Muscarinic receptor 4 antagonists and methods of use

Abstract

The present invention relates to compounds of formula (Ia), pharma- ceutically acceptable salts of the compounds of formula (Ia), and pharmaceutical compositions thereof, that modulate the activity of the muscarinic acetylcholine receptor M4. TIFF2024528091000139.tif3364 The compounds, pharmaceutical salts of the compounds and pharmaceutical compositions of the present invention relate to methods useful for treating or preventing neurological diseases, disorders or conditions and symptoms associated therewith. One aspect of the present invention relates to pharmaceutical products selected from pharmaceutical compositions, formulations, unit dosage forms, and kits each comprising a compound of the present invention or a pharma-ceutical acceptable salt thereof.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compounds of formula (Ia) and pharmaceutical compositions thereof that modulate the activity of muscarinic acetylcholine receptor M4. The compounds of the present invention and pharmaceutical compositions thereof are useful for treating or preventing neurological diseases, disorders, or symptoms, such as Tourette's syndrome (TS), Alzheimer's disease (AD), schizophrenia, dementia with Lewy bodies (LBD), cognitive impairment associated with schizophrenia, Parkinson's disease, parkinsonism, tremor, dyskinesia, excessive daytime sleepiness, dystonia, chorea, levodopa-induced dyskinesia, attention deficit hyperactivity disorder (ADHD), cerebral palsy, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), Huntington's disease (HD), and chorea associated with Huntington's disease and symptoms thereof. [Background technology]

[0002] Background of the Invention Muscarinic acetylcholine receptors are autonomic receptors that form G protein-receptor complexes in the cell membranes of certain neurons and other cell types (e.g., vascular endothelial cells). Muscarinic receptors are located postsynaptically at parasympathetic effector junctions, where they function to increase or decrease the activity of effector cells. Extrapyramidal symptoms are observed in patients treated with antipsychotic drugs, as well as in patients with neuroleptic malignant syndrome, brain injury (e.g., athetoid cerebral palsy), encephalitis, and meningitis. Drugs other than antipsychotics, such as antidopaminergic drugs (e.g., the antiemetic metoclopramide and the antidepressant amoxapine) and selective serotonin reuptake inhibitors (SSRs), which indirectly reduce dopamine, also cause extrapyramidal symptoms. Symptoms associated with extrapyramidal symptoms include acute dystonic reactions, akathisia, pseudoparkinsonism, and tardive dyskinesia. Extrapyramidal symptoms caused by antipsychotic drugs are treated with anticholinergic drugs that lack selectivity for any of the five muscarinic receptor subtypes (see, for example, Erosa-Rivero et al., Neuropharmacology 81:176-87 (2014)). Classical muscarinic receptor antagonists (e.g., atropine and scopolamine) and 3-quinuclidinyl benzilate (QNB) lack selectivity for human muscarinic acetylcholine receptor subtypes (i.e., M1, M2, M3, M4, and M5) (see, for example, Bolden et al., J Pharmacol Exp Ther. 260 (2):576-580 (1992)). Anticholinergic drugs that act on multiple muscarinic receptors can cause distinct, and sometimes opposing, effects, so therapeutic agents that exhibit selectivity for specific receptors are desirable. For example, M4 antagonists inhibit striatal acetylcholine release, and M2 antagonists increase striatal acetylcholine release (see, e.g., Quik et al., Nicotine & Tobacco Research 21(3):357-369 (2019)). Additionally, the muscarinic receptor pan-antagonist trihexyphenidyl (M1(K i = 1 nM), M2(K i= 20 nM), M3 (K i = 10 nM), M4(K i = 10 nM) and M5 (K i =30 nM) are believed to have use-limiting side effects such as cognitive impairment, tachycardia, and gastrointestinal function associated with antagonism of M1, M2, and M3. Thus, selective M4 antagonists may provide treatment for parkinsonism or dystonia without the side effects associated with inhibiting other muscarinic receptor subtypes (see https: / / doi.org / 10.1101 / 2020.10.12.324152). Despite the advances made in this field, there remains a need in the art for improved M4 antagonists, including compounds, compositions, and methods related thereto. The present disclosure meets these and other needs, as will become apparent with reference to the disclosure that follows. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Erosa-Rivero et al. Neuropharmacology 81:176-87 (2014) [Non-patent document 2] Bolden et al., J Pharmacol Exp Ther. 260(2):576-580 (1992) [Non-patent document 3] Quik et al., Nicotine & Tobacco Research 21(3):357-369(2019) Summary of the Invention [Means for solving the problem]

[0004] Summary of the Invention One aspect of the present invention relates, inter alia, to certain 2-azaspiro[3.3]heptane derivatives of formula (Ia): [ka] [In the formula, Each of X, Y, and Z is independently 8 or N, where R 8 is hydrogen, C1-C4 alkyl, halogen, C1-C4 alkoxy, or cyano; R 1 and R 2 each independently represents hydrogen, halogen, amino, R 10 NH-S(=O)2-, R 9 -S(=O)2-, R 9 -S(=O)-, R 9 -S-, R 9 -S(=O)(=NR 10 )-, R 9 -O-, [ka] (n=1, 2, or 3), cyano, or C1-C4 alkyl, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, where R 9 or [ka] is C1-C4 alkyl, C1-C4 alkoxy, -OH, -NHR 10 , halogen, or cyano, where R 10 is hydrogen, C1-C4 alkyl, or C3-C7 cycloalkyl; or R 1 , R 2 and the carbon atoms to which they are attached form a 3- to 7-membered ring having one or more heteroatoms selected from N, O, and S; X1 is O or NH; X2 is hydrogen or C1-C4 alkyl; R 3 and R 4 are each independently selected from H and C1-C4 alkyl; R 3 and R 4 are attached to different ethylene groups on the piperazine ring; R5 and R 6 are each independently hydrogen or C1-C4 alkyl, or R 5 , R 6 and the carbon atoms to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocyclyl, each of which is a C1-C4 alkyl, a C1-C4 alkoxy, -OH, or -NHR 10 , optionally substituted with halogen, and cyano; R 7 is hydrogen, halogen, or C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with halogen, amino, —OH, C1-C4 alkoxy, or cyano; m is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.

[0005] One aspect of the present invention pertains to pharmaceutical products selected from pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0006] One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0007] One aspect of the present invention relates to a method for preparing a pharmaceutical composition comprising the step of mixing a compound according to the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0008] One aspect of the present invention relates to a method of antagonizing muscarinic receptor 4 (M4) in a cell, comprising contacting the cell with a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0009] One aspect of the present invention relates to a method of treating or preventing a neurological disease, disorder, or condition in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof; a pharmaceutical product of the invention; or a pharmaceutical composition of the invention.

[0010] One aspect of the present invention relates to a method for treating or preventing a muscarinic receptor 4 (M4)-mediated disease, disorder, or symptom in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof; a pharmaceutical product of the invention; or a pharmaceutical composition of the invention.

[0011] One aspect of the present invention pertains to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a neurological disease, disorder, or condition in an individual.

[0012] One aspect of the present invention pertains to the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a muscarinic receptor 4 (M4)-mediated disease, disorder, or condition in an individual.

[0013] One aspect of the present invention pertains to a compound of the present invention or a pharmaceutically acceptable salt thereof; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method of treatment or protection of the human or animal body by therapy.

[0014] One aspect of the present invention pertains to a compound of the present invention, or a pharmaceutically acceptable salt thereof; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention, for use in a method for treating or preventing a neurological disease, disorder, or symptom in an individual.

[0015] One aspect of the present invention pertains to a compound of the present invention or a pharmaceutically acceptable salt thereof; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method for treating or preventing a muscarinic receptor 4 (M4)-mediated disease, disorder, or symptom in an individual.

[0016] These and other aspects of the invention disclosed herein will be set forth in more detail as the patent disclosure proceeds. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description of the Invention definition

[0018] For clarity and consistency, the following definitions are used throughout this patent document.

[0019] As used herein, "administering" refers to providing a compound of the present invention or other treatment, therapy, or procedure to an individual in need of treatment in a form that can be introduced into the individual's body in a therapeutically useful form and in a therapeutically useful amount, including, but not limited to, oral dosage forms such as tablets, capsules, syrups, and suspensions; injectable dosage forms such as IV, IM, and IP; transdermal dosage forms including creams, jellies, powders, and patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories. A healthcare professional can provide the compound directly to an individual in the form of a sample, or can provide the compound indirectly to an individual by providing an oral or written prescription for the compound. Also, for example, an individual can obtain the compound independently without the involvement of a healthcare professional. When the compound is administered to an individual, the body is transformed in some way by the compound. When a compound of the present invention is provided in combination with one or more other agents, "administration" is understood to include administration of the compound and the other agents at the same time or at different times. When agents of a combination are administered simultaneously, they can be administered together in a single composition, or they can be administered separately. The preferred method of administration may vary depending on various factors, such as the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

[0020] The term "composition" refers to a compound or crystalline form thereof, including but not limited to salts, solvates, and hydrates of a compound of the present invention, in combination with at least one additional component, such as compositions obtained / prepared during synthesis, preformulation, in-process testing (e.g., TLC, HPLC, NMR samples), etc.

[0021] The term "hydrate," as used herein, refers to a compound of the present invention or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0022] The terms "in need of treatment," and "in need of," when referring to treatment, are used interchangeably to mean the judgment made by a caregiver (e.g., in the case of humans, a doctor, nurse, medical attendant, etc.; in the case of animals, including non-human mammals, a veterinarian) that an individual or animal needs or will benefit from treatment. This judgment is within the expertise of the caregiver, but is made based on a variety of factors, including knowledge that the individual or animal is ill or will become ill as a result of a disease, condition, or disorder that is treatable by the compounds of the invention. Thus, the compounds of the invention can be used in a protective or preventative manner; or the compounds of the invention can be used to alleviate, inhibit, or alleviate a disease, condition, or disorder.

[0023] The term "individual" or "subject" refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, "individual" refers to a human. In the context of a clinical trial or screening or activity experiment, a subject may be a healthy subject or participant with no potential M4-mediated disorder or symptoms, or a subject or participant who has been diagnosed with a disorder or condition that requires medical treatment as determined by a medical professional. In the context of a non-clinical trial, a subject under the care of a medical professional who has been diagnosed with a disorder or condition is typically referred to as a patient.

[0024] The term "pediatric subject" refers to a subject under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations, including neonates (birth to 1 month old), infants (1 month to 2 years old), children (2 to 12 years old), and adolescents (12 to 21 years old (up to but not including their 22nd birthday)). See, e.g., Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph et al., Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0025] The phrase "pharmaceutically acceptable" refers to compounds (and their salts), compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0026] The term "pharmaceutical composition" refers to a specific composition comprising at least one active ingredient, including, but not limited to, salts, solvates, and hydrates of the compounds of the present invention, such that the composition is suitable for investigation for a defined efficacious outcome in a mammal (e.g., but not limited to, a human). Those of skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based on the needs of the artisan.

[0027] The term "prescribing" refers to directing, authorizing, or recommending the use of a drug or other treatment, therapy, or procedure. In some embodiments, a healthcare provider verbally advises, recommends, or authorizes the use of a compound, dosage regimen, or other treatment to an individual. A healthcare provider may or may not provide a written prescription for a compound, dosage regimen, or treatment. Furthermore, a healthcare provider may or may not provide a compound or treatment to an individual. For example, a healthcare provider may advise an individual on where to obtain a compound without providing the compound. In some embodiments, a healthcare provider may provide an individual with a written prescription for a compound, dosage regimen, or treatment. The prescription may be written on paper or recorded in an electronic medium. Furthermore, the prescription may be telephoned (verbally) or faxed (in writing) to a pharmacy or dispensing pharmacy. In some embodiments, a sample of the compound or treatment is given to the individual. As used herein, giving a sample of the compound constitutes an implicit prescription of the compound. Different healthcare systems around the world use different methods for prescribing and administering compounds or treatments, and these methods are encompassed by the disclosure herein. A healthcare provider can include, for example, a doctor, nurse, nurse practitioner, or other healthcare professional who can prescribe or administer a compound (drug) for a disorder disclosed herein. Additionally, a healthcare provider can include anyone who can recommend, prescribe, administer, or prevent an individual from receiving a compound or drug, including, for example, an insurance provider.

[0028] The terms "prevent," "preventing," and "prevention" refer to the elimination or reduction of the occurrence or onset of one or more symptoms associated with a particular disorder. For example, the terms "prevent," "preventing," and "prevention" can refer to the administration of a treatment on a defensive or prophylactic basis to an individual who may eventually, but has not yet, exhibited at least one symptom of a disorder. Such individuals can be identified based on risk factors known to correlate with subsequent development of the disease, such as the presence of a biomarker. Alternatively, a prophylactic treatment can be administered as a preventative measure without prior identification of risk factors. A delay in the onset of at least one episode and / or symptom of a disorder can also be considered prevention or protection.

[0029] The term "solvate" refers to a solid form of a compound of the present invention (or a pharmaceutically acceptable salt thereof) that contains one or more molecules of a solvent in a stoichiometric or non-stoichiometric amount. When the solvent is water, the solvate is a hydrate. Alternatively, the solvent can be an organic solvent. Organic solvents include, but are not limited to, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, acetone, ethyl methyl ketone, 4-methyl-2-pentanone, cyclohexanone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and ethyl acetate.

[0030] The process for preparing a solvate of the compound of the present invention (or a pharmaceutically acceptable salt thereof) may include: (a) reacting the compound of the present invention (or a pharmaceutically acceptable salt thereof) with a solvent; (b) precipitating the complex from a solution of the compound of the present invention (or a pharmaceutically acceptable salt thereof) and a solvent; and (c) crystallizing the complex from a solution of the compound of the present invention (or a pharmaceutically acceptable salt thereof) and a solvent. The solvate may be in crystalline form. Alternatively, the solvate may be in amorphous form.

[0031] The terms "treat", "treating" and "treatment" refer to the medical management of a disease, disorder or condition of a subject (e.g., patient) (see, for example, Stedman's Medical Dictionary). Generally, an appropriate dosage and treatment regimen provides a sufficient amount of M4 antagonist to provide therapeutic benefit. The therapeutic benefit to a subject to whom the M4 antagonist compound(s) described herein are administered includes, for example, improved clinical outcome, and the purpose is to prevent, slow down or delay (reduce) the undesirable physiological changes associated with a disease, or to prevent, slow down or delay (reduce) the progression or severity of such a disease. The efficacy of one or more M4 antagonists may include beneficial or desired clinical results, including, but not limited to, a diminution, reduction, or alleviation of symptoms resulting from or associated with the disease being treated; a reduction in the occurrence of symptoms; an improvement in quality of life; a longer disease-free state (i.e., a reduction in the likelihood or propensity of a subject to exhibit symptoms based on the criteria by which a diagnosis of the disease is made); a gradual decrease in the extent of the disease; a stabilized (i.e., non-worsening) state of the disease; a delay or slowing of disease progression; a palliation or temporary alleviation of the disease state; and detectable or undetectable (whether partial or total) remission and / or overall survival.

[0032] The term "therapeutically effective amount" refers to an amount of a compound of the invention or a pharmaceutically acceptable salt thereof, or an amount of a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof, that elicits in a tissue, system, animal, or human the biological or medical response that is desired by an individual, researcher, veterinarian, physician, or other clinician or caregiver, which response may include one or more of the following:

[0033] (1) Preventing a disorder, e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but who has not yet experienced or exhibited the associated pathology or symptomology; (2) inhibiting a disorder, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the associated pathology or symptomology (i.e., halting further progression of the pathology and / or symptomology); and

[0034] (3) Alleviating the disorder, e.g., alleviating a disease, symptom, or disorder in an individual experiencing or exhibiting the associated pathology or symptomology (i.e., reversing the pathology and / or symptomology).

[0035] Chemical groups, moieties, or radicals

[0036] The term "amino" refers to the group -NH2.

[0037] "C6~C 10 The term "aryl" refers to a saturated ring system containing 6 to 10 carbon atoms that can include a single ring or two fused rings and is aromatic, such as phenyl and naphthalenyl. When one or more substituents are present on an "aryl" ring, the substituents can be attached to any available ring carbon.

[0038] The terms "C1-C6 alkyl" and "C1-C4 alkyl" refer to saturated straight-chain or branched carbon radicals containing 1 to 6 carbons (i.e., "C1-C6 alkyl") or 1 to 4 carbons (i.e., "C1-C4 alkyl"). Some embodiments are 1 to 5 carbons (i.e., C1-C5 alkyl), some embodiments are 1 to 4 carbons (i.e., C1-C4 alkyl), some embodiments are 1 to 3 carbons (i.e., C1-C3 alkyl), and some embodiments are 1 or 2 carbons. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neo-pentyl, 1-methylbutyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], n-hexyl, and the like.

[0039] The term "C1-C6 alkylamino" refers to a radical consisting of a C1-C6 alkyl group bonded to an NH group, where C1-C6 alkyl has the same meaning as described herein. Some embodiments are "C1-C2 alkylamino." Some examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, s-butylamino, isobutylamino, t-butylamino, and the like.

[0040] The term "C1-C6 alkylcarbamoyl" refers to a radical consisting of a single C1-C6 alkyl group attached to the nitrogen of a carbamoyl group, where carbamoyl and C1-C6 alkyl have the same definitions as found herein. Some embodiments include C1-C4 alkylcarboxamides. Some embodiments include C1-C2 alkylcarboxamides. Examples include N-methylcarboxamide, N-ethylcarboxamide, Nn-propylcarboxamide, N-isopropylcarboxamide, Nn-butylcarboxamide, Ns-butylcarboxamide, N-isobutylcarboxamide, Nt-butylcarboxamide, and the like.

[0041] The term "C1-C4 alkylene" refers to a straight-chain or branched saturated aliphatic divalent radical having one to four carbon atoms. Some embodiments contain one to three carbons (i.e., "C1-C3 alkylene"). Some embodiments contain one or two carbons (i.e., "C1-C2 alkylene"). Some embodiments contain one carbon atom (i.e., CH2). Examples include methylene (i.e., CH2), ethylene (i.e., CH2CH2), n-propylene (i.e., CH2CH2CH2), propane-1,1-diyl [i.e., CH(CH2CH3)], propane-1,2-diyl [i.e., CH2CH(CH3)], n-butylene (i.e., CH2CH2CH2CH2), and the like.

[0042] The term "C1-C6 alkoxy" refers to a radical consisting of a C1-C6 alkyl group directly bonded to an oxygen atom, where C1-C6 alkyl has the same definition as found herein. Some embodiments contain 1 to 5 carbons (i.e., C1-C5 alkoxy). Some embodiments contain 1 to 4 carbons (i.e., C1-C4 alkoxy). Some embodiments contain 1 to 3 carbons (i.e., C1-C3 alkoxy). Some embodiments contain 1 or 2 carbons. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, ses-butoxy, and the like.

[0043] The term "C1-C6 alkoxycarbonyl" refers to a radical consisting of a single C1-C6 alkoxy group where an oxygen is attached to the carbon of the carbonyl group, where C1-C6 alkoxy has the same definition as found herein. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, and the like.

[0044] The term "C1-C6 alkylcarbonyl" refers to a radical consisting of a C1-C6 alkyl group directly bonded to a carbonyl group, where C1-C6 alkyl has the same definition as found herein. Examples include acetyl, propionyl, butyryl, isobutyryl, pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl, pivaloyl, and the like.

[0045] The term "C1-C6 alkylsulfanyl" or "C1-C6 alkylthio" refers to a radical consisting of a C1-C6 alkyl group directly bonded to a sulfur atom, where C1-C6 alkyl has the same definition as found herein. Examples include methylsulfanyl (i.e., -S-CH3), ethylsulfanyl (i.e., -S-CH2CH3), n-propylsulfanyl (i.e., -S-CH2CH2CH3), isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl, t-butylsulfanyl, and the like.

[0046] The term "C1-C6 haloalkyl" refers to a radical consisting of a C1-C6 alkyl group substituted with one or more halogens, where C1-C6 alkyl has the same definition as found herein. A C1-C6 haloalkyl can be fully substituted, in which case it can be represented by the formula C n L 2n+1where L is a halogen and "n" is 1, 2, 3, 4, 5, or 6. When more than one halogen is present, they may be the same or different and may be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, a haloalkyl contains 1 to 5 carbons (i.e., a C1-C5 haloalkyl). In some embodiments, a haloalkyl contains 1 to 4 carbons (i.e., a C1-C4 haloalkyl). In some embodiments, a haloalkyl contains 1 to 3 carbons (i.e., a C1-C3 haloalkyl). In some embodiments, a haloalkyl contains 1 or 2 carbons. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, and the like.

[0047] The term "C1-C6 alkylsulfinyl" refers to a radical consisting of a C1-C6 alkyl radical attached to the sulfoxide radical sulfur of the formula: -S(=O)-, where C1-C6 alkyl has the same definition as described herein. Examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, isobutylsulfinyl, t-butylsulfinyl, and the like.

[0048] The term "carbonyl" refers to the group -C(=O)-.

[0049] The term "C3-C7 cycloalkyl" refers to a saturated ring radical containing 3 to 7 carbons. Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0050] The term "C2-C6 dialkylamino" refers to a radical consisting of an amino group substituted with two alkyl groups, where the alkyl groups can be the same or different, so long as the two alkyl groups together do not exceed a total of six carbon atoms between the two alkyl groups. Some embodiments include C2-C4 dialkylamino. Some examples include dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylbutylamino, methylpentylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino, and the like.

[0051] The term "C2-C6 dialkylcarbamoyl" refers to a radical consisting of two alkyl groups attached to the nitrogen of a carbamoyl group, where the two alkyl groups together do not exceed a total of six carbon atoms between the two alkyl groups. Some embodiments include C2-C4 dialkylaminocarboxamido. Examples include dimethylcarbamoyl, ethyl(methyl)carbamoyl, diethylcarbamoyl, methyl(propyl)carbamoyl, butyl(methyl)carbamoyl, and the like.

[0052] The term "C5-C8 bicycloalkanyl" refers to a cyclic alkyl system characterized by the presence of two atoms called "bridgehead atoms" that are attached to each other through one or more "bridging atoms." Examples include bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octane, and the like.

[0053] The term "C6-C8 bicycloalkenyl" refers to a cyclic alkyl system characterized by the presence of two atoms called "bridgehead atoms" connected to each other through one or more "bridging atoms" and containing one double bond, but the bridgehead carbon is not part of the double bond (i.e., the C6-C8 bicycloalkenyl group follows Brett's rule). Examples include bicyclo[2.1.1]hex-2-enyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.1]hept-5-enyl, bicyclo[3.1.1]hept-2-enyl, bicyclo[2.2.2]oct-2-enyl, bicyclo[3.2.1]oct-2-enyl, bicyclo[3.2.1]oct-3-enyl, bicyclo[3.2.1]oct-6-en-2-yl, and the like.

[0054] The term "carbamoyl" refers to the group -C(=O)NH2.

[0055] The term "cyano" refers to the group --CN.

[0056] The term "ethylene" refers to the group -CH2CH2-.

[0057] The term "halogen" refers to a fluoro, chloro, bromo, or iodo group. In some embodiments, halogen is fluoro, chloro, or bromo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0058] The term "5-10-membered heteroaryl" refers to an aromatic ring system containing 5-10 ring atoms in a single ring or in two fused rings and having at least one ring group selected from O, S, N, and NH. Some embodiments are "5-6-membered heteroaryl," which refers to an aromatic ring containing 5-6 ring atoms in a single ring and having at least one ring group selected from O, S, N, and NH. In some embodiments, "5-10-membered heteroaryl" refers to furanyl, thiophenyl (i.e., thienyl), pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, triazinyl, benzofuranyl, 1H-indolyl, benzo[b]thiophenyl, and the like. In some embodiments, "5- to 10-membered heteroaryl" refers to pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, 1H-indolyl, quinoxalinyl, thiadiazolyl, etc. References to the heteroaryl groups thiophenyl (thienyl), thiophen-2-yl (thien-2-yl), and thiophen-3-yl (thien-3-yl) are understood to correspond to the following structures, respectively: [ka]

[0059] The term "3- to 7-membered heterocyclyl" refers to a non-aromatic ring system containing 3 to 7 ring atoms and having one, two, or three ring groups in the ring system independently selected from O, S, S(=O), S(=O)2, and NH. In some embodiments, "3- to 7-membered heterocyclyl" refers to a non-aromatic ring radical containing 3 to 7 ring atoms and having one or two ring groups in the ring system independently selected from O, S, S(=O), S(=O)2, and NH. In some embodiments, "3- to 6-membered heterocyclyl" refers to a non-aromatic ring radical containing 3 to 6 ring atoms and having one or two ring groups in the ring system independently selected from O, S, S(=O), S(=O)2, and NH. In some embodiments, "4- to 6-membered heterocyclyl" refers to a non-aromatic ring radical containing 4 to 6 ring atoms and having one or two ring groups in the ring system independently selected from O, S, S(=O), S(=O)2, and NH. In some embodiments, the one or two ring groups in the ring system are independently selected from O and NH. Examples of "heterocyclyl" groups include aziridinyl, azetidinyl, piperidinyl, morpholinyl, oxetanyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl, oxolanyl (tetrahydrofuranyl), oxanyl (tetrahydropyranyl), and the like.

[0060] The term "nitro" refers to the group -NO2. sulfoximine moiety R 9 -S(=O)(=NR 10 )- is understood to have a stereocenter. Chiral sulfoximines can be separated, for example, by chiral HPLC. Unless otherwise specified, the sulfoximine moiety R 9 -S(=O)(=NR 10 )- includes both the R and S isomers.

[0061] Compounds of the Invention

[0062] One aspect of the present invention is, inter alia, certain 2-azaspiro[3.3]heptane compounds of formula (Ia): [ka] (In the formula, X, Y, Z, X1, X2, R 1 ~R 7 and m all have the same definitions as provided herein above and below. or a pharmaceutically acceptable salt thereof.

[0063] R in formula (Ia) 3 and R 4 base

[0064] R 3 and R 4 It is understood that R is attached to a different ethylene (i.e., CHCH) group on the piperazine ring. 3 and R 4 are not attached to the same carbon. Representative examples include, but are not limited to: [ka]

[0065] It is further understood that the remainder of each of formulas (Ia-1) to (Ia-6) refers to the following substructures, although not explicitly shown: [ka] The variables resulting from the combination of this moiety with any one of formulas (Ia-1) to (Ia-6) have the same definitions as described hereinabove and hereinafter, and an example of formula (Ia-1) is shown below: [ka]

[0066] It is understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention, which are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. The variables (e.g., X, Y, Z, X1, X2, R) included in the general chemical formulas described herein, e.g., formulas (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), and (Ia-6), may be any of the following: 1 ~R 7 ), are specifically encompassed by the present invention, as if every combination were individually and explicitly recited, so long as such combinations include compounds that result in stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups recited in the embodiments describing such variables, and all subcombinations of the uses and medical indications described herein, are also specifically encompassed by the present invention, as if every subcombination of chemical groups and subcombinations of uses and medical indications were individually and explicitly recited herein.

[0067] As used herein, "substituted" refers to at least one hydrogen atom of a chemical group being replaced with a non-hydrogen substituent or group, which may be monovalent or divalent. When a chemical group or substituent is divalent, it is understood that the group is further substituted with another substituent or group. When a chemical group is "substituted" herein, it may have up to full substitution. For example, a methyl group can be substituted with one, two, or three substituents; a methylene group can be substituted with one or two substituents; a phenyl group can be substituted with one, two, three, four, or five substituents; a naphthyl group can be substituted with one, two, three, four, five, six, or seven substituents, etc. Similarly, "substituted with one or more substituents" refers to substitution of a group with from one to the total number of substituents physically allowed by the group. As used herein, "optionally substituted" is understood to refer to a group that is "unsubstituted" or "substituted" with a group. Thus, when a group is "optionally substituted with one or more substituents," it is understood that the group is either "unsubstituted" or "substituted," and if substituted, the group is substituted with from 1, up to the total number of substituents physically permissible by the group, as described above. In some embodiments, a group can be "optionally substituted with 1, 2, 3, or 4 substituents." In some embodiments, a group can be "optionally substituted with 1, 2, or 3 substituents." In some embodiments, a group can be "optionally substituted with 1 or 2 substituents." In some embodiments, a group can be "optionally substituted with 1 substituent." Furthermore, when a group is substituted with more than one substituent, the substituents can be the same or different.

[0068] It is understood and appreciated that compounds of Formula (Ia) and related formulae may have one or more chiral centers and therefore may exist as enantiomers and / or diastereoisomers. Accordingly, compounds of Formula (Ia) and formulae as used throughout this disclosure are understood to encompass all such enantiomers, diastereoisomers, and mixtures thereof, including, but not limited to, racemates, unless otherwise specifically stated or indicated.

[0069] The X, Y and Z groups in formula (Ia)

[0070] In some embodiments, X is CH, Y is N, and Z is N, represented by formula (IIa): [ka]

[0071] In some embodiments, each of X, Y, and Z is CH and is represented by formula (IIIa): [ka]

[0072] In some embodiments, each of X and Z is N and Y is CH and is represented by formula (IVa): [ka]

[0073] In some embodiments, each of X and Z is N and Y is CH and is represented by formula (Va): [ka]

[0074] In some embodiments, each of X and Z is N and Y is CH and is represented by formula (VIa): [ka]

[0075] In some embodiments, each of X and Z is N and Y is CH and is represented by formula (VIIa): [ka] In the formula, X1, X2, R 1 ~R 7 Each of m has the same definition as set forth herein above and below.

[0076] R in formula (Ia) 1 Groups and R 2 base

[0077] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is hydrogen, halogen, C1-C4 alkyl or cyano.

[0078] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen, halogen, C1-C4 alkyl, or cyano, where R 10 is hydrogen.

[0079] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, halogen, C1-C4 alkyl, or cyano, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, and is selected from C1-C4 alkyl, C1-C4 alkoxy, —OH, —NHR 10 , halogen, and cyano.

[0080] In some embodiments, R 2is R 9 -S(=O)2- and R 1 is hydrogen, halogen, C1-C4 alkyl, or cyano, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, and is selected from C1-C4 alkyl, C1-C4 alkoxy, —OH, —NHR 10 , halogen, and cyano.

[0081] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, halogen, C1-C4 alkyl, or cyano, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, and is selected from C1-C4 alkyl, C1-C4 alkoxy, —OH, —NHR 10 , halogen, and cyano.

[0082] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, halogen, C1-C4 alkyl, or cyano, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, and is selected from C1-C4 alkyl, C1-C4 alkoxy, —OH, —NHR 10 , halogen, and cyano.

[0083] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, halogen, C1-C4 alkyl, or cyano, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, and is selected from C1-C4 alkyl, C1-C4 alkoxy, —OH, —NHR 10, halogen, and cyano.

[0084] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, halogen, C1-C4 alkyl, or cyano, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, and is selected from C1-C4 alkyl, C1-C4 alkoxy, —OH, —NHR 10 , halogen, and cyano.

[0085] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, halogen, C1-C4 alkyl, or cyano, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, and is selected from C1-C4 alkyl, C1-C4 alkoxy, —OH, —NHR 10 , halogen, and cyano.

[0086] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, halogen, C1-C4 alkyl, or cyano, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, and is selected from C1-C4 alkyl, C1-C4 alkoxy, —OH, —NHR 10 , halogen, and cyano.

[0087] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2is hydrogen, halogen, C1-C4 alkyl or cyano, where [ka] is C1-C4 alkyl, C1-C4 alkoxy, -OH, -NHR 10 , halogen, and cyano.

[0088] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is hydrogen, halogen, C1-C4 alkyl or cyano, where [ka] is C1-C4 alkyl, C1-C4 alkoxy, -OH, -NHR 10 , halogen, and cyano.

[0089] Specific combinations

[0090] In one embodiment, the present invention provides a compound according to any one of formulas (IIa-1) to (VIIa-1): [ka] [In the formula, R 1 and R 2 each independently represents hydrogen, halogen, amino, R 10 NH-S(=O)2-, R 9 -S(=O)2-, R 9 -S(=O)-, R 9 -S-, R 9 -S(=O)(=NR 10 )-, R 9 -O-, [ka] (n=1, 2, or 3), cyano, or C1-C4 alkyl, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, where R 9 or [ka] is C1-C4 alkyl, C1-C4 alkoxy, -OH, -NHR 10 , halogen, or cyano, where R 10 is hydrogen, C1-C4 alkyl, or C3-C7 cycloalkyl; or R 1 , R 2 and the carbon atoms to which they are attached form a 3- to 7-membered ring having one or more heteroatoms selected from N, O, and S; X1 is O or NH; X2 is hydrogen or C1-C4 alkyl; R 5 and R 6 are each independently hydrogen or C1-C4 alkyl, or R 5 , R 6 and the carbon atoms to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocyclyl, each of which is a C1-C4 alkyl, a C1-C4 alkoxy, -OH, or -NHR 10 , optionally substituted with halogen, and cyano; R 7 is hydrogen, halogen, or C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with halogen, amino, —OH, C1-C4 alkoxy, or cyano; m is 0, 1 or 2.

[0091] In another embodiment, the present invention provides a compound according to any one of formulas (IIa-2) to (VIIa-2): [ka] [In the formula, R 1 and R 2 each independently represents hydrogen, halogen, amino, R 10 NH-S(=O)2-, R 9 -S(=O)2-, R 9 -S(=O)-, R 9 -S-, R 9 -S(=O)(=NR 10 )-, R 9 -O-, [ka] (n=1, 2, or 3), cyano, or C1-C4 alkyl, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, where R 9 or [ka] is C1-C4 alkyl, C1-C4 alkoxy, -OH, -NHR 10 , halogen, or cyano, where R 10 is hydrogen, C1-C4 alkyl, or C3-C7 cycloalkyl; or R 1 , R 2 and the carbon atoms to which they are attached form a 3- to 7-membered ring having one or more heteroatoms selected from N, O, and S; X1 is O or NH; X2 is C1-C4 alkyl; R 5 and R 6 are each independently hydrogen or C1-C4 alkyl, or R 5 , R 6 and the carbon atoms to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocyclyl, each of which is a C1-C4 alkyl, a C1-C4 alkoxy, -OH, or -NHR 10 , optionally substituted with halogen, and cyano; R 7is hydrogen, halogen, or C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with halogen, amino, —OH, C1-C4 alkoxy, or cyano; m is 0, 1 or 2.

[0092] In another embodiment, the present invention provides a compound according to any one of formulas (IIa-3) to (VIIa-3): [ka] [In the formula, R 1 and R 2 each independently represents hydrogen, halogen, amino, R 10 NH-S(=O)2-, R 9 -S(=O)2-, R 9 -S(=O)-, R 9 -S-, R 9 -S(=O)(=NR 10 )-, R 9 -O-, [ka] (n=1, 2, or 3), cyano, or C1-C4 alkyl, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, where R 9 or [ka] is C1-C4 alkyl, C1-C4 alkoxy, -OH, -NHR 10 , halogen, or cyano, where R 10 is hydrogen, C1-C4 alkyl, or C3-C7 cycloalkyl; or R 1 , R 2 and the carbon atoms to which they are attached form a 3- to 7-membered ring having one or more heteroatoms selected from N, O, and S; X1 is O or NH; X2 is C1-C4 alkyl; R 5 and R 6 are each independently hydrogen or C1-C4 alkyl, or R 5 , R 6 and the carbon atoms to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocyclyl, each of which is a C1-C4 alkyl, a C1-C4 alkoxy, -OH, or -NHR 10 , optionally substituted with halogen, and cyano; R 7 is hydrogen, halogen, or C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with halogen, amino, —OH, C1-C4 alkoxy, or cyano; m is 0, 1 or 2.

[0093] In another embodiment, the present invention provides a compound according to any one of formulas (IIa-4) to (VIIa-4): [ka] [In the formula, R 1 and R 2 each independently represents hydrogen, halogen, R 10 NH-S(=O)2-, amino, R 9 -S(=O)2-, R 9 -S(=O)-, R 9 -S-, R 9 -S(=O)(=NR 10 )-, R 9 -O-, [ka] (n=1, 2, or 3), cyano, or C1-C4 alkyl, where R 9 is selected from C1-C4 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocyclyl, where R 9 or [ka] is C1-C4 alkyl, C1-C4 alkoxy, -OH, -NHR 10 , halogen, or cyano, where R 10 is hydrogen, C1-C4 alkyl, or C3-C7 cycloalkyl; or R 1 , R 2 and the carbon atoms to which they are attached form a 3- to 7-membered ring having one or more heteroatoms selected from N, O, and S; X1 is O or NH; X2 is hydrogen or C1-C4 alkyl; R 5 and R 6 are each independently hydrogen or C1-C4 alkyl, or R 5 , R 6 and the carbon atoms to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocyclyl, each of which is a C1-C4 alkyl, a C1-C4 alkoxy, -OH, or -NHR 10 , optionally substituted with halogen, and cyano; R 7 is hydrogen, halogen, or C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with halogen, amino, —OH, C1-C4 alkoxy, or cyano; m is 0, 1 or 2.

[0094] R in formulas (Ia), (IIa-1) to (VIIa-1), (IIa-2) to (VIIa-2), (IIa-3) to (VIIa-3), and (IIa-4) to (VIIa-4) 1 and R 2 base

[0095] In some embodiments, R 1 is R 10 NH-S(=O)2-.

[0096] In some embodiments, R 1 is R 9-S(=O)2-.

[0097] In some embodiments, R 1 is R 9 -S(=O)-.

[0098] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )-.

[0099] In some embodiments, R 1 is R 9 -O-.

[0100] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3).

[0101] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is hydrogen.

[0102] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is a halogen.

[0103] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is C1-C4 alkyl.

[0104] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen.

[0105] In some embodiments, R 1 is R9 -S(=O)2- and R 2 is a halogen.

[0106] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl.

[0107] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen.

[0108] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen.

[0109] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl.

[0110] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen.

[0111] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen.

[0112] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl.

[0113] In some embodiments, R 1 is R9 -O- and R 2 is hydrogen.

[0114] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen.

[0115] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl.

[0116] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is hydrogen.

[0117] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is a halogen.

[0118] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is C1-C4 alkyl.

[0119] In some embodiments, R 2 is R 10 NH-S(=O)2-.

[0120] In some embodiments, R 2 is R 9 -S(=O)2-.

[0121] In some embodiments, R 2 is R 9 -S(=O)-.

[0122] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )-.

[0123] In some embodiments, R 2 is R 9 -O-.

[0124] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3).

[0125] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen.

[0126] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is a halogen.

[0127] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is C1-C4 alkyl.

[0128] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen.

[0129] In some embodiments, R 2 is R 9 -S(=O)2- and R1 is a halogen.

[0130] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl.

[0131] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen.

[0132] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen.

[0133] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl.

[0134] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen.

[0135] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen.

[0136] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl.

[0137] In some embodiments, R 2 is R 9 -O- and R 1is hydrogen.

[0138] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen.

[0139] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl.

[0140] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is hydrogen.

[0141] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is a halogen.

[0142] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is C1-C4 alkyl.

[0143] It is understood that any and all embodiments in this section are applicable to any and all of Formulas (IIa-1) through (VIIa-1), (IIa-2) through (VIIa-2), (IIa-3) through (VIIa-3), or (IIa-4) through (VIIa-4).

[0144] R in formulas (Ia), (IIa-1) to (VIIa-1), (IIa-2) to (VIIa-2), (IIa-3) to (VIIa-3), and (IIa-4) to (VIIa-4) 1 , R 2 and X1 group

[0145] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is hydrogen and X1 is NH.

[0146] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is hydrogen and X1 is NH, where R 10 is hydrogen.

[0147] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen and X1 is NH.

[0148] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0149] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0150] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen and X1 is NH.

[0151] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0152] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0153] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl and X1 is NH.

[0154] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl and X1 is NH, where R 9 is C1-C4 alkyl.

[0155] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0156] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen and X1 is NH.

[0157] In some embodiments, R 1 is R 9 -S(=O)- and R 2is hydrogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0158] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0159] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen and X1 is NH.

[0160] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0161] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0162] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl and X1 is NH.

[0163] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl and X1 is NH, where R 9 is C1-C4 alkyl.

[0164] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0165] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen and X1 is NH.

[0166] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0167] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0168] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen and X1 is NH.

[0169] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0170] In some embodiments, R1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0171] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl and X1 is NH.

[0172] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl and X1 is NH, where R 9 is C1-C4 alkyl.

[0173] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0174] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen and X1 is NH.

[0175] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen and X1 is NH, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0176] In some embodiments, R1 is R 9 -O- and R 2 is hydrogen and X1 is NH, where R 9 is a 3- to 7-membered heterocyclyl.

[0177] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen and X1 is NH.

[0178] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen and X1 is NH, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0179] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen and X1 is NH, where R 9 is a 3- to 7-membered heterocyclyl.

[0180] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl and X1 is NH.

[0181] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl and X1 is NH, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0182] In some embodiments, R 1 is R 9 -O- and R 2is C1-C4 alkyl and X1 is NH, where R 9 is a 3- to 7-membered heterocyclyl.

[0183] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is hydrogen and X1 is NH.

[0184] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is a halogen and X1 is NH.

[0185] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is C1-C4 alkyl and X1 is NH.

[0186] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen and X1 is NH.

[0187] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen and X1 is NH, where R 10 is hydrogen.

[0188] In some embodiments, R 2 is R 10 NH-S(=O)2- and R1 is hydrogen and X1 is NH.

[0189] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0190] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0191] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen and X1 is NH.

[0192] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0193] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0194] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl and X1 is NH.

[0195] In some embodiments, R 2is R 9 -S(=O)2- and R 1 is C1-C4 alkyl and X1 is NH, where R 9 is C1-C4 alkyl.

[0196] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0197] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen and X1 is NH.

[0198] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0199] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0200] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen and X1 is NH.

[0201] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0202] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0203] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl and X1 is NH.

[0204] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl and X1 is NH, where R 9 is C1-C4 alkyl.

[0205] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0206] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen and X1 is NH.

[0207] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0208] In some embodiments, R2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0209] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen and X1 is NH.

[0210] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen and X1 is NH, where R 9 is C1-C4 alkyl.

[0211] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0212] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl and X1 is NH.

[0213] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl and X1 is NH, where R 9 is C1-C4 alkyl.

[0214] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl and X1 is NH, where R 9 is a C3-C7 cycloalkyl.

[0215] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen and X1 is NH.

[0216] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen and X1 is NH, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0217] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen and X1 is NH, where R 9 is a 3- to 7-membered heterocyclyl.

[0218] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen and X1 is NH.

[0219] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen and X1 is NH, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0220] In some embodiments, R 2 is R 9 -O- and R1 is a halogen and X1 is NH, where R 9 is a 3- to 7-membered heterocyclyl.

[0221] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl and X1 is NH.

[0222] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl and X1 is NH, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0223] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl and X1 is NH, where R 9 is a 3- to 7-membered heterocyclyl.

[0224] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is hydrogen and X1 is NH.

[0225] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is a halogen and X1 is NH.

[0226] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is C1-C4 alkyl and X1 is NH.

[0227] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is hydrogen and X1 is O.

[0228] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is hydrogen and X1 is O, where R 10 is hydrogen.

[0229] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen and X1 is O.

[0230] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen and X1 is O, where R 9 is C1-C4 alkyl.

[0231] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0232] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen and X1 is O.

[0233] In some embodiments, R1 is R 9 -S(=O)2- and R 2 is a halogen and X1 is O, where R 9 is C1-C4 alkyl.

[0234] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0235] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl and X1 is O.

[0236] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl and X1 is O, where R 9 is C1-C4 alkyl.

[0237] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0238] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen and X1 is O.

[0239] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen and X1 is O, where R 9is C1-C4 alkyl.

[0240] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0241] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen and X1 is O.

[0242] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen and X1 is O, where R 9 is C1-C4 alkyl.

[0243] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0244] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl and X1 is O.

[0245] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl and X1 is O, where R 9 is C1-C4 alkyl.

[0246] In some embodiments, R 1 is R 9-S(=O)- and R 2 is C1-C4 alkyl and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0247] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen and X1 is O.

[0248] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen and X1 is O, where R 9 is C1-C4 alkyl.

[0249] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0250] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen and X1 is O.

[0251] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen and X1 is O, where R 9 is C1-C4 alkyl.

[0252] In some embodiments, R 1 is R 9 -S(=O)(=NR 10)- and R 2 is a halogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0253] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl and X1 is O.

[0254] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl and X1 is O, where R 9 is C1-C4 alkyl.

[0255] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0256] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen and X1 is O.

[0257] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen and X1 is O, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0258] In some embodiments, R 1 is R 9 -O- and R 2is hydrogen and X1 is O, where R 9 is a 3- to 7-membered heterocyclyl.

[0259] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen and X1 is O.

[0260] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen and X1 is O, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0261] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen and X1 is O, where R 9 is a 3- to 7-membered heterocyclyl.

[0262] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl and X1 is O.

[0263] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl and X1 is O, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0264] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl and X1 is O, where R 9 is a 3- to 7-membered heterocyclyl.

[0265] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is hydrogen and X1 is O.

[0266] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is a halogen and X1 is O.

[0267] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is C1-C4 alkyl and X1 is O.

[0268] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen and X1 is O.

[0269] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen and X1 is O, where R 10 is hydrogen.

[0270] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen and X1 is O.

[0271] In some embodiments, R2 is R 9 -S(=O)2- and R 1 is hydrogen and X1 is O, where R 9 is C1-C4 alkyl.

[0272] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0273] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen and X1 is O.

[0274] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen and X1 is O, where R 9 is C1-C4 alkyl.

[0275] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0276] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl and X1 is O.

[0277] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl and X1 is O, where R 9is C1-C4 alkyl.

[0278] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0279] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen and X1 is O.

[0280] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen and X1 is O, where R 9 is C1-C4 alkyl.

[0281] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0282] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen and X1 is O.

[0283] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen and X1 is O, where R 9 is C1-C4 alkyl.

[0284] In some embodiments, R 2 is R 9 -S(=O)- and R1 is a halogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0285] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl and X1 is O.

[0286] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl and X1 is O, where R 9 is C1-C4 alkyl.

[0287] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0288] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen and X1 is O.

[0289] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen and X1 is O, where R 9 is C1-C4 alkyl.

[0290] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen and X1 is O, where R 9is a C3-C7 cycloalkyl.

[0291] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen and X1 is O.

[0292] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen and X1 is O, where R 9 is C1-C4 alkyl.

[0293] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen and X1 is O, where R 9 is a C3-C7 cycloalkyl.

[0294] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl and X1 is O.

[0295] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl and X1 is O, where R 9 is C1-C4 alkyl.

[0296] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl and X1 is O, where R9 is a C3-C7 cycloalkyl.

[0297] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen and X1 is O.

[0298] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen and X1 is O, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0299] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen and X1 is O, where R 9 is a 3- to 7-membered heterocyclyl.

[0300] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen and X1 is O.

[0301] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen and X1 is O, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0302] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen and X1 is O, where R 9 is a 3- to 7-membered heterocyclyl.

[0303] In some embodiments, R2 is R 9 -O- and R 1 is C1-C4 alkyl and X1 is O.

[0304] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl and X1 is O, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0305] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl and X1 is O, where R 9 is a 3- to 7-membered heterocyclyl.

[0306] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is hydrogen and X1 is O.

[0307] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is a halogen and X1 is O.

[0308] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is C1-C4 alkyl and X1 is O.

[0309] R in formulas (Ia), (IIa-1) to (VIIa-1), (IIa-2) to (VIIa-2), (IIa-3) to (VIIa-3), and (IIa-4) to (VIIa-4) 1 , R 2 , R 5 , R 6 , and X1 group

[0310] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0311] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 10 is hydrogen.

[0312] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0313] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 10 is hydrogen.

[0314] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0315] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 10 is hydrogen.

[0316] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0317] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0318] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3 to C7 alkyl.

[0319] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is NH, and R 5 and R 6Each of is hydrogen.

[0320] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0321] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0322] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0323] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0324] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9is a C3-C7 cycloalkyl.

[0325] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0326] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0327] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0328] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0329] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0330] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0331] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0332] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0333] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0334] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0335] In some embodiments, R 1is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0336] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0337] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0338] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0339] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0340] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0341] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0342] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0343] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0344] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0345] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0346] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0347] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0348] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0349] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0350] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0351] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0352] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0353] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0354] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0355] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0356] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 10 is hydrogen.

[0357] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0358] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 10 is hydrogen.

[0359] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is NH, and R 5 and R6 Each of is hydrogen.

[0360] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0361] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3 to C7 alkyl.

[0362] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0363] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0364] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0365] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0366] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0367] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0368] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0369] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0370] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0371] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0372] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0373] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0374] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0375] In some embodiments, R 2 is R 9-S(=O)- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0376] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0377] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0378] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0379] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0380] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0381] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0382] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0383] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0384] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9is C1-C4 alkyl.

[0385] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0386] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0387] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0388] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0389] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0390] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0391] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0392] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0393] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0394] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 is hydrogen, where R 9is a 3- to 7-membered heterocyclyl.

[0395] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is hydrogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0396] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is a halogen, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0397] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is C1-C4 alkyl, X1 is NH, and R 5 and R 6 Each of is hydrogen.

[0398] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0399] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is hydrogen, X1 is O, and R5 and R 6 is hydrogen, where R 10 is hydrogen.

[0400] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0401] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 10 is hydrogen.

[0402] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0403] In some embodiments, R 1 is R 10 NH-S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 10 is hydrogen.

[0404] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0405] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0406] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3 to C7 alkyl.

[0407] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0408] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0409] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0410] In some embodiments, R1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0411] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0412] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0413] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0414] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0415] In some embodiments, R 1 is R 9 -S(=O)- and R 2is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0416] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0417] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0418] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0419] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0420] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6is hydrogen, where R 9 is C1-C4 alkyl.

[0421] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0422] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0423] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0424] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0425] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0426] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0427] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0428] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0429] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0430] In some embodiments, R 1 is R 9-S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0431] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0432] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0433] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0434] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0435] In some embodiments, R 1 is R 9 -O- and R 2is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0436] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0437] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0438] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0439] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0440] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0441] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0442] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0443] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0444] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 10 is hydrogen.

[0445] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0446] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 10 is hydrogen.

[0447] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0448] In some embodiments, R 2 is R 10 NH-S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 10 is hydrogen.

[0449] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0450] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is O, and R5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0451] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3 to C7 alkyl.

[0452] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0453] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0454] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0455] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R6 Each of is hydrogen.

[0456] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0457] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0458] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0459] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0460] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0461] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0462] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0463] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0464] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0465] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0466] In some embodiments, R2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0467] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0468] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0469] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0470] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0471] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0472] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0473] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0474] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0475] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0476] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0477] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0478] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0479] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0480] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0481] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0482] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0483] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0484] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0485] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R1 is hydrogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0486] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is a halogen, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0487] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is C1-C4 alkyl, X1 is O, and R 5 and R 6 Each of is hydrogen.

[0488] R in formulas (Ia), (IIa-1) to (VIIa-1), (IIa-2) to (VIIa-2), (IIa-3) to (VIIa-3), and (IIa-4) to (VIIa-4) 1 , R 2 , R 5 , R 6 , X1 and X2 groups

[0489] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0490] In some embodiments, R 1 is R 9 -S(=O)2- and R 2is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0491] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0492] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0493] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0494] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0495] In some embodiments, R 1 is R 9-S(=O)2- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0496] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0497] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0498] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0499] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0500] In some embodiments, R 1 is R9 -S(=O)- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0501] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0502] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0503] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0504] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0505] In some embodiments, R 1 is R9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0506] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0507] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0508] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0509] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9is a C3-C7 cycloalkyl.

[0510] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0511] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0512] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0513] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0514] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0515] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0516] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0517] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0518] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0519] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0520] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0521] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0522] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0523] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0524] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0525] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0526] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0527] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0528] In some embodiments, R 1 is R9 -S(=O)2- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0529] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0530] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0531] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0532] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0533] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0534] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0535] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0536] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0537] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6Each of is hydrogen.

[0538] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl and hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0539] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0540] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0541] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0542] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0543] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0544] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0545] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0546] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0547] In some embodiments, R 1 is R 9-S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0548] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0549] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0550] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0551] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0552] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0553] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0554] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0555] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0556] In some embodiments, R1 is R 9 -O- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0557] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0558] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0559] In some embodiments, R 1 is R 9 -O- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0560] In some embodiments, R 1 is R 9 -O- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0561] In some embodiments, R 1 is R 9 -O- and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0562] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0563] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0564] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0565] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0566] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0567] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0568] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0569] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6is hydrogen, where R 9 is C1-C4 alkyl.

[0570] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0571] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0572] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0573] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0574] In some embodiments, R 2 is R 9 -S(=O)2- and R 1is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0575] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0576] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0577] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0578] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0579] In some embodiments, R 2 is R 9 -S(=O)- and R1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0580] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0581] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0582] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0583] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0584] In some embodiments, R 2 is R 9 -S(=O)- and R1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0585] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0586] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0587] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0588] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0589] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0590] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0591] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0592] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0593] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0594] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0595] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0596] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0597] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0598] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0599] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0600] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0601] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0602] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0603] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0604] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is hydrogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0605] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is a halogen, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0606] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is C1-C4 alkyl, X1 is NH, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0607] In some embodiments, R 2 is R9 -S(=O)2- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0608] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0609] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0610] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0611] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0612] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0613] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0614] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0615] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0616] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6Each of is hydrogen.

[0617] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl and hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0618] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0619] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0620] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0621] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0622] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0623] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0624] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0625] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0626] In some embodiments, R 2 is R 9-S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0627] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0628] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0629] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0630] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0631] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0632] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0633] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0634] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0635] In some embodiments, R2 is R 9 -O- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0636] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0637] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0638] In some embodiments, R 2 is R 9 -O- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0639] In some embodiments, R 2 is R 9 -O- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0640] In some embodiments, R 2 is R 9 -O- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0641] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0642] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0643] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0644] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is hydrogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0645] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0646] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is C1-C4 alkyl, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0647] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0648] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6is hydrogen, where R 9 is C1-C4 alkyl.

[0649] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0650] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0651] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0652] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0653] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R5 and R 6 Each of is hydrogen.

[0654] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0655] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0656] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0657] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0658] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0659] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0660] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0661] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0662] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0663] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0664] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0665] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0666] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0667] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0668] In some embodiments, R 1is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0669] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0670] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0671] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0672] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R9 is C1-C4 alkyl.

[0673] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0674] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0675] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0676] In some embodiments, the compound is a compound of formula (IIa-1), wherein R 1 is R 9 -O- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0677] In some embodiments, R 1 is R 9-O- and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0678] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0679] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0680] In some embodiments, R 1 is R 9 -O- and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0681] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0682] In some embodiments, R 1 is R 9-O- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0683] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0684] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0685] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0686] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0687] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0688] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0689] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0690] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0691] In some embodiments, R 1 is R 9 -S(=O)2- and R 2is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0692] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0693] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0694] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0695] In some embodiments, R 1 is R 9 -S(=O)2- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0696] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0697] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl and is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0698] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0699] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0700] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0701] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0702] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0703] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0704] In some embodiments, R 1 is R 9 -S(=O)- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0705] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0706] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0707] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0708] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0709] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0710] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0711] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0712] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0713] In some embodiments, R 1 is R 9 -S(=O)(=NR 10 )- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0714] In some embodiments, R 1 is R 9-O- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0715] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0716] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0717] In some embodiments, R 1 is R 9 -O- and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0718] In some embodiments, R 1 is R 9 -O- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0719] In some embodiments, R 1 is R 9 -O- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0720] In some embodiments, R 1 is R 9 -O- and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0721] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0722] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0723] In some embodiments, R 1 is R 9 -O- and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0724] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0725] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0726] In some embodiments, R 1 teeth, [ka] (n=1, 2, or 3), and R 2 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0727] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0728] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0729] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0730] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0731] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0732] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0733] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0734] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0735] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0736] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0737] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0738] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0739] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0740] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0741] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0742] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0743] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0744] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0745] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0746] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0747] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0748] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0749] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0750] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0751] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0752] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0753] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0754] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0755] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0756] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0757] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0758] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0759] In some embodiments, R 2 is R 9 -O- and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0760] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0761] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0762] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0763] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is hydrogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0764] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is a halogen, X1 is O, X2 is hydrogen, and R 5 and R 6 Each of is hydrogen.

[0765] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is C1-C4 alkyl, X1 is O, X2 is hydrogen, and R 5 and R 6Each of is hydrogen.

[0766] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0767] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0768] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0769] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0770] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6is hydrogen, where R 9 is C1-C4 alkyl.

[0771] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0772] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0773] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0774] In some embodiments, R 2 is R 9 -S(=O)2- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0775] In some embodiments, R 2 is R 9 -S(=O)- and R1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0776] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl and hydrogen, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0777] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0778] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0779] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is halogen, X1 is NH, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0780] In some embodiments, R 2 is R9 -S(=O)- and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0781] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0782] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0783] In some embodiments, R 2 is R 9 -S(=O)- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0784] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0785] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0786] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0787] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0788] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0789] In some embodiments, R 2 is R 9 -S(=O)(=NR 10)- and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0790] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0791] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0792] In some embodiments, R 2 is R 9 -S(=O)(=NR 10 )- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a C3-C7 cycloalkyl.

[0793] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6Each of is hydrogen.

[0794] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0795] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0796] In some embodiments, R 2 is R 9 -O- and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0797] In some embodiments, R 2 is R 9 -O- and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0798] In some embodiments, R 2 is R 9 -O- and R 1is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl optionally substituted with halogen, cyano, or -OH.

[0799] In some embodiments, R 2 is R 9 -O- and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0800] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0801] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is C1-C4 alkyl.

[0802] In some embodiments, R 2 is R 9 -O- and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 is hydrogen, where R 9 is a 3- to 7-membered heterocyclyl.

[0803] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is hydrogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0804] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is halogen, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0805] In some embodiments, R 2 teeth, [ka] (n=1, 2, or 3), and R 1 is C1-C4 alkyl, X1 is O, X2 is C1-C4 alkyl, and R 5 and R 6 Each of is hydrogen.

[0806] R in formulas (Ia), (IIa-1) to (VIIa-1), (IIa-2) to (VIIa-2), (IIa-3) to (VIIa-3), and (IIa-4) to (VIIa-4) 5 and R 6 base

[0807] In some embodiments, R 5 and R 6 Each of is hydrogen.

[0808] In some embodiments, R5 and R 6 Each of is a C1-C4 alkyl.

[0809] In some embodiments, R 5 is hydrogen and R 6 is C1-C4 alkyl.

[0810] The m group in formulae (Ia), (IIa-1) to (VIIa-1), (IIa-2) to (VIIa-2), (IIa-3) to (VIIa-3), and (IIa-4) to (VIIa-4)

[0811] In some embodiments, m is 0 in any one of the above embodiments.

[0812] In some embodiments, m is 1 in any one of the above embodiments.

[0813] In some embodiments, m is 2 in any one of the above embodiments.

[0814] R in formulas (Ia), (IIa-1) to (VIIa-1), (IIa-2) to (VIIa-2), (IIa-3) to (VIIa-3), and (IIa-4) to (VIIa-4) 7 base

[0815] In some embodiments, R 7 is hydrogen.

[0816] In some embodiments, R 7 is a halogen.

[0817] In some embodiments, R 7 is C1-C4 alkyl.

[0818] Table A provides certain compounds of the present invention. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0819] Furthermore, the chemical structures of the present invention, for example, the compounds found in Table A, encompass all possible stereoisomers, all pharmaceutically acceptable salts and solvates thereof.

[0820] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be of the (R) or (S) configuration, or a mixture thereof. Accordingly, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Preparation of enantiomerically pure or enantiomerically enriched forms can be achieved by resolution of racemic mixtures, by using enantiomerically pure or enriched starting materials, or by stereoselective or stereospecific synthesis. Definitions of stereochemistry are available in E.L. Eliel, S.H. Wilen & L.N. Mander, Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, NY, 1994, which is incorporated herein by reference in its entirety. In some embodiments, when the compounds of the invention are chiral or otherwise contain one or more stereocenters, the compounds can be prepared in enantiomeric or diastereomeric excess of greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99%.

[0821] Resolution of racemic mixtures of compounds can be achieved by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving organic acid with a racemic compound containing a basic group. Suitable resolving agents for fractional recrystallization include optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, the D- and L-forms of lactic acid, or various optically active camphorsulfonic acids. Other chiral resolving agents suitable for fractional crystallization include stereomerically pure forms (e.g., S- and R-forms, or diastereomerically pure forms) of methylbenzylamine, 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Similarly, fractional recrystallization using a chiral resolving base can be utilized with a racemic compound containing a basic group.

[0822] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0823] In some embodiments, compounds of the invention can be prepared having an enantiomeric excess of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 99.9%, or an enantiomeric excess within a range defined by any of the foregoing numbers.

[0824] Additionally, when the compounds described herein contain one or more double bonds (e.g., C=C, C=N, etc.) or other centers of geometric asymmetry, unless otherwise specified, the compounds are understood to include both E and Z geometric isomers (e.g., cis or trans). Cis and trans geometric isomers of the compounds described herein may be isolated as a mixture of isomers or as separated isomeric forms.

[0825] The compounds described herein also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond, accompanied by a simultaneous proton transfer. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically fixed into one form by appropriate substitution.

[0826] The compound of the present invention and its pharmaceutically acceptable salts can be found with other substances such as water and solvent, for example, in the form of hydrate or solvate.When in solid state, the compound described herein and its salts can occur in various forms, for example, can take the form of solvate, including hydrate.Compound can be in any solid form such as crystalline form, amorphous form, solvate form, etc., and unless otherwise clearly indicated, the reference herein to compound and its salts should be understood as reading any solid form of compound.

[0827] The compounds described herein can be used in a neutral form, such as a free acid or free base form. Alternatively, the compounds can be used in the form of acid addition salts or base addition salts. The term "pharmaceutically acceptable salt" refers to a salt of a compound having an acidic or basic moiety that is not biologically or otherwise undesirable for pharmaceutical use. In many cases, the compounds disclosed herein can form acid salts and / or base salts due to the presence of an acidic or basic moiety (e.g., amino and / or carboxyl groups, or groups similar thereto). Pharmaceutically acceptable acid addition salts can be formed by combining compounds having a basic moiety with inorganic and organic acids. Inorganic acids that can be used to prepare salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids that can be used to prepare salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed by combining a compound having an acidic moiety with an inorganic base or an organic base. Inorganic bases that can be used to prepare salts include, for example, hydroxides, carbonates, bicarbonates, phosphates, etc. of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, and aluminum. Particularly preferred are hydroxides, carbonates, bicarbonates, or phosphates of ammonium, potassium, sodium, calcium, and magnesium. Organic bases that can be used to prepare salts include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with at least stoichiometric amount of suitable base or acid in water or organic solvent; generally in non-aqueous medium such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (ACN), or in the mixture of the two.Lists of suitable salts can be found in WO 87 / 05297; Johnston et al., published September 11, 1987; Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418; and J.Pharm.Sci., 66, 2 (1977), each of which is incorporated herein by reference in its entirety. A reference for the preparation and selection of pharmaceutical salts of the present disclosure is P.H. Stahl & C.G. Wermuth, Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta, Zurich, 2002, which is incorporated herein by reference in its entirety.

[0828] In some embodiments, the compounds described herein or salts thereof are substantially isolated. The phrase "substantially isolated" refers to a compound that is at least partially or substantially separated from the environment in which it was formed or detected. Partial isolation can include, for example, a composition enriched for the compound of the present invention. Substantial isolation can include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, at least about 80% by weight, at least about 85% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound of the present invention or salt thereof.

[0829] Polymorphs and pseudopolymorphs

[0830] Polymorphism is the ability of a single-component substance to exist as two or more crystalline phases, which have different arrangements and / or conformations of the molecules within the crystal lattice. Polymorphs exhibit the same properties in the liquid or gas state, but behave differently in the solid state.

[0831] In addition to single-component polymorphs, compounds (e.g., drugs) can also exist as salts and other multi-component crystalline phases. For example, solvates and hydrates contain the compound as the host and can contain either solvent or water molecules as the guest, respectively. Similarly, when the guest compound is solid at room temperature, the resulting form is often called a cocrystal. Salts, solvates, hydrates, and cocrystals can also exhibit polymorphism. Crystalline phases that share the same compound host but differ with respect to the guest can be called pseudopolymorphs of each other.

[0832] Solvates contain molecules of the crystallization solvent within a defined crystal lattice. Solvates in which the crystallization solvent is water are called hydrates. Because water is a component of the atmosphere, hydrates of drugs can be formed quite easily.

[0833] For example, Stahly published a polymorph screen of 245 compounds consisting of "a wide variety of structural types," revealing that approximately 90% of them exhibit multiple solid forms. Overall, approximately half of the compounds are polymorphic, often with one to three forms. Approximately one-third of the compounds formed hydrates, and approximately one-third formed solvates. Data from a cocrystal screen of 64 compounds showed that 60% formed cocrystals other than hydrates or solvates (GP Stahly, Crystal Growth & Design (2007), 7(6), 1007-1026).

[0834] Isotopes

[0835] By the compounds disclosed and described herein, unless the context clearly dictates otherwise, atoms at each position of the compound can independently have: 1) an isotopic distribution of chemical elements in amounts proportional to those normally found in nature, or 2) an isotopic distribution in a different amount than that normally found in nature. A particular chemical element has an atomic number defined by the number of protons in the atom's nucleus. Each atomic number identifies a specific element but not an isotope. Atoms of a given element can have a wide range of neutron numbers. The number of both protons and neutrons in the nucleus is the atom's mass number, and each isotope of a given element has a different mass number. Compounds in which one or more atoms have an isotopic distribution of chemical elements in amounts different from those normally found in nature are commonly referred to as isotopically labeled compounds. Each chemical element represented in a compound structure can include any isotopic distribution of the element. For example, in a compound structure, hydrogen atoms may be explicitly disclosed or understood as being present in the compound. At any position in the compound where a hydrogen atom can be present, the hydrogen atom may be replaced by, but is not limited to, protium ( 1 H) and deuterium ( 2 The isotope distribution of hydrogen may include hydrogen isotopes, including hydrogen (H) in proportions relative to those normally found in nature and in proportions different from those normally found in nature. Thus, reference to a compound herein encompasses all potential isotope distributions of each atom, unless the context clearly indicates otherwise. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As those skilled in the art will recognize, any of the compounds disclosed and described herein may contain radioactive isotopes. Thus, one or more atoms may have an isotope distribution different from that normally found in nature, for example, a distribution higher than that found in nature. 2 H or 3 A larger proportion of H, or 11 C. 13 C or 14 Also contemplated is the use of compounds as disclosed and described herein in which the proportion of C is greater than 0. By way of general example and without limitation, isotopes of hydrogen include protium ( 1 H), deuterium ( 2H) and tritium ( 3 H). Carbon isotopes include carbon-11 ( 11 C), carbon-12( 12 C), carbon-13( 13 C) and carbon-14 ( 14 C). Nitrogen isotopes include nitrogen-13 ( 13 N), nitrogen-14( 14 N) and nitrogen-15( 15 N). Oxygen isotopes include oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O) and oxygen-18( 18 O). Fluorine isotopes include fluorine-17( 17 F), fluorine-18( 18 F) and fluorine-19( 19 F). Phosphorus isotopes include phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), phosphorus-34( 34 P), phosphorus-35( 35 P) and phosphorus-36( 36 P). Sulfur isotopes include sulfur-32 ( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S) and sulfur-38( 38 S). Chlorine isotopes include chlorine-35( 35 Cl), chlorine-36( 36 Cl) and chlorine-37( 37 The isotopes of bromine include bromine-75( 75 Br), Bromine-76( 76 Br), Bromine-77( 77 Br), Bromine-79( 79 Br), Bromine-81( 81 Br) and bromine-82( 82Br). Iodine isotopes include iodine-123 ( 123 I), iodine-124( 124 I), iodine-125( 125 I), iodine-131( 131 I) and iodine-135( 135 I). In some embodiments, atoms at any position of the compound have an isotopic distribution of each chemical element in a proportional amount relative to that normally found in nature. In some embodiments, atoms at one position of the compound have an isotopic distribution of the chemical element in a different proportional amount than that normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportional amount relative to that normally found in nature). In some embodiments, atoms at at least two positions of the compound independently have an isotopic distribution of the chemical element in a different proportional amount than that normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportional amount relative to that normally found in nature). In some embodiments, atoms at at least three positions of the compound independently have an isotopic distribution of the chemical element in a different proportional amount than that normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportional amount relative to that normally found in nature). In some embodiments, atoms at at least four positions of the compound independently have an isotopic distribution of the chemical element in a proportional amount different from that normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportional amount relative to that normally found in nature). In some embodiments, atoms at at least five positions of the compound independently have an isotopic distribution of the chemical element in a proportional amount different from that normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportional amount relative to that normally found in nature). In some embodiments, atoms at at least six positions of the compound independently have an isotopic distribution of the chemical element in a proportional amount different from that normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportional amount relative to that normally found in nature).

[0836] A compound, e.g. 3 H and 14Compounds incorporating radioactive isotopes, such as C, are also useful in drug or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes are particularly preferred for their ease of preparation and detectability. 2 Compounds bearing isotopes such as H may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds can generally be prepared by procedures routinely practiced in the chemical arts. Methods for measuring such isotopic perturbations or enrichments are readily available, such as mass spectrometry, and for isotopes that are radioactive, additional methods are available, such as radio detectors used in conjunction with HPLC or GC.

[0837] As used herein, "isotopic variant" refers to a compound that contains unnatural proportions of isotopes of one or more atoms that constitute such compound. In certain embodiments, an "isotopic variant" of a compound is an isotope of protium ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), sulfur-33(33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-36( 36 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., is non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (I). 1 H), deuterium ( 2 H), carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O) and oxygen-18( 18 In certain embodiments, an "isotopic variant" of a compound of the present invention is in an unstable form, i.e., radioactive. ... 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O) and oxygen-15( 15 In the compounds provided herein, any hydrogen may contain unnatural proportions of one or more isotopes, including, but not limited to, hydrogen, fluorine, iodine ... 2H, or any carbon, for example, containing 13C as the major isotopic form, or any nitrogen, for example, containing 13C as the major isotopic form. 15 Any oxygen can include N as the major isotopic form, for example 18 It will be understood that the isotope variants of a compound may contain deuterium ( 2 H) in non-naturally occurring proportions.

[0838] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium, or "D" or "d," it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor, in certain embodiments, at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.

[0839] Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds of the present invention and are well known in the art. For example, these synthetic methods for incorporating activity levels of tritium into target molecules are as follows:

[0840] A. Catalytic reduction with tritium gas: This procedure usually gives products with high specific activity and requires halogenated or unsaturated precursors.

[0841] B. Sodium borohydride [ 3Reduction with [H]: This procedure is fairly inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, and esters.

[0842] C. Lithium aluminum hydride [ 3 Reduction with [H]: This procedure affords products at nearly theoretical specific activities. This procedure also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, and esters.

[0843] D. Tritium Gas Exposure Labeling: This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

[0844] E. Methyl iodide [ 3 N-Methylation using [H]: This procedure is typically performed using high specific activity methyl iodide ( 3 O-methyl or N-methyl ( 3 H) product. This method generally allows for higher specific activities, e.g., about 70-90 Ci / mmol.

[0845] 125 Synthetic methods for incorporating the activity level of I into target molecules include the following.

[0846] A. Sandmeyer and similar reactions: This procedure converts an aryl or heteroaryl amine into a diazonium salt, such as diazonium tetrafluoroborate, followed by the addition of Na 125 Using I 125 I-labeled compounds. A representative procedure was reported by Zhu, GD. and coworkers in J. Org. Chem., 2002, 67, 943-948.

[0847] B. Ortho-phenols 125Iodination - This procedure allows the iodination of phenols at the ortho position, as reported by Collier, TL and coworkers in J. Labeled Compd. Radiopharm., 1999, 42, S264-S266. 125 It becomes possible to incorporate I.

[0848] C. 125 Aryl and heteroaryl bromide exchange with I: This method is generally a two-step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding trialkyltin intermediate using, for example, Pd catalysis [i.e., Pd(PhP)] in the presence of a trialkyltin halide or hexaalkylditin [e.g., (CH)Sn(CH)], or with an aryl or heteroaryllithium. A representative procedure was reported by Le Bas, M.-D., and coworkers in J. Labelled Compd. Radiopharm., 2001, 44, S280-S282.

[0849] The radiolabeled form of the compound of the present invention can be used in screening assays to identify / evaluate compounds.Generally, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce the binding of the radiolabeled form of the compound disclosed herein to M4 receptor.The ability of the test compound to compete with the radiolabeled form of the compound of the present invention for binding to M4 receptor correlates with its binding affinity.

[0850] Disorders, Uses and Treatment Methods

[0851] The compounds disclosed and described herein are muscarinic receptor antagonists. Thus, the compounds and their salts or polymorphs can be used in methods for antagonizing muscarinic receptors (e.g., muscarinic receptor 4) by contacting the receptor. In some embodiments, the compounds and their salts or polymorphs can be used in methods for antagonizing muscarinic receptor 4 (i.e., M4) in patients in need thereof by administering an effective amount of the compound or its salt. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is ex vivo.

[0852] The compounds provided herein can be selective. As used herein, the term "selective" means that a compound antagonizes the M4 receptor with greater affinity or potency than at least one other muscarinic receptor (e.g., M1, M2, M3 and / or M5). In some embodiments, the selectivity is at least about 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 50-fold or 100-fold relative to at least one other muscarinic receptor, as measured by the assays described herein.

[0853] Provided herein are methods for treating or preventing (i.e., reducing the likelihood of occurrence) neurological diseases / disorders or symptoms, including, but not limited to, Tourette's syndrome (TS), Alzheimer's disease (AD), schizophrenia, dementia with Lewy bodies (LBD), cognitive impairment associated with schizophrenia, Parkinson's disease, parkinsonism, tremor, dyskinesia, excessive daytime sleepiness, dystonia, chorea, levodopa-induced dyskinesia, attention deficit hyperactivity disorder (ADHD), cerebral palsy, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), Huntington's disease (HD) and chorea associated with Huntington's disease. Some of these diseases / disorders or symptoms are considered cognitive disorders (e.g., Alzheimer's disease), others are considered neurological movement diseases / disorders, while some have both cognitive and motor deficits or associated symptoms (e.g., Parkinson's disease, Huntington's disease).

[0854] The effectiveness of muscarinic receptor antagonists, such as M4 antagonists, for treating neurological symptoms, diseases or disorders or symptoms described herein can be easily determined by those skilled in the art of medicine and clinical practice.For example, one or any combination of diagnostic methods suitable for specific diseases or disorders or symptoms can be used to monitor the health status of subjects and the effectiveness of antagonists, including physical examination, patient self-evaluation, clinical symptom evaluation and monitoring, laboratory tests, physical examinations and analytical tests and methods, including exploratory surgery.The effectiveness of the treatment methods described herein can be analyzed using techniques known in the art, such as comparing the symptoms of patients who suffer from or are at risk of specific diseases or disorders and have been administered pharmaceutical compositions containing antagonists with those who have not been treated with antagonists or have been administered placebo treatment.

[0855] The compounds disclosed herein (and their pharmaceutically acceptable salts or polymorphs) are useful for the treatment or prevention of several diseases, disorders, conditions, or symptoms. Those skilled in the art will recognize that when a disease, disorder, or symptom, or a method of treatment or prevention is disclosed herein, such disclosure also encompasses secondary medical uses (e.g., the compound, or its pharmaceutically acceptable salts or polymorphs, for use in the treatment of a disease, disorder, or symptom; the use of a compound, or its pharmaceutically acceptable salts or polymorphs, for the treatment of a disease, disorder, or symptom; and the use of a compound, or its pharmaceutically acceptable salts or polymorphs, in the manufacture of a medicament for the treatment of a disease, disorder, or symptom).

[0856] In some embodiments, the compounds disclosed herein (and pharmaceutically acceptable salts or polymorphs thereof) are useful for treating or preventing a disease, disorder, or symptom. In some embodiments, the compounds disclosed herein (and pharmaceutically acceptable salts or polymorphs thereof) are useful for treating or preventing a subtype of a disease, disorder, or symptom. In some embodiments, the compounds disclosed herein (and pharmaceutically acceptable salts or polymorphs thereof) are useful for treating or preventing a symptom of a disease or disorder.

[0857] Provided herein are methods for treating or preventing neurological diseases, disorders, or conditions with compounds of the present invention (and pharmaceutically acceptable salts or polymorphs thereof). In some embodiments, the methods are for treating neurological diseases, disorders, or conditions with compounds of the present invention (and pharmaceutically acceptable salts or polymorphs thereof). In some embodiments, the methods are for preventing neurological diseases, disorders, or conditions with compounds of the present invention (and pharmaceutically acceptable salts or polymorphs thereof).

[0858] Provided herein are compounds of the present invention (and pharmaceutically acceptable salts or polymorphs thereof) useful for treating or preventing neurological diseases, disorders or symptoms. Provided herein are compounds of the present invention (and pharmaceutically acceptable salts or polymorphs thereof) useful for treating neurological diseases, disorders or symptoms. Provided herein are compounds of the present invention (and pharmaceutically acceptable salts or polymorphs thereof) useful for preventing neurological diseases, disorders or symptoms associated with M4 activity.

[0859] One aspect of the present invention relates to a method of treating or preventing a neurological disease, disorder, or condition in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof; a pharmaceutical product of the invention; or a pharmaceutical composition of the invention.

[0860] One aspect of the present invention relates to a method for treating or preventing a muscarinic receptor 4 (M4)-mediated disease, disorder, or symptom in an individual, comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt or polymorph thereof; a pharmaceutical product of the invention; or a pharmaceutical composition of the invention.

[0861] One aspect of the present invention pertains to the use of a compound of the present invention, or a pharmaceutically acceptable salt or polymorph thereof, in the manufacture of a medicament for treating or preventing a neurological disease, disorder, or condition in an individual.

[0862] One aspect of the present invention pertains to the use of a compound of the present invention, or a pharmaceutically acceptable salt or polymorph thereof, in the manufacture of a medicament for treating or preventing a muscarinic receptor 4 (M4)-mediated disease, disorder, or symptom in an individual.

[0863] One aspect of the present invention pertains to a compound of the present invention or a pharmaceutically acceptable salt or polymorph thereof; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method of treatment or protection of the human or animal body by therapy.

[0864] One aspect of the present invention pertains to a compound of the present invention, or a pharmaceutically acceptable salt or polymorph thereof; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention, for use in a method for treating or preventing a neurological disease, disorder, or symptom in an individual.

[0865] One aspect of the present invention pertains to a compound of the present invention or a pharmaceutically acceptable salt or polymorph thereof; a pharmaceutical product of the present invention; or a pharmaceutical composition of the present invention for use in a method for treating or preventing a muscarinic receptor 4 (M4)-mediated neurological disease, disorder, or symptom in an individual.

[0866] One aspect of the present invention relates to the use of a compound, a pharmaceutically acceptable salt or crystalline form thereof, for treating a neurological disease, disorder or condition in a patient.

[0867] One aspect of the present invention pertains to the use of a compound, a pharmaceutically acceptable salt, or a crystalline form thereof, for the manufacture of a medicament for treating a neurological disease, disorder, or symptom in a patient.

[0868] In some embodiments, the neurological disease, disorder, or symptom is selected from Tourette's syndrome (TS), Alzheimer's disease (AD), schizophrenia, dementia with Lewy bodies (LBD), cognitive impairment associated with schizophrenia, Parkinson's disease, parkinsonism, tremor, dyskinesia, excessive daytime sleepiness, dystonia, chorea, levodopa-induced dyskinesia, attention deficit hyperactivity disorder (ADHD), cerebral palsy, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), Huntington's disease (HD), and chorea associated with Huntington's disease.

[0869] In some embodiments, the neurological disease, disorder or symptom is Tourette's syndrome (TS).

[0870] In some embodiments, the neurological disease, disorder or symptom is schizophrenia.

[0871] In some embodiments, the neurological disease, disorder, or symptom is progressive supranuclear palsy.

[0872] In some embodiments, the neurological disease, disorder or symptom is tremor. In some further embodiments, the neurological disease, disorder or symptom is Parkinsonian tremor.

[0873] In some embodiments, the neurological disease, disorder or symptom is Parkinsonism.In some further embodiments, Parkinsonism is drug-induced Parkinsonism.In some further embodiments, one or more symptoms of Parkinsonism are selected from tremor, bradykinesia, rigidity and postural instability.

[0874] In some embodiments, the neurological disease, disorder or symptom is Parkinson's disease (PD).

[0875] In some embodiments, the neurological disease, disorder, or symptom is Lewy body dementia (LBD).

[0876] In some embodiments, the neurological disease, disorder, or symptom is levodopa-induced dyskinesia.

[0877] In some embodiments, the neurological disease, disorder or symptom is Huntington's disease (HD).

[0878] In some embodiments, the neurological disease, disorder or symptom is excessive daytime sleepiness.

[0879] In some embodiments, the neurological disease, disorder, or symptom is dystonia. In some embodiments, the dystonia is generalized dystonia. In some further embodiments, the generalized dystonia is Oppenheim dystonia or DYT1 dystonia. In some other further embodiments, the generalized dystonia is non-DYT1 generalized dystonia. In some embodiments, the dystonia is focal dystonia. In some embodiments, the dystonia is caused by an infection. In some embodiments, the dystonia is caused by a birth injury. In further embodiments, the birth injury is cerebral palsy.

[0880] In some embodiments, the neurological disease, disorder or symptom is dyskinesia.

[0881] In some embodiments, the neurological disease, disorder, or symptom is cognitive impairment associated with schizophrenia.

[0882] In some embodiments, the neurological disease, disorder, or symptom is chorea.

[0883] In some embodiments, the neurological disease, disorder or symptom is chorea associated with Huntington's disease (HD).

[0884] In some embodiments, the neurological disease, disorder or symptom is cerebral palsy.

[0885] In some embodiments, the neurological disease, disorder or symptom is attention deficit hyperactivity disorder (ADHD).

[0886] In some embodiments, the neurological disease, disorder or symptom is Alzheimer's disease (AD).

[0887] As used herein, the term "subject" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and most preferably humans.In the context of clinical trials or screening or activity experiments, a subject can be a healthy subject or participant with no potential M4-mediated disorder or symptoms, or a subject or participant who has been diagnosed with a disorder or condition that requires medical treatment as determined by a medical professional.In the context of other than clinical trials, a subject who has been diagnosed with a disorder or condition and is under the care of a medical professional is typically referred to as a patient.

[0888] The term "pediatric subject," as used herein, refers to a subject who is under 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including neonates (birth to 1 month old), infants (1 month to 2 years old), children (2 to 12 years old), and adolescents (12 to 21 years old (up to, but not including, their 22nd birthday)). See, for example, Berhman et al., Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph et al., Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0889] As used herein, the terms "treat" and "treatment" refer to the medical management of a disease, disorder, symptom or condition in a subject (i.e., patient) (see, e.g., Stedman's Medical Dictionary). Generally, an appropriate dosage and treatment regimen provides an amount of M4 antagonist sufficient to provide therapeutic and / or prophylactic benefit. The term "treat" or "treatment" includes slowing, delaying, reducing or reversing a disease, disorder, or undesirable physiological changes or symptoms associated with the disease or disorder. The term "treat" or "treatment" also includes preventing, slowing or delaying the progression or severity of such disease, disorder or symptom. As discussed herein, the efficacy of treatment with one or more M4 antagonists may include beneficial or desired clinical results, including, but not limited to, a diminution, reduction, or alleviation of symptoms resulting from or associated with the disease or disorder being treated; a reduction in the incidence of symptoms associated with the disease or disorder being treated; an improvement in quality of life; a longer disease-free state (i.e., a reduction in the likelihood or propensity of a subject to exhibit symptoms based on the criteria by which the diagnosis of the disease or disorder is made); a gradual decrease in the extent of the disease; a stabilized (i.e., non-worsening) state of the disease or disorder; a delay or slowing of the progression of the disease or disorder; a palliation or temporary alleviation of the disease or disorder state; and remission (whether partial or total), whether detectable or undetectable, and / or overall survival.

[0890] The terms "treat" and "treatment" can also mean prolonging survival as compared to expected survival if the subject does not receive treatment. Subjects in need of treatment include those already with the disease or disorder as well as those susceptible to or at risk of developing the disease or disorder and those in whom the disease, condition, disorder or symptom is to be prevented (i.e., reducing the likelihood of the disease or disorder occurring or recurring).

[0891] The term "preventing" as used herein means preventing the onset, recurrence or spread of a disease or condition described herein, or a symptom thereof, in whole or in part.

[0892] The terms "administration" or "administering" refer to a method of providing a dosage of a compound or pharmaceutical formulation to a vertebrate or invertebrate, including a mammal, bird, fish, or amphibian. The preferred method of administration can vary depending on various factors, such as the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

[0893] As used herein, "therapeutically effective amount" refers to the amount of the compound of the present invention or its pharmaceutically acceptable salt, or the amount of a pharmaceutical composition containing the compound of the present invention or its pharmaceutically acceptable salt, that is sufficient to achieve the desired effect, and can vary according to the nature and severity of the disease symptoms and the efficacy of the compound. The therapeutic effect is a degree of alleviation of one or more symptoms of the disease, and can include curing the disease. "Cure" means that the symptoms of active disease are eliminated. However, even after a cure is achieved, there may be some long-term or permanent effects of the disease (such as extensive tissue damage).

[0894] Pharmaceutical Compositions, Formulations and Dosage Forms

[0895] The present disclosure further provides a composition for use in a method for treating an M4-mediated disease or disorder, such as a neurological disease or disorder, comprising any of the compounds of the present invention (e.g., compounds of Formula (Ia), including the specific compounds described herein) or a pharmaceutically acceptable salt thereof disclosed and described herein, and an excipient, e.g., a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable, non-toxic, inert material or ingredient that does not interfere with the activity of the drug substance; an excipient may also be referred to as a carrier. The formulation methods and excipients described herein are exemplary and in no way limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical arts and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed., Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.

[0896] In the composition formulated as liquid solution, acceptable carrier and / or diluent include physiological saline and sterilized water, and can contain antioxidant, buffer, bacteriostatic agent and other common additives as needed.Composition can also be formulated as pill, capsule, granule or tablet containing diluent, dispersant and surfactant, binder and lubricant in addition to M4 antagonist.Those skilled in the art can further formulate M4 antagonist in suitable manner according to accepted practice, such as disclosed in Remington above.

[0897] Administration method includes systemic administration of the M4 antagonist described herein, preferably in the form of pharmaceutical compositions as discussed above.As used herein, systemic administration includes oral and parenteral administration methods.For oral administration, suitable pharmaceutical compositions include powder, granules, pills, tablets and capsules, as well as liquids, syrups, suspensions and emulsions.These compositions can also contain flavorings, preservatives, suspending agents, thickening agents and emulsifying agents, and other pharmaceutically acceptable additives.For parenteral administration, the compound of the present invention (or its pharmaceutically acceptable salt) can be prepared in aqueous injection solution, which can contain, in addition to the M4 antagonist, buffers, antioxidants, bacteriostatic agents, and other additives commonly used in such solutions.

[0898] Pharmaceutical preparations for oral administration can be obtained by any suitable method, typically by uniformly mixing the compound(s) with a liquid or finely divided solid carrier, or both, in the required proportions, then treating the mixture as necessary, adding suitable auxiliaries if desired, and shaping the resulting mixture into the desired shape to give tablets or dragee cores.

[0899] Conventional excipients such as binders, fillers, adjuvants, carriers, acceptable wetting agents, tableting lubricants and disintegrants can be used in tablets and capsules for oral administration.Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups.Or, oral preparations can be in the form of dry powders that can be reconstituted with water or another suitable liquid vehicle before use.Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring and coloring agents can be added to liquid preparations.Non-oral dosage forms can be prepared by dissolving the compound of the present invention in a suitable liquid vehicle, and sterilizing the solution by filtration before lyophilization, or simply filling suitable vials or ampoules and sealing them.

[0900] As used herein, a "drug substance" defined in the context of a "pharmaceutical composition" refers to the component of a pharmaceutical composition, such as any one of the compounds disclosed and described herein, that provides the primary pharmacological effect, as opposed to an "inactive ingredient" that is generally recognized as not providing a therapeutic benefit.

[0901] As used herein, "excipient" refers to a substance added to a composition to provide the composition with, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. A "diluent" is a type of excipient and refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small to manufacture and / or administer. A diluent may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic inert material or ingredient that does not interfere with the activity of the drug substance. Pharmaceutically acceptable excipients are well known in the pharmaceutical arts and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. Additionally, antioxidants and suspending agents may also be used. For compositions formulated as liquid solutions, acceptable carriers and / or diluents include saline and sterile water, and may include antioxidants, buffers, bacteriostats, and other common additives as needed. In some embodiments, the diluent may be an aqueous buffer solution, such as, without limitation, phosphate-buffered saline. The compositions may also be formulated as capsules, granules, or tablets containing, in addition to the compounds disclosed and described herein, diluents, dispersants and surfactants, binders, and lubricants. Those skilled in the art can further formulate the compounds disclosed and described herein in an appropriate manner and in accordance with accepted practices, such as those disclosed in Remington, supra.

[0902] One aspect of the present invention relates to a method for preparing a pharmaceutical composition comprising the step of mixing a compound according to the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0903] In preparing pharmaceutical compositions containing the compounds of the present invention or their pharmaceutically acceptable salts, the drug substance is typically mixed (i.e., blended) with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container.When an excipient functions as a diluent, the excipient can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the drug substance.Thus, the composition can be in the form of a tablet, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment, soft and hard gelatin capsules, suppositories, sterile injection solution, and sterile packaged powder.

[0904] To prepare pharmaceutical compositions in solid forms, such as powders, tablets, capsules, cachets, suppositories, and dispersible granules, excipients can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Also included are solid form preparations intended to be converted immediately before use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0905] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein as by stirring, etc. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0906] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0907] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0908] The pharmaceutical compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the pharmaceutical compositions may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0909] Pharmaceutical compositions may be formulated as aqueous solutions, hydroalcoholic solutions, solid suspensions, emulsions, liposomal suspensions, or lyophilized powders for reconstitution. Such pharmaceutical compositions may be administered directly or as a mixture for further dilution / reconstitution. Routes of administration include intravenous bolus, intravenous infusion, irrigation, and dropwise injection. Suitable solvents include water, alcohol, PEG, propylene glycol, and lipids. pH adjustment using an acid, such as HCl or citric acid, can be used to increase solubility, and the resulting composition can be subjected to suitable sterilization procedures known in the art, such as sterile filtration. In some embodiments, the pH of the aqueous solution is about 2.0 to about 4.0. In some embodiments, the pH of the aqueous solution is about 2.5 to about 3.5.

[0910] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active ingredient in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.

[0911] Aqueous suspensions suitable for oral use can be made by dispersing finely divided drug substance in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0912] For topical administration to the epidermis, the compound of the present invention or its pharmaceutically acceptable salts can be formulated as gel, ointment, cream or lotion, or as a transdermal patch.In addition, suitable formulations for topical administration in the mouth include lozenges containing active ingredients in a flavored base, usually sucrose and acacia or tragacanth; troches containing active ingredients in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwash containing active ingredients in a suitable liquid carrier.Ointments and creams can be formulated using an aqueous or oily base, for example, with the addition of suitable thickeners and / or gelling agents.Lotions can be formulated using an aqueous or oily base, and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants.In some embodiments, topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. The carrier composition of creams can be based on water combined with glycerol and one or more other ingredients, for example, glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably combined with other ingredients, for example, glycerol, hydroxyethylcellulose, etc.

[0913] Solution or suspension can be directly applied to nasal cavity by conventional means, for example, by using dropper, pipette or spray.Preparation can be provided in single or multiple dose form.In the latter case of dropper or pipette, this can be achieved by patient administering appropriate predetermined amount of solution or suspension.In the case of spray, this can be achieved by, for example, metered atomizing spray pump.

[0914] Administration to the respiratory tract can also be achieved by aerosol formulations provided in pressurized packs containing a suitable propellant. When the compounds of the present invention or their pharmaceutically acceptable salts, or pharmaceutical compositions containing them, are administered as aerosols, e.g., nasal aerosols, or by inhalation, this can be achieved using, for example, sprays, nebulizers, pump nebulizers, inhalation devices, metered-dose inhalers, or dry-powder inhalers. Pharmaceutical forms for administration of the compounds of the present invention (or their pharmaceutically acceptable salts) as aerosols can be prepared by methods well known to those skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the present invention (or their pharmaceutically acceptable salts) in water, water / alcohol mixtures, or appropriate saline solutions can be used, using conventional additives, such as benzyl alcohol, or other suitable preservatives, absorption enhancers to enhance bioavailability, solubilizers, dispersants, etc., where appropriate, and conventional propellants include, for example, carbon dioxide, CFCs, such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane. The aerosol can also advantageously contain a surfactant, such as lecithin. The dose of drug may be controlled by providing a metered valve.

[0915] Alternatively, the pharmaceutical composition may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base, such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose, and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier forms a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example, in capsules or cartridges, such as gelatin or blister packs, from which the powder can be administered by inhaler.

[0916] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may also be administered in fast-dissolving or sustained-release compositions, which include biodegradable fast-dissolving or sustained-release carriers (e.g., polymeric carriers, etc.). Fast-dissolving or sustained-release carriers are well known in the art and are used to entrap the compounds of the present invention, or pharmaceutically acceptable salts thereof, in a complex that degrades / dissolves either rapidly or slowly in a suitable environment (e.g., aqueous, acidic, basic, etc.).

[0917] Pharmaceutical preparations are preferably in unit dosage form.In this form, preparations are divided into unit doses that contain appropriate amounts of active pharmaceutical ingredients.Unit dosage form can also be the preparation packaged in vial or ampule, and the package contains individual amounts of preparations such as packaged tablets, capsules and powders.Also, unit dosage form can be capsules, tablets, cachets or lozenges themselves, or any of these in appropriate number in packaged form.

[0918] Tablets or capsules for oral administration and solutions for intravenous administration are preferred compositions.

[0919] The compositions can be formulated in unit dosage form, each dosage containing the drug substance or an equivalent mass of the drug substance. The term "unit dosage form" refers to a physically discrete unit of formulation suitable as a unit dosage for human subjects and other mammals, each unit containing a predetermined quantity of the drug substance calculated to produce the desired therapeutic effect, in association with suitable excipients, as described herein.

[0920] The compositions described herein can be formulated to provide immediate and / or timed release (also known as extended, sustained, controlled, or extended release) of the active ingredient after administration to a subject using procedures known in the art. For example, tablets containing the compounds of the present invention or their pharmaceutically acceptable salts can be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action. For example, a tablet can contain an inner dosage component and an outer dosage component, the latter in the form of an envelope surrounding the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to delay release. A wide variety of materials can be used for such enteric layers or coatings, including numerous polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0921] Liquid forms containing the drug substance can be incorporated for oral or injectable administration and include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, and similar excipients.

[0922] The pharmaceutical compositions described herein can be sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions can be packaged for immediate use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically 3-11, more preferably 5-9, and most preferably 7-8. It is understood that the use of certain of the aforementioned excipients may result in the formation of pharmaceutically acceptable salts.

[0923] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable excipients as described herein. In some embodiments, the compositions are administered orally or nasally for local or systemic effects. The compositions can be nebulized by using an inert gas. The nebulized solution can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0924] The compositions may be provided in a pack or dispenser device, if desired, which may contain one or more unit dosage forms containing the active pharmaceutical ingredient. The pack may comprise, for example, metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container, in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or veterinary administration. Such notice may be, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. Compositions that can include the compounds described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0925] As used herein, "dose" or "dosage" refers to a measured amount of a drug substance that a patient should take at one time. In certain embodiments where the drug substance is not the free base or free acid, the amount is the molar equivalent to the corresponding amount of the free base or free acid.

[0926] To prepare solid compositions such as tablets, the drug substance may be mixed with excipients to form a solid preformulation composition containing a uniform mixture of ingredients. When these preformulation compositions are referred to as homogeneous, the drug substance is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets and capsules.

[0927] The kit provided herein has a unit dose of one or more compounds, usually in oral or injectable dose.Such kit can include a container that contains a unit dose, an information package insert that describes the use of the drug in treating the pathological symptoms of the subject and the accompanying benefits, and optionally the instrument or device that delivers the composition.

[0928] Dosage schedule / amount

[0929] The compound of the present invention or its pharmaceutically acceptable salt can be effective over a wide dosage range and is generally administered in a therapeutically effective amount.However, it is understood that the amount of compound actually administered will usually be determined by a physician according to the relevant circumstances, including the symptoms to be treated, the selected administration route, the actual administered compound, the age, weight and response of individual subjects, the severity of the symptoms of the subject, etc.

[0930] The amount of compound or composition administered to a subject will also vary depending on what is being administered, the purpose of administration, such as prophylaxis or treatment, the condition of the subject, the mode of administration, etc. In therapeutic applications, the composition can be administered to a subject already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms and / or pathology of the disease and its complications. The therapeutically effective dose will depend on the disease symptoms being treated and the judgment of the attending physician, depending on factors such as the severity of the disease, the age, weight, and general condition of the subject.

[0931] Desired dose can be conveniently presented in a single dose, or can be presented as divided doses administered at appropriate intervals, for example, as 2, 3, 4 or more sub-doses per day.Sub-dose itself can be further divided, for example, into several separate, loosely spaced administrations.Daily dose can be divided into several, for example, 2, 3 or 4 partial administrations, especially when it is considered appropriate to administer a relatively large amount.If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.

[0932] It will be apparent to those skilled in the art that the dosage forms described herein may contain, as the drug substance, any of the compounds described herein or their pharmaceutically acceptable salts, solvates, or hydrates. Exemplary procedures for making and identifying suitable hydrates and solvates, other than those described herein, are well known to those skilled in the art; see, for example, pages 202-209 of K. J. Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999, incorporated herein by reference in its entirety. Accordingly, one aspect of the present invention relates to methods of administering hydrates and solvates of the compounds described herein and / or their pharmaceutically acceptable salts, which can be isolated and characterized by methods known in the art, such as thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, powder X-ray diffraction (PXRD), Karl Fischer titration, high-resolution X-ray diffraction, and the like. [Example]

[0933] Synthesis of Compounds of the Invention

[0934] Detailed compound synthesis methods are described in the examples provided herein. Those skilled in the chemical arts will be able to prepare compounds of Formula (Ia) and related formulae, including the specific compounds described herein, by these or similar methods or other methods practiced by those skilled in the art. Generally, the starting components are commercially available chemicals and can be obtained from commercial sources, or can be prepared starting from commercially available chemicals and / or compounds described in the chemical literature according to organic synthesis techniques known to those skilled in the art. The compounds described herein above and below are named according to MarvinSketch 18.24.0 or ChemDraw Professional 18.2.0.48. In some instances, when common names are used, it is understood that these common names are recognized by those skilled in the art.

[0935] In general, the compounds used in the reactions described herein can be made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature."Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwell, UK), Chemservice Inc. (Westchester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwell, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwell, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0936] Some intermediates are commercially available or can be prepared according to the methods provided herein, including 2,5-difluoro-4-(piperazin-1-yl)benzonitrile, 3-fluoro-4-(piperazin-1-yl)benzonitrile, 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine, 2-(piperazin-1-yl)-5-(trifluoromethyl)benzonitrile, 1-(4-(trifluoromethyl)phenyl)piperazine, 2-azaspiro[3.3]heptan-6-ol, tert-butyl N-{2-azaspiro[3.3]heptan-6-yl}carbamate, tert-butyl ((2-azaspiro[3.3]heptan-6-yl)methyl)carbamate, and tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate.

[0937] The method known to those skilled in the art can be identified through various reference books and databases.The appropriate reference books and specialized textbooks that describe the synthesis of the reactant that is useful for preparing the compound of the present disclosure or that refer to the paper that describes the preparation include, for example: Synthetic Organic Chemistry, John Wiley&Sons,Inc.,New York;SRSandler et al., Organic Functional Group Preparations, 2nd Ed.,Academic Press,New York,1983;HO House, Modern Synthetic Reactions, 2nd Ed.,WA Benjamin, Inc.Menlo Park,California.1972;TLG Ilchrist, Heterocyclic Chemistry, 2nd Ed.,John Wiley&Sons,New York,1992;J.March, Advanced Organic Chemistry:Reactions, Mechanisms and Structure, 4th Ed.,Wiley Interscience,New York,1992. Additional suitable reference books and treatises detailing the synthesis of reactants useful in preparing the compounds of the present disclosure, or referencing treatises describing the preparation, include, for example, Fuhrhop, J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV; Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RCComprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th Edition (1992) John Wiley&Sons,ISBN:0-471-60180-2;Otera, J.(editor)Modern Carbonyl Chemistry,(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.,Patai's 1992 Guide to the Chemistry of Functional Groups,(1992)Interscience ISBN:0-471-93022-9;Quin, LD et al., A Guide to Organophosphorus Chemistry,(2000)Wiley-Interscience,ISBN:0-471-31824-8;Solomons,TWGO Organic Chemistry,7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0;Stowell,JC,Intermediate Organic Chemistry,2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2;Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann's Encyclopedia,(1999)John Wiley&Sons,ISBN:3-527-29645-X,8 volumes;Organic Reactions,(1942-2019)John Wiley & Sons, Volume 95 et seq; and Chemistry of Functional Groups, John Wiley & Sons, hardcover edition (86) and electronic edition (26).

[0938] Specific and similar reactants can also be identified through the index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries and online databases (the American Chemical Society, Washington, D.C., can be contacted for further details). Chemical products that are known but not commercially available in catalogs can be produced by custom chemical synthesis companies according to known methods, with many standard chemical supply companies (e.g., as listed above) offering custom synthesis services.

[0939] Specific Abbreviations

[0940] This specification contains a number of abbreviations, the definitions of which are listed in the table below. [Table 2]

[0941] The following examples are included to demonstrate embodiments of the present disclosure, however, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0942] Analytical HPLC analysis was performed on an LC-MS system equipped with a UV detector (Dionex™ UVD 170u UV / VIS detector), a corona array detector (Thermo™ Veo™ RS), and a mass spectrometer (Dionex MSQ Plus™). Reverse-phase preparative HPLC purification was performed on a Phenomenex LCMS system C18 Kinetix 5µ 100A 150 x 21.2mm column using an ACN / water gradient containing 0.05% TFA. All final compounds were analyzed by analytical HPLC, monitoring peaks at 210, 254, and 280nM for purity. The peaks were analyzed on a Bruker 400MHz spectrometer equipped with a Broad Band NMR probe in an appropriate NMR solvent, such as DMSO-d6. 1 H was recorded. 1 H chemical signals are given in parts per million (ppm) using the residual solvent signal as reference. Chemical shifts are expressed in ppm (δ) and coupling constants (J) are reported in hertz (Hz). Unless otherwise stated, reactions were carried out under a dry nitrogen atmosphere.

[0943] Example 1: Preparation of intermediate 2-benzyl-2-azaspiro[3.3]heptan-6-amine. [ka]

[0944] To a solution of tert-butyl N-{2-azaspiro[3.3]heptan-6-yl}carbamate (2.5 g, 11.8 mmol, 1.0 equiv.) in dichloroethane (100 mL) was added benzaldehyde (1.8 mL, 17.7 mmol, 1.5 equiv.), followed by sodium triacetoxyborohydride (7.5 g, 35.4 mmol, 3.0 equiv.). The resulting mixture was stirred overnight at room temperature. The formed suspension was carefully diluted and stirred with saturated NaHCO3 until gas evolution ceased. The aqueous mixture was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered to remove solids, and concentrated in vacuo. A silica gel column (80 g) was loaded with DCM and run down an increasing gradient (0-15%) of MeOH in DCM over 25 min to give the Boc-protected intermediate: [ka]

[0945] The isolated Boc-protected intermediate was redissolved in DCM (35 mL), treated with TFA (5 mL), and stirred at room temperature overnight. Additional TFA (2.5 mL) was added, and the mixture was stirred until complete. The reaction was carefully quenched with saturated NaHCO3, brought to pH > 10 with 2 M NaOH, and extracted with 5:1 DCM:2-propanol. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated in vacuo to give 2-benzyl-2-azaspiro[3.3]heptan-6-amine (2.3 g, 11.4 mmol, 97% over two steps) as a yellow liquid.

[0946] Example 2: Preparation of (3R,5S)-1-(4-methanesulfinylphenyl)-3,5-dimethylpiperazine [ka]

[0947] To a solution of (2R,6S)-2,6-dimethylpiperazine (0.30 g, 2.6 mmol, 1.0 equiv.) and 1-bromo-4-methanesulfinylbenzene (0.58 g, 2.6 mmol, 1.0 equiv.) in a degassed mixture of toluene / tert-butanol (5:1, 12 mL), sodium tert-butoxide (0.76 g, 7.9 mmol, 3.0 equiv.) was added, followed by palladium diacetate (0.059 g, 0.26 mmol, 0.10 equiv.) and XPhos (0.063 g, 0.13 mmol, 0.050 equiv.). The resulting mixture was heated to 110 °C for 24 h. The mixture was then cooled, diluted with EtOAc, passed through a pad of Celite®, and concentrated in vacuo. The crude material was purified on a 40 g silica gel column using DCM and eluted with an increasing gradient of methanol in DCM (0 to 50%) over 20 min. The isolated material was dissolved in 2 mL of diethyl ether, treated with 4 mL of a 2 M HCl solution in diethyl ether, and stirred overnight at room temperature. The resulting suspension was filtered and washed with diethyl ether to give (3R,5S)-1-(4-methanesulfinylphenyl)-3,5-dimethylpiperazine hydrochloride (0.20 g, 0.69 mmol, 26% over two steps), isolated as a white solid.

[0948] Other intermediates useful in preparing compounds of the invention were made using essentially the same procedures described above, including: [ka]

[0949] Example 3 Preparation of 2-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-5-(ethanesulfonyl)pyrimidine [ka]

[0950] To a solid mixture of tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (0.30 g, 1.4 mmol, 1.0 equiv.) and 2-chloro-5-(ethanesulfonyl)pyrimidine (0.29 g, 1.4 mmol, 1.0 equiv.), dry ACN (7 mL) was added, followed by TEA (0.78 mL, 5.6 mmol, 4.0 equiv.). The resulting mixture was stirred at room temperature overnight. The formed suspension was filtered to remove TEA hydrochloride and concentrated in vacuo. The residue was then redissolved in 1,4-dioxane (4 mL), treated with 4 N HCl in 1,4-dioxane (4 mL), and stirred overnight. The mixture was diluted with diethyl ether and the resulting solid was collected by vacuum filtration to give 2-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-5-(ethanesulfonyl)pyrimidine hydrochloride (0.44 g, 96% yield over two steps) as a white solid.

[0951] Other intermediates useful in preparing compounds of the invention were made using essentially the same procedures described above, including: [ka] [ka]

[0952] Example 4: Preparation of 2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-5-ol [ka]

[0953] To a solid mixture of tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.7 g, 13 mmol, 1.0 equiv.) and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (2.8 g, 13 mmol, 1.0 equiv.), dry DMF (63 mL) was added, followed by TEA (3.5 mL, 25 mmol, 2.0 equiv.). The resulting mixture was heated at 120° C. for 4 days. The reaction was then cooled to room temperature and diluted with water and ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This material was purified by silica chromatography (120 g) using an increasing gradient of ethyl acetate in hexanes (0-80%) over 20 minutes to give tert-butyl (2R,6S)-4-[5-(benzyloxy)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carboxylate (1.6 g, 4.0 mmol, 31% yield) as a white solid: [ka]

[0954] To a nitrogen-purged 100 mL flask was added wet 10% Pd / C (0.43 g, 0.40 mmol, 0.10 equiv.) followed by the addition of substituted piperazine (1.6 g, 4.0 mmol, 1.0 equiv.) in wet THF (20 mL). The reaction was then charged with hydrogen gas and stirred overnight at room temperature. The reaction was then diluted with ethyl acetate and filtered through celite under nitrogen. The organics were concentrated in vacuo, and the material was purified by silica chromatography (80 g) using an increasing gradient of ethyl acetate in hexanes (0-100%) over 15 minutes to afford tert-butyl (2R,6S)-4-(5-hydroxypyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate (1.2 g, 3.9 mmol, 97% yield) as a white solid: [ka]

[0955] The Boc-protected intermediate (0.16 g, 0.52 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (3 mL), treated with 4 N HCl in 1,4-dioxane (3 mL), and heated at 40° C. for 1 h. The reaction was then cooled to room temperature, diluted with diethyl ether, and the resulting solid was collected by vacuum filtration to give 2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-5-ol hydrochloride (0.12 g, 0.49 mmol, 94%) as a white solid.

[0956] Example 5: Preparation of 2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-methanesulfinylpyrimidine [ka]

[0957] To a solution containing tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (0.50 g, 2.3 mmol, 1.0 equiv.) and 2-chloro-5-(methylsulfanyl)pyrimidine (0.37 g, 2.3 mmol, 1.0 equiv.), dry ACN (11 mL) was added, followed by TEA (1.3 mL, 9.2 mmol, 4.0 equiv.). The resulting mixture was stirred at room temperature overnight. The formed suspension was filtered to remove TEA hydrochloride and concentrated in vacuo. This material was purified by silica chromatography (24 g) using an increasing gradient of ethyl acetate in hexanes (0-50%) over 15 minutes to give tert-butyl (2R,6S)-2,6-dimethyl-4-[5-(methylsulfanyl)pyrimidin-2-yl]piperazine-1-carboxylate (0.34 g, 1.0 mmol, 43% yield) as an orange solid. [ka]

[0958] To a solution of the substituted piperazine intermediate (0.34 g, 1.0 mmol, 1.0 equiv) in dry DCM (1 mL) at 0 °C was added 3-chlorobenzene-1-carboperoxoic acid (0.22 g, 1.3 mmol, 1.3 equiv) in small portions. Upon completion, the reaction was quenched with saturated sodium carbonate, and the organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This material was purified by silica chromatography (40 g) using an increasing gradient of ethyl acetate in hexanes (0 to 100%) over 20 minutes to afford tert-butyl (2R,6S)-4-(5-methanesulfinylpyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate (0.16 g, 0.45 mmol, 45% yield) as an orange solid: [ka]

[0959] The isolated Boc-protected intermediate (0.16 g, 0.45 mmol, 1.0 equiv.) was dissolved in dry DCM (2 mL) and treated with TFA (0.2 mL) overnight at room temperature. The reaction was then concentrated, dissolved in methanol, and made basic with MP-carbonate resin. The resin was filtered off, and the organics were concentrated to give 2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-methanesulfinylpyrimidine (0.11 g, 0.43 mmol, 96%) as an orange solid.

[0960] Example 6: 2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-6H,7H-5λ 6 Preparation of -thieno[3,2-d]pyrimidine-5,5-dione [ka]

[0961] To a solution containing 2,4-dichloro-6H,7H-thieno[3,2-d]pyrimidine (1.0 g, 4.8 mmol, 1.0 equiv.) in THF (10 mL) and water (5 mL) was added zinc dust (0.57 g, 8.7 mmol, 1.8 equiv.). After refluxing the solution at 90° C., acetic acid (0.58 mL, 9.7 mmol, 2.0 equiv.) in THF (10 mL) was added dropwise. After 20 minutes, additional zinc dust (0.57 g, 8.7 mmol, 1.8 equiv.) was added to the reaction mixture. The mixture was stirred overnight. Upon completion, the reaction was cooled to room temperature and then diluted with ethyl acetate and water. The organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated to give 2-chloro-6H,7H-thieno[3,2-d]pyrimidine (0.52 g, 3.0 mmol, 63% yield) as an orange solid: [ka]

[0962] To a solid mixture of 2-chloropyrimidine (0.52 g, 3.0 mmol, 1.0 equiv.) and tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (0.64 g, 3.0 mmol, 1.0 equiv.), dry DMF (15 mL) was added, followed by TEA (2.0 mL, 15 mmol, 5.0 equiv.). The reaction was heated at 60° C. for 3 days and then warmed to 90° C. overnight. The reaction was then cooled to room temperature and diluted with water and ethyl acetate. The organic layer was washed with brine and concentrated. The residue was dissolved in DCM, dried over anhydrous magnesium sulfate, filtered, and concentrated to give tert-butyl (2R,6S)-2,6-dimethyl-4-{6H,7H-thieno[3,2-d]pyrimidin-2-yl}piperazine-1-carboxylate (0.65 g, 1.8 mmol, 62% yield) as an orange solid: [ka]

[0963] To a solution containing the substituted piperazine intermediate (0.65 g, 1.8 mmol, 1.0 equiv.) in dry DCM (19 mL) was added 3-chlorobenzene-1-carboperoxoic acid (1.9 g, 11 mmol, 6.0 equiv.). The reaction was refluxed for 4 hours, after which additional 3-chlorobenzene-1-carboperoxoic acid (2.0 equiv.) was added until the reaction was complete. Upon completion, the reaction was cooled to room temperature and then quenched with saturated sodium bicarbonate. The reaction was diluted with water and DCM. The organic layer was collected and washed with saturated sodium bicarbonate. The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated to give tert-butyl (2R,6S)-4-(5,5-dioxide-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate (0.61 g, 1.6 mmol, 86% yield) as an orange solid: [ka]

[0964] The Boc-protected intermediate (0.25 g, 0.65 mmol, 1.0 equiv.) was dissolved in dry DCM (10 mL) and treated with TFA (2 mL) overnight at room temperature. The reaction was then concentrated, dissolved in methanol, and basified with MP-carbonate resin. The resin was filtered off, and the organics were concentrated to give 2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-6H,7H-5λ. 6 -thieno[3,2-d]pyrimidine-5,5-dione (0.18 g, 0.64 mmol, 97% yield) was obtained as an orange solid.

[0965] Example 7 Preparation of 2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-methanesulfonyl-4-methylpyrimidine [ka]

[0966] To a solid mixture of (2R,6S)-2,6-dimethylpiperazine (0.25 g, 2.2 mmol, 1.0 equiv.) and 2-chloro-5-methanesulfonyl-4-methylpyrimidine (0.45 g, 2.2 mmol, 1.0 equiv.), dry ACN (10 mL) was added, followed by TEA (0.61 mL, 4.4 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature overnight. The resulting suspension was diluted with ethyl acetate, filtered to remove TEA hydrochloride, and then concentrated in vacuo to give 2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-methanesulfonyl-4-methylpyrimidine as a white solid.

[0967] Other intermediates useful in preparing compounds of the invention were made using essentially the same procedure described above (i.e., room temperature overnight), although heating may be required. Intermediates prepared by this procedure include: [ka]

[0968] Example 8: Preparation of (2R,6S)-4-[5-(ethanesulfonyl)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carbonyl chloride [ka]

[0969] To a suspension of 2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-(ethanesulfonyl)pyrimidine (28.7 g, 101 mmol, 1.00 equiv) in dry DCM (600 mL) was added triphosgene (15.0 g, 50.6 mmol, 0.500 equiv) in small portions, followed by the dropwise addition of pyridine (8.14 mL, 101 mmol, 1.00 equiv). The reaction was stirred at room temperature for 48 hours and then quenched with 1 N HCl (200 mL) and water (200 mL). The product was extracted with DCM and the combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated to give crude (2R,6S)-4-[5-(ethanesulfonyl)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carbonyl chloride (Intermediate #, 35.0 g, 101 mmol, 100%) as a white solid which was used without further purification.

[0970] Other intermediates required for the preparation of compounds of the present invention were made using essentially the same procedure described above (i.e., room temperature), although in some cases heat may be required. Intermediates prepared by this procedure include: [ka]

[0971] Example 9 Preparation of (2R,6S)—N-{2-benzyl-2-azaspiro[3.3]heptan-6-yl}-4-(5-methanesulfonylpyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide [ka]

[0972] To a solution of (2R,6S)-N-{2-benzyl-2-azaspiro[3.3]heptan-6-yl}-4-(5-methanesulfonylpyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide (0.26 g, 1.3 mmol) in water (7.8 mL) was added carbonyldiimidazole (0.25 g, 1.6 mmol), and the resulting mixture was stirred at 0° C. overnight. To an aliquot of the mixture (0.30 mL, 0.050 mmol, 1.0 equiv.) was added a solution of (3S,5R)-3,5-dimethyl-1-(4-(methylsulfonyl)phenyl)piperazine hydrochloride (15 mg, 0.050 mmol, 1.0 equiv.), 4-DMAP (0.012 g, 0.098 mmol, 2.0 equiv.), and TEA (30 μL) in dry DMF (0.3 mL) and stirred overnight at room temperature. (Additional aliquots were used to prepare the remaining compounds listed in Table A, substituting the appropriate secondary amine for (3S,5R)-3,5-dimethyl-1-(4-(methylsulfonyl)phenyl)piperazine.) The mixture was then diluted to a total volume of 1 mL with MeOH and directly subjected to preparative chromatography to give (2R,6S)-N-{2-benzyl-2-azaspiro[3.3]heptan-6-yl}-4-(5-methanesulfonylpyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxamide.

[0973] Example 10: Preparation of 2-benzyl-2-azaspiro[3.3]heptan-6-ol [ka]

[0974] To a suspension of 2-azaspiro[3.3]heptan-6-ol hydrochloride (4.6 g, 30.7 mmol, 1.0 equiv.) in dichloroethane (160 mL) was added benzaldehyde (4.6 mL, 46.0 mmol, 1.5 equiv.), followed by sodium triacetoxyborohydride (32 g, 153 mmol, 5.0 equiv.). The resulting mixture was stirred at room temperature overnight. The formed suspension was carefully diluted and stirred with saturated NaHCO3 until hydrogen evolution ceased. The aqueous mixture was extracted with 5:1 DCM:2-propanol. The combined organic layers were dried over MgSO4, filtered to remove solids, and concentrated in vacuo. The crude material was purified on a silica gel column (120 g) using DCM and an increasing gradient of MeOH (0-20%) in DCM over 20 min, followed by flushing with 50% MeOH to give 2-benzyl-2-azaspiro[3.3]heptan-6-ol (6.1 g, 30.0 mmol, 98%) as an orange liquid.

[0975] Other intermediates useful in preparing compounds of the invention were made using essentially the same procedures described above, including: [ka]

[0976] Example 11 Preparation of 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,5S)-4-[5-(ethanesulfonyl)pyrimidin-2-yl]-2,5-dimethylpiperazine-1-carboxylate [ka]

[0977] To a solution of 2-benzyl-2-azaspiro[3.3]heptan-6-ol (0.10 g, 0.49 mmol, 1.0 equiv.) in dry DCM (0.24 mL) was added N,N'-disuccinimidyl carbonate (0.14 g, 0.54 mmol, 1.1 equiv.), and the reaction was stirred at room temperature overnight. To an aliquot of the resulting solution (0.049 mL, 0.10 mmol, 1.0 equiv) was added 2-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-5-(ethanesulfonyl)pyrimidine hydrochloride (0.032 g, 0.10 mmol, 1.0 equiv), 4-DMAP (0.024 g, 0.20 mmol, 2.0 equiv), and TEA (0.028 mL, 0.20 mmol, 2.0 equiv) in dry DCM (0.049 mL), and the reaction was stirred at room temperature for 2 hours, then at 40° C. overnight if incomplete. (Further aliquots were used to prepare the remaining compounds by substituting the appropriate secondary amine hydrochloride for 2-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-5-(ethanesulfonyl)pyrimidine hydrochloride.) The reaction mixture was diluted to a total volume of 1 mL with MeOH and directly subjected to preparative chromatography to give 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,5S)-4-[5-(ethanesulfonyl)pyrimidin-2-yl]-2,5-dimethylpiperazine-1-carboxylate.

[0978] Example 12 Preparation of 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,6S)-2,6-dimethyl-4-[5-(2-oxoazetidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxylate [ka]

[0979] 2-Benzyl-2-azaspiro[3.3]heptan-6-yl (2R,6S)-4-(5-iodopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate was prepared according to Example 3: [ka]

[0980] A solution of the above 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,6S)-4-(5-iodopyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate (0.020 g, 0.037 mmol, 1.0 equiv.), azetidin-2-one (0.0026 g, 0.037 mmol, 1.0 equiv.) in degassed 1,4-dioxane (0.5 mL) was added. A solution of (2R,6S)-2,6-dimethyl-4-[5-(2-oxoazetidin-1-yl)pyrimidin-2-yl]piperazine-1-carboxylate ...

[0981] Example 13 Preparation of 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,6S)-4-[5-(ethanesulfonyl)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carboxylate [ka]

[0982] To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (36.0 g, 104 mmol, 1.00 equiv.) in dry THF (260 mL) was added KHMDS (42.0 g, 208 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 20 minutes. The suspension was then added in one portion to a suspension of (2R,6S)-4-[5-(ethanesulfonyl)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carbonyl chloride (36.0 g, 104 mmol, 1.00 equiv.) in dry ACN (260 mL), and the resulting mixture was stirred at 40 °C for 6 days. Upon completion, the reaction was concentrated. The residue was diluted with ethyl acetate and washed sequentially with water, saturated ammonium chloride, saturated sodium bicarbonate, and 2N NaOH. The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a dark orange oil. This material was partially purified on a 220 g silica column using an increasing gradient of acetone in hexanes (0 to 100%) over 30 minutes to give a yellow solid. The material was then recrystallized in IPA to give 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,6S)-4-[5-(ethanesulfonyl)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carboxylate (14.8 g, 28.8 mmol, 28% yield) as a white solid.

[0983] Example 14 Preparation of 2-benzyl-2-azaspiro[3.3]heptan-6-yl (2R,6S)-4-(5-ethoxypyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0984] To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (5.0 g, 23 mmol, 1.0 equiv.) in dry THF (60 mL) was added KHMDS (9.3 g, 47 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 20 minutes. The suspension was then added in one portion to a suspension of (2R,6S)-4-[5-(benzyloxy)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carbonyl chloride (8.4 g, 23 mmol, 1.0 equiv.) in dry ACN (60 mL). The reaction was stirred overnight at room temperature. Upon completion, the reaction was concentrated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. This material was purified by silica chromatography (220 g) using an increasing gradient of ethyl acetate in hexanes (0-50%) over 25 minutes to give tert-butyl 6-[(2R,6S)-4-[5-(benzyloxy)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carbonyloxy]-2-azaspiro[3.3]heptane-2-carboxylate (5.3 g, 9.9 mmol, 43% yield) as an orange solid: [ka]

[0985] To a nitrogen-purged 250 mL flask was added wet 10% Pd / C (1.1 g, 1.0 mmol, 0.10 equiv.), followed by the isolated carbamate (5.3 g, 9.9 mmol, 1.0 equiv.) in wet THF (50 mL). The reaction was then charged with hydrogen gas and stirred overnight at room temperature. The reaction was then diluted with ethyl acetate and filtered through celite under nitrogen. The organics were concentrated in vacuo to give tert-butyl 6-[(2R,6S)-4-(5-hydroxypyrimidin-2-yl)-2,6-dimethylpiperazine-1-carbonyloxy]-2-azaspiro[3.3]heptane-2-carboxylate (3.9 g, 8.7 mmol, 88% yield) as an orange solid: [ka]

[0986] To a solid mixture of the 5-hydroxypyrimidine intermediate (0.13 g, 0.29 mmol, 1.0 equiv.) and cesium carbonate (0.19 g, 0.58 mmol, 2.0 equiv.), dry DMF (1.5 mL) was added, followed by iodoethane (0.045 g, 0.29 mmol, 1.0 equiv.). The reaction was stirred overnight at room temperature. Upon completion, the reaction was diluted with water and ethyl acetate, and the organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. (Other compounds were prepared using the corresponding iodides instead of iodoethane.)

[0987] The residue was then dissolved in DCM (1 mL), treated with TFA (0.2 mL), and stirred at room temperature overnight. The reaction was then concentrated under nitrogen, diluted with ethyl acetate, and carefully basified with saturated sodium bicarbonate and 2N NaOH. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the free amine.

[0988] To a portion of the free amine (0.010 g, 0.027 mmol, 1.0 equiv.) in DCE (0.5 mL) was added benzaldehyde (3.3 μL, 0.032 mmol, 1.2 equiv.), followed by sodium triacetoxyborohydride (0.017 g, 0.081 mmol, 3.0 equiv.). The resulting mixture was stirred overnight at room temperature. The mixture was diluted to a total volume of 1 mL with MeOH and directly subjected to preparative chromatography to give 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,6S)-4-(5-ethoxypyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate.

[0989] Example 15: Preparation of 2-benzyl-2-azaspiro[3.3]heptan-6-yl (2R,6S)-4-(5-hydroxypyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0990] tert-Butyl 6-(((2R,6S)-4-(5-hydroxypyrimidin-2-yl)-2,6-dimethylpiperazine-1-carbonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (0.50 g, 1.1 mmol, 1.0 equiv) in DCM (5.5 mL) was treated with TFA (1 mL) and stirred at room temperature overnight. The reaction was then concentrated, dissolved in methanol, and basified with MP-carbonate resin. The resin was filtered off and the organics were concentrated in vacuo.

[0991] To the free amine in DCE (5 mL) was added benzaldehyde (0.12 mL, 1.2 mmol, 1.1 equiv.), followed by sodium triacetoxyborohydride (0.35 g, 3.3 mmol, 3.0 equiv.). The resulting mixture was stirred at room temperature overnight. Upon completion, the reaction was quenched with saturated sodium bicarbonate and made basic with 2 N NaOH. The product was extracted with 20% IPA in DCM. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. A small portion of the residue (20 mg) was diluted to a total of 1 mL with MeOH and directly subjected to preparative chromatography to afford 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,6S)-4-(5-hydroxypyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate.

[0992] Example 16: Preparation of 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,6S)-4-[5-(2-hydroxyethoxy)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carboxylate [ka]

[0993] To a solid mixture of compound X (0.020 g, 0.046 mmol, 1.0 equiv.) and cesium carbonate (0.045 g, 0.14 mmol, 3.0 equiv.), dry DMF (0.4 mL) was added, followed by oxirane (0.037 mL, 0.09 mmol, 2.5 M in THF, 2.0 equiv.). The reaction was heated at 70 °C overnight. Upon completion, the reaction was cooled to room temperature, diluted to a total volume of 1 mL with MeOH, and directly subjected to preparative chromatography to yield 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,6S)-4-[5-(2-hydroxyethoxy)pyrimidin-2-yl]-2,6-dimethylpiperazine-1-carboxylate.

[0994] Example 17: 2-[(4-methoxyphenyl)methyl]-2-azaspiro[3.3]heptan-6-yl (2R,6S)-4-(5-methanesulfonylpyrimidin-2-yl)-2,6-dimethylpiperazine-1-carboxylate [ka]

[0995] A solution of tert-butyl 6-[(2R,6S)-4-(5-methanesulfonylpyrimidin-2-yl)-2,6-dimethylpiperazine-1-carbonyloxy]-2-azaspiro[3.3]heptane-2-carboxylate (0.80 g, 1.6 mmol, 1.0 equiv.) in DCM (20 mL) was treated with TFA (2 mL) and stirred at room temperature overnight. The reaction was then concentrated, dissolved in methanol, and basified with MP-carbonate resin. The resin was filtered off, and the organics were concentrated in vacuo.

[0996] To the free amine formed above (15 mg, 0.037 mmol, 1.0 equiv.) in methanol (0.30 mL) was added 4-methoxybenzaldehyde (5.0 mg, 0.037 mmol, 1.0 equiv.). After 15 min, 0.5 M borane-pyridine complex (0.037 mmol, 1.0 equiv.) was added, and the reaction was stirred at room temperature for 3 days. The reaction mixture was diluted to a total volume of 1 mL with MeOH and directly subjected to preparative chromatography to yield 2-benzyl-2-azaspiro[3.3]heptan-6-yl(2R,5S)-4-[5-(ethanesulfonyl)pyrimidin-2-yl]-2,5-dimethylpiperazine-1-carboxylate.

[0997] Example 18: Binding assays.

[0998] The binding affinity (K i ) was measured by inhibition of radioligand binding to membranes from CHO cells expressing the human M4 receptor. Membranes were prepared by nitrogen cavitation and differential centrifugation as previously described (Hoare et al., Mol. Pharmacol. 2003 Mar;63(3):751-65). The radioligand used was tritiated N-methylscopolamine at a concentration of 1.5 nM. A dose response of 12 concentrations of compound ranging from 10 μM to 32 pM was used. The assay buffer was 50 mM HEPES, 100 mM NaCl, 5 mM MgCl2, 1 mM ethylenediaminetetraacetic acid, pH adjusted to 7.4. Membranes, radioligand, and compounds were incubated together in a 96-well plate in a total volume of 150 μL at 37°C for 90 min. The receptor-bound radioligand was then recovered by rapid vacuum filtration onto glass fiber filters pretreated with polyethyleneimine to capture cell membranes. Harvesting and radioactivity counting were performed as previously described (see, e.g., Hoare et al., Mol. Pharmacol. 2003 63(3):751-65; Erratum at Mol. Pharmacol. 2005 Jul;68(1):260).

[0999] The binding affinity of certain exemplary compounds described in the Examples and listed in the Table above is less than 1 μM for the M4 receptor. More specifically, the specificity for the M4 receptor for each compound listed in Table B is as follows: (1) "+" indicates that the compound has a K equal to or greater than 500 nM for the M4 receptor. i (2) "++" means that the compound had a K of less than 500 nM but greater than or equal to 100 nM for the M4 receptor; i and (3) "+++" means that the compound had a K of less than 100 nM for the M4 receptor. i This means that the [Table 3]

[1000] Example 19: Functional assays.

[1001] Functional antagonism of the acetylcholine response was assessed using a fluorescence-based functional calcium assay. Acetylcholine binding to muscarinic receptors activates G proteins. The human muscarinic receptor 4 (CHRM4) was stably expressed in CHO-K1 cells and co-transfected with a promiscuous Gα16 construct. This cell line was commercially available through PerkinElmer (product number ES-213-A). After ligand binding, activation of the Gα16 subunit induces calcium release from the endoplasmic reticulum. Prior to ligand screening, receptor-expressing cells were loaded with the fluorescent calcium indicator FLIPR Calcium 6 (Molecular Devices). Antagonist activity of compounds was assessed by the EC for inhibition of the acetylcholine response. 50The assay buffer used was a 1:1 solution of buffer (1x Hank's balanced salt solution + 20 mM HEPES buffer, pH 7.4) and cell culture medium (Ham's F-12, 10% FBS, 0.4 mg / mL Geneticin, 0.25 mg / mL Zeocin). The day before the assay, 4 x 10 cells per well were seeded in 25 μL of medium into assay plates and incubated overnight at 37°C and 5% CO2. The next day, 25 μL of calcium 6 dye was added to each well and incubated for an additional 2 hours at 37°C and 5% CO2. Test compounds (11 concentrations ranging from 10 μM to 100 pM, dose response) were added to the cells to a final DMSO concentration of 0.56% v / v. After 1 hour, acetylcholine was added to a final concentration of 100 nM by the instrument, and calcium flux-dependent fluorescence was measured in real time. The concentration of acetylcholine used was that which stimulated 80% of the maximum response.

[1002] Example 20: Electrophysiological assays.

[1003] Adult (>8 weeks old) female Lister hooded rats (Harlan, UK) were decapitated, and the brains were removed and placed in ice-cold oxygenated sucrose Krebs' medium containing (mM): sucrose (202), KCl (2), KH2PO4 (1.25), MgSO4 (10), CaCl2 (0.5), NaHCO3 (26), and glucose (10). The brains were bisected along the midline to create 300 μM sagittal slices using a vibrating microtome (Integraslice; Campden Instruments Ltd., Loughborough, UK). The slices were then transferred to a room-temperature collection chamber containing oxygenated Krebs' solution (mM): NaCl (124), KCl (2), KH2PO4 (1.25), MgSO4 (1), CaCl2 (2), NaHCO3 (26), and glucose (10). After at least 1 h of recovery, individual slices were transferred to an interface recording chamber, where they were perfused with Krebs' solution (33 °C). Extracellular potential recordings were performed using an Axoprobe 1A amplifier (Axon Instruments Ltd., USA) via a Krebs'-filled glass micropipette (resistance 2-5 mΩ) placed in the stratum radiatum of CA1. The recordings were digitized (10 kHz) via a CED1401 interface and stored on a computer using Spike2 software (Cambridge Electronic Design Ltd., Cambridge, UK). Field excitatory postsynaptic potential (fEPSP) responses were evoked by a bipolar stimulating electrode placed in the stratum radiatum near the CA3-CA1 border (pairs of 0.02 ms pulses 40 ms apart; applied every 10 s; adjusted to approximately 60% of the maximum spike-free response).

[1004] The cholinergic agonist carbachol (aza-acetylcholine resistant to degradation by acetylcholinesterase) is used to stimulate muscarinic receptors. M1 muscarinic receptors are blocked using 5 μM VU0255035, a selective M1 antagonist. The resulting inhibitory signal is primarily M4-mediated based on its sensitivity to the M4 activator VU010010. The effect of M4 antagonists on this M4-mediated inhibition of fEPSPs is measured by adding the compounds 20 min before carbachol application.

[1005] Example 21: 6-OHDA Surgical Lesion and Behavioral Testing Procedures.

[1006] 6-OHDA Lesion Protocol: Male Sprague-Dawley rats were anesthetized with isoflurane and placed in a stereotaxic frame. Thirty minutes before the 6-OHDA injection, rats were administered desipramine (15 mg / kg, i.p.) to prevent the toxin from entering noradrenergic cells. Unilateral lesions were induced by injecting 6-OHDA (8 μg / 4 μL / site / rat; flow rate 1 μL / min; dissolved in 0.9% NaCl containing 0.02% ascorbic acid) or vehicle into the left and right medial forebrain bundles at the following coordinates: AP -4.4 mm; L ±1.2 mm; V -7.8 mm relative to bregma (Paxinos and Watson, 2007). Rats are allowed to recover for 14 days and then tested for novelty (rat placed in a new cage for 30 min)-induced locomotor activity and apomorphine (0.2 mg / kg, sc)-induced contralateral turning behavior.

[1007] Inclusion criteria: Only rats with activity levels above 5 rotations per minute after apomorphine treatment are enrolled in the study. Rats that do not meet these criteria are excluded from the study (typically 20%). Rotational activity is then recorded for each group once a week for four consecutive weeks.

[1008] Example 22: Haloperidol-induced catalepsy.

[1009] Young adult male Sprague-Dawley (SD) rats (175-200 grams) from Envigo, Indianapolis, IL are used. Upon arrival, rats are housed three per cage in ventilated cages and allowed to acclimate for at least 7 days before testing. Animals are maintained on a 12 / 12 hour light / dark cycle (lights on at 06:00) with room temperature maintained at 22±1°C and relative humidity maintained at approximately 50%. Food and water are available ad libitum. Animals are randomly assigned to treatment groups. Experiments are performed during the animals' light cycle.

[1010] Catalepsy is assessed using the bar test. The rat's forepaws are placed on a horizontal metal bar elevated 6 inches above a Plexiglas platform, and the time for each trial is recorded for a maximum of 60 seconds. The test ends when the animal's forepaws return to the platform or 60 seconds later. The test is repeated three times, and the average of the three trials is reported as the catalepsy intensity index. Rats are placed in the laboratory for at least 1 hour to acclimate to the laboratory conditions before testing. Rats are injected with vehicle or compound, and catalepsy is assessed 30 and 60 minutes after haloperidol injection. Data are analyzed by analysis of variance (ANOVA) followed by Dunnett's post-hoc comparisons.

[1011] Various modifications of the embodiments, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

Claims

1. Compounds of formula (Ia): 【Chemistry 121】 [In the formula, Each of X, Y, and Z is independently CR ８ or N, where R ８ is hydrogen, C １ ~C ４ Alkyl, halogen, C １ ~C ４ alkoxy, or cyano; R 1 is R 9 —S(═O) 2 —; R 2 is hydrogen, halogen, amino, R １０ NH-S(=O) ２ -, R ９ -S(=O) ２ -, R ９ -S(=O)-, R ９ -S-, R ９ -S(=O)(=NR １０ ) -, R ９ -O-, 【Chemistry 122】 (n=1, 2, or 3), cyano or C １ ~C ４ alkyl, where R ９ is C １ ~C ４ Alkyl, C ３ ~C ７ cycloalkyl, and 3- to 7-membered heterocyclyl, wherein R ９ or 【Chemical 123】 is C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, —OH, —NHR １０ , halogen, or cyano, where R １０ is hydrogen, C １ ~C ４ Alkyl, or C ３ ~C ７ cycloalkyl; or R １ , R ２ and the carbon atoms to which they are attached form a 3- to 7-membered ring having one or more heteroatoms selected from N, O, and S; X １ is O or NH; X ２ is hydrogen or C １ ~C ４ is alkyl; R ３ and R ４ are each independently hydrogen and C １ ~C ４ alkyl, and R ３ and R ４ are attached to different ethylene groups on the piperazine ring; R ５ and R ６ Each of is independently hydrogen or C １ ~C ４ alkyl or R ５ , R ６ and the carbon atom to which they are attached is C ３ ~C ７ cycloalkyl or 3- to 7-membered heterocyclyl, each of which is C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, —OH, —NHR １０ , optionally substituted with halogen, and cyano; R ７ is hydrogen, halogen, or C １ ~C ４ alkyl, where C １ ~C ４ Alkyl is a group that includes halogen, amino, —OH, C １ ~C ４ optionally substituted with alkoxy, or cyano; m is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

2. 【Catalog 124】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

3. 【Chemical 125】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

4. 【Catalog 126】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

5. 【Catalog 127】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

6. [Catalog 128] 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

7. R ２ The compound of claim 1 , wherein is hydrogen.

8. R ２ The compound of claim 1 , wherein is a halogen.

9. R ２ is C １ ~C ４ The compound of claim 1 , wherein the aryl group is alkyl.

10. X １ The compound of claim 1 , wherein is NH.

11. X １ The compound of claim 1 , wherein is O.

12. X ２ The compound of claim 1 , wherein is hydrogen.

13. X ２ is C １ ~C ４ The compound of claim 1 , wherein the aryl group is alkyl.

14. X １ is O and X ２ The compound of claim 1 , wherein is hydrogen.

15. R ５ and R ６ 10. The compound of claim 1, wherein each of is hydrogen.

16. R ５ and R ６ Each of these is C １ ~C ４ The compound of claim 1 , wherein the aryl group is alkyl.

17. R ５ is hydrogen, and R ６ is C １ ~C ４ The compound of claim 1 , wherein the aryl group is alkyl.

18. The compound of claim 1 , wherein m is 0.

19. The compound of claim 1 , wherein m is 1.

20. 2. The compound of claim 1, wherein m is 2.

21. R １０ The compound of claim 1 , wherein is hydrogen.

22. R １０ is C １ ~C ４ The compound of claim 1 , wherein the aryl group is alkyl.

23. R ９ But C １ ~C ４ The compound of claim 1 , wherein the aryl group is alkyl.

24. R ９ is C ３ ~C ７ The compound of claim 1 which is cycloalkyl.

25. R ９ The compound of claim 1, wherein is a 3- to 7-membered heterocyclyl.

26. Said C １ ~C ４ Alkyl, C ３ ~C ７ 24. The compound of claim 23, wherein the cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted with halogen, cyano, or -OH.

27. The compound of claim 24, wherein said C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocyclyl is optionally substituted with halogen, cyano, or —OH.

28. The compound of claim 25, wherein said C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocyclyl is optionally substituted with halogen, cyano, or —OH.

29.

130. 【Chemistry 131】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

30. Structure: 【132】 2. The compound of claim 1, having the formula:

31. Structure: 【Chemistry 133】 A compound having the formula:

32. Structure: 【134】 2. The compound of claim 1, having the formula:

33. Structure: 【Chemistry 135】 A compound having the formula:

34. Structure: 【Chemistry 136】 2. The compound of claim 1, having the formula:

35. Structure: 【Chemistry 137】 A compound having the formula:

36.

138. 1. A compound selected from:

37. 37. A pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form and a kit, each comprising a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof.

38. 37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

39. 37. A method for preparing a pharmaceutical composition, comprising the step of mixing a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

40. 40. A composition comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or a pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form and a kit comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, respectively, for use in a method of treatment or protection of the human or animal body by therapy; or a pharmaceutical composition comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

41. 40. A composition comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or a pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form and a kit comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, respectively, for use in a method for treating or preventing a neurological disease, disorder or symptom in an individual.

41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

42. Muscarinic receptor 4 (M ４ 37. A composition comprising a compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or a pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form and a kit comprising a compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, respectively, for use in a method for treating or preventing a pulmonary arterial disease, disorder or symptom, or a pharmaceutical composition comprising a compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

43. 42. The composition, pharmaceutical product, or pharmaceutical composition for use of claim 41, wherein the disease, disorder, or symptom is selected from Tourette's syndrome (TS), Alzheimer's disease (AD), schizophrenia, dementia with Lewy bodies (LBD), cognitive impairment associated with schizophrenia, Parkinson's disease, parkinsonism, parkinsonian tremor, tremor, dyskinesia, excessive daytime sleepiness, dystonia, generalized dystonia, Oppenheim dystonia, DYT1 dystonia, non-DYT1 generalized dystonia, focal dystonia, dystonia caused by infection, dystonia caused by birth injury (wherein the birth injury is cerebral palsy), chorea, levodopa-induced dyskinesia, attention deficit hyperactivity disorder (ADHD), cerebral palsy, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), Huntington's disease (HD), and chorea associated with Huntington's disease.

44. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 41, wherein the disease, disorder, or symptom is selected from dystonia, generalized dystonia, Oppenheim dystonia, DYT1 dystonia, non-DYT1 generalized dystonia, focal dystonia, dystonia caused by an infectious disease, and dystonia caused by a birth injury (wherein the birth injury is cerebral palsy).

45. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 41, wherein the disease, disorder, or symptom is selected from Parkinson's disease, Parkinsonism, and Parkinsonian tremor.

46. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 41, wherein the disease, disorder, or symptom is Parkinson's disease.

47. 42. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 41, wherein the disease, disorder, or symptom is Parkinsonism.

48. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 41, wherein the disease, disorder, or symptom is Parkinson's tremor.

49. 42. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 41, wherein the disease, disorder, or symptom is tremor.

50. 42. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 41, wherein the disease, disorder, or symptom is dystonia.

51. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 41, wherein the disease, disorder, or symptom is generalized dystonia.

52. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 42, wherein the disease, disorder, or symptom is selected from Tourette's syndrome (TS), Alzheimer's disease (AD), schizophrenia, dementia with Lewy bodies (LBD), cognitive impairment associated with schizophrenia, Parkinson's disease, parkinsonism, parkinsonian tremor, tremor, dyskinesia, excessive daytime sleepiness, dystonia, generalized dystonia, Oppenheim dystonia, DYT1 dystonia, non-DYT1 generalized dystonia, focal dystonia, dystonia caused by infection, dystonia caused by birth injury (wherein the birth injury is cerebral palsy), chorea, levodopa-induced dyskinesia, attention deficit hyperactivity disorder (ADHD), cerebral palsy, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), Huntington's disease (HD), and chorea associated with Huntington's disease.

53. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 42, wherein the disease, disorder, or symptom is selected from dystonia, generalized dystonia, Oppenheim dystonia, DYT1 dystonia, non-DYT1 generalized dystonia, focal dystonia, dystonia caused by an infectious disease, and dystonia caused by a birth injury (wherein the birth injury is cerebral palsy).

54. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 42, wherein the disease, disorder, or symptom is selected from Parkinson's disease, Parkinsonism, and Parkinsonian tremor.

55. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 42, wherein the disease, disorder, or symptom is Parkinson's disease.

56. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 42, wherein the disease, disorder, or symptom is Parkinsonism.

57. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 42, wherein the disease, disorder, or symptom is Parkinson's tremor.

58. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 42, wherein the disease, disorder, or symptom is tremor.

59. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 42, wherein the disease, disorder, or symptom is dystonia.

60. The composition, pharmaceutical product, or pharmaceutical composition for use according to claim 42, wherein the disease, disorder, or symptom is generalized dystonia.

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