T-type calcium channel regulator and method of use thereof

Abstract

The present invention is directed, in part, to deuterium-enriched compounds and compositions comprising deuterium-enriched compounds useful for preventing and / or treating diseases or conditions associated with abnormal function of T-type calcium channels. As described herein, deuteration of the T-type calcium channel inhibitors can significantly affect metabolic clearance. Surprisingly, some of the deuterated compounds described herein exhibit significantly improved metabolic stability compared to non-deuterated compounds. Because metabolic clearance often leads to improved bioavailability, deuterated compounds are expected to have improved bioavailability compared to non-deuterated compounds.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest to U.S. Provisional Patent Application No. 63 / 111,358, filed on 9 November 2020, U.S. Provisional Patent Application No. 63 / 111,361, filed on 9 November 2020, and U.S. Provisional Patent Application No. 63 / 150,397, filed on 17 February 2021, each of which is incorporated herein by reference in whole.

[0002] This disclosure generally relates to compounds that selectively modulate T-type calcium channels, and more specifically, to deuterium-enriched compounds designed to act as T-type calcium channel regulators. [Background technology]

[0003] T-type calcium channels are low-potential activated ion channels that mediate the influx of calcium into cells. Abnormal function of these ion channels is associated with several diseases or conditions, including mental disorders (e.g., mood disorders (e.g., major depressive disorder)), pain, tremors (e.g., essential tremor), epilepsy, or epileptic syndromes (e.g., absence seizures and juvenile myoclonic epilepsy). Therefore, compounds that selectively modulate T-type calcium channels in mammals may be useful in the treatment of such diseases. [Overview of the Initiative] [Means for solving the problem]

[0004] This specification provides, for example, deuterium-enriched compounds designed to act as T-type calcium channel modulators. In particular, this disclosure provides deuterium-enriched compounds of T-type calcium channel modulators having the following formula: [ka]

[0005] As described herein, the deuteration of this T-type calcium channel inhibitor can have a significant impact on metabolic clearance. Surprisingly, some of the deuterated compounds described herein exhibit a marked improvement in metabolic stability compared to the non-deuterated compounds. Since metabolic clearance often leads to improved bioavailability, the deuterated compounds are expected to have improved bioavailability compared to the non-deuterated compounds.

[0006] The deuterium-enriched compounds of formula (I) include compounds having a deuterium level above the naturally occurring level.

[0007] Thus, in one aspect, provided herein is a compound of formula (I),

Chemical formula

[0008] , , , , 、R 1b 、R 2a 、R 2b each of R6 and R7 is independently hydrogen or deuterium, each of R3, R4, and R5 is -C(R a )3, and each R a is independently hydrogen or deuterium, n is an integer selected from 0 to 9, m is an integer selected from 0 to 3, R 1a 、R 1b 、R 2a 、R 2b 、R6, R7, and R a at least one of which is deuterium, provided that the compound is not

Chemical formula

[0008] Furthermore, this specification also describes pharmaceutical compositions comprising a deuterium concentrate of formula (I) and pharmaceutically acceptable excipients. The pharmaceutical compositions require the presence of the deuterium concentrate of formula (I) in amounts greater than its natural abundance.

[0009] In another embodiment, this specification refers to a compound of formula (I), [ka] A pharmaceutical composition is provided comprising a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein, R 1a , R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b , R6, R7, and R a At least one of them is deuterium.

[0010] The compounds of this specification (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) are considered useful in preventing and / or treating diseases or conditions associated with abnormal function of T-type calcium channels, such as mental disorders (e.g., mood disorders (e.g., major depressive disorder)), pain, tremors (e.g., essential tremor), seizures (e.g., absence seizures), epilepsy, or epileptic syndromes (e.g., juvenile myoclonic epilepsy). The present invention further includes methods for modulating the function of T-type calcium channels.

[0011] In one embodiment, this specification provides a method for treating a neurological disorder in a person requiring treatment, the method comprising an effective amount of a compound of formula (I), [ka] or administering a pharmaceutically acceptable salt thereof to a subject, in the formula, R 1a , R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b , R6, R7, and R a At least one of them is deuterium.

[0012] In another aspect, this specification provides a method for treating a mental disorder (e.g., a mood disorder (e.g., major depressive disorder)) in a person requiring treatment, wherein the method involves an effective amount of a compound of formula (I), [ka] or administering a pharmaceutically acceptable salt thereof to a subject, in the formula, R 1a , R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b, R6, R7, and R a At least one of them is deuterium.

[0013] In one embodiment, this specification provides a method for treating pain in a person requiring treatment, the method comprising an effective amount of a compound of formula (I), [ka] or administering a pharmaceutically acceptable salt thereof to a subject, in the formula, R 1a , R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b , R6, R7, and R a At least one of them is deuterium.

[0014] In one embodiment, this specification provides a method for treating a tremor (e.g., essential tremor) in a person requiring treatment, the method comprising an effective amount of a compound of formula (I), [ka] or administering a pharmaceutically acceptable salt thereof to a subject, in the formula, R 1a , R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b , R6, R7, and R a At least one of them is deuterium.

[0015] In one embodiment, this specification provides a method for treating a seizure (e.g., absence seizure) in a person requiring treatment, the method comprising an effective amount of a compound of formula (I), [ka] or administering a pharmaceutically acceptable salt thereof to a subject, in the formula, R 1a , R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b , R6, R7, and R a At least one of them is deuterium.

[0016] In one embodiment, this specification provides a method for treating epilepsy or an epileptic syndrome (e.g., juvenile myoclonus epilepsy) in a person requiring treatment, the method comprising an effective amount of a compound of formula (I), [ka] or administering a pharmaceutically acceptable salt thereof to a subject, in the formula, R 1a, R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b , R6, R7, and R a At least one of them is deuterium.

[0017] Other purposes and advantages will become apparent to those skilled in the art by considering the following embodiments, examples, and claims for carrying out the invention. [Modes for carrying out the invention]

[0018] Generally as described herein, the present invention provides pharmaceutical compositions comprising a deuterium concentrate (e.g., a compound of formula (I)), a compound described herein (e.g., a compound of formula (I)) and a pharmaceutically acceptable excipient, and methods for preventing and / or treating diseases or conditions associated with abnormal function of T-type calcium channels, such as mental disorders (e.g., mood disorders (e.g., major depressive disorder)), pain, tremors (e.g., essential tremor), seizures (e.g., absence seizures), epilepsy, or epileptic syndromes (e.g., juvenile myoclonic epilepsy). Methods for treating tremors (e.g., essential tremor, Parkinsonian tremor, or cerebellar tremor), or epilepsy or epileptic syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or hereditary epilepsy) are also presented. Furthermore, methods for treating mood disorders (e.g., depression, major depressive disorder, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), and / or obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD)) are presented. Methods useful for modulating the function of T-type calcium channels and enhancing their effectiveness are also presented. Methods for treating pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain, e.g., thalamic pain, or migraine) are also presented. Methods for treating ataxia (e.g., spinocerebellar ataxia, or spinocerebellar ataxia with CACNA1G mutation) are also presented. Methods for treating tinnitus are also presented. Methods for treating arousal disorders are also presented.

[0019] definition chemical definition The definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. thIdentified according to the front and back covers of the Ed., and the specific functional groups are generally defined as described in the same book. Further, the general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, Smith and March, March’s Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0020] Deuterium (D or 2 H) is a stable, non-radioactive hydrogen isotope with an atomic weight of 2.0144. Hydrogen occurs naturally as a mixture of isotopes 1 H (hydrogen or protium), D ( 2 H or deuterium), and T ( 3 H or tritium). The natural abundance of deuterium is 0.015%. One of ordinary skill in the art will recognize that in all compounds having H atoms, the H atoms actually represent a mixture of H and D, with approximately 0.015% being D. Thus, compounds having deuterium levels enriched above its natural abundance of 0.015% are considered non-natural and, as a result, should be considered more novel than their non-enriched counterparts.

[0021] The effect of deuterium modification on the metabolic properties of a compound is unpredictable, even when deuterium atoms are introduced into known metabolic sites. Only by actually preparing and testing the deuterated compound can it be determined whether, and how, its metabolic rate differs from that of its non-deuterated compound. See, for example, Fukuto et al. (J.Med.Chem. 1991, 34, 2871-76). Many compounds have multiple metabolic sites. The sites requiring deuterium substitution, and the degree of deuteration necessary to observe its effect on metabolism, will, in some cases, vary from compound to compound.

[0022] Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to contain hydrogen in its naturally occurring isotopic composition. Furthermore, unless otherwise specified, when a position is specifically designated as "D" or "deuterium," that position is understood to contain deuterium at an abundance at least 3000 times greater than its naturally occurring abundance, i.e., 0.015% (i.e., the terms "D" or "deuterium" indicate at least 45% deuterium contamination).

[0023] As used herein, the term “isotope enrichment factor” means the ratio between the isotopic abundance of D at a particular position in the compound of the present invention and the natural abundance of that isotope.

[0024] Increasing the amount of deuterium present in a compound (for example, the compound of formula (I)) is called "deuterium enrichment," and such compounds are called "deuterium-enriched" compounds. Unless otherwise specified, the percentage of enrichment refers to the percentage of deuterium present in the compound.

[0025] In other embodiments, the compounds of the present invention have isotopic enrichment factors of at least 3500 (52.5% deuterium), at least 4000 (60% deuterium), at least 4500 (67.5% deuterium), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium), at least 6000 (90% deuterium), at least 6466.7 (97% deuterium), and at least 6633.3 (99.5% deuterium) for each deuterium present at a site designated as a deuterated site. It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a deuterated site is independent of other deuterated sites. For example, if there are two deuterated sites on a compound, one site may be deuterated at 52.5% and the other at 75%. The resulting compound is thought to have an isotope enrichment factor of at least 3500 (52.5%).

[0026] Since the natural abundance of deuterium is approximately 0.015%, it is expected that about one in 6,667 naturally occurring compounds described herein, for example, compounds of formula (I), will contain one naturally occurring compound described herein, for example, a compound of formula (I) containing one deuterium.

[0027] In some embodiments, the compounds described herein, for example, the compound of formula (I), contain a deuterium concentration greater than that present in the naturally occurring compounds described herein, for example, the compound of formula (I).

[0028] All percentages given for the amount of deuterium present are expressed in mole percent.

[0029] In the laboratory, it may be difficult to achieve 100% deuteration at any one site of a compound in laboratory-scale amounts (e.g., milligrams or more). If 100% deuteration is listed or deuterium atoms are specifically shown within the structure, it is assumed that a small percentage of hydrogen may still be present. Deuterium enrichment can be achieved by exchanging protons with deuterium or by synthesizing the molecule using a concentrated starting material.

[0030] Also described herein is the isolation or purification of the deuterium-enriched compounds described herein, e.g., compounds of formula (I). The isolated or purified deuterium-enriched compounds described herein, e.g., compounds of formula (I), are above naturally occurring levels.

[0031] The compounds described herein may contain one or more chiral centers and therefore may exist in various isomers, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers, including a racemic mixture and a mixture rich in one or more stereoisomers. The isomers can be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). In addition, the invention encompasses the compounds described herein as individual isomers substantially free from other isomers, or as mixtures of various isomers.

[0032] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and thus is in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.2%, greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 99.9% enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0033] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound can contain, for example, about 90% excipient and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition can contain, for example, at least about 95% R compound and at most about 5% S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound can contain, for example, about 90% excipient and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition can contain, for example, at least about 95% S compound and at most about 5% R compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated without substantially any excipient or carrier.

[0034] The compounds described herein can also include one or more isotope substitutions. For example, H can be 1 H, 2 H (D or deuterium), and 3C may be any isotope containing H (T or tritium), 12 C, 13 C, and 14 O may be any isotope containing C, 16 O and 18 This could include any isotope containing oxygen, for example.

[0035] Other definitions The articles "a" and "an" may be used herein to refer to one or more (i.e., at least one) of the grammatical objects of the articles. For example, "an analogue" means one analogue or two or more analogues.

[0036] The term "pharmaceutically acceptable salt" refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that offers a reasonable benefit-risk ratio. pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Examples of pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. Examples include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0037] As used herein, the “subjects” to which administration is intended includes, but is not limited to, human beings (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals including primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0038] Diseases, disorders, and conditions are used interchangeably in this specification.

[0039] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to an action (including “therapeutic action”) that reduces the severity of a disease, disorder, or condition, or interferes with or slows the progression of a disease, disorder, or condition, while the subject is suffering from the specified disease, disorder, or condition.

[0040] Generally, the “effective amount” of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the method of administration, and factors such as the age, weight, health, and condition of the subject.

[0041] As used herein, and unless otherwise specified, the “therapeutic dose” of a compound is an amount sufficient to provide therapeutic benefit to the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. The therapeutic dose of a compound means the amount of the therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit to the treatment of a disease, disorder, or condition. The term “therapeutic dose” may include an amount that improves the overall therapy, reduces or avoids the symptoms or causes of the disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0042] In alternative embodiments, the present invention intends to administer a compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, as a prophylactic agent before a subject begins to develop a specified disease, disorder, or condition. As used herein, “prophylactic treatment” intends to be an effect that occurs before a subject begins to develop a specified disease, disorder, or condition. As used herein, and unless otherwise specified, “prophylactic effective dose” of a compound is an amount sufficient to prevent or prevent the recurrence of one or more symptoms of a disease, disorder, or condition, or a disease, disorder, or condition. The prophylactic effective dose of a compound means an amount of therapeutic agent, either alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term “prophylactic effective dose” may include an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

[0043] As used herein, the term “refractory” means a disease, disorder, or condition that does not readily succumb to or respond to therapy or treatment, or is not controlled by therapy or treatment. In some embodiments, the diseases, disorders, or conditions described herein are refractory (e.g., refractory epilepsy or refractory absence seizures) and do not respond to standard therapy or treatment.

[0044] compound In one embodiment, the compound of formula (I) is used herein. [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b , R6, R7, and R a At least one of them is deuterium, however the compound is [ka] Or it is not a pharmaceutically acceptable salt.

[0045] In some embodiments, R 1a , R 1b , R 2a , and R 2b At least one of them is deuterium. In other embodiments, R 1a , R 1b , R 2a , and R 2b It is hydrogen.

[0046] In some embodiments, R 1a and R 1b In other embodiments, R 1a and R 1b It is hydrogen.

[0047] In some embodiments, R 2a and R 2b In other embodiments, R 2a and R 2b It is hydrogen.

[0048] In some embodiments, at least one of R a is deuterium.

[0049] In some embodiments, R3 is -CH3. In other embodiments, R3 is -CD3.

[0050] In some embodiments, R4 is -CH3. In other embodiments, R4 is -CD3.

[0051] In some embodiments, R5 is -CH3. In other embodiments, R5 is -CD3.

[0052] In some embodiments, R3 and R4 are -CD3. In some embodiments, R3 and R5 are -CD3. In some embodiments, R4 and R5 are -CD3. In some embodiments, R3, R4, and R5 are -CD3.

[0053] In some embodiments, R6 is deuterium.

[0054] In some embodiments, n is 0. In some embodiments, n is an integer selected from 1 to 9. In some embodiments, n is 2. In some embodiments, n is 4. In some embodiments, n is 6. In some embodiments, n is 8. In some embodiments, n is 9.

[0055] In some embodiments, n is an integer selected from 1 to 9 and R6 is deuterium.

[0056] In some embodiments, n is 1 and R6 is deuterium. In some embodiments, n is 2 and R6 is deuterium. In some embodiments, n is 4 and R6 is deuterium. In some embodiments, n is 6 and R6 is deuterium. In some embodiments, n is 8 and R6 is deuterium. In some embodiments, n is 9 and R6 is deuterium.

[0057] In some embodiments, R7 is deuterium.

[0058] In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In other embodiments, m is 0.

[0059] In some embodiments, the following compounds are provided herein: [ka] , JPEG0007841757000014.jpg2870, JPEG0007841757000015.jpg2875, JPEG0007841757000016.jpg2570, JPEG0007841757000017.jpg2567, JPEG0007841757000018.jpg2670, JPEG0007841757000019.jpg2566, JPEG0007841757000020.jpg2977, JPEG0007841757000021.jpg2572, JPEG0007841757000022.jpg2773, JPEG0007841757000023.jpg2673, JPEG0007841757000024.jpg2773, JPEG0007841757000025.jpg2468, JPEG0007841757000026.jpg2670, JPEG0007841757000027.jpg3173, JPEG0007841757000028.jpg2774, JPEG0007841757000029.jpg2673, JPEG0007841757000030.jpg2871, JPEG0007841757000031.jpg2874, JPEG0007841757000032.jpg2973, JPEG0007841757000033.jpg3074, and JPEG0007841757000034.jpg2366, or a pharmaceutically acceptable salt thereof.

[0060] Surprisingly, deuteration of one or both carbon atoms adjacent to the nitrogen atom of the piperidine core has been found to significantly improve metabolic stability compared to non-deuterated compounds. In one embodiment, the present disclosure relates to deuterated analogs of the following compounds, [ka] Or a pharmaceutically acceptable salt thereof is provided, wherein at least one of the carbon atoms adjacent to the nitrogen on the piperidine ring is substituted with one or two deuterium atoms. In one such embodiment, both carbon atoms adjacent to the nitrogen on the piperidine ring are substituted with one or two deuterium atoms. In another embodiment, both carbon atoms adjacent to the nitrogen on the piperidine ring are each substituted with two deuterium atoms.

[0061] In some embodiments, the compound of formula (I) is the compound of formula (IA), [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1b , R 2a , R 2b R3, R4, R5, R7, and m are as defined herein for formula (I), R 6a , R 6b , R 6c , and R 6d At least one of them is deuterium, R 6e , R 6f , R 6g , R 6h Each of them is independently hydrogen or deuterium.

[0062] In some variations, R 6a , R 6b , R 6c , and R 6d One, two, three, or all four of them are deuterium. In some variations, R 6a and R 6b is hydrogen, and R 6c and R 6d It is deuterium. In some variations, R 6a and R 6b is deuterium, and R 6c and R 6d is hydrogen. In other variations, R 6a and R 6c It is deuterium, and R 6b and R 6d It is hydrogen.

[0063] In some embodiments, the compounds are from the group consisting of the following: [ka] , JPEG0007841757000038.jpg2671, JPEG0007841757000039.jpg2764, JPEG0007841757000040.jpg2763, JPEG0007841757000041.jpg2663, JPEG0007841757000042.jpg2562, and JPEG0007841757000043.jpg2665, Alternatively, a selection is made from its pharmaceutically acceptable salts.

[0064] Pharmaceutical composition and route of administration In another embodiment, this specification refers to a compound of formula (I), [ka] A pharmaceutical composition is provided comprising a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein, R 1a , R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b , R6, R7, and R a At least one of them is deuterium.

[0065] In some embodiments, R 1a , R 1b , R 2a , and R 2b At least one of them is deuterium. In other embodiments, R 1a , R 1b , R 2a , and R 2b It is hydrogen.

[0066] In some embodiments, R 1a and R 1b In other embodiments, R 1a and R 1b It is hydrogen.

[0067] In some embodiments, R 2a and R 2b In other embodiments, R 2a and R 2b It is hydrogen.

[0068] In some embodiments, R a At least one of them is deuterium.

[0069] In some embodiments, R3 is -CH3. In other embodiments, R3 is -CD3.

[0070] In some embodiments, R4 is -CH3. In other embodiments, R4 is -CD3.

[0071] In some embodiments, R5 is -CH3. In other embodiments, R5 is -CD3.

[0072] In some embodiments, R3 and R4 are -CD3. In some embodiments, R3 and R5 are -CD3. In some embodiments, R4 and R5 are -CD3. In some embodiments, R3, R4, and R5 are -CD3.

[0073] In some embodiments, R6 is deuterium.

[0074] In some embodiments, n is 0. In some embodiments, n is an integer selected from 1 to 9. In some embodiments, n is 2. In some embodiments, n is 4. In some embodiments, n is 6. In some embodiments, n is 8. In some embodiments, n is 9.

[0075] In some embodiments, n is an integer selected from 1 to 9, and R6 is deuterium.

[0076] In some embodiments, n is 1 and R6 is deuterium. In some embodiments, n is 2 and R6 is deuterium. In some embodiments, n is 4 and R6 is deuterium. In some embodiments, n is 6 and R6 is deuterium. In some embodiments, n is 8 and R6 is deuterium. In some embodiments, n is 9 and R6 is deuterium.

[0077] In some embodiments, R7 is deuterium.

[0078] In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In other embodiments, m is 0.

[0079] In another embodiment, the compounds provided herein are selected from the group consisting of the following: [ka] , JPEG0007841757000046.jpg2668, JPEG0007841757000047.jpg3075, JPEG0007841757000048.jpg2671, JPEG0007841757000049.jpg2771, JPEG0007841757000050.jpg2667, JPEG0007841757000051.jpg2664, JPEG0007841757000052.jpg2773, JPEG0007841757000053.jpg2775, JPEG0007841757000054.jpg2668, JPEG0007841757000055.jpg2875, JPEG0007841757000056.jpg2571, JPEG0007841757000057.jpg2570, JPEG0007841757000058.jpg2977, JPEG0007841757000059.jpg2773, JPEG0007841757000060.jpg2669, JPEG0007841757000061.jpg2771, JPEG0007841757000062.jpg2571, JPEG0007841757000063.jpg2571, JPEG0007841757000064.jpg2669, and JPEG0007841757000065.jpg2769, A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable excipient.

[0080] In some embodiments, the pharmaceutical composition includes pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition includes an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition includes a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition includes a preventively effective amount of the active ingredient.

[0081] The present invention provides a pharmaceutical composition comprising, as an active ingredient, one of the compounds described herein (e.g., the compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a carrier comprising one or more pharmaceutically acceptable excipients, an inert solid diluent and a filler, a sterile aqueous solution and a diluent comprising various organic solvents, a permeation enhancer, a solubilizer and an adjuvant. The pharmaceutical composition may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in ways well known in the pharmaceutical art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GSBanker & CTRhodes, Eds.)).

[0082] The pharmaceutical composition may be administered in single or multiple doses by any of the acceptable methods of administration of the drug having similar utility to those described in the patents and patent applications incorporated by reference, including, for example, intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via an impregnated or coated device such as a stent or an arterial insertion cylindrical polymer.

[0083] One method of administration is parenteral, particularly by injection. Forms into which the novel compositions of the present invention may be incorporated for injection include aqueous or oily suspensions, emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in physiological saline have also been conventionally used for injection, but are less preferred in relation to the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial activity can be achieved by various antimicrobial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0084] Sterile injectable solutions are prepared by incorporating the required amount of the compound according to the present invention into a suitable solvent containing, if necessary, various other components listed above, and then sterilizing by filtration. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other required components from those listed above. In the case of sterile powders for preparing sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying techniques to obtain powders of the active ingredients and any additional desired components from the sterile solution that has been pre-sterilized and filtered.

[0085] Oral administration is another route for administering the compounds according to the present invention. Administration may be via capsules or enteric-coated tablets, etc. In the preparation of pharmaceutical compositions comprising at least one compound described herein, the active ingredient is usually diluted with an excipient and / or encapsulated in a carrier, which may be in the form of a capsule, pouch, paper, or other container. When the excipient functions as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material (as described above) acting as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, licks, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, sterile injection solutions, and sterile packaging powders containing up to 10% by weight of the active compound.

[0086] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further contain lubricants, wetting agents, emulsifiers and suspending agents such as talc, magnesium stearate, and mineral oil, as well as preservatives, sweeteners, and flavoring agents such as methyl and propyl hydroxybenzoates.

[0087] The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug polymer matrix formulations. Examples of controlled-release systems are described in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the method of the present invention is a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The configuration and use of transdermal patches for drug delivery are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous, pulsed, or on-demand delivery of pharmaceuticals.

[0088] The composition is preferably formulated in unit dosage forms. The term “unit dosage form” refers to a physically distinct unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in relation to a suitable pharmaceutically effective excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharmaceutically effective dose. Preferably, for oral administration, each dose unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of the compound described herein. However, it will be understood that the actual amount of compound administered will usually be determined by a physician in consideration of relevant circumstances, including the condition being treated, the route of administration selected, the actual compound administered and its relative activity, the individual patient’s age, weight, and response, and the severity of the patient’s symptoms.

[0089] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of the present invention. When these preliminary formulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, thereby allowing the composition to be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0090] The tablets or pills of the present invention may be coated or otherwise formulated to provide a dosage form that offers the advantage of sustained action or to protect from the acidic conditions of the stomach. For example, the tablets or pills may contain an inner dosing component and an outer dosing component, the latter in the form of a coating covering the former. The two components may be separated by an enteric coating that functions to withstand disintegration in the stomach and allow the inner component to pass through the duodenum intact or be released with delayed release. A variety of materials may be used for such enteric coatings or coatings, including many polymer acids, as well as mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0091] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. Preferably, compositions in pharmaceutically acceptable solvents may be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spray device, or the spray device may be attached to a face mask tent or an intermittent positive airway pressure (PAP) respirator. The solution, suspension, or powder composition may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0092] In some embodiments, a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0093] Treatment method Epilepsy and epileptic syndromes The compounds and compositions described herein are useful in the treatment of epilepsy and epileptic syndromes. Epilepsy is a CNS disorder in which the activity of nerve cells in the brain is disrupted, causing seizures that can manifest as abnormal movements, unusual behavior, sensations, and sometimes periods of loss of consciousness. Seizure symptoms vary greatly, from simple blank stares lasting a few seconds to recurrent spasms of the arms or legs during a seizure.

[0094] Epilepsy can include generalized seizures, partial seizures, or focal seizures. All areas of the brain are involved in generalized seizures. People experiencing generalized seizures may scream or make some noise, stiffen for a few seconds to about a minute, and then have rhythmic movements of the limbs. The eyes are generally open, and the person may appear not to be breathing and may actually turn blue. Consciousness gradually returns, and the person may be confused for several minutes to several hours. The main types of generalized seizures are: tonic-clonic seizures, tonic seizures, clonic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, atonic seizures, and absence seizures (typical, atypical, myoclonus, blepharoplasty), as well as epileptic spasms. In partial or focal seizures, only a part of the brain is involved, and therefore only a part of the body is affected. Depending on the part of the brain that has abnormal electrical activity, the symptoms may vary.

[0095] Epilepsy as described herein includes generalized seizures, partial seizures, complex partial seizures (for example, seizures involving only a portion of the brain but in which consciousness is impaired), tonic-clonic seizures, clonic seizures, tonic seizures, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0096] The compounds and compositions described herein may also be useful in the treatment of epileptic syndromes. Severe syndromes with diffuse brain dysfunction caused at least partially by certain forms of epilepsy are also called epileptic encephalopathy. These are associated with frequent seizures that are resistant to treatment, and severe cognitive impairment, such as West syndrome.

[0097] In some embodiments, the epileptic syndrome includes epileptic encephalopathy, Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency. In some embodiments, the epileptic syndrome is childhood absence epilepsy (CAE). In some embodiments, the epileptic syndrome is juvenile absence epilepsy (JAE). In some embodiments, the epileptic syndrome is Lennox-Gastaut syndrome. In some embodiments, the epileptic syndrome is SLC6A1 epileptic encephalopathy. In some embodiments, epileptic syndrome is associated with mutations in genes encoding T-type calcium channels (e.g., CACNA1G, EEF1A2, and GABRG2 for hereditary generalized epilepsy (GGE), and LGI1, TRIM3, and GABRG2 for non-acquired focal epilepsy (NAFE)). Am J Hum Genet. 2019 Aug 1;105(2):267-28. In some embodiments, epileptic syndrome is Dossé syndrome or myoclonic ataxia. In some embodiments, epileptic syndrome is epileptic encephalopathy with persistent spike-and-wave syndrome (CSWS) during sleep. In some embodiments, epileptic syndrome is Landau-Kleffner syndrome (LKS). In some embodiments, epileptic syndrome is Sievons syndrome.

[0098] Absence seizure Absence seizures are one of the most common seizure types in patients with idiopathic generalized epilepsy (IGE) (Berg et al., Epilepsia 2000). Absence seizures are relatively short, non-convulsive seizures characterized by a sudden onset of loss of consciousness and loss of responsiveness, usually lasting 10–30 seconds, with rapid return to normal consciousness without post-seizure confusion. The seizures are characterized by the sudden onset and disappearance of generalized 1–6 Hz (e.g., 3 Hz) spike discharges on accompanying EEG recordings. Absence seizures often occur multiple times a day, disrupting learning and psychosocial functioning, and pose a risk of injury due to the frequent onset of loss of consciousness. Typically, absence seizures begin in infancy and remit by late adolescence. However, in a small number of patients, they often persist into adulthood, are drug-resistant, and may be associated with other types of epileptic seizures, such as generalized tonic-clonic seizures. In these adult patients, absence seizures, in particular, are usually highly physically debilitating, and the period accompanying the seizure, during which the affected person is unconscious, poses a safety risk and results in significant psychosocial impairment, such as being unable to obtain a driver's license or to pursue occupational and recreational activities (Wirrell et al., 1997).

[0099] While absence seizures are generally perceived as relatively "easy" to treat, randomized controlled trials in children with absence epilepsy have shown that even the most effective antiepileptic drugs, ethosuximide and valproic acid, as evaluated by video EEG recordings, completely controlled only 53% and 58% of patients at 16 weeks (Glauser et al., 2010) and only 45% and 44% of patients at 12 months (Glauser et al., 2013). Lamotrigine, another AED commonly used to treat absence seizures, controlled epileptic seizures in only 29% of patients at 16 weeks and 21% at 12 months. Furthermore, both ethosuximide and valproic acid are commonly associated with intolerable side effects (occurring in 24% of patients treated with either of these drugs) (Glauser et al., 2010), and the latter is now generally considered contraindicated in girls and women of childbearing age. Other treatment options for absence seizures are limited, with only benzodiazepines having established efficacy, and these are generally poorly tolerated due to sedative and cognitive side effects. Absence seizures that persist into adulthood are particularly difficult to treat, and patients are often treated with multiple medications, resulting in serious side effects without achieving seizure control.

[0100] There is extensive evidence that low-threshold (T-type) calcium channels play a crucial role in the development and maintenance of absence seizures and are major components of oscillatory burst firing that occurs in thalamocortical neurons during absence seizures (Pinault and O'Brien, 1997). In some embodiments, the present invention features a method for treating absence seizures using compositions described herein. In some embodiments, the absence seizures are refractory absence seizures. In some embodiments, the absence seizures are refractory to antiepileptic drugs (e.g., ethosuximide, valproic acid, or lamotrigine).

[0101] In some embodiments, the subject has epilepsy. In some embodiments, the absence seizure is an atypical absence seizure. In some embodiments, the absence seizure includes adult absence seizures, juvenile absence seizures, or childhood absence seizures.

[0102] In some embodiments, the methods described herein further include identifying a subject having absence seizures.

[0103] Hereditary epilepsy In some embodiments, epilepsy or epileptic syndrome is hereditary epilepsy or hereditary epileptic syndrome. In some embodiments, epilepsy or epileptic syndrome is hereditary generalized epilepsy. In some embodiments, epilepsy or epileptic syndromes include epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, and SCN8A mutations, early-onset infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0104] In some embodiments, the method described herein involves administering the composition described herein to a patient with epilepsy or epileptic syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early-onset infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy) before administration of the composition described herein. This further includes identifying subjects with infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic partial epilepsy in children with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant partial seizures in infants with shifting focal points, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0105] In one embodiment, the present invention relates to epilepsy or epileptic syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early-onset infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, SCN3 A method for treating cryptogenic childhood partial epilepsy with A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, infantile malignant shift-focus partial seizures, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy, characterized by a method comprising administering a compound or composition described herein to a subject in need of treatment.

[0106] The compounds or compositions of the present invention also include those targeting ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C It may be used to treat epileptic encephalopathy having mutations in one or more of the following: NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0107] In some embodiments, the methods described herein involve administering ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, before administering the compounds or compositions described herein. This further includes identifying subjects having mutations in one or more of the following: MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, WWOX, CACNA1G, CACNA1H, and CACNA1I.

[0108] 、ARG1、ARHGEF9、AR X,ATP1A2,ATP1A3,ATRX,BRAT1,C12orf57,CACNA1A,CACNA2D2,CARS2,CAS K, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK1A EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABBRB2, GABBRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN1, GRIN2 A、GRIN2B、HCN1、HNRNPU、IER3IP1、IQSEC2、ITPA、JMJD1C、KANSL1、KCNA2、K CNB1、KCNC1、KCNH2、KCNJ10、KCNMA1、KCNQ2、KCNQ3、KCNT1、KCTD7、LGI1、LIA S、MBD5、MECP2、MEF2C、MFSD8、MOCS1、MOCS2、MTOR、NEDD4L、NEXMIF、NGLY1、 NHLRC1、NPRL3、NRXN1、PACS1、PCDH19、PIGA、PIGN、PIGO、PLCB1、PNKD、PNKP 、PNPO、POLG、PPT1、PRICKLE1、PRIMA1、PRRT2、PURA、QARS、RELN、ROGDI、SAT B2、SCARB2、SCN1A、SCN1B、SCN2A、SCN3A、SCN8A、SCN9A、SERPINI1、SGCE、SIK 1、SLC12A5、SLC13A5、SLC19A3、SLC25A12、SLC25A22、SLC2A1、SLC35A2、SLC 6A1、SLC6A8、SLC9A6、SMC1A、SNX27、SPATA5、SPTAN1、ST3GAL5、STRADA、STX1 B、STXBP1、SUOX、SYN1、SYNGAP1、SYNJ1、SZT2、TBC1D24、TCF4、TPK1、TSC1、T SC2、UBE3A、WDR45、WWOX、ZDHHC9、ZEB2、ABAT、ARHGEF15、ATP6AP2、CACNA1H、It may be used to treat epileptic encephalopathy with mutations in one or more of the following: CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RFBOX1, RFBOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0109] In some embodiments, the methods described herein include ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK 1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN1, GRI N2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, L IAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNK P, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SERPINI1, SGCE, SI K1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3GAL5, STRADA, STX 1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2, CACNA1H,This further includes identifying subjects having mutations in one or more of the following: CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBBOX1, RBBOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0110] The compounds or compositions of the present invention also include ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD(CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, F OLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1 , KCNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3. NR2F1, NRXN1, PACS1, PCDH19, PIGA It may be used to treat epileptic encephalopathy with mutations in one or more of the following genes: PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0111] In some embodiments, the methods described herein include ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD(CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA , FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC 1, KCNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3. This further includes identifying subjects having mutations in one or more of the following: NR2F1, NRXN1, PACS1, PCDH19, PIGA PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0112] The compounds or compositions of the present invention also include those targeting ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KC TD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT 1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC It may be used to treat epileptic encephalopathy having mutations in one or more of the following: 35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0113] In some embodiments, the methods described herein include ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KC NT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, P OLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5, SLC25A22, SLC This further includes identifying subjects having mutations in one or more of the following: 2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0114] Mood disorder Methods for treating mental disorders such as mood disorders, including clinical depression, postpartum depression or postnatal depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent short-term depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic conditions, treatment-resistant depression, treatment-intractable depression, suicidal tendencies, suicidal ideation, or suicidal behavior are also provided herein. In some embodiments, the methods described herein produce a therapeutic effect on subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with the diseases or disorders described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), motor disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0115] Clinical depression, also known as major depressive disorder, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by widespread and persistent low mood, often accompanied by low self-esteem and loss of interest or pleasure in typically enjoyable activities. Some individuals with clinical depression may also experience sleep disturbances, weight loss, and general agitation and irritability. Clinical depression can affect how an individual feels, thinks, and behaves, potentially leading to a range of emotional and physical problems. Individuals with clinical depression may struggle to perform everyday activities and may feel that life is not worth living.

[0116] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, sleep disturbances, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feeling disconnected from the infant and / or fetus, and loss of interest in previously enjoyable activities.

[0117] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression affecting women after childbirth. Symptoms may include grief, fatigue, changes in sleep and eating habits, decreased libido, crying, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0118] In some embodiments, subjects having PND also experienced depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In embodiments, subjects experiencing perinatal depression have an increased risk of experiencing PND.

[0119] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anemia) and positivity, significant weight gain or increased appetite. Individuals with AD may also have significant social impairment as a result of excessive sleep or somnolence (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived rejection in interpersonal relationships.

[0120] Melancholic depression is characterized by a loss of pleasure in most or all activities (anhedonic syndrome), unresponsiveness to pleasant stimuli, depressed mood more pronounced than sadness or loss, excessive weight loss, or excessive guilt.

[0121] Psychotic major depressive disorder (PMD), or psychotic depression, specifically refers to a major depressive episode of melancholic nature in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0122] Catatonic depression refers to major depressive disorder accompanied by impaired motor skills and other symptoms. Individuals may be mutated and stupored, unable to move, or exhibit aimless or bizarre movements.

[0123] Seasonal affective disorder (SAD) is a type of seasonal depression in which individuals experience a seasonal pattern of depressive episodes during the fall or winter.

[0124] Dysthymia refers to a condition associated with unipolar depression, characterized by the presence of both physical and cognitive problems. These conditions tend to be less severe but more prolonged (e.g., at least two years).

[0125] Double depression refers to a condition characterized by a significant depressed mood (dysthymia) lasting at least two years, interrupted by a period of major depression.

[0126] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive traits. Recurrent short-term depression (RBD) refers to a condition in which an individual experiences depressive episodes approximately once a month, each episode lasting less than two weeks, typically less than two to three days.

[0127] Minor depressive disorder, or mild depression, refers to depression characterized by the presence of at least two symptoms for two weeks.

[0128] Bipolar disorder, or manic-depressive disorder, involves extreme mood swings, including periods of heightened emotion (mania or hypomania) and low mood (depression). During manic episodes, individuals may feel or act unusually happy, energetic, or irritable. They often make decisions with little consideration for the consequences. The need for sleep is usually reduced. During depressive episodes, individuals may cry out, avoid eye contact with others, and have a negative outlook on life. The suicide risk in individuals with the disorder is high, over 6% over 20 years, while self-harm occurs in 30-40%. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

[0129] Depression caused by a chronic illness refers to depression caused by a chronic illness such as cancer, chronic pain, chemotherapy, or chronic stress.

[0130] Treatment-resistant depression refers to a condition in which an individual is being treated for depression, but their symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms in individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve their symptoms but then relapse. Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagal stimulation and / or transcranial magnetic stimulation).

[0131] Postoperative depression refers to feelings of depression that occur after a surgical procedure (for example, as a result of having to confront one's own mortality). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in typically enjoyable hobbies and activities, or persistent feelings of worthlessness or despair.

[0132] Mood disorders related to a woman's health condition or disorder refer to mood disorders (e.g., depression) related to (e.g., caused by) a woman's health condition or disorder (e.g., as described herein).

[0133] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's suicidal tendencies. Suicidal ideation concerns thoughts about suicide or an abnormal preoccupation with suicide. The range of suicidal ideation varies greatly, for example, from fleeting thoughts to extensive thoughts, detailed plans, role-playing, and unsuccessful attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social contact, being preoccupied with death, feeling trapped in a situation or becoming desperate, increased use of alcohol or drugs, doing dangerous or self-destructive things, and saying goodbye to people as if never to see them again.

[0134] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, despair, pessimism, worthlessness, lethargy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty moving, loss of interest in enjoyable activities or hobbies, loss of concentration, low self-esteem, lack of positive thinking or planning, excessive sleep, overeating, loss of appetite, insomnia, self-injury, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from person to person. The symptoms of depression, and their alleviation, may be confirmed by a physician or psychologist (e.g., by a mental health assessment).

[0135] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, dysthymic disorder, anxiety disorder, stress disorder, post-traumatic stress disorder, bipolar disorder, and obsessive-compulsive disorder. In some embodiments, the mood disorder is major depressive disorder.

[0136] In some embodiments, the method includes monitoring subjects using known depression scales, such as the Hamilton Depression-D Scale, the Clinical Global Impression-Improvement Scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by a reduction in the Hamilton Depression-D total score presented by the subject. The therapeutic effect can be evaluated over a specific treatment period. For example, the therapeutic effect can be determined by a reduction from baseline in the HAM-D total score after administration of the composition described herein (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more after administration; or 1, 2, 14, 21, or 28 days after administration; or 1, 2, 3, or 4 weeks after administration; or 1, 2, 6, or 10 months after administration; or 1, 2, or lifetime after administration).

[0137] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with the composition described herein) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is between 14 and 18. In some embodiments, the subject's baseline HAM-D total score is between 19 and 22. In some embodiments, the subject's HAM-D total score before treatment with the composition described herein is 23 or higher. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the HAM-D total score of a subject after treatment with the compositions described herein is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total score after treatment with the compositions described herein is 10, 7, 5, or less than 3. In some embodiments, the reduction in the HAM-D total score is from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a HAM-D total score of about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with the compositions described herein. In some embodiments, the reduction in the HAM-D total score from the baseline total score to the HAM-D total score after treatment with the compositions described herein is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, or 50.In some embodiments, the percentage reduction in the HAM-D total score from the baseline HAM-D total score after treatment with the composition described herein is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as the reduction in the HAM-D total score after treatment with the composition described herein compared to the baseline HAM-D total score.

[0138] In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., measured by a reduction in the Hamilton Depression Score (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., determined by a statistically significant reduction in the HAM-D total score) within the first or second day of treatment with the composition described herein. In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., determined by a statistically significant reduction in the HAM-D total score) within 14 days of the start of treatment with the composition described herein. In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (e.g., determined by a statistically significant reduction in the HAM-D total score) within 21 days of the start of treatment with the composition described herein. In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect (determined, for example, by a statistically significant reduction in the HAM-D total score) within 28 days of initiating treatment with the composition described herein. In some embodiments, the therapeutic effect is a decrease from baseline in the HAM-D total score after treatment with the composition described herein. In some embodiments, the subject's HAM-D total score before treatment with the composition described herein is at least 24. In some embodiments, the subject's HAM-D total score before treatment with the composition described herein is at least 18. In some embodiments, the subject's HAM-D total score before treatment with the composition described herein is between 14 and 18. In some embodiments, the decrease in the HAM-D total score after treatment with the composition described herein, compared to the baseline HAM-D total score, is at least 10.In some embodiments, the reduction in the total HAM-D score after treating the subject with the composition described herein, compared to the baseline total HAM-D score, is at least 15. In some embodiments, the total HAM-D score associated with treating the subject with the composition described herein is less than or equal to a number in the range of 6 to 8. In some embodiments, the total HAM-D score associated with treating the subject with the composition described herein is 7 or less.

[0139] In some embodiments, the method produces a therapeutic effect (e.g., measured by a reduction in the Clinical Global Impression Improvement Scale (CGI)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, produces a therapeutic effect within 2 days of the treatment period. In some embodiments, the therapeutic effect is a reduction from baseline in the CGI score at the end of the treatment period (e.g., 14 days after administration).

[0140] In some embodiments, the CNS disorder is a depressive disorder, such as major depressive disorder. In some embodiments, the method for treating a depressive disorder, such as major depressive disorder, produces a therapeutic effect within two days of the treatment period. In some embodiments, the therapeutic effect is a reduction from baseline in the MADRS score at the end of the treatment period (e.g., 14 days after administration).

[0141] The effectiveness of treatment for major depressive disorder can be determined by the reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score presented by the patient. For example, the MADRS score may be reduced within 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders, covering outward sadness, reported sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, numbness, pessimistic thoughts, and suicidal thoughts.

[0142] pain The compounds and compositions described herein may be useful in the treatment of pain. In some embodiments, pain includes acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine. In some embodiments, pain includes acute pain or chronic pain. In some embodiments, pain includes neuropathic pain, inflammatory pain, or nociceptive pain. In some embodiments, pain includes central pain (e.g., thalamic pain). In some embodiments, pain includes migraine.

[0143] In some embodiments, the methods described herein further include identifying subjects having pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine) before administering the dosage form or composition described herein (e.g., a dosage form or composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof).

[0144] tremor The methods described herein may be used to treat tremors, for example, the drugs or compositions disclosed herein may be used to treat cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's disease tremor, physiological tremor, or rubral tremor. Tremors include, respectively, hereditary, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor; metabolic disorders; peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Lucie-Lévy disease, diabetes mellitus, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced disorders (tricyclic nerve blockers, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproic acid, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremors can be classified into physiological tremors, amplified physiological tremors, essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and movement-specific and location-specific tremors), dystonic tremors, Parkinson's disease tremors, cerebellar tremors, Holmes tremor (i.e., red tremor), palatal tremors, neuropathic tremors, toxin or drug-induced tremors, and psychogenic tremors. Tremors may also be familial tremors.

[0145] Tremor is an involuntary rhythmic muscle contraction and relaxation that may include vibration or spasm of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0146] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after a purposeful movement. Cerebellar tremor can be caused by lesions or damage to the cerebellum resulting from, for example, a tumor, stroke or other localized disease (e.g., multiple sclerosis) or neurodegenerative disease.

[0147] Dystonic tremor is a movement disorder that occurs in individuals with dystonia, characterized by persistent, involuntary muscle contractions that cause twisting and repetitive movements and / or painful abnormal postures or positions. Dystonic tremor can affect any muscle in the body. It occurs irregularly and can often be alleviated by complete rest or certain sensory manipulation.

[0148] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, and may slowly progress, starting on one side of the body and typically affecting both sides. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk may also be involved. The frequency of tremors may decrease with age, but their severity may increase. Amplified emotions, stress, fever, physical exhaustion, or hypoglycemia can trigger and / or increase the severity of tremors. Symptoms generally progress over time, may be visible after onset, and may persist.

[0149] Orthostatic tremor is characterized by rapid (over 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. The spasms are felt in the thighs and legs, and patients may tremble uncontrollably when asked to stand in one place. Orthostatic tremor may occur in patients with essential tremor.

[0150] Parkinson's tremor is caused by damage to the brain structures that control movement. It typically manifests as "pill-making" movements of the hands, which can also affect the jaw, lips, legs, and trunk. The onset of Parkinson's tremor usually begins after age 60. The movement may begin in one leg or one side of the body and progress to the other side as well.

[0151] Red tremor is characterized by a coarse, slow tremor that can be present at rest, in any position, and during intention. The tremor is associated with conditions affecting the red nucleus in the midbrain, such as stroke.

[0152] In some embodiments, the tremor is selected from essential tremor, Parkinson's disease tremor, or cerebellar tremor.

[0153] The efficacy of the compounds or compositions described herein for the treatment of essential tremor can be measured by the methods described in the following references: Ferreira, J.J. et al., “MDS Evidence-Based Review of Treatments for Essential Tremor.” Mov. Disord. 2019 Jul;34(7):950-958; Elble, R. et al., “Task Force Report: Scales for Screening and Evaluating Tremor.” Mov. Disord. 2013 Nov;28(13):1793-800; Deuschl, G. et al., “Treatment of patients with essential tremor.” Lancet Neurol. 2011;10:148-61; Reich, S.Get et al. “Essential Tremor.” Med. Clin. N. Am. 2019;103:351-356. The disclosures of the references are incorporated herein by reference in their entirety.

[0154] In some embodiments, the method described herein results in at least a 25% reduction in the upper limb tremor score compared to baseline. For example, in certain embodiments, the method described herein results in an average reduction of approximately 40% in tremor amplitude as measured by the TETRAS upper limb score. In some embodiments, the method described herein results in at least a 25% reduction in the TETRAS performance score compared to baseline. In some embodiments, the method described herein results in an average reduction of at least 35% in symptom severity compared to baseline, as measured by the TETRAS performance score.

[0155] ataxia Ataxia, including both cerebellar and spinal ataxia (e.g., posterior spinal ataxia), is generally associated with loss or impairment of coordination. Patients exhibiting ataxia may have difficulty regulating the forces, range, direction, velocity, and rhythm involved in posture, balance, and limb movement. Trunk ataxia, for example, can lead to increased postural sway and an inability to maintain the center of gravity on the base of support. Primary or secondary symptoms of ataxia and ataxic gait, as well as limb tremors, may be accompanied by speech disorders, dysphagia, abnormal respiration and speech, and involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, which can substantially impair activities of daily living.

[0156] As described above, ataxia can result from a wide range of underlying diseases and conditions in a patient, including cerebellar and neurodegenerative disorders and diseases resulting from chronic or long-term exposure to toxins. Symptoms of ataxia can result from a wide range of diseases, disorders, and environmental factors, including infectious diseases, metabolic diseases, neurodegenerative diseases, genetic diseases, vascular diseases, neoplasms, demyelinating diseases, neuromuscular diseases, and diseases resulting from long-term or chronic exposure to toxins (including drugs and alcohol). In one embodiment, for example, ataxia is a result of a metabolic disease, neurodegenerative disease, vascular disease, neuromuscular disease, or a disease resulting from long-term or chronic exposure to toxins. Diseases, disorders, syndromes, and conditions that may result in ataxic symptoms treatable by the methods described herein include, but are not limited to, a variety of other conditions, including amyotrophic lateral sclerosis, benign paroxysmal positional vertigo, cerebellar ataxia type 1 (autosomal recessive inheritance), cerebellar ataxia (autosomal recessive inheritance), cerebellar ataxia (dominant and pure), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar hypoplasia, cerebellar hypoplasia (endosteal sclerosis), cerebellar hypoplasia (lamellar retinal degeneration), cerebellar parenchymal autosomal recessive disorder 3, cerebellar parenchymal disorder V, cerebellar aplasia (hydrocephalus), cerebral amyloid angiopathy (familial), cerebral palsy, demyelinating disorders, spinal cord retrograde state, autonomic nervous system dysfunction, balance disorders, dysethesis, endocrine disorders, and conditions resulting from chronic exposure to toxins (e.g., alcohol, drugs, antiepileptic drugs, neuroleptics). Diseases caused by, Fragile X-related / tremor ataxia syndrome, Friedreich's ataxia, frontal lobe dysfunction, genetic disorders, granulomatous vasculitis of the central nervous system, Haller-Holden-Spats disease, genetic sensorimotor neuropathy, hydrocephalus (e.g., hypotonia or normal pressure), hypotonia, congenital nystagmus, ataxia and abnormal auditory brainstem response, infant-onset spinocerebellar ataxia, Machado-Joseph disease, Meniere's disease, metabolic disorders, Lar-Fischer syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonus ataxia, neurodegenerative diseases, olivopontocerebellar atrophy, paraneoplastic disorders, atypical parkinsonism, peroneal atrophy, phenyloin toxicity, posterior column ataxia with retinitis pigmentosa, post-polio syndrome, severe brain injury (e.g., head injury, brain surgery, multiple sclerosis or cerebral palsy),(caused by chronic alcohol / drug abuse, chronic exposure to toxins, viral infections, or brain tumors), spastic hemiplegia, spastic paraplegia 23, spastic paraplegia glaucoma precocious puberty, SPG, spinocerebellar ataxia, spinocerebellar ataxia (muscular atrophy - hearing loss), spinocerebellar ataxia (dysplasia), spinocerebellar ataxia 11, spinocerebellar ataxia 17, spinocerebellar ataxia 20, spinocerebellar ataxia 25, spinocerebellar ataxia 29, spinocerebellar ataxia 42, spinocerebellar ataxia 3, spinocerebellar ataxia (autosomal recessive inheritance 1), spinocerebellar ataxia (autosomal recessive inheritance) Diseases include those caused by: 3), spinocerebellar ataxia (autosomal recessive inheritance 4), spinocerebellar ataxia (autosomal recessive inheritance 5), spinocerebellar ataxia (autosomal recessive inheritance with axonal nerve damage), spinocerebellar ataxia (Machado-Joseph disease type II), spinocerebellar ataxia (X-linked, 2), spinocerebellar ataxia (X-linked, 3), spinocerebellar ataxia (X-linked, 4), spinocerebellar degeneration (Book type), stroke (e.g., acute or hemorrhagic), vertebral artery dissection, vertebrobasilar insufficiency, and vitamin deficiencies. In one embodiment, ataxia is a result of a disease selected from spinocerebellar ataxia, Friedreich's ataxia, and fragile X-associated / tremor ataxia syndrome. In another specific embodiment, ataxia is a result of spinocerebellar ataxia or fragile X-associated / tremor ataxia syndrome.

[0157] Tinnitus A method is provided for treating tinnitus in subjects requiring treatment, using a disclosed dosage form or composition. Tinnitus is a condition in which an affected person perceives sounds in one or both ears or in the head when no external sounds are present. Often referred to as a “ringing” in the ear, tinnitus occurs intermittently or consistently, with perceived volume ranging from low to painfully high. However, the perceived volume of tinnitus can vary from patient to patient, and an objective measurement of tinnitus volume in one patient may be perceived as painful, while the same volume may be perceived as slight in another patient.

[0158] Sleep disorders Methods for treating or preventing sleep disorders (e.g., narcolepsy) using drugs or compositions disclosed herein are provided herein. For example, sleep disorders may include central hypersomnia, narcolepsy type I, narcolepsy type II, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to medical disorder, hypersomnia due to drug treatment or substance, hypersomnia associated with mental disorder, sleep deprivation syndrome, circadian rhythm sleep-wake disorder, delayed sleep-wake phase disorder, advanced sleep-wake phase disorder, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, and unspecified (NOS) circadian rhythm sleep-wake disorder.

[0159] Combination therapy The compounds or compositions described herein (for example, for use in the modification of T-type calcium ion channels) may be administered in combination with other agents or therapies. Subjects to whom the compounds disclosed herein should be administered may have diseases, disorders, or conditions, or symptoms thereof, that would benefit from treatment with other agents or therapies. These diseases or conditions may relate to epilepsy or epileptic syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or hereditary epilepsy) or tremors (e.g., essential tremor).

[0160] Antiepileptic drugs Examples of antiepileptic drugs include brivalacetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0161] Pain relievers Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opiates and morphine-like agonists, such as fentanyl and morphine; paracetamol; NSAIDs; and COX-2 inhibitors. Given the ability of the compounds of the present invention to treat pain through inhibition of T-type calcium channels (e.g., Cav3.1, Cav3.2, and Cav3.3), combinations with analgesics are particularly envisioned.

[0162] Tremor treatment drugs Examples of tremor treatments include propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, topamax, neurontin, atenolol, clonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin enacarbil, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide.

[0163] Listed embodiments The following listed embodiments represent several aspects of the present invention. 1. Compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1a , R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b, R6, R7, and R a At least one of them is deuterium, but the compound is not a compound or a pharmaceutically acceptable salt thereof. [ka] 2.R 1a , R 1b , R 2a , and R 2b The compound according to Embodiment 1, wherein at least one of the elements is deuterium. 3.R 1a , R 1b , R 2a , and R 2b However, the compound described in Embodiment 1 is hydrogen. 4.R a A compound according to any one of embodiments 1 to 3, wherein at least one of the elements is deuterium. 5. The compound according to any one of Embodiments 1 to 3, wherein R3 is -CH3. 6. The compound according to any one of Embodiments 1 to 4, wherein R3 is -CD3. 7. The compound according to any one of Embodiments 1 to 6, wherein R4 is -CH3. 8. The compound according to any one of Embodiments 1 to 6, wherein R4 is -CD3. 9. The compound according to any one of Embodiments 1 to 8, wherein R5 is -CH3. 10. The compound according to any one of Embodiments 1 to 8, wherein R5 is -CD3. 11. The compound according to any one of Embodiments 1 to 10, wherein R6 is deuterium. 12. The compound according to any one of Embodiments 1 to 11, wherein n is an integer selected from 1 to 9 and R6 is deuterium. 13. The compound according to any one of Embodiments 1 to 13, wherein n is 9 and R6 is deuterium. 14. The compound according to any one of Embodiments 1 to 12, wherein R7 is deuterium. 15. Compounds selected from the group consisting of the following: [ka] , JPEG0007841757000069.jpg2670, JPEG0007841757000070.jpg2673, JPEG0007841757000071.jpg2974, JPEG0007841757000072.jpg2773, JPEG0007841757000073.jpg2772, JPEG0007841757000074.jpg2766, JPEG0007841757000075.jpg2568, JPEG0007841757000076.jpg2470, JPEG0007841757000077.jpg2976, JPEG0007841757000078.jpg2576, JPEG0007841757000079.jpg2871, JPEG0007841757000080.jpg2973, JPEG0007841757000081.jpg2874, JPEG0007841757000082.jpg2873, JPEG0007841757000083.jpg2773, JPEG0007841757000084.jpg2771, JPEG0007841757000085.jpg2570, JPEG0007841757000086.jpg2367, and JPEG0007841757000087.jpg2568, or a pharmaceutically acceptable salt thereof. 16. Compounds of formula (I), [ka] A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein, R 1a , R 1b , R 2a , R 2b Each of R6 and R7 is independently hydrogen or deuterium. Each of R3, R4, and R5 is -C(R a )3, and each R a These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a , R 1b , R 2a , R 2b , R6, R7, and R a A pharmaceutical composition in which at least one of the elements is deuterium. 17.R 1a , R 1b , R 2a , and R 2b The pharmaceutical composition according to Embodiment 16, wherein at least one of the elements is deuterium. 18.R 1a , R 1b , R 2a , and R 2b The pharmaceutical composition according to Embodiment 16, wherein the hydrogen is hydrogen. 19.R a A pharmaceutical composition according to any one of embodiments 16 to 18, wherein at least one of the elements is deuterium. 20. A pharmaceutical composition according to any one of embodiments 16 to 18, wherein R3 is -CH3. 21. A pharmaceutical composition according to any one of embodiments 16 to 19, wherein R3 is -CD3. 22. A pharmaceutical composition according to any one of embodiments 16 to 21, wherein R4 is -CH3. 23. A pharmaceutical composition according to any one of embodiments 16 to 21, wherein R4 is -CD3. 24. A pharmaceutical composition according to any one of embodiments 16 to 23, wherein R5 is -CH3. 25. A pharmaceutical composition according to any one of embodiments 16 to 23, wherein R5 is -CD3. 26. A pharmaceutical composition according to any one of embodiments 16 to 25, wherein n is an integer selected from 1 to 9 and R6 is deuterium. 27. A pharmaceutical composition according to any one of Embodiments 16 to 26, wherein n is 9 and R6 is deuterium. 28. A pharmaceutical composition according to any one of embodiments 16 to 27, wherein R7 is deuterium. 29. Compounds selected from the group consisting of the following: [ka] , JPEG0007841757000090.jpg2669, JPEG0007841757000091.jpg2668, JPEG0007841757000092.jpg2774, JPEG0007841757000093.jpg2569, JPEG0007841757000094.jpg2879, JPEG0007841757000095.jpg2772, JPEG0007841757000096.jpg2875, JPEG0007841757000097.jpg2571, JPEG0007841757000098.jpg2772, JPEG0007841757000099.jpg2769, JPEG0007841757000100.jpg2670, JPEG0007841757000101.jpg2974, JPEG0007841757000102.jpg2771, JPEG0007841757000103.jpg2769, JPEG0007841757000104.jpg2671, JPEG0007841757000105.jpg2469, JPEG0007841757000106.jpg2978, JPEG0007841757000107.jpg2669, JPEG0007841757000108.jpg2769, JPEG0007841757000109.jpg2669, JPEG0007841757000110.jpg2973, and JPEG0007841757000111.jpg2567, A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 30. A method for treating a neurological disorder in a subject requiring treatment, the method comprising administering an effective amount of the compound described in any one of Embodiments 1 to 15 or the composition described in any one of Embodiments 16 to 29 to the subject. 31. A method for treating a mental disorder (e.g., a mood disorder (e.g., major depressive disorder)) in a subject requiring treatment, the method comprising administering an effective amount of any one compound from Embodiments 1 to 15 or any one of the compositions described in Embodiments 16 to 29 to the subject. 32. A method for treating pain in a subject requiring treatment, the method comprising administering an effective amount of the compound described in any one of Embodiments 1 to 15 or the composition described in any one of Embodiments 16 to 29 to the subject. 33. A method for treating a subject in need of treatment for a tremor (e.g., essential tremor), the method comprising administering an effective amount of any one compound from Embodiments 1 to 15 or any one composition from Embodiments 16 to 29 to the subject. 34. A method for treating a seizure (e.g., absence seizure) in a subject requiring treatment, the method comprising administering an effective amount of any one compound from Embodiments 1 to 15 or any one composition from Embodiments 16 to 29 to the subject. 35. A method for treating epilepsy or an epileptic syndrome (e.g., juvenile myoclonic epilepsy) in a subject requiring treatment, the method comprising administering an effective amount of any one compound from Embodiments 1 to 15 or any one composition from Embodiments 16 to 29 to the subject. 36. The compound according to any one of Embodiments 1 to 15, wherein the compound has an isotopic enrichment factor of at least 4500 (67.5% deuterium contamination) for each deuterium present at a site designated as a site on the compound where deuteration is possible. 37. The compound according to any one of Embodiments 1 to 15, wherein the compound has an isotopic enrichment factor of at least 5000 (75% deuterium contamination) for each deuterium present at a site designated as a site on the compound where deuteration is possible. 38. A pharmaceutical composition according to any one of Embodiments 16 to 29, wherein the compound has an isotopic enrichment factor of at least 4500 (67.5% deuterium contamination) for each deuterium present at a site designated as a site on the compound where deuteration is possible. 39. A pharmaceutical composition according to any one of Embodiments 16 to 29, wherein the compound has an isotopic enrichment factor of at least 5000 (75% deuterium contamination) for each deuterium present at a site designated as a site on the compound where deuteration is possible. [Examples]

[0164] To allow for a better understanding of the inventions described herein, the following examples are provided. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed as limiting their scope in any way.

[0165] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by those skilled in the art through routine optimization.

[0166] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as their introduction and removal, are described in TW Greene and PGMWuts, *Protecting Groups in Organic Synthesis*, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0167] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, polishing, high-pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). It should be noted that flash chromatography can be performed manually or via an automated system. The compounds provided herein can be characterized by known standard procedures such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography-mass spectrometry (LCMS). NMR chemical shifts are reported in parts per million (ppm) and are generated using methods well known to those skilled in the art. [Table 1]

[0168] Example 1. Synthesis of Compound 1 [ka] 3-Chloro-5-fluorobenzoyl chloride (D2): To a solution of 3-chloro-5-fluorobenzoic acid (3 g, 17.2 mmol) and 0.5 mL of DMF in DCM (30 mL), (COCl)2 (2.21 mL, 25.8 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure and used directly.

[0169] tert-butyl 2,2,3,3,4,5,5,6,6-nonaduterio-4-hydroxypiperidine-1-carboxylate (D8-1): To a solution of 2,2,3,3,4,5,5,6,6-nonaduteriopiperidine-4-ol (4.5 g, 40.8 mmol) in THF (45 mL) and water (45 mL), Boc2O (8.91 g, 40.8 mmol) in THF (45 mL) was added dropwise at 0°C. The mixture was heated to 25°C and stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure to obtain the product (8.5 g, 99% yield) as an oil, which was used directly in the next step. 1 1H NMR (400MHz, CDCl3)δ H =1.45(s,9H). LCMS R t = 3 minutes chromatography, 1.762 minutes, 10⁻⁸ CD, MS ESI C6H3D9NO2[M-tBu+H] + The calculated value for this is 155.1, and the measured value is 155.1.

[0170] tert-butyl 2,2,3,3,4,5,5,6,6-nonaduterio-4-methylsulfonyloxypiperidine-1-carboxylate (D8-2): To a solution of tert-butyl 2,2,3,3,4,5,5,6,6-nonaduterio-4-hydroxy-piperidine-1-carboxylate (8.5 g, 40.4 mmol) and TEA (9.51 mL, 68.7 mmol) in dichloromethane (100 mL) at 0°C, MsCl (4.07 mL, 52.5 mmol) was slowly added under N2. The resulting mixture was stirred at 0°C for 2 hours. The mixture was then concentrated, the residue was diluted with DCM (200 mL), and washed with saturated sodium chloride solution (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (12.4 g) as an oil, which was used directly in the next step. 1 1H NMR (400MHz, CDCl3)δ H = 3.03 (s, 3H), 1.45 (s, 9H).

[0171] tert-butyl 4-cyano-2,2,3,3,4,5,5,6,6-nonaduterio-piperidine-1-carboxylate (D8-3): To a solution of tert-butyl 2,2,3,3,4,5,5,6,6-nonaduterio-4-methylsulfonyloxypiperidine-1-carboxylate (12.4 g, 43.0 mmol) in dimethyl sulfoxide (130 mL), sodium cyanide (3.582 g, 73.1 mmol) was added at 25°C under N2. The mixture was heated to 80°C and stirred for 16 minutes. The mixture was quenched with water (300 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic phase was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The combined aqueous layer was treated with NaOH to pH approximately 11, treated with saturated NaClO solution (500 mL), and left overnight. The residue was purified by flash column chromatography (10%-20% Â in PE) to obtain the product (300 mg, 40% yield) as an oil. 1 1H NMR (400MHz, CDCl3)δ H = 1.46 (s, 9H).

[0172] tert-butyl 4-(aminomethyl)-2,2,3,3,4,5,5,6,6-nonaduterio-piperidine-1-carboxylate (D8-4): To a solution of tert-butyl 4-cyano-2,2,3,3,4,5,5,6,6-nonaduterio-piperidine-1-carboxylate (3.5 g, 16.0 mmol) in THF (50 mL), LiAlH4 (1.21 g, 31.9 mmol) was slowly added at 0°C. The suspension was stirred at 0°C for 1 hour. To the mixture, water (1.2 mL), 15% NaOH aqueous solution (1.2 mL), and then water again (3.6 mL) were added very slowly. The precipitate was filtered and washed with ELISA (50 mL). The combined organic phase was concentrated under reduced pressure to obtain the product (2 g, yield 56%) as an oil. LCMS R t = 3 minutes chromatography, 2.036 minutes, 10⁻⁸ CD, MS ESI C7H6D9N2O2[M-tBu+H] + The calculated value for this is 168.1, and the measured value is 168.1.

[0173] tert-butyl 4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,3,3,4,5,5,6,6-nonaduterio-piperidine-1-carboxylate(D8-5): To a solution of tert-butyl 4-(aminomethyl)-2,2,3,3,4,5,5,6,6-nonaduteriopiperidine-1-carboxylate (2 g, 8.95 mmol) in DCM (20 mL), Et3N (3.72 mL, 26.9 mmol) and 3-chloro-5-fluorobenzoyl chloride (3.32 g, 17.2 mmol) in DCM (20 mL) were added at 25°C. The mixture was stirred at 25°C for 1 hour. The mixture was quenched with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (10%-30% ethyl acetate in PE) to obtain the product (1.8 g, yield 53%) as an oil. 1 1H NMR (400MHz, CDCl3)δ H=7.53-7.48(s,1H), 7.41-7.35(m,1H), 7.26-7.20(m,1H), 6.14(br s,1H), 3.34(br s,2H), 1.45(s,9H). LCMS R t = 0.924 min by chromatography at 1.5 min, 5-95AB, MS ESI C 13 H8D9ClFN2O[M-Boc+H] + The calculated value for this is 280.1, and the measured value is 280.1.

[0174] 3-Chloro-5-fluoro-N-[(2,2,3,3,4,5,5,6,6-nonaduterio-4-piperidyl)methyl]benzamide hydrochloride (D9): To a solution of tert-butyl 4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,3,3,4,5,5,6,6-nonaduterio-piperidine-1-carboxylate (1 g, 2.63 mmol) in 1,4-dioxane (5 mL), 4 M HCl / dioxane (5 mL, 99.3 mmol) was added at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was filtered, the residue was washed with dioxane (5 mL), and the mother liquor was concentrated under reduced pressure to obtain the product (520.8 mg, yield 72%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.91-8.73(m,2H), 8.60-8.42(m,1H), 7.81-7.76(s,1H), 7.72-7.61(m,2H), 3.18(d,2H). LCMS R t = 3 minutes chromatography for 1.635 minutes, 10⁻⁸ AB, MS ESI C 13 H8D9ClFN2O[M+H] + The calculated value for this is 280.1, and the measured value is 280.1.

[0175] Methyl 2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]-2,2,3,3,4,5,5,6,6-nonaduterio-1-piperidyl]acetate (D10): To a solution of 3-chloro-5-fluoro-N-[(2,2,3,3,4,5,5,6,6-nonaduterio-4-piperidyl)methyl]benzamide hydrochloride (90 mg, 0.28 mmol) in DMF (1.0 mL), Et3N (143 mg, 1.4 mmol) and methyl bromoacetate (87 mg, 0.57 mmol) were added at 25°C. After stirring at 25°C for 2 hours, the mixture was quenched with water (30 mL) and extracted with ₹ (2 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (115 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =7.51(s,1H), 7.42-7.35(m,1H), 7.24-7.18(m,1H), 6.20(s,1H), 3.72(s,3H), 3.35(d,2H), 3.31-3.20(m,2H). LCMS R t = 0.760 min chromatography for 1.5 min, 5-95AB, MS ESI C 16 H 12 D9ClFN2O3[M+H] + The calculated value for this is 352.1, and the measured value is 352.1.

[0176] [2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]-2,2,3,3,4,5,5,6,6-nonaduterio-1-piperidyl]acetyl]oxylithium (D11): To a solution of methyl 2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,3,3,4,5,5,6,6-nonaduterio-1-piperidyl]acetate (115 mg, 0.33 mmol) in methanol (1.0 mL) / THF (1.0 mL) / water (0.50 mL), LiOH.H2O (41 mg, 0.98 mmol) was added at 25°C. After stirring at 25°C for 3 hours, the mixture was concentrated under reduced pressure to obtain the product (120 mg) as a solid, which was used directly in the next step. 1 1H NMR (400MHz, DMSO-d6)δ H=7.77(s,1H), 7.69-7.53(m,2H), 3.16(s,1H), 3.11(s,2H), 2.60(s,2H).

[0177] N-[[1-[2-(tert-butylamino)-2-oxo-ethyl]-2,2,3,3,4,5,5,6,6-nonaduterio-4-piperidyl]methyl]-3-chloro-5-fluorobenzamide (compound 1): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,3,3,4,5,5,6,6-nonaduterio-1-piperidyl]acetyl]oxylithium (110 mg, 0.32 mmol) in DCM (2.0 mL), DIEA (330 mg, 2.6 mmol) and T3P (730 mg, 0.96 mmol) were added. After stirring at 25°C for 20 minutes, tert-butylamine (0.10 mL, 0.96 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40mm×3μm, conditions: water (0.05% NH3H2O)-ACN, start B: 34, end B: 64, gradient time (min): 8, 100% B retention time (min): 2, flow rate (mL / min): 30, injection: 6) to obtain the product (81.38 mg, yield 65%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.66-8.63(m,1H), 7.76(s,1H), 7.63(d,2H), 7.12(s,1H), 3.14(d,2H), 2.77(s,2H), 1.26(s,9H). 19 F NMR (376.5 MHz, DMSO-d6) δ F = -110.149. LCMS R t = 2.014 min chromatography in 3 mins, 10⁻⁸ AB, MS ESI C 19 H 19 D9ClFN3O2[M+H] +The calculated value for this is 393.2, and the measured value is 393.2.

[0178] Example 2. Synthesis of Compound 2 [ka] Methyl 1-nitrosopiperidine-4-ol (D13): To a solution of piperidine-4-ol (10 g, 0.10 mol) in water (20 mL), NaNO2 (14 g, 0.20 mol) in water (40 mL) was added. After cooling to 0°C, HOAc (8.6 mL, 0.15 mol) was added dropwise to the mixture at 0°C for 30 minutes. After stirring the mixture at 0°C for 30 minutes, Na2CO3 (16 g, 0.15 mol) was gradually added. The mixture was stirred at 20°C for 5 hours. The mixture was extracted with DCM (2 × 100 mL). The combined organic phases were washed with saturated brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the product (8.0 g, 62 mmol, yield 62%) as an oil. 1 1H NMR (DMSO-d6, 400MHz) δ H =4.92(d,1H), 4.38-4.28(m,1H), 4.07-3.93(m,2H), 3.92-3.83(m,1H), 3. 52-3.41(m,1H), 1.95-1.84(m,1H), 1.70-1.51(m,2H), 1.35-1.24(m,1H).

[0179] Methyl 2,2,6,6-tetraduterio-1-nitrosopiperidine-4-ol (D14): MeONa (8.3 g, 0.15 mol) was added to a mixture of 1-nitrosopiperidine-4-ol (4.0 g, 31 mmol) in D2O (40 mL, 0.20 mol). After stirring at 100°C for 24 hours, the mixture was concentrated to remove some of the solvent. Then, D2O (40 mL, 0.20 mol) was added to the mixture and stirred at 100°C for 16 hours. The solution was cooled and used directly in the next step.

[0180] 2,2,6,6-Tetraduteriopiperidine-4-ol (D15): A mixture of 2,2,6,6-tetraduterio-1-nitroso-piperidine-4-ol (4 g, 30 mmol) in D2O (40 mL, 0.20 mol) was mixed with nickel-aluminum alloy (3.7 g). After stirring at 80°C for 1 hour, the solution was filtered, and the filtrate was used directly in the next step.

[0181] Methyl 2,2,6,6-tetraduterio-4-hydroxypiperidine-1-carboxylate (D16): To a solution of 2,2,6,6-tetraduteriopiperidine-4-ol in D2O (0.10 L, 5.0 mol), (Boc)2O (5.5 g, 25 mmol) was added. After stirring at 20°C for 16 hours, the mixture was extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / siRNA = 3 / 1 to 1 / 1) to obtain the product (0.68 g, 3.3 mmol, yield 12%) as an oil. 1 1H NMR (CDCl3, 400MHz) δ H =3.90-3.80(m,1H), 1.88-1.79(m,2H), 1.56(s,1H), 1.46(s,9H), 1.45-1.42(m,2H).

[0182] tert-butyl 2,2,6,6-tetraduterio-4-methylsulfonyloxypiperidine-1-carboxylate (D17): To a solution of tert-butyl 2,2,6,6-tetraduterio-4-hydroxy-piperidine-1-carboxylate (0.68 g, 3.3 mmol) and Et3N (0.92 mL, 6.6 mmol) in DCM (10 mL), MsCl (0.38 mL, 5.0 mmol) was slowly added under N2 at 0°C. After stirring at 0°C for 16 hours, the mixture was concentrated under reduced pressure, the residue was diluted with dichloromethane (50 mL), and washed with saturated sodium chloride solution (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (0.94 g, 3.3 mmol, 100% yield) as an oil, which was used directly in the next step.

[0183] Methyl tert-butyl 4-cyano-2,2,6,6-tetraduterio-piperidine-1-carboxylate (D18): To a solution of tert-butyl 2,2,6,6-tetraduterio-4-methylsulfonyloxypiperidine-1-carboxylate (0.94 g, 3.3 mmol) in DMSO (15 mL), NaCN (0.49 g, 10 mmol) was added under N2 at 25 °C. The mixture was heated to 80 °C and stirred for 16 hours. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate in PE, 10%-20%) to obtain the product (0.25 g, 1.1 mmol, yield 35%) as an oil. 1 1H NMR (CDCl3, 400MHz) δ H =2.84-2.75(m,1H), 1.91-1.72(m,4H), 1.46(s,9H).

[0184] Methyl tert-butyl 4-(aminomethyl)-2,2,6,6-tetraduterio-piperidine-1-carboxylate (D19): To a solution of tert-butyl 4-cyano-2,2,6,6-tetraduterio-piperidine-1-carboxylate (0.24 g, 1.1 mmol) in THF (10 mL), LiAlH4 (85 mg, 2.2 mmol) was slowly added at 0°C. The suspension was stirred at 0°C for 1 hour. To the mixture, water (0.10 mL), 15% NaOH aqueous solution (0.10 mL), and water again (0.30 mL) were added very slowly. The precipitate was filtered and washed with toluene (50 mL). The combined organic phase was concentrated under reduced pressure to obtain the product (100 mg, 0.46 mmol, yield 41%) as an oil. 1 1H NMR (DMSO-d6, 400MHz) δ H =2.41-2.35(m,2H), 2.27(s,1H), 1.71-1.49(m,4H), 1.38(s,9H), 0.95-0.78(m,2H).

[0185] tert-butyl 4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,6,6-tetraduterio-piperidine-1-carboxylate (D20): To a solution of 3-chloro-5-fluorobenzoic acid (80 mg, 0.46 mmol) in DMF (2.0 mL), HATU (0.35 g, 0.92 mmol), Et3N (0.32 mL, 2.3 mmol), and tert-butyl 4-(aminomethyl)-2,2,6,6-tetraduteriopiperidine-1-carboxylate (0.1 g, 0.46 mmol) were added at 25°C, and the mixture was stirred at 25°C for 12 hours. The mixture was poured into water (15 mL) and extracted with ELISA (15 mL x 2). The combined organic phase was washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by a flash column eluting with acetate (0%~30%) in PE to obtain the product (104 mg, 0.28 mmol, yield 61%, 4D deuterated purity: 95%) as an oily substance. 1 1H NMR (CDCl3, 400MHz) δ H =7.55-7.48(m,1H), 7.40-7.35(m,1H), 7.25-7.21(m,1H), 6.21-6.06(m,1H), 3. 38-3.31(m,2H), 1.84-1.75(m,1H), 1.74-1.67(m,2H), 1.45(s,9H), 1.18(t,2H). HRMS MS-TOF C 14 H 13 D4ClFN2O3[M+H-56] + The calculated value for this is 319.1157, and the measured value is 319.1100. Deuterated purity: 1% 3D, 1% 2D, 3% 3D, and 95% 4D.

[0186] 3-Chloro-5-fluoro-N-[(2,2,6,6-tetraduterio-4-piperidyl)methyl]benzamide hydrochloride (D21): To a solution of tert-butyl 4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,6,6-tetraduterio-piperidine-1-carboxylate (104 mg, 0.28 mmol) in 1,4-dioxane (2.0 mL), 4 M HCl / dioxane (0.53 mL, 11 mmol) was added at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the product (100 mg, 0.32 mmol) as a solid. 1 1H NMR (DMSO-d6, 400MHz) δ H =8.85-8.74(m,1H), 7.82-7.74(m,1H), 7.70-7.59(m,2H), 3.57(s,2H), 3.18(t,2H), 1.82-1.70(m,2H), 1.42-1.25(m,2H).

[0187] Methyl 2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]-2,2,6,6-tetraduterio-1-piperidyl]acetate (D22): To a solution of 3-chloro-5-fluoro-N-[(2,2,6,6-tetraduterio-4-piperidyl)methyl]benzamide hydrochloride (90 mg, 0.28 mmol) in DMF (2.0 mL), Et3N (139 mg, 1.4 mmol) and methyl bromoacetate (84 mg, 0.55 mmol) were added at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was quenched with water (30 mL) and extracted with  (2 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (100 mg) as an oil, which was used directly in the next step. 1 1H NMR (DMSO-d6, 400MHz) δ H =8.66(t,1H), 7.77(s,1H), 7.64(dd,2H), 3.60(s,3H), 3.27-3.06(m,4H), 1.65-1.57(m,2H), 1.55-1.47(m,1H), 1.20-1.09(m,2H). 19 F NMR (376.5 MHz, DMSO-d6) δ F -110.137.

[0188] [2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]-2,2,6,6-tetraduterio-1-piperidyl]acetyl]oxylithium (D23): To a solution of methyl 2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,6,6-tetraduterio-1-piperidyl]acetate (100 mg, 0.29 mmol) in MeOH (1.0 mL) / THF (1.0 mL) / H2O (0.50 mL), LiOH.H2O (36 mg, 0.87 mmol) was added at 25°C. The mixture was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure to obtain the product (100 mg) as a solid, which was used directly in the next step. 1 1H NMR (DMSO-d6, 400MHz) δ H =7.78(s,1H), 7.65(d,1H), 7.57(d,1H), 3.17(s,1H), 3.14-3.08(m,2H), 2.61(s,2H), 1.60-1.33(m,3H), 1.26-1.19(m,2H). 19 F NMR (376.5 MHz, DMSO-d6) δ F = -110.579.

[0189] N-[[1-[2-(tert-butylamino)-2-oxo-ethyl]-2,2,6,6-tetraduterio-4-piperidyl]methyl]-3-chloro-5-fluorobenzamide (compound 2): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,6,6-tetraduterio-1-piperidyl]acetyl]oxylithium (100 mg, 0.30 mmol) in DCM (2.0 mL), DIEA (305 mg, 2.4 mmol) and T3P (674 mg, 0.89 mmol, 50% siRNA solution) were added at 25°C. After stirring for 10 minutes, tert-butylamine (0.09 mL, 0.89 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40mm×3μm, conditions: water (0.05% NH3H2O)-ACN, start B: 34, end B: 64, gradient time (min): 8, 100% B retention time (min): 2, flow rate (mL / min): 30, injection: 5) to obtain the product (21.3 mg, 0.055 mmol, yield 19%, 4D deuterated purity: 93.40%) as a solid. 1 1H NMR (CDCl3, 400MHz) δ H =7.52(s,1H), 7.39(d,1H), 7.23(d,1H), 7.04(s,1H), 6.22(s,1H), 3.36(t, 2H), 2.86(s,2H), 1.78-1.70(m,2H), 1.63-1.58(m,1H), 1.44-1.20(m,11H). 19 F NMR (CDCl3, 376.5 MHz) δ F = -109.225. LCMS R t = 3 minutes chromatography for 1.302 minutes, 10⁻⁸ AB, MS ESI C 19 H 24 D4ClF4N3O2[M+H] + Calculated value: 388.2, measured value: 388.2. HRMS MS-TOF C 19 H 24 D4ClF4N3O2[M+H] +The calculated value for this is 388.2057, and the measured value is 388.2057. Deuterated purity: 0.96% for 0D, 0.96% for 1D, 1.27% for 2D, 3.41% for 3D, and 93.40% for 4D.

[0190] Example 3. Synthesis of Compound 3 [ka] tert-butyl 3,3,5,5-tetraduterio-4-oxopiperidine-1-carboxylate (D25): To a solution of 1-Boc-4-piperidine (10 g, 50 mmol) in CDCl3 (100 mL), 1,5,7-triazabicyclo[4.4.0]deca-5-ene (0.50 g, 3.6 mmol) was added under N2 at 25°C, and the mixture was stirred at 25°C for 16 hours. After cooling the mixture to 25°C, it was diluted with 1 M HCl (100 mL) and extracted with ELISA (2 × 100 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (10 g, 49 mmol) as an oil. LCMS R t = Chromatography for 2 minutes, 0.865~0.874 minutes, 10⁻⁸ AB, MS ESI C6H6D4NO3[M-tBu+H] + The calculated value for this is 148.1, and the measured value is 148.1.

[0191] tert-butyl 3,3,5,5-tetraduterio-4-hydroxypiperidine-1-carboxylate (D26): To a solution of tert-butyl 3,3,5,5-tetraduterio-4-oxopiperidine-1-carboxylate (5 g, 24.6 mmol) in MeOD (30 mL, 24.6 mmol), NaBH4 (1.03 g, 27.1 mmol) was added under N2 at 25°C, and the mixture was stirred at 25°C for 16 hours. After cooling to room temperature, the mixture was diluted with saturated NH4Cl (20 mL) and extracted with SiO4 (2 × 15 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (4.5 g, 20.1 mmol) as an oil. LCMS R t = 0.834 min chromatography for 2 min, 10⁻⁸⁰AB₄E, MS ESI C7H 11 D4N2O2[M-tBu+H] + The calculated value for this is 150.1, and the measured value is 150.1.

[0192] tert-butyl 3,3,5,5-tetraduterio-4-methylsulfonyloxypiperidine-1-carboxylate (D27): To a solution of tert-butyl 3,3,5,5-tetraduterio-4-hydroxy-piperidine-1-carboxylate (9.0 g, 44 mmol) and Et3N (12 mL, 88 mmol) in DCM (100 mL) at 0°C, MsCl (5.1 mL, 66 mmol) was slowly added under N2. After stirring at 20°C for 16 hours, the mixture was concentrated, the residue was diluted with dichloromethane (100 mL), and washed with saturated sodium chloride solution (100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (8.0 g, 28 mmol) as an oil, which was used directly in the next step. 1 1H NMR (400MHz, CDCl3)δ H =4.86(s,1H), 3.69(d,2H), 3.28(d,2H), 3.04(s,3H), 1.46(s,9H).

[0193] tert-butyl 4-cyano-3,3,5,5-tetraduterio-piperidine-1-carboxylate (D28): To a solution of tert-butyl 3,3,5,5-tetraduterio-4-methylsulfonyloxypiperidine-1-carboxylate (8.0 g, 28 mmol) in DMSO (60 mL), NaCN (2.1 g, 42 mmol) was added at 25 °C under N2. The mixture was heated to 80 °C and stirred under N2 for 16 hours. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate in PE, 10%~20%) to obtain the product (1.7 g, 7.9 mmol) as an oil. 1 1H NMR (400MHz, CDCl3)δ H =3.67-3.60(m,2H), 3.37-3.29(m,2H), 2.77(s,1H), 1.46(s,9H).

[0194] tert-butyl 4-(aminomethyl)-3,3,5,5-tetraduterio-piperidine-1-carboxylate (D29): To a solution of tert-butyl 4-cyano-3,3,5,5-tetraduterio-piperidine-1-carboxylate (700 mg, 3.3 mmol) in THF (10 mL), LiAlH4 (248 mg, 6.5 mmol) was slowly added at 0°C. After stirring at 0°C for 1 hour, water (0.25 mL), 15% NaOH aqueous solution (0.25 mL), and then water again (0.75 mL) were very slowly added to the mixture. The precipitate was filtered and washed with toluene (30 mL). The combined organic phase was concentrated under reduced pressure to obtain the product (500 mg, 2.3 mmol) as an oily substance. LCMS R t = 3.773 mins in 7 min chromatography, 0-60 CD_E, MS ESI C7H 11 D4N2O2[M-tBu+H] + The calculated value for this is 163.2, and the measured value is 163.2.

[0195] tert-butyl 4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-3,3,5,5-tetraduterio-piperidine-1-carboxylate (D30): To a solution of Et3N (2.5 mL, 18 mmol) in DMF (10 mL), tert-butyl 4-(aminomethyl)-3,3,5,5-tetraduterio-piperidine-1-carboxylate (800 mg, 3.7 mmol), 3-chloro-5-fluorobenzoic acid (707 mg, 3.7 mmol), and HATU (2.8 g, 7.3 mmol) were added at 25°C, and the mixture was stirred at 25°C for 12 hours. The mixture was poured into water (15 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate in PE = 0%~10%~25%) to obtain the product (400 mg, 1.1 mmol) as an oil. 1 1H NMR (400MHz, CDCl3)δ H =7.51(s,1H), 7.41-7.35(m,1H), 7.25-7.20(m,1H), 6.24-6.15(m,1H), 4.15-4. 09(m,2H), 3.40-3.30(m,2H), 2.74-2.66(m,2H), 1.80-1.72(m,1H), 1.45(s,9H). HRMS MS-TOF C 14 H 13 The calculated value for D4ClFN2O3[M-tBu+H]+ was 319.1157, and the measured value was 319.1124. Deuterated purity: 0D at 1.51%, 1D at 2.17%, 2D at 2.60%, 3D at 7.51%, and 4D at 86.21%.

[0196] 3-Chloro-5-fluoro-N-[(3,3,5,5-tetraduterio-4-piperidyl)methyl]benzamide (D31): To a solution of tert-butyl 4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]-3,3,5,5-tetraduterio-piperidine-1-carboxylate (400 mg, 1.1 mmol) in 1,4-dioxane (5.0 mL), 4M HCl / dioxane (2.2 mL, 43 mmol) was added at 25°C. The mixture was stirred at 25°C for 16 hours, and then concentrated under reduced pressure to obtain the product (300 mg, 1.1 mmol) as a solid. LCMS R t = 0.731 min by chromatography at 1.5 min, 5-95AB, MS ESI C 13 H 13 D4ClFN2O[M+H] + The calculated value for this is 275.1, and the measured value is 275.1.

[0197] Methyl 2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]-3,3,5,5-tetraduterio-1-piperidyl]acetate (D32): To a solution of 3-chloro-5-fluoro-N-[(3,3,5,5-tetraduterio-4-piperidyl)methyl]benzamide (300 mg, 1.1 mmol) in DMF (5.0 mL), Et3N (0.76 mL, 5.5 mmol) and methyl bromoacetate (0.20 mL, 2.2 mmol) were added at 25°C. After stirring at 25°C for 2 hours, the mixture was quenched with water (15 mL) and extracted with  (2 × 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (300 mg, 0.87 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =7.51(s,1H), 7.40-7.35(m,1H), 7.24-7.20(m,1H), 6.17-6.10(m,1H), 3.72( s,3H), 3.36(t,2H), 3.23(s,2H), 2.96(d,2H), 2.18(d,2H), 1.65-1.63(m,1H). LCMS R t = 0.754 min by chromatography at 1.5 min, 5-95AB, MS ESI C 16 H 17 D4ClFN2O3[ M+H] + The calculated value for this is 347.1, and the measured value is 347.1.

[0198] [2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]-3,3,5,5-tetraduterio-1-piperidyl]acetyl]oxylithium (D33): To a solution of methyl 2-[4-[[[(3-chloro-5-fluorobenzoyl)amino]methyl]-3,3,5,5-tetraduterio-1-piperidyl]acetate (300 mg, 0.87 mmol) in methanol (2.0 mL) / THF (2.0 mL) / water (1.0 mL), LiOH.H2O (109 mg, 2.6 mmol) was added at 25°C. The mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated under reduced pressure to obtain the product (300 mg, 0.89 mmol) as a solid, which was used directly in the next step. LCMS R t = 0.747 min by chromatography at 1.5 min, 5-95AB, MS ESI C 15 H 24 D4ClFN3O 3[ M+H] + The calculated value for this is 333.0, and the measured value is 333.0.

[0199] N-[[1-[2-(tert-butylamino)-2-oxo-ethyl]-3,3,5,5-tetraduterio-4-piperidyl]methyl]-3-chloro-5-fluorobenzamide (compound 3): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-3,3,5,5-tetraduterio-1-piperidyl]acetyl]oxylithium (50 mg, 0.15 mmol) in DCM (2 mL), DIEA (190 mg, 1.5 mmol) and T3P (337 mg, 0.44 mmol) were added. The mixture was stirred at 25°C for 20 minutes, then tert-butylamine (0.050 mL, 0.44 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The mixture was quenched with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×30mm×3μm, conditions: water (10mM NH3H2O)-ACN, start B: 40, end B: 70, gradient time (min): 9, 100% B retention time (min): 1.5, flow rate (mL / min): 30, injection: 3) to obtain the product (17.5 mg, 0.045 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.73-8.61(m,1H), 7.77(s,1H), 7.68-7.59(m,2H), 7.12(s,1H), 3.16( t,2H), 2.80-2.73(m,4H), 2.00(d,2H), 1.57-1.47(m,1H), 1.27(s,9H). LCMS R t = 1.222 min chromatography in 2 mins, 10⁻⁸ AB, MS ESI C 19 H 24 D4ClFN3O 2[ M+H] + Calculated value: 388.2, measured value: 388.2. HRMS MS-TOF C 19 H 24 D4ClFN3O 2[ M+H] + The calculated value for this is 388.2100, and the measured value is 388.2043. Deuterated purity: 1.71% 0D, 2.58% 1D, 3.04% 2D, 8.02% 3D, 84.37% 4D, and 0.28% 5D.

[0200] Example 4. Synthesis of Compounds 4 and 5 [ka] tert-butyl 4-[diduterio(hydroxy)methyl]piperidine-1-carboxylate (D35): To a stirred solution of 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (5.0 g, 20.6 mmol) in CD3OD (25 mL, 20.6 mmol), tetraduterio(sodio)boron (3.44 g, 82.2 mmol) was added in batches at 0°C. After stirring at 0°C for 2 hours, the mixture was adjusted to pH 7 with 1 M CHl (10 mL) and extracted with DCM (3 × 25 mL). The organic layer was washed with brine (2 × 25 mL) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 5% MeOH in DCM to obtain the product (3.30 g, 15.2 mmol, yield 74%, 2D deuterated purity: 92.80%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =4.16-4.08(m,2H),2.74-2.65(m,2H)1.74-1.67(m,2H),1.66-1.57(m,1H),1.45(s,10H),1.20-1.07(m.2H). HRMS MS-TOF C7H 12 D2NO3[M-tBu+H] + The calculated value for this is 162.1094, and the measured value is 162.1083. Deuterated purity: 0.19% (0D), 6.84% (1D), 92.80% (2D), 0.17% (3D).

[0201] tert-butyl 4-[dijuterio-(1,3-dioxoisoindolin-2-yl)methyl]piperidine-1-carboxylate (D36): To a solution of tert-butyl 4-[diduterio(hydroxy)methyl]piperidine-1-carboxylate (3.30 g, 15.2 mmol) in THF (30 mL), PPh3 (5.17 g, 19.8 mmol) and phthalimide (4.02 g, 27.3 mmol) were added. After stirring for 30 minutes, DIAD (5.53 g, 27.3 mmol) was added while the mixture was cooled to 0°C. The mixture was then stirred at 25°C for 16 hours. The resulting mixture was quenched with H2O (20 mL) and siRNA (3 × 20 mL). The combined organic phase was washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue product was purified by flash column elution with siRNA (0-20%) in PE to obtain the product (4.50 g, 13.0 mmol, yield 86%) as a solid. 1 1H NMR (400MHz CDCl3)δ H =7.95-7.83(m,2H), 7.80-7.65(m,2H), 4.18-4.02(m,2H), 2.76-2.59(m,2H), 1.73-1.57(m,2H), 1.51-1.39(m,9H), 1.36-1.15(m,3H).

[0202] tert-butyl 4-[amino(diduterio)methyl]piperidine-1-carboxylate (D37): To a solution of tert-butyl 4-[diduterio-(1,3-dioxoisoindorin-2-yl)methyl]piperidine 1-carboxylate (4.50 g, 13.0 mmol) in DCM (50 mL) and ethanol (10 mL), N2H4.H2O (7.79 mL, 156 mmol) was added dropwise at 25°C. After stirring at 25°C for 16 hours, the mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). The filtrate was concentrated to obtain the product (4.0 g, 18.5 mmol) as a solid. 1 1H NMR (400MHz DMSO-d6)δ H=3.99-3.86(m,2H), 3.48-3.45(m,2H), 2.79-2.53(m,2H), 1.73-1.59(m,2H), 1.47-1.24(m,9H), 1.20-1.11(m,1H), 1.09-0.85(m,2H).

[0203] tert-butyl 4-[[(3-chloro-5-fluoro-benzoyl)amino]-diduterio-methyl]piperidine-1-carboxylate (D38): To a solution of 3-chloro-5-fluorobenzoic acid (0.81 g, 4.62 mmol) in DMF (10 mL), HATU (3.52 g, 9.25 mmol) and Et3N (3.20 mL, 23.1 mmol) were added. After stirring at 20°C for 30 minutes, tert-butyl 4-[amino(diduterio)methyl]piperidine-1-carboxylate (1.0 g, 4.62 mmol) was added, and the mixture was stirred for 16 hours. The mixture was poured into water (10 mL) and extracted with ELISA (2 × 10 mL). The combined organic phases were washed with brine (2 × 10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by flash chromatography on silica gel (0% to 30% siRNA in PE) to obtain the product (1.50 g, 4.02 mmol, yield 87%) as an oil. This was washed with hot water (20 mL) and stirred at 60°C for 2 hours. The mixture was then extracted with siRNA (2 × 20 mL). The combined organic phases were washed with water (10 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the product (800 mg, 2.15 mmol, yield 53%) as an oil. 1 1H NMR (400MHz, CDCl3)δ H =7.52(s,1H), 7.42-7.35(m,1H), 7.24-7.20(m,1H), 6.35-6.25(m,1H), 4.17-4.06( m,2H), 2.76-2.63(m,2H), 1.75-1.68(m,2H), 1.49-1.40(m,9H), 1.29-1.13(m,3H).

[0204] 3-Chloro-N-[diduterio(1λ2-azinan-4-yl)methyl]-5-fluorobenzamide hydrochloride (D39): To a solution of tert-butyl 4-[[(3-chloro-5-fluoro-benzoyl)amino]-diduterio-methyl]piperidine-1-carboxylate (800 mg, 2.15 mmol) in 1,4-dioxane (4.0 mL), 4 M HCl / dioxane (4.0 mL, 79.5 mmol) was added at 25°C. After stirring at 25°C for 16 hours, the mixture was filtered, the residue was washed with dioxane (5.0 mL), and the mother liquor was concentrated under reduced pressure to obtain the product (400 mg, 1.30 mmol, yield 60%, 2D deuteration purity: 93.20%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.79(s,1H), 8.67-8.40(m,1H), 7.77(s,1H), 7.70-7.60(m,2H), 3.30 -3.21(m,2H), 2.90-2.76(m,2H), 1.87-1.74(m,3H), 1.41-1.26(m,2H). HRMS MS-TOF C 13 H 15 D2ClFN2O[M+H] + The calculated value for this is 273.1133, and the measured value is 273.1085. Deuterated purity: 0.23% (0D), 6.57% (1D), 93.20% (2D).

[0205] Methyl 2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]-diduterio-methyl]-1-piperidyl]acetate (D40): To a solution of 3-chloro-N-[diduterio(4-piperidyl)methyl]-5-fluorobenzamide hydrochloride (200 mg, 0.65 mmol) in DMF (5.0 mL), Et3N (0.45 mL, 3.23 mmol) and methyl bromoacetate (0.12 mL, 1.29 mmol) were added at 25°C. After stirring at 25°C for 2 hours, the mixture was quenched with water (5.0 mL) and extracted with ₹ (2 × 5.0 mL). The combined organic layer was washed with brine (5.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (600 mg, 1.74 mmol) as a solid.1 1H NMR (400MHz, CDCl3)δ H =7.53(s,1H), 7.43-7.37(m,1H), 7.24-7.19(m,1H), 6.34-6.24(m,1H), 3.74(s,3H), 3. 33(s,2H), 3.11-3.01(m,2H), 2.43-2.31(m,2H), 1.84-1.66(m,3H), 1.63-1.48(m,2H).

[0206] [2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]-diduterio-methyl]-1-piperidyl]acetyl]oxylithium (D41): To a solution of methyl (2-[4-[[(3-chloro-5-fluorobenzoyl)amino]-diduterio-methyl]-1-piperidyl]acetate (195 mg, 0.57 mmol) in methanol (1.0 mL) / THF (1.0 mL) / water (0.50 mL), LiOH.H2O (71.2 mg, 1.70 mmol) was added at 25°C. After stirring at 25°C for 0.5 hours, the mixture was concentrated under reduced pressure to obtain the product (250 mg, 0.76 mmol, 2D deuteration purity: 91.76%) as a solid, which was used directly in the next step. 1 1H NMR (400MHz, DMSO-d6)δ H =7.77(s,1H), 7.68-7.54(m,2H), 2.84-2.75(m,2H), 2.62-2.58(m,3H), 1. 90-1.81(m,2H), 1.61-1.52(m,2H), 1.50-1.41(m,1H), 1.30-1.13(m,2H). HRMS MS-TOF C 15 H 17 D2ClFN2O 3[ M+H] + The calculated value for this is 331.1188, and the measured value is 331.1160. Deuterated purity: 0.20% (0D), 6.85% (1D), 91.76% (2D), and 1.18% (3D).

[0207] N-[[1-[2-(tert-butylamino)-2-oxo-ethyl]-4-piperidyl]-diduterio-methyl]-3-chloro-5-fluorobenzamide (compound 4): To a solution of 2-[4-[[(3-chloro-5-fluorobenzoyl)amino]-diduterio-methyl]-1-piperidyl]acetic acid (250 mg, 0.76 mmol) in DCM (2.50 mL), DIEA (1.75 g, 13.6 mmol) and T3P (5.17 g, 6.80 mmol) were added. After stirring at 25°C for 20 minutes, tert-butylamine (0.72 mL, 6.80 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (2.0 mL) and extracted with DCM (2 × 2.0 mL). The combined organic layers were washed with brine (2.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 35, end B: 65, gradient time (min): 8, 100% B retention time (min): 2, flow rate (mL / min): 30) to obtain the product (107 mg, 0.28 mmol, yield 43%) as a solid. The product (107 mg, 0.28 mmol) was poured into NaHCO3 (2 × 1.0 mL) and stirred at 40°C for 20 minutes. The aqueous phase was extracted with DCM (2 × 1.0 mL). The combined organic phases were washed with brine (2 × 1.0 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the product (90.0 mg, 0.23 mmol, yield 84%) as an oil. The product (90 mg, 0.23 mmol) was purified by pre-TLC and flash column (MeOH / DCM = 1 / 10) to obtain the product (40.5 mg, 0.11 mmol, yield 45%, 2D deuterated purity: 93.0%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.48-8.36(m,1H), 7.75(s,1H), 7.65-7.58(m,1H), 7.56-7.50(m,1H), 7.09-6.97(m,1H), 2.82-2. 77(m,4H), 2.13-2.05(m,2H), 1.71-1.65(m,2H), 1.61-1.52(m,1H), 1.29(s,9H), 1.27-1.19(m,2H). LCMS R t= 1.2 minutes in chromatography for 2.0 minutes, 10⁻⁸ AB, MS ESI C 19 H 26 D2ClFN3O 2[ M+H] + Calculated value: 386.1, measured value: 386.1. HRMS MS-TOF C 19 H 26 D2ClFN3O 2[ M+H] + The calculated value for this is 386.1974, and the measured value is 386.1966. Deuterated purity: 0.20% (0D), 6.80% (1D), 93.0% (2D).

[0208] 3-Chloro-N-[diduterio-[1-[2-oxo-2-[[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]-5-fluorobenzamide (compound 5): To a solution of 2-[4-[[(3-chloro-5-fluorobenzoyl)amino]-diduteriomethyl]-1-piperidyl]acetic acid (100 mg, 0.30 mmol) in DCM (1.0 mL), DIEA (312 mg, 2.42 mmol) and T3P (690 mg, 0.91 mmol) were added. After stirring at 25°C for 20 minutes, 1,1,1,3,3,3-hexaduterio-2-(triduteriomethyl)propan-2-amine (74.5 mg, 0.91 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (2.0 mL) and extracted with DCM (2 × 2.0 mL). The combined organic layers were washed with brine (2.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm, conditions: water (10 mM NH4HCO3)-ACN, start B: 42, end B: 72, gradient time (min): 9, 100% B retention time (min): 1.5, flow rate (mL / min): 30) to obtain the product (45.5 mg, 0.12 mmol, yield 45%, deuterated purity of 11D: 87.46%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H=8.64(s,1H), 7.76(s,1H), 7.67-7.60(m,2H), 7.15-7.05(m,1H), 2.81-2.72(m, 4H), 2.07-1.96(m,2H), 1.72-1.60(m,2H), 1.57-1.45(m,1H), 1.25-1.14(m,2H). LCMS R t = 1.205 min by chromatography at 2.0 min, 10⁻⁸ AB, MS ESI C 19 H 17 D 11 ClFN3O 2[ M+H] + Calculated value: 395.3, measured value: 395.3. HRMS MS-TOF C 19 H 17 D 11 ClFN3O 2[ M+H] + The calculated value for this was 395.2539, and the measured value was 395.2534. Deuterated purity: 0.04% for 8D, 0.72% for 9D, 11.78% for 10D, and 87.46% for 11D.

[0209] Example 5. Synthesis of Compound 6 [ka] Methyl 2-(4-cyano-1-piperidyl)acetate (D43): To a solution of piperidine-4-carbonile (6.0 g, 41.1 mmol) in DMF (60 mL), Et3N (28.4 mL, 205 mmol) and methyl bromoacetate (7.57 mL, 82.1 mmol) were added at 25°C. After stirring at 25°C for 2 hours, the mixture was quenched with water (100 mL) and extracted with siRNA (3 × 50 mL). The combined organic layer was washed with brine (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (2.0 g, 11.0 mmol, yield 27%) as an oil. 1 1H NMR (400MHz, CDCl3)δ H =3.71(s,3H), 3.23(s,2H), 2.80-2.61(m,3H), 2.58-2.48(m,2H), 2.02-1.86(m,4H).

[0210] [2-(4-cyano-1-piperidyl)acetyl]oxylithium (D44): To a solution of methyl 2-(4-cyano-1-piperidyl) acetate (2.0 g, 11.0 mmol) in methanol (3.0 mL) / THF (3.0 mL) / water (1.0 mL), LiOH.H2O (1.38 g, 32.9 mmol) was added at 25°C. After stirring at 25°C for 3 hours, the mixture was concentrated under reduced pressure to obtain the product (2.80 g, 16.1 mmol) as a solid, which was used directly in the next step.

[0211] N-tert-butyl-2-(4-cyano-1-piperidyl)acetamide (D45): To a solution of [2-(4-cyano-1-piperidyl)acetyl]oxylithium (2.80 g, 16.1 mmol) in DCM (25 mL), DIEA (16.6 g, 128 mmol) and T3P (36.7 g, 48.2 mmol) were added. After stirring at 25°C for 20 minutes, tert-butylamine (5.11 mL, 48.2 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (40 mL) and extracted with DCM (2 × 20 mL). The combined organic layer was washed with brine (60 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-70% ethyl acetate in PE) to obtain the product (770 mg, 3.45 mmol, yield 21%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =7.01-6.71(m,1H), 2.94-2.85(s,2H), 2.79-2.57(m,3H), 2.51-2.31(m,2H), 2.00-1.81(m,4H), 1.35(s,9H).

[0212] 2-[4-(aminomethyl)-1-piperidyl]-N-tert-butyl-acetamide(D46): To a solution of N-tert-butyl-2-(4-cyano-1-piperidyl)acetamide (300 mg, 1.34 mmol) in methanol (10 mL), cobalt(II) chloride hexahydrate (160 mg, 0.67 mmol) was added at 0°C, followed by the slow addition of sodium borohydride (229 mg, 6.05 mmol) under N2. After stirring at 25°C for 15 hours, the mixture was diluted with 25 mL of 5% aqueous ammonium hydroxide solution and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain the product (260 mg, 1.14 mmol, yield 85%) as an oil, which was used in the next step without further purification.

[0213] 2-[4-(aminomethyl)-1-piperidyl]-N-tert-butyl-2,2-diduterioacetamide(D47): MeONa (250 mg, 4.62 mmol) was added to a mixture of 2-[4-(aminomethyl)-1-piperidyl]-N-tert-butylacetamide (210 mg, 0.92 mmol) in CD3OD (8 mL, 0.92 mmol). After stirring at 80°C for 72 hours, the mixture was cooled to 25°C, poured into D2O (10 mL), and extracted with DCM (3 × 10 mL). The combined organic layer was washed with brine (2 × 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the product (210 mg, 0.92 mmol) as an oil.

[0214] N-[[1-[2-(tert-butylamino)-1,1-diduterio-2-oxo-ethyl]-4-piperidyl]methyl]-3-chloro-5-fluorobenzamide (compound 6): To a solution of 3-chloro-5-fluorobenzoic acid (167 mg, 0.96 mmol) in DCM (10 mL), DIEA (990 mg, 7.67 mmol) and T3P (2.19 g, 2.88 mmol) were added at 25°C. After stirring at 25°C for 20 minutes, 2-[4-(aminomethyl)-1-piperidyl]-N-tert-butyl-2,2-diduterioacetamide (220 mg, 0.96 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-10% MeOH in DCM) to obtain the product (210 mg, 0.38 mmol, yield 40%) as an oil. The product (110 mg, 0.29 mmol) was purified twice by preparative TLC (DCM / MeOH = 10 / 1) to obtain the product (45.7 mg, 0.119 mmol, yield 41%, 2D deuterated purity: 96.78%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.70-8.60(m,1H), 7.76(s,1H), 7.70-7.55(m,2H), 7.13(s,1H), 3.20-3.07(m,2H), 2.83-2.70( m,2H), 2.07-1.95(m,2H), 1.71-1.60(m,2H), 1.58-1.46(m,1H), 1.26(s,9H), 1.22-1.12(m,2H). 19 F NMR (376.5 MHz, CDCl3) δ F = -110.137. LCMS R t = 0.823 min chromatography at 1.5 min, 5-95AB, MS ESI C 19 H 26 D2ClFN3O 2[ M+H] + Calculated value: 395.9, measured value: 395.9. HRMS MS-TOF-B C 19 H 26 D2ClFN3O 2[ M+H] +The calculated value for this is 396.1964, and the measured value is 396.1964. Deuterated purity: 0.07% (0D), 3.15% (1D), 96.78% (2D).

[0215] Example 6. Synthesis of Compound 7 [ka] 2-Methyl-N-(propan-2-ylidene)propan-2-sulfinamide (D49): To a solution of acetone (45.5 mL, 620 mmol) in THF (500 mL), Ti(OEt)4 (141 g, 620 mmol) and 2-methyl-2-propanesulfinamide (15.0 g, 124 mmol) were gradually added under N2 conditions at 25°C. The mixture was stirred at 60°C for a further 16 hours to obtain a suspension. After cooling to 25°C, the mixture was poured into a rapidly stirring solution of NaHCO3 (300 mL). After stirring the solution for 5 minutes, the mixture was filtered through a Celite pad, and the residue was washed with siRNA (3 × 800 mL). The filtrate was extracted with siRNA (2 × 800 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (siRNA in PE, 5%-20%) to obtain the product (15.0 g, 83.7 mmol, yield 67%) as an oil. 1 1H NMR (400MHz, CDCl3)δ H =2.28(s,3H), 2.13(s,3H), 1.18(s,9H).

[0216] 2-Methyl-N-(2,2,2-triduterio-1,1-dimethylethyl)propane-2-sulfinamide (D52): To Mg (3.02 g, 124 mmol) and I2 (0.32 g, 1.24 mmol), a solution of triduterio(iodo)methane (9.0 g, 62.1 mmol) in ether (100 mL) was added dropwise under N2 at 0°C. The mixture was stirred at 0°C for 1 hour. A solution of N-isopropylidene-2-methylpropane-2-sulfinamide (5.0 g, 31 mmol) in ether (10 mL) was added dropwise over 30 minutes at 0°C under N2, while maintaining the temperature below 25°C. A saturated NH4Cl solution (40 mL) was added to the mixture, and the aqueous layer was extracted with SiO2 (40 mL x 2). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. The residue was purified by column chromatography (PE / siRNA = 5 / 1 to 3 / 1) to obtain the product (2.20 g, 3.66 mmol, yield 12%) in liquid form. 1 1H NMR (400MHz, CDCl3)δ H =2.98(s,1H), 1.29(s,6H), 1.19-1.17(m,9H).

[0217] 1,1,1-Triduterio-2-methylpropane-2-amine hydrochloride (D53): A mixture of 2-methyl-N-(2,2,2-triduterio-1,1-dimethyl-ethyl)propan-2-sulfinamide (200 mg, 1.11 mmol) in 1,4-dioxane (1.0 mL) was mixed with HCl / dioxane (1.0 mL, 4.0 mmol) at 20°C and stirred for 2 hours at 20°C. The filtrate was concentrated to obtain the product (100 mg, 0.89 mmol, 80% yield) as a solid, which was used directly in the next step.

[0218] 3-Chloro-5-fluoro-N-[[1-[2-oxo-2-[(2,2,2-triduterio-1,1-dimethyl-ethyl)amino]ethyl]-4-piperidyl]methyl]benzamide (compound 7): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-1-piperidyl]acetyl]oxylithium (120 mg, 0.36 mmol) in DCM (2.0 mL), DIEA (0.63 mL, 3.59 mmol) and T3P (0.82 g, 1.08 mmol) were added at 25°C. After stirring for 10 minutes, 1,1,1-triduterio-2-methylpropan-2-amine (32.8 mg, 0.43 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (column: Phenomenex Gemini-NX 80×30mm×3μm, conditions: water (10mM NH3H2O)-ACN, start B: 31, end B: 61, gradient time (min): 9, 100% B retention time (min): 1.5, flow rate (mL / min): 30, injection: 5) to obtain the product (45.6 mg, 0.12 mmol, yield 32%, 3D deuteration purity: 99.63%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.72-8.60(m,1H), 7.76(s,1H), 7.70-7.57(m,2H), 7.12(s,1H), 3.19-3.11(m,2H), 2 .82-2.71(m,4H), 2.0-1.96(m,2H), 1.73-1.46(m,3H), 1.26(s,6H), 1.22-1.08(m,2H). LCMS R t = 1.429 min chromatography in 2 mins, 0-60 AB, MS ESI C 19 H 25 D3ClFN3O 2[ M+H] + Calculated value: 387.2, measured value: 387.2. HRMS MS-TOF C 19 H 25 D3ClFN3O 2[ M+H] + The calculated value for this is 387.2037, and the measured value is 387.2095. Deuterated purity: 0.37% for 2D, and 99.63% for 3D.

[0219] Example 7. Synthesis of Compound 8 [ka] 3-Chloro-5-fluoro-N-[[3,3,5,5-tetraduterio-1-[2-oxo-2-[[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]benzamide (compound 8): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-3,3,5,5-tetraduterio-1-piperidyl]acetyl]oxylithium (50.0 mg, 0.15 mmol) in DCM (2.0 mL), DIEA (0.26 mL, 1.48 mmol) and T3P (337 mg, 0.44 mmol) were added. After stirring at 25°C for 20 minutes, 1,1,1,3,3,3-hexaduterio-2-(triduteriomethyl)propan-2-amine (0.05 mL, 0.39 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The mixture was quenched with water (10.0 mL) and extracted with DCM (2 × 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×30mm×3μm, conditions: water (10mM NH3H2O)-ACN, start B: 31, end B: 61, gradient time (min): 9, 100% B retention time (min): 1.5, flow rate (mL / min): 30, injection: 3), and the product (27.4 mg, 0.069 mmol, deuterated purity of 13D: 77.61%) was obtained as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.74-8.62(m,1H), 7.83-7.73(m,1H), 7.64(dd,2H), 7.23-7.02(m,1H) , 3.15(t,2H), 2.87-2.69(m,4H), 2.13-1.87(m,2H), 1.56-1.45(m,1H). LCMS R t = 1.224 min chromatography in 2 mins, 10⁻⁸ AB, MS ESI C 19 H 15 D13 ClFN3O 2[ M+H] + Calculated value: 397.2, measured value: 397.6. HRMS MS-TOF C 19 H 15 D 13 ClFN3O 2[ M+H] + The calculated value for this is 397.2665, and the measured value is 397.2703. Deuterated purity: 0.11% 8D, 1.83% 9D, 2.86% 10D, 3.81% 11D, 13.12% 12D, 77.61% 13D, 0.51% 14D, and 0.16% 15D.

[0220] Example 8. Synthesis of Compound 9 [ka] 3-Chloro-5-fluoro-N-[[3,3,5,5-tetraduterio-1-[2-oxo-2-[(2,2,2-triduterio-1,1-dimethyl-ethyl)amino]ethyl]-4-piperidyl]methyl]benzamide (compound 9): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-3,3,5,5-tetraduterio-1-piperidyl]acetyl]oxylithium (80.0 mg, 0.24 mmol) in DCM (2.0 mL), DIEA (0.33 mL, 1.89 mmol) and T3P (0.21 mL, 0.71 mmol) in 50% ethyl acetate were added. After stirring at 25°C for 20 minutes, 1,1,1-triduterio-2-methyl-propan-2-amine (36.0 mg, 0.47 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The mixture was quenched with water (10.0 mL) and extracted with DCM (2 × 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 150×25mm×5μm, conditions: water (10mM NH3H2O)-ACN, start B: 34, end B: 64, gradient time (min): 9, 100% B retention time (min): 1.5, flow rate (mL / min): 30, injection: 3), and the product (27.9 mg, 0.072 mmol, 7D deuterated purity: 81.4%) was obtained as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.72-8.60(m,1H), 7.81-7.73(m,1H), 7.66-7.58(m,2H), 7.20-7.06(m,1H), 3. 15(t,2H), 2.89-2.73(m,4H), 2.05-1.95(m,2H), 1.55-1.45(m,1H), 1.26(s,6H). LCMS R t = 1.229 min by chromatography in 2 mins, 10⁻⁸ AB, MS ESI C 19 H 21 D7ClFN3O 2[ M+H] + Calculated value: 391.2, measured value: 391.1. HRMS MS-TOF C 19 H 21 D7ClFN3O 2[ M+H] +The calculated value for this was 391.2288, and the measured value was 397.2321. Deuterated purity: 1.80% 3D, 2.81% 4D, 3.37% 5D, 9.13% 6D, 81.43% 7D, and 1.45% 8D.

[0221] Example 9. Synthesis of Compound 10 [ka] 3-Chloro-N-[diduterio-[1-[2-oxo-2-[(2,2,2-triduterio-1,1-dimethyl-ethyl)amino]ethyl]-4-piperidyl]methyl]-5-fluorobenzamide (compound 10): To a solution of 2-[4-[[(3-chloro-5-fluorobenzoyl)amino]-diduterio-methyl]-1-piperidyl]peroxyacetic acid (50.0 mg, 0.14 mmol) in DCM (1.0 mL), DIEA (0.25 mL, 1.44 mmol) and T3P (165 mg, 0.43 mmol) were added at 25°C. After stirring for 20 minutes, 1,1,1-triduterio-2-methyl-propan-2-amine (32.9 mg, 0.43 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (1.0 mL) and extracted with DCM (2 × 1.0 mL). The combined organic layers were washed with brine (1.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the solid product (50.0 mg, 0.13 mmol, yield 89%). This was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm, conditions: water (10 mM NH4HCO3)-ACN, start B: 45, end B: 75, gradient time (min): 9, 100% B retention time (min): 1.5, flow rate (mL / min): 30) to obtain the solid product (15.4 mg, 0.04 mmol, yield 30%, 5D deuterated purity: 91.95%). 1 1H NMR (400MHz, DMSO-d6)δ H=8.64(s,1H), 7.76(s,1H), 7.66-7.61(m,2H), 7.15-7.08(m,1H), 2.84-2.72(m,4H), 2. 10-1.97(m,2H), 1.70-1.61(m,2H), 1.57-1.46(m,1H), 1.26(s,6H), 1.23-1.12(m,2H). LCMS R t = 1.233 min by chromatography at 2.0 min, 10⁻⁸ AB, MS ESI C 19 H 23 D5ClFN3O 2[ M+H] + Calculated value: 389.1, measured value: 389.1. HRMS MS-TOF C 19 H 23 D5ClFN3O 2[ M+H] + The calculated value for this is 389.2162, and the measured value is 389.2191. Deuterated purity: 0.23% for 3D, 7.82% for 4D, and 91.95% for 5D.

[0222] Example 10. Synthesis of Compound 11 [ka] 3-Chloro-5-fluoro-N-[[2,2,3,3,4,5,5,6,6-nonaduterio-1-[2-oxo-2-[(2,2,2-triduterio-1,1-dimethyl-ethyl)amino]ethyl]-4-piperidyl]methyl]benzamide (compound 11): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,3,3,4,5,5,6,6-nonaduterio-1-piperidyl]acetyl]oxylithium (100 mg, 0.29 mmol) in DCM (3.0 mL), DIEA (0.41 mL, 2.33 mmol) and T3P (664 mg, 0.87 mmol) were added. After stirring at 25°C for 20 minutes, 1,1,1-triduterio-2-methyl-propan-2-amine (65.5 mg, 0.58 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product. This product was then purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 34, end B: 64, gradient time (min): 8, 100% B retention time (min): 2.3, flow rate (mL / min): 30, injection: 6) to obtain the product (51.6 mg, 0.13 mmol, yield 44%) as a solid. 1H NMR (400MHz, CDCl3) δH=7.51(s,1H), 7.42-7.35(m,1H), 7.25-7.20(m,1H), 7.03(s,1H), 6.18(s,1H), 3.36(d,2H), 2.86(s,2H), 1.35(s,6H). LCMS R t Chromatography for 3.0 minutes yielded 2.034 minutes, 10⁻⁸ AB, MS ESI for C19H16D12ClFN3O2[M+H]+, calculated value 396.4, measured value 396.4.

[0223] Example 11. Synthesis of Compound 12 [ka] 3-Chloro-5-fluoro-N-[[2,2,3,3,4,5,5,6,6-nonaduterio-1-[2-oxo-2-[[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]benzamide (compound 12): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,3,3,4,5,5,6,6-nonaduterio-1-piperidyl]acetyl]oxylithium (100 mg, 0.29 mmol) in DCM (3.0 mL), DIEA (0.51 mL, 2.91 mmol) and T3P (664 mg, 0.87 mmol) were added. After stirring at 25°C for 20 minutes, 1,1,1,3,3,3-hexaduterio-2-(triduteriomethyl)propan-2-amine (71.7 mg, 0.87 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 34, end B: 64, gradient time (min): 8, 100% B retention time (min): 2, flow rate (mL / min): 30, injection: 6) to obtain the product (58.4 mg, 0.14 mmol, yield 49%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =7.52(s,1H), 7.43-7.35(m,1H), 7.25-7.20(m,1H), 7.02(s,1H), 6.21(s,1H), 3.36(d,2H), 2.86(s,2H). LCMS R t = 3.0 minutes chromatography for 1.880 minutes, 10⁻⁸ AB, MS ESI C 19 H 10 D 18 ClFN3O 2[ M+H] + The calculated value for this is 402.4, and the measured value is also 402.4.

[0224] Example 12. Synthesis of Compound 13 [ka] tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (D55): To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (5.0 g, 24 mmol) in THF (100 mL), LiAlH4 (1.8 g, 48 mmol) was slowly added at 0°C. After stirring at 0°C for 2 hours, water (1.8 mL), 15% NaOH aqueous solution (12 mL), and then water again (5.4 mL) were added very slowly to the reaction mixture. The precipitate was filtered and washed with siRNA (30 mL). The combined organic layers were concentrated under reduced pressure to obtain the product (1.6 g, 7.5 mmol, 31% yield) as an oil, which was used directly in the next step. 1 1H NMR (400MHz, CDCl3)δ H =4.25-4.01(m,2H), 3.33-3.25(m,1H), 3.01-2.65(m,1H), 2.75-2.60(m,2H), 2.59 -2.5(m,1H), 1.75-1.55(m,2H), 1.45(s,9H), 1.44-1.38(m,2H), 1.35-1.0(m,2H).

[0225] tert-butyl 4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]piperidine-1-carboxylate (D56): To a solution of 3-chloro-5-fluorobenzoic acid (1.1 g, 6.5 mmol) in DMF (30 mL), HATU (5.0 g, 13 mmol), Et3N (4.5 mL, 33 mmol), and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.4 g, 6.5 mmol) were added at 25°C. After stirring at 25°C for 12 hours, the reaction mixture was poured into water (60 mL) and extracted with Depositphotos (2 × 30 mL). The combined organic phase was washed with water (2 × 60 mL) and brine (2 × 60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column using Depositphotos (0%~30%) in PE to obtain the product (1.1 g, 2.7 mmol, yield 41%) as an oil. 1 1H NMR (400MHz, CDCl3)δ H=7.51(s,1H), 7.43-7.34(m,1H), 7.25-7.13(m,1H), 6.32-6.08(m,1H), 4.18-4.05(m,3H) , 3.40-3.28(m,2H), 2.77-2.58(m,2H), 1.85-1.65(m,2H), 1.45(s,9H), 1.21-1.02(m,2H). 19 F NMR (376.5 MHz, CDCl3) δ F = -109.216.

[0226] 3-Chloro-5-fluoro-N-(4-piperidylmethyl)benzamide (D57): To a solution of tert-butyl 4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]piperidine-1-carboxylate (1.7 g, 4.5 mmol) in 1,4-dioxane (10 mL), 4 M HCl / dioxane (5.0 mL, 36 mmol) was added at 25 °C. After stirring at 25 °C for 12 hours, the mixture was concentrated under reduced pressure to obtain the product (1.5 g) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =7.79(s,1H), 7.72-7.59(m,2H), 3.56(s,2H), 3.29-3.12(m,4H), 2.94-2.73(m,2H), 1.90-1.73(m,3H), 1.44-1.26(m,2H). 19 F NMR (376.5 MHz, CDCl3) δ F = -110.063.

[0227] Methyl 2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]-1-piperidyl]acetate (D58): To a solution of 3-chloro-5-fluoro-N-(4-piperidylmethyl)benzamide hydrochloride (1.5 g, 4.9 mmol) in DMF (15 mL), Et3N (3.4 mL, 24 mmol) and methyl bromoacetate (0.90 mL, 9.8 mmol) were added at 25°C. After stirring at 25°C for 2 hours, the reaction mixture was quenched with water (30 mL) and extracted with ₹ (2 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (1.6 g, 4.2 mmol, yield 86%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =7.51(s,1H), 7.23-7.19(m,1H), 7.22(m,1H), 6.35-6.18(m,1H), 3.72(s,3H), 3.35(t,2H) , 3.25(s,2H), 3.05-2.94(m,2H), 2.29-2.17(m,2H), 1.81-1.61(m,3H), 1.55-1.39(m,2H).

[0228] 2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]methyl]-1-piperidyl]acetic acid (D59): To a solution of methyl 2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-1-piperidyl]acetate (1.6 g, 4.7 mmol) in methanol (3.0 mL) / THF (3.0 mL) / water (1.0 mL), LiOH.H2O (0.59 g, 14 mmol) was added at 25°C. After stirring at 25°C for 3 hours, the reaction mixture was concentrated under reduced pressure to obtain the product (1.9 g, 5.8 mmol) as a solid, which was used directly in the next step. 1 1H NMR (400MHz, CDCl3)δ H =7.77(s,1H), 7.70-7.52(m,2H), 7.32-7.09(m,2H), 3.16(s,2H), 3.14-3.09(m, 2H), 2.83-2.74(m,2H), 1.90-1.78(m,2H), 1.63-1.52(m,2H), 1.30-1.10(m,2H). 19 F NMR (376.5 MHz, CDCl3) δ F = -110.450.

[0229] 3-Chloro-N-[[1-[1,1-diduterio-2-oxo-2-[[2,2,2-triduterio-1,1bis(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]-5-fluorobenzamide (compound 13): To a solution of lithium 2-(4-((3-chloro-5-fluorobenzamide)methyl)piperidine-1-yl)acetate (100 mg, 0.30 mmol) in DCM (10 mL), DIEA (314 mg, 2.4 mmol), T3P (347 mg, 0.91 mmol), and 1,1,1,3,3,3-hexaduterio-2-(triduteriomethyl)propan-2-amine (75 mg, 0.91 mmol) were added. After stirring at 25°C for 16 hours, the reaction product was quenched with water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (150 mg, 0.38 mmol) as an oily substance. This was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 30 mm × 3 μm, conditions: water (10 mM NH4HCO3)-CAN, start B: 36, end B: 66, gradient time (min): 9, 100% B retention time (min): 1.5, flow rate (mL / min): 30, injection: 5) to obtain the product (29.32 mg, 0.075 mmol, yield 20%, deuterated purity of 9D: 94.21%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =7.53(s,1H), 7.43-7.36(m,1H), 7.31-7.20(m,1H), 7.11-7.04(m,1H), 6.29-6.15(m,1H) , 3.38(t,2H), 2.96-2.77(m,4H), 2.22-2.09(m,2H), 1.80-1.71(m,2H), 1.46-1.22(m,3H). 19 F NMR (400 MHz, CDCl3) δ F = -109.216. LCMS R t = 0.784 min by chromatography at 1.5 min, 5-95AB, MS ESI C 19 H19 D9ClFN3O 2[ M+H] + Calculated value: 393.2, measured value: 393.2. HRMS MS-TOF-B C 19 H 19 D9ClFN3O 2[ M+H] + The calculated value for this is 393.2414, and the measured value is 393.2341. Deuterated purity: 0.19% for 7D, 5.60% for 8D, and 94.21% for 9D.

[0230] Example 13. Synthesis of Compound 14 [ka] 2-Methyl-N-[2,2,2-triduterio-1-(triduteriomethyl)ethylidene]propane-2-sulfinamide (D61): To a solution of acetone-d6 (1.15 mL, 15.6 mmol) in THF (10.0 mL), Ti(OEt)4 (7.11 g, 31.2 mmol) and 2-methyl-2-propanesulfinamide (2.08 g, 17.2 mmol) were gradually added under N2 conditions at 25°C. The reaction mixture was stirred at 60°C for a further 16 hours. After cooling to 25°C, the mixture was used directly in the next step.

[0231] 2-Methyl-N-[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]propan-2-sulfinamide (D62): A solution of MeMgBr (50.0 mL, 150 mmol) was added to a solution of 2-methyl-N-[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]propan-2-sulfinamide in THF (10.0 mL) under N2 conditions at 0°C. After stirring at 10°C for 16 hours, the solution was poured into ice water (200 mL), stirred for 20 minutes, and filtered. The aqueous phase was extracted with siRNA (2 × 100 mL). The combined organic phases were washed with brine (2 × 30.0 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / siRNA = 5 / 1 to 3 / 1) to obtain the product (1 g, 5.45 mmol, yield 35%) as an oil. 1 1H NMR (400MHz, CDCl3)δ H =2.97(s,1H), 1.28(s,3H), 1.18(s,9H).

[0232] 1,1,1,3,3,3-Hexaduterio-2-methylpropane-2-amine hydrochloride (D63): A mixture of 2-methyl-N-[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]propan-2-sulfinamide (1 g, 5.45 mmol) in 4 M HCl / dioxane (10.0 mL, 40 mmol) was stirred at 20°C for 16 hours. The mixture was filtered and concentrated under reduced pressure to obtain the product (490 mg, 4.23 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H = 8.02 (s, 2 hours), 1.24 (s, 3 hours).

[0233] 3-Chloro-5-fluoro-N-[[1-[2-oxo-2-[[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]benzamide (compound 14): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-1-piperidyl]acetyl]oxylithium (70.0 mg, 0.21 mmol) in DCM (2.0 mL), DIEA (0.29 mL, 2.09 mmol) and T3P (1.27 g, 1.67 mmol) were added at 25°C. After stirring for 10 minutes, 1,1,1,3,3,3-hexaduterio-2-methylpropane-2-amine hydrochloride (31.9 mg, 0.28 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. The mixture was poured into water (4.0 mL) and stirred for 2 minutes. The mixture was extracted with DCM (2 × 4.0 mL). The combined organic phase was washed with brine (2 × 2.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5μm, conditions: water (10mM NH4HCO3-ACN, start B:37, end B:67, gradient time (min):9) to obtain the product (23.1 mg, 0.059 mmol, yield 28%, deuterated purity of 6D: 88.38%) as a solid. 1 1H NMR (400MHz, DMSO-d 6, )δ H =8.73-8.60(m,1H), 7.82-7.70(m,1H), 7.63(dd,2H), 7.11(s,1H), 3.18-3.10(m,2H), 2.81 -2.72(m,4H), 2.06-1.94(m,2H), 1.71-1.61(m,2H), 1.57-1.44(m,1H), 1.28-1.09(m,5H). 19 F NMR (376.5 MHz, DMSO-d6) δ F = -110.124. LCMS R t = 2 minutes chromatography for 0.837 minutes, 10⁻⁸ AB, MS ESI C 19 H 22 D6ClFN3O 2[ M+H] + Calculated value: 390.2, measured value: 390.0. HRMS MS-TOF C 19 H 22 D6ClFN3O 2[ M+H] +The calculated value for this was 390.2225, and the measured value was 390.2195. Deuterated purity: 11.62% for 5D and 88.38% for 6D.

[0234] Example 14. Synthesis of Compound 15 [ka] 2-(4-cyano-1-piperidyl)-N-[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]acetamide (D64): To a solution of [2-(4-cyano-1-piperidyl)acetyl]oxylithium (800 mg, 4.59 mmol) in DCM (10.0 mL), DIEA (5.93 g, 45.9 mmol) and T3P (17.5 g, 23.0 mmol) were added. After stirring at 25°C for 30 minutes, 1,1,1,3,3,3-hexaduterio-2-(triduteriomethyl)propan-2-amine (755.2 mg, 9.19 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (20.0 mL) and extracted with DCM (2 × 20.0 mL). The combined organic layers were washed with brine (60.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (20-40% Â in PE) to obtain the product (590 mg, 2.54 mmol, yield 55%) as an oily substance. 1 1H NMR (400MHz, CDCl3)δ H =6.84(s,1H), 2.89(s,2H), 2.77-2.70(m,2H), 2.67-2.60(m,1H), 2.45-2.31(m,2H), 2.01-1.94(m,2H), 1.92-1.84(m,2H).

[0235] 2-[4-(aminomethyl)-1-piperidyl]-N-[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]acetamide (D65): To a cold (0°C) solution of 2-(4-cyano-1-piperidyl)-N-[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]acetamide (650 mg, 2.80 mmol) in MeOH (5.0 mL), cobalt(II) chloride hexahydrate (333 mg, 1.40 mmol) was added. Then, sodium borohydride (423 mg, 11.2 mmol) was slowly added under N2. After stirring at 25°C for 4 hours, the reaction solution was diluted with 10.0 mL of 5% aqueous ammonium hydroxide solution and extracted with DCM (3 × 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (600 mg, 2.03 mmol, yield 73%) as an oil. 1 1H NMR (400MHz, CDCl3)δ H =7.15-6.90(m,1H), 2.87-2.80(m,4H), 2.63(d,2H), 2.40(s,2H), 2.17 -2.08(m,2H), 1.83-1.69(m,2H), 1.41-1.28(m,1H), 1.26-1.15(m,2H).

[0236] 2-[4-(aminomethyl)-1-piperidyl]-N-[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]acetamide (D66): A mixture of 2-[4-(aminomethyl)-1-piperidyl]-N-[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]acetamide (200 mg, 0.85 mmol) in CH3OD (5.0 mL) was mixed with CH3ONa (228.5 mg, 4.23 mmol). After stirring at 80 °C for 3 days, the mixture was cooled to 25 °C, poured into D2O (10.0 mL), and extracted with DCM (3 × 10.0 mL). The combined organic layer was washed with brine (2 × 40.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (160 mg, 0.54 mmol, yield 64%, deuterated purity of 11D: 92.5%) as an oil. 1 1H NMR (400MHz, CDCl3)δ H=2.88-2.76(m,2H), 2.58(d,2H), 2.16-2.08(m,3H), 1.79-1.68(m,2H), 1.33-1.12(m,5H). HRMS MS-TOF-B C 12 H 15 D 11 N3O[M+H] + The calculated value for this was 239.2761, and the measured value was 239.2692. Deuterated purity: 0.34% for 9D, 7.16% for 10D, and 92.50% for 11D.

[0237] 3-Chloro-N-[[1-[1,1-diduterio-2-oxo-2-[[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]-5-fluorobenzamide (compound 15): To a solution of 3-chloro-5-fluoro-benzoyl chloride (130 mg, 0.67 mmol) in DCM (3.0 mL), DIEA (693 mg, 5.37 mmol) and T3P (1.53 g, 2.01 mmol) were added. After stirring at 25°C for 30 minutes, 2-[4-(aminomethyl)-1-piperidyl]-2,2-diduterio-N-[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]acetamide (160 mg, 0.67 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (5.0 mL) and extracted with DCM (2 × 10.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (20-40% of siRNA in PE) to obtain the product, which was then purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the solid product (56.1 mg, 0.14 mmol, yield 21%, deuterated purity of 11D: 91.70%). 1 1H NMR (400MHz, DMSO-d6)δ H=8.70-8.61(m,1H), 7.76(s,1H), 7.67-7.60(m,2H), 7.12(s,1H), 3.19-3.10(m,2H), 2.80 -2.73(m,2H), 2.07-1.95(m,2H), 1.70-1.61(m,2H), 1.58-1.46(m,1H), 1.24-1.13(m,2H). 19 F NMR (376.5 MHz, DMSO-d6) δ F = -110.124. LCMS R t = 1.081 min by chromatography at 2.0 min, 0-60 AB, MS ESI C 19 H 17 D 11 ClFN3O 2[ M+H] + Calculated value: 395.3, measured value: 395.3. HRMS MS-TOF-B C 19 H 17 D 11 ClFN3O 2[ M+H] + The calculated value for this was 395.2539, and the measured value was 395.2516. Deuterated purity: 0.37% for 9D, 7.93% for 10D, and 91.70% for 11D.

[0238] Example 15. Synthesis of Compound 16 [ka] 3-Chloro-5-fluoro-N-[[2,2,6,6-tetraduterio-1-[2-oxo-2-[[2,2,2-triduterio-1,1-bis(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]benzamide (compound 16): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,6,6-tetraduterio-1-piperidyl]acetyl]oxylithium (50.0 mg, 0.15 mmol) in DCM (2.0 mL), T3P (0.90 g, 1.18 mmol) and DIEA (0.20 mL, 1.48 mmol) were added at 25°C. After stirring for 10 minutes, 1,1,1,3,3,3-hexaduterio-2-(triduteriomethyl)propan-2-amine (24.3 mg, 0.30 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The mixture was poured into water (4.0 mL) and stirred for 2 minutes. The aqueous phase was extracted with DCM (2 × 4.0 mL). The combined organic phases were washed with brine (2 × 2.0 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm, conditions: water (10 mM NH₄HCO₃)-ACN, start B 42, end B 72, gradient time (min) 9) to obtain the product (10.1 mg, 0.03 mmol, yield 17%, deuterated purity of 13D: 83%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.72-8.59(m,1H), 7.80-7.74(m,1H), 7.68-7.59(m,2H), 7.17-7.03(m,1H), 3.18-3. 10(m,2H), 2.82-2.70(m,2H), 1.69-1.59(m,2H), 1.58-1.46(m,1H), 1.23-1.11(m,2H). 19 F NMR (376.5 MHz, DMSO-d6) δ F -110.132. LCMS R t = 0.893 minutes by chromatography at 2.0 minutes, 10⁻⁸ AB, MS ESI C 19 H 15 D 13 ClFN3O 2[ M+H] + Calculated value: 397.3, measured value: 397.2. HRMS MS-TOF C 19 H 15 D 13 ClFN3O 2[ M+H] +The calculated value for this is 397.2665, and the measured value is 397.2622. Deuterated purity: 1.0% 9D, 0.9% 10D, 1.9% 11D, 11.9% 12D, 82.8% 13D, 0.6% 14D, and 0.9% 15D.

[0239] Example 16. Synthesis of Compound 17 [ka] 2-(4-cyano-1-piperidyl)-N-[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]acetamide (D67): To a solution of [2-(4-cyano-1-piperidyl)acetyl]oxylithium (1.0 g, 5.74 mmol) in DCM (20.0 mL), DIEA (7.41 g, 57.4 mmol) and T3P (21.8 g, 28.7 mmol) were added. After stirring at 25°C for 30 minutes, 1,1,1,3,3,3-hexaduterio-2-methylpropane-2-amine hydrochloride (332 mg, 2.87 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (80.0 mL) and extracted with DCM (3 × 40.0 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (60-80% siRNA in PE) to obtain the product (350 mg, 1.53 mmol, yield 27%) as an oily substance. 1 1H NMR (400MHz, CDCl3)δ H =6.85(s,1H), 2.90(s,2H), 2.78-2.58(m,3H), 2.46-2.31(m,2H), 2.03-1.93(m,2H), 1.92-1.81(m,2H), 1.34(s,3H).

[0240] 2-[4-(aminomethyl)-1-piperidyl]-N-[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]acetamide (D68): To a cold (0°C) solution of 2-(4-cyano-1-piperidyl)-N-[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]acetamide (350 mg, 1.53 mmol) in methanol (10.0 mL), cobalt(II) chloride hexahydrate (182 mg, 0.76 mmol) was added, followed by the gradual addition of sodium borohydride (260 mg, 6.87 mmol) under N2. After stirring at 25°C for 16 hours, the reaction solution was diluted with 25.0 mL of 5% aqueous ammonium hydroxide solution and extracted with DCM (3 × 10.0 mL). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (330 mg, 1.41 mmol, yield 93%) as an oily substance, which was used in the next step without further purification. 1 1H NMR (400MHz, CDCl3)δ H =7.07(s,1H), 2.89-2.80(m,4H), 2.65-2.52(m,2H), 2.18-2.06(m,2H), 1.82-1.67(m,2H), 1.37-1.30(m,3H), 1.27-1.08(m,3H).

[0241] 2-[4-(aminomethyl)-1-piperidyl]-2,2-diduterio-N-[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]acetamide (D69): To a solution of 2-[4-(aminomethyl)-1-piperidyl]-N-[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]acetamide (330 mg, 1.41 mmol) in CH3OD (8.0 mL, 1.41 mmol), CH3ONa (382 mg, 7.07 mmol) was added. After stirring at 80°C for 3 days, the mixture was concentrated, diluted with D2O (20.0 mL), and extracted with DCM (3 × 10.0 mL). The combined organic layer was washed with brine (2 × 40.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (240 mg, 0.71 mmol, yield 51%, deuterated purity of 8D: 85.8%) as an oil. LCMS R t= 2.0 min chromatography for 0.236 min, 0-60 AB, MS ESI C 12 H 18 D8N3O[M+H] + Calculated value: 236.3, measured value: 236.3. HRMS MS-TOF-B C 12 H 18 D8N3O[M+H] + The calculated value for this was 236.2573, and the measured value was 236.2572. Deuterated purity: 1.0% for 6D, 13.2% for 7D, and 85.8% for 8D.

[0242] 3-Chloro-N-[[1-[1,1-diduterio-2-oxo-2-[[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]-5-fluorobenzamide (compound 17): To a solution of 3-chloro-5-fluorobenzoic acid (178 mg, 1.02 mmol) in DCM (10.0 mL), DIEA (1.05 g, 8.16 mmol) and T3P (2.33 g, 3.06 mmol) were added. After stirring at 25°C for 30 minutes, 2-[4-(aminomethyl)-1-piperidyl]-2,2-diduterio-N-[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]acetamide (240 mg, 1.02 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (30.0 mL) and extracted with DCM (2 × 20.0 mL). The combined organic layers were washed with brine (40.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 10 / 1) to obtain the product (140 mg), which was then purified by preparative TLC (DCM / MeOH = 15 / 1) to obtain the product (47.52 mg, 0.14 mmol, yield 20%, deuterated purity of 8D: 86.8%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H=8.74-8.56(m,1H), 7.76(s,1H), 7.68-7.60(m,2H), 7.12(s,1H), 3.19-3.06(m,2H), 2.81-2.71( m,2H), 2.06-1.95(m,2H), 1.75-1.59(m,2H), 1.56-1.44(m,1H), 1.25(s,3H), 1.22-1.11(m,2H). 19 F NMR (376.5 MHz, DMSO-d6) δ F = -110.124. LCMS R t = 0.815 min chromatography for 1.5 min, 5-95AB, MS ESI C 19 H 20 D8ClFN3O 2[ M+H] + Calculated value: 392.0, measured value: 392.0. HRMS MS-TOF-B C 19 H 20 D8ClFN3O 2[ M+H] + The calculated value for this was 392.2351, and the measured value was 392.2407. Deuterated purity: 0.8% for 6D, 12.4% for 7D, and 86.8% for 8D.

[0243] Example 17. Synthesis of Compound 18 [ka] 3-Chloro-N-[diduterio-[1-[2-oxo-2-[(2,2,2-triduterio-1,1-dimethyl-ethyl)amino]ethyl]-4-piperidyl]methyl]-5-fluorobenzamide (compound 18): A solution of 2-[4-[[(3-chloro-5-fluoro-benzoyl)amino]-diduterio-methyl]-1-piperidyl]acetic acid (80 mg, 0.24 mmol) in DCM (1.0 mL) is mixed with DIEA (0.42 mL, 2.42 0.28 g, 0.73 mmol) and T3P were added at 25°C. After stirring for 20 minutes, 1,1,1,3,3,3-hexaduterio-2-methylpropan-2-amine (57.4 mg, 0.73 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (1.0 mL) and extracted with DCM (2 × 1.0 mL). The combined organic layers were washed with brine (1.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the solid product (60.0 mg, 0.15 mmol, yield 63%). This was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 34, end B: 64, gradient time (min): 8, 100% B retention time (min): 2, flow rate (mL / min): 30) to obtain the solid product (35.4 mg, 0.09 mmol, deuterated purity of 8D: 80.47%). 1 HNMR (400 MHz, DMSO-d6)δ H =8.65(s,1H), 7.76(s,1H), 7.67-7.59(m,2H), 7.11(s,1H), 2.82-2.72(m,4H), 2.06 -1.96(m,2H), 1.70-1.61(m,2H), 1.55-1.45(m,1H), 1.25(s,3H), 1.22-1.11(m,2H). LCMS R t = 0.833 min chromatography at 2.0 min, 10⁻⁸ AB, MS ESI C 19 H 20 D8ClFN3O 2[ M+H] + Calculated value: 392.2, measured value: 392.2. HRMS MS-TOF C 19 H 20 D8ClFN3O 2[ M+H] + The calculated value for this is 392.2351, and the measured value is 392.2391. Deuterated purity: 0.15% for 5D, 1.85% for 6D, 17.53% for 7D, and 80.47% for 8D.

[0244] Example 18. Synthesis of Compound 19 [ka] 3-Chloro-5-fluoro-N-[[2,2,6,6-tetraduterio-1-[2-oxo-2-[[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]benzamide (compound 19): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,6,6-tetraduterio-1-piperidyl]acetyl]oxylithium (50.0 mg, 0.15 mmol) in DCM (2.0 mL), DIEA (0.20 mL, 1.48 mmol) and T3P (0.90 g, 1.18 mmol) were added at 25°C. After stirring for 10 minutes, 1,1,1,3,3,3-hexaduterio-2-methylpropane-2-amine hydrochloride (34.1 mg, 0.30 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. The mixture was poured into water (4.0 mL) and stirred for 2 minutes. The aqueous phase was extracted with DCM (2 × 4.0 mL). The combined organic phases were washed with brine (2 × 2.0 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm, conditions: water (10 mM NH₄HCO₃)-ACN, start B 42, end B 72, gradient time (min) 9) to obtain the product (4.67 mg, 0.01 mmol, yield 8%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.69-8.60(m,1H), 7.80-7.71(m,1H), 7.64(dd,2H), 7.16-7.03(m,1H), 3.18-3.10(m, 2H), 2.78(s,2H), 1.68-1.59(m,2H), 1.58-1.45(m,1H), 1.25(s,3H), 1.21-1.12(m,2H). 19 F NMR (376.5 MHz, DMSO-d6) δ F -110.132. LCMS R t = 0.899 min by chromatography at 2.0 min, 10⁻⁸ AB, MS ESI C 19 H 18 D 10 ClFN3O2[ M+H] + Calculated value: 394.2, measured value: 394.2. HRMS MS-TOF C 19 H 18 D 10 ClFN3O 2[ M+H] + The calculated value for this is 394.2476. Measured value: 394.2430. Deuterated purity: 1.2% 7D, 2.6% 8D, 15.0% 9D, and 81.2% 10D.

[0245] Example 19. Synthesis of Compound 20 [ka] 3-Chloro-5-fluoro-N-[[2,2,3,3,4,5,5,6,6-nonaduterio-1-[2-oxo-2-[[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]benzamide (compound 20): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,3,3,4,5,5,6,6-nonaduterio-1-piperidyl]acetyl]oxylithium (100 mg, 0.29 mmol) in DCM (3.0 mL), DIEA (0.40 mL, 2.91 mmol) and T3P (664 mg, 0.87 mmol) were added. After stirring at 25°C for 20 minutes, 1,1,1,3,3,3-hexaduterio-2-methylpropane-2-amine hydrochloride (50.5 mg, 0.44 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (10.0 mL) and extracted with DCM (2 × 10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product. This product was purified by preparative HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm, conditions: water (0.05% NH3H2O)-ACN, start B: 34, end B: 64, gradient time (min): 8, 100% B retention time (min): 2, flow rate (mL / min): 30, injection: 5) to obtain the product (37.43 mg, 0.09 mmol, yield 32%) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =7.52(s,1H), 7.39(d,1H), 7.25-7.20(m,1H), 7.04(s,1H), 6.26-6.16(m,1H), 3.36(d,2H), 2.87(s,2H), 1.34(s,3H). 19 F NMR (376.5 MHz, CDCl3) δ F =-109.207. LCMS R t = 3.0 minutes chromatography for 1.917 minutes, 10⁻⁸ CD, MS ESI C 19 H 13 D 15 ClFN3O 2[ M+H] + The calculated value for this is 399.2, and the measured value is 399.2.

[0246] Example 20. Synthesis of Compound 21 [ka] 2-(4-cyano-1-piperidyl)-N-(2,2,2-triduterio-1,1-dimethylethyl)acetamide (D70): To a solution of [2-(4-cyano-1-piperidyl)acetyl]oxylithium (1.0 g, 5.74 mmol) in DCM (20.0 mL), DIEA (7.41 g, 57.4 mmol) and T3P (21.8 g, 28.7 mmol) were added. After stirring at 25°C for 30 minutes, 1,1,1-triduterio-2-methylpropane-2-amine hydrochloride (300 mg, 2.66 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction product was quenched with water (60.0 mL) and extracted with DCM (3 × 20.0 mL). The combined organic layers were washed with brine (60.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (60-80% siRNA in PE) to obtain the product (300 mg, 1.33 mmol, yield 23%) as an oily substance. 1 1H NMR (400MHz, CDCl3)δ H =6.92-6.64(m,1H), 2.88(s,2H), 2.78-2.66(m,2H), 2.65-2.57(m,1H) , 2.43-2.31(m,2H), 2.02-1.91(m,2H), 1.91-1.79(m,2H), 1.33(s,6H).

[0247] 2-[4-(aminomethyl)-1-piperidyl]-N-(2,2,2-triduterio-1,1-dimethylethyl)acetamide (D71): To a cold (0°C) solution of 2-(4-cyano-1-piperidyl)-N-(2,2,2-triduterio-1,1-dimethyl-ethyl)acetamide (300 mg, 1.33 mmol) in methanol (10.0 mL), cobalt(II) chloride hexahydrate (158 mg, 0.66 mmol) was added, followed by the gradual addition of sodium borohydride (226 mg, 5.96 mmol) under N2. After stirring at 25°C for 16 hours, the reaction solution was diluted with 25.0 mL of 5% aqueous ammonium hydroxide solution and extracted with DCM (3 × 10.0 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (260 mg, 1.13 mmol, yield 85%) as an oily substance, which was used in the next step without further purification. 1 1H NMR (400MHz, CDCl3)δ H =7.17-6.98(m,1H), 2.91-2.71(m,4H), 2.68-2.62(m,1H), 2.19-2.02(m,2H), 1.81-1.67(m,2H), 1.34(s,6H), 1.32-1.08(m,4H).

[0248] 2-[4-(aminomethyl)-1-piperidyl]-2,2-diduterio-N-(2,2,2-triduterio-1,1-dimethylethyl)acetamide (D72): To a solution of 2-[4-(aminomethyl)-1-piperidyl]-N-(2,2,2-triduterio-1,1-dimethyl-ethyl)acetamide (170 mg, 0.74 mmol) in CH3OD (5.0 mL, 5.90 mmol), CH3ONa (199 mg, 3.69 mmol) was added. After stirring at 80°C for 3 days, the mixture was concentrated, diluted with D2O (20.0 mL), and extracted with DCM (3 × 10.0 mL). The combined organic layers were washed with brine (2 × 40.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (140 mg, 0.42 mmol, yield 57%, deuterated purity of 5D: 95.9%) as an oil. HRMS MS-TOF-B C 12 H 21 D5N3O[M+H] +The calculated value for this is 233.2384, and the measured value is 233.2389. Deuterated purity: 4.12% for 4D, and 95.9% for 5D.

[0249] 3-Chloro-N-[[1-[1,1-diduterio-2-oxo-2-[(2,2,2-triduterio-1,1-dimethyl-ethyl)amino]ethyl]-4-piperidyl]methyl]-5-fluorobenzamide (compound 21): To a solution of 3-chloro-5-fluorobenzoic acid (105 mg, 0.60 mmol) in DCM (8.0 mL), DIEA (622 mg, 4.82 mmol) and T3P (1.37 g, 1.81 mmol) were added. After stirring at 25°C for 20 minutes, 2-[4-(aminomethyl)-1-piperidyl]-2,2-diduterio-N-(2,2,2-triduterio-1,1-dimethyl-ethyl)acetamide (140 mg, 0.60 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (30.0 mL) and extracted with DCM (2 × 20.0 mL). The combined organic layers were washed with brine (40.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM / MeOH = 10 / 1) to obtain the product, which was then purified by preparative TLC (DCM / MeOH = 15 / 1) to obtain the solid product (41.77 mg, 0.11 mmol, yield 18%, 5D deuterated purity: 95.5%). 1 1H NMR (400MHz, DMSO-d6)δ H =8.71-8.58(m,1H), 7.76(s,1H), 7.66-7.63(m,1H), 7.63-7.59(m,1H), 7.12(s,1H), 3.20-3.11(m,2H), 2. 82-2.70(m,2H), 2.08-1.96(m,2H), 1.70-1.61(m,2H), 1.58-1.46(m,1H), 1.25(s,6H), 1.23-1.12(m,2H). 19 F NMR (376.5 MHz, DMSO-d6) δ F = -110.124. LCMS R t = 0.823 min chromatography at 1.5 min, 5-95AB, MS ESI C 19 H23 D5ClFN3O 2[ M+H] + Calculated value: 389.0, measured value: 389.0. HRMS MS-TOF-B C 19 H 23 D5ClFN3O2[M+H] + The calculated value for this is 389.2162, and the measured value is 389.2136. Deuterated purity: 4.47% for 4D, and 95.5% for 5D.

[0250] Example 21. Synthesis of Compound 22 [ka] 3-Chloro-5-fluoro-N-[[2,2,6,6-tetraduterio-1-[2-oxo-2-[(2,2,2-triduterio-1,1-dimethyl-ethyl)amino]ethyl]-4-piperidyl]methyl]benzamide (compound 22): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-2,2,6,6-tetraduterio-1-piperidyl]acetyl]oxylithium (50.0 mg, 0.15 mmol) in DCM (2.0 mL), DIEA (0.20 mL, 1.48 mmol) and T3P (0.90 g, 1.18 mmol) were added at 25°C. After stirring for 10 minutes, 1,1,1-triduterio-2-methylpropane-2-amine hydrochloride (33.3 mg, 0.30 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. The mixture was poured into water (4.0 mL) and stirred for 2 minutes. The aqueous phase was extracted with DCM (2 × 4.0 mL). The combined organic phase was washed with brine (2 × 2.0 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (column: Welch Xtimate C18 150×25mm×5μm, conditions: water (10mM NH4HCO3)-ACN, start B 42, end B 72, gradient time (min) 9) to obtain the product (4.20 mg, 0.01 mmol, yield 7%, deuterated purity of 7D: 89.1%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H=8.70-8.60(m,1H), 7.81-7.71(m,1H), 7.67-7.57(m,2H), 7.19-7.04(m,1H), 3.20-3.08(m,2 H), 2.82-2.72(m,2H), 1.69-1.59(m,2H), 1.57-1.46(m,1H), 1.26(s,6H), 1.21-1.11(m,2H). 19 F NMR (376.5 MHz, DMSO-d6) δ F -110.132. LCMS R t = 2 minutes chromatography, 0.893 minutes, 10⁻⁸ AB, MS ESI C 19 H 21 D7ClFN3O 2[ M+H] + Calculated value: 391.2, measured value: 391.1. HRMS MS-TOF C 19 H 21 D7ClFN3O 2[ M+H] + The calculated value for this was 391.2288, and the measured value was 391.2248. Deuterated purity: 1.8% 5D, 8.0% 6D, 89.1% 7D, 0.4% 8D, and 0.7% 10D.

[0251] Example 22. Synthesis of Compound 23 [ka] 3-Chloro-5-fluoro-N-[[3,3,5,5-tetraduterio-1-[2-oxo-2-[[2,2,2-triduterio-1-methyl-1-(triduteriomethyl)ethyl]amino]ethyl]-4-piperidyl]methyl]benzamide (compound 23): To a solution of [2-[4-[[(3-chloro-5-fluorobenzoyl)amino]methyl]-3,3,5,5-tetraduterio-1-piperidyl]acetyl]oxylithium (80.0 mg, 0.24 mmol) in DCM (1.0 mL), DIEA (305 mg, 2.36 mmol) and T3P (1.44 g, 1.89 mmol) were added. After stirring at 25°C for 30 minutes, 1,1,1,3,3,3-hexaduterio-2-methylpropane-2-amine hydrochloride (37.4 mg, 0.32 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (5.0 mL) and extracted with DCM (2 × 10.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenommenex Genmini-NX 80×40mm×3μm, conditions: water (0.05% NH3H2O)-ACN, start B:42, end B:72) to obtain the product, which was then purified by preparative TLC (DCM / MeOH=10 / 1) to obtain the product (4.47 mg, 0.01 mmol, yield 4%, deuterated purity of 10D: 70.43%) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.72-8.63(m,1H), 7.76(s,1H), 7.64(d,2H), 7.12(s,1H), 3.20-3.11(m, 2H), 2.82-2.73(m,4H), 2.05-1.97(m,2H), 1.54-1.46(m,1H), 1.25(s,3H). 19 F NMR (376.5 MHz, DMSO-d6) δ F -110.120. LCMS R t = 1.087 min by chromatography at 2.0 min, 0-60 AB, MS ESI C 19 H 18 D 10 ClFN3O 2[ M+H] + Calculated value: 394.2, measured value: 394.2. HRMS MS-TOF C 19 H 18 D 10 ClFN3O 2[ M+H] +The calculated value for this is 394.2476, and the measured value is 394.2469. Deuterated purity: 0.24% 5D, 2.14% 6D, 3.14% 7D, 4.69% 8D, 18.04% 9D, 70.43% 10D, and 1.32% 11D.

[0252] Example 23. Hμrel low clearance assay The Hμrel low clearance assay was performed to determine the stability of the deuterated compounds described herein and to calculate the change in clearance against a control compound (non-deuterated compound) having the following structure. [ka]

[0253] Experimental Procedure The culture medium in the HμREL Human Pool® 96-well liver co-culture plates was changed, and the cells were acclimatized at 37°C for 20 hours. Test compounds diluted from HμREL® incubation medium (serum-free) and 1000x DMSO stock (final substrate concentration 1 μM, final DMSO concentration 0.1%) were added to the HμREL® 96-well co-culture system to a final cell count of 30,000 cells per well, and the reaction was initiated. The final incubation volume at each time point was 80 μL and included two control compounds (ketoprofen and prednisolone) for reference. All clearance evaluations were performed singly, except for the non-deuterated control compound, which was tested a total of four times (duplicate) on two different days. Each compound was incubated for 0, 2, 6, 24, 48, and 72 hours. At the appropriate time, the reaction was terminated by transferring 60 μL of incubation to 180 μL of acetonitrile containing an internal standard. The crush plate was centrifuged at 3000 rpm for 20 minutes at 4°C to precipitate residual proteins. After protein precipitation, the sample supernatant was collected in cassettes of up to four compounds and analyzed using standard LC-MS / MS conditions.

[0254] Data Analysis The LC-MS / MS chromatogram was analyzed using the peak area ratio (peak area of ​​the test substance / internal standard peak area) and natural logarithmic transformation, and plotted against time. The slope of the line was determined, and the elimination rate constant was calculated. Subsequently, the half-life (t) was calculated. 1 / 2 ) and inherent clearance (CL int ) was calculated using the following equation: The vanishing rate constant (k) = (-gradient) Half-life (t 1 / 2 )(minutes)=

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[0255] The mean clearance of the control compound was determined by taking the geometric mean of three out of four replicates. The fourth replicate was excluded from the mean determination as an outlier. Subsequently, the percentage of intrinsic clearance relative to the control compound was calculated for each test compound by dividing the observed intrinsic clearance by the mean intrinsic clearance of the control compound, and significance was observed for compounds with intrinsic clearance of less than 2 geometric standard deviations from the mean control compound GeoMean.

[0256] The results of the HμREL clearance assay are shown in Table 1 below. As shown in Table 1, some of the disclosed compounds showed significantly reduced clearance compared to the control compounds, indicating improved bioavailability. [Table 2]

[0257] Example 24. CYP3A4 clearance assay The CYP3A4 clearance assay was performed to determine the stability of the deuterated compounds described herein and to calculate the change in clearance against a control compound (non-deuterated compound) having the following structure. [ka]

[0258] Experimental Procedure Recombinant CYP3A4 supersomes were prepared in 100 mM potassium phosphate buffer (50 pmol / mL final recombinase), and 80 μL aliquots per well were delivered to a 96-well reaction plate containing 10 μL / well working solution with the substrate at 10 times the final concentration in 0.1:9.9:90 DMSO:ACN:100 mM phosphate buffer. The final substrate concentration during incubation was 1 pM. After pre-incubating the reaction mixture at 37°C for 10 minutes, 10 μL / well of NADPH regeneration system (β-nicotinamide adenine dinucleotide phosphate) or 100 mM phosphate was added as a buffer control to initiate the reaction.

[0259] Clearance assessment was performed once for each test compound, except for the control compound which was tested three times. Incubation was maintained at 37°C for 0, 5, 15, 30, 45, 60, 90, and 120 minutes (or 0 and 120 minutes for the buffer control). The reaction was terminated with three times the volume of cold (4°C) acetonitrile (ACN) containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS). The crushed plates were centrifuged at 4000 rpm for 20 minutes at 4°C to precipitate residual proteins. After protein precipitation, the sample supernatant was collected and three times the volume of HPLC-grade water was added to each sample for chromatographic purposes. The plates were sealed and shaken for 10 minutes, and then LCMS / MS analysis was performed using standard LCMS / MS conditions.

[0260] Data Analysis The LC-MS / MS chromatogram was analyzed using the peak area ratio (peak area of ​​the test substance / internal standard peak area) and natural logarithmic transformation, and plotted against time. The slope of the line was determined, and the elimination rate constant was calculated. Subsequently, the half-life (t) was calculated. 1 / 2 ) and inherent clearance (CL int ) was calculated using the following equation: The vanishing rate constant (k) = (-gradient) Half-life (t 1 / 2 )(minutes)=

number

number

[0261] The mean intrinsic clearance of the control compound was determined by taking the geometric mean of three replicates. Subsequently, the percentage of intrinsic clearance relative to the control compound was calculated for each test compound by dividing the observed intrinsic clearance by the mean intrinsic clearance of the control compound, and significance was observed for compounds with an intrinsic clearance of less than 2 geometric standard deviations from the mean control compound GeoMean.

[0262] The results of the CYP3A4 clearance assay are shown in Table 2 below. As shown in Table 2, some of the disclosed compounds showed significantly reduced clearance compared to the control compounds, indicating improved bioavailability. [Table 3]

[0263] Equivalents and range In the claims, articles such as “a,” “an,” and “the” may mean one or more unless otherwise indicated or the context makes it clear. A claim or specification containing “or” between one or more elements of a group is deemed satisfied if one, two or more, or all of the elements of the group are present in, used in, or related to a given product or process, unless otherwise indicated or the context makes it clear. The present invention includes embodiments in which exactly one element of the group is present in, used in, or related to a given product or process. The present invention includes embodiments in which two or more, or all, elements of the group are present in, used in, or related to a given product or process.

[0264] Furthermore, the invention encompasses all variations, combinations, and rearrangements in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. If elements are presented as a list, for example in Markush group form, each subgroup of elements is also disclosed, and any element may be removed from this group. In general, where the present invention or an aspect of the invention is deemed to include certain elements and / or features, it should be understood that certain embodiments or aspects of the invention consist of, or essentially consist of, such elements and / or features. For the sake of brevity, those embodiments are not specifically described verbatim in this specification. It should also be noted that the terms “including” and “containing” are intended to be open and may allow for the inclusion of additional elements or steps. Where a scope is given, endpoints are included. Furthermore, unless otherwise indicated or is evident from the context and the understanding of those skilled in the art, values ​​expressed as a range may, unless otherwise clearly indicated by the context, be any specific value or subrange within the range described in different embodiments of the present invention, up to one-tenth of the lower limit unit of the range.

[0265] This application references various published patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any of the incorporated references and this specification, this specification shall prevail. In addition, any particular embodiment of the Invention within the scope of the prior art may be clearly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not clearly stated herein, as they are considered to be known to those skilled in the art. Any particular embodiment of the Invention may be excluded from any claim for any reason, whether or not it relates to the existence of the prior art.

[0266] Those skilled in the art will be able to recognize or confirm many equivalents to the specific embodiments described herein by means of routine experiments alone. The scope of the embodiments described herein is not intended to be limited to embodiments for carrying out the above invention, but rather as described in the appended claims. Those skilled in the art will understand that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims. In embodiments of the present invention, for example, the following items are provided. (Item 1) Compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1a 、R 1b 、R 2a 、R 2b 、R 6 , and R 7 Each of them is independently hydrogen or deuterium, R 3 、R 4 , and R 5 Each of these is -C(R a ) 3 And each Ra These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R 1a 、R 1b 、R 2a 、R 2b 、R 6 、R 7 , and R a At least one of them is deuterium, however, the compound is

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Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ６ , and R ７ Each of them is independently hydrogen or deuterium, R ３ , R ４ , and R ５ each is -C(R ａ ), ３ and each R ａ is independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ６ , R ７ , and R ａ At least one of them is deuterium, however, the compound is 【Chemistry 2】 A compound or a pharmaceutically acceptable salt thereof, other than its pharmaceutically acceptable salt.

2. The aforementioned compound is a compound of formula (I-A), 【Transformation 3】 or a pharmaceutically acceptable salt thereof, in the formula, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ , R ７ , and m are defined for equation (I), R ６ａ , R ６ｂ , R ６ｃ , and R ６ｄ At least one of them is deuterium, R ６ｅ , R ６ｆ , R ６ｇ , R ６ｈ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each of them is independently hydrogen or deuterium.

3. R １ａ , R １ｂ , R ２ａ , and R ２ｂ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein at least one of the elements is deuterium.

4. R １ａ , R １ｂ , R ２ａ , and R ２ｂ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

5. R ａ A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein at least one of the elements is deuterium.

6. (i) R ３ However, -CH ３ Or -CD ３ is, or (ii) R ４ However, -CH ３ Or CD ３ is, or (iii) R ５ However, -CH ３ Or -CD ３ Is it, or any combination of (i) to (iii), the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

7. R ６ The compound according to any one of claims 1 and 3 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is deuterium.

8. n is an integer selected from 1 to 9, and R ６ The compound according to any one of claims 1 and 3 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound is deuterium.

9. n is 9, R ６ The compound according to any one of claims 1 and 3 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound is deuterium.

10. R ７ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the compound is deuterium.

11. A compound selected from the following group: 【Chemistry 4】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 、 【change】 , and 【change】 、 or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein the compound has an isotopic enrichment factor of at least 4500 (67.5% deuterium contamination) for each deuterium present at a site designated as a site on the compound where deuteration is possible.

13. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein the compound has an isotopic enrichment factor of at least 5000 (75% deuterium contamination) for each deuterium present at a site designated as a site on the compound where deuteration is possible.

14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

15. Compound of formula (I), 【Transformation 5】 A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ６ , and R ７ Each of them is independently hydrogen or deuterium, R ３ , R ４ , and R ５ Each of these is -C(R ａ ) ３ And each R ａ These are independently hydrogen or deuterium, n is an integer selected from 0 to 9. m is an integer selected from 0 to 3. R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ６ , R ７ , and R ａ A pharmaceutical composition in which at least one of the elements is deuterium.

16. A composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14 or 15, for use in the treatment of neurological disorders, mental disorders, pain, tremors, seizures, epilepsy, or epileptic syndromes.

17. The composition according to claim 16, wherein the mental disorder is a mood disorder or major depressive disorder.

18. The composition according to claim 16, wherein the tremor is an essential tremor.

19. The composition according to claim 16, wherein the seizure is an absence seizure.

20. The composition according to claim 16, wherein the epilepsy is juvenile myoclonic epilepsy.

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