WO2021026375A1

WO2021026375A1 - Fused bicyclic compounds for the treatment of pain

Info

Publication number: WO2021026375A1
Application number: PCT/US2020/045244
Authority: WO
Inventors: Brian M. Aquila; Lewis D. Pennington; James R. Woods; Hoan Huynh; Ingo Andreas Mugge; Yuan HU; Younggi Choi; Thomas Andrew Wynn; Baudouin Gerard; Todd Bosanac
Original assignee: Alkermes, Inc.
Priority date: 2019-08-07
Filing date: 2020-08-06
Publication date: 2021-02-11

Abstract

Provided herein are compounds that are useful in the treatment of pain in a subject. Also provided herein is a pharmaceutical composition comprising compounds or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier and methods of treating pain in a subject in need thereof.

Description

FUSED BICYCLIC COMPOUNDS FOR THE TREATMENT OF PAIN Related Applications This application claims priority to U.S. Provisional Application No.62/883,816; U.S. Provisional Application No.62/883,863; and U.S. Provisional Application No.62/883,823, all of which were filed on August 7, 2019. The contents of these applications are hereby incorporated in their entireties. Background Pain is the most common reason for physician consultation, and can be caused by a variety of medical conditions and procedures. Both chronic and acute pain can lead to a significant reduction in the quality of life, with many individuals facing long term disablement and handicaps. Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified. Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) have been employed in human therapy. The actions of endogenous opioids and opiates are mediated by three receptor types (m, d, and k receptors), which are coupled to different intracellular effector systems. [Berrocoso E. et. al., Current Pharmaceutical Design, 15(14) 2009, 1612-22]. As such, agents that can modulate the actions of one or more of the opioid receptor types with selectivity and sensitivity are important to treat the various diseases and disorders regulated by the opioid system. Compounds that bind to opioid receptors are likely to be useful in the treatment of diseases and conditions modulated by opiate receptors. Traditional opioid analgesics exert their pharmacological activity once they have passed into the central nervous system (CNS). But this can lead to undesirable CNS- mediated side effects, such as respiratory depression, increased drug tolerance, increased drug dependence, constipation and unwanted euphoria. There remains a continuing need for new drugs that can be used to treat or prevent pain, and that reduce or avoid one or more side effects associated with traditional opioid therapy. While certain treatments for pain do exist, many commonly used analgesics suffer from significant drawbacks including inefficacy, tolerance, and chemical dependence. There is therefore a need for new compounds and methods of treatment for pain that may be used alone or in conjunction with existing therapeutic modalities. Summary Provided herein are compounds useful for the treatment of pain in a subject in need thereof. In an aspect, provided herein are compounds having the structure of Formula (A)

or a pharmaceutically acceptable salt thereof. In another aspect, provided herein are compounds of the Fomula I:

or a pharmaceutically acceptable salt thereof. In yet another aspect, provided herein are compounds of the Fomula II:

or a pharmaceutically acceptable salt thereof. In still another aspect, provided herein are compounds of the Fomula III:

or a pharmaceutically acceptable salt thereof. In another aspect, provided herein are compounds of Formula Ia, or pharmaceutically acceptable salts thereof. In another aspect, provided herein are compounds of Formula Ib, or pharmaceutically acceptable salts thereof. Also provided herein is a pharmaceutical composition comprising a compound of any of Formula A, I, Ia, Ib, II, or III, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. In an aspect, provided herein is a method of treating pain in a subject in need thereof comprising administering to the subject a compound of Formula A, I, Ia, Ib, II, or III, or pharmaceutically acceptable salts thereof. In an embodiment, the pain is inflammatory pain, thermal pain, acute pain, chronic pain, traumatic pain, chemical pain, ischemic pain, centrally mediated pain, peripherally mediated pain, prickling pain, visceral pain, progressive disease pain, musculoskeletal pain (e.g., back pain, neck pain), post-surgical pain, bone pain (e.g., osteoarthritis), nociceptive pain, or neuropathic pain. In another embodiment, the pain is inflammatory pain, thermal pain, acute pain, chronic pain, or neuropathic pain. In another embodiment, the pain is musculoskeletal pain (e.g., back pain, neck pain), post-surgical pain, or bone pain (e.g., osteoarthritis). In another aspect, provided herein is a method of treating depression in a subject in need thereof comprising administering to the subject a compound of Formula A, I, Ia, Ib, II, or III, or a pharmaceutically acceptable salt thereof. In still another aspect, provided herein is a method of treating addiction in a subject in need thereof comprising administering to the subject a compound of Formula A, I, Ia, Ib, II, or III, or a pharmaceutically acceptable salt thereof. In an embodiment, the addiction is drug addiction. In an embodiment, the addiction is opioid addiction. In another embodiment, the addiction is alcohol addiction. Detailed Description Provided herein are compounds, e.g., the compounds of Formula A, I, Ia, Ib, II, or III, or pharmaceutically acceptable salts thereof, that are useful in the treatment of pain in a subject. In a non-limiting aspect, these compounds may modulate the µ-opioid receptor. In a particular embodiment, the compounds provided herein are considered µ-receptor agonists. As such, in one aspect, the compounds provided herein are useful in treatment of pain in a subject by acting as an agonist of the µ-receptor. Definitions Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art. As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. As used to herein, the term “EC₅₀” refers to the concentration of a compound required to achieve an effect that is 50% of the maximal observed effect of a compound. The term “agonist,” as used herein, refers to a compound that, when contacted with a target of interest (e.g., the µ-opioid receptor) causes an increase in the magnitude of a certain activity or function of the target compared to the magnitude of the activity or function observed in the absence of the agonist. As used herein, “pain” is generally defined as physical suffering or discomfort caused by illness or injury, and can be thought of as encompassing inflammatory pain, thermal pain, acute pain, chronic pain, musculoskeletal pain, post-surgical pain, nociceptive pain, neuropathic pain, and the like. As used herein, the term “depression” can be generally defined as a mental condition characterized by feelings of severe despondency and dejection. “Depression” can also be referred to as major depression, clinical depression, major depressive illness, major affective disorder and unipolar mood disorder. The depressive condition can be an anxiety disorder, a mental condition, recurrent depression, and the like. As used herein, addiction is generally defined as a chronic brain disease that causes compulsive drug seeking and use, or alcohol seeking and use. Drug addicition can be opioid addiction (i.e., opioid dependence), stimulant addiction, and the like. The term “treat,” “treated,” “treating,” or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. In certain embodiments, the treatment comprises bringing into contact with the opioid receptor an effective amount of a compound of the invention for conditions related to pain, depression or addiction. As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease. As used herein, the term “patient,” “individual” or “subject” refers to a human or a non- human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the patient, subject, or individual is human. As used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase “pharmaceutically acceptable salt” is not limited to a mono, or 1:1, salt. For example, “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration. As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen- free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C_1-6 alkyl means an alkyl having one to six carbon atoms) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C₁-C₆-alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl. As used herein, the term “alkoxy,” refers to the group –O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy and the like. As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine. As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. Compounds of the Invention In an aspect, provided herein are compounds having the structure of Formula (A)

or a pharmaceutically acceptable salt thereof, wherein: A is a five-membered heteroaryl having two or three nitrogen atoms; R₁ is C_1-4 alkyl or C_1-4 alkoxy, wherein the C_1-4 alkyl or C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms; R₂, R₃, and R₄, are each, independently, selected from the group consisting of H, halogen, C_1-4 alkoxy, hydroxyl, and C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms;R5 is H or C₁-C₄ alkyl; and R₆ is selected from the group consisting of H, C₁-C₄ alkyl, halogen, -NR_aR_b, -CN, and -C(=O)NR_aR_b, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen; wherein R_a and R_b are each, independently, H or C₁-C₆ alkyl. Also provided herein are compounds having the structure of Formula (I):

(I), or a pharmaceutically acceptable salt thereof, wherein: R₁ is C_1-4 alkyl or C_1-4 alkoxy, wherein the C_1-4 alkyl or C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms; and R₂, R₃, and R₄, are each, independently, selected from the group consisting of H, halogen, C_1-4 alkoxy, hydroxyl, and C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_1-3 alkyl, wherein the C_1-3 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_1-2 alkyl, wherein the C_1-2 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_2-4 alkyl, wherein the C_2-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_2-3 alkyl, wherein the C_2-3 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_3-4 alkyl, wherein the C_3-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is methyl, wherein the methyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is ethyl, wherein the ethyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C₃ alkyl, wherein the C₃ alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C₄ alkyl, wherein the C₄ alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is unsubstituted C_1-4 alkyl. In another embodiment of Formula (I), R₁ is unsubstituted C_1-3 alkyl. In another embodiment of Formula (I), R₁ is unsubstituted C_1-2 alkyl. In another embodiment of Formula (I), R₁ is unsubstituted C_2-4 alkyl. In another embodiment of Formula (I), R₁ is unsubstituted C_2-3 alkyl. In another embodiment of Formula (I), R₁ is unsubstituted C_3-4 alkyl. In another embodiment of Formula (I), R₁ is unsubstituted methyl. In another embodiment of Formula (I), R₁ is unsubstituted ethyl. In another embodiment of Formula (I), R₁ is unsubstituted C₃ alkyl. In another embodiment of Formula (I), R₁ is unsubstituted C₄ alkyl. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, wherein the C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_1-3 alkoxy, wherein the C_1-3 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_1-2 alkoxy, wherein the C_1-2 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_2-4 alkoxy, wherein the C_2-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_2-3 alkoxy, wherein the C_2-3 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C_3-4 alkoxy, wherein the C_3-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is methoxy, wherein the methoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is ethoxy, wherein the ethoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C₃ alkoxy, wherein the C₃ alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is C₄ alkoxy, wherein the C₄ alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (I), R₁ is unsubstituted C_1-4 alkoxy. In another embodiment of Formula (I), R₁ is unsubstituted C_1-3 alkoxy. In another embodiment of Formula (I), R₁ is unsubstituted C_1-2 alkoxy. In another embodiment of Formula (I), R₁ is unsubstituted C_2-4 alkoxy. In another embodiment of Formula (I), R₁ is unsubstituted C_2-3 alkoxy. In another embodiment of Formula (I), R₁ is unsubstituted C_3-4 alkoxy. In another embodiment of Formula (I), R₁ is unsubstituted methoxy. In another embodiment of Formula (I), R₁ is unsubstituted ethoxy. In another embodiment of Formula (I), R₁ is unsubstituted C₃ alkoxy. In another embodiment of Formula (I), R₁ is unsubstituted C₄ alkoxy. In another embodiment of Formula (I), R₁ is –OCF₃. In another embodiment of Formula (I), R₁ is –OCH₂CF₃. In another embodiment of Formula (I), R₂, R₃, and R₄ are each hydrogen. In another embodiment of Formula (I), R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₂ is hydrogen. In another embodiment of Formula (I), R₃ is hydrogen. In another embodiment of Formula (I), R₄ is hydrogen. In another embodiment of Formula (I), R₂ is halogen. In another embodiment of Formula (I), R₂ is fluoro or chloro. In another embodiment of Formula (I), R₂ is fluoro. In another embodiment of Formula (I), R₂ is chloro. In another embodiment of Formula (I), R₂ is CF₃. In another embodiment of Formula (I), R₂ is CF₂H. In another embodiment of Formula (I), R₂ is CH₂F. In another embodiment of Formula (I), R₃ is halogen. In another embodiment of Formula (I), R₃ is fluoro or chloro. In another embodiment of Formula (I), R₃ is fluoro. In another embodiment of Formula (I), R₃ is chloro. In another embodiment of Formula (I), R₃ is CF₃. In another embodiment of Formula (I), R₃ is CF₂H. In another embodiment of Formula (I), R₃ is CH₂F. In another embodiment of Formula (I), R₄ is halogen. In another embodiment of Formula (I), R₄ is fluoro or chloro. In another embodiment of Formula (I), R₄ is fluoro. In another embodiment of Formula (I), R₄ is chloro. In another embodiment of Formula (I), R₄ is CF₃. In another embodiment of Formula (I), R₄ is CF₂H. In another embodiment of Formula (I), R₄ is CH₂F. In another embodiment of Formula (I), R₂ is halogen, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₂ is fluoro or chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₂ is fluoro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₂ is chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₂ is CF₃, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₂ is CF₂H, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₂ is CH₂F, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₃ is halogen, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₃ is fluoro or chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₃ is fluoro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₃ is chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₃ is CF₃, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₃ is CF₂H, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₃ is CH₂F, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₄ is halogen, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₄ is fluoro or chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₄ is fluoro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₄ is chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₄ is CF₃, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₄ is CF₂H, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₄ is CH₂F, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ is halogen, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ is halogen, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ is fluoro or chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ is fluoro or chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ is fluoro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ is fluoro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ is chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ is chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ is CF₃, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ is CF₃, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ is CF₂H, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ is CF₂H, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ is CH₂F, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ is CH₂F, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ is halogen, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ is halogen, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ is fluoro or chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ is fluoro or chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ is fluoro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ is fluoro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ is chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ is chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ is CF₃, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ is CF₃, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ is CF₂H, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ is CF₂H, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ is CH₂F, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ is CH₂F, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₄ is halogen, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₄ is halogen, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₄ is fluoro or chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₄ is fluoro or chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₄ is fluoro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₄ is fluoro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₄ is chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₄ is chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₄ is CF₃, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₄ is CF₃, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₄ is CF₂H, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₄ is CF₂H, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₄ is CH₂F, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₄ is CH₂F, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (I), R₂ and R₃ are each halogen. In another embodiment of Formula (I), R₂ and R₃ are each fluoro or chloro. In another embodiment of Formula (I), R₂ and R₃ are each fluoro. In another embodiment of Formula (I), R₂ and R₃ are each chloro. In another embodiment of Formula (I), R₂ and R₄ are each halogen. In another embodiment of Formula (I), R₂ and R₄ are each fluoro or chloro. In another embodiment of Formula (I), R₂ and R₄ are each fluoro. In another embodiment of Formula (I), R₂ and R₄ are each chloro. In another embodiment of Formula (I), R₃ and R₄ are each halogen. In another embodiment of Formula (I), R₃ and R₄ are each fluoro or chloro. In another embodiment of Formula (I), R₃ and R₄ are each fluoro. In another embodiment of Formula (I), R₃ and R₄ are each chloro. In another embodiment of Formula (I), R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (I), R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (I), R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (I), R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (I), R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (I), R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (I), R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (I), R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (I), R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (I), R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (I), R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (I), R₃ and R₄ are each chloro, and R₂ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₃ and R₄ are each chloro, and R₂ is hydrogen. In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ and R₄ are each chloro, and R₂ is hydrogen. In an embodiment, the compound of Formula (I) has the structure of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: R₁ is C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms; and R₂, R₃, and R₄, are each, independently, selected from the group consisting of H, halogen, and C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is C_1-3 alkyl, wherein the C_1-3 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is C_1-2 alkyl, wherein the C_1-2 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is C_2-4 alkyl, wherein the C_2-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is C_2-3 alkyl, wherein the C_2-3 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is C_3-4 alkyl, wherein the C_3-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is methyl, wherein the methyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is ethyl, wherein the ethyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is C₃ alkyl, wherein the C₃ alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is C₄ alkyl, wherein the C₄ alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ia), R₁ is unsubstituted C_1-4 alkyl. In another embodiment of Formula (Ia), R₁ is unsubstituted C_1-3 alkyl. In another embodiment of Formula (Ia), R₁ is unsubstituted C_1-2 alkyl. In another embodiment of Formula (Ia), R₁ is unsubstituted C_2-4 alkyl. In another embodiment of Formula (Ia), R₁ is unsubstituted C_2-3 alkyl. In another embodiment of Formula (Ia), R₁ is unsubstituted C_3-4 alkyl. In another embodiment of Formula (Ia), R₁ is unsubstituted methyl. In another embodiment of Formula (Ia), R₁ is unsubstituted ethyl. In another embodiment of Formula (Ia), R₁ is unsubstituted C₃ alkyl. In another embodiment of Formula (Ia), R₁ is unsubstituted C₄ alkyl. In another embodiment of Formula (Ia), R₂, R₃, and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₂ is hydrogen. In another embodiment of Formula (Ia), R₃ is hydrogen. In another embodiment of Formula (Ia), R₄ is hydrogen. In another embodiment of Formula (Ia), R₂ is halogen. In another embodiment of Formula (Ia), R₂ is fluoro or chloro. In another embodiment of Formula (Ia), R₂ is fluoro. In another embodiment of Formula (Ia), R₂ is chloro. In another embodiment of Formula (Ia), R₂ is CF₃. In another embodiment of Formula (Ia), R₂ is CF₂H. In another embodiment of Formula (Ia), R₂ is CH₂F. In another embodiment of Formula (Ia), R₃ is halogen. In another embodiment of Formula (Ia), R₃ is fluoro or chloro. In another embodiment of Formula (Ia), R₃ is fluoro. In another embodiment of Formula (Ia), R₃ is chloro. In another embodiment of Formula (Ia), R₃ is CF₃. In another embodiment of Formula (Ia), R₃ is CF₂H. In another embodiment of Formula (Ia), R₃ is CH₂F. In another embodiment of Formula (Ia), R₄ is halogen. In another embodiment of Formula (Ia), R₄ is fluoro or chloro. In another embodiment of Formula (Ia), R₄ is fluoro. In another embodiment of Formula (Ia), R₄ is chloro. In another embodiment of Formula (Ia), R₄ is CF₃. In another embodiment of Formula (Ia), R₄ is CF₂H. In another embodiment of Formula (Ia), R₄ is CH₂F. In another embodiment of Formula (Ia), R₂ is halogen, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₂ is fluoro or chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₂ is fluoro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₂ is chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₂ is CF₃, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₂ is CF₂H, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₂ is CH₂F, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₃ is halogen, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₃ is fluoro or chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₃ is fluoro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₃ is chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₃ is CF₃, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₃ is CF₂H, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₃ is CH₂F, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₄ is halogen, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₄ is fluoro or chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₄ is fluoro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₄ is chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₄ is CF₃, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₄ is CF₂H, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₄ is CH₂F, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ is halogen, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ is fluoro or chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ is fluoro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ is chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ is CF₃, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ is CF₂H, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ is CH₂F, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ is halogen, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ is fluoro or chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ is fluoro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ is chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ is CF₃, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ is CF₂H, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ is CH₂F, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₄ is halogen, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₄ is fluoro or chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₄ is fluoro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₄ is chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₄ is CF₃, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₄ is CF₂H, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₄ is CH₂F, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ia), R₂ and R₃ are each halogen. In another embodiment of Formula (Ia), R₂ and R₃ are each fluoro or chloro. In another embodiment of Formula (Ia), R₂ and R₃ are each fluoro. In another embodiment of Formula (Ia), R₂ and R₃ are each chloro. In another embodiment of Formula (Ia), R₂ and R₄ are each halogen. In another embodiment of Formula (Ia), R₂ and R₄ are each fluoro or chloro. In another embodiment of Formula (Ia), R₂ and R₄ are each fluoro. In another embodiment of Formula (Ia), R₂ and R₄ are each chloro. In another embodiment of Formula (Ia), R₃ and R₄ are each halogen. In another embodiment of Formula (Ia), R₃ and R₄ are each fluoro or chloro. In another embodiment of Formula (Ia), R₃ and R₄ are each fluoro. In another embodiment of Formula (Ia), R₃ and R₄ are each chloro. In another embodiment of Formula (Ia), R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (Ia), R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (Ia), R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (Ia), R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (Ia), R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (Ia), R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (Ia), R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (Ia), R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (Ia), R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (Ia), R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (Ia), R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (Ia), R₃ and R₄ are each chloro, and R₂ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (Ia), R₁ is C_1-4 alkyl, R₃ and R₄ are each chloro, and R₂ is hydrogen. In an embodiment, the compound of Formula (I) has the structure of Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein: R₁ is C_1-4 alkoxy, wherein the C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms; and R₂, R₃, and R₄, are each, independently, selected from the group consisting of H, halogen, and C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, wherein the C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is C_1-3 alkoxy, wherein the C_1-3 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is C_1-2 alkoxy, wherein the C_1-2 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is C_2-4 alkoxy, wherein the C_2-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is C_2-3 alkoxy, wherein the C_2-3 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is C_3-4 alkoxy, wherein the C_3-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is methoxy, wherein the methoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is ethoxy, wherein the ethoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is C₃ alkoxy, wherein the C₃ alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is C₄ alkoxy, wherein the C₄ alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (Ib), R₁ is unsubstituted C_1-4 alkoxy. In another embodiment of Formula (Ib), R₁ is unsubstituted C_1-3 alkoxy. In another embodiment of Formula (Ib), R₁ is unsubstituted C_1-2 alkoxy. In another embodiment of Formula (Ib), R₁ is unsubstituted C_2-4 alkoxy. In another embodiment of Formula (Ib), R₁ is unsubstituted C_2-3 alkoxy. In another embodiment of Formula (Ib), R₁ is unsubstituted C_3-4 alkoxy. In another embodiment of Formula (Ib), R₁ is unsubstituted methoxy. In another embodiment of Formula (Ib), R₁ is unsubstituted ethoxy. In another embodiment of Formula (Ib), R₁ is unsubstituted C₃ alkoxy. In another embodiment of Formula (Ib), R₁ is unsubstituted C₄ alkoxy. In another embodiment of Formula (Ib), R₁ is –OCF₃. In another embodiment of Formula (Ib), R₁ is –OCH₂CF₃. In another embodiment of Formula (Ib), R₂, R₃, and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₂ is hydrogen. In another embodiment of Formula (Ib), R₃ is hydrogen. In another embodiment of Formula (Ib), R₄ is hydrogen. In another embodiment of Formula (Ib), R₂ is halogen. In another embodiment of Formula (Ib), R₂ is fluoro or chloro. In another embodiment of Formula (Ib), R₂ is fluoro. In another embodiment of Formula (Ib), R₂ is chloro. In another embodiment of Formula (Ib), R₂ is CF₃. In another embodiment of Formula (Ib), R₂ is CF₂H. In another embodiment of Formula (Ib), R₂ is CH₂F. In another embodiment of Formula (Ib), R₃ is halogen. In another embodiment of Formula (Ib), R₃ is fluoro or chloro. In another embodiment of Formula (Ib), R₃ is fluoro. In another embodiment of Formula (Ib), R₃ is chloro. In another embodiment of Formula (Ib), R₃ is CF₃. In another embodiment of Formula (Ib), R₃ is CF₂H. In another embodiment of Formula (Ib), R₃ is CH₂F. In another embodiment of Formula (Ib), R₄ is halogen. In another embodiment of Formula (Ib), R₄ is fluoro or chloro. In another embodiment of Formula (Ib), R₄ is fluoro. In another embodiment of Formula (Ib), R₄ is chloro. In another embodiment of Formula (Ib), R₄ is CF₃. In another embodiment of Formula (Ib), R₄ is CF₂H. In another embodiment of Formula (Ib), R₄ is CH₂F. In another embodiment of Formula (Ib), R₂ is halogen, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₂ is fluoro or chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₂ is fluoro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₂ is chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₂ is CF₃, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₂ is CF₂H, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₂ is CH₂F, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₃ is halogen, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₃ is fluoro or chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₃ is fluoro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₃ is chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₃ is CF₃, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₃ is CF₂H, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₃ is CH₂F, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₄ is halogen, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₄ is fluoro or chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₄ is fluoro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₄ is chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₄ is CF₃, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₄ is CF₂H, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₄ is CH₂F, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ is halogen, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ is fluoro or chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ is fluoro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ is chloro, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ is CF₃, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ is CF₂H, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ is CH₂F, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ is halogen, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ is fluoro or chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ is fluoro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ is chloro, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ is CF₃, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ is CF₂H, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ is CH₂F, and R₂ and R₄ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₄ is halogen, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₄ is fluoro or chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₄ is fluoro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₄ is chloro, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₄ is CF₃, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₄ is CF₂H, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₄ is CH₂F, and R₂ and R₃ are each hydrogen. In another embodiment of Formula (Ib), R₂ and R₃ are each halogen. In another embodiment of Formula (Ib), R₂ and R₃ are each fluoro or chloro. In another embodiment of Formula (Ib), R₂ and R₃ are each fluoro. In another embodiment of Formula (Ib), R₂ and R₃ are each chloro. In another embodiment of Formula (Ib), R₂ and R₄ are each halogen. In another embodiment of Formula (Ib), R₂ and R₄ are each fluoro or chloro. In another embodiment of Formula (Ib), R₂ and R₄ are each fluoro. In another embodiment of Formula (Ib), R₂ and R₄ are each chloro. In another embodiment of Formula (Ib), R₃ and R₄ are each halogen. In another embodiment of Formula (Ib), R₃ and R₄ are each fluoro or chloro. In another embodiment of Formula (Ib), R₃ and R₄ are each fluoro. In another embodiment of Formula (Ib), R₃ and R₄ are each chloro. In another embodiment of Formula (Ib), R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (Ib), R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (Ib), R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (Ib), R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (Ib), R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (Ib), R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (Ib), R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (Ib), R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (Ib), R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (Ib), R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (Ib), R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (Ib), R₃ and R₄ are each chloro, and R₂ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (Ib), R₁ is C_1-4 alkoxy, R₃ and R₄ are each chloro, and R₂ is hydrogen. Certain embodiments of compounds of Formula I or pharmaceutically acceptable salts thereof, are shown below in Table 1. Compounds of Formula I or pharmaceutically acceptable salts thereof, and compounds of Table 1, or pharmaceutically acceptable salts thereof, are sometimes referred to herein as “compounds of the invention,” or “compounds provided herein.” Table 1.

*EC₅₀ >90nM; **EC₅₀30-90nM (inclusive); ***EC₅₀ <30nM Also provided herein are compounds having the structure of Formula (II):

or a pharmaceutically acceptable salt thereof; wherein R₁ is C₁-C₆ alkyl or C₁-C₄ alkoxy, wherein the C_1-6 alkyl or C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen; R₂, R₃, and R₄ are each, independently, selected from the group consisting of H, C1- C₄ alkyl, C₁-C₄ alkoxy, hydroxy, and halogen, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen; R₅ is H or C₁-C₄ alkyl; R₆ is selected from the group consisting of H, C₁-C₄ alkyl, halogen, -NR_aR_b, -CN, and -C(=O)NR_aR_b, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen; wherein Ra and Rb are each, independently, H or C₁-C₆ alkyl. In another embodiment of Formula (II), R₁ is C_1-6 alkyl, wherein the C_1-6 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C_1-2 alkyl, wherein the C_1-2 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C_2-4 alkyl, wherein the C_2-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C_2-3 alkyl, wherein the C_2-3 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C_3-4 alkyl, wherein the C_3-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is methyl, wherein the methyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is ethyl, wherein the ethyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C₃ alkyl, wherein the C₃ alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C₄ alkyl, wherein the C₄ alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is unsubstituted C_1-4 alkyl. In another embodiment of Formula (II), R₁ is unsubstituted C_1-3 alkyl. In another embodiment of Formula (II), R₁ is unsubstituted C_1-2 alkyl. In another embodiment of Formula (II), R₁ is unsubstituted C_2-4 alkyl. In another embodiment of Formula (II), R₁ is unsubstituted C_2-3 alkyl. In another embodiment of Formula (II), R₁ is unsubstituted C_3-4 alkyl. In another embodiment of Formula (II), R₁ is unsubstituted methyl. In another embodiment of Formula (II), R₁ is unsubstituted ethyl. In another embodiment of Formula (II), R₁ is unsubstituted C₃ alkyl. In another embodiment of Formula (II), R₁ is unsubstituted C₄ alkyl. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, wherein the C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C_1-3 alkoxy, wherein the C_1-3 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C_1-2 alkoxy, wherein the C_1-2 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C_2-4 alkoxy, wherein the C_2-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C_2-3 alkoxy, wherein the C_2-3 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C_3-4 alkoxy, wherein the C_3-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is methoxy, wherein the methoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is ethoxy, wherein the ethoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C₃ alkoxy, wherein the C₃ alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is C₄ alkoxy, wherein the C₄ alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (II), R₁ is unsubstituted C_1-4 alkoxy. In another embodiment of Formula (II), R₁ is unsubstituted C_1-3 alkoxy. In another embodiment of Formula (II), R₁ is unsubstituted C_1-2 alkoxy. In another embodiment of Formula (II), R₁ is unsubstituted C_2-4 alkoxy. In another embodiment of Formula (II), R₁ is unsubstituted C_2-3 alkoxy. In another embodiment of Formula (II), R₁ is unsubstituted C_3-4 alkoxy. In another embodiment of Formula (II), R₁ is unsubstituted methoxy. In another embodiment of Formula (II), R₁ is unsubstituted ethoxy. In another embodiment of Formula (II), R₁ is unsubstituted C₃ alkoxy. In another embodiment of Formula (II), R₁ is unsubstituted C₄ alkoxy. In another embodiment of Formula (II), R₁ is –OCF₃. In another embodiment of Formula (II), R₁ is –OCH₂CF₃. In another embodiment of Formula (II), R₂, R₃, and R₄ are each hydrogen. In another embodiment of Formula (II), R₂ and R₄ are each hydrogen. In another embodiment of Formula (II), R₂ and R₃ are each hydrogen. In another embodiment of Formula (II), R₃ and R₄ are each hydrogen. In another embodiment of Formula (II), R₂ is hydrogen. In another embodiment of Formula (II), R₃ is hydrogen. In another embodiment of Formula (II), R₄ is hydrogen. In another embodiment of Formula (II), R₂ is halogen. In another embodiment of Formula (II), R₂ is fluoro or chloro. In another embodiment of Formula (II), R₂ is fluoro. In another embodiment of Formula (II), R₂ is chloro. In another embodiment of Formula (II), R₂ is CF₃. In another embodiment of Formula (II), R₂ is CF₂H. In another embodiment of Formula (II), R₂ is CH₂F. In another embodiment of Formula (II), R₃ is halogen. In another embodiment of Formula (II), R₃ is fluoro or chloro. In another embodiment of Formula (II), R₃ is fluoro. In another embodiment of Formula (II), R₃ is chloro. In another embodiment of Formula (II), R₃ is CF₃. In another embodiment of Formula (II), R₃ is CF₂H. In another embodiment of Formula (II), R₃ is CH₂F. In another embodiment of Formula (II), R₄ is halogen. In another embodiment of Formula (II), R₄ is fluoro or chloro. In another embodiment of Formula (II), R₄ is fluoro. In another embodiment of Formula (II), R₄ is chloro. In another embodiment of Formula (II), R₄ is CF₃. In another embodiment of Formula (II), R₄ is CF₂H. In another embodiment of Formula (II), R₄ is CH₂F. In another embodiment of Formula (II), R5 is hydrogen. In another embodiment of Formula (II), R5 is C₁-C₄ alkyl. In another embodiment of Formula (II), R₅ and R₆ are each hydrogen. In another embodiment of Formula (II), R₂, R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₆ is C₁-C₄ alkyl, optionally substituted by 1, 2, or 3 halogen, and R5 is hydrogen. In another embodiment of Formula (II), R₆ is C₁-C₂ alkyl, optionally substituted by 1, 2, or 3 halogen, and R5 is hydrogen. In another embodiment of Formula (II), R₆ is methyl, optionally substituted by 1, 2, or 3 halogen, and R₅ is hydrogen. In another embodiment of Formula (II), R₆ is -CN, and R₅ is hydrogen. In another embodiment of Formula (II), R₆ is C₁-C₄ alkyl, halogen, -NR_aR_b, -CN, or - C(=O)NRaRb, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen, and R5 is hydrogen. In another embodiment of Formula (II), R₆ is H, C₁-C₄ alkyl, halogen, or -CN, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen, and R5 is hydrogen. In another embodiment of Formula (II), R₂ is halogen, and R₃ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (II), R₂ is fluoro or chloro, and R₃ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (II), R₂ is fluoro, and R₃ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (II), R₂ is chloro, and R₃ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (II), R₂ is CF₃, and R₃ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (II), R₂ is CF₂H, and R₃ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (II), R₂ is CH₂F, and R₃ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (II), R₃ is halogen, and R₂ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (II), R₃ is fluoro or chloro, and R₂ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (II), R₃ is fluoro, and R₂ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (II), R₃ is chloro, and R₂ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (II), R₃ is CF₃, and R₂ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (II), R₃ is CF₂H, and R₂ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (II), R₃ is CH₂F, and R₂ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (II), R₄ is halogen, and R₂ and R₃ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (II), R₄ is fluoro or chloro, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (II), R₄ is fluoro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₄ is chloro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₄ is CF₃, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₄ is CF₂H, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (II), R₄ is CH₂F, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ is halogen, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ is halogen, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ is fluoro or chloro, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ is fluoro or chloro, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ is fluoro, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ is fluoro, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ is chloro, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ is chloro, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ is CF₃, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ is CF₃, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ is CF₂H, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ is CF₂H, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ is CH₂F, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ is CH₂F, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ is halogen, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ is halogen, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ is fluoro or chloro, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ is fluoro or chloro, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ is fluoro, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ is fluoro, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ is chloro, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ is chloro, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ is CF₃, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ is CF₃, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ is CF₂H, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ is CF₂H, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ is CH₂F, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ is CH₂F, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₄ is halogen, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₄ is halogen, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₄ is fluoro or chloro, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₄ is fluoro or chloro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₄ is fluoro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₄ is fluoro, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₄ is chloro, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₄ is chloro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₄ is CF₃, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₄ is CF₃, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₄ is CF₂H, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₄ is CF₂H, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₄ is CH₂F, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₄ is CH₂F, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (II), R₂ and R₃ are each halogen. In another embodiment of Formula (II), R₂ and R₃ are each fluoro or chloro. In another embodiment of Formula (II), R₂ and R₃ are each fluoro. In another embodiment of Formula (II), R₂ and R₃ are each chloro. In another embodiment of Formula (II), R₂ and R₄ are each halogen. In another embodiment of Formula (II), R₂ and R₄ are each fluoro or chloro. In another embodiment of Formula (II), R₂ and R₄ are each fluoro. In another embodiment of Formula (II), R₂ and R₄ are each chloro. In another embodiment of Formula (II), R₃ and R₄ are each halogen. In another embodiment of Formula (II), R₃ and R₄ are each fluoro or chloro. In another embodiment of Formula (II), R₃ and R₄ are each fluoro. In another embodiment of Formula (II), R₃ and R₄ are each chloro. In another embodiment of Formula (II), R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (II), R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (II), R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (II), R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (II), R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (II), R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (II), R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (II), R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (II), R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (II), R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (II), R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (II), R₃ and R₄ are each chloro, and R₂ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkyl, R₃ and R₄ are each chloro, and R₂ is hydrogen. In another embodiment of Formula (II), R₁ is C_1-4 alkoxy, R₃ and R₄ are each chloro, and R₂ is hydrogen. Certain embodiments of compounds of Formula II, or pharmaceutically acceptable salts thereof, are shown below in Table 2. Compounds of Formula II or pharmaceutically acceptable salts thereof, and compounds of Table 2, or pharmaceutically acceptable salts thereof, are sometimes referred to herein as “compounds of the invention,” or “compounds provided herein.” Table 2.

Also provided herein are compounds having the structure of Formula (III):

(III), or a pharmaceutically acceptable salt thereof; wherein R₁ is C₁-C₆ alkyl or C₁-C₄ alkoxy, wherein the C_1-6 alkyl or C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen; R₂, R₃, and R₄ are each, independently, selected from the group consisting of H, C1- C₄ alkyl, C₁-C₄ alkoxy, hydroxy, and halogen, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen; R₅ is H or C₁-C₄ alkyl; R₆ is selected from the group consisting of H, C₁-C₄ alkyl, halogen, -NR_aR_b, -CN, and -C(=O)NRaRb, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen; wherein Ra and Rb are each, independently, H or C₁-C₆ alkyl. In another embodiment of Formula (III), R₁ is C_1-6 alkyl, wherein the C_1-6 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C_1-2 alkyl, wherein the C_1-2 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C_2-4 alkyl, wherein the C_2-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C_2-3 alkyl, wherein the C_2-3 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C_3-4 alkyl, wherein the C_3-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is methyl, wherein the methyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is ethyl, wherein the ethyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C₃ alkyl, wherein the C₃ alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C₄ alkyl, wherein the C₄ alkyl is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is unsubstituted C_1-4 alkyl. In another embodiment of Formula (III), R₁ is unsubstituted C_1-3 alkyl. In another embodiment of Formula (III), R₁ is unsubstituted C_1-2 alkyl. In another embodiment of Formula (III), R₁ is unsubstituted C_2-4 alkyl. In another embodiment of Formula (III), R₁ is unsubstituted C_2-3 alkyl. In another embodiment of Formula (III), R₁ is unsubstituted C_3-4 alkyl. In another embodiment of Formula (III), R₁ is unsubstituted methyl. In another embodiment of Formula (III), R₁ is unsubstituted ethyl. In another embodiment of Formula (III), R₁ is unsubstituted C₃ alkyl. In another embodiment of Formula (III), R₁ is unsubstituted C₄ alkyl. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, wherein the C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C_1-3 alkoxy, wherein the C_1-3 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C_1-2 alkoxy, wherein the C_1-2 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C_2-4 alkoxy, wherein the C_2-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C_2-3 alkoxy, wherein the C_2-3 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C_3-4 alkoxy, wherein the C_3-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is methoxy, wherein the methoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is ethoxy, wherein the ethoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C₃ alkoxy, wherein the C₃ alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is C₄ alkoxy, wherein the C₄ alkoxy is optionally substituted with 1, 2, or 3 halogen atoms. In another embodiment of Formula (III), R₁ is unsubstituted C_1-4 alkoxy. In another embodiment of Formula (III), R₁ is unsubstituted C_1-3 alkoxy. In another embodiment of Formula (III), R₁ is unsubstituted C_1-2 alkoxy. In another embodiment of Formula (III), R₁ is unsubstituted C_2-4 alkoxy. In another embodiment of Formula (III), R₁ is unsubstituted C_2-3 alkoxy. In another embodiment of Formula (III), R₁ is unsubstituted C_3-4 alkoxy. In another embodiment of Formula (III), R₁ is unsubstituted methoxy. In another embodiment of Formula (III), R₁ is unsubstituted ethoxy. In another embodiment of Formula (III), R₁ is unsubstituted C₃ alkoxy. In another embodiment of Formula (III), R₁ is unsubstituted C₄ alkoxy. In another embodiment of Formula (III), R₁ is –OCF₃. In another embodiment of Formula (III), R₁ is –OCH₂CF₃. In another embodiment of Formula (III), R₂, R₃, and R₄ are each hydrogen. In another embodiment of Formula (III), R₂ and R₄ are each hydrogen. In another embodiment of Formula (III), R₂ and R₃ are each hydrogen. In another embodiment of Formula (III), R₃ and R₄ are each hydrogen. In another embodiment of Formula (III), R₂ is hydrogen. In another embodiment of Formula (III), R₃ is hydrogen. In another embodiment of Formula (III), R₄ is hydrogen. In another embodiment of Formula (III), R₂ is halogen. In another embodiment of Formula (III), R₂ is fluoro or chloro. In another embodiment of Formula (III), R₂ is fluoro. In another embodiment of Formula (III), R₂ is chloro. In another embodiment of Formula (III), R₂ is CF₃. In another embodiment of Formula (III), R₂ is CF₂H. In another embodiment of Formula (III), R₂ is CH₂F. In another embodiment of Formula (III), R₃ is halogen. In another embodiment of Formula (III), R₃ is fluoro or chloro. In another embodiment of Formula (III), R₃ is fluoro. In another embodiment of Formula (III), R₃ is chloro. In another embodiment of Formula (III), R₃ is CF₃. In another embodiment of Formula (III), R₃ is CF₂H. In another embodiment of Formula (III), R₃ is CH₂F. In another embodiment of Formula (III), R₄ is halogen. In another embodiment of Formula (III), R₄ is fluoro or chloro. In another embodiment of Formula (III), R₄ is fluoro. In another embodiment of Formula (III), R₄ is chloro. In another embodiment of Formula (III), R₄ is CF₃. In another embodiment of Formula (III), R₄ is CF₂H. In another embodiment of Formula (III), R₄ is CH₂F. In another embodiment of Formula (III), R5 is hydrogen. In another embodiment of Formula (III), R₅ is C₁-C₄ alkyl. In another embodiment of Formula (III), R₅ and R₆ are each hydrogen. In another embodiment of Formula (III), R₂, R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₆ is C₁-C₄ alkyl, optionally substituted by 1, 2, or 3 halogen, and R5 is hydrogen. In another embodiment of Formula (III), R₆ is C₁-C₂ alkyl, optionally substituted by 1, 2, or 3 halogen, and R5 is hydrogen. In another embodiment of Formula (III), R₆ is methyl, optionally substituted by 1, 2, or 3 halogen, and R₅ is hydrogen. In another embodiment of Formula (III), R₆ is -CN, and R₅ is hydrogen. In another embodiment of Formula (III), R₆ is C₁-C₄ alkyl, halogen, -NR_aR_b, -CN, or - C(=O)NRaRb, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen, and R5 is hydrogen. In another embodiment of Formula (III), R₆ is H, C₁-C₄ alkyl, halogen, or -CN, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen, and R5 is hydrogen. In another embodiment of Formula (III), R₂ is halogen, and R₃ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (III), R₂ is fluoro or chloro, and R₃ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (III), R₂ is fluoro, and R₃ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (III), R₂ is chloro, and R₃ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (III), R₂ is CF₃, and R₃ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (III), R₂ is CF₂H, and R₃ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (III), R₂ is CH₂F, and R₃ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (III), R₃ is halogen, and R₂ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (III), R₃ is fluoro or chloro, and R₂ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (III), R₃ is fluoro, and R₂ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (III), R₃ is chloro, and R₂ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (III), R₃ is CF₃, and R₂ and R₄ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (III), R₃ is CF₂H, and R₂ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (III), R₃ is CH₂F, and R₂ and R₄ are each hydrogen, and R5 is hydrogen. In another embodiment of Formula (III), R₄ is halogen, and R₂ and R₃ are each hydrogen, and R₅ is hydrogen. In another embodiment of Formula (III), R₄ is fluoro or chloro, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (III), R₄ is fluoro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₄ is chloro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₄ is CF₃, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (III), R₄ is CF₂H, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₄ is CH₂F, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ is halogen, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ is halogen, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ is fluoro or chloro, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ is fluoro or chloro, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ is fluoro, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ is fluoro, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ is chloro, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ is chloro, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ is CF₃, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ is CF₃, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ is CF₂H, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ is CF₂H, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ is CH₂F, and R₃, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ is CH₂F, and R₃, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ is halogen, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ is halogen, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ is fluoro or chloro, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ is fluoro or chloro, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ is fluoro, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ is fluoro, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ is chloro, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ is chloro, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ is CF₃, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ is CF₃, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ is CF₂H, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ is CF₂H, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ is CH₂F, and R₂, R₄, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ is CH₂F, and R₂, R₄, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₄ is halogen, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₄ is halogen, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₄ is fluoro or chloro, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₄ is fluoro or chloro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₄ is fluoro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₄ is fluoro, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₄ is chloro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₄ is chloro, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₄ is CF₃, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₄ is CF₃, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₄ is CF₂H, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₄ is CF₂H, and R₂, R₃, and R5 are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₄ is CH₂F, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₄ is CH₂F, and R₂, R₃, and R₅ are each hydrogen. In another embodiment of Formula (III), R₂ and R₃ are each halogen. In another embodiment of Formula (III), R₂ and R₃ are each fluoro or chloro. In another embodiment of Formula (III), R₂ and R₃ are each fluoro. In another embodiment of Formula (III), R₂ and R₃ are each chloro. In another embodiment of Formula (III), R₂ and R₄ are each halogen. In another embodiment of Formula (III), R₂ and R₄ are each fluoro or chloro. In another embodiment of Formula (III), R₂ and R₄ are each fluoro. In another embodiment of Formula (III), R₂ and R₄ are each chloro. In another embodiment of Formula (III), R₃ and R₄ are each halogen. In another embodiment of Formula (III), R₃ and R₄ are each fluoro or chloro. In another embodiment of Formula (III), R₃ and R₄ are each fluoro. In another embodiment of Formula (III), R₃ and R₄ are each chloro. In another embodiment of Formula (III), R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (III), R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (III), R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (III), R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (III), R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (III), R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (III), R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (III), R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (III), R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (III), R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (III), R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (III), R₃ and R₄ are each chloro, and R₂ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ and R₃ are each halogen, and R₄ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ and R₃ are each fluoro or chloro, and R₄ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ and R₃ are each fluoro, and R₄ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ and R₃ are each chloro, and R₄ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ and R₄ are each halogen, and R₃ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ and R₄ are each fluoro or chloro, and R₃ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ and R₄ are each fluoro, and R₃ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₂ and R₄ are each chloro, and R₃ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ and R₄ are each halogen, and R₂ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ and R₄ are each fluoro or chloro, and R₂ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ and R₄ are each fluoro, and R₂ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkyl, R₃ and R₄ are each chloro, and R₂ is hydrogen. In another embodiment of Formula (III), R₁ is C_1-4 alkoxy, R₃ and R₄ are each chloro, and R₂ is hydrogen. Certain embodiments of compounds of Formula III or pharmaceutically acceptable salts thereof, are shown below in Table 3. Compounds of Formula III or pharmaceutically acceptable salts thereof, and compounds of Table 3, or pharmaceutically acceptable salts thereof, are sometimes referred to herein as “compounds of the invention,” or “compounds provided herein.” Table 3.

The disclosed compounds may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration. In one embodiment, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.

Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In one embodiment, a mixture of two or more isomers is utilized as the disclosed compound described herein. In another embodiment, a pure isomer is utilized as the disclosed compound described herein. In another embodiment, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis or separation of a mixture of enantiomers or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, and ³⁵S. In one embodiment, isotopically-labeled compounds are useful in drug or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In another embodiment, the compounds described herein include a ²H (i.e., deuterium) isotope. In yet another embodiment, substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non- labeled reagent otherwise employed. The specific compounds described herein, and other compounds encompassed by one or more of the Formulas described herein having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4^th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the Formulas as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. Methods of Treatment The compounds of the invention can be used in a method of treating a disease or condition in a subject, said method comprising administering to the subject a compound of the invention, or a pharmaceutical composition comprising a compound of the invention. The compounds of the invention can be used to treat a disease or condition selected from the group consisting of pain, depression, or addiction in a subject in need thereof. In one embodiment, the compounds of the invention can be used to treat pain in a subject. In another embodiment, the pain is selected from inflammatory pain, thermal pain, acute pain, chronic pain, traumatic pain, chemical pain, ischemic pain, centrally mediated pain, peripherally mediated pain, prickling pain, visceral pain, progressive disease pain, musculoskeletal pain (e.g., back pain, neck pain), post-surgical pain, bone pain (e.g., osteoarthritis), nociceptive pain, or neuropathic pain. In another embodiment, the pain is inflammatory pain, thermal pain, acute pain, chronic pain, or neuropathic pain. In another embodiment, the pain is musculoskeletal pain (e.g., back pain, neck pain), post-surgical pain, or bone pain (e.g., osteoarthritis). In another embodiment, the pain is musculoskeletal pain. In another embodiment, the pain is chronic pain. In another embodiment, the pain is chronic musculoskeletal pain. In another embodiment, the pain is chronic back pain. In another embodiment, the pain is chronic lower back pain. In another embodiment, the pain is chronic neck pain. In yet another embodiment, the pain can be chronic pain, wherein the pain is chronic pain from headache, chronic pain from neuropathic conditions, chronic pain from post-stroke conditions or chronic pain from migraine. In still another embodiment, the pain can be acute pain, wherein the pain is acute pain from acute injury, acute pain from trauma, or acute pain from surgery. In one embodiment, the pain can be neuropathic pain, wherein the pain is neuropathic pain from alcoholic polyneuropathy, phantom limb pain, chemotherapy, diabetic pain, pain from HIV infection or AIDS, multiple sclerosis, shingles, Parkinson’s disease, spine surgery, or postherpetic neuralgia. In one embodiment, the pain can be inflammatory pain, wherein the pain is pain associated with arthritis such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, or scapulohumeral periarthritis. In one embodiment, the compounds of the invention can be used to treat depression in a subject in need thereof. As used herein, the term “depression” refers to “clinical depression” or “major depressive disorder.” In another embodiment, the compounds of the invention can be used to treat a depressive condition in a subject in need thereof. In an embodiment, the depressive condition is depressed mood, diminshed concentration, insomnia, fatigue, loss of appetite, excessive guilt, and suicidal thoughts. The depressive condition can be an anxiety disorder, wherein the anxiety disorder is generalized anxiety disorder, panic, or agoraphobia. The depressive condition can be associated with a mental condition, wherein the mental condition is schizoaffective disorder, or seasonal affective disorder. The depressive condition can be associated with chronic or recurrent depression. The depressive condition can be depressed mood, loss of pleasure, loss of appetite, sleep disturbance, psychomotor changes, fatigue, or post-partum depression. The depressive condition can be adjustment disorders with depressed mood, Asperger syndrome, attention deficit, bereavement, bipolar I disorder, bipolar II disorder, borderline and personality disorder, cyclothymia and dysthymia, Dysthymic disorder, hyperactivity disorder, impulse control disorder, mixed mania, obsessive- compulsive personality disorder (OCD), paranoid, seasonal affective disorder, self-injury separation, sleep disorder, substance-induced mood disorder, Tourette syndrome, tic disorder, or Trichotillomania. In another embodiment, the compounds of the invention can be used to treat addiction in a subject in need thereof. The addiction can be drug addiction or alcohol addiction. The drug addiction can be one or more of opioid addiction (i.e., opioid dependence) or stimulant addiction. The opioid can be one or more of fentanyl, morphine, oxymorphone, buprenorphine, hydromorphone, oxycodone, hydrocodone, or the like. The drug addiction can also be one or more of diamorphine (i.e., heroin), ***e, nicotine, and amphetamine. In one embodiment, compounds of the invention can be used to treat a disease or condition in a subject, wherein the subject has a tolerance to opioid medication, the subject has a history of opioid dependency or abuse, the subject is at risk of opioid dependency or abuse, or in circumstances wherein it is desirable that the risk of opioid dependence, opioid addiction, or symptoms of opioid withdrawal in the subject is minimized. The compounds of the invention can also be used to treat alcohol addiction, which can also be referred to as alcoholism. “Alcoholism” refers to an addictive disease or disorder characterized by an inability to control the intake of alcohol, i.e., a continued excessive or compulsive use of alcoholic drinks. Alcoholism may involve changes an individual’s ability to metabolize alcohol as well. Diagnosis of alcoholism can be made by psychiatric examination. In one aspect, the compounds provided herein are useful in treatment of pain by acting as an agonist of the µ-opioid receptor. In one embodiment of the methods described herein, the subject is human. Administration / Dosage / Formulations In another aspect, provided herein is a pharmaceutical composition comprising at least one compound of the invention, together with a pharmaceutically acceptable carrier. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a disclosed compound for the treatment of pain, a depressive disorder, or drug addiction in a patient. In one embodiment, the compounds of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier. In some embodiments, the dose of a disclosed compound is from about 1 mg to about 1,000 mg. In some embodiments, a dose of a disclosed compound used in compositions described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 20 mg, or less than about 10 mg. For example, a dose is about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or about 600 mg. Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein. For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For parenteral administration, the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The following examples further illustrate aspects of the present invention. However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth Examples The invention is further illustrated by the following examples, which should not be construed as further limiting. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, molecular biology, transgenic biology, microbiology and immunology, which are within the skill of the art. Example 1: Synthesis Procedures Synthesis procedures for preparation of the compounds of the invention are readily available to the ordinary skilled artisan. Unless otherwise indicated, starting materials were generally obtained from commercial sources. Abbreviations ACN acetonitrile Boc₂O di-tert-butyl dicarbonate DCM dichloromethane DMF dimethylformamide DMSO dimethylsulfoxide Et₂O diethyl ether EtOAc/EA ethyl acetate EtOH ethanol MeOH methanol NBS N-bromosuccinimide NCS N-chlorosuccinimide PE petroleum ether t-BuLi tert-butyl lithium TEA triethylamine THF tetrahydrofuran Compounds of Formula I can be prepared by the method illustrated in Scheme 1 below. Scheme 1.

To a stirred solution of 4-bromo-1H-1,2,3-benzotriazole (700 mg, 3.53 mmol, 1.0 equiv) in THF was added NaH (84.8 mg, 3.53 mmol, 1.0 equiv) at 0 ºC under nitrogen atmosphere, and the resulting mixture was stirred for 30 min at 0 ºC. To the stirred mixture was added t-BuLi (250 mg, 3.89 mmol, 1.1 equiv) dropwise at -78 ºC under nitrogen atmosphere, and the resulting mixture was stirred for 1 h at -78 ºC under nitrogen atmosphere.3-Benzyl-3-azabicyclo[3.3.1]nonan-9-one (973 mg, 4.24 mmol, 1.2 equiv) in THF was added to the above mixture. The resulting mixture was stirred for additional 2 h at 60 ºC. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of NaHCO₃ solution. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash to afford 9-(1H-1,2,3-benzotriazol-4-yl)-3-benzyl- 3-azabicyclo[3.3.1]nonan-9-ol as a mixture of A1 (455 mg, 33%) and A2 (245 mg,18%), as a brown solid. LCMS m/z (ES+), [M+H]⁺ = 349.

To a stirred solution of 9-(1H-1,2,3-benzotriazol-4-yl)-3-benzyl-3- azabicyclo[3.3.1]nonan-9-ol (A1 and A2) (300 mg, 0.862 mmol, 1.0 equiv) in MeOH was added sulfuric acid (2 mL) dropwise at room temperature under air atmosphere. To the above mixture was added trimethoxymethane (15 mL, 1.30 mmol, 1.5 equiv) dropwise over 1 min at room temperature, and the resulting mixture was stirred for additional 10 min at room temperature. To the above mixture was added sulfuric acid (4 mL) dropwise over 1 min at room temperature, and the resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was diluted with water (5mL). The aqueous layer was extracted with diethyl ether (3x10 mL). The aqueous layer was basified to pH 8 with saturated aqueous NaHCO₃, and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous NaCl (2 x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole (174 mg, 55%) as a white solid. LCMS m/z (ES+), [M+H]⁺ = 363.

To a stirred solution of 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H- 1,2,3-benzotriazole (B) (90 mg, 0.249 mmol, 1.0 equiv) and Pd(OH)₂/C (17 mg, 0.122 mmol, 0.5 equiv) in MeOH was added HCO₂NH₄(190 mg, 3.02 mmol, 10 equiv) in portions at room temperature under hydrogen atmosphere, and the resulting mixture was stirred for 2 h at room temperature .The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford 4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole (61 mg, 91%) as a white solid. LCMS m/z (ES+), [M+H]⁺ = 273.

To a stirred solution of 4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole (50 mg, 0.18 mmol, 1 equiv) in 2 mL MeOH was added hydrogen chloride (0.18 mL, 0.22 mmol, 1.2 equiv) in diethyl ether dropwise at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting solid was dried by lyophilization to give 4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H- 1,2,3-benzotriazole hydrochloride (52 mg, 90.8%) as a white solid. LCMS m/z (ES+), [M+H]⁺ = 273.¹H NMR (400 MHz, D₂O) d 1.28 (1 H, d), 1.47 (1 H, dt), 1.58 (1 H, dq), 1.70 (1 H, d), 1.95 (1 H, d), 2.18 (1 H, d), 2.73 (3 H, d), 3.04 (1 H, s), 3.40 (2 H, d), 3.66 (2 H, s), 3.89 (1 H, d), 7.45-7.61 (2 H, m), 7.85 (1 H, d). Compound 2

To a stirred solution of 4-bromo-1H-1,2,3-benzotriazole (500 mg, 2.53 mmol, 1.0 equiv) in THF were added NaH (260 mg, 10.1 mmol, 4.0 equiv) at 0 ºC under N2 atmosphere. The mixture was stirred for 0.5 h at this temperature. To the stirred mixture was added t-BuLi (13 ml, 10.1 mmol, 4.0 equiv) dropwise at -78 ºC under N₂ atmosphere. Stirred 1 h at -78 ºC. To the above mixture was added 3-benzyl-3-azabicyclo[3.3.1]nonan-9-one (870 mg, 3.8 mmol, 1.5 equiv) in THF by syringe, The mixture was stirred for additional 2 h at 60 ºC. The mixture was allowed to cool down to room temperature. The reaction was quenched with NaHCO3 at 0 ºC. The resulting mixture was extracted with ethylacetate (3 x 2 ml). The combined organic layers were washed with brine (3 x 2 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (20:1) to afford 9-(1H-1,2,3- benzotriazol-4-yl)-3-benzyl-3-azabicyclo[3.3.1]nonan-9-ol (160 mg, 18% ) as a light yellow solid and 9-(1H-1,2,3-benzotriazol-4-yl)-3-benzyl-3-azabicyclo[3.3.1]nonan-9-ol (160 mg, 18%) as a light yellow solid. LCMS m/z (ES+), [M+H]⁺ = 349.

To a stirred solution of 9-(1H-1,2,3-benzotriazol-4-yl)-3-benzyl-3-azabicyclo[3.3.1]- nonan-9-ol(110 mg, 0.287 mmol, 1.0 equiv) in EtOH was added sulfuric acid (3 mL) dropwise at room temperature under air atmosphere. To the above mixture was added triethoxy- methane (15 mL) dropwise over 1 min at room temperature. The resulting mixture was stirred for additional 10 min at room temperature. To the above mixture was added sulfuric acid (3 mL) dropwise over 1 min at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was diluted with water (5 mL). The aqueous layer was extracted with diethyl ether (3x10 mL). The aqueous layer was basified to pH 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous NaCl (2x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole (77 mg, 59%) as a brown yellow solid.

To a stirred solution of 4-[3-benzyl-9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole(70 mg, 0.19 mmol, 1.0 equiv) and 4-[3-benzyl-9-ethoxy-3-azabicyclo[3.3.1]- nonan-9-yl]-1H-1,2,3-benzotriazole (70 mg, 0.19 mmol, 1.0 equiv) in 5 mL MeOH was added Pd(OH)₂/C (261.1 mg, 1.86 mol, 10 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 2 h at 70 ºC under hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3x5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30×150mm 5um;Mobile Phase A: water (10MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 40% B in 8 min; 254 nm; Rt: 6.65 min) to afford 4-[9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole (20 mg, 37.6%) as a white solid. LCMS m/z (ES+), [M+H]⁺ = 287.

To a stirred mixture of 4-[9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole (20 mg, 0.07 mmol, 1.0 equiv) in MeOH was added hydrogen chloride in diethyl ether (0.08 mL, 0.08 mmol, 1.2 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. This resulted in 4-[9-ethoxy- 3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole hydrochloride (21 mg ,91.3%) as a white solid. LCMS m/z (ES+), [M+H]+ = 287.¹H NMR (400 MHz, D2O) d 0.79 (3 H, t), 1.29 (1 H, d), 1.54 (2 H, ddp), 1.71 (1 H, d), 1.95 (1 H, dd), 2.21 (1 H, q), 2.60-2.73 (1 H, m), 3.02 (1 H, s), 3.10- 3.22 (1 H, m), 3.40 (2 H, d), 3.61 (1 H, s), 3.68 (1 H, d), 3.96 (1 H, dd), 7.46 - 7.59 (2 H, m), 7.85 (1 H, dd). Scheme 2.

Step 2-1.

A solution of 4-fluoro-2-nitroaniline (10.0 g, 64.1 mmol, 1.0 equiv) in DMF (100 mL) was added NBS (11.4 g, 64.1 mmol, 1.0 equiv) in DMF (100 mL) dropwise for 15 min at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (6x150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by column chromatography (PE/EtOAc 2:1) to provide 2- bromo-4-fluoro-6-nitroaniline (10.7 g, 71%) as a yellow solid.¹H NMR (400 MHz, DMSO) d 7.11 (2 H, s), 7.94 (1 H, dd, J 9.2, 3.0), 8.03 (1 H, dd, J 7.6, 3.0). Step 2-2.

To a stirred solution of 2-bromo-4-fluoro-6-nitroaniline (10.9 g, 46.4 mmol, 1 equiv) was added SnCl₂ (52.8 g, 278.5 mmol, 6.0 equiv) in EtOAc and EtOH (2:190 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 5 h at 70 ºC under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was treated with saturated aqueous NH4Cl. The precipitated solids were collected by filtration and washed with EtOAc (2 x 300 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc/NH₄OH 10:1:0.00000004) to afford 3-bromo-5-fluorobenzene-1,2-diamine (10.7 g ,71%) as a yellow solid.¹H NMR (400 MHz, DMSO) d 4.44 (2 H, s), 5.20 (2 H, s), 6.39 (1 H, dd, J 10.8, 2.9), 6.51 (1 H, dd, J 8.4, 2.9).

To a stirred solution of 3-bromo-5-fluorobenzene-1,2-diamine (10.0 g, 48.8 mmol, 1.0 equiv) and NaNO2 (34.6 g, 501.3 mmol, 10.3 equiv) in water (600 mL) was added HCl (46.0 mL, 1513.9 mmol, 31.0 equiv) dropwise in portions at room temperature under air atmosphere. The resulting mixture was stirred for 1h at room temperature under air atmosphere. The aqueous layer was extracted with EtOAc (3 x150 mL), dried over anhydrous Na₂SO₄, filtered, the resulting mixture was concentrated under reduced pressure to provide 4-bromo-6-fluoro-1H-1,2,3-benzotriazole (9.0 g, 85%) as brown solid. LCMS m/z (ES+), [M+H]+ = 217. Compound 3

To a stirred solution of 4-bromo-6-fluoro-1H-1,2,3-benzotriazole (5.0 g, 23.1 mmol, 1.0 equiv) in THF was added NaH (3.7 g, 154.2 mmol, 6.7 equiv) in portions at 0 ºC under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 ºC under nitrogen atmosphere. To the above mixture was added 3-benzyl-3-azabicyclo[3.3.1]nonan-9-one(8.02 g, 35.0 mmol, 1.5 equiv) in portions over 1 min at -78 ºC. To the above mixture was added t- BuLi (44.5 mL, 57.850 mmol, 2.5 equiv) dropwise over 2 min at -78 ºC. The resulting mixture was stirred for additional 2 h at -78 ºC. The reaction was quenched with saturated, aqueous NH4Cl at 0 ºC. The resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Desired product could be detected by LCMS. The solid freeze dried from water to give 3-benzyl-9-(6-fluoro-1H-1,2,3- benzotriazol-4-yl)-3-azabicyclo[3.3.1]nonan-9-ol (6.1 g, 70%) as yellow solid. LCMS m/z (ES+), [M+H]+ = 367.¹H NMR (400 MHz, MeOD) d 1.26 (1 H, t), 1.60 (1 H, dt), 1.75 (2 H, dd), 2.39 (1 H, d), 2.55 (1 H, m), 2.90 (3 H, dd), 3.02 (2 H, d), 3.17 (1 H, d), 3.25 (1 H, s), 3.55 (1 H, s), 7.21 (1 H, m), 7.25 (1 H, d), 7.28 (1 H, m), 7.35 (3 H, m), 7.45 (1 H, td).

To a stirred solution of 3-benzyl-9-(6-fluoro-1H-1,2,3-benzotriazol-4-yl)-3- azabicyclo[3.3.1]nonan-9-ol (15.0 g, 40.9 mmol, 1 equiv) in trimethoxymethane (50 mL) at room temperature under air atmosphere. To the above mixture was added H₂SO₄ (15 ml) dropwise over 2 min at 0 ºC. The resulting mixture was stirred for 30 min at 0 ºC under nitrogen atmosphere. The resulting mixture was added water. The resulting mixture was extracted with ethylether (2 x 50 mL). The water layer was basified to pH 10 with aq. NH₄OH. The water phase was extracted with EtOAc (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography. The product, 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6- fluoro-1H-1,2,3-benzotriazole (7.8 g, 50.1%), was obtained as an off-white solid. The residue was purified by trituration with diethylether:hexane (50 mL:10 mL). The precipitated solids were collected by filtration and washed with hexane (1x100 mL). The product, 4-[3-benzyl-9- methoxy-3-azabicyclo [3.3.1]nonan-9-yl] -6-fluoro-1H-1,2,3-benzotriazole (7.5 g, 48.2%), was obtained as an off-white solid. LCMS m/z (ES+), [M+H]+ = 367.¹H NMR (400 MHz, CDCl3) d 1.29 (1 H, s), 1.45 (1 H, d), 1.73 (1 H, s), 2.01 (1 H, s), 2.23 (1 H, s), 2.61 (1 H, s), 2.86 (6 H, s), 3.15 (1 H, s), 3.54 (2 H, d), 7.33 (6 H, d), 7.59 (1 H, s).

To a stirred solution/mixture of 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]- 6-fluoro-1H-1,2,3- benzotriazole (7.5 g, 19.7 mmol, 1.0 equiv) and HCO₂NH₄ (12.4 g, 197.1 mmol, 10 equiv) in MeOH (100 mL) were added Pd(OH)2/C (1.38 g, 9.9 mmol, 0.50 equiv) dropwise in portions at 70 ºC under nitrogen atmosphere. The precipitated solids were collected by filtration and washed with MeOH (2 x 100 mL). The resulting mixture was concentrated under vacuum. The crude product (1.8 g) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 5um,19*150mm; Mobile Phase A: water (10MMOL/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 35% B in 7 min; 254 nm; Rt: 6.37 min) to afford 6-fluoro-4- [9-methoxy-3- azabicyclo [3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole(5g,87.36%) as a off-white solid. LCMS m/z (ES+), [M+H]+ = 291.¹H NMR (400 MHz, CDCl3) d 1.29 (1 H, s), 1.45 (1 H, d), 1.73 (1 H, s), 2.01 (1 H, s), 2.23 (1 H, s), 2.61 (1 H, s), 2.86 (6 H, s), 3.15 (1 H, s), 3.54 (2 H, d), 7.33 (6 H, d), 7.59 (1 H, s).

To a stirred solution/mixture of 6-fluoro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]- 1H-1,2,3-benzotriazole (5.0 g, 17.2 mmol, 1 equiv) in MeOH (100 mL) were added a solution of hydrogen chloride in diethylether (34.4 mL, 34.4 mmol, 2.0 equiv) dropwise in portions at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (80mL). The resulting mixture was filtered, The aqueous layer was dried by lyophilization to afford 6-fluoro-4-[9-methoxy-3- azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole hydrochloride (5.0 g, 88.0%) as a off- white solid. LCMS m/z (ES+), [M+H]+ = 291.¹H NMR (400 MHz, MeOD) d 7.61 (1 H, dd, J 7.6, 2.1), 7.48 (1 H, dd, J 10.7, 2.2), 3.99 (2 H, m), 3.76 (1 H, m), 3.47 (2 H, m), 3.07 (1 H, s), 2.90 (3 H, s), 2.18 (1 H, d, J 14.1), 2.07 (1 H, d, J 13.7), 1.87 (2 H, m), 1.56 (2 H, m).

To a stirred solution of 3-benzyl-9-(6-fluoro-1H-1,2,3-benzotriazol-4-yl)-3-azabicyclo- [3.3.1]nonan-9-ol (100 mg, 0.27 mmol, 1.0 equiv) in HC(OiPr)3 (5 mL) was added sulfuric acid (1.5 mL) dropwise at 0 ºC under air atmosphere. The resulting mixture was stirred for 10 min at 0 ºC. The reaction was monitored by LCMS. The mixture was basified to pH 7 with saturated aq.NaHCO₃ (5 mL) at 0 ºC. The resulting mixture was extracted with CH₂Cl₂ (3 x 10 mL). The aqueous layer was extracted with CH₂Cl₂ (3x5 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 10:1) to afford 4-[3-benzyl-9-(propan-2-yloxy)-3-azabicyclo[3.3.1]nonan-9-yl]-6- fluoro-1H-1,2,3-benzotriazole (100 mg, 89.7%) as a light yellow solid. LCMS m/z (ES+), [M+H]+ = 409.

To a stirred mixture 4-[3-benzyl-9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-fluoro-1H- 1,2,3-benzotriazole (180 mg, 0.46 mmol, 1 equiv) in HCO₂NH₄ (57.5 mg, 0.91 mmol, 2 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added Pd(OH)₂/C (64.1 mg, 0.46 mmol, 1 equiv) and HCO₂NH₄ (28.5 mg, 0.05 mmol, 2 equiv). The resulting mixture was stirred for additional 0.5 h at 65 ºC. The resulting mixture was filtered, the filter cake was washed with EtOH (3x10 mL). Column: XBridge Prep C18 OBD Column 19 A150mm 5um; Mobile Phase A: water (10MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 37% B in 7 min; 254/220 nm; Rt: 6.50 min. This resulted in 4-[9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-fluoro-1H-1,2,3-benzotriazole (110 mg, 79.2%) as a light yellow solid. LCMS m/z (ES+), [M+H]+ = 319.

Into a 50 mL round-bottom flask were added6-fluoro-4-[9-(propan-2-yloxy)-3-aza- bicyclo[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole(30 mg) and HCl/diethyl ether (1.5 mL). The resulting mixture was stirred for 10 min under air atmosphere. The resulting mixture was concentrated under reduced pressure. The solid was freeze dried from water to give 6-fluoro- 4-[9-(propan-2-yloxy)-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole hydrochloride (28 mg) as a off-white solid. LCMS m/z (ES+), [M+H]+ = 319. ¹H NMR (400 MHz, MeOD) d 7.58 (dd, J = 7.5, 2.1 Hz, 1H), 7.49 (dd, J = 10.9, 2.2 Hz, 1H), 4.25 (s, 1H), 4.02 (ddd, J = 12.8, 4.5, 1.5 Hz, 1H), 3.94 (ddd, J = 12.8, 4.1, 1.9 Hz, 1H), 3.75 (hept, J = 6.1 Hz, 1H), 3.47 (dd, J = 12.9, 8.2 Hz, 2H), 3.07 – 3.01 (m, 1H), 2.15 (t, J = 10.1 Hz, 1H), 2.07 – 1.98 (m, 1H), 1.95 – 1.86 (m, 1H), 1.80 (td, J = 16.4, 14.8, 8.3 Hz, 1H), 1.53 (tt, J = 13.8, 7.0 Hz, 2H), 0.90 (d, J = 6.1 Hz, 3H), 0.53 (d, J = 6.0 Hz, 3H).

A mixture of 7-bromo-5-(trifluoromethyl)-1H-1,2,3-benzotriazole (480 mg, 1.80 mmol, 1 eq.) and NaH (173.2 mg, 7.22 mmol, 4.0 equiv) in THF (20 mL) was stirred for 0.5 h at 0 ºC under nitrogen atmosphere. Then the mixture was added 3-benzyl-3-azabicyclo[3.3.1]nonan- 9-one (620.7 mg, 2.71 mmol, 1.5 equiv) in portions. To the above mixture was added t-BuLi (346.7 mg, 5.41 mmol, 3.0 equiv) dropwise over 5 min at -78 ºC. The resulting mixture was stirred for additional 1 h at this temperature. After the temperature increased to 0 ºC, the reaction was quenched by the addition of sat. NH4Cl (aq.) (5 mL) at 0 ºC. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 2:1) to afford bis-3-benzyl-9-[6-(trifluoromethyl)-1H-1,2,3-benzotriazol-4-yl]-3-azabicyclo- [3.3.1]nonan-9-ol (500 mg, 66.6%) as a brown solid. LCMS m/z (ES+), [M+H]+ = 417.

To a stirred solution of bis-3-benzyl-9-[6-(trifluoromethyl)-1H-1,2,3-benzotriazol-4-yl]- 3-azabicyclo[3.3.1]nonan-9-ol (500 mg, 1.20 mmol, 1 equiv) in trimethoxymethane (3 mL) was added sulfuric acid (0.5 mL) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for additional 1 min at room temperature. The reaction was monitored by LCMS. The mixture was basified to pH 7 with saturated aq. NaHCO₃ (5 mL) at 0 ºC. The resulting mixture was extracted with CH₂Cl₂ (3 x 10 mL). The aqueous layer was extracted with CH₂Cl₂ (3x5 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 3:1) to afford 4-[3- benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-(trifluoromethyl)-1H-1,2,3-benzotriazole (300 mg, 72.1%) as a off-white solid. LCMS m/z (ES+), [M+H]+ = 431.

To a stirred solution of 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6- (trifluoromethyl)-1H-1,2,3-benzotriazol) (300 mg, 0.70 mmol, 1 equiv) and HCO₂NH₄ (439.5 mg, 6.98 mmol, 10 equiv) in MeOH (10 ml) was added Pd(OH)₂/C (43.8 mg, 0.35 mmol, 0.5 equiv) in portions. The mixture was evacuated and refilled with N₂ for three times. The resulting mixture was stirred at 60 ºC for 0.5 h under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford 4-[9- methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-(trifluoromethyl)-1H-1,2,3-benzotriazole (30 mg, 12.7%) as a off-white solid. LCMS m/z (ES+), [M+H]+ = 341.

A solution of 4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-(trifluoromethyl)-1H-1,2,3- benzotriazole (30 mg, 0.09 mmol, 1 equiv) in MeOH (5 mL) was added hydrogen chloride (0.18 mL, 0.18 mmol, 2 equiv) and stirred for 1 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL) and filtered. The flask was washed with water (2 x 5 mL). The aqueous phases were combined, and the resulting salt was obtained by freeze drying. This resulted in 4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-(trifluoromethyl)-1H- 1,2,3-benzotriazole hydrochloride (11.5 mg, 34.6%) as a white solid. LCMS m/z (ES+), [M+H]+ = 341. ¹H NMR (400 MHz, MeOD) d 8.32 (s, 1H), 7.75 (s, 1H), 4.01 (d, J = 12.9 Hz, 1H), 3.97 (s, 1H), 3.81 – 3.72 (m, 1H), 3.47 (dd, J = 12.9, 4.5 Hz, 2H), 3.16 (s, 1H), 2.89 (d, J = 1.0 Hz, 3H), 2.20 (s, 1H), 2.12 (s, 1H), 1.93 – 1.73 (m, 2H), 1.59 (dd, J = 14.9, 7.2 Hz, 1H), 1.44 (s, 1H), 1.39 – 1.29 (m, 1H), 1.12 (dd, J = 7.6, 3.2 Hz, 1H).

To a stirred solution of 3-benzyl-9-(6-fluoro-1H-1,2,3-benzotriazol-4-yl)-3-azabicyclo- [3.3.1]nonan-9-ol (100 mg, 0.27 mmol, 1 equiv) in HC(OEt)₃ (10 mL) was added sulfuric acid (1 mL) dropwise at 0 ºC under air atmosphere. The resulting mixture was stirred for 10 min at 0 ºC. The reaction was monitored by LCMS. The mixture was basified to pH 7 with saturated NaHCO3 (aq.) (5 mL) at 0 ºC. The resulting mixture was extracted with CH₂Cl₂ (3 x 10mL). The aqueous layer was extracted with CH₂Cl₂ (3x5 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 10:1) to afford 4-[3-benzyl-9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-fluoro-1H-1,2,3- benzotriazole (85.0 mg, 79.0%) as a light yellow solid. LCMS m/z (ES+), [M+H]+ = 367.

To a stirred solution/mixture 4-[3-benzyl-9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6- fluoro-1H-1,2,3-benzotriazole (180 mg, 0.46 mmol, 1 equiv) in HCO2NH4 (57.5 mg, 0.91 mmol, 2 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added Pd(OH)₂/C (64.1 mg, 0.46 mmol, 1 equiv) and HCO₂NH₄ (28.5 mg, 0.05 mmol, 2 equiv). The resulting mixture was stirred for additional 0.5 h at 65 ºC. The resulting mixture was filtered, the filter cake was washed with EtOH (3x10 mL). Column: XBridge Prep C18 OBD Column 19A150mm 5um;Mobile Phase A: water (10MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 37.7% B in 7 min; 254/220 nm; Rt: 6.50 min.This resulted in 4-[9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-fluoro-1H-1,2,3- benzotriazole (110mg, 79.2%) as a light yellow solid. LCMS m/z (ES+), [M+H]+ = 305.

Into a 50 mL round-bottom flask were added 4-[9-ethoxy-3-azabicyclo[3.3.1]nonan-9- yl]-6-fluoro-1H-1,2,3-benzotriazole (30 mg) and HCl/diethyl ether (1.5 mL). The resulting mixture was stirred for 10 min under air atmosphere. The resulting mixture was concentrated under reduced pressure. The solid freeze dried from water to give 4-[9-ethoxy-3-azabicyclo- [3.3.1]nonan-9-yl]-6-fluoro-1H-1,2,3-benzotriazole hydrochloride (27.5 mg) as an off-white solid. LCMS m/z (ES+), [M+H]+ = 305.¹H NMR (400 MHz, MeOD) d 7.57 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 10.7 Hz, 1H), 4.08 (s, 1H), 4.05 – 3.96 (m, 1H), 3.78 (d, J = 12.7 Hz, 1H), 3.51 – 3.42 (m, 2H), 3.33 (s, 1H), 3.19 (p, J = 7.3 Hz, 1H), 3.05 (s, 1H), 2.87 (p, J = 7.2 Hz, 1H), 2.18 (s, 1H), 2.10 – 2.01 (m, 1H), 1.89 (d, J = 14.9 Hz, 1H), 1.82 (s, 1H), 1.61 – 1.52 (m, 1H), 1.50 (s, 1H), 0.98 (t, J = 7.0 Hz, 3H).

Into a 100 mL round-bottom flask were added 4,5-difluorobenzene-1,2-diamine (2.0 g, 13.9 mmol, 1 equiv) and HCl (11.6 mL, 138.8 mmol, 10 equiv) in water at room temperature. NaNO2 (2.87 g, 41.6 mmol, 3 equiv) in water was added dropwise to the above mixture over 5 min. The resulting mixture was stirred for additional 2 h at room temperature under air atmosphere. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3:1) to afford 5,6-difluoro-1H-1,2,3-benzotriazole (1.86 g, 86.4%) as a brown yellow solid. LCMS m/z (ES+), [M+H]+ = 156.

Into a 100 mL round-bottom flask were added 5,6-difluoro-1H-1,2,3-benzotriazole (1.5 g, 9.67 mmol, 1 equiv) and THF (50 mL) at room temperature. To a stirred mixture was added NaH (348.1 mg, 14.5 mmol, 1.5 equiv) at 0 ºC under nitrogen atmosphere for 15 mins. To the above mixture was added t-BuLi (743.4 mg, 11.6 mmol, 1.2 equiv) dropwise over 10 min at -78 ºC. The resulting mixture was stirred for additional 1 h at -78 ºC. To the resulting mixture was added 3-benzyl-3-azabicyclo[3.3.1]nonan-9-one (2.22 g, 9.67 mmol, 1.0 equiv). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was added water and extracted with EtOAc (3 x100 mL). The combined organic layers were washed with NaCl (aq), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography. This resulted in 3-benzyl-9-(5,6-difluoro-1H-1,2,3-benzotriazol-4-yl)-3- azabicyclo[3.3.1]nonan-9-ol (2.2g, 59.2%) as a white solid. LCMS m/z (ES+), [M+H]+ = 385.

Into 50 a mL round-bottom flask were added 3-benzyl-9-(5,6-difluoro-1H-1,2,3- benzotriazol-4-yl)-3-azabicyclo[3.3.1]nonan-9-ol (1.0 g) and trimethoxymethane (30 mL) at room temperature. To the above mixture was added sulfuric acid (5 mL) dropwise at room temperature. The resulting mixture was stirred for additional 10 min at room temperature. The reaction was quenched with water 100 mL, the resulting mixture was extracted with Et2O (3 x 50 mL), basified with sat. NaHCO3, and extracted with EtOAc (50 mL X3). The organic layer was dried over brine and Na2SO4, concentrated to give the crude product, and was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford 4-[3-benzyl-9- methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-5,6-difluoro-1H-1,2,3-benzotriazole (212mg, 20.5%) as a light yellow solid. LCMS m/z (ES+), [M+H]+ = 399.

Into a 50 mL round-bottom flask were added 4-[3-benzyl-9-methoxy-3- azabicyclo[3.3.1]nonan-9-yl]-5,6-difluoro-1H-1,2,3-benzotriazole (150 mg, 0.38 mmol, 1 equiv), THF (10 mL), Boc2O (32.9 mg, 0.15 mmol, 1.2 equiv) and Pd(OH)2/C (5 mg, 0.036 mmol, 0.28 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (4:1) to afford tert-butyl 9-(5,6-difluoro-1H-1,2,3- benzotriazol-4-yl)-9-methoxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (100 mg, 65.0%) as an off-white solid. LCMS m/z (ES+), [M+H]+ = 409.

Into a 25 mL round-bottom flask were added tert-butyl 9-(5,6-difluoro-1H-1,2,3- benzotriazol-4-yl)-9-methoxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (20.0 mg) and HCl (g) in MeOH (5 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 5um,19*150mm; Mobile Phase A: water (10% HCl), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 10% B to 40% B in 7 min; 220/254 nm; Rt: 6.5 min) to afford 5,6-difluoro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]- 1H-1,2,3-benzotriazole (100 mg, 88.3%) as a off-white solid. LCMS m/z (ES+), [M+H]+ = 309.

A mixture of 5,6-difluoro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole (100 mg, 0.32 mmol, 1 equiv) in HCl (g) in MeOH (3 mL) was stirred for 1 h at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The solid was freeze dried from water to give 5,6-difluoro-4-[9-methoxy-3- azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole hydrochloride (58.0 mg, 51.9%) as a white solid. LCMS m/z (ES+), [M+H]+ = 309. ¹H NMR (400 MHz, MeOD) d 7.86 (m, 1H), 4.43 (s, 1H), 3.92 (dd, J = 13.1, 4.4 Hz, 1H), 3.75 (m, 2H), 3.45 (dd, J = 13.1, 8.7 Hz, 2H), 3.33 (s, 1H), 3.07 (s, 3H), 2.22 ~2.10 (m, 1H), 2.08 ~1.89 (m, 3H), 1.71~1.51 (m, 2H).

To a stirred solution of 2-bromo-3-fluoro-6-nitroaniline (4.4 g, 18.7 mmol, 1 equiv) in MeOH (30 mL) THF (30 mL) and H₂O (30 mL) were added tin(II) chloride (6.0 g, 112.3 mmol, 6 equiv) and iron (6.3 g, 112.3 mmol, 6 equiv) at 60 ºC under air atmosphere. The resulting mixture was stirred for 1h at 60 ºC under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered; the filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with DCM (100 mL). The resulting mixture was filtered, the filter cake was washed with DCM (3 x 50 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-bromo-4-fluorobenzene-1,2- diamine (3.6 g, 93.8%) as a black solid. ¹H NMR (400 MHz, MeOD) d 6.65 (d, J = 9.0 Hz, 1H), 6.38 (t, J = 8.5 Hz, 1H).

To a stirred solution of 3-bromo-4-fluorobenzene-1,2-diamine (3.0 g, 14.6 mmol, 1 equiv) in hydrogen chloride (117.1 mL, 117.1 mmol, 8 equiv) was added sodium nitrite (8.1 g, 117.1 mmol, 8 equiv) dropwise in water (50 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 10 min at room temperature under air atmosphere. Desired product could be detected by LCMS. The mixture/residue was neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-bromo-5-fluoro-1H-1,2,3-benzotriazole (2.9 g, 91.8%) as a brown solid. LCMS m/z (ES+), [M+H]+ = 218. ¹H NMR (400 MHz, MeOD) d 7.90 (dd, J = 9.0, 4.0 Hz, 1H), 7.38 (m, 1H).

A solution of 4-bromo-5-fluoro-1H-1,2,3-benzotriazole (1.00 g, 4.63 mmol, 1 equiv) in 50 mL THF was treated with sodium hydride (166.6 mg, 6.94 mmol, 1.5 equiv) for 1 hour at room temperature under nitrogen atmosphere followed by the addition of t-BuLi (8.9 mL, 11.6 mmol, 2.5 equiv) and 3-benzyl-3-azabicyclo[3.3.1]nonan-9-one (1.27 g, 5.56 mmol, 1.2 equiv) dropwise at -78 ºC. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with ice/salt at 0 ºC. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 2:1) to afford 3- benzyl-9-(5-fluoro-1H-1,2,3-benzotriazol-4-yl)-3-azabicyclo[3.3.1]nonan-9-ol (800 mg, 47.2%) as a light yellow solid. LCMS m/z (ES+), [M+H]+ = 367.

To the stirred solution of 3-benzyl-9-(5-fluoro-1H-1,2,3-benzotriazol-4-yl)-3- azabicyclo[3.3.1]nonan-9-ol (500 mg, 1.36 mmol, 1 equiv) in trimethoxymethane (20 mL) was added sulfuric acid (5 mL) at 0 ºC. The solution was stirred for 2 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was washed with Et2O (5 x 50 mL). The mixture basified to pH 8 with saturated Na2CO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3x150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 3:1) to afford 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-5- fluoro-1H-1,2,3-benzotriazole (400 mg, 77.1%) as a light brown solid. LCMS m/z (ES+), [M+H]+ = 381. ¹H NMR (400 MHz, DMSO-d6) d 7.65 (dd, J = 8.8, 4.2 Hz, 1H), 7.35 (d, J = 4.4 Hz, 4H), 7.25 (h, J = 4.0 Hz, 1H), 6.85 (dd, J = 13.5, 8.7 Hz, 1H), 4.40 (s, 1H), 3.51 – 3.30 (m, 2H), 2.87 – 2.59 (m, 8H), 1.75 (d, J = 12.8 Hz, 2H), 1.60 (s, 1H), 1.48 (s, 2H), 1.21 – 1.06 (m, 2H).

To the stirred solution of 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-5- fluoro-1H-1,2,3-benzotriazole (150 mg, 0.39 mmol, 1 equiv) in MeOH (15 mL) were added Pd(OH)₂/C (74.7 mg, 0.53 mmol, 1.4 equiv) and HCO₂NH₄ (124.3 mg, 1.97 mmol, 5 equiv). The solution was stirred for 20 min at 65 ºC. The reaction was monitored by LCMS. The resulting mixture was filtered, the filtrate was concentrated under reduced pressure to afford crude product as an off-white solid. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150mm, 5 µm; Mobile Phase A: water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 32% B in 7 min; 254 nm; Rt: 6.5 min) to afford 5-fluoro-4-[9-methoxy-3- azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole (85 mg, 74.3%) as a off-white solid. LCMS m/z (ES+), [M+H]+ = 291.

To the stirred solution of 5-fluoro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H- 1,2,3-benzotriazole (85 mg, 0.29 mmol, 1 equiv) in MeOH (5 mL) was added 1 M hydrogen chloride in Et2O (0.35 mL, 1.2 equiv). The solution was stirred for 0.5 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in pure water (5 mL). The resulting solid was dried by lyophilization to afford 5-fluoro-4-[9-methoxy-3-azabicyclo- [3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole hydrochloride (85 mg, 88.8%) as off-white solid. LCMS m/z (ES+), [M+H]+ = 291. ¹H NMR (400 MHz, Deuterium Oxide) d 7.88-7.80 (m, 1H), 7.38-7.24 (m, 1H), 3.97 (s, 1H), 3.81 (dd, J = 13.0, 4.3 Hz, 1H), 3.68-3.58 (m, 1H), 3.34 (m, 3H), 2.87 (s, 3H), 1.97 (m, 2H), 1.77 (m, 1H), 1.56 (m, 1H), 1.44 (m, 2H).

To a stirred mixture of 3-benzyl-9-(6-fluoro-1H-1,2,3-benzotriazol-7-yl)-3- azabicyclo[3.3.1]nonan-9-ol (500 mg, 1.36 mmol, 1 equiv) in (diethoxymethoxy)ethane(5 mL, 0.034 mmol, 0.02 equiv) was added H₂SO₄ (2 mL, 0.020 mmol, 0.01 equiv) dropwise at room temperature. The reaction was stirred for 0.5 h. The reaction was quenched with water at room temperature. The resulting mixture was washed with 3x10 mL of Et2O. The mixture was basified to pH 10 with aqueous NH4OH. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. LCMS m/z (ES+), [M+H]+ = 395.

To a stirred solution of 4-[3-benzyl-9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-5-fluoro- 1H-1,2,3-benzotriazole (630 mg, 1.60 mmol, 1.0 equiv) and HCO2NH4 (960 mg, 15.2 mmol, 9.5 equiv) in methanol (8 mL, 0.25 mmol, 0.16 equiv) was added Pd(OH)2/C (300 mg, 2.14 mmol, 1.3 equiv) in portions at 65 ºC. The reaction was stirred for 20 min. The resulting mixture was filtered and concentrated under reduced pressure. The crude product 4-[9- ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-5-fluoro-1H-1,2,3-benzotriazole (300.0 mg, 0.99 mmol, 1.0 equiv) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 5um,19*150mm; Flow rate: 25 mL/min; Gradient: 15%B to 27% B in 8 min; 220 nm; Rt: 6.55 min ) to afford 4-[9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-5-fluoro-1H- 1,2,3-benzotriazole (200mg) as a white solid. LCMS m/z (ES+), [M+H]+ = 305.

To a stirred solution of 4-[9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-5-fluoro-1H-1,2,3- benzotriazole (200.0 mg, 0.68 mmol, 1.0 equiv) in MeOH was added HCl/Et2O (1.0 mL) dropwise at room temperature for 0.5 h. The resulting solid was dried by lyophilization to give 4-[9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-5-fluoro-1H-1,2,3-benzotriazole hydrochloride (65.9 mg) as a white solid. LCMS m/z (ES+), [M+H]+ = 305. ¹H NMR (400 MHz, Deuterium Oxide) d 7.76 (m, 1H), 7.21 (m, 1H), 3.81 (m, 2H), 3.59 (m, 1H), 3.32 (m, 2H), 3.17 (s, 2H), 2.85 (s, 1H), 1.90 (m, 2H), 1.68-1.53 (m, 1H), 1.33 (m, 2H), 0.85 – 0.74 (m, 3H).

To a stirred mixture of 3-bromo-5-chlorobenzene-1,2-diamine (2.0 g, 9.03 mmol, 1 equiv) in HCl (10.0 mL, 274.29 mmol, 37 equiv)/water was added NaNO2 (6.0 g, 87.0 mmol, 9.6 equiv) in water dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under air atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with hexane/EtOAc to afford 4-bromo-6-chloro-1H-1,2,3-benzotriazole (1.4 g, 60.0%). LCMS m/z (ES+), [M+H]+ = 233.

To a stirred mixture of 4-bromo-6-chloro-1H-1,2,3-benzotriazole (2.5 g, 10.8 mmol, 1 equiv) in THF (25 mL) was added NaH (0.52 g, 21.5 mmol, 2 equiv) in portions at 0 ºC under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 ºC under nitrogen atmosphere. To the above mixture was added tert-butyl 9-oxo-3-azabicyclo[3.3.1]nonane-3- carboxylate (3.1 g, 12.9 mmol, 1.2 equiv).The resulting mixture was stirred for additional 30 min at 0 ºC. To the above mixture was added t-BuLi (16.5 mL, 21.5 mmol, 2 equiv) dropwise. The resulting mixture was stirred for additional 1 h at -78 ºC. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water. The resulting mixture was extracted with CH₂Cl₂.The combined organic layers were washed with water, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (12:1) to afford tert-butyl 9-(6-chloro-1H-1,2,3- benzotriazol-4-yl)-9-hydroxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (2 g) .The product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um n; Mobile Phase A: water (0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 55% B in 8 min; 220 nm; Rt: 6.83,7.30 min) to afford 1.3 g of the product. LCMS m/z (ES+), [M+H]+ = 375.

To a stirred mixture of tert-butyl 9-(6-chloro-1H-1,2,3-benzotriazol-4-yl)-9-hydroxy-3- azabicyclo[3.3.1]nonane-3-carboxylate (124 mg, 0.32 mmol, 1 equiv) in DMF (5 mL) was added NaH (11.4 mg, 0.47 mmol, 1.5 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. To the above mixture was added [2-(chloromethoxy)ethyl]trimethylsilane (78.9 mg, 0.47 mmol, 1.5 equiv). The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH₂Cl₂. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 5:1) to afford tert-butyl 9-(6- chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,2,3-benzotriazol-4-yl)-9-hydroxy-3- azabicyclo[3.3.1]nonane-3-carboxylate(120 mg,65.4%) as a off-white solid. LCMS m/z (ES+), [M+H]+ = 449.

To a stirred mixture of tert-butyl 9-(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H- 1,2,3-benzotriazol-4-yl)-9-hydroxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (120 mg, 0.23 mmol, 1 equiv) in DMF (5 mL) was added NaH (8.3 mg, 0.34 mmol, 1.5 equiv). The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. To the above mixture was added iodomethane (48.8 mg, 0.34 mmol, 1.5 equiv). The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH₂Cl₂. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 10:1) to afford 6-chloro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1-[[2-(trimethylsilyl)- ethoxy]methyl]-1H-1,2,3-benzotriazole(80 mg, 71.8%) as a off-white solid. LCMS m/z (ES+), [M+H]+ = 505.

A solution/mixture of tert-butyl-9-(6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H- 1,2,3-benzotriazol-4-yl)-9-methoxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (80 mg) in CF₃COOH (3 mL) and DCM (3 mL) was stirred overnight at room temperature under nitrogen atmosphere. Water (0.04 mL) was added to the mixture. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions to afford 6-chloro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole (15 mg) as a white solid. LCMS m/z (ES+), [M+H]+ = 307.

To a stirred solution of 6-chloro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H- 1,2,3-benzotriazole(60 mg, 0.196 mmol, 1 equiv) in MeOH (1 mL) was added hydrogen chloride (2.0 mL, 10 equiv).The resulting mixture was stirred for 30 min at room temperature.The resulting mixture was concentrated under vacuum. The solid was freeze dried from water to afford 6-chloro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole hydrochloride (16.5 mg, 24.6%) as a white solid. LCMS m/z (ES+), [M+H]+ = 307. ¹H NMR (400 MHz, D₂O) d 7.81 (d, J = 1.6 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 3.92 - 3.79 (m, 1H), 3.66 - 3.53 (m, 2H), 3.42 - 3.30 (m, 2H), 2.94 (s, 1H), 2.68 (s, 3H), 2.09 (m, 1.92 (m, 1H), 1.71-1.38 (m, 3H), 1.12 (m, 1H).

To a stirred solution of 4-bromo-1H-1,2,3-benzotriazole (500 mg, 2.52 mmol, 1.0 equiv) in 30 mL THF were added NaH (121.2 mg, 5.05 mmol, 2.0 equiv) at 0 ºC under nitrogen atmosphere. To the above mixture was added t-BuLi (3.9 mL, 60.6 mmol, 2.0 equiv) dropwise over 15 min at -78 ºC. The resulting mixture was stirred for additional 1 h at -78 ºC. Then to the above mixture was added benzyl 9-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate (1.04 g, 3.79 mmol, 1.5 equiv) at -10 ºC. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH₄Cl (aq.) (10 mL) at 0 ºC. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 1:1) to afford benzyl 9-(1H-1,2,3-benzotriazol- 4-yl)-9-hydroxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (515mg, 46.8%) as a yellow solid. LCMS m/z (ES+), [M-OH]⁺ = 375.

To a stirred solution of benzyl 9-(1H-1,2,3-benzotriazol-4-yl)-9-hydroxy-3-azabicyclo- [3.3.1]nonane-3-carboxylate(150 mg, 0.38 mmol, 1 equiv) were added thionyl chloride (15 mL) at 0 ºC under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at 60 ºC. When the reaction was completed the resulting mixture was concentrated under reduced pressure and used in the next step without purification. To a stirred solution of benzyl 9-(1H-1,2,3-benzotriazol-4-yl)-9-chloro-3-azabicyclo[3.3.1]nonane-3-carboxylate (160 mg, 0.39 mmol, 1.0 equiv) in dichloromethane were added triethylaluminium (1.6 mL, 1.60 mmol, 4.1 equiv) dropwise at -50 ºC under nitrogen atmosphere.The resulting mixture was stirred for additional 1 h at -50 ºC. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NaHCO₃ (aq.) (3 mL) at 0 ºC. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 1:1) to afford benzyl 9- (1H-1,2,3-benzotriazol-4-yl)-9-ethyl-3-azabicyclo[3.3.1]nonane-3-carboxylate(118 mg, 45.6%). LCMS m/z (ES+), [M+H]+ = 405.

A mixture of benzyl 9-(1H-1,2,3-benzotriazol-4-yl)-9-ethyl-3-azabicyclo[3.3.1]nonane- 3-carboxylate (100 mg, 0.25 mmol, 1 equiv) and HCO2NH4 (155.9 mg, 2.5 mmol, 10.0 equiv) and Pd(OH)2/C (86.8 mg, 0.12 mmol, 0.5 equiv, 20%) in 20 mL MeOH was stirred for 30 min at 65 ºC under hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The crude product (68 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep C18 OBD Column 19×150mm 5um; Mobile Phase A: water(10MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 34% B in 7 min; 254/220 nm; Rt: 6.7 min) to afford 4-[9-ethyl-3- azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole (63 mg, 90.5%) as a white solid. LCMS m/z (ES+), [M+H]+ = 271.

To a stirred solution of 4-[9-ethyl-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole (63 mg, 0.23 mmol, 1 equiv) in 5 mL MeOH was added HCl/Et2O (0.35 mL, 0.35 mmol, 1.5 equiv) dropwise at 0 ºC. The resulting mixture was stirred for additional 15 min at room temperature. The resulting mixture was concentrated under reduced pressure then washed with water (5 mL) and filtered. The filtrate was freeze to afford 4-[9-ethyl-3- azabicyclo-[3.3.1]nonan-9-yl]-1H-1,2,3-benzotriazole hydrochloride (58 mg,79.5%) as a white solid. LCMS m/z (ES+), [M+H]+ = 271. ¹H NMR (400 MHz, D2O) d 7.55 (d, J = 8.3 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 3.85 – 3.72 (m, 1H), 3.61 (dd, J = 13.9, 3.5 Hz, 1H), 3.50 (s, 1H), 3.44 – 3.30 (m, 2H), 2.57 (s, 1H), 2.07 – 1.87 (m, 2H), 1.70 (dd, J = 14.6, 7.4 Hz, 1H), 1.63 – 1.40 (m, 3H), 1.24 – 1.00 (m, 2H), 0.18 (t, J = 7.4 Hz, 3H).

To a stirred solution of 4-bromo-1H-1,2,3-benzotriazole(1 g, 5.05 mmol, 1.0 equiv) in THF at room temperature under air atmosphere. To the above mixture was added NaH (225 mg, 9.38 mmol, 1.9 equiv) in portions over 3 min at 0 ºC. The resulting mixture was stirred for additional 30 min at 0 ºC. To the above mixture was added 3-benzyl-3-azabicyclo[3.3.1]- nonan-9-one(1.4 g, 6.06 mmol, 1.20 equiv) dropwise over 2 min at -78 ºC. To the above mixture was added t-BuLi (4.3 mL, 67.3 mmol, 1.1 equiv) dropwise over 5 min at -78 ºC. The resulting mixture was stirred for additional 2 h at -78 ºC to room temperature. The desired product could be detected by LCMS. The reaction was quenched carefully with cool water then extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give a mixture of 9-(1H-1,2,3-benzotriazol-4-yl)-3-benzyl-3-azabicyclo[3.3.1]nonan-9-ol.The resulting mixture was purified by TLC(PE/EtOAc 2:1) to afford 9-(1H-1,2,3-benzotriazol-4-yl)-3-benzyl- 3-azabicyclo[3.3.1]nonan-9-ol (1.2 g , 67%) as a yellow solid. LC-MS: m/z (ES+), [M+H]+ = 349.

To a stirred solution/mixture of 9-(1H-1,2,3-benzotriazol-4-yl)-3-benzyl-3-azabicyclo- [3.3.1]nonan-9-ol (1.0 g, 2.87 mmol, 1 equiv) in CH₂Cl₂ at room temperature under air atmosphere. To the above mixture was added AlCl₃ (1.91 g, 14.4 mmol, 5.0 equiv) in portions over 5 min at 0 ºC. The resulting mixture was stirred for additional 30 min at 0 ºC. To the above mixture was added aluminum trichloride (14.3 mL, 199.1 mmol, 5.0 equiv) dropwise over 5 min at 0 ºC. The resulting mixture was stirred for additional 2 h at 0 ºC. Water was added to resulting mixture. The water phase was basified to pH 10 with NH3.H₂O. The water phase was extracted with EtOAc (2x 100 mL). The organic phases were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 1:1) to afford 4-[3-benzyl-9-methyl-3-azabicyclo[3.3.1]nonan-9-yl]- 1H-1,2,3-benzotriazole (530 mg, 53%) as a yellow solid. LC-MS m/z (ES+), [M+H]+ = 347.

To a stirred solution/mixture of 4-[3-benzyl-9-methyl-3-azabicyclo[3.3.1]nonan-9-yl]- 1H-1,2,3-benzotriazole (400 mg, 1.15 mmol, 1 equiv) in ethanol was added Pd(OH)2/C (100.5 mg, 0.72 mmol, 0.6 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 3 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. Column: XBridge Shield RP18 OBD Column, 5um,19*150mm; Mobile Phase A: water (0.05%TFA ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 4% B to 20% B in 13 min; 220/254 nm; Rt: 12.13 min Got 4-[9-methyl-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole (240 mg, 80%) as a off-white solid. LC-MS m/z (ES+), [M+H]+ = 257.

To a stirred solution/mixture of 4-[9-methyl-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole (120 mg, 0.42 mmol, 1.0 equiv) in EtOAc was added hydrogen chloride in diethyl ether (0.85 mL, 0.85 mmol, 2.0 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 20 min at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The solid was freeze dried from water to give 4-[9-methyl-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,2,3- benzotriazole hydrochloride (100.6 mg, 0.35 mmol, 95%). LC-MS m/z (ES+), [M+H]+ = 257. 1H NMR (400 MHz, MeOD) d 1.50 (2 H, m), 1.58 (3 H, s), 1.79 (3 H, s), 2.42 (1 H, s), 2.73 (1 H, s), 3.53 (2 H, d, J 13.5), 3.88 (2 H, m), 4.09 (1 H, s), 7.39 (1 H, d, J 7.2), 7.53 (1 H, t, J 7.7, 7.7), 7.69 (1 H, d, J 8.1).

To a stirred mixture 3-benzyl-9-(6-fluoro-1H-1,2,3-benzotriazol-4-yl)-3-azabicyclo- [3.3.1]nonan-9-ol (1.0 g, 2.73 mmol, 1 equiv) in EtOH (15 mL) at room temperature under nitrogen atmosphere. To the above mixture was added Pd(OH)2/C (383.2 mg, 2.73 mmol, 1 equiv) and HCOONH4 (860.4 mg, 13.6 mmol, 5.0 equiv), the resulting mixture was stirred for additional 0.5 h at 65 ºC. The resulting mixture was filtered, the filter cake was washed with EtOH (3x10 mL). This resulted in9-(6-fluoro-1H-1,2,3-benzotriazol-4-yl)-3-azabicyclo[3.3.1]- nonan-9-ol (500mg, 66.3%) as a light yellow solid. LCMS (m/z (ES+), [M+H]⁺ = 277.

To a stirred mixture of 9-(6-fluoro-1H-1,2,3-benzotriazol-4-yl)-3-azabicyclo[3.3.1]- nonan-9-ol (50 mg, 0.181 mmol, 1 equiv) and n,n-diethyl-ethanamine (54.8 mg, 0.54 mmol, 3 equiv) in DCM (5 mL) were added benzyl chloroformate (92.3 mg, 0.54 mmol, 3 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with water at 0 ºC. The resulting mixture was extracted with CH₂Cl₂ (3 x 50 mL). The combined organic layers were washed with brine (3 x 3 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH(10:1) to afford benzyl 9-(6- fluoro-1H-1,2,3-benzotriazol-4-yl)-9-hydroxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (370 mg, 49.8%) as a light yellow solid. LCMS (m/z (ES+), [M+H]⁺ = 411.

To a stirred mixture of benzyl 9-(6-fluoro-1H-1,2,3-benzotriazol-4-yl)-9-hydroxy-3- azabicyclo[3.3.1]nonane-3-carboxylate (370 mg, 0.90 mmol, 1 equiv) in CH₂Cl₂ (5 mL) was added SOCl₂ (7.5 mL, 63.0 mmol, 141 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h and concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (m/z (ES+), [M+H]⁺ = 429.

To a stirred solution of benzyl 9-chloro-9-(6-fluoro-1H-1,2,3-benzotriazol-4-yl)-3- azabicyclo[3.3.1]nonane-3-carboxylate (390 mg, 0.91 mmol, 1 equiv) and Et3N (276.0 mg, 2.73 mmol, 3 equiv) in DCM (10 mL) was added tripropylaluminum (426.2 mg, 2.73 mmol, 3 equiv) at 0 ºC under nitrogen atmosphere and allowed to stir for 3 h. The reaction was quenched with sat. NH₄Cl (aq.) at 0 ºC. The resulting mixture was extracted with CH₂Cl₂ (3 x 50 mL). The combined organic layers were washed with brine (3 x 5 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford benzyl 9-(6-fluoro-1H-1,2,3-benzotriazol-4-yl)-9-propyl-3-azabicyclo[3.3.1]nonane-3- carboxylate(120mg,30.23%) as a light yellow solid. LCMS (m/z (ES+), [M+H]⁺ = 437.

4-[3-Benzyl-9-propyl-3-azabicyclo[3.3.1]nonan-9-yl]-6-fluoro-1H-1,2,3-benzotriazole (120 mg, 0.31 mmol, 1 equiv) was dissolved in EtOH (12.0 mL, 260.5 mmol, 675 equiv) at room temperature under nitrogen atmosphere. Pd(OH)₂/C (42.9 mg, 0.31 mmol, 1 equiv) and HCOONH₄ (96.4 mg, 1.53 mmol, 5 equiv) were added, and the resulting mixture was stirred for additional 0.5 h at 65 ºC. The resulting mixture was filtered, the filter cake was washed with EtOH (3x10 mL). Column: Xselect CSH OBD Column 30*150mm 5um n; Mobile Phase A: water (0.05%HCl ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 28% B in 7 min; 220 nm; Rt: 5.87,7.43 min. This resulted in 6-fluoro-4-[9-propyl-3-azabicyclo[3.3.1]- nonan-9-yl]-1H-1,2,3-benzotriazole (60mg, 64.9%) as a light yellow solid. LCMS (m/z (ES+), [M+H]⁺ = 303.

Into a 50 mL round-bottom flask were added6-fluoro-4-[9-propyl-3-azabicyclo[3.3.1]- nonan-9-yl]-1H-1,2,3-benzotriazole (50 mg) and HCl/diethyl ether (0.5 mL). The resulting mixture was stirred for 10 min under air atmosphere. The resulting mixture was concentrated under reduced pressure. The solid was freeze dried from water to give 4-[9-ethoxy-3- azabicyclo[3.3.1]nonan-9-yl]-6-fluoro-1H-1,2,3-benzotriazole hydrochloride (170mg, 63.3%) as a off-white solid. LCMS (m/z (ES+), [M+H]⁺ = 303.¹H NMR (400 MHz, Methanol-d₄) d 7.40 (dd, J = 7.6, 2.0 Hz, 1H), 7.18 (dd, J = 11.4, 2.2 Hz, 1H), 4.11 (s, 1H), 3.92 (dd, J = 13.8, 4.7 Hz, 1H), 3.74 (d, J = 13.5 Hz, 1H), 3.50 (dd, J = 13.7, 7.9 Hz, 2H), 2.75 (s, 1H), 2.31 (m, 1H), 2.12 – 1.95 (m, 2H), 1.93 – 1.69 (m, 3H), 1.53 (m, 2H), 1.07 (m, 1H), 0.83 – 0.71 (m, 4H). Compounds of Formula II and III can be prepared by the method provided in Scheme 5 below.

To a stirred solution of 4-bromo-1H-1,3-benzodiazole (1.0 g, 5.08 mmol, 1 equiv) in THF at room temperature under air atmosphere. To the above mixture was added NaH (800 mg, 33.34 mmol, 6.57 equiv) in portions over 3 min at 0 ºC. The resulting mixture was stirred for additional 30 min at 0 ºC. To the above mixture was added 3-benzyl-3-azabicyclo[3.3.1]- nonan-9-one(1.7 g, 7.41 mmol, 1.5 equiv) dropwise over 2 min at -78 ºC. The reaction was quenched carefully with cool water then extracted with ethyl acetate (x3). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give a mixture of 9-(1H-1,3-benzodiazol-4-yl)-3-benzyl-3-azabicyclo- [3.3.1]nonan-9-ol (1.13 g ,60%) as a yellow solid. LC-MS: m/z (ES+), [M+H]+ = 348; 1H NMR (400 MHz, MeOD) d 1.09 (1 H, d, J 13.7), 1.31 (1 H, s), 1.60 (1 H, dt, J 13.4, 7.0, 7.0), 1.72 (2 H, dd, J 13.1, 7.0), 1.79 (1 H, d, J 7.7),2.48 (2 H, d, J 11.2), 2.57 (3 H, s), 3.25 (2 H, s), 3.51 (1 H, m), 7.26 (5 H, m), 7.32 (1 H, q, J 6.2, 6.2, 5.6), 7.42 (2 H, m), 7.58 (1 H, d, J 8.0), 8.09 (1 H, d, J 3.6).

To a stirred solution/mixture of 9-(1H-1,3-benzodiazol-4-yl)-3-benzyl-3-azabicyclo- [3.3.1]nonan-9-ol(500 mg) in trimethoxymethane (20 mL) at room temperature under air atmosphere. To the above mixture was added H₂SO₄ (3 mL) dropwise over 2 min at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was added water and extracted with Et₂O (2 x 50 mL). The water phase was basified to pH 10 with NH4OH. The water pahse was then extracted with EtOAc (2x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 2:1) to afford 4-[3-benzyl-9-methoxy-3- azabicyclo-[3.3.1]nonan-9-yl]-1H-1,3-benzodiazole (420 mg ,80%) as a yellow solid. LC-MS: m/z (ES+), [M+H]+ = 362; 1H NMR:(400 MHz, MeOD) d 1.34 (2 H, s), 1.64 (2 H, d, J 13.1), 1.94 (2 H, s), 2.36 (1 H, s), 2.73 (1 H, s), 2.80 (3 H, s), 2.84 (1 H, s), 2.89 (2 H, s), 3.20 (1 H, s), 3.52 (2 H, s), 5.51 (1 H, s), 7.26 (1 H, m), 7.30 (2 H, m), 7.37 (2 H, t, J 8.8, 8.8), 7.45 (1 H, d, J 7.7), 7.63 (1 H, d, J 8.0), 8.08 (1 H, s).

To a stirred solution/mixture of 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]- 1H-1,3-benzodiazole (420.0 mg, 1 equiv) in EtOH was added Pd(OH)₂/C (100 mg) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 3 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2x50 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The product, 4-[9-methoxy-3- azabicyclo[3.3.1]nonan-9-yl]-1H-1,3-benzodiazole (140 mg, 44%), was obtained as an off- white solid.

To a stirred solution/mixture of 4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,3- benzodiazole (150.0 mg, 0.55 mmol, 1 equiv) in EtOAc was added HCl in diethyl ether (1.1 mL, 1.10 mmol, 1.99 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 20 min at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The solid freeze dried from water to give 4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-1,3-benzodiazole hydrochloride (117.4 mg,0.431 mmol, 78%). LC-MS: m/z (ES+), [M+H]+ = 271; ¹H NMR : d H (400 MHz, D₂O) 1.12 (1 H, m), 1.61 (3 H, m), 2.04 (1 H, m), 2.44 (1 H, m), 2.67 (1 H, d), 2.75 (3 H, s), 3.01 (1 H, d), 3.37 (2 H, dd), 3.65 (1 H, dt), 3.98 (1 H, m), 7.58 (1 H, m), 7.78 (1 H, m),7.81 (1 H, m), 9.09 (1 H, s).

To a stirred solution/mixture of 3-benzyl-9-(2-methyl-1H-1,3-benzodiazol-4-yl)-3- azabicyclo[3.3.1]nonan-9-ol (500 mg, 1.38 mmol, 1 equiv), AlCl3 (922.2 mg, 6.92 mmol, 5 equiv) in DCE (25 mL) was added allyltrimethylsilane (790.2 mg, 6.92 mmol, 5 equiv) dropwise/in portions at 0 ºC under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (hexane/EtOAc 1:1) to afford 4-[3-benzyl-9-(prop-2-en-1-yl)-3-azabicyclo[3.3.1]nonan-9-yl]-2-methyl-1H-1,3- benzodiazole (460 mg, 86.3%) as a yellow solid. LC-MS: m/z (ES+), [M+H]+ = 360; .1H NMR: d H (400 MHz, CDCl3) 0.86 (1 H, dt), 1.12 (1 H, d), 1.31 (2 H, d), 1.41 (3 H, s), 1.65 (2 H, s), 2.36 (1 H, d), 2.62 (3 H, s), 2.74 (1 H, m), 2.96 (4 H, m), 3.54 (2 H, d), 7.20 (2 H, d), 7.29 (2 H, s), 7.38 (4 H, m).

To a stirred solution/mixture of 4-[3-benzyl-9-(prop-2-en-1-yl)-3-azabicyclo[3.3.1]- nonan-9-yl]-2-methyl-1H-1,3 benzodiazole (360 mg, 0.93 mmol, 1 equiv) and HCOONH₄ (588.8 mg, 9.34 mmol, 10 equiv) in EtOH (15 mL) were added Pd(OH)₂/C (131.1 mg, 0.93 mmol, 1 equiv) at 72 ºC under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOH (2x100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The crude product (300 mg) was purified by Prep-HPLC to afford 2-methyl-4-[9-propyl-3- azabicyclo[3.3.1]nonan-9-yl]-1H-1,3-benzodiazole (100mg,36.01%) as an off-white solid. LC- MS: m/z (ES+), [M+H]+ = 298.

To a stirred solution/mixture of 2-methyl-4-[9-propyl-3-azabicyclo[3.3.1]nonan-9-yl]- 1H-1,3 benzodiazole (100 mg, 0.34 mmol, 1 equiv) in ethyl acetate (20 mL) were added hydrogen chloride (0.68 mL, 0.68 mmol, 2.0 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was dissolved in water (30 mL). The resulting mixture was filtered. The aqueous layer was dried by lyophilization, to afford 2-methyl-4-[9-propyl-3-azabicyclo[3.3.1]nonan-9-yl]-1H- 1,3benzodiazole hydrochloride (80mg, 67.5%), as a yellow solid. LC-MS: m/z (ES+), [M+H]+ = 298; 1H NMR: d H (400 MHz, MeOD) 1.60 (5 H, s), 1.82 (3 H, d), 2.41 (1 H, d),2.71 (1 H, d), 2.94 (3 H, s), 3.11 (1 H, s), 3.54 (2 H, d), 3.88 (2 H, d), 7.61 (2 H, d), 7.68 (1 H, d).

To a stirred solution of 4-bromo-6-fluoro-1H-indazole (13.0 g, 60.5 mmol, 1 equiv) in THF (150 mL) was added sodium hydride (1.74 g, 72.6 mmol, 1.2 equiv) in portions at 0 ºC under nitrogen atmosphere. To the above mixture was added 3-benzyl-3-azabicyclo[3.3.1]- nonan-9-one (15.3 g, 66.5 mmol, 1.1 equiv) in portions over 0.5 h at 0 ºC. The resulting mixture was stirred for additional 5 min at -78 ºC. To the above mixture was added tert- butyllithium (102.31 mL, 133.0 mmol, 2.2 equiv) dropwise over 5 min at -78 ºC. The resulting mixture was stirred for additional 2h at -78 ºC to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous MgSO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (4:1) to afford 3-benzyl-9-(6-fluoro-1H-indazol-4-yl)-3-azabicyclo[3.3.1]nonan-9-ol (9.4 g, 42.5%) as a brown solid. m/z (ES+), [M+H]+ = 366.

To a stirred solution of 3-benzyl-9-(6-fluoro-1H-indazol-4-yl)-3- azabicyclo[3.3.1]nonan-9-ol (350 mg, 0.958 mmol, 1 equiv) in trimethoxymethane (5 mL) was added sulfuric acid (939.2 mg, 9.58 mmol, 10 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH₃Cl:MeOH (10 x 50 mL). The combined organic layers were washed with brine (1x 500 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6- fluoro-1H-indazole (280mg, 77.0%) as a brown solid. m/z (ES+), [M+H]+ = 380.

To a stirred mixture of 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-fluoro- 1H-indazole (400.0 mg, 1.05 mmol, 1 equiv) and Pd(OH)2/C (200 mg, 1.42 mmol, 1.35 equiv) in MeOH (10 mL) was added di-tert-butyl dicarbonate (276.1 mg, 1.27 mmol, 1.2 equiv) in portions at room temperature under nitrogen atmosphere. The mixture was stirred for additional 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2x10 mL). The filtrate was concentrated under reduced pressure to afford crude product tert-butyl 9-(6-fluoro-1H-indazol-4-yl)-9- methoxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (200 mg, 48.7%) as a white solid. m/z (ES+), [M+H]+ = 390.

A solution of tert-butyl 9-(6-fluoro-1H-indazol-4-yl)-9-methoxy-3-azabicyclo[3.3.1]- nonane-3-carboxylate (200 mg, 0.514 mmol, 1 equiv) and Selectfluor (272.8 mg, 0.770 mmol, 1.5 equiv) in DMSO (5 mL) was stirred for 12h at 65 ºC under nitrogen atmosphere. Desired product was detected by LCMS. The residue was purified by reverse flash chromatography to afford crude product 3,6-difluoro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-indazole (180 mg, 114.1%) as a white solid. m/z (ES+), [M+H]+ = 308.

A mixture of 3,6-difluoro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-indazole (60 mg, 0.195 mmol, 1 equiv), di-tert-butyl dicarbonate (93.73 mg, 0.429 mmol, 2.2 equiv) and TEA (59.26 mg, 0.586 mmol, 3 equiv) in DCM (2 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2x5 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford tert-butyl 9-(3,6-difluoro-1H-indazol-4-yl)-9-methoxy-3-azabicyclo[3.3.1]nonane-3- carboxylate (30 mg, 37.7%) as a white solid. m/z (ES+), [M+H]+ = 508.

To a stirred solution of tert-butyl 4-[3-[(tert-butoxy)carbonyl]-9-methoxy-3- azabicyclo[3.3.1]nonan-9-yl]-3,6-difluoro-1H-indazole-1-carboxylate (30 mg, 0.059 mmol, 1 equiv) was added HCl in dioxane (1 mL, 4.00 mmol, 67.7 equiv) in portions at room temperature under nitrogen atmosphere. The mixture was stirred for additional 4 h at 60 ºC under nitrogen atmosphere. The crude product was purified by Prep-HPLC to afford Compound 19, 3,6-difluoro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-indazole hydrochloride (7.4 mg, 36.4%), as a white solid. m/z (ES+), [M+H]+ = 308 ; 1H NMR (400 MHz, Methanol-d4) d 7.31-7.19 (m, 2H), 3.99 (m, 1H), 3.68 (m, 1H), 3.46-3.37 (m, 2H), 3.05(s, 1H), 2.95 (s, 1H), 2.90 (s, 3H), 2.45 (m, 1H), 2.13 (m, 1H), 1.82-1.60 (m, 3H), 1.37- 1.25 (m, 1H).

To a stirred solution 3-benzyl-9-[7-chloro-6-fluoro-3-(trifluoromethyl)-1H-indazol-4-yl]- 3-azabicyclo[3.3.1]nonan-9-ol (3.0 g, 6.41 mmol, 1 equiv) in (diethoxymethoxy)ethane (20 mL, 0.135 mmol) was added sulfuric acid (4 mL, 0.041 mmol,) dropwise at room temperature. The reaction was stirred 0.5 h. The reaction was quenched with water at rt. The resulting mixture was washed with 3x100 mL of Et₂O. The mixture was basified to pH 10 with NH₄OH. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:20) to afford 4-[3-benzyl-9-ethoxy-3- azabicyclo[3.3.1]nonan-9-yl]-7-chloro-6-fluoro-3-(trifluoromethyl)-1H-indazole (1 g, 31.5%) as a white solid. m/z (ES+), [M+H]+ = 496.

4-[3-benzyl-9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-7-chloro-6-fluoro-3- (trifluoromethyl)-1H-indazole (500.0 mg) was dissolved in THF (3 mL) and MeOH (25.0 mL). Then Pd(OH)₂/C (200.0 mg) was added at room temperature under nitrogen atmosphere. The reaction was stirred 10h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford a crude oil (220 mg). m/z (ES+), [M+H]+ = 372.

The crude product 6-fluoro-4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-3- (trifluoromethyl)-1H-indazole(220.00 mg) was purified by Prep-HPLC to afford Compound 20, 4-[9-ethoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-fluoro-3-(trifluoromethyl)-1H-indazole hydrochloride (63.3 mg), as a white solid. m/z (ES+), [M+H]+ = 372; ¹H NMR: (400 MHz, Deuterium Oxide) d 7.30 (dd, J = 7.8, 2.2 Hz, 1H), 7.23 (dd, J = 11.2, 2.2 Hz, 1H), 3.96 – 3.87 (m, 1H), 3.68 – 3.60 (m, 1H), 3.34 – 3.14 (m, 3H), 2.97 (s, 1H), 2.74 (s, 1H), 2.57 (m, 1H), 2.36 (m, 1H), 1.94 (m, 1H), 1.47 (m, 3H), 0.89 (t, J = 7.0 Hz, 3H), 0.81 (m, 1H).

To a stirred solution of 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H- indazole (3.70 g, 10.24 mmol, 1.0 equiv) in THF (100.0 mL) were added Boc2O (3.35 g, 15.35 mmol, 1.5 equiv) and Pd(OH)2/C (1.8 g, 0.013 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 10h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford tert-butyl 9-(1H-indazol-4-yl)-9-methoxy-3- azabicyclo[3.3.1]nonane-3-carboxylate (2.53 g, 66.5%) as a white solid.¹H NMR (400 MHz, DMSO-d6) d 13.14 (s, 1H), 8.22 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 8.3, 7.1 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.91 (t, J = 12.6 Hz, 1H), 3.82 (dd, J = 21.2, 8.9 Hz, 1H), 2.90 (s, 1H), 2.78 (d, J = 15.7 Hz, 1H), 2.69 (s, 2H), 2.13 (s, 1H), 1.99 (s, 1H), 1.83 (d, J = 14.2 Hz, 1H), 1.68 (s, 1H), 1.64 – 1.55 (m, 1H), 1.44 (s, 7H), 1.30 – 1.22 (m, 1H), 1.18 (t, J = 7.1 Hz, 1H), 1.11 (s, 1H).

To a stirred solution of tert-butyl 9-(3-amino-2-methylphenyl)-9-methoxy-3- azabicyclo[3.3.1]nonane-3-carboxylate (1.11g, 3.09 mmol, 1 equiv) in DMF (15 mL) was added NCS (432.9 mg, 3.24 mmol, 1.1 equiv) portions at room temperature under nitrogen atmosphere then stirred for 4h at rt. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (1x10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (2:1) to afford tert-butyl 9-(3- chloro-1H-indazol-4-yl)-9-methoxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (1.0 g, 79.8%) as a white solid. m/z (ES+), [M+H]+ = 406.20.

Into a 250 mL round-bottom flask were added tert-butyl 9-(3-chloro-1H-indazol-4-yl)- 9-methoxy-3-azabicyclo[3.3.1]nonane-3-carboxylate (1.0 g, 2.46 mmol, 1 equiv) and HCl (g) in MeOH (12.3 mL) at room temperature. The reaction was stirred 10 h. The mixture was concentrated under reduced pressure to afford a crude product (800 mg). The crude product was purified by Prep-HPLC and freeze-drying to afford Compound 8, 3-chloro-4-[9-methoxy- 3-azabicyclo[3.3.1]nonan-9-yl]-1H-indazole (280.1 mg), as a white solid. m/z (ES+), [M+H]+ = 306; ¹H NMR (400 MHz, Methanol-d4) d 7.62 (d, J = 8.2 Hz, 1H), 7.48 (m, 1H), 7.42 (d, J = 7.2 Hz, 1H), 4.16 – 4.07 (m, 1H), 3.76 (m, 1H), 3.40 (m, 2H), 3.31 (s, 1H), 3.07 (s, 1H), 2.90 (s, 3H), 2.63 – 2.51 (m, 1H), 2.13 (m, 1H), 1.91 – 1.68 (m, 2H), 1.62 (m, 1H), 1.18 (m, 1H).

To a stirred solution of 4-bromo-1H-indazole (10.0 g, 50.8 mol, 1 equiv) in THF (50 mL) was added sodium hydride (2.4 g, 59.9 mol, 1.2 equiv, 60%) in portions at 0 ºC under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 ºC under nitrogen atmosphere. To the above mixture was added Sec-BuLi (8.4 mL, 131.3 mol, 2.0 equiv) dropwise over 10 min at -78 ºC. The resulting mixture was stirred for additional 1h at -78 ºC. To the above mixture was added 3-benzyl-3-azabicyclo[3.3.1]nonan-9-one (23.3 g, 101.5 mol, 2 equiv) dropwise over 10 min at -78 ºC. The resulting mixture was stirred for additional 4 h at 60 ºC and then for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched with water at 0 ºC. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (1x100mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with DCM (10 mL). This resulted in a 1:1 mixture of 3-benzyl-9-(1H-indazol-4-yl)-3- azabicyclo[3.3.1]nonan-9-ol (8.0 g, 43.2%) as a light yellow solid as a light yellow solid . m/z (ES+), [M+H]+ = 348; d H (400 MHz, DMSO-d6) 1.12 -1.30 (1 H, m), 1.44 - 1.79 (4 H, m), 2.33 (1 H, d), 2.46 (1 H, d), 2.56 - 2.85 (5 H, m), 3.09 (1 H, d), 3.47 (1 H, s), 4.88 (1 H, d), 7.08 -7.50 (9 H, m), 8.18 (1 H, d), 13.00 (1 H, d).

To a stirred solution of a 1:1 mixture of 3-benzyl-9-(1H-indazol-4-yl)-3-azabicyclo- [3.3.1]nonan-9-ol (400.0 mg, 1.15 mol, 1 equiv) in HC(OEt)3 (3 mL) was added sulfuric acid (112.9 mg, 1.15 mol, 2 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was diluted with water (10mL). The resulting mixture was washed with 3 x 50 mL of ethyl ether. The mixture/residue was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (2 x 100mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-[3-benzyl-9-ethoxy-3- azabicyclo-[3.3.1]nonan-9-yl]-1H-indazole (380mg,175.8%) as a white solid. m/z (ES+), [M+H]+ = 376; d H (400 MHz, DMSO-d6) 0.82 (3 H, t), 1.22 (3 H, dt), 1.56 (1 H, d), 1.80 (1 H, d), 2.17 (1 H, s), 2.60 - 2.94 (6 H, m), 3.13 (2 H, td), 3.47 (2 H, d), 7.05 -7.61 (9 H, m), 8.18 (1 H, s), 13.06 (1 H, s).

To a stirred solution of 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H- indazole (400 mg, 1.11 mol, 1 equiv) was dissolved in THF (3 mL) and MeOH (25.0 mL). Then Pd(OH)2/C (200.0 mg) was added at room temperature under nitrogen atmosphere. The reaction was stirred 10h under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford a crude oil (220 mg).

To a stirred solution of 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H- indazole(400 mg, 1.11 mol, 1 equiv) in 20 mL MeOH was added hydrogen chloride (0.1 mL, 2.31 mmol, 1.2 equiv) at room temperature under air atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The crude product (410 mg) was purified by Prep-HPLC to afford Compound 6, 4-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-1H-indazole (250 mg, 83.3%), as a white solid. m/z (ES+), [M+H]+ = 286; d H (400 MHz, DMSO-d6) 0.83 (3 H, t), 1.05 - 1.34 (2 H, m), 1.60 (1 H, d), 1.86 (2 H, dd), 2.15 -2.28 (1 H, m), 2.42 (1 H, dq), 2.65 (1 H, s), 2.75 - 2.90 (2 H, m), 3.42 (1 H, d), 3.73 (1 H, dd), 4.10 (2 H, s), 7.21 (1 H, d), 7.32 (1 H, t), 7.46 (1 H, d), 8.18 (1 H, s), 13.06 (1 H, s).

A solution of 4-bromo-1H-indazole (500 mg, 2.54 mmol, 1 equiv) in 50 mL THF was treated with NaH (121.8 mg, 5.08 mmol, 2.0 equiv) for 1 h at 0 ºC under nitrogen atmosphere. To the above mixture was added t-BuLi (3.9 mL, 5.07 mmol, 2.0 equiv) dropwise over 15 min at -78 ºC. The resulting mixture was stirred for additional 1 h at -78 ºC. Then to the above mixture was added benzyl 9-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate (1.04 g, 3.81 mmol, 1.5 equiv) at -10 ºC. The resulting mixture was stirred for additional 1 h at -10 ºC. The reaction was quenched by the addition of sat. NH₄Cl (aq.) (2 mL) at 0 ºC. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography. This resulted in benzyl 9-hydroxy-9-(1H-indazol-4-yl)-3- azabicyclo[3.3.1]nonane-3-carboxylate (661 mg, 59.9%) as a yellow solid. LCMS: (m/z (ES+), [M+H]⁺ = 392.

Into a 50 mL round-bottom flask were added benzyl 9-hydroxy-9-(1H-indazol-4-yl)-3- azabicyclo[3.3.1]nonane-3-carboxylate (500 mg, 1.28 mmol, 1 equiv) and sulfuroyl dichloride (15 mL) at 0 ºC. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was monitored by TLC. When the reaction was completed the resulting mixture was concentrated under reduced pressure and use next step without purification. To a stirred solution of benzyl 9-chloro-9-(1H-indazol-4-yl)-3-azabicyclo[3.3.1]nonane-3-carboxylate (300 mg, 0.73 mmol, 1 equiv) in 20 mL CH₂Cl₂ were added triethylaluminum (2.9 mL, 2.90 mmol, 3.96 equiv) dropwise at -75 ºC under nitrogen atmosphere. The resulting mixture was stirred for additional 1 h at -50 ºC. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (5 mL) at 0 ºC. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-TLC to afford benzyl 9-ethyl-9-(1H-indazol-4-yl)-3-azabicyclo[3.3.1]nonane- 3-carboxylate(138 mg, 26.6%) as a white solid. LCMS: m/z (ES+), [M+H]⁺ = 404.

A mixture of benzyl 9-ethyl-9-(1H-indazol-4-yl)-3-azabicyclo[3.3.1]nonane-3- carboxylate (138 mg, 0.342 mmol, 1 equiv) and HCOONH₄ (107.6 mg, 1.71 mmol, 5.0 equiv) and Pd(OH)₂/C (120.1 mg, 0.171 mmol, 0.50 equiv, 20%) in 20 mL MeOH was stirred for 30 min at 65 ºC under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The crude product (92 mg) was purified by Prep-HPLC to afford 4-[9-ethyl-3- azabicyclo[3.3.1]nonan-9-yl]-1H-indazole (85 mg, 87.7%) as a white solid: m/z (ES+), [M+H]⁺ = 270.

To a stirred solution of 4-[9-ethyl-3-azabicyclo[3.3.1]nonan-9-yl]-1H-indazole(85 mg, 0.32 mmol, 1 equiv) in 5 mL MeOH was added HCl/Et2O (0.5 mL, 0.50 mmol, 1.58 equiv) dropwise at 0 ºC.The resulting mixture was stirred for additional 15 min at room temperature. The resulting mixture was concentrated under reduced pressure. Then added 5 mL water and filtered to afford Compound 9, 4-[9-ethyl-3-azabicyclo[3.3.1]nonan-9-yl]-1H-indazole hydrochloride (83 mg, 85.2%), as a white solid. LCMS: m/z (ES+), [M+H]⁺ = 270; ¹H NMR (400 MHz, Chloroform-d) d 8.65 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 4.06 (dd, J = 14.0, 4.7 Hz, 1H), 3.87 (d, J = 13.5 Hz, 1H), 3.65 (dd, J = 13.7, 6.8 Hz, 2H), 3.17 (s, 1H), 2.83 (s, 1H), 2.42 – 2.15 (m, 2H), 1.97 - 1.67 (m, 4H), 1.49 (d, J = 12.3 Hz, 2H), 0.50 (t, J = 7.3 Hz, 3H). In Vitro Characterization Functional Activity (GTPgS Binding) Assay The [³⁵S]GTPgS assay measures the functional properties of a compound by quantifying the level of G-protein activation following agonist binding in studies using stably transfected cells, and is considered to be a measure of the efficacy of a compound. Membranes from CHO (Chinese Hamster Ovary) cells that stably expressed one type of the cloned human opioid receptor human were used in the experiments. The assay buffer consisted of 50 mM Tris-HCl, pH 7.4, 3 mM MgCl₂, 0.2 mM EGTA, 5 mM GDP, and 100 mM NaCl. CHO cell membranes stably expressing the human µ opioid receptor were pre- incubated with scintillation proximity assay beads from PerkinElmer® (WGA PVT SPA) for 30 minutes, at 8 µg membrane and 350 µg beads in a volume of 0.1 mL per reaction. In a final volume of 0.2 mL, 11 different concentrations of each test compound were incubated with the membrane-SPA bead mixture and a final concentration of 0.020 nM [35S]GTPgS for 1.5 hours with gentle shaking. Reactions were then incubated for 5 hours . Data are the mean EC₅₀ values ± S.E.M and are shown in Tables 1, 2, and 3. In Vivo Characterization CFA Assay Evaluation of the Efficacy of Compound 3 in the CFA-Induced Inflammatory Pain Model in Rats Summary This study examined the potential activity of treatment with Compound 3 at three doses (0.1 mg/kg, 1 mg/kg or 10 mg/kg) in the CFA-induced inflammatory pain model in Sprague Dawley® rats. An incapacitance (weight bearing) test was used. Morphine hydrochloride was used as the positive control in this study. On study day 0, 0.1 ml of complete Freund’s adjuvant (CFA; 1 mg/ml) was injected into the plantar area of the right hind paw. Immediately after CFA injection animals were treated with Compound 3, vehicle, or morphine hydrochloride. Incapacitance (Weight Bearing) Test Weight bearing test was performed on study day 0 at 30, 60 or 120 minutes after dosing. Vehicle treated animals experienced a gradual elevation in the difference between the two paws.120 minutes post dosing: 19.46±2.20% compared to -0.11±0.42 % at Baseline. Treatment with morphine hydrochloride, the positive control, resulted in a statistically significantly decrease in the difference between the two paws, at 60 or 120 minutes post dosing, compared to the vehicle-treated animals: 0.44±1.87% vs.14.82±1.70% for the vehicle, at 60 minutes post dosing; p<0.001). Treatment with Compound 3 at a dose level of 1 or 10 mg/kg, resulted in a statistically significantly decrease in the difference between the two paws, at 60 and 120 minutes post dosing, compared to the vehicle-treated animals: 3.17±2.13% or 2.62±2.04 %, respectively, vs.19.46±2.20% for the vehicle, at 120 minutes post dosing; p<0.0001. Treatment with Compound 3 at a dose level of 0.1 mg/kg, resulted in a statistically significantly decrease in the difference between the two paws, at 120 minutes post dosing, compared to the vehicle-treated animals: 9.60±2.22 % vs.19.46±2.20% for the vehicle, at 120 minutes post dosing; p<0.01. Conclusion In view of the findings obtained under the conditions of this study, treatment with Compound 3 at all doses: 0.1, 1 or 10 mg/kg, was effective in significantly reducing the difference in weight bearing between the two paws. Treatment with the low dose (0.1 mg/kg) was effective at 120 minutes post dosing, whereas treatment with the middle and high doses (1 mg/kg and 10 mg/kg) was effective at 60 and 120 minutes post dosing. In Vivo Self-Administration (IVSA) Assay Evaluation of the Reinforcing Effect of Compound 3 Compared with Oxycodone Using a Self- Administration Procedure in Heroin-Maintained Rats Mildly food restricted male, Sprague-Dawley rats were trained to lever-press for food rewards using a fixed ratio 3 (FR₃) schedule of reinforcement (3 lever-presses delivered 1 food reward). When the responding was stable, each rat was surgically implanted with an indwelling jugular catheter for the intravenous (i.v.) self-administration experiments. Following recovery, rats were trained to self-administer a low dose of heroin (0.015 mg/kg/injection i.v.) on a FR5 reinforcement schedule (5 lever-presses delivered 1 heroin infusion). Saline (0.5 ml/kg/injection i.v.) was the non-reinforcing substance used as the negative control. The reinforcing effects of Compound 3 (0.003, 0.03, 0.3 and 0.6 mg/kg/injection i.v.) and the reference comparator, oxycodone (0.1 mg/kg/injection i.v.), were compared with heroin on a FR5 schedule of reinforcement. In addition, the relative reinforcing effects of these doses of Compound 3 were compared with oxycodone and heroin by determining the break-points for reinforcement on a progressive ratio (PR) schedule of operant responding. Doses of heroin, Compound 3 and oxycodone are expressed as base equivalents. Heroin (0.015 mg/kg/injection i.v.) maintained robust intravenous self-administration on a FR5 schedule of reinforcement (19.3 ± 0.4 injections[inj]/session; n = 20), demonstrating the sensitivity of this procedure to the positive reinforcing effects of a drug with well- established abuse liability in humans. When saline was substituted for heroin, self-administration decreased markedly and significantly (4.3 ± 0.3 inj/session; n = 20), confirming the selective, positive reinforcing effect of heroin in the rats. Only the highest dose of Compound 3 (0.6 mg/kg/injection i.v.) maintained self- administration at levels significantly (p<0.05) greater than saline on a FR5 schedule of reinforcement thereby meeting the criteria for a positive reinforcer. This Compound 3 dose supported a statistically-adjusted group mean of 9.7 ± 2.4 injections/session (n=8) compared with 4.3 ± 0.3 injections/session for saline (n=20). The statistically-adjusted group mean number of injections/session for Compound 3 doses of 0.003, 0.03 and 0.3 mg/kg/injection were 4.6 ± 1.6 (n=4), 8.8 ± 2.6 (n=8) and 7.0 ± 2.1 (n=8), respectively, and they were not significantly different from the statistically-adjusted group mean number of saline injections/session (4.3 ± 0.3 injections/session; n=20). Moreover, the statistically-adjusted group mean injections/session of all doses of Compound 3 were all significantly lower (p<0.001) than the statistically-adjusted group mean injections/session of heroin (19.3 ± 0.4; 0.015 mg/kg/injection; n=20). Oxycodone (0.1 mg/kg/injection; n=7/group) was positively reinforcing (p<0.001) compared with saline on a FR5 schedule. Oxycodone supported statistically-adjusted group mean of 15.0 ± 2.0 injections/session at 0.1 mg/kg/injection i.v. The number of injections/session of oxycodone taken by the rats was significantly lower (p<0.01) than the number of injections/sessions of heroin. The statistically-adjusted mean number of FR5 injections of Compound 3 (0.003, 0.03, 0.3 and 0.6 mg/kg/injection) were statistically significantly lower (p<0.05 - p<0.001) than the statistically-adjusted mean number for oxycodone (0.1 mg/kg/injection). The mean injection intervals for Compound 3 doses of 0.003, 0.03, 0.3 and 0.6 mg/kg/injection i.v. were 1053 ± 133, 992 ± 221, 1286 ± 357 and 973 ± 286 seconds respectively. The injection intervals for Compound 3 were not significantly different from the mean injection interval for saline (1258 ± 120; n=20). The mean injection intervals for all doses of Compound 3 were significantly greater (p<0.01 - p<0.001) than the mean injection interval for heroin (305 ± 29; n=20). The mean injection interval for oxycodone (0.1 mg/kg/injection) was 500 ± 70 seconds which was significantly (p<0.001) shorter than the mean injection interval during saline extinction (1258 ± 120 seconds; n=20), but it was not significantly different from that during heroin acquisition (305 ± 29 seconds; n=20). The mean injection intervals for all doses of Compound 3 (0.003, 0.03, 0.3 and 0.6 mg/kg/injection i.v.) were significantly greater (p<0.05 - p<0.01) than the mean injection interval for oxycodone (0.1 mg/kg/injection). The PR break-points for 0.003, 0.03, 0.3 and 0.6 mg/kg/injection Compound 3 were 7.4 ± 1.7 (n=4), 14.2 ± 3.6 (n=8), 15.9 ± 5.1 (n=8) and 22.8 ± 6.3 (n=8) lever-presses/injection, respectively, which were all significantly lower (p<0.001) than the break-point of 71.8 ± 11.7 (n=20) lever-presses/injection for heroin (0.015 mg/kg/injection). The break-point for oxycodone (0.1 mg/kg/injection) of 53.3 ± 6.3 (n=7) lever- presses/injection was not significantly different to the break-point for heroin (0.015 mg/kg/injection). The PR break-points for all doses of Compound 3 (0.003, 0.03, 0.3 and 0.6 mg/kg/injection) were significantly lower (p<0.05 - p<0.01) than the break-point for oxycodone (0.1 mg/kg/injection). The plasma concentrations of Compound 3 were determined in a separate group of rats to those used in the self-administration experiment. Compound 3 (0.03, 0.3, 0.60 and 6.12 mg/kg i.v.) was injected as bolus i.v. doses and blood samples were taken up to 120 min after drug administration. The maximum plasma concentration was observed in the rats injected with 6.12 mg/kg Compound 3 (4280.0 ± 470.0 ng/ml). As expected, the maximum plasma concentration was observed at 5 min post-dosing in all Compound 3 dose groups. In summary, heroin served as a powerful reinforcer in rats, consistent with its profile as a Schedule I Controlled Drug in the USA and a drug of abuse. This was demonstrated by the number of injections rats self-administered in FR5 test sessions and the high PR break-points for reinforcement. The positive reference comparator and Schedule II Controlled Drug, oxycodone, was also a powerful positive reinforcer on the FR5 schedule. In contrast, only the highest (0.60 mg/kg/injection i.v.) of the 4 doses of Compound 3 tested was reinforcing on FR5 schedule when compared with responding of the rats for saline. Moreover, the FR5 responding for all 4 doses of Compound 3 was significantly lower than the responding of rats for heroin and oxycodone. On evaluation of the relative reinforcing effect of Compound 3 on an ascending PR schedule, all 4 doses were significantly less reinforcing than heroin and oxycodone. These results suggest that the weak reinforcing properties of Compound 3 will provide little potential for recreational abuse. Conditioned Place Preference (CPP) The protocol consisted of one baseline habituation day, 8 conditioning days and one post conditioning test day (expression of CPP). The study was performed in two identical cohorts, 30 animals per cohort. Locomotor activity during the conditioning and expression phases was recorded using 16 x 16 photo beams with a space of 2 cm between beams (Med Associates®), located in the CPP apparatus. Movement was recorded using the Activity Monitor™ program designed by Med Associates®. Distance travelled and vertical activity was recorded and analyzed. Day One: Pre-conditioning Phase Rats were placed into testing arenas and allowed to freely move between the two distinct but connected chambers for 15 minutes. Time spent in each chamber was recorded automatically by instrument software for baseline purposes. In a biased design, the chamber in which any one animal spent the most time was designated its “preferred chamber”. The “less preferred’ chamber was assigned as the drug-associated chamber. If rats failed to show a preference for one chamber, vehicle and drug chambers were assigned randomly. Days 2-9: Conditioning Phase (CPP acquisition) Following the pre-conditioning phase, rats underwent eight daily 30 minute conditioning sessions. After habituation to the lab and chambers, rats were injected with the compounds or vehicle as described in Table 4. Animals received test compounds on days 2, 4, 6, 8 and vehicle on days 3, 5, 7, 9. Controls were injected with vehicle for all conditioning sessions (days 2-9) (vehicle-conditioned rats, negative control). Immediately after injections, rats were confined to the appropriate side of the box for 30 minutes. Expression of CPP (day 10) is described below. Table 4.

Locomotor activity was measured during 30 minutes on conditioning days 2-9. Time spent in drug paired chamber and locomotor activity were measured on expression day 10. Day 10: Testing Phase (CPP expression) Rats were placed in the testing arenas for 30 minutes. Access to both chambers was freely available. Time spent in each chamber was recorded. Compound was not administered prior to this test session. Results Morphine (5 mg/kg), induced a conditioned place preference in rats. The results reproduce literature data, demonstrating the effect of this compound in the assay. Analysis of locomotor activity behaviors in rats during the conditioning sessions revealed the effects of morphine, which resulted in decrease of distance traveled on day 2 and vertical activity on days 2 and 4, in line with known pharmacological action of morphine. Compound 3 at 10 mg/kg, significantly increased the time animals spent in the drug- paired compartment on the post-conditioning day. The result indicates that Compound 3 at 10 mg/kg induces a conditioned place preference in rats. Compound 3 at 0.1 or 1 mg/kg did not significantly change time and percentage of time animals spent in the drug-paired chamber. It is concluded that Compound 3 at 0.1 or 1 mg/kg does not induce a conditioned place preference. There was no significant effect of Compound 3 at tested doses on the locomotor activity of animals.

Claims

CLAIMS 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein R₁ is C_1-4 alkyl or C_1-4 alkoxy, wherein the C_1-4 alkyl or C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms; and R₂, R₃, and R₄, are each, independently, selected from the group consisting of H, halogen, C_1-4 alkoxy, hydroxyl, and C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2 or 3 halogen atoms.

2. The compound claims 1 or 2, wherein R₁ is C_1-3 alkyl.

3. The compound of any of claims 1-3, wherein R₁ is methyl.

4. The compound of any of claims 1-3, wherein R₁ is ethyl.

5. The compound of any of claims 1-3, wherein R₁ is C₃ alkyl.

6. The compound of claim 1, wherein R₁ is C_1-4 alkoxy.

7. The compound of claim 7, wherein R₁ is methoxy.

8. The compound of claim 7, wherein R₁ is ethoxy.

9. The compound of claim 7, wherein R₁ is C₃ alkoxy.

10. The compound of any one of claims 1-9, wherein R₂, R₃, and R₄, are each hydrogen.

11. The compound of any one of claims 1-9, wherein R₂ is fluoro, and R₃ and R₄ are each hydrogen.

12. The compound of any one of claims 1-9, wherein R₃ is fluoro, and R₂ and R₄ are each hydrogen.

13. The compound of any one of claims 1-9, wherein R₄ is hydrogen, and R₂ and R₃ are each fluoro.

14. The compound of any one of claims 1-9, wherein R₃ is chloro, and R₂ and R₄ are each hydrogen.

15. The compound of any one of claims 1-9, wherein R₃ is CF₃, and R₂ and R₄ are each hydrogen.

16. The compound of any one of claims 1-9, wherein R₂ is CH₂F, CF₂H, or CF₃, and R₃ and R₄ are each hydrogen.

17. The compound of any one of claims 1-9, wherein R₃ is CH₂F, CF₂H, or CF₃, and R₂ and R₄ are each hydrogen.

18. The compound of any one of claims 1-9, wherein R₄ is CH₂F, CF₂H, or CF₃, and R₂ and R₃ are each hydrogen.

19. The compound of claim 1, wherein the compound of Formula I is of the Formula Ia:

or a pharmaceutically acceptable salt thereof; wherein R₁ is C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2, or 3 halogen atoms; and R₂, R₃, and R₄, are each, independently, selected from the group consisting of H, halogen, and C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2 or 3 halogen atoms.

20. The compound of claim 19, wherein R₁ is unsubstituted C_1-4 alkyl.

21. The compound of claim 19 or 20, wherein R₁ is unsubstituted methyl.

22. The compound of claim 19 or 20, wherein R₁ is unsubstituted ethyl.

23. The compound of claim 19 or 20, wherein R₁ is unsubstituted C₃ alkyl.

24. The compound of any one of claims 19-23, wherein R₂, R₃, and R₄ are each hydrogen.

25. The compound of any one of claims 19-23, wherein R₃ is fluoro, and R₂ and R₄ are each hydrogen.

26. The compound of claim 1, wherein the compound of Formula I is of the Formula Ib:

or a pharmaceutically acceptable salt thereof; wherein R₁ is C_1-4 alkoxy, wherein the C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen atoms; and R₂, R₃, and R₄, are each, independently, selected from the group consisting of H, halogen, and C_1-4 alkyl, wherein the C_1-4 alkyl is optionally substituted with 1, 2 or 3 halogen atoms.

27. The compound of claim 26, wherein R₁ is C_1-3 alkoxy.

28. The compound of claim 26, wherein R₁ is methoxy.

29. The compound of claim 26, wherein R₁ is ethoxy.

30. The compound of claim 26, wherein R₁ is C₃ alkoxy.

31. The compound of any one of claims 26-30, wherein R₂, R₃, and R₄ are each hydrogen.

32. The compound of any one of claims 26-30, wherein R₂ is fluoro, and R₃ and R₄ are each hydrogen.

33. The compound of any one of claims 26-30, wherein R₃ is fluoro, and R₂ and R₄ are each hydrogen.

34. The compound of any one of claims 26-30, wherein R₃ is CF₃, and R₂ and R₄ are each hydrogen.

35. The compound of any one of claims 26-30, wherein R₃ is chloro, and R₂ and R₄ are each hydrogen.

36. The compound of any one of claims 26-30, wherein R₄ is hydrogen, and R₂ and R₃ are each fluoro.

37. The compound of of any one of claims 1-36, wherein the compound of Formula I, Formula Ia, or Formula Ib is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

38. A compound of the Formula II:

or a pharmaceutically acceptable salt thereof; wherein: R₁ is C₁-C₆ alkyl or C₁-C₄ alkoxy, wherein the C_1-6 alkyl or C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen; R₂, R₃, and R₄ are each, independently, selected from the group consisting of H, C1- C₄ alkyl, C₁-C₄ alkoxy, hydroxy, and halogen, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen; R₅ is H or C₁-C₄ alkyl; R₆ is selected from the group consisting of H, C₁-C₄ alkyl, halogen, -NR_aR_b, -CN, and -C(=O)NR_aR_b, wherein C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen; wherein Ra and Rb are each, independently, H or C₁-C₆ alkyl.

39. The compound according to claim 38, wherein R₄ is halogen.

40. The compound according to claim 38 or 39, wherein R₄ is fluoro, R₃ is H, and R₄ is H.

41. The compound according to any one of claims 38-40, wherein R₆ is C₁-C₄ alkyl optionally substituted by 1, 2, or 3 halogen atoms.

42. The compound according to claim 41, wherein R₆ is methyl.

43. The compound according to claim 41, wherein R₆ is ethyl.

44. The compound according to claim 41, wherein R₆ is CF₃.

45. The compound according to any one of claims 38-40, wherein R₆ is H.

46. The compound according to any one of claims 38-40, wherein R₆ is NRaRb.

47. The compound according to claim 46, wherein R₆ is NH₂.

48. The compound according to any one of claims 38-40, wherein R₆ is CN.

49. The compound according to any one of claims 38-40, wherein R₆ is C(=O)NRaRb.

50. The compound according to claim 49, wherein R₆ is C(=O)NH₂.

51. The compound according to claim 38, wherein R₁ is C₁-C₄ alkyl or C₁-C₂ alkoxy; R₂, R₃ and R₄ are each, independently, H or halogen; and R₅ is H.

52. The compound according to claim 38, wherein R₁ is C₁-C₄ alkyl or C₁-C₂ alkoxy; R₂, R₃ and R₄ are H; and R₅ is H.

53. The compound according to any one of claims 38-52, wherein the compound of Formula II is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

54. A compound of Formula III:

or a pharmaceutically acceptable salt thereof; wherein: R₁ is C₁-C₆ alkyl or C₁-C₄ alkoxy, wherein the C_1-6 alkyl or C_1-4 alkoxy is optionally substituted with 1, 2, or 3 halogen; R₂, R₃, and R₄ are each, independently, selected from the group consisting of H, C₁- C₄ alkyl, C₁-C₄ alkoxy, hydroxy, and halogen, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen; R₅ is H or C₁-C₄ alkyl; and R₆ is selected from the group consisting of H, C₁-C₄ alkyl, halogen, -NR_aR_b, -CN, and -C(=O)NRaRb, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen; wherein Ra and Rb are each, independently, H or C₁-C₆ alkyl.

55. The compound according to any one of claims 38-54, wherein R₁ is C₁-C₄ alkoxy.

56. The compound according to any one of claims 38-55, wherein R₁ is methoxy.

57. The compound according to any one of claims 38-55, wherein R₁ is ethoxy.

58. The compound according to any one of claims 38-54, wherein R₁ is C₁-C₆ alkyl.

59. The compound according to any one of claims 38-55 and 58, wherein R₁ is methyl.

60. The compound according to any one of claims 38-54 and 58, wherein R₁ is ethyl.

61. The compound according to any one of claims 38-54 and 58, wherein R₁ is propyl.

62. The compound according to any one of claims 38-61, wherein R₂, R₃, and R₄ are each H.

63. The compound according to any one of claims 54-61, wherein R₂ is C₁-C₄ alkyl optionally substituted by 1, 2, or 3 halogen.

64. The compound according to claim 63, wherein R₂ is CF₃, R₃ is H, and R₄ is H.

65. The compound according to any one of claims 38-61, wherein R₂ is halogen.

66. The compound according to claim 65, wherein R₂ is fluoro, R₃ is H, and R₄ is H.

67. The compound according to any one of claims 54-61, wherein R₂ is C₁-C₄ alkoxy.

68. The compound according to claim 67, wherein R₂ is methoxy, R₃ is H, and R₄ is H.

69. The compound according to any one of claims 38-68, wherein R₃ is halogen.

70. The compound according to claim 69, wherein R₃ is fluoro, R₂ is H, and R₄ is H.

71. The compound according to any one of claims 54-69, wherein R₄ is halogen.

72. The compound according to claim 71, wherein R₄ is fluoro, R₃ is H, and R₂ is H.

73. The compound according to any one of claims 38-72, wherein R₅ is C₁-C₄ alkyl.

74. The compound according to any one of claims 38-72, wherein R5 is H.

75. The compound according to any one of claims 54-74, wherein R₆ is H.

76. The compound according to any one of claims 54-74, wherein R₆ is halogen.

77. The compound according to any one of claims 54-72, wherein R₆ is C₁-C₄ alkyl optionally substituted by 1, 2, or 3 halogen.

78. The compound according to claim 77, wherein R₆ is CF₃.

79. The compound according to claim 77, wherein R₆ is CH₃.

80. The compound according to any one of claims 54-72, wherein R₆ is CN.

81. The compound according to any one of claims 38-80, wherein R₁ is C₁-C₄ alkyl or C₁-C₂ alkoxy; R₂, R₃, and R₄ are each, independently, selected from the group consisting of H, C1- C₄ alkoxy, and halogen; and R₅ is H.

82. The compound according to any one of claims 38-80, wherein R₁ is C₁-C₄ alkyl or C₁-C₂ alkoxy; R₂, R₃, and R₄ are each, independently, selected from the group consisting of H, C1- C₄ alkoxy, and halogen; R5 is H; and R₆ is selected from the group consisting of H, NR_aR_b, CN, C(=O)NR_aR_b, and C₁-C₄ alkyl, wherein C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen.

83. The compound according to any one of claims 54-82, wherein the compound of Formula III is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

84. A pharmaceutical composition comprising the compound of any of claims 1-83, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier

85. A method of treating pain in a subject in need thereof comprising administering to the subject the compound of any one of claims 1-83, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 85.

86. The method of claim 85, wherein the pain is inflammatory pain, thermal pain, acute pain, chronic pain, traumatic pain, chemical pain, ischemic pain, centrally mediated pain, peripherally mediated pain, prickling pain, visceral pain, progressive disease pain, or musculoskeletal pain.

87. The method of claim 85, wherein the pain is inflammatory pain, thermal pain, acute pain, chronic pain, or musculoskeletal pain.

88. The method of claim 87, wherein the pain is chronic pain.

89. The method of claim 87, wherein the pain is musculoskeletal pain.

90. Use of a compound of any one of claims 1 to 83 for the manufacture of a medicament for pain.

91. Use of a compound of any one of claims 1 to 83 for the manufacture of a medicament for chronic pain.

92. Use of a compound of any one of claims 1 to 83 for the manufacture of a medicament for musculoskeletal pain.