 5.5, 2.0 Hz, 1H), 4.32 (d, J = 13.6 Hz, 1H), 4.10–4.00 (m, 1H), 3.82 (d, J = 14.4 Hz, 1H), 3.14 (td, J = 12.9, 2.7 Hz, 1H), 2.68 (td, J = 12.3, 2.8 Hz, 1H), 2.01 (s, 3H), 1.87 (d, J = 11.5 Hz, 1H), 1.81 (dd, J = 12.7, 2.2 Hz, 1H), 1.49 (qd, J = 12.2, 4.2 Hz, 1H), 1.38 (qd, J = 12.2, 4.3 Hz, 1H); ESI MS m / z 342 [C14H17BrN2O3+ H]+; UPLC (BEH C18, Method A) 95.7% (AUC), tR= 3.53 min. Example 92 Preparation of N-(1-Acetylpiperidin-4-yl)-3-hydroxy-2-naphthamide [ANA-158]

[0287] N-(1-Acetylpiperidin-4-yl)-3-hydroxy-2-naphthamide was prepared as an off-white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d6(s, 1H), 8.84 (d, J = 7.6 Hz, 1H), 8.50 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.50 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 7.34 (ddd, J = 8.2, 6.8, 1.1 Hz, 1H), 7.27 (s, 1H), 4.33 (d, J = 13.8 Hz, 1H), 4.17–4.08 (m, 1H), 3.85 (d, J = 13.8 Hz, 1H), 3.18 (td, J = 12.9, 2.7 Hz, 1H), 2.74 (td, J = 12.6, 2.8 Hz, 1H), 2.03 (s, 3H), 1.94 (dd, J = 12.6, 2.3 Hz, 1H), 1.88 (dd, J = 12.7, 2.4 Hz, 1H), 1.55 (qd, J = 12.1, 4.2 Hz, 1H), 1.44 (qd, J = 12.2, 4.4 Hz, 1H); ESI MS m / z 311 [C18H20N2O3- H]-; UPLC (BEH C18, Method A) 97.0% (AUC), tR= 3.45 min. Example 93 Preparation of N-(1-Benzoylpiperidin-4-yl)-3,5-dichloro-2-hydroxybenzamide [ANA- 159]

[0288] N-(1-Benzoylpiperidin-4-yl)-3,5-dichloro-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 8:1H NMR (500 MHz, DMSO- d6–7.43 (m, 3H), 7.40–7.35 (m, 2H), 4.50–4.36 (m, 1H), 4.18–4.07 (m, 1H), 3.69–3.50 (m, 1H), 3.24–3.10 (m, 1H), 3.08–2.88 (m, 1H), 2.01–1.70 (m, 2H), 1.67–1.40 (m, 2H); ESI MS m / z 393 [C19H18Cl2N2O3 + H]+; UPLC (BEH C18, Method A) 98.4% (AUC), tR = 5.15 min. Example 94 Preparation of N-(1-Acetylpiperidin-4-yl)-3-bromo-2-hydroxy-5-methylbenzamide [ANA-160]

[0289] N-(1-Acetylpiperidin-4-yl)-3-bromo-2-hydroxy-5-methylbenzamide was prepared as an off-white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d6J = 7.7 Hz, 1H), 7.73 (d, J = 1.3 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 4.37 (d, J = 13.4 Hz, 1H), 4.12–4.02 (m, 1H), 3.85 (d, J = 14.0 Hz, 1H), 3.13 (td, J = 13.0, 2.6 Hz, 1H), 2.65 (td, J = 12.8, 2.6 Hz, 1H), 2.25 (s, 3H), 2.02 (s, 3H), 1.87 (dd, J = 12.7, 2.1 Hz, 1H), 1.81 (dd, J = 12.7, 2.1 Hz, 1H), 1.51 (qd, J = 12.4, 4.3 Hz, 1H), 1.41 (qd, J = 12.4, 4.4 Hz, 1H); ESI MS m / z 355 [C15H19BrN2O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 3.82 min. Example 95 Preparation of 3,5-Dichloro-N-(1-(2-cyclopropylacetyl)piperidin-4-yl)-2- hydroxybenzamide [ANA-161]

[0290] 3,5-Dichloro-N-(1-(2-cyclopropylacetyl)piperidin-4-yl)-2- hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6–3.92 (m, 2H), 3.70 (d, J = 13.4 Hz, 1H), 3.23 (t, J = 10.5 Hz, 2H), 3.00 (t, J = 10.0 Hz, 1H), 2.26 (t, J = 6.5 Hz, 2H), 1.89–1.75 (m, 2H), 1.36 (q, J = 9.4 Hz, 1H), 1.27 (q, J = 7.3 Hz, 1H), 1.00–0.90 (m, 1H), 0.48–0.41 (m, 2H), 0.13–0.09 (m, 2H); ESI MS m / z 371 [C17H20Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 98.1% (AUC), tR= 4.53 min. Example 96 Preparation of N-(1-Acetylpiperidin-4-yl)-5-chloro-4-hydroxy-[1,1'-biphenyl]-3- carboxamide [ANA-162]

[0291] N-(1-Acetylpiperidin-4-yl)-5-chloro-4-hydroxy-[1,1'-biphenyl]-3- carboxamide was prepared as a white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d6J = 7.5 Hz, 1H), 8.17 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 4.40 (d, J = 13.3 Hz, 1H), 4.19–4.10 (m, 1H), 3.87 (d, J = 14.1 Hz, 1H), 3.15 (td, J = 13.1, 2.5 Hz, 1H), 2.66 (td, J = 13.2, 2.3 Hz, 1H), 2.03 (s, 3H), 1.91 (dd, J = 12.7, 2.1 Hz, 1H), 1.85 (dd, J = 12.6, 2.1 Hz, 1H), 1.53 (qd, J = 12.4, 4.3 Hz, 1H), 1.43 (qd, J = 12.5, 4.4 Hz, 1H); ESI MS m / z 373 [C20H21ClN2O3+ H]+; UPLC (BEH C18, Method A) 95.7% (AUC), tR= 4.51 min. Example 97 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(3,3,3-trifluoropropanoyl)piperidin-4- yl)benzamide [ANA-163]

[0292] 3,5-Dichloro-2-hydroxy-N-(1-(3,3,3-trifluoropropanoyl)piperidin-4- yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 6.7 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.36 (d, J = 13.6 Hz, 1H), 4.15–4.05 (m, 1H), 3.88 (d, J = 13.3 Hz, 1H), 3.79–3.56 (m, 2H), 3.16 (td, J = 13.0, 2.5 Hz, 1H), 2.75 (td, J = 12.8, 2.7 Hz, 1H), 1.90–1.83 (m, 2H), 1.53 (qd, J = 12.4, 4.2 Hz, 1H), 1.41 (qd, J = 12.4, 4.4 Hz, 1H); ESI MS m / z 399 [C15H15Cl2F3N2O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.57 min. Example 98Preparation of N-(1-Acetylpiperidin-4-yl)-3-fluoro-2-hydroxybenzamide [ANA-164] O

[0293] N-(1-Acetylpiperidin-4-yl)-3-fluoro-2-hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d612.94 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.39 (ddd, J = 11.0, 8.0, 1.5 Hz, 1H), 6.88 (td, J = 8.0, 5.0 Hz, 1H), 4.35 (d, J = 13.5 Hz, 1H), 4.12–4.02 (m, 1H), 3.84 (d, J = 14.1 Hz, 1H), 3.14 (td, J = 13.0, 2.6 Hz, 1H), 2.67 (td, J = 12.7, 2.7 Hz, 1H), 2.02 (s, 3H), 1.87 (dd, J = 11.6, 2.0 Hz, 1H), 1.81 (dd, J = 12.7, 2.0 Hz, 1H), 1.51 (qd, J = 12.3, 4.3 Hz, 1H), 1.40 (qd, J = 12.3, 4.4 Hz, 1H); ESI MS m / z 281 [C14H17FN2O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 2.87 min. Example 99 Preparation of N-(1-Acetylpiperidin-4-yl)-3-bromo-2-hydroxybenzamide [ANA-165]

[0294] N-(1-Acetylpiperidin-4-yl)-3-bromo-2-hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d613.79 (s, 1H), 8.82 (d, J = 7.7 Hz, 1H), 7.92 (dd, J = 8.0, 1.4 Hz, 1H), 7.74 (dd, J = 7.9, 1.4 Hz, 1H), 6.86 (t, J = 7.9 Hz, 1H), 4.37 (d, J = 13.5 Hz, 1H), 4.13–4.02 (m, 1H), 3.85 (d, J = 13.9 Hz, 1H), 3.13 (td, J = 13.1, 2.6 Hz, 1H), 2.65 (td, J = 12.9, 2.7 Hz, 1H), 2.02 (s, 3H), 1.87 (dd, J = 12.8, 2.2 Hz, 1H), 1.81 (dd, J = 12.7, 2.1 Hz, 1H), 1.51 (qd, J = 12.4, 4.3 Hz, 1H), 1.41 (qd, J = 12.4, 4.4 Hz, 1H); ESI MS m / z 341 [C14H17BrN2O3- H]-; UPLC (BEH C18, Method A) 97.8% (AUC), tR= 3.11 min. Example 100 Preparation of 3,5-Dichloro-N-(1-(2-cyclobutylacetyl)piperidin-4-yl)-2- hydroxybenzamide [ANA-166]

[0295] 3,5-Dichloro-N-(1-(2-cyclobutylacetyl)piperidin-4-yl)-2- hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 6.7, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 4.36 (d, J = 13.4 Hz, 1H), 4.12–4.03 (m, 1H), 3.89 (d, J = 13.6 Hz, 1H), 3.10 (t, J = 11.9 Hz, 1H), 2.58–2.52 (m, 2H), 2.46 (t, J = 6.8 Hz, 2H), 2.09– 2.00 (m, 2H), 1.91–1.84 (m, 1H), 1.84–1.75 (m , 3H), 1.65 (quint, J = 9.0 Hz, 2H), 1.47 (qd, J = 12.0, 4.0 Hz, 1H), 1.36 (qd, J = 12.0, 4.0 Hz, 1H); ESI MS m / z 385 [C18H22Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 96.1% (AUC), tR= 4.87 min. Example 101 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-picolinoylpiperidin-4-yl)benzamide [ANA-167]

[0296] 3,5-Dichloro-2-hydroxy-N-(1-picolinoylpiperidin-4-yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 4.9, 1.0 Hz, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.94 (td, J = 7.7, 1.8 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.55 (dt, J = 7.8, 1.0 Hz, 1H), 7.48 (ddd, J = 7.7, 4.9, 1.2 Hz, 1H), 4.51 (d, J = 13.4 Hz, 1H), 4.21–4.11 (m, 1H), 3.70 (d, J = 13.8 Hz, 1H), 3.16 (td, J = 12.9, 2.5 Hz, 1H), 2.96 (td, J = 12.7, 2.8 Hz, 1H), 1.86 (dd, J = 12.9, 2.3 Hz, 1H), 1.80 (d, J = 12.6, 2.1 Hz, 1H), 1.68–1.53 (m, 2H); ESI MS m / z 392 [C18H17Cl2N3O3- H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.09 min. Example 102Preparation of 3,5-Dichloro-N-(1-(3,3-dimethylbutanoyl)piperidin-4-yl)-2- hydroxybenzamide [ANA-168]

[0297] 3,5-Dichloro-N-(1-(3,3-dimethylbutanoyl)piperidin-4-yl)-2- hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 7.5 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 4.46 (d, J = 13.3 Hz, 1H), 4.13–4.05 (m, 1H), 4.02 (d, J = 13.7 Hz, 1H), 3.12 (t, J = 12.3 Hz, 1H), 2.63 (t, J = 12.8 Hz, 1H), 2.25 (s, 2H), 1.85 (t, J = 11.6 Hz, 2H), 1.48 (qd, J = 11.9, 3.5 Hz, 1H), 1.38 (qd, J = 11.9, 3.8 Hz, 1H), 1.00 (s, 9H); ESI MS m / z 385 [C18H24Cl2N2O3- H]-; UPLC (BEH C18, Method A) 97.5% (AUC), tR= 4.95 min. Example 103 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(2-phenylacetyl)piperidin-4- yl)benzamide [ANA-169]

[0298] 3,5-Dichloro-2-hydroxy-N-(1-(2-phenylacetyl)piperidin-4-yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (300 MHz, DMSO-d6J = 7.5 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.37–7.20 (m, 5H), 4.40 (d, J = 13.8 Hz, 1H), 4.14–3.95 (m, 2H), 3.77 (d, J = 15.3 Hz, 1H), 3.71 (d, J = 15.0 Hz, 1H), 3.12 (t, J = 13.2 Hz, 1H), 2.71 (t, J = 11.4 Hz, 1H), 1.81 (t, J = 9.9 Hz, 2H), 1.46–1.24 (m, 2H); ESI MS m / z 407 [C20H20Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 98.5% (AUC), tR= 4.80 min. Example 104Preparation of N-(1-Acetylpiperidin-4-yl)-2-hydroxy-3-nitrobenzamide [ANA-170]

[0299] N-(1-Acetylpiperidin-4-yl)-2-hydroxy-3-nitrobenzamide was prepared as a yellow-green solid according to Synthetic Scheme 1:1H NMR (300 MHz, DMSO-d614.37 (br s, 1H), 9.03 (d, J = 7.7 Hz, 1H), 8.21 (dd, J = 8.0, 1.6 Hz, 1H), 8.10 (dd, J = 8.2, 1.5 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 4.37 (d, J = 13.2 Hz, 1H), 4.18–4.03 (m, 1H), 3.85 (d, J = 14.7 Hz, 1H), 3.14 (td, J = 12.9, 2.3 Hz, 1H), 2.67 (td, J = 12.7, 2.6 Hz, 1H), 2.02 (s, 3H), 1.86 (td, J = 15.0, 2.6 Hz, 2H), 1.51 (qd, J = 12.2, 4.2 Hz, 1H), 1.40 (qd, J = 12.2, 4.2 Hz, 1H); ESI MS m / z 308 [C14H17N3O5+ H]+; UPLC (BEH C18, Method A) 95.2% (AUC), tR= 2.82 min. Example 105 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-propionylpiperidin-4-yl)benzamide [ANA-171]

[0300] 3,5-Dichloro-2-hydroxy-N-(1-propionylpiperidin-4-yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 7.1 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 4.38 (d , J = 13.4 Hz, 1H), 4.11–4.03 (m, 1H), 3.88 (d, J = 13.9 Hz, 1H), 3.53– 3.30 (m, 1H), 3.11 (t, J = 11.8 Hz, 1H), 2.33 (qd, J = 7.3, 2.0 Hz, 2H), 1.87 (d, J = 12.1 Hz, 1H), 1.83 (d, J = 11.3 Hz, 1H), 1.48 (qd, J = 12.0, 3.9 Hz, 1H), 1.39 (qd, J = 12.0, 3.9 Hz, 1H), 1.00 (t, J = 7.4 Hz, 3H); ESI MS m / z 345 [C15H18Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 96.6% (AUC), tR= 4.25 min. Example 106Preparation of N-(1-Acetylpiperidin-4-yl)-2-hydroxy-5-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)benzamide [ANA-172]

[0301] N-(1-Acetylpiperidin-4-yl)-2-hydroxy-5-(2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)benzamide was prepared as a light brown solid according to Synthetic Scheme 16:1H NMR (500 MHz, DMSO-d6 10.63 (s, 1H), 8.07 (s, 1H), 7.61 (d, J = 6.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.13 (s, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 4.34 (d, J = 11.1 Hz, 1H), 4.16–4.06 (m, 1H), 3.84 (d, J = 12.0 Hz, 1H), 3.16 (t, J = 11.4 Hz, 1H), 2.70 (t, J = 12.0 Hz, 1H), 2.02 (s, 3H), 1.92 – 1.78 (m, 3H), 1.52 (qd, J = 11.3, 4.1 Hz, 1H), 1.42 (qd, J = 13.3, 3.8 Hz, 1H); ESI MS m / z 395 [C21H22N4O4+ H]+; UPLC (BEH C18, Method A) 95.1% (AUC), tR= 2.83 min. Example 107 Preparation of 3,5-Dichloro-N-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2- hydroxybenzamide [ANA-173]

[0302] 3,5-Dichloro-N-(1-(cyclopropanecarbonyl)piperidin-4-yl)-2- hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 7.6 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.78–7.76 (m, 1H), 4.40–4.22 (m, 2H), 4.16–4.06 (m, 1H), 3.27–3.15 (m, 1H), 2.78–2.55 (m, 1H), 2.05–1.98 (m, 1H), 1.98–1.78 (m, 2H), 1.59–1.33 (m, 2H), 0.78–0.65 (m, 4H); ESI MS m / z 357 [C16H18Cl2N2O3 - H]-; UPLC (BEH C18, Method A) 98.1% (AUC), tR= 4.38 min.Example 108 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(2-(pyridin-2-yl)acetyl)piperidin-4- yl)benzamide [ANA-174]

[0303] 3,5-Dichloro-2-hydroxy-N-(1-(2-(168yridine-2-yl)acetyl)piperidin-4- yl)benzamide was prepared as a yellow-green solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6–8.46 (m, 1H), 8.02 (d, J = 2.2 Hz, 1H), 7.78–7.71 (m, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.25 (dd, J = 7.4, 4.9 Hz, 1H), 4.37 (d, J = 13.3 Hz, 1H), 4.12–4.03 (m, 2H), 3.92 (d, J = 14.9 Hz, 1H), 3.87 (d, J = 14.9 Hz, 1H), 3.15 (t, J = 12.0 Hz, 1H), 2.73 (t, J = 12.2 Hz, 1H), 1.88–1.80 (m, 2H), 1.46–1.34 (m, 2H); ESI MS m / z 408 [C19H19Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 95.1% (AUC), tR= 3.50 min. Example 109 Preparation of N-(1-Acetylpiperidin-4-yl)-3-cyano-2-hydroxybenzamide [ANA-175]

[0304] N-(1-Acetylpiperidin-4-yl)-3-cyano-2-hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 1:1H NMR (500 MHz, DMSO-d614.17 (s, 1H), 8.96 (d, J = 7.5 Hz, 1H), 8.22 (dd, J = 8.1, 1.5 Hz, 1H), 7.90 (dd, J = 7.7, 1.5 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 4.37 (d, J = 13.4 Hz, 1H), 4.14–4.05 (m, 1H), 3.85 (d, J = 14.0 Hz, 1H), 3.14 (td, J = 13.0, 2.7 Hz, 1H), 2.66 (td, J = 12.8, 2.6 Hz, 1H), 2.02 (s, 3H), 1.88 (dd, J = 11.1, 2.0 Hz, 1H), 1.83 (dd, J = 12.7, 2.1 Hz, 1H), 1.51 (qd, J = 12.3, 4.3 Hz, 1H), 1.41 (qd, J = 12.3, 4.3 Hz, 1H); ESI MS m / z 288 [C15H17N3O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 3.00 min. Example 110Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(5- (trifluoromethyl)picolinoyl)piperidin-4-yl)benzamide [ANA-176]

[0305] 3,5-Dichloro-2-hydroxy-N-(1-(5-(trifluoromethyl)picolinoyl)piperidin-4- yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6–9.00 (m, 1H), 8.97 (d, J = 7.7 Hz, 1H), 8.37 (dd, J = 8.2, 1.9 Hz, 1H), 8.05 (d, J = 2.5 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 4.51 (d, J = 13.4 Hz, 1H), 4.22–4.12 (m, 1H), 3.61 (d, J = 14.3 Hz, 1H), 3.40–3.30 (m, 1H), 3.19 (td, J = 12.9, 2.7 Hz, 1H), 3.01 (td, J = 13.0, 2.8 Hz, 1H), 1.98 (dd, J = 12.8, 2.3 Hz, 1H), 1.81 (dd, J = 12.6, 2.3 Hz, 1H), 1.67–1.55 (m, 1H); ESI MS m / z 462 [C19H16Cl2F3N3O3+ H]+; UPLC (BEH C18, Method A) 99.0% (AUC), tR= 5.12 min. Example 111 Preparation of 3,5-Dichloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-2- hydroxybenzamide [ANA-177]

[0306] 3,5-Dichloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6– 3.94 (m, 1H), 3.65 (d, J = 11.9 Hz, 2H), 2.97 (td, J = 12.3, 2.3 Hz, 2H), 2.61–2.56 (m, 1H), 1.93 (d, J = 10.5 Hz, 2H), 1.62 (qd, J = 12.0, 3.8 Hz, 2H), 1.02–0.96 (m, 2H), 0.96–0.90 (m, 2H); ESI MS m / z 393 [C15H18Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 97.2% (AUC), tR= 4.72 min. Example 112Preparation of 3,5-Dichloro-N-(trans-4-((cyclopropylmethyl)carbamoyl)cyclohexyl)- 2-hydroxybenzamide [ANA-178]

[0307] 3,5-Dichloro-N-(trans-4-((cyclopropylmethyl)carbamoyl)cyclohexyl)-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 10:1H NMR (500 MHz, DMSO-d6J = 2.4 Hz, 1H), 7.78 (t, J = 5.5 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 3.84–3.72 (m, 1H), 2.93 (t, J = 6.1 Hz, 2H), 3.14 (tt, J = 11.6, 3.3 Hz, 1H), 1.89 (d, J = 11.8 Hz, 2H), 1.78 (d, J = 12.1 Hz, 2H), 1.50– 1.32 (m, 4H), 0.91–0.82 (m, 1H), 1.38 (dq, J = 8.1, 4.3 Hz, 2H), 0.15–0.10 (m, 2H); ESI MS m / z 385 [C18H22Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 95.1% (AUC), tR= 4.60 min. Example 113 Preparation of 3,5-Dichloro-N-(trans-4-((cyclobutylmethyl)carbamoyl)cyclohexyl)-2- hydroxybenzamide [ANA-179]

[0308] 3,5-Dichloro-N-(trans-4-((cyclobutylmethyl)carbamoyl)cyclohexyl)-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 10:1H NMR (500 MHz, DMSO-d6J = 2.3 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.69 (t, J = 5.7 Hz, 1H), 3.83–3.73 (m, 1H), 3.06 (t, J = 6.6 Hz, 2H), 2.42–2.33 (m, 1H), 2.09 (tt, J = 11.7, 3.2 Hz, 1H), 1.98–1.85 (m, 4H), 1.84–1.72 (m, 4H), 1.68–1.59 (m, 2H), 1.50–1.32 (m, 4H); ESI MS m / z 399 [C19H24Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 95.1% (AUC), tR= 4.84 min. Example 114Preparation of 3,5-Dichloro-2-hydroxy-N-((1-isobutyrylpiperidin-4- yl)methyl)benzamide [ANA-180]

[0309] 3,5-Dichloro-2-hydroxy-N-((1-isobutyrylpiperidin-4-yl)methyl)benzamide was prepared as an off-white solid according to Synthetic Scheme 8:1H NMR (500 MHz, DMSO-d6J = 5.6 Hz 1H), 7.49 (d, J = 3.1 Hz, 1H), 7.06 (d, J = 3.1 Hz, 1H), 4.40 (d , J = 13.9 Hz, 1H), 3.94 (d, J = 14.5 Hz, 1H), 3.14 (t, J = 6.1 Hz, 2H), 3.00–2.92 (m, 1H), 2.90–2.79 (m, 1H), 1.78–1.61 (m, 3H), 1.11–1.01 (m, 1H), 1.00–0.92 (m, 8H), amide NH not observed; ESI MS m / z 373 [C17H22Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 97.2% (AUC), tR= 4.63 min. Example 115 Preparation of 3,5-Dichloro-2-hydroxy-N-((1-(3-methylbutanoyl)piperidin-4- yl)methyl)benzamide [ANA-181]

[0310] 3,5-Dichloro-2-hydroxy-N-((1-(3-methylbutanoyl)piperidin-4- yl)methyl)benzamide was prepared as a white solid according to Synthetic Scheme 8:1H NMR (500 MHz, DMSO-d6J = 5.2 Hz, 1H), 7.49 (d, J = 3.2 Hz, 1H), 7.06 (d, J = 2.9 Hz, 1H), 4.40 (d, J = 10.9 Hz, 1H), 3.88 (d , J = 13.0 Hz, 1H), 3.13 (t, J = 6.2 Hz, 2H), 2.94 (t, J = 11.8 Hz, 1H), 2.60–2.51 (m, 1H), 2.17 (dd, J = 6.9, 1.8 Hz, 2H), 1.96 (quint, J = 6.6 Hz, 1H), 1.75–1.61 (m, 3H), 1.11–1.02 (m, 1H), 1.02–0.92 (m, 1H), 0.88 (dd, J = 6.5, 1.6 Hz, 6H), amide NH not observed; ESI MS m / z 387 [C18H24Cl2N2O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.82 min. Example 116 Preparation of N-((1-Acetylpiperidin-4-yl)methyl)-3,5-dichloro-2- hydroxybenzamide [ANA-182]

[0311] N-((1-Acetylpiperidin-4-yl)methyl)-3,5-dichloro-2-hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 8:1H NMR (500 MHz, DMSO-d6J = 13.2 Hz, 1H), 3.79 (d, J = 13.6 Hz, 1H), 3.24–3.15 (m, 2H), 2.97 (td, J = 12.9, 2.6 Hz, 1H), 2.47– 2.44 (m, 1H), 1.97 (s, 3H), 1.86–1.74 (m, 1H), 1.69 (t, J = 15.3 Hz, 2H), 1.12 (qd, J = 12.0, 4.1 Hz, 1H), 0.99 (qd, J = 12.0, 4.1 Hz, 1H); ESI MS m / z 345 [C15H18Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 98.5% (AUC), tR= 4.07 min. Example 117 Preparation of N-(1-Acetylpiperidin-4-yl)-3,5-dichloro-2- hydroxybenzenesulfonamide [ANA-183]

[0312] N-(1-Acetylpiperidin-4-yl)-3,5-dichloro-2-hydroxybenzenesulfonamide was prepared as a white solid according to Synthetic Scheme 14:1H NMR (500 MHz, DMSO-d6J = 2.3 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 2.6 Hz, 1H), 4.10 (d, J = 14.5 Hz, 1H), 3.67 (d, J = 14.3 Hz, 1H), 3.40–3.34 (m, 1H), 3.02 (ddd, J = 14.1, 11.2, 2.9 Hz, 1H), 2.68–2.60 (m, 1H), 1.94 (s, 3H), 1.67–1.55 (m, 2H), 1.80 (qd, J = 11.6, 4.1 Hz, 1H), 1.25 (qd, J = 11.6, 4.2 Hz, 1H); ESI MS m / z 367 [C13H16Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 90.0% (AUC), tR= 3.82 min. Example 118 Preparation of 3,5-Dichloro-2-hydroxy-N-((1-(isopropylsulfonyl)piperidin-4- yl)methyl)benzamide [AN-184]

[0313] 3,5-Dichloro-2-hydroxy-N-((1-(isopropylsulfonyl)piperidin-4- yl)methyl)benzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6J = 5.6 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 3.64 (d, J = 12.6 Hz, 2H), 3.40–3.18 (m, 3H), 2.85 (td, J = 12.6, 2.0 Hz, 2H), 1.97 (s, 1H), 1.73 (d, J = 12.5 Hz, 2H), 1.20 (d, J = 6.7 Hz, 6H), 1.15– 1.10 (m, 2H); ESI MS m / z 409 [C16H22Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 98.8% (AUC), tR= 5.32 min. Example 119 Preparation of 3,5-Dichloro-N-(1-(ethylsulfonyl)piperidin-4-yl)-2- hydroxybenzamide [ANA-185]

[0314] 3,5-Dichloro-N-(1-(ethylsulfonyl)piperidin-4-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO- d6–3.95 (m, 1H), 3.64 (d, J = 12.3 Hz, 2H), 3.07 (q, J = 7.4 Hz, 2H), 2.95 (td, J = 11.4, 2.0 Hz, 2H), 1.90 (d, J = 9.8 Hz, 2H), 1.61 (qd, J = 7.9, 4.0 Hz, 2H), 1.21 (t, J = 7.4 Hz, 3H); ESI MS m / z 381 [C14H18Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 95.2% (AUC), tR= 5.09 min. Example 120 Preparation of 4-(3,5-Dichloro-2-hydroxybenzamido)-N-methylpiperidine-1- carboxamide [ANA-186]

[0315] 4-(3,5-Dichloro-2-hydroxybenzamido)-N-methylpiperidine-1-carboxamide was prepared as a white solid according to Synthetic Scheme 5:1H NMR (500 MHz, DMSO-d6J = 4.4 Hz,1H), 4.03–3.99 (m, 1H), 3.94 (d, J = 13.1 Hz, 2H), 2.76 (t, J = 11.9 Hz, 2H), 2.57 (d, J = 4.4 Hz, 3H), 1.76 (dd, J = 12.4, 2.8 Hz, 2H), 1.42 (q, J = 11.9 Hz, 2H); ESI MS m / z 346 [C14H17Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 98.4% (AUC), tR= 4.36 min. Example 121 Preparation of 3,5-Dichloro-N-((1-(ethylsulfonyl)piperidin-4-yl)methyl)-2- hydroxybenzamide [ANA-187]

[0316] 3,5-Dichloro-N-((1-(ethylsulfonyl)piperidin-4-yl)methyl)-2- hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d63.59 (d, J = 12.1 Hz, 2H), 3.22 (t, J = 6.1 Hz, 2H), 3.01 (q, J = 7.4 Hz, 2H), 2.76 (td, J = 12.3, 2.2 Hz, 2H), 1.79–1.68 (m, 3H), 1.24–1.14 (m, 5H); ESI MS m / z 395 [C15H20Cl2N2O4S + H]+; UPLC (BEH C18, Method A) >99% (AUC), tR = 4.79 min. Example 122 Preparation of 3,5-Dichloro-N-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-2- hydroxybenzamide [ANA-188]

[0317] 3,5-Dichloro-N-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6 3.60 (d, J = 12.0 Hz, 2H), 3.22 (t, J = 6.1 Hz, 2H), 2.79 (td, J = 12.2, 2.1 Hz, 2H), 2.59– 2.54 (m, 1H), 1.77 (d, J = 12.6 Hz, 2H), 1.75–1.68 (m, 1H), 1.22 (qd, J = 12.6, 3.7 Hz, 2H), 0.99–0.94 (m, 2H), 0.94–0.88 (m, 2H); ESI MS m / z 407 [C16H20Cl2N2O4S + H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.83 min. Example 123Preparation of N-(Cyclobutylmethyl)-4-(3,5-dichloro-2- hydroxybenzamido)piperidine-1-carboxamide [ANA-189]

[0318] N-(Cyclobutylmethyl)-4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxamide was prepared as a white solid according to Synthetic Scheme 5:1H NMR (500 MHz, DMSO-d6J = 5.4 Hz, 1H), 4.05–3.91 (m, 3H), 3.05 (dd, J = 7.0, 5.5 Hz, 2H), 2.75 (t, J = 12.6 Hz, 2H), 2.40 (quint, J = 7.5 Hz, 1H), 1.97–1.89 (m, 2H), 1.83–1.72 (m, 4H), 1.68–1.59 (m, 2H), 1.41 (q, J = 10.5 Hz, 2H); ESI MS m / z 400 [C18H23Cl2N3O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.69 min. Example 124 Preparation of 3,5-Dichloro-N-((1R,3r,5S)-8-(2-cyclobutylacetyl)-8- azabicyclo[3.2.1]octan-3-yl)-2-hydroxybenzamide [ANA-190]

[0319] 3,5-Dichloro-N-((1R,3r,5S)-8-(2-cyclobutylacetyl)-8- azabicyclo[3.2.1]octan-3-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 29 with the following modifications: the crude reaction mixture was charged to a stirred solution of 5% lithium chloride (20 mL) and extracted into ethyl acetate (20 mL). The aqueous phase was back extracted with ethyl acetate (2 × 20 mL). The combined organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was then purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) followed by precipitation from methanol to afford the title compound:1H NMR (500 MHz, DMSO-d61H), 8.72 (br s, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 4.43–4.42 (m, 1H), 4.25 (br s, 1H), 3.98 (br s, 1H), 2.63–2.57 (m, 1H), 2.48–2.43 (m, 1H), 2.36–2.31 (m, 1H), 2.13–1.89 (m, 8H), 1.84–1.76 (m, 4H), 1.71–1.61 (m, 2H); ESI MS m / z 409 [C20H24Cl2N2O3– H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.88 min. Example 125 Preparation of 1-(2-(5-Chloro-2,3-dihydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)- 2-cyclobutylethan-1-one [ANA-191] OH O

[0320] 1-(2-(5-Chloro-2,3-dihydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)-2- cyclobutylethan-1-one was prepared as a white solid according to Synthetic Scheme 29 with the following modification: the crude residue was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water):1H NMR (500 MHz,DMSO-d6J = 2.1 Hz, 1H), 7.26 (d, J = 34.3 Hz, 1H), 3.52–3.36 (m, 7H), 3.14 (s, 1H), 2.63–2.54 (m, 1H), 2.42 (dd, J = 23.0, 7.2 Hz, 2H), 2.02 (br s, 2H), 1.80–1.75 (m, 4H), 1.68–1.36 (m, 6H); ESI MS m / z 423 [C21H26Cl2N2O3– H]-; UPLC (BEH C18, Method A) 98.8% (AUC), tR= 4.45 min. Example 126 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(phenylsulfonyl)piperidin-4- yl)benzamide [ANA-192]

[0321] 3,5-Dichloro-2-hydroxy-N-(1-(phenylsulfonyl)piperidin-4-yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6–7.71 (m, 4H), 7.69–7.64 (m, 2H), 3.85–3.76 (m, 1H), 3.67 (d, J = 12.2 Hz, 2H), 2.44 (t, J = 12.4 Hz, 2H), 1.90 (d, J =10.2 Hz, 2H), 1.61 (qd, J = 12.0, 3.8 Hz, 2H); ESI MS m / z 429 [C18H18Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 96.8% (AUC), tR= 5.21 min. Example 127 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-((trifluoromethyl)sulfonyl)piperidin-4- yl)benzamide [ANA-193]

[0322] 3,5-Dichloro-2-hydroxy-N-(1-((trifluoromethyl)sulfonyl)piperidin-4- yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d64.18–4.08 (m, 1H), 3.84 (d, J = 13.4 Hz, 2H), 3.38 (t, J = 12.1 Hz, 2H), 1.98 (d, J = 11.4 Hz, 2H), 1.62 (qd, J = 11.7, 3.3 Hz, 2H); ESI MS m / z 421 [C13H13Cl2F3N2O4S + H]+; UPLC (BEH C18, Method A) 96.2% (AUC), tR= 5.33 min. Example 128 Preparation of 1-(2-(5-Chloro-2,3-dihydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)- 2-methylpropan-1-one [ANA-194]

[0323] 1-(2-(5-Chloro-2,3-dihydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)-2- methylpropan-1-one was prepared as a white solid according to Synthetic Scheme 29 with the following modification: the crude residue was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water):1H NMR (500 MHz,DMSO-d6 J = 1.9 Hz, 1H), 7.26 (d, J = 34.0 Hz, 1H), 3.54–3.35 (m, 7H), 3.15 (s, 1H), 2.88–2.81 (m, 1H), 1.81–1.77 (m, 2H), 1.57–1.38 (m, 4H), 0.99–0.96 (m, 6H); ESI MS m / z 397 [C19H24Cl2N2O3– H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.06 min.Example 129 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(2-(4- (trifluoromethyl)phenyl)acetyl)piperidin-4-yl)benzamide [ANA-195]

[0324] 3,5-Dichloro-2-hydroxy-N-(1-(2-(4- (trifluoromethyl)phenyl)acetyl)piperidin-4-yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d68.90 (br s, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.37 (d, J = 13.3 Hz, 1H), 4.12–3.98 (m, 2H), 3.91–3.81 (m, 2H), 3.17 (t, J = 12.0 Hz, 1H), 2.74 (t, J = 12.0 Hz, 1H), 1.85 (d, J = 12.0 Hz, 2H), 1.47–1.35 (m, 2H); ESI MS m / z 475 [C21H19Cl2F3N2O3+ H]+; UPLC (BEH C18, Method A) 95.1% (AUC), tR= 5.34 min. Example 130 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(4-(trifluoromethyl)benzoyl)piperidin- 4-yl)benzamide [ANA-196]

[0325] 3,5-Dichloro-2-hydroxy-N-(1-(4-(trifluoromethyl)benzoyl)piperidin-4- yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 8.0 Hz, 2H), 7.76, (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 4.50–4.42 (m, 1H), 4.19–4.08 (m, 1H), 3.57–3.48 (m, 1H), 3.25–3.16 (m, 1H), 3.05–2.94 (m, 1H), 2.01–1.92 (m, 1H), 1.86–1.78 (m, 1H), 1.65–1.54 (m, 1H), 1.54–1.43 (m, 1H); ESI MS m / z 461 [C20H17Cl2F3N2O3+ H]+; UPLC (BEH C18, Method A) 92.9% (AUC), tR= 5.23 min. Example 131Preparation of N-(1-(Benzylsulfonyl)piperidin-4-yl)-3,5-dichloro-2- hydroxybenzamide [ANA-197]

[0326] N-(1-(Benzylsulfonyl)piperidin-4-yl)-3,5-dichloro-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6–7.34 (m, 5H), 4.42 (s, 2H), 3.97–3.89 (m, 1H), 3.58 (d, J = 12.4 Hz, 2H), 2.85 (t, J = 11.4 Hz, 2H), 1.86 (d, J = 9.8 Hz, 2H), 1.54 (qd, J = 11.9, 3.5 Hz, 2H); ESI MS m / z 443 [C19H20Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 95.8% (AUC), tR= 5.17 min. Example 132 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(3-methylbutanoyl)piperidin-4- yl)benzamide [ANA-198]

[0327] 3,5-Dichloro-2-hydroxy-N-(1-(3-methylbutanoyl)piperidin-4- yl)benzamide was prepared as a white solid according to Synthetic Scheme 8:1H NMR (500 MHz, DMSO-d6J = 7.0 Hz, 1H),7.49 (d, J = 3.1 Hz, 1H), 7.07 (d, J = 3.1 Hz, 1H), 4.04–3.91 (m, 2H), 3.77–3.68 (m, 1H), 3.28–3.20 (m, 1H), 3.04–2.96 (m, 1H), 2.20 (qd, J = 14.5, 7.0 Hz, 2H), 1.98 (sept, J = 6.7 Hz, 1H), 1.89–1.76 (m, 2H), 1.38–1.28 (m, 1H), 1.28–1.19 (m, 1H), 0.90 (d, J = 6.7 Hz, 6H), amide NH not observed; ESI MS m / z 373 [C17H22Cl2N2O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.85 min. Example 133 Preparation of 1-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8- yl)ethan-1-one [ANA-199]

[0328] 1-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8- yl)ethan-1-one was prepared as a white solid according to Synthetic Scheme 29 with the following modifications: at the completion of the reaction, the mixture was added to an aqueous solution of 5% lithium chloride (15 mL) and extracted into ethyl acetate (10 mL). The crude residue was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water). Desired fractions were concentrated under reduced pressure to remove acetonitrile and then was made basic (pH ~ 9) with 2 N aqueous sodium hydroxide solution and extracted into ethyl acetate. The organic phase was removed and the aqueous phase was then acidified (pH ~ 2-3) with a 2 N solution of hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica, 10–100% acetonitrile / water):1H NMR (500 MH,DMSO- d6 J = 2.2 Hz, 1H), 7.26 (d, J = 34.2 Hz, 1H), 3.54–3.36 (m, 7H), 3.14 (s, 1H), 1.98 (d, J = 21.6 Hz, 3H), 1.80–1.74 (m, 2H), 1.57–1.38 (m, 4H); ESI MS m / z 369 [C17H20Cl2N2O3– H]-; UPLC (BEH C18, Method A) 99% (AUC), tR= 3.34 min. Example 134 Preparation of 1-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)- 3-methylbutan-1-one [ANA-200]

[0329] 1-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)-3- methylbutan-1-one was prepared as a white solid according to Synthetic Scheme 29 with the following modifications: once the reaction was complete, it was added to an aqueous solution of 5% lithium chloride (30 mL) and extracted into ethyl acetate (50 mL). Theorganic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude oil was then purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water):1H NMR (500 MHz,DMSO-d6–10.38 (m, 1H), 7.57 (s, 1H), 7.27 (d, J = 34.8 Hz, 1H), 3.57–3.30 (m, 7H), 3.14 (br s, 1H), 2.17 (dd, J = 22.7, 6.6 Hz, 2H), 2.00–1.91 (m, 1H), 1.82–1.75 (m, 2H), 1.49–1.37 (m, 4H), 0.90– 0.86 (m, 6H); ESI MS m / z 411 [C20H26Cl2N2O3 – H]-; UPLC (BEH, Method A) 98.2% (AUC), tR= 4.40 min. Example 135 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(phenethylsulfonyl)piperidin-4- yl)benzamide [ANA-201]

[0330] 3,5-Dichloro-2-hydroxy-N-(1-(phenethylsulfonyl)piperidin-4- yl)benzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6J = 4.4 Hz, 4H), 7.23 (sx, J = 4.4 Hz, 1H), 4.03–3.94 (m, 1H), 3.67 (d, J = 12.2 Hz, 2H), 3.39–3.34 (m, 2H), 3.03–2.95 (m, 4H), 1.90 (dd, J = 12.7, 2.4 Hz, 2H), 1.60 (qd, J = 11.5, 2.8 Hz, 2H); ESI MS m / z 457 [C20H22Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 94.7% (AUC), tR= 5.55 min. Example 136 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(isobutylsulfonyl)piperidin-4- yl)benzamide [ANA-202]

[0331] 3,5-Dichloro-2-hydroxy-N-(1-(isobutylsulfonyl)piperidin-4-yl)benzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz,DMSO-d6–3.94 (m, 1H), 3.63 (d, J = 12.7 Hz, 2H), 2.95–2.87 (m, 4H), 2.12 (sept, J = 6.6 Hz, 1H), 1.91 (dd, J = 9.8, 2.7 Hz, 2H), 1.60 (qd, J = 11.9, 3.6 Hz, 2H), 1.04 (d, J = 6.6 Hz, 6H); ESI MS m / z 409 [C16H22Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 97.1% (AUC), tR= 5.28 min. Example 137 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(pyridin-3-ylsulfonyl)piperidin-4- yl)benzamide [ANA-203]

[0332] 3,5-Dichloro-2-hydroxy-N-(1-(pyridin-3-ylsulfonyl)piperidin-4- yl)benzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6J = 2.0 Hz, 1H), 8.90 (dd, J = 4.8, 1.5 Hz, 2H), 8.18 (ddd, J = 8.0, 2.0, 1.5 Hz, 1H), 7.99 (s, 1H), 7.75 (s, 1H), 7.70 (dd, J = 8.0, 4.8 Hz, 1H), 3.91–3.82 (m, 1H), 3.71 (d, J = 12.1 Hz, 2H), 2.57 (t, J = 11.2 Hz, 2H), 1.90 (d, J = 10.0 Hz, 2H), 1.60 (q, J = 10.7 Hz, 2H); ESI MS m / z 430 [C17H17Cl2N3O4S + H]+; UPLC (BEH C18, Method A) 96.2% (AUC), tR= 4.66 min. Example 138 Preparation of 5-(3,5-Dichloro-2-hydroxybenzoyl)-5-azaspiro[2.3]hexane-1- carboxamide [ANA-204]

[0333] 5-(3,5-Dichloro-2-hydroxybenzoyl)-5-azaspiro[2.3]hexane-1-carboxamide was prepared as a white solid according to Synthetic Scheme 43:1H NMR (500 MHz,DMSO-d6J = 2.5 Hz, 1H), 7.65 (s, 1H), 7.42 (d, J = 2.4 Hz, 1H), 6.95 (s, 1H), 4.48–4.41 (m, 2H), 4.15 (br s, 2H), 1.81 (br s, 1H), 1.11 (br s, 1H), 1.06–1.05 (m, 1H); ESI MS m / z 313 [C13H12Cl2N2O3– H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 3.77 min. Example 139 Preparation of N-(Cyclobutylmethyl)-5-(3,5-dichloro-2-hydroxybenzoyl)-5- azaspiro[2.3]hexane-1-carboxamide [ANA-205]

[0334] N-(Cyclobutylmethyl)-5-(3,5-dichloro-2-hydroxybenzoyl)-5- azaspiro[2.3]hexane-1-carboxamide was prepared as a white solid according to Synthetic Scheme 43:1H NMR (500 MHz,DMSO-d6J = 5.6 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 4.52–4.48 (m, 1H), 4.35 (br s, 0.5H), 4.15– 4.02 (m, 2.5H), 3.11 (br s, 2H), 2.40–2.34 (m, 1H), 1.95 (br s, 2H), 1.83–1.78 (m, 3H), 1.65–1.63 (m, 2H), 1.05–1.06 (m, 2H); ESI MS m / z 381 [C18H20Cl2N2O3– H]-; UPLC (BEH C18, Method A) >99% (AUC), tR = 4.72 min. Example 140 Preparation of 3,5-Dichloro-N-((1R,3s,5S)-8-(2-cyclobutylacetyl)-8- azabicyclo[3.2.1]octan-3-yl)-2-hydroxybenzamide [ANA-206]

[0335] 3,5-Dichloro-N-((1R,3s,5S)-8-(2-cyclobutylacetyl)-8- azabicyclo[3.2.1]octan-3-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 29 with the following modifications: the crude reaction mixture was charged to a stirred solution of 5% lithium chloride (20 mL) and extracted into ethyl acetate (20 mL). The aqueous phase was back extracted with ethyl acetate (2 × 20 mL) and the combined organic phase was concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography (C18 silica gel, 10–100%acetonitrile / water) followed by precipitation from water to afford the title compound:1H NMR (500 MHz, DMSO-d6J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 4.50–4.42 (m, 2H), 4.30–4.29 (m, 1H), 2.64–2.51 (m, 2H), 2.31 (dd, J = 15.1, 6.9 Hz, 1H), 2.10–1.96 (m, 3H), 1.91–1.56 (m, 11H); ESI MS m / z 409 [C20H24Cl2N2O3– H]-; UPLC (BEH C18, Method A) 98.6% (AUC), tR= 5.23 min. Example 141 Preparation of 3,5-Dichloro-2-hydroxy-N-(piperidin-4-ylmethyl)benzamide [ANA- 207]

[0336] 3,5-Dichloro-2-hydroxy-N-(piperidin-4-ylmethyl)benzamide was prepared as an off-white solid according to Synthetic Scheme 15:1H NMR (500 MHz, DMSO-d6) –8.85 (m, 2H), 7.52 (s, 1H), 7.13 (s, 1H), 3.41–3.33 (m, 2H), 3.28– 3.20 (m, 4H), 3.16–3.10 (m, 1H), 2.87 (dd, J = 11.6, 7.9 Hz, 1H), 2.47–2.43 (m, 1H), 2.06– 1.97 (m, 1H), 1.64 (dq, J = 12.9, 8.0 Hz, 1H); ESI MS m / z 303 [C13H16Cl2N2O2+ H]+; UPLC (BEH C18, Method A) 97.2% (AUC), tR= 3.11 min. Example 142 Preparation of 3,5-Dichloro-2-hydroxy-N-(pyrrolidin-3-yl)benzamide [ANA-208]

[0337] 3,5-Dichloro-2-hydroxy-N-(pyrrolidin-3-yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 15:1H NMR (500 MHz, DMSO-d6 12.52 (d, J = 5.8 Hz, 1H), 8.04 (br s, 1H), 7.49 (d, J = 3.1 Hz, 1H), 7.11 (d, J = 3.1 Hz, 1H), 4.38 (q, J = 5.9 Hz, 1H), 3.37–3.33 (m, 1H), 3.25–3.17 (m, 1H), 3.16–3.07 (m, 1H), 2.93 (dd, J = 12.2, 4.2 Hz, 1H), 2.15 (sx, J = 7.5 Hz, 1H), 1.79 (sx, J = 6.5 Hz, 1H), amide NH not observed; ESI MS m / z 275 [C11H12Cl2N2O2+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 3.08 min.Example 143 Preparation of 3,5-Dichloro-2-hydroxy-N-(pyrrolidin-3-ylmethyl)benzamide [ANA- 209]

[0338] 3,5-Dichloro-2-hydroxy-N-(pyrrolidin-3-ylmethyl)benzamide was prepared as an off-white solid according to Synthetic Scheme 15:1H NMR (500 MHz, DMSO-d6J = 5.0 Hz, 1H), 7.50 (d, J = 3.2 Hz, 1H), 7.24 (br s, 1H), 7.08 (d, J = 3.1 Hz, 1H), 3.21–3.12 (m, 3H), 2.73 (t, J = 12.3 Hz, 1H), 1.74 (d, J = 13.7 Hz, 2H), 1.70–1.61 (m, 1H), 1.31–1.21 (m, 2H), amide NH not observed; ESI MS m / z 289 [C12H14Cl2N2O2+ H]+; UPLC (BEH C18, Method A) 95.0% (AUC), tR= 3.24 min. Example 144 Preparation of N-((1R,3s,5S)-8-Acetyl-8-azabicyclo[3.2.1]octan-3-yl)-3,5-dichloro-2- hydroxybenzamide [ANA-210]

[0339] N-((1R,3s,5S)-8-Acetyl-8-azabicyclo[3.2.1]octan-3-yl)-3,5-dichloro-2- hydroxybenzamide was prepared as a light brown solid according to Synthetic Scheme 29 with the following modifications: the crude reaction mixture was charged to a stirred aqueous solution of 5% lithium chloride (20 mL) and extracted into ethyl acetate (20 mL). The aqueous phase was back extracted with ethyl acetate (2 × 20 mL) and the combined organic phase was concentrated under reduced pressure. The crude residue was purified by precipitation from methanol to afford the title compound:1H NMR (500 MHz, DMSO- d6J = 6.6 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 4.51–4.42 (m, 2H), 4.26–4.24 (m, 1H), 2.05–2.00 (m, 4H), 1.89–1.60 (m, 7H); ESIMS m / z 355 [C16H18Cl2N2O3– H]-; UPLC (BEH C18, Method A) 97.1% (AUC), tR= 4.38 min. Preparation of 3,5-Dichloro-N-((1R,3s,5S)-8-(cyclopropylsulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2-hydroxybenzamide [ANA-211]

[0340] 3,5-Dichloro-N-((1R,3s,5S)-8-(cyclopropylsulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 33:1H NMR (500 MHz, DMSO-d6 J = 6.9 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 4.38–4.32 (m, 1H), 4.18 (s, 2H), 2.60–2.57 (m, 1H), 2.10–2.07 (m, 2H), 1.92–1.89 (m, 2H), 1.88–1.74 (m, 4H), 0.98– 0.95 (m, 4H); ESI MS m / z 417 [C17H20Cl2N2O4S – H]-; UPLC (BEH C18, Method A) 98.9% (AUC), tR= 4.96 min. Example 145 Preparation of (1R,5S,6r)-N-(Cyclobutylmethyl)-3-(3,5-dichloro-2-hydroxybenzoyl)- 3-azabicyclo[3.1.0]hexane-6-carboxamide [ANA-212]

[0341] (1R,5S,6r)-N-(Cyclobutylmethyl)-3-(3,5-dichloro-2-hydroxybenzoyl)-3- azabicyclo[3.1.0]hexane-6-carboxamide was prepared as a white solid according to Synthetic Scheme 43 with the following modification: the reaction was quenched by addition to a 5% aqueous solution of lithium chloride and extraction into ethyl acetate. The organic phase was separated and concentrated under reduced pressure. The solid was precipitated from acetonitrile / water (2:1) and the filtrate was concentrated under reduced pressure. The residue was then purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water):1H NMR (500 MHz,DMSO-d67.95 (t, J = 5.6 Hz, 1H), 7.59 (d, J = 2.6 Hz, 1H), 7.17 (d, J = 2.6 Hz, 1H), 3.88 (d, J = 12.2 Hz, 1H), 3.57 (d, J = 7.6 Hz, 1H), 3.44 (d, J = 9.5 Hz, 1H), 3.22 (d, J = 10.8 Hz, 1H), 3.07– 3.05 (m, 2H), 2.38–2.32 (m, 1H), 1.98–1.86 (m, 4H), 1.83–1.77 (m, 2H), 1.66–1.59 (m, 2H), 1.44 (t, J = 3.1 Hz, 1H); ESI MS m / z 381 [C18H20Cl2N2O3– H]-; UPLC (BEH C18, Method A) 95.3% (AUC), tR= 3.92 min. Example 146 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-((tetrahydro-2H-pyran-4- yl)sulfonyl)piperidin-4-yl)benzamide [ANA-213]

[0342] 3,5-Dichloro-2-hydroxy-N-(1-((tetrahydro-2H-pyran-4- yl)sulfonyl)piperidin-4-yl)benzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d67.76 (s, 1H), 4.08–3.98 (m, 1H), 3.93 (dd, J = 11.1, 4.2 Hz, 2H), 3.68 (d, J = 11.5 Hz, 2H), 3.44 (tt, J = 12.0, 3.7 Hz, 1H), 3.33 (td, J = 11.7, 1.5 Hz, 2H), 3.06 (t, J = 11.5 Hz, 2H), 1.91–1.83 (m, 4H), 1.50 (sxd, J = 12.2, 4.5 Hz, 4H); ESI MS m / z 437 [C17H22Cl2N2O5S + H]+; UPLC (BEH C18, Method A) 95.6% (AUC), tR= 4.57 min. Example 147 Preparation of 3,5-Dichloro-N-(1-((cyclobutylmethyl)sulfonyl)piperidin-4-yl)-2- hydroxybenzamide [ANA-214]

[0343] 3,5-Dichloro-N-(1-((cyclobutylmethyl)sulfonyl)piperidin-4-yl)-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d64.02–3.93 (m, 1H), 3.61 (d, J = 12.4 Hz, 2H), 3.16 (d, J = 7.3 Hz, 2H), 2.90 (td, J = 12.4,2.1 Hz, 2H), 2.75–2.65 (m, 1H), 2.13–2.05 (m, 2H), 1.83–1.75 (m, 6H), 1.58 (qd, J = 12.0, 3.4 Hz, 2H); ESI MS m / z 421 [C17H22Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 95.2% (AUC), tR= 5.19 min. Example 148 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(piperidin-4-ylsulfonyl)piperidin-4- yl)benzamide Hydrochloride [ANA-215]

[0344] 3,5-Dichloro-2-hydroxy-N-(1-(piperidin-4-ylsulfonyl)piperidin-4- yl)benzamide hydrochloride was prepared according to Synthetic Scheme 9 with the following modification: the purified product was suspended in 4M hydrochloric acid (0.1 mL, 0.4 mmol) and allowed to stir overnight, then concentrated under reduced pressure to provide 3,5-dichloro-2-hydroxy-N-(1-(piperidin-4-ylsulfonyl)piperidin-4-yl)benzamide hydrochloride as a white solid:1H NMR (500 MHz, DMSO-d6 1H), 8.72 (br s, 1H), 8.42 (br s, 1H), 8.06 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 4.09–4.00 (m, 1H), 3.73–3.65 (m, 2H), 3.54–3.44 (m, 1H), 3.38 (d, J = 13.1 Hz, 2H), 3.07 (t, J = 11.6 Hz, 2H), 2.96–2.86 (m, 2H), 2.11 (d, J = 12.4 Hz, 2H), 1.94–1.87 (m, 2H), 1.80 (q, J = 12.4 Hz, 2H), 1.59 (q, J = 11.3 Hz, 2H); ESI MS m / z 436 [C17H23Cl2N3O4S + H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 3.75 min. Example 149 Preparation of (1R,5S,6r)-3-(3,5-Dichloro-2-hydroxybenzoyl)-3- azabicyclo[3.1.0]hexane-6-carboxamide [ANA-216]

[0345] (1R,5S,6r)-3-(3,5-Dichloro-2-hydroxybenzoyl)-3- azabicyclo[3.1.0]hexane-6-carboxamide was prepared as a white solid according toSynthetic Scheme 43 with the following modifications: the crude reaction mixture was added to stirring water (20 mL) and the resulting precipitate removed by filtration. The filtrate was extracted into ethyl acetate (50 mL). The organic phase was washed with an aqueous solution of 5% lithium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water):1H NMR (500 MHz,DMSO-d6J = 2.5 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.84 (s, 1H), 3.88 (d, J = 12.2 Hz, 1H), 3.56 (d, J = 7.9 Hz, 1H), 3.46–3.43 (m, 1H), 3.23 (d, J = 10.8 Hz, 1H), 1.89 (d, J = 12.3 Hz, 2H), 1.42 (t, J = 3.1 Hz, 1H); ESI MS m / z 313 [C13H12Cl2N2O3– H]-; UPLC (BEH C18, Method A) 98.4% (AUC), tR= 2.77 min. Example 150 Preparation of 3,5-Dichloro-N-((1R,4R,5R)-2-(2-cyclobutylacetyl)-2- azabicyclo[2.2.1]heptan-5-yl)-2-hydroxybenzamide [ANA-217]

[0346] 3,5-Dichloro-N-((1R,4R,5R)-2-(2-cyclobutylacetyl)-2- azabicyclo[2.2.1]heptan-5-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 29 with the following modification: the solid was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford the title compound:1H NMR (500 MHz, DMSO-d6–13.56 (m, 1H), 9.00 (br s, 1H), 8.12 (dd, J = 14.9, 2.4 Hz, 1H), 7.76 (t, J = 2.2 Hz, 1H), 4.35–4.25 (m, 2H), 3.34–3.23 (m, 2.6H), 3.09 (dd, J = 11.3, 1.9 Hz, 0.4H), 2.87 (s, 0.5H), 2.80 (s, 0.5H), 2.63– 2.60 (m, 1H), 2.30–2.26 (m, 1H), 2.16–2.11 (m, 0.5H), 2.07–2.00 (m, 2.5H), 1.81–1.73 (m,2H), 1.71–1.58 (m, 5H); ESI MS m / z 395 [C19H22Cl2N2O3– H]-; UPLC (BEH C18, MethodA) 97.1% (area%), tR= 4.88 min. Example 151Preparation of 3,5-Dichloro-N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-2- hydroxybenzamide [ANA-218]

[0347] 3,5-Dichloro-N-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d64.53 (sx, J = 6.2 Hz, 1H), 3.65 (dd, J = 6.8, 10.4 Hz, 1H), 3.53–3.46 (m, 1H), 3.43–3.37 (m, 1H), 3.28 (dd, J = 10.4, 5.2 Hz, 1H), 2.75–2.68 (m, 1H), 2.25 (sx, J = 7.0 Hz, 1H), 2.02 (sx, J = 6.5 Hz, 1H), 1.00–0.94 (m, 4H); ESI MS m / z 379 [C14H16Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 98.2% (AUC), tR= 4.50 min. Example 152 Preparation of 3,5-Dichloro-N-((1R,5S,6r)-3-(2-cyclobutylacetyl)-3- azabicyclo[3.1.1]heptan-6-yl)-2-hydroxybenzamide [ANA-219]

[0348] 3,5-Dichloro-N-((1R,5S,6r)-3-(2-cyclobutylacetyl)-3- azabicyclo[3.1.1]heptan-6-yl)-2-hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 29 with the following modifications: the crude reaction mixture was added to a stirred aqueous solution of 5% lithium chloride (25 mL) and extracted into ethyl acetate (45 mL). The organic phase was separated and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford the title compound:1H NMR (500 MHz, DMSO-d6J = 2.5 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 4.04–4.01 (m, 1H), 3.71–3.63 (m, 2H), 3.54–3.45 (m, 2H), 2.74– 2.71 (m, 2H), 2.59–2.56 (m, 1H), 2.45–2.40 (m, 1H), 2.35–2.30 (m, 1H), 1.98–1.92 (m,3H), 1.76–1.70 (m, 2H), 1.64–1.55 (m, 2H), 1.37 (d, J = 9.5 Hz, 1H); ESI MS m / z 395 [C19H22Cl2N2O3– H]-; UPLC (Method X) 97.1% (area%), tR= 4.76 min. Example 153 Preparation of 3,5-Dichloro-N-((1R,4R,5R)-2-(cyclopropylsulfonyl)-2- azabicyclo[2.2.1]heptan-5-yl)-2-hydroxybenzamide [ANA-220]

[0349] 3,5-Dichloro-N-((1R,4R,5R)-2-(cyclopropylsulfonyl)-2- azabicyclo[2.2.1]heptan-5-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 33. The compound was purified by trituration in water to afford the title compound:1H NMR (500 MHz, DMSO-d6 8.22 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 4.28–4.25 (m, 1H), 4.05 (s, 1H), 3.30– 3.25 (m, 2H), 2.89 (s, 1H), 2.69–2.67 (m, 1H), 2.13–2.08 (m, 1H), 1.80–1.78 (m, 2H), 1.67 (d, J = 9.9 Hz, 1H), 0.99–0.96 (m, 4H); ESI MS m / z 403 [C16H18Cl2N2O4– H]-; UPLC (BEH C18, Method A) 98.2% (area%), tR= 4.73 min. Example 154 Preparation of N-((1R,5S,6r)-3-Acetyl-3-azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro- 2-hydroxybenzamide [ANA-221]

[0350] N-((1R,5S,6r)-3-Acetyl-3-azabicyclo[3.1.1]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 32. Reaction mixture was further purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford the title compound:1H NMR (500 MHz, DMSO-d6J = 2.5 Hz, 1H), 7.76 (d, J = 2.5 Hz,1H), 4.07–4.04 (m, 1H), 3.71–3.64 (m, 2H), 3.55–3.48 (m, 2H), 2.74–2.70 (m, 2H), 1.99– 1.94 (m, 4H), 1.39 (d, J = 9.6 Hz, 1H); ESI MS m / z 341 [C15H16Cl2N2O3– H]-; UPLC (BEH C18, Method A) 97.6% (AUC), tR= 3.72 min. Example 155 Preparation of 3,5-Dichloro-N-(1-(2-cyclobutylacetyl)pyrrolidin-3-yl)-2- hydroxybenzamide [ANA-222]

[0351] 3,5-Dichloro-N-(1-(2-cyclobutylacetyl)pyrrolidin-3-yl)-2- hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 7.5 Hz, 1H), 7.77 (s, 1H), 4.55–4.40 (m, 1H), 3.78–3.32 (m, 4H), 2.65–2.56 (m, 2H), 2.42–2.33 (m, 1H), 2.24–2.08 (m, 1H), 2.08–1.88 (m, 3H), 1.87–1.73 (m, 2H), 1.70–1.59 (m, 2H); ESI MS m / z 371 [C17H20Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 95.2% (AUC), tR= 4.68 min. Example 156 Preparation of 3,5-Dichloro-N-((1-(2-cyclobutylacetyl)pyrrolidin-3-yl)methyl)-2- hydroxybenzamide [ANA223]

[0352] 3,5-Dichloro-N-((1-(2-cyclobutylacetyl)pyrrolidin-3-yl)methyl)-2- hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d63.58–3.32 (m, 3H), 3.27–3.01 (m, 2H), 2.62–2.54 (m, 1H), 2.41 (quint, J = 7.0 Hz, 1H), 2.34 (d, J = 7.0 Hz, 2H), 2.07–1.97 (m, 3H), 1.96–1.72 (m, 3H), 1.72–1.55 (m, 3H); ESI MS m / z 385 [C18H22Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 96.1% (AUC), tR= 4.73 min. Example 157Preparation of 3,5-Dichloro-N-((1R,5S,6r)-3-(cyclopropylsulfonyl)-3- azabicyclo[3.1.1]heptan-6-yl)-2-hydroxybenzamide [ANA-224]

[0353] 3,5-Dichloro-N-((1R,5S,6r)-3-(cyclopropylsulfonyl)-3- azabicyclo[3.1.1]heptan-6-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 33:1H NMR (500 MHz, DMSO-d6(br s, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.00 (td, J = 5.9, 2.5 Hz, 1H), 3.60 (d, J = 10.5 Hz, 2H), 3.50 (d, J = 10.5 Hz, 2H), 2.76 (t, J = 5.7 Hz, 2H), 2.65–2.60 (m, 1H), 2.00–1.96 (m, 1H), 1.54 (d, J = 9.7 Hz, 1H), 0.93–0.90 (m, 2H), 0.81–0.76 (m, 2H); ESI MS m / z 403 [C16H18Cl2N2O4S – H]-; UPLC (BEH C18, Method A) 97.1% (AUC), tR= 4.57 min. Example 158 Preparation of N-((1R,4R,5R)-2-Acetyl-2-azabicyclo[2.2.1]heptan-5-yl)-3,5-dichloro- 2-hydroxybenzamide [ANA-225]

[0354] N-((1R,4R,5R)-2-Acetyl-2-azabicyclo[2.2.1]heptan-5-yl)-3,5-dichloro-2- hydroxybenzamide was prepared as a light brown solid according to Synthetic Scheme 32 with the following modification: purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford the title compound:1H NMR (500 MHz, DMSO-d6 –9.00 (m, 1H), 8.13 (dd, J = 22.2, 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.35–4.28 (m, 1.6H), 4.20 (s, 0.4H), 3.36–3.25 (m, 1.5H), 3.09–3.07 (m, 0.5H), 2.83 (d, J = 20.3 Hz, 1H), 2.15–1.98 (m, 2H), 1.88 (s, 2H), 1.74–1.64 (m, 3H); ESIMS m / z 341 [C15H16Cl2N2O3– H]-; UPLC (BEH C18, Method A) >99% (area%), tR= 3.90 min. Example 159 Preparation of 2-(3-(3,5-Dichloro-2-hydroxybenzamido)pyrrolidin-1-yl)acetic Acid [ANA-226]

[0355] 2-(3-(3,5-Dichloro-2-hydroxybenzamido)pyrrolidin-1-yl)acetic acid was prepared as an off-white solid according to Synthetic Scheme 11:1H NMR (500 MHz, DMSO-d6–4.41 (m, 1H), 3.40 (s, 2H), 3.13 (dd, J = 10.2, 7.8 Hz, 1H), 3.04 (dd, J = 14.9, 9.2 Hz, 1H), 2.88 (dd, J = 10.1, 4.7 Hz, 1H), 2.83 (dd, J = 16.8, 7.6 Hz, 1H), 2.27–2.17 (m, 1H), 1.93–1.84 (m, 1H), phenol OH and carboxylic acid OH not observed; ESI MS m / z 333 [C13H14Cl2N2O4+ H]+; UPLC (BEH C18, Method A) 95.3% (AUC), tR = 3.04 min. Example 160 Preparation of 3,5-Dichloro-N-((1-(cyclopropylsulfonyl)pyrrolidin-3-yl)methyl)-2- hydroxybenzamide [ANA-227]

[0356] 3,5-Dichloro-N-((1-(cyclopropylsulfonyl)pyrrolidin-3-yl)methyl)-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6 3.40 (dd, J = 10.0, 7.3 Hz, 1H), 3.42–3.32 (m, 3H), 3.29–3.24 (m, 1H), 3.08 (dd, J = 10.0, 6.8 Hz, 1H), 2.72–2.65 (m, 1H), 2.58–2.51 (m, 1H), 2.07–1.99 (m, 1H), 1.72–1.64 (m, 1H), 0.98–0.91 (m, 4H); ESI MS m / z 393 [C15H18Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 96.2% (AUC), tR= 4.55 min. Example 161Preparation of N-((1-Acetylpyrrolidin-3-yl)methyl)-3,5-dichloro-2- hydroxybenzamide [ANA-228]

[0357] N-((1-Acetylpyrrolidin-3-yl)methyl)-3,5-dichloro-2-hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 8:1H NMR (500 MHz, DMSO-d6J = 5.6 Hz, 1H), 7.50 (t, J = 3.0 Hz, 1H), 7.08 (dd, J = 3.1, 2.1 Hz, 1H), 3.56–3.48 (m, 1H), 3.46–3.36 (m, 2H), 3.30–3.24 (m, 2H), 3.15–2.93 (m, 1H), 2.44– 2.27 (m, 1H), 2.02–1.88 (m, 1H), 1.91 (s, 3H), 1.72–1.52 (m, 1H), amide NH not observed; ESI MS m / z 331 [C14H16Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 96.7% (AUC), tR= 3.79 min. Example 162 Preparation of N-(1-(3,5-Dichloro-2-hydroxybenzoyl)piperidin-4- yl)cyclopropanesulfonamide [ANA-229]

[0358] N-(1-(3,5-Dichloro-2-hydroxybenzoyl)piperidin-4- yl)cyclopropanesulfonamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6J = 2.3 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 4.27 (br s, 1H), 3.47–3.38 (m, 2H), 3.07–2.96 (m, 2H), 2.60–2.53 (m, 1H), 1.87 (br s, 2H), 1.43 (q, J = 9.3 Hz, 2H), 0.97–0.88 (m, 4H); ESI MS m / z 393 [C15H18Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 96.3% (AUC), tR = 3.43 min. Example 163 Preparation of 3,5-Dichloro-N-((1R,4R,5S)-2-(2-cyclobutylacetyl)-2- azabicyclo[2.2.2]octan-5-yl)-2-hydroxybenzamide [ANA-230]

[0359] 3,5-Dichloro-N-((1R,4R,5S)-2-(2-cyclobutylacetyl)-2- azabicyclo[2.2.2]octan-5-yl)-2-hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 29:1H NMR (500 MHz, DMSO-d6(br s, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.37 (s, 0.5H), 4.22-4.27 (m, 0.5H), 4.15–4.08 (m, 0.5H), 3.91 (s, 0.5H), 3.57–3.48 (m, 1H), 3.33–3.23 (m, 1H), 2.67– 254 (m, 1H), 2.42–2.38 (m, 1H), 2.38–2.28 (m, 1H), 2.28–2.22 (m, 0.5), 2.14–2.06 (m, 1.5H), 2.06–2.00 (m, 2H), 1.89–1.70 (m, 6H), 1.68–1.61 (m, 2H), 1.55–1.46 (m, 1H); ESI MS m / z 409 [C20H24Cl2N2O3– H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 5.06 min. Example 164 Preparation of N-((1R,4R,5S)-2-Acetyl-2-azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide [ANA-231]

[0360] N-((1R,4R,5S)-2-Acetyl-2-azabicyclo[2.2.2]octan-5-yl)-3,5-dichloro-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 32:1H NMR (500 MHz, DMSO-d6) 13.57 (s, 1H), 9.00 (br s, 1H), 8.12 (t, J = 2.9 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 4.39–4.36 (m, 0.5H), 4.23–4.18 (m, 0.5H), 4.14–4.09 (m, 0.5H), 3.87– 3.84 (m, 0.5H), 3.56–3.46 (m, 1H), 3.38–3.25 (m, 1H), 2.31–2.25 (m, 0.5H), 2.15–2.09 (m, 1.5H), 1.96–1.91 (m, 3H), 1.89–1.70 (m, 3.5H), 1.67–1.61 (0.5H), 1.54–1.45 (m, 1H); ESI MS m / z 355 [C16H18Cl2N2O3– H]-; UPLC (BEH C18, Method A) 97.3% (AUC), tR= 4.12 min. Example 165Preparation of 3,5-Dichloro-N-((1R,4R,5S)-2-(cyclopropylsulfonyl)-2- azabicyclo[2.2.2]octan-5-yl)-2-hydroxybenzamide [ANA-232]

[0361] 3,5-Dichloro-N-((1R,4R,5S)-2-(cyclopropylsulfonyl)-2- azabicyclo[2.2.2]octan-5-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 33:1H NMR (500 MHz, DMSO-d68.13 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.26–4.24 (m, 1H), 3.68 (d, J = 2.4 Hz, 1H), 3.44–3.38 (m, 2H), 2.74–2.69 (m, 1H), 2.40–2.35 (m, 1H), 2.14–2.11 (m, 1H), 1.96– 1.86 (m, 2H), 1.83–1.74 (m, 2H), 1.61–1.54 (m, 1H), 0.98–0.92 (m, 4H); ESI MS m / z 417 [C17H20Cl2N2O4S – H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.88 min. Example 166 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(pyridin-2-ylsulfonyl)piperidin-4- yl)benzamide [ANA-233]

[0362] 3,5-Dichloro-2-hydroxy-N-(1-(pyridin-2-ylsulfonyl)piperidin-4- yl)benzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6J = 7.5, 4.7 Hz, 1H), 8.12 (td, J = 7.8, 1.7 Hz, 1H), 8.01 (s, 1H), 7.94 (d, J =7.8 Hz, 1H), 7.76 (s, 1H), 7.72 (ddd, J = 7.7, 4.7, 1.0 Hz, 1H), 3.94–3.85 (m, 1H), 3.78 (d, J = 12.6 Hz, 2H), 2.83 (td, J = 12.2, 1.9 Hz, 2H), 1.89 (dd, J = 12.6, 2.65 Hz, 2H), 1.58 (qd, J = 12.1, 3.7 Hz, 2H); ESI MS m / z 430 [C17H17Cl2N3O4S + H]+; UPLC (BEH C18, Method A) 96.9% (AUC), tR= 4.81 min. Example 167 Preparation of N-(1-(3,5-Dichloro-2-hydroxybenzoyl)piperidin-4-yl)acetamide [ANA-234]

[0363] N-(1-(3,5-Dichloro-2-hydroxybenzoyl)piperidin-4-yl)acetamide was prepared as an off-white solid according to Synthetic Scheme 8:1H NMR (500 MHz, DMSO-d6J = 7.2, 1H), 7.01 (s, 1H), 6.70 (s, 1H), 4.25 (br s, 1H), 3.79–3.68 (m, 1H), 3.55 (br s, 1H), 3.02–2.72 (m, 2H), 1.78 (s, 3H), 1.75–1.59 (m, 2H), 1.40–1.19 (m, 2H); ESI MS m / z 331 [C14H16Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 95.3% (AUC), tR= 2.82 min. Example 168 Preparation of N-(1-(2-Amino-2-oxoethyl)pyrrolidin-3-yl)-3,5-dichloro-2- hydroxybenzamide [ANA-235]

[0364] N-(1-(2-Amino-2-oxoethyl)pyrrolidin-3-yl)-3,5-dichloro-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 11:1H NMR (500 MHz, DMSO-d6(s, 1H), 4.50–4.41 (m, 1H), 3.25–3.14 (m, 3H), 3.04–2.90 (m, 2H), 2.84–2.74 (m, 1H), 2.73–2.62 (m, 1H), 2.28–2.19 (m, 1H), 1.89–1.79 (m, 1H); ESI MS m / z 332 [C13H15Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 95.5% (AUC), tR= 2.96 min. Example 169 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,5S,6r)-3-(3,3,3-trifluoropropanoyl)-3- azabicyclo[3.1.1]heptan-6-yl)benzamide [ANA-236]

[0365] 3,5-Dichloro-2-hydroxy-N-((1R,5S,6r)-3-(3,3,3-trifluoropropanoyl)-3- azabicyclo[3.1.1]heptan-6-yl)benzamide was prepared according to Synthetic Scheme 29with the following modifications: the crude reaction mixture was added to a 0.1 N aqueous hydrochloric acid solution (20 mL) and then extracted into dichloromethane (50 mL). The organic phase was washed with a 5% lithium chloride aqueous solution (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified twice by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford the title compound as a light yellow solid:1H NMR (500MHz, DMSO-d6J = 2.4 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 4.07–4.03 (m, 1H), 3.71–3.65 (m, 2H), 3.62–3.53 (m, 4H), 2.76–2.71 (m, 2H), 2.00–1.95 (m, 1H), 1.40 (d, J = 9.6 Hz, 1H); ESI MS m / z 409 [C16H15Cl2F3N2O3– H]-; UPLC (BEH C18, Method A) 98.9% (AUC), tR= 4.46 min. Example 170 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,5S,6r)-3-isobutyryl-3- azabicyclo[3.1.1]heptan-6-yl)benzamide [ANA-237]

[0366] 3,5-Dichloro-2-hydroxy-N-((1R,5S,6r)-3-isobutyryl-3- azabicyclo[3.1.1]heptan-6-yl)benzamide was prepared as a white solid according to Synthetic Scheme 29:1H NMR (500 MHz, DMSO-d67.91 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H), 4.04–4.01 (m, 1H), 3.80–3.72 (m, 2H), 3.58–3.46 (m, 2H), 2.76–2.73 (m, 2H), 1.99–1.95 (m, 1H), 1.40 (d, J = 9.6 Hz, 1H), 1.21 (d, J = 7.0 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H); ESI MS m / z 369 [C17H20Cl2N2O3– H]-; UPLC (BEH C18, Method A) 96.3% (AUC), tR= 4.38 min. Example 171 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-isobutyryl-2- azabicyclo[2.2.1]heptan-5-yl)benzamide [ANA-238]

[0367] 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-isobutyryl-2- azabicyclo[2.2.1]heptan-5-yl)benzamide was prepared as a light brown solid according to Synthetic Scheme 29 with the following modification: purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford the title compound:1H NMR (500 MHz, DMSO-d6 –13.52 (m, 1H), 9.00 (br s, 1H), 8.12 (dd, J = 23.0, 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.37–4.23 (m, 2H), 3.40 (d, J = 9.7 Hz, 0.5H), 3.33– 3.31 (m, 0.5H), 3.25 (d, J = 11.6 Hz, 0.5H), 3.13–3.11 (m, 0.5H), 2.93 (br s, 0.5H), 2.81 (br s, 0.5H), 2.73–2.67 (m, 0.5H), 2.55–2.53(m, 0.5H), 2.20–2.14 (m, 0.5H), 2.07–2.02 (m, 0.5H), 1.72–1.62 (m, 3H), 1.04–1.00 (m, 4.5H), 0.97 (d, J = 6.7 Hz, 1.5H); ESI MS m / z 369 [C17H20Cl2N2O3– H]-; UPLC (BEH C18, Method A) 98.3% (area%), tR= 4.43 min. Example 172 Preparation of 3,5-Dichloro-N-(1-(dimethylglycyl)piperidin-4-yl)-2- hydroxybenzamide [ANA239]

[0368] 3,5-Dichloro-N-(1-(dimethylglycyl)piperidin-4-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 8.6 Hz, 1H), 4.09–4.00 (m, 2H), 3.85–3.55 (m, 6H), 3.23–3.15 (m, 2H), 3.02–2.90 (m, 1H), 1.87 (td, J = 12.7, 3.2 Hz, 2H), 1.48 (q, J = 9.5 Hz, 1H), 1.35 (q, J = 9.5 Hz, 1H), 1.32–1.10 (m, 2H), amide NH and phenol OH not observed; ESI MS m / z 374 [C16H21Cl2N3O3 + H]+; UPLC (BEH C18, Method A) 96.3% (AUC), tR= 3.37 min. Example 173Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(3,3,3-trifluoropropanoyl)- 2-azabicyclo[2.2.1]heptan-5-yl)benza OH ClCl

[0369] 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(3,3,3-trifluoropropanoyl)-2- azabicyclo[2.2.1]heptan-5-yl)benzamide was prepared as a brown-red solid according to Synthetic Scheme 29 with the following modification: the crude solid was further purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to provide the title compound:1H NMR (500 MHz, DMSO-d6–8.99 (m, 1H), 8.11–8.08 (m, 1H), 7.77–7.76 (m, 1H), 4.37 (d, J = 30.0 Hz, 1H), 4.32–4.28 (m, 1H), 3.75–3.65 (m, 0.5H), 3.50–3.32 (m, 2.5H), 3.30–3.15 (m, 1H), 2.89–2.82 (m, 1H), 2.16–2.11 (m, 0.4H), 2.09–2.04 (m, 0.6H), 1.73–1.64 (m, 3H); ESI MS m / z 409 [C16H15Cl2F3N2O3– H]-; UPLC (BEH C18, Method A) 97.2% (areaExample 174 Preparation of 3,5-Dichloro-N-((1R,4R,5R)-2-(2-cyclobutylideneacetyl)-2- azabicyclo[2.2.1]heptan-5-yl)-2-hydroxybenzamide [ANA-241] OH Cl Cl

[0370] 3,5-Dichloro-N-((1R,4R,5R)-2-(2-cyclobutylideneacetyl)-2- azabicyclo[2.2.1]heptan-5-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 29 with the following modifications: sodium 2-(1- fluorocyclobutyl)acetate was used as the acid coupling partner. During the reaction, the fluorine was eliminated and the alkene byproduct was isolated by precipitation in aqueous 0.5 N hydrochloric acid, followed by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford the title compound:1H NMR (500 MHz,DMSO-d6J = 21.8 Hz, 1H), 8.14 (dd, J = 15.1, 2.4 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 5.98–5.78 (m, 1H), 4.38 (d, J = 20.7 Hz, 1H), 4.32–4.30 (m, 1H), 3.43 (d, J = 9.7 Hz, 0.5H), 3.30–3.26 (m, 1H), 3.17–2.96 (m, 2.5H), 2.87–2.75 (m, 3H), 2.14–1.97 (m, 3H), 1.70–1.59 (m, 3H); ESI MS m / z 393 [C19H20Cl2N2O3– H]-; UPLC (BEH C18, Method A) 99% (area%), tR= 4.81 min. Example 175 Preparation of 3,5-Dichloro-N-((1R,4R,5S)-2-(2-cyclobutylacetyl)-2- azabicyclo[2.2.1]heptan-5-yl)-2-hydroxybenzamide [ANA-242] OH Cl Cl

[0371] 3,5-Dichloro-N-((1R,4R,5S)-2-(2-cyclobutylacetyl)-2- azabicyclo[2.2.1]heptan-5-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 29:1H NMR (500 MHz, DMSO-d6(t, J = 6.9 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H),4.42 (s, 0.5H), 4.34 (s, 0.5H), 4.03–3.94 (m, 1H), 3.37 (dd, J = 9.4, 3.7 Hz, 0.5H), 3.17–3.14 (m, 1H), 2.96 (d, J = 11.0 Hz, 0.5H), 2.61–2.56 (m, 2H), 2.47–2.44 (m, 0.5H), 2.34–2.21 (m, 1.5H), 2.06– 1.90 (m, 2.5H), 1.97–1.92 (m, 0.5H), 1.84–1.71 (m, 4H), 1.68–1.48 (m, 3H); ESI MS m / z 395 [C19H22Cl2N2O3– H]-; UPLC (BEH C18, Method A) 98.0% (area%), tR= 4.78 min. Example 176 Preparation of 3,5-Dichloro-N-((1R,4R,5S)-2-(cyclopropylsulfonyl)-2- azabicyclo[2.2.1]heptan-5-yl)-2-hydroxybenzamide [ANA-243] OH Cl Cl

[0372] 3,5-Dichloro-N-((1R,4R,5S)-2-(cyclopropylsulfonyl)-2- azabicyclo[2.2.1]heptan-5-yl)-2-hydroxybenzamide was prepared as a white solidaccording to Synthetic Scheme 33 with the following modification: the title compound required no further purification besides acidification and filtration:1H NMR (500 MHz, DMSO-d6J = 6.1 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.12 (s, 1H), 4.07–4.03 (m, 1H), 3.34–3.32 (m, 1H), 3.00 (d, J = 9.3 Hz, 1H), 2.71–2.66 (m, 2H), 2.20–2.15 (m, 1H), 1.83–1.77 (m, 2H), 1.68 (d, J = 10.4 Hz, 1H), 1.01– 0.96 (m, 4H); ESI MS m / z 403 [C16H18Cl2N2O4 – H]-; UPLC (BEH C18, Method A) 95.4% (area%), tR= 4.64 min. Example 177 Preparation of Cyclobutyl 4-(3,5-Dichloro-2-hydroxybenzamido)piperidine-1- carboxylate [ANA-244] OH Cl Cl

[0373] Cyclobutyl 4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1-carboxylate was prepared as an off-white solid according to Synthetic Scheme 6:1H NMR (500 MHz, DMSO-d6 J = 7.4 Hz, 1H), 4.09–4.00 (m, 1H), 3.97 (d, J = 12.8 Hz, 2H), 2.90 (br s, 2H), 2.30–2.20 (m, 2H), 2.05–1.95 (m, 2H), 1.83 (d, J = 11.2 Hz, 2H), 1.71 (q, J = 10.0 Hz, 1H), 1.63–1.50 (m, 1H), 1.45 (qd, J = 11.2, 2.8 Hz, 2H); ESI MS m / z 387 [C17H20Cl2N2O4+ H]+; UPLC (BEH C18, Method A) 96.2% (AUC), tR= 5.27 min. Example 178 Preparation of N-((1R,4R,5S)-2-Acetyl-2-azabicyclo[2.2.1]heptan-5-yl)-3,5-dichloro- 2-hydroxybenzamide [ANA 245]

[0374] N-((1R,4R,5S)-2-Acetyl-2-azabicyclo[2.2.1]heptan-5-yl)-3,5-dichloro-2- hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 32:1H NMR (500 MHz, DMSO-d6J = 5.7 Hz, 1H), 8.10–8.09 (m, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.43 (s, 0.5H), 4.29 (s, 0.5H), 4.05–3.95 (m, 1H), 3.36 (dd, J = 9.4, 3.7 Hz, 0.5H), 3.18–3.15 (m, 1H), 2.99 (d, J = 10.9 Hz, 0.5H), 2.59 (dd, J = 19.1, 1.6 Hz, 1H), 2.11–2.06 (m, 0.5H), 2.00–1.98 (m, 2H), 1.84–1.72 (m, 3.5H), 1.55 (dd, J = 45.0, 10.0 Hz, 1H); ESI MS m / z 341 [C15H16Cl2N2O3– H]-; UPLC (BEH C18, Method A) 96.6% (area%), tR= 3.86 min. Example 179 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,4R,5S)-2-isobutyryl-2- azabicyclo[2.2.1]heptan-5-yl)benzamide [ANA-246] OH Cl Cl

[0375] 3,5-Dichloro-2-hydroxy-N-((1R,4R,5S)-2-isobutyryl-2- azabicyclo[2.2.1]heptan-5-yl)benzamide was prepared as a white solid according to Synthetic Scheme 29:1H NMR (500 MHz, DMSO-d6J = 5.9 Hz, 1H), 8.10 (t, J = 2.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.43 (d, J = 13.3 Hz, 1H), 4.04–3.97 (m, 1H), 3.42 (dd, J = 9.4, 3.7 Hz, 0.5H), 3.21–3.17 (m, 1H), 2.95 (d, J = 11.2 Hz, 0.5H), 2.72–2.69 (m, 0.5H), 2.60 (dd, J = 23.7, 1.82 Hz, 1H), 2.53–2.48 (m, 0.5H), 2.06–2.00 (m, 0.5H), 1.97–1.91 (m, 0.5 H), 1.88–1.85 (m, 1H), 1.79–1.72 (m, 1H), 1.55 (dd, J = 31.9, 10.2 Hz, 1H), 1.23–0.95 (m, 6H); ESI MS m / z 369 [C17H20Cl2N2O3– H]-; UPLC (BEH C18, Method A) 95.6% (area%), tR= 4.39 min. Example 180 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,4R,5S)-2-(3,3,3-trifluoropropanoyl)- 2-azabicyclo[2.2.1]heptan-5-yl)benzamide [ANA-247]OH Cl Cl

[0376] 3,5-Dichloro-2-hydroxy-N-((1R,4R,5S)-2-(3,3,3-trifluoropropanoyl)-2- azabicyclo[2.2.1]heptan-5-yl)benzamide was prepared as an orange-yellow solid according to Synthetic Scheme 26 with the following modification: the crude solid was further purified by reverse phase column chromatography (C18, 10–100% acetonitrile / water) to provide the title compound:1H NMR (500 MHz, DMSO-d6 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 4.46 (d, J = 17.1 Hz, 1H), 4.05– 3.96 (m, 1H), 3.68–3.37 (m, 2.5H), 3.25–3.22 (m, 1H), 3.01 (d, J = 11.3 Hz, 0.5H), 2.63– 2.61 (m, 1H), 2.11–2.08 (m, 0.5H), 2.01–1.98 (m, 0.5H), 1.86–1.74 (m, 2H), 1.57 (dd, J = 36.5, 10.2 Hz, 1H); ESI MS m / z 409 [C16H15Cl2F3N2O3– H]-; UPLC (BEH C18, Method A) 94.6% (area%), tR= 4.50 min. Example 181 Preparation of N-(1-(3,5-Dichloro-2-hydroxybenzoyl)piperidin-3- yl)cyclopropanesulfonamide [ANA-2 OH Cl Cl

[0377] N-(1-(3,5-Dichloro-2-hydroxybenzoyl)piperidin-3- yl)cyclopropanesulfonamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d61H), 4.40–4.09 (m, 1H), 3.50–3.11 (m, 1H), 2.98–2.78 (m, 2H), 2.61–2.39 (m, 1H), 1.95 20 (br s, 1H), 1.76–1.57 (m, 1H), 1.47 (br s, 2H), 1.05–0.89 (m, 2H), 0.89–0.60 (m, 3H); ESI MS m / z 393 [C15H18Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 97.9% (AUC), tR= 3.46 min. Example 182 4357-P1WO -205-Preparation of N-Cyclobutyl-4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxamide [ANA-249] OH Cl Cl

[0378] N-Cyclobutyl-4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxamide was prepared as a white solid according to Synthetic Scheme 5:1H NMR (500 MHz, DMSO-d6J = 7.6 Hz, 1H), 4.10 (sx, J = 8.2 Hz, 1H), 4.06–3.99 (m, 1H), 3.97 (d, J = 13.2 Hz, 2H), 2.74 (t, J = 12.0 Hz, 2H), 2.10 (tt, J = 7.9, 2.5 Hz, 2H), 1.91 (quintd, J = 9.1, 2.6 Hz, 2H), 1.75 (dd, J = 11.5, 2.5 Hz, 2H), 1.63–1.50 (m, 2H), 1.39 (qd, J = 12.2, 3.7 Hz, 2H); ESI MS m / z 386 [C17H21Cl2N3O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.55 min. Example 183 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(2-(piperidin-1-yl)acetyl)piperidin-4- yl)benzamide [ANA-250] O Cl Cl

[0379] 3,5-Dichloro-2-hydroxy-N-(1-(2-(piperidin-1-yl)acetyl)piperidin-4- yl)benzamide was prepared as a white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6–4.00 (m, 3H), 3.96–3.55 (m, 2H), 3.18 (t, J = 11.2 Hz, 1H), 3.02–2.84 (m, 2H), 1.87 (td, J = 12.6, 4.2 Hz, 3H), 1.64 (br s, 4H), 1.56–1.30 (m, 5H), 1.29–1.10 (m, 1H), phenol OH not observed; ESI MS m / z 414 [C19H25Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 97.2% (AUC), tR= 3.55 min. Example 184Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(2-(pyrrolidin-1-yl)acetyl)piperidin-4- yl)benzamide [ANA-251] OH Cl Cl

[0380] 3,5-Dichloro-2-hydroxy-N-(1-(2-(pyrrolidin-1-yl)acetyl)piperidin-4- yl)benzamide was prepared as a white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6–4.00 (m, 4H), 3.66 (d, J = 13.4 Hz, 1H), 3.21 (t, J = 10.7 Hz, 2H), 3.15–2.97 (m, 4H), 1.96–1.80 (m, 6H), 1.48 (qd, J = 10.0, 4.1 Hz, 1H), 1.35 (qd, J = 10.0, 4.1 Hz, 1H), 1.27–1.19 (m, 1H), phenol OH not observed; ESI MS m / z 400 [C18H23Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 95.6% (AUC), tR= 3.42 min. Example 185 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-5- yl)benzamide [ANA-252] OH Cl Cl

[0381] 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-5-yl)benzamide was prepared as a white solid according to Synthetic Scheme 29 with the following modification: the crude solid was further purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to provide the title compound:1H NMR (500 MHz, DMSO-d6J = 1.9 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 4.51 (s, 1H), 4.38–4.21 (m, 1H), 3.50 (dd, J = 64.2, 10.2 Hz, 0.5H), 3.28–3.20 (m, 1.5H), 2.97 (br s, 0.5H), 2.82 (s, 0.5H), 2.23–2.19 (m, 0.7H),2.09–2.04 (m, 0.3H), 1.72–1.64 (m, 3H), 1.33–1.21 (m, 4H); ESI MS m / z 435 [C18H17Cl2F3N2O3– H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.91 min. Example 186 Preparation of 3,5-Dichloro-N-((1R,5S,8s)-3-(2-cyclobutylacetyl)-3- azabicyclo[3.2.1]octan-8-yl)-2-hydroxybenzamide [ANA-253] OH Cl Cl

[0382] 3,5-Dichloro-N-((1R,5S,8s)-3-(2-cyclobutylacetyl)-3- azabicyclo[3.2.1]octan-8-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 29 with the following modification: the isolated solid from work up was further purified by trituration in acetonitrile warmed to 50 °C:1H NMR (500 MHz, DMSO-d6J = 4.2 Hz, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 4.19 (dd, J = 13.0, 2.3 Hz, 1H), 3.92 (d, J = 4.5 Hz, 1H), 3.70 (dd, J = 12.6, 2.2 Hz, 1H), 3.22 (d, J = 12.4 Hz, 1H), 2.70 (d, J = 12.7 Hz, 1H), 2.62–2.50 (m, 2H), 2.41– 2.36 (m, 3H), 2.07–2.00 (m, 2H), 1.92–1.75 (m, 4H), 1.68–1.59 (m, 2H), 1.47–1.43 (m, 1H), 1.30–1.26 (m, 1H); ESI MS m / z 409 [C20H24Cl2N2O3– H]-; UPLC (BEH C18, Method A) 95.1% (AUC), tR = 5.12 min. Example 187 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,5S,8s)-3-isobutyryl-3- azabicyclo[3.2.1]octan-8-yl)benzamide [ANA-254] OH Cl Cl

[0383] 3,5-Dichloro-2-hydroxy-N-((1R,5S,8s)-3-isobutyryl-3- azabicyclo[3.2.1]octan-8-yl)benzamide was prepared as a white solid according to Synthetic Scheme 29:1H NMR (500 MHz, DMSO-d6J = 4.2Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 4.22 (dd, J = 12.9, 2.2 Hz, 1H), 3.94 (d, J = 4.4 Hz, 1H), 3.79 (dd, J = 12.2, 1.8 Hz, 1H), 3.26 (d, J = 12.4 Hz, 1H), 2.91– 2.85 (m, 1H), 2.73–2.69 (m, 1H), 2.42–2.39 (m, 2H), 1.93–1.83 (m, 2H), 1.45–1.39 (m, 1H), 1.31–1.22 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H); ESI MS m / z 383 [C18H22Cl2N2O3– H]-; UPLC (BEH C18, Method A) 96.1% (AUC), tR= 4.77 min. Example 188 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(2-morpholinoacetyl)piperidin-4- yl)benzamide [ANA-255] O Cl Cl

[0384] 3,5-Dichloro-2-hydroxy-N-(1-(2-morpholinoacetyl)piperidin-4- yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6–4.18 (m, 1H), 4.10–3.98 (m, 2H), 3.59 (t, J = 4.2 Hz, 4H), 3.20–3.02 (m, 2H), 2.85–2.71 (m, 1H), 2.42 (s, 3H), 1.92–1.80 (m, 2H), 1.51 (q, J = 9.5 Hz, 1H), 1.34 (q, J = 9.5 Hz, 1H), 1.25 (d, J = 5.5 Hz, 3H); ESI MS m / z 416 [C18H23Cl2N3O4+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 3.56 min. Example 189 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(2-(4-methylpiperazin-1- yl)acetyl)piperidin-4-yl)benzamide [ANA-256] O Cl Cl

[0385] 3,5-Dichloro-2-hydroxy-N-(1-(2-(4-methylpiperazin-1-yl)acetyl)piperidin- 4-yl)benzamide was prepared as a light yellow solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 2.5 Hz, 1H), 7.79(d, J = 2.5 Hz, 1H), 4.35 (d , J = 13.3 Hz, 1H), 4.28–4.05 (m, 3H), 3.70–3.60 (m, 1H), 3.68–3.59 (m, 2H), 3.23–3.10 (m, 4H), 2.85 (s, 4H), 1.92 (t, J = 12.6 Hz, 2H), 1.56 (qd, J = 10.6, 4.3 Hz, 1H), 1.46 (qd, J = 10.6, 4.1 Hz, 1H), 1.26 (t, J = 6.9 Hz, 3H); ESI MS m / z 429 [C19H26Cl2N4O3+ H]+; UPLC (BEH C18, Method A) 97.7% (AUC), tR= 3.27 min. 5 Example 190 Preparation of 3,5-Dichloro-N-(1-(2-(1,1-dioxidothiomorpholino)acetyl)piperidin-4- yl)-2-hydroxybenzamide [ANA-257]

[0386] 3,5-Dichloro-N-(1-(2-(1,1-dioxidothiomorpholino)acetyl)piperidin-4-yl)- 10 2-hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6J = 2.5 Hz, 1H), 7.79 (d, J = 2.5 Hz, 1H), 4.56 (d, J = 16.6 Hz, 1H), 4.46 (d, J = 16.2 Hz, 1H), 4.35 (d, J = 13.2 Hz, 1H), 4.18–4.09 (m, 1H), 3.80–3.70 (m, 3H), 3.66–3.58 (m, 4H), 3.20 (t, J = 11.9 Hz, 1H), 2.91 (t, J = 11.9 Hz, 1H), 1.94 (td, J = 13.8, 2.0 Hz, 2H), 1.58 (qd, J = 11.9, 3.4 Hz, 1H), 1.48 (qd, J = 11.9, 15 3.4 Hz, 1H), 1.26 (t, J = 6.8 Hz, 3H), phenol OH not observed; ESI MS m / z 464 [C18H23Cl2N3O5S + H]+; UPLC (BEH C18, Method A) 98.3% (AUC), tR = 3.59 min. Example 191 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,4R,5S)-2-(1 (trifluoromethyl)cyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-5- 20 yl)benzamide [ANA-258]

[0387] 3,5-Dichloro-2-hydroxy-N-((1R,4R,5S)-2-(1- (trifluoromethyl)cyclopropane-1-carbonyl)-2-azabicyclo[2.2.1]heptan-5-yl)benzamidewas prepared as an off-white solid according to Synthetic Scheme 29:1H NMR (500 MHz, DMSO-d6J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.56–4.47 (m, 1H), 3.99 (br s, 1H), 3.57–3.52 (0.5H), 3.37–3,28 (m, 1.0H), 2.94 (d, J = 11.5 Hz, 0.5H), 2.65–2.63 (m, 1H), 2.15–2.11 (m, 0.5H), 2.00–1.97 (m, 0.5H), 1.87–

[0388] 3,5-Dichloro-N-((1R,5S,8s)-3-(cyclopropylsulfonyl)-3- azabicyclo[3.2.1]octan-8-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 33 with the following modification: the compound was acidified and the slurry collected as directed. No further purification was needed:1H NMR (500 MHz, DMSO-d6) 13.43 (s, 1H), 8.57 (d, J = 3.6 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 3.88 (d, J = 4.4 Hz, 1H), 3.41–3.31 (m, 2H), 3.11 (d, J = 11.1 Hz, 2H), 2.63– 2.58 (m, 1H), 2.50–2.47 (m, 2H), 1.92–1.90 (m, 2H), 1.61–1.52 (m, 2H), 0.99–0.88 (m, 4H); ESI MS m / z 417 [C17H20Cl2N2O4S – H]-; UPLC (BEH C18, Method A) 95.0% (AUC), tR= 4.99 min. Example 193 Preparation of N-((1R,5S,8s)-3-Acetyl-3-azabicyclo[3.2.1]octan-8-yl)-3,5-dichloro-2- hydroxybenzamide [ANA260]

[0389] N-((1R,5S,8s)-3-Acetyl-3-azabicyclo[3.2.1]octan-8-yl)-3,5-dichloro-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 32:1H NMR (500 MHz, DMSO-d6, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 4.19 (dd, J = 13.0, 2.2 Hz, 1H), 3.93 (d, J = 4.5 Hz, 1H), 3.65 (dd, J = 5 12.6, 2.1 Hz, 1H), 3.27 (d, J = 12.4 Hz, 1H), 2.72 (d, J = 12.8 Hz, 1H), 2.40–2.38 (m, 2H), 2.01 (s, 3H), 1.91–1.83 (m, 2H), 1.50–1.46 (m, 1H), 1.33–1.29 (m, 1H); ESI MS m / z 355 [C16H18Cl2N2O3– H]-; UPLC (BEH C18, Method A) 96.0% (AUC), tR= 4.29 min. Example 194 Preparation of 1-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)- 10 2-(4-hydroxypiperidin 1 l)ethan 1 one [ANA 261]

[0390] 1-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)-2- (4-hydroxypiperidin-1-yl)ethan-1-one was prepared as a white solid according to Synthetic Scheme 29 with the following modifications: the reaction was directly 15 concentrated under reduced pressure and purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water):1H NMR (500 MHz,DMSO- d6 + 3 drops d- J = 34.4 Hz, 1H), 4.31–4.21 (m, 2H), 3.91 (brs, 0.5H), 3.65–3.54 (m, 2H), 3.42 (br s, 2H), 3.42–3.39 (m, 3H), 3.28–3.17 (m, 4.5H), 3.02– 2.97 (m, 1H), 1.95 (br s, 2H), 1.87–1.45 (m, 8H); ESI MS m / z 468 [C22H29Cl2N3O4– H]-;20 UPLC (BEH C18, Method A) 96.6% (AUC), tR= 2.90 min. Example 195 Preparation of 1-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)- 2-(4-(hydroxymethyl)piperidin 1yl)ethan 1 one [ANA 262]

[0391] 1-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)-2- (4-(hydroxymethyl)piperidin-1-yl)ethan-1-one was prepared as a light yellow solid according to Synthetic Scheme 29 with the following modifications: the reaction was directly concentrated under reduced pressure and purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water):1H NMR (500 MHz,DMSO- d6 + 3 drops d- J = 32.5 Hz, 1H), 4.29–4.20 (m, 2H), 3.62–3.17 (m, 12.5H), 2.95–2.90 (m, 1.5H), 1.84–1.77 (m, 4H), 1.65–1.46 (m, 7H); ESI MS m / z 482 [C23H31Cl2N3O4– H]-; UPLC (BEH C18, Method A) 96.1% (AUC), tR= 3.06 min. Example 196 Preparation of 1-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)- 2-(3-hydroxypyrrolidin-1-yl)ethan-1-one [ANA-263] OH O Cl C

[0392] 1-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-8-yl)-2- (3-hydroxypyrrolidin-1-yl)ethan-1-one was prepared as a white solid according to Synthetic Scheme 29 with the following modifications: the reaction was directly concentrated under reduced pressure and purified twice by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water):1H NMR (500 MHz,DMSO-d6 + 3 drops d- J = 32.8 Hz, 1H), 4.43–4.26 (m,3H), 3.70–3.16 (m, 11.5H), 3.00–2.95 (m, 0.5H), 2.26–2.18 (m, 0.5H), 2.07–1.78 (m, 20 3.5H), 1.62–1.45 (m, 4H); ESI MS m / z 454 [C21H27Cl2N2O4– H]-; UPLC (BEH C18, Method A) 93.5% (AUC), tR= 3.01 min. Example 197 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(2-(1- (trifluoromethyl)cyclopropyl)acetyl)-2-azabicyclo[2.2.1]heptan-5-yl)benzamide 25 [ANA-264] 4357-P1WO -213-O Cl Cl

[0393] 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(2-(1- (trifluoromethyl)cyclopropyl)acetyl)-2-azabicyclo[2.2.1]heptan-5-yl)benzamide was prepared as a light yellow solid according to Synthetic Scheme 29 with the following modification: the crude solid was further purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) followed by trituration in acetonitrile / water (1:3) to provide the title compound:1H NMR (500 MHz, DMSO-d613.55 (s, 1H), 8.99 (br s, 1H), 8.09 (t, J = 2.6 Hz, 1H), 7.77 (t, J = 2.3 Hz, 1H), 4.39 (s, 1H), 4.29–4.26 (m, 1H), 3.43 (d, J = 9.7 Hz, 0.5H), 3.28–3.26 (m, 1H), 3.03–3.01 (m, 0.5H), 3.05–2.90 (m, 1H), 2.82 (s, 0.5H), 2.71 (d, J = 15.4 Hz, 0.5H), 2.36 (t, J = 14.7 Hz, 1H), 2.18–2.14 (m, 0.4H), 2.09–2.03 (m, 0.6H), 1.72–1.60 (m, 3H), 0.98–0.88 (m, 4H); ESI MS m / z 449 [C19H19Cl2F3N2O3– H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 5.06 min. Example 198 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(2-(piperazin-1-yl)acetyl)piperidin-4- yl)benzamide Hydrochloride [ANA-265] O Cl C

[0394] 3,5-Dichloro-2-hydroxy-N-(1-(2-(piperazin-1-yl)acetyl)piperidin-4- yl)benzamide hydrochloride was prepared according to Synthetic Scheme 7 with the following modification: the purified product was suspended in 4M hydrochloric acid (0.40 mL, 1.6 mmol) and allowed to stir overnight, then concentrated under reduced pressure to provide 3,5-dichloro-2-hydroxy-N-(1-(2-(piperazin-1-yl)acetyl)piperidin-4-yl)benzamide hydrochloride as a white solid:1H NMR (500 MHz, DMSO-d6J = 2.5 Hz, 1H),7.78 (d, J = 2.5 Hz, 1H), 4.57 (d, J = 16.4 Hz, 1H), 4.46 (d, J = 16.4 Hz, 1H), 4.36 (d, J = 12.9 Hz, 1H), 4.18–4.10 (m, 1H), 3.73–3.65 (m, 1H), 3.65–3.58 (m, 1H), 3.54–3.36 (m, 5H), 3.20 (t, J = 12.3 Hz, 1H), 3.14 (q, J = 7.4 Hz, 1H), 2.91 (t, J = 11.8 Hz, 1H), 1.99– 1.90 (m, 2H), 1.60 (qd, J = 12.4, 3.9 Hz, 1H), 1.49 (qd, J = 12.4, 3.6 Hz, 1H), 1.30–1.21 (m, 4H); ESI MS m / z 415 [C18H24Cl2N4O3+ H]+; UPLC (BEH C18, Method A) 96.0% (AUC), tR = 3.23 min. Example 199 Preparation of 3,5-Dichloro-N-(1-(3-(dimethylamino)propanoyl)piperidin-4-yl)-2- hydroxybenzamide [ANA

[0395] 3,5-Dichloro-N-(1-(3-(dimethylamino)propanoyl)piperidin-4-yl)-2- hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6–3.99 (m, 2H), 3.76 (d, J = 14.3 Hz, 1H), 3.24 (t, J = 10.8 Hz, 1H), 3.18–3.05 (m, 2H), 3.05–2.95 (m, 1H), 2.84– 2.70 (m, 2H), 2.70–2.56 (m, 6H), 1.94–1.87 (m, 1H), 1.87–1.80 (m, 1H), 1.45 (qd, J = 9.3, 4.7 Hz, 1H), 1.33 (qd, J = 9.3, 4.7 Hz, 1H), 1.24 (br s, 2H); ESI MS m / z 388 [C17H23Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 91.2% (AUC), tR= 3.51 min. Example 200 Preparation of 3,5-Dichloro-N-((1R,5S,8r)-3-(2-cyclobutylacetyl)-3- azabicyclo[3.2.1]octan-8-yl)-2-hydroxybenzamide [ANA-267] OH Cl Cl

[0396] 3,5-Dichloro-N-((1R,5S,8r)-3-(2-cyclobutylacetyl)-3- azabicyclo[3.2.1]octan-8-yl)-2-hydroxybenzamide was prepared as a light yellow solidaccording to Synthetic Scheme 29 with the following modification: filtered solid was further purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water):1H NMR (500 MHz, DMSO-d6(d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 3.94 (dd, J = 13.5, 3.1 Hz, 1H), 3.82 (q, J = 4.6 Hz, 1H), 3.48–3.42 (m, 2H), 2.99 (d, J = 13.4 Hz, 1H), 2.63–2.50 (m, 2H), 2.40–2.33 (3H), 2.07–1.99 (m, 2H), 1.86–1.68 (m, 4H), 1.67–1.59 (m, 2H), 1.54–1.48 (m, 1H), 1.40– 1.33 (m, 1H); ESI MS m / z 409 [C20H24Cl2N2O3– H]-; UPLC (BEH C18, Method A) 98.2% (AUC), tR= 5.22 min. Example 201 Preparation of N-(1-(3,5-Dichloro-2-hydroxybenzoyl)piperidin-3-yl)acetamide [ANA-268] OH Cl Cl

[0397] N-(1-(3,5-Dichloro-2-hydroxybenzoyl)piperidin-3-yl)acetamide was prepared as a white solid according to Synthetic Scheme 8:1H NMR (500 MHz, DMSO- d6J = 13.9 Hz, 1H), 2.62–2.55 (m, 1H), 2.02–1.91 (m, 1H), 1.87 (s, 3H), 1.85–1.80 (m, 1H), 1.59–1.40 (m, 3H), amide NH not observed; ESI MS m / z 331 [C14H16Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 97.1% (AUC), tR= 3.03 min. Example 202 Preparation of 3,5-Dichloro-2-hydroxy-N-((2-((2,2,2- trifluoroethyl)carbamoyl)cyclopropyl)methyl)benzamide [ANA-269] OH Cl Cl

[0398] 3,5-Dichloro-2-hydroxy-N-((2-((2,2,2- trifluoroethyl)carbamoyl)cyclopropyl)methyl)benzamide was prepared as a white solid according to Synthetic Scheme 19:1H NMR (500 MHz, DMSO-d6(br s, 1H), 8.71 (t, J = 6.3 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.00– 3.79 (m, 2H), 3.40–3.32 (m, 1H), 3.25–3.17 (m, 1H), 1.65 (quint, J = 4.4 Hz, 1H), 1.59– 1.50 (m, 1H), 0.94 (quint, J = 4.4 Hz, 1H), 1.42 (ddd, J = 9.7, 6.0, 4.0 Hz, 1H); ESI MS m / z 383 [C14H13Cl2F3N2O3- H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.80 min. Example 203 Preparation of 3,5-Dichloro-N-((2- ((cyclobutylmethyl)carbamoyl)cyclopropyl)methyl)-2-hydroxybenzamide [ANA-270] OH Cl Cl

[0399] 3,5-Dichloro-N-((2-((cyclobutylmethyl)carbamoyl)cyclopropyl)methyl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 19:1H NMR (500 MHz, DMSO-d6J = 2.4 Hz, 1H), 7.97 (t, J = 5.6 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 3.36–3.32 (m, 1H), 3.22–3.16 (m, 1H), 3.13– 3.00 (m, 2H), 2.36 (sept, J = 7.5 Hz, 1H), 1.97–1.89 (m, 2H), 1.84–1.72 (m, 2H), 1.66– 1.56 (m, 2H), 1.53 (quint, J = 4.4 Hz, 1H), 1.50–1.42 (m, 1H), 0.89 (quint, J = 4.4 Hz, 1H), 0.71 (ddd, J = 9.4, 5.9, 3.8 Hz, 1H); ESI MS m / z 369 [C17H20Cl2N2O3- H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.85 min. Example 204 Preparation of 3,5-Dichloro-2-hydroxy-N-(1-(2-(4-hydroxypiperidin-1- yl)acetyl)piperidin-4-yl)benzamide [ANA-271] O Cl C

[0400] 3,5-Dichloro-2-hydroxy-N-(1-(2-(4-hydroxypiperidin-1- yl)acetyl)piperidin-4-yl)benzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6–4.63 (m, 1H), 4.25–4.12 (m, 1H), 4.10–4.00 (m, 3H), 3.99–3.78 (m, 3H), 3.66–3.46 (m, 2H), 3.17 (t, J = 10.9 Hz, 2H), 3.00–2.80 (m, 3H), 1.95–1.75 (m, 4H), 1.60–1.44 (m, 3H), 1.34 (q, J = 10.3 Hz, 1H); ESI MS m / z 430 [C19H25Cl2N3O4+ H]+; UPLC (BEH C18, Method A) 95.1% (AUC), tR= 3.68 min. Example 205 Preparation of 3,5-Dichloro-N-((1R,5S,8r)-3-(cyclopropylsulfonyl)-3- azabicyclo[3.2.1]octan-8-yl)-2-hydroxybenzamide [ANA-272] OH Cl Cl

[0401] 3,5-Dichloro-N-((1R,5S,8r)-3-(cyclopropylsulfonyl)-3- azabicyclo[3.2.1]octan-8-yl)-2-hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 33 with the following modification: after acidification of the reaction mixture, the solids collected by filtration were found to be of unacceptable purity. However, the filtrate had precipitated and these solids were collected and dried to afford the title compound:1H NMR (500 MHz, DMSO-d68.11 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 3.74 (q, J = 4.3 Hz, 1H), 3.32 (d, J = 11.6 Hz, 2H), 3.18 (dd, J = 12.0, 3.3 Hz, 2H), 2.64–2.59 (m, 1H), 2.54–2.50 (m, 2H), 1.78– 1.76 (m, 2H), 1.64–1.62 (m, 2H), 0.94–0.90 (m, 4H); ESI MS m / z 417 [C17H20Cl2N2O4S – H]-; UPLC (BEH C18, Method A) 98.0% (AUC), tR= 4.96 min. Example 206 Preparation of N-((1R,5S,8r)-3-Acetyl-3-azabicyclo[3.2.1]octan-8-yl)-3,5-dichloro-2- hydroxybenzamide [ANA273]

[0402] N-((1R,5S,8r)-3-Acetyl-3-azabicyclo[3.2.1]octan-8-yl)-3,5-dichloro-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 32:1H NMR (500 MHz, DMSO-d6J = 2.2 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 3.95 (dd, J = 13.5, 3.1 Hz, 1H), 3.86 (q, J = 4.7 Hz, 1H), 3.48– 3.39 (m, 2H), 2.97 (d, J = 13.4 Hz, 1H), 2.34 (d, J = 15.0 Hz, 2H), 1.99 (s, 3H), 1.78–1.71 (m, 2H), 1.57–1.52 (m, 1H), 1.40–1.38 (m, 1H); ESI MS m / z 355 [C16H18Cl2N2O3 – H]-; UPLC (BEH C18, Method A) 96.4% (AUC), tR= 4.35 min. Example 207 Preparation of (1R,4R,5R)-N-Cyclobutyl-5-(3,5-dichloro-2-hydroxybenzamido)-2- azabicyclo[2.

[0403] (1R,4R,5R)-N-Cyclobutyl-5-(3,5-dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.1]heptane-2-carboxamide was prepared as a white solid according to Synthetic Scheme 31 with the following modifications: fractions from column chromatography were concentrated under reduced pressure to a low volume of water and the resulting precipitate was filtered. The filtrate was acidified to pH 3-4 with a 0.1 N aqueous solution of hydrochloric acid and the resulting precipitates were cooled in an ice- bath for 10 min. The solid was collected by vacuum filtration, rinsing with water (20 mL, in portions) and then dried under high vacuum at 50 °C:1H NMR (500 MHz, DMSO-d6) J = 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 6.4 Hz, 1H), 4.24–4.21 (m, 2H), 4.20–4.11 (m, 1H), 3.16 (d, J = 9.7 Hz, 1H), 3.06 (dd, J = 9.7, 2.2 Hz, 1H), 2.84 (br s, 1H), 2.22–2.07 (m, 2H), 2.02–1.87 (m, 3H), 1.71 (dd, J = 13.2, 4.1 Hz, 1H), 1.58–1.48 (m, 4H); ESI MS m / z 396 [C18H21Cl2N3O3– H]-; UPLC (BEH C18, Method A) 98.2% (AUC), tR= 4.56 min. Example 208Preparation of 3,5-Dichloro-N-(2-(cyclopropylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)- 2-hydroxybenzamide [ANA

[0404] 3,5-Dichloro-N-(2-(cyclopropylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)-2- hydroxybenzamide was prepared as a light brown solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 4.30 (sx, J = 7.7 Hz, 1H), 3.98 (s, 2H), 3.88 (s, 2H), 2.75–2.68 (m, 1H), 2.60–2.55 (m, 2H), 2.47–2.29 (m, 2H), 1.04–0.98 (m, 2H), 0.95–0.89 (m, 2H); ESI MS m / z 405 [C16H18Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 98.1% (AUC), tR= 4.94 min. Example 209 Preparation of N-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2-azaspiro[3.3]heptan-6- yl)cyclopropanesulfonamide [ANA-2 OH Cl Cl

[0405] N-(2-(3,5-Dichloro-2-hydroxybenzoyl)-2-azaspiro[3.3]heptan-6- yl)cyclopropanesulfonamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6J = 2.5, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.38 (s, 1H), 4.60–4.50 (m, 1H), 4.49–4.39 (m, 1H), 4.21–4.11 (m, 1H), 4.10– 3.99 (m, 1H), 3.69 (q, J = 7.7 Hz, 1H), 2.60–2.53 (m, 2H), 2.45–2.38 (m, 1H), 2.17 (td, J = 9.1, 3.0 Hz, 2H), 0.95–0.85 (m, 4H); ESI MS m / z 405 [C16H18Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 95.3% (AUC), tR= 4.67 min. Example 210 Preparation of N-(2-Acetyl-2-azaspiro[3.3]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide [ANA-277]OH Cl Cl

[0406] N-(2-Acetyl-2-azaspiro[3.3]heptan-6-yl)-3,5-dichloro-2- hydroxybenzamide was prepared as a white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d6(q, J = 7.5 Hz, 1H), 4.18 (s, 1H), 4.07 (s, 1H), 3.89 (s, 1H), 3.79 (s, 1H), 2.60–2.52 (m, 2H), 2.31 (t, J = 10.5 Hz, 2H), 1.72 (d, J = 5.2 Hz, 3H); ESI MS m / z 343 [C15H16Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 96.5% (AUC), tR= 4.40 min. Example 211 Preparation of (1R,5S,6r)-N-Cyclobutyl-6-(3,5-dichloro-2-hydroxybenzamido)-3- azabicyclo[3.1.1]heptane-3-carboxamide [ANA-278] OH Cl Cl

[0407] (1R,5S,6r)-N-Cyclobutyl-6-(3,5-dichloro-2-hydroxybenzamido)-3- azabicyclo[3.1.1]heptane-3-carboxamide was prepared as a white solid according to Synthetic Scheme 31 with the following modification: the crude residue was purified (C18 silica gel, 10–100% acetonitrile / water) followed by precipitation from water.1H NMR (500 MHz, DMSO-d6) 13.2 (br s, 1H), 8.84 (br s, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 6.21 (d, J = 7.7 Hz, 1H), 4.11–4.06 (m, 1H), 4.02–3.99 (m, 1H), 3.48–3.42 (m, 4H), 2.70 (t, J = 5.6 Hz, 2H), 2.09–2.04 (m, 2H), 1.94–1.86 (m, 3H), 1.57– 1.46 (m, 2H), 1.36 (d, J = 9.4 Hz, 1H); ESI MS m / z 396 [C18H21Cl2N3O3– H]-; UPLC (BEH C18, Method A) >99% (area%), tR= 4.50 min. Example 212 Preparation of N-(1-Acetyl-2,2-dimethylpiperidin-4-yl)-3,5-dichloro-2- hydroxybenzamide [ANA-279]OH Cl Cl

[0408] N-(1-Acetyl-2,2-dimethylpiperidin-4-yl)-3,5-dichloro-2- hydroxybenzamide was prepared as an off-white solid according to Synthetic Scheme 7:1H NMR (500 MHz, DMSO-d64.20–4.11 (m, 1H), 3.63 (ddd, J = 11.7, 7.3, 4.3 Hz, 1H), 3.29–3.21 (m, 1H), 2.09–2.01 (m, 1H), 2.00 (s, 3H), 1.78–1.65 (m, 2H), 1.65–1.54 (m, 1H), 1.51 (s, 3H), 1.36 (s, 3H); ESI MS m / z 359 [C16H20Cl2N2O3+ H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.92 min. Example 213 Preparation of 3,5-Dichloro-N-(1-ethylpiperidin-4-yl)-2-hydroxybenzamide hydrochloride [ANA-280] OH Cl Cl

[0409] 3,5-Dichloro-N-(1-ethylpiperidin-4-yl)-2-hydroxybenzamide hydrochloride was prepared according to Synthetic Scheme 1 with the following modification: the reaction mixture was quenched with 2M hydrochloric acid, and the precipitates were collected by vacuum filtration and dried under vacuum to provide 3,5- dichloro-N-(1-ethylpiperidin-4-yl)-2-hydroxybenzamide hydrochloride as a white solid:1H NMR (500 MHz, DMSO-d6 J = 2.5 Hz, 1H), 7.92 (d, J = 2.5 Hz, 1H), 4.95(tt, J = 12.1, 3.5 Hz, 1H), 3.58 (d, J = 11.0 Hz, 2H), 3.16–3.05 (m, 4H), 2.67 (qd, J = 12.6, 3.4 Hz, 2H), 1.94 (d, J = 12.5 Hz, 2H), 1.29–1.19 (m, 4H); ESI MS m / z 317 [C14H18Cl2N2O2+ H]+; UPLC (BEH C18, Method A) 95.7% (AUC), tR= 3.41 min. Example 214 Preparation of Cyclobutyl (1R,5S,6r)-6-(3,5-Dichloro-2-hydroxybenzamido)-3- azabicyclo[3.1.1]heptane-3-carboxylate [ANA-281]OH Cl Cl

[0410] Cyclobutyl (1R,5S,6r)-6-(3,5-dichloro-2-hydroxybenzamido)-3- azabicyclo[3.1.1]heptane-3-carboxylate was prepared as a white solid according to Synthetic Scheme 30:1H NMR (500 MHz, DMSO-d67.96 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 4.85–4.79 (m, 1H), 4.04 (q, J = 9.3, 5.8 Hz, 1H), 3.60–3.43 (m, 4H), 2.71–2.67 (m, 2H), 2.25–2.18 (m, 2H), 2.01–1.89 (m, 3H), 1.68 (q, J = 20.5, 10.5 Hz, 1H), 1.58–1.48 (m, 1H), 1.40 (d, J = 9.6 Hz, 1H); ESI MS m / z 397 [C18H20Cl2N2O4– H]-; UPLC (BEH C18, Method A) 97.5% (area%), tR= 5.59 min. Example 215 Preparation of Cyclobutyl (1R,4R,5R)-5-(3,5-Dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.1]heptane-2-carboxylate [ANA-282] OH Cl Cl

[0411] Cyclobutyl (1R,4R,5R)-5-(3,5-dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.1]heptane-2-carboxylate was prepared as a white solid according to Synthetic Scheme 30 with the following modification: the purified solid was triturated in acetonitrile / water (0.2 / 0.4 mL) and filtered. The solid was rinsed with water and then dried under high vacuum at 50 °C to afford the title compound:1H NMR (500 MHz, DMSO-d6) 9.04 (br s, 1H), 8.14 (s, 1H), 7.76 (s, 1H), 4.90–4.86 (m, 1H), 4.29–4.27 (m, 1H), 4.14 (d, J = 23.0 Hz, 1H), 3.25–3.20 (m, 1H), 3.15–3.08 (m, 1H), 2.82 (d, J = 12.1 Hz, 1H), 2.24–2.23 (m, 2H), 2.10–1.90 (m, 3H), 1.76–1.64 (m, 4H), 1.57–1.50 (m, 1H); ESI MS m / z 397 [C18H20Cl2N2O4– H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 5.55 min. Example 216Preparation of (1R,4R,5S)-N-Cyclobutyl-5-(3,5-dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.1]heptane-2-carb Cl

[0412] (1R,4R,5S)-N-Cyclobutyl-5-(3,5-dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.1]heptane-2-carboxamide was prepared as a white solid according to Synthetic Scheme 31:1H NMR (500 MHz, DMSO-d68.09 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 6.28 (d, J = 7.9 Hz, 1H), 4.23 (s, 1H), 4.14–4.06 (m, 1H), 3.93–3.89 (m, 1H), 3.16 (dd, J = 9.6, 3.8 Hz, 1H), 2.91 (d, J = 9.5 Hz, 1H), 2.54 (s, 1H), 2.12–2.06 (m, 2H), 2.10–1.85 (m, 3H), 1.74–1.69 (m, 2H), 1.57–1.49 (m, 3H); ESI MS m / z 396 [C18H21Cl2N3O3– H]-; UPLC (BEH C18, Method A) 98.9% (AUC), tR= 4.70 min. Example 217 Preparation of Cyclobutyl (1R,4R,5S)-5-(3,5-Dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.1]heptane-2-carboxylate [ANA-284] O Cl Cl

[0413] Cyclobutyl (1R,4R,5S)-5-(3,5-dichloro-2-hydroxybenzamido)-2- azabicyclo[2.2.1]heptane-2-carboxylate was prepared as a white solid according to Synthetic Scheme 30 with the following modifications: the crude residue was triturated in acetonitrile and the filtrate was concentrated under reduced pressure. The residue was then precipitated in a minimum volume of methanol to afford the title compound:1H NMR (500 MHz, DMSO-d6J = 2.4 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 4.84–4.80 (m, 1H), 4.18 (d, J = 19.7 Hz, 1H), 3.98 (br s, 1H), 3.25–3.17 (m, 1H), 7.98 (dd, J = 32.1, 9.8 Hz, 1H), 2.57 (s, 1H), 2.26–2.21 (m, 2H), 2.04–1.94 (m, 3H),1.79–1.67 (m, 3H), 1.59–1.49 (m, 2H); ESI MS m / z 397 [C18H20Cl2N4O4– H]-; UPLC (BEH C18, Method A) 95.2% (AUC), tR= 5.45 min. Example 218 Preparation of (1R,5S,8r)-N-Cyclobutyl-8-(3,5-dichloro-2-hydroxybenzamido)-3- azabicyclo[3.2.1]octane-3-carbo Cl

[0414] (1R,5S,8r)-N-Cyclobutyl-8-(3,5-dichloro-2-hydroxybenzamido)-3- azabicyclo[3.2.1]octane-3-carboxamide was prepared as a white solid according to Synthetic Scheme 31 with the following modification. It was necessary to purify the compound a second time by reverse phase column chromatography (C18 silica gel, 10– 100% acetonitrile / water):1H NMR (500 MHz, DMSO-d68.13 (s, 1H), 7.75 (s, 1H), 6.41 (d, J = 7.6 Hz, 1H), 4.13–4.08 (m, 1H), 3.84 (q, J = 4.8 Hz, 1H), 3.49 (dd, J = 12.7, 2.7 Hz, 2H), 3.10 (d, J = 12.4 Hz, 2H), 2.33 (br s, 2H), 2.11–2.05 (m, 2H), 1.92–1.88 (m, 2H), 1.73–1.72 (m, 2H), 1.57–1.48 (m, 4H); ESI MS m / z 410 [C19H23Cl2N3O3– H]-; UPLC (BEH C18, Method A) >99% (AUC), tR= 4.94 min. Example 219 Preparation of 3,5-Dichloro-N-(1-(cyclopropylsulfonyl)azepan-3-yl)-2- hydroxybenzamide [ANA

[0415] 3,5-Dichloro-N-(1-(cyclopropylsulfonyl)azepan-3-yl)-2- hydroxybenzamide was prepared as a light yellow solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6 4.18–4.09 (m, 1H), 3.60 (dd, J = 14.3, 4.7 Hz, 1H), 3.41–3.31 (m, 3H), 2.71–2.61 (m, 1H), 1.96–1.88 (m, 1H), 1.85–1.76 (m, 2H), 1.76–1.60 (m, 2H), 1.51 (q, J = 10.5 Hz, 1H), 0.99–0.90 (m, 4H); ESI MS m / z 407 [C16H20Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 98.5% (AUC), tR= 5.38 min. Example 220 Preparation of 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(3-(3-oxopiperazin-1- yl)propanoyl)-2-azabicyclo[2.2.1]heptan-5-yl)benzamide [ANA-287] OH Cl Cl

[0416] 3,5-Dichloro-2-hydroxy-N-((1R,4R,5R)-2-(3-(3-oxopiperazin-1- yl)propanoyl)-2-azabicyclo[2.2.1]heptan-5-yl)benzamide was prepared as a white solid according to Synthetic Scheme 29 with the following modifications: at the completion of reaction, the mixture was dropped into a stirring ice cold 0.1 N aqueous solution of hydrochloric acid (10 mL) and extracted into ethyl acetate (15 mL). The aqueous phase was back extracted into ethyl acetate (10 mL). The combined organic phase was then washed with a saturated solution of sodium chloride (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography (C18 silica gel, 10–100% acetonitrile / water) to afford the title compound:1H NMR (500 MHz, DMSO-d6–8.08 (m, 1H), 7.73 (s, 2H), 4.38 (s, 1H), 4.34–4.28 (m, 1H), 3.39 (d, J = 9.8 Hz, 1H), 3.31–3.26 (m, 1H), 3.14–3.09 (m, 3H), 2.98 (d, J = 10.1 Hz, 2H), 2.86–2.80 (m, 1H), 2.64–2.60 (m, 4H), 2.42–2.34 (m, 2H), 2.16–2.01 (m, 1H), 1.69–1.64 (m, 3H); ESI MS m / z 453 [C20H24Cl2N4O4– H]-; UPLC (BEH C18, Method A) 98.6% (AUC), tR= 3.52 min. Example 221 Preparation of N-Cyclopropyl-4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxamide [ANA 288]

[0417] N-Cyclopropyl-4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxamide was prepared as an off-white solid according to Synthetic Scheme 5:1H NMR (500 MHz, DMSO-d66.60 (d, J = 2.5 Hz, 1H), 4.05–3.98 (m, 1H), 3.93 (d, J = 12.8 Hz, 2H), 2.74 (t, J = 12.2 Hz, 2H), 2.07 (s, 1H), 1.74 (d, J = 10.0 Hz, 2H), 1.40 (q, J = 11.9 Hz, 2H), 0.53 (td, J = 7.0, 4.8 Hz, 2H), 0.37 (td, J = 6.6, 4.2 Hz, 2H); ESI MS m / z 372 [C16H19Cl2N3O3 + H]+; UPLC (BEH C18, Method A) 96.8% (AUC), tR= 4.27 min. Example 222 Preparation of N-Cyclohexyl-4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxamide [ANA-289] O Cl Cl

[0418] N-Cyclohexyl-4-(3,5-dichloro-2-hydroxybenzamido)piperidine-1- carboxamide was prepared as an off-white solid according to Synthetic Scheme 5:1H NMR (500 MHz, DMSO-d66.16 (d, J = 7.9 Hz, 1H), 4.05–3.94 (m, 3H), 3.45–3.35 (m, 1H), 2.73 (t, J = 12.2 Hz, 2H), 1.80–1.64 (m, 6H), 1.57 (d, J = 13.0 Hz, 1H), 1.41 (qd, J = 11.7, 3.2 Hz, 2H), 1.29–1.11 (m, 4H), 1.11–1.01 (m, 1H); ESI MS m / z 414 [C19H25Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 96.8% (AUC), tR= 5.14 min. Example 223 Preparation of 2-Cyclobutyl-1-(8-(3,5-dichloro-2-hydroxybenzoyl)-2,8- diazaspiro[4.5]decan-2-yl)e

[0419] 2-Cyclobutyl-1-(8-(3,5-dichloro-2-hydroxybenzoyl)-2,8- diazaspiro[4.5]decan-2-yl)ethan-1-one was prepared as a white solid according toSynthetic Scheme 29 with the following modifications: the crude oil was adsorbed onto celite and purified by column chromatography (silica gel, 0–10% methanol / dichloromethane). The product was then dissolved in a minimum volume of dichloromethane and purified a second time by column chromatography (silica gel, 0–50% ethyl acetate / hexanes). The material was solvent swapped into acetonitrile, concentrated under reduced pressure, and the process repeated. The material was then dried under high vacuum at 50 °C:1H NMR (500 MHz,DMSO-d6J = 2.7 Hz, 1H), 7.19 (q, J = 2.7 Hz, 1H), 3.65–3.45 (m, 3H), 3.32–3.31 (m, 0.5H), 3.16 (br s, 2.5 H), 2.63– 2.55 (m, 1H), 2.34 (t, J = 7.7 Hz, 2H), 2.05–1.99 (m, 2H), 1.83–1.76 (m, 3H), 1.71–1.60 (m, 3H), 1.49 (br s, 4H), 2H obscured by solvent; ESI MS m / z 425 [C21H26Cl2N2O3+ H]+; UPLC (BEH C18, Method A) 97.6% (AUC), tR = 4.32 min. Example 224 Preparation of 4-(3,5-Dichloro-2-hydroxybenzamido)-N-isopropylpiperidine-1- carboxamide [ANA-291] OH Cl Cl

[0420] 4-(3,5-Dichloro-2-hydroxybenzamido)-N-isopropylpiperidine-1- carboxamide was prepared as an off-white solid according to Synthetic Scheme 5:1H NMR (500 MHz, DMSO-d6J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.05–3.95 (m, 3H), 3.75 (sx, J = 6.6 Hz, 1H), 2.73 (t, J = 11.8 Hz, 2H), 1.75 (dd, J = 12.4, 2.5 Hz, 2H), 1.42 (qd, J = 12.0, 3.9 Hz, 2H), 1.05 (d, J = 6.6 Hz, 6H); ESI MS m / z 374 [C16H21Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 95.5% (AUC), tR= 4.57 min. Example 225 Preparation of 3,5-Dichloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-2-hydroxy-N- methylbenzamide [ANA-292]OH Cl Cl

[0421] 3,5-Dichloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-2-hydroxy-N- methylbenzamide was prepared as a white solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d6J = 2.5 Hz, 1H), 7.20 (s, 1H), 3.76– 3.55 (m, 2H), 3.03–2.90 (m, 1H), 2.88–2.82 (m, 2H), 2.74–2.54 (m, 4H), 1.87–1.66 (m, 4H), 1.04–0.83 (m, 4H); ESI MS m / z 407 [C16H20Cl2N2O4S + H]+; UPLC (BEH C18, Method A) 98.3% (AUC), tR= 3.79 min. Example 226 Preparation of 2-Chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-3- hydroxyisonicotinamide [ANA-2 Cl

[0422] 2-Chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-3- hydroxyisonicotinamide was prepared as a light brown solid according to Synthetic Scheme 9:1H NMR (500 MHz, DMSO-d67.80 (d, J = 4.8 Hz, 1H), 4.03–3.95 (m, 1H), 3.63 (d, J = 12.5 Hz, 2H), 2.99 (td, J = 12.0, 2.0 Hz, 2H), 2.62–2.56 (m, 1H), 1.94 (d, J = 10.1 Hz, 2H), 1.62 (qd, J = 12.0, 3.5 Hz, 2H), 1.03–0.95 (m, 2H), 0.95–0.90 (m, 2H); ESI MS m / z 360 [C14H18ClN3O4S + H]+; UPLC (BEH C18, Method A) >99% (AUC), tR= 3.62 min. Example 227 Preparation of N-Cyclobutyl-4-(3,5-dichloro-2-hydroxy-N- methylbenzamido)piperidine 1 carboxamide [ANA294]

[0423] N-Cyclobutyl-4-(3,5-dichloro-2-hydroxy-N-methylbenzamido)piperidine- 1-carboxamide was prepared as a white solid according to Synthetic Scheme 5:1H NMR (500 MHz, DMSO-d6–3.90 (m, 4H), 2.86–2.74 (m, 1H), 2.74–2.65 (m, 3H), 2.45–2.36 (m, 1H), 2.13–2.04 (m, 2H), 1.94–1.83 (m, 2H), 1.61–1.48 (m, 6H); ESI MS m / z 400 [C18H23Cl2N3O3+ H]+; UPLC (BEH C18, Method A) 96.0% (AUC), tR = 3.54 min. Example 228 Preparation of 2-Chloro-N-(1-(cyclobutylcarbamoyl)piperidin-4-yl)-3- hydroxyisonicotinamide [ANA-2 Cl N

[0424] 2-Chloro-N-(1-(cyclobutylcarbamoyl)piperidin-4-yl)-3- hydroxyisonicotinamide...

Claims

CLAIMS The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound having Structure (I):or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, C1-C6alkyl, or C3-C6cycloalkyl;R2 is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstitutedC3-C6cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted bicycloheterocyclyl, substitutedor unsubstituted C6-C10aryl, substituted or unsubstituted C6-C10aryl fused withsubstituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C3-C6cycloalkyl fused with substituted or unsubstituted C6-C10aryl, substituted or unsubstituted5- to 10-membered heteroaryl, or -SO2CH3, orR1and R2, together with the N atom to which they are attached, form a substitutedor unsubstituted 4- to 10-membered heterocyclyl, a substituted or unsubstituted 5- to 10- membered bicycloheterocyclyl, or a substituted or unsubstituted 3- to 10-memberedheterocyclyl fused with C6-C10aryl, and wherein L is absent;A is a substituted or unsubstituted C6-C10aryl or a substituted or unsubstituted C5-C10heteroaryl; andL is a C1-C6alkyl or absent.[0673] 2. The compound of Claim 1, wherein A is selected from the group consisting of:

3. The compound of Claim 1, wherein A is selected from the group consisting of:

4. The compound of any one of Claims 1-3, wherein R1is selected from thegroup consisting of hydrogen, methyl, ethyl, isopropyl, and cyclopropyl.

5. The compound of any one of Claims 1-4, wherein R1is hydrogen.

6. The compound of any one of Claims 1-5, wherein R2is selected from thegroup consisting of:

7. The compound of any one of Claims 1-5, wherein R2is selected from thegroup consisting of:

8. The compound of any one of Claims 1-5, wherein R2is selected from the group consisting of:

9. The compound of any one of Claims 1-5, wherein R2is selected from the group consisting of:

10. The compound of any one of Claims 1-5, wherein R2is selected from thegroup consisting of:

11. The compound of any one of Claims 1-5, wherein R2is selected from thegroup consisting of: hydrogen and .

12. The compound of any one of Claims 1-5, wherein R2is selected from thegroup consisting of:

13. The compound of any one of Claims 1-5, wherein R2is selected from thegroup consisting of:

14. The compound of any one of Claims 1-5, wherein R2is selected from the group consisting of:

15. The compound of any one of Claims 1-5, wherein R2is selected from the groupconsisting of:

16. The compound of any one of Claims 1-5, wherein R2is selected from thei ti f17. The compound of any one of Claims 1-3, wherein R1and R2, together withthe N atom to which they are attached, form a substituted or unsubstituted heterocyclyl, wherein L is absent, and wherein the heterocyclyl is selected from the group consisting of:

18. The compound of any one of Claims 1-3, wherein R1and R2, together withthe N atom to which they are attached, form a substituted or unsubstituted bicycloheterocyclyl, wherein L is absent, and wherein the bicycloheterocyclyl is selected from the group consisting of:.

19. The compound of any one of Claims 1-3, wherein R1and R2, together withthe N atom to which they are attached, form a substituted or unsubstituted heterocyclyl fused with aryl, wherein L is absent, and wherein the heterocyclyl fused with aryl is selected from the group consisting of:

20. The compound of any one of Claims 1-3, wherein R1and R2, together withthe N atom to which they are attached, form a substituted or unsubstituted spiro-fused heterocyclyl ring, wherein L is absent, and wherein the spiro-fused heterocyclyl ring is selected from the group consisting of:

21. The compound of any one of Claims 7-20, wherein Rais selected from thegroup consisting of:-H, -CH3, -NH2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -COOH, -C(O)OtBu,- C(O)OCH3, -NHC(O)CH3, -NHC(O)CH2CF3, -C(O)CH3, -C(O)NHCH2CF3, -SO2CH3, - CH2C(O)NH2, -CH2COOH, -C(O)CH2CH(CH3)2, -C(O)CH(CH3)2, -SO2CH(CH3)2, - SO2CH2CH3, -C(O)CH2CF3, -OCH3, -C(O)NH(CH2)3SO2CH3, -CH2CH3, - C(O)CH2N(CH3)2, -SO2CF3, -C(O)CH2CH2N(CH3)2, -C(O)NHtBu, -C(O)CH2tBu, - C(O)NHCH(CH3)2, -C(O)CH2CH3, -SO2CH2CH(CH3)2, -SO2NH2, -NHC(O)OtBu, -OH, - C(O)OCH2CH3, -C(O)C(CH3)2CH2CH322. The compound of any one of Claims 6-20, wherein Rais selected from thegroup consisting of: -C(O)NH2, -CO2H, -SO2CH(CH3)2, -SO2CH3,.

23. The compound of Claim 12 or 13, wherein Rbis selected from the groupconsisting of: hydrogen, halogen, -OCH3, and -OH.

24. The compound of any one of Claims 1-23, wherein L is selected from the group consisting of -CH2-, -CH2CH2-, -CH(CH3)-, and -CH2CH2CH2-.

25. The compound of any one of Claims 1-23, wherein L is absent.

26. The compound of any one of Claims 1-25, wherein: AL is absent; R1is H; R2is selected from the group consisting of:Rais selected from the group consisting of:-C(O)NH2, -CO2H, -SO2CH(CH3)2, -SO2CH3, -SO2NH2,<img src='' class="img-anchor img-center" img-id="IMGF000397_0001" / >27. A compound having Structure (II):wherein: B is N or CH; Cis absent or -CH2-;D is absent or -CH2-;E is absent or -CH2-;F is absent, -CH2-, or -CH2-CH2-;R3ais selected from the group consisting of hydrogen and hydroxy;R4ais selected from the group consisting of hydrogen, halogen, cyano, and nitro;R5ais selected from the group consisting of hydrogen, halogen, phenyl, and C1-6alkyl; and Rais selected from the group consisting of;-H, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -COOH, -C(O)OtBu, - NHC(O)CH2CF3,-C(O)CH3, -SO2CH3, - CH2C(O)NH2, -CH2COOH, -C(O)CH2CH(CH3)2, -C(O)CH(CH3)2, -SO2CH(CH3)2, - SO2CH2CH3, -C(O)CH2CF3, -CH2CH3,- C(O)CH2N(CH3)2, -SO2CF3, -C(O)CH2CH2N(CH3)2, -C(O)NHtBu, -C(O)CH2tBu,- C(O)NHCH(CH3)2, -C(O)CH2CH3, -SO2CH2CH(CH3)2, -SO2NH2,<img src='' class="img-anchor img-center" img-id="IMGF000404_0001" / >.

28. The compound of Claim 27, wherein R3ais hydroxy, R4ais halogen, andR5ais halogen.

29. The compound of Claim 28, wherein the structure isCl.<img src='' class="img-anchor img-center" img-id="IMGF000404_0002" / >30. The compound of any one of Claims 27-29, wherein Bis nitrogen; C is absent; D is absent; E is -CH2-; and F is -CH2-, and thestructure is:<img src='' class="img-anchor img-center" img-id="IMGF000404_0003" / >31. The compound of any one of Claims 27-29, wherein B is carbon; C is - CH2-; D is -CH2-; E is -CH2-; and F is -CH2-, and the structure is:<img src='' class="img-anchor img-center" img-id="IMGF000404_0004" / >32. The compound of any one of Claims 27-30, wherein Rais selected from thegroup consisting of: -C(O)NH2, -CO2H, -SO2CH(CH3)2, -SO2CH3, -SO2NH2,<img src='' class="img-anchor img-center" img-id="IMGF000406_0001" / >33. A pharmaceutical composition, comprising a compound of any one of Claims 1-32, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

34. A method of disrupting formation of a multi-protein complex in a subject, the method comprising administering to the subject a compound of any one of Claims 1- 32, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount effective to disrupt the multi-protein complex formation.

35. A method of disrupting formation of a multi-protein complex in a subject, the method comprising administering to the subject the pharmaceutical composition of Claim 33, in an amount effective to disrupt the multi-protein complex formation.

36. The method of Claim 34 or 35, wherein the multi-protein complex comprises an NMDA receptor, a scaffolding protein, a postsynaptic density protein 95 (PSD95), a neuronal nitric oxide synthase (nNOS), or a combination thereof.

37. The method of any one of Claims 34-36, wherein the disrupting the formation of the multi-protein complex comprises inhibiting a protein-protein interaction.

38. The method of any one of Claims 34-37, wherein the disrupting the formation of the multi-protein complex comprises binding of the compound to nNOS, inhibiting binding of PSD95 to NMDA, inhibiting binding of nNOS to PSD95, inhibiting binding of NOS1AP to nNOS, inhibiting nitric oxide production, inhibiting cGMP synthesis, inhibiting p38 MAPK activity, or a combination thereof.

39. The method of any one of Claims 34-38, wherein the compound of Formula (I) or Formula (II) acts in a neuron.

40. The method of any one of Claims 34-39, wherein the subject is a human.

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