WO2021026377A1 - Lactam-containing compounds for the treatment of pain - Google Patents

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

LACTAM-CQNTAlNiNG COMPOUNDS FOR THE TREATMENT OF PAIN

Related Applications

This application claims priority to U.S. Provisional Application No, 62/883,852, filed on August 7, 2019, the content of which are hereby incorporated in its entirety.

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,, naitrexone 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 Pharmaceuticsl 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 usefui in the treatment of diseases and conditions modulated by opiate receptors.

Traditional opioid analgesics exert their pharmacological activity once they have passed into the centra! nervous system (CNS). But this can iead 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 of the Fomula !: or a pharmaceutically acceptable salt thereof.

Also provided herein is a pharmaceutical composition comprising a compound of any of Formula l, 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 l, 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 l, 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 l, 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 l, 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 m-opioid receptor. In a particular embodiment, the compounds provided herein are considered p-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 p-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 c!aims, unless otherwise limited in specific instances, either individually or as part of a larger group.

Unless defined otherwise, ail 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 m-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” « 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 ail 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 in di vidua! 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 aiteration 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 biologicai 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 sail form. Examples of pharmaceutically acceptable salts include, but are not limited to, minerai 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 saits of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such saits 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 acetonitrlie are preferred. The phrase “pharmaceuticaiiy acceptable salt" Is not limited to a mono, or 1:1, salt. For example, “pharmaceutically acceptable salt” also includes bis-salis, 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 carrylng 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 materiais 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, com oii and soybean oil; glycols, such as propylene glycol; poiyols, 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 inciudes any and all coatings, antibacterial and antifungal agents, and absorption delaylng agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologicaliy acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceuticaiiy 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 pharmaceuiicaf 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, isobutl , 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. Aikoxy 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

Provided herein are compounds having the structure of Formula (I): or a pharmaceutically acceptable salt thereof; wherein

R₁ is C₁-C₆ alkyl or C₁-C₄ alkoxy, wherein the C₁- ₆akyl or C1-4 alkoxy is optionally substituted with 1 , 2, or 3 halogen;

R_2, R₃, and R₄ are each, independently, selected from the group consisting of H, C_1-C₄ alkyl, G1-G4 alkoxy, hydroxy, and halogen, wherein the C_1-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen;

R₅ Is H or C_1-C₄ alkyl;

X is selected from the group consisting of OR_aR_b, 0, S, NR_a, and C(» O); and

R_a and R₅ are each, independently, H or C_1-C₆ alkyl. in another embodiment of Formula (I), 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 (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 (l), 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 (l), 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 (l), R₁ is methyl, wherein the methyl is optionally substituted with 1, 2, or 3 halogen atoms.

In another embodiment of Formula (l), 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 (l), R₁ is C₄ alkyl, wherein the C₄ alkyl is optionally substituted with 1 , 2, or 3 halogen atoms.

In another embodiment of Formula (l), R₁ is unsubstituted G_1-4 alkyl.

In another embodiment of Formula (I), R₁ is unsubstituted C_1-3 aikyl.

In another embodiment of Formula (I), R₁ is unsubstituted C_1-2 aikyl.

In another embodiment of Formula (I), R₁ is unsubstituted C_2-4 aikyl. in another embodiment of Formula (l), 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 unsubsiltuted ethyl.

In another embodiment of Formula (I), R₁ is unsubstituted C₃ alkyl.

In another embodiment of Formula (l), R₁ is unsubstituted C₄ alkyl.

In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, wherein the C« alkoxy is Optionally substituted with 1 , 2, or 3 haiogen atoms, in another embodiment of Formula (I), R₁ is G_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 haiogen atoms. in another embodiment of Formula (l), 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 (l), R₁ is methoxy, wherein the methoxy is optionally substituted with 1 , 2, or 3 haiogen 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 (l), R₁ is unsubstituted C_1-3 alkoxy. in another embodiment of Formula (l), 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 C₃-4 alkoxy.

In another embodiment of Formula (I), R₁ is unsubstituted methoxy.

In another embodiment of Formula (l), R₁ is unsubstituted ethoxy.

In another embodiment of Formula (l), R₁ is unsubstituted C₃ alkoxy.

In another embodiment of Formula (I), R₁ is unsubstituted C₄ alkoxy.

In another embodiment of Formula (I), R₁ is -OCF_3, in another embodiment of Formula (I), R₁ is — OCH₂CF_3. 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 (l), R₂ is hydrogen.

In another embodiment of Formula (I), R₃ is hydrogen.

In another embodiment of Formula (l), R₄ is hydrogen in another embodiment of Formula (I), R₂ is haiogen. in another embodiment of Formula (I), R₂ is fiuoro or chloro. in another embodiment of Formula (i), R₂ is fiuoro. in another embodiment of Formula (i), R₃ is chloro. in another embodiment of Formula (I), R₂ is CF₃. in another embodiment of Formula (I), Rs is CF₃H. 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 (l), R₃ is fluoro. In another embodiment of Formula (l), R₃ is chloro. in another embodiment of Formula (i), R₃ is CF₃. in another embodiment of Formula (l), R₃ is CF₂H. in another embodiment of Formula (i), R₃ is CH₂F. in another embodiment of Formula (l), R₄ Is halogen. in another embodiment of Formula (I), R₄ is fluoro or chloro. In another embodiment of Formula (l), R₄ is fluoro, In another embodiment of Formula :(l), R₄ is chloro. in another embodiment of Formula (I), R₄ is CF₃. In another embodiment of Formula (l), R₄ is CF₂H. in another embodiment of Formula (I), R₄ is CH₂F. in another embodiment of Formula (I), R₃ is hydrogen, in another embodiment of Formula (I), R₃ is C_1-C₄ alkyl. in another embodiment of Formula (i), X is CR_aR_b. In another embodiment of Formula (i), X is O. In another embodiment of Formula (l), X is S, In another embodiment of Formula (l), X is NR₃. In another embodiment of Formula (l), X is C(» O). in another embodiment of Formula (I), X is CR_aR_b,,_. O, or S. in another embodiment of Formula (I), X is CR_aR_b,_. O, or NRa. in another embodiment of Formula (i), Rs is halogen, and R₃ and R₄ are each hydrogen, in another embodiment of Formula (i), R₃ is fluoro or chloro, and R₃ and R₄ are each hydrogen. in another embodiment of Formula (l), R₂ is fluoro, and R₃ and R₄ are each hydrogen. in another embodiment of Formula (l), R₂ is chloro, and R₃ and R₄ are each hydrogen. in another embodiment of Formula (l), 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), Rs 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 (l), R₃ is fluoro or chloro, and and R_a. are each hydrogen. in another embodiment of Formula (I), R₃ is f!uoro, and R₂ and R₄ are each hydrogen.

In another embodiment of Formula (I), R₃ is chloro, and R₃ and R₄ are each hydrogen.

In another embodiment of Formula (I), R₃ is CF_3, and and R₄ are each hydrogen.

In another embodiment of Formula (l), R₃ is CF₂H, and R₂ and R₄ are each hydrogen.

In another embodiment of Formula (l), 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 R₂ are each hydrogen.

In another embodiment of Formula (I), R₄ is chloro, and R₂ and R₃ are each hydrogen.

In another embodiment of Formula (l), Rt is CFs, and and R₃ are each hydrogen.

In another embodiment of Formula (l), R₄ is CF₂H, and R₂ and R₃ are each hydrogen.

In another embodiment of Formula (l), R₄ is CH₂P, and R₂ and R₃ are each hydrogen.

In another embodiment of Formula (l), 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, R₃ is fluoro or chloro, and R₃ and R₄ are each hydrogen.

In another embodiment of Formula (l), R₁ is C_1-4 alkoxy, R₂ Is fluoro or chloro, and R₃ and R₄ are each hydrogen.

In another embodiment of Formula (I), Rt 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 (l), R₁ is C_1-4 alkoxy, R₂ is chloro, and R₃ and R₄ are each hydrogen.

In another embodiment of Formula (l), R₁ is C_1-4 alkyl, R₂ is CFs, and R₂ and R₄ are each hydrogen. in another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₂ is CFs, 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 CF>H, and R₃ and R₄ are each hydrogen. In another embodiment of Formula (l), R₁ is C_1-4 aikyl, 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 R,_; are each hydrogen. in another embodiment of Formula (i), R₁ is C_1-4 aikyl, R₃ is halogen, and R₂ and R₄ are each hydrogen. in another embodiment of Formula (l), 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 aikyl, R₃ is fluoro or chloro, and R³ and R₁ are each hydrogen. in another embodiment of Formula (l), R₁ is C_1-4 alkoxy, R₃ is fluoro or eh loro, 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 (l), R₁ is C_1-4 alkoxy, R3 is chloro, and R₂ and R₄ are each hydrogen. in another embodiment of Formula (l), R₁ is C_1-4 aikyl, R₃ is GF₃, and R₂ and R₄ are each hydrogen. in another embodiment of Formula (i), R₁ is C_1-4 alkoxy, R₃ is CFs, and R₂. and R₄ are each hydrogen, in another embodiment of Formula (i), R₁ is C_1-4 aikyl, R₂ is CFgH, and R₂ and R₄ are each hydrogen. in another embodiment of Formula (l), R₁ is C_1-4 alkoxy, R₃ is CFgH, and R₂ and R₄ are each hydrogen.

In another embodiment of Formula (i), R₁ is C_1-4 aikyl, 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 (l), R₁ is C_1-4 alkyl, R₄ is halogen, and and l¾ 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 (l), R₁ is C_1-4 alkyl, R₄ is fluoro or chloro, and R³ and R_s are each hydrogen. in another embodiment of Formula (l), R₁ is C_1-4 alkoxy, R₁ is fluoro or chloro, and R³ and R₃ are each hydrogen. in another embodiment of Formula (l), R₁ is C_1-4 alkyl, R₄ is fluoro, and R₂ and R₃ are each hydrogen. in another embodiment of Formula (l), 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, R$ is chloro, and R₂ and R₃ are each hydrogen. in another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₁ Is chloro, and R₂ and R₃ are each hydrogen. in another embodiment of Formula (i), R₁ is C_1-4 alkyl, R₄ is CF_3, and R- and R₃ are each hydrogen. in another embodiment of Formula (I), R₁ is C_1.4 alkoxy, R₄ is CF_3, 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 (l), R₁ is C_1-4 alkoxy, R₁ is CF₂H, and R₂ and R₃ are each hydrogen. in another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₄ is GHaF, and and R₃ are each hydrogen. in another embodiment of Formula (i), R₁ is C_1-4 alkoxy, R₃ is CH₂F, and R₂ and R₃ are each hydrogen, in another embodiment of Formula (i), and R₃ are each halogen, In another embodiment of Formula (I), R₂ and R₃ are each fluoro or chloro. in another embodiment of Formula (l), R₃ and R₃ are each fluoro.

In another embodiment of Formula (l), R₂ and R₃ are each chloro. in another embodiment of Formula (i), R₃ and R₄ are each halogen. in another embodiment of Formula (l), R₂ and R₄ are each fluoro or chloro. in another embodiment of Formula (l), 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 (l), R₂ and R₄ are each fiuoro or chloro. in another embodiment of Formula (I), R₂ and R₂ are each fiuoro. in another embodiment of Formula (l), R₂ and R₃ are each chloro in another embodiment of Formula (I), R₃ and R₃ are each halogen, and FU is hydrogen. in another embodiment of Formula (l), R₂ and R₃ are each fiuoro or chloro, and R₄ is hydrogen. in another embodiment of Formula (I), R₂. and R₃, are each fiuoro, and S¾ is hydrogen, in another embodiment of Formula (l), and R₂ 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 fiuoro or chloro, and R₃ is hydrogen. in another embodiment of Formula (l), R₂ and R₄ are each fiuoro, and R₃ is hydrogen.

In another embodiment of Formula (l), R₂ and R₄ are each chloro, and R₂ is hydrogen.

In another embodiment of Formula (l), R₃ and R₄ are each halogen, and R₂ is hydrogen.

In another embodiment of Formula (l), R₂ and !¾. are each fiuoro or chloro, and R₂ is hydrogen.

In another embodiment of Formula (I), R₂ and R₄ are each fiuoro, and R₂ Is hydrogen.

In another embodiment of Formula (l), R₂ and R₄ are each chloro, and R₂ is hydrogen.

In another embodiment of Formula (l), R₁ is C_1-4 alkyl, R₂ and R_;¾ are each halogen, and R₄ is hydrogen,

In another embodiment of Formula (I), R₁ is C_1-4 alkoxy, Rz and R₃ are each halogen, and R₄ is hydrogen.

In another embodiment of Formula (l), R₁ is C_1-4 alkyl, R₂ and R₂ are each fiuoro or chloro, and R₄ is hydrogen.

In another embodiment of Formula (l), R₁ Is C_1-4 alkoxy, R₂ and R₃ are each fiuoro or chloro, and R₄ is hydrogen.

In another embodiment of Formula (I), R₁ is C_1-4 alkyl, R₂ and R₃ are each fiuoro, and R₄ is hydrogen.

In another embodiment of Formula (l), R₁ is C_1-4 alkoxy, R₂ and R3 are each fiuoro, 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 R₂ are each chloro, and R₄ is hydrogen. in another embodiment of Formula (l), R₁ is C_1-4 alkyl, R₃ and R₄ are each halogen, and R;i 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 (l), 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 (l), R₁ is C_1-4 alkyl, R_;> and R₄ are each fluoro, and R₃ is hydrogen. in another embodiment of Formula (l), 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, R₃ and R₃ are each chloro, and R₃ is hydrogen.

In another embodiment of Formula (l), 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 R₃ is hydrogen. in another embodiment of Formula (I), R₁ is C_1-4 alkoxy, R₃ and R₄ are each halogen, and R₃ is hydrogen.

In another embodiment of Formula (i), R₁ is C_1-4 alkyl, R₃ and R₄ are each fluoro or chloro, and R₃ is hydrogen.

In another embodiment of Formula (l), R₁ is C_1-4 alkoxy, R₃ and R₃ are each fluoro or chloro, and R₃ is hydrogen.

In another embodiment of For mu fa (I), R₁ is C_1-4 alkox,y R₃ and R₄ are each fluoro, and R₃ is hydrogen. in another embodiment of Formula (i), R₁ is C_1-4 alkoxy, R₃ and R₄ are each fluoro, and R₃ is hydrogen. in another embodiment of Formula (i), R₁ is C_1-4 alkyl, R₃ and R₄ are each chloro, and R₃ is hydrogen. in another embodiment of Formula (l), 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 sails thereof, are shown beiow in Table 1 , Compounds of Formula l 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.

The disclosed compounds may possess one or more stereocenters, and each stereoeenter 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, opticaiiy-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 opticaiiy-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, enantloselective 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 exampie, 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 isotopicaily-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, ⁿC, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³i, ^l25f, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,

³²P, and ³⁵S In one embodiment, isotopicaiiy-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, ^1sO and ¹³N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy isotopicaliy-iabeied compounds are prepared by any suitable method or by processes using an appropriate isotopically-iabeled 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 Fiesers Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementa!s (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) (ail 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 muscuioskeletal 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 IE disorder, borderline and personality disorder, cyclothymia and dysthymia, Dysthymic disorder, hyperactivity disorder, impulse control disorder, mixed mania, obsessive-compulsive personalty disorder (GCD), paranoid, seasons! 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 alcohoi 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 m-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 pharmaceuticai 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 compound ing/formulating such a disciosed 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 disciosed 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 800 mg, or iess than about 300 mg, or less than about 200 mg, or iess than about 100 mg, or iess 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, fransdermai, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethrai, vaginai (e.g., trans- and perivaginally), (intra)nasal and (trans)rectall, intravesical, intrapulmonary, intraduodenal, intragastrical intrathecal, subcutaneous, intramuscular, intradermai, intra-arterial, intravenous, intra bronchial, 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, soiutions, 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 geicaps. 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 he 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, soiutions 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 buf 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 vaiues and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all vaiues that fail within these ranges, as weii 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, cel! culture, molecular biology, transgenic biology, microbiology and immunology, which are within the skill of the art.

General Procedures

Abbreviations

GDI carbonyldiimidazole

DCM dichloromethane

DMF dimethylformamide

Et₂O diethyl ether

EtOAc/EA ethyl acetate

EtOH ethanol

MeOH methanol

NBS N-bromosuccinimide

PE petroleum ether t-BuLi tert-butyl lithium

TEA triethylamine

THF tetrahydrofuran

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.

Compound 2

To a stirred solution of 4-bromo-2,3~dihydro-1,3-benzoxazol-2-one (2,0 g, 9,34 mmol, 1 equiv) in THF (100 mL) was added NaH (448 mg, 18,7 mmol, 2 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at 0 °C under nitrogen atmosphere. To the above mixture was added i-BuLi (898 mg, 14.0 mmol, 1.5 equiv) dropwise over 5 min at -78 °C. The resulting mixture was stirred for additional 1 h at -78 °C. To the above mixture was added 3-benzyl-3-azabicyclo[3.3.1 ]nonan-9-one (2.8 g, 12.1 mmol, 1 ,3 equiv) dropwise over 5 min at -78 °C. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched with sat. NH₄CI (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na₂SO_4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was diluted with MeOH (20 mL). The precipitated solids were collected by filtration and washed with MeOH (3 x 50 mL). This resuited in 7-[3-benzyl-9-hydroxy-3-azabicyclo[3.3.1 ]nonan-9-yl]-2,3-dihydro-1 ,3-benzoxazol- 2-one (2.1g, 61.0%) as a white solid. LCMS: m/z (ES+), [M+H] = 365. ¹H NMR (400 MHz, DMSO-d6) d 11.59 (s, 1 H), 7.38-7.06 (m, 7H), 7.02-6.94 (m, 1 H), 4.98 (d, 0 = 8.2 Hz, 1 H),

3.38 (d, J ~ 40.3 Hz, 2H), 2.94 (d, J ~ 10.3 Hz, 1 H), 2.85-2.56 (m, 5H), 2.37-2.16 (m, 3H), 1.75-1.50 (m, 2H), 1.49-1.39 (m, 1 H), 1.19 (q, j ~ 8.6, 7.1 Hz, 1 H).

To a stirred soiution/mixture of 7-[3-benzyl~9-hydroxy~3~azabicyclo[3.3.1]nonan-9-yl]- 2,3-dihydro-1,3-benzoxazoi-2-one (2,1 g, 5,87 mmol, 1 equiv) in CH(OMe)3 (10 mL) was added H3SG4 (5.8 g, 587 mmol, 10 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 0,5 h at 0 °C under nitrogen atmosphere. The mixture/residue was neutralized to pH 8 with saturated, aqueous NaHCO_3. The resulting mixture was extracted with EtOAc (3 x 50 mL), The combined organic layers were washed with water (3x50 ml), dried over anhydrous NaHSO₄, _. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 4:1) to afford 7-[3- benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan~9~yl]-2,3-dihydro-1,3-benzoxazol~2~one (670 mg, 30.1%) as a colorless solid. LCMS: m/z (ES+), (M+Hf ~ 365. NMR (400 MHz, DMSG-d6) 6 11.69 (S, 1H), 7.40-7.12 (m, 7H), 7.06 (dd, J = 6.4, 2.4 Hz, 1H), 2.98 (s, 1H), 2,75 (d, J = 23.8 Hz, 9H), 2.59 (s, 1 H), 1.69 (s, 3H), 1.47 (s, 1 H), 1.23 (s, 2H).

To a mixture of Pd(OH)₂/C (122.1 mg, 0.87 mmoi, 0.5 equiv) and 7-[3~benzyl-9- methoxy-3-azabicyclo[3.3.1 ]nonan-9-yl|-2,3-dihydro-1 ,3-benzoxazoi-2-one (658 mg, 1.74 mmol, 1 equiv) in THF was added HCO₂NH₄ (1.09 g, 17.4 mmol, 10 equiv) In portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 10 min at 65 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 20 mL), The filtrate was concentrated under reduced pressure to afford 7-(9- methoxy-3-azabicyclo[3.3 , 1 ] non an~9~yl]~2 , 3-dihyd ro- 1 ,3-benzoxazol~2~one (320 mg, 63,8%} as a yeiiow oil. LCMS: m/z (ES+), [M+H]⁺ = 289.

To a stirred solution of 7-[9-methoxy-3~azabicyclo[3.3.1]nonan-9-yl]-2,3~dihydro-1 ,3- benzoxazol-2-one (127 mg, 0.440 mmol, 1 equiv) in water was added HGI (g) (375 uL, 375.0 mmol, 851.4 equiv) dropwise at room temperature. Then freeze drylng to afford Compound 2, 7-[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-2,3-dihydro-1 ,3-benzoxazol-2-one hydrochloride, (86 mg, 80.1%) as a light pink solid. LCMS: m/z (ES+), [M+H]⁺ =289. ¹H NMR (400 MHz, Deuterium Oxide) d 7.22-7.11 (m, 3H), 3.58 (m, 2H), 3.38-3.29 (m, 2H). 3.23 (s, 1H). 2.84 (s, 1H), 2.80 (s, 3H), 1.80 (m, 3H), 1.43 (m, 3H).

Compound 8

A mixture of 2~bromo-4-fiuoro-6-nitrophenol (2,0 g, 8.48 mmol, 1.0 equiv) and PtO₂ (1.92 g, 8.46 mmol, 1.0 equiv) in 20 mL MeOH was stirred for 1 h at room temperature under hydrogen atmosphere. The solids were filtered out and the resulting mixture was concentrated under reduced pressure. The crude products (2.23 g) was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford 2-ami no-6~bromo-4-f I uoroph enoi (1.56 g, 66.5%) as a yellow solid. LCMS: m/z (ES+), (M+Hf * 206. ¹H NMR (400 MHz, methanol- d4) d 6.66 (dd, J = 8.2, 3.0 Hz, 1H), 6.56 (dd, J = 9.9, 2.9 Hz, 1H).

To a stirred solution of 2-amino-6-bromo-4-fluorophenol (1.00 g, 4.85 mmol, 1.0 equiv) in 20 mL DMF was added CD! (1.57 g, 9.68 mmol, 2.0 equiv) in portions at 0 °C. The resulting mixture was stirred for overnight at room temperature. The reaction was quenched by the addition of water (50 mL) at room temperature, The resuiting mixture was extracted with EtGAc (3 x 50 ml). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.23 g) was purified by reverse flash chromatography to afford 7-bromo-5- fiuoro-2,3-dihydro-1 ,3~benzoxazol~2~one (800 mg, 61.8%) as a yeiiow solid. ¹H NMR (400 MHz, methanol-d4) d 7.08 (dd, J * 9.5, 2.4 Hz, 1 H), 6.90 (dd, J * 8.0, 2.4 Hz, 1 H).

NaH (232.7 mg, 9.70 mmoS, 3.0 equiv) was added to a stirred solution of 7-bromo~5~ fiuoro-2, 3-dihydro- 1 ,3~benzoxazol~2~one (750.0 mg, 3.23 mmol, 1.0 equiv) in THE (50 ml) at 0 °C under nitrogen atmosphere, The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added 3-benzyl-3-azabicyclo[3.3.1]nonan-9-one (815.5 mg, 3.56 mmol, 1.1 equiv). Then to the above mixture was added t-BuLi (7.46 ml, 9,70 mmol, 3.0 equiv) dropwlse over 15 min at -78 ^C'C. The resulting mixture was stirred for additional 1 h at same temperature. The reaction was monitored by LCMS, The reaction was quenched by the addition of sat. NH₄CI (aq.) (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3x100 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 7-[3-benzyl-9~hydroxy-3~aza~ bicycio[3.3.1]nonan-9-yl]-5-fluoro-2 3-dihydro-1,3-benzoxazoi-2-one (730 mg, 53.1%) as a yellow solid. LCMS; m/z (ES+), [M+H]^÷ = 383.

To a stirred solution of 7 [3-benzyl 9 hydroxy-3~azabicycfo[3.3.1]nanan-9~yl]-5-f]uoro- 2,3-dihydro-1,3-benzoxazol-2-one (700,0 mg, 1,83 mmol, 1.0 equiv) in trimethoxymethane (10 mL) was added H2SQ4 (1 -00 mL, 18.8 mrnoi, 10.1 equiv) dropwise at 0 °C. The resulting mixture was stirred for additional 30 min at room temperature. When the reaction was complete the reaction was quenched with water (20 mL) at room temperature. The aqueous layer was extracted with Ef₂O {3 x 20 mL). The mixture was neutralized to pH 8 with saturated Na₂CO₃ (aq.). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na₂SO₄. After fiitration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLG (PE/EtOAc 5:1) to afford 7-[3-benzyl-9-methoxy-3-azabicyclo[3.3,1)nonan-9-yl]-5- fluoro-2,3~dihydro-1 ,3-benzoxazo!-2-one (388.0 mg, 48.7%) as a yellow solid.

To a stirred mixture of 7-f3-benzyl-9-methoxy-3-azabicyclo[3,3,1]nonan~9-yl]-5~fluoro- 2,3-dihydro-1 ,3-benzoxazol-2-one (380.0 mg, 0.958 mmol, 1.0 equiv) and Pd(OH)³/C (403.8 mg, 1.150 mmol, 1.20 equiv, 40%) in MeOH (20 mL) were added HCOONH₄ (604.4 mg, 9.59 mmol, 10.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 20 min at 65 °C. The resuiting mixture was filtered, the filter cake was washed with MeOH (3 X 50 mL). The filtrate was concentrated under reduced pressure to afford crude product 5-fluoro-7-[9-methoxy~3~azabicyclo[3.3.1]nonan-9-yl]-2,3~dihydro~1 ,3~benzoxazol-2- one (189mg, 54.7%) as a yellow solid. LCMS: m/z (ES+), [M+H]⁺ * 307.

To a stirred solution of 5-fluoro-7~[9-meiha>ty~3~azabicyGlo[3.3.1]nonan~9~yl]-2,3- dihydro-1 ,3-benzoxazol-2-one (80 mg, 0.261 mmol, 1.0 equiv) in 5 mL MeOH were added HCI/MeOH (0.39 mL, 0,390 mmol, 1.5 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 30 min at room temperature then concentrated under reduced pressure. The crude product (103 mg) was purified by Prep-HPLC to afford Compound 8, 5-fluoro-7-(9-methoxy-3-azabicyclo(3.3.1]nonan-9-yl]-2,3-dihydro-1 ,3- benzoxazoS-2-one hydrochloride {60 mg, 52.6%), as a white solid. LCMS : m/z (ES+), [M+H]⁺ = 307, [M-OCH₃]⁺ “ 275. ¹H NMR (400 MHz, Methanol-d4) 6 7.04 {dd, J ~ 11.4, 2.5 Hz, 1 H),

6.99 (dd, J = 7.4, 2.3 Hz, 1H), 3.73 (dd, J = 13.3. 4.0 Hz, 2H), 3.40 (q, J = 11,5, 8.4 Hz, 3H),

2.99 (s, 3H), 2.87 (s, 1 H), 2.06-1.55 (m, 6H).

Compound 1

Into a 500 mL round-bottom flask were added 4~bromo-1 ,3-dihydroindol~2-one (5.0 g, 23.6 mmol, 1.0 equiv) and THF (150.0 mL) at room temperature. Then NaH (2,83 g, 70.7 mmol, 3.0 equiv, 60%) was added at 0 °C. After stirred for 1 h, to the above mixture was added t-BuLi (36.3 mL, 47.2 mmol, 2.0 equiv) dropwise over 20 min at -78 °C and stirred for additional 1 h at -78 °C under nitrogen atmosphere. Then 3-benzyl-3-azabicyclo[3.3.1|nonan- 9-one (5,94 g, 25.9 mmol, 1.1 equiv) was added and stirred for overnight at room temperature. The reaction was quenched with sat. NH₄CI (aq.) at 0 °C. The resulting mixture was extracted with EfOAc, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (5 g) was purified by Prep-TLC with the following conditions (EA:PE=1 :3) to afford 4~[3-benzyl~9-hydroxy~3~azabicycio[3.3.1]nonan-9-yl]-6- fluoro-2,3-dihydro-1 H-indol-2-one (2,3 g, 26,9%) as a light yellow solid. LCMS: m/z (ES+), EM+HG = 363. ¹H NMR {400 MHz, DMSO-d6) d 10.36 (d, J = 9.7 Hz, 1 H), 7.37 ~ 7.27 (m, 3H), 7.27 - 7.11 (m, 3H), 7.07 (dd, J = 8.1, 4.3 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 4.66 (d, J = 11.5 Hz, 1 H), 3.56 (d, J = 5.0 Hz, 2H), 3.23 - 3.14 (m, 2H), 2.92 (d, J = 10.3 Hz, 1H), 2.78 (d, J = 11.0 Hz, 1H), 2.68 (d, J = 10.4 Hz, 2H), 2.45 (s, 1 H)„ 2.38 (s, 1H), 2.28 (d, J = 11.3 Hz, 1 H), 1.65 (t, J = 9,6 Hz, 2H), 1,54 {dd, J = 13.1 , 6.7 Hz, 1H), 1.40 (id, J = 15.6, 14.3, 6.9 Hz, 1 H), 1.23 (d, J = 12.0 Hz, 1H),

Into a 50 mL sealed tube were added 4-[3~benzyl-9-hydroxy-3~azabicyclo[3.3,1]nonan- 9-yl]-1 ,3-dihydroindol-2-one (2.0 g, 5.52 mmol, 1.0 equiv) and HC(OMe)₃ (10.0 mL) at room temperature. Then H₂SO₄ (1.50 mL) was added dropwise, and the mixture stirred for 5 min at room temperature. The reaction was quenched with HCi 2N (50 mL) at 0 °C, washed with PE/EA = 3:1 (3 x 50 mi). The water phases were extracted with CH₂CI₂/CH₃OH = 10:1 (3 x 50 mL), then basifsed the organic layers to pH 10 with NH3Ή2O. Combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was dissolved in THF (7 mL), then hexane (21 mL) was added slowly, the solid was re-crystallized and collected by filtration to afford 4~[3~ benzyl-9-methoxy-3-azahicyclo[3.3.1]nonan-9-yl]-1,3-dihydroindol-2-one (1.2 g, 57.8%) as light yellow solid. LCMS: m/z (ES+), [M+Hf =377.

Into a 8 mL sealed tube were added 4-[3~benzyl-9-methoxy~3-azabicyc!o[3.3.1]norian- 9-yS]-2,3-dihydro-1 H-indol-2-one (100 mg, 0,27 mmol, 1 equiv) and Pd(OH)z/C (20 mg) in MeOH (10 mL). The reaction was stirred under hydrogen atmosphere for 6 h. The solid was filtered out, and the solvent was concentrated. The crude product was purified by Prep-HPLC to afford 4-[9-methoxy~3~azabicyclo[3.3.1]nonan-9-yl]~2,3-dihydro~1H~indoS~2-one (42 mg, 55.2%) as a white solid. LCMS; m/z (ES+), [M+H)+ = 287.

Into a 8 mL sealed tube were added 4-[9-meihoxy-3-azabicyclo[3.3.1]nonan-9-yS]-2,3- dihydro-1H-indol-2~one( 34 mg, 0.12 mmol, 1 equiv) and MeOH (1 mL). To the above mixture was added hydrogen chloride (0.12 mL, 0,12 mmol, 1,0 equiv) dropwise. The resulting mixture was stirred for 30 min and then concentrated. The solid was freeze dried from water to afford Compound 1, 4-[9-m8thoxy-3-azabicyclo[3,3.1]nonan-9-yl]-2,3-dihydro-1 H-indol-2-one hydrochloride, (28,3 mg, 73.8%) as a white solid. ¹H NMR (Deuterium Oxide, 400 MHz) 1.43 - 1.63 (2H, ddt), 1.75 -1.83 (1 H, d), 1.86 -1.94 {1 H, d), 2.74-2.79 (3H, s), 2.93 - 2.98 (1 H, s), 3.29- 3,40 (2H, t), 3.54 - 3.62 (1H, d), 3.62 -3.72 (3H, d), 6.95 -7.02 (1 H, d), 7.15 - 7.22 (1 H, d), 7.25 - 7,34 (1 H, t).

To a stirred solution of 3-bromohenzene-l ,2-diamine (2.0 g, 10.7 mmol, 1 equiv) and CDl (2.60 g, 16.0 mmol, 1.5 equiv) in 10 ml DMF at room temperature under air atmosphere. The resuiting mixture was stirred for additional overnight at room temperature. The reaction was monitored by ICMS. The reaction was quenched by the addition of water (50 mL) at room temperature. The aqueous fayer was extracted with EtOAc (3x50mL), the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to afford 4-bromo-2,3-dihydro-1H-1,3-benzodiazoi-2-one (1.3 g, 57.1%) as a yellow solid. LCMS: m/z (ES+), [M+H]⁺ = 212.95.

A solution of 4~bromo~2,3~dihydro-1H~1,3-benzodiazol~2-one (800 mg, 3,76 mmol, 1 equiv) in 20 mL THF was treated with NaH (901.3 mg, 22,5 mmol, 6.0 equiv) at 0 °C under nitrogen atmosphere.The resulting mixture was stirred for additional 30 min. 3-Benzyl-3- azabicyclo[3,3.1]nonan-9~one (1,03 g, 4.51 mmol, 1.2 equiv) and t-BuLi (8.67 ml, 11.3 mmoi, 3.0 equiv) were added dropwise over 15 min at -78 °C. The resulting mixture was stirred for additional 2 h at -78 °C. The reaction was monitored by LGMS. The reaction was quenched by the addition of sat, NH₄CI (aq.) (20 mL) at 0 °C. Then the aqueous layer was extracted with EtOAc (3 x 100 mL), The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAe 2:1) to afford 4-[3-benzyl-9~hydrQxy-3~ azabicyclo(3.3.13nonan-9-yl]-2,3-dihydro-1 H-1 ,3-benzodiazoi-2-one (500 mg, 36.4%) as a brown solid. LCMS: m/z (ES+), [M+H] = 364.20.

To a stirred solution of 4-[3-benzyl-9-hydroxy-3-azabicyclo[3.3.1]nonan-9-yl]-2,3- dihydro-1H-1,3-benzodiazol-2-one (400.0 mg, 1.10 mmol, 1.0 equiv) in trimethoxymethane (5 mL) was added sulfuric acid (2,5 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 30 min at room temperature. The reaction was monitored by LCMS. The reaction was quenched with water (10mL) at 0 °C, The resulting mixture was washed with 3x100 mL of Et_?.0. The mixture was basified to pH 9 with saturated Na₂CO₃ (aq.). The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (3x50 mL) and dried over anhydrous Na₂SO₄, After filtration, the fiitrate was concentrated under reduced pressure. The residue was purified by Prep-TLG (PE/EtOAc 1 :1) to afford 4-[3-benzyl-9-methoxy-3-azabicyclo[3.3.13nonan-9-yl]-2,3- dihydro-1H-1,3-benzodiazol-2-one (160 mg, 39%) as a yellow oil, LCMS: m/z (ES+),[M+H]⁺ = 378.20.

To a stirred solution of 4-[3-benzyl-9-meihGxy-3-azabicyclo[3.3,1]nonan~9-yl]-2,3- dihydro-1H-1,3-benzodiazol-2-one (160.0 mg, 0.42 mmol, 1 equiv) in 5 mL MeOH were added HCO₂NH₄ (267.3 mg, 4.24 mmol, 10 equiv) and Pd(OH)₃/C (119.0 mg, 0.85 mmol, 2 equiv) at room temperature under hydrogen atmosphere. The resulting mixture was stirred for additional 15 min at 65 °C. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3x20mL). The filtrate was concentrated under reduced pressure.to afford crude product 4~[9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-2,3- dihydro-f H-1,3-benzodiazol-2-one (105 mg, 86.2%) as a colorless oil and was purified next step. LCMS: m/z (ES+), [M+H]⁺ =288.15.

A soiution of crude product 4~[9-methoxy~3 azabicyclo[3.3.1]nonan-9-yl]-2,3-dihydro- 1H-1 ,3-benzodiazol-2-one (105.0 mg) in 3 mL MeOH was treated with HCI/EbO (0,81 mL, 0.82 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred for additional 30 min at room temperature. The crude product (113 mg) was purified by Prep-HPLC to afford Compound 5, 4~[9-methoxy~3-azabicyclo[3.3.1]nonan-9~yl]-2,3-dihydro~1 H~1 ,3-benzodiazol-2-one hydrochloride (104 mg, 88.7%), as a white solid. LCMS : m/z (ES+), [M+H]⁺ “288.15. ¹H NMR (400 MHz, Methanol-d4) d 7.23 (m, 1 H), 7,18 - 7.07 (m, 2H), 4.11 - 3.97 (m, 1 H). 3.67 (m, 1H), 3.38 (m, 2H), 2.99 (s, 1 H), 2.93 (s, 3H), 2.85 (s, 1 H), 2.49 (m, 1 H), 2.09 (m, 1 H), 1.91 - 1.73 (m, 2H), 1.63 (m, 1H). 1.34 (m, 1 H).

Compound 4

Into a 250 mL round-bottom flask were added NBS (5.32 g, 29,9 mmol, 1.4 equiv), benzoylperoxide (0.52 g, 2.14 mmol, 0.1 equiv), CCl₄ (100mL) and 1 -bromo-5-fiuoro-2- methyl-3-nitro benzene (5.00 g, 21.4 mmol, 1 equiv) at room temperature. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The resulting mixture was added water and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with NaCI (aq), 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 (9:1) to afford 1~bromo~2-(bromomethyl)~5~fiuoro-3- nltrobenzene (6.0 g, 89.7%) as a Sight yellow liquid. ^!H NMR (400 MHz, Methanol-ct<) d 7.85 (ddd, J = 13.8, 7.8, 2.7 Hz, 2H), 4.84 (s, 2H).

Into a 250 ml round-bottom flask were added 1-bromo-2-(bromomefhyl)-5-fluoro~3~ nitrobenzene (2.6 g, 8.31 mmol, 1 equiv), MeOH (100 mL) and potassium cyanide (649.3 mg, 9.97 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The crude reaction was diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NaCI (aq) 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 (3:1 ) to afford 2-(2-bromo-4-fluoro-6-nitrophenyl)acetonitrile (1.80 g, 83.6%) as a light yellow liquid. ¹H NMR (400 MHz, Methano!-d4) d 7.98 (dq, J = 8.4, 2.7 Hz, 2H), 4.19 (s, 2H),

Into a 100 mL round-bottom flask were added 2-(2-bromo-4-f!uoro~6~nitrophenyl)- acetonitrile (1.8 g), HCI (5 mL) and 1,4-dioxane (20 mL) at room temperature. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. To the resulting mixture was added water and extracted with EtOAc (3x 20 ml). The combined organic layers were washed with NaCI (aq), dried over anhydrous NaaSCL. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-(2-bromo-4-fluoro-6-nitrophenyl)- acetic acid (1.6 g, 82.8%) as a yellow solid. ¹H NMR (400 MHz, DMSG-efe) d 12.72 (s, 1 H), 8.13 (dd, J= 7.9, 2.7 Hz, 1H), 8.05 (dd, J = 8.4, 2.8 Hz, 1 H), 3.98 (s, 2H).

To a stirred solution of 2-(2-bromo-4-fluoro-6-nitrophenyl)acetic acid (14,0 g, 50,4 mmol, 1 equiv) in MeOH (60 mL) was added SOGh (12,0 g, 100.7 mmol, 2 equiv) dropwise a! 0 °C under air atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with PE/EtOAe (6:1) to afford methyl 2 -2-bromo-4-fluoro-6-nitrophenyl)acetate (10 9,68.0%) as a yellow solid. LCMS: m/z (ES+), [M+H]⁺ ^291.9. ¹H NMR (400 MHz, Methanol- d₄) d 7,93 - 7.85 (m, 2H), 4.15 (s, 2H).

To a stirred solution of methyl 2-(2-bromo-4-fiuoro~6~nitrophenyl)acetate (10.0 g, 34,2 mmol, 1 equiv) and NH₄Cl (0.1 mL) in EtOH (90 mL) were added Fe (15.3 g, 273,9 mmol, 8 equiv) at room temperature under air atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere, The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (8:1) to afford 4-bromo-6-fiuoro-2,3-dihydro-1H-indol- 2-one (5.0 g, 63,5%) as a yellow solid, LCMS: m/z (ES+), [M+H]⁺ 229,95. ¹H NMR (400 MHz,

Methanol-d₄) d 6.96 (dd, J = 9.3, 2 2 Hz, 1 H), 6.68 (dd, J = 8.8, 2,2 Hz, 1 H), 3.47 (d, J = 1.9 Hz, 2H).

4-bromo-6-fluoro-2_!3-dihydro-1H-sndoS-2-one (1.0 g, 4.35 mmol, 1 equiv) was dissolved in THF (30 mL) in a seated tubed at room temperature. NaH (125.2 mg, 5.22 mmol, 1.2 equiv) was added at 0 °C, t-BuLi (55.7 mg, 0.87 mmol, 2 equiv) was added dropwise over 2 min at -78 °C and stirred for additional 1 h at -78 °C under nitrogen atmosphere. 3-Benzyl-3- azabicyc!o[3.3.1]nonan-9-one (1.10 g, 4.78 mmol, 1.1 equiv) was added and the reaction was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resuiting mixture was extracted with EtOAc (3 x30 mL), The combined organic layers were washed with brine (3x5 ml), dried over anhydrous Na₂SO₄ After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.50 g) was purified by Prep-HPLC with the following conditions (EA:PE=1:3) to afford 4-[3-benzyl- 9-hydroxy-3-azabicyclo[3.3,1]nonan-9-yl]-6-fiuoro-2,3-dihydro-1 H-indoi-2-one (0.8 g, 48.37%) as a light yellow solid. LCMS: m/z (ES+), [M+H]⁺ = 381,

into a 50 mL sealed tube were added 4-[3-benzyl-9-hydroxy-3-azabicydo[3.3.1]nonan- 9~yl]-6-fiuoro-2,3~dihydro-1H-indoS-2~one (300 mg, 0.79 mmol, 1 equiv) and HC(OMe)₃(15 mL) at room temperature. To the above mixture was added H₂SO₄ (0.3 mL) dropwise over 0.5 min at room temperature. The resulting mixture was stirred for additional 20 min at 0 °C. The resulting mixture was extracted with DCM(3 x 50 mL). The combined organic layers were washed with brine (3x15mL) and 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 silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 4-(3-benzyl-9-methoxy-3-azabicyclo[3.3.1]nonan-9-yl]-6-fluoro-2,3- dihydro-1H-indol-2~one (200 mg, 64.3%) as light yellow solid. LCMS: m/z (ES+), [M+H]⁺ =

395.

To a stirred solution 4-[3-benzyl-9-methoxy-3-azabicyclo[3-3.1]nonan-9-yl]-6-fluoro- 2,3-dihydro-1 H-indoi-2-one (800,0 mg, 2,03 mmol, 1.0 equiv) in EtOH (30.0 mL) at room temperature under nitrogen atmosphere. To the above mixture was added Pd(OH)₂/C (800.2 mg, 570 rnmof, 2 8 equiv) hydrogen atmosphere, the resuiting mixture was stirred for additional 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EtOH (3x10 mL). This resulted in 6-fluoro-4~[9-methoxy-3-azabicycla[3,3.1]- nonan-9-yl]-2,3-dihydro-1H-indol-2-one (50Gmg, 81.0%) as a Sight yei!ow solid. LCMS: m/z (ES+), [M+H]^* = 305. ¹H NMR (400 MHz, DMSO-d₆) d 10.73 (S, 1 H), 8.75 (s, 1 H), 6.86 (dd, J ^ 12.2, 2.4 Hz, 1 H), 6.70 (dd, J = 8.5, 2.2 Hz, 1 H), 3.51 - 3.43 (m, 2H), 3.30 (d, J = 3.7 Hz, 1H), 3.16 (dd, J= 19.5, 12.7 Hz, 2H), 2,83 (s, 1H), 2.77 (s, 3H), 2.74 2.69 (m, 1 H), 2.11

1,80 (m, 3H), 1.73 (d, J ~ 12.9 Hz, 1H), 1 ,35 {d, J ~ 8.4 Hz, 2H).

Into a 50 mL round-bottom flask were added6-fiuoro-4-[9-m8thoxy-3-azabicyclo- [3,3,1]nonan-9-yl]~2,3-dihydro-1 H-indol-2-one (150 mg, 1 equiv) and HCI/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 soiid freeze dried from water to give Compound 4, 6-fiuoro-4-[9-methoxy-3-azabicyclo[3,3.1lnonan-9-yl]-2,3-dihydro-1 H-indof-2- one hydrochloride, (140 mg, 83,4%) as a light yei!ow soiid. LCMS: m/z (ES+), [M+H]⁺ = 305, 1H NMR (400 MHz, DMSO-d₆) d 10.73 (s, 1H), 8.75 (bs, 1H), 6.86 (d, J - 12 Hz, 1H), 6.70 (d, J= 8.4 Hz, 1 H), 3.67-3.12 (m, 6H), 2.83 (s, 1 H), 2.77 (s, 3H), 2.72 (s, 1H), 2.11-1.80 (m, 3H), 1.73 (m , 1 H), 1,35 (m, 2H),

Scheme 2.

Compound 7

To a stirred solution of 4-[3-benzyl-9-nnethoxy-3-azabseyclo[3.3.1|nonan-9-yl]-6-fiuoro- 2,3-dihydro-1 H-indoi-2-one (500,0 mg, 1.27 mmol, 1.0 equiv) in MeOH (20.0 mL) were added Pd(OH)2/C (500.2 mg, 3,56 mmol, 2.8 equiv) in portions at room temperature under nitrogen atmosphere. The mixture was stirred for additional 4 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2x20 ml). The filtrate was concentrated under reduced pressure to afford 6-fiuoro-4-[9-methoxy-3- azabicyclo[3,3.13nonan-9-yl]-2,3-dihydro-1 H-indoi-2 one (300,0 mg, 77.8%) as a brown solid. The crude product mixture was used in the next step directly without further purification. LCMS: m/z (ES+), [M+H]⁺ =291.9.

To a stirred mixture of 6-fluoro~4~[9-hydroxy-3-azabicyclo[3.3.1]nonan-9-yl]~2,3~ dihydro-1 H-indoi-2-one (500,0 mg, 1 ,72 mmoi, 1.0 equiv) and TEA (261.4 mg, 2,58 mmoi, 1.5 equiv) in DCM (25.0 mL) was added N-(Benzyloxycarbonyloxy)succinimide (471,7 mg, 1 ,89 mmol, 1.1 equiv) in portions at room temperature under nitrogen atmosphere. The mixture was stirred for additional 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH2CI2 (3 x 50 mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous MgSCTt. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to afford benzyl 9-(6-fiuoro-2-oxo- 2,3-dihydro-1 H-indo 4-yl)-9-hydroxy-3~azabicydo[3.3.1]nonane~3 carboxylate(450 mg, 61.6%) as a tight yellow solid, LCMS; m/z (ES+), [M+H]^* = 425.

To a stirred solution of benzyl 9-(6-fluoro-2-oxo-2,3-dihydro-1 H-indol-4-yl)-9-fiydroxy-3- azabicyclo[3.3.1]nonane-3-carboxylate (200.0 mg, 0.471 mmol, 1.0 equiv) in CH₂Cl₂(20.0 mL) was added AiCl₃(314.1 mg, 2.36 mmol, 5.0 equiv) in portions at 0 °C under nitrogen atmosphere was stirred for 30 min. Then added AllylTMS (537.1 mg, 4.71 mmol, 10.0 equiv) was stirred for 30 min. The mixture was basified to pH 10 with NaOH. The resulting mixture was extracted with EtOAc (3 x 15mL). The combined organic layers were washed with brine (3x3 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 6-fiuoro~4- (9-(prop-2-en-1-yl)-3-azabicyclo[3.3.13nonan-9-yl]-2,3-dihydro-1 H-indol-2-one(85mg,38.25%) as a light yellow solid. LCMS: m/z (ES+), [M+H]⁺ =315.

To a stirred solution of 6-fluoro-4-[9-(prop-2-en-1-yl)-3-azabicyclo[3,3.1]nonan-9-yl]- 2,3~dihydro-1H-indoi-2~one (300.0 mg, 0.954 mrnol, 1.0 equiv) in ethyl acetate (15.0 ml) was added HCI in Et₂O (1.5 mL) dropwise at room temperature under nitrogen atmosphere. The mixture was stirred for additional 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford the crude product, The resulting mixture was Stile red, the filter cake was washed with MeOH (2x20 ml). The filtrate was concentrated under reduced pressure to afford the crude product 6-fiuoro-4-(9-(prop-2- en-1 -yl)-3~azabicydo[3.3.1 ]nonan-9~yl]-2,3-dihydro~1 H-indol-2-one hydrochloride (300 mg, 89.6%) as a white solid, LCMS: m/z (ES+), [M+H]⁺ =315.

To a stirred solution of 6-fluoro-4-[9-(prop-2-en-1-yl)-3-azabicyclo[3,3.1]nonan-9-yl]- 2,3-dihydro-1 H-indoi-2-one hydrochloride (200.0 mg, 0.570 rrsmoi, 1.0 equiv) in CH3OH (10 ml) was added PtO₂ (129.4 mg, 0.570 mmol, 1.0 equiv) dropwise at room temperature under hydrogen 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 (2x20 mL) to afford the 6-f1uoro-4-[9-propyl-3-azabicyc!o[3.3.1]nonan-9-yl]-2,3-dihydro- 1H-indol-2-one (150mg, 83.2%). LCMS: m/z (ES+), [M+H]⁺ =317.

Into a 50 mL round-bottom flask were added 6-fIuoro-4-(9-(prop-2-en- 1 -yI )-3- azabicyclo[3.3.13nonan-9-yl]-2,3-dihydro-1 H-indol-2-one (200 mg) and HCI/diethyl ether (1.5 ml). The resulting mixture was stirred for 10 min at under air atmosphere. The resulting mixture was concentrated under reduced pressure. The solid was freeze dried from water to one hydrochloride (173mg,77.6%), as a Sight yeilow solid, LCMS: m/z (ES+), [M+H]⁺ = 317, ¹H NMR (400 MHz, DMSO-d₆) d 10.64 (s, 1H), 10,21 - 9.64 (m, 1H), 8.25 (s, 1H), 6.66 (dd, J =

12.8, 2.5 Hz, 1 H), 6.56 (dd, J ^ 8.4, 2.3 Hz, 1H), 3.55 (dd, J 46.8, 17.6 Hz, 2H), 3.33 (s, 1 H), 3.29 — 3.13 (m, 3H), 2.55 (s, 2H), 1.97 - 1.79 (m, 2H), 1.72 - 1.46 (m, 5H), 1.32 (dt, J = 11.8,

5.4 Hz, 1 H), 1.05 - 0.95 (m, 1 H), 0.72 (d, J ~ 4.1 Hz, 4H).

In Vitro Characterization

Functional Activity (GTPvS Binding) Assay

The (³⁵S]GTPyS assay measures the functional properties of a compound by quantifylng the level of G-protein activation foilowing agonist binding in studies using stably transfected ceils, 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-HCi, pH 7.4, 3 mM MgCl₂, 0.2 mM EQTA, 5 mM GDP, and 100 mM NaCI. CHO cei! membranes stably expressing the human p opioid receptor were pre- incubated with scintillation proximity assay beads from PerkinElmer© (WGA PVT SPA) for 30 minutes, at 8 mg membrane and 350 mg 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 finai concentration of 0.020 nM [35S]GTPyS 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 Table 1.

Claims

CLAE&!S

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein

R₁ is C_1-C₆ alkyl or C_1-C₄ alkoxy, wherein the alkyl or C_1-4 alkoxy is optionally substituted with 1, 2, or 3 haiogen; R₂, R₃, and R₄ are each, independently, selected from the group consisting of H, C₁- C₄ alkyl, C₁-C₄ alkoxy, hydroxy, and haiogen, wherein the C₁-C₄ alkyl is optionally substituted by 1, 2, or 3 halogen; R₃ is H or C_1-C₄ alkyl;

X is selected from the group consisting of CR_aR_b, O, S, NR_a, and C(=O); and R_a and R_b are each, independently, H or C_1-C₆ alkyl,

2. The compound claim 1 , wherein R₁ is C_1-3 alkoxy.

3. The compound of claim 1 or 2, wherein R₁ is me!hoxy.

4. The compound of claim 1 or 2, wherein R₁ is ethoxy.

5. The compound claim 1 , wherein R₁ is C_1-3 aikyl.

6. The compound of ciaim 1 or 5, wherein R₁ is methyl.

7. The compound of ciaim 1 or 5, wherein R₁ is ethyl.

8. The compound of ciaim 1 or 5, wherein R₁ is propyl.

9. The compound of any one of claims 1-8, wherein R₄, R3, and R₄, are each H.

10. The compound of any one of claims 1-8, wherein R_2: is haiogen.

11. The compound of any one of claims 1-8, wherein R₃ is fluoro, R₃ is H, and R₄ is H.

12. The compound of any one of claims 1-8, wherein R₂ is halogen.

13. The compound of any one of claims 1-8, wherein R₂ is fluoro, R₂ is H, and R₄ is H.

14. The compound of any one of claims 1-8, wherein R₄ is halogen.

15. The compound of any one of claims 1-8, wherein R₄ is fluoro, R₃ is H, and R₂. is H.

16. The compound of any one of claims 1-15, wherein X is CR_aR_b.

17. The compound of any one of ciaims 1-16, wherein X is CH_2.

18. The compound of any one of claims 1-16, wherein X is C(CH3)_2.

19. The compound of any one of claims 1-15, wherein X is O.

20. The compound of any one of claims 1-15, wherein X is NH,

21. The compound of claim 1 , wherein X is O;

R₁ is C_1-C₄ alkyl or C_1-C₄ alkoxy; and

R₂, R₃, and R₄, are each H.

22. The compound of claim 1 , wherein X is NH;

R₁ is C_1-C₄ alkyl or C₁-C₄ alkoxy; and

R₁, R_3, and R₄, are each, independently, H or halogen.

23. The compound of claim 1 , wherein X is CR_aR_b;

R₁ is C₁-C₄ alkyl or C₁-C₄ alkoxy; and

R₂, R₃ and R₄, are each, independently, H or halogen,

24. The compound according to claim 23, wherein R_a and R_a are both H.

25. The compound according to claim 23, wherein R₃ and R₃ are both methyl

26. The compound according to any one of c!airns 1-25, wherein the compound of Formula l is selected from the group consisting of:

27. A pharmaceutical composition comprising the compound of any of claims 1-26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

28. A method of treating pain in a subject in need thereof comprising administering to the subject the compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27.

29. The method of claim 28, 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, musculoskeletal pain and neuropathic pain.

30. The method of claim 28, wherein the pain is inflammatory pain, thermal pain, acute pain, chronic pain, musculoskeletal pain, and neuropathic pain.

31. The method of claim 28, wherein the pain is chronic pain.

32. The method of claim 28, wherein the pain is muscuioskeletal pain.

33. Use of a compound of any one of claims 1 fo 26 for the manufacture of a medicament for pain.

34. Use of a compound of any one of claims 1 to 26 for the manufacture of a medicament for chronic pain.

35. Use of a compound of any one of claims 1 to 26 for the manufacture of a medicament for musculoskeletal pain.