DHCR24 inhibitor compounds

Abstract

The present disclosure relates to compounds suitable for the inhibition of Δ24-dehydrocholesterol reductase (DHCR24), in particular for the selective inhibition of DHCR24. These compounds are for use as therapeutic agents, in particular as drugs for use in treating and / or preventing DHCR24-mediated disorders, such as non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (asCVD), or multiple sclerosis (MS).

Description

[Technical field]

[0001] FIELD OF THE PRESENT APPLICATION The present invention relates to compounds suitable for the inhibition of Δ24-dehydrocholesterol reductase (DHCR24), in particular for the selective inhibition of DHCR24, for use as therapeutic agents, in particular for use in the treatment and / or prevention of DHCR24-mediated disorders, such as non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (asCVD), or multiple sclerosis (MS). [Background technology]

[0002] background Cholesterol is known to be an important storage lipid and cell building material. The understanding of the biological role of cholesterol biosynthesis and its biosynthetic precursors has progressed significantly in the last decade. Cholesterol biosynthesis is associated with a variety of different diseases, and research has focused on the biological functions of key intermediates and enzymes involved in cholesterol biosynthesis.

[0003] Cholesterol biosynthesis is divided into the pre-mevalonate pathway and the post-squalene pathway, the latter also known as distal cholesterol biosynthesis. De novo cholesterol biosynthesis is accomplished by 11 enzymes in the mevalonate pathway (starting with acetyl-coenzyme A), while distal cholesterol biosynthesis involves 9 enzymes. The latter is further divided into the Bloch pathway and the Kandutsch-Russell pathway (see Figure 1).

[0004] The Bloch pathway contains a Δ24-unsaturated intermediate and is interconnected with the Kandutsch-Russell branch by the action of the enzyme DHCR24. DHCR24 is a membrane-bound enzyme that catalyzes the anaerobic reduction of the Δ24-double bond in the side chain of precursor sterols (see Figures 1 and 2). It has been shown that both pathways are not strictly separate, rather, tissue- and cell type-specific interactions of both pathways are observed, with the Kandutsch-Russell pathway being favored. The main substrates of DHCR24 are lanosterol (4,4,14-trimethylcholesta-8,24-dien-3β-ol, see Figure 1(1)) and zymosterol (cholesta-8,24-dien-3β-ol, see Figure 1(11)) as well as cholesta-7,24-dien-3β-ol (see Figure 1(12)).

[0005] The reduction of the Δ24 double bond can occur in the last step of the Bloch pathway that converts desmosterol (cholesta-5,24-dien-3β-ol, see (14) in Figures 1 and 2) to cholesterol (see (8) in Figures 1 and 2). DHCR24 does not require cofactors other than NADPH. The reduction of the Δ24 double bond proceeds in two steps, through the initial introduction of a proton at C24 to generate a cationic high-energy intermediate (HEI) at C25, followed by the nucleophilic addition of a hydride from NADPH (see Figure 2). Dysfunction or inhibition of DHCR24 causes mammalian cholesterol biosynthesis to proceed via the Bloch pathway, ultimately resulting in the accumulation of desmosterol.

[0006] Desmosterolosis (MIM 602398) is a rare genetic disorder that affects the DHCR24 gene. Desmosterolosis is a very rare disease with only a few clinically described cases. Desmosterolosis is associated with severe abnormalities such as microcephaly with agenesis of the corpus callosum, convulsions, nystagmus, strabismus, and micrognathia. As exemplified by heterozygous carriers of DHCR24 mutations, mild accumulation of desmosterol has been found to have no effect on viability, especially in combination with a cholesterol-rich diet. Thus, moderate in vivo accumulation of desmosterol by inhibiting DHCR24 appears to be non-toxic. Carriers of DHCR24 mutations in one allele have been shown to have normal cholesterol levels and only a 1.5-fold increase in plasma concentrations of desmosterol.

[0007] Biologically, the roles of DHCR24 are diverse, and inhibition of DHCR24 is a promising drug target for the treatment of various diseases. Therefore, there is a need for selective, potent, and non-toxic inhibitors of DHCR24 that may be useful in many therapeutic areas. Summary of the Invention [Means for solving the problem]

[0008] Summary of the Invention In a first aspect, the present invention provides a compound of formula (10) or a salt, solvate, hydrate, or prodrug thereof: [ka] (In the formula, G is [ka] is a fused ring system selected from: B is, [ka] Selected from; R 1 is hydrogen, -C(=O)R 6 , and C 1~6 alkyl; R 2 is hydrogen and C 1~6 alkyl; R 3 is a group represented by formula (2), -[C(R 7 )2] n -X, -CH=CR 6 R 7 , -CR 7 =NN(R 6 )2, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, where 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl are selected from -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more groups selected from alkoxy; [ka] n is an integer from 1 to 6; W is O and NR 6 Selected from; Y is selected from hydrogen and C2 alkenyl, where C2 alkenyl is optionally substituted with one or more halo; X is selected from halo, -OH, -SH, -OZ, -SZ, -SSZ, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, where 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are selected from -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more groups selected from alkoxy; Each R 4 is hydrogen and C 1~6 independently selected from alkyl; R 5 is hydrogen and C 1~6 alkyl; Each R 6 is hydrogen and C 1~6 independently selected from alkyl; Each R 7 , H, C 1~6 Alkyl, and C 2~6 alkenyl, wherein C 1~6 Alkyl and C 2~6 The alkenyl is optionally substituted with one or more halo; Z is C 6~10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 alkoxy).

[0009] The compound of formula (10) [ka] [ka] It is never one of them.

[0010] The dashed lines in formula (10) represent the location of the fused ring system represented by G. Similarly, the dashed lines in one of the structures of G represent the location of the group represented by B.

[0011] The present inventors have unexpectedly identified a class of compounds that inhibit DHCR24. The compounds are selective, potent and non-toxic inhibitors of DHCR24. Considering the diverse biological roles of DHCR24, the selectivity of a compound to inhibit DHCR24 is important for its pharmaceutical or clinical use in treating or preventing DHCR24-mediated disorders. The inhibition of DHCR24 by the compounds of the present invention increases endogenous desmosterol levels.

[0012] Compared with other inhibitors of DHCR24, the compound identified by the present invention has advantageous properties when formulating drug products for clinical use (e.g., Lipinski's rule may be applied).Therefore, the compound has increased water solubility and good stability.It is also expected that the compound is suitable for direct oral administration.

[0013] A further aspect of the present invention provides a compound of formula (10) or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof for use in treating or preventing a DHCR24-mediated disorder. This aspect of the present invention also provides a method of treating or preventing a DHCR24-mediated disorder. The method comprises administering to a subject a compound of formula (10) or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0014] In a second aspect, the present invention provides a compound of formula (1) or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof for use in the treatment or prophylaxis of a DHCR24-mediated disorder.

[0015] The second aspect of the present invention also provides a method of treating or preventing a DHCR24-mediated disorder, comprising administering to a subject a compound of formula (1) or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0016] In a second aspect of the invention, the compound of formula (1) [ka] (In the formula, G is [ka] is a fused ring system selected from: B is, [ka] Selected from; R 1 is hydrogen, -C(=O)R 6 , and C 1~6 alkyl; R 2 is hydrogen and C 1~6 alkyl; R 3 is a group represented by formula (2), -[C(R 7 )2] n -X, -C(=O)NHOR 8 , -C(=O)OR 8 , -CR 7 =NN(R 6 )2, -CH=CR 6 R 7 , C 6~10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more groups selected from alkoxy; [ka] n is an integer from 1 to 6; W is O, S, and NR 6 Selected from; Y is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, Amino-C 1~6 Alkyl, (mono-C 1~6 Alkylamino)C 1~6 Alkyl, and (di-C 1~6 Alkylamino)C 1~6 alkyl, wherein C 1~6 Alkyl and C 2~6 The alkenyl is optionally substituted with one or more halo; X is halo, -OH, -SH, -N(R 6)2, -OZ, -SZ, -SSZ, -C(=O)R 7 , C 6~10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more groups selected from alkoxy; Each R 4 is hydrogen and C 1~6 independently selected from alkyl; R 5 is hydrogen and C 1~6 alkyl; Each R 6 is hydrogen and C 1~6 independently selected from alkyl; Each R 7 , H, C 1~6 Alkyl, and C 2~6 alkenyl, wherein C 1~6 Alkyl and C 2~6 The alkenyl is optionally substituted with one or more halo; R 8 is C 1~6 Alkyl and C 2~6 alkenyl; Z is C 6~10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 alkoxy).

[0017] The dashed lines in formula (1) represent the location of the fused ring system represented by G. Similarly, the dashed lines in one of the structures of G represent the location of the group represented by B.

[0018] The experimental data presented herein, particularly the in vivo data, provide convincing evidence that the compound can be used clinically in treating or preventing DHCR24-mediated disorders.The compound can exert its effect in the brain (e.g., it is not blocked by the blood-brain barrier).

[0019] Another aspect of the present invention is the provision of a pharmaceutical composition comprising a compound of formula (1) or (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a pharma- ceutically acceptable excipient.

[0020] In another aspect, the present invention provides a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition as defined herein, for use in therapy and / or for use as a medicament.

[0021] In another aspect, the present invention provides the use of a compound of formula (1) or formula (10), or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a DHCR24-mediated disorder.

[0022] A further aspect of the present invention provides a method for inhibiting the activity of DHCR24 in vivo or in vitro. The in vivo or in vitro method comprises contacting a cell with a compound of formula (1) or formula (10), or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein. Alternatively, the in vivo method may comprise administering to a subject a compound of formula (1) or formula (10), or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein.

[0023] In another aspect, the present invention provides a combination comprising a compound of Formula (1) or Formula (10), or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, and one or more additional therapeutic agents.

[0024] The preferred, expedient and optional features of any one particular embodiment of the invention are also preferred, expedient and optional features of any other embodiment.

[0025] The invention is further explained below with reference to the accompanying drawings. [Brief description of the drawings]

[0026] [Figure 1]Figure 1 is a scheme showing the enzymatic steps of distal cholesterol biosynthesis. Involved enzymes: (A) sterol C24-reductase (Δ24-dehydrocholesterol reductase (DHCR24)), (B) sterol C14-demethylase (CYP51), (C) sterol C14-reductase (Δ14-dihydrocholesterol reductase (DHCR14)), (D) sterol C4-methyloxidase, (E) sterol C3-dehydrogenase, (F) sterol C3-ketoreductase, (G) sterol C8-isomerase (emapomil binding protein (EBP)), (H) sterol C5-desaturase (SC5D)), (I) sterol C7-reductase (Δ7-dehydrocholesterol reductase (DHCR7)). Intermediates: (1) 4,4,14-trimethylcholesta-8,24-dien-3β-ol (lanosterol), (2) 4,4,14-trimethylcholesta-8-en-3β-ol (dihydrolanosterol), (3) 4,4-dimethylcholesta-8,14-dien-3β-ol, (4) 4,4-dimethylcholesta-8-en-3β-ol, (5) cholesta-8-en-3β-ol (zymostenol), (6) cholesta-7-en-3β-ol (latosterol), cholesta-5,7-dien-3β-ol (7-dehydrocholesterol), (8) cholesta-5-en-3β-ol (7-dehydrocholesterol), (9) cholesta-5-en-3β-ol (7-dehydrocholesterol), (10) cholesta-5-en-3β-ol (7-dehydrocholesterol), (11) cholesta-5-en-3β-ol (7-dehydrocholesterol), (12) cholesta-5-en-3β-ol (7-dehydrocholesterol), (13) cholesta-5-en-3β-ol (7-dehydrocholesterol), (14) cholesta-5-en-3β-ol (7-dehydrocholesterol), (15) cholesta-5-en-3β-ol (7-dehydrocholesterol), (16) cholesta-5-en-3β-ol (7-dehydrocholesterol), (17) cholesta-5-en-3β-ol (7-dehydrocholesterol), (18) cholesta-5-en-3β-ol (7-dehydrocholesterol), (19) cholesta-5-en-3β-ol (7-dehydrocholesterol), (19) cholesta-5-en-3β-ol (7-dehydrocholesterol), (19 (9) 4,4-dimethylcholesta-8,14,24-trien-3β-ol (follicular fluid meiosis activating sterol (FF-MAS)), (10) 4,4-dimethylcholesta-8,24-dien-3β-ol (testicular meiosis activating sterol (T-MAS)), (11) cholesta-8,24-dien-3β-ol (zymosterol), (12) cholesta-7,24-dien-3β-ol, (13) cholesta-5,7,24-trien-3β-ol (7-dehydrocholesterol), (14) cholesta-5,24-dien-3β-ol (desmosterol).

[0027] [Diagram 2] FIG. 2 is a reaction scheme showing the proposed mechanism of the DHCR24 enzymatic reaction.

[0028] [Diagram 3] FIG. 3 is a series of histograms showing the results of various in vivo experiments using Example 11 (SH42).

[0029] [Figure 4] 4 and 5 show the results of an in vivo experiment in which desmosterol levels were measured in the brains of mice following treatment with Example 11 or Example 33. [Diagram 5] 4 and 5 show the results of an in vivo experiment in which desmosterol levels were measured in the brains of mice following treatment with Example 11 or Example 33. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Detailed Description definition The compounds and intermediates described herein may be named according to either the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems. Unless expressly stated to the contrary, the terms "compound of formula (1)" and "compound of formula (10)" should be understood to refer to and include any and all compounds described by and / or with reference to formula (1) or formula (10), respectively. These terms should also be understood to encompass all stereoisomers, i.e., cis and trans isomers, and optical isomers, i.e., R and S enantiomers, and diastereomers, of such compounds and all salts thereof, in substantially pure form and / or in any mixture of the foregoing in any ratio. This understanding also extends to pharmaceutical compositions and methods of treatment that employ or include one or more compounds of formula (1) or formula (10), either by themselves or in combination with additional agents.

[0031] The various hydrocarbon-containing moieties provided herein may be designated by prefixes that designate the minimum and maximum number of carbon atoms in the moiety, e.g., "C a~b " or "C a ~C b For example, C a~b Alkyl refers to an alkyl moiety having a number of carbon atoms from integer "a" to integer "b" (inclusive). Certain moieties may also be described according to a minimum and maximum number of members, with or without specific reference to particular atoms or the overall structure. For example, the term "a-b membered ring" or "having a-b members" refers to a moiety having a number of atoms from integer "a" to integer "b" (inclusive).

[0032] The term "about," when used herein in connection with a measurable value, such as an amount or duration, is intended to encompass reasonable variations in the value, for example, allowing for experimental error in the measurement of said value.

[0033] The term "alkyl" or "alkyl group" as used herein by itself or with another term(s) refers to a branched or unbranched saturated hydrocarbon chain. Unless otherwise specified, an alkyl group typically contains 1 to 6 carbon atoms, e.g., 1 to 4 carbon atoms or 1 to 3 carbon atoms, and may be substituted or unsubstituted. An alkyl group is unsubstituted unless the context indicates otherwise. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, isobutyl, and the like.

[0034] The term "alkenyl" or "alkenyl group" as used herein by itself or with another term(s) refers to a branched or unbranched hydrocarbon chain containing at least one double bond. Unless otherwise specified, an alkenyl group typically contains 2 to 6 carbon atoms, for example 2 to 4 carbon atoms, and may be substituted or unsubstituted. An alkenyl group is unsubstituted unless the context indicates otherwise. Representative examples include, but are not limited to, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl.

[0035] The term "amino-alkyl" or "amino-alkyl group" as used herein by itself or with another term(s) preferably refers to an alkyl group in which one hydrogen atom is replaced by a primary amino group (-NH). 1~6 Alkyl" and "Amino-C 1~6 The term "alkyl group" refers to an amino-alkyl group, where the alkyl group contains 1 to 6 carbon atoms. Representative examples include, but are not limited to, -CH2NH2, CH2CH2NH2, and -CH(CH3)NH2. An amino-alkyl group may be substituted or unsubstituted. An amino-alkyl group is unsubstituted unless the context indicates otherwise.

[0036] As used herein by itself or with another term(s), the term "(mono-alkylamino)-alkyl" or "(mono-alkylamino)-alkyl group" refers to an alkyl group in which preferably one hydrogen atom is replaced by an amino group (-NHR'), where the amino group has a single alkyl substituent (e.g., R'). 1~6 Alkylamino)C 1~6 The expression "mono-C alkyl" 1~6The term "alkylamino" refers to a single alkyl group on an amino group containing 1 to 6 carbon atoms. Representative examples include, but are not limited to, -CH2NH(CH3), -CH2NH(CH2CH3), and -CH2CH2NH(CH3). (mono-alkylamino)-alkyl groups may be substituted or unsubstituted. (mono-alkylamino)-alkyl groups are unsubstituted unless the context indicates otherwise.

[0037] As used herein by itself or with another term(s), the term "(di-alkylamino)-alkyl" or "(di-alkylamino)-alkyl group" refers to an alkyl group in which preferably one hydrogen atom is replaced by an amino group (-NR'), where the amino group has two alkyl substituents (e.g., each represented by R'). 1~6 Alkylamino)C 1~6 The expression "di-C alkyl" 1~6 The term "alkylamino" refers to two alkyl groups on an amino group, where each alkyl group independently contains 1 to 6 carbon atoms. Representative examples include, but are not limited to, -CH2N(CH3)2, -CH2N(CH2CH3)(CH3), and -CH2CH2N(CH3)2. (di-alkylamino)-alkyl groups may be substituted or unsubstituted. (di-alkylamino)-alkyl groups are unsubstituted unless the context indicates otherwise.

[0038] As used herein, by itself or with another term(s), the terms "alkoxy" and "alkoxy group" refer to an alkyl-oxy group, i.e., an alkyl group in which one hydrogen atom is replaced by an oxy group (-O-). Representative examples include, but are not limited to, OCH3, OCH2CH3, and OCH(CH3)2. An alkoxy group may be substituted or unsubstituted. An alkoxy group is unsubstituted unless the context indicates otherwise.

[0039] The term "aromatic" as used herein by itself or with another term(s) refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer. Aromatic should be understood to refer to and include ring systems containing only carbon atoms (i.e., "aryl"), and ring systems containing at least one heteroatom selected from N, O, or S (i.e., "heteroaromatic" or "heteroaryl"). Aromatic ring systems may be substituted or unsubstituted.

[0040] The term "non-aromatic" as used herein by itself or with another term(s) refers to a monocyclic or polycyclic ring system having at least one double bond that is saturated or not part of an extended conjugated π-system. As used herein, non-aromatic refers to and includes ring systems that contain only carbon atoms and ring systems that contain at least one heteroatom selected from N, O, or S. Non-aromatic ring systems may be substituted or unsubstituted.

[0041] As used herein, by itself or with another term(s), the term "aryl" or "aryl group" refers to phenyl and 6-10 membered bicyclic hydrocarbon ring systems (including fused ring systems) in which at least one of the rings is aromatic. Aryl groups may be substituted or unsubstituted. Unless otherwise specified, aryl groups may include ring systems containing 6 ring atoms (i.e., phenyl) or 6-10 atoms (e.g., 9 or 10 ring atoms). Representative examples include, but are not limited to, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. Preferably, the aryl group is phenyl or naphthyl, more preferably phenyl. Aryl groups may be substituted or unsubstituted. Aryl groups are unsubstituted unless the context indicates otherwise.

[0042] As used herein, by itself or with another term(s), the terms “halo,” “halo group,” “halogen,” and “halogen group” include fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I) atoms and fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I) substituents.

[0043] As used herein, by itself or with another term(s), the term "heteroaryl" or "heteroaryl group" means: (a) 5- and 6-membered monocyclic aromatic rings that contain, in addition to carbon atoms, at least one heteroatom, such as nitrogen, oxygen, or sulfur; and (b) refers to a 7-10 membered bicyclic ring containing at least one heteroatom, such as nitrogen, oxygen, or sulfur, in addition to carbon atoms, where at least one of the rings is aromatic. In some cases, a heteroaryl group can contain two or more heteroatoms, which can be the same or different. Heteroaryl groups can be substituted or unsubstituted and can be fused. In some cases, a heteroaryl group can contain 5, 6, or 8-10 ring atoms. In other cases, a heteroaryl group can contain 5-10 ring atoms, such as 5, 6, 9, or 10 ring atoms. Representative examples include 2,3-dihydrobenzofuranyl, 1,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzothiazinyl, chromanyl, furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl (e.g., 2-, 3-, or 4-pyridinyl), pyrimidinyl (e.g., 2-, 4-, or 5-pyrimidinyl), pyrazolyl, pyrrolyl (e.g., 2- or 3-pyrrolyl), pyrazinyl, pyridazinyl (e.g., 3- or 4-pyridazinyl, 2-pyrazinyl), thienyl (e.g., 2-thienyl, 3-thienyl). , tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl, pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indolizinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl, quinazolinyl, quinoxalinyl, isoindolyl, and isoquinolinyl.Heteroaryl is preferably a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O, or S. A heteroaryl group is unsubstituted unless the context indicates otherwise.

[0044] The terms "heterocycloalkyl" or "heterocycloalkyl group" as used herein by themselves or with another term(s) refer to a 3-10 membered monocyclic or bicyclic non-aromatic ring system that contains, in addition to carbon atoms, at least one heteroatom, such as nitrogen, oxygen, sulfur, or phosphorus. Heterocycloalkyl groups can be fully saturated or contain unsaturated moieties, and can also be bridged, spiro, and / or fused ring systems. In some cases, heterocycloalkyl groups can contain at least two (or) heteroatoms, which can be the same or different. Heterocycloalkyl groups can be substituted or unsubstituted. In some cases, heterocycloalkyl groups can contain 3-10 ring atoms or 3-7 ring atoms or 5-7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.Representative examples include tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, azetidinyl, azepanyl, dihydropyrazole ... These include, but are not limited to, zepanyl (e.g., 1,4-diazepanyl), oxazepanyl (e.g., 1,4-oxazepanyl), thiazepanyl (e.g., 1,4-thiazepanyl), tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-5-oxide, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 2,5-diaza-bicyclo[2.2.1]heptanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3,9-diaza-bicyclo[4.2.1]nonanyl, and 2,6-diaza-bicyclo[3.2.2]nonanyl. Heterocyclylalkyl groups as defined herein are preferably monocyclic, bicyclic, or spiro groups containing 1, 2, or 3 heteroatoms selected from N, O, or S. Heterocycloalkyl groups are unsubstituted unless the context indicates otherwise.

[0045] As used herein, either by itself or in conjunction with another term(s), the term "pharmaceutical acceptable" refers to a material that is generally chemically and / or physically compatible with other ingredients (e.g., with respect to a formulation, etc.) and / or generally physiologically compatible with its recipient (e.g., a subject, etc.).

[0046] The term "pharmaceutical composition," as used herein by itself or with another term(s), refers to a composition that can be used to treat a disease, condition, or disorder in a subject, including a human.

[0047] The terms "subject" and "patient," as used herein by themselves or in conjunction with another term(s), suitably refer to a mammal, particularly a human.

[0048] As used herein, by itself or with another term(s), the term "substituted" indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms, and the atom or group of atoms replacing the hydrogen atom is a "substituent." It should be understood that "substituent," "substituents," "moiety," "moieties," "group," or "groups" refer to substituents.

[0049] The terms "therapeutic" and "therapeutically effective amount," as used herein by themselves or with another term(s), refer to an amount of a compound, composition, or medicament that (a) inhibits or causes improvement in a particular disease, condition, or disorder; (b) attenuates, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder; (c) or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. It should be understood that the terms "therapeutic" and "therapeutically effective" encompass any one of the aforementioned effects (a)-(c), either alone or in combination with any of the other (a)-(c). For example, in humans or other mammals, it should be understood that a therapeutically effective amount can be determined empirically in a laboratory or clinical setting, or that a therapeutically effective amount can be the amount required by the guidelines of the U.S. Food and Drug Administration (FDA) or an equivalent foreign regulatory agency for a particular disease and subject to be treated. It should be understood that the determination of appropriate dosage forms, dosages, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.

[0050] As used herein, whether by themselves or with another term(s), the terms "treat", "treated" and "treatment" refer to and include preventative, ameliorative, palliative and curative uses and results. In some embodiments, the terms "treat", "treated" and "treatment" refer to curative uses and results as well as uses and results that alleviate or reduce the severity of a particular condition, characteristic, symptom, disorder or disease described herein. For example, treatment may include the alleviation of some symptoms of a condition or disorder or the complete eradication of said condition or disorder. It should be understood that the term "prophylactic" as used herein is not absolute, but rather refers to uses and results in which administration of a compound or composition reduces the likelihood or severity of a condition, symptom or condition and / or delays the onset of a condition, symptom or condition for a period of time.

[0051] As used herein, a "therapeutically active agent," whether used alone or with another term(s), refers to any compound, i.e., a drug, that is found to be useful in the treatment of a disease, disorder, or condition and is not described by Formula (1) or Formula (10). It should be understood that a therapeutically active agent may not have been approved by the FDA or an equivalent foreign regulatory agency.

[0052] "Therapeutically effective amount" means the amount of a compound that, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject or patient being treated. As used herein, the term "DHCR24-mediated disorder" refers to any disease, disorder, or other condition in which DHCR24 and / or desmosterol, preferably DCHR24, are known to play a role. In particular, the term "DHCR24-mediated disorder" includes any disease, disorder, or other condition that can be treated and / or prevented by inhibiting DHCR24. Inhibition of DHCR24 increases desmosterol, which activates liver X receptors, particularly liver X receptor alpha (LXRα). Thus, in some embodiments, the present disclosure relates to treating or reducing the severity of one or more diseases in which DHCR24 is known to play a role. Description of the invention

[0053] In general, the present invention relates to compounds of formula (1) or compounds of formula (10). [ka]

[0054] In formula (1) or formula (10), G is [ka] is a fused ring system selected from:

[0055] When G in formula (1) or formula (10) is a fused ring system represented by (G1), the compounds can be represented by formula (2-G1) or formula (20-G1), respectively. [ka]

[0056] When G in formula (1) or formula (10) is a fused ring system represented by (G2), the compounds can be represented by formula (2-G2) or formula (20-G2), respectively. [ka]

[0057] When G in formula (1) or formula (10) is a fused ring system represented by (G3), the compounds can be represented by formula (2-G3) or formula (20-G3), respectively. [ka]

[0058] When G is a fused ring system represented by (G1), B is [ka] is selected from.

[0059] When B is represented by formula (B1) and the compound is represented by formula (2-G1) or formula (20-G1), the compound can be represented by formula (2-B1) or formula (20-B1), respectively. [ka]

[0060] When B is represented by formula (B2) and the compound is represented by formula (2-G1) or formula (20-G1), the compound can be represented by formula (2-B2) or formula (20-B2), respectively. [ka]

[0061] When B is represented by formula (B3) and the compound is represented by formula (2-G1) or formula (20-G1), the compound can be represented by formula (2-B3) or formula (20-B3), respectively. [ka]

[0062] When B is represented by formula (B4) and the compound is represented by formula (2-G1) or formula (20-G1), the compound can be represented by formula (2-B4) or formula (20-B4), respectively. [ka]

[0063] When B is represented by formula (B5) and the compound is represented by formula (2-G1) or formula (20-G1), the compound can be represented by formula (2-B5) or formula (20-B5), respectively. [ka]

[0064] When B is represented by formula (B6) and the compound is represented by formula (2-G1) or formula (20-G1), the compound can be represented by formula (2-B6) or formula (20-B6), respectively. [ka]

[0065] When B is represented by formula (B7) and the compound is represented by formula (2-G1) or formula (20-G1), the compound can be represented by formula (2-B3) or formula (20-B3), respectively. [ka]

[0066] In the compound of formula (1), formula (10), or any of the above formulas, R 3 may be expressed by equation (2). [ka]

[0067] R 3 When represented by formula (2), the compound of formula (1) or formula (10) can be represented by formula (1-R3) or formula (10-R3), respectively. [ka]

[0068] The invention will now be further described by the following numbered paragraphs:

[0069] In a first aspect, the present invention provides a compound of formula (10) as hereinbefore and hereinafter defined, or a salt, solvate, hydrate or prodrug thereof. The salt is preferably a pharma-ceutically acceptable salt. 1. The compound of formula (10) [ka] where: G is [ka] is a fused ring system selected from: B is, [ka] Selected from; R 1 is hydrogen and -C(=O)R 6 Selected from; R 2 is hydrogen and C 1~6 alkyl; R 3 is a group represented by formula (2), -[C(R 7 )2] n -X, -CH=CR 6 R 7 , -CR 7 =NN(R 6 )2, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl are selected from -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more groups selected from alkoxy; [ka] n is an integer from 1 to 6; W is O and NR 6 Selected from; Y is selected from hydrogen and C2 alkenyl, wherein said C2 alkenyl is optionally substituted with one or more halo; X is selected from halo, -OH, -SH, -OZ, -SZ, -SSZ, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein said 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are selected from -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more groups selected from alkoxy; Each R 4 is hydrogen and C 1~6 independently selected from alkyl; R 5 is hydrogen and C 1~6 alkyl; Each R 6 is hydrogen and C 1~6 independently selected from alkyl; Each R 7 , H, C 1~6 Alkyl, and C 2~6 alkenyl, wherein 1~6 Alkyl and C 2~6 The alkenyl is optionally substituted with one or more halo; Z is C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 and optionally substituted with one or more groups selected from alkoxy. Prodrugs are typically esters, amides, hydrazones, or disulfides of the compounds of formula (10). 2. R 3 is a group represented by formula (2), -[C(R 7 )2] n -X, and -CH=CR 6 R 7 Selected from; The compound according to clause 1, wherein X is selected from halo and -OH. 3. Formula (10a): [ka] The compound according to item 1 or 2, represented by: 4. Formula (10b): [ka] The compound according to item 1 or 2, represented by: 5. Formula (10p): [ka] The compound according to item 1 or 2, represented by: 6. Formula (10q): [ka] The compound according to item 1 or 2, represented by: 7. Formula (10ap): [ka] The compound according to any one of items 1 to 3 or 5, wherein the compound is represented by: 8. Formula (10aq): [ka] The compound according to any one of items 1 to 3 or 6, wherein the compound is represented by: 9. Formula (10bp): [ka] The compound according to any one of items 1, 2, 4, or 5, represented by: 10. Formula (10bq): [ka] The compound according to any one of items 1, 2, 4, or 6, represented by: 11. R 1 The compound according to any one of items 1 to 10, wherein is hydrogen. 12. R 1 But -C(=O)R 6 The compound according to any one of items 1 to 10, wherein 13. R 1 -C(=O)R 6 When R 6 But, C 1~6 is alkyl (e.g., R 1 But -C(=O)-C 1~6 13. The compound according to any one of items 1 to 12, wherein R is an alkyl group. 14. The above R 6is methyl or ethyl (e.g., R 1 is -C(=O)Me or -C(=O)Et), 15. The above R 6 is methyl (e.g., R 1 is -C(=O)-Me), the compound according to item 14. 16. G. [ka] Item 16. The compound according to any one of items 1 to 15, wherein 17. G. [ka] Item 17. The compound according to item 16, wherein 18. R 5 is selected from hydrogen, methyl, and ethyl. 19. R 5 is selected from hydrogen and methyl. 20. R 5 20. The compound according to any one of claims 1 to 19, wherein is hydrogen. 21. R 5 20. The compound according to any one of items 1 to 19, wherein is methyl. 22. Each R 4 is independently selected from hydrogen, methyl, and ethyl. 23. Each R 4 is independently selected from hydrogen and methyl. 24. At least one R 4 24. The compound according to any one of claims 1 to 23, wherein is hydrogen. 25. At least one R 4 25. The compound according to any one of items 1 to 24, wherein is methyl. 26. Both R's 4 25. The compound according to any one of claims 1 to 24, wherein is hydrogen. 27. Both R's 4 24. The compound according to any one of items 1 to 23, wherein is methyl. 28. B: [ka] 28. The compound according to any one of claims 1 to 27, selected from: 29. B [ka] 29. The compound according to any one of claims 1 to 28, wherein 30. B [ka] 29. The compound according to any one of claims 1 to 28, wherein 31. R 2 The compound according to any one of the preceding claims, wherein is hydrogen. 32. R 3 But equation (2): [ka] Item 32. The compound according to any one of items 1 to 31, wherein the compound is a group represented by: 33. R 3 is a group represented by formula (2), each R 6 is independently selected from hydrogen, methyl, and ethyl. 34. R 3 is a group represented by formula (2), at least one R 6 The compound according to any one of the preceding claims, wherein is hydrogen. 35. R 3 But equation (2a): [ka] Item 35. The compound according to any one of items 1 to 34, wherein the compound is a group represented by: 36. R 3is a group represented by formula (2) or formula (2a), and W is NR 6 When R 6 is selected from hydrogen, methyl, and ethyl (eg, W is selected from NH, NMe, and NEt). 37. The above R 6 is selected from hydrogen and methyl (e.g., W is selected from NH and NMe). 38. The above R 6 is hydrogen (eg, W is NH). 39. The above R 6 is methyl (eg, W is NMe). 40. R 3 The compound according to any one of the preceding claims, wherein when is a group represented by formula (2) or formula (2a), Y is selected from hydrogen, C2 alkenyl, and halo-C2 alkenyl, wherein the halo-C2 alkenyl is C2 alkenyl substituted with one or more halo. 41. The compound according to item 40, wherein the halo-C2 alkenyl is a C2 alkenyl substituted with one, two, or three halo. 42. The compound according to item 41, wherein the halo-C2 alkenyl is a C2 alkenyl substituted with one halo. 43. The compound according to any one of clauses 40 to 42, wherein each of the halo of the halo-C2 alkenyl is independently selected from chloro (-Cl), bromo (-Br), and fluoro (-F). 44. The compound according to item 43, wherein the halo of the halo-C2 alkenyl is fluoro (-F). 45. The compound according to paragraph 40, wherein Y is hydrogen. 46. ​​The compound according to item 40, wherein Y is C2 alkenyl. 47. The compound according to paragraph 40, wherein Y is halo-C2 alkenyl (eg, Y is C2 alkenyl substituted with one or more halo groups). 48. R 3 But -[C(R 7 )2] n -X. 49. R 3 -[C(R 7 )2] n -X, then each R 7 But hydrogen, C 1~6 Alkyl, halo-C 1~6 Alkyl, C 2~6 Alkenyl, and halo-C 2~6 The compound according to any one of claims 1 to 31 or 48, wherein the halo-C is independently selected from the group consisting of halo-C 1~6 Alkyl is a C substituted with one or more halo. 1~6 The halo-C 2~6 Alkenyl is a C substituted with one or more halo. 2~6 It is alkenyl. 50. The above-mentioned Halo-C 1~6 C alkyl substituted with 1, 2 or 3 halo 1~6 50. The compound according to item 49, wherein the aryl group is alkyl. 51. The above-mentioned Halo-C 1~6 Alkyl substituted with one halo 1~6 51. The compound according to item 50, wherein the aryl group is alkyl. 52. The above-mentioned Halo-C 2~6 Alkenyl is substituted with 1, 2, or 3 halo. 2~6 50. The compound according to claim 49, wherein the compound is alkenyl. 53. The above-mentioned Halo-C 2~6 Alkenyl is C substituted with 1 halo 2~6 53. The compound according to claim 52, wherein the compound is alkenyl. 54. The above-mentioned Halo-C 1~6 Alkyl and the halo-C 2~6 54. The compound according to any one of clauses 49 to 53, wherein each of said halos of alkenyl is independently selected from chloro (-Cl), bromo (-Br), and fluoro (-F). 55. The above-mentioned Halo-C 1~6 Alkyl and the halo-C 2~6Item 55. The compound according to item 54, wherein said halo of alkenyl is fluoro (-F). 56. R 3 -[C(R 7 )2] n -X, then each R 7 But hydrogen, C 1~6 Alkyl, and C 2~6 The compound according to any one of claims 1 to 55, wherein the C is independently selected from the group consisting of aryl, aryl, aryl, aryl and alkenyl. 1~6 The alkyl is unsubstituted. 2~6 The alkenyl is unsubstituted. 57. R 3 -[C(R 7 )2] n -X, at least one R on each carbon atom 7 is hydrogen, and the other R on each carbon atom 7 But hydrogen, C 1~6 Alkyl, halo-C 1~6 Alkyl, C 2~6 Alkenyl, and halo-C 2~6 alkenyl (e.g., R 3 But -[CHR 7 ] n -X), the compound according to any one of items 1 to 55. 58. R 3 -[C(R 7 )2] n -X, at least one R on each carbon atom 7 is hydrogen, and the other R on each carbon atom 7 But hydrogen, C 1~6 Alkyl, and C 2~6 58. The compound according to clause 57, selected from alkenyl. 59. R 3 -[C(R 7 )2] n -X, at least one R on each carbon atom 7 is hydrogen and at least one R 7 But, C 1~6 Alkyl and C 2~6 59. The compound according to clause 58, selected from alkenyl. 60. R 3-[C(R 7 )2] n -X, at least one R on each carbon atom 7 is hydrogen, and other R 7 One of them is C. 2~6 Item 60. The compound according to item 59, wherein the compound is alkenyl. 61. R 3 -[C(R 7 )2] n -X, then all R 7 is hydrogen (e.g., R 3 But -[CH2] n -X), the compound according to any one of items 1 to 55. 62. R 3 -[C(R 7 )2] n The compound according to any one of clauses 1 to 61, wherein when -X, X is selected from halo and -OH. Preferably, X is selected from fluoro (-F) and -OH. 63. R 3 -[C(R 7 )2] n 62. The compound according to any one of the preceding paragraphs, wherein -X, when X is halo, then X is chloro (-Cl), bromo (-Br), or fluoro (-F). 64. The compound according to paragraph 63, wherein X is fluoro (-F). 65. The compound according to any one of clauses 1 to 31 or 48 to 62, wherein X is -OH. 66. The compound according to any one of paragraphs 1 to 31 or 48 to 61, wherein X is -SH. 67. R 3 -[C(R 7 )2] n -X, where X is -OZ, -SZ, or -SSZ, Z is C 6~10 The compound according to any one of items 1 to 31 or 48 to 61, wherein the 5-10 membered heteroaryl and the 5-10 membered heterocycloalkyl each contain at least one nitrogen atom. 68. R 3 -[C(R 7 )2] n -X, where X is -OZ, -SZ, or -SSZ, Z is C 6~10 70. The compound according to any one of items 1 to 31, 48 to 61, or 67, wherein the aryl is selected from aryl and 5- to 10-membered heteroaryl. 69. R 3 -[C(R 7 )2] n 70. The compound of any one of paragraphs 1 to 31, 48 to 61, 67, or 68, wherein -X, where X is -OZ, -SZ, or -SSZ, Z is selected from phenyl and 5-, 6-, 9-, or 10-membered heteroaryl. 70. R 3 -[C(R 7 )2] n The compound of any one of paragraphs 1 to 31, 48 to 61, or 67 to 69, wherein -X, where X is -OZ, -SZ, or -SSZ, Z is selected from phenyl and 6- or 9-membered heteroaryl. 71. R 3 -[C(R 7 )2] n The compound of any one of paragraphs 1 to 31, 48 to 61, or 67 to 70, wherein -X, where X is -OZ, -SZ, or -SSZ, then Z is selected from phenyl, pyridinyl, and benzothiazolyl. 72. Z is C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, 6~10 Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are each independently selected from the group consisting of -OH, chloro, bromo, fluoro, -NH2, C 1~6 Alkyl, and C 1~6 The compound according to any one of clauses 1 to 31, 48 to 61, or 67 to 71, optionally substituted with one or more groups selected from alkoxy. 73. Said C 6~10Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, -NH2, C 1~6 Alkyl, and C 1~6 73. The compound according to clause 72, optionally substituted with one or more groups selected from alkoxy. 74. Said C 6~10 74. The compound according to item 73, wherein the aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more groups selected from -OH and -NH2. 75. The compound of any one of paragraphs 1 to 31, 48 to 61, or 67 to 74, wherein X is -OZ, -SZ, or -SSZ. 76. The compound according to paragraph 75, wherein X is -OZ. 77. The compound according to paragraph 75, wherein X is -SZ. 78. The compound according to paragraph 75, wherein X is -SSZ. 79. R 3 -[C(R 7 )2] n When -X, X is selected from 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl are -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 62. The compound according to any one of clauses 1 to 31 or 48 to 61, optionally substituted with one or more groups selected from alkoxy. 80. The compound according to item 79, wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl each contain at least one nitrogen atom. 81. The compound according to item 80, wherein X is a 5- to 10-membered heteroaryl. 82. The compound according to paragraph 81, wherein X is a 5-, 6-, 9-, or 10-membered heteroaryl. 83. The compound according to paragraph 82, wherein X is a 5- or 6-membered heteroaryl. 84. The compound according to paragraph 83, wherein X is triazolyl. 85. When X is selected from 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl, the 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl are each independently selected from -OH, chloro, bromo, fluoro, -NH2, C 1~6 Alkyl, and C 1~6 The compound according to any one of clauses 1 to 31, 48 to 61, or 79 to 84, optionally substituted with one or more groups selected from alkoxy. 86. The 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are -OH, -NH2, C 1~6 Alkyl, and C 1~6 86. The compound according to clause 85, optionally substituted with one or more groups selected from alkoxy. 87. The compound according to paragraph 86, wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more groups selected from -OH and -NH2. 88. R 3 But -CH=CR 6 R 7 Item 32. The compound according to any one of items 1 to 31, wherein 89. The above R 6 is H (e.g., R 3 But -CH=CHR 7 Item 88. The compound according to item 88, wherein 90. R 7 But hydrogen, C 1~6 Alkyl, halo-C 1~6 Alkyl, C 2~6 Alkenyl, and halo-C 2~6 89. The compound according to claim 88 or 89, wherein the halo-C is selected from the group consisting of halo-C 1~6 Alkyl is a C substituted with one or more halo. 1~6 The halo-C 2~6 Alkenyl is a C substituted with one or more halo. 2~6 It is alkenyl. 91. The above-mentioned Halo-C1~6 C alkyl substituted with 1, 2 or 3 halo 1~6 91. The compound according to claim 90, wherein said compound is alkyl. 92. The above-mentioned Halo-C 1~6 Alkyl substituted with one halo 1~6 92. The compound according to item 91, wherein the aryl group is alkyl. 93. The above-mentioned Halo-C 2~6 Alkenyl is substituted with 1, 2, or 3 halo. 2~6 93. The compound according to any one of clauses 90 to 92, which is alkenyl. 94. The above-mentioned Halo-C 2~6 Alkenyl is C substituted with 1 halo 2~6 94. The compound according to claim 93, which is alkenyl. 95. The above-mentioned Halo-C 1~6 Alkyl and the halo-C 2~6 95. The compound according to any one of clauses 90 to 94, wherein each of said halos of alkenyl is independently selected from chloro (-Cl), bromo (-Br), and fluoro (-F). 96. The above-mentioned Halo-C 1~6 Alkyl and the halo-C 2~6 Item 96. The compound according to item 95, wherein said halo of alkenyl is fluoro (-F). 97. R 7 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, and halo-C 2~6 97. The compound according to any one of clauses 90 to 96, wherein said compound is selected from the group consisting of alkenyl. 98. R 7 But, Halo-C 2~6 98. The compound according to claim 97, which is alkenyl. 99. R 3 But -CR 7 =NN(R 6 32. The compound according to any one of items 1 to 31, wherein R is 0, R is 1, R is 2, and R is 3. 100. The above R 7 But H and C 1~6 99. The compound according to claim 99, wherein said alkyl is selected from the group consisting of aryl, aryl, aryl and alkyl. 101. The above R 7is H. 102. Both of the above R 6 is hydrogen (e.g., R 3 But -CR 7 ═N—NH2), the compound according to any one of items 99 to 101. 103. R 3 is selected from 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl each contain at least one nitrogen atom. 104. R 3 is selected from 5, 6, 9, or 10 membered heteroaryl and 5, 6, 9, or 10 membered heterocycloalkyl. 105. R 3 is selected from 5- or 6-membered heteroaryl and 5- or 6-membered heterocycloalkyl. 107. R 3 is 5- or 6-membered heterocycloalkyl. 108. R 3 Item 108. The compound according to item 107, wherein is imidazolinyl. 109. R 3 is selected from 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl, the 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl being selected from -OH, -NH2, C 1~6 Alkyl, and C 1~6 109. The compound according to any one of clauses 1 to 31 or 103 to 108, optionally substituted with one or more groups selected from alkoxy. 110. The compound according to paragraph 109, wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more groups selected from -OH and -NH2. 111. Each n is independently an integer selected from 1, 2, 3, 4, and 5 (e.g., R 3is a group represented by formula (2) or formula (2a), or -[C(R 7 )2] n -X), the compound according to any one of items 1 to 110. 112. The compound according to paragraph 111, wherein each n is independently an integer selected from 1, 2, and 3. 113. The compound according to paragraph 112, wherein n is 1 (eg, when X is -OH). 114. The compound according to paragraph 112, wherein n is 3 (eg, when X is -OH). 115. n is 2 (e.g., R 3 is formula (2), the compound according to item 112. 116. A compound of formula (10): [ka] [ka] 116. The compound according to any one of claims 1 to 115, wherein the compound is not one of: 117. [ka] [ka] [ka] [ka] 117. The compound according to any one of claims 1 to 116, selected from: 118. [ka] [ka] 118. The compound according to any one of claims 1 to 117, selected from:

[0070] The present invention also provides a compound of formula (10) as defined in paragraphs 1 to 118 above, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in treating or preventing a DHCR24-mediated disorder. This aspect of the invention also provides a method of treating or preventing a DHCR24-mediated disorder. The method comprises administering to a subject a compound of formula (10) or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0071] A second aspect of the invention described herein relates to a compound of formula (1) or a salt, solvate, hydrate or prodrug thereof, wherein said salt is preferably a pharma- ceutically acceptable salt. 2.1. In a second aspect of the invention, the compound of formula (1) [ka] where: G is [ka] is a fused ring system selected from: B is, [ka] Selected from; R 1 is hydrogen, -C(=O)R 6 , and C 1~6 alkyl; R 2 is hydrogen and C 1~6 alkyl; R 3 is a group represented by formula (2), -[C(R 7 )2] n -X, -C(=O)NHOR 8 , -C(=O)OR 8 , -CR 7 =NN(R 6 )2, -CH=CR 6 R 7 , C 6~10aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more groups selected from alkoxy; [ka] n is an integer from 1 to 6; W is O, S, and NR 6 Selected from; Y is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, Amino-C 1~6 Alkyl, (mono-C 1~6 Alkylamino)C 1~6 Alkyl, and (di-C 1~6 Alkylamino)C 1~6 alkyl, wherein said C 1~6 Alkyl and C 2~6 The alkenyl is optionally substituted with one or more halo; X is halo, -OH, -SH, -N(R 6 )2, -OZ, -SZ, -SSZ, -C(=O)R 7 , C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 optionally substituted with one or more groups selected from alkoxy; Each R 4 is hydrogen and C 1~6 independently selected from alkyl; R 5 is hydrogen and C 1~6 alkyl; Each R 6 is hydrogen and C 1~6 independently selected from alkyl; Each R 7 , H, C 1~6 Alkyl, and C 2~6 alkenyl, wherein 1~6 Alkyl and C 2~6 The alkenyl is optionally substituted with one or more halo; R 8 is C 1~6 Alkyl and C 2~6 alkenyl; Z is C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 and optionally substituted with one or more groups selected from alkoxy. 2.2. Formula (1a): [ka] The compound according to item 2.1, represented by: 2.3. Formula (1b): [ka] The compound according to item 2.1, represented by: 2.4. Formula (1p): [ka] The compound according to item 2.1, represented by: 2.5. Formula (1q): [ka] The compound according to item 2.1, represented by: 2.6. Formula (1ap): [ka] The compound according to any one of paragraphs 2.1, 2.2, or 2.4, wherein the compound is represented by: 2.7. Equation (1aq): [ka] The compound according to any one of paragraphs 2.1, 2.2, or 2.5, represented by: 2.8. Formula (1bp): [ka] The compound according to any one of paragraphs 2.1, 2.3, or 2.4, wherein the compound is represented by: 2.9. Formula (1bq): [ka] The compound according to any one of paragraphs 2.1, 2.3, or 2.5, represented by: 2.10. R 1 is hydrogen or -C(=O)R 6 The compound according to any one of paragraphs 2.1 to 2.9, wherein 2.11. R 1 The compound according to any one of paragraphs 2.1 to 2.10, wherein is hydrogen. 2.12. R 1 But -C(=O)R 6 The compound according to any one of paragraphs 2.1 to 2.10, wherein 2.13. R 1 -C(=O)R 6 When R 6 But, C 1~6 is alkyl (e.g., R 6 But -C(=O)-C 1~6 alkyl), a compound according to any one of items 2.1 to 2.12. 2.14. R 6 is methyl or ethyl (e.g., R 1is -C(=O)Me or -C(=O)Et), the compound according to item 2.13. 2.15. R 6 is methyl (e.g., R 1 is -C(=O)-Me), the compound described in item 2.14. 2.16. G, [ka] The compound according to any one of paragraphs 2.1 to 2.15, wherein 2.17. G, [ka] The compound according to item 2.16, wherein 2.18. R 5 The compound according to any one of paragraphs 2.1 to 2.17, wherein is selected from hydrogen, methyl, and ethyl. 2.19. R 5 is selected from hydrogen and methyl. 2.20. R 5 The compound according to any one of paragraphs 2.1 to 2.19, wherein is hydrogen. 2.21. R 5 The compound according to any one of paragraphs 2.1 to 2.19, wherein is methyl. 2.22. Each R 4 is independently selected from hydrogen, methyl, and ethyl. 2.23. Each R 4 is independently selected from hydrogen and methyl. 2.24. At least one R 4 The compound according to any one of paragraphs 2.1 to 2.23, wherein is hydrogen. 2.25. At least one R 4 The compound according to any one of paragraphs 2.1 to 2.24, wherein is methyl. 2.26. Both R 4The compound according to any one of paragraphs 2.1 to 2.24, wherein is hydrogen. 2.27. Both R 4 The compound according to any one of paragraphs 2.1 to 2.23, wherein is methyl. 2.28. B: [ka] The compound according to any one of paragraphs 2.1 to 2.27, selected from: 2.29. B: [ka] The compound according to any one of paragraphs 2.1 to 2.28, wherein 2.30. B: [ka] The compound according to any one of paragraphs 2.1 to 2.28, wherein 2.31. B: [ka] The compound according to any one of paragraphs 2.1 to 2.28, wherein 2.32. R 2 The compound according to any one of paragraphs 2.1 to 2.31, wherein is hydrogen. 2.33. R 3 But equation (2): [ka] The compound according to any one of items 2.1 to 2.32, wherein the compound is a group represented by: 2.34. R 3 is a group represented by formula (2), each R 6 is independently selected from hydrogen, methyl, and ethyl. 2.35. R 3 is a group represented by formula (2), at least one R 6The compound according to any one of paragraphs 2.1 to 2.34, wherein is hydrogen. 2.36. R 3 But equation (2a): [ka] The compound according to any one of items 2.1 to 2.35, wherein the compound is a group represented by: 2.37. R 3 is a group represented by formula (2) or formula (2a), and W is NR 6 When R 6 The compound according to any one of paragraphs 2.1 to 2.36, wherein W is selected from hydrogen, methyl, and ethyl (e.g., W is selected from NH, NMe, and NEt). 2.38. The above R 6 is selected from hydrogen and methyl (e.g., W is selected from NH and NMe). 2.39. The above R 6 is hydrogen (eg, W is NH). 2.40. The above R 6 is methyl (eg, W is NMe). 2.41. R 3 is a group represented by formula (2) or formula (2a), Y is hydrogen, C 1~6 Alkyl, halo-C 1~6 Alkyl, C 2~6 Alkenyl, Halo-C 2~6 Alkenyl, Amino-C 1~6 Alkyl, (mono-C 1~6 Alkylamino)C 1~6 Alkyl, and (di-C 1~6 Alkylamino)C 1~6 The compound according to any one of paragraphs 2.1 to 2.40, wherein the halo-C is selected from the group consisting of alkyl, aryl ... 1~6 Alkyl is a C substituted with one or more halo. 1~6 The halo-C 2~6Alkenyl is a C substituted with one or more halo. 2~6 It is alkenyl. 2.42. The halo-C 1~6 C alkyl substituted with 1, 2 or 3 halo 1~6 The compound according to paragraph 2.41, wherein the compound is alkyl. 2.43. The halo-C 1~6 Alkyl substituted with one halo 1~6 The compound according to paragraph 2.42, wherein the compound is alkyl. 2.44. The halo-C 2~6 Alkenyl is substituted with 1, 2, or 3 halo. 2~6 The compound according to any one of paragraphs 2.41 to 2.43, which is alkenyl. 2.45. The halo-C 2~6 Alkenyl is C substituted with 1 halo 2~6 The compound according to paragraph 2.44, which is alkenyl. 2.46. The halo-C 1~6 Alkyl and the halo-C 2~6 The compound according to any one of paragraphs 2.41 to 2.45, wherein each halo of the alkenyl is independently selected from chloro (-Cl), bromo (-Br), and fluoro (-F). 2.47. The halo-C 1~6 Alkyl and the halo-C 2~6 The compound according to item 2.46, wherein the halo of alkenyl is fluoro (-F). 2.48.R 3 is a group represented by formula (2) or formula (2a), Y is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, Halo-C 2~6 Alkenyl, Amino-C 1~6 Alkyl, (mono-C 1~6 Alkylamino)C 1~6 Alkyl, and (di-C 1~6 Alkylamino)C 1~6 The compound according to any one of paragraphs 2.41 to 2.47, wherein the compound is selected from alkyl. 2.49. The compound according to any one of paragraphs 2.41 to 2.48, wherein Y is hydrogen. 2.50. Y is C 1~6 The compound according to any one of paragraphs 2.41 to 2.48, wherein the compound is alkyl. 2.51. Y is C 1~3 The compound according to paragraph 2.50, wherein the compound is alkyl. 2.52. Y is C 2~6 The compound according to any one of paragraphs 2.41 to 2.48, which is alkenyl. 2.53. Y is C 2~4 The compound according to item 2.52, which is alkenyl. 2.54. Y is halo-C 2~6 alkenyl (e.g., Y is C substituted with one or more halo groups). 2~6 alkenyl), a compound according to any one of items 2.41 to 2.48. 2.55. Y is halo-C 2~4 The compound according to item 2.54, wherein the compound is alkenyl. 2.56. Y is amino-C 1~6 Alkyl, (mono-C 1~6 Alkylamino)C 1~6 Alkyl, and (di-C 1~6 Alkylamino)C 1~6 The compound according to any one of paragraphs 2.41 to 2.48, wherein the compound is selected from alkyl. 2.57. Y is amino-C 1~3 Alkyl, (mono-C 1~3 Alkylamino)C 1~3 Alkyl, and (di-C 1~3 Alkylamino)C 1~3 The compound according to paragraph 2.56, wherein the aryl group is selected from alkyl. 2.58.R 3 The compound according to any one of paragraphs 2.1 to 2.36 or 2.41 to 2.57, wherein W is S when is a group represented by formula (2) or formula (2a). 2.59. Y is hydrogen or C 1~6 The compound according to item 2.58, wherein the compound is alkyl. 2.60.R3 is a group represented by formula (3) or formula (3a), W is O or NR 6 The compound according to any one of paragraphs 2.1 to 2.57, wherein 2.61. R 3 The compound according to item 2.60, wherein W is O when is a group represented by formula (3) or formula (3a). 2.62. R 3 is a group represented by formula (3) or formula (3a), W is NR 6 The compound according to paragraph 2.60, wherein 2.63. R 3 But -[C(R 7 )2] n -X. 2.64.R 3 -[C(R 7 )2] n -X, then each R 7 But hydrogen, C 1~6 Alkyl, halo-C 1~6 Alkyl, C 2~6 Alkenyl, and halo-C 2~6 The compound according to any one of paragraphs 2.1 to 2.32 or 2.63, wherein the halo-C is independently selected from the group consisting of halo-C 1~6 Alkyl is a C substituted with one or more halo. 1~6 The halo-C 2~6 Alkenyl is a C substituted with one or more halo. 2~6 It is alkenyl. 2.65. The halo-C 1~6 C alkyl substituted with 1, 2 or 3 halo 1~6 The compound according to paragraph 2.64, wherein the compound is alkyl. 2.66. The halo-C 1~6 Alkyl substituted with one halo 1~6 The compound according to paragraph 2.65, wherein the compound is alkyl. 2.67. The halo-C 2~6 Alkenyl is substituted with 1, 2, or 3 halo. 2~6The compound according to any one of paragraphs 2.64 to 2.66, wherein the compound is alkenyl. 2.68. The halo-C 2~6 Alkenyl is C substituted with 1 halo 2~6 The compound according to paragraph 2.67, which is alkenyl. 2.69. The halo-C 1~6 Alkyl and the halo-C 2~6 The compound according to any one of paragraphs 2.64 to 2.68, wherein each halo of the alkenyl is independently selected from chloro (-Cl), bromo (-Br), and fluoro (-F). 2.70. The halo-C 1~6 Alkyl and the halo-C 2~6 The compound according to item 2.69, wherein the halo of alkenyl is fluoro (-F). 2.71. R 3 -[C(R 7 )2] n -X, then each R 7 But hydrogen, C 1~6 Alkyl, and C 2~6 The compound according to any one of paragraphs 2.1 to 2.32, 2.63, or 2.64, wherein the C is independently selected from the group consisting of aryl, ... 1~6 The alkyl is unsubstituted. 2~6 The alkenyl is unsubstituted. 2.72. R 3 -[C(R 7 )2] n -X, at least one R on each carbon atom 7 is hydrogen, and the other R on each carbon atom 7 But hydrogen, C 1~6 Alkyl, halo-C 1~6 Alkyl, C 2~6 Alkenyl, and halo-C 2~6 alkenyl (e.g., R 3 But -[CHR 7 ] n -X), a compound according to any one of items 2.1 to 2.32 or 2.63 to 2.71. 2.73. R 3 -[C(R7 )2] n -X, at least one R on each carbon atom 7 is hydrogen, and the other R on each carbon atom 7 But hydrogen, C 1~6 Alkyl, and C 2~6 The compound according to paragraph 2.72, selected from alkenyl. 2.74. R 3 -[C(R 7 )2] n -X, at least one R on each carbon atom 7 is hydrogen and at least one R 7 But, C 1~6 Alkyl and C 2~6 The compound according to paragraph 2.73, selected from alkenyl. 2.75.R 3 -[C(R 7 )2] n -X, at least one R on each carbon atom 7 is hydrogen, and other R 7 One of them is C. 2~6 The compound according to paragraph 2.74, which is alkenyl. 2.76.R 3 -[C(R 7 )2] n -X, then all R 7 is hydrogen (e.g., R 3 But -[CH2] n -X), a compound according to any one of items 2.1 to 2.32 or 2.63 to 2.73. 2.77.R 3 -[C(R 7 )2] n The compound according to any one of paragraphs 2.1 to 2.32 or 2.63 to 2.76, wherein when X is halo, X is chloro (-Cl), bromo (-Br), or fluoro (-F). 2.78. The compound according to paragraph 2.77, wherein X is fluoro (-F). 2.79. The compound according to any one of paragraphs 2.1 to 2.32 or 2.63 to 2.76, wherein X is -OH. 2.80. The compound according to any one of paragraphs 2.1 to 2.32 or 2.63 to 2.76, wherein X is -SH. 2.81. R 3 -[C(R 7 )2] n -X, where X is -N(R 6 )2, then each R 6 But hydrogen and C 1~3 The compound according to any one of paragraphs 2.1 to 2.32 or 2.63 to 2.76, wherein: 2.82. R 3 -[C(R 7 )2] n -X, where X is -N(R 6 )2, then at least one R 6 is hydrogen, and other R 6 But hydrogen and C 1~6 alkyl (e.g., X is -NHR 6 2.81), a compound according to any one of paragraphs 2.1 to 2.32, 2.63 to 2.76, or 2.81. 2.83. Both R 6 is hydrogen (eg, X is -NH2). 2.84. X is -N(R 6 2.) The compound according to any one of paragraphs 2.1 to 2.32, 2.63 to 2.76, or 2.81 to 2.83, wherein 2.85.R 3 -[C(R 7 )2] n -X, where X is -OZ, -SZ, or -SSZ, Z is C 6~10 The compound according to any one of paragraphs 2.1 to 2.32 or 2.63 to 2.76, wherein the aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl each contain at least one nitrogen atom. 2.86.R 3 -[C(R 7 )2]n -X, where X is -OZ, -SZ, or -SSZ, Z is C 6~10 The compound according to any one of paragraphs 2.1 to 2.32, 2.63 to 2.76, or 2.85, wherein the compound is selected from aryl and 5-10 membered heteroaryl. 2.87.R 3 -[C(R 7 )2] n The compound according to any one of paragraphs 2.1 to 2.32, 2.63 to 2.76, 2.85, or 2.86, wherein -X, where X is -OZ, -SZ, or -SSZ, Z is selected from phenyl and 5-, 6-, 9-, or 10-membered heteroaryl. 2.88.R 3 -[C(R 7 )2] n The compound according to any one of paragraphs 2.1 to 2.32, 2.63 to 2.76, or 2.85 to 2.87, wherein -X, where X is -OZ, -SZ, or -SSZ, then Z is selected from phenyl and 6- or 9-membered heteroaryl. 2.89.R 3 -[C(R 7 )2] n The compound according to any one of paragraphs 2.1 to 2.32, 2.63 to 2.76, or 2.85 to 2.88, wherein -X, where X is -OZ, -SZ, or -SSZ, then Z is selected from phenyl, pyridinyl, and benzothiazolyl. 2.90. Z is C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, 6~10 Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are each independently selected from the group consisting of -OH, chloro, bromo, fluoro, -NH2, C 1~6 Alkyl, and C 1~6 The compound according to any one of paragraphs 2.1 to 2.32, 2.63 to 2.76, or 2.85 to 2.89, optionally substituted with one or more groups selected from alkoxy. 2.91. Said C 6~10Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, -NH2, C 1~6 Alkyl, and C 1~6 The compound according to paragraph 2.90, optionally substituted with one or more groups selected from alkoxy. 2.92. Said C 6~10 The compound according to paragraph 2.91, wherein the aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are optionally substituted with one or more groups selected from -OH and -NH2. 2.93. The compound according to any one of paragraphs 2.1 to 2.32, 2.63 to 2.76, or 2.85 to 2.92, wherein X is -OZ, -SZ, or -SSZ. 2.94. The compound according to paragraph 2.93, wherein X is -OZ. 2.95. The compound according to paragraph 2.93, wherein X is -SZ. 2.96. The compound according to paragraph 2.93, wherein X is -SSZ. 2.97. X is -C(=O)R 7 The compound according to any one of paragraphs 2.1 to 2.32 or 2.63 to 2.76, 2.98.R 3 -[C(R 7 )2] n -X, where X is C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, 6~10 Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are each independently selected from the group consisting of -OH, halo, -CN, -NH2, -NO2, C 1~6 Alkyl, and C 1~6 The compound according to any one of paragraphs 2.1 to 2.32 or 2.63 to 2.76, optionally substituted with one or more groups selected from alkoxy. 2.99. X is C 6~10The compound according to paragraph 2.98, wherein the aryl is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl each contain at least one nitrogen atom. 2.100. X is C 6~10 The compound according to item 2.99, wherein the aryl is selected from aryl and 5-10 membered heteroaryl. 2.101. The compound according to paragraph 2.100, wherein X is selected from phenyl and 5-, 6-, 9-, or 10-membered heteroaryl. 2.102. The compound according to paragraph 2.101, wherein X is a 5- or 6-membered heteroaryl. 2.103. The compound according to paragraph 2.102, wherein X is triazolyl. 2.104. X is C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein 6~10 Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are each independently selected from the group consisting of -OH, chloro, bromo, fluoro, -NH2, C 1~6 Alkyl, and C 1~6 The compound according to any one of paragraphs 2.1 to 2.32, 2.63 to 2.76, or 2.98 to 2.103, optionally substituted with one or more groups selected from alkoxy. 2.105. Said C 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, -NH2, C 1~6 Alkyl, and C 1~6 The compound according to paragraph 2.104, optionally substituted with one or more groups selected from alkoxy. 2.106. Said C 6~10 The compound according to paragraph 2.105, wherein the aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are optionally substituted with one or more groups selected from -OH and -NH2. 2.107.R 3 But -C(=O)NHOR8 The compound according to any one of paragraphs 2.1 to 2.32, wherein 2.108. The above R 8 But, C 1~6 The compound according to paragraph 2.107, wherein the compound is alkyl. 2.109. The above R 8 But, C 1~3 The compound according to paragraph 2.108, wherein the compound is alkyl. 2.110.R 3 But -C(=O)OR 8 The compound according to any one of paragraphs 2.1 to 2.32, wherein 2.111.R 8 But, C 2~6 The compound according to paragraph 2.110, which is alkenyl. 2.112.R 3 But -CR 7 =NN(R 6 2.) The compound according to any one of items 2.1 to 2.32, wherein 2.113. The above R 7 But H and C 1~6 The compound according to paragraph 2.112, wherein the alkyl is selected from the group consisting of aryl, aryl, aryl and alkyl. 2.114. R 7 The compound according to paragraph 2.113, wherein is H. 2.115. Both of the above R 6 is hydrogen (e.g., R 3 But -CR 7 =N-NH2), a compound according to any one of items 2.112 to 2.114. 2.116.R 3 But -CH=CR 6 R 7 The compound according to any one of paragraphs 2.1 to 2.32, wherein 2.117. The above R 6 is H (e.g., R 3 But -CH=CHR 7 ) the compound described in item 2.116. 2.118.R 7 But hydrogen, C 1~6 Alkyl, halo-C 1~6 Alkyl, C 2~6Alkenyl, and halo-C 2~6 The compound according to claim 2.116 or 2.117, wherein the halo-C is selected from the group consisting of halo-C 1~6 Alkyl is a C substituted with one or more halo. 1~6 The halo-C 2~6 Alkenyl is a C substituted with one or more halo. 2~6 It is alkenyl. 2.119. The halo-C 1~6 C alkyl substituted with 1, 2 or 3 halo 1~6 The compound according to paragraph 2.118, wherein the compound is alkyl. 2.120. The halo-C 1~6 Alkyl substituted with one halo 1~6 The compound according to paragraph 2.119, wherein the compound is alkyl. 2.121. The halo-C 2~6 Alkenyl is substituted with 1, 2, or 3 halo. 2~6 The compound according to any one of paragraphs 2.118 to 2.120, which is alkenyl. 2.122. The halo-C 2~6 Alkenyl is C substituted with 1 halo 2~6 The compound according to paragraph 2.121, which is alkenyl. 2.123. The halo-C 1~6 Alkyl and the halo-C 2~6 The compound according to any one of paragraphs 2.118 to 2.122, wherein each said halo of alkenyl is independently selected from chloro (-Cl), bromo (-Br), and fluoro (-F). 2.124. The halo-C 1~6 Alkyl and the halo-C 2~6 The compound according to item 2.123, wherein the halo of alkenyl is fluoro (-F). 2.125.R 7 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, and halo-C 2~6 The compound according to any one of paragraphs 2.118 to 2.124, wherein the compound is selected from alkenyl. 2.126.R 7 But, Halo-C 2~6 The compound according to paragraph 2.125, which is alkenyl. 2.127.R 3 But, C 6~10 The compound according to any one of paragraphs 2.1 to 2.32, wherein the aryl is selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl each contain at least one nitrogen atom. 2.128.R 3 is selected from 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl. 2.129.R 3 is selected from 5, 6, 9, or 10 membered heteroaryl and 5, 6, 9, or 10 membered heterocycloalkyl. 2.130.R 3 is selected from 5- or 6-membered heteroaryl and 5- or 6-membered heterocycloalkyl. 2.131.R 3 is a 5- or 6-membered heterocycloalkyl. 2.132.R 3 The compound according to paragraph 2.131, wherein is imidazolinyl. 2.133. Said C 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are each independently selected from the group consisting of -OH, -NH2, C 1~6 Alkyl, and C 1~6 The compound according to any one of paragraphs 2.127 to 2.132, optionally substituted with one or more groups selected from alkoxy. 2.134. Said C 6~10 The compound according to paragraph 2.133, wherein the aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are optionally substituted with one or more groups selected from -OH and -NH2. 2.135. The compound according to any one of paragraphs 2.1 to 2.134, wherein n is an integer selected from 1, 2, 3, 4, and 5. 2.136. The compound according to paragraph 2.135, wherein n is an integer selected from 1, 2, and 3. 2.137. The compound according to paragraph 2.136, wherein n is 1 (eg, when X is -OH or -OZ). 2.138. The compound according to paragraph 2.136, wherein n is 3 (eg, when X is -OH or -OZ). 2.139. n is 2 (e.g., R 3 is formula (2), the compound according to item 2.136. 2.140. [ka] [ka] [ka] [ka] [ka] [ka] [ka] The compound according to paragraph 2.1, selected from:

[0072] In the second aspect of the invention, the compound of formula (1) is preferably [ka] It is.

[0073] Another aspect of the invention is the provision of a pharmaceutical composition comprising a compound of formula (1) as defined in sections 2.1 to 2.140 above, or a compound of formula (10) as defined in sections 1 to 118 above, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a pharma- ceutically acceptable excipient.

[0074] In another aspect, the present invention provides a compound of formula (1) as defined in sections 2.1 to 2.140 above, or a compound of formula (10) as defined in sections 1 to 118 above, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition as defined herein, for use in therapy and / or for use as a medicament.

[0075] In another aspect, the present invention provides the use of a compound of formula (1) as defined in sections 2.1 to 2.140 above, or a compound of formula (10) as defined in sections 1 to 118 above, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a DHCR24-mediated disorder.

[0076] A further aspect of the present invention provides a method of inhibiting the activity of DHCR24 in vivo or in vitro. The in vivo or in vitro method comprises contacting a cell with a compound of formula (1) as defined in paragraphs 2.1 to 2.140 above, or a compound of formula (10) as defined in paragraphs 1 to 118 above, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein. Alternatively, the in vivo method may comprise administering to a subject a compound of formula (1) as defined in paragraphs 2.1 to 2.140 above, or a compound of formula (10) as defined in paragraphs 1 to 118 above, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein.

[0077] In another aspect, the present invention provides a combination comprising a compound of formula (1) as defined in sections 2.1 to 2.140 above, or a compound of formula (10) as defined in sections 1 to 118 above, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, and one or more additional therapeutic agents.

[0078] As a general feature of the present invention, the DHCR24-mediated disorder may be selected from non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (asCVD), multiple sclerosis, hepatocellular carcinoma, breast cancer, endometrial cancer, B-cell lymphoma, drug-resistant cancer, and hepatitis C. Preferably, the DHCR24-mediated disorder is selected from non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (asCVD), multiple sclerosis (MS), and a combination of non-alcoholic steatohepatitis (NASH) and atherosclerotic cardiovascular disease (asCVD).

[0079] The DHCR24-mediated disorder is preferably non-alcoholic steatohepatitis (NASH).

[0080] The DHCR24-mediated disorder is preferably atherosclerotic cardiovascular disease (asCVD).

[0081] The DHCR24 mediated disorder is preferably multiple sclerosis (MS).

[0082] Generally, a prodrug of a compound of formula (1) as defined in sections 2.1 to 2.140 above, or a compound of formula (10) as defined in sections 1 to 118 above, is an ester, amide, hydrazone, or disulfide of a compound of formula (1) or formula (10), respectively. Preferably, the prodrug is an ester, amide, or disulfide of a compound of formula (1) or formula (10). More preferably, the prodrug is an ester or amide of a compound of formula (1) or formula (10).

[0083] When the prodrug is an ester or amide, the ester or amide group is represented by R 1 and / or R 3 may be present in, preferably, R 1 When the prodrug is a disulfide, the disulfide group is represented by R 3 It may exist in.

[0084] The present invention may relate to any compound, or particular group of compounds, defined herein by optional, preferred or expedient features or otherwise with respect to particular embodiments, but the present invention may also relate to any compound, or particular group of compounds, which specifically excludes said optional, preferred or expedient features or particular embodiments.

[0085] Suitably, the present invention excludes any individual compounds that do not have biological activity as defined herein. Salts and solvates

[0086] The compounds described herein (including final products and intermediates) can be isolated and used as such, or can be isolated in the form of a salt, suitably a pharma-ceutically acceptable salt. The terms "salt" and "salt form", used by themselves or with another term(s), should be understood to include all inorganic and organic salts, including industrially acceptable salts as defined herein, and pharma-ceutically acceptable salts as defined herein, unless otherwise specified. As used herein, an industrially acceptable salt is a salt that is generally suitable for manufacturing and / or processing (including purification), as well as for transportation and storage, but may not be a salt that is typically administered for clinical or therapeutic use. An industrially acceptable salt can be prepared on a laboratory scale, i.e., on a scale of a few grams or less, or on a larger scale, i.e., up to and including a kilogram or more.

[0087] A pharmaceutically acceptable salt, as used herein, is a salt that is generally chemically and / or physically compatible with other components that make up the formulation, and / or generally physiologically compatible with its recipient. Pharmaceutically acceptable salts can be prepared on a laboratory scale, i.e., on a scale of a few grams or less, or on a larger scale, i.e., up to and including a scale of a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered for clinical or therapeutic use in humans or that are approved by FDA or equivalent foreign regulatory agencies. Those skilled in the art will easily understand that some salts are both industrially acceptable and pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of this application.

[0088] In one embodiment, the compound of Formula (1) or Formula (10) is isolated as a pharma- ceutically acceptable salt.

[0089] Suitable pharma- ceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of the compounds of the invention that are sufficiently basic, for example, with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid. Furthermore, suitable pharma- ceutically acceptable salts of the compounds of the invention that are sufficiently acidic are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts with organic bases that provide a physiologically acceptable cation (e.g., salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine).

[0090] In general, the salts of the present application may be prepared in situ during the isolation and / or purification of the compounds (including intermediates), or by separately reacting the compounds (or intermediates) with an appropriate organic or inorganic acid or base (if necessary) and isolating the salt thus formed. The degree of ionization of the salts may vary from completely ionized to barely ionized. In practice, various salts may be precipitated (with or without the addition of one or more co-solvents and / or anti-solvents) and collected by filtration, or the salts may be recovered by evaporation of the solvent. The salts of the present application may also be formed via a "salt switch" or ion exchange / double replacement reaction, i.e., a reaction in which one ion is replaced (in whole or in part) by another ion having the same charge. Those skilled in the art will appreciate that the salts may be prepared and / or isolated using a single method or a combination of methods.

[0091] Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate, and the like. Other examples of representative salts include alkali or alkaline earth metal cations, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine, and the like.

[0092] Certain compounds of formula (1) or formula (10) can exist in solvated and unsolvated forms, for example, hydrated forms. It should be understood that the present invention encompasses all such solvated forms that possess antiproliferative activity. polymorphism

[0093] It is also to be understood that certain compounds of formula (1) or formula (10) may exhibit polymorphism, and the invention encompasses all such forms that possess antiproliferative activity. N-Oxide

[0094] Compounds of formula (1) or formula (10) containing an amine function may also form N-oxides. Reference herein to compounds of formula (1) or formula (10) containing an amine function also includes the corresponding N-oxides. When a compound contains several amine functions, one or more nitrogen atoms may be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amines with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 1010-1015. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn.Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane. Tautomers

[0095] Compounds of formula (1) or formula (10) may exist in several different tautomeric forms, and a reference to a compound of formula (1) or formula (10) includes all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all others are nevertheless encompassed by formula (1) or formula (10). Examples of tautomeric forms include keto, enol, and enolate forms, such as in the case of the following tautomeric pairs: keto / enol (illustrated below), pyrimidon / hydroxypyrimidine, imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. [ka] Isomers

[0096] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers may be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomer, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture". Certain compounds of formula (1) or formula (10) may have one or more asymmetric centers and therefore may exist in several stereoisomeric configurations. As a result, such compounds may be synthesized and / or isolated as mixtures of enantiomers and / or individual (pure) enantiomers, and in the case of two or more asymmetric centers, as single diastereomers and / or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios. Isotopes

[0097] The compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or isotopic ratios of the constituent atoms. Thus, the present application is intended to include compounds in which the constituent atoms are present in any ratio of isotopic forms. For example, carbon atoms may be present in any ratio of isotopic forms. 12 C. 13 C, and 14 C, hydrogen atoms may be present in any ratio 1 H, 2 H, and 3H, etc. Preferably, the constituent atoms in the compounds of the present invention are present in their naturally occurring isotopic form. Prodrugs and Metabolites

[0098] The compounds of formula (1) or formula (10) may be administered in the form of prodrugs that are broken down in the human or animal body to release the compounds of the invention. Prodrugs may be used to change the physical and / or pharmacokinetic properties of the compounds of the invention. Prodrugs may be formed when the compounds of the invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that may be formed at carboxy or hydroxy groups in the compounds of formula (1) or formula (10), and in vivo cleavable amide derivatives that may be formed at carboxy or amino groups in the compounds of formula (1) or formula (10).

[0099] The present invention therefore includes these compounds of formula (1) or formula (10) as defined herein above when they are made available by organic synthesis and when they are made available in the human or animal body by cleavage of a prodrug thereof. The present invention therefore also includes these compounds of formula (1) or formula (10) produced by organic synthetic means, and such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., the compounds of formula (1) or formula (10) may be synthetically produced or metabolically produced compounds.

[0100] Suitable pharma- ceutically acceptable prodrugs of a compound of Formula (1) or Formula (10) are those that are based on reasonable medical judgment, suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity.

[0101] Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0102] A suitable pharma- ceutically acceptable prodrug of a compound of formula (1) or formula (10) having a carboxy group is, for example, an in vivo cleavable ester thereof. 1 and / or R 3In vivo cleavable esters of compounds of formula (1) or formula (10) containing a carboxy group are, for example, pharma- ceutically acceptable esters that are cleaved in the human or animal body to produce the parent acid. Suitable pharma- ceutically acceptable esters for carboxy include C 1~6 Alkyl esters, such as methyl, ethyl, and tert-butyl, C 1~6 Alkoxymethyl esters, such as methoxymethyl esters, C 1~6 Alkanoyloxymethyl esters, such as pivaloyloxymethyl esters, 3-phthalidyl esters, C 3~8 Cycloalkylcarbonyloxy-C 1~6 Alkyl esters, such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolenylmethyl esters, such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and C 1~6 Alkoxycarbonyloxy-C 1~6 Alkyl esters include, for example, methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester.

[0103] A suitable pharma- ceutically acceptable prodrug of a compound of formula (1) or formula (10) having a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. The hydroxy group (—OH) can be represented by R 1 and / or R 3 In vivo cleavable esters or ethers of a compound of formula (1) or formula (10) containing a hydroxy group are, for example, pharma- ceutically acceptable esters or ethers which are cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharma-ceutically acceptable ester-forming groups for hydroxy groups include inorganic esters such as phosphate esters (including phosphoramide cyclic esters). Suitable pharma-ceutically acceptable ester-forming groups for further hydroxy groups include C 1~10Alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, C 1~10 Alkoxycarbonyl groups, such as ethoxycarbonyl groups, N,N-(C 1~6 ) 2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups are aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1~4 Suitable pharma- ceutical-acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl.

[0104] Suitable pharma- ceutically acceptable prodrugs of compounds of formula (1) or formula (10) having a carboxy group include, for example, in vivo cleavable amides thereof, e.g., amines, e.g., ammonia, methylamine, and the like. 1~4 (C) such as alkylamines, dimethylamine, N-ethyl-N-methylamine, or diethylamine 1~4 C alkyl) 2 amine, 2-methoxyethylamine, etc. 1~4 Alkoxy-C 2~4 Phenyl-C such as alkylamines and benzylamines 1~4 alkylamines, and amides formed with amino acids such as glycine or their esters. These groups are R 1 and / or R 3 may exist in

[0105] Suitable pharma- ceutically acceptable prodrugs of the compounds of formula (1) or formula (10) having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharma- ceutically acceptable amides from the amino group include, for example, 1~10Alkanoyl groups include, for example, acetyl, benzoyl, phenylacetyl, and amides formed with substituted benzoyl and substituted phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups are aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1~4 These groups include R 1 and / or R 3 may exist in

[0106] The in vivo effects of the compounds of formula (1) or formula (10) may be exerted in part by one or more metabolites formed in the human or animal body following administration of the compounds of formula (1) or formula (10), respectively. As noted herein above, the in vivo effects of the compounds of formula (1) or formula (10) may also be exerted by metabolism of a precursor compound (prodrug). Pharmaceutical Compositions

[0107] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the invention as defined herein above, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, in association with a pharma- ceutically acceptable excipient, such as a pharma- ceutically acceptable diluent or a pharma- ceutically acceptable carrier.

[0108] The pharmaceutical compositions preferably contain an effective amount, more preferably a therapeutically effective amount, of a compound of Formula (1) or Formula (10), or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0109] The pharmaceutical composition may be formulated for delivery, particularly selective delivery, to macrophages.

[0110] For example, the pharmaceutical composition may comprise a compound of the invention as defined hereinabove, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, in the form of nanoparticles.

[0111] In general, compositions of the invention may be in a form suitable for oral use (for example as tablets (e.g., swallowable tablets), troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), in a form suitable for topical use (for example as a cream, ointment, gel, or aqueous or oily solution or suspension), in a form suitable for administration by inhalation (for example as a finely divided powder or liquid aerosol), in a form suitable for administration by insufflation (for example as a finely divided powder), or in a form suitable for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as a suppository for rectal administration).

[0112] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical additives well known in the art.Thus, compositions intended for oral use can contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0113] For use in therapy, an effective amount, particularly a therapeutically effective amount, of a compound of the invention is an amount sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with a DHCR24-mediated disorder referred to herein.

[0114] The amount of active ingredient that is combined with one or more additives to produce a single dosage form will necessarily vary depending on the individual being treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain 0.5 mg to 0.5 g of active agent (more appropriately 0.5 to 100 mg, e.g., 1 to 30 mg), combined with an appropriate and convenient amount of additive, which may vary, for example, from about 5 weight percent to about 98 weight percent of the total composition.

[0115] The magnitude of a therapeutic or prophylactic dose of a compound of formula (1) or formula (10) will of course vary according to well-known principles of medicine, according to the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0116] It should be noted that dosages and administration regimens may vary with the type and severity of the condition to be alleviated and may include administration of a single dose or multiple doses, i.e., QD (once a day), BID (twice a day), etc., over a particular period (days or hours). It should further be understood that for any particular subject or patient, a particular dosage regimen may need to be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present application encompasses intra-patient dose escalation as determined by one of skill in the art. Procedures and processes for determining appropriate dosages and administration regimens are well known in the relevant art and readily ascertained by one of skill in the art. Thus, one of skill in the art will readily understand and appreciate that the dosage ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.

[0117] When using the compound of the present invention for therapeutic or prophylactic purposes, it is generally administered so that a daily dose ranging, for example, from 0.1 mg / kg body weight to 75 mg / kg body weight is received, and if necessary, in divided doses. Generally, smaller doses are administered when parenteral routes are used. Thus, for example, for intravenous or intraperitoneal administration, a dose ranging, for example, from 0.1 mg / kg body weight to 30 mg / kg body weight is generally used. Similarly, for administration by inhalation, a dose ranging, for example, from 0.05 mg / kg body weight to 25 mg / kg body weight is used. Oral administration may also be appropriate, particularly in tablet form. Typically, a unit dosage form contains about 0.5 mg to 0.5 g of the compound of the present invention. Therapeutic Uses and Applications

[0118] In another aspect, the present invention provides a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition as defined herein, for use in therapy and / or for use as a medicament. The therapy may be treatment of the human or animal body.

[0119] In another aspect, the present invention provides a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of a DHCR24-mediated disorder.

[0120] In another aspect, there is provided a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of non-alcoholic steatohepatitis (NASH). The compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein, may be for use in the treatment or prevention of non-alcoholic steatohepatitis (NASH) without inducing hyperlipidemia and / or hypertriglyceridemia.

[0121] In another aspect, the present invention provides a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of atherosclerotic cardiovascular disease (asCVD). A compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein, may be for use in the treatment or prevention of atherosclerotic cardiovascular disease (asCVD) without inducing hyperlipidemia and / or hypertriglyceridemia.

[0122] In another aspect, the present invention provides a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prophylaxis of multiple sclerosis (MS).

[0123] In another aspect, the present invention provides the use of a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, in the manufacture of a medicament for the treatment or prophylaxis of a DHCR24-mediated disorder.

[0124] In another aspect, the present invention provides the use of a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of non-alcoholic steatohepatitis (NASH), preferably without inducing hyperlipidemia and / or hypertriglyceridemia.

[0125] In another aspect, the present invention provides the use of a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of atherosclerotic cardiovascular disease (asCVD), preferably without inducing hyperlipidemia and / or hypertriglyceridemia.

[0126] In another aspect, the present invention provides the use of a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, in the manufacture of a medicament for the treatment or prophylaxis of multiple sclerosis (MS).

[0127] In another aspect, the present invention provides a method of treating or preventing a DHCR24-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein.

[0128] In another aspect, the present invention provides a method of treating or preventing non-alcoholic steatohepatitis (NASH) without inducing hyperlipidemia and / or hypertriglyceridemia, comprising administering to a subject in need thereof an effective amount of a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein.

[0129] In another aspect, the present invention provides a method of treating or preventing atherosclerotic cardiovascular disease (asCVD) without inducing hyperlipidemia and / or hypertriglyceridemia, comprising administering to a subject in need thereof an effective amount of a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein.

[0130] In another aspect, the present invention provides a method of treating or preventing multiple sclerosis (MS), comprising administering to a subject in need thereof an effective amount of a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition as defined herein.

[0131] A further aspect of the invention provides methods of inhibiting the activity of DHCR24 in vivo or in vitro.

[0132] The in vivo or in vitro method includes contacting a cell with a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition.

[0133] Alternatively, the in vivo method may comprise administering to a subject in need thereof a therapeutically effective amount of a compound of formula (1) or formula (10) as defined herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition.

[0134] In another aspect, the present invention provides a combination comprising a compound of Formula (1) or Formula (10), or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, and one or more additional therapeutic agents.

[0135] In each of the above aspects, the DHCR24-mediated disorder may be selected from non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (asCVD), multiple sclerosis (MS), hepatocellular carcinoma (HCC), breast cancer, endometrial cancer, B-cell lymphoma, drug-resistant cancer, and hepatitis C.

[0136] In addition to or instead of the DHCR24-mediated disorder defined above, in each of the above aspects of the invention, the DHCR24-mediated disorder may be hepatitis, liver fibrosis, and / or liver injury.Preferably, the DHCR24-mediated disorder is liver fibrosis and / or liver injury.

[0137] The breast cancer is preferably luminal breast cancer or HER2 positive breast cancer.

[0138] The drug-resistant cancer is preferably a methotrexate-resistant cancer. The cancer may be a gestational trophoblastic neoplasia (GTN).

[0139] DHCR24-mediated disorder is preferably non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (asCVD) or multiple sclerosis (MS).DHCR24-mediated disorder is preferably non-alcoholic steatohepatitis (NASH).DHCR24-mediated disorder is preferably atherosclerotic cardiovascular disease (asCVD).DHCR24-mediated disorder is preferably multiple sclerosis (MS).

[0140] Nonalcoholic steatohepatitis (NASH) and atherosclerotic cardiovascular disease (asCVD) result in significant morbidity and mortality. As a matter of fact, asCVD is the leading cause of death in the Western world. Both diseases are driven by lipids / cholesterol and inflammation. While asCVD is primarily treated with cholesterol-lowering statins, there are currently no effective drugs for NASH, which is primarily treated with lifestyle interventions. In addition to lipid-lowering approaches, both diseases would greatly benefit from a simultaneous anti-inflammatory approach.

[0141] The terminal step in the de novo synthesis of cholesterol is mediated by inhibiting the enzyme 24-dehydrocholesterol reductase (DHCR24). This is the step where the enzyme converts desmosterol to cholesterol. DHCR24 inhibition not only reduces cholesterol synthesis but also induces an increase in desmosterol, an endogenous ligand of liver X receptor alpha (LXRα). Activation of LXRα leads to an efficient anti-inflammatory effect, which suppresses macrophage activation. Synthetic LXRα ligands of the prior art cause severe hypertriglyceridemia (another risk factor for asCVD) by inducing SREBP-mediated lipid biosynthesis in hepatocytes. In contrast, the increase in desmosterol caused by the selective DHCR24 inhibitor compounds of the present invention activates LXRα without side effects such as inducing hypertriglyceridemia.

[0142] Desmosterol has been found to play an important role in resolving inflammation in demyelinating lesions in multiple sclerosis (see Nature Neuroscience, 2021, 24(1), pp. 47-60). The increase in desmosterol caused by selective DHCR24 inhibitor compounds can be used in the treatment or prevention, preferably in the treatment of multiple sclerosis.

[0143] Overexpression of DHCR24 has been shown to correlate with poor clinical outcome in patients with hepatocellular carcinoma (see British Journal of Cancer, 2000, 123, pp. 1673-1685). Therefore, DCHR24 inhibitors may be useful in preventing or treating HCC.

[0144] Cholesterol has been shown to be a risk factor for breast cancer. It has been shown that DHCR24 expression is higher in breast cancer tissue, especially luminal breast cancer and HER2-positive breast cancer tissue, compared to normal breast (see Cancer Sci., 2020, 111(10), pp. 3653-3664). Compounds that inhibit DHCR24 may therefore be useful in treating or preventing breast cancer.

[0145] DHCR24 is also associated with genitourinary neoplasms. It has been shown that DHCR24 is significantly elevated in patients with endometrial cancer (EC), and upregulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival (see Scientific Reports, 2017, 7(1), pp. 41404; DOI: 10.1038 / srep41404). Compounds that inhibit DHCR24 may therefore be useful in treating or preventing EC.

[0146] DHCR24 has been shown to be a direct target of SOX9, a tumorigenic stem cell regulator, in B-cell lymphoma. It has been shown that SOX9 can promote lymphomagenesis through DHCR24 and cholesterol biosynthesis pathway (see Blood, 2022, 139(1), pp. 73-86). Compounds that inhibit DHCR24 may therefore be useful in treating or preventing B-cell lymphoma.

[0147] DHCR24 has been identified as a potential downstream effector of DPP4 (Front. Oncol., 2 December 2021; see https: / / doi.org / 10.3389 / fonc.2021.704024). Targeting DPP4 / DHCR24 signaling may help sensitize methotrexate-resistant cancers, especially gestational trophoblastic neoplasia (GTN).

[0148] It has been shown that the expression of DHCR24 in human hepatocytes is induced by hepatitis C virus (HCV) infection (see J. Hepatol., 2011, 55(3), pp. 512-521). Inhibition of DHCR24 can reduce HCV replication. Therefore, compounds that inhibit DHCR24 may be useful in treating or preventing hepatitis C. Route of administration

[0149] The compounds or pharmaceutical compositions of the invention may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, at the site of desired action).

[0150] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., by patches, plasters, etc.); intranasal (e.g., by nasal spray); intraocular (e.g., by eye drops); pulmonary (e.g., via the mouth or nose, e.g., using an aerosol, e.g., by inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal); by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly. Combination therapy

[0151] The treatment defined herein above may be employed as a sole therapy or may involve the administration of one or more therapeutic agents in addition to the compound of formula (1) or formula (10).

[0152] The therapeutic agent can be a lipid-lowering agent, such as a statin, a PCSK9 inhibitor (e.g., evolocumab, alirocumab), or an NPC1L1 inhibitor (e.g., Ezetemibe), particularly when the DHCR24-mediated disorder is atherosclerotic cardiovascular disease (asCVD).

[0153] According to this aspect of the invention there is provided a combination for use in the treatment or prevention of a DHCR24 mediated disorder, in particular the treatment or prevention of non-alcoholic steatohepatitis (NASH) or atherosclerotic cardiovascular disease (asCVD), comprising a compound of formula (1) or formula (10) as defined herein above, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, and another therapeutic agent, such as a therapeutic agent for treating or preventing non-alcoholic steatohepatitis (NASH) or atherosclerotic cardiovascular disease (asCVD).

[0154] In this specification, when the term "combination" is used, it should be understood that it refers to simultaneous, separate or sequential administration. In one aspect of the present invention, "combination" refers to simultaneous administration. In another aspect of the present invention, "combination" refers to separate administration. In a further aspect of the present invention, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such that the beneficial effect of the combination is lost. In one embodiment, combination refers to a combination product.

[0155] According to a further aspect of the present invention there is provided a combination comprising a compound of formula (1) or formula (10) as defined hereinabove, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, and a therapeutic agent (such as those described above).

[0156] In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (1) or formula (10) as defined herein above, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, and another therapeutic agent, in combination with a therapeutic agent (such as those described above), together with a pharma- ceutically acceptable diluent or carrier. EXAMPLES

[0157] The following examples are provided to illustrate the invention and are not intended to limit the scope of the invention described herein.

[0158] The compounds of the invention can be prepared using synthetic techniques known in the art (illustrated by the Examples herein).

[0159] Several methods for chemical synthesis of the compounds of the present application are described herein. These and / or other known methods may be modified and / or adapted in various ways to facilitate the synthesis of further compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood to be within the spirit and scope of the present application and claims. Therefore, it should be understood that the methods described in the following description, schemes, and examples are intended for illustrative purposes and should not be interpreted as limiting the scope of the present disclosure. Synthesis of compounds

[0160] The compounds were prepared from commercially available starting materials. The general reaction scheme shown in Scheme 1 illustrates the published synthesis of versatile / reactive key intermediates starting from commercially available ergosterol, which can be used for the synthesis of most of the compounds described below. [ka]

[0161] Compounds of Examples 1, 9-11, 16, 21, 25, 28, and 29 were prepared as described in C. Mueller et al., Eur. J. Med. Chem., 2017, 140, 305-320.

[0162] The compounds of Examples 2-8, 12, 14, 15, 17-20, 22-24, 26, and 27 were prepared as described in Sandra Hemmers, "Seitenkettenfunktionalisierte Steroides as Inhibitors of Ergosterol- and Cholesterolbiosynthesis", PhD thesis, LMU Munich, 2012 (DOI: 10.5282 / edoc.15485).

[0163] The compound of Example 13 was prepared as described in D. Renard et al., Bioorg. Med. Chem., 2009, 17, 8123-8137. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (3S,20R)-20-(Hydroxymethyl)-pregn-7-en-3-yl acetate (MiH-7)

[0164] A flame-dried Schlenk flask was charged with (3S,20S)-20-formylpregn-7-en-3-yl acetate (151 mg, 0.405 mmol) and p-toluenesulfonic acid (7.8 mg, 0.041 mmol). After dissolution in dry toluene (1 mL) under nitrogen atmosphere, piperidine (0.642 mL, 6.5 mmol) was added and the solution was stirred at 70° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (EtOAc) and washed three times with 0.1 M HCl. The organic layer was dried using hydrophobic filter paper and the solvent was removed in vacuum. The crude product was purified by flash column chromatography (FCC) (hexane / EtOAc, 90:10) to give 95 mg (63%) of a white solid, which was directly subjected to reduction. Thus, the previously obtained aldehyde (184 mg, 0.494 mmol) was dissolved in a 3:2 mixture of dry CHCl3 / MeOH in a flame-dried Schlenk flask under nitrogen atmosphere. After addition of sodium borohydride (18.9 mg, 0.5 mmol), the mixture was stirred at room temperature for 2 h. The reaction was quenched using saturated NH4Cl solution and the aqueous layer was extracted with CHCl3 (3 x 3 mL). The combined organic layers were dried using hydrophobic filter paper and the solvent was removed in vacuum. After purification using FCC (hexane / EtOAc, 90:10 to 80:20), (3S,20R)-20-(hydroxymethyl)-pregn-7-en-3-yl acetate was obtained as a colorless solid (65 mg, 0.17 mmol, 35%).

[0165] 1 H NMR (500 MHz, CDCl3) δ 5.16 (m, 1H, H-7), 4.69 (tt, 3 J H3-H2,H4 = 11.3, 4.6 Hz, 1H, H-3), 3.73 (dd, 3 J H22-H22 = 10.6, 3 J H22-H20 = 3.6 Hz, 1H, H-22), 3.49 (dd, 3 J H22-H22 = 10.6, 3 J H22-H20= 6.9 Hz, 1H, H-22), 2.02 (s, 3H, CH3CO), 1.93 - 1.30 (m, 20H), 1.25 (tdz, J = 12.9, 4.2 Hz, 1H), 1.17 - 1.09 (m, 1H, H-17), 0.96 (d, 3 J H21-H20 = 6.7 Hz, 3H, H-21), 0.81 (s, 3H, H-19), 0.55 (s, 3H, H-18). 13 C NMR (126 MHz, CDCl3) δ 170.8 (CH3CO), 139.3 (C-8), 117.8 (C-7), 73.6 (C-3), 67.1 (C-22), 55.0 (C-14), 52.6 (C-C20), 49.3 (C-9), 43.3 (C-13), 40.2 (C-5), 39.1 (C-12), 38.4 (C-17), 37.0 (C-1), 34.34 (C-10), 33.9 (C-11), 29.7 (C-6), 27.6 (C-2 or C-4), 27.4 (C-2 or C-4), 22.9(C-15 or C-16), 21.6 (CH3CO), 21.6 (C-15 or C-16), 16.8 (C-21), 13.1 (C-19), 12.4 (C-18).HR-MS(EI):C 24 H 38 O3's calculated value: 374.2821, measured value 374.2816. (3S,20R)-20-(ヒドロキシメチル)-プレグナ-7-エン-3-オール(MiH-8)

[0166] To a stirred solution of (3S,20R)-20-(hydroxymethyl)-pregn-7-en-3-yl acetate (65 mg, 0.174 mmol) in MeOH was added a solution of K2CO3 (288 mg, 174 mmol) in water (2.35 mL). The mixture was heated to reflux for 2 h, then cooled to room temperature and concentrated under reduced pressure. The precipitate was redissolved in EtOAc and the organic layer was washed twice each with saturated KHCO3 solution, water, and brine. After filtering the organic layer through hydrophobic filter paper to remove water, the solvent was removed in vacuum. After purification by FCC (hexane / EtOAc, 70:30), (3S,20R)-20-(hydroxymethyl)-pregn-7-en-3-ol was obtained as a colorless to off-white solid (28 mg, 0.084 mmol, 48%).

[0167] 1 H NMR (400 MHz, DMSO-d6) δ 5.14 - 5.08 (m, 1H, H-7), 4.45 (s, 1H, OH), 4.27 (s, 1H, OH), 3.54 (d, J = 10.3 Hz, 1H, H-22), 3.33 (s, 6H, H-3 underneath), 3.10 (t, J = 8.9 Hz, 1H, H-22), 1.91 - 0.93 (m, 27H), 0.85 (d, J = 6.6 Hz, 3H, H-21), 0.72 (s, 3H, H-19), 0.49 (s, 3H, H-18). 13C NMR (101 MHz, DMSO-d6) δ 139.1 (C-8), 117.2 (C-7), 68.90 (C-3), 64.9 (C-22), 54.4 (C-14), 52.4 (C-17), 48.9 (C-9), 42.8 (C-13), 39.5 (C-5, underlying DMSO), 38.4 (C-12), 38.1 (C-20), 37.9 (CH2), 36.7 (CH2), 33.8 (C-10), 31.3 (C-1), 29.3 (CH2), 26.6 (CH2), 22.4 (CH2), 21.0 (CH2), 16.7 (C-21), 12.9 (C-19), 12.1 (C-18).HR-MS(EI):C 22 H 36 Calculated O2 value 332.2715, measured value 332.2711. Example 31 [ka] (3S,20S)-20-(hydroxymethyl)-pregn-7-en-3-ol (MiH-10)

[0168] Lithium aluminum hydride (56.7 mg, 1.49 mmol) was dispersed in dry THF in a flame-dried Schlenk flask under nitrogen atmosphere. The mixture was cooled to 0° C. in an ice bath and a solution of (3S,20S)-20-formylpregn-7-en-3-yl acetate (105 mg, 0.282 mmol) in THF (1 mL) was added dropwise. Stirring was continued overnight while the mixture warmed to room temperature. The reaction was quenched with water and the mixture was acidified with 1 M HCl. The aqueous layer was extracted with EtOAc (3×3 mL) and the combined organic layers were filtered through hydrophobic filter paper to remove water. After removal of the solvent under reduced pressure, the crude product was subjected to FCC (hexane / EtOAc, 1:1). The diol was obtained as a colorless solid (63 mg, 0.19 mmol, 67%).

[0169] 1 H NMR (400 MHz, CDCl3) δ 5.19 - 5.14 (m, 1H, H-7), 3.64 (dd, J = 10.8, J = 3.5 Hz, 1H, H-22), 3.58 (dt, J = 10.6, 4.5 Hz, 1H, H-3), 3.39 (dd, J = 10.3, J = 7.0 Hz, 1H, H-22), 2.05 - 1.98 (m, 1H, H-6), 1.93 - 1.17 (m, 22H), 1.06 (d, J = 6.6 Hz, 3H, H-21), 0.80 (s, 3H, H-19), 0.56 (s, 3H, H-18). 13 C NMR (101 MHz, CDCl3) δ 139.5 (C-8), 117.8 (C-7), 71.2 (C-3), 68.1 (C-22), 54.9 (C-14), 52.5 (C-17), 49.6 (C-5), 43.6 (C-13), 40.4 (C-9), 39.6 (C-6), 39.3 (C-20), 38.1 (C-2), 37.3 (C-1), 34.4 (C-10), 31.6 (CH2), 29.8 (CH2), 27.6 (CH2), 23.2 (CH2), 21.7 (CH2), 17.0 (C-21), 13.2 (C-19), 12.1 (C-18).HR-MS(EI):C 22 H 36 Calculated O2: 332.2715, measured 332.2710. (3R,20S)-20-[(4-nitrobenzoyloxy)methyl]-pregn-7-en-3-yl 4-nitrobenzoate

[0170] (3S,20S)-20-(hydroxymethyl)-pregn-7-en-3-ol (54 mg, 0.16 mmol), 4-nitrobenzoic acid (204 mg, 1.22 mmol), and triphenylphosphine (319 mg, 1.22 mmol) were dissolved in dry THF (1 mL) under nitrogen atmosphere, and the mixture was then cooled to 0° C. in an ice bath. Diisopropyl azodicarboxylate (DIAD) (0.113 mL, 0.568 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight, then quenched by the addition of saturated NH4Cl (2 mL). The aqueous layer was extracted with DCM (3×3 mL), and the combined organic extracts were filtered through hydrophobic filter paper to remove water. The solvent was removed under reduced pressure, and the crude product was subjected to FCC (hexane / EtOAc, 80:20). (3R,20S)-20-[(4-nitrobenzoyloxy)methyl]-pregn-7-en-3-yl 4-nitrobenzoate was obtained as a colorless solid (76 mg, 0.12 mmol, 74%).

[0171] 1 H NMR (500 MHz, CDCl3) δ 8.32 - 8.26 (m, 4H, aromatic), 8.23 ​​- 8.18 (m, 4H, aromatic), 5.35 (t, J = 2.8 Hz, 1H, H-3), 5.24 (m, 1H, H-7), 4.41 (dd, J = 10.7, 3.5 Hz, 1H, H-22), 4.10 (dd, J = 10.7, 7.6 Hz, 1H, H-22), 2.08 (dt, J = 12.5, 3.7 Hz, 1H, H-6), 2.00 - 1.24 (m, 22H), 1.15 (d, J = 6.6 Hz, 3H, H-21), 0.87 (s, 3H, H-19), 0.63 (s, 3H, H-18). 13C NMR (126 MHz, CDCl3) δ 165.0 (COO), 164.1 (COO), 150.7 (aromatic), 150.6 (aromatic), 139.3 (C-8), 136.6 (aromatic), 136.1 (aromatic), 130.8 (aromatic), 123.7 (aromatic), 123.7 (aromatic), 118.1 (C-7), 72.1 (C-3), 71.0 (C-22), 55.0 (C-14), 53.0 (C-17), 49.7 (C-9), 43.9 (C-13), 39.5 (C-6), 36.6 (C-20), 36.1 (C-5), 34.7 (C-10), 33.2 (CH2) , 32.6 (C-4), 29.5 (CH2), 27.7 (CH2), 26.2 (C-2), 23.2 (CH2), 21.4 (C-1), 17.6 (C-21), 12.4 (C-19), 12.1 (C-18). HR-MS (EI): calcd. for C 36 H 42 N2O8630.2941, found 630.2932. (3R,20S)-20-(hydroxymethyl)-pregn-7-en-3-ol (MiH-12)

[0172] (3R,20S)-20-[(4-nitrobenzoyl)methyl]-pregn-7-en-3-yl 4-nitrobenzoate (80 mg, 0.13 mmol) was dissolved in THF (2 mL) and cooled to 0 °C in an ice bath, 0.38 mL of 2 M NaOH solution was added slowly, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with DCM (5 mL) and the organic layer was washed three times each with water, 1 M HCl, and brine. After filtration through hydrophobic filter paper to remove water, the solvent was removed under reduced pressure. The crude product was subjected to FCC (hexane / EtOAc, 70:30) to give (3R,20S)-20-(hydroxymethyl)-pregn-7-en-3-ol as a colorless to pale yellow solid (36 mg, 0.11 mmol, 85%).

[0173] 1 1H NMR (500 MHz, DMSO) δ 5.13 (m, 1H, H-7), 4.28 (dd, 3 J H22-OH = 5.7, 4.8 Hz, 1H, OH), 4.20 (d, 3 J H3-OH = 3.2 Hz, 1H, OH), 3.83 (q, 3 J H3-H2 , J H3-H4 = 2.9 Hz, 1H, H-3), 3.42 (s, 1H, H-22), 3.07 (ddd, 3 J H17-H20 = 10.3, 3 J H20-H22 = 7.1, 3 J H20-H21 = 5.8 Hz, 1H, H-22), 1.99 - 1.09 (m, 21H), 0.95 (d, 3 J H21-H20 = 6.5 Hz, 3H, H-21), 0.71 (s, 3H, H-19), 0.50 (s, 3H, H-18). 13 13C NMR (126 MHz, DMSO) δ 139.1 (C-8), 117.5 (C-7), 65.7 (C-22), 64.0 (C-3), 54.3 (C-14), 52.2 (C-17), 49.1 (C-5), 43.1 (C-13), 40.1 (C-20), 38.9 (C-6), 35.3 (C-2), 34.3 (C-10), 34.2 (C-9), 31.7 (C-1), 29.2 (C-11), 28.5 (C-12), 27.1 (C-4), 22.7 (CH2), 20.8 (CH2), 17.2 (C-20), 12.1 (C-19), 11.9 (C-18). HR-MS (EI): calcd. for C 22 H 36 O2332.2715, found 332.2711. Example 32

Chemical Structure

[0174] (3S,20S)-20-Formylpregn-7-en-3-yl acetate (250 mg, 0.671 mmol) and KOtBu (753 mg, 6.71 mmol) were dissolved in dry DCM (10 mL) at room temperature under nitrogen atmosphere. When a white precipitate formed, methyl iodide (1.25 mL, 20.1 mmol) was added dropwise. The mixture was stirred for 3 h and then quenched by adding saturated NH4Cl solution (5 mL). The aqueous layer was extracted three times with DCM and the combined organic extracts were filtered through hydrophobic filter paper to remove water. The solvent was removed under reduced pressure and the crude product was subjected to FCC (hexane / EtOAc, 95:5). (3S)-20-Formyl-20-methylpregn-7-en-3-yl acetate was obtained as a colorless solid (155 mg, 0.401 mmol, 59%).

[0175] 1 H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H, CHO), 5.18 - 5.14 (m, 1H, H-7), 3.34 (s, 3H, H3CCOO), 3.12 (tt, J = 11.1, 4.4 Hz, 1H, H-3), 1.93 - 1.53 (m, 18H), 1.50 - 1.13 (m, 10H), 1.11 (s, 3H, H-21 or H-21'), 1.09 (s, 3H, H-21 or H-21'), 1.03 (td, J = 13.5, 3.4 Hz, 1H, H-1 ), 0.76 (s, 3H, H-19), 0.55 (s, 3H, H-18). 13C NMR (101 MHz, CDCl3) δ 206.80 (CHO), 170.8 (H3CCOO), 138.8 (C-8), 118.5 (C-7), 79.7 (C-3), 57.5 (C-17), 55.7 (H3CCOO), 55.0 (C-14), 49.5 (C-9), 48.9 (C-20), 44.2 (C-13), 40.3 (C-5), 39.5 (C-12), 37.2 (C-1), 34.7 (C-10), 34.3 (CH2), 29.9 (CH2), 27.8 (CH2), 23.0 (C-21 or C-21'), 22.6 (CH2), 22.4 (CH2), 21.5 (CH2), 20.9 (C-21 or C-21'), 14.7 (C-18), 13.1 (C-19). HR-MS (EI): calcd. For C 25 H 38 O3386.2821, found 386.2826. (3S)-20-Hydroxymethyl-20-methylpregn-7-en-3-yl acetate (MiH-9)

[0176] (3S)-20-formyl-20-methylpregn-7-en-3-yl acetate (128 mg, 0.331 mmol) was dissolved in a 3:2 mixture of dry CHCl3 / MeOH in a flame-dried Schlenk flask under nitrogen atmosphere. After addition of sodium borohydride (12.7 mg, 0.335 mmol), stirring was continued at room temperature for 1 h. The reaction was quenched using saturated NH4Cl solution (3 mL) and the aqueous layer was extracted with CHCl3 (3 x 3 mL). The combined organic extracts were dried using hydrophobic filter paper and the solvent was removed under reduced pressure. After purification using FCC (hexane / EtOAc, 90:10 to 80:20), (3S)-20-hydroxymethyl-20-methylpregn-7-en-3-yl acetate was obtained as a colorless solid (87 mg, 0.22 mmol, 67%).

[0177] 1H NMR (500 MHz, CDCl3) δ 5.16 (dq, J = 4.6, 2.3 Hz, 1H, H-7), 3.35 (s, 3H, CH3CO), 3.40 - 3.31 (m, 2H, H-22), 3.12 (tt, J = 11.2, 4.4 Hz, 1H, H-3), 2.06 - 2.01 (m, 1H, H-9), 1.91 - 1.00 (m, 20H), 0.99 (s, 3H, H-21 or H-2 1 ), 0.90 (s, 3H, H-21 or H-21 1 ), 0.78 (s, 3H, H-19), 0.62 (s, 3H, H-18). 13 C NMR (126 MHz, CDCl3) δ 139.4 (H3CCO), 118.1 (C-7), 79.7 (C-3), 77.4 (C-8), 72.8 (C-22), 55.7 (H3CCO), 55.5 (C-5), 55.4 (C-17), 49.5 (C-14), 44.4 (C-13), 40.3 (C-9), 40.0, 39.0 (C-20), 37.2, 34.7 (C-10), 34.4, 29.9, 27.9, 23.6 (C-21 or C-21). 1 ), 23.5 (C-21 or C-21 1 ), 22.8 (CH2), 22.6 (CH2), 21.6 (CH2), 14.6 (C-19), 13.1 (C-18). HR-MS (EI): calcd. for C 22 H 36 O2388.2977, found 388.2975. (3S)-20-Synthetic-20-Synthetic-7-Synthetic-3-Synthetic(MiH-13)

[0178] To a stirred solution of (3S)-20-hydroxymethyl-20-methylpregn-7-en-3-yl acetate (80 mg, 0.21 mmol) in MeOH (25 mL) was added a solution of K2CO3 (342 mg, 2.06 mmol) in water (2.8 mL). The mixture was heated to reflux for 4 h, then cooled to room temperature and concentrated under reduced pressure. The precipitate was redissolved in EtOAc and the organic layer was washed successively with saturated KHCO3 solution (2 x 5 mL), water, and brine. The organic layer was filtered through hydrophobic filter paper to remove water, and the solvent was removed in vacuo. After purification by FCC (hexane / EtOAc, 70:30), (3S)-20-hydroxymethyl-20-methylpregn-7-en-3-ol was obtained as a colorless solid (24 mg, 0.069 mmol, 33%).

[0179] 1 H NMR (500 MHz, CDCl3) δ 5.16 (m, 1H, H-7), 3.59 (tt, J= 11.0, 4.5 Hz, 1H, H-3), 3.35 (q, J = 10.6 Hz, 2H, H-22), 2.03 (ddd, J = 12.3, 4.0, 2.6 Hz, 1H, H-9), 1.86 - 1.04 (m, 22H), 0.99 (s, 3H, H-21 or H-21 1 ), 0.90 (s, 3H, H-21 or H-21 1 ), 0.79 (s, 3H, H-19), 0.62 (s, 3H, H-18). 13 C NMR (126 MHz, CDCl3) δ 139.4 (C-8), 118.1 (C-7), 72.8 (C-22), 71.2 (C-3), 55.5 (C-14), 55.4 (C-17), 49.5 (C-5), 44.4 (C-13), 40.4 (C-9), 40.0 (C-2), 39.0 (C-20), 38.1 (C-4), 37.3 (C-6), 34.3 (C-10), 31.6 (C-1), 29.8 (C-11), 23.6 (C-21 or C-21 1 ), 23.5 (C-21 or C-21 1), 22.8 (C-15), 22.6 (C-16), 21.6 (C-12), 14.6 (C-18), 13.2 (C-19). HR-MS (EI): calcd. for C 23 H 38 O2346.2872, found 346.2876. Example 33 [ka] (3S,20S)-20-(3,4-Dimethylpent-1-en-yl)-pregna-5,7,9-trien-3-ol (MiH-16)

[0180] To a solution of eosin Y (5015 mg, 7.25 mmol) in 95% EtOH (150 mL) was added concentrated H2SO4 (0.402 mL, 7.25 mmol). The white precipitate that formed was removed from the solution by vacuum filtration and nitrogen was passed through for 30 min. Ergosterol (5000 mg, 12.6 mmol) and 75 mL of THF were added in the dark. The 500 mL round-bottom flask containing the reaction mixture and stirring beads was placed in a highly polished box with an LED band fixed inside. The reaction mixture was vigorously stirred for 38 h while exposed to blue LED light. The colorless precipitate that formed was filtered, washed using cold EtOH, and then dried in vacuum to give bisergostatrienol as a colorless to pale yellow solid (3510 mg, 4.44 mmol, 70%), which was used in the next step without further purification. The above solid (930 mg, 1.18 mmol) suspended in dry toluene was added to a flame-dried 500 mL round-bottom flask equipped with a boiling bead and a reflux condenser under nitrogen atmosphere. The mixture was heated to reflux and when all the solid was dissolved, N,O-bis(trimethylsilyl)acetamide (0.632 mL, 2.59 mmol) was added dropwise. Stirring was continued for 5.5 h, then the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. 30 mL of acetone was added to the precipitate and heated to reflux for 5 min. On cooling, a white precipitate formed which was collected by filtration and dried under vacuum to give bis-TMS-bisergostatrienol as crude product (816 mg, 0.872 mmol, 74%). The crude product (753 mg, 0.805 mmol) was then dissolved in diethylene glycol ethyl ether (40 mL) in a round-bottom flask equipped with a reflux condenser and a boiling bead under nitrogen atmosphere. The mixture was heated to reflux for 10 min, then rapidly cooled to 100°C and poured into a stirred mixture of ice and water containing a small amount of p-toluenesulfonic acid crystals. After 24 h at -20°C, the white precipitate was collected by filtration and washed with cold water. Recrystallization from MeOH gave neoergosterol as a white powder (401 mg, 1.05 mmol, 65%).

[0181] 1H NMR (400 MHz, CDCl3) δ 6.90 (d, J = 7.9 Hz, 1H, H-6), 6.85 (d, J = 7.8 Hz, 1H, H-7), 5.30 - 5.18 (m, 2H, H-22, H-23), 4.17 - 4.07 (m, 1H, H-3), 3.10 - 3.02 (m, 1H, CH2), 2.82 - 2.72 (m, 2H, CH2), 2.70 - 2.59 (m, 4H, CH2), 2.27 - 2.19 (m, 1H, CH2), 2.16 - 2.00 (m, 4H, CH2, H-20), 1.97 - 1.77 (m, 4H, CH2, H-24), 1.73 - 1.32 (m, 9H, CH2, H-17, H-25), 1.09 (d, J = 6.6 Hz, 3H, H-21), 0.97 - 0.90 (m, 3H, H-24 1 ), 0.84 (ddq, J = 7.1, 4.5, 2.2, 1.8 Hz, 6H, H-26, H-27), 0.60 (s, 3H, H-18). 13 C NMR (101 MHz, CDCl3) δ 138.1 (C-9), 135.7 (C-22), 134.2 (C-8), 133.6 (C-10), 132.2 (C-23), 131.3 (C-5), 127.0 (C-6), 124.0 (C-7), 67.3 (C-3), 55.2 (C-17), 52.0 (C-14), 43.0 (C-24), 41.9 (C-13), 40.7 (C-20), 39.1 (CH2) , 37.0 (CH2), 33.3 (C-25), 31.8 (CH2), 29.3 (CH2), 25.3 (CH2), 24.8 (CH2), 24.3 (CH2), 21.2 (C-21), 20.1 (C-25 or C-26), 19.8 (C-25 or C-26), 17.8 (C-24 1 ), 11.4 (C-18). HR-MS (EI): calcd. for C 27 H 40O1380.3079, found 380.3079. (3S,20S)-20-(Hydroxymethyl)-pregna-5,7,9-trien-3-ol (MiH-17, Example 33)

[0182] To a solution of neoergosterol (180 mg, 0.473 mmol) in DCM (23 mL) in a 100 mL gas washing bottle equipped with stirring beads and a glass frit, pyridine (0.191 mL, 2.36 mmol) and a few crystals of Sudan III were added. The solution was cooled to -50 °C while passing nitrogen. Ozone was then introduced through the glass frit (60 L / h, 60 W) until the color of the solution changed to pale yellow. Nitrogen was introduced for 10 min, then methanol (3.6 mL) was added, followed by sodium borohydride (179 mg, 4.73 mmol) in small portions. Stirring was continued while the temperature was slowly raised to room temperature. The reaction was quenched by the addition of 0.1 M HCl (10 mL) and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were washed with 0.1 M HCl (3 × 15 mL) and then filtered through hydrophobic filter paper to remove water. The solvent was removed under reduced pressure, and the crude product was subjected to FCC (hexane / EtOAc, 70:30 to 1:1) to give (3S,20S)-20-(hydroxymethyl)-pregna-5,7,9-trien-3-ol as a colorless solid (80 mg, 0.25 mmol, 53%).

[0183] 11H NMR (400 MHz, DMSO) δ 6.79 (d, J = 7.8 Hz, 1H, H-6), 6.72 (d, J = 7.7 Hz, 1H, H-7), 4.72 (d, J = 3.8 Hz, 1H, HO-C-3), 4.30 (t, J = 5.3 Hz, 1H, CH2-OH), 3.82 (tt, J = 8.5, 3.7 Hz, 1H, H-3), 3.48 - 3.41 (m, 1H, H-22), 3.13 (dt, J = 10.2, 6.3 Hz, 1H, H-22), 2.85 (dd, J = 16.0, 4.7 Hz, 1H, H-4)), 2.69 - 2.47 (m, 13H), 2.16 (dt, J = 12.7, 4.7 Hz, 1H, H-12 und CH2), 2.06 - 1.89 (m, 3H), 1.66 - 1.54 (m, 2H, H-12 und CH2), 1.51 - 1.29 (m, 4H, H-17, H-20 und CH2), 1.02 (d, J = 6.4 Hz, 3H, H-21), 0.51 (s, 3H, H-18). 13 13C NMR (101 MHz, DMSO) δ 136.7 (C-9), 133.3 (C-8), 133.1 (C-10), 132.0 (C-5), 126.4 (C-6), 123.1 (C-7), 65.6 (C-22), 65.1 (C-3), 51.2 (C-17), 51.0 (C-14), 41.4 (C-13), 39.0 (C-20), 38.8 (C-4), 36.3 (C-12), 31.6 (CH2), 28.0 (CH2), 24.4 (CH2), 24.0 (2xCH2), 17.0 (C-21), 11.0 (C-18). HR-MS (EI): calcd. for C 21 H 30 O2314.2246, found 314.2237. Example 34

Chem.

[0184] In a flame-dried round-bottom flask equipped with a stirrer bead, (3S,20R)-20-(hydroxyethyl)-pregn-7-en-3-yl acetate (60 mg, 0.15 mmol) (prepared as described in Sandra Hemmers, "Seitenkettenfunktionalisierte Steroide als Inhibitoren der Ergosterol- und Cholesterolbiosynthese", PhD thesis, LMU Munich, 2012, DOI: 10.5282 / edoc.15485) and DMAP (9.4 mg, 0.077 mmol) were dissolved in dry DCM (4 mL) under a nitrogen atmosphere. To this solution was added dropwise a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (136 mg, 0.695 mmol) and formic acid (0.029 mL, 0.70 mmol) in dry DCM (3 mL). The mixture was stirred at room temperature for 6 days and then quenched with 1 M HCl (4 mL). The aqueous layer was extracted with DCM (3×3 mL) and the combined organic extracts were washed with water and brine. Water was removed by filtration through hydrophobic filter paper before the solvent was removed in vacuo. Purification by FCC (hexane / EtOAc, 90:10) gave (3S,20R)-20-(hydroxyethyl)-pregn-7-en-3-yl acetate as a colorless solid (44 mg, 0.11 mmol, 68%).

[0185] 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H, CHO), 5.15 (dd, J = 5.2, 2.5 Hz, 1H, H-7), 4.69 (tt, J = 11.2, 4.6 Hz, 1H, H-3), 4.24 (ddd, J = 10.7, 7.8, 5.0 Hz, 1H, H-23), 4.16 (dt, J = 10.9, 7.6 Hz, 1H, H-23), 2.02 (s, 3H, H3CCOO), 2.00 (t, J = 3.6 Hz, 1H, H-12), 1.97 - 1.09 (m, 25H), 0.98 (d, J = 6.7 Hz, 3H, H-21), 0.81 (s, 3H, H-18), 0.54 (s, 3H, H-19). 13C NMR (101 MHz, CDCl3) δ 170.83 (H3CCOO), 161.38 (CHO), 139.38 (C-8), 117.70 (C-7), 73.59 (C-3), 62.40 (C-23), 56.13 (C-17), 55.08 (C-14), 49.35 (C-9), 43.58 (C-13), 40.17 (C-5), 39.60 (C-12), 36.97 (C-1), 34.55 (C-22), 34.34 (C-10), 33.93 (C-4), 33.62 (C-20), 29.66 (C-6), 28.07 (C-16), 27.63 (C-2), 23.04 (C-15), 21.61 (H3CCOO), 21.58 (C-11), 18.93 (C-21), 13.08 (C-19), 11.95 (C-18). HR-MS (EI): calcd. for C26H40O4 416.2927, found 416.2919. Example 35

change

[0186] Neoergosterol (1976 mg, 5.19 mmol) was added to a round-bottom flask containing acetic anhydride (41 mL) and pyridine (0.83 mL, 10 mmol). The mixture was heated to 120° C. for 2 h and then cooled to room temperature overnight. A white precipitate formed, which was filtered and washed with cold MeOH. After drying in vacuum, neoergosteryl acetate was obtained as a colorless solid (1452 mg, 3.44 mmol, 66%).

[0187] 1 H NMR (400 MHz, CDCl3) δ 6.87 (q, J = 7.9 Hz, 2H, H-6, H-7), 5.31 - 5.20 (m, 2H, H-22, H-23), 5.15 (tdd, J = 8.1, 6.2, 4.2 Hz, 1H, H-3), 3.09 (dd, J = 16.3, 5.0 Hz, 1H, H-4), 2.87 (dd, J = 16.2, 7.7 Hz, 1H, H-4), 2.67 (d, J = 6.1 Hz, 5H, H-14 und CH2), 2.23 (ddd, J = 12.9, 6.7, 2.5 Hz, 1H, CH2), 2.10 (ddd, J = 15.9, 5.4, 4.0 Hz, 2H, H-20 und CH2), 2.06 (s, 3H, H3CCOO), 1.98 - 1.84 (m, 3H, H-24 und CH2), 1.73 - 1.63 (m, 1H, CH2), 1.54 - 1.13 (m, 5H, H-17 und CH2), 1.09 (d, J = 6.6 Hz, 3H, H-21), 0.94 (d, J = 6.9 Hz, 3H, H-24 1 ), 0.89 - 0.82 (m, 6H, H-27, H-26), 0.61 (s, 3H, H-18). 13C NMR (101 MHz, CDCl3) δ 171.0 (H3CCOO), 138.1 (C-9), 135.7 (C-22), 134.2 (C-8), 133.2 (C-10), 132.2 (C-23), 130.8 (C-5), 126.7 (C-6), 124.0 (C-7), 70.0 (C-3), 55.2 (C-17), 51.9 (C-14), 43.0 (C-24), 41.9 (C-13), 40.7 (C-20), 37.0 (C-12), 35.2 (CH2), 33.3 (C-25), 29.3 (CH2), 28.2 (CH2), 25.2 (CH2), 24.3 (CH2), 24.3 (CH2), 21.6 (H3CCOO), 21.2 (C-21), 20.1 (C-26 or C-27), 19.8 (C-26 or C-27), 17.8 (C-24) 1 ), 11.5 (C-18). HR-MS (EI): calcd. for C 29 H 42 O2422.3185, found 362.3080 (-H3CCOOH). (3S,20S)-20-Formylpregna-5,7,9-trien-3-yl acetate (MiH-32)

[0188] To a solution of neoergosteryl acetate (1700 mg, 4.02 mmol) in dry DCM in a gas washing bottle equipped with stirring beads and a glass frit, pyridine (2.0 mL, 25 mmol) and a few crystals of Sudan III were added. The solution was cooled to −78° C. using a dry ice-acetone bath while passing nitrogen through the solution using the glass frit. Ozone was then introduced through the glass frit (60 L / h, 60 W) until the color of the solution changed from pale pink to pale yellow. Nitrogen was again passed through the solution, followed after 10 min by the addition of dimethyl sulfide (0.59 mL, 8.0 mmol) dissolved in MeOH (20 mL). Stirring was continued at −78° C. for another 30 min, and then the reaction mixture was allowed to warm to room temperature. After removal of the solvent under reduced pressure, the oily residue was dissolved in ethyl acetate (40 mL) and washed with 5% KHSO4 solution (3×40 mL). The organic layer was filtered through hydrophobic filter paper to remove water and the solvent was removed in vacuo. The crude product was subjected to FCC (hexane / EtOAc, 90:10) to give (3S,20S)-20-formylpregna-5,7,9-trien-3-yl acetate as a colorless solid (1090 mg, 3.08 mmol, 76%).

[0189] 1H NMR (400 MHz, CDCl3) δ 9.64 (d, J = 3.1 Hz, 1H, CHO), 6.90 (d, J = 7.9 Hz, 1H, H-6), 6.85 (d, J = 7.8 Hz, 1H, H-7), 5.15 (dddd, J = 9.1, 7.9, 5.0, 3.1 Hz, 1H, H-3), 3.09 (dd, J = 16.3, 5.0 Hz, 1H, H-4), 2.87 (dd, J = 16.3, 7.7 Hz, 1H, H-4), 2.77 - 2.60 (m, 5H, H-14 und CH2), 2.46 (dqd, J = 10.0, 6.8, 3.1 Hz, 1H, H-20), 2.24 - 2.08 (m, 4H, CH2), 2.06 (s, 3H, H3CCOO), 1.98 - 1.88 (m, 1H, H-2), 1.74 (dt, J = 14.5, 8.2 Hz, 2H, H-17, CH2), 1.60 (ddd, J = 10.9, 8.2, 4.1 Hz, 2H, CH2), 1.21 (d, J = 6.8 Hz, 3H, H-21), 0.65 (s, 3H, H-18). 13 C NMR (101 MHz, CDCl3) δ 205.0 (CHO), 171.0 (H3CCOO), 137.3 (C-9), 133.9 (C-8), 133.3 (C-10), 131.2 (C-5), 126.9 (C-6 or C-7), 124.0 (C-6 or C-7), 69.9 (C-3), 51.2 (C-1), 50.2 (C-17), 50.0 (C-20), 42.6 (C-13), 36.8 (C-12), 35.2 (C-4), 28.1 (C-2), 27.9 (CH2), 25.0 (CH2), 24.7 (CH2), 24.3 (CH2), 21.6 (H3CCOO) , 13.7 (C-21), 11.7 (C-18). HR-MS (EI): calcd. for C 23 H 30 O3: 354.2195, found 294.1978 (-H3CCOOH). (3S,20S)-20-(Hydroxymethyl)-pregna-5,7,9-trien-3-yl acetate (MiH-45)

[0190] (3S,20S)-20-Formylpregna-5,7,9-trien-3-yl acetate (140 mg, 0.395 mmol) was dissolved in a 3:2 mixture of dry CHCl3 / MeOH (4 mL) in a flame-dried Schlenk flask under nitrogen atmosphere. After addition of sodium borohydride (15 mg, 0.40 mmol), stirring was continued at room temperature for 1 h. The reaction was quenched using saturated NH4Cl solution (3 mL) and the aqueous layer was extracted with CHCl3 (3 x 3 mL). The combined organic extracts were dried by filtration through hydrophobic filter paper and the solvent was removed in vacuum. After purification using FCC (hexane / EtOAc, 70:30), (3S,20S)-20-(hydroxymethyl)-pregna-5,7,9-trien-3-yl acetate was obtained as a colorless solid (130 mg, 0.365 mmol, 92%).

[0191] 1H NMR (400 MHz, CDCl3) δ 6.87 (q, J = 7.9 Hz, 2H, H-6 und H-7), 5.15 (dddd, J = 9.1, 8.0, 5.0, 3.1 Hz, 1H, H-3), 3.70 (dd, J = 10.5, 3.2 Hz, 1H, H-22), 3.45 (dd, J = 10.5, 6.7 Hz, 1H, H-22), 3.09 (dd, J = 16.3, 5.1 Hz, 1H, H-4), 2.87 (dd, J = 16.3, 7.7 Hz, 1H, H-4), 2.75 - 2.62 (m, 5H, H-11, H-14, H-15, H16, H-17), 2.25 (ddd, J = 13.2, 6.8, 2.5 Hz, 1H, H-12), 2.16 - 2.08 (m, 3H, H-2, H-15, H-16), 2.06 (s, 3H, H3CCOO), 1.98 - 1.88 (m, 1H, H-2), 1.74 - 1.40 (m, 7H, H-12, H-14, H-15, H-16, H-17, H-20), 1.14 (d, J = 6.6 Hz, 3H, H-21), 0.62 (s, 3H, H-18). 13 C NMR (101 MHz, CDCl3) δ 171.0 (H3CCOO), 137.9 (C-9), 134.2 (C-8), 133.2 (C-10), 130.9 (C-5), 126.8 (C-6), 124.0 (C-7), 70.0 (C-3), 68.1 (C-22), 51.6 (C-14 or C-17), 51.6 (C-14 or C-17), 42.1 (C-13), 39.3 (C-20), 36.9 (C-12), 35.2 (C-4), 28.5 (C-1), 28.2 (C-2), 25.2 (C-11), 24.4 (C-15 or C-16), 24.3 (C-15 or C-16), 21.6 (H3CCOO), 17.0 (C-21), 11.3 (C-18). HR-MS (EI): calcd. for C 23 H 32O3356.2351, found 338.2241 (-H2O). (3S,20S)-20-[(2-fluoroacryloyloxy)methyl]-pregna-5,7,9-trien-3-yl acetate (MiH-46, Example 35)

[0192] In a flame-dried round-bottom flask equipped with a stir bead, (3S,20S)-20-(hydroxymethyl)-pregna-5,7,9-trien-3-yl acetate (36 mg, 0.10 mmol), 2-fluoropropenoic acid (11.2 mg, 0.121 mmol), and DMAP (6.2 mg, 0.051 mmol) were dissolved in dry DCM (2 mL) under a nitrogen atmosphere. To this solution was added dropwise a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.7 mg, 0.121 mmol) in dry DCM (1 mL). The reaction was stirred for 48 h and then quenched with 1 M HCl (2 mL). The aqueous layer was extracted with DCM (3×3 mL) and the combined organic extracts were washed with water and brine. Water was removed by filtration through hydrophobic filter paper before the solvent was removed in vacuo. Purification by FCC (hexane / EtOAc, 90:10) gave (3S,20S)-20-[(2-fluoroacryloyloxy)methyl]-pregna-5,7,9-trien-3-yl acetate as a colorless solid (31.6 mg, 0.0737 mmol, 73%).

[0193] 1H NMR (500 MHz, CDCl3) δ 6.89 (d, J = 7.8 Hz, 1H, H-6), 6.85 (d, J = 7.8 Hz, 1H, H-7), 5.68 (dd, J = 43.4, 3.2 Hz, 1H, CFCH2), 5.33 (dd, J = 13.0, 3.2 Hz, 1H, CFCH2), 5.15 (dddd, J = 9.2, 7.9, 5.0, 3.0 Hz, 1H, H-3), 4.30 (dd, J = 10.8, 3.5 Hz, 1H, H-22), 4.03 (dd, J = 10.8, 7.4 Hz, 1H, H-22), 3.09 (dd, J = 16.3, 5.0 Hz, 1H, H-4), 2.87 (dd, J = 16.2, 7.7 Hz, 1H, H-4), 2.74 - 2.63 (m, 5H, H-11, H-13), 2.25 (ddd, J = 13.0, 7.1, 2.1 Hz, 1H, H-12), 2.17 - 2.07 (m, 3H, H-1, H-15, H-16), 2.06 (s, 3H, H3CCOO), 1.98 - 1.87 (m, 2H, H-2), 1.75 - 1.67 (m, 1H, H-12), 1.62 - 1.52 (m, 4H, H-1, H-15, H-16), 1.49 - 1.42 (m, 1H H-17), 1.14 (d, J = 6.6 Hz, 3H, H-21), 0.63 (s, 3H, H-18). 13C NMR (126 MHz, CDCl3) δ 171.0 (H3CCOO), 160.8 (d, J = 36.3 Hz, OOCCF), 153.6 (d, J = 262.3 Hz, OCOCF), 137.6 (C-9), 134.0 (C-8), 133.2 (C-10), 131.0 (C-5), 126.8 (C-6), 124.0 (C-7), 102.7 (d, J = 15.3 Hz, CFCH2), 70.9 (C-22), 69.9 (C-3), 51.9 (C-17), 51.5 (C-14), 42.3 (C-13), 36.9 (C-12), 36.4 (C-20), 35.2 (C-4), 28.5 (C-16), 28.2 (C-2), 25.1 (C-11), 24.4 (C-1 or C-15), 24.3 (C-1 or C-15), 21.6 (H3CCOO), 17.4 (C-21), 11.3 (C-18). HR-MS (EI): calcd. for C 26 H 33 FO4428.2363, found 368.2127 (-H3CCOOH). Example 36

change

[0194] A solution of tetra-n-butylammonium fluoride (TBAF) (1M in THF, 0.024 mL, 0.082 mmol) in THF (2 mL) was cooled to -78 °C, then a solution of fluorovinyldiphenylsilane (0.187 mL, 0.816 mmol) and (3S,20S)-20-formyl-pregn-7-en-3-yl acetate (152 mg, 0.408 mmol) in dry THF (2 mL) was added dropwise. Stirring was continued at -78 °C for 1 h, then the mixture was allowed to warm to room temperature and stirred overnight. The reaction was then quenched by the addition of water, the two layers were separated, and the aqueous layer was extracted with DCM (3 x 5 mL). The combined organic layers were dried by filtration through hydrophobic filter paper and the solvent was removed under reduced pressure. Purification by FCC (hexane / EtOAc, 90:10) gave (3S,20RS)-20-(2-fluoro-1-hydroxyprop-2-enyl)-pregn-7-en-3-yl acetate as a mixture of epimers as a colorless solid (40 mg, 0.096 mmol, 23%).

[0195] 1 H NMR (500 MHz, CDCl3) δ 5.20 - 5.14 (m, 1H, H-7), 4.76 - 4.53 (m, 3H, H-3, CFCH2), 4.48 (s, 1H, H-22), 4.29 (s, 1H, H-22), 2.03 (s, 3H, H3CCOO), 2.01 - 1.27 (m, 21H), 1.14 (td, J = 14.4, 13.9, 4.0 Hz, 1H, H-4), 0.94 (d, J = 6.8 Hz, 2H, H-21), 0.86 (d, J = 7.0 Hz, 1H, H-21), 0.81 (s, 3H, H-19), 0.59 (s, 1H, H-18), 0.57 (s, 2H, H-18). 13C NMR (126 MHz, CDCl3) δ 170.9 (H3CCOO), 166.8 (d, J = 259.0 Hz, CF), 166.8 (d, J = 258.6 Hz, CF), 139.3 (C-8), 139.1 (C-8), 117.9 (C-7), 117.8 (C-7), 89.8 (d, J = 16.9 Hz, CFCH2), 89.6 (d, J = 16.6 Hz, CFCH2), 73.6 (C-3), 73.6 (C-3), 71.8 (d, J = 34.8 Hz, C-22), 70.8 (d, J = 34.6 Hz, C-22), 55.1 (C-14), 55.0 (C-14), 52.1 (C-17), 51.7 (C-17), 49.3 (C-5), 43.5 (C-13), 43.3 (C-13), 40.2 (C-12), 39.5 (C-12), 39.2 (C-20), 38.2 (C-20), 37.1 (C-4), 37.0 (C-4), 34.4 (C-10), 33.9 (C-1 or C-2), 29.7 (C-6), 27.7 (C-11), 27.6 (C-11), 27.6 (C-1 or C-2), 23.0 (C-15 or C-16), 22.9 (C-15 or C-16), 21.6 (H3CCOO), 21.6 (C-15 or C-16), 13.1 (C-19), 13.1 (C-19), 12.3 (C-21), 12.0 (C-18), 12.0 (C-18), 11.8 (C-21). HR-MS (EI): calcd. for C 26 H 39 FO3418.2883, found 418.2877. Example 37 [ka] (3S,20S)-20-[(2-fluoro-N-methylacrylamide)methyl]-pregn-7-en-3-yl acetate

[0196] In a flame-dried round-bottom flask equipped with a boiling bead, the secondary amine from Example 13 (61 mg, 0.16 mmol), 2-fluoropropenoic acid (17.5 mg, 0.189 mmol), and DMAP (9.6 mg, 0.079 mmol) were dissolved in dry DCM (2 mL) under a nitrogen atmosphere. To this solution was added dropwise a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.9 mg, 0.189 mmol) in dry DCM (1 mL). The reaction was stirred for 48 h and then quenched with 1 M HCl (2 mL). The aqueous layer was extracted with DCM (3×3 mL) and the combined organic extracts were washed with water (2×5 mL) and brine (5 mL). The combined organic extracts were dried by filtration through hydrophobic filter paper and the solvent was removed under reduced pressure. Purification by FCC (hexane / EtOAc, 70:30) gave (3S,20S)-20-[(2-fluoro-N-methylacrylamido)methyl]-pregn-7-en-3-yl acetate as a colorless solid (42.3 mg, 0.092 mmol, 58%).

[0197] 1 H NMR (500 MHz, CDCl3; mixture of rotamers) δ 5.31 - 5.03 (m, 3H, H-7, CFCH2), 4.69 (tt, J = 11.3, 4.6 Hz, 1H, H-3), 3.52 - 3.08 (m, 2H. H-22), 3.04 (s, 3H, NCH3), 2.92 (s, 3H, NCH3), 2.02 (s, 4H, H3CCOO, with H-12 underlying), 1.97 - 1.17 (m, 19H), 1.13 (td, J = 14.6, 13.9, 3.9 Hz, 1H, H-4), 0.90 (dd, J = 13.2, 6.1 Hz, 3H, H-21), 0.81 (s, 3H, H-19), 0.57 (s, 3H, H-18). 13C NMR (126 MHz, CDCl3; mixture of rotamers) δ 170.8 (H3CCOO), 163.2 (d, J = 29.0 Hz, COCF), 162.8 (d, J = 30.1 Hz, COCF), 159.4 (d, J = 23.3 Hz, CF), 157.2 (d, J = 22.2 Hz, CF), 139.2 (C-8), 139.1 (C-8), 118.0 (C-7), 117.8 (C-7), 99.2 (CFCH2), 99.1 (CFCH2), 73.6 (C-3), 55.7 (C-22), 54.8 (C-14), 54.6 (C-14), 53.8 (C-22), 49.3 (C-5), 43.9 (C-13), 40.2 (C-9), 39.5 (C-12), 37.0 (C-4), 36.9 (NCH3), 35.7 (C-17), 35.2 (C-20), 34.3 (C-10), 34.0 (NCH3), 33.9 (C-11), 29.6 (C-6), 27.8 (C-1 or C-2), 27.6 (C-1 or C-2), 23.2 (C-16), 21.6 (H3CCOO), 21.5 (C-15), 16.8 (C-21), 16.3 (C-21), 13.1 (C-19), 12.1 (C-18). HR-MS (EI): calcd. for C 28 H 42 FNO3459.3149, found 459.3144. Biological activity of the compound Assay

[0198] A GC / MS-based screening assay for distal cholesterol biosynthesis inhibitors was used (see Mueller et al., Nature Protocols, 2019, 14(8), pp. 2546-2570).

[0199] Two test concentrations (1 μM and 50 μM) were used. Compounds were dissolved in ethanol or DMSO and test stock solutions were prepared considering a final dilution of 1:100. Finally, 10 μL of test stock solution was added to 990 μL of lipid-free medium containing 1% lipoprotein-deficient serum (LPDS) without antibiotics. HL-60 cells (1×106 cells) were incubated in 1.0 mL of medium consisting of 990 μL of lipid-free medium containing 1% LPDS and 10 μL of the respective inhibitor solution in a 24-well plate.

[0200] After a 24-h incubation period (conditions: 37°C in a humidified atmosphere containing 5% CO2), the contents of each well were transferred to a 2-mL plastic tube, the wells were washed with 750 μL of phosphate-buffered saline (PBS), and the wash was combined with the medium sample. Cells were harvested by centrifugation at 540 x g for 5 min, washed once with 1 mL of cold PBS, and centrifuged again under the same conditions. Samples were transferred to glass vials, 1 mL of 1 M NaOH was added to each vial, and saponification was carried out at 70°C for 60 min.

[0201] After the samples were cooled to room temperature, they were returned to 2 mL plastic vials and lipids were extracted by adding 100 μL of internal standard solution (cholestane in MtBE, 10 μg / mL) and 650 μL of MtBE. The tubes were vigorously shaken for 1 min and then centrifuged at 9200 × g for 5 min. The extraction was repeated with 750 μL of MtBE and the organic extracts were combined in a plastic tube containing 40 mg of dry sodium sulfate and 5 mg of Bondesil PSA. The samples were then centrifuged at 9200 × g for 5 min. One milliliter of the purified extract was transferred to an autosampler glass vial and evaporated to dryness under a gentle nitrogen stream.

[0202] To each vial, 950 μL of MtBE and 50 μL of a mixture of N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) and N-trimethylsilylimidazole (TSIM) (10:1) were added. The silylation reaction was carried out at room temperature for 1 h. The samples thus prepared were analyzed on a GC-MS system equipped with helium as carrier gas and a 5-MS separation column. The obtained sterol patterns qualitatively indicate the target enzymes in distal cholesterol biosynthesis (for details, see Mueller et al., Nature Protocols, 2019, 14(8), pp. 2546-2570).

[0203] I C 50 For the determination of , evaluating the incorporation of labeled acetate in the target molecule cholesterol, the protocol is modified as follows: add sterile 2- 13 Add 10 μL of C-sodium acetate solution (6.25 mg / mL) to final 13 The C-acetate concentration was 62.5 μg / mL. After saponification, 3 × 25 μL aliquots were set aside for protein determination applying Bradford reagent. After work-up and silylation, GC-MS analysis revealed the protein binding to cholesterol according to the formula shown below: 13 This allows quantification of C incorporation. The percentage inhibition (see formula) relative to untreated control samples (0% inhibition) was plotted against the log inhibitor concentration using Graph Pad Prism 4 (or newer versions). A sigmoidal dose-response model with variable slope is used, setting a minimum level constant equal to 0 as constraint. All samples are normalized to their protein. For each concentration, the percentage inhibition is determined in triplicate.

number

[0204] The above formula is the calculation of percentage inhibition, where A S represents the sample area; A I.S.C. represents the control internal standard area; PCC represents the control protein content; A C represents the control area; A I.S.S. represents the sample internal standard area; PC S represents the sample protein content. result

[0205] The results are shown in Table 1. [Table 1-1] [Table 1-2] In vivo experiment using Example 11 (SH42)

[0206] Hemizygous APOE *APOE*3-Leiden (E3L) mice were crossed with homozygous human cholesteryl ester transfer protein (CETP) transgenic mice to generate heterozygous E3L.CETP mice on a C57BL / 6J background [M. Westerterp et al., "Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice"; Arterioscler Thromb Vasc Biol 26, 2552-2559 (2006)]. Due to the phenotypic heterogeneity of E3L.CETP mice, non-responders were identified by plasma lipid levels after 4 h fasting, i.e., total cholesterol level <2 mM and triglyceride level <2 mM, and were excluded before specific dietary treatment. LXRα-deficient mice (also on a C57BL / 6J background) generated by Deltagen using gene targeting methods as described in [T. Plosch et al., "Abcg5 / Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice"; Am J Physiol Gastrointest Liver Physiol, 291, G414-423 (2006) (33)] were provided by Tularik (San Francisco, CA, US). Mice were group-housed in individually ventilated cages under standard conditions of room temperature (22°C), relative humidity of 40±5%, and a 12-h light / dark (lights on 7 am; lights off 7 pm) cycle. All animals were given humane care according to the standards outlined in the NIH "Guide for the Care and Use of Laboratory Animals."All animal activities were carried out in accordance with the guidelines of Directive 2010 / 63 / EU of the European Parliament on the protection of animals used for scientific purposes.

[0207] Ten to 12 week old male E3L.CETP and LXRα null mice were fed a high-fat, high-cholesterol diet (HFCD; Altromin, Germany) containing 60% (energy) fat and 1% (wt / wt) cholesterol, randomly divided into two groups, and administered the DHCR24 inhibitor compound of Example 11 [also referred to herein as SH42] (0.5 mg·mouse -1 ) or vehicle (saline containing 3.3% ethanol and 3.3% Cremophor EL) by intraperitoneal injection three times a week. E3L.CETP mice were treated for 4 weeks (n = 6 mice per group) and 8 weeks (n = 8 mice per group) to assess effects on hepatic immune cells by flow cytometric analysis and on hepatic steatosis by quantitative lipidomics analysis, respectively. LXRα-deficient mice were treated for 4 weeks with either SH42 (n = 11 mice) or vehicle (n = 10 mice) to assess effects on hepatic steatosis and immune cells. In rescue experiments, male E3L.CETP mice were initially fed HFCD for 10 weeks and then treated with SH42 (0.5 mg·mouse) by intraperitoneal injection three times a week for an additional 8 weeks. -1 ) or co-treated with vehicle (saline containing 3.3% ethanol and 3.3% Cremophor EL).

[0208] Body weight was measured weekly. Body composition (i.e., fat and lean body mass; EchoMRI-100; EchoMRI, Houston, TX, USA) was assessed before and after the intervention. Food intake was determined during the treatment period. result Inhibition of DHCR24 by SH42 significantly increases hepatic desmosterol levels and ameliorates hepatic steatosis

[0209] To evaluate the effect of DHCR24 inhibition on fatty liver, E3L.CETP mice were fed HFCD while treated with vehicle or the synthetic DCHR24 inhibitor SH42 for a period of 8 weeks. SH42 treatment did not affect food intake but temporarily blocked HFCD-induced weight gain compared to the control group. After 8 weeks of treatment, the body weight and body composition, i.e., lean body mass and fat body mass, of SH42-treated mice were comparable to those of the control group. Furthermore, the weights of various tissues (i.e., liver, white adipose tissue, kidney, heart, lung, spleen, and brown adipose tissue) were not altered by SH42 treatment. SH42 significantly increased hepatic desmosterol levels (10-fold, see Figure 3A).

[0210] Fatty liver was assessed and scored by HE staining. Compared with the control treatment, SH42 treatment improved diet-induced fatty liver, as evidenced by a clear decrease in fatty liver score (-58%) and liver lipid area (-35%). Liver lipid profile was analyzed by comprehensive lipidomics analysis. First, a clear change in lipid class composition was observed after SH42 treatment. Specifically, SH42 treatment caused a relative decrease in TAG (-21%) and DAG (-22%), accompanied by a relative increase in other lipid classes, including CER, PC, PE, and SM.

[0211] The majority of significantly altered lipid species were downregulated, many of them TAG. Consistently, SH42 tended to decrease hepatic concentrations of triacylglycerides (TAG) (-39%; see Figure 3B) and diacylglycerides (DAG) (-20%; see Figure 3C). Furthermore, SH42 treatment reduced hepatic free fatty acids (FFA) (-16%; see Figure 3D) and cholesterol esterase (CE) levels (-25%; see Figure 3E). Despite these strong effects on hepatic lipid content, SH42 did not affect fasting plasma glucose, insulin, or homeostasis model assessment of insulin resistance (HOMA-IR) scores. Together, inhibition of DHCR24 by SH42 markedly increased hepatic desmosterol levels and was accompanied by amelioration of diet-induced hepatic steatosis without significant effects on body composition and glucose homeostasis. Inhibition of DHCR24 by SH42 prevents Kupffer cell activation and reduces immune cell infiltration into the liver

[0212] Impact of DHCR24 inhibition on hepatic inflammation in mice treated with SH42 or vehicle for 8 weeks by immunohistochemistry. SH42 treatment significantly reduced hepatic F4 / 80 content (-29%) and the number of hepatic crown-like structures of macrophages surrounding dying hepatocytes (-79%), a hallmark of NASH development.

[0213] Flow cytometry of MACS-purified liver leukocytes revealed that SH42 treatment for 4 weeks tended to decrease total liver leukocytes (-37%; p=0.09). A significant increase in total Kupffer cells (KC) was observed with SH42 treatment (+44%). SH42 binds MHCII + / CD11c + It did not significantly reduce activated KCs, but MHCII - / CD11c -Resting KCs were significantly increased (+21%), representing a blockade of KC activation. Furthermore, SH42 treatment reduced monocytes in both liver (-79%) and blood (-43%; p=0.06) and reduced hepatic neutrophils (-50%) without affecting circulating neutrophils. Together, these data indicate that SH42 treatment blocks KC activation, limits immune cell recruitment in the liver, and reduces hepatic inflammation. Inhibition of DHCR24 by SH42 does not increase circulating lipids

[0214] Consistent with the robust increase in hepatic desmosterol levels, SH42 also reduced plasma desmosterol levels to undetectable levels (0.5 μg mL -1 (less than 0.05 mg) to 3.1 ± 0.4 μg mL -1 DHCR24 significantly increased circulating lipid levels to 100%. Since synthetic LXR agonists usually induce lipid biosynthesis and hypertriglyceridemia as undesired effects, the effect of 8 weeks of SH42 treatment on circulating lipid levels was determined using quantitative global lipidomics analysis. Analysis of the plasma lipidome revealed that SH42 treatment relatively decreased circulating CE, while relatively increased lactosylceramide (LCER), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). In terms of absolute lipid concentrations, SH42 did not affect plasma levels of total TAG and DAG, while significantly decreased plasma levels of FFA (-16%) and CE (-24%; p=0.08). These data imply that inhibition of DHCR24 by SH42 increases plasma desmosterol levels and decreases FFA and CE levels, importantly without inducing hypertriglyceridemia. Inhibition of DHCR24 by SH42 delays high-fat diet-induced hepatitis, liver fibrosis, and liver injury

[0215] E3L.CETP mice were first fed HFCD for 10 weeks to establish NAFLD, and then treated with vehicle or SH42 while continuing HFCD for an additional 8 weeks. SH42 treatment did not significantly affect total body weight or body composition. No differences in liver weight and hepatic steatosis were observed, and SH42 treatment reduced hepatitis primarily by reducing hepatic crown-like structures (-89%) without significantly affecting F4 / 80-positive area, and ameliorated liver fibrosis as evidenced by reduced collagen content (-50%). Furthermore, SH42 treatment reduced plasma levels of plasma alanine transaminase (ALT), a liver injury marker (-42%). These effects were accompanied by a strong increase (>400-fold) in plasma desmosterol levels. Taken together, inhibition of DHCR24 by SH42 delays the progression of high-fat diet-induced NAFLD / NASH from simple steatosis to an advanced stage with severe hepatitis, liver fibrosis, and liver injury. In vivo experiments using Example 11 (SH42) and Example 33 (MiH-17)

[0216] Experiments were performed to determine whether the compound of Example 33 (MIH17) increases brain and circulating desmosterol levels.

[0217] Mice were given daily intraperitoneal injections of vehicle (6% ethanol and 6% Cremophor EL in saline; 5 μl / g mouse) and either SH42 or MIH17 (50 μg / g mouse; 5 μl / g mouse) for 3 days. 24 h after the last injection and after 4 h fasting (10-14 h), mice were sacrificed by CO2 inhalation (according to Zenya: 'Euthanasia with the use of the CO2box (version 4)'), after which blood was collected by cardiac puncture and organs were isolated. Desmosterol levels were determined by GC / MS as described below.

[0218] To each sample, 5 μL of an internal standard mixture consisting of 1 mg / mL cholesterol, 20 μg / mL desmosterol-d6, and 20 μg / mL 25-OH-cholesterol-d6 was added. After hydrolysis with 80% (v / v) ethanolic sodium hydroxide (1M), lipids were extracted twice into methyl-tert-butyl ether. After drying under nitrogen and derivatization with N-methyl-N-(trimethylsilyl)trifluoroacetamide, sterols were analyzed on an Agilent GC-MS 5977B gas chromatograph coupled to a single quadrupole mass spectrometer. For sterol quantification, the following ion traces were monitored: 333 and 327 for desmosterol-d6 and desmosterol, respectively. Group comparisons were performed based on area ratios, and the desmosterol signal was corrected with its internal standard desmosterol-d6.

[0219] The desmosterol signal detected in the samples is shown in Figure 4 and Figure 5 (Figure 5; brain: p-value 0.059; plasma: p-value 0.017).

[0220] All references cited herein, including publications, patent applications, and patents, are incorporated by reference in their entirety to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein (to the maximum extent permitted by law).

[0221] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0222] Any and all examples provided herein, or the use of exemplary language (e.g., "etc.") are intended merely to better clarify the invention and do not pose a limitation on the scope of the invention unless otherwise stated. No language in the specification should be construed as indicating that any unterminated element is essential to the practice of the invention.

[0223] Citation and incorporation of patent documents herein is done merely for convenience and does not reflect any opinion of the validity, patentability, and / or enforceability of such patent documents.

[0224] This invention includes all modifications and equivalents of the subject matter recited in the sections appended hereto as permitted by applicable law.

Claims

1. A compound of formula (10) or its salt, solvate, hydrate, or prodrug, 【Chem.98】 During the ceremony, G is, 【Chem.99】 A condensed ring system selected from; B is, 【Chemistry 100】 Selected from; R １ This is hydrogen and -C(=O)R ６ Selected from; R ２ is hydrogen and C １～６ Selected from alkyl groups; R ３ is selected from a group represented by formula (2), -[C(R ７ ), ２ -X, -CH=CR ｎ R ６ R ７ , -CR ７ =N-N(R ６ ), ２ a 5- to 10-membered heteroaryl, and a 5- to 10-membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally substituted by one or more groups selected from -OH, halo, -CN, -NH ２ , -NO ２ , C １～６ alkyl, and C １～６ alkoxy; 【Chemistry 101】 n is an integer between 1 and 6; W is O and NR ６ Selected from; Y is hydrogen and C ２ Selected from alkenyls, where C ２ The alkenil is replaced as needed by one or more halos; X is selected from halo, -OH, -SH, -O-Z, -S-Z, -S-S-Z, 5-10 member heteroaryl, and 5-10 member heterocycloalkyl, where the 5-10 member heteroaryl and 5-10 member heterocycloalkyl are -OH, halo, -CN, -NH ２ , -NO ２ , C １～６ Alkyl and C １～６ It is optionally substituted with one or more groups selected from alkoxy; Each R ４ is hydrogen and C １～６ Selected independently of alkyl; R ５ is hydrogen and C １～６ Selected from alkyl groups; Each R ６ is hydrogen and C １～６ Selected independently of alkyl; Each R ７ H, C １～６ Alkyl and C ２～６ Selected independently of alkenyl, where C １～６ Alkyl and C ２～６ The alkenil is replaced as needed by one or more halos; Z is C ６～１０ Selected from aryl, 5-10 member heteroaryl, and 5-10 member heterocycloalkyl, where C ６～１０ Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl groups include -OH, halo, -CN, and -NH. ２ , -NO ２ , C １～６ Alkyl and C １～６ It is optionally substituted with one or more groups selected from alkoxy; The prodrug is an ester, amide, hydrazone, or disulfide of the compound of formula (10); The aforementioned compound, 【Chemical Engineering 102】 【Chemistry 103】 It is not one of them. A compound or its salt, solvate, hydrate, or prodrug.

2. G is 【Chemical 104】 The compound according to claim 1, or a salt, solvate, hydrate, or prodrug thereof.

3. R ５ The compound according to claim 1, or a salt, solvate, hydrate, or prodrug thereof, selected from hydrogen, methyl, and ethyl.

4. Each R ４ The compound according to claim 1, or a salt, solvate, hydrate, or prodrug thereof, independently selected from hydrogen, methyl, and ethyl.

5. B, 【Chemistry 105】 A compound according to claim 1, or a salt, solvate, hydrate, or prodrug thereof, selected from the above.

6. R ２ The compound according to claim 1, or a salt, solvate, hydrate, or prodrug thereof, wherein the compound is hydrogen.

7. R ３ However, equation (2): 【Chemistry 106】 The compound according to claim 1 or its salt, solvate, hydrate, or prodrug, which is represented by the group.

8. Each R ６ However, the compound according to claim 7, or a salt, solvate, hydrate, or prodrug thereof, independently selected from hydrogen, methyl, and ethyl.

9. R ３ However, -[C(R ７ ) ２ ] ｎ -X, the compound according to claim 1, or a salt, solvate, hydrate, or prodrug thereof.

10. The compound according to claim 9, or a salt, solvate, hydrate, or prodrug thereof, wherein X is selected from halo and -OH.

11. The compound according to claim 9, or a salt, solvate, hydrate, or prodrug thereof, wherein X is -SH.

12. X is -O-Z, -S-Z, or -S-S-Z, and then Z is C ６～１０ A compound according to claim 9, or a salt, solvate, hydrate, or prodrug thereof, selected from aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl each contain at least one nitrogen atom.

13. The compound according to claim 9, or a salt, solvate, hydrate, or prodrug thereof, wherein X is a 5- to 10-membered heteroaryl compound.

14. R ３ However, -CH = CR ６ R ７ The compound according to claim 1, or a salt, solvate, hydrate, or prodrug thereof.

15. The aforementioned R ６ The compound according to claim 14, or a salt, solvate, hydrate, or prodrug thereof, wherein H is present.

16. R ７ However, hydrogen, C １～６ Alkyl, Halo-C １～６ Alkyl, C ２～６ Alkenyl and Halo-C ２～６ A compound according to claim 14, or a salt, solvate, hydrate, or prodrug thereof, selected from alkenyls.

17. R ３ However, -CR ７ = N - N (R ６ ) ２ The compound according to claim 1, or a salt, solvate, hydrate, or prodrug thereof.

18. R ３ The compound according to claim 1, or a salt, solvate, hydrate, or prodrug thereof, which is selected from a 5-10 member heteroaryl and a 5-10 member heterocycloalkyl, preferably wherein the 5-10 member heteroaryl and the 5-10 member heterocycloalkyl each contain at least one nitrogen atom. 【Request Item 19】 【Chemistry 107】 【Chemistry 108】 【Chemistry 109】 【Chemical 110】 A compound according to claim 1, or a salt, solvate, hydrate, or prodrug thereof, selected from the above.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a pharmaceutically acceptable additive.

21. A composition for therapeutic use and / or pharmacopoeia, comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

22. A composition for use in the treatment or prevention of DHCR24-mediated disorders, the composition comprising a compound of formula (10) or a salt thereof, solvate, hydrate, or prodrug as described in any one of claims 1 to 19, wherein the DHCR24-mediated disorder is selected from non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (asCVD), multiple sclerosis, hepatocellular carcinoma, breast cancer, endometrial cancer, B-cell lymphoma, drug-resistant cancer, and hepatitis C.

23. A composition for use in the treatment or prevention of DHCR24-mediated disorders, wherein the composition is of the formula: 【Chemistry 111】 A composition comprising the compound, wherein the DHCR24-mediated disorder is selected from non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (asCVD), multiple sclerosis, hepatocellular carcinoma, breast cancer, endometrial cancer, B-cell lymphoma, drug-resistant cancer, and hepatitis C.

24. A composition for use in the treatment or prevention of DHCR24-mediated disorders, wherein the composition is of the formula: 【Chemistry 112】 A composition comprising the compound, wherein the DHCR24-mediated disorder is selected from non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (asCVD), multiple sclerosis, hepatocellular carcinoma, breast cancer, endometrial cancer, B-cell lymphoma, drug-resistant cancer, and hepatitis C, and is preferably multiple sclerosis.

25. The composition according to claim 22, wherein the DHCR24-mediated disorder is selected from non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (asCVD), and multiple sclerosis.

26. The composition according to claim 25 for the treatment or prevention of non-alcoholic steatohepatitis (NASH) or atherosclerotic cardiovascular disease (asCVD) without inducing hyperlipidemia and / or hypertriglyceridemia.

27. A composition for use in the treatment or prevention of DHCR24-mediated disorders, wherein the composition comprises a compound, or a salt thereof, solvate, hydrate, or prodrug, the DHCR24-mediated disorder being hepatitis, hepatic fibrosis, and / or liver injury, and the compound, or a salt thereof, solvate, hydrate, or prodrug is as defined in any one of claims 1 to 19, 23, or 24.

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