Inhibition of USP19

Abstract

The present disclosure relates to compounds of Formulas (I)-(VI), which are useful as modulators of USP19. The compounds are further useful for inhibiting USP19 and treating diseases or disorders associated with the inhibition of USP19. For example, the present disclosure relates to compounds and compositions for the inhibition of USP19 and methods for treating diseases associated with the inhibition of USP19 (e.g., Parkinson's disease, Ewing's sarcoma, and other metabolic diseases, including muscle wasting and diabetes). [Formula 1] JPEG2022535496000002.jpg206153

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 62 / 843,801, filed May 6, 2019, and U.S. Provisional Application No. 62 / 857,598, filed June 5, 2019, which are incorporated herein by reference in their entireties.

[0002] (Technical field) The present disclosure relates to compounds useful for inhibiting USP19. Inhibitors of USP19 are useful compounds for treating Parkinson's disease, Ewing's sarcoma, and other metabolic diseases such as muscle wasting and diabetes. [Background technology]

[0003] The ubiquitin proteasome system (UPS) is a master regulator of protein homeostasis in eukaryotic cells. Control of protein turnover by the UPS is governed in part by ubiquitin-activating, conjugating, and ligating enzymes, which post-translationally modify target proteins with ubiquitin, an 8-kDa protein covalently attached to the ubiquitin bond. The nature and length of the covalent ubiquitin bond often determine the fate and / or degradation of the target protein by the proteasome. Importantly, ubiquitination is a reversible process catalyzed by deubiquitinating enzymes (DUBs). In humans, there are approximately 100 unique DUBs, which are grouped into five subfamilies. The ubiquitin-specific peptidase (USP) family is the largest DUB subfamily, with over 50 members, including USP19, a 150-kDa protein expressed in various tissues. In addition to its USP catalytic core, USP19 possesses several interesting structural domains, including myeloid translocation protein 8, Nervy and Deaf (MYND), and CHORD / SGT1 (CS / p23) domains, which may mediate protein-protein interactions and protein chaperoning. Summary of the Invention [Problem to be solved by the invention]

[0004] USP19 is involved in many cellular processes, including autophagy and immune response, endoplasmic reticulum-associated degradation, misfolding-associated protein secretion, cell proliferation, and hypoxia. In particular, USP19 plays a crucial role in muscle, regulating myogenic differentiation and muscle mass in women through an estrogen receptor-dependent mechanism. USP19 expression is induced in muscle tissue under catabolic stimuli, and inactivation of this gene protects against muscle wasting in mice. Furthermore, mice lacking USP19 activity exhibit reduced fat mass, in part due to a reduced adipogenic capacity of adipocyte precursor cells. Reduced fat mass in USP19- / - mice increases lean body mass, and glucose tolerance and insulin sensitivity / signaling are improved in the liver and skeletal muscle of mice fed a high-fat diet. Similarly, USP19 mRNA expression positively correlates with adipogenic gene expression in human adipose tissue samples, suggesting that USP19 may be important for human adipose tissue function. USP19 may also have unrelated functions in the unconventional secretion of misfolded cytosolic proteins, such as tau and α-synuclein. In this role, USP19 associates with HSC70 and acts upstream of HSC70 and DNAJC5, an essential mediator of misfolded-associated protein secretion (MAP). Once secreted, misfolded proteins are internalized by endocytosis and ultimately degraded in lysosomes. These findings suggest a transcellular protein quality control pathway in which the deubiquitinase-chaperone axis forms a "triage hub" to transfer abnormal polypeptides from stressed cells to healthy cells for disposal. However, in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, this process may contribute to the intercellular transmission of misfolded proteins and disease progression. USP19 was recently identified as a stabilizing regulator of EWS-FL1 using an siRNA-based screening approach. Depletion of USP19 reduced the levels of EWS-FLI1 protein, and conversely, upregulation of activated USP19 stabilized the fusion protein.Importantly, although USP19 binds to the N-terminal EWS region and regulates the deubiquitination of both EWS-FLI1 and EWSR1, stabilization appeared to be specific to the fusion protein, as no stabilization was observed for either wild-type EWSR1 or FLI1 proteins. Furthermore, stable depletion of shUSP19 reduced cell growth and colony formation in vitro and significantly delayed tumor growth in vivo. [Means for solving the problem]

[0005] In one embodiment, a compound of formula (I) [ka] and the pharmaceutically acceptable salts, hydrates, solvates, isomers, enantiomers, diastereomers, and tautomers thereof, the components of which are described herein.

[0006] In another aspect, a method for treating, preventing, inhibiting, or eliminating a disease or disorder associated with the activity of USP19 in a patient is disclosed, said method comprising administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutical composition thereof to a patient in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[0007] The present disclosure relates to compounds and pharmaceutical compositions thereof that can modulate the activity of ubiquitin-specific peptidase 19 (USP19). The disclosure features a method for treating, preventing, or ameliorating a disease or disorder in which USP19 plays a role by administering a therapeutically effective amount of a compound of any one of Formulas (I)-(VI), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, to a patient in need thereof. The disclosure also features a method for treating, preventing, or ameliorating a disease or disorder in which USP19 plays a role by administering a therapeutically effective amount of a pharmaceutical composition of a compound of any one of Formulas (I)-(VI), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, to a patient in need thereof. The disclosed method can be used to treat various diseases and disorders that depend on USP19 by inhibiting its activity. Inhibiting USP19 provides a new approach to the treatment of diseases, including, but not limited to, Parkinson's disease, Ewing's sarcoma, muscle wasting, and other metabolic diseases such as diabetes.

[0008] definition The articles "a" and "an" are used in this disclosure to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0009] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0010] The term "optionally substituted" is understood to mean that a particular chemical moiety may (but need not) be attached to another substituent. Unless otherwise defined, an optional substituent may be attached to the chemical moiety at any chemically possible regiochemistry and / or stereochemistry (if applicable). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (e.g., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents in place of one or more hydrogen atoms. For example, a substituent may be attached at any position in the chain. Thus, the term "optionally substituted" means that a particular chemical moiety may contain other functional groups, but does not necessarily have additional functional groups. Also, as used herein, "optionally substituted" refers to substituted or unsubstituted, and its meaning is described below.

[0011] As used herein, the term "substituted" means that the specified group or moiety has one or more of the listed substituents, and that the substituents may be attached to the specified group or moiety at a single position. Unless otherwise defined, a substituent may be attached to the chemical moiety in any regiochemistry and / or stereochemistry that is chemically possible (if applicable).

[0012] As used herein, the term "unsubstituted" means that the specified group bears no substituents.

[0013] As used herein, the term "aryl" refers to a monocyclic aromatic hydrocarbon group containing one aromatic ring having a total of 5 to 10 carbon atoms, such as, for example, phenyl.

[0014] The term "heteroaryl," as used herein, refers to a monocyclic or bicyclic aromatic group having 5 to 10 ring atoms containing one or more ring heteroatoms selected from the group consisting of N, O, and S, with the remaining ring atoms being C. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, thiophen-2-yl, isothiazolyl, thiazolyl, thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, and triazinyl.Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, quinolyl, benzopyranyl, indazolyl, benzimidazolyl, thieno[3,2-b]thiophene, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, Indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3- b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1 ,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, and imidazo[2,1-b][1,3,4]thiadiazolyl.Unless otherwise defined, a "heteroaryl" group is unsubstituted.

[0015] As used herein, the term "5-membered heteroaryl" refers to a heteroaryl as defined herein having a total of 5 ring atoms. Examples of "5-membered heteroaryl" groups include, but are not limited to, pyrazolyl, oxazolyl, and thiazolyl. Unless otherwise defined, "5-membered heteroaryl" groups are unsubstituted.

[0016] As used herein, "(C 1-4 The term "alkyl" refers to a straight or branched saturated hydrocarbon chain group having 1 to 4 carbon atoms. 1-4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl), isopropyl, butyl (e.g., n-butyl), sec-butyl, isobutyl, and tert-butyl. "C1 alkyl" refers to an alkyl chain having one carbon atom, such as methyl. "C2 alkyl" refers to an alkyl chain having two carbon atoms, such as ethyl. "C3 alkyl" refers to an alkyl chain having three carbon atoms, such as propyl (e.g., n-propyl) or isopropyl. "C4 alkyl" refers to an alkyl chain having four carbon atoms, such as butyl (e.g., n-butyl), isobutyl, sec-butyl, or tert-butyl. Unless otherwise defined, a "(C1-C4) alkyl" group is unsubstituted.

[0017] As used herein, "C 1-4 The term "alkoxy" refers to a straight or branched saturated hydrocarbon chain containing 1 to 4 carbon atoms and a terminal oxygen atom, i.e., -O-(C 1-4 ) refers to alkyl. C 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. 1-4 An "alkoxy" group is unsubstituted except as that term is defined herein.

[0018] As used herein, the term "haloalkyl" refers to a C alkyl group, as defined herein, that is substituted with one or more halogens. 1-4 refers to an alkyl group. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like. Unless otherwise defined, a "haloalkyl" group is unsubstituted except as the term is defined herein.

[0019] The term "cycloalkyl" as used herein refers to a monocyclic saturated ring having 3 to 8 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. "C3 cycloalkyl" refers to a cycloalkyl having 3 carbon atoms, such as cyclopropyl. "C4 cycloalkyl" refers to a cycloalkyl having 4 carbon atoms, such as cyclobutyl. "C5 cycloalkyl" refers to a cycloalkyl having 5 carbon atoms, such as cyclopentyl. "C6 cycloalkyl" refers to a cycloalkyl having 6 carbon atoms, such as cyclohexyl. Unless otherwise defined, "cycloalkyl" groups are unsubstituted.

[0020] The term "spirocycloalkyl," as used herein, refers to a bicyclic ring system having 6 to 12 carbon atoms in which the rings are linked together through a single atom. The rings may be of different sizes and nature or may be the same. Examples include, but are not limited to, spirohexane, spiroheptane, spirooctane, spirononane, spirodecane, spiroundecane, and spirododecane. Unless otherwise defined, "spirocycloalkyl" groups are unsubstituted.

[0021] As used herein, the term "5- to 6-membered heterocyclyl" refers to a monocyclic ring containing a total of 5 to 6 carbon atoms and heteroatoms selected from oxygen, nitrogen, or sulfur, and the ring is either saturated or partially unsaturated. Examples of heterocyclyl rings include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, and oxazolidinonyl. Unless otherwise defined, "5- to 6-membered heterocyclyl" groups are unsubstituted.

[0022] As used herein, the term "spiroheterocyclyl" refers to a bicyclic ring system containing a total of 6 to 12 carbon and heteroatoms selected from oxygen, nitrogen, or sulfur, which rings are either saturated or partially unsaturated and are connected to each other through a single atom. The rings may be different in size and nature or may be the same. An example of a spiroheterocyclyl is 7-azaspiro[4.5]decane. Unless otherwise defined, a "spiroheterocyclyl" group is unsubstituted.

[0023] As used herein, the term "alkylcycloalkyl" refers to a group having a terminal C 3-6 C having a cycloalkyl ring and optionally substituted 1-4 It refers to a functional group composed of an alkyl chain. Non-limiting examples of alkylcycloalkyl groups include: [ka]

[0024] As used herein above, the term "alkylaryl" refers to an optionally substituted C alkyl group having a terminal aryl ring. 1-4 It refers to a functional group composed of an alkyl chain. Non-limiting examples of alkylaryl groups include: [ka] These may be referred to as "alkylphenyl".

[0025] As used herein, the term "alkylheteroaryl" refers to an optionally substituted C alkyl group having a terminal heteroaryl ring. 1-4 It refers to a functional group composed of an alkyl chain. Non-limiting examples of alkylheteroaryl groups are listed below. [ka]

[0026] The term "halogen" or "halo" as used herein refers to fluorine (i.e., "F" or "fluoro"), chlorine (i.e., "Cl" or "chloro"), bromine (i.e., "Br" or "bromo"), or iodine (i.e., "i" or "iodo").

[0027] As used herein, the term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences may be in constitution (e.g., geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of formulas (I)-(VI) may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, or as individual enantiomers or diastereomers.

[0028] As used herein, the term "pharmaceutical composition" refers to a composition in which the individual components or ingredients are themselves pharmaceutically acceptable, e.g., orally acceptable when oral administration is anticipated; topically acceptable when topical administration is anticipated; and intravenously acceptable when intravenously administration is anticipated.

[0029] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. For purposes of this disclosure, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are generally referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0030] "Pharmaceutically acceptable salts" are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Representative pharmaceutically acceptable salts include, for example, water-soluble salts and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium salt, edetate calcium salt, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, edetate ... Sulphate, esylate, fumarate, fiunalate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium salt, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, sulfuric acid Salts include methyl acetate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 2-hydroxy-3-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate), embonate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. Compounds of formula (I)-(VI) can form salts, which are also within the scope of the present disclosure. Reference herein to any one of compounds (I)-(VI) is understood to include a reference to a salt thereof, unless otherwise indicated.

[0031] New USP19 inhibitors are provided. Unless otherwise specified, a "USP19 inhibitor compound" as used herein refers to a compound that exhibits a detectable IC when tested according to the USP19 inhibition biochemical assay in Example 4 below. 50 This refers to compounds with a β-amyloid value of 15 micromolar or less.

[0032] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0033] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to ameliorate one or more symptoms of a disorder, or to prevent the progression of a disorder, or to cause regression of a disorder.

[0034] As used herein, the term "carrier" encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a therapeutic agent from one organ or body part of a subject to another organ or body part. The term "treatment" with respect to a subject refers to ameliorating at least one symptom of the subject's disorder. Treatment includes curing, ameliorating, or at least partially ameliorating the disorder.

[0035] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms "disease," "condition," or "illness," unless otherwise indicated.

[0036] The terms "administer," "administering," or "administration" as used in this disclosure refer to either administering a compound of the present disclosure, a pharmaceutically acceptable salt of a compound of the present disclosure that is capable of forming an equivalent amount of an active compound in the subject's body, or a composition comprising a compound of the present disclosure directly to a subject.

[0037] Compounds of the Disclosure The present disclosure relates to compounds, or pharmaceutically acceptable salts and isomers thereof, that can modulate USP19 and are useful in treating diseases and disorders associated with modulation of USP19. The present disclosure further relates to compounds, or pharmaceutically acceptable salts and isomers thereof, that are useful in inhibiting USP19.

[0038] Unless otherwise indicated herein, all isomeric forms of a particular chemical compound, including mixtures thereof, are provided by the present disclosure, and all tautomeric forms are intended to be included.

[0039] The compounds of Formulas (I)-(VI), unless otherwise indicated, contain one or more stereocenters and may therefore exist in different stereoisomeric forms. Unless otherwise specified, all stereoisomeric forms of the compounds of Formulas (I)-(VI), as well as mixtures thereof, including racemic mixtures, are intended to form part of this disclosure. Furthermore, the present disclosure encompasses all geometric and positional isomers. For example, if a compound of any one of Formulas (I)-(VI) contains a double bond or a fused ring, both the cis- and trans-forms and mixtures thereof are encompassed within the scope of the present disclosure. Each compound disclosed herein includes all enantiomers consistent with the compound's general structure. Compounds may be in racemic or enantiomerically pure form, or any other stereochemical form. Analytical results may reflect data collected for a racemic form, an enantiomerically pure form, or any other stereochemical form. Individual stereoisomers of the compounds of the present disclosure may be, for example, substantially free of other isomers, e.g., as a racemate, or mixed with all or selected other stereoisomers. In some embodiments of the present disclosure, the compounds of Formulas (I)-(VI) are enantiomers. In some embodiments, the compounds are (S)-enantiomers. In other embodiments, the compounds are (R)-enantiomers. In some embodiments, the compounds of Formulas (I)-(VI) may be (+) or (-) enantiomers.

[0040] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral alcohol or a chiral adjuvant such as Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds of Formulas (I)-(VI) may also be atropisomers (e.g., substituted biaryls) and are considered part of this disclosure. Enantiomers can also be separated using a chiral HPLC column.

[0041] The compounds of the present disclosure, as well as their pharmaceutically acceptable salts and stereoisomers, may exist in tautomeric form (e.g., as amides or imino ethers). Additionally, all keto-enol and imine-enamine forms of the compounds are encompassed by the present disclosure. All such tautomeric forms are considered herein to be part of the present disclosure.

[0042] When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, tertiary, and quaternary amines such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like, substituted amines, cyclic amines, and naturally occurring amines.

[0043] When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Acids suitable for preparing pharmaceutically acceptable acid addition salts include acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glucoronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.

[0044] The use of terms like "salts" is intended to apply equally to enantiomers, stereoisomers, rotamers, tautomers, positional isomers, and racemic salts of the compounds of the present invention.

[0045] The compounds of formulas (I) to (VI) may form acid addition salts or base addition salts, which may be pharmaceutically acceptable salts.

[0046] Compounds of formula (I) [ka] and pharmaceutically acceptable salts, hydrates, solvates, isomers, enantiomers, diastereomers, and tautomers thereof are disclosed; X is N or C; However, if X is N, then R 1 and R 1’ One of the does not exist; Y is N or CR 7 and; Z is CH2; R 1 and R 1’ However, independently, H, C 1-4 alkyl, and one R 8 aryl optionally substituted with; R 2 and R 2’ are independently H and C 1-4 alkyl; R 1 or R 1’ One of them is R 2 or R 2’ and one R 9 may form a substituted aryl or heteroaryl ring; Ring A is X and R 2 and R 2’ R contains an unsaturated bond between the carbon to which it is attached. 1 or R 1’ One of the R 2 or R2’ One of the and may be absent; R 3 But, H, -OR 10 and halogens; R 4 But H or C 1-4 is alkyl; R 5 But H or C 1-4 is alkyl; R 4 and R 5 may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R 6 is selected from alkylcycloalkyl, alkylaryl, and alkylheteroaryl, each of which is selected from one C 1-4 optionally substituted with alkyl; R 7 -C(O)R 11 and; R 8 But halogen, C 1-4 Alkyl, and C 1-4 selected from alkoxy; R 9 But H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)N(R 12 )2, and heteroaryl; R 10 But H or C 1-4 is alkyl; R 11 But -N(R 12 )2, or a 5-6 membered heterocycle containing two heteroatoms selected from N and O; R 12 C 1-4 is an alkyl group; When m is 0 or 1 and m is 1, Ring A contains an unsaturated bond between Y and Z; X is N; If both X and Y are N, then R 9 is H.

[0047] In some embodiments, the compound of formula (IA) [ka] and pharmaceutically acceptable salts, hydrates, solvates, isomers, enantiomers, diastereomers, and tautomers thereof are disclosed; X is N or C; If X is N, then R 1 and R 1’ One of the does not exist; Y is N or CR 7 and; Z is CH2; m is 0 or 1, and when m is 1, ring A contains an unsaturated bond between Y and Z; R 1 and R 1’ However, independently, H, C 1-4 alkyl, and one R 8 aryl optionally substituted with; R 2 and R 2’ are independently H and C 1-4 alkyl, R 1 or R 1’ One of them is R 2 or R 2’ and one R 9 may form an optionally substituted aryl or heteroaryl ring; Ring A is X and R 2 and R 2’ R contains an unsaturated bond between the carbon to which it is attached. 1 or R 1’ One of the R 2 or R 2’ One of the and may be absent; R 3 But, H, -OR 10 and halogens; R 4 and R 5But H or C 1-4 alkyl, and R 4 and R 5 may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R 6 is selected from alkylcycloalkyl, alkylaryl, and alkylheteroaryl, each of which is selected from one C 1-4 optionally substituted with alkyl; R 7 -C(O)R 11 and; R 8 But halogen, C 1-4 Alkyl, and C 1-4 selected from alkoxy; R 9 But halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)N(R 12 )2, and heteroaryl; R 10 But H or C 1-4 is alkyl; R 11 But -N(R 12 )2, or a 5-6 membered heterocycle containing two heteroatoms selected from N and O; R 12 C 1-4 It is an alkyl group.

[0048] In some embodiments, X is N or C. In some embodiments, X is N. In some embodiments, X is C.

[0049] In some embodiments, Y is N or CR 7 In some embodiments, Y is N. In some embodiments, Y is CR 7 is.

[0050] In some embodiments, R 1 and R 1’ However, independently, H, C 1-4alkyl, and one R 8 In some embodiments, R 1 and R 1’ However, independently, H, C 1-3 alkyl, and one R 8 In some embodiments, R 1 and R 1’ are each independently H, methyl, ethyl, propyl, and one R 8 In some embodiments, R 1 and R 1’ are each independently methyl, ethyl, propyl, and one R 8 In some embodiments, R 1 and R 1’ are each independently H, ethyl, propyl, and one R 8 In some embodiments, R 1 and R 1’ are each independently H, methyl, propyl, and one R 8 In some embodiments, R 1 and R 1’ are each independently H, methyl, ethyl, and one R 8 In some embodiments, R 1 and R 1’ are each independently selected from H, methyl, ethyl, and propyl. In some embodiments, R 1 and R 1’ are each H. In some embodiments, R 1 and R 1’ are each independently H or methyl. In some embodiments, R 1 and R 1’ are each independently H or ethyl. In some embodiments, R 1and R 1’ are each independently H or propyl. In some embodiments, R 1 and R 1’ are each independently H or one R 8 is phenyl optionally substituted with

[0051] In some embodiments, R 2 and R 2’ are independently H and C 1-4 In some embodiments, R 2 and R 2’ are independently H and C 1-3 In some embodiments, R 1 and R 1’ are each independently selected from H, methyl, ethyl, and propyl. In some embodiments, R 2 and R 2’ are each independently selected from methyl, ethyl, and propyl. In some embodiments, R 2 and R 2’ are each independently selected from H, ethyl, and propyl. In some embodiments, R 2 and R 2’ are each independently selected from H, methyl, and propyl. In some embodiments, R 2 and R 2’ are each independently selected from H, methyl, and ethyl. In some embodiments, R 2 and R 2’ are each H. In some embodiments, R 2 and R 2’ are each independently H or methyl. In some embodiments, R 1 and R 1’ are each independently H or ethyl. In some embodiments, R 2 and R 2’ are H or propyl, respectively.

[0052] In some embodiments, R 1 or R 1’ One of them is R 2 or R 2’ and one R 9 In some embodiments, R 1 or R 1’ One of them is R 2 or R 2’ and one R 9 forming a phenyl ring substituted with

[0053] In some embodiments, ring A is selected from X and R 2 and R 2’ R contains an unsaturated bond between the carbon to which it is attached. 1 or R 1’ One of the R 2 or R 2’ One of the two may not be present.

[0054] In some embodiments, R 3 But, H, -OR 10 and halogen. In some embodiments, R 3 But, H, -OR 10 and F. In some embodiments, R 3 -OR 10 or F. In some embodiments, R 3 is H or F. In some embodiments, R 3 is H or -OR 10 In some embodiments, R 3 is H. In some embodiments, R 3 -OR 10 In some embodiments, R 3 is F.

[0055] In some embodiments, R 4 But H or C1-4 In some embodiments, R 4 is selected from H, methyl, ethyl, propyl, and butyl. In some embodiments, R 4 is selected from methyl, ethyl, propyl, and butyl. In some embodiments, R 4 is selected from H, methyl, propyl, and butyl. In some embodiments, R 4 is selected from H, methyl, ethyl, propyl, and butyl. In some embodiments, R 4 is selected from H, methyl, ethyl, and butyl. In some embodiments, R 4 is selected from H, methyl, ethyl, and propyl. In some embodiments, R 4 is H. In some embodiments, R 4 is methyl.

[0056] In some embodiments, R 5 But H or C 1-4 In some embodiments, R 5 is selected from H, methyl, ethyl, propyl, and butyl. In some embodiments, R 5 is selected from methyl, ethyl, propyl, and butyl. In some embodiments, R 5 is selected from H, methyl, propyl, and butyl. In some embodiments, R 5 is selected from H, methyl, ethyl, propyl, and butyl. In some embodiments, R 5 is selected from H, methyl, ethyl, and butyl. In some embodiments, R 5 is selected from H, methyl, ethyl, and propyl. In some embodiments, R 5 is H. In some embodiments, R 5 is methyl.

[0057] In some embodiments, R 4 and R 5are linked together to form a cycloalkyl that includes the carbon to which they are attached. In some embodiments, R 4 and R 5 are linked together to form a C5 cycloalkyl that includes the carbon to which they are attached. In some embodiments, R 4 and R 5 Both are H.

[0058] In some embodiments, R 6 is selected from alkylcycloalkyl, alkylaryl, and alkylheteroaryl, each of which is selected from one C 1-4 In some embodiments, R 6 but, [ka] In some embodiments, R 6 but, [ka] In some embodiments, R 6 but, [ka] In some embodiments, R 6 but, [ka] In some embodiments, R 6 but, [ka] In some embodiments, R 6 but, [ka] In some embodiments, R 6 but, [ka] In some embodiments, R 6 but, [ka] In some embodiments, R 6 but, [ka] In some embodiments, R 6 but, [ka] In some embodiments, R 6 but, [ka] In some embodiments, [ka] has the following stereochemistry: [ka]

[0059] In some embodiments, R 8 But halogen, C 1-4 Alkyl, and C 1-4 In some embodiments, R 8 is selected from Cl, methyl, and methoxy. In some embodiments, R 2 is methyl or methoxy. In some embodiments, R 13 is Cl or methoxy. In some embodiments, R 13 is Cl or methyl. In some embodiments, R 8 is Cl. In some embodiments, R 8 is methyl. In some embodiments, R 8 is methoxy.

[0060] In some embodiments, R 9 But H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)N(R 12 )2, and heteroaryl. In some embodiments, R 9 H, Cl, methyl, methoxy, -C(O)N(R 12 )2, thiazolyl, oxazolyl, and pyrazolyl. In some embodiments, R 9 Cl, methyl, methoxy, -C(O)N(R 12 )2, thiazolyl, oxazolyl, and pyrazolyl. In some embodiments, R 9 H, methyl, methoxy, -C(O)N(R 12 )2, thiazolyl, oxazolyl, and pyrazolyl. In some embodiments, R 9 H, Cl, methoxy, -C(O)N(R 12 )2, thiazolyl, oxazolyl, and pyrazolyl. In some embodiments, R 9 H, Cl, methyl, -C(O)N(R 12 )2, thiazolyl, oxazolyl, and pyrazolyl. In some embodiments, R 9 is selected from H, Cl, methyl, methoxy, thiazolyl, oxazolyl, and pyrazolyl. 9 H, Cl, methyl, methoxy, -C(O)N(R 12 )2, oxazolyl, and pyrazolyl. In some embodiments, R 9 H, Cl, methyl, methoxy, -C(O)N(R 12 )2, thiazolyl, and pyrazolyl. In some embodiments, R 9 H, Cl, methyl, methoxy, -C(O)N(R 12 )2, thiazolyl, and oxazolyl. In some embodiments, R 9 is H. In some embodiments, R9 is Cl. In some embodiments, R 9 is methyl. In some embodiments, R 9 is methoxy. In some embodiments, R 9 -C(O)N(R 12 )2. In some embodiments, R 9 is thiazolyl. In some embodiments, R 9 is oxazolyl. In some embodiments, R 9 is pyrazolyl.

[0061] In some embodiments, R 10 But H or C 1-4 In some embodiments, R 10 is H or methyl. In some embodiments, R 10 is H. In some embodiments, R 10 is methyl.

[0062] In some embodiments, R 11 But -N(R 12 )2, or a 5-6 membered heterocycle containing two heteroatoms selected from N and O. In some embodiments, R 11 But -N(R 12 )2, or a 6-membered heterocycle containing two heteroatoms selected from N and O. In some embodiments, R 11 But -N(R 12 )2 or morpholinyl. In some embodiments, R 11 -N(R 12 )2. In some embodiments, R 11 is morpholinyl.

[0063] In some embodiments, R 12 C 1-4 In some embodiments, R 10 is methyl.

[0064] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0065] In some embodiments, the present disclosure provides a compound of formula (I) or formula (IA), further defined by formula (II): [ka] and its pharmaceutically acceptable salts, hydrates, solvates, isomers, enantiomers, diastereomers, and tautomers, R 13 But, H, Halo, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)N(R 19 ) 2-, or 5-membered heteroaryl rings; R 14 But H, C 1-4 Alkyl, and C(O)N(R 19 )2 is selected; R 13 and R 14 One of the must be H; R 15 is H or OH; R 16 and R 17 are C 1-4 is an alkyl group, and R 16 and R 17 may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R 18 is selected from alkylcycloalkyl, alkylphenyl, and alkylheteroaryl, each of which is selected from one C 1-4 optionally substituted with alkyl; R 19 C 1-4 It is an alkyl group.

[0066] In some embodiments, the compound of formula (II) has the stereochemistry of formula (II-A). [ka]

[0067] In some embodiments, R 13 But, H, Halo, C 1-4 Alkyl, C 1-4 Alkoxy, -C(O)N(R 19 ) 2-, or 5-membered heteroaryl ring. In some embodiments, the present disclosure provides 13 is selected from -Cl, methyl, methoxy, -C(O)N(CH), thiazolyl, pyrazolyl, and oxazolyl. 13 is selected from methyl, methoxy, —C(O)N(CH), thiazolyl, pyrazolyl, and oxazolyl. 13 is selected from -Cl, methoxy, -C(O)N(CH), thiazolyl, pyrazolyl, and oxazolyl. 13 is selected from -Cl, methyl, -C(O)N(CH), thiazolyl, pyrazolyl, and oxazolyl. 13 is selected from -Cl, methyl, methoxy, thiazolyl, pyrazolyl, and oxazolyl. 13 is selected from -Cl, methyl, methoxy, -C(O)N(CH), pyrazolyl, and oxazolyl. 13 is selected from -Cl, methyl, methoxy, -C(O)N(CH), thiazolyl, and oxazolyl. 13 is selected from -Cl, methyl, methoxy, -C(O)N(CH), thiazolyl, and pyrazolyl. 13 is -Cl. In some embodiments, R 13 is methyl. In some embodiments, R 13 is methoxy. In some embodiments, R 13 is —C(O)N(CH) . In some embodiments, R 13is thiazolyl. In some embodiments, R 13 is pyrazolyl. In some embodiments, R 13 is oxazolyl.

[0068] In some embodiments, R 14 But H, C 1-4 Alkyl, and C(O)N(R 19 In some embodiments, the present disclosure provides a compound selected from R 14 is selected from methyl and —C(O)N(CH) . In some embodiments, R 14 is H. In some embodiments, R 14 is methyl. In some embodiments, R 14 is -C(O)N(CH3)2.

[0069] R 16 and R 17 are C 1-4 In some embodiments, R 16 and R 17 are each independently selected from methyl, ethyl, propyl, and butyl. In some embodiments, R 16 and R 17 are each independently selected from ethyl, propyl, and butyl. In some embodiments, R 16 and R 17 are each independently selected from methyl, propyl, and butyl. In some embodiments, R 16 and R 17 are each independently selected from methyl, ethyl, and propyl. In some embodiments, R 16 and R 17 and each is methyl. In some embodiments, R 16 and R 17 are linked together to form a cyclopentyl containing the carbon to which they are attached.

[0070] In some embodiments, R 18 but, [ka] In some embodiments, R 18 but, [ka] In some embodiments, R 18 but, [ka] In some embodiments, R 18 but, [ka] In some embodiments, R 18 but, [ka] In some embodiments, R 18 but, [ka] In some embodiments, R 18 but, [ka] In some embodiments, R 18 but, [ka] In some embodiments, R 18 but, [ka] In some embodiments, [ka] has the following stereochemistry: [ka]

[0071] In some embodiments, the compound of formula (II) is [ka] [ka] and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

[0072] In some embodiments, the present disclosure provides a compound of formula (I) or formula (IA), further defined by formula (III): [ka] and its pharmaceutically acceptable salts, hydrates, solvates, isomers, enantiomers, diastereomers, and tautomers, R 20 But H, halo, and C 1-4 alkyl; R 21 But H or C 1-4 is alkoxy; R 22 But H or C 1-4 is alkyl; R 20 , R 21 , and R 23 Two of them must be H; R 23 is hydrogen or C 1-4 is an alkyl group; R 24 and R 25 are C 1-4 is an alkyl group, and R 24 and R 25 may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R 26 But one C1-4 It is an alkylcycloalkyl group substituted with an alkyl group.

[0073] In some embodiments, the compound of formula (III) has the stereochemistry further given by formula (III-A). [ka]

[0074] In some embodiments, the compound of formula (III) has the stereochemistry further given by formula (III-B). [ka]

[0075] In some embodiments, R 20 But H, halo, and C 1-4 In some embodiments, R 20 is selected from H, Cl, and methyl. In some embodiments, the present disclosure provides 20 is selected from -Cl and methyl. 20 is H or methyl. In some embodiments, R 20 is H or Cl. In some embodiments, R 20 is H. In some embodiments, R 20 is methyl. In some embodiments, R 20 is Cl.

[0076] In some embodiments, R 21 But H or C 1-4 In some embodiments, R 21 is H or methoxy. In some embodiments, R 21 is H. In some embodiments, the present disclosure provides 21 is methoxy.

[0077] In some embodiments, R 22 But H or C 1-4 In some embodiments, R 22 is H or methyl. In some embodiments, the present disclosure provides 22 is H. In some embodiments, R 22 is H. In some embodiments, the present disclosure provides 22 is methyl.

[0078] In some embodiments, R 23 But H or C 1-4 In some embodiments, R 23 is H or methyl. In some embodiments, R 23 is H. In some embodiments, the present disclosure provides 23 is methyl.

[0079] In some embodiments, R 24 and R 25 are C 1-4 In some embodiments, R 24 and R 25 are each independently methyl, ethyl, propyl, or butyl. In some embodiments, R 24 and R 25 are each independently ethyl, propyl, or butyl. In some embodiments, R 24 and R 25 are each independently methyl, propyl, or butyl. In some embodiments, R 24 and R 25 are each independently methyl, ethyl, or butyl. In some embodiments, R 24 and R 25 are each independently methyl, ethyl, or propyl. In some embodiments, R 24 and R 25 and each is methyl. In some embodiments, the present disclosure provides 24 and R25 are linked together to form a cyclopentyl containing the carbon to which they are attached.

[0080] In some embodiments, the present disclosure provides R 26 The present invention relates to compounds of formula (III) wherein: [ka] In some embodiments, the present disclosure provides R 26 The present invention relates to compounds of formula (III) wherein: [ka]

[0081] In some embodiments, the compound of formula (III) is [ka] [ka] and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

[0082] In some embodiments, the present disclosure provides a compound of formula (I) or formula (IA), further defined by formula (IV): [ka] and its pharmaceutically acceptable salts, hydrates, solvates, isomers, enantiomers, diastereomers, and tautomers, R 27 and R 28 are C 1-4 is an alkyl group, and R 27 and R 28 may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R 29 But one C 1-4It is an alkylcycloalkyl group substituted with an alkyl group.

[0083] In some embodiments, the compound of formula (IV) has the stereochemistry further given by formula (IV-A). [ka]

[0084] In some embodiments, R 27 and R 28 are C 1-4 In some embodiments, R 27 and R 28 are each independently methyl, ethyl, propyl, or butyl. In some embodiments, R 27 and R 28 are each independently ethyl, propyl, or butyl. In some embodiments, R 27 and R 28 are each independently methyl, propyl, or butyl. In some embodiments, R 27 and R 28 are each independently methyl, ethyl, or butyl. In some embodiments, R 27 and R 28 are each independently methyl, ethyl, or propyl. In some embodiments, the present disclosure provides 27 and R 28 are linked together to form a cyclopentyl containing the carbon to which they are attached.

[0085] In some embodiments, the present disclosure provides R 29 The present invention relates to compounds of formula (III) wherein: [ka] In some embodiments, the present disclosure provides R 29 The present invention relates to compounds of formula (IV) wherein: [ka]

[0086] In some embodiments, the compound of formula (IV) is: [ka]

[0087] In some embodiments, the present disclosure provides a compound of formula (I) or formula (IA), further defined by formula (V): [ka] and its pharmaceutically acceptable salts, hydrates, solvates, isomers, enantiomers, diastereomers, and tautomers, R 30 and R 31 But H or C 1-4 alkyl, and R 30 and R 31 may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R 32 But -OH, C 1-4 alkoxy, and halogen; R 33 But one C 1-4 It is an alkylcycloalkyl or alkylheteroaryl group substituted with an alkyl group.

[0088] In some embodiments, the compound of formula (V) has the stereochemistry of formula (VA). [ka]

[0089] In some embodiments, the compound of formula (V) has the stereochemistry of formula (VB). [ka]

[0090] In some embodiments, R 30 and R 31 But H or C 1-4 In some embodiments, R 30 and R 31 are C 1-4 In some embodiments, R 30 and R 31 are each independently methyl, ethyl, propyl, or butyl. In some embodiments, R 30 and R 31 are each independently ethyl, propyl, or butyl. In some embodiments, R 30 and R 31 are each independently methyl, propyl, or butyl. In some embodiments, R 30 and R 31 are each independently methyl, ethyl, or butyl. In some embodiments, R 30 and R 31 are each independently methyl, ethyl, or propyl. In some embodiments, the present disclosure provides 30 and R 31 are linked together to form a cyclopentyl that includes the carbon to which they are attached. In some embodiments, the present disclosure relates to compounds of formula (V) 30 and R 31 and each represents H.

[0091] In some embodiments, R 32 But -OH, C 1-4 In some embodiments, R is selected from alkoxy, and halogen. 32 is selected from —OH, methoxy, and F. In some embodiments, the present disclosure provides 32 In some embodiments, R 32 is —OH or methoxy. In some embodiments, R 32 is —OH or F. In some embodiments, R32 is —OH. In some embodiments, R 32 is methoxy. In some embodiments, R 32 is F.

[0092] In some embodiments, the present disclosure provides R 33 The present invention relates to compounds of formula (III) wherein: [ka] In some embodiments, R 33 but, [ka] In some embodiments, R 33 but, [ka] In some embodiments, [ka] has the following stereochemistry: [ka]

[0093] In some embodiments, the compound of formula (V) is [ka] and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

[0094] In some embodiments, the present disclosure provides a compound of formula (I) or formula (IA), further defined by formula (VI): [ka] and its pharmaceutically acceptable salts, hydrates, solvates, isomers, enantiomers, diastereomers, and tautomers, R 33 and R 34 are C 1-4 is an alkyl group, and R 33 and R 34 may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R 35 But one C 1-4 an alkylcycloalkyl group substituted with an alkyl group; R 36 But -N(R 37 )2, or a 5-6 membered heterocycle containing two heteroatoms selected from N and O; R 37 C 1-4 It is an alkyl group.

[0095] In some embodiments, R 33 and R 34 are each independently H or C 1-4 In some embodiments, R 33 and R 34 are C 1-4 In some embodiments, R 33 and R 34 are each independently methyl, ethyl, propyl, or butyl. In some embodiments, R 33 and R 34 are each independently ethyl, propyl, or butyl. In some embodiments, R 33 and R 34 are each independently methyl, propyl, or butyl. In some embodiments, R 33 and R 34 are each independently methyl, ethyl, or butyl. In some embodiments, R 33 and R 34 are each independently methyl, ethyl, or propyl. In some embodiments, the present disclosure provides 33and R 34 are linked together to form a cyclopentyl containing the carbon to which they are attached.

[0096] In some embodiments, the present disclosure provides R 35 The present invention relates to compounds of formula (VI) wherein: [ka] In some embodiments, the present disclosure provides R 35 The present invention relates to compounds of formula (VI) wherein: [ka]

[0097] In some embodiments, R 36 But -N(R 37 )2, or a 5-6 membered heterocycle containing two heteroatoms selected from N and O. In some embodiments, R 36 But -N(R 37 )2, or a 6-membered heterocycle containing two heteroatoms selected from N and O. In some embodiments, R 36 -N(R 37 )2. In some embodiments, R 36 is a 6-membered heterocycle containing two heteroatoms selected from N and O. In some embodiments, R 36 But -N(R 37 )2 or morpholinyl. In some embodiments, the present disclosure provides 36 is morpholinyl.

[0098] In some embodiments, the present disclosure provides R 37 is methyl.

[0099] In some embodiments, the compound of formula (VI) is [ka] and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

[0100] Non-limiting specific embodiments of USP19 inhibitor compounds are shown in Table B below.

[0101] Methods for Preparing the Compounds of the Disclosure The compounds of the present disclosure can be made by a variety of methods, including standard chemistry. Suitable synthetic routes are illustrated in the Examples below.

[0102] The compounds of the present disclosure, i.e., compounds of Formulas (I) to (VI) or pharmaceutically acceptable salts thereof, may be prepared by methods known in the art of organic synthesis, some of which are illustrated in the synthetic schemes set forth in the Examples. It is well understood that in the schemes described below, protecting groups for sensitive or reactive groups may be used as needed, in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at the appropriate stage of the compound synthesis in a manner readily apparent to one skilled in the art. The processes selected, as well as the reaction conditions and the order in which they are carried out, are consistent with the preparation of the compounds of Formulas (I) to (VI).

[0103] Those skilled in the art will recognize that stereocenters exist in compounds of Formulas (I)-(VI). Accordingly, the present disclosure (unless otherwise indicated and / or specified in the synthesis) encompasses both possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. Unless otherwise indicated, if a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any suitable intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, EL Eliel, SH Wilen, and LN Mander, "Stereochemistry of Organic Compounds" (Wiley-Interscience, 1994).

[0104] The compounds of formulas (I)-(VI) may be made by methods known in the art, including variations within the skill of the art, including those specifically described below. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. The formulas and descriptions of variables used to describe the synthesis of the compounds should not be confused with variables used in the claims or elsewhere in this specification. The following methods are for illustrative purposes only and are not intended to limit the scope of the invention. These schemes encompass reasonable variations known in the art.

[0105] Isoindolinones of formula (II) can be prepared by many different methods. Scheme 1 illustrates the preparation of isoindolinone-piperidinol analogs of formula (II-1). In this method, isoindolinones (1) of various substitution states are treated with substituted tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2) (accessible in two routine steps from the corresponding ketone) in a high-boiling dipolar aprotic solvent such as dimethylformamide or N,N-dimethylacetamide in the presence of a base such as cesium carbonate or N,N-diisopropylethylamine with external heating to give the corresponding N-alkylisoindolinones (3). The tert-butyloxycarbonyl group present in N-alkylisoindolinones (3) can be removed by treatment with a strong acid such as trifluoroacetic acid / dichloromethane or hydrochloric acid / dioxane to give NH-piperidinols (4). Coupling of NH-piperidine 4 with variously substituted carboxylic acids (5) under standard conditions for amide bond formation, such as HATU or diisopropylethylamine / N,N-dimethylformamide, can provide compounds of formula (II-1). Diastereomers and / or enantiomers of the final products can be separated using high pressure liquid chromatography and / or supercritical fluid chromatography (SFC) techniques using commercially available chiral stationary phases known in the art.

[0106] Scheme 1 [ka]

[0107] Isoindolinones of formula (II-2) can be readily prepared from compounds of formula (II-1), as shown in Scheme 2. Dehydration of compounds of formula (II-1) using trimethylsilyl chloride and triethylamine affords a mixture of trisubstituted alkenes (6). Reduction of the exocyclic olefin mixture (6) with a palladium carbon catalyst under a hydrogen atmosphere affords the reduction product (7). The tert-butyloxycarbonyl group present in N-alkylisoindolinones (7) can be removed by treatment with a strong acid, such as trifluoroacetic acid / dichloromethane or hydrochloric acid / dioxane, to afford NH-piperidinols (8). NH-piperidinols (8) can be coupled with various substituted carboxylic acids (5) under standard conditions for amide bond formation, such as HATU or diisopropylethylamine / N,N-dimethylformamide, to afford compounds of formula (II-2). Diastereomers and / or enantiomers of the final products can be separated using high pressure liquid chromatography and / or supercritical fluid chromatography (SFC) techniques using commercially available chiral stationary phases known in the art.

[0108] Scheme 2 [ka]

[0109] Phenyl lactams of formula (III) can be prepared by many different methods. Scheme 3 illustrates one such method for preparing compounds of formula (III). In this method, phenyl lactams (9) of various substitution states are treated with substituted tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2) in a high-boiling dipolar aprotic solvent such as dimethylformamide or N,N-dimethylacetamide in the presence of a base such as cesium carbonate or N,N-diisopropylethylamine with external heating to give the corresponding N-alkylisoindolinones (10). The tert-butyloxycarbonyl group present in N-alkylisoindolinones (10) can be removed by treatment with a strong acid such as trifluoroacetic acid / dichloromethane or hydrochloric acid / dioxane to give NH-piperidinols (11). NH-Piperidinol (11) can be coupled with variously substituted carboxylic acids (5) under standard conditions for amide bond formation, such as HATU or diisopropylethylamine / N,N-dimethylformamide, to give compounds of formula (III). Diastereomers and / or enantiomers of the final product can be separated using high-pressure liquid chromatography and / or supercritical fluid chromatography (SFC) techniques using commercially available chiral stationary phases known in the art. Similarly, compounds of formula (IV) and their respective diastereomers can be prepared from variously substituted 4-phenyl-1,5-dihydro-2H-pyrrol-2-ones.

[0110] Scheme 3 [ka]

[0111] Pharmaceutical Compositions of the Compounds of the Present Disclosure The present disclosure also relates to pharmaceutical compositions comprising a compound of any one of Formulas (I)-(VI) for use in medicine. Pharmaceutical compositions of a compound of any one of Formulas (I)-(VI) disclosed herein are useful in methods for modulating USP19. Pharmaceutical compositions of a compound of any one of Formulas (I)-(VI) disclosed herein are also useful in methods for inhibiting USP19.

[0112] USP19 inhibitor compounds are useful for the development of pharmaceutical compositions suitable for promoting muscle growth after injury or muscle-wasting diseases, protecting against the adverse consequences of obesity and diabetes, treating neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease, and treating various cancers such as Ewing's sarcoma.

[0113] The compounds of formulae (I) to (VI) may form acid addition salts, which may be pharmaceutically acceptable salts.

[0114] The present disclosure also encompasses pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions reported herein can be provided in a unit dosage form (e.g., capsule, tablet, etc.). In some embodiments, the pharmaceutical compositions reported herein can be provided in an oral dosage form. In some embodiments, the oral dosage form of a compound of any one of Formulas (I)-(VI) can be a capsule. In some embodiments, the oral dosage form of a compound of any one of Formulas (I)-(VI) is a tablet. In some embodiments, the oral dosage form includes one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and / or antistatic agents. In some embodiments, the oral dosage form is prepared by dry blending. In some embodiments, the oral dosage form is a tablet and is prepared by dry granulation.

[0115] The compositions of the present invention may be used for administration in any suitable form (e.g., oral or buccal administration). For oral administration, the compound of Formula I may be prepared in solution or suspension in the form of hard or soft capsules, including gelatin capsules, sachets, or lozenges, in a mixture with excipients suitable for the manufacture of oral dosage forms such as tablets. Suspensions for oral administration can be prepared according to any method known to those skilled in the art. For example, the suspension may be an oily suspension in which a compound of any one of Formulas (I) to (VI) is suspended in a liquid suspension containing, for example, a vegetable oil such as olive oil, sesame oil, or coconut oil. Alternatively, the liquid suspension may contain mineral oil.

[0116] The compositions may also be administered topically, for example, for application to the skin in the form of, for example, a cream, paste, lotion, gel, ointment, compress, cataplasm, salve, skin patch, etc., or for ophthalmic application in the form of, for example, eye drops, lotion or gel formulations.

[0117] The composition may also be administered parenterally (e.g., intravenously). Intravenous administration forms include, but are not limited to, bolus injection and infusion. In some embodiments, intravenous dosage forms are usually sterile or can be sterilized before administration to a subject, since they bypass the subject's natural defense mechanism against contaminants. Examples of intravenous dosage forms include, but are not limited to, water for injection USP; aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0118] They may also be administered in easily flowable forms, such as solutions, emulsions, and suspensions, for example, for intralesional injection; rectally, for example, as enemas or suppositories; or intranasally, for example, as nasal sprays or aerosols. Macrocrystalline powders may also be formulated for inhalation, for example, for delivery to the nose, nasal cavity, pharynx, or lungs. Transdermal compositions / devices and pessaries may also be used to deliver the compounds of the present invention. The compositions may further include an agent that enhances delivery of the compound having any one of Formulas (I)-(VI) (or other active agent), such as, for example, a liposome, a polymer, or a copolymer (e.g., a branched polymer).

[0119] The pharmaceutical composition of the present invention may further comprise one or more additives. Additives known in the art include, for example, detackifiers, antifoaming agents, buffering agents, antioxidants (e.g., ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, malic acid, fumaric acid, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, and tocopherols such as α-tocopherol (vitamin E)), preservatives, chelating agents, viscosity modifiers, tonicifiers, flavoring agents, coloring agents, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. The amount of such additives can be easily determined by one skilled in the art according to the specific properties desired, and can be formulated to stabilize the compound having Formula I, for example, to prevent it from being reduced by the antioxidant additives.

[0120] The additive may also include a thickener. Suitable thickeners may be those known and used in the art, such as, for example, pharmaceutically acceptable polymeric materials and inorganic thickeners. Exemplary thickeners for use in the pharmaceutical composition include polyacrylic acid resins, polyacrylic acid copolymer resins, such as polyacrylic acid and polyacrylic acid / methacrylic acid resins; cellulose and cellulose derivatives, including alkylcelluloses (e.g., methylcellulose, ethylcellulose, and propylcellulose); hydroxyalkylcelluloses (e.g., hydroxypropyl cellulose, hydroxypropyl alkylcelluloses such as hydroxypropylmethylcellulose); acylated celluloses (e.g., cellulose acetate, cellulose acetate phthalate, cellulose acetate succinate, and hydroxypropylethylcellulose phthalate). and salts thereof, such as sodium-carboxymethylcellulose; polyvinylpyrrolidones, such as poly-N-vinylpyrrolidone and vinylpyrrolidone copolymers, such as vinylpyrrolidone-vinyl acetate copolymers; polyvinyl resins, such as polyvinyl acetate and alcohols, and other polymeric materials, such as gum tragacanth, gum arabic, alginates, such as alginic acid, and salts thereof, such as sodium alginate; inorganic thickeners, such as attapulgite, bentonite, and silicates, including hydrophilic silicon dioxide products, such as alkylated (e.g., methylated) silica gels, especially colloidal silicon dioxide products.

[0121] A thickener, such as those listed above, may be included, for example, to provide a sustained release effect. However, if oral administration is intended, the use of a thickener may not be necessary. On the other hand, for example, if topical application is anticipated, the use of a thickener is suggested.

[0122] Disclosed are pharmaceutical compositions of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles.

[0123] In some embodiments, a pharmaceutical composition comprises a compound of Formula (I) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (I) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (I) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a compound of Formula (I) and one or more pharmaceutically acceptable vehicles.

[0124] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (I) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (I) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (I) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (I) and one or more pharmaceutically acceptable vehicles.

[0125] In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), further given by Formula (IA), as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles.

[0126] In some embodiments, a pharmaceutical composition comprises a compound of Formula (IA) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (IA) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (IA) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a compound of Formula (IA) and one or more pharmaceutically acceptable vehicles.

[0127] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (IA) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (IA) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (IA) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (IA) and one or more pharmaceutically acceptable vehicles.

[0128] In some embodiments, the pharmaceutical composition comprises a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, as further provided by Formula (II), as described herein, and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles.

[0129] In some embodiments, a pharmaceutical composition comprises a compound of Formula (II) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (II) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (II) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a compound of Formula (II) and one or more pharmaceutically acceptable vehicles.

[0130] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (II) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (II) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (II) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (II) and one or more pharmaceutically acceptable vehicles.

[0131] Disclosed are pharmaceutical compositions of a compound of Formula (I) or Formula (IA), further given by Formula (III), as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles.

[0132] In some embodiments, a pharmaceutical composition comprises a compound of Formula (III) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (III) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (III) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a compound of Formula (III) and one or more pharmaceutically acceptable vehicles.

[0133] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (III) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (III) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (III) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (III) and one or more pharmaceutically acceptable vehicles.

[0134] Disclosed are pharmaceutical compositions of a compound of Formula (I) or Formula (IA), further given by Formula (IV), as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles.

[0135] In some embodiments, a pharmaceutical composition comprises a compound of Formula (IV) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (IV) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (IV) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a compound of Formula (IV) and one or more pharmaceutically acceptable vehicles.

[0136] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (IV) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (IV) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (IV) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (IV) and one or more pharmaceutically acceptable vehicles.

[0137] Disclosed are pharmaceutical compositions of a compound of Formula (I) or Formula (IA), further given by Formula (V), as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles.

[0138] In some embodiments, a pharmaceutical composition comprises a compound of Formula (V) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (V) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (V) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a compound of Formula (V) and one or more pharmaceutically acceptable vehicles.

[0139] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (V) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (V) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (V) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (V) and one or more pharmaceutically acceptable vehicles.

[0140] Disclosed are pharmaceutical compositions of a compound of Formula (I) or Formula (IA), further given by Formula (VI), as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles.

[0141] In some embodiments, a pharmaceutical composition comprises a compound of Formula (VI) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (VI) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a compound of Formula (VI) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a compound of Formula (VI) and one or more pharmaceutically acceptable vehicles.

[0142] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (VI) and one or more pharmaceutically acceptable carriers, adjuvants, or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (VI) and one or more pharmaceutically acceptable carriers or vehicles. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (VI) and one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of Formula (VI) and one or more pharmaceutically acceptable vehicles.

[0143] Methods of Use of the Disclosed Compounds One aspect of the present disclosure relates to a compound of Formula (I)-(VI) for use in medicine. Another aspect of the present disclosure relates to a method for modulating USP19, comprising administering a therapeutically effective amount of a compound of any one of Formulas (I)-(VI) to a patient in need thereof. Another aspect of the present disclosure relates to a method for inhibiting one or more of USP19, comprising administering a therapeutically effective amount of a compound of any one of Formulas (I)-(VI) to a patient in need thereof. In another aspect, the present disclosure relates to a method for modulating or inhibiting USP19, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of Formulas (I)-(VI) to a patient in need thereof.

[0144] USP19 inhibitor compounds are useful for treating disease conditions that respond to USP19 inhibition.For example, USP19 inhibitor compounds are useful for promoting muscle growth after injury or muscle wasting disease, protecting against the adverse consequences of obesity and diabetes, treating neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease, and treating various cancers such as Ewing's sarcoma.USP19 inhibitor compounds are useful for developing pharmaceutical compositions suitable for promoting muscle growth after injury or muscle wasting disease, protecting against the adverse consequences of obesity and diabetes, treating neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease, and treating various cancers such as Ewing's sarcoma.

[0145] The dosage of a compound of any one of formulas (I) to (VI) varies depending on the activity and / or toxicity of the particular compound, the condition to be treated, and the physical form of the pharmaceutical composition used for administration, but as a guideline, a dosage selected from the range of 1 to 2000 mg / kg body weight per day can be said to be appropriate in most cases. Methods for determining appropriate dosages are well known to those skilled in the art.

[0146] The USP19 inhibitor compounds of the present disclosure can be administered at therapeutically effective levels.

[0147] Disclosed is a method of modulating or inhibiting USP19 in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof.

[0148] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).

[0149] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (I).

[0150] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) as described herein.

[0151] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (I) as described herein.

[0152] In some embodiments, the method of modulating or inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, further provided by Formula (IA) as described herein.

[0153] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (IA).

[0154] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (IA).

[0155] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (IA) as described herein.

[0156] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (IA) as described herein.

[0157] In some embodiments, the method of modulating or inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, further provided by Formula (II) as described herein.

[0158] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (II).

[0159] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (II).

[0160] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (II) as described herein.

[0161] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (II) as described herein.

[0162] In some embodiments, the method of modulating or inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, further provided by Formula (III) as described herein.

[0163] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (III).

[0164] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (III).

[0165] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (III) as described herein.

[0166] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (III) as described herein.

[0167] In some embodiments, the method of modulating or inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, further provided by Formula (IV) as described herein.

[0168] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (IV).

[0169] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (IV).

[0170] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (IV) as described herein.

[0171] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (IV) as described herein.

[0172] In some embodiments, the method of modulating or inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt, hydrate, solvate, isomer, enantiomer, diastereomer, or tautomer thereof, further provided by Formula (V), as described herein.

[0173] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (V).

[0174] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (V).

[0175] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (V) as described herein.

[0176] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (V) as described herein.

[0177] In some embodiments, the method of modulating or inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (IA), or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or tautomer thereof, further provided by Formula (VI), as described herein.

[0178] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (VI).

[0179] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (VI).

[0180] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (VI) as described herein.

[0181] In some embodiments, the method of inhibiting USP19 in a patient comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of Formula (VI) as described herein. [Example]

[0182] Materials and equipment All solvents used were commercially available and were used without purification. Reactions were typically carried out using anhydrous solvents under an inert atmosphere of nitrogen.

[0183] Proton NMR spectra were recorded using either a Bruker BFO ASCEND™ 400 AVANCE III 400 MHz or a Bruker BBFO ULTRASHIELD™ 300. Deuterated solvents typically contained 0.03%–0.05% (v / v) tetramethylsilane, which was used as the reference signal ( 1 H is set to δ 0.00).

[0184] LCMS analysis was performed using a Shimadzu LCMS equipped with ESI electrospray ionization (m / z 90-900) consisting of an SPD-M20A PDA (190-400 nm), an Alltech 3300 ELSD, and an LCMS 2020 MS detector. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. This instrument used reversed-phase conditions (acetonitrile / water containing 0.05% acetic acid).

[0185] The following abbreviations are used in the examples below and elsewhere in the specification:

[0186] [Table 1]

[0187] Example 1 Synthesis of (S)-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one (13) and (R)-1-((((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one (14) [ka]

[0188] Step 1: tert-butyl (S)-10-hydroxy-10-(((R)-2-oxo-4-phenylpyrrolidin-1-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (first eluting isomer), and tert-butyl (S)-10-hydroxy-10-(((S)-2-oxo-4-phenylpyrrolidin-1-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (second eluting isomer) A mixture of 4-phenylpyrrolidin-2-one (1.00 g, 6.20 mmol) and tert-butyl 1-oxa-10-azadispiro[2.0.4^[4].4^[3]]dodecane-10-carboxylate (3.32 g, 12.4 mmol) in DMF (30 mL) was stirred, and Cs2CO3 (4.04 g, 12.4 mmol) was added. The resulting mixture was stirred at 85 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure.

[0189] The crude product was purified by reverse phase column chromatography (column: C 18 Purification on silica gel, 120 g, 20–45 μm, 100 Å; mobile phase: water with 0.05% TFA and ACN (0%–60% in 40 min); detector: UV 220 / 254 nm) afforded a mixture of all four diastereomers of tert-butyl 10-hydroxy-10-((2-oxo-4-phenylpyrrolidin-1-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (500 mg, 17%) as an off-white solid. LCMS (ES, m / z): 429 [M+H] + .

[0190] This diastereomeric mixture was analyzed by column: CHIRALPAK IC, 2 x 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 15% B to 15% B in 17 min; UV 220 / 254 nm; R t 1:9.883min;R t 2:11.259 minutes;R t The separation was carried out by chiral prep HPLC under the following conditions: 3:13.822 min; injection volume: 1 ml; number of runs: 10. The collected fractions were concentrated to give tert-butyl (S)-10-hydroxy-10-(((R)-2-oxo-4-phenylpyrrolidin-1-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (first eluting isomer, 100 mg, off-white solid, chiral HPLC). t =9.883min, LCMS(ES,m / z):429[M+H] + ), (S)-10-hydroxy-10-(((S)-2-oxo-4-phenylpyrrolidin-1-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate tert-butyl (2nd isomer, 100 mg, off-white solid, chiral HPLC R t =11.259 min, LCMS(ES,m / z):429[M+H] +, and a diastereomeric mixture of tert-butyl 10-hydroxy-10-((2-oxo-4-phenylpyrrolidin-1)-1-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (third and fourth eluting isomers, 230 mg, chiral HPLC R t = 13.822 min).

[0191] Step 2: (R)-1-(((S)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one hydrochloride To tert-butyl (S)-10-hydroxy-10-(((R)-2-oxo-4-phenylpyrrolidin-1-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (first eluting isomer, 100 mg, 0.23 mmol) was added a solution of hydrochloric acid in 1,4-dioxane (3.00 mL, 4 M). The resulting mixture was stirred at 25° C. for 0.5 h and concentrated under reduced pressure to give (R)-1-(((S)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one hydrochloride (85 mg, 100%) as a white solid. LCMS (ES, m / z): 329 [M-HCl + H] + .

[0192] Step 3: (S)-1-(((S)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one hydrochloride To tert-butyl (S)-10-hydroxy-10-((((S)-2-oxo-4-phenylpyrrolidin-1-yl)methyl)-7-azaspiro[4.5]decane-7-carboxylate (second eluting isomer, 100 mg, 0.23 mmol) was added a solution of hydrochloric acid in 1,4-dioxane (3.00 mL, 4 M). The resulting mixture was stirred at 25° C. for 0.5 h and concentrated under reduced pressure to give (S)-1-(((S)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one hydrochloride (85 mg, 100%) as an off-white solid. LCMS (ES, m / z): 329 [M-HCl + H] + .

[0193] Step 4: (R)-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one (second eluting isomer, 14) A mixture of (R)-1-(((S)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one hydrochloride (85 mg, 0.23 mmol) and racemic 3-cyclohexyl-2-methylpropanoic acid (46 mg, 0.27 mmol) in DMF (1.00 mL) was stirred, and HATU (208 mg, 0.54 mmol) and DIEA (226 μL, 1.37 mmol) were added. The resulting mixture was stirred at 25 °C for 2 h.

[0194] This mixture was subjected to reverse phase column chromatography (column: C 18 Purification using silica gel, 40 g, 20–35 μm, 100 Å; mobile phase: water and ACN containing 0.05% NH4CO3 (ACN 0%–60% in 40 min); detector: UV 220 / 254 nm gave (4R)-1-(((10S)-7-(3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one (100 mg).

[0195] This diastereomeric mixture was purified by column: CHIRALPAK IF, 2 x 25 cm, 5 μm; mobile phase A: hexane (10 mM NH3), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 15% B to 15% B in 16 min; UV 220 / 254 nm; R t 1:11.247 minutes;R tThe mixture was separated by chiral prep HPLC under the following conditions: 2:13.452 min; injection volume: 0.3 mL; run number: 7. The collected fractions were concentrated under reduced pressure and re-lyophilized to give (R)-1-(((S)-7-((S)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one (first eluting isomer, 19 mg (14% yield), white solid, chiral HPLC R t = 11.247 min), and (R)-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one (14) (second eluting isomer, 21 mg (15% yield), white solid, chiral HPLC t = 13.452 min). Compound 14: 1 H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.34-7.24 (m, 5H), 4.62-4.58 (m, 1H), 4.11-4.09 (m, 1H), 3.95-3.91 (m, 1H), 3.61-3.55 (m, 3H), 3.33-3.31 (m, 2H), 3.18-3.05 (m, 1H), 2.91-2.85 (m, 2H), 2.73-2.67 (m, 1H), 2.43-2.36 (m, 1H), 1.84-1.79 (m, 1H), 1.65-1.44 (m, 14H), 1.42-1.07 (m, 6H), 0.96-0.94 (m, 3H), 0.84-0.82 (m, 2H). LCMS(ES,m / z):481[M+H] + .

[0196] Step 5: (S)-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one (second eluting isomer, 13) A mixture of (S)-1-(((S)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one hydrochloride (80 mg, 0.22 mmol, 1.00 equiv) and racemic 3-cyclohexyl-2-methylpropanoic acid (41 mg, 0.24 mmol) in DMF (2.00 mL) was stirred, and HATU (185 mg, 0.48 mmol, 2.00 equiv) and DIEA (200 μL, 1.21 mmol) were added. The resulting mixture was stirred at 25 °C for 2 h.

[0197] This mixture was subjected to reverse phase column chromatography (column: C 18 Purification with silica gel, 40 g, 20–35 μm, 100 Å; mobile phase: water and ACN containing 0.05% NH4CO3 (ACN 0%–60% in 40 min); detector: UV 220 / 254 nm gave (4S)-1-(((10S)-7-(3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one (100 mg).

[0198] This diastereomeric mixture was purified by column: CHIRALPAK IF, 2 x 25 cm, 5 μm; mobile phase A: hexane (10 mM NH3), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 15% B to 15% B in 19 min; UV 220 / 254 nm; R t 1:13.435 minutes;R t The mixture was separated by chiral prep HPLC under the following conditions: 2:17.026 min; injection volume: 0.4 mL; run number: 6. The collected fractions were concentrated under reduced pressure and re-lyophilized to give (S)-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one (first eluting isomer, 21 mg (17% yield), white solid, chiral HPLC R t= 13.435 min), and (S)-1-(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7-azaspiro[4.5]decan-10-yl)methyl)-4-phenylpyrrolidin-2-one (13) (second eluting isomer, 23 mg (19% yield), white solid, chiral HPLC t = 13.435 min).

[0199] Compound 13: 1 H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.35-7.31 (m, 4H), 7.27-7.24 (m, 1H), 4.59-4.55 (m, 1H), 3.95-3.92 (m, 1H), 3.74-3.72 (m, 2H), 3.64-3.54 (m, 3H), 3.45-3.33 (m, 1H), 3.15-2.85 (m, 3H), 2.65-2.62 (m, 1H), 2.50-2.47 (m, 1H), 1.85-1.79 (m, 1H), 1.64-1.43 (m, 14H), 1.40-1.06 (m, 6H), 0.96-0.94 (m, 3H), 0.87-0.81 (m, 2H). LCMS(ES,m / z):481[M+H] + .

[0200] Example 2 Synthesis of 2-((7-(3-cyclohexyl-2-methylpropanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-1-oxoisoindoline-4-carboxamide (30) [ka]

[0201] Step 1: N,N-dimethyl-1-oxo-2,3-dihydroisoindole-4-carboxamide To a stirred mixture of 4-bromo-2,3-dihydroisoindol-1-one (10.0 g, 47.2 mmol) and dimethylamine (21.3 g, 471 mmol) in DMF (150 mL) was added EtN (47.7 g, 471 mmol) and Pd(dppf)Cl (6.90 g, 9.43 mmol). The resulting solution was stirred in a pressure tank under an atmosphere of CO(g) (60 atm) at 120 °C for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure.

[0202] The crude product was purified by reverse phase column chromatography (column: C 18 Purification by silica gel, 330 g, 20-35 μm, 100 Å; mobile phase: water and ACN containing 0.05% TFA (ACN 0% to 60% in 40 min); detector: UV 220 / 254 nm gave N,N-dimethyl-1-oxo-2,3-dihydroisoindole-4-carboxamide (3.00 g, 34%) as a yellow oil. LCMS (ES, m / z): 205 [M+H] + .

[0203] Step 2: tert-butyl 10-[[4-(dimethylcarbamoyl)-1-oxo-3H-isoindol-2-yl]methyl]-10-hydroxy-7-azaspiro[4.5]decane-7-carboxylate A mixture of N,N-dimethyl-1-oxo-2,3-dihydroisoindole-4-carboxamide (500 mg, 2.44 mmol) and tert-butyl 1-oxa-10-azadispiro[2.0.4^[4].4^[3]]dodecane-10-carboxylate (982 mg, 3.67 mmol) in DMF (6.00 mL) was stirred and Cs2CO3 (2.39 g, 7.34 mmol) was added. The resulting mixture was stirred at 85 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature, diluted with water (50 mL), and extracted with DCM (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

[0204] The crude product was purified by reverse phase column chromatography (column: C 18Purification using silica gel, 40 g, 20-45 μm, 100 Å; mobile phase: water with 0.05% TFA and ACN (0% to 60% in 40 min); detector: UV 220 / 254 nm) gave tert-butyl 10-[[4-(dimethylcarbamoyl)-1-oxo-3H-isoindol-2-yl]methyl]-10-hydroxy-7-azaspiro[4.5]decane-7-carboxylate (500 mg, 43%) as a yellow solid. LCMS (ES, m / z): 472 [M+H] + .

[0205] Step 3: (10Z)-10-[[4-(dimethylcarbamoyl)-1-oxo-3H-isoindol-2-yl]methylidene]-7-azaspiro[4.5]decane-7-carboxylate To a stirred mixture of tert-butyl 10-[[4-(dimethylcarbamoyl)-1-oxo-3H-isoindol-2-yl]methyl]-10-hydroxy-7-azaspiro[4.5]decane-7-carboxylate (500 mg, 1.06 mmol) and MsCl (242 mg, 2.12 mmol) in DCM (25 mL), TEA (441 μL, 3.18 mmol) and DIEA (250 μL, 2.12 mmol) were added dropwise under a nitrogen atmosphere at 0° C. The resulting mixture was stirred at 25° C. for 12 h. The mixture was concentrated in vacuo.

[0206] The crude product was purified by reverse phase column chromatography (column: C 18 Purification using silica gel, 40 g, 20-45 μm, 100 Å; mobile phase: water and ACN containing 0.05% TFA (ACN 0% to 60% over 40 min); detector: UV 220 / 254 nm) gave tert-butyl (10Z)-10-[[4-(dimethylcarbamoyl)-1-oxo-3H-isoindol-2-yl]methylidene]-7-azaspiro[4.5]decane-7-carboxylate (140 mg, 28%) as a white solid. LCMS (ES, m / z): 454 [M+H] + .

[0207] Step 4: tert-butyl 10-[[4-(dimethylcarbamoyl)-1-oxo-3H-isoindol-2-yl]methyl]-7-azaspiro[4.5]decane-7-carboxylate A mixture of tert-butyl (10Z)-10-[[4-(dimethylcarbamoyl)-1-oxo-3H-isoindol-2-yl]methylidene]-7-azaspiro[4.5]decane-7-carboxylate (130 mg, 0.28 mmol) and Pd / C (30 mg, 10%) in MeOH (5 mL) was stirred under a hydrogen atmosphere at 25° C. for 12 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 10-[[4-(dimethylcarbamoyl)-1-oxo-3H-isoindol-2-yl]methyl]-7-azaspiro[4.5]decane-7-carboxylate (100 mg, 73%) as a white solid. LCMS (ES, m / z): 456 [M+H] + .

[0208] Step 5: 2-[7-Azaspiro[4.5]decan-10-ylmethyl]-N,N-dimethyl-1-oxo-3H-isoindole-4-carboxamide A mixture of tert-butyl 10-[[4-(dimethylcarbamoyl)-1-oxo-3H-isoindol-2-yl]methyl]-7-azaspiro[4.5]decane-7-carboxylate (150 mg, 0.32 mmol) in a solution of HCl in 1,4-dioxane (3 mL, 4 M) was stirred at 25 °C for 0.5 h.

[0209] The mixture was concentrated under reduced pressure, and the crude product was purified by reversed-phase column chromatography (column: C 18 Purification by silica gel, 40 g, 20-45 μm, 100 Å; mobile phase: water and ACN containing 0.05% NH₄CO₃ (ACN 0% to 60% in 40 min); detector: UV 220 / 254 nm gave 2-[7-azaspiro[4.5]decan-10-ylmethyl]-N,N-dimethyl-1-oxo-3H-isoindole-4-carboxamide (100 mg, 81%) as a white solid. LCMS (ES, m / z): 356 [M+H] + .

[0210] Step 6: 2-((7-(3-cyclohexyl-2-methylpropanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-1-oxoisoindoline-4-carboxamide (third eluting isomer, 30) A mixture of 2-[7-azaspiro[4.5]decan-10-ylmethyl]-N,N-dimethyl-1-oxo-3H-isoindole-4-carboxamide (80 mg, 0.22 mmol) and 3-cyclohexyl-2-methylpropanoic acid (38 mg, 0.22 mmol) in DMF (2 mL) was stirred, and HATU (171 mg, 0.45 mmol) and DIEA (185 μL, 1.12 mmol) were added. The resulting mixture was stirred at 25 °C for 1 h.

[0211] This mixture was subjected to reverse phase column chromatography (column: C 18 Purification by silica gel, 40 g, 20-45 μm, 100 Å; mobile phase: water and ACN containing 0.05% NH4HCO3 (ACN 0%-60% in 40 min); detector: UV 220 / 254 nm) gave the racemic product (100 mg) as a yellow oil.

[0212] The racemate was purified using a column: Chiralpak IA, 2 x 25 cm, 5 μm; mobile phase A: MTBE (10 mM NH3 / MEOH), mobile phase B: EtOH; flow rate: 18 mL / min; gradient: 40% B to 40% B in 30 min; UV: 220 / 254 nm; R t 1:12.922 minutes;R t 2:15.888 minutes;R t The mixture was separated by chiral prep HPLC under the following conditions: 3:24.417 min; injection volume: 0.5 mL; run number: 12. The collected fractions were concentrated under reduced pressure and re-lyophilized to give 2-((7-(3-cyclohexyl-2-methylpropanoyl)-7-azaspiro[4.5]decan-10-yl)-N,N-dimethyl-1-oxoisoindoline-4-carboxamide (first eluting isomer, 7 mg (6% yield)), an off-white solid, purified by chiral HPLC. t: 12.922 min), a diastereomeric mixture of 2-((7-(3-cyclohexyl-2-methylpropanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-1-oxoisoindoline-4-carboxamide (second and third eluting isomers, 30 mg, chiral HPLC R t : 15.888 min), and 2-((7-(3-cyclohexyl-2-methylpropanoyl)-7-azaspiro[4.5]decan-10-yl)-methyl)-N,N-dimethyl-1-oxoindoline-4-carboxamide (fourth eluting isomer, 6.7 mg (6% yield), off-white solid, chiral HPLC t :24.417 minutes).

[0213] The diastereomeric mixture of the second and third eluting isomers was separated using a column: CHIRALPAK ID, 3 × 25 cm, 5 μm; mobile phase A: MTBE (10 mM NH3 / MEOH), mobile phase B: EtOH; flow rate: 30 mL / min; gradient: 50% B to 50% B in 25 min; UV: 254 / 220 nm; R t 1:15.9 minutes;R t The mixture was re-separated by chiral prep HPLC under the following conditions: Evaporation rate: 2:21.3 min; injection volume: 3 ml; run number: 2. The collected fractions were concentrated under reduced pressure and re-lyophilized to give 2-((7-(3-cyclohexyl-2-methylpropanoyl)-7-azaspiro[4.5]decan-10-yl)-N,N-dimethyl-1-oxoisoindoline-4-carboxamide (second eluting isomer, 9.2 mg (8% yield)), an off-white solid, purified by chiral HPLC. t 15.9 min), and 2-((7-(3-cyclohexyl-2-methylpropanoyl)-7-azaspiro[4.5]decan-10-yl)methyl)-N,N-dimethyl-1-oxoisoindoline-4-carboxamide (30) (third eluting isomer, 10.8 mg (9% yield), off-white solid, chiral HPLC Rt: 21.3 min).

[0214] Compound 30: 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.73 (d, J = 6.8 Hz, 1H), 7.59-7.53 (m, 2H), 4.53-4.41 (m, 2H), 4.10-3.75 (m, 2H), 3.70-3.50 (m, 1H), 3.38-3.34 (m, 1H), 3.21-3.11 (m, 1H), 3.02 (br s, 3H), 2.91-2.76 (m, 5H), 1.93-1.85 (m, 1H), 1.70-1.46 (m, 12H), 1.36-1.33 (m, 3H), 1.22-1.04 (m, 6H), 0.97-0.91 (m, 3H), 0.84-0.78 (m, 2H). LCMS(ES,m / z):508[M+H] + .

[0215] Example 3 Synthesis of compounds 1–12 and 15–29 Examples 1-12 and 15-29 were prepared from commercially available materials using procedures similar to those used above to prepare Examples 13, 14, and 30. In many cases, the absolute and relative stereochemistry is arbitrary and may differ from that shown. Liquid chromatography-mass spectrometry data for all examples, including retention times and confirmatory mass ions, are provided in Table A below.

[0216] Examples 31-36 are prepared from commercially available materials using the procedures and examples described above.

[0217] The LC-MS analysis conditions were as follows: HPLC: Waters Acquity Binary Solvent Manager; UV: Waters Acquity PDA; ELSD: Water Acquity ELSD; column: Waters Acquity UPLC CSH C 18, 1.7 μm, 2.1 × 50 mm; column temperature: 35 °C; mobile phase A: 95% water / 5% acetonitrile containing 0.1% formic acid; mobile phase B: 95% acetonitrile / 5% water containing 0.085% formic acid; gradient: 5 to 100% B in 2.0 min; hold: 100% B to 2.2 min; flow rate: 0.6 mL / min; UV wavelength: 220 nm; ionization: electrospray, positive and negative modes. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0218] Example 4 USP19 Inhibition Biochemical Assay Protocol USP19 enzyme assays were performed in a buffer solution (final volume: 6 μL) containing 20 mM Tris-HCl (Corning 46-031-CM) at pH 8.0, 1 mM GSH (Sigma, G4251), 0.03% BGG (Sigma, G7516), and 0.01% Triton X-100 (Sigma, 93443). Test compounds were serially diluted with DMSO (Sigma, G7516) to obtain a 10-point, 3-fold series. Nanoliter amounts were pre-aliquoted into a 1536-well assay plate (Corning, 9110BC) for a concentration response range of 26.6 μM to 1.35 nM. 3 μL of 2× enzyme was added to the assay plate and preincubated with compound for 30 minutes, after which 3 μL of 2× substrate was added to initiate the reaction (final concentrations of 0.3 nM human USP19 (Boston Biochem, E-576) and 25 nM Ub-Rh110MP (UbiQ, UbiQ-126)). Enzyme and substrate concentrations, as well as incubation times, were optimized for maximum signal-to-background ratio while maintaining linear initial rate conditions at a fixed substrate concentration below the Km.

[0219] The fluorescence signal was measured using an EnVision Plate Reader (PerkinElmer) equipped with a 485 nm excitation filter and a 535 nm emission filter. Measurements were performed at 2.5 min intervals for 10 min, and the curve was shown to be linear.

[0220] The rate was calculated using the formula: Rate = ((Final FLU - Initial FLU) / 600 seconds), where Final FLU = fluorescence emission at 10 minutes, Initial FLU = fluorescence emission at 0 minutes, and 600 = reaction time (seconds).

[0221] Data were expressed as percent inhibition compared to control wells using the formula: %inh = 100 × ((Rate - AveLow) / (AveHigh - AveLow)), where Rate = measured rate of fluorescence generated during the assay, AveLow = average rate for no enzyme control (n = 32), and AveHigh = average rate for DMSO control (n = 32).

[0222] I C 50 Values ​​were determined by curve fitting using the standard four-parameter logistic fitting algorithm included in the Activity Base software package (IDBS) using XE Designer Model 250. Data fitting was performed using the Levenberg-Marquardt algorithm. IC values ​​for specific substances were calculated. 50 is shown in Table B.

[0223] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10]

[0224] The present disclosure enables those skilled in the relevant art to make and use the inventions provided herein according to multiple and varied embodiments. Various changes, substitutions, and improvements to the present disclosure that may be readily apparent to those skilled in the art, including specific changes, variations, substitutions, and improvements, are incorporated herein by reference. Therefore, the above description is an illustrative example of the findings provided herein. Furthermore, the above description and examples are illustrative of the present invention, not limiting. The scope of the present invention is therefore defined by the appended claims.

Claims

1. Compounds of formula (I) 【Chemical 1】 and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, X is N or C; However, if X is N, then R １ and R １’ One of the is not present; Y is N or CR ７ and Z is CH ２ and R １ and R １’ are independently H, C １－４ alkyl, and one R ８ aryl optionally substituted with R ２ and R ２’ are each independently H and C １－４ alkyl; R １ or R １’ One of them is R ２ or R ２’ and one R ９ may form a substituted aryl or heteroaryl ring; Ring A is composed of X and R ２ and R ２’ R is selected so as to include an unsaturated bond between the carbon atom to which R is bonded. １ or R １’ One of the R ２ or R ２’ and one of may be absent; R ３ But H, -OR １０ and halogen; R ４ is H or C １－４ is alkyl; R ５ is H or C １－４ is alkyl; R ４ and R ５ may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R ６ is selected from alkylcycloalkyl, alkylaryl, and alkylheteroaryl, each of which is selected from one C １－４ optionally substituted with alkyl; R ７ -C(O)R １１ and R ８ But halogen, C １－４ Alkyl, and C １－４ alkoxy; R ９ H, halogen, C １－４ Alkyl, C １－４ Alkoxy, —C(O)N(R １２ ) ２ and heteroaryl; R １０ is H or C １－４ is alkyl; R １１ But -N(R １２ ) ２ or a 5- to 6-membered heterocycle containing two heteroatoms selected from N and O; R １２ is C １－４ is an alkyl group; The compound wherein m is 0. However, the following compounds are excluded: 【Chemistry 2】

2. R ６ but, 【Chemistry 3】 2. The compound of claim 1 selected from the group consisting of:

3. R ４ and R ５ However, each independently, C １－４ 2. The compound of claim 1, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

4. Compounds further given by formula (II) 【Chemistry 4】 and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, R １３ H, halogen, C １－４ Alkyl, C １－４ Alkoxy, —C(O)N(R １９ ) ２ or a 5-membered heteroaryl ring; R １４ But H, C １－４ Alkyl, and —C(O)N(R １９ ) ２ Selected from: R １３ and R １４ One of must be H; R １５ is H or OH; R １６ is C １－４ is an alkyl group; R １７ is C １－４ is an alkyl group; R １６ and R １７ may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R １８ is selected from alkylcycloalkyl, alkylphenyl, and alkylheteroaryl, each of which is selected from one C １－４ optionally substituted with alkyl; R １９ is C １－４ The compound of claim 1 which is an alkyl group.

5. The compound has the stereochemistry of formula (II-A) 【Chemistry 5】 5. The compound of claim 4, wherein:

6. R １３ -Cl, methyl, methoxy, -C(O)N(CH ３ ) ２ 6. The compound of claim 4 or claim 5, wherein the compound is selected from the group consisting of thiazolyl, pyrazolyl, and oxazolyl.

7. R １４ methyl and -C(O)N(CH ３ ) ２ The compound according to any one of claims 4 to 6, selected from the group consisting of:

8. R １８ but, 【Chemistry 6】 The compound according to any one of claims 4 to 7, selected from the group consisting of: 【Request 9】 【Chemical 7-1】 【Chemistry 7-2】 The compound of any one of claims 4 to 8, selected from the group consisting of: and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

10. Compounds further given by formula (III) 【Chemistry 8】 and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, R ２０ is H, halogen, and C １－４ alkyl; R ２１ is H or C １－４ is alkoxy; R ２２ is H or C １－４ is alkyl; R ２０ , R ２１ , and R ２３ Two of them must be H; R ２３ is hydrogen or C １－４ is an alkyl group; R ２４ is C １－４ is an alkyl group; R ２５ is C １－４ is an alkyl group; R ２４ and R ２５ may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R ２６ But one C １－４ The compound of claim 1 which is an alkylcycloalkyl group substituted with an alkyl group.

11. The compound has the stereochemistry of formula (III-A) 【Chemistry 9】 11. The compound of claim 10, wherein:

12. The compound has the stereochemistry of formula (III-B) 【Chemistry 10】 11. The compound of claim 10, wherein:

13. R ２０ The compound of any one of claims 10 to 12, wherein is selected from the group consisting of -Cl and methyl.

14. R ２１ The compound of any one of claims 10 to 13, wherein is methoxy.

15. R ２２ The compound according to any one of claims 10 to 14, wherein is methyl.

16. R ２６ but 【Chemistry 11】 The compound according to any one of claims 10 to 15,

17. 【Catalog 12】 17. The compound of any one of claims 10 to 16, selected from the group consisting of: and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

18. Compounds further given by formula (IV) 【Chemistry 13】 and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, R ２７ is C １－４ is an alkyl group; R ２８ is C １－４ is an alkyl group; R ２７ and R ２８ may be linked together to form a cycloalkyl that includes the carbon to which they are attached; R ２９ But one C １－４ The compound of claim 1 which is an alkylcycloalkyl group substituted with an alkyl group.

19. The compound has the stereochemistry of formula (IV-A) 【Chemistry 14】 20. The compound of claim 18, wherein:

20. The compound is 【Chemistry 15】 20. The compound of claim 18, wherein:

21. 【Catalog 16】 and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

22. 【Catalog 17】 and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

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