Substituted pyrrolidinyl and piperidinyl compounds and related therapeutic methods

Abstract

The present invention provides compounds useful in the treatment of narcolepsy or cataplegia in a subject in need thereof. Also provided herein are related pharmaceutical compositions and methods.

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 353,985, filed on June 21, 2022. The entire contents of the above-identified application are incorporated herein by reference. Technical Field

[0003] The present invention relates to substituted pyrrolidinyl and piperidinyl compounds, in particular to substituted pyrrolidinyl and piperidinyl compounds having agonist activity. Background Art

[0004] Orexin is a neuropeptide synthesized and released by a subpopulation of neurons in the lateral hypothalamus and its surrounding areas. It consists of two subtypes: orexin A and orexin B. Orexin A and orexin B bind to orexin receptors. Orexin receptors are G protein-coupled receptors that are preferentially expressed in the brain. There are two subtypes of orexin receptors (type 1 and type 2) (Cell, Vol. 92, 573-585, 1998). It is known that the activation of orexin receptors is important for a variety of central nervous system functions, such as maintaining wakefulness, energy homeostasis, reward processing and motivation (Saper et al., TRENDS in Neuroscience 2001; Yamanaka et al., Neuron 2003; Sakurai, Nature Reviews Neuroscience 2014).

[0005] Narcolepsy is a neurological disease that causes excessive daytime sleepiness, sudden muscle paralysis attacks (cataplexy) and disturbed sleep patterns (Mahoney et al., Nature Reviews Neuroscience, 2019). It is known that narcolepsy is caused by the degeneration of orexin neurons. Narcolepsy symptoms can be simulated in transgenic mice designed to degenerate orexin neurons, and orexin peptides can be administered intraventricularly to reverse its symptoms (Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004). Studies on orexin-2 receptor knockout mice have shown that orexin-2 receptors play a priority role in maintaining wakefulness (Cell, Vol. 98, 437-451, 1999, Neuron, Vol. 38, 715-730, 2003). Therefore, orexin-2 receptor agonists may be therapeutic agents for narcolepsy or other disorders exhibiting excessive daytime sleepiness, such as Parkinson's disease (CNS Drugs, Vol. 27, 83-90, 2013; Brain, Vol. 130, 2007, 1586-1595).

[0006] It is assumed that compounds having agonist activity at orexin-2 receptors can be used as novel therapeutic agents for narcolepsy, idiopathic hypersomnia, narcolepsy, sleep apnea syndrome, disturbances of consciousness such as coma, narcolepsy syndrome, hypersomnia syndrome characterized by hypersomnia (e.g., in Parkinson's disease, Guillain-Barre syndrome or Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss or sepsis, etc. (Cell Metabolism, Vol. 9, 64-76, 2009; Neuroscience, Vol. 121, 855-863, 2003; Respiration, Vol. 71, 575-579, 2004; Peptides, Vol. 23, 1683-1688, 2002; WO 2015 / 073707; Journal of the American College of Cardiology, Vol. 66, 2015, pages 2522-2533; WO 2015 / 048091; WO 2015 / 147240).

[0007] Some compounds with orexin-2 receptor agonist activity have been reported (U.S. Patent No. 8,258,163; WO2015 / 088000; WO 2014 / 198880; Journal of Medicinal Chemistry, Vol. 58, pages 7931-7937; US20190040010; US20190031611; US ​​20170226137). However, it is believed that these compounds are not satisfactory, for example, in terms of activity, pharmacokinetics, penetration into the brain / central nervous system, or safety, and it is desirable to develop improved compounds with orexin-2 receptor agonist activity. Summary of the invention

[0008] The object of the present invention is to provide piperidinyl and pyrrolidinyl compounds having orexin-2 receptor agonist activity.

[0009] Therefore, in a first aspect, the present invention provides a compound represented by Formula IA or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] Ring A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, further wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen;

[0013] X is N or CH;

[0014] Y is S(=O) 2 , C(=O) or S(=O)(=NR e );

[0015] R e Choose from H, C 1 -C 3 Alkyl or C 3 -C 5 A group consisting of cycloalkyl groups;

[0016] E is selected from the group consisting of: NR a R b , C 1 -C 3 Alkylene-NR a R b , C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group, C 1 -C 3 Alkylene-(4- to 10-membered heterocyclic group), C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5- to 7-membered heteroaryl and C 1 -C 3 Alkylene-(5- to 7-membered heteroaryl), wherein the C 1 -C 3 Alkylene-NR a R b , C 1 -C 3 Alkyl, C2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group, C 1 -C 3 Alkylene-(4- to 10-membered heterocyclic group), C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5- to 7-membered heteroaryl or C 1 -C 3 Alkylene-(5- to 7-membered heteroaryl) is unsubstituted or substituted by one or more halogen, hydroxy, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution;

[0017] R a and R b Each independently selected from H, C 1 -C 3 Alkyl, C 3 -C 5 A group consisting of a cycloalkyl group and a 4- to 7-membered heterocyclic group; wherein said C 1 -C 3 Alkyl, C 3 -C 5 The cycloalkyl or 4- to 7-membered heterocyclyl is unsubstituted or substituted by one or more halogen, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution;

[0018] Or, alternatively, R a and R b Together with the N atom to which they are attached, they form a 4- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl, wherein the 4- to 7-membered heterocyclyl or the 5- to 7-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxyl, NR c Rd , C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or C substituted by 1-3 halogens 1 -C 3 Alkyl substitution;

[0019] R 1 Selected from the group consisting of: C(=O)-C 1 -C 4 Alkyl, C(=O)-C 1 -C 4 Alkoxy, C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C 6 -C 10 Aryl), C(=O)-(CR c R d ) n -(5- to 10-membered heteroaryl), C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclic group), (CR c R d ) n -(C 6 -C 10 Aryl) and (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl, 4- to 7-membered heterocyclic group, C 6 -C 10The aryl or 5- to 10-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution;

[0020] R c and R d are independently H, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 alkyl;

[0021] n is 0, 1, or 2;

[0022] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is independently H, halogen, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 alkyl;

[0023] Or, alternatively, R 3 and R 6 Together they form unsubstituted C 1 -C 3 Alkylene or C substituted by one or more halogen 1 -C 3 Alkylene;

[0024] Or, alternatively, R 4 and R 5 Together they form unsubstituted C 1 -C 3 Alkylene or C substituted by one or more halogen 1 -C 3 Alkylene;

[0025] m is 0 or 1;

[0026] p is 0, 1, 2, 3 or 4; and

[0027] Each R 9 Independently selected from the group consisting of deuterium, halogen, hydroxyl and cyano.

[0028] In one embodiment, provided herein is a compound of Formula IA having the structure of Formula I or a pharmaceutically acceptable salt thereof:

[0029]

[0030] in:

[0031] Ring A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, further wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen;

[0032] X is N or CH;

[0033] Y is S(=O) 2 , C(=O) or S(=O)(=NR e );

[0034] R e Choose from H, C 1 -C 3 Alkyl or C 3 -C 5 A group consisting of cycloalkyl groups;

[0035] E is selected from the group consisting of: NR a R b , C 1 -C 3 Alkylene-NR a R b , C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group, C 1 -C 3 Alkylene-(4- to 10-membered heterocyclic group), C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5- to 7-membered heteroaryl and C1 -C 3 Alkylene-(5- to 7-membered heteroaryl), wherein the C 1 -C 3 Alkylene-NR a R b , C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group, C 1 -C 3 Alkylene-(4- to 10-membered heterocyclic group), C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5- to 7-membered heteroaryl or C 1 -C 3 Alkylene-(5- to 7-membered heteroaryl) is unsubstituted or substituted by one or more halogen, hydroxy, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution;

[0036] R a and R b Each independently selected from H, C 1 -C 3 Alkyl, C 3 -C 5 A group consisting of a cycloalkyl group and a 4- to 7-membered heterocyclic group; wherein said C 1 -C 3 Alkyl, C 3 -C 5 The cycloalkyl or 4- to 7-membered heterocyclyl is unsubstituted or substituted by one or more halogen, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution;

[0037] Or, alternatively, R a and R b Together with the N atom to which they are attached, they form a 4- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl, wherein the 4- to 7-membered heterocyclyl or the 5- to 7-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxyl, NR c R d , C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or C substituted by 1-3 halogens 1 -C 3 Alkyl substitution;

[0038] R 1 Selected from the group consisting of: C(=O)-C 1 -C 4 Alkyl, C(=O)-C 1 -C 4 Alkoxy, C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C 6 -C 10 Aryl), C(=O)-(CR c R d ) n -(5- to 10-membered heteroaryl), C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclic group), (CR c R d ) n -(C 6 -C 10 Aryl) and (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 1 -C4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl, 4- to 7-membered heterocyclic group, C 6 -C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution;

[0039] R c and R d are independently H, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 alkyl;

[0040] n is 0, 1, or 2;

[0041] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is independently H, halogen, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 alkyl;

[0042] Or, alternatively, R 3 and R 6 Together they form unsubstituted C 1 -C 3 Alkylene or C substituted by one or more halogen 1 -C 3 Alkylene;

[0043] Or, alternatively, R 4 and R 5 Together they form unsubstituted C 1 -C 3 Alkylene or C substituted by one or more halogen 1 -C 3 Alkylene;

[0044] m is 0 or 1;

[0045] p is 0, 1, 2, 3 or 4; and

[0046] Each R 9 Independently selected from the group consisting of deuterium, halogen, hydroxyl and cyano.

[0047] Also provided herein is a pharmaceutical composition comprising a compound of any one of Formula IA or I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0048] In another aspect, provided herein is a method of treating narcolepsy in a subject in need thereof, the method comprising administering to the subject a compound of Formula IA or I, or a pharmaceutically acceptable salt thereof.

[0049] In another aspect, provided herein is a method of treating cataplexy in a subject in need thereof, the method comprising administering to the subject a compound of Formula IA or I, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0050] Provided herein are compounds useful for treating narcolepsy or cataplexy in a subject, for example, a compound of Formula IA or I, or a pharmaceutically acceptable salt thereof.

[0051] In non-limiting aspects, these compounds can modulate orexin-2 receptors. In specific embodiments, provided herein are compounds that are considered orexin-2 agonists. Therefore, in one aspect, provided herein are compounds that can be used to treat narcolepsy in a subject by acting as an agonist of orexin-2 receptors.

[0052] definition

[0053] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as used throughout the specification and claims, unless otherwise limited in specific instances, whether individually or as part of a larger group.

[0054] 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 the 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 used in the art.

[0055] As used herein, the articles "a" and "an" refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "element" means one element or more than one element. Furthermore, the use of the term "including" as well as other forms such as "include," "includes," and "included" is not limiting.

[0056] As used herein, the term "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to a measurable value such as an amount, a duration of time, etc., 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 suitable for performing the disclosed methods.

[0057] As used herein, the term “EC 50 ” refers to the concentration of a compound required to achieve 50% of the maximum observed effect of the compound.

[0058] As used herein, the term "agonist" refers to a compound that, when contacted with a target of interest (e.g., orexin-2 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.

[0059] The terms "treat," "treated," "treating," or "treatment" include reducing or alleviating at least one symptom associated with or caused by the state, disorder, or disease being treated. In certain embodiments, treatment comprises contacting an effective amount of a compound of the invention for a condition associated with narcolepsy or cataplexy with an orexin-2 receptor.

[0060] As used herein, the term "prevent" or "prevention" means that if a disorder or disease has not occurred, then there is no development, or if a disorder or disease has developed, then there is no further development of the disorder or disease. Also contemplated is the ability of an individual to prevent some or all symptoms associated with a disorder or disease.

[0061] As used herein, the term "patient", "individual" or "subject" refers to a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as sheep, cattle, pigs, dogs, cats and mice. Preferably, the patient, subject or individual is a human.

[0062] As used herein, the terms "effective amount", "pharmaceutically effective amount" and "therapeutically effective amount" refer to an amount of an agent that is non-toxic but sufficient to provide the desired biological result. The result can be a reduction or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0063] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., the material can be administered to a subject without causing adverse biological effects or interacting in a deleterious manner with any component of the composition in which it is contained.

[0064] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into 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. Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound, such as conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. The phrase "pharmaceutically acceptable salt" is not limited to monosalts or 1:1 salts. For example, "pharmaceutically acceptable salts" also include disalts, such as dihydrochloride. 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.

[0065] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful in the present invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate administration of the compound to a patient or subject. There are a variety of techniques for administering compounds in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0066] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle involved in carrying or transporting a compound useful in the present invention in or to a patient so that the compound can perform its intended function, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material. Typically, such a construct is carried or transported from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation (including the compounds useful in the present invention) and not harmful to the patient. Some examples of materials that can 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 carboxymethylcellulose, ethylcellulose, 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 glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic compatible substances used in pharmaceutical formulations.

[0067] As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, etc., which are compatible with the activity of the compounds useful in the present invention and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds useful in the present invention. Other additional ingredients that may be included in the pharmaceutical compositions for practicing the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which are incorporated herein by reference.

[0068] As used herein, unless otherwise indicated, the term "alkyl", by itself or as part of another substituent, means a straight or branched chain hydrocarbon (i.e., C 1-6 Alkyl means an alkyl group 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. 1 -C 6 Other examples of -alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl and n-hexyl.

[0069] As used herein, unless otherwise stated, the term "halo" or "halogen" alone or as part of another substituent means a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0070] As used herein, the term "alkylene" refers to a divalent aliphatic hydrocarbon group, for example, having 1 to 4 carbon atoms, which is straight or branched. This term includes, for example, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n-propylene (-CH 2 CH 2 CH 2 -), isopropylidene (-CH 2 CH(CH 3 )-)wait.

[0071] As used herein, the term "alkenyl" refers to a monovalent group derived from a hydrocarbon portion comprising at least two carbon atoms and at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. An alkenyl group (e.g., C 2 -C 8 -alkenyl) includes, but is not limited to, for example, ethenyl, propenyl, prop-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0072] As used herein, the term "alkynyl" refers to a monovalent group derived from a hydrocarbon portion containing at least two carbon atoms and at least one carbon-carbon triple bond. The triple bond may or may not be a point of attachment to another group. An alkynyl group (e.g., C 2 -C 8 -alkynyl) includes, but is not limited to, for example, ethynyl, propynyl, prop-1-yn-2-yl, butynyl, 1-methyl-2-butyn-1-yl, heptynyl, octynyl, and the like.

[0073] As used herein, the term "alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, and the like.

[0074] As used herein, the term "cycloalkyl" means a partially or fully saturated non-aromatic carbocyclic ring system with 1, 2 or 3 rings, wherein such rings can be fused. The term "fused" means that the second ring exists (i.e., is connected or formed) by having (i.e., sharing) two adjacent atoms with the first ring. Cycloalkyl also includes a bicyclic structure, which can be bridged or spirocyclic in nature, wherein each individual ring in the bicyclic changes from 3-8 atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [3.1.0] hexyl, spiro [3.3] heptyl and bicyclo [1.1.1] pentyl.

[0075] As used herein, the term "heterocyclyl" means a non-aromatic carbocyclic ring system containing 1, 2, 3 or 4 heteroatoms (independently selected from N, O and S) and having 1, 2 or 3 rings, wherein such rings may be fused, wherein the fusion is defined above. Heterocyclyl also includes bicyclic structures, which may be bridged or spirocyclic in nature, wherein each individual ring within the bicyclic ring varies from 3-8 atoms and contains 0, 1 or 2 N, O or S atoms. The term "heterocyclyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and also specifically includes, but is not limited to, epoxidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinyl, 1,3-thiazinyl, and the like. For example, the term "heterocyclyl" can include a 4- to 10-membered heterocyclyl, a 4- to 7-membered heterocyclyl, a 5- to 10-membered heterocyclyl, a 6- to 10-membered heterocyclyl, a 4- to 6-membered heterocyclyl, a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, a 7-membered heterocyclyl, an 8-membered heterocyclyl, a 9-membered heterocyclyl, or a 10-membered heterocyclyl.

[0076] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic character, ie, having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0077] As used herein, the term "aryl" means an aromatic carbocyclic ring system comprising 1, 2 or 3 rings, wherein such rings may be fused, wherein fusion is defined above. If the rings are fused, one of the rings must be fully unsaturated, and one or more of the fused rings may be fully saturated, partially unsaturated or fully unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indanyl and 1,2,3,4-tetrahydronaphthyl. For example, the term "aryl" may include C 6 -C 10 Aryl, C6 -C 8 Aryl or C 6 Aryl (ie, phenyl).

[0078] As used herein, the term "heteroaryl" means an aromatic carbocyclic ring system comprising 1, 2, 3 or 4 heteroatoms (independently selected from N, O and S) and having 1, 2 or 3 rings, wherein such rings may be fused, wherein the fused is defined above. The term "heteroaryl" includes, but is not limited to, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. For example, the term "heteroaryl" can include 5- to 10-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 6-membered heteroaryl, 6- to 10-membered heteroaryl, 6- to 8-membered heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl.

[0079] It should be understood that if an aryl, heteroaryl, cycloalkyl or heterocyclyl moiety can be bonded or otherwise attached to a specified moiety through different ring atoms (i.e., is shown or described without indicating a specific point of attachment), all possible points are contemplated, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" means 2-, 3-, or 4-pyridyl, the term "thienyl" means 2- or 3-thienyl, and so on.

[0080] As used herein, the term "substituted" means that an atom or group of atoms has replaced a hydrogen as a substituent attached to another group.

[0081] Compounds of the present invention

[0082] Therefore, in a first aspect, the present invention provides a compound represented by Formula IA or a pharmaceutically acceptable salt thereof:

[0083]

[0084] in:

[0085] Ring A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, further wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen;

[0086] X is N or CH;

[0087] Y is S(=O)2 , C(=O) or S(=O)(=NR e );

[0088] R e Choose from H, C 1 -C 3 Alkyl or C 3 -C 5 A group consisting of cycloalkyl groups;

[0089] E is selected from the group consisting of: NR a R b , C 1 -C 3 Alkylene-NR a R b , C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group, C 1 -C 3 Alkylene-(4- to 10-membered heterocyclic group), C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5- to 7-membered heteroaryl and C 1 -C 3 Alkylene-(5- to 7-membered heteroaryl), wherein the C 1 -C 3 Alkylene-NR a R b , C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group, C 1 -C 3Alkylene-(4- to 10-membered heterocyclic group), C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5- to 7-membered heteroaryl or C 1 -C 3 Alkylene-(5- to 7-membered heteroaryl) is unsubstituted or substituted by one or more halogen, hydroxy, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution;

[0090] R a and R b Each independently selected from H, C 1 -C 3 Alkyl, C 3 -C 5 A group consisting of a cycloalkyl group and a 4- to 7-membered heterocyclic group; wherein said C 1 -C 3 Alkyl, C 3 -C 5 The cycloalkyl or 4- to 7-membered heterocyclyl is unsubstituted or substituted by one or more halogen, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution;

[0091] Or, alternatively, R a and R b Together with the N atom to which they are attached, they form a 4- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl, wherein the 4- to 7-membered heterocyclyl or the 5- to 7-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxyl, NR c R d , C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or C substituted by 1-3 halogens 1 -C 3 Alkyl substitution;

[0092] R 1 Selected from the group consisting of: C(=O)-C 1 -C 4Alkyl, C(=O)-C 1 -C 4 Alkoxy, C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C 6 -C 10 Aryl), C(=O)-(CR c R d ) n -(5- to 10-membered heteroaryl), C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclic group), (CR c R d ) n -(C 6 -C 10 Aryl) and (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl, 4- to 7-membered heterocyclic group, C 6 -C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution;

[0093] R c and R d are independently H, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium1 -C 3 alkyl;

[0094] n is 0, 1, or 2;

[0095] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is independently H, halogen, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 alkyl;

[0096] Or, alternatively, R 3 and R 6 Together they form unsubstituted C 1 -C 3 Alkylene or C substituted by one or more halogen 1 -C 3 Alkylene;

[0097] Or, alternatively, R 4 and R 5 Together they form unsubstituted C 1 -C 3 Alkylene or C substituted by one or more halogen 1 -C 3 Alkylene;

[0098] m is 0 or 1;

[0099] p is 0, 1, 2, 3 or 4; and

[0100] Each R 9 Independently selected from the group consisting of deuterium, halogen, hydroxyl and cyano.

[0101] In one embodiment, provided herein is a compound of Formula IA having the structure of Formula I or a pharmaceutically acceptable salt thereof:

[0102]

[0103] in:

[0104] Ring A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, further wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C5 Cycloalkyl or halogen;

[0105] X is N or CH;

[0106] Y is S(=O) 2 , C(=O) or S(=O)(=NR e );

[0107] R e Choose from H, C 1 -C 3 Alkyl or C 3 -C 5 A group consisting of cycloalkyl groups;

[0108] E is selected from the group consisting of: NR a R b , C 1 -C 3 Alkylene-NR a R b , C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group, C 1 -C 3 Alkylene-(4- to 10-membered heterocyclic group), C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5- to 7-membered heteroaryl and C 1 -C 3 Alkylene-(5- to 7-membered heteroaryl), wherein the C 1 -C 3 Alkylene-NR a R b , C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group, C 1 -C 3 Alkylene-(4- to 10-membered heterocyclic group), C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5- to 7-membered heteroaryl or C 1 -C 3 Alkylene-(5- to 7-membered heteroaryl) is unsubstituted or substituted by one or more halogen, hydroxy, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution;

[0109] R a and R b Each independently selected from H, C 1 -C 3 Alkyl, C 3 -C 5 A group consisting of a cycloalkyl group and a 4- to 7-membered heterocyclic group; wherein said C 1 -C 3 Alkyl, C 3 -C 5 The cycloalkyl or 4- to 7-membered heterocyclyl is unsubstituted or substituted by one or more halogen, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution;

[0110] Or, alternatively, R a and R b Together with the N atom to which they are attached, they form a 4- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl, wherein the 4- to 7-membered heterocyclyl or the 5- to 7-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxyl, NR c R d , C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or C substituted by 1-3 halogens 1 -C 3Alkyl substitution;

[0111] R 1 Selected from the group consisting of: C(=O)-C 1 -C 4 Alkyl, C(=O)-C 1 -C 4 Alkoxy, C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C 6 -C 10 Aryl), C(=O)-(CR c R d ) n -(5- to 10-membered heteroaryl), C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclic group), (CR c R d ) n -(C 6 -C 10 Aryl) and (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl, 4- to 7-membered heterocyclic group, C 6 -C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution;

[0112] Rc and R d are independently H, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 alkyl;

[0113] n is 0, 1, or 2;

[0114] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is independently H, halogen, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 alkyl;

[0115] Or, alternatively, R 3 and R 6 Together they form unsubstituted C 1 -C 3 Alkylene or C substituted by one or more halogen 1 -C 3 Alkylene;

[0116] Or, alternatively, R 4 and R 5 Together they form unsubstituted C 1 -C 3 Alkylene or C substituted by one or more halogen 1 -C 3 Alkylene;

[0117] m is 0 or 1;

[0118] p is 0, 1, 2, 3 or 4; and

[0119] Each R 9 Independently selected from the group consisting of deuterium, halogen, hydroxyl and cyano.

[0120] In one embodiment of formula (I), Ring A is a phenyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0121] In another embodiment of formula (I), Ring A is a phenyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0122] In another embodiment of formula (I), Ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0123] In another embodiment of formula (I), Ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl or halogen.

[0124] In another embodiment of formula (I), Ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from halogen.

[0125] In another embodiment of formula (I), Ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from F or Cl.

[0126] In another embodiment of formula (I), Ring A is a phenyl ring, wherein said ring is substituted with 1-2 F substituents.

[0127] In another embodiment of Formula (I), Ring A is 3-fluorophenyl.

[0128] In another embodiment of formula (I), Ring A is a pyridyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0129] In another embodiment of formula (I), Ring A is a pyridyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0130] In another embodiment of formula (I), Ring A is a pyridyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0131] In another embodiment of formula (I), Ring A is a pyridyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl or halogen.

[0132] In another embodiment of formula (I), Ring A is a pyridyl ring, wherein said ring is substituted with 1-2 substituents, each of said substituents being independently selected from halogen.

[0133] In another embodiment of formula (I), Ring A is a pyridyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 alkyl.

[0134] In another embodiment of formula (I), Ring A is a pyridyl ring, wherein the ring is C 3 -C 5 The cycloalkyl group is monosubstituted.

[0135] In another embodiment of formula (I), Ring A is a pyridazinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0136] In another embodiment of formula (I), Ring A is a pyridazinyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0137] In another embodiment of formula (I), Ring A is a pyridazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0138] In another embodiment of formula (I), Ring A is a pyridazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl or halogen.

[0139] In another embodiment of formula (I), Ring A is a pyridazinyl ring, wherein said ring is substituted with 1-2 substituents, each of said substituents being independently selected from halogen.

[0140] In another embodiment of formula (I), Ring A is a pyridazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 alkyl.

[0141] In another embodiment of formula (I), Ring A is a pyridazinyl ring, wherein the ring is C 3 -C 5 The cycloalkyl group is monosubstituted.

[0142] In another embodiment of formula (I), Ring A is a pyrimidinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0143] In another embodiment of formula (I), Ring A is a pyrimidinyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0144] In another embodiment of formula (I), Ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0145] In another embodiment of formula (I), Ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl or halogen.

[0146] In another embodiment of formula (I), Ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from halogen.

[0147] In another embodiment of formula (I), Ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 alkyl.

[0148] In another embodiment of formula (I), Ring A is a pyrimidinyl ring, wherein the ring is C 3 -C 5 The cycloalkyl group is monosubstituted.

[0149] In another embodiment of formula (I), Ring A is a pyrazinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0150] In another embodiment of formula (I), Ring A is a pyrazinyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0151] In another embodiment of formula (I), Ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0152] In another embodiment of formula (I), Ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl or halogen.

[0153] In another embodiment of formula (I), Ring A is a pyrazinyl ring, wherein said ring is substituted with 1-2 substituents, each of said substituents being independently selected from halogen.

[0154] In another embodiment of formula (I), Ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3alkyl.

[0155] In another embodiment of formula (I), Ring A is a pyrazinyl ring, wherein the ring is C 3 -C 5 The cycloalkyl group is monosubstituted.

[0156] In another embodiment of formula (I), Ring A is a triazine ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0157] In another embodiment of formula (I), Ring A is a triazine ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0158] In another embodiment of formula (I), Ring A is a triazine ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl, C 3 -C 5 Cycloalkyl or halogen.

[0159] In another embodiment of formula (I), Ring A is a triazine ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 Alkyl or halogen.

[0160] In another embodiment of formula (I), Ring A is a triazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from halogen.

[0161] In another embodiment of formula (I), Ring A is a triazine ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C 1 -C 3 alkyl.

[0162] In another embodiment of formula (I), Ring A is a triazine ring, wherein the ring is C 3 -C 5 The cycloalkyl group is monosubstituted.

[0163] In another embodiment of formula (I), p is 0. In another embodiment of formula (I), p is 1. In another embodiment of formula (I), p is 2. In another embodiment of formula (I), p is 3. In another embodiment of formula (I), p is 4. In another embodiment of formula (I), p is 0, 1 or 2. In another embodiment of formula (I), p is 0 or 1.

[0164] In another embodiment of Formula (I), p is 1 and R 9 In another embodiment of Formula (I), p is 1 and R 9 In another embodiment of formula (I), p is 1 and R 9 In another embodiment of formula (I), p is 1 and R 9 In another embodiment of formula (I), p is 1 and R 9 In another embodiment of formula (I), p is 2 and each R 9 In another embodiment of formula (I), p is 2 and each R 9 In another embodiment of formula (I), p is 2 and each R 9 It's fluorine.

[0165] In another embodiment of Formula (I), E is NR a R b In another embodiment of formula (I), E is C 1 -C 3 Alkylene-NR a R b In another embodiment of formula (I), E is unsubstituted C 1 -C 3 Alkyl, unsubstituted C 2 -C 4 Alkenyl or unsubstituted C 2 -C 4 In another embodiment of formula (I), E is substituted by one or more halogen, hydroxyl, C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substituted C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl or C 2 -C 4 In another embodiment of formula (I), E is unsubstituted C 1 -C 3In another embodiment of formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substituted C 1 -C 3 In another embodiment of formula (I), E is an unsubstituted C 3 -C 8 In another embodiment of formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substituted C 3 -C 8 In another embodiment of formula (I), E is unsubstituted C 1 -C 3 Alkylene-(C 3 -C 8 In another embodiment of formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substituted C 1 -C 3 Alkylene-(C 3 -C 8 In another embodiment of formula (I), E is an unsubstituted 4- to 10-membered heterocyclyl. In another embodiment of formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C3 In another embodiment of formula (I), E is an unsubstituted C 1 -C 3 In another embodiment of Formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substituted C 1 -C 3 In another embodiment of Formula (I), E is unsubstituted C 6 -C 10 In another embodiment of formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substituted C 6 -C 10 In another embodiment of formula (I), E is unsubstituted C 1 -C 3 Alkylene-(C 6 -C 10 In another embodiment of formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substituted C 1 -C 3 Alkylene-(C 6 -C 10 In another embodiment of formula (I), E is an unsubstituted 5- to 7-membered heteroaryl. In another embodiment of formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 In another embodiment of formula (I), E is unsubstituted C 1 -C 3 In another embodiment of Formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substituted C 1 -C 3 Alkylene-(5- to 7-membered heteroaryl).

[0166] In another embodiment of Formula (I), E is C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group or C 1 -C 3 Alkylene-(4- to 10-membered heterocyclic group), wherein the C 1 -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group or C 1 -C 3 Alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted by one or more halogen, hydroxy, NR c Rd CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution.

[0167] In another embodiment of Formula (I), E is C 1 -C 3 Alkyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group or C 1 -C 3 Alkylene-(4- to 10-membered heterocyclic group), wherein the C 1 -C 3 Alkyl, C 3 -C 8 Cycloalkyl, C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclic group or C 1 -C 3 Alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted by one or more halogen, hydroxy, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution.

[0168] In another embodiment of Formula (I), E is C 1 -C 3 Alkyl, C 3 -C 8 Cycloalkyl or C 1 -C 3 Alkylene-(C 3 -C 8 cycloalkyl), wherein the C 1 -C 3 Alkyl, C 3 -C 8 Cycloalkyl or C 1 -C 3 Alkylene-(C3 -C 8 Cycloalkyl) is unsubstituted or substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substitution.

[0169] In another embodiment of formula (I), E is methyl. In another embodiment of formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 In another embodiment of formula (I), E is CF 3 In another embodiment of formula (I), E is CHF 2 In another embodiment of formula (I), E is CH 2 In another embodiment of Formula (I), E is NH(CH 3 In another embodiment of Formula (I), E is N(CH 3 ) 2 .

[0170] In another embodiment of Formula (I), E is C 6 -C 10 Aryl, C 1 -C 3 Alkylene-(C 6 -C 10 aryl), 5- to 7-membered heteroaryl or C 1 -C 3 In another embodiment of Formula (I), E is unsubstituted C 6 -C 10 Aryl or C 1 -C 3 Alkylene-(C 6 -C 10 In another embodiment of formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3, CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy substituted C 6 -C 10 Aryl or C 1 -C 3 Alkylene-(C 6 -C 10 aryl).

[0171] In another embodiment of Formula (I), E is a 5- to 7-membered heteroaryl or C 1 -C 3 In another embodiment of Formula (I), E is an unsubstituted 5- to 7-membered heteroaryl or C 1 -C 3 In another embodiment of Formula (I), E is substituted by one or more halogen, hydroxyl, NR c R d CF 3 , CHF 2 , CH 2 F.C 1 -C 3 Alkyl or C 1 -C 3 Alkoxy-substituted 5- to 7-membered heteroaryl or C 1 -C 3 Alkylene-(5- to 7-membered heteroaryl).

[0172] In another embodiment of formula (I), Y is S(=O) 2 In another embodiment of formula (I), Y is C(=O). In another embodiment of formula (I), Y is S(=O)(=NR e ).

[0173] In another embodiment of formula (I), X is N. In another embodiment of formula (I), X is CH.

[0174] In another embodiment of Formula (I), R 1 Selected from the group consisting of: C(=O)-C 1 -C 4 Alkyl, C(=O)-C 1 -C 4 Alkoxy, C(=O)-(CR c R d ) n -C3 -C 8 Cycloalkyl, C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C 6 -C 10 aryl) and C(═O)-(CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl, 4- to 7-membered heterocyclic group, C 6 -C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0175] In another embodiment of Formula (I), R 1 Selected from the group consisting of: C(=O)-C 1 -C 4 Alkyl, C(=O)-C 1 -C 4 Alkoxy and C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, wherein the C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy or C 3 -C 8 Cycloalkyl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0176] In another embodiment of Formula (I), R 1 Selected from the group consisting of: C(=O)-(CRc R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C 6 -C 10 aryl) and C(═O)-(CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 4- to 7-membered heterocyclyl, C 6 -C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0177] In another embodiment of Formula (I), R 1 is C(=O)-C 1 -C 4 Alkyl, wherein the C 1 -C 4 Alkyl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0178] In another embodiment of Formula (I), R 1 is C(=O)-C 1 -C 4 Alkoxy, wherein the C 1 -C 4 Alkoxy is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0179] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, wherein the C 3 -C 8Cycloalkyl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0180] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), wherein the 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0181] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl), wherein the C 6 -C 10 Aryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0182] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0183] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n-(5- to 7-membered heterocyclyl), wherein the 5- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0184] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 6-membered heterocyclyl), wherein the 5- to 6-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0185] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), wherein the 5-membered heterocyclyl is unsubstituted or substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0186] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), wherein the 6-membered heterocyclyl is unsubstituted or substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0187] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl), wherein the C 6 Aryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0188] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 8 aryl), wherein the C 8 Aryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0189] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 10 aryl), wherein the C 10 Aryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0190] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0191] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C3 Alkyl substitution.

[0192] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0193] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(7-membered heteroaryl), wherein the 7-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0194] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl or C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclic group), wherein the C 3 -C 8 The cycloalkyl or 4- to 7-membered heterocyclic group is unsubstituted or substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0195] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, wherein the C 3 -C 8Cycloalkyl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), wherein the 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 5 Cycloalkyl, wherein the C 3 -C 5 Cycloalkyl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5- to 6-membered heterocyclyl), wherein the 5- to 6-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), wherein the 5-membered heterocyclyl is unsubstituted or substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), wherein the 6-membered heterocyclyl is unsubstituted or substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0196] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 6 -C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 6 -C 10 The aryl or 5- to 10-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0197] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 6 -C 10The aryl or 5- to 10-membered heteroaryl is unsubstituted, and further wherein n is 0. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 6 -C 10 The aryl or 5- to 10-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 0.

[0198] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 6 -C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted, and further wherein n is 1. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 6 -C 10 The aryl or 5- to 10-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 1.

[0199] In another embodiment of Formula (I), R 1 Yes (CR c Rd ) n -(C 6 -C 10 aryl), wherein the C 6 -C 10 Aryl is unsubstituted. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 aryl), wherein the C 6 -C 10 The aryl group is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0200] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 aryl), wherein the C 6 -C 10 Aryl is unsubstituted, and further wherein n is 0. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 aryl), wherein the C 6 -C 10 The aryl group is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 0.

[0201] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 aryl), wherein the C 6 -C 10 Aryl is unsubstituted, and further wherein n is 1. In another embodiment of formula (I), R 1 Yes (CRc R d ) n -(C 6 -C 10 aryl), wherein the C 6 -C 10 The aryl group is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 1.

[0202] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0203] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted, and further wherein n is 0. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 0.

[0204] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n-(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted, and further wherein n is 1. In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 1.

[0205] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0206] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is unsubstituted, and further wherein n is 0. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d )n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 0.

[0207] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is unsubstituted, and further wherein n is 1. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 1.

[0208] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium1 -C 3 Alkyl substitution.

[0209] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is unsubstituted, and further wherein n is 0. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 0.

[0210] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is unsubstituted, and further wherein n is 1. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is replaced by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 1.

[0211] In another embodiment of Formula (I), R 1 Yes (CR c Rd ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 In another embodiment of formula (I), R 1 In another embodiment of formula (I), R 1 It is 3-pyridazinyl.

[0212] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is unsubstituted, and further wherein n is 0. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 0.

[0213] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is unsubstituted, and further wherein n is 1. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 1.

[0214] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl substitution.

[0215] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is unsubstituted, and further wherein n is 0. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 0.

[0216] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is unsubstituted, and further wherein n is 1. In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is substituted by one or more halogen, hydroxyl, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 Alkyl is substituted, and further wherein n is 1.

[0217] In another embodiment of Formula (I), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is independently H, halogen, unsubstituted C 1 -C 3 Alkyl or C substituted by one or more halogen or deuterium 1 -C 3 In another embodiment of formula (I), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is independently H, halogen or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is independently H or halogen. In another embodiment of formula (I), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is independently H or C 1 -C 3 In another embodiment of formula (I), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of them is H.

[0218] In another embodiment of Formula (I), R 3and R 6 Together they form unsubstituted C 1 -C 3 Alkylene or C substituted by one or more halogen 1 -C 3 In another embodiment of formula (I), R 3 and R 6 Together they form unsubstituted C 2 Alkylene or C substituted by one or more halogen 2 In another embodiment of formula (I), R 3 and R 6 Together they form an azabicyclo[3.2.1]octyl-bridged bicyclic heterocyclyl.

[0219] In another embodiment of Formula (I), R 4 and R 5 Together they form unsubstituted C 1 -C 3 Alkylene or C substituted by one or more halogen 1 -C 3 In another embodiment of formula (I), R 4 and R 5 Together they form unsubstituted C 2 Alkylene or C substituted by one or more halogen 2 In another embodiment of formula (I), R 4 and R 5 Together they form an azabicyclo[3.2.1]octyl-bridged bicyclic heterocyclyl.

[0220] In another embodiment of Formula (I), R 1 is C(=O)-C 1 -C 4 Alkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-C 1 -C 4 Alkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1-C 3 In another embodiment of formula (I), R 1 is C(=O)-C 1 -C 4 Alkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-C 1 -C 4 Alkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0221] In another embodiment of Formula (I), R 1 is C(=O)-C 1 -C 4 Alkoxy and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-C 1 -C 4 Alkoxy and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-C 1 -C 4 Alkoxy and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8In another embodiment of formula (I), R 1 is C(=O)-C 1 -C 4 Alkoxy and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0222] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c Rd ) n -C 3 -C 8 Cycloalkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0223] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d) n -C 3 -C 8 Cycloalkyl, n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0224] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d) n -C 3 -C 8 Cycloalkyl, n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0225] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl) and R 2 , R 3 , R 4 , R5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0226] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0227] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0228] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n-(5-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0229] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0230] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n-(5-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0231] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0232] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c Rd ) n -(6-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0233] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0234] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0235] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0236] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 -C 10 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0237] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1is C(=O)-(CR c R d ) n -(C 6 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0238] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0239] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(C 6 aryl), n is 1 or 2, and R 2 , R 3 , R 4, R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0240] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0241] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0242] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n-(5- to 7-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0243] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0244] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d )n -(5-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0245] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0246] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0247] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 0, and R 2 , R 3 , R4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0248] In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8In another embodiment of formula (I), R 1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0249] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0250] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0251] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -C 3 -C 8 Cycloalkyl, n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0252] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c Rd ) n -(4- to 7-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0253] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4, R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0254] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0255] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0256] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n-(5-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0257] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0258] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c Rd ) n -(6-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0259] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0260] In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0261] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(5- to 10-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(5- to 10-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(5- to 10-membered heteroaryl) and R 2 , R3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(5- to 10-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0262] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(5- to 7-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(5- to 7-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(5- to 7-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 Yes (CRc R d ) n -(5- to 7-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0263] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R8 Each of is H or fluorine.

[0264] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0265] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n-(6-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0266] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 -C 10 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0267] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1Yes (CR c R d ) n -(C 6 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0268] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl), n is 0, and R 2 , R 3, R 4 , R 5 , R 6 , R 7 and R 8 Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl), n is 0, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0269] In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H. In another embodiment of Formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8Each of which is H or unsubstituted C 1 -C 3 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 In another embodiment of formula (I), R 1 Yes (CR c R d ) n -(C 6 aryl), n is 1 or 2, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 Each of is H or fluorine.

[0270] Each of the embodiments described herein with respect to compounds of Formula I also applies to compounds of Formula IA.

[0271] According to Formula IA or I herein, when Ring A is a pyridyl group, the position of the pyridyl group N atom is specifically illustrated as follows:

[0272]

[0273] Further, according to Formula IA or I herein, when Ring A is a pyridazinyl group, the position of the N atom of the pyridazinyl group is specifically illustrated as follows:

[0274]

[0275] Further, according to Formula IA or I herein, when Ring A is a pyrimidinyl group, the position of the N atom of the pyrimidinyl group is specifically described as follows:

[0276]

[0277] Further, according to Formula IA or I herein, when Ring A is a pyrazinyl group, the position of the pyrazinyl N atom is specifically illustrated as follows:

[0278]

[0279] Further, according to Formula IA or I herein, when Ring A is a triazine group, the position of the triazine group N atom is specifically illustrated as follows:

[0280]

[0281] All other variables described in Formulas IA and I are as defined above.

[0282] Certain embodiments of compounds of Formula IA or I, or pharmaceutically acceptable salts thereof, are shown below in Table 1. Compounds of Formula IA or I, or pharmaceutically acceptable salts thereof, and compounds of Table 1, or pharmaceutically acceptable salts thereof, are sometimes collectively or individually referred to herein as "compounds of the invention" or "compounds provided herein."

[0283] Table 1

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296] The disclosed compounds have one or more stereocenters, and each stereocenter can independently exist in the R or S configuration. In one embodiment, the compounds described herein exist in optically active or racemic forms. It should be understood that the compounds described herein include racemic, optically active, regioisomeric and stereoisomeric forms or combinations thereof having the therapeutically useful properties described herein.

[0297] The preparation of optically active forms is achieved in any suitable manner, including, for example, but not limited to, by resolving racemic forms with recrystallization techniques, synthesizing 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 used as the disclosed compounds described herein. In another embodiment, pure isomers are used as the disclosed compounds described herein. In another embodiment, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, or separation of enantiomers or mixtures of diastereomers. The resolution of compounds and isomers thereof is achieved by any means, including, for example, but not limited to chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0298] In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0299] The compounds described herein also include isotopically labeled compounds in which one or more atoms are 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 suitable isotopes for inclusion in the compounds described herein include, but are not limited to 2 H. 3 H. 11 C. 13 C. 14 C. 36 Cl, 18 F. 123 I. 125 I. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P and 35 S. 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 provides greater metabolic stability (e.g., increasing in vivo half-life or reducing dosage requirements). In another embodiment, the compounds described herein include 2 H (i.e. deuterium) isotope.

[0300] In yet another embodiment, a positron emitting isotope such as 11 C. 18 F. 15 O and 13N) substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process by using an appropriate isotopically labeled reagent in place of the unlabeled reagent otherwise employed.

[0301] Specific compounds described herein, as well as other compounds encompassed by one or more of the formulae described herein with various substituents, are synthesized using the techniques and materials described herein and as described in, for example, 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 disclosures). The general methods for preparing the compounds described herein are modified by using appropriate reagents and conditions to introduce the various moieties present in the formulas provided herein.

[0302] The compounds described herein are synthesized using any suitable procedures starting from compounds available from commercial sources or prepared using the procedures described herein.

[0303] Treatment

[0304] The compounds of the present invention can be used in a method for treating a disease or condition in a subject, the method comprising administering to the subject a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. In one embodiment of the methods described herein, the subject is a human. In one aspect, the compounds provided herein can be used to treat a disease or condition by acting as an agonist of the orexin-2 receptor.

[0305] The compounds of the present invention are useful for treating a disease or condition selected from the group consisting of narcolepsy, cataplexy or hypersomnia in a subject in need thereof.

[0306] In one embodiment, the compounds of the invention are useful for treating narcolepsy in a subject. In one embodiment, the compounds of the invention are useful for treating cataplexy in a subject. In one embodiment, the compounds of the invention are useful for treating hypersomnia in a subject.

[0307] Orexin-2 receptors are important in a wide range of biological functions. This suggests that orexin-2 receptors play a role in a variety of disease processes in humans or other species. The compounds of the present invention can be used to treat, prevent or ameliorate one or more of the following symptoms or risks of various neurological and psychiatric diseases associated with alterations in sleep / wake function. That is, narcolepsy, narcolepsy with cataplexy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome characterized by hypersomnia (e.g., in subjects with Kleine-Levin syndrome, major depression with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Mobius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, multiple system atrophy, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, or Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g.,Malignant mastocytosis, exogenous obesity, hyperinsulinar obesity, hyperplasmic obesity, hypopituitarism, hypoplasmosis, hypothyroidism, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, dietary obesity, hypogonadism, systemic mastocytosis, simple obesity or central obesity), insulin resistance syndrome, Alzheimer's disease, consciousness disorders such as coma, side effects and complications due to anesthesia, sleep disorders, excessive daytime sleepiness, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep disorders, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's sunset syndrome (Alzheimer's dusk,sundowning), circadian rhythm-related disorders, fibromyalgia, disorders caused by decreased sleep quality, overeating, compulsive eating disorders, obesity-related disorders, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disease, polycystic ovary disease, craniopharyngioma, Prader-Willi syndrome, Froelich's syndrome syndrome), growth hormone deficiency, normal mutant short stature, Turner's syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, sexual and reproductive dysfunction such as hirsutism in women, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, kidney cancer, risk of secondary consequences of obesity such as reduced risk of left ventricular hypertrophy, migraine pain, headache, neuropathic pain, Parkinson's disease, psychosis, autoimmune encephalitis, cancer-related fatigue (such as,excessive daytime sleepiness or fatigue related to cancer and / or chemotherapy), cancer-related nausea and vomiting, corticobasal degeneration, Huntington's disease, neuromyelitis optica, nociception, progressive supranuclear palsy, schizophrenia, systemic lupus erythematosus, traumatic brain injury, facial flushing, night sweats, reproductive / urinary system disorders, disorders related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymia, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder (PTSD), separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric Disorders such as brain defect after heart bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neurological damage, Huntington's disease, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorders related to muscle spasticity, delirium, amnestic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, drug-induced parkinsonism, Tourette's syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, movement disorders, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, neurological damage, retinopathy, macular degeneration, vomiting, brain edema, pain, bone pain, joint pain, toothache, cataplexy and traumatic brain injury (TBI). ,

[0308] In particular, the compound of the present invention can be used as a therapeutic or preventive drug for narcolepsy, idiopathic hypersomnia, somnolence, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome characterized by somnolence (for example, in Parkinson's disease, Guillain-Barré syndrome or Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases associated with bone loss, sepsis, consciousness disorders such as coma, side effects and complications due to anesthesia, etc., or an anesthetic antagonist.

[0309] In one embodiment, the compound of the present invention has orexin-2 receptor agonist activity and is useful as a preventive or therapeutic agent for narcolepsy.

[0310] In another embodiment, the compounds of the present invention can be used as a preventive or therapeutic agent for narcolepsy type 1. In another embodiment, the compounds of the present invention can be used as a preventive or therapeutic agent for narcolepsy type 2. In another embodiment, the compounds of the present invention can be used as a preventive or therapeutic agent for narcolepsy and excessive daytime sleepiness. In another embodiment, the compounds of the present invention can be used as a preventive or therapeutic agent for narcolepsy, cataplexy, and excessive daytime sleepiness. In another embodiment, the compounds of the present invention can be used as a preventive or therapeutic agent for narcolepsy and cataplexy. In another embodiment, the compounds of the present invention can be used as a preventive or therapeutic agent for excessive daytime sleepiness. In another embodiment, the compounds of the present invention can be used as a preventive or therapeutic agent for idiopathic hypersomnia. In another embodiment, the compounds of the present invention can be used as a preventive or therapeutic agent for obstructive sleep apnea.

[0311] In another embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as preventive or therapeutic agents for somnolence in Parkinson's disease.

[0312] In another embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as preventive or therapeutic agents for drowsiness. In another embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as preventive or therapeutic agents for excessive daytime sleepiness associated with Parkinson's disease.

[0313] In another embodiment, the compounds of the present invention have orexin-2 receptor agonist activity and are useful as preventive or therapeutic agents for excessive daytime sleepiness or fatigue associated with cancer and / or chemotherapy.

[0314] In another embodiment, the present invention provides a method of treating narcolepsy in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0315] In another embodiment, the present invention provides a method of treating narcolepsy type 1 in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0316] In another embodiment, the present invention provides a method of treating narcolepsy type 2 in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0317] In another embodiment, the present invention provides a method of treating narcolepsy and excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0318] In another embodiment, the present invention provides a method of treating narcolepsy, cataplexy, and excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0319] In another embodiment, the present invention provides a method of treating narcolepsy and cataplexy in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0320] In another embodiment, the present invention provides a method of treating excessive daytime sleepiness in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0321] In another embodiment, the present invention provides a method of treating idiopathic hypersomnia in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0322] In another embodiment, the present invention provides a method of treating excessive daytime sleepiness and essential hypersomnia in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0323] In another embodiment, the present invention provides a method of treating obstructive sleep apnea in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0324] In another embodiment, the present invention provides a method of treating excessive daytime sleepiness and obstructive sleep apnea in a subject in need thereof, comprising administering to the subject a compound of Formula IA or I or a pharmaceutically acceptable salt thereof.

[0325] In any of the methods described herein, a compound of Formula I is administered to a subject. In any of the methods described herein, a compound of Formula IA is administered to a subject.

[0326] Each embodiment described herein with respect to the use of compounds of Formula I also applies to compounds of Formula IA.

[0327] In any of the compositions or methods described herein, the compound of Formula IA or I, or a pharmaceutically acceptable salt thereof, is present and / or administered in a therapeutically effective amount.

[0328] Administration / dosage / formulation

[0329] In another aspect, provided herein are pharmaceutical compositions comprising at least one compound of the present invention and a pharmaceutically acceptable carrier.

[0330] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0331] In particular, the selected dosage level will depend upon a variety of factors, including the activity of the specific 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 to be treated, and like factors well known in the medical arts.

[0332] A physician, such as a doctor or veterinarian, having ordinary skills in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can initially administer the pharmaceutical composition, dosing the disclosed compound at a level below that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0333] In certain embodiments, it is particularly advantageous to formulate the compounds in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as unitary dosages for the patient to be treated; each unit containing a predetermined amount of a disclosed compound calculated to produce the desired therapeutic effect in combination with the required drug carrier. The dosage unit form of the present invention is dictated by and directly dependent on (a) the unique characteristics of the disclosed compounds and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such disclosed compounds for use in treating narcolepsy or cataplexy in patients.

[0334] 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 include a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0335] In some embodiments, the dosage of the disclosed compound is from about 1 mg to about 1,000 mg. In some embodiments, the dosage of the disclosed compound used in the 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, the dosage 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.

[0336] Any one of the routes of administration in the composition of the present invention includes oral, nasal, rectal, intravaginal, parenteral, oral, sublingual or local. Compounds used for the present invention can be formulated for administration by any suitable route, such as for oral or parenteral, for example, percutaneous, through mucosal (for example, sublingual, tongue, (through) oral cavity, (through) urethra, vagina (for example, vaginal and around vagina), nose (in) and (through) rectum), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, suction and topical administration. In one embodiment, preferred route of administration is oral.

[0337] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, sera, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions that will be useful in the present invention are not limited to the specific formulations and compositions described herein.

[0338] For oral use, tablets, dragees, liquids, drops, suppositories or capsules, caplets and gelatin capsules are particularly suitable. Compositions intended for oral use can 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 pharmaceutical excipients suitable for making tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may not be coated, or they may be coated by known techniques to improve quality or delay the release of the active ingredient. Preparations for oral use may also be present in hard gelatin capsules, in which the active ingredient is mixed with an inert diluent.

[0339] For parenteral administration, the disclosed compounds can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration by bolus dose or continuous infusion. Suspensions, solutions or emulsions in oily or aqueous vehicles can be used, optionally containing other formulating agents, such as suspending agents, stabilizers or dispersing agents.

[0340] Those skilled in the art will recognize or be able to determine many equivalents of the specific procedures, embodiments, claims and embodiments described herein using only routine experiments. Such equivalents are considered to be within the scope of the present invention and are covered by the claims appended hereto. For example, it should be understood that modifications of reaction conditions including but not limited to reaction time, reaction size / volume and experimental reagents such as solvents, catalysts, pressures, atmospheric conditions (e.g., nitrogen atmosphere) and reducing / oxidizing agents using art-recognized alternatives and using only routine experiments are within the scope of the present application.

[0341] It should be understood that no matter where values ​​and ranges are provided herein, all values ​​and ranges encompassed by these values ​​and ranges are intended to be encompassed within the scope of the present invention. In addition, this application also contemplates all values ​​falling within these ranges and the upper or lower limit of the value range.

[0342] The following examples further illustrate aspects of the present invention. However, they in no way limit the teachings or disclosure of the present invention set forth herein.

[0343] Example

[0344] The present invention is further illustrated by the following examples, which should not be construed as further limiting. Unless otherwise indicated, the practice of the present invention will employ conventional techniques of organic synthesis, cell biology, cell culture, molecular biology, transgenic biology, microbiology and immunology, which are within the skill of the art.

[0345] General Procedures

[0346] Example 1: Synthesis Procedure

[0347] For those of ordinary skill in the art, the synthetic procedures for preparing the compounds of the present invention are readily available. Unless otherwise specified, the starting materials are generally obtained from commercial sources. The synthetic procedures for the related compounds can be found, for example, in U.S. Application No. 17 / 556,295 filed on December 20, 2021 and PCT Application No. PCT / US21 / 64484 filed on December 21, 2021; both are expressly incorporated herein by reference in their entirety.

[0348] The following abbreviations may be used in the following synthetic examples:

[0349] DCM = dichloromethane

[0350] MeOH = methanol

[0351] THF = Tetrahydrofuran

[0352] PPh 3 =Triphenylphosphine

[0353] DIAD = diisopropyl azodicarboxylate

[0354] DME = 1,2-dimethoxyethane

[0355] tBuXphos=2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0356] EA = Ethyl acetate

[0357] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0358] DIEA=N,N-diisopropylethylamine

[0359] NMP = 1-methyl-2-pyrrolidone

[0360] EDCI = 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide

[0361] HOBt = 1-hydroxybenzotriazole

[0362] STAB = Sodium triacetoxyborohydride

[0363] BH 3 .THF = Borane Tetrahydrofuran

[0364] ACN = acetonitrile

[0365] PE = Petroleum Ether

[0366] EtOAc = Ethyl acetate

[0367] DMF = dimethylformamide

[0368] LiOH = Lithium Hydroxide

[0369] min = minutes

[0370] h = hours

[0371] NaH = Sodium hydride

[0372] Pd 2 (dba) 3 =Tris(dibenzylideneacetone)dipalladium(0)

[0373] DMSO = dimethyl sulfoxide

[0374] Boc=tert-butyloxycarbonyl

[0375] Ms = Methanesulfonyl

[0376] Bn=Benzyl

[0377] Et=ethyl

[0378] Cbz = carboxybenzyl

[0379] TEA = triethylamine.

[0380]

[0381] Intermediates

[0382]

[0383] At 0 ° C, 4-bromopyridin-3-olate (1 g, 5.747 mmol, 1.00 equiv), (cis-4-phenylcyclohexyl)methanol (1.42 g, 7.462 mmol, 1.3 equiv), PPh 3 To a solution of 4-bromo-3-[(cis-4-phenylcyclohexyl)methoxy]pyridine (3.01 g, 11.476 mmol, 2 eq.) in THF (2 mL) was added DIAD (2.28 mL, 11.501 mmol, 2 eq.). The resulting solution was stirred at 70 °C for 2 h. The resulting solution was concentrated and then purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give the product 4-bromo-3-[(cis-4-phenylcyclohexyl)methoxy]pyridine (1 g, 50% yield) as a solid.

[0384] LCMS: m / z(ES+),[M+H] + =346

[0385]

[0386] In N 2 To a solution of 4-bromo-3-[(cis-4-phenylcyclohexyl)methoxy]pyridine (1 g, 2.89 mmol, 1 eq.) in DME (20 mL) was added methanesulfonamide (1.38 g, 14.508 mmol, 5 eq.), Cs 2 CO 3 (1.41 g, 4.328 mmol, 1.5 eq), Pd 2 (dba) 3 =Toluene (264.45 mg, 0.289 mmol, 0.1 eq) and tBuXphos (245.3 mg, 0.578 mmol, 0.2 eq). The resulting solution was stirred overnight at 80 °C. The resulting mixture was concentrated and purified by silica gel chromatography (0-20% MeOH / DCM) to give the product N-(3-[[cis-4-phenylcyclohexyl]methoxy]pyridin-4-yl)methanesulfonamide (977 mg, 94% yield) as a solid.

[0387] LCMS: m / z(ES+),[M+H] + =361

[0388]

[0389] To a solution of N-(3-[[cis-4-phenylcyclohexyl]methoxy]pyridin-4-yl)methanesulfonamide (562 mg, 1.559 mmol, 1 eq) in ACN (10 mL) was added benzyl bromide (0.19 mL, 1.597 mmol, 1.02 eq) at room temperature. The resulting solution was stirred at 80 °C overnight. The mixture was concentrated and purified by reverse phase chromatography to give 1-benzyl-4-methanesulfonamido-3-[(cis-4-phenylcyclohexyl)methoxy]pyridin-1-ium-1-yl)-λ2-bromide (1-benzyl-4-methanesulfonamido-3-[(cis-4-phenylcyclohexyl)methoxy]pyridin-1-ium-1-yl)-lambda2-bromanide) (474 ​​mg, 67.3% yield) as a solid.

[0390] LCMS: m / z(ES+),[M] + =451

[0391]

[0392] To a solution of (1-benzyl-4-methanesulfonamido-3-[[cis-4-phenylcyclohexyl]methoxy]-1lambda4-pyridin-1-ium-1-yl)-lambda2-bromanide (474 ​​mg, 0.892 mmol, 1 eq) in THF (40 mL) was added LiAlH 4 The resulting solution was stirred at 70 ° C for 1 h. The reaction was quenched by MeOH (2 mL) at 0 ° C and then filtered. The filtrate was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give N-[1-benzyl-3-[(cis-4-phenylcyclohexyl)methoxy]-2H-pyridin-4-yl]methanesulfonamide (500 mg, crude) as an oil.

[0393] LCMS: m / z(ES+),[M+1] + =453

[0394]

[0395] In H 2 Under atmosphere, (N-[1-benzyl-3-[(cis-4-phenylcyclohexyl)methoxy]-4H-pyridin-4-yl]methanesulfonamide (500 mg, 1.10 mmol, 1.00 equivalent) and Pd(OH) 2 A mixture of 4-[4-[(cis-4-phenylcyclohexyl)methoxy]piperidin-4-yl]methanesulfonamide (200 mg, 49.4%) was stirred at room temperature for 20 h. The mixture was filtered, and the filtrate was concentrated and purified by reverse phase chromatography to give N-[cis-3-[(cis-4-phenylcyclohexyl)methoxy]piperidin-4-yl]methanesulfonamide (200 mg, 49.4%) as an oil.

[0396] LCMS: m / z(ES+),[M+1] + =367

[0397] Compounds of the present invention

[0398] Compound 37

[0399]

[0400] Method 1: To a solution of N-[cis-3-[(cis-4-phenylcyclohexyl)methoxy]piperidin-4-yl]methanesulfonamide (112 mg, 0.306 mmol, 1 eq) in DMF (4 mL) was added cyclopropanecarboxylic acid (39.46 mg, 0.458 mmol, 1.5 eq), DIEA (78.99 mg, 0.611 mmol, 2 eq) and HATU (174.28 mg, 0.458 mmol, 1.5 eq) at room temperature. The resulting solution was stirred at room temperature for 2 h. After work-up, the crude material was purified by preparative HPLC to give N-[cis-1-cyclopropanecarbonyl-3-[(cis-4-phenylcyclohexyl)methoxy]piperidin-4-yl]methanesulfonamide (86 mg, 65% yield) as a solid as a mixture of isomers. The isomeric mixture was purified by preparative chiral HPLC to give compound 37 (36.5 mg, 42% yield) as a solid (absolute configuration not confirmed).

[0401] LCMS: m / z(ES+),[M+1] + =435

[0402] 1 H NMR (400 MHz, methanol-d 4 )δ7.30–7.22(m,4H),7.14–7.12(m,1H),4.79–4.20(m,2H),3.84 3.80(m,1H),3.66–3.64(m,3H),3.47–3.35(m,1H),3.02(s,3H),2.92–2.90(m,1 H),2.70–2.51(m,1H),2.16–1.75(m,6H),1.74–1.53(m,6H),0.87–0.75(m,4H).

[0403] Compound 38

[0404]

[0405] At 0 ° C, N-(cis-3-((cis-4-phenylcyclohexyl)methoxy)piperidin-4-yl)methanesulfonamide (100.00 mg, 0.273 mmol, 1.00 equiv), TEA (82.82 mg, 0.819 mmol, 3 equiv) and 1-chloro-2-methyl-1-oxyylidenepropane-2-yl acetate (89.81 mg, 0.546 mmol, 2 equiv) in DCM (2.00 mL) were added to a 8 mL vial. The resulting mixture was stirred at room temperature for 1 h under an argon atmosphere. The reaction was quenched with water. The resulting mixture was extracted with DCM (2x 5 mL). The combined organic layer was washed with brine (5 mL) and purified by anhydrous Na2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 1-(4-methanesulfonamido-3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-1-yl)-2-methyl-1-oxopropan-2-yl acetate (130 mg, 96.3%) as a foam.

[0406] LCMS: m / z(ES+),[M+H] + =495

[0407] In a 50 mL round-bottom flask, THF (3.00 mL) and H 2 2-Methyl-1-(cis-4-(methylsulfonamido)-3-((cis-4-phenylcyclohexyl)methoxy)piperidin-1-yl)-1-oxypropan-2-yl acetate (130.00 mg, 0.263 mmol, 1.00 equiv) and LiOH.H 2 O (55.14 mg, 1.314 mmol, 5.00 equiv). The resulting mixture was stirred at room temperature overnight under argon atmosphere. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (2x5 mL). The combined organic layers were washed with brine (5 mL) and purified by anhydrous Na 2 SO 4 Dried. After filtration, the filtrate was concentrated under reduced pressure. The crude product (130 mg) was purified by preparative HPLC to give a crude product (70 mg, 59%) as a solid. The crude product (70 mg) was purified by chiral preparative HPLC to give compound 38 (17.1 mg, 24%) as a solid.

[0408] LCMS: m / z(ES+),[M+H] + =453

[0409] 1 H NMR (400 MHz, DMSO-d 6 )δ7.27(d,J=4.5Hz,4H),7.16(h,J=4.1Hz,1H),6.87(s,1H),5.34(s,1H),4.58(s,2H),3.64(d,J=103.3Hz,4H),3.26(s,1H),2. 95(s,3H),2.80(d,J=18.4Hz,1H),2.52(s,1H),1.97(s,1H),1.84–1.64(m,4H),1.56(s,4H),1.48(s,2H),1.29(d,J=9.6Hz,6H).

[0410] Compound 39

[0411]

[0412] N-(cis-3-((cis-4-phenylcyclohexyl)methoxy)piperidin-4-yl)methanesulfonamide (90.0 mg, 0.246 mmol, 1.00 equiv), DIEA (95.21 mg, 0.737 mmol, 3 equiv) and 2-chloro-1,3-oxazole (50.83 mg, 0.491 mmol, 2.00 equiv) in NMP (2.00 mL) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at 120 °C overnight under an argon atmosphere. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (5 mL) and purified by anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by preparative HPLC to give N-(cis-1-(oxazol-2-yl)-3-((cis-4-phenylcyclohexyl)methoxy)piperidin-4-yl)methanesulfonamide (60 mg, 56.3%) as a solid.

[0413] The above product (60 mg) was purified by chiral preparative HPLC to give compound 39 (10.6 mg, 18%) as a solid.

[0414] LCMS: m / z(ES+),[M+H] + =434

[0415] 1 H NMR (400 MHz, DMSO-d 6 )δ7.46(d,J=1.0Hz,1H),7.28(dd,J=8.0,6.9Hz,2H),7.25–7.20(m,2H),7.19–7.13(m,1H ),6.93(d,J=7.6Hz,1H),6.78(d,J=1.0Hz,1H),4.12–4.00(m,1H),3.83(dd,J=13.3,5.0Hz ,1H),3.68–3.50(m,3H),3.45(dd,J=9.0,7.0Hz,1H),3.21–3.07(m,2H),2.96(s,3H),2.5 2(s,1H),1.91–1.77(m,2H),1.71(d,J=11.0Hz,1H),1.67–1.54(m,5H),1.53–1.38(m,3H).

[0416] Compounds 40 and 41

[0417]

[0418] Method 2: To a solution of N-(cis-3-(((1s,4S)-4-phenylcyclohexyl)methoxy)piperidin-4-yl)methanesulfonamide (200 mg, 0.546 mmol, 1 eq) and TEA (165.65 mg, 1.637 mmol, 3 eq) in DCM (10 mL) was added methyl chloroformate (103.12 mg, 1.091 mmol, 2 eq) at 0 °C. The resulting solution was stirred at room temperature for 2.5 h. The reaction was quenched with water (20 mL). The resulting mixture was extracted with dichloromethane (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by preparative HPLC to give methyl-cis-4-(methylsulfonamido)-3-(((1s,4S)-4-phenylcyclohexyl)methoxy)piperidine-1-carboxylate (102 mg, 44% yield) as a solid. The above material was purified by preparative chiral HPLC to give compound 40 (36.0 mg (35% yield) as a solid and compound 41 (35.6 mg, 34% yield) as a solid.

[0419] Compound 40:

[0420] LCMS: m / z(ES+),[M+NH4] + =442

[0421] 1 H NMR (400 MHz, methanol-d 4 )δ7.30–7.27(m,4H),7.19–7.09(m,1H),4.41–4.34(m,1H),4.10–4.05(m,1H),3.90–3.81(m,1H),3.72–3. 62(m,5H),3.52–3.46(m,1H),3.00(s,5H),2.60(s,1H),2.05(s,1H),1.92–1.87(m,4H),1.74–1.61(m,6H).

[0422] Compound 41:

[0423] LCMS: m / z(ES+),[M+NH4] + =442

[0424] 1 H NMR (400 MHz, methanol-d 4)δ7.30–7.27(m,4H),7.19–7.09(m,1H),4.41–4.34(m,1H),4.10–4.05(m,1H),3.90–3.81(m,1H),3.72–3. 62(m,5H),3.52–3.46(m,1H),3.00(s,5H),2.60(s,1H),2.05(s,1H),1.92–1.87(m,4H),1.74–1.61(m,6H).

[0425] Compound 42

[0426]

[0427] Method 3: A mixture of N-[(3R,4S)-3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (100.00 mg, 0.273 mmol, 1.00 equiv), EDCI (78.45 mg, 0.409 mmol, 1.5 equiv), HOBt (55.30 mg, 0.409 mmol, 1.5 equiv), DIEA (105.79 mg, 0.819 mmol, 3 equiv) and 1-methoxycyclobutane-1-carboxylic acid (53.26 mg, 0.409 mmol, 1.5 equiv) in DCM (1.00 mL) was stirred at room temperature for 3 h. The residue was purified by preparative TLC (PE / EtOAc 2:1) to give the crude product (100 mg, 76.57%) as a solid. The crude product was purified by chiral HPLC to give compound 42 (43 mg) as a solid.

[0428] LCMS: m / z(ES+),[M+H] + =479.25

[0429] 1H NMR (400MHz, methanol-d4) δ7.26(dd,J=5.5,3.9Hz,4H),7.15(tq,J=5.0,3.3,2.9Hz,1H),4.83(dt,J=14.1,3.0Hz,1H),4.19(dp,J=13.8,2.8Hz ,1H),3.89(t,J=8.6Hz,1H),3.79–3.58(m,2H),3.44(dd,J=8.8,6.8Hz,1H),3.16(s,2H),3.21–3.06(m,2H),3.01(d,J=4.5Hz,3H),2.84(d d,J=14.0,1.4Hz,1H),2.63(tt,J=12.1,4.0Hz,1H),2.61–2.46(m,1H),2.33–2.16(m,1H),2.19–2.07(m,1H),2.04(dt,J=8.3,4.4Hz,1H), 1.98–1.84(m,1H),1.85(s,2H),1.82(ddt,J=12.9,7.8,4.1Hz,1H),1.80–1.66(m,2H),1.70–1.55(m,2H),1.61(s,2H),1.37–1.28(m,1H).

[0430] Compounds 43 and 44

[0431]

[0432] Compounds 43 and 44 were synthesized using Method 3.

[0433] Compound 43: (12.6 mg), as solid.

[0434] LCMS72: m / z(ES+),[M+H] + =465.2

[0435] 1 H NMR (400 MHz, methanol-d 4)δ7.32–7.22(m,5H),7.19–7.10(m,2H),4.70(d,J=14.0Hz,1H),4.16(d,J=14.1Hz,1H),3.90(t,J=8.7Hz,1H) ,3.86–3.73(m,1H),3.67(s,2H),3.42(dd,J=8.7,6.5Hz,1H),3.21(d,J=14.4Hz,1H),3.02(s,1H),3.01(s,4H ),2.90(d,J=13.8Hz,1H),2.74(s,2H),2.59(d,J=11.2Hz,3H),2.12(dq,J=39.6,9.7Hz,4H),1.98–1.81(m,2H ),1.84–1.77(m,1H),1.70(s,9H),1.68(s,1H),1.62(s,2H),1.54(dt,J=17.0,8.7Hz,1H),1.38–1.29(m,1H).

[0436] Compound 44: (11 mg), as solid.

[0437] LCMS: m / z(ES+),[M+H] + =465.2

[0438] 1H NMR (400MHz, methanol-d4) δ7.32–7.22(m,5H),7.14(s,1H),4.70(d,J=14.1Hz,1H),4.16(d,J=14.0Hz,1H),3.90(t,J= 8.7Hz,1H),3.76(d,J=7.6Hz,1H),3.65(d,J=16.6Hz,3H),3.42(dd,J=8.7,6.4Hz,1H),3.19(s,1H),3.01(s,3H) ,2.90(d,J=14.0Hz,1H),2.74(s,2H),2.59(d,J=10.2Hz,2H),2.16(dt,J=19.5,9.9Hz,1H),2.07(q,J=9.8,8.6H z,2H),1.98–1.77(m,3H),1.69(s,8H),1.68(s,1H),1.64–1.49(m,1H),1.32(q,J=7.7,7.0Hz,1H),0.12(s,1H).

[0439] Compounds 45 and 46

[0440]

[0441] Compounds 45 and 46 were synthesized using Method 3.

[0442] Compound 45: (90 mg, 71%), solid.

[0443] 1 H NMR (400 MHz, methanol-d 4 )δ7.27(d,J=5.6Hz,4H),7.14(s,1H),4.93(d,J=5.9Hz,2H),4.81(d,J=14.5Hz,1H ),4.34(dd,J=5.9,18.7Hz,2H),3.91(t,J=8.8Hz,1H),3.71-3.61(m,2H),3.42-3. 36(m,1H),3.20-3.09(m,2H),3.02(d,J=4.8Hz,3H),2.82(d,J=14.2Hz,1H),2.58( s,1H),2.08(s,1H),1.98-1.85(m,2H),1.77(d,J=13.5Hz,3H),1.72-1.60(m,8H).

[0444] LCMS: m / z(ES+),[M+H] + =465.2

[0445] Compound 46: (10 mg, 7%), as solid.

[0446] 1 H NMR (400 MHz, DMSO-d 6 )δ7.27(d,J=4.5Hz,4H),7.16(t,J=4.1Hz,1H),6.95(dd,J=7.2,19.8Hz,1H),4.76(t,J=5.5Hz ,2H),4.59(d,J=13.8Hz,1H),4.24(dd,J=5.8,9.7Hz,2H),3.76(t,J=9.0Hz,1H),3.55(s,2H),3 .28(dd,J=5.9,8.6Hz,1H),3.07(t,J=12.8Hz,1H),2.95(d,J=6.0Hz,4H),2.76(d,J=13.9Hz,1H ), 1.99 (s, 1H), 1.79 (t, J = 11.4Hz, 1H), 1.70 (t, J = 13.8Hz, 3H), 1.64-1.54 (m, 5H), 1.50 (s, 5H).

[0447] LCMS: m / z(ES+),[M+H] + =465.2

[0448] Compounds 47 and 48

[0449]

[0450] Method 4: To a stirred mixture of NaH (39.72 mg, 0.99 mmol, 2.80 equiv., 60%) and ional (218.84 mg, 0.993 mmol, 2.80 equiv.) was added THF (2.00 ml) dropwise at 0°C under a nitrogen atmosphere. After stirring for about 5 minutes, the ice bath was removed and the solution was allowed to warm to room temperature over 10 minutes. An aliquot of the solution (volume = 1.2 mL, 0.60 mmol, 1.5 equiv.) was transferred to a dry 7 mL vial. The resulting mixture was concentrated under reduced pressure. Pd-PEPPSI-IPentCl o-methylpyridine (29.80 mg, 0.035 mmol, 0.10 equiv.), N-[(3R, 4S)-3-[[(1s, 4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (130.00 mg, 0.355 mmol, 1.00 equiv.) and 3-bromo-1-methylpyrazole (57.11 mg, 0.355 mmol, 1.00 equiv.) were added to the above mixture under nitrogen atmosphere at 120°C and stirred overnight. After the starting material was consumed, the residue was purified by preparative TLC (CH2Cl2 / MeOH 10:1) to give a crude product (120 mg) as a solid. The crude product (120 mg) was purified by preparative chiral HPLC to give Compound 47 and Compound 48.

[0451] Compound 47: (13.8 mg, 18.65%), solid.

[0452] LCMS: m / z (ES+), [M+H]+=447

[0453] 1H NMR (400MHz, methanol-d4) δ7.32 (d, J = 2.2 Hz, 1H), 7.26 (t, J = 7.4 Hz, 2H), 7.22–7.17 (m, 2H), 7.14 (t, J = 7.2 Hz, 1H), 5.72 (t, J = 1.9 Hz, 1H), 3.76 (q, J = 7.9, 7.2 Hz, 2H), 3.69–3.66 (m, 5H), 3. 62–3.47(m,2H),3.06(m,1H),3.02–2.90(m,5H),2.61–2.52(m,1H),2.08(ddd,J=23.4,9. 8,3.9Hz,2H),1.83(dp,J=17.3,5.9,4.1Hz,3H),1.75–1.55(m,6H),1.32(t,J=7.3Hz,3H).

[0454] Compound 48: (12.3 mg, 16.62%), as solid.

[0455] LCMS: m / z (ES+), [M+H]+=447.10

[0456] 1H NMR (400MHz, methanol-d4) δ7.32 (d, J = 2.2 Hz, 1H), 7.26 (t, J = 7.4 Hz, 2H), 7.22–7.17 (m, 2H), 7.14 (t, J = 7.2 Hz, 1H), 5.72 (t, J = 1.9 Hz, 1H), 3.76 (q, J = 7.9, 7.2 Hz, 2H), 3.69–3.66 (m, 5H), 3. 62–3.47(m,2H),3.06(m,1H),3.02–2.90(m,5H),2.61–2.52(m,1H),2.08(ddd,J=23.4,9. 8,3.9Hz,2H),1.83(dp,J=17.3,5.9,4.1Hz,3H),1.75–1.55(m,6H),1.32(t,J=7.3Hz,3H).

[0457] Compounds 49 and 50

[0458]

[0459] Compounds 49 and 50 were synthesized using Method 3.

[0460] Compound 49: (93.1 mg, 33.2%), solid.

[0461] LCMS: m / z (ES+), [M+H]+=467.0

[0462] 1 H NMR (400MHz, methanol-d4) δ7.30–7.20(m,4H),7.17–7.12(m,1H),4.79(d,1H),3.92(d,2H),3.77–3.61(m,2H),3.40–3.34(m,1H),3.24–3.14(m ,1H),3.01(d,3H),2.89(d,1H),2.70(d,2H),2.56(s,1H),2.41(dp,2H),1.92(d,3H),1.81–1.71(m,3H),1.67(d,3H),1.63–1.49(m,3H).

[0463] Compound 50: (75.5 mg, 26.96%), solid.

[0464] LCMS: m / z (ES+), [M+H]+=467.0

[0465] 1 H NMR(400MHz, methanol-d4)δ7.31–7.23(m,4H),7.14(d,1H),4.79(d,1H),3.96–3.62(m,4H),3.40–3.35(m,1H),3.20(d,1H),3.01(d,3H), 2.89(d,1H),2.70(s,2H),2.56(s,1H),2.41(dt,2H),2.09(d,1H),1.97–1.84(m,3H),1.76(d,3H),1.68(d,3H),1.61–1.51(m,2H).

[0466] Compounds 51 and 52

[0467]

[0468] To a stirred solution of N-[(3R,4S)-3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (200.00 mg, 0.546 mmol, 1.00 equiv) in MeOH (5 mL) was added ZnCl portionwise at 0 °C under nitrogen atmosphere. 2 (0.74 mg, 0.005 mmol, 0.01 eq) and NaBH 3 CN (51.44 mg, 0.819 mmol, 1.50 equiv). The resulting mixture was stirred at 50 ° C for 3 h under nitrogen atmosphere. The residue was filtered through a silica gel column with DCM / MeOH (20: 1). The crude product (54 mg) was purified by preparative HPLC followed by chiral HPLC to give the product.

[0469] Compound 51: (1.5 mg, 0.65%), as solid.

[0470] LCMS: m / z (ES+), [M+H]+=423.20

[0471] 1H-NMR (400MHz, methanol-d4) δ7.26(d,J=6.0Hz,3H),7.15(td,J=5.9,2.9Hz,1H),4.75–4.55(m,5H),3.77–3.69(m,1H),3.69–3.48(m,3 H),3.00(s,3H),2.76(s,1H),2.61(s,2H),2.21(s,2H),2.08(s,1H),2.04–1.94(m,1H),1.90(d,J=11.4Hz,2H),1.82–1.64(m,6H).

[0472] Compound 52: (0.6 mg, 0.26%).

[0473] LCMS: m / z (ES+), [M+H]+=423.20

[0474] 1H-NMR (E05570-026): (400MHz, methanol-d4) δ7.26 (d, J=6.0Hz, 3H), 7.15 (td, J=5.9, 2.9Hz, 1H), 4.75–4.55 (m, 5H), 3.77–3.69 (m, 1H), 3.69–3. 48(m,3H),3.00(s,3H),2.76(s,1H),2.61(s,2H),2.21(s,2H),2.08(s,1H),2.04–1.94(m,1H),1.90(d,J=11.4Hz,2H),1.82–1.64(m,6H).

[0475] Compounds 53 and 54

[0476]

[0477] Compounds 53 and 54 were synthesized using Method 4.

[0478] Compound 53: (6.3 mg), as solid.

[0479] LCMS: m / z (ES+), [M+H]+=447.1

[0480] 1H NMR (400MHz, methanol-d4) δ7.28–7.22 (m, 2H), 7.22–7.11 (m, 3H), 6.82 (d, J = 1.5 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 4.60 (s, 1H), 3.73 (t, J = 8.7 Hz, 2H), 3.70–3.64 (m, 1H), 3.60 (dd, J = 9.1, 6.8 Hz, 1H), 3.53 (s, 3H), 3.4 6(dd,J=12.6,5.0Hz,1H),3.24(d,J=12.3Hz,1H),3.03(s,3H),2.96(dd,J=20.7,10.7Hz,2H),2.58(s, 1H), 2.13 (ddd, J=23.3, 11.4, 7.7Hz, 2H), 1.94–1.79 (m, 3H), 1.65 (dt, J=25.9, 8.0Hz, 6H), 1.31 (s, 2H).

[0481] Compound 54: (8.8 mg, 98%), solid.

[0482] LCMS: m / z (ES+), [M+H]+=447.3

[0483] 1 H NMR (400 MHz, methanol-d 4 )δ7.28–7.22(m,2H),7.22–7.11(m,3H),6.82(d,J=1.5Hz,1H),6.71(d,J=1.6Hz,1H),4.60(s,1H) ,3.73(t,J=8.7Hz,2H),3.70–3.64(m,1H),3.60(dd,J=9.1,6.8Hz,1H),3.53(s,3H),3.46(dd,J=1 2.6,5.0Hz,1H),3.24(d,J=12.3Hz,1H),3.03(s,3H),2.96(dd,J=20.7,10.7Hz,2H),2.58(s,1H), 2.13(ddd,J=23.3,11.4,7.7Hz,2H),1.94–1.79(m,3H),1.65(dt,J=25.9,8.0Hz,6H),1.31(s,2H).

[0484] Compounds 55 and 56

[0485]

[0486] To a stirred solution of N-(3-(((1s, 4s)-4-phenylcyclohexyl)methoxy)piperidin-4-yl)methanesulfonamide (150.00 mg, 0.409 mmol, 1.00 equiv) in DMF (10.00 mL) was added 3-chloropyridazine (70.31 mg, 0.614 mmol, 1.50 equiv) and CsF (124.33 mg, 0.819 mmol, 2.00 equiv). The mixture was stirred at 120 ° C for 48 hours. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (3x20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 / MeOH 20:1) to give the product (50 mg, 27.48%) as a mixture of isomers. The mixture was purified by chiral HPLC to give:

[0487] Compound 55: (6.3 mg, 90.00%), solid.

[0488] LCMS: m / z (ES+), [M+H]+=445.1

[0489] 1 H NMR (E05616-059): (400 MHz, methanol-d4) δ 8.38 (dd, J = 4.2, 1.5 Hz, 1H), 7.36–7.29 (m, 2H), 7.29–7.23 (m, 2H), 7.22–7.11 (m, 3H), 4.68 (d, J = 14.4 Hz, 1H), 4.34 (d, J = 13.8 Hz, 1H), 3.76–3.68 (m, 3H), 3.54–3 .46(m,1H),3.26–3.14(m,2H),3.03(s,3H),2.51(s,1H),2.01(dd,J=13.1,9.1Hz,1H),1.89(s,1H) ,1.85–1.78(m,1H),1.74(d,J=11.7Hz,1H),1.69–1.56(m,4H),1.49(d,J=6.1Hz,3H),1.31(s,1H).

[0490] Compound 56: (3 mg), as solid.

[0491] LCMS: m / z (ES+), [M+H]+=445.1

[0492] 1H NMR (E05616-059): (400MHz, methanol-d4) δ8.38 (dd, J = 4.2, 1.5Hz, 1H), 7.36–7.29 (m, 2H), 7.29–7.23 (m, 2H), 7.22–7.11 (m, 3H), 4.68 (d, J = 14.4Hz, 1H), 4.34 (d, J = 13.8Hz, 1H), 3.76–3.68 (m, 3H), 3.54–3 .46(m,1H),3.26–3.14(m,2H),3.03(s,3H),2.51(s,1H),2.01(dd,J=13.1,9.1Hz,1H),1.89(s,1H) ,1.85–1.78(m,1H),1.74(d,J=11.7Hz,1H),1.69–1.56(m,4H),1.49(d,J=6.1Hz,3H),1.31(s,1H).

[0493] Compounds 57 and 58

[0494]

[0495] To a stirred solution of N-(3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl)methanesulfonamide (100.0 mg, 0.273 mmol, 1.00 equiv) and oxetane-3-carbaldehyde (35.2 mg, 0.409 mmol, 1.50 equiv) in MeOH (6.00 mL) was added STAB (86.7 mg, 0.409 mmol, 1.50 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by preparative TLC (CH 2 Cl 2 / MeOH 20:1) to give the product (60 mg, 50.37%) as a mixture of isomers as a solid. The mixture was purified by chiral HPLC to give:

[0496] Compound 57: (25 mg, 42%), oil.

[0497] LCMS: m / z (ES+), [M+H]+=437.25

[0498] 1 H NMR (400 MHz, methanol-d 4)δ7.34-7.20(m,4H),7.19-7.08(m,1H),4.82-4.77(m,2H),4.43(t,J=6.2Hz,2H),3.75-3.50(m,4H),3.30-3.24(m,1H),2.9 9(s,3H),2.75(d,J=4.1Hz,3H),2.69-2.56(m,2H),2.29(d,J=9.5Hz,2H),2.11-1.92(m,2H),1.90-1.80(m,2H),1.70(m,7H).

[0499] Compound 58: (20 mg, 33%), oil.

[0500] LCMS: m / z (ES+), [M+H]+=437.20

[0501] 1 H NMR (400 MHz, methanol-d 4 )δ7.32-7.21(m,4H),7.15(t,J=2.2Hz,1H),4.81(d,J=5.8Hz,2H),4.43(t,J=6.2Hz,2H),3.75-3.49(m,4H),3.30-3.23(m,1H),2.99(s,3H), 2.85-2.72(m,3H),2.62(d,J=9.5Hz,2H),2.29(d,J=10.0Hz,2H),2.12 -2.01(m,1H),2.01-1.91(m,1H),1.91-1.80(m,2H),1.78-1.64(m,7H).

[0502] Compounds 59 and 60

[0503]

[0504] Compounds 59 and 60 were synthesized using Method 4.

[0505] Compound 59: (10 mg, 23%), as solid.

[0506] LCMS: m / z (ES+), [M+H]+=447

[0507] 1H NMR (400MHz, methanol-d4) δ7.35 -7.18(m,5H),7.18-7.11(m,1H),6.39(d,1H),3.87-3.79(m,1H),3.71(dt,1H),3.67-3.56(m,6H),3.39-3.35(m,1H ),3.02(s,3H),2.93-2.87(m,1H),2.82(dd,1H),2.61-2.52(m,1H),2.10(dt,2H),1.91-1.79(m,3H),1.69(dd,6H).

[0508] Compound 60: (10 mg, 23%), solid.

[0509] LCMS: m / z (ES+), [M+H]+=447

[0510] 1 H NMR (400 MHz, methanol-d 4 )δ7.36-7.18(m,5H),7.18-7.09(m,1H),6.39(d,1H),3.79(dd,1H),3.71(dd,1H),3.68-3.57(m,5H),3. 37(s,1H),3.02(s,3H),2.92-2.77(m,2H),2.58(dd,1H),2.10(dt,2H),1.94-1.81(m,3H),1.69(dd,6H).

[0511] Compounds 61, 62, 63 and 64

[0512]

[0513] To a stirred solution of N-[(3S,4R)-3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (100.0 mg, 0.273 mmol, 1.00 equiv) and 1-(oxetan-3-yl)ethanone (81.95 mg, 0.819 mmol, 3.00 equiv) in MeOH (3 mL) was added ZnCl at room temperature. 2 (37.19 mg, 0.273 mmol, 1.00 equiv) and NaBH 3 CN (51.44 mg, 0.819 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature overnight. The residue was analyzed by preparative TLC (CH 2 Cl 2 / MeOH 15:1) to give the product as a mixture of isomers (100 mg, 81%) as a solid.

[0514] The crude product (96 mg) was purified by preparative chiral HPLC to give:

[0515] Compound 61: (30 mg, 31.25%), as solid.

[0516] LCMS: m / z (ES+), [M+H]+=451

[0517] 1 H NMR (400MHz, methanol-d4) δ7.27(s,4H),7.15(t,1H),4.73(dt,2H),4.61(t,1H),4.44(t,1H),3.67-3.51(m,4H),3.25-3.10(m,1H),3.09-2.9 8(m,1H),2.98(s,3H),2.82(dd,1H),2.61(s,2H),2.46(dd,1H),2.35(d,1H),1.94(dt,1H),1.85(t,2H),1.79-1.62(m,7H),0.95(d,3H).

[0518] Compound 62: (20 mg, 21%), as solid.

[0519] LCMS: m / z (ES+), [M+H]+=451

[0520] 1 H NMR (400 MHz, methanol-d 4 )δ7.35-7.21(m,4H),7.15(t,1H),4.72(dd,2H),4.61(t,1H),4.44(t,1H),3.69(dd,1H),3.62-3.47(m,3H),3.20(dd,1H),3.11 -2.93(m,4H),2.81(s,1H),2.65(dt,2H),2.55-2.47(m,1H),2.30(dd,1H),2.05(d,1H),1.88(dt,3H),1.79-1.64(m,7H),1.40.

[0521] Compound 63: (12 mg, 30%), as solid.

[0522] LCMS: m / z (ES+), [M+H]+=451.2

[0523] 1H NMR (E05616-153): (400 MHz, methanol-d4) δ 7.32-7.22 (m, 4H), 7.18-7.12 (m, 1H), 4.73 (ddd, J = 8.1, 6.0, 4.0 Hz, 2H), 4.61 (t, J = 6.4 Hz, 1H), 4.47 (t, J = 6.4 Hz, 1H), 3.71 (t, J = 8.4 Hz, 1H), 3.60 (dd, J = 16.4, 7.4 Hz, 3H), 3 .24(s,1H),3.17-3.03(m,1H),2.99(s,3H),2.96-2.69(m,2H),2.61(dt,J=11.3,5.9Hz,2H),2.40(s,1H ), 2.06 (s, 1H), 1.87 (d, J = 10.2Hz, 3H), 1.82-1.60 (m, 7H), 1.31 (d, J = 3.5Hz, 1H), 0.97 (d, J = 41.5Hz, 3H).

[0524] Compound 64: (13 mg, 32.5%), as solid.

[0525] LCMS: m / z (ES+), [M+H]+=451.2

[0526] 1 H NMR (E05616-154): (400 MHz, methanol-d4) δ 7.30-7.22 (m, 4H), 7.15 (ddd, J = 8.6, 6.0, 2.2 Hz, 1H), 4.78-4.69 (m, 2H), 4.61 (t, J = 6.4 Hz, 1H), 4.45 (t, J = 6.3 Hz, 1H), 3.72-3.48 (m, 4H), 3.20 (d, J = 8.0 Hz, 1H), 3.06 (q, J = 7 .3Hz,1H),2.99(s,3H),2.84(d,J=22.3Hz,1H),2.62(d,J=8.6Hz,2H),2.47(d,J=39.2Hz,2H),2.08-1.9 1(m,2H),1.84(td,J=11.5,9.5,5.2Hz,2H),1.71(p,J=7.9Hz,7H),1.39-1.27(m,1H),1.05-0.88(m,3H).

[0527] Compounds 65 and 66

[0528]

[0529] Compound 65 and Compound 66 were synthesized using Method 3.

[0530] Compound 65: (27.7 mg, 25.18%), solid.

[0531] LCMS: m / z (ES+), [M+H]+=449.6

[0532] 1 H NMR (400MHz, methanol-d4) δ7.33–7.23(m,4H),7.18–7.13(m,1H),4.61(s,1H),3.91(dt,1H),3.77(dt,1H),3.70–3.59(m,2H),3.50–3 .35(m,2H),3.19–3.10(m,1H),3.01(d,3H),2.81(d,1H),2.58(s,1H),2.38–2.31(m,1H),2.26–2.04(m,3H),1.97–1.60(m,11H).

[0533] Compound 66: (32.3 mg, 29%), solid.

[0534] LCMS: m / z (ES+), [M+H]+=449.6

[0535] 1 H NMR (400MHz, methanol-d4) δ7.32–7.25(m,4H),7.17–7.12(m,1H),4.77(d,1H),4.60(s,1H),3.91(dt,1H),3.77(dt,1H),3.70–3.59(m,2H ),3.47–3.35(m,2H),3.18–3.10(m,1H),3.01(d,3H),2.81(d,1H),2.58(s,1H),2.41–2.14(m,3H),2.08–1.62(m,13H),1.31(s,1H).

[0536] Compounds 67 and 68

[0537]

[0538] Compound 67 and Compound 68 were synthesized using Method 3.

[0539] Compound 67: (22.9 mg, 22.9%), solid.

[0540] LCMS: m / z (ES+), [M+H]+=453.5

[0541] 1 H NMR (400 MHz, methanol-d 4)δ7.26(d,4H),7.15(h,1H),4.73(d,1H),4.45(d,1H),3.87(s,1H),3.74–3.64(m,2H),3.47(s, 1H),3.02(s,3H),2.57(s,1H),2.06(s,2H),1.79(s,4H),1.70–1.50(m,5H),1.39–1.12(m,5H).

[0542] Compound 68: (22.9 mg, 22.9%), solid.

[0543] LCMS (E05569-095): m / z (ES+), [M+H]+ = 453.59; NH4HCO3, HPLC tR = 1.689 min.

[0544] 1 H NMR (400 MHz, methanol-d 4 )δ7.26(d,4H),7.14(dt,1H),4.73(d,1H),4.32(s,1H),3.87(s,1H),3.69(d,2H ),3.02(s,4H),2.97–2.51(m,2H),2.06(s,4H),1.73–1.51(m,7H),1.25(d,5H).

[0545] Compounds 69 and 70

[0546]

[0547] Under nitrogen atmosphere at room temperature, N-[(3R,4S)-1-(1-fluorocyclobutanecarbonyl)-3-[[(1s,4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (95.00 mg, 0.204 mmol, 1.00 equiv) and BH 3 The mixture was stirred in a stirred solution of THF (4.00 mL, 41.796 mmol, 205.29 equiv) for 3 h. The resulting mixture was concentrated under reduced pressure. MeOH (5.00 mL) was added portionwise to the above mixture at room temperature.

[0548] The resulting mixture was stirred additionally overnight at 50 ° C. The desired product can be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 1: 1) to obtain N-[(3R, 4S)-1-[(1-fluorocyclobutyl)methyl]-3-[[(1s, 4s)-4-phenylcyclohexyl]methoxy]piperidin-4-yl]methanesulfonamide (91 mg, 98.75%) as a solid. The crude product (91 mg) was purified by preparative chiral HPLC to obtain:

[0549] Compound 69: (35 mg, 39%), oil.

[0550] LCMS: m / z (ES+), [M+H]+=452.6

[0551] 1 H NMR (400 MHz, methanol-d 4 )δ7.26(d,4H),7.16(d,1H),3.73(d,1H),3.62–3.47(m,3H),2.99(d,4H),2.77(d,1H),2.71(d,1H),2.67–2.55(m,2 H),2.42(d,2H),2.30–2.12(m,4H),2.11–1.94(m,2H),1.85(td,3H),1.69(td,7H),1.58–1.43(m,1H),1.31(s,1H).

[0552] Compound 70: (30 mg, 33%), oil.

[0553] LCMS: m / z (ES+), [M+H]+=452.6

[0554] 1 H NMR (400 MHz, methanol-d 4 )δ7.30–7.21(m,4H),7.15(dt,1H),3.73(dt,1H),3.65–3.48(m,3H),2.99(d,4H),2.77(d,1H),2.74–2.68(m,1H),2.67–2 .56(m,2H),2.42(t,2H),2.22(dt,4H),2.05(d,1H),2.02–1.93(m,1H),1.93–1.76(m,3H),1.76–1.60(m,7H),1.52(d,1H).

[0555] Example 2: Human OX 2 R IP1 assay

[0556] Stable overexpression of human orexin-2 receptor (OX2 R) T-Rex CHO cells were induced with 1 μg / mL doxycycline overnight in T225 flasks. 24 hours after induction, cells were lifted with accutase and plated at 30,000 cells / well in 384-well proxy plates. Cells were then treated with different test compounds for 1 hour at 37°C in 1X stimulation buffer containing 10 mM Hepes, 1 mM CaCl 2 , 0.5 mM MgCl 2 , 4.2mM KCl, 146mM NaCl, 5.5mM glucose and 50mM LiCl. After incubation, the reaction was terminated by adding a detection mixture consisting of IP1-d2 and anti-IP1-cryptate diluted in lysis buffer and 1X stimulation buffer. The plate was incubated at room temperature for 1 hour and then The inositol phosphate levels were measured by reading in a multimode plate reader.

[0557] Cisbio IP1 is a cell-based functional assay that quantifies the accumulation of inositol monophosphate (IP), a metabolite released as a result of activation of the orexin 2 receptor via the phospholipase C-Gq signaling pathway. This is a competitive immunoassay in which IP1 produced by cells upon receptor activation competes with an IP1 analog (acceptor) coupled to a d2 fluorophore for binding to an anti-IP1 monoclonal antibody (donor) labeled with Eu cryptate. The HTRF-FRET-based signal measured is inversely proportional to the concentration of IP1 produced.

[0558] According to the above description of the person OX 2 The R IP1 assay obtained the ECs reported in Table 2 50 Values. Data are mean EC 50 Values ​​± SEM.

[0559] Table 2.

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566] *** is EC 50 <100nM

[0567] ** is EC 50 100-10,000nM

[0568] *EC 50 >10,000nM

[0569] While the invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof; in: Ring A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, further wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen; X is N or CH; Y is S(=O)2, C(=O) or S(=O)(=NR e ); R e Selected from the group consisting of H, C1-C3 alkyl or C3-C5 cycloalkyl; E is selected from the group consisting of: NR a R b 、C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C 10 Aryl, C1- C3 alkylene-(C6-C 10 aryl), 5- to 7-membered heteroaryl, and C1-C3 alkylene-(5- to 7-membered heteroaryl), wherein the C1-C3 alkylene-NR a R b , C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 7-membered heteroaryl or C1-C3 alkylene-(5- to 7-membered heteroaryl) is unsubstituted or substituted by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substitution; R a and R b Each independently selected from the group consisting of H, C1-C3 alkyl, C3-C5 cycloalkyl and 4- to 7-membered heterocyclyl; wherein the C1-C3 alkyl, C3-C5 cycloalkyl or 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy; Or, alternatively, R a and R b Together with the N atom to which they are attached, they form a 4- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl, wherein the 4- to 7-membered heterocyclyl or the 5- to 7-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxyl, NR c R d , C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkyl substituted by 1-3 halogens; R1 is selected from the group consisting of: C(=O)-C1-C4 alkyl, C(=O)-C1-C4 alkoxy, C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C6-C 10 Aryl), C(=O)-(CR c R d ) n -(5- to 10-membered heteroaryl), C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclic group), (CR c R d ) n -(C6-C 10 Aryl) and (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted by one or more halogen or deuterium; R c and R d Each is independently H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted by one or more halogens or deuterium; n is 0, 1, or 2; Each of R2, R3, R4, R5, R6, R7 and R8 is independently H, halogen, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium; Or, alternatively, R3 and R6 together form an unsubstituted C1-C3 alkylene or a C1-C3 alkylene substituted by one or more halogens; Or, alternatively, R4 and R5 together form an unsubstituted C1-C3 alkylene or a C1-C3 alkylene substituted by one or more halogens; m is 0 or 1; p is 0, 1, 2, 3 or 4; and Each R9 is independently selected from the group consisting of deuterium, halogen, hydroxyl and cyano.

2. The compound according to claim 1, wherein Ring A is a phenyl ring, wherein the ring is unsubstituted or substituted with 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

3. The compound according to claim 1 or 2, wherein Ring A is a phenyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

4. A compound according to any one of the preceding claims, wherein Ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

5. A compound according to any one of the preceding claims, wherein Ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl or halogen.

6. A compound according to any one of the preceding claims, wherein Ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from halogen.

7. A compound according to any one of the preceding claims, wherein Ring A is a phenyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from F or Cl.

8. A compound according to any one of the preceding claims, wherein Ring A is a phenyl ring, wherein the ring is substituted with 1-2 F substituents.

9. A compound according to any one of the preceding claims, wherein Ring A is 3-fluorophenyl.

10. The compound according to claim 1, wherein Ring A is a pyridyl ring, wherein the ring is unsubstituted or substituted with 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

11. The compound according to claim 1 or claim 10, wherein Ring A is a pyridyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

12. The compound according to any one of claims 1, 10 or 11, wherein Ring A is a pyridyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

13. A compound according to any one of claims 1 or 10-12, wherein Ring A is a pyridyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl or halogen.

14. A compound according to any one of claims 1 or 10-13, wherein Ring A is a pyridyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from halogen.

15. The compound according to any one of claims 1 or 10-14, wherein Ring A is a pyridyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl.

16. A compound according to any one of claims 1 or 10-15, wherein Ring A is a pyridyl ring, wherein the ring is monosubstituted with a C3-C5 cycloalkyl group.

17. The compound according to claim 1, wherein Ring A is a pyridazinyl ring, wherein the ring is unsubstituted or substituted with 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

18. The compound according to claim 1 or 17, wherein Ring A is a pyridazinyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

19. The compound according to any one of claims 1, 17 or 18, wherein Ring A is a pyridazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

20. The compound according to any one of claims 1 or 17-19, wherein Ring A is a pyridazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl or halogen.

21. A compound according to any one of claims 1 or 17-20, wherein Ring A is a pyridazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from halogen.

22. A compound according to any one of claims 1 or 17-19, wherein Ring A is a pyridazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl.

23. A compound according to any one of claims 1 or 17-19, wherein Ring A is a pyridazinyl ring, wherein the ring is monosubstituted with a C3-C5 cycloalkyl group.

24. The compound according to claim 1, wherein Ring A is a pyrimidinyl ring, wherein the ring is unsubstituted or substituted with 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

25. The compound according to claim 1 or 24, wherein Ring A is a pyrimidinyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

26. A compound according to any one of claims 1, 24 or 25, wherein Ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

27. A compound according to any one of claims 1 or 24-26, wherein Ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl or halogen.

28. A compound according to any one of claims 1 or 24-27, wherein Ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from halogen.

29. A compound according to any one of claims 1 or 24-28, wherein Ring A is a pyrimidinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl.

30. A compound according to any one of claims 1 or 24-29, wherein Ring A is a pyrimidinyl ring, wherein the ring is monosubstituted with a C3-C5 cycloalkyl group.

31. The compound according to claim 1, wherein Ring A is a pyrazinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

32. The compound according to claim 1 or 31, wherein Ring A is a pyrazinyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

33. A compound according to any one of claims 1, 31 or 32, wherein Ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

34. A compound according to any one of claims 1 or 31-33, wherein Ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl or halogen.

35. A compound according to any one of claims 1 or 31-34, wherein Ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from halogen.

36. A compound according to any one of claims 1 or 31-35, wherein Ring A is a pyrazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl.

37. A compound according to any one of claims 1 or 31-36, wherein Ring A is a pyrazinyl ring, wherein the ring is monosubstituted with a C3-C5 cycloalkyl group.

38. The compound according to claim 1, wherein Ring A is a triazinyl ring, wherein the ring is unsubstituted or substituted with 1 to 3 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

39. The compound according to claim 1 or 38, wherein Ring A is a triazinyl ring, wherein the ring is unsubstituted or substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

40. A compound according to any one of claims 1, 38 or 39, wherein Ring A is a triazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl, C3-C5 cycloalkyl or halogen.

41. A compound according to any one of claims 1 or 38-40, wherein Ring A is a triazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from C1-C3 alkyl or halogen.

42. A compound according to any one of claims 1 or 38-41, wherein Ring A is a triazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from halogen.

43. A compound according to any one of claims 1 or 38-42, wherein Ring A is a triazinyl ring, wherein the ring is substituted with 1-2 substituents, each of which is independently selected from a C1-C3 alkyl group.

44. A compound according to any one of claims 1 or 38-43, wherein Ring A is a triazinyl ring, wherein the ring is monosubstituted with a C3-C5 cycloalkyl group.

45. A compound according to any one of claims 1 to 44, wherein p is 0.

46. ​​A compound according to any one of claims 1 to 44, wherein p is 1.

47. A compound according to any one of claims 1 to 44, wherein p is 2.

48. A compound according to any one of claims 1 to 44, wherein p is 3.

49. A compound according to any one of claims 1 to 44, wherein p is 4.

50. A compound according to any one of claims 1 to 44, wherein p is 0, 1 or 2.

51. A compound according to any one of claims 1 to 44, wherein p is 0 or 1.

52. A compound according to any one of claims 1 to 51, wherein E is NR a R b .

53. A compound according to any one of claims 1 to 51, wherein E is C1-C3 alkylene-NR a R b .

54. A compound according to any one of claims 1 to 51, wherein E is an unsubstituted C1-C3 alkyl group, an unsubstituted C2-C4 alkenyl group or an unsubstituted C2-C4 alkynyl group.

55. A compound according to any one of claims 1 to 51, wherein E is C1-C3 alkyl, C2-C4 alkenyl or C2-C4 alkynyl substituted by one or more halogen, hydroxy, C1-C3 alkyl or C1-C3 alkoxy.

56. A compound according to any one of claims 1 to 51, wherein E is an unsubstituted C1-C3 alkyl group.

57. A compound according to any one of claims 1 to 51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkyl substituted with C1-C3 alkoxy.

58. A compound according to any one of claims 1 to 51, wherein E is an unsubstituted C3-C8 cycloalkyl group.

59. A compound according to any one of claims 1 to 51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substituted C3-C8 cycloalkyl.

60. A compound according to any one of claims 1 to 51, wherein E is unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl).

61. A compound according to any one of claims 1 to 51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substituted C1-C3 alkylene-(C3-C8 cycloalkyl).

62. A compound according to any one of claims 1 to 51, wherein E is an unsubstituted 4- to 10-membered heterocyclic group.

63. A compound according to any one of claims 1 to 51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, a 4- to 10-membered heterocyclic group substituted with a C1-C3 alkyl group or a C1-C3 alkoxy group.

64. A compound according to any one of claims 1 to 51, wherein E is unsubstituted C1-C3 alkylene-(4- to 10-membered heterocyclic group).

65. A compound according to any one of claims 1 to 51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substituted C1-C3 alkylene-(4- to 10-membered heterocyclic group).

66. A compound according to any one of claims 1 to 51, wherein E is unsubstituted C6-C 10 Aryl.

67. A compound according to any one of claims 1 to 51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C6-C substituted by C1-C3 alkyl or C1-C3 alkoxy 10 Aryl.

68. A compound according to any one of claims 1 to 51, wherein E is an unsubstituted C1-C3 alkylene-(C6-C 10 aryl).

69. A compound according to any one of claims 1 to 51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substituted C1-C3 alkylene-(C6-C 10 aryl).

70. A compound according to any one of claims 1 to 51, wherein E is an unsubstituted 5- to 7-membered heteroaryl group.

71. A compound according to any one of claims 1 to 51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substituted 5- to 7-membered heteroaryl.

72. A compound according to any one of claims 1 to 51, wherein E is unsubstituted C1-C3 alkylene-(5- to 7-membered heteroaryl).

73. A compound according to any one of claims 1-51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substituted C1-C3 alkylene-(5- to 7-membered heteroaryl).

74. A compound according to any one of claims 1-51, wherein E is C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl or C1-C3 alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl or C1-C3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substituted.

75. A compound according to any one of claims 1 to 51, wherein E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl or C1-C3 alkylene-(4- to 10-membered heterocyclyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl or C1-C3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substitution.

76. A compound according to any one of claims 1-51, wherein E is C1-C3 alkyl, C3-C8 cycloalkyl or C1-C3 alkylene-(C3-C8 cycloalkyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl C8 cycloalkyl or C1-C3 alkylene-(C3-C8 cycloalkyl) is unsubstituted or substituted by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substitution.

77. A compound according to any one of claims 1-51, wherein E is methyl.

78. A compound according to any one of claims 1-51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substituted methyl.

79. A compound according to any one of claims 1-51, wherein E is CF3.

80. A compound according to any one of claims 1 to 51, wherein E is CHF2.

81. A compound according to any one of claims 1 to 51, wherein E is CH2F.

82. A compound according to any one of claims 1-51, wherein E is NH(CH3).

83. A compound according to any one of claims 1-51, wherein E is N(CH3)2.

84. A compound according to any one of claims 1-51, wherein E is C6-C 10 Aryl, C1-C3 alkylene-(C6-C 10 aryl), 5- to 7-membered heteroaryl, or C1-C3 alkylene-(5- to 7-membered heteroaryl).

85. A compound according to any one of claims 1-51, wherein E is unsubstituted C6-C 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl).

86. A compound according to any one of claims 1-51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C6-C substituted by C1-C3 alkyl or C1-C3 alkoxy 10 Aryl or C1-C3 alkylene-(C6-C 10 aryl).

87. A compound according to any one of claims 1-51, wherein E is a 5- to 7-membered heteroaryl group or a C1-C3 alkylene-(5- to 7-membered heteroaryl group).

88. A compound according to any one of claims 1-51, wherein E is unsubstituted 5- to 7-membered heteroaryl or C1-C3 alkylene-(5- to 7-membered heteroaryl).

89. A compound according to any one of claims 1-51, wherein E is replaced by one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxy substituted 5- to 7-membered heteroaryl or C1-C3 alkylene-(5- to 7-membered heteroaryl).

90. A compound according to any one of claims 1 to 89, wherein Y is S(=O)2.

91. A compound according to any one of claims 1 to 89, wherein Y is C(=O).

92. A compound according to any one of claims 1 to 89, wherein Y is S(=O)(=NR e ).

93. A compound according to any one of claims 1 to 92, wherein X is N.

94. A compound according to any one of claims 1 to 92, wherein X is CH.

95. A compound according to any one of claims 1 to 94, wherein R1 is selected from the group consisting of: C(=O)-C1-C4 alkyl, C(=O)-C1-C4 alkoxy, C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C6-C 10 aryl) and C(═O)-(CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

96. A compound according to any one of claims 1 to 94, wherein R1 is selected from the group consisting of C(=O)-C1-C4 alkyl, C(=O)-C1-C4 alkoxy and C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, wherein the C1-C4 alkyl, C1-C4 alkoxy or C3-C8 cycloalkyl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted by one or more halogen or deuterium.

97. A compound according to any one of claims 1 to 94, wherein R1 is selected from the group consisting of: C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), C(=O)-(CR c R d ) n -(C6-C 10 aryl) and C(═O)-(CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 4- to 7-membered heterocyclyl, C6-C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

98. A compound according to any one of claims 1-94, wherein R1 is C(=O)-C1-C4 alkyl, wherein the C1-C4 alkyl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted by one or more halogen or deuterium.

99. A compound according to any one of claims 1 to 94, wherein R1 is C(=O)-C1-C4 alkoxy, wherein the C1-C4 alkoxy is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted by one or more halogen or deuterium.

100. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted by one or more halogen or deuterium.

101. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), wherein the 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

102. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl), wherein the C6-C 10 Aryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen or deuterium.

103. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

104. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heterocyclyl), wherein the 5- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

105. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5- to 6-membered heterocyclyl), wherein the 5- to 6-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

106. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), wherein the 5-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

107. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), wherein the 6-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

108. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(C6 aryl), wherein the C6 aryl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted by one or more halogen or deuterium.

109. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(C8 aryl), wherein the C8 aryl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted by one or more halogen or deuterium.

110. A compound according to any one of claims 1 to 94, wherein R1 is C(=O)-(CR c R d ) n -(C 10 aryl), wherein the C 10 Aryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen or deuterium.

111. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

112. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

113. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

114. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(7-membered heteroaryl), wherein the 7-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

115. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl or C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), wherein the C3-C8 cycloalkyl or 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

116. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted by one or more halogen or deuterium.

117. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), wherein the 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

118. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl is unsubstituted or substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted by one or more halogen or deuterium.

119. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(5- to 6-membered heterocyclyl), wherein the 5- to 6-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

120. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), wherein the 5-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

121. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), wherein the 6-membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

122. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C6-C 10 The aryl or 5- to 10-membered heteroaryl group is unsubstituted.

123. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C6-C 10 The aryl or 5- to 10-membered heteroaryl is substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted by one or more halogen or deuterium.

124. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C6-C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted, and further wherein n is 0.

125. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C6-C 10 The aryl or 5- to 10-membered heteroaryl is substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted by one or more halogen or deuterium, and further wherein n is 0.

126. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C6-C 10 The aryl or 5- to 10-membered heteroaryl is unsubstituted, and further wherein n is 1.

127. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 Aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C6-C 10 The aryl or 5- to 10-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 1.

128. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 aryl), wherein the C6-C 10 Aryl groups are unsubstituted.

129. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 aryl), wherein the C6-C 10 The aryl group is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

130. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 aryl), wherein the C6-C 10 Aryl is unsubstituted, and further wherein n is zero.

131. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 aryl), wherein the C6-C 10 The aryl group is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 0.

132. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 aryl), wherein the C6-C 10 Aryl is unsubstituted, and further wherein n is 1.

133. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 aryl), wherein the C6-C 10 The aryl group is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 1.

134. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted.

135. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

136. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted, and further wherein n is 0.

137. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 0.

138. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted, and further wherein n is 1.

139. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 1.

140. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is unsubstituted.

141. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

142. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is unsubstituted, and further wherein n is 0.

143. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 0.

144. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is unsubstituted, and further wherein n is 1.

145. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 1.

146. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is unsubstituted.

147. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

148. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is unsubstituted, and further wherein n is 0.

149. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 0.

150. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is unsubstituted, and further wherein n is 1.

151. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 1.

152. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is unsubstituted.

153. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

154. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is unsubstituted, and further wherein n is 0.

155. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 0.

156. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is unsubstituted, and further wherein n is 1.

157. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(6-membered heteroaryl), wherein the 6-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 1.

158. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is unsubstituted.

159. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is substituted by one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted by one or more halogen or deuterium.

160. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is unsubstituted, and further wherein n is 0.

161. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 0.

162. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is unsubstituted, and further wherein n is 1.

163. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5-membered heteroaryl), wherein the 5-membered heteroaryl is substituted with one or more halogen, hydroxy, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium, and further wherein n is 1.

164. A compound according to any one of claims 1-94, wherein R1 is C(═O)-C1-C4 alkyl, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

165. A compound according to any one of claims 1-94, wherein R1 is C(═O)-C1-C4 alkyl, and each of R2, R3, R4, R5, R6, R7 and R8 is H or unsubstituted C1-C3 alkyl.

166. A compound according to any one of claims 1-94, wherein R1 is C(═O)-C1-C4 alkoxy, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

167. A compound according to any one of claims 1-94, wherein R1 is C(═O)-C1-C4 alkoxy, and each of R2, R3, R4, R5, R6, R7 and R8 is H or unsubstituted C1-C3 alkyl.

168. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

169. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7 and R8 is H or unsubstituted C1-C3 alkyl.

170. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

171. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

172. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

173. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

174. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

175. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

176. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

177. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

178. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

179. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

180. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

181. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

182. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

183. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(C6-C 10 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

184. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

185. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(C6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

186. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(C6 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

187. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

188. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

189. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5- to 7-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

190. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

191. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

192. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

193. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

194. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

195. A compound according to any one of claims 1-94, wherein R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

196. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

197. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

198. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

199. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

200. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

201. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

202. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

203. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

204. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

205. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

206. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

207. A compound according to any one of claims 1-94, wherein R1 is C(=O)-O-(CR c R d ) n -(6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

208. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5- to 10-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

209. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(5- to 7-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

210. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

211. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

212. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(6-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

213. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

214. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7 and R8 is H.

215. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6 aryl), n is 0, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

216. A compound according to any one of claims 1-94, wherein R1 is (CR c R d ) n -(C6 aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7 and R8 is H.

217. A compound according to any one of claims 1-94, wherein R1 is 3-pyridazinyl.

218. A compound according to any one of claims 1-217, wherein Each of R2, R3, R4, R5, R6, R7 and R8 is independently H, halogen, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogen or deuterium.

219. A compound according to any one of claims 1-217, wherein Each of R2, R3, R4, R5, R6, R7 and R8 is independently H, halogen or unsubstituted C1-C3 alkyl.

220. A compound according to any one of claims 1-217, wherein Each of R2, R3, R4, R5, R6, R7 and R8 is independently H or halogen.

221. A compound according to any one of claims 1-217, wherein Each of R2, R3, R4, R5, R6, R7 and R8 is independently H or fluoro.

222. A compound according to any one of claims 1-217, wherein Each of R2, R3, R4, R5, R6, R7 and R8 is independently H or C1-C3 alkyl.

223. A compound according to any one of claims 1-217, wherein Each of R2, R3, R4, R5, R6, R7 and R8 is H.

224. A compound according to any one of claims 1-217, wherein R3 and R6 together form an unsubstituted C1-C3 alkylene group or a C1-C3 alkylene group substituted by one or more halogen groups.

225. A compound according to any one of claims 1-217, wherein R4 and R5 together form an unsubstituted C1-C3 alkylene group or a C1-C3 alkylene group substituted by one or more halogen groups.

226. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

227. A pharmaceutical composition comprising a compound according to any one of claims 1-225 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

228. A method of treating narcolepsy in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1-226 or a pharmaceutically acceptable salt thereof, or a composition according to claim 227.

229. A method of treating cataplexy in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1-226 or a pharmaceutically acceptable salt thereof, or a composition according to claim 227.

230. Use of a compound according to any one of claims 1-226 or a pharmaceutically acceptable salt thereof, or a composition according to claim 227, for the manufacture of a medicament for narcolepsy.

231. Use of a compound according to any one of claims 1-226 or a pharmaceutically acceptable salt thereof, or a composition according to claim 227 for the manufacture of a medicament for cataplexy.

232. Use of a compound according to any one of claims 1-226 or a pharmaceutically acceptable salt thereof, or a composition according to claim 227, for use in a method of treating narcolepsy in a subject in need thereof.

233. Use of a compound according to any one of claims 1-226 or a pharmaceutically acceptable salt thereof, or a composition according to claim 227, for use in a method of treating cataplexy in a subject in need thereof.

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