Replacement Condensed Bicyclic Compounds and Related Therapeutic Methods

Abstract

The present invention provides compounds useful for the treatment of narcolepsy or cataplexy in a subject in need of treatment thereof. Also provided are related pharmaceutical compositions and methods for treating narcolepsy or cataplexy in a subject in need of treatment thereof, which comprise administering to the subject a compound or a pharmaceutically acceptable salt thereof, or a composition.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 353,998, filed on June 21, 2022. The entire content of the above application is incorporated herein by reference.

[0002] The present invention relates to substituted bicyclic compounds, particularly substituted fused bicyclic compounds having agonist activity.

Background Art

[0003] Orexin is a neuropeptide synthesized and released by a subpopulation of neurons in the lateral hypothalamus and its surrounding regions. Orexin consists of two subtypes, namely 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 (type 1 and type 2) of orexin receptors (Cell, Vol. 92, 573-585, 1998). Activation of orexin receptors is known to be important for various central nervous system functions such as maintenance of the awake state, energy homeostasis, reward processing, and motivation (Saper et al., TRENDS in Neuroscience 2001; Yamanaka et al., Neuron 2003; Sakurai, Nature Reviews Neuroscience 2014).

[0004] Narcolepsy is a neurological disorder that causes excessive daytime sleepiness, sudden episodes of muscle paralysis (cataplexy), and disrupted sleep patterns (Mahoney et al., Nature Reviews Neuroscience, 2019). Narcolepsy is known to be caused by the degeneration of orexin neurons. Narcolepsy symptoms can be modeled in transgenic mice engineered to degenerate orexin neurons, and those symptoms can be reversed by intracerebroventricular administration of orexin peptides (Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004). Studies of orexin 2 receptor knockout mice suggest that the orexin 2 receptor plays a preferential role in maintaining the wake state (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 showing excessive daytime sleepiness, such as Parkinson's disease (CNS Drugs, Vol. 27, 83-90, 2013; Brain, Vol. 130, 2007, 1586-1595).

[0005] Compounds having agonist activity for orexin 2 receptor have been considered useful as novel therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disorders of consciousness such as coma, narcolepsy syndrome, hypersomnia syndrome characterized by hypersomnia (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, or sepsis. (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; International Publication No. 2015 / 073707; Journal of the American College of Cardiology, Vol.66, 2015, pages 2522-2533; International Publication No. 2015 / 048091; International Publication No. 2015 / 147240).

[0006] Some compounds having orexin 2 receptor agonist activity have been reported (U.S. Patent No. 8,258,163; International Publication No. 2015 / 088000; International Publication No. 2014 / 198880; Journal of Medicinal Chemistry, Vol.58, pages 7931-7937; U.S. Patent Application Publication No. 20190040010; U.S. Patent Application Publication No. 20190031611; U.S. Patent Application Publication No. 20170226137). However, these compounds are considered not satisfactory in terms of activity, pharmacokinetics, permeability to the brain / central nervous system, safety, etc., and the development of improved compounds having orexin 2 receptor agonist activity is desired.

Summary of the Invention

[0007] An object of the present invention is to provide a condensed bicyclic compound having orexin 2 receptor agonist activity.

[0008] Accordingly, in a first aspect, the present invention provides a compound represented by formula I-A or a pharmaceutically acceptable salt thereof: [Chemical Formula] (wherein, ring A is fused to ring B, ring A is selected from the group consisting of C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl and 5-7 membered heteroaryl, and C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl or 5-7 membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium, ring B is selected from the group consisting of C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl and 5-7 membered heteroaryl, and C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl or 5-7 membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium, X is N or CH, Y is S(=O)2, C(=O), or S(=O)(=NR e ), R e is selected from the group consisting of H, C1-C3 alkyl or C3-C5 cycloalkyl, E is 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), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-7 membered heteroaryl and C1-C3 alkylene-(5-7 membered heteroaryl) selected from the group consisting of, 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), 4-10 membered heterocyclyl, C1-C3 alkylene-(4-10 membered heterocyclyl), C6-C 10 aryl, C1-C3 alkylene-(C6-C 10 aryl), 5-7 membered heteroaryl or C1-C3 alkylene-(5-7 membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl, R a and R b are each independently selected from the group consisting of H, C1-C3 alkyl, C3-C5 cycloalkyl, and 4-7 membered heterocyclyl, C1-C3 alkyl, C3-C5 cycloalkyl, or 4-7 membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl, or, R a and R b together with the N atom to which they are attached form a 4-7 membered heterocyclyl or 5-7 membered heteroaryl, 4-7 membered heterocyclyl or 5-7 membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d、 substituted by C1-C3 alkyl, C1-C3 alkoxyl or C1-C3 alkyl substituted with 1 to 3 halogens, R1 is C(=O)-C1-C4 alkyl, C(=O)-C1-C4 alkoxyl, C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, C(=O)-(CR c R d ) n -(4-7 membered heterocyclyl), C(=O)-(CR c R d ) n -(C6-C 10 aryl), C(=O)-(CR c R d ) n -(5-10 membered heteroaryl), C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, C(=O)-O-(CR c R d ) n -(4-7 membered heterocyclyl), (CR c R d ) n -(C6-C 10 aryl) and (CR c R d ) n -(5-10 membered heteroaryl), selected from the group consisting of, C1-C4 alkyl, C1-C4 alkoxyl, C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, R c and R d are each independently H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, 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 halogens or deuteriums, or alternatively, R3 and R6 together form unsubstituted C1-C3 alkylene or C1-C3 alkylene substituted with one or more halogens, alternatively, R4 and R5 together form unsubstituted C1-C3 alkylene or C1-C3 alkylene substituted with one or more halogens, m is 0 or 1, p is 0, 1, 2, 3, or 4, each R9 is independently selected from the group consisting of deuterium, halogen, hydroxyl, and cyano).

[0009] In one embodiment, provided herein is a compound of formula I-A having the structure of formula I or a pharmaceutically acceptable salt thereof: [Chemical formula] (wherein, ring A is fused to ring B, ring A is selected from the group consisting of C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl and 5-7 membered heteroaryl, and C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl or 5-7 membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, ring B is selected from the group consisting of C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl and 5-7 membered heteroaryl, and C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10Aryl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, X is N or CH, Y is S(=O)2, C(=O), or S(=O)(=NR e ) R e is selected from the group consisting of H, C1-C3 alkyl, or C3-C5 cycloalkyl, E is 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) selected from the group consisting of, 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 with one or more halogens, hydroxyls, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl, R a and R bare each independently selected from the group consisting of H, C1-C3 alkyl, C3-C5 cycloalkyl, and 4-7 membered heterocyclyl, and C1-C3 alkyl, C3-C5 cycloalkyl, or 4-7 membered heterocyclyl is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl, or R a and R b together with the N atom to which they are attached form a 4-7 membered heterocyclyl or 5-7 membered heteroaryl, and the 4-7 membered heterocyclyl or 5-7 membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , C1-C3 alkyl, C1-C3 alkoxyl or C1-C3 alkyl substituted with 1-3 halogen, R1 is C(=O)-C1-C4 alkyl, C(=O)-C1-C4 alkoxyl, C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, C(=O)-(CR c R d ) n -(4-7 membered heterocyclyl), C(=O)-(CR c R d ) n -(C6-C 10 aryl), C(=O)-(CR c R d ) n -(5-10 membered heteroaryl), C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, C(=O)-O-(CR c R d ) n -(4-7 membered heterocyclyl), (CR c R d ) n -(C6-C 10 aryl) and (CR c R d ) n- selected from the group consisting of (5- to 10-membered heteroaryl), C1-C4 alkyl, C1-C4 alkoxyl, C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, R c and R d are each, independently, H, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, 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 halogens or deuteriums, or alternatively, R3 and R6 together form unsubstituted C1-C3 alkylene or C1-C3 alkylene substituted with one or more halogens, alternatively, R4 and R5 together form unsubstituted C1-C3 alkylene or C1-C3 alkylene substituted with one or more halogens, m is 0 or 1, p is 0, 1, 2, 3 or 4, each R9 is independently selected from the group consisting of deuterium, halogen, hydroxyl and cyano).

[0010] Also provided herein is a pharmaceutical composition comprising a compound of formula I-A or I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0011] 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 I-A or I or a pharmaceutically acceptable salt thereof.

[0012] 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 I-A or I or a pharmaceutically acceptable salt thereof.

Best Mode for Carrying Out the Invention

[0013] Provided herein are compounds useful for treating narcolepsy or cataplexy in a subject, such as a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0014] In a non-limiting aspect, these compounds may modulate the orexin 2 receptor. In certain embodiments, the compounds provided herein are believed to be orexin 2 agonists. Thus, in one aspect, the compounds provided herein are useful for treating narcolepsy in a subject by acting as an agonist of the orexin 2 receptor.

[0015] Definitions The following are definitions of various terms used to describe the present invention. These definitions apply to the terms used throughout this specification and the claims, individually or as part of a larger group, unless otherwise specifically limited in a particular instance.

[0016] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are well known and commonly employed in the art.

[0017] As used herein, the articles "a" and "an" refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or a plurality of elements. Further, the use of the term "including" and other forms such as "include", "includes", and "included" is not limiting.

[0018] As used herein, the term "about" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. When used herein in reference to measurable values such as amounts, durations, etc., the term "about" means to encompass variations of ±20% or ±10% including ±5%, ±1%, and ±0.1% from the specified value, such variations being suitable for carrying out the disclosed methods.

[0019] As used herein, "EC 50 " refers to the concentration of a compound required to achieve an effect that is 50% of the maximum observed effect of the compound.

[0020] As used herein, the term "agonist" refers to a compound that, when contacted with a target of interest (e.g., the orexin 2 receptor), causes an increase in the magnitude of a particular activity or function of the target as compared to the magnitude of the activity or function observed in the absence of the agonist.

[0021] The terms "treat", "treated", "treating" or "treatment" include a reduction or alleviation of at least one symptom associated with or caused by the condition, disorder or disease being treated. In certain embodiments, treatment includes contacting an orexin 2 receptor with an effective amount of a compound of the invention for a condition associated with narcolepsy or cataplexy.

[0022] As used herein, the terms "prevent" or "prevention" mean, when a disorder or disease has not occurred, the absence of the occurrence of the disorder or disease, or when the disorder or disease has already occurred, the absence of the occurrence of further disorders or diseases. The ability to prevent some or all of the symptoms associated with a disorder or disease is also contemplated.

[0023] As used herein, the terms "patient", "individual" or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, mammals such as livestock and pets, such as sheep, cows, pigs, dogs, cats and mice. Preferably, the patient, subject or individual is human.

[0024] As used herein, the terms "effective amount", "pharmaceutically effective amount", and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent 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.

[0025] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not inactivate the biological activity or properties of a compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained.

[0026] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present invention include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent, or in a mixture of the two, and generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase "pharmaceutically acceptable salt" is not limited to mono-salts or 1:1 salts. For example, "pharmaceutically acceptable salts" also include bis-salts such as bis-hydrochloride. 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.

[0027] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of the compounds to a patient or subject. A plurality of techniques for administering compounds exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0028] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention in or to a patient so as to perform the intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a formulation containing a compound useful within the invention and not injurious to the patient. Some examples of substances which can function as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethylcellulose sodium, ethyl cellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate, ethyl laurate; agar; buffering agents such as magnesium hydroxide, aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations.

[0029] As used herein, "pharmaceutically acceptable carrier" also includes any coating, antibacterial and antifungal agents, absorption delaying agents, etc. that are compatible with the activity of the compounds useful within the present invention and are physiologically acceptable to the patient. Additionally, auxiliary active compounds may be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds useful within the present invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of 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 is incorporated herein by reference.

[0030] As used herein, the term "alkyl", by itself or as part of another substituent, unless otherwise specified, means a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-6 alkyl means alkyl having 1 to 6 carbon atoms), including straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl and hexyl. Other examples of C1-C6-alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl and n-hexyl.

[0031] As used herein, the term "halo" or "halogen", by itself or as part of another substituent, unless otherwise specified, means a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0032] As used herein, the term "alkylene" refers to a divalent aliphatic hydrocarbyl group having 1 to 4 carbon atoms, which can be either straight-chain or branched-chain. By way of example, this term includes methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), and the like.

[0033] As used herein, the term "alkenyl" means a monovalent group derived from a hydrocarbon moiety containing at least 2 carbon atoms and at least 1 carbon-carbon double bond. The double bond may or may not be a point of attachment to another group. Examples of alkenyl groups (e.g., C2-C8-alkenyl) include, but are not limited to, ethenyl, propenyl, prop-1-en-2-yl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0034] As used herein, the term "alkynyl" means a monovalent group derived from a hydrocarbon moiety containing at least 2 carbon atoms and at least 1 carbon-carbon triple bond. The triple bond may or may not be a point of attachment to another group. Examples of alkynyl groups (e.g., C2-C8-alkynyl) include, but are not limited to, ethynyl, propynyl, prop-1-yn-2-yl, butynyl, 1-methyl-2-butyn-1-yl, heptynyl, octynyl, and the like.

[0035] As used herein, the term "alkoxy" refers to an -O-alkyl group where alkyl is as defined herein. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, and the like.

[0036] As used herein, the term "cycloalkyl" means a partially or fully saturated non-aromatic carbocyclic system having 1, 2, or 3 rings, such rings may be fused. The term "fused" means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures that may be essentially bridged or spirocyclic, with each individual ring within the cycle varying from 3 to 8 atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl.

[0037] As used herein, the term "heterocyclyl" means a non-aromatic carbocyclic system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, having 1, 2, or 3 rings, such rings may be fused, and the fusion is defined above. Heterocyclyl also includes bicyclic structures that can be essentially bridged or spirocyclic, each individual ring within the bicyclic having from 3 to 8 atoms and containing 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 specifically includes, but is not limited to, epoxyxyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, etc. For example, the term "heterocyclyl" may include 4- to 10-membered heterocyclyl, 4- to 7-membered heterocyclyl, 5- to 10-membered heterocyclyl, 6- to 10-membered heterocyclyl, 4- to 6-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, or 10-membered heterocyclyl.

[0038] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromaticity, i.e., having (4n + 2) delocalized π (pi) electrons, where n is an integer.

[0039] As used herein, the term "aryl" means an aromatic carbocyclic system containing 1, 2 or 3 rings, such rings may be fused, and the fusion is defined above. When the rings are fused, one of the rings must be completely unsaturated, and the fused ring(s) may be completely saturated, partially unsaturated or completely unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. For example, the term "aryl" may include C6-C 10 aryl, C6-C8 aryl, or C6 aryl (i.e., phenyl).

[0040] As used herein, the term "heteroaryl" means an aromatic carbocyclic system having 1, 2 or 3 rings and containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, such rings may be fused, and the fusion is defined above. The term "heteroaryl" includes, but is not limited to, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. For example, the term "heteroaryl" may 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.

[0041] When an aryl, heteroaryl, cycloalkyl or heterocyclyl moiety can be attached or otherwise bonded to a designated moiety via different ring atoms (i.e., shown or described without indication of a specific point of attachment), it should be understood that all possible points are intended, whether via a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3- or 4-pyridinyl, the term "thiophenyl" means 2- or 3-thiophenyl, and so on.

[0042] As used herein, the term "substituted" means that an atom or group of atoms has replaced hydrogen as a substituent bonded to another group.

[0043] The compounds of the present invention Accordingly, in a first aspect, the present invention provides a compound represented by formula I-A or a pharmaceutically acceptable salt thereof:

Chemical formula

[0044] In one embodiment, provided herein are compounds of formula I-A having the structure of formula I or pharmaceutically acceptable salts thereof:

Chemical Formula

[0045] In one embodiment of formula (I), ring A is selected from the group consisting of 4- to 7-membered heterocyclyl, C6-C 10 aryl and 5- to 7-membered heteroaryl, and the 4- to 7-membered heterocyclyl, C6-C 10 aryl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0046] In another embodiment of formula (I), ring A is selected from the group consisting of C3-C8 cycloalkyl, C6-C 10 aryl and 5- to 7-membered heteroaryl, and the C3-C8 cycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0047] In another embodiment of formula (I), ring A is selected from the group consisting of C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl, and 5- to 7-membered heteroaryl, and the C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0048] In another embodiment of formula (I), ring A is selected from the group consisting of C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl, and C6-C 10 aryl, and the C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl, C6-C 10Aryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0049] In another embodiment of formula (I), ring A is selected from the group consisting of C6-C 10 Aryl and 5- to 7-membered heteroaryl, selected from the group consisting of C6-C 10 Aryl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0050] In another embodiment of formula (I), ring A is selected from the group consisting of C3-C8 cycloalkyl and 4- to 7-membered heterocyclyl, and C3-C8 cycloalkyl or 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0051] In another embodiment of formula (I), ring A is selected from the group consisting of C3-C8 cycloalkyl and C6-C 10 Aryl, and C3-C8 cycloalkyl or C6-C 10 Aryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0052] In another embodiment of formula (I), ring A is selected from the group consisting of 4- to 7-membered heterocyclyl and C6-C 10 Aryl, and 4- to 7-membered heterocyclyl or C6-C 10Aryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0053] In another embodiment of formula (I), ring A is selected from the group consisting of 4- to 7-membered heterocyclyls and 5- to 7-membered heteroaryls, and the 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0054] In another embodiment of formula (I), ring A is C3-C8 cycloalkyl, and the C3-C8 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0055] In another embodiment of formula (I), ring A is 4- to 7-membered heterocyclyl, and the 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0056] In another embodiment of formula (I), ring A is C6-C 10 aryl, and C6-C 10 aryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0057] In another embodiment of formula (I), ring A is a 5- to 7-membered heteroaryl, and the 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0058] In another embodiment of formula (I), ring B is selected from the group consisting of a 4- to 7-membered heterocyclyl, C6-C 10 aryl and a 5- to 7-membered heteroaryl, and the 4- to 7-membered heterocyclyl, C6-C 10 aryl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0059] In another embodiment of formula (I), ring B is selected from the group consisting of a C3-C8 cycloalkyl, C6-C 10 aryl and a 5- to 7-membered heteroaryl, and the C3-C8 cycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0060] In another embodiment of formula (I), ring B is selected from the group consisting of a C3-C8 cycloalkyl, a 4- to 7-membered heterocyclyl, and a 5- to 7-membered heteroaryl, and the C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0061] In another embodiment of formula (I), ring B is a C3-C8 cycloalkyl, a 4- to 7-membered heterocyclyl, and C6-C10 Selected from the group consisting of aryl, C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 The aryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0062] In another embodiment of formula (I), ring B is selected from the group consisting of C6-C 10 Selected from the group consisting of aryl and 5-7 membered heteroaryl, C6-C 10 The aryl or 5-7 membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0063] In another embodiment of formula (I), ring B is selected from the group consisting of C3-C8 cycloalkyl and 4-7 membered heterocyclyl, and the C3-C8 cycloalkyl or 4-7 membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0064] In another embodiment of formula (I), ring B is selected from the group consisting of C3-C8 cycloalkyl and C6-C 10 Selected from the group consisting of aryl, and the C3-C8 cycloalkyl or C6-C 10 The aryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0065] In another embodiment of formula (I), ring B is selected from the group consisting of 4-7 membered heterocyclyl and C6-C 10 Selected from the group consisting of aryl, and the 4-7 membered heterocyclyl or C6-C 10Aryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0066] In another embodiment of formula (I), ring B is selected from the group consisting of 4- to 7-membered heterocyclyls and 5- to 7-membered heteroaryls, and the 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0067] In another embodiment of formula (I), ring B is C3-C8 cycloalkyl, and the C3-C8 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0068] In another embodiment of formula (I), ring B is a 4- to 7-membered heterocyclyl, and the 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0069] In another embodiment of formula (I), ring B is C6-C 10 aryl, and C6-C 10 aryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0070] In another embodiment of formula (I), ring B is a 5- to 7-membered heteroaryl, and the 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0071] In another embodiment of formula (I), ring A and ring B are each independently selected from the group consisting of 4- to 7-membered heterocyclyl, C6-C 10 aryl and 5- to 7-membered heteroaryl, and the 4- to 7-membered heterocyclyl, C6-C 10 aryl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0072] In another embodiment of formula (I), ring A and ring B are each independently selected from the group consisting of C3-C8 cycloalkyl, C6-C 10 aryl and 5- to 7-membered heteroaryl, and the C3-C8 cycloalkyl, C6-C 10 aryl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0073] In another embodiment of formula (I), ring A and ring B are each independently selected from the group consisting of C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl, and 5- to 7-membered heteroaryl, and the C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0074] In another embodiment of formula (I), ring A and ring B are each independently selected from the group consisting of C3-C8 cycloalkyl, 4-7 membered heterocyclyl, and C6-C 10 aryl, and C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0075] In another embodiment of formula (I), ring A and ring B are each independently selected from the group consisting of C6-C 10 aryl and 5-7 membered heteroaryl, and C6-C 10 aryl or 5-7 membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0076] In another embodiment of formula (I), ring A and ring B are each independently selected from the group consisting of C3-C8 cycloalkyl and 4-7 membered heterocyclyl, and C3-C8 cycloalkyl or 4-7 membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0077] In another embodiment of formula (I), ring A and ring B are each independently selected from the group consisting of C3-C8 cycloalkyl and C6-C 10 aryl, and C3-C8 cycloalkyl or C6-C 10 aryl is unsubstituted or substituted with one or more halogens, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0078] In another embodiment of formula (I), ring A and ring B are each independently selected from the group consisting of 4- to 7-membered heterocyclyl and C6-C 10 aryl, and the 4- to 7-membered heterocyclyl or C6-C 10 aryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0079] In another embodiment of formula (I), ring A and ring B are each independently selected from the group consisting of 4- to 7-membered heterocyclyl and 5- to 7-membered heteroaryl, and the 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0080] In another embodiment of formula (I), ring A is 5- to 7-membered heteroaryl and ring B is C6-C 10 aryl, and the 5- to 7-membered heteroaryl and C6-C 10 aryl are each independently unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0081] In another embodiment of formula (I), ring A is 5- to 7-membered heteroaryl and ring B is 5- to 7-membered heteroaryl, and each 5- to 7-membered heteroaryl is independently unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0082] In another embodiment of formula (I), ring A is 4- to 7-membered heterocyclyl and ring B is C6-C 10Aryl, 4- to 7-membered heterocyclyl, and C6-C 10 Each aryl is independently unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0083] In another embodiment of formula (I), ring A is a 4- to 7-membered heterocyclyl, ring B is a 5- to 7-membered heteroaryl, and each of the 4- to 7-membered heterocyclyl and 5- to 7-membered heteroaryl is independently unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0084] In another embodiment of formula (I), ring A is C3-C8 cycloalkyl, ring B is C6-C 10 Aryl, and each of C3-C8 cycloalkyl and C6-C 10 Aryl is independently unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0085] In another embodiment of formula (I), ring A is C3-C8 cycloalkyl, ring B is a 5- to 7-membered heteroaryl, and each of C3-C8 cycloalkyl and 5- to 7-membered heteroaryl is independently unsubstituted or substituted with one or more halogens, hydroxyls, C1-C3 alkoxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0086] In another embodiment of formula (I),

Chemical formula

[0087] In another embodiment of formula (I),

Chemical formula

[0088] In another embodiment of formula (I),

Chemical formula

[0089] In another embodiment of formula (I),

Chemical formula

[0090] In another embodiment of formula (I),

Chemical formula

[0091] In another embodiment of formula (I),

Chemical formula

[0092] In another embodiment of formula (I), [Chemical formula] is indolinyl, and indolinyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0093] In another embodiment of formula (I), [Chemical formula] is indazolyl, and indazolyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0094] In another embodiment of formula (I), [Chemical formula] is isoindazolyl, and isoindazolyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0095] In another embodiment of formula (I), [Chemical formula] is benzothiazolyl, and the benzothiazolyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0096] In another embodiment of formula (I),

Chemical formula

[0097] In another embodiment of formula (I),

Chemical formula

[0098] In another embodiment of formula (I),

Chemical formula

[0099] In another embodiment of formula (I), [Chemistry] is benzisothiazolyl, and the benzisothiazolyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0100] In another embodiment of formula (I), [Chemistry] is isobenzofuranyl, and the isobenzofuranyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0101] In another embodiment of formula (I), [Chemistry] is benzothiophenyl, and the benzothiophenyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0102] In another embodiment of formula (I), [Chemistry] is indoleninyl, and the indoleninyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0103] In another embodiment of formula (I),

Chemical formula

[0104] In another embodiment of formula (I),

Chemical formula

[0105] In another embodiment of formula (I),

Chemical formula

[0106] In another embodiment of formula (I), [Chem.] is anthranil, and anthranil is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0107] In another embodiment of formula (I), [Chem.] is indolizinyl, and indolizinyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0108] In another embodiment of formula (I), [Chem.] is [Chem.] and is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0109] In another embodiment of formula (I), [Chem.] is [Chem.] and is unsubstituted or substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-C3 alkoxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with 1 to 3 halogen atoms or deuterium atoms.

[0110] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0111] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0112] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0113] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0114] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0115] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0116] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0117] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0118] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0119] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0120] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0121] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0122] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0123] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0124] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0125] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0126] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0127] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0128] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0129] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0130] In another embodiment of formula (I),

Chemical formula

Chemical formula

[0131] 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.

[0132] In another embodiment of formula (I), p is 1 and R9 is deuterium. In another embodiment of formula (I), p is 1 and R9 is halogen. In another embodiment of formula (I), p is 1 and R9 is fluorine. In another embodiment of formula (I), p is 1 and R9 is hydroxyl. In another embodiment of formula (I), p is 1 and R9 is cyano. In another embodiment of formula (I), p is 2 and each R9 is hydroxyl. In another embodiment of formula (I), p is 2 and each R9 is halogen. In another embodiment of formula (I), p is 2 and each R9 is fluorine.

[0133] In another embodiment of formula (I), E is NR a R b In another embodiment of formula (I), E is C1-C3 alkylene-NR a R b In another embodiment of formula (I), E is unsubstituted C1-C3 alkyl, unsubstituted C2-C4 alkenyl or unsubstituted C 2~is C4 alkynyl. In another embodiment of formula (I), E is C1-C3 alkyl, C2-C4 alkenyl or C2-C4 alkynyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C1-C3 alkyl. In another embodiment of formula (I), E is C1-C3 alkyl substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkyl substituted with C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C3-C8 cycloalkyl. In another embodiment of formula (I), E is C3-C8 cycloalkyl substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(C3-C8 cycloalkyl). In another embodiment of formula (I), E is C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted 4- to 10-membered heterocyclyl. In another embodiment of formula (I), E is 4- to 10-membered heterocyclyl substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(4- to 10-membered heterocyclyl). In another embodiment of formula (I), E is C1-C3 alkylene-(4- to 10-membered heterocyclyl) substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl. In another embodiment of formula (I), E is unsubstituted C6-C 10is aryl. In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl substituted C6-C 10 aryl. In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(C6-C 10 aryl). In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl substituted C1-C3 alkylene-(C6-C 10 aryl). In another embodiment of formula (I), E is unsubstituted 5-7 membered heteroaryl. In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl substituted 5-7 membered heteroaryl. In another embodiment of formula (I), E is unsubstituted C1-C3 alkylene-(5-7 membered heteroaryl). In another embodiment of formula (I), E is one or more halogens, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl substituted C1-C3 alkylene-(5-7 membered heteroaryl).

[0134] In another embodiment of formula (I), E is C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, or C1-C3 alkylene-(4-10 membered heterocyclyl), and C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, or C1-C3 alkylene-(4-10 membered heterocyclyl) is unsubstituted or one or more halogens, hydroxyl, NRc R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl.

[0135] In another embodiment of formula (I), E is C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, or C1-C3 alkylene-(4-10 membered heterocyclyl), wherein the C1-C3 alkyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4-10 membered heterocyclyl, or C1-C3 alkylene-(4-10 membered heterocyclyl) is unsubstituted or is substituted with one or more of halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl.

[0136] In another embodiment of formula (I), E is C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl), wherein C1-C3 alkyl, C3-C8 cycloalkyl, or C1-C3 alkylene-(C3-C8 cycloalkyl) is unsubstituted or substituted with one or more of halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl.

[0137] In another embodiment of formula (I), E is methyl. In another embodiment of formula (I), E is one or more of halogen, hydroxyl, NR c R d , methyl substituted with CF3, CHF2, CH2F, C1-C3 alkyl, or C1-C3 alkoxyl. In another embodiment of Formula (I), E is CF3. In another embodiment of Formula (I), E is CHF2. In another embodiment of Formula (I), E is CH2F. In another embodiment of Formula (I), E is NH(CH3). In another embodiment of Formula (I), E is N(CH3)2.

[0138] In another embodiment of formula (I), 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). In another embodiment of formula (I), E is unsubstituted C6-C 10 aryl or C1-C3 alkylene-(C6-C 10 aryl). In another embodiment of formula (I), E is C6-C c aryl or C1-C3 alkylene-(C6-C d aryl) substituted with one or more halogen, hydroxyl, NR 10 R 10 , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl.

[0139] In another embodiment of formula (I), E is 5- to 7-membered heteroaryl or C1-C3 alkylene-(5- to 7-membered heteroaryl). In another embodiment of formula (I), E is unsubstituted 5- to 7-membered heteroaryl or C1-C3 alkylene-(5- to 7-membered heteroaryl). In another embodiment of formula (I), E is 5- to 7-membered heteroaryl or C1-C3 alkylene-(5- to 7-membered heteroaryl) substituted with one or more halogen, hydroxyl, NR c R d , CF3, CHF2, CH2F, C1-C3 alkyl or C1-C3 alkoxyl.

[0140] 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 ).

[0141] In another embodiment of formula (I), X is N. In another embodiment of formula (I), X is CH.

[0142] In another embodiment of formula (I), R1 is 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 -(4-7 membered heterocyclyl), C(=O)-(CR c R d ) n -(C6-C 10 aryl), and C(=O)-(CR c R d ) n -(5-10 membered heteroaryl), and is selected from the group consisting of; C1-C4 alkyl, C1-C4 alkoxyl, C3-C8 cycloalkyl, 4-7 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0143] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, C(=O)-C1-C4 alkoxyl, and C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, and is selected from the group consisting of; C1-C4 alkyl, C1-C4 alkoxyl, or C3-C8 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0144] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(4-7 membered heterocyclyl), C(=O)-(CR c R d ) n -(C6-C 10Aryl), and C(=O)-(CR c R d ) n -(5 to 10-membered heteroaryl) and is selected from the group consisting of, 4 to 7-membered heterocyclyl, C6 to C 10 Aryl, or 5 to 10-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0145] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, and C1-C4 alkyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0146] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkoxy, and C1-C4 alkoxy is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0147] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3-C8 cycloalkyl, and C3-C8 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0148] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 4- to 7-membered heterocyclyl), wherein the 4- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0149] In another embodiment of formula (I), R1 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 halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0150] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0151] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5- to 7-membered heterocyclyl), wherein the 5- to 7-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0152] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 5- to 6-membered heterocyclyl), where the 5- to 6-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums.

[0153] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), where the 5-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums.

[0154] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), where the 6-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums.

[0155] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a C6 aryl), where the C6 aryl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums.

[0156] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a C8 aryl), where the C8 aryl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums.

[0157] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C 10 aryl), and the C 10 aryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0158] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5- to 6-membered heteroaryl), and the 5- to 6-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0159] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(5-membered heteroaryl), and the 5-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0160] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(6-membered heteroaryl), and the 6-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0161] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(7-membered heteroaryl), and the 7-membered heteroaryl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0162] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl or C(=O)-O-(CR c R d ) n -(4-7-membered heterocyclyl), and the C3-C8 cycloalkyl or 4-7-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3-C8 cycloalkyl, and the C3-C8 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(4-7-membered heterocyclyl), and the 4-7-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3-C5 cycloalkyl, and the C3-C5 cycloalkyl is unsubstituted or substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is C(=O)-O-(CRc R d ) n - (5- to 6-membered heterocyclyl), wherein the 5- to 6-membered heterocyclyl is unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums. In another embodiment of formula (I), 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 halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums. 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 with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums.

[0163] In another embodiment of formula (I), 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 aryl or 5- to 10-membered heteroaryl is unsubstituted. In another embodiment of formula (I), 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 10Aryl or 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0164] In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), where C6-C 10 aryl or 5- to 10-membered heteroaryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), where C6-C 10 aryl or 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 0.

[0165] In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl), where C6-C 10 aryl or 5- to 10-membered heteroaryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl) or (CR c R d ) n-(a 5- to 10-membered heteroaryl), and C6-C 10 The aryl or 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 1.

[0166] In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl), and the C6-C 10 aryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(a C 6~ C 10 aryl), and the C 6~ C 10 aryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0167] In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C 10 aryl), and the C6-C 10 aryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(a C 6~ C 10 aryl), and the C 6~ C 10 aryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 0.

[0168] In another embodiment of formula (I), R1 is (CR c R d ) n -(a C6-C10 is (aryl), and C6~C 10 The aryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(C 6~ C 10 is (aryl), and C 6~ C 10 The aryl is substituted with one or more halogens, hydroxyls, unsubstituted C1~C3 alkyls, or C1~C3 alkyls substituted with one or more halogens or deuteriums, and further n is 1.

[0169] In another embodiment of formula (I), R1 is (CR c R d ) n -(5~10-membered heteroaryl), and the 5~10-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(5~10-membered heteroaryl), and the 5~10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1~C3 alkyls, or C1~C3 alkyls substituted with one or more halogens or deuteriums.

[0170] In another embodiment of formula (I), R1 is (CR c R d ) n -(5~10-membered heteroaryl), and the 5~10-membered heteroaryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(5~10-membered heteroaryl), and the 5~10-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1~C3 alkyls, or C1~C3 alkyls substituted with one or more halogens or deuteriums, and further n is 0.

[0171] In another embodiment of formula (I), R1 is (CR c R d )n -(a 5- to 10-membered heteroaryl), the 5- to 10-membered heteroaryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 10-membered heteroaryl), the 5- to 10-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium, and further n is 1.

[0172] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(a 5- to 7-membered heteroaryl), the phenyl or 5- to 7-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(a 5- to 7-membered heteroaryl), the phenyl or 5- to 7-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

[0173] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(a 5- to 7-membered heteroaryl), the phenyl or 5- to 7-membered heteroaryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n-(a 5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 0.

[0174] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(a 5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(a 5- to 7-membered heteroaryl), wherein the phenyl or 5- to 7-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 1.

[0175] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(a 6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(a 6-membered heteroaryl), wherein the phenyl or 6-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums.

[0176] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), the phenyl or 6-membered heteroaryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), the phenyl or 6-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, and further n is 0.

[0177] In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), the phenyl or 6-membered heteroaryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl), the phenyl or 6-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, and further n is 1.

[0178] In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), the 6-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CRc R d ) n -(a 6-membered heteroaryl), and the 6-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums. In another embodiment of formula (I), R1 is pyridazinyl. In another embodiment of formula (I), R1 is 3-pyridazinyl.

[0179] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 6-membered heteroaryl), the 6-membered heteroaryl is unsubstituted, and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 6-membered heteroaryl), the 6-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 0.

[0180] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 6-membered heteroaryl), the 6-membered heteroaryl is unsubstituted, and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 6-membered heteroaryl), the 6-membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuteriums, and further n is 1.

[0181] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5-membered heteroaryl), and the 5-membered heteroaryl is unsubstituted. In another embodiment of formula (I), R1 is (CR c Rd ) n -(a 5-membered heteroaryl), wherein the 5-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums.

[0182] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5-membered heteroaryl), wherein the 5-membered heteroaryl is unsubstituted and further n is 0. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5-membered heteroaryl), wherein the 5-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, and further n is 0.

[0183] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5-membered heteroaryl), wherein the 5-membered heteroaryl is unsubstituted and further n is 1. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5-membered heteroaryl), wherein the 5-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuteriums, and further n is 1.

[0184] In another embodiment of formula (I), 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 halogens or deuteriums. In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is independently H, halogen, or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is independently H, or halogen. In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is independently H, or fluorine. In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is independently H, or C1-C3 alkyl. In another embodiment of formula (I), each of R2, R3, R4, R5, R6, R7, and R8 is H.

[0185] In another embodiment of formula (I), R3 and R6 together form unsubstituted C1-C3 alkylene or C1-C3 alkylene substituted with one or more halogens. In another embodiment of formula (I), R3 and R6 together form unsubstituted C2 alkylene or C2 alkylene substituted with one or more halogens. In another embodiment of formula (I), R3 and R6 together form azabicyclo[3.2.1]octanyl-bridged bicyclic heterocyclyl.

[0186] In another embodiment of formula (I), R4 and R5 together form unsubstituted C1-C3 alkylene or C1-C3 alkylene substituted with one or more halogens. In another embodiment of formula (I), R4 and R5 together form unsubstituted C2 alkylene or C2 alkylene substituted with one or more halogens. In another embodiment of formula (I), R4 and R5 together form azabicyclo[3.2.1]octanyl-bridged bicyclic heterocyclyl.

[0187] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), 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. In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0188] In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkoxy, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), 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. In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkoxy, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-C1-C4 alkoxy, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0189] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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. In another embodiment of formula (I), R1 is C(=O)-(CR c R d) n -C3 to C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0190] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0191] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0192] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0193] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0194] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0195] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0196] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or a halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0197] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or a halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0198] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0199] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0200] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0201] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C10 is aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0202] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0203] In another embodiment of formula (I), 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. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6-C 10is aryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0204] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0205] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0206] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0207] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0208] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0209] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0210] In another embodiment of formula (I), 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. In another embodiment of formula (I), R1 is C(=O)-(CR c R d )n -(a 5-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0211] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0212] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n-(a 5-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 5-membered heteroaryl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0213] In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-(CR c R d ) n -(a 6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), 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 or fluorine.

[0214] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0215] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0216] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0217] In another embodiment of formula (I), 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. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n-C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0218] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 to C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -C3 to C8 cycloalkyl, n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0219] In another embodiment of formula (I), R1 is C(=O)-O-(CRc R d ) n -(4 - to 7 - membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), 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 or unsubstituted C1 - C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0220] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1 - C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n-(a 4- to 7-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0221] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 4- to 7-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0222] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c Rd ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0223] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0224] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 5-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0225] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0226] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d )n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0227] In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n -(a 6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is C(=O)-O-(CR c R d ) n-(a 6-membered heterocyclyl), n is 1 or 2, and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0228] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 10-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 10-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 10-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 10-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0229] In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 7-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(a 5- to 7-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0230] In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(6-membered heteroaryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0231] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), R1 is (CRc R d ) n -(6-membered heteroaryl), n is 0, and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), 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 or fluorine.

[0232] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0233] In another embodiment of formula (I), R1 is (CR c R d ) n -(C6-C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d )n -(C6 to C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 - C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 to C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 to C 10 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0234] In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or unsubstituted C1 - C3 alkyl. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or halogen. In another embodiment of formula (I), R1 is (CR c R d ) n -(C6 aryl), and each of R2, R3, R4, R5, R6, R7, and R8 is H or fluorine.

[0235] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0236] In another embodiment of formula (I), 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. In another embodiment of formula (I), 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 or unsubstituted C1-C3 alkyl. In another embodiment of formula (I), 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 or halogen. In another embodiment of formula (I), 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 or fluorine.

[0237] Each of the embodiments described herein with respect to the compound of formula I also applies to the compound of formula I-A.

[0238] Certain embodiments of the compound of formula I-A or I, or a pharmaceutically acceptable salt thereof, are shown in Table 1 below. The compound of formula I-A or I, or a pharmaceutically acceptable salt thereof, and the compounds of Table 1, or a pharmaceutically acceptable salt thereof, may be referred to herein collectively or individually as "the compounds of the invention" or "the compounds provided herein". [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

[0239] The disclosed compounds have one or more stereocenters, and each stereocenter can independently exist in either the R configuration or the S configuration. In one embodiment, the compounds described herein exist in optically active forms or racemates. It should be understood that the compounds described herein include racemates, optically active forms, positional isomers and stereoisomers having the therapeutically useful properties described herein, or combinations thereof.

[0240] The preparation of the optically active substance is achieved by any suitable method including, as non-limiting examples, resolution of a racemate by a recrystallization technique, synthesis from an optically active starting material, chiral synthesis, or chromatographic separation using a chiral stationary phase. In one embodiment, a mixture of two or more isomers is utilized as the disclosed compounds described herein. In another embodiment, a pure isomer is utilized 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 a mixture of enantiomers or diastereomers. The resolution of the compounds and their isomers is achieved by any means including, as non-limiting examples, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0241] In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0242] The compounds described herein also include isotopically labeled compounds in which one or more atoms have an atomic mass or mass number different from the atomic mass or mass number typically found in nature while having the same atomic number as the corresponding atom in the unlabeled compound. Examples of isotopes suitable for inclusion in the compounds described herein include 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 35Examples of S include, but are not limited to. In one embodiment, the isotope-labeled compound is useful for drug or substrate tissue distribution studies. In another embodiment, substitution with a heavier isotope such as deuterium confers greater metabolic stability (e.g., increased in vivo half-life or decreased required dosage). In another embodiment, the compounds described herein 2 contain H (i.e., deuterium) isotopes.

[0243] In yet another embodiment, 11 C, 18 F, 15 O and 13 substitution with positron-emitting isotopes such as N is useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. The isotope-labeled compounds are prepared by any suitable method or process that uses a suitable isotope-labeled reagent in place of the unlabeled reagent used in other methods.

[0244] The specific compounds described herein, and other compounds encompassed by one or more of the formulas described herein having different substituents, are described herein and are, 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 thEd.,(Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for preparing the compounds as described herein are varied by the use of appropriate reagents and conditions for introducing the various moieties found in the formulas as provided herein.

[0245] The compounds described herein are synthesized starting from compounds available from commercial sources or using any suitable procedure prepared using the procedures described herein.

[0246] Therapeutic methods The compounds of the present invention can be used in a method of treating a disease or condition of 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 are useful for the treatment of a disease or condition by acting as an agonist of the orexin 2 receptor.

[0247] The compounds of the present invention can be used to treat a disease or condition selected from the group consisting of narcolepsy, cataplexy or hypersomnia in a subject in need of such treatment.

[0248] In one embodiment, the compounds of the present invention can be used to treat narcolepsy in a subject. In one embodiment, the compounds of the present invention can be used to treat cataplexy in a subject. In one embodiment, the compounds of the present invention can be used to treat hypersomnia in a subject.

[0249] The orexin 2 receptor is important in a wide range of biological functions. This suggests that the orexin 2 receptor plays a role in diverse disease processes in humans or other species. The compounds of the present invention are useful for treating, preventing, or ameliorating one or more of the following symptoms or diseases associated with changes in sleep / wake functions. Namely, narcolepsy, narcolepsy with cataplexy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome characterized by hypersomnia (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, multisystem atrophy, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen encephalitis, Wernicke encephalitis, limbic encephalitis, or Hashimoto's encephalopathy in subjects having), lethargy, loss of consciousness, obesity (e.g., malignant obesity, exogenous obesity, hyperinsulinemic obesity, hypervolemic obesity, pituitary obesity, hypovolemic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, diet-induced obesity, hypogonadal obesity, general obesity, simple obesity, or central obesity), insulin resistance syndrome, Alzheimer's disease, disorders of consciousness such as lethargy, side effects and complications of anesthesia, sleep disturbance, excessive daytime sleepiness, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep disruption, jet lag, jet lag syndrome, shift work sleep disorder, sleep disorder, night terrors, depression, major depression, sleepwalking, nocturia, sleep disorder, sundown syndrome (Alzheimer’s dusk), diseases associated with the circadian rhythm, fibromyalgia, conditions resulting from a decrease in the quality of sleep, overeating, binge eating disorder, obesity-related diseases, hypertension, diabetes, increased plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipemia, 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 disorders, polycystic ovary disease, craniopharyngioma, Prader-Willi syndrome, Froehlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, reduced fertility, infertility, male hypogonadism, female hirsutism and other sexual and reproductive dysfunctions, fetal defects related to obesity in pregnant women, obesity-related gastroesophageal reflux, gastrointestinal motility disorders such as 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, renal cancer, risk of secondary consequences of obesity (e.g., reduction in the risk of left ventricular hypertrophy), migraine, 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, genital / urinary system diseases, diseases related to sexual function or fertility, mood modulation disorders, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder (PTSD), separation anxiety disorder, social phobia, anxiety disorder, acute neurological and mental disorders such as brain dysfunction after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's chorea, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive impairment, muscle contracture, tremor, epilepsy, disorders related to muscle spasm, delirium, amnestic disorder, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue, drug-induced parkinsonism syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), behavioral disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy and traumatic brain injury (TBI).

[0250] Particularly, it is useful as a therapeutic or preventive agent for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome, hypersomnia syndrome characterized by hypersomnia (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 osteopenia, sepsis, disorders of consciousness such as coma, side effects and complications caused by anesthesia, etc.

[0251] 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.

[0252] In another embodiment, the compound of the present invention is useful as a preventive or therapeutic agent for type 1 narcolepsy. In another embodiment, the compound of the present invention is useful as a preventive or therapeutic agent for type 2 narcolepsy. In another embodiment, the compound of the present invention is useful as a preventive or therapeutic agent for narcolepsy and excessive daytime sleepiness. In another embodiment, the compound of the present invention is useful as a preventive or therapeutic agent for narcolepsy cataplexy and excessive daytime sleepiness. In another embodiment, the compound of the present invention is useful as a preventive or therapeutic agent for narcolepsy and cataplexy. In another embodiment, the compound of the present invention is useful as a preventive or therapeutic agent for excessive daytime sleepiness. In another embodiment, the compound of the present invention is useful as a preventive or therapeutic agent for idiopathic hypersomnia. In another embodiment, the compound of the present invention is useful as a preventive or therapeutic agent for obstructive sleep apnea.

[0253] In another embodiment, the compound of the present invention has orexin 2 receptor agonist activity and is useful as a preventive or therapeutic agent for hypersomnia in Parkinson's disease.

[0254] In another embodiment, the compound of the present invention has orexin 2 receptor agonist activity and is useful as a preventive or therapeutic agent for hypersomnia. In another embodiment, the compound of the present invention has orexin 2 receptor agonist activity and is useful as a preventive or therapeutic agent for excessive daytime sleepiness associated with Parkinson's disease.

[0255] In another embodiment, the compounds of the present invention have orexin 2 receptor agonist activity and are useful as prophylactic or therapeutic agents for cancer and / or daytime excessive sleepiness or fatigue associated with chemotherapy.

[0256] In another embodiment, the present invention provides a method for treating narcolepsy in a subject in need thereof, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0257] In another embodiment, the present invention provides a method for treating type 1 narcolepsy in a subject in need thereof, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0258] In another embodiment, the present invention provides a method for treating type 2 narcolepsy in a subject in need thereof, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0259] In another embodiment, the present invention provides a method for treating narcolepsy and daytime excessive sleepiness in a subject in need thereof, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0260] In another embodiment, the present invention provides a method for treating narcolepsy, cataplexy and daytime excessive sleepiness in a subject in need thereof, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0261] In another embodiment, the present invention provides a method for treating narcolepsy and cataplexy in a subject in need of treatment for narcolepsy and cataplexy, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0262] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness in a subject in need of treatment for excessive daytime sleepiness, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0263] In another embodiment, the present invention provides a method for treating idiopathic hypersomnia in a subject in need of treatment for idiopathic hypersomnia, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0264] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and idiopathic hypersomnia in a subject in need of treatment for excessive daytime sleepiness and idiopathic hypersomnia, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0265] In another embodiment, the present invention provides a method for treating obstructive sleep apnea in a subject in need of treatment for obstructive sleep apnea, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0266] In another embodiment, the present invention provides a method for treating excessive daytime sleepiness and obstructive sleep apnea in a subject in need of treatment for excessive daytime sleepiness and obstructive sleep apnea, the method comprising administering to the subject a compound of formula I-A or I or a pharmaceutically acceptable salt thereof.

[0267] In any of the methods as described herein, a compound of formula I is administered to the subject.

[0268] Each embodiment described herein with respect to the use of the compound of formula I also applies to the compound of formula I-A.

[0269] In any of the compositions or methods described herein, the compound of formula I-A or I or a pharmaceutically acceptable salt thereof is present in and / or administered in a therapeutically effective amount.

[0270] Administration / Dosage / Formulation In another aspect, provided herein is a pharmaceutical composition comprising at least one compound of the invention together with a pharmaceutically acceptable carrier.

[0271] The actual dosage level of the active ingredient in the pharmaceutical compositions of the invention may vary so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0272] In particular, the selected dosage level will depend on various factors including the activity of the particular compound being used, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0273] A physician or veterinarian, who is a person skilled in the art, can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can initiate the administration of the pharmaceutical composition by dosing the compound at a level lower than the required level in order to achieve the desired therapeutic effect and to increase the dosage gradually until the desired effect is achieved.

[0274] 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, a dosage unit form refers to physically discrete units suitable as unit dosages for the patient to be treated, each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are determined by and directly depend on (a) the particular characteristics of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such disclosed compounds for the treatment of narcolepsy or cataplexy in a patient.

[0275] In one embodiment, the compounds of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition of the invention comprises a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0276] 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.

[0277] As any administration route of the composition of the present invention, oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical may be mentioned. The compounds for use in the present invention can be formulated for administration by any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., intravaginal and perivaginal), nasal (intra) and (trans)rectal), intravesical, intralung, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intratracheal, inhalation, and topical administration, etc. In one embodiment, the preferred administration route is oral.

[0278] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma, lozenges, creams, pastes, plasters, lotions, disks, 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 may be useful in the present invention are not limited to the specific formulations and compositions described herein.

[0279] For oral application, tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gel caps are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions can contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may or may not be coated, or they may be coated by known techniques to extend or delay the release of the active ingredient. Formulations for oral use can also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0280] 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 as a bolus dose or by continuous infusion. Suspensions, solutions or emulsions in oily or aqueous vehicles, optionally containing other formulating agents such as suspending, stabilizing or dispersing agents, may be used.

[0281] One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this invention and are encompassed by the appended claims. For example, modifications to reaction times, reaction sizes / volumes, and experimental reagents such as solvents, catalysts, pressures, atmospheric conditions such as nitrogen atmosphere, and reducing / oxidizing agents, including but not limited to these, are within the scope of this application using recognized alternatives in the art and no more than routine experimentation.

[0282] Whenever values and ranges are provided herein, it is to be understood that all values and ranges subsumed by these values and ranges are meant to be included within the scope of this invention. Further, all values falling within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by this application.

[0283] The following examples further illustrate aspects of the invention. However, they are in no way intended to limit the teachings or disclosure of the invention described herein.

Example

[0284] Example The invention is further illustrated by the following examples, which should not be construed as further limitations. The practice of the invention, unless otherwise indicated, uses conventional techniques of organic synthesis, cell biology, cell culture, molecular biology, transgenic biology, microbiology, and immunology, which are within the skill of one of ordinary skill in the art.

[0285] General Procedure Example 1: Synthesis Procedure The synthesis procedures for preparing the compounds of the present invention are readily available to those skilled in the art. Unless otherwise specified, starting materials were generally obtained from commercial sources. Synthesis procedures for other related compounds can be found, for example, in U.S. Patent Application No. 17 / 556,295 filed on December 20, 2021 and PCT Application No. PCT / US21 / 64484 filed on December 21, 2021, both of which are hereby expressly incorporated by reference herein.

[0286] In the following synthesis examples, the following abbreviations may be used. DCM = dichloromethane MeOH = methanol EtOH = ethanol DIPEA or DIEA = N,N - diisopropylethylamine ACN or MeCN = acetonitrile PE = petroleum ether EtOAc = ethyl acetate TFA = trifluoroacetic acid DMSO = dimethyl sulfoxide i - PrOH = isopropanol EA = ethyl acetate Pd / C = palladium on carbon Boc = tert - butyloxycarbonyl Ms = methanesulfonyl Bn = benzyl Bz = benzoyl P(OPh)3 = triphenyl phosphite Et = ethyl h = hour min = minute PdCl2(dppf) = [1,1’ - bis(diphenylphosphino)ferrocene]dichloropalladium(II) DMAP = 4 - (dimethylamino)pyridine KOAc = potassium acetate Et3N or TEA = triethylamine TMS - Cl = trimethylsilyl chloride LiNEt2 = Lithium diethylamide SFC = Supercritical fluid chromatography PEPPSI = Pyridine enhanced precatalyst preparation stabilization initiation Pd(PPh3)4 or Pd(Ph3P)4 = Tetrakis(triphenylphosphine)palladium(0) HOBt = 1-Hydroxybenzotriazole EDC = N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride.

Chem.

Chem.

Chem.

Chem.

Chem.

[0287] To a solution of 4-hydroxycyclohexan-1-one (10 g, 1 equiv, 88 mmol) and DMAP (1.1 g, 0.1 equiv, 8.8 mmol) in DCM (200 mL) was added benzoyl chloride (15 g, 1.2 equiv, 0.11 mol) and triethylamine (13 g, 18 mL, 1.5 equiv, 0.13 mol) at 0 °C. The resulting mixture was stirred at 25 °C for 3 h. The desired product could be detected by LCMS. The resulting mixture was diluted with water and extracted with DCM (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel, eluting with EtOAc / PE (20% gradient), to give 4-oxocyclohexyl benzoate (7.4 g, 34 mmol, 39%) as an oil. 1H NMR (400 MHz, Methanol-d4) δ8.14-7.97 (m, 2H), 7.59 (dt, 1H), 7.47 (q, 2H), 5.39 (p, 1H), 2.62 (dt, 1H), 2.42 (dt, 1H), 2.19 (q, 3H), 2.01-1.69 (m, 3H).

Chemical Structure

[0288] To a stirred solution of triphenyl phosphite (8 g, 1.1 eq, 0.03 mol) in DCM (50 mL) was added Br2 (4 g, 1 mL, 1.2 eq, 0.03 mol) at -60 °C. The mixture was stirred at 25 °C for 30 min. 4-Oxocyclohexyl benzoate (5 g, 1 eq, 0.02 mol) and triethylamine (3 g, 1.3 eq, 0.03 mol) were added to the mixture at -60 °C. The resulting mixture was stirred at 25 °C for 16 h. The resulting mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 210 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel, eluting with EtOAc / PE (0 - 25% gradient), to give 4-bromocyclohex-3-en-1-yl benzoate (5 g, 0.02 mol, 80%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 2.00 - 2.17 (2H, m), 2.30 - 2.43 (1H, m), 2.50 - 2.59 (1H, m), 2.59 - 2.77 (2H, m), 5.34 (1H, dtd), 6.01 (1H, tt), 7.42 - 7.51 (2H, m), 7.54 - 7.63 (1H, m), 8.02 - 8.09 (2H, m).

Chemical Structure

[0289] To a stirred solution of 4-bromocyclohex-3-en-1-yl benzoate (15 g, 1 equiv, 53 mmol) in MeOH (150 mL), sodium methoxide (3.2 g, 1.1 equiv, 59 mmol) was added portionwise at 25 °C under N2 atmosphere. The resulting mixture was stirred at 25 °C for 16 h. The desired product could be detected by TLC. The resulting mixture was extracted with DCM (3 × 80 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel, eluting with EtOAc / PE (20% gradient) to afford 4-bromocyclohex-3-en-1-ol (7 g, 0.04 mol, 70%) as an oil. 1H NMR (400 MHz, Methanol-d4) δ5.92 (ddt, 1H), 3.93 (dddd, 1H), 2.72 - 2.28 (m, 3H), 2.16 - 1.69 (m, 4H).

Chemical formula

[0290] To a stirred solution of 4-bromocyclohex-3-en-1-ol (6.15 g, 1 equiv, 34.7 mmol) and TMS-Cl (15.1 g, 17.6 mL, 4 equiv, 139 mmol) in TMS-Cl (17 mL), paraformaldehyde (1.56 g, 1.5 equiv, 52.1 mmol) was added portionwise at 25 °C. The resulting mixture was stirred at 25 °C for 16 h. The resulting mixture was filtered and the filter cake was washed with TMS-Cl (3 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3, 22 °C) δ1.8 - 2.05 (m, 2H), 2.13 - 2.44 (m, 2H), 2.45 - 2.66 (m, 2H), 4.12 (dddd, 1H), 5.58 (s, 1H), 5.94 (tt, 1H).

Chemical formula

[0291] To a stirred solution of diethylamine (0.9 g, 1 mL, 1.2 eq, 0.01 mol) in tetrahydrofuran (24 mL) under a N2 atmosphere, n-butyllithium (0.8 g, 1.2 eq, 0.01 mol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 30 minutes. To the above reaction mixture, a solution of 1-benzyl-N-(1-phenylethyl)piperidin-4-imine (3 g, 1 eq, 0.01 mol) in tetrahydrofuran (15 mL) was added dropwise. The reaction mixture was stirred at -78 °C for an additional 1 hour. To the above reaction mixture, a solution of 1-bromo-4-(chloromethoxy)cyclohex-1-ene (3 g, 1.2 eq, 0.01 mol) in tetrahydrofuran (15 mL) was added dropwise. The reaction mixture was stirred at -78 °C for an additional 1 hour. The reaction was quenched by the addition of saturated ammonium chloride solution and stirred for 1 hour. The resulting mixture was extracted with DCM (3 × 80 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in NH4HCO3 water, 0% - 100% gradient in 25 minutes) to give 1-benzyl-3-(((4-bromocyclohex-3-en-1-yl)oxy)methyl)piperidin-4-one (1.8 g, 4.8 mmol, 50%) as an oil. LCMS: m / z (ES+), [M+H]+ = 378.1.

Chemical Structure

[0292] To a stirred solution of 1-benzyl-3-((((4-bromocyclohex-3-en-1-yl)oxy)methyl)piperidin-4-one (2 g, 1 equiv, 5 mmol) in MeOH (100 mL), ammonium formate (5 g, 15 equiv, 0.08 mol) was added followed by sodium cyanoborohydride (2 g, 6 equiv, 0.03 mol) portionwise over 15 min at 25 °C. The resulting mixture was stirred at 25 °C for 3 h. The reaction was quenched by the addition of saturated ammonium chloride solution and stirred for 15 min. The resulting mixture was extracted with DCM (3 × 80 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in NH4HCO3 water, 0% to 100% gradient over 20 min) to afford 1-benzyl-3-(((4-bromocyclohex-3-en-1-yl)oxy)methyl)piperidin-4-amine (1.5 g, 4.0 mmol, 70%) as an oil. LCMS: m / z (ES+), [M+H]+ = 379.25.

Chemical formula

[0293] To a stirred solution of 1-benzyl-3-(((4-bromocyclohex-3-en-1-yl)oxy)methyl)piperidin-4-amine (5 g, 1 eq, 0.01 mol) and Et3N (7 g, 9 mL, 5 eq, 0.07 mol) in DCM (250 mL) was added trifluoromethanesulfonic anhydride (4 g, 1.2 eq, 0.02 mol) portionwise at -50 °C under N2 atmosphere. The resulting mixture was stirred at -50 °C for 15 minutes. The reaction was quenched by the addition of saturated ammonium bicarbonate solution and stirred for 3 minutes. The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in NH4HCO3 water, 0% - 100%) to give the desired product (5 g, 0.01 mol, 70%) as an oil.

[0294] The mixture product (13.25 g, combined from multiple batches) was purified by chiral SFC (column: DAICEL DCpak P4VP, 5 × 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: ACN:MEOH = 4:1 (0.1% 2M NH3-MEOH); flow rate: 200 mL / min; gradient: isocratic 30% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm) to give the product (3.18 g, 4.8 mmol, 24%, purity 97%) as an oil. LCMS: m / z (ES+), [M+H]+ = 513.0. (300 MHz, Chloroform-d) δ 7.53 - 7.02 (m, 6H), 5.89 (t, J = 4.4 Hz, 1H), 4.21 (t, J = 9.9 Hz, 1H), 3.79 - 3.22 (m, 5H), 2.80 (d, J = 11.7 Hz, 1H), 2.67 - 2.30 (m, 4H), 2.29 - 2.02(m, 4H), 2.02 - 1.72 (m, 4H).

Chemical Structure

[0295] To a solution of 1-benzyl-3-(((4-bromocyclohex-3-en-1-yl)oxy)methyl)piperidin-4-amine (13.00 g, 1 equiv, 34.27 mmol) in DCM (150 mL) was added TEA (10.40 g, 14.3 mL, 3 equiv, 102.8 mmol). Then methanesulfonic anhydride (7.163 g, 1.2 equiv, 41.12 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred at 25 °C for 1.5 h. The reaction was monitored by LCMS. The reaction was quenched with saturated NaHCO3 solution. The resulting mixture was extracted with DCM (3 × 200 mL). The combined organic layers were concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, 10% - 80% gradient over 40 min, held at 60% for 15 min), and the crude product (13.00 g, 28.42 mmol, 82.93%) was obtained as an oil.

[0296] The product mixture (62 g, combined from multiple batches) was purified by achiral SFC (column: DAICEL Dcpak P4VP, 4.6 × 50 mm, 3 um; mobile phase B: ACN:MeOH = 80:20 (1% 2M NH3-MeOH)) to give the product (15 g, 33 mmol, 24.2%). (400 MHz, Chloroform-d) δ 7.38 - 7.24 (m, 5H), 5.92 (tq, J = 3.5, 1.8 Hz, 1H), 5.78 (d, J = 25.8 Hz, 1H), 3.99 (d, J = 17.4 Hz, 1H), 3.70 - 3.58 (m, 2H), 3.54 (td, J = 11.2, 10.2, 5.5Hz, 2H), 3.42 (d, J = 13.2 Hz, 1H), 2.97 (s, 3H), 2.69 (s, 1H), 2.63 - 2.43 (m, 3H), 2.43 - 2.25 (m, 3H), 2.25 - 2.03 (m, 2H), 2.03 - 1.76 (m, 4H). Scheme 2: [Chemical formula]

[0297] To a solution of 1-benzyl-3-(((4-bromocyclohex-3-en-1-yl)oxy)methyl)piperidin-4-amine (8.02 g, 1 equiv, 21.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (8.20 g, 3 equiv, 63.4 mmol) in DCM (80 mL), di-tert-butyl dicarbonate (4.61 g, 1 equiv, 21.1 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. The crude material was purified by flash chromatography on silica gel and eluting with PE / EtOAc (0 - 12% gradient) to give 4.5 g of the crude product as an oil.

[0298] Purification of the above mixture by achiral SFC rep-achiral-SFC (column: Viridis BEH 2-EP, 100×4.6 mm m, 5 µm; mobile phase B: MeOH (1% 2M NH3-MeOH); flow rate: 4 mL / min; gradient: isocratic 5% B) gave the product (1.79 g, 3.73 mmol, 17.9%) as an oil. LCMS: m / z (ES+), [M+H]+ = 481.1. 1H NMR (400 MHz, Chloroform-d) δ 7.33 (s, 5H), 5.91 (s, 1H), 5.68 (s, 1H), 3.83 (d, J = 47.2 Hz, 2H), 3.64 - 3.33 (m, 3H), 2.76 - 2.23 (m, 6H), 2.14 (d, J = 17.9 Hz, 2H), 2.03 (s, 1H), 1.97 - 1.73 (m, 3H), 1.46 (s, 9H). [Chemical formula]

[0299] A solution of vinyl bromide (1.79 g, 1 equiv, 3.73 mmol) and (1-methyl-1H-indazol-5-yl)boronic acid (723 mg, 1.1 equiv, 4.11 mmol) in 1,4-dioxane (30 mL) and water (6.0 mL) was added with Na2CO3 (1.19 g, 3 equiv, 11.2 mmol) and PdCl2(dppf).CH2Cl2 (305 mg, 0.1 equiv, 373 μmol). After stirring at 80 °C for 22 h under a nitrogen atmosphere, the resulting mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC using EtOAc / PE (2 / 1) to give the product (1.68 g, 3.17 mmol, 84.8%) as an oil. LCMS: m / z (ES+), [M+H]+ = 531.5. 1H NMR (400 MHz, Chloroform-d) δ 7.96 (dd, J = 2.0, 1.0 Hz, 1H), 7.77 - 7.64 (m, 1H), 7.51 (dd, J = 8.8, 1.7 Hz, 1H), 7.41 - 7.25 (m, 7H), 6.01 (s, 1H), 4.09 (s, 3H), 3.94 (d, J = 25.8 Hz, 1H), 3.80 (s, 1H), 3.51 (s, 6H), 2.72 - 2.50 (m, 4H), 2.28 (d, J = 9.2 Hz, 2H), 2.07 (s, 1H), 1.86 (s, 2H), 1.65 (s, 2H), 1.51 - 1.22 (m, 9H), 1.05 (s, 1H).

Chemical formula

[0300] To a solution of tert-butyl olefin (1.65 g, 1 equiv, 3.11 mmol) and 1,1,2-trichloroethane (498 mg, 347 μL, 1.2 equiv, 3.73 mmol) in i-PrOH (40 mL), Pd / C (1.65 g, 10 wt%, 0.5 equiv, 1.55 mmol) and palladium(II) dihydroxide (2.18 g, 10 wt%, 0.5 equiv, 1.55 mmol) were added under a nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 4 h under a hydrogen atmosphere using a hydrogen balloon. The crude reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to give the crude product. The crude product was used directly in the next step without further purification. LCMS: m / z (ES+), [M+H]+ = 443.2.

Chemical formula

[0301] To a solution of amine (100.0 mg, 1 equiv, 225.9 μmol) and 3-bromopyridazine (71.84 mg, 2 equiv, 451.9 μmol) in DMSO (5 mL), Cs2CO3 (147.2 mg, 2 equiv, 451.9 μmol) and PEPPSI-Pd (19.00 mg, 0.1 equiv, 22.59 μmol) were added. The resulting mixture was stirred at 120 °C for 4 h under a nitrogen atmosphere. A total of 12 reactions were carried out in parallel. The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM = 1 / 15) to give the product (620 mg, 1.19 mmol, 47.7%) as an oil. LCMS: m / z (ES+), [M+H]+ = 521.2.

Chemical formula

[0302] To a stirred solution of the Boc-protected amine (200 mg, 1 equiv, 384.1 μmol) in 1,4-dioxane (6 mL), HCl (70 mg, 480.1 μL, 4 mol, 5 equiv, 1.921 mmol) was added at room temperature. The mixed solution was stirred at room temperature for 1 h. The resulting solution was evaporated under reduced pressure to give the product amine (150.0 mg, 356.7 μmol, 92.85%) as a solid as the HCl salt. The crude product was used directly in the next step without further purification. LCMS: m / z (ES+), [M+H]+ = 421.30. Scheme 3:

Chemical formula

[0303] To a solution of vinyl bromide (1.50 g, 1 equiv, 2.93 mmol) and Pd(Ph3P)4 (339 mg, 0.1 equiv, 293 μmol) in 1,4-dioxane (20 mL) and water (4.0 mL), Cs2CO3 (2.87 g, 3 equiv, 8.80 mmol) and (1-methyl-1H-indazol-6-yl)boronic acid (671 mg, 1.3 equiv, 3.81 mmol) were added. After stirring at 80 °C for 3 h under a nitrogen atmosphere, the resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC using EtOAc / PE (5% TEA) to give the product (930 mg, 1.65 mmol, 56.4%) as a solid. LCMS: m / z (ES+), [M+H]+ = 563.25.

Chemical formula

[0304] To a solution of olefin (300 mg, 1 equiv, 533 μmol) in i-PrOH (60 mL) were added Pd(OH)2 (37.4 mg, 0.5 equiv, 267 μmol), Pd / C (28.4 mg, 0.5 equiv, 267 μmol) and 1,1,2-trichloroethane (142 mg, 2 equiv, 1.07 mmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 3 h under a hydrogen atmosphere using a hydrogen balloon. The resulting mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the crude product as the HCl salt. The crude material was used directly in the next step. LCMS: m / z (ES+), [M+H]+ = 475.10.

Chemical Structure

[0305] To a solution of vinyl bromide (2.00 g, 1 equiv, 4.37 mmol) in 1,4-dioxane (20 mL) were added (1-methyl-1H-indazol-5-yl)boronic acid (846 mg, 1.1 equiv, 4.81 mmol), K2CO3 (1.81 g, 3 equiv, 13.1 mmol), water (4.0 mL) and Pd(PPh3)4 (505 mg, 0.1 equiv, 437 μmol) at room temperature. The mixed solution was stirred at 80 °C for 2 h under a N2 atmosphere. The reaction was monitored by LCMS. The mixture was diluted with water and extracted with EA. The combined organic phases were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, gradient from 5% to 65% in 30 min; detector, UV254 nm) to obtain the desired product (1.70 g, 3.34 mmol, 76.4%) as an oil. LCMS: m / z (ES+), [M+H]+ = 509.3.

Chemical Structure

[0306] To a solution of olefin (1.70 g, 1 equiv, 3.34 mmol) in i-PrOH (5 mL) were added 1,1,2-trichloroethane (892 mg, 621 μL, 2 equiv, 6.68 mmol), Pd(OH)2 (1.41 g, 10 wt%, 0.3 equiv, 1.00 mmol) and Pd / C (1.07 g, 10 wt%, 0.3 equiv, 1.00 mmol) at room temperature. The mixture was stirred at 20 °C for 32 h under a H2 atmosphere. The reaction was monitored by LCMS. The solution was filtered through a Celite pad and concentrated under reduced pressure to give the product (1.40 g, 3.06 mmol, 92%). LCMS: m / z (ES+), [M+Na]+ = 421.25.

Chemical formula

[0307] To a solution of vinyl bromide (2.00 g, 1 equiv, 4.37 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (1.67 g, 1.5 equiv, 6.56 mmol) and KOAc (858 mg, 2 equiv, 8.74 mmol) in dioxane (20 mL) was added PdCl2(dppf)-CH2Cl2 adduct (179 mg, 0.05 equiv, 219 μmol). The resulting mixture was stirred at 100 °C for 4 h under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EA (3 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product (1.8 g) was used directly in the next step without further purification. LCMS: m / z (ES+), [M+H]+ = 505.

Chemical formula

[0308] A solution of boronic ester (550 mg, 1 equiv, 1.09 mmol) and 5-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (231 mg, 1 equiv, 1.09 mmol) in 1,4-dioxane (8 mL) and H2O (0.2 mL) was added with Na2CO3 (347 mg, 3 equiv, 3.27 mmol) and PdCl2(dppf)CH2Cl2 adduct (44.5 mg, 0.05 equiv, 54.5 μmol) under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water (NH4HCO3), mobile phase B: ACN, gradient of 55% - 65% in 10 min; detector, UV254 nm) to obtain the crude material (220 mg) as a solid. The crude material was purified by preparative TLC (EA / PE = 4 / 1, 5% TEA) to obtain the product (180 mg, 353 μmol, 32.4%) as a solid. LCMS: m / z (ES+), [M+H]+ = 510.0.

Chemical formula

[0309] To a solution of olefin (150 mg, 1 equiv, 294 μmol) and Boc2O (128 mg, 135 μL, 2 equiv, 589 μmol) in i-PrOH (18 mL) was added Pd / C (150 mg, 10 wt%, 0.479 equiv, 141 μmol) under a nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 30 h under a hydrogen atmosphere using a hydrogen balloon. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the crude product. The crude product was used directly in the next step without further purification. LCMS: m / z (ES+), [M+H]+ = 522.

Chemical formula

[0310] A solution of N-Boc protected amine (150 mg, 1 equiv, 288 μmol) and HCl in 1,4-dioxane (2 mL) was stirred at 25 °C for 1.5 h. The resulting mixture was concentrated under reduced pressure to give a crude product. The crude material was lyophilized to give the product amine as the HCl salt (110 mg, 240 μmol, 83.5%) as a solid. LCMS: m / z (ES+), [M+H]+ = 422.

Chem.

[0311] To a solution of vinyl bromide (1.68 g, 1 equiv, 3.29 mmol) and 7-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1 g, 1 equiv, 4 mmol) and PdCl2(dppf), was added CH2Cl2 adduct (240 mg, 0.1 equiv, 329 μmol) and Na2CO3 (1.04 g, 3 equiv, 9.86 mmol) in dioxane (10 mL) and water (2 mL). The resulting mixture was stirred at 80 °C for 4 h. The resulting mixture was extracted with ethyl acetate / water (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluted with EtOAc / PE (0 - 100% gradient) to give the product (3.17 g, 5.46 mmol, 60%). LCMS: m / z (ES+), [M+H]+ = 581.45.

Chem.

[0312] To a solution of olefin (2.17 g, 1 eq, 3.74 mmol), Pd(OH)2 (2.10 g, 4 eq, 14.9 mmol), 1,1,2-trichloroethane (499 mg, 347 μL, 1 eq, 3.74 mmol), and Pd / C (1.99 g, 5 eq, 18.7 mmol) in i-PrOH (10 mL) were added. The resulting mixture was stirred at 25 °C for 3 h. The resulting mixture was filtered, and the filter cake was washed with [isopropanol + hydrochloric acid (10%)] (3 × 100 mL). The filtrate was concentrated under reduced pressure to obtain the product (1.92 g, 2.7 mmol, 73%, purity 73%). LCMS: m / z (ES+), [M+H]+ = 493.10. Scheme 4:

Chem.

[0313] To a test tube equipped with an airtight screw cap, vinyl bromide (100 mg, 1 eq, 219 μmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate (97.8 mg, 1.3 eq, 284 μmol), Na2CO3 (69.5 mg, 3 eq, 656 μmol), dioxane (2 mL), and H2O (0.7 mL) were added, followed by PdCl2(dppf) (16.0 mg, 0.1 eq, 21.9 μmol). The resulting mixture was stirred at 80 °C for 1 h. The reaction mixture was extracted with DCM (3 × 100 mL) and water. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by thin-layer chromatography (PE:EA = 1:3) to obtain the product (70 mg, 0.10 mmol, 47%, purity 87%) as a solid. LCMS: m / z (ES+), [M+H]+ = 595.30. 1H NMR (400 MHz, Chloroform-d) δ 1.24-1.32 (m, 2H), 1.73 (s, 9H), 1.89 (s, 3H), 2.07 (s, 1H), 2.31 (s, 5H), 2.58 (s, 3H), 2.65 (s, 3H), 2.93 (d, 3H), 3.43 (s, 1H), 3.51 (s, 1H), 3.69 (s, 3H), 4.15 (q, 1H), 6.07 (s, 1H), 7.33 (s, 6H), 7.43 (dd, 1H), 7.72 (d, 1H), 8.05 (s, 1H), 8.41 (s, 1H).

Chem.

[0314] To a test tube equipped with an airtight screw cap, tert-butyl 5-((4-(((3R,4S)-1-benzyl-4-(methylsulfonamido)piperidin-3-yl)methoxy)cyclohex-1-en-1-yl)-1H-benzo[d]imidazole-1-carboxylate (150 mg, 1 equiv, 252 μmol), H2 (5.09 mg, 10 equiv, 2.52 mmol), and i-PrOH (4 mL) were added, followed by Pd / C (8.05 mg, 0.3 equiv, 75.7 μmol). The resulting mixture was stirred at 25 °C for 12 h. At that point, LCMS analysis indicated completion of the reaction, and then the reaction mixture was filtered through a Celite pad and washed thoroughly with methylene chloride. The filtrate was concentrated under reduced pressure, and the crude material was purified by thin-layer chromatography (PE:EA = 1:2) to afford the product amine (60 mg, 0.12 mmol, 47%) as a solid. LCMS: m / z (ES+), [M+H]+ = 507.25. 1H NMR (400 MHz, Chloroform-d) δ 0.04 - 0.13 (m, 1H), 0.09 (s, 12H), 1.22 - 1.33 (m, 5H), 1.30 (s, 1H), 1.39 - 1.53 (m, 1H), 1.72 (d, 11H), 1.79 (d, 1H), 1.90 (s, 1H), 1.94 - 2.14 (m, 2H), 2.22 (d, 2H), 2.63 - 2.74 (m, 1H), 2.83 - 3.15 (m, 2H), 3.01 (s, 2H), 3.59 - 3.74 (m, 2H), 3.78 (s, 1H), 3.93 (q, 1H), 6.06 (s, 1H), 6.19 (s, 0H), 7.26 - 7.37 (m, 1H), 7.71 (dd, 1H), 7.86 - 7.93 (m, 1H), 8.35 - 8.43 (m, 1H).

Chem.

[0315] Vinyl bromide (3.60 g, 1 equiv, 7.87 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate (2.84 g, 1.05 equiv, 8.26 mmol), and Na2CO3 (139 mg, 3 equiv, 1.31 mmol) in 1,4-dioxane (32 mL) and H2O (0.4 mL) were stirred, and PdCl2(dppf) (576 mg, 0.1 equiv, 787 μmol) was added under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, 90% - 100% gradient in 20 min; detector, UV 254 nm) to give a mixture. The mixture was concentrated under reduced pressure to give the crude material (4.3 g) as a solid. This material was repurified by flash chromatography on silica gel eluted with EtOAc / PE (100% gradient) to give the product (2.56 g, 4.30 mmol, 54.7%) as a solid. LCMS: m / z (ES+), [M+H]+ = 595. [Chemical Formula]

[0316] To a solution of tert-butyl olefin (1.500 g, 1 equiv, 2.522 mmol) in i-PrOH (170 mL), Pd / C (1.5 g, 10 wt%, 0.56 equiv, 1.4 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 days under a hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure to give the crude product (1 g). LCMS: m / z (ES+), [M+H]+ = 507. [Chemical Formula]

[0317] A solution of vinyl bromide (250 mg, 1 equiv, 489 μmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (143 mg, 1.2 equiv, 587 μmol) in water (5 mL) and 1,4-dioxane (20 mL) was added with Na2CO3 (155 mg, 3 equiv, 1.47 mmol) and PdCl2(dppf) (200 mg, 0.5 equiv, 244 μmol). The resulting mixture was stirred at 80 °C for 8 h. The resulting mixture was extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE = 1 / 1) to give the product (100 mg, 182 μmol, 37.3%) as a solid. LCMS: m / z (ES+), [M+H]+ = 549.20. [Chemical formula]

[0318] To a solution of olefin (139 mg, 1 equiv, 253 μmol) in i-PrOH (20 mL) was added Pd / C (135 mg, 5 equiv, 1.27 mmol). The resulting mixture was stirred at 25 °C for 8 h under a hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give the product amine (68 mg, 148 μmol, 58.7%) as a solid. LCMS: m / z (ES+), [M+H]+ = 461.35. [Chemical formula]

[0319] A stirred mixture of vinyl bromide (300 mg, 1 equiv, 656 μmol) and 3-hydroxy-2,3-dimethylbutan-2-yl hydrogen (1-methyl-1H-benzo[d]imidazol-6-yl)boronate (217 mg, 1.2 equiv, 787 μmol) in 1,4-dioxane (15 mL) and water (0.8 mL) was added with Cs2CO3 (641 mg, 3 equiv, 1.97 mmol) and Pd(Ph3P)4 (152 mg, 0.2 equiv, 131 μmol) under a nitrogen atmosphere at room temperature. The final reaction mixture was stirred at 80 °C for 3 h. The resulting mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: 8 mmol NH4HCO3, mobile phase B: ACN, gradient of 10% - 90% over 45 min), and the product (180 mg, 354 μmol, 54.0%) was obtained as an oil. LCMS: m / z (ES+), [M+H]+ = 509.

Chem.

[0320] To a solution of the olefin (180 mg, 1 equiv, 354 μmol) in i-PrOH (10 mL) was added Pd(OH)2 (24.8 mg, 0.5 equiv, 177 μmol) and ammonium formate (223 mg, 176 μL, 10 equiv, 3.54 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 1 h. After filtration, the filtrate was concentrated under reduced pressure to give the crude product (130 mg, 309 μmol, 87.4%) as a solid. LCMS: m / z (ES+), [M+H]+ = 421.

Chem.

[0321] A solution of vinyl bromide (1.0 g, 1 equiv, 2.2 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.68 g, 1.2 equiv, 2.6 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added with Pd(Ph3P)4 (0.51 g, 0.2 equiv, 0.44 mmol) and Cs2CO3 (2.1 g, 3 equiv, 6.6 mmol). The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM = 1 / 10) to obtain the product (678 mg, 1.2 mmol, 55%, purity 90%) as a semi-solid. LCMS: m / z (ES+), [M+H]+ = 509.30. [Chemical formula]

[0322] To a solution of olefin (400 mg, 1 equiv, 786 μmol) and 1,1,2-trichloroethane (210 mg, 2 equiv, 1.57 mmol) in ethyl acetate (18 mL) were added Pd / C (400 mg, 10 wt%, 0.478 equiv, 376 μmol) and Pd(OH)2 (400 mg, 3.62 equiv, 2.85 mmol). The resulting mixture was hydrogenated at room temperature for 16 h under a hydrogen atmosphere using a hydrogen balloon. The reaction was monitored by LCMS. The mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the crude product (330 mg). LCMS: m / z (ES+), [M+H]+ = 421.20. Compound 1: [Chemical formula]

[0323] To a solution of amine (700 mg, 1 equiv, 1.38 mmol) and pyridin-2-yl trifluoromethanesulfonate (471 mg, 1.5 equiv, 2.07 mmol) in DMSO (13 mL) was added TEA (280 mg, 385 μL, 2 equiv, 2.76 mmol). The resulting mixture was stirred at 120 °C for 5 h. The resulting mixture was extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water (NH4HCO3), mobile phase B: ACN, 45% - 55% gradient over 10 min) to give a mixture of isomers of the product (330 mg, 565 μmol, 40.9%) as a solid.

[0324] The mixture of isomers was separated by chiral preparative HPLC (column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: MeOH:DCM = 1:1; flow rate: 20 mL / min; gradient: 45% B - 45% B over 19 min) to give N-((3R,4S)-3-((((1s,4S)-4-(1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (101 mg, 209 μmol, 34%) as a solid. LCMS: m / z (ES+), [M+H]+ = 484. 1H NMR (400 MHz, Methanol-d4) δ 8.07 (ddd, J = 5.1, 2.0, 0.9 Hz, 1H), 7.97 (d, J = 1.0 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.55 - 7.43 (m, 2H), 7.33 (dd, J = 8.7, 1.6 Hz, 1H), 6.88 (dt, J = 8.7, 0.9 Hz, 1H), 6.63 (ddd, J = 7.1, 5.0, 0.8 Hz, 1H), 3.88 (dq, J = 12.0, 6.7, 6.1 Hz, 2H), 3.78 (dd, J = 13.3, 6.8 Hz, 1H), 3.69 (dd, J = 9.4, 5.9 Hz, 1H), 3.64 (d, J = 4.0 Hz, 1H), 3.61 - 3.54 (m, 2H), 3.50 - 3.42 (m, 1H), 3.37 (s, 1H), 3.06 (s, 3H), 2.72 - 2.64 (m, 1H), 2.30 (dq, J = 10.7, 7.3, 5.5 Hz, 1H), 2.09 (d, J = 12.9 Hz, 2H), 1.97 - 1.82 (m, 4H), 1.72 - 1.56 (m, 4H). Compound 2:

Chem.

[0325] To a solution of amine (80 mg, 1 equiv, 0.17 mmol) in DMSO (4 mL) was added TEA (35 mg, 48 μL, 2 equiv, 0.35 mmol) and 1,1,1-trifluoro-N-(pyridin-2-yl)methanesulfonamide (59 mg, 1.5 equiv, 0.26 mmol). The resulting mixture was stirred at 120 °C for 8 h. The reaction was monitored by LCMS and the crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, 0% - 55% gradient in 20 min, held for 30 min; detector, UV 254 nm) to give a mixture of isomers of the product (17 mg, 32 μmol, 18%) as a solid. Repurification of the 17 mg of the above material by reverse-phase flash chromatography (column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40%B - 68%B in 8 min, 68%B) gave a racemic mixture of N-((3R,4S)-3-((((1s,4S)-4-(1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridin-2-yl)piperidin-4-yl)-1,1,1-trifluoromethanesulfonamide and N-((3R,4S)-3-((((1s,4S)-4-(1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridin-2-yl)piperidin-4-yl)-1,1,1-trifluoromethanesulfonamide (4.1 mg, 7.6 μmol, 24%) as a solid. LCMS: m / z (ES+), [M+H]+ = 538.1. 1H NMR (400 MHz, Chloroform-d) δ 8.19 (d, J = 5.1 Hz, 1H), 8.04 (s, 1H), 7.87 (d, J = 6.4 Hz, 1H), 7.60 (s, 1H), 7.54 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 6.69 (s, 2H), 4.31 (d, J = 13.7 Hz, 1H), 4.06 (dq, J = 22.6, 13.0 Hz, 3H), 3.78 (s, 1H), 3.68 (s, 1H), 3.18 (d, J = 52.7 Hz, 2H), 2.66 (s, 1H), 2.53 (d, J = 8.3 Hz, 1H), 2.09 (s, 4H), 1.76 (d, J = 9.1 Hz, 6H). Compound 3:

[0326] ​To a solution of amine (300 mg, 1 equiv, 713 μmol) and Et3N (144 mg, 199 μL, 2 equiv, 1.43 mmol) in DMSO (5 mL) was added pyridin-2-yl trifluoromethanesulfonate (243 mg, 1.5 equiv, 1.07 mmol). The resulting mixture was stirred at 120 °C for 12 h. The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to give a mixture of isomers of the product (135 mg, 271 μmol, 38.0%) as a solid. The product (135 mg) was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 39% B - 63% B in 8 min, 63% B) to give two peaks. The more polar product (50 mg) was purified by chiral preparative HPLC (column: DZ-CHIRALPAK IG-3, 4.6 × 50 mm, 3.0 μm; mobile phase A: Hex(0.2% DEA):(EtOH:DCM = 1:1) = 60:40) to give N-((3R,4S)-3-(((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (11.9 mg, 23.9 μmol, 24%) as a solid. LCMS: m / z (ES+), [M+H]+ = 498. 1H NMR (400 MHz, Methanol-d4) δ 8.15 - 8.05 (m, 1H), 7.92 (d, J = 0.9 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.50 - 7.44 (m, 1H), 7.35 (dd, J = 8.7, 1.6 Hz, 1H), 6.92 - 6.85 (m, 1H), 6.71 - 6.9 (m, 1H), 4.05 (s, 3H), 3.87 - 3.78 (m, 2H), 3.77 - 3.48 (m, 6H), 3.05 (s, 3H), 2.70 - 2.61 (m, 1H), 2.27 - 2.16 (m, 3H), 2.00 - 1.82 (m, 4H), 1.66 - 1.35 (m, 5H). Compound 4:

Chem.

[0327] To a solution of the amine (50 mg, 1 equiv, 99 μmol) and 1-fluorocyclobutane-1-carboxylic acid (17 mg, 1.5 equiv, 0.15 mmol) in DCM (2 mL) were added N-ethyl-N-isopropylpropan-2-amine (38 mg, 3 equiv, 0.30 mmol), N,N-dimethylpyridin-4-amine (1.2 mg, 0.1 equiv, 9.9 μmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (23 mg, 1.5 equiv, 0.15 mmol), and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (23 mg, 1.5 equiv, 0.15 mmol). The resulting mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS. The resulting mixture was extracted with dichloromethane (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a mixture of isomers of the product (58 mg, 96 μmol, 97%) as an oil. LCMS: m / z (ES+), [M+H]+ = 607.55.

[0328] A solution of TFA (1 mL) was added dropwise to a stirred mixture of tert-butyl 5-(4-(((3R,4S)-1-(1-fluorocyclobutane-1-carbonyl)-4-(methylsulfonamido)piperidin-3-yl)methoxy)cyclohexyl)-1H-indazole-1-carboxylate (78 mg, 1 eq., 0.13 mmol) in DCM (5 mL) at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 0.5 h. The resulting mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: X Bridge Shield RP18 OBD Column, 30 × 150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 38% B - 48% B in 8 min, 48% B), followed by chiral preparative HPLC (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH:DCM = 1:1-HPLC; flow rate: 20 mL / min; gradient: 40% B - 40% B in 14 min) to give the desired isomer N-((3R,4S)-3-((((1s,4R)-4-(1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(1-fluorocyclobutane-1-carbonyl)piperidin-4-yl)methanesulfonamide (6 mg, 0.01 mmol, 30%, 99.5% purity) as a solid. LCMS: m / z (ES+), [M+H]+ = 507.45. 1H NMR (400 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.66 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 6.58 (d, J = 5.2 Hz, 1H), 4.06 - 3.83 (m, 2H), 3.82 - 3.59 (m, 5H), 3.46 (dd, J = 56.8, 13.4 Hz, 2H), 3.01 (s, 3H), 2.72 (d, J = 30.5 Hz, 3H), 2.37 (d, J = 58.6 Hz, 3H), 2.17 - 1.86 (m, 6H), 1.72 (d, J = 46.7 Hz, 6H). Compound 5:

Chem.

[0329] To a solution of amine (70 mg, 1 equiv, 0.14 mmol) in DCM (2 mL) was added pyridine (87 mg, 89 μL, 8 equiv, 1.1 mmol) and triphosgene (20 mg, 0.5 equiv, 69 μmol). The resulting mixture was stirred at 25 °C for 2 h. The solvent was removed and MeOH (2 ml) was added to the mixture. The resulting mixture was stirred at 80 °C for 0.5 h and the reaction mixture was monitored by LCMS. The crude material was purified by reverse phase chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, gradient 5% - 95% in 30 min; detector, UV254 nm) to give a mixture of isomers of the product (78 mg, 0.14 mmol, 100%) as a solid. LCMS: m / z (ES+), [M+H]+ = 565.20.

[0330] The above mixture was purified by preparative HPLC (column: XSelect CSH Prep C18 OBD Column, 19×250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 30 mL / min; gradient: 37% B - 48% B in 7 minutes, 48% B), followed by preparative chiral HPLC (column: DZ-CHIRALPAK IF-3, 4.6×50 mm, 3.0 μm; mobile phase A: Hex(0.2% DEA):(MeOH:DCM = 1:1)=80:20) to obtain methyl (3R,4S)-3-((((1s,4R)-4-(1H-indazol-5-yl)cyclohexyl)oxy)methyl)-4-(methylsulfonamido)piperidine-1-carboxylate (13.6 mg, 29.1 μmol, 39%, 99.5% purity) as a solid. LCMS: m / z (ES+), [M+H]+ = 465.35. 1H NMR (400 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.66 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.41 - 7.35 (m, 1H), 6.48 (s, 1H), 3.80 (dd, J = 11.2, 7.0 Hz, 4H), 3.72 (s, 3H), 3.67 (s, 2H), 3.45 - 3.24 (m, 2H), 3.00 (s, 3H), 2.66 (d, J = 15.1 Hz, 1H), 2.26 (s, 1H), 2.09 (d, J = 13.9 Hz, 2H), 1.96 (dd, J = 9.0, 4.4 Hz, 1H), 1.89 - 1.72 (m, 5H), 1.63 (s, 2H). Compound 6:

Chemical Structure

[0331] An amine, TEA (24 mg, 33 μL, 2 eq, 0.24 mmol) and DMSO (2 mL) were added to a test tube equipped with an airtight screw cap, followed by addition of pyridin-2-yl trifluoromethanesulfonate (40 mg, 1.5 eq, 0.18 mmol). The resulting mixture was stirred at 120 °C for 12 h. The reaction mixture was extracted with DCM (3 × 100 mL) and water. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography (PE:EA = 1:1) to obtain a mixture of isomers of the product (35 mg, 72 μmol, 61%) as a solid. This compound was further purified by preparative HPLC (column: XBridge Prep C18 OBD Column, 30 × 50 mm, 5 μm 13 nm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN) to obtain N-(((3R,4S)-3-((((1s,4S)-4-(1H-benzo[d]imidazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (3.6 mg, 7.1 μmol, 17%) as a solid. LCMS: m / z (ES+), [M+H]+ = 484.20. 1H NMR (400 MHz, Chloroform-d) δ 1.28 (s, 1H), 1.55 - 1.67 (m, 3H), 1.78 (s, 4H), 1.83 (d, 1H), 2.05 (s, 4H), 2.09 (s, 1H), 2.40 (s, 2H), 2.69 (s, 2H), 3.04 (s, 3H), 3.44 (dd, 1H), 3.64 (s, 1H), 3.68 (dd, 1H), 3.83 - 3.88 (m, 1H), 3.95 (q, 2H), 4.06 (dd, 1H), 6.52 (d, 1H), 6.60 - 6.67 (m, 1H), 6.69 (d, 1H), 7.19 (d, 1H), 7.45 - 7.54 (m, 1H), 7.58 - 7.67 (m, 2H), 8.05 (s, 1H), 8.19 (d, 1H). Compound 7: [Chemistry]

[0332] To a solution of amine (110 mg, 1 equiv, 261 μmol) and pyridin-2-yl trifluoromethanesulfonate (88.9 mg, 1.5 equiv, 391 μmol) in DMSO (3 mL), TEA (79.2 mg, 109 μL, 3 equiv, 783 μmol) was added. The resulting mixture was stirred at 120 °C for 6 h. The crude material was purified by reverse-phase chromatography (C18 column; mobile phase A: water (NH4HCO3), mobile phase B: ACN, gradient of 40% - 55% in 30 min; detector, UV 254 nm) to afford a mixture of isomers of the product (50 mg, 0.10 mmol, 39%) as a solid.

[0333] The crude product was purified by preparative chiral HPLC (column: DZ-CHIRALPAK IG-3, 4.6×50 mm, 3.0 μm; mobile phase A: Hex(0.2% DEA):(EtOH:DCM = 1:1) = 50:50) to give N-((3R,4S)-3-((((1s,4S)-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclohexyl)oxy)methyl)-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (18 mg, 36 μmol, 36%) as a solid. LCMS: m / z (ES+), [M+H]+ = 499. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.1 Hz, 1H), 8.09 - 8.04 (m, 2H), 7.51 - 7.43 (m, 2H), 7.22 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.56 (dd, J = 7.1, 4.9 Hz, 1H), 4.15 (s, 3H), 3.73 (dt, J = 14.1, 8.5 Hz, 2H), 3.61 - 3.47 (m, 6H), 2.99 (s, 3H), 2.81 (ddd, J = 11.5, 8.1, 3.7 Hz, 1H), 2.12 (d, J = 29.1 Hz, 2H), 1.99 - 1.82 (m, 5H), 1.78 - 1.50 (m, 7H), 1.36 - 1.22 (m, 1H). Compound 8:

Chem.

[0334] To a solution of amine (100 mg, 1 equiv, 238 μmol) and triethylamine (48.1 mg, 66.3 μL, 2 equiv, 476 μmol) in DMSO (2 mL), pyridin-2-yl trifluoromethanesulfonate (81.0 mg, 1.5 equiv, 357 μmol) was added. The resulting mixture was stirred at 120 °C for 3 h. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, 35% - 65% gradient) to give the racemic mixture of the product (4.9 mg, 9.8 μmol, 16%) as a solid. LCMS: m / z (ES+), [M+H]+ = 498.25. 1H NMR (400 MHz, Methanol-d4) δ 8.10 - 8.04 (m, 1H), 8.07 (s, 1H), 7.57 - 7.43 (m, 3H), 7.27 (dd, 1H), 6.92 - 6.85 (m, 1H), 6.62 (ddd, 1H), 3.90 (s, 3H), 3.86 (d, 1H), 3.77 (dd, 1H), 3.69 (dd, 1H), 3.64 (s, 1H), 3.62 - 3.54 (m, 2H), 3.54 - 3.43 (m, 1H), 3.06 (s, 3H), 2.71 (t, 1H), 2.31 (s, 1H), 2.09 (d, 2H), 2.01 - 1.81 (m, 4H), 1.66 (q, 4H). Compound 9:

[0335] ​To a solution of amine (130 mg, 1 equiv, 309 μmol) and pyridin-2-yl trifluoromethanesulfonate (84.3 mg, 1.2 equiv, 371 μmol) in DMSO (5 mL) was added TEA (93.8 mg, 129 μL, 3 equiv, 927 μmol). After stirring at 120 °C for 3 h under a nitrogen atmosphere, the resulting mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: 8 mmol NH4HCO3, mobile phase B: ACN, gradient of 20% - 70% in 30 min; detector, UV 254 nm) to give a mixture of isomers of the product (minor peak 5 mg, major peak 18 mg). This mixture of isomers (18 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B - 58% B in 8 min, 58% B) to give a mixture of enantiomers of N-((3R,4S)-3-((((1s,4S)-4-(1-methyl-1H-benzo[d]imidazol-6-yl)cyclohexyl)oxy)methyl)-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide and N-((3S,4R)-3-((((1s,4S)-4-(1-methyl-1H-benzo[d]imidazol-6-yl)cyclohexyl)oxy)methyl)-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (7.2 mg, 14 μmol, 40%) as a solid. LCMS: m / z (ES+), [M+H]+ = 498. 1H NMR (400 MHz, Methanol-d4) δ 8.10 - 8.02 (m, 2H), 7.61 - 7.48 (m, 2H), 7.46 (d, 1H), 7.19 (dd, , 1H), 6.91 - 6.84 (m, 1H), 6.70 - 6.59 (m, 1H), 3.89 (s, 5H), 3.82 - 3.43 (m, 6H), 3.06 (s, 3H), 2.81 - 2.68 (m, 1H), 2.38 - 2.29 (m, 1H), 2.10 (d, 2H), 2.01 - 1.85 (m, 4H), 1.76 - 1.58 (m, 4H), 1.41 - 1.23 (m, 2H), 0.96 - 0.86 (m, 1H). Compound 10: [Chem.]

[0336] To a solution of amine (700 mg, 1 equiv, 1.48 mmol) and 2-bromopyridine (466 mg, 2 equiv, 2.95 mmol) in 1,4-dioxane (36 mL), Cs2CO3 (1.44 g, 3 equiv, 4.43 mmol) and Pd-PEPPSI-Ipent (124 mg, 0.1 equiv, 148 μmol) were added. After stirring at 100 °C overnight under a nitrogen atmosphere, the resulting mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude material by reverse-phase flash chromatography (C18 column; mobile phase A: 0.9 g / L NH4HCO3 in water, mobile phase B: ACN, gradient of 5% - 95% in 30 min) gave a mixture of isomers of the product (550 mg, 997 μmol, 67.6%) as a solid.

[0337] The above isomer mixture was purified by chiral preparative HPLC (column: DZ-CHIRALPAK IC-3, 4.6×50 mm, 3.0 μm; mobile phase A: Hex(0.2% DEA):EtOH = 80:20; flow rate: 1 mL / min; gradient: 0% B - 0% B) to obtain 1,1,1-trifluoro-N-(((3R,4S)-3-((((1s,4R)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridin-2-yl)piperidin-4-yl)methanesulfonamide (98.5 mg, 174 μmol, 29.1%) as a solid. LCMS: m / z (ES+), [M+H]+ = 552.25. 1H NMR (400 MHz, Methanol-d4) δ 8.09 - 8.03 (m, 1H), 7.92 (d, 1H), 7.59 - 7.49 (m, 2H), 7.47 (d, 1H), 7.36 (d, 1H), 6.91 (d, 1H), 6.65 (dd, 1H), 4.05 (d, 3H), 4.01 (d, 1H), 3.88 (ddd, 2H), 3.66 - 3.60 (m, 2H), 3.59 - 3.51 (m, 2H), 3.44 (dd, 1H), 2.69 (t, 1H), 2.32 (s, 1H), 2.14 - 2.03 (m, 2H), 1.99 - 1.79 (m, 4H), 1.65 (q, 4H), 1.34 - 1.28 (m, 1H). Compound 11:

Chemical Structure

[0338] To a solution of amine (220.00 mg, 1 equiv, 523.10 μmol) and N-ethyl-N-isopropylpropan-2-amine (202.83 mg, 3 equiv, 1.5693 mmol) in DCM (15 mL), 1H-benzo[d][1,2,3]triazol-1-ol (106.03 mg, 1.5 equiv, 784.65 μmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (150.4 mg, 1.5 equiv, 784.65 μmol) and 1-fluorocyclobutane-1-carboxylic acid (61.783 mg, 1 equiv, 523.10 μmol) were added, and the resulting mixture was stirred at 25 °C for 2 h. The resulting mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude material was purified by reverse phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, gradient from 60% to 80% in 10 min; detector, UV254 nm), and a mixture of isomers of the product (200.00 mg, 384.13 μmol, 73%) was obtained as an oil.

[0339] This mixture of isomers was purified by preparative chiral HPLC (column: DZ-CHIRALPAK IC-3, 4.6 × 50 mm, 3.0 μm; mobile phase A: Hex(0.2%DEA):(EtOH:DCM = 1:1) = 60:40; flow rate: 1 mL / min; gradient: 0%B to 0%B) to give N-((3R,4S)-1-(1-fluorocyclobutane-1-carbonyl)-3-((((1s,4R)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (65.00 mg, 124.8 μmol, 32.50%) as a solid. LCMS: m / z (ES+), [M+H]+ = 521.20. 1H NMR (400 MHz, Methanol-d4) δ 7.92 (s, 1H), 7.62 (d, J = 16.1 Hz, 1H), 7.49 - 7.35 (m, 2H), 4.05 (d, J = 2.0 Hz, 4H), 3.97 - 3.77 (m, 2H), 3.74 - 3.58 (m, 3H), 3.49 (q, J = 9.0 Hz, 2H), 3.37 (s, 1H), 3.04 (d, J = 4.0 Hz, 3H), 2.73 (s, 3H), 2.07 (d, J = 14.9 Hz, 3H), 1.90 (dd, J = 19.0, 9.3 Hz, 5H), 1.65 (d, J = 9.5 Hz, 5H). Compound 12:

Chem.

[0340] To a solution of amine (HCl salt) (400 mg, 1 equiv, 875 μmol) in DCM (5 mL), pyridine (208 mg, 212 μL, 3 equiv, 2.63 mmol) and triphosgene (130 mg, 0.5 equiv, 438 μmol) were added at room temperature. The solution was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was redissolved in MeOH (28.0 g, 35.4 mL, 1000 equiv, 875 mmol), and the resulting solution was heated to 80 °C and stirred for 30 min. The mixture was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, 0% - 70% gradient) to give the crude material as a solid, a mixture of four isomers (350 mg, 731 μmol, 83.6%). The mixture was purified by preparative chiral HPLC (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH:DCM = 1:1) to give methyl (3R,4S)-3-((((1s,4R)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-4-(methylsulfonamido)piperidine-1-carboxylate (60 mg, 0.13 mmol, 17%) as a solid. LCMS: m / z (ES+), [M+H]+ = 479.25. 1H NMR (SNB06-439): (400 MHz, Methanol-d4) δ 7.93 (d, J = 1.0 Hz, 1H), 7.61 (s, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.05 (s, 3H), 3.81 (s, 1H), 3.65 (d, J = 22.4 Hz, 10H), 3.03 (s, 3H), 2.69 (d, J = 12.1 Hz, 1H), 2.19 (s, 1H), 2.10 (s, 2H), 1.90 (s, 2H), 1.80 (s, 2H), 1.74 - 1.57 (m, 4H). Compound 13:

Chemical Structure

[0341] To a solution of amine (150 mg, 1 equiv, 316 μmol) and 3-bromopyridazine (101 mg, 2 equiv, 632 μmol) in 1,4-dioxane (2 mL) were added PEPPSI-Pd (26.6 mg, 0.1 equiv, 31.6 μmol) and Cs2CO3 (309 mg, 3 equiv, 948 μmol). The resulting mixture was stirred at 100 °C for 3 h. The reaction was monitored by LCMS. The resulting mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE = 2 / 1) to give a mixture of isomers of the product (140 mg, 155 μmol, 49.0%) as a solid. Purification of the crude product by preparative HPLC (column: DZ-CHIRALPAK IC-3, 4.6 × 50 mm, 3.0 μm; mobile phase A: Hex(0.2%DEA):(EtOH:DCM = 1:1) = 60:40) gave 1,1,1-trifluoro-N-(((3R,4S)-3-((((1s,4R)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridazin-3-yl)piperidin-4-yl)methanesulfonamide (115 mg, 207 μmol, 76.7%) as a solid. LCMS: m / z (ES+), [M+H]+ = 553.25. 1H NMR (400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.4, 1.6 Hz, 1H), 3.89 (s, 3H), 3.87 - 3.82 (m, 1H), 3.78 - 3.65 (m, 2H), 3.65 - 3.54 (m, 1H),3.51 (d, J = 9.4 Hz, 1H), 3.46 - 3.35 (m, 2H), 3.03 (s, 3H), 2.83 - 2.60 (m, 3H), 2.46 (dq, J = 22.5, 10.2 Hz, 2H), 2.28 - 2.04 (m, 3H), 2.02 - 1.89 (m, 3H), 1.84 (d, J = 13.4 Hz, 2H), 1.62 (q, J = 13.5, 12.6 Hz, 3H), 1.55 - 1.33 (m, 3H). Compound 14:

[0342] ​To a solution of amine (HCl salt) (260 mg, 1 equiv, 548 μmol) and 1-fluorocyclobutanecarboxylic acid (77.7 mg, 1.2 equiv, 657 μmol) in DCM (6 mL), DIPEA (212 mg, 286 μL, 3 equiv, 1.64 mmol), HOBt (126 mg, 1.5 equiv, 822 μmol), and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (158 mg, 1.5 equiv, 822 μmol) were added. The resulting mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a crude product. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, 5% - 95% gradient in 30 min) to afford the crude product as a solid, a mixture of 4 isomers (260 mg, 452 μmol, 82.6%). The isomer mixture was purified by chiral preparative HPLC (column: DZ-CHIRALPAK IC-3, 4.6×50 mm, 3.0 μm; mobile phase A: Hex(0.2% DEA):(EtOH:DCM = 1:1) = 70:30) to give the desired isomer 1,1,1-trifluoro-N-((3R,4S)-1-(1-fluorocyclobutanecarbonyl)-3-((((1s,4R)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (48.4 mg, 83.6 μmol, 17.8%) as a solid. LCMS: m / z (ES+), [M+Na]+ = 597.15. 1H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.85 (dd, J = 15.6, 6.4 Hz, 1H), 7.57 (d, J = 1.3 Hz, 1H), 7.42 - 7.31 (m, 2H), 4.38 (dd, J = 26.6, 13.9 Hz, 1H), 4.09 (s, 3H), 3.99 - 3.65 (m, 5H), 3.33 - 3.02 (m, 2H), 2.97 - 2.74 (m, 1H), 2.70 - 2.58 (m, 2H), 2.46 (dq, J = 22.9, 12.5 Hz, 4H), 2.12 - 1.89 (m, 5H), 1.76 (s, 1H), 1.68 (dd, J = 24.1, 13.9 Hz, 4H). Compound 15: [Chem.]

[0343] To a solution of amine (450 mg, 1 equiv, 1.07 mmol) and 3-bromopyridazine (255 mg, 148 μL, 1.5 equiv, 1.60 mmol) in 1,4-dioxane (18 mL) were added Cs2CO3 (1.05 g, 3 equiv, 3.21 mmol) and Pd-PEPPSI (89.9 mg, 0.1 equiv, 107 μmol). After stirring at 100 °C for 3 h under a nitrogen atmosphere, the resulting mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude material by reverse-phase flash chromatography (C18 column; mobile phase A: 0.9 g / L NH4HCO3 in water, mobile phase B: ACN, 5% - 95% gradient in 30 min) afforded a mixture of isomers of the product (330 mg, 662 μmol, 62%) as a solid.

[0344] The above-mentioned isomer mixture was purified by chiral HPLC (column: DZ-CHIRALPAK IF-3, 4.6×50 mm, 3.0 μm; mobile phase A: MtBE (0.2% DEA):(MeOH:DCM = 1:1)=85:15; flow rate: 1 mL / min; gradient: 0% B~0% B) to obtain N-((3R,4S)-3-((((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridazin-3-yl)piperidin-4-yl)methanesulfonamide (69.5 mg, 139 μmol, 38.5%) as a solid. LCMS: m / z (ES+), [M+H]+ = 499.25. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, 1H), 7.96 (d, 1H), 7.56 - 7.49 (m, 2H), 7.35 - 7.21 (m, 4H), 4.01 (s, 3H), 3.88 (dt, 1H), 3.74 (dd, 2H), 3.70 - 3.48 (m, 4H), 3.38 (d, 1H), 3.00 (s, 3H), 2.69 - 2.58 (m, 1H), 2.14 (s, 1H), 1.95 (t, 2H), 1.85 - 1.66 (m, 4H), 1.62 - 1.44 (m, 4H). Compound 16:

Chemical Structure

[0345] To a solution of amine (300.0 mg, 1 equiv, 713.3 μmol) and 1-fluorocyclobutane-1-carboxylic acid (101.1 mg, 1.2 equiv, 856.0 μmol) in DCM (8 mL) were added 1H-benzo[d][1,2,3]triazol-1-ol hydrate (163.9 mg, 1.5 equiv, 1.070 mmol), EDC (205.1 mg, 1.5 equiv, 1.070 mmol) and DIEA (276.6 mg, 373 μL, 3 equiv, 2.140 mmol). The resulting mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS. The resulting mixture was extracted with dichloromethane (3 × 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM = 1 / 12) to give a mixture of isomers of the product (190 mg, 324 μmol, 45.4%) as a solid.

[0346] Purification of the crude product by preparative chiral HPLC (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH:DCM = 1:1-HPLC; flow rate: 20 mL / min; gradient: 70% B to 70% B in 11 min) afforded N-((3R,4S)-1-(1-fluorocyclobutan-1-carbonyl)-3-((((1s,4S)-4-(1-methyl-1H-benzo[d]imidazol-5-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (49.6 mg, 94.4 μmol, 25%) as a solid. LCMS: m / z (ES+), [M+H]+ = 521.30. 1H NMR (400 MHz, Methanol-d4) δ 8.06 (d, J = 3.2 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.36 - 7.25 (m, 1H), 3.89 (d, J = 1.3 Hz, 4H), 3.74 (s, 1H), 3.72 - 3.58 (m, 3H), 3.49 (q, J = 9.1, 8.4 Hz, 2H), 3.04 (d, J = 5.6 Hz, 3H), 2.82 - 2.64 (m, 3H), 2.48 (d, J = 20.9 Hz, 2H), 2.31 - 1.99 (m, 3H), 2.00 - 1.75 (m, 6H), 1.75 - 1.53 (m, 5H). Compound 17:

Chem.

[0347] To a stirred solution of the amine (80 mg, 1 equiv, 0.19 mmol) and (R)-tetrahydrofuran-3-carboxylic acid (33 mg, 1.5 equiv, 0.29 mmol) in DCM (2 mL), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (44 mg, 1.5 equiv, 0.29 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (55 mg, 1.5 equiv, 0.29 mmol) and DIPEA (74 mg, 99 μL, 3 equiv, 0.57 mmol) were added portionwise at 25 °C under a nitrogen atmosphere. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, 0% - 100% gradient in 30 min; detector, UV 220 nm) to afford a mixture of isomers of the product (90 mg, 0.17 μmol, 91%) as an oil. Purification of the crude product (100 mg) by preparative chiral HPLC (column: DZ-CHIRALPAK IC-3, 4.6×50 mm, 3.0 μm; mobile phase A: Hex(0.2%DEA):(EtOH:DCM = 1:1)=30:70) gave N-((3R,4S)-3-(((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-((R)-tetrahydrofuran-3-carbonyl)piperidin-4-yl)methanesulfonamide (30 mg, 58 μmol, 30%) as a solid. LCMS: m / z (ES+), [M+H]+ = 519.3. 1H NMR (400 MHz, Methanol-d4) δ 7.93 (d, 1H), 7.61 (d, 1H), 7.47 (dd, 1H), 7.38 (ddd, 1H), 4.05 (d, 3H), 4.01 - 3.72 (m, 7H), 3.71 - 3.45 (m, 6H), 3.04 (d, 3H), 2.70 (q, 1H), 2.31 - 1.97 (m, 5H), 1.95 - 1.55 (m, 8H). Compound 18:

Chemical Structure

[0348] To a solution of amine (80.0 mg, 1 equiv, 190 μmol), HOBt (43.7 mg, 1.5 equiv, 285 μmol), and EDC (54.7 mg, 1.5 equiv, 285 μmol) in DCM (2 mL), DIEA (49.2 mg, 66.3 μL, 2 equiv, 380 μmol) and cyclopropanecarboxylic acid (24.6 mg, 1.5 equiv, 285 μmol) were added. The resulting mixture was stirred at 25 °C for 2 h. The reaction was concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, 30% - 60% gradient in 20 min; detector, UV254 nm), and a mixture of isomers of the product (90.0 mg, 184 μmol, 96.8%) was obtained as an oil. Purification of the crude product (95 mg) by preparative chiral HPLC (column: DZ-CHIRALPAK IG-3, 4.6×50 mm, 3.0 μm; mobile phase A: Hex(0.2% DEA):(IPA:DCM = 1:1) = 55:45) gave N-((3R,4S)-1-(cyclopropanecarbonyl)-3-((((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (37.0 mg, 75.7 μmol, 39%) as a solid. LCMS: m / z (ES+), [M+H]+ = 489.20. 1H NMR (400 MHz, Methanol-d4) δ 7.93 (d, 1H), 7.59 (d, 1H), 7.46 (d, 1H), 7.38 (dd, 1H), 4.05 (s, 4H), 3.94 - 3.77 (m, 2H), 3.68 (d, 3H), 3.50 (dd, 1H), 3.05 (d, 3H), 2.70 (d, 1H), 2.33 - 2.02 (m, 4H), 1.97 - 1.83 (m, 3H), 1.78 - 1.59 (m, 5H), 0.96 - 0.77 (m, 4H). Compound 19:

Chemical Structure

[0349] To a solution of amine (330 mg, 1 equiv, 785 μmol) in DCM (14 mL), 3(((ethylimino)methylene)amino)-N,N-dimethylpropane-1-amine hydrochloride (226 mg, 1.5 equiv, 1.18 mmol), DIEA (304 mg, 410 μL, 3 equiv, 2.35 mmol), HOBt (180 mg, 1.5 equiv, 1.18 mmol), and 1-fluorocyclobutanecarboxylic acid (111 mg, 1.2 equiv, 942 μmol) were added. The resulting mixture was stirred at room temperature for 2 h. The filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, 5% - 95% gradient in 30 min; detector, UV254 nm), and a mixture of isomers of the product (68 mg, 0.13 mmol, 17%) was obtained as a solid.

[0350] The mixture of isomers was purified by chiral HPLC (column: DZ-CHIRALPAK IC-3, 4.6×50 mm, 3.0 μm; mobile phase A: MtBE(0.2%DEA):(MeOH:DCM = 1:1)=75:25; flow rate: 1 mL / min; gradient: 0%B - 0%B) to give N-((3R,4S)-1-(1-fluorocyclobutan-1-carbonyl)-3-((((1s,4S)-4-(1-methyl-1H-benzo[d]imidazol-6-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (7.6 mg, 14 μmol, 27%) as a solid. LCMS: m / z (ES+), [M+H]+ = 521.25. 1H NMR (400 MHz, Methanol-d4) δ 8.07 (d, 1H), 7.57 (dd, 1H), 7.49 (d, 1H), 7.26 - 7.19 (m, 1H), 3.91 (d, 5H), 3.77 - 3.59 (m, 3H), 3.52 (dd, 2H), 3.39 (d, 2H), 3.05 (d, 3H), 2.85 - 2.65 (m, 3H), 2.45 (tp,2H), 2.32 - 2.04 (m, 3H), 2.02 - 1.78 (m, 5H), 1.75 - 1.53 (m, 5H). Compound 20:

Chem.

[0351] To a stirred solution of the amine (70 mg, 1 equiv, 0.17 mmol) in DCM (2 mL), triethylamine (51 mg, 3 equiv, 0.50 mmol) and acetic anhydride (34 mg, 2 equiv, 0.33 mmol) were added dropwise at 25 °C under a nitrogen atmosphere. The residue was purified by preparative TLC (CH2Cl2 / MeOH 10:1) to afford a mixture of isomers of the product (70 mg, 0.11 mmol, 64%) as a solid. Purification of the crude product (78 mg) by preparative chiral HPLC (column: DZ-CHIRALPAK IH-3, 4.6×50 mm, 3.0 μm; mobile phase A: Hex(0.2% DEA):(EtOH:DCM = 1:1) = 60:40) gave N-((3R,4S)-1-acetyl-3-((((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (23.2 mg, 48.1 μmol, 29%) as a solid. LCMS: m / z (ES+), [M+H]+ = 463.2. 1H NMR (400 MHz, Methanol-d4) δ 7.93 (s, 1H), 7.60 (d, 1H), 7.47 (d, 1H), 7.42 - 7.34 (m, 1H), 4.09 - 3.94 (m, 4H), 3.82 (dd, 2H), 3.73 - 3.61 (m, 3H), 3.52 (dd, 2H), 3.38 (d, 1H), 3.04 (d, 3H), 2.69 (t, 1H), 2.31 - 2.04 (m, 6H), 1.90 (d, 3H), 1.71 (ddd, 16.6, 9.0 Hz, 5H), 0.11 (d, 1H). Compound 21: [Chemical formula]

[0352] To a stirred solution of amine (65 mg, 1 equiv, 0.15 mmol) and 2-hydroxy-2-methylpropanoic acid (48 mg, 3 equiv, 0.46 mmol) in DCM (2 mL), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (71 mg, 3 equiv, 0.46 mmol), EDC (89 mg, 3 equiv, 0.46 mmol), and DIEA (0.12 g, 0.16 mL, 6 equiv, 0.93 mmol) were added portionwise at 25 °C under a nitrogen atmosphere. The residue was purified by preparative TLC (CH2Cl2 / MeOH 10:1) to give a mixture of isomers of the product (70 mg, 0.14 mmol, 89%) as a solid. Purification of the crude product (70 mg) by preparative chiral HPLC (column: DZ-CHIRALPAK IG-3, 4.6 × 50 mm, 3.0 μm; mobile phase A: Hex(0.2% DEA):(EtOH:DCM = 1:1) = 60:40) gave N-((3R,4S)-1-(2-hydroxy-2-methylpropanoyl)-3-((((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (25.1 mg, 48 μmol, 35%) as a solid. LCMS: m / z (ES+), [M+H]+ = 507.3. 1H NMR (400 MHz, Methanol-d4) δ 7.92 (s, 1H), 7.63 (s, 1H), 7.46 (d, 1H), 7.43 - 7.38 (m, 1H), 4.05 (s, 4H), 3.88 (d, 1H), 3.70 - 3.59 (m, 3H), 3.51 (dd, 1H), 3.04 (s, 3H), 2.69 (t, 1H), 2.22 (s, 1H), 2.16 - 2.03 (m, 2H), 1.91 (d, 4H), 1.67 (d, 4H), 1.47 (s, 6H), 1.31 (s, 2H), 0.12 (s, 1H). Compound 22:

Chem.

[0353] To a solution of amine (100 mg, 1 equiv, 238 μmol) and TEA (72.2 mg, 99.4 μL, 3 equiv, 713 μmol) in DCM (1.5 mL) was added trimethylacetyl chloride (34.4 mg, 35.0 μL, 1.2 equiv, 285 μmol). The resulting mixture was stirred at room temperature for 30 minutes. The residue was purified by preparative TLC (EA / PE = 1 / 3) to give the crude material as a solid. The filtrate was concentrated under reduced pressure. Purification of the crude material by reverse-phase flash chromatography (C18 column; mobile phase A: 0.9 g / L aqueous NH4HCO3 solution, mobile phase B: ACN, 5% - 95%) gave a mixture of isomers of the product (80 mg, 0.16 mmol, 67%) as a solid.

[0354] The crude product was purified by preparative chiral HPLC (column: DZ-CHIRALPAK IF-3, 4.6×50 mm, 3.0 μm; mobile phase A: Hex(0.2% DEA):(EtOH:DCM = 1:1) = 80:20) to obtain N-((3R,4S)-3-((((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-pivaloylpiperidin-4-yl)methanesulfonamide (30.7 mg, 60.5 μmol, 38%) as a solid. LCMS: m / z (ES+), [M+H]+ = 505.25. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.55 - 7.52 (m, 2H), 7.29 (dd, 2H), 4.01 (s, 3H), 3.93 (s, 2H), 3.75 - 3.68 (m, 1H), 3.59 (s, 1H), 3.43 (dd, 1H), 3.38 (s, 2H), 3.30 (s, 1H), 2.96 (s, 3H), 2.64 (d, 1H), 1.96 (dd, 3H), 1.75 - 1.50 (m, 8H). Compound 23:

Chem.

[0355] A solution of amine (100 mg, 1 equiv, 238 μmol) and TEA (120 mg, 166 μL, 5 equiv, 1.19 mmol) in DCM (1.5 mL) was added with triphosgene (42.3 mg, 26 μL, 0.6 equiv, 143 μmol). The resulting mixture was stirred at 0 °C for 30 minutes. To the above mixture, a solution of azetidine hydrochloride (26.7 mg, 1.2 equiv, 285 μmol) in DCM (0.2 mL) was added dropwise over 1 minute at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 1 hour. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B - 48% B in 8 minutes, 48% B; wavelength: 254 nm). The solvent was evaporated to obtain a mixture of isomers of the product (60 mg, 0.12 mmol, 50%) as a solid.

[0356] The above mixture of isomers was purified by preparative chiral HPLC (CHIRALPAK IE-3, 4.6×50 mm; mobile phase A: MtBE(0.2%DEA):EtOH = 80:20; flow rate: 1 mL / min; gradient: 0% B - 0% B) to obtain N-((3R,4S)-1-(azetidine-1-carbonyl)-3-((((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (22.4 mg, 43.3 μmol, 36%) as a solid. LCMS: m / z (ES+), [M+H]+ = 504.30. 1H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.60 (s, 1H), 7.37 (d, 2H), 6.44 (d, 1H), 4.09 (s, 3H), 4.05 - 3.97 (m, 4H), 3.80 (td, 2H), 3.70 - 3.59 (m, 4H), 3.31 (dd, 1H), 3.17 (td, 1H), 3.00 (s, 3H), 2.67 (dq, 1H), 2.25 (p, 3H), 2.12 - 2.02 (m, 2H), 1.95 (dtd,1H), 1.89 - 1.73 (m, 5H), 1.68 - 1.53 (m, 2H). Compound 24:

Chem.

[0357] To a solution of amine (120.0 mg, 1 equiv, 252.9 μmol) and 2-fluoropyrimidine (29.76 mg, 1.2 equiv, 303.5 μmol) in DMSO (1.2 mL), K2CO3 (87.37 mg, 2.5 equiv, 632.2 μmol) was added. The resulting mixture was stirred at 100 °C for 2 h. The reaction was monitored by LCMS. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: NH4HCO3, mobile phase B: ACN, 5% - 100% gradient in 30 min, maintaining a gradient of 61.5% in 8 min), and 1,1,1-trifluoro-N-(((3R,4S)-3-((((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyrimidin-2-yl)piperidin-4-yl)methanesulfonamide (117.1 mg, 210 μmol, 83.2%, purity 99.3%) was obtained as a solid. LCMS: m / z (ES+), [M+H]+ = 553.25. 1H NMR (400 MHz, Chloroform-d) δ 8.34 (d, J = 4.8 Hz, 2H), 7.96 (s, 1H), 7.86 (d, J = 6.4 Hz, 1H), 7.56 (s, 1H), 7.42 - 7.30 (m, 2H), 6.55 (t, J = 4.7 Hz, 1H), 4.68 (t, J = 13.1 Hz, 2H), 4.07 (s, 3H), 4.01 (s,1H), 3.91 (t, J = 9.9 Hz, 1H), 3.78 (dd, J = 9.8, 3.8 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.36 (d, J = 13.9 Hz, 1H), 3.29 - 3.13 (m, 1H), 2.75 - 2.58 (m, 1H), 2.52 (t, J = 5.8 Hz, 1H), 2.19 - 1.95 (m, 4H), 1.88 - 1.66 (m, 4H), 1.66 - 1.52 (m, 2H). Compound 25: [Chem.]

[0358] To a solution of amine (120.0 mg, 1 equiv, 252.9 μmol) and 2-fluoropyrazine (49.60 mg, 2 equiv, 505.8 μmol) in DMSO (1 mL), K2CO3 (104.8 mg, 3 equiv, 758.6 μmol) was added. The resulting mixture was stirred at 25 °C for 16 h. The reaction was monitored by LCMS. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water (5 mmol NH4HCO3), mobile phase B: ACN, 5% - 95% gradient in 30 min; detector, UV254 nm) to give a mixture of isomers of the product (119.4 mg, 213 μmol, 87%) as a solid. LCMS: m / z (ES+), [M+H]+ = 553.3. 1H NMR (400 MHz, Chloroform-d) δ 8.18 (s, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 0.9 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J = 6.3 Hz, 1H), 7.56 (s, 1H), 7.38 - 7.29 (m, 2H), 4.33 - 4.25 (m, 1H), 4.19 (d, J = 13.8 Hz, 1H), 4.07 (s, 3H), 4.04 - 3.91 (m, 2H), 3.76 (dd, J = 9.8, 3.9 Hz, 1H), 3.68 (t, J = 2.9 Hz, 1H), 3.33 (dd, J = 13.8, 3.4 Hz, 1H), 3.21 (ddd, J = 13.7, 9.1, 4.8 Hz, 1H), 2.71 - 2.62 (m, 1H), 2.54 (t, J = 5.0 Hz, 1H), 2.17 - 2.00 (m, 4H), 1.82 - 1.69 (m, 4H), 1.59 (s, 2H). Compound 26: [Chem.]

[0359] A solution of amine (800 mg, 80 wt%, 1 eq., 1.30 mmol), 3-bromopyridazine (620 mg, 3 eq., 3.90 mmol), PEPPSI-pd (111 mg, 0.1 eq., 130 μmol) and Cs2CO3 (1.27 g, 3 eq., 3.90 mmol) in DMSO (5 mL) was taken. The resulting mixture was stirred at 120 °C for 8 h. The resulting mixture was extracted with ethyl acetate / water (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to give the crude product (220 mg, 386 μmol, 30%) as a solid. Purification of the crude material by reverse phase flash chromatography (C18 column; mobile phase A: water (NH4HCO3), mobile phase B: ACN, 5% - 95% gradient in 30 min; detector, UV 220 nm) gave a mixture of isomers of the product (150 mg, 263 μmol, 58%) as a solid. Further purification of this isomer mixture by reverse phase flash chromatography (column: DZ-CHIRALPAK IC-3, 4.6 × 50 mm, 3.0 μm; mobile phase A: MtBE (0.2% DEA):(EtOH:DCM = 1:1) = 70:30) gave 1,1,1-trifluoro-N-(((3R,4S)-3-((((1s,4S)-4-(7-fluoro-1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridazin-3-yl)piperidin-4-yl)methanesulfonamide (21.9 mg, 38.4 μmol, 23%) as a solid. LCMS: m / z (ES+), [M+H]+ = 571.20. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (dd, J = 4.2, 1.4 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.05 (dd, J = 13.5, 1.3 Hz, 1H), 4.20 (d, J = 0.9 Hz, 3H), 4.07 (dq, J = 11.7, 5.9 Hz, 2H), 3.90 (dt, J = 12.7, 6.3 Hz, 1H), 3.76 - 3.46 (m, 5H), 3.06 (q, J = 7.3 Hz, 3H), 2.67 (t, J = 12.0 Hz, 1H), 2.33 (s, 1H), 2.09 (d, J = 12.8 Hz, 2H), 1.99 - 1.76 (m, 4H), 1.74 - 1.55 (m, 4H), 1.31 (t, J = 7.3 Hz, 5H). Compound 27: [Chem.]

[0360] To a solution of amine (80 mg, 1 eq, 0.19 mmol) and thiazole-5-carboxylic acid (37 mg, 1.5 eq, 0.29 mmol) in DCM (3 mL), HOBt (44 mg, 1.5 eq, 0.29 mmol), EDC (55 mg, 1.5 eq, 0.29 mmol) and DIEA (74 mg, 99 μL, 3 eq, 0.57 mmol) were added. The resulting mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS. The resulting mixture was extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water, mobile phase B: ACN, gradient from 25% to 60% in 30 min; detector, UV 254 nm), and a mixture of isomers of the product (50 mg, 94 μmol, 49%) was obtained as a solid.

[0361] The above-mentioned isomer mixture (50 mg) was purified by chiral HPLC (column: DZ-CHIRALPAK IC-3, 4.6×50 mm, 3.0 μm; mobile phase A: Hex(0.2%DEA):(EtOH:DCM = 1:1)=35:65) to obtain N-((3R,4S)-3-((((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(thiazole-5-carbonyl)piperidin-4-yl)methanesulfonamide (21.6 mg, 40.6 μmol, 43%) as a solid. LCMS: m / z (ES+), [M+H]+ = 532.20. 1H NMR (400 MHz, Methanol-d4) δ 9.10 (s, 1H), 8.25 (s, 1H), 7.93 (s, 1H), 7.54 (s, 1H), 7.45 (d, 1H), 7.32 (s, 1H), 4.04 (s, 3H), 3.95 - 3.84 (m, 4H), 3.72 - 3.44 (m, 3H), 3.04 (s, 3H), 2.62 (d, 1H), 2.17 (d, 3H), 1.97 - 1.53 (m, 9H). Compound 28:

Chemical Structure

[0362] To a solution of amine (50 mg, 1 equiv, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (34 mg, 1.5 equiv, 0.18 mmol), 3-methyltetrahydrofuran-3-carboxylic acid (31 mg, 2 equiv, 0.24 mmol), 1-hydroxy-1H-benzotriazole (24 mg, 25 μL, 1.5 equiv, 0.18 mmol) and diisopropylethylamine (46 mg, 61 μL, 3 equiv, 0.36 mmol) in DCM (1 mL). The resulting mixture was stirred at 25 °C for 2 h. The crude material was purified by reverse-phase flash chromatography (C18 column; mobile phase A: water (NH4HCO3), mobile phase B: ACN, 5% - 95% gradient in 30 min) to give the crude product as a solid, a mixture of isomers (60 mg, 0.11 mmol, 95%). The isomer mixture was purified by preparative HPLC (column: CHIRALPAK IC, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)) to give the desired isomer N-(((3R,4S)-3-((((1s,4R)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-((S)3-methyltetrahydrofuran-3-carbonyl)piperidin-4-yl)methanesulfonamide (10.8 mg, 12%) as a solid. LCMS: m / z (ES+), [M+H]+ = 533.20. 1H NMR (400 MHz, Methanol-d4) δ 7.91 (d, J = 0.9 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 4.08 (d, J = 8.9 Hz, 1H), 4.03 (s, 3H), 3.83 (ddt, J = 22.4, 8.5, 4.6 Hz, 4H), 3.68 - 3.62 (m, 2H), 3.59 (dd, J = 9.5, 5.3 Hz, 1H), 3.47 (t, J = 8.9 Hz, 1H), 3.01 (s, 3H), 2.68 (t, J = 12.3 Hz, 1H), 2.42 (q, J = 10.4, 9.2 Hz, 1H), 2.25 - 2.13 (m, 1H), 2.07 (t, J = 14.3 Hz, 2H), 2.01 - 1.75 (m, 5H), 1.64 (dd, J = 21.1, 9.0 Hz, 4H), 1.41 (s, 3H), 0.10 (s, 1H). Compound 29: [Chem.]

[0363] To a solution of amine (150.0 mg, 1 equiv, 288.1 μmol) and TEA (87.45 mg, 120 μL, 3 equiv, 864.3 μmol) in DCM (8 mL), methylsulfamoyl chloride (74.65 mg, 2 equiv, 576.2 μmol) was added. The resulting mixture was stirred at 25 °C for 16 h. The residue was purified by preparative TLC (MeOH / DCM = 1 / 12) to give a mixture of four isomers (120.0 mg, 233.6 μmol, 81.09%) as an oil. The isomers were separated by preparative chiral HPLC (conditions: column: CHIRALPAK IH, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: IPA:DCM = 1:1-HPLC; flow rate: 20 mL / min; gradient: 40% B to 40% B in 16.5 min) to give the desired isomer N-(((3R,4S)-3-((((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridazin-3-yl)piperidin-4-yl)methylsulfamide (24.4 mg, 47.3 μmol, 20.3%, purity 99.6%) as a solid. LCMS: m / z (ES+), [M+H]+ = 514.20. 1H NMR (400 MHz, Chloroform-d) δ 8.58 (d, J = 4.4 Hz, 1H), 7.94 (s, 1H), 7.60 (s, 1H), 7.36 (d, J = 1.2 Hz, 3H), 7.19 (d, J = 9.4 Hz, 1H), 6.44 (d, J = 4.7 Hz, 1H), 4.30 (d, J = 5.6 Hz, 1H), 4.07 (s, 5H), 3.96 - 3.80 (m, 3H), 3.74 (dd, J = 9.9, 3.8 Hz, 1H), 3.67 (s, 1H), 3.55 (s, 1H), 2.79 (d, J = 5.3 Hz, 3H), 2.74 - 2.63 (m, 1H), 2.39 (s, 1H), 2.19 (s, 1H), 2.06 (t, J = 13.1 Hz, 2H), 1.94 (s, 1H), 1.84 (d, J = 11.9 Hz, 4H), 1.61 (m, J = 13.7 Hz, 2H). Compound 30:

Chem.

[0364] To a solution of amine (200.0 mg, 1 equiv, 475.6 μmol) and triethylamine (288.7 mg, 6 equiv, 2.853 mmol) in DCM (2 mL) was added dimethylsulfamoyl chloride (136.6 mg, 2 equiv, 951.1 μmol). The resulting mixture was stirred at 25 °C for 16 h. The residue was purified by preparative TLC (MeOH / DCM = 1 / 12) to afford a mixture of four isomers (81.0 mg, 153 μmol, 32.4%) as a solid. The isomers were separated by preparative chiral HPLC (column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH:DCM = 1:1-HPLC; flow rate: 20 mL / min; gradient: 50% B to 50% B in 23 min) to give N-((3R,4S)-3-(((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridazin-3-yl)piperidin-4-yl)dimethylsulfamide (15.3 mg, 28.9 μmol, 18.9%, purity 99.8%) as a solid. LCMS: m / z (ES+), [M+H]+ = 528.30. 1H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J = 4.4 Hz, 1H), 7.91 (s, 1H), 7.56 (d, J = 1.3 Hz, 1H), 7.33 (d, J = 1.2 Hz, 2H), 7.20 (dd, J = 9.3, 4.4 Hz, 1H), 6.94 (dd, J = 9.3, 1.2 Hz, 1H), 6.38 (d, J = 5.5 Hz, 1H), 4.23 - 4.11 (m, 1H), 4.04 (s, 4H), 3.86 (dd, J = 9.8, 7.7 Hz, 1H), 3.78 (m, J = 9.1, 4.2 Hz, 1H), 3.74 - 3.59 (m, 3H), 3.48 (s, 1H), 3.35 (m, J = 12.9, 8.6, 3.6 Hz, 1H), 2.83 (s, 6H), 2.64 (m, J = 11.6, 3.7 Hz, 1H), 2.45 - 2.32 (m, 1H), 2.17 - 2.00 (m, 4H), 1.95 (m, J = 9.9, 6.3, 3.5 Hz, 1H), 1.81 (m, J = 24.7, 13.9, 10.7 Hz, 4H), 1.66 - 1.49 (m, 2H). Compound 58: [Chem.]

[0365] A solution of (3R,4S)-3-(((4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)-1-(pyridazin-3-yl)piperidin-4-amine (90.0 mg, 1 equiv, 214 μmol) and TEA (130 mg, 179 μL, 6 equiv, 1.28 mmol) in DCM (6 mL) was added dimethylcarbamic chloride (34.5 mg, 1.5 equiv, 321 μmol). The resulting mixture was stirred at 25 °C for 16 h. The residue was purified by preparative TLC (MeOH / DCM = 1 / 12) to give the crude product (85.0 mg, 161 μmol, 75%, purity 93.0%) as an oil. The crude product was purified by preparative chiral HPLC to give the desired compound (20.2 mg, 40.9 μmol, 16.7%, purity 99.5%) as a solid. LCMS: m / z (ES+), [M+H]+ = 492.2 1 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.2 Hz, 1H), 7.95 (s, 1H), 7.60 - 7.45 (m, 2H), 7.34 - 7.17 (m, 3H), 5.97 (d, J = 7.3 Hz, 1H), 4.04 (d, J = 20.1 Hz, 6H), 3.45 (d, J = 5.7 Hz, 3H), 2.80 (s, 6H), 2.60 (d, J = 12.5 Hz, 1H), 2.18 (s, 1H), 1.93 (d, J = 13.1 Hz, 2H), 1.73 (dd, J = 27.7, 13.2 Hz, 4H), 1.51 (s, 4H). Compounds 59 and 60:

Chemical Structure

[0366] To a solution of N-((3R,4S)-3-(((1S,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (50 mg, 1 equiv, 0.12 mmol) and tetrahydrofuran-2-carboxylic acid (28 mg, 2 equiv, 0.24 mmol) in DCM (1 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (34 mg, 1.5 equiv, 0.18 mmol), 1-hydroxy-1H-benzotriazole (24 mg, 25 μL, 1.5 equiv, 0.18 mmol), and diisopropylethylamine (46 mg, 61 μL, 3 equiv, 0.36 mmol). The resulting mixture was stirred at 25 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography followed by preparative chiral HPLC to afford the following:

[0367] As a solid, isomer 1 (12.9 mg, 24.9 μmol, 14%) LCMS: m / z (ES+), [M+H]+ = 519.20 1H NMR (400 MHz, Methanol-d4) δ 7.93 - 7.89 (m, 1H), 7.62 - 7.56 (m, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.37 (td, J = 9.2, 8.7, 1.5 Hz, 1H), 4.90 (dd, J = 8.2, 5.4 Hz, 1H), 4.03 (d, J = 0.9 Hz, 3H), 4.00 - 3.53 (m, 8H), 3.52 - 3.37 (m, 2H), 3.34 (s, 7H), 3.01 (d, J = 8.7 Hz, 3H), 2.66 (dd, J = 12.2, 8.9 Hz, 1H), 2.34 - 2.14 (m, 2H), 2.14 - 1.51 (m, 13H), 1.29 (s, 1H).

[0368] As a solid, isomer 2 (12.7 mg, 24.5 μmol, 13%) LCMS: m / z (ES+), [M+H]+ = 519.2 1 H NMR (400 MHz, Methanol-d4) δ 7.93 - 7.88 (m, 1H), 7.58 (d, J = 11.1 Hz, 1H), 7.47 - 7.32 (m, 2H), 4.94 - 4.87 (m, 1H), 4.02 (d, J = 1.1 Hz, 3H), 3.99 - 3.88 (m, 2H), 3.88 - 3.77 (m,2H), 3.76 - 3.54 (m, 5H), 3.51 - 3.38 (m, 2H), 3.01 (d, J = 8.5 Hz, 3H), 2.74 - 2.60 (m, 1H), 2.33 - 2.14 (m, 2H), 2.05 (td, J = 13.4, 12.7, 4.8 Hz, 3H), 1.97 - 1.55 (m, 11H). Compound 61:

Chem.

[0369] To a stirred solution of N-((3R,4S)-3-(((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (100 mg, 1 equiv, 238 μmol) in acetonitrile (2 mL), 2-chloro-1-(piperidin-1-yl)ethan-1-one (38.4 mg, 1 equiv, 238 μmol), N-ethyl-N-isopropylpropan-2-amine (36.9 mg, 1.2 equiv, 285 μmol) and potassium iodide (39.5 mg, 1 equiv, 238 μmol) were added dropwise in small portions at 25 °C under a hydrogen / nitrogen atmosphere. The residue was purified by preparative TLC, followed by preparative chiral HPLC to give the product (23.5 mg, 42.2 μmol, 21%, purity 97.9%) as a solid. LCMS: m / z (ES+), [M+H]+ =546.4 11H NMR (400 MHz, Methanol-d4) δ 7.93 (d, 1H), 7.60 (d, 1H), 7.47 (d, 1H), 7.38 (dd, 1H), 4.05 (s, 3H), 3.71 - 3.56 (m, 6H), 3.51 - 3.44 (m, 1H), 3.42 - 3.36 (m, 1H), 3.28 (s, 1H), 3.16 (d, 1H), 3.01 (s, 3H), 2.75 - 2.51 (m, 5H), 2.26 (d, 1H), 2.09 (d, 2H), 1.93 - 1.81 (m, 4H), 1.69 - 1.48 (m, 11H). Compound 62:

Chem.

[0370] To a solution of N-((3R,4S)-3-(((1s,4S)-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (80 mg, 1 equiv, 0.19 mmol) and HOBt (44 mg, 1.5 equiv, 0.29 mmol) in DCM (2 mL) were added EDC (55 mg, 1.5 equiv, 0.29 mmol), DIEA (74 mg, 99 μL, 3 equiv, 0.57 mmol), and (S)-tetrahydrofuran-3-carboxylic acid (33 mg, 1.5 equiv, 0.29 mmol). The resulting mixture was stirred at 25 °C for 8 h under a nitrogen atmosphere and then concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography followed by preparative chiral HPLC to afford the desired product (16 mg, 31 μmol, 16%, purity 99%) as a solid. LCMS: m / z (ES+), [M+H]+ = 519.3 11H NMR (400 MHz, Methanol-d4) δ 7.93 (s, 1H), 7.60 (d, 1H), 7.47 (d, 1H), 7.38 (dd, 1H), 4.09 - 4.02 (m, 3H), 4.00 - 3.73 (m, 7H), 3.70 - 3.44 (m, 6H), 3.04 (d, 3H), 2.70 (d, 1H), 2.32 - 1.99 (m, 5H), 1.97 - 1.57 (m, 8H). Compounds 63 and 64:

Chemical formula

[0371] To a solution of N-((3R,4S)-3-(((4-(1-methyl-1H-benzo[d]imidazol-6-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (130 mg, 1 equiv, 309 μmol) and pyridin-2-yl trifluoromethanesulfonate (84.3 mg, 1.2 equiv, 371 μmol) in DMSO (5 mL) was added TEA (93.8 mg, 129 μL, 3 equiv, 927 μmol). The resulting mixture was stirred at 120 °C for 3 h under a nitrogen atmosphere, then the obtained mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.

[0372] The crude material was purified by reverse-phase flash chromatography to give the following: As a solid, isomer 1 (7.2 mg, 14 μmol, 40%). LCMS: m / z (ES+), [M+H]+ = 498 11H NMR (400 MHz, Methanol-d4) δ 8.10 - 8.02 (m, 2H), 7.61 - 7.48 (m, 2H), 7.46 (d, 1H), 7.19 (dd,, 1H), 6.91 - 6.84 (m, 1H), 6.70 - 6.59 (m, 1H), 3.89 (s, 5H), 3.82 - 3.43 (m, 6H), 3.06 (s, 3H), 2.81 - 2.68 (m, 1H), 2.38 - 2.29 (m, 1H), 2.10 (d, 2H), 2.01 - 1.85 (m, 4H), 1.76 - 1.58 (m, 4H), 1.41 - 1.23 (m, 2H), 0.96 - 0.86 (m, 1H).

[0373] As a solid, isomer 2 (1 mg, 2 μmol, 20%). LCMS: m / z (ES+), [M+H]+ = 498 1 1H NMR (400 MHz, Methanol-d4) δ 8.08 (d, 1H), 7.57 (t, 1H), 7.41 (s, 1H), 7.19 (d, 1H), 6.89 (d, 1H), 6.72 - 6.63 (m, 1H), 4.64 (s, 2H), 3.89 (s, 3H), 3.75 (dd, 2H), 3.65 - 3.54 (m, 3H), 3.05 (s, 2H), 2.71 (s, 1H), 2.21 (s, 3H), 1.98 (d, 1H), 1.87 (d, 1H), 1.64 (d, 2H), 1.43 (s, 2H), 1.31 (s, 3H), 0.92 (s, 1H). Compounds 65 and 66: [Chemical formula]

[0374] To a solution of N-((3R,4S)-3-(((4-(1-methyl-1H-indazol-6-yl)cyclohexyl)oxy)methyl)piperidin-4-yl)methanesulfonamide (100 mg, 1 equiv, 238 μmol) and pyridin-2-yl trifluoromethanesulfonate (59.4 mg, 1.1 equiv, 262 μmol) in DMSO (5 mL) was added TEA (72.2 mg, 99.4 μL, 3 equiv, 713 μmol). The resulting mixture was stirred at 120 °C for 3 h under a nitrogen atmosphere and then concentrated under reduced pressure. The crude material was purified by reverse-phase flash chromatography followed by chiral HPLC to afford the following:

[0375] Isomer 1: LCMS: m / z (ES+), [M+H]+ = 498 1 1H NMR (400 MHz, Chloroform-d) δ 8.19 (dd, 1H), 7.92 (s, 1H), 7.63 (d, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.04 (d, 1H), 6.78 - 6.64 (m, 2H), 6.57 (d, 1H), 4.10 (s, 3H), 4.05 (dd, 1H), 3.96 (t, 2H), 3.87 (s, 1H), 3.73 (d, 1H), 3.67 (s, 1H), 3.55 (s, 1H), 3.33 (s, 1H), 3.03 (s, 3H), 2.69 (d, 1H), 2.41 (s, 1H), 2.10 (d, 3H), 2.03 (s, 1H), 1.83 (d, 4H), 1.28 (s, 1H), 0.09 (s, 7H).

[0376] As a solid, isomer 2 (5.7 mg, 11 μmol, 38%). LCMS: m / z (ES+), [M+H]+ = 498 11H NMR (400 MHz, Methanol-d4) δ 8.08 (dd, 1H), 7.92 (d, 1H), 7.65 (d, 1H), 7.62 - 7.55 (m, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.08 (dd, 1H), 6.90 (d, 1H), 6.67 (dd, 1H), 4.04 (s, 3H), 3.89 - 3.79 (m, 2H), 3.75 (dd, 1H), 3.69 - 3.47 (m, 4H), 3.40 (dd,, 1H), 3.05 (s, 3H), 2.70 (t, 1H), 2.22 (d, 3H), 1.99 (d, 2H), 1.87 (q, 2H), 1.74 - 1.53 (m, 2H), 1.44 (q, 2H), 1.31 (s, 1H).

[0377] Example 2: Human OX2R IP1 Assay In a T225 flask, T-Rex CHO cells stably overexpressing human orexin 2 receptor (OX2R) were induced overnight with 1 μg / mL doxycycline. 24 hours after induction, the cells were lifted with Accutase and seeded at 30,000 cells / well in a 384-well ProxiPlate. The cells were then treated with different test compounds for 1 hour at 37 °C in 1× stimulation buffer containing 10 mM Hepes, 1 mM CaCl2, 0.5 mM MgCl2, 4.2 mM KCl, 146 mM NaCl, 5.5 mM glucose, and 50 mM LiCl, pH 7.4. After incubation, the reaction was stopped by adding a detection mixture composed of lysis buffer and IP1-d2 and anti-IP1 cryptate diluted in 1× stimulation buffer. The plate was incubated at room temperature for 1 hour and then read on an EnVision® multimode plate reader to measure inositol phosphate levels.

[0378] Cisbio IP1 is a cell-based functional assay that quantifies the accumulation of inositol monophosphate (IP), a metabolite released as a result of orexin 2 receptor activation 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 coupled to a d2 fluorophore (acceptor) for binding to an anti-IP1 monoclonal antibody labeled with Eu cryptate (donor). The measured HTRF-FRET-based signal is inversely proportional to the concentration of IP1 produced.

[0379] The EC values reported in Table 2 50 were obtained according to the above-described human OX2R IP1 assay. The data are mean EC 50 values ± S.E.M. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

[0380] The present invention has been specifically shown and described with reference to its preferred embodiments, but it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. Equation (I-A): 【Chemistry 1】 (In the formula, Ring A is condensed with ring B, Ring A is C ３ to C ８ cycloalkyl, 4- to 7-membered heterocyclyl, C ６ to C １０ aryl and 5- to 7-membered heteroaryl, and is selected from the group consisting of, and said C ３ to C ８ cycloalkyl, 4- to 7-membered heterocyclyl, C ６ to C １０ aryl or 5- to 7-membered heteroaryl is unsubstituted or is substituted with one or more halogens, hydroxyls, C １ to C ３ alkoxyls, unsubstituted C １ to C ３ alkyls, or C １ to C ３ alkyls substituted with one or more halogens or deuteriums, Ring B is C ３ ~C ８ Cycloalkyl, 4-7 membered heterocyclyl, C ６ ~C １０ Selected from the group consisting of aryls and 5- to 7-membered heteroaryls, the C ３ ~C ８ Cycloalkyl, 4-7 membered heterocyclyl, C ６ ~C １０ The aryl or 5- to 7-membered heteroaryl is either unsubstituted or contains one or more halogens, hydroxyl, or C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ It is substituted with alkyl, X is N or CH, Y is S (=O) ２ , C (=O), or S (=O) (=NR ｅ ) and R ｅ H, C １ ~C ３ Alkyl or C ３ ~C ５ Selected from the group consisting of cycloalkyl groups, E is NR ａ R ｂ , C １ ~C ３ Alkylene-NR ａ R ｂ , C １ ~C ３ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C ３ ~C ８ Cycloalkyl, C １ ~C ３ Alkylene-(C) ３ ~C ８ Cycloalkyl), 4-10 membered heterocyclyl, C １ ~C ３ Alkilen-(4-10 membered heterocyclyl), C ６ ~C １０ Ariel, C １ ~C ３ Alkylene-(C) ６ ~C １０ aryl), 5-7 member heteroaryl and C １ ~C ３ Selected from the group consisting of alkylene-(5-7 member heteroaryl), the C １ ~C ３ Alkylene-NR ａ R ｂ , C １ ~C ３ Alkyl, C ２ ~C ４ Alkenil, C ２ ~C ４ Alkinyl, C ３ ~C ８ Cycloalkyl, C １ ~C ３ Alkylene-(C) ３ ~C ８ Cycloalkyl), 4-10 membered heterocyclyl, C １ ~C ３ Alkilen-(4-10 membered heterocyclyl), C ６ ~C １０ Ariel, 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 is substituted with 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 alkoxyl, R ａ and R ｂ These are H and C, respectively, independently. １ ~C ３ Alkyl, C ３ ~C ５ Selected from the group consisting of cycloalkyl and 4- to 7-membered heterocyclyl, the C １ ~C ３ Alkyl, C ３ ~C ５ Cycloalkyls, or 4- to 7-membered heterocyclines, are either unsubstituted or contain one or more halogens, hydroxyls, or C １ ~C ３ Alkyl, or C １ ~C ３ Is it substituted with an alkoxyl? Alternatively, R ａ and R ｂ These, together with the N atoms to which they are bonded, form a 4-7 membered heterocycline or a 5-7 membered heteroaryl, and the 4-7 membered heterocycline or 5-7 membered heteroaryl is unsubstituted or contains one or more halogens, hydroxyls, NR ｃ R ｄ , C １ ~C ３ Alkyl, C １ ~C ３ C substituted with alkoxy or 1 to 3 halogens １ ~C ３ It is substituted with alkyl, R １ is C(=O)-C １ ~C ４ Alkyl, C(=O)-C １ ~C ４ Alkoxyl, C(=O)-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ Cycloalkyl, C(=O)-(CR ｃ R ｄ ) ｎ - (4-7 member heterocyclyl), C(=O)-(CR ｃ R ｄ ) ｎ - (C ６ ~C １０ Ayl), C(=O)-(CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), C(=O)-O-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ Cycloalkyl, C(=O)-O-(CR ｃ R ｄ ) ｎ - (4-7 member heterocyclyl), (CR ｃ R ｄ ) ｎ - (C ６ ~C １０ (Aryl) and (CR ｃ R ｄ ) ｎ - Selected from the group consisting of (5-10 member heteroaryls), C １ ~C ４ Alkyl, C １ ~C ４ Alkoxyl, C ３ ~C ８ Cycloalkyl, 4-7 membered heterocyclyl, C ６ ~C １０ The aryl or 5- to 10-membered heteroaryl is unsubstituted, or one or more halogens, hydroxyls, or unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ It is substituted with alkyl, R ｃ and R ｄ These are H and unsubstituted C, respectively, independently. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ It is alkyl, n is 0, 1, or 2. R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ Each of these is independently H, halogen, and unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ Is it alkyl? Alternatively, R ３ and R ６ They come together as non-substituted C １ ~C ３ C substituted with alkylene or one or more halogens １ ~C ３ Forming alkylenes, Alternatively, R ４ and R ５ They come together as non-substituted C １ ~C ３ C substituted with alkylene or one or more halogens １ ~C ３ Forming alkylenes, m is either 0 or 1. p is 0, 1, 2, 3, or 4. Each R ９ (These are independently selected from the group consisting of deuterium, halogens, hydroxyl, and cyano.) Compounds of or pharmaceutically acceptable salts thereof.

2. Formula (I-A) or a pharmaceutically acceptable salt thereof is formula I: 【Chemistry 2】 The compound according to claim 1, which is a compound or a pharmaceutically acceptable salt thereof.

3. Ring A is C ３ ~C ８ It is a cycloalkyl, and the C ３ ~C ８ The cycloalkyl group is unsubstituted, or contains one or more halogens, hydroxyls, or C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

4. Ring A is a 4- to 7-membered heterocycline, and the 4- to 7-membered heterocycline is unsubstituted, or contains one or more halogens, hydroxyls, and C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

5. Ring A is C ６ ~C １０ It is aryl, and the C ６ ~C １０ The aryl is unsubstituted, or contains one or more halogens, hydroxyls, or C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

6. Ring A is a 5-7 member heteroaryl group, and the 5-7 member heteroaryl group is unsubstituted, or contains one or more halogens, hydroxyls, and C. １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

7. Ring B is C ３ ~C ８ It is a cycloalkyl, and the C ３ ~C ８ The cycloalkyl group is unsubstituted, or contains one or more halogens, hydroxyls, or C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

8. Ring B is a 4- to 7-membered heterocycline, and the 4- to 7-membered heterocycline is unsubstituted, or contains one or more halogens, hydroxyls, and C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

9. Ring B is C ６ ~C １０ It is aryl, and the C ６ ~C １０ The aryl is unsubstituted, or contains one or more halogens, hydroxyls, or C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

10. Ring B is a 5-7 member heteroaryl, and the 5-7 member heteroaryl is unsubstituted, or contains one or more halogens, hydroxyls, and C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group. 【Request Item 11】 【Chemistry 3】 However, the following is selected from the group consisting of benzimimidazolyl, 1H-pyrazolo[3,4-c]pyridinyl, imidazo[1,5-a]pyridinyl, indolyl, isoindolyl, indazolyl, isoindazolyl, benzothiazolyl, purinyl, benzofuranil, benzoisoxazolyl, benzoisothiazolyl, isobenzofuranil, benzothiofuranil, indoleninyl, pyrano[3,4-b]-pyrrolyl, indoxadinyl, benzoxazolyl, anthranil, and indolidinyl, and the benzimi Dazolyl, 1H-pyrazolo[3,4-c]pyridinyl, imidazo[1,5-a]pyridinyl, indolyl, isoindolyl, indazolyl, isoindazolyl, benzothiazolyl, prinyl, benzofuranil, benzoisoxazolyl, benzoisothiazolyl, isobenzofuranil, benzothiofuranil, indoleninyl, pyrano[3,4-b]-pyrrolyl, indoxadinyl, benzoxazolyl, anthranil, and indolidinyl are either unsubstituted or have a halogen, hydroxyl, or C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl, or 1 to 3 halogen or deuterium atoms １ ~C ３ The compound according to claim 1 or 2, which is substituted with one to three substituents selected from alkyl groups. 【Request Item 12】 【Chemistry 4】 The benzimidazolyl is either unsubstituted or a halogen, hydroxyl, or C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl, or 1 to 3 halogen or deuterium atoms １ ~C ３ The compound according to claim 11, which is substituted with one to three substituents selected from alkyl groups. 【Request Item 13】 【Chemistry 5】 The compound is imidazo[1,5-a]pyridinyl, and the imidazo[1,5-a]pyridinyl is either unsubstituted or a halogen, hydroxyl, C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl, or 1 to 3 halogen or deuterium atoms １ ~C ３ The compound according to claim 11, which is substituted with one to three substituents selected from alkyl groups. 【Request Item 14】 【Chemistry 6】 The indolyl is either unsubstituted or a halogen, hydroxyl, or C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl, or 1 to 3 halogen or deuterium atoms １ ~C ３ The compound according to claim 11, which is substituted with one to three substituents selected from alkyl groups. 【Request Item 15】 【Chemistry 7】 The indazolyl is either unsubstituted or a halogen, hydroxyl, or C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl, or 1 to 3 halogen or deuterium atoms １ ~C ３ The compound according to claim 11, which is substituted with one to three substituents selected from alkyl groups. 【Request Item 16】 【Chemistry 8】 The benzoxazolyl is either unsubstituted or a halogen, hydroxyl, or C １ ~C ３ Alkoxyl, unsubstituted C １ ~C ３ C substituted with alkyl, or 1 to 3 halogen or deuterium atoms １ ~C ３ The compound according to claim 11, which is substituted with one to three substituents selected from alkyl groups.

17. The compound according to claim 1 or 2, wherein p is 0 or 1.

18. E is NR ａ R ｂ The compound according to claim 1 or 2.

19. E is C １ ~C ３ Alkylene-NR ａ R ｂ The compound according to claim 1 or 2.

20. E is an unsubstituted C １ ~C ３ Alkyl, unsubstituted C ２ ~C ４ Alkenyl or unsubstituted C ２～ C ４ The compound according to claim 1 or 2, wherein E is an alkynyl, or a C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl, which is substituted with one or more halogens, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl.

21. E is an unsubstituted C １ ~C ３ The compound according to claim 1 or 2, wherein E is alkyl, or a C1-C3 alkyl substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl, or C1-C3 alkoxyl.

22. E is an unsubstituted C ３ ~C ８ The compound according to claim 1 or 2, wherein E is a cycloalkyl or a C3-C8 cycloalkyl substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl or C1-C3 alkoxyl.

23. E is an unsubstituted C １ ~C ３ Alkylene-(C) ３ ~C ８ The compound according to claim 1 or 2, wherein E is a cycloalkyl or a C1-C3 alkylene-(C3-C8 cycloalkyl) substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl or C1-C3 alkoxyl.

24. The compound according to claim 1 or 2, wherein E is an unsubstituted 4- to 10-membered heterocycline, or E is a 4- to 10-membered heterocycline substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C 1-C 3 alkyl, or C 1-C 3 alkoxyl.

25. E is an unsubstituted C １ ~C ３ The compound according to claim 1 or 2, wherein E is an alkylene (4-10 membered heterocycline) or a C1-C3 alkylene (4-10 membered heterocycline) substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl, or C1-C3 alkoxyl.

26. E is an unsubstituted C ６ ~C １０ The compound according to claim 1 or 2, wherein E is an aryl or a C6-C10-aryl substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl or C1-C3 alkoxyl.

27. E is an unsubstituted C １ ~C ３ Alkylene-(C) ６ ~C １０ The compound according to claim 1 or 2, wherein E is an aryl or a C1-C3 alkylene-(C6-C10-aryl) substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl or C1-C3 alkoxyl.

28. The compound according to claim 1 or 2, wherein E is an unsubstituted 5-7 membered heteroaryl, or E is a 5-7 membered heteroaryl substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C 1-C 3 alkyl, or C 1-C 3 alkoxyl.

29. E is an unsubstituted C １ ~C ３ The compound according to claim 1 or 2, wherein E is an alkylene-(5-7 member heteroaryl) or a C1-C3 alkylene-(5-7 member heteroaryl) substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl, or C1-C3 alkoxyl.

30. The compound according to claim 1 or 2, wherein E is methyl, or E is methyl substituted with one or more halogens, hydroxyl, NR c R d, CF 3, CHF 2, CH 2 F, C1-C3 alkyl, or C1-C3 alkoxyl.

31. E is CF ３ The compound according to claim 1 or 2, wherein the compound is CHF2 or CH2F.

32. E is NH(CH ３ The compound according to claim 1 or 2, wherein it is either N(CH3)2.

33. Y is S (=O) ２ The compound according to claim 1 or 2.

34. The compound according to claim 1 or 2, wherein Y is C (=O).

35. The compound according to claim 1 or 2, wherein X is CH.

36. R １ However, 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 - (4-7 member heterocyclyl), C(=O)-(CR ｃ R ｄ ) ｎ - (C ６ ~C １０ aryl), and C(=O)-(CR ｃ R ｄ ) ｎ - Selected from the group consisting of (5-10 member heteroaryls), C １ ~C ４ Alkyl, C １ ~C ４ Alkoxyl, C ３ ~C ８ Cycloalkyl, 4-7 membered heterocyclyl, C ６ ~C １０ The aryl or 5- to 10-membered heteroaryl is unsubstituted, or one or more halogens, hydroxyls, or unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

37. R １ However, C(=O)-C １ ~C ４ Alkyl, and the C １ ~C ４ The alkyl group is unsubstituted, or it contains one or more halogens, hydroxyls, and unsubstituted C atoms. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

38. R １ However, C(=O)-C １ ~C ４ It is an alkoxy, and the C １ ~C ４ The alkoxy is unsubstituted, or one or more halogens, hydroxyls, and unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

39. R １ is C(=O)-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ It is a cycloalkyl, and the C ３ ~C ８ The cycloalkyl group is unsubstituted, or it contains one or more halogens, hydroxyls, or unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

40. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (4-7 member heterocycline), where the 4-7 member heterocycline is unsubstituted, or contains one or more halogens, hydroxyl groups, and unsubstituted C groups. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

41. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (C ６ ~C １０ It is aryl, and the C ６ ~C １０ The aryl is unsubstituted, or one or more halogens, hydroxyls, and unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

42. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), where the 5-10 member heteroaryl is unsubstituted, or contains one or more halogens, hydroxyl, and unsubstituted C １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ The compound according to claim 1 or 2, which is substituted with an alkyl group.

43. R １ is C(=O)-O-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ It is a cycloalkyl, and the C ３ ~C ８ The cycloalkyl group is unsubstituted, or it contains one or more halogens, hydroxyls, or unsubstituted C. １ ~C ３ C substituted with alkyl or one or more halogens or deuterium １ ~C ３ Substituted with alkyl, or R1 is C(=O)-O-(CR c R d) n-(4-7 member heterocyclil), and the 4-7 member heterocyclil is either unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium. or R1 is a C(=O)-O-(CR c R d)n-C3-C5 cycloalkyl group, where the C3-C5 cycloalkyl group is either unsubstituted or substituted with one or more halogens, hydroxyl groups, unsubstituted C1-C3 alkyl groups, or C1-C3 alkyl groups substituted with one or more halogens or deuterium groups. or R1 is C(=O)-O-(CR c R d) n-(5-6 member heterocyclyl), and the 5-6 member heterocyclyl is either unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium. or R1 is C(=O)-O-(CR c R d) n-(5-membered heterocyclyl), and the 5-membered heterocyclyl is either unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium. or The compound according to claim 1 or 2, wherein R1 is C(=O)-O-(CR c R d) n-(6-membered heterocyclyl), and the 6-membered heterocyclyl is either unsubstituted or substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

44. R １ However, (CR ｃ R ｄ ) ｎ - (C ６ ~C １０ (Aryl) or (CR ｃ R ｄ ) ｎ - (5-10 member heteroaryl), and the above C ６ ~C １０ The compound according to claim 1 or 2, wherein the aryl or 5-10 membered heteroaryl is unsubstituted, or the C6-C10 aryl or 5-10 membered heteroaryl is substituted with one or more halogens, hydroxyls, unsubstituted C1-C3 alkyls, or C1-C3 alkyls substituted with one or more halogens or deuterium.

45. R １ However, (CR ｃ R ｄ ) ｎ The compound according to claim 1 or 2, wherein the compound is a (six-membered heteroaryl), and the six-membered heteroaryl is unsubstituted, or the six-membered heteroaryl is substituted with one or more halogens, hydroxyl, unsubstituted C1-C3 alkyl, or C1-C3 alkyl substituted with one or more halogens or deuterium.

46. R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ Each of these independently consists of H, halogen, and unsubstituted C. １ ~C ３ The compound according to claim 1 or 2, which is an alkyl or a C1-C3 alkyl substituted with one or more halogens or deuterium.

47. R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ Each of these independently consists of H, halogen, and unsubstituted C. １ ~C ３ The compound according to claim 46, wherein it is alkyl.

48. R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ The compound according to claim 46, wherein each of them is independently H.

49. R １ However, C(=O)-C １ ~C ４ It is alkyl, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ Each of these is either H or unsubstituted C １ ~C ３ The compound according to claim 1 or 2, wherein it is alkyl.

50. R １ However, C(=O)-C １ ~C ４ It is an alkoxy, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ Each of these is either H or unsubstituted C １ ~C ３ The compound according to claim 1 or 2, wherein it is alkyl.

51. R １ is C(=O)-(CR ｃ R ｄ ) ｎ -C ３～ C ８ It is a cycloalkyl, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ Each of these is either H or unsubstituted C １ ~C ３ The compound according to claim or 2, wherein it is alkyl.

52. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (4-7 member heterocyclyl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

53. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (5-membered heterocycline), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

54. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (6-membered heterocyclyl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

55. 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 The compound according to claim 1 or 2, wherein each of them is H.

56. 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 The compound according to claim 1 or 2, wherein each of them is H.

57. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (5-7 member heteroaryl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

58. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (5-membered heteroaryl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

59. R １ is C(=O)-(CR ｃ R ｄ ) ｎ - (6-membered heteroaryl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

60. R １ is C(=O)-O-(CR ｃ R ｄ ) ｎ -C ３ ~C ８ It is a cycloalkyl, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

61. R １ is C(=O)-O-(CR ｃ R ｄ ) ｎ - (4-7 member heterocyclyl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

62. R １ is C(=O)-O-(CR ｃ R ｄ ) ｎ - (5-membered heterocycline), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

63. R １ is C(=O)-O-(CR ｃ R ｄ ) ｎ - (6-membered heterocyclyl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

64. R １ However, (CR ｃ R ｄ ) ｎ - (5-7 member heteroaryl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ and R ８ The compound according to claim 1 or 2, wherein each of them is H.

65. R １ However, (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 The compound according to claim 1 or 2, wherein each of them is H.

66. R １ The compound according to claim 1 or 2, wherein the compound is 3-pyridazinyl.

67. below: 【Chemistry 24-1】 【Chemistry 24-2】 【Chemistry 24-3】 【Chemistry 24-4】 【Chemistry 24-5】 【Chemistry 24-6】 【Chemistry 24-7】 【Chemistry 24-8】 【Chemistry 24-9】 and 【Chemistry 25】 A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

68. A pharmaceutical composition comprising a compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

69. Use of a compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, or a composition thereof, for the manufacture of a medicine for narcolepsy.

70. Use of a compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, or a composition thereof, for the manufacture of a pharmacopoeia for cataplexy.

71. A compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, or a composition thereof, for use in a method of treating narcolepsy in a subject requiring treatment for narcolepsy.

72. A compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, or a composition thereof, for use in a method of treating cataplexy in a subject requiring treatment for cataplexy.

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