Cyclophilin inhibitors and their use

Abstract

Compounds as defined by formulas 1-6 and their uses as cyclophylline inhibitors for the prevention or treatment of diseases or conditions such as cyclophylline-mediated diseases or conditions, particularly cyclophylline A-mediated diseases or conditions.

Description

[Technical Field]

[0001] This disclosure relates to cyclosporine analogs and their use for the treatment or prevention of diseases or disorders, particularly those related to the proliferation of cytokines in inflammatory pathways. In particular, this disclosure relates to compounds that can be provided as potent cyclophyllin A inhibitors, cyclophyllin D inhibitors, or both cyclophyllin A inhibitors and cyclophyllin D inhibitors. [Background technology]

[0002] It is well recognized that acute and chronic inflammation involves complex interactions of various cellular (neutrophils, macrophages) and extracellular (complement, histamine) factors acting in response to PAMP (pathogen-activating molecular pattern) and DAMP (damage-activating molecular pattern) signaling, which resolve the initial injury. Cyclophilin A has been demonstrated to function as a chemokine that directs the inflammatory response and promotes leukocyte migration, and blocking cyclophylin A has been shown to be beneficial in animal models of acute and chronic inflammation. The modulation or inhibition of cyclophyllin A is involved in the treatment of a variety of diseases and conditions, including cardiovascular disease, viral infections including human immunodeficiency virus (HIV) and influenza virus, and severe acute respiratory syndrome coronavirus (SARS-CoV), cancers including breast cancer, small cell lung cancer, non-small cell lung cancer and renal cell carcinoma, renal diseases including acute kidney injury, nephritis and renal fibrosis, rheumatoid arthritis, sepsis, asthma, colitis, ulcerative colitis, Crohn's disease, allergic rhinitis, atherosclerosis, vascular smooth muscle cell diseases, myocarditis, myocardial fibrosis, central nervous system diseases, Alzheimer's disease and amyotrophic lateral sclerosis.

[0003] More recently, severe forms of inflammation involving cell death and tissue necrosis have been described. Numerous data now support the opening of mitochondrial membrane pores called mitochondrial permeability transition pores (MPTPs) as crucial for the development and maintenance of this necrotizing inflammation. A key regulator of MPTP opening is cyclophyllin D (CypD), and CypD inhibitors have shown good activity in preventing tissue damage associated with necrotizing inflammation.

[0004] Cyclosporine A is a compound well known for its immunosuppressive properties, but other biological properties have also been described. Cyclosporine A has the following chemical structure: [ka] Cyclosporine A (CsA) Biologically active derivatives of cyclosporine A have also been created. For example, Patent Documents 1, 2, and 3 describe cyclosporine derivatives having various properties, including immunosuppressive, antiparasitic, and antiviral properties. Patent Document 1 describes a cyclosporine derivative modified at the 3-position (sarcosine) of the macrocyclic molecule of cyclosporine. In particular, Patent Document 1 discloses compound 0: [ka] Compound 0 Patent Document 4 also describes compound 0 for use in the treatment or prevention of acute or chronic inflammatory disorders. Patent Documents 5 and 6 describe cyclosporine derivatives for use in the treatment or prevention of diseases or conditions such as organ injury or organ failure.

[0005] The object of this disclosure is to provide further cyclosporine analogs, particularly analogs that may be useful for inhibiting cyclophyllines such as cyclophyllines A, B, and D, and for diseases and conditions associated therewith. In particular, this disclosure relates to compounds that can be provided as potent cyclophylline A inhibitors, cyclophylline D inhibitors, or both cyclophylline A and cyclophylline D inhibitors.

[0006] Specifically, this disclosure relates to compounds that can be provided as potent cyclophyllin A inhibitors. Further objectives of this disclosure will become apparent based on the following description, examples, and claims. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] U.S. Patent No. 6,583,265 [Patent Document 2] European Patent No. 0484281 [Patent Document 3] European Patent No. 0194972 [Patent Document 4] International Publication No. 2019 / 016572 [Patent Document 5] International Publication No. 2021 / 190601 [Patent Document 6] International Publication No. 2021 / 190603 [Overview of the Initiative]

[0008] In a first aspect, the disclosure relates to compounds as defined in the detailed description, namely compounds of formulas 1 to 6.

[0009] In a further aspect, the present disclosure provides use of the compound as a cyclophilin inhibitor. In a still further aspect, the present disclosure provides use of the compound in a method for preventing and / or treating a cyclophilin-mediated disease or condition, such as a cyclophilin A- or cyclophilin D-mediated disease or condition, specifically a cyclophilin A-mediated disease or condition. [MEANS FOR SOLVING THE PROBLEMS]

[0010] In a first aspect, the present disclosure relates to a compound of Formula 1, or a pharmaceutically acceptable salt thereof, [Chemical Formula] Formula 1 In the formula, X is [Chemical Formula] or [Chemical Formula] , n is 0, 1, 2, 3 or 4, c, d and e are each 0 or 1, Y is CH2 or NR x , R x is H or C1-C6 alkyl, R 1 and R 2 are each independently selected from H, aryl, arylalkyl, C1-C6 alkyl, C6-C 10 bicyclyl, (C1-C6 alkyl)C(O)2R 9 , and R 1 and R 2 are bonded together to form a C3-C6 cycloalkyl ring, R 3 and R 4 are each independently selected from H and C1-C6 alkyl, or R 3 and R 4They are bonded together to form a C3-C6 cycloalkyl ring, R 5 and R 6 Each is independently selected from H or C1-C6 alkyl groups. R 7 is OR 8 And, R 8 H, C1-C6 alkyl, CHR 10 OC(O)CHNH2R 11 , CHR 12 OC(O)R 13 , CH2CH2OH, CH2CH(OH)CH2OH or [ka] Selected from, where m is between 0 and 20, R 9 , R 10 , R 11 and R 12 Each is independently selected from H or C1-C6 alkyl groups. R 13 It is selected from O(C1-C6 alkyl) or C1-C6 alkyl, R 14 H, NR 15 R 16 , selected from a heteroalkyl ring or a heteroaryl ring, R 15 and R 16 Each is independently selected from H or C1-C6 alkyl, or R 15 and R 16 These are bonded together to form a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl ring.

[0011] In a second aspect, the disclosure relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof. [ka] formula 1 During the ceremony, X is [ka] or [ka] , n is 0, 1, 2, or 3. R 1 and R 2 These are H, C1-C6 alkyl, and (C1-C6 alkyl)C(O)2R, each independently. 9 Selected from, or R 1 and R 2 They are bonded together to form a C3-C6 cycloalkyl ring, R 3 and R 4 Each is independently selected from H, C1-C6 alkyl, or R 3 and R 4 They are bonded together to form a C3-C6 cycloalkyl ring, R 5 and R 6 Each is independently selected from H or C1-C6 alkyl groups. R 7 is OR 8 And, R 8 H, C1-C6 alkyl, CHR 10 OC(O)CHNH2R 11 , CHR 12 OC(O)R 13 , selected from CH2CH2OH or CH2CH(OH)CH2OH, R 9 , R 10 , R 11 and R 12 Each is independently selected from H or C1-C6 alkyl groups. R 13 This is selected from O(C1-C6 alkyl) or C1-C6 alkyl. [Modes for carrying out the invention]

[0012] In one embodiment, the cyclosporine compound according to this disclosure is a cyclosporine A compound comprising a substituent at the 3-position sarcosine residue of a macrocyclic ring, as defined in any one or combination of the embodiments described herein.

[0013] The positional numbering used herein refers to the commonly used nomenclature and the numbering of 11 amino acid residues characteristic of the cyclosporine core. Based on cyclosporine A, the amino acid residues may be numbered as follows: methyl-butenyl-threonine (1), aminobutyric acid (2), sarcosine (3), N-methylleucine (4), valine (5), N-methylleucine (6), alanine (7), D-alanine (8), N-methylleucine (9), N-methylleucine (10), and N-methylvaline (11).

[0014] For example, a wave-like coupling as shown below [ka] The arrow indicates a bond site to a part of the compound that is not shown. In the example shown, there are two bond sites to two parts of the compound that are not shown.

[0015] As used herein, the term "H" refers to hydrogen. As used herein, the term "alkyl" is defined as a saturated or unsaturated alkyl hydrocarbon moiety in any isomeric composition. This includes linear alkyls such as methyl, ethyl, n-propyl, n-butyl, 1-pentyl, and n-hexyl. Branched alkyls (e.g., branched C3-C6 alkyls) such as isopropyl, sec-butyl, isobutyl, tert-butyl, 2-pentyl, 3-pentyl, isopentyl, tert-pentyl, neopentyl, and hexyl isomers are also included. Within the definition of "alkyl," cyclic isomers such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are also included. Examples of unsaturated alkyls include vinyl, allyl, butenyl, pentenyl, and hexenyl, as well as other alkenyl or alkylene moieties containing one or more double bonds, such as pentadienyl.

[0016] The term "C1-C6" is defined as a part containing 1 to 6 carbon atoms. "C3-C6" and "C6-C6" are also used. 10 The term should be understood similarly, but it refers to a portion containing 3 to 6 carbon atoms or 6 to 10 carbon atoms, respectively.

[0017] In preferred embodiments, the C1-C6 alkyl group refers to an unsubstituted hydrocarbon moiety as defined above. In any embodiment, the C1-C6 alkyl group may be substituted with one or more substituents, but one or more hydrogen atoms are replaced by bonding with the substituent or non-hydrogen moiety.

[0018] When the term "alkyl" is expressed together with another radical, such as "arylalkyl," the alkyl portion has the same meaning as the definition of "alkyl" and is bonded to the other radical.

[0019] As used herein, the term “aryl” refers to a monocyclic or polycyclic aromatic ring assembly typically containing 6 to 14 ring atoms, all of which are carbon atoms. Typically, aryls are 6-membered (ring atom) monocyclic aromatic ring systems, 10 to 12-membered bicyclic aromatic ring systems, or 14-membered condensed tricyclic aromatic ring systems. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, and anthracenyl. When the term “aryl” is expressed with another radical, such as “arylalkyl,” the aryl portion has the same meaning as “aryl” in the definition and is bonded to the other radical.

[0020] As used herein, the terms “bicyclic” or “bisicryl” refer to a ring assembly in which the rings are fused together, held together by single bonds, or held together by bridging atoms.

[0021] The term "substituted," such as substituted alkyl (e.g., substituted C1-C6 alkyl), can refer to a part or radical in which one or more hydrogens are independently replaced by at least one (e.g., two, three or more) substituents, including halogens, haloalkyls, hydroxy(-OH), C1-C6 alkoxys, amino(-NH2), monoalkylaminos, dialkylaminos, thioalkyls, nitros, cyanos, carboxys, alkoxycarbonyls, aryls, and heteroaryls.

[0022] The term "halogen" is interchangeable with "halo" and can refer to a chloro, bromo, iodo, or fluoro atom. "Haloalkyl" refers to an alkyl substituent in which one or more hydrogen atoms are replaced by one or more halogen atoms. An example of a haloalkyl is a trifluoroalkyl such as trifluoromethyl.

[0023] The term "hydroxy" refers to the -OH radical. In some embodiments, the hydrogen may be substituted with a hydroxy protecting group or prodrug moiety, for example, within the scope of the art. Terms such as "alkoxy" mean alkylated hydroxy substituent, i.e., the hydrogen is replaced by an alkyl group. "C1-C6 alkoxy" refers to the substitution of hydroxy hydrogen with a C1-C6 alkyl group as defined above. Examples include methoxy, isopropoxy, phenoxy, or t-butoxy.

[0024] The term "amino" refers to the -NH2 radical. In some embodiments, one or more hydrogens may be substituted with one or more further substituents, such as protecting groups or alkyl groups. The term "monoalkylamino" refers to an amino radical in which one of the hydrogens is replaced with an alkyl group, such as a C1-C6 alkyl group as defined above (i.e., -NHR, where R is alkyl). "Dialkylamino" refers to an amino radical in which both hydrogens are independently replaced with alkyl groups (i.e., -NRR', where R and R' are alkyl groups, which may be the same (e.g., dimethylamino) or different).

[0025] "Thioalkyl" can refer to a radical -SR'', where R'' is alkyl, for example, a C1-C6 alkyl as defined above. The term "carboxy" as used herein refers to a radical -C(O)-R'' a It refers to, and in the formula, R a The radical can be selected from hydrogen, alkyl, aryl, hetalyl, hydroxy, alkoxy (e.g., -OCH3), amino, alkylamino, dialkylamino, thioalkyl, etc. The term "alkoxycarbonyl" is derived from the radical -OC(O)-R a It can refer to R, in the formula a The elements are selected from alkyl (e.g., C1-C6 alkyl, e.g., methyl), aryl, hetalyl, alkoxy, amino, alkylamino, dialkylamino, thioalkyl, etc.

[0026] When the term "hetero" is used to describe a compound or substituent, it means that one or more carbon atoms are replaced by oxygen, nitrogen, or sulfur atoms. In further embodiments of this disclosure, substituent R 1 and R 2 These can be bonded together to form a heterocycloalkyl ring, such as a C3-C6 heterocycloalkyl ring. Unless otherwise specified, “heterocycloalkyl” refers to a saturated or unsaturated non-aromatic ring that forms at least a portion of a cyclic structure and in which at least one or more carbon atoms are replaced by oxygen, nitrogen, or sulfur atoms (and in the case of a C3-C6 heterocycloalkyl containing 3 to 6 carbon atoms). For example, substituent R 1 and R 2 These can be bonded together to form a 4-membered, 5-membered, or 6-membered saturated non-aromatic ring containing at least one heteroatom. The heterocycloalkyl ring may contain at least one heteroatom selected from O, N, or S.

[0027] Compound substituent R of formula 1 8 Hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, CHR 10 OC(O)CHNH2R 11 , CH2OC(O)CHNH2CH(CH3)2, CHR 12 OC(O)R 13 , CH2OC(O)OCH(CH3)2, CH(CH3)OC(O)OCH(CH3)2, CH2OC(O)C(CH3)3, CH(CH3)OC(O)C(CH3)3, CH2CH2OH, CH2CH(OH)CH2OH, (CH2)(CH2) m R 14 , (CH2)(CH2) m NR 15 R 16 (CH2)2NR 15 R 16, (CH2)2N(CH3)2 and (CH2)2N(CH2)4N(CH3) (for example, (CH2)2N-methylpiperazinyl). In a specific embodiment, the substituent R of the compound of formula 1 8 is hydrogen, methyl, tert-butyl, CHR 10 OC(O)CHNH2R 11 , CH2OC(O)CHNH2CH(CH3)2, CHR 12 OC(O)R 13 , CH2OC(O)C(CH3)3, CH2CH2OH, CH2CH(OH)CH2OH, (CH2)(CH2) m R 14 , (CH2)(CH2) m NR 15 R 16 , (CH2)2NR 15 R 16 , (CH2)2N(CH3)2 and (CH2)2N(CH2)4N(CH3) (for example, (CH2)2N-methylpiperazinyl).

[0028] In another embodiment, the substituent R of the compound of formula 1 8 is

Chemical Formula

Chemical Formula

Chemical Formula

[0029] Prodrugs of the compound of formula 1 as disclosed in the present specification are contemplated. The term "prodrug" refers to a drug substance that is metabolized into a pharmacologically active drug after ingestion via metabolic or physicochemical transformation. In some embodiments, when the compound of formula 1 comprises one or more hydroxy groups (-OH), any of the one or more hydroxy groups can be optionally converted into a prodrug moiety. In specific embodiments, substituent R of the compound of formula 1 8 is hydrogen, or when substituent R 8 comprises a hydroxy group (-OH), the hydrogen of any hydroxy group present in the compound can be optionally converted into a prodrug moiety. In further specific embodiments, the prodrug moiety is CHR 10 OC(O)CHNH2R 11 , CH2OC(O)CHNH2CH(CH3)2, CHR 12 OC(O)R 13 , CH2OC(O)OCH(CH3)2, CH(CH3)OC(O)OCH(CH3)2, CH2OC(O)C(CH3)3, CH(CH3)OC(O)C(CH3)3 and CH2CH(OH)CH2OH. In other specific embodiments, the prodrug moiety is CHR 10 OC(O)CHNH2R 11 , CH2OC(O)CHNH2CH(CH3)2, CHR 12 OC(O)R 13 , CH2OC(O)C(CH3)3 and CH2CH(OH)CH2OH. In specific embodiments, the prodrug compound is a compound as disclosed as Compounds 47, 48 and 49 in the Examples.

[0030] In another embodiment, the compound is a compound of formula 2.

Chemical Formula

[0031] In another embodiment, the compound is the compound of formula 3. [ka] formula 3 In the formula, the substituents are as described for the compound of Formula 1. In some embodiments, R 5 and R 6 These are H, respectively. In other embodiments, R 5 and R 6 These are each C1-C6 alkyl groups. In other embodiments, R 5 H is R 6 is a C1-C6 alkyl group. In other embodiments, R 5 It is a C1-C6 alkyl group, and R 6 is H. In some embodiments, -CHR 5 -and-CHR 6 Each stereocenter defined by - is a racemic mixture or any mixture of (R) enantiomer and (S) enantiomer, (R) enantiomer or (S) enantiomer. In other embodiments, any R disclosed herein 8 Substituents can be combined with the combinations listed above. In certain embodiments, hydrogen, methyl, tert-butyl, CHR 10 OC(O)CHNH2R 11 , CH2OC(O)CHNH2CH(CH3)2, CHR 12 OC(O)R 13 , CH2OC(O)C(CH3)3, CH2CH2OH, CH2CH(OH)CH2OH, (CH2)(CH2) m R 14 , (CH2)(CH2) m NR 15 R 16 (CH2)2NR 15 R 16 Any substituent R selected from the group consisting of (CH2)2N(CH3)2, (CH2)2N(CH2)4N(CH3) (e.g., (CH2)2N-methylpiperazinyl) 8 And, [ka] In the formula, m is between 0 and 20, and R 14 teeth, [ka] or [ka] Any substituent R 8 The R listed above is 5 and R 6 It can be combined with any of the following combinations. In a particular embodiment, m is 1 to 6.

[0032] In another embodiment, the compound is the compound of formula 4. [ka] formula 4 In the formula, the substituents are as described for the compound of Formula 1. In some embodiments, Y is CH2. In some embodiments, each potential stereocenter present in the X group is a racemic mixture or any mixture of (R) and (S) enantiomers, (R) enantiomer or (S) enantiomer. In certain embodiments, X is [ka] or [ka] In other embodiments, Y is NR x And R x is H, C1-C6 alkyl or CH3. In certain embodiments, hydrogen, methyl, tert-butyl, CHR 10 OC(O)CHNH2R 11 , CH2OC(O)CHNH2CH(CH3)2, CHR 12 OC(O)R 13 , CH2OC(O)C(CH3)3, CH2CH2OH, CH2CH(OH)CH2OH, (CH2)(CH2) m R 14 , (CH2)(CH2) m NR 15 R 16 (CH2)2NR15 R 16 , (CH2)2N(CH3)2, (CH2)2N(CH2)4N(CH3) (e.g., (CH2)2N-methylpiperazinyl) and [ka] Selected from the group consisting of, where m is 0 to 20, R 14 teeth, [ka] or [ka] Any substituent R 8 m can be combined with any of the combinations of X and / or Y listed above. In a particular embodiment, m is 1 to 6.

[0033] In another embodiment, the compound is the compound of formula 5. [ka] formula 5 In the formula, the substituents are as described for the compound of Formula 1. In some embodiments, Y is CH2. In some embodiments, each potential stereocenter present in the X group is a racemic mixture or any mixture of (R) and (S) enantiomers, (R) enantiomer or (S) enantiomer. In some embodiments, X is [ka] or [ka] In other embodiments, Y is NR x And R x is H, C1-C6 alkyl or CH3. In certain embodiments, hydrogen, methyl, tert-butyl, CHR 10 OC(O)CHNH2R 11, CH2OC(O)CHNH2CH(CH3)2, CHR 12 OC(O)R 13 , CH2OC(O)C(CH3)3, CH2CH2OH, CH2CH(OH)CH2OH, (CH2)(CH2) m R 14 , (CH2)(CH2) m NR 15 R 16 (CH2)2NR 15 R 16 , (CH2)2N(CH3)2, (CH2)2N(CH2)4N(CH3) (e.g., (CH2)2N-methylpiperazinyl) and [ka] Selected from the group consisting of, where m is 0 to 20, R 14 teeth, [ka] or [ka] Any substituent R 8 m can be combined with any of the combinations of X and / or Y listed above. In a particular embodiment, m is 1 to 6.

[0034] In another embodiment, the compound is the compound of formula 6. [ka] formula 6 In the formula, the substituents are as described for the compound of Formula 1. In some embodiments, each potential stereocenter present in the X group is a racemic mixture or any mixture of (R) and (S) enantiomers, the (R) enantiomer or the (S) enantiomer. In some embodiments, X is [ka] or [ka] In certain embodiments, hydrogen, methyl, tert-butyl, CHR 10 OC(O)CHNH2R 11 , CH2OC(O)CHNH2CH(CH3)2, CHR 12 OC(O)R 13 , CH2OC(O)C(CH3)3, CH2CH2OH, CH2CH(OH)CH2OH, (CH2)(CH2) m R 14 , (CH2)(CH2) m NR 15 R 16 (CH2)2NR 15 R 16 , (CH2)2N(CH3)2, (CH2)2N(CH2)4N(CH3) (e.g., (CH2)2N-methylpiperazinyl) and [ka] Selected from the group consisting of, where m is 0 to 20, R 14 teeth, [ka] or [ka] Any substituent R 8 This can be combined with any of the X groups listed above. In certain embodiments, m is 1 to 6.

[0035] In another embodiment, substituent X is [ka] And, n is 0, and in the formula, R 1 and R 2 Each of them is either H or R 1 It is CH3, and R 2 Is it CH3, or R 1 H is R 2Is C1-C6 alkyl, or R 1 H is R 2 Is it CH3, or R 1 H is R 2 Is it CH2CH3, or R 1 H is R 2 Is it CH(CH3)2 or R 1 H is R 2 (C1-C6 alkyl)C(O)2R 9 Is R 1 H is R 2 Is it CH2CH2C(O)2H or R 1 H is R 2 Is it CH2CH2C(O)2CH3, or R 1 and R 2 These are bonded together to form a C3 cycloalkyl ring. In another embodiment, -CR 1 R 2 The stereocenters defined by - are racemic mixtures or any mixture of (R) and (S) enantiomers, (R) enantiomer or (S) enantiomer.

[0036] In another embodiment, substituent X is [ka] And, n is 1, and in the formula, R 1 and R 2 H and R 3 and R 4 They are either H and CH3 respectively, or bonded together to form a C3 cycloalkyl ring, or R 1 and R 2 Each of these is CH3, and R 3 and R 4 Each of them is either H or R 1 H is R 2 is C1-C6 alkyl, CH3 or CH2CH3, or R 3 and R 4 H is H, and R is R 1 and R 2 H and R3 H is R 4 In yet another embodiment, -CR 1 R 2 The stereocenter defined by - is a racemic mixture or any mixture of (R) and (S) enantiomers, (R) enantiomer or (S) enantiomer. In yet another embodiment, -CR 3 R 4 The stereocenters defined by - are racemic mixtures or any mixture of (R) and (S) enantiomers, (R) enantiomer or (S) enantiomer.

[0037] In another embodiment, substituent X is [ka] And, n is 2, and in the formula, R 1 , R 2 , R 3 and R 4 These are H.

[0038] In another embodiment, substituent X is [ka] And, n is 3, and in the formula, R 1 , R 2 , R 3 and R 4 These are H.

[0039] In another embodiment, substituent X is [ka] In the formula, R 5 and R 6 These are H or CH3, respectively. In other embodiments, -CHR 5 -and-CHR 6Each stereocenter defined by - is a racemic mixture, any mixture of the (R) and (S) enantiomers, the (R) enantiomer, or the (S) enantiomer.

[0040] In a specific embodiment, the compound is a compound of formula 2, wherein n is 0, 1, 2 or 3, and R 1 is [Chemical Formula] [Chemical Formula] or [Chemical Formula] wherein f and g are each independently 0 to 4, and R 2 is H.

[0041] In a specific embodiment, the compound is a compound of formula 2, wherein n is 0, 1, 2 or 3, the stereocenter defined by -CR 1 R 2 - is the (S) enantiomer, and R 1 is [Chemical Formula] and [Chemical Formula] selected from the group consisting of, R 2 is H, and R 8 is [Chemical Formula] and [Chemical Formula] selected from the group consisting of.

[0042] In another specific embodiment, the compound is a compound of formula 2, n is 0, 1, 2 or 3, and -CR 1 R 2 - the stereocenter defined by is the (S) enantiomer, and R 1 is selected from the group consisting of

化

化

化

[0043] In another specific embodiment, the compound is a compound of formula 2, n is 0, 1, 2 or 3, and -CR 1 R 2 - the stereocenter defined by is the (S) enantiomer, and R 1 is selected from the group consisting of

化

化

化

[0044] In still another specific embodiment, X is selected from the group consisting of

化

化

[0045] The compounds relating to this disclosure can be selected from compounds 1, 2, 3, 4, etc., or from pharmaceutically acceptable salts as defined in Table 1.

[0046] [Table 1] JPEG2026532573000062.jpg209160JPEG2026532573000063.jpg222160JPEG2026532573000064.jpg234160JPEG2026532573000065.jpg229160JPEG2026532573000066.jpg231160JPEG2026532573000067.jpg224160JPEG2026532573000068.jpg238160JPEG2026532573000069.jpg229160JPEG2026532573000070.jpg217160JPEG2026532573000071.jpg218160JPEG2026532573000072.jpg223160JPEG2026532573000073.jpg180160JPEG2026532573000074.jpg194160JPEG2026532573000075.jpg186160JPEG2026532573000076.jpg196160JPEG2026532573000077.jpg189160JPEG2026532573000078.jpg192160JPEG2026532573000079.jpg238160JPEG2026532573000080.jpg238160JPEG2026532573000081.jpg212160JPEG2026532573000082.jpg213160JPEG2026532573000083.jpg217160JPEG2026532573000084.jpg226160JPEG2026532573000085.jpg219160JPEG2026532573000086.jpg218160JPEG2026532573000087.jpg60160

[0047] The compounds of this disclosure may exist in a variety of stereoisomeric forms and mixtures. It should be understood that this disclosure may include not only stereocenters as specified or shown in the formulas, but also all of their enantiomers, diastereomers, racemates or other mixtures, and polymorphs, solvates, hydrates, complexes, free forms or salt forms. Unless otherwise indicated, compounds within the scope of this disclosure that contain one or more chiral centers not specified or shown in the formulas or not specifically named / described may also include all enantiomers, diastereomers or mixtures thereof, racemates or other thereof. The representation of double bonds in this disclosure refers to the isomers shown, but can be considered to include other Z (or E) isomers as well. The use of any optically pure or stereochemically pure stereoisomers, and any combination of stereoisomers, as determined or prepared by methods well known in the art, is also included. Optionally, the compounds of this disclosure may also include their isotopes, such compounds in which atoms are replaced by isotopes, for example, hydrogen and deuterium, or carbon and carbon-13.

[0048] In some embodiments, the compounds of the disclosure comprise a cyclosporine ring, and the substituent at position 4, for example, the isobutyl group of the cyclosporine ring, is substituted with at least one hydroxy(-OH) substituent. In specific embodiments, for example, the at least one hydroxy(-OH) substituent is located on a carbon atom substituted with two methyl groups (e.g., -CH2C(OH)(CH3)2). In other embodiments, the compounds of the disclosure comprise a cyclosporine ring, and the substituent at position 8, for example, the methyl group of the cyclosporine ring, is substituted with at least one hydroxy(-OH) substituent (e.g., 8-D-serine-cyclosporine).

[0049] As defined herein, pharmaceutically acceptable compounds are generally safe, non-toxic, not biologically or otherwise undesirable, and are acceptable and suitable for pharmaceutical use in humans. A pharmaceutically acceptable salt is a salt of a compound, such as those provided herein, that retains its biological properties, is non-toxic, and is suitable for pharmaceutical use.

[0050] The salts according to this disclosure can be produced by adding an acid to any one of the compounds of formulas 1 to 6 or any specific compounds described herein. The resulting acid addition salts include acetic acid, 2,2-dichloroacetic acid, citric acid, lactic acid, mandelic acid, glycolic acid, adipic acid, alginic acid, aryl sulfonic acid (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)camphoric acid, camphor-sulfonic acid, (+ )-(1S)-Camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glyco Malic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid, (±)-DL-mandelic acid), metaphosphate, methanesulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitrate, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid Examples include those formed using sebacic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid. In particular, examples of acid addition salts include those derived from mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid, and those derived from organic acids such as tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, and arylsulfonic acid.

[0051] Surprisingly, some of the compounds, especially acids (here, R 7(=OH) is far more water-soluble than many already known cyclosporine derivatives (see Table 5 below). Therefore, these compounds offer a more advantageous means for the formulation of pharmaceuticals, whether for its primary use (smaller amounts for injection) or for better oral bioavailability (solid dosage form).

[0052] The compounds of this disclosure may be useful for the prevention and / or treatment of a disease or condition, or in the manufacture of pharmaceuticals for the prevention and / or treatment of a disease or condition. In some embodiments, the compounds of this disclosure, for example, any compound of formulas 1 to 6, or any compound disclosed in Table 1, or pharmaceutically acceptable salts thereof, may be used as pharmaceuticals. In specific embodiments, pharmaceuticals may be used to prevent and / or treat a disease or condition. In some embodiments, the compounds of this disclosure may be used in a method for preventing and / or treating a disease or condition, which includes administering any compound of formulas 1 to 6, or any compound disclosed in Table 1, or pharmaceutically acceptable salts thereof, to a subject in need, preferably a human subject. In some embodiments, a therapeutically effective amount of any compound of formulas 1 to 6, or any compound disclosed in Table 1, or pharmaceutically acceptable salts thereof, is administered to a subject in need, preferably a human subject.

[0053] As used herein, the term "therapy," which may be used synonymously with the term "treatment," relates to a therapeutic intervention that can affect a cure, improvement, recovery, control, control of progression, prevention of progression, prevention of disease recurrence, or a condition or symptom associated with the disease or condition.

[0054] As understood herein, the term "prevention," which may be used interchangeably with the term "prophylaxis," refers to the use of a compound or composition to prevent the onset of a disease, condition, or symptom, or to significantly reduce the likelihood of the onset of a disease, condition, or symptom, such as further recurrence of the disease, condition, or associated symptom. Prevention of progression of a disease, condition, or associated symptom after the initial improvement or after the initial removal of the cause of the disease, condition, or symptom is also included within the scope of the term.

[0055] In particular, the compounds disclosed herein can be used for the prevention and treatment of cyclophylline-mediated diseases or conditions.

[0056] In particular, compounds such as those described herein can be used as inhibitors of cyclophylline, especially cyclophylline A (CypA) and / or cyclophylline D (CypD). In one embodiment, the compound is used as an inhibitor of cyclophylline A and is provided or administered, for example, in a therapeutically appropriate amount for the inhibition of cyclophylline A. As is commonly understood herein, the term “therapeutic effective dose” is an amount of the compound that, when administered to a subject (e.g., a human subject) for the treatment and / or prevention of a disease or condition, is sufficient to have an effect of such treatment and / or prevention.

[0057] Overexpression of cyclophyllins has been associated with or correlated with various diseases and conditions, particularly inflammatory diseases in humans. For example, cyclophyllin A has been demonstrated to function as a chemokine that supports inflammatory responses and promotes leukocyte migration, and blockade of cyclophyllin A has been shown to be beneficial in animal models of acute inflammation. Importantly, the opening of mitochondrial membrane pores called mitochondrial permeability transition pores (MPTPs) is also supported as crucial for the development and maintenance of necrotizing inflammation, a severe form of inflammation. A key regulator of this MPTP opening is cyclophyllin D, and inhibition of CypD has shown good activity in preventing tissue damage associated with necrotizing inflammation. MPTP opening, and the subsequent initiation of necrotizing cell death, are triggered by elevated intracellular calcium levels resulting from various factors, including oxidative stress, hypoxia, and bile salt toxins. Therefore, pharmacological inhibition of CypD may be protective against tissue degradation due to ischemia-reperfusion injury of organ tissues.

[0058] In some embodiments, certain compounds according to this disclosure have been found to be remarkably effective as inhibitors of cyclophylline, particularly cyclophylline A, as demonstrated in the examples, but surprisingly non-immunosuppressive. The compounds may be useful in the treatment or prevention of diseases or conditions in which elevated levels or activity of cyclophylline are associated with, contribute to, or cause such diseases or conditions. In particular, cyclophylline-mediated diseases or conditions that can be treated or prevented according to this disclosure may be cyclophylline A or cyclophylline D-mediated diseases or conditions. Such compounds have high CypA / D binding affinity and high mitochondrial function protection. Examples of such compounds include compounds 53, 58, and 59.

[0059] In other embodiments, certain compounds according to this disclosure have been found to be remarkably effective as inhibitors of cyclophylline, particularly cyclophylline A, as demonstrated in the examples, but surprisingly, immunosuppressive with little to no effect on mitochondrial activity, thereby providing improvements over cyclosporine A (CsA) and compound 0. Examples of such compounds include compounds 1, 8, 12, 16, 18, 20, 22, 27, 31, 35, 37, 38, 41, 43, 54, 61, and 63.

[0060] In further embodiments, certain compounds according to this disclosure have been found to be remarkably effective as inhibitors of cyclophylline, particularly cyclophylline A, as demonstrated in the examples, but surprisingly possess anti-inflammatory activity, be non-immunosuppressive, and have little to no effect on mitochondrial activity. Such compounds can be used in certain embodiments to treat patients with chronic inflammation requiring long-term drug administration. Examples of such compounds include compounds 10, 29, 51, and 62.

[0061] In some embodiments, the compounds of the Disclosure inhibit cyclophyllin intracellularly. In other embodiments, the compounds of the Disclosure inhibit cyclophyllin extracellularly. In yet another embodiment, the compounds of the Disclosure inhibit cyclophyllin both intracellularly and extracellularly. In certain embodiments, elevated levels of extracellular cyclophyllin may contribute to a disease or condition that can be treated with the compounds of the Disclosure, for example, a disease or condition associated with elevated levels of extracellular cyclophyllin A.

[0062] Cyclophilin-mediated diseases or conditions are typically diseases and conditions associated with inflammatory responses, cell damage, injury, and / or cell death (e.g., necrosis), and may include, but are not limited to, the diseases and conditions further described below.

[0063] In one embodiment, cyclophyllin A-mediated diseases or conditions are selected from the group consisting of cardiovascular diseases, viral infections (e.g., human immunodeficiency virus (HIV), influenza virus, and severe acute respiratory syndrome (SARS-CoV)), cancers (e.g., breast cancer, small cell lung cancer, non-small cell lung cancer, and renal cell carcinoma), kidney diseases (e.g., acute kidney injury, nephritis, and renal fibrosis), rheumatoid arthritis, sepsis, asthma, colitis, ulcerative colitis, Crohn's disease, allergic rhinitis, atherosclerosis, vascular smooth muscle cell diseases, myocarditis, myocardial fibrosis, and central nervous system diseases (e.g., Alzheimer's disease and amyotrophic lateral sclerosis).

[0064] In another embodiment, a cyclophyllin D-mediated disease or condition is a disease or condition associated with cytotoxicity or cell death, such as cytotoxicity or cell death in an organ, organ injury, or organ failure. In a particular embodiment, the organ is selected from the group consisting of the kidney, liver, heart, lung, pancreas, intestine, cornea, skin, brain, and nerve tissue.

[0065] Furthermore, “subject” or “patient” can be used interchangeably and, in one embodiment, refers to a human subject. Preferably, the subject or patient is human. These terms can also refer to other animals, such as other mammals. Further embodiments of this disclosure can also apply to livestock or other veterinary subjects, particularly mammals such as cats, dogs, primates, horses, cattle, and pigs.

[0066] The compounds of this disclosure may be administered together with one or more additional active substances of optional choice.

[0067] As used herein, the terms “dose” or “administered amount” refer to a single dose or unit dose of a compound as described herein, or a pharmaceutically acceptable salt thereof, or the active pharmaceutical ingredient, unless a time, interval, or volume instruction is given before or after it. “Daily dose” or “daily dosage” refers, for example, to the total dose of a compound as described herein, or the active pharmaceutical ingredient administered over a 24-hour period. The daily dose may include a single dose if it is administered only once per day, but is also a total amount based on the sum of multiple unit doses administered during the day, for example, if two or more unit doses are administered at intervals of two or more times during the day. The intervals between doses may be, for example, two doses administered approximately every 12 hours, or three doses administered approximately every 8 hours. As used herein, the dose of a compound may refer to a unit dose of a compound of formulas 1 to 6, or a pharmaceutically acceptable salt thereof, but may be applicable to a pharmaceutical product, composition, or dosage form containing such unit dose of the compound or a pharmaceutically acceptable salt thereof.

[0068] Where used herein, terms such as “about” in relation to an attribute or value, including dose, include the exact attribute or exact value, and any attribute or value that is typically considered to be within the range of variability that is normally or technically permissible in relation to the art, as well as methods for measuring or determining such attribute or value. This terminology allows for any modifications that, in general practice, enable the product being evaluated to be considered, in mammals, biologically equivalent to the stated strength or the claimed dose of the product.

[0069] It should be understood that the use of compounds of formulas 1 to 6, or pharmaceutically acceptable salts thereof, or their use in methods for the prevention and / or treatment of diseases or conditions as described in the embodiments or combinations of embodiments described herein, may also provide the manufacture or preparation of pharmaceuticals or medicines that are suitable for such use or methods for the treatment and / or prevention of disease onset, and that are formulated for such purposes.

[0070] The compounds or pharmaceutically acceptable salts thereof according to this disclosure can be administered to a subject enterally or parenterally. In one embodiment, the compounds of formulas 1 to 6, or compositions or pharmaceuticals containing such compounds, or pharmaceutically acceptable salts thereof, can be adapted for administration or can be administered parenterally, for example, by intravenous injection, subcutaneous injection, intramuscular injection, or intravenous or subcutaneous injection. In an alternative embodiment, the compounds, or compositions or pharmaceuticals containing such compounds, can be adapted for administration or can be administered enterally to a subject, for example, orally.

[0071] This disclosure also relates to pharmaceuticals or pharmaceutical compositions comprising compounds in any one of the embodiments described herein above, or in combination thereof, such as compounds of formulas 1 to 6, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients. The pharmaceutical or composition may contain a therapeutically effective amount or one or more unit doses of the compound.

[0072] A pharmaceutical product, or a pharmaceutical composition containing such compound, may be formulated in a dosage form suitable or adapted for injection or infusion by any of the above methods of administration. Alternatively, for oral administration, a pharmaceutical product or pharmaceutical composition containing the compound according to this disclosure may be provided in a dosage form suitable or adapted for oral administration, such as, but not limited to, tablets, capsules, gel caps, or films. Such pharmaceutical product or pharmaceutical composition may be used in accordance with any of the therapeutic or preventive methods or uses described herein.

[0073] The following numbered list includes embodiments of the present disclosure:

[0074] 1. A compound of formula 1, or a pharmaceutically acceptable salt thereof, [ka] formula 1 During the ceremony, X is [ka] or [ka] And, n is 0, 1, 2, 3, or 4. c, d, and e are either 0 or 1, Y is CH2 or NR x And, R x is H or C1-C6 alkyl, R 1 and R 2 These are, independently, H, aryl, arylalkyl, C1-C6 alkyl, and C6-C 10 Bicyclyl, (C1-C6 alkyl)C(O)2R 9 Selected from, R 1 and R 2 They are bonded together to form a C3-C6 cycloalkyl ring, R 3 and R 4 Each of these is independently selected from H, C1-C6 alkyl, or R 3 and R 4 They are bonded together to form a C3-C6 cycloalkyl ring, R 5 and R 6 Each is independently selected from H or C1-C6 alkyl groups. R 7 is OR 8 And, R 8 H, C1-C6 alkyl, CHR 10 OC(O)CHNH2R 11 , CHR 12 OC(O)R 13 , CH2CH2OH, CH2CH(OH)CH2OH or [ka] Selected from, where m is between 0 and 20, R 9 , R 10 , R 11 and R 12 Each is independently selected from H or C1-C6 alkyl groups. R 13 It is selected from O(C1-C6 alkyl) or C1-C6 alkyl, R 14 H, NR 15 R 16 , selected from a heteroalkyl ring or a heteroaryl ring, R 15 and R 16 Each of these is independently selected from H, C1-C6 alkyl, or R 15 and R 16 These are bonded together to form a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl ring. or During the ceremony, X is [ka] , or [ka] , n is 0, 1, 2, or 3. R 1 and R 2 These are H, C1-C6 alkyl, and (C1-C6 alkyl)C(O)2R, each independently. 9 Selected from, or R 1 and R 2 They are bonded together to form a C3-C6 cycloalkyl ring, R 3 and R 4 Each of these is independently selected from H, C1-C6 alkyl, or R 3 and R 4 They are bonded together to form a C3-C6 cycloalkyl ring, R 5 and R6 Each is independently selected from H or C1-C6 alkyl groups. R 7 is OR 8 And, R 8 H, C1-C6 alkyl, CHR 10 OC(O)CHNH2R 11 , CHR 12 OC(O)R 13 , selected from CH2CH2OH or CH2CH(OH)CH2OH, R 9 , R 10 , R 11 and R 12 Each is independently selected from H or C1-C6 alkyl groups. R 13 This is selected from O(C1-C6 alkyl) or C1-C6 alkyl.

[0075] 2.R 8 The compound listed in item 1, where H is present.

[0076] 3.R 8 The compound is CH3, as described in item 1.

[0077] 4.R 8 The compound is C(CH3)3, as described in item 1.

[0078] 5.R 8 is CHR 10 OC(O)CHNH2R 11 And R is an optional choice. 10 is H, or R 11 This is a compound listed in item 1, which is a C1-C6 alkyl group.

[0079] 6.R 8 The compound is CH2OC(O)CHNH2CH(CH3)2, as described in item 5.

[0080] 7.R 8 is CHR 12 OC(O)R 13 The compound described in item 1.

[0081] 8.R 8 The compounds listed in item 7, which are CH2OC(O)OCH(CH3)2 or CH(CH3)OC(O)OCH(CH3)2.

[0082] 9.R 8 The compounds listed in item 7, which are CH2OC(O)C(CH3)3 or CH(CH3)OC(O)C(CH3)3.

[0083] 10.R 8 The compound is CH2CH2OH, as described in item 1.

[0084] 11.R 8 The compound is CH2CH(OH)CH2OH, as described in item 1.

[0085] 12.R 8 teeth [ka] The compound described in item 1.

[0086] 13.R 8 (CH2)(CH2) m NR 15 R 16 The compound described in item 12, wherein m is 1 to 6 in the formula.

[0087] 14.R 8 (CH2)2NR 15 R 16 The compound described in item 12.

[0088] 15.NR 15 R 16 The compound is N(CH3)2, as described in item 13 or 14.

[0089] 16.R 14 teeth, [ka] or [ka] The compound described in item 12.

[0090] 17.X is, [ka] And, A compound listed in any one of items 1-16, where n is 0.

[0091] 18.R 1 and R 2 The compounds listed in item 17, where each is H.

[0092] 19.R 1 It is CH3, and R 2 The compound is CH3, as described in item 17.

[0093] 20.R 1 H is R 2 The compound is a C1-C6 alkyl compound, as described in item 17.

[0094] 21.R 2 The compound is CH3, as described in item 20.

[0095] 22.R 2 The compound is CH2CH3, as described in item 20.

[0096] 23.R 2 The compound is CH(CH3)2, as described in item 20.

[0097] 24.R 1 H is R 2 (C1-C6 alkyl)C(O)2R 9 The compound described in item 17.

[0098] 25.R 2 The compound is CH2CH2C(O)2H, as described in item 24.

[0099] 26.R 2 The compound is CH2CH2C(O)2CH3, as described in item 24.

[0100] 27.R 1 teeth, [ka] [ka] or [ka] In the formula, f and g are each independently between 0 and 4, and R 2 The compound is H, as described in item 17.

[0101] 28.-CR 1 R 2 - The stereocenter defined by is a racemic mixture or any mixture of the (R) enantiomer and the (S) enantiomer of any compound as described in any one of items 20-27.

[0102] 29.-CR 1 R 2 - The stereocenter defined by is the (R) enantiomer of any one of the compounds listed in items 20-27.

[0103] 30.-CR 1 R 2 - The stereocenter defined by is the (S) enantiomer of any one of the compounds listed in items 20-27.

[0104] 31.R 1 and R 2 The compounds described in item 17, which are bonded together to form a C3 cycloalkyl ring.

[0105] 32.X is, [ka] And, A compound listed in any one of items 1-16, where n is 1.

[0106] 33.R 1 and R 2 The compounds listed in item 32, where each is H.

[0107] 34.R 3 and R 4 The compounds listed in item 33, where each is H.

[0108] 35.R 3 and R 4 Each of these compounds is CH3, as described in item 33.

[0109] 36.R 3 and R 4 The compounds described in item 33, which are bonded together to form a C3 cycloalkyl ring.

[0110] 37.R 1 and R 2 The compounds listed in item 32, each being CH3.

[0111] 38.R 3 and R 4 The compounds listed in item 37, where each is H.

[0112] 39.R 1 H is R 2 The compound is a C1-C6 alkyl compound, as described in item 32.

[0113] 40.R 2 Compounds listed in item 39, wherein the compound is CH3 or CH2CH3.

[0114] 41.R 3 and R 4 A compound listed in any one of items 39-40, where each of the elements is H.

[0115] 42.-CR 1 R2 - The stereocenter defined by is a racemic mixture or any mixture of the (R) enantiomer and the (S) enantiomer of any compound as described in any one of items 39-41.

[0116] 43.-CR 1 R 2 - The stereocenter defined by is the (R) enantiomer of any one of the compounds listed in items 39-41.

[0117] 44.-CR 1 R 2 - The stereocenter defined by is the (S) enantiomer of any one of the compounds listed in items 39-41.

[0118] 45.R 3 H is R 4 The compound is a C1-C6 alkyl compound, as described in item 33.

[0119] 46.R 4 The compound is CH3, as described in item 45.

[0120] 47.-CR 3 R 4 - The stereocenter defined by is a racemic mixture or any mixture of the (R) enantiomer and the (S) enantiomer of any compound as described in any one of items 45-46.

[0121] 48.-CR 3 R 4 - The stereocenter defined by is the (R) enantiomer of any one of the compounds listed in items 45-46.

[0122] 49.-CR 3 R 4 - The stereocenter defined by is the (S) enantiomer of any one of the compounds listed in items 45-46.

[0123] 50.X is [ka] And, A compound listed in any one of items 1-16, where n is 2.

[0124] 51.R 1 and R 2 The compounds listed in item 50, where each is H.

[0125] 52.R 3 and R 4 The compounds listed in item 51, where each is H.

[0126] 53.X is [ka] And, A compound listed in any one of items 1-16, where n is 3.

[0127] 54.R 1 and R 2 The compounds listed in item 53, where each is H.

[0128] 55.R 3 and R 4 The compounds listed in item 54, where each is H.

[0129] 56.X is [ka] A compound listed in any one of items 1 to 16.

[0130] 57.R 5 and R 6 The compounds listed in item 56, where each is H.

[0131] 58.R 5 and R 6 Each of these is a CH3 compound, as described in item 57.

[0132] 59.-CHR 5-and-CHR 6 Each stereocenter defined by - is a racemic mixture or any mixture of (R) enantiomer and (S) enantiomer of any compound as described in any one of items 56-58.

[0133] 60.-CHR 5 -and-CHR 6 Each stereocenter defined by - is the (R) enantiomer of any of the compounds listed in items 56-58.

[0134] 61.-CHR 5 -and-CHR 6 Each stereocenter defined by - is the (S) enantiomer of any compound listed in any one of items 56-58.

[0135] 62.X is, [ka] A compound listed in any one of items 1 to 16.

[0136] 63. Y is CH2, the compound described in item 62.

[0137] 64.X is, [ka] or [ka] The compound described in item 63.

[0138] 65.Y is NR x The compound described in item 62.

[0139] 66.R x The compound is H, as described in item 65.

[0140] 67.R xThe compound is a C1-C6 alkyl compound, as described in item 65.

[0141] 68.R x The compound is CH3, as described in item 67.

[0142] 69.X is, [ka] A compound listed in any one of items 1 to 16.

[0143] 70.X is, [ka] A compound listed in any one of items 1 to 16.

[0144] 71. Y is CH2, the compound described in item 70.

[0145] 72.X is, [ka] or [ka] The compound described in item 71.

[0146] 73.Y is NR x The compound described in item 70.

[0147] 74.X is, [ka] A compound listed in any one of items 1 to 16.

[0148] 75.X is, [ka] A compound listed in any one of items 1 to 16.

[0149] 76.X is, [ka] A compound listed in any one of items 1 to 16.

[0150] 77.-CR 1 R 2 The stereocenter defined by - is the (S) enantiomer, and R 1 teeth, [ka] and [ka] Selected from the group consisting of R 2 H is R 8 teeth, [ka] and [ka] A compound selected from the group consisting of the following, which is one of the compounds described in item 17, 32, 50, or 53.

[0151] 78.-CR 1 R 2 The stereocenter defined by - is the (S) enantiomer, and R 1 teeth, [ka] and [ka] Selected from the group consisting of R 2 H is R 8 teeth, [ka] The compound described in any one of items 17, 32, 50, or 53.

[0152] 79.-CR 1 R 2 The stereocenter defined by - is the (S) enantiomer, and R 1 teeth, [ka] and [ka] Selected from the group consisting of R 2 H is R 8 teeth, [ka] The compound described in any one of items 17, 32, 50, or 53.

[0153] 80.X is, [ka] [ka] Selected from the group consisting of R 8 teeth [ka] The compound described in item 1.

[0154] 81. The compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka] A compound selected from the group consisting of the compounds listed in item 1.

[0155] 82. A compound or pharmaceutically acceptable salt is a compound or pharmaceutically acceptable salt as defined in any one of items 1 to 81, comprising a cyclosporine ring, wherein the isobutyl group at position 4 of the cyclosporine ring is substituted with at least one hydroxy substituent.

[0156] 83. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt as defined in any one of items 1 to 82, and one or more pharmaceutically acceptable excipients.

[0157] 84. Use of compounds or pharmaceutically acceptable salts as defined in any one of items 1 to 82 in the manufacture of medicinal products for the prevention and / or treatment of a disease or condition.

[0158] 85. A compound or pharmaceutically acceptable salt as defined in any one of items 1 to 82 for use as a pharmaceutical, wherein the pharmaceutical is for the prevention and / or treatment of a disease or condition.

[0159] 86. A method of treating and / or preventing a disease or condition, comprising administering a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in any one of items 1 to 83.

[0160] 87. The disease or condition is a cyclophylline-mediated disease or condition, as described in any one of items 84-86.

[0161] 88. Cyclophiline is cyclophylline A, as used or in the manner described in item 87.

[0162] 89. Cyclophilin A-mediated diseases or conditions are selected from the group consisting of cardiovascular disease, viral infections, cancer, kidney disease, rheumatoid arthritis, sepsis, asthma, colitis, ulcerative colitis, Crohn's disease, allergic rhinitis, atherosclerosis, vascular smooth muscle cell disease, myocarditis, myocardial fibrosis, central nervous system diseases, Alzheimer's disease, and amyotrophic lateral sclerosis, as described in item 88.

[0163] 90. Cyclophilin A-mediated disease or condition is a viral infection, use or method as described in item 89.

[0164] 91. Viral infections are selected from the group consisting of human immunodeficiency virus (HIV), influenza virus, and severe acute respiratory syndrome (SARS-CoV), and the use or method described in item 90.

[0165] 92. Cyclophilin A-mediated disease or condition is cancer, use or method as described in item 89.

[0166] 93. Cancer, selected from the group consisting of breast cancer, small cell lung cancer, non-small cell lung cancer, and renal cell carcinoma, used or by the method described in item 92.

[0167] 94. Cyclophilin A-mediated disease or condition is a renal disease, use or method as described in item 89.

[0168] 95. Renal diseases are selected from the group consisting of acute kidney injury, nephritis, and renal fibrosis, and are used or used in the manner described in item 94.

[0169] 96. Cyclophiline is cyclophylline D, as described in item 87 for use or method.

[0170] 97. Cyclophilin D-mediated disease or condition is a disease or condition associated with cytotoxicity or cell death, for example, cytotoxicity or cell death in an organ, as described in item 96.

[0171] 98. A disease or condition related to cell injury or cell death is organ injury or organ failure, as described in item 97.

[0172] 99. The organs are selected from the group consisting of the kidneys, liver, heart, lungs, pancreas, intestines, cornea, skin, brain, and nerve tissue, as described in any one of items 97-98.

[0173] 100. A compound, or a pharmaceutically acceptable salt, or a medicinal product, is suitable for oral administration or for administration by intravenous injection or infusion, as described in any one of items 84-99.

[0174] 101. Intravenous injection or infusion is the use or method described in item 100, selected from the group consisting of subcutaneous injection, intramuscular injection or intravenous injection, and intravenous infusion or subcutaneous infusion.

[0175] The following embodiments are useful in illustrating embodiments of the present disclosure, but should not be understood as limiting the scope of the present disclosure. [Examples]

[0176] Example 1 - Preparation of the compound Compounds described herein are obtained by reacting a cyclosporine compound (e.g., cyclosporine A, C, D, G, etc.) with dipyridyl disulfide to obtain a thiopyridyl intermediate ([(2'-(2-thiopyridyl)-Sar]) such as the compound of formula II shown below. 3 It can be obtained by following a general synthetic route as shown below, which includes a first step of forming cyclosporine (such as A, C, D, or G), followed by a second step of reacting this intermediate with a hydroxyalkyl carboxylate ester compound (HO-XC(O)OR) in the presence of copper triflate. Examples of hydroxyalkyl carboxylate ester compounds used include, but are not limited to, methyl glycolate or 2-tert-butyl glycolate.

[0177] Those skilled in the art will know that different analogues can be prepared in the second step using different hydroxyalkylcarboxylate ester compounds (HO-XC(O)OR), for example, in which the X group changes in alkyl chain length and / or structure, or the carboxylate ester substituent-R changes in alkyl chain length and / or structure.

[0178] Preparation of Compound III [ka] [ka] Anhydrous LiCl was added to a solution of starting material I (CsA) in ultra-dried THF at 0°C, followed by the dropwise addition of lithium diisopropylamide (LDA). After addition, the reaction mixture was maintained at 0°C for 1 hour, followed by the addition of the substituted disulfide, and the reaction was continued at the same temperature for another 1 hour. After confirmation by HPLC, methanol was added. The resulting mixture was maintained at room temperature for 16 hours. The mixture was then poured into an aqueous solution of NaH2PO4 and extracted with methyl tert-butyl ether (MTBE). The organic phase was washed with 0.25 M HCl, then dried and concentrated to obtain a crude gel. This was purified by column chromatography on silica gel to obtain isomers of compound II.

[0179] A first flask containing Cu(OTf)2 or AgOTf was dried at 120°C under vacuum for 4 hours. After cooling to room temperature, the reactor was placed in a dry ice bath, and THF was slowly added under a nitrogen atmosphere. Compound II, a hydroxyalkyl carboxylate ester compound (HO-XC(O)OR), and THF were added to a second flask under a nitrogen atmosphere. This solution was then added dropwise to the first reactor flask containing Cu(OTf)2 or AgOTf / THF at room temperature, followed by the addition of trimethylsilyl chloride (TMSCl). The reaction mixture was stirred for a further 16 hours at the same room temperature. After confirmation by HPLC, isopropyl acetate (iPrOAc) was added, followed by washing with aqueous K2CO3. The organic phase was dried and concentrated to obtain a crude gel. This was purified on silica gel by column chromatography, preparative TLC, or preparative HPLC to obtain the desired compound III as a white solid. Compounds 1, 5-8, 10, 12, 14, 16, 18, 20, 22, 25, 27, 29, 31, 33, 35, 37-38, 41, 43, 46, 50, 55-64, and 71-78 were prepared using this methodology.

[0180] Preparation of compounds IV and V [ka] Compound IV was prepared in the same manner as compound III above, where R is a -CH3 group. A solution of compound IV in THF was mixed with a room-temperature LiOH aqueous solution and maintained for 18 hours. After confirmation by HPLC, the reaction mixture was acidified to pH 2-3 with a 1M HCl aqueous solution and extracted with ethyl acetate (RINKAN). The organic phase was dried and concentrated to obtain a crude gel. This was purified on silica gel by column chromatography, preparative TLC, or preparative HPLC to obtain the desired compound V as a white solid. Compounds 2-4, 9, 13, 15, 17, 19, 21, 23-24, 26, 28, 32, 34, 36, 39-40, 42, 44, and 45 were prepared using this methodology.

[0181] Preparation of compounds VI and VII [ka] Compound VI was prepared in the same manner as compound III above, where R is a -tert-butyl group. Compound VI was added to a solution of ZnCl2 in THF (1M). The stirred mixture was heated to 40°C under N2 and maintained for 18 hours. After confirmation by HPLC, the mixture was added to a 1M aqueous HCl solution and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated to obtain the crude. The crude was further purified by preparative TLC or preparative HPLC to obtain the desired compound VII as a white solid. Compounds 11 and 30 were prepared using this methodology.

[0182] Preparation of compounds XIII and XV [ka] [ka] Compound XIII was prepared in the same manner as compound III above, where R is a -CH3 group and X is a -CH2 group. To a solution of compound XIII (11.8 g, 9.14 mmol, 1.0 equivalent) in DMF (60 mL), tert-butyldimethylsilyltrifluoromethanesulfonate (TBDMSOTf, 12.08 g, 45.7 mmol, 5.0 equivalents), 4-dimethylaminopyridine (DMAP, 112 mg, 0.914 mmol, 0.1 equivalent), and triethylamine (TEA, 9.25 g, 91.4 mmol, 10 equivalents) were added under N2 conditions. The mixture was stirred at room temperature. After 3.5 hours, HPLC showed that compound XIII had been consumed. The reaction mixture was poured into 300 mL of water and extracted with 100 mL x 3 MTBE streams. The organic phase was combined, washed with 150 mL x 2 of 0.5 M citric acid aqueous solution and 150 mL of saturated NaCl aqueous solution, dried on Na2SO4, and concentrated to obtain crude compound XIV (18.6 g, purity: 93.39%) as a grayish-white solid. This was used directly in the next step.

[0183] Compound XIV (18.6 g) and KOH (5.0 equivalents) were added to a mixture of THF (100 mL) and H2O (100 mL). The mixture was stirred at room temperature. After 18 hours, HPLC showed that compound XIV had been consumed. The mixture was concentrated under vacuum to remove THF. The residual water was acidified to a pH of 1-2 with 1 M HCl. The mixture was extracted with 100 mL x 3 MTBEs. The organic phases were combined, dried over Na2SO4, and concentrated to obtain crude compound XV (13.9 g, purity: 93.45%) as a grayish-white solid. This was used directly in the next synthesis step.

[0184] Preparation of compound 47 [ka] [ka] Compound XVI (2.30 g, 8.64 mmol, 4.0 equivalents) and TEA (1.75 g, 17.28 mmol, 8.0 equivalents) were successively added to a solution of compound XV (3.0 g, 2.16 mmol, 1.0 equivalent) in DMF (30 mL) under N2 conditions. The mixture was stirred at 80°C. After 1.5 hours, HPLC showed that compound XV had been consumed. The mixture was quenched with 150 mL of saturated NH4Cl aqueous solution. Extraction was performed with 100 mL x 3 MTBEs. The combined organic phase was washed with 100 mL of saturated NaCl aqueous solution, dried over Na2SO4, and concentrated to obtain crude compound XVII (4.8 g, purity: 88.63%) as a grayish-white solid. This was used directly in the next step.

[0185] To a solution of compound XVII (1.0 g, 0.62 mmol, 1.0 equivalent) in DCM (10 mL) at 0°C, TFA (4 mL) was added. The reaction mixture was stirred at 0°C. After 1.5 hours, HPLC showed that compound XVII had been consumed. The mixture was quenched with 150 mL of saturated NaHCO3 aqueous solution and extracted with 50 mL x 3 MTBE. The organic phases were combined and washed with 100 mL of saturated NaHCO3 aqueous solution and 100 mL of brine. The organic phases were dried over Na2SO4 and concentrated to obtain a crude gel (890 mg, purity: 83.81%). This was purified by preparative TLC (DCM / EtOH = 20:1) to obtain compound 47 (60 mg, purity: 93.83%) as a white solid.

[0186] Preparation of compound 48 [ka] [ka] Compound XV (1.0 g, 0.72 mmol, 1.0 equivalent) was dissolved in DMF (10 mL) and compound XVIII (216 mg, 1.44 mmol, 2.0 equivalents) and TEA (291 mg, 2.88 mmol, 4.0 equivalents) were successively added under N2 conditions. The mixture was stirred at 80°C. After 1.5 hours, HPLC showed that compound XV had been consumed. The reaction mixture was cooled to room temperature, quenched with 50 mL of saturated NH4Cl aqueous solution, and extracted with 30 mL x 3 MTBE. The combined organic phase was washed with 50 mL of saturated NH4Cl aqueous solution and 50 mL of brine, dried over Na2SO4, and concentrated to obtain crude compound XIX (1.02 g, purity: 90.19%) as a grayish-white solid. This was used directly in the next step.

[0187] To a solution of compound XIX (200 mg, 0.13 mmol, 1.0 equivalent) at 0°C in dichloromethane (DCM, 2 mL), trifluoroacetic acid (TFA, 0.4 mL) was added. The reaction mixture was stirred at 0°C. After 1 hour, HPLC showed that compound XIX had been consumed. The reaction mixture was quenched with 15 mL of saturated NaHCO3 aqueous solution and extracted with 10 mL x 3 MTBE. The combined organic phase was washed with 15 mL of saturated NaHCO3 aqueous solution and 15 mL of brine, dried on Na2SO4, and concentrated to obtain a crude gel (192 mg, purity: 85.32%). This was purified by preparative TLC (DCM / acetone = 5:1) to obtain compound 48 (51 mg, purity: 92.13%) as a white solid.

[0188] Preparation of compound 49 [ka] [ka] To a 20 mL solution of compound XV (2.0 g, 1.44 mmol, 1.0 equivalent) in DMF, compound XX (286 mg, 2.16 mmol, 1.5 equivalents), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl, 414 mg, 2.16 mmol, 1.5 equivalents), and DMAP (264 mg, 2.16 mmol, 1.5 equivalents) were successively added under N2 conditions. The mixture was stirred at 10-15°C. After 20 hours, HPLC showed that compound XV had been consumed. The reaction mixture was quenched with 100 mL of saturated NH4Cl aqueous solution and extracted with 3 x 50 mL of MTBE. The combined organic phases were washed with 100 mL of saturated NH4Cl aqueous solution and 100 mL of brine, dried on Na2SO4, and concentrated to obtain crude compound XXI (2.02 g, purity: 89.41%) as a grayish-white solid. This was used directly in the next step.

[0189] To a solution of compound XXI (1.0 g, 0.13 mmol, 1.0 equivalent) in DCM (10 mL) at 0°C, TFA (4 mL) was added. The reaction mixture was stirred at 0°C. After 1 hour, HPLC showed that compound XXI had been consumed. The reaction mixture was quenched with 150 mL of saturated NaHCO3 aqueous solution and extracted with 50 mL x 3 MTBE. The combined organic phase was washed with 100 mL of saturated NaHCO3 aqueous solution and 100 mL of brine, dried over Na2SO4, and concentrated to obtain a crude solid (930 mg, purity: 87.30%). The crude solid (200 mg) was purified by preparative TLC (DCM / EtOH = 20:1) to obtain compound 49 (60 mg, purity: 95.22%) as a white solid.

[0190] Preparation of compound XXV [ka] In a solution of compound V in DMF, R 7-OH, coupling reagent, and DIPEA were added under N2 at room temperature. The mixture was stirred at room temperature and maintained for 15-24 hours. After confirmation by HPLC, the reaction mixture was quenched with water and extracted with iso-PrOAc. The organic phases were combined, washed with brine, dried over Na2SO4, and concentrated to obtain a crude gel. This was purified by column chromatography, preparative TLC, or preparative HPLC on silica gel to obtain the desired compound XXV as a white solid. Compounds 51-54, 65-70, and 79-96 were prepared using this methodology.

[0191] Example 2 - Prodrug Stability Assay in Different Matrices Chemical stability assay protocol Terfenadine (stored at 4°C), tolbutamide (stored at 4°C), NaH2PO4·2H2O (stored at room temperature), Na2HPO4·12H2O (stored at room temperature), and NaCl (stored at room temperature) were obtained from Sigma-Aldrich. FaSSIF, FeSSIF, FaSSGF, and FaSSIF-V2 were obtained from Biorelevant and stored at 4°C. Filter plates were obtained from Merck Millipore and stored at room temperature. Mass spectra were obtained using a Q Trap 4500 mass spectrometer obtained from AB Sciex. LC-MS / MS analysis was performed in ESI positive ionization mode with a run time of 3 minutes using an ACE Excel 5 C4 50*2.1 mm column containing mobile phase A of 0.1% formic acid in H2O and mobile phase B of 0.1% formic acid in acetonitrile.

[0192] A FaSSIF solution containing pancreatin was prepared in maleate buffer solution. First, the maleate buffer solution was prepared from 0.695 g of NaOH, 1.115 g of maleic acid, and 2.005 g of NaCl dissolved in 0.49 L of distilled water. The pH was adjusted to 6.8 with HCl, and the volume was reduced to 0.5 L with distilled water. The maleate buffer solution was filtered through a 0.22 μm filter. Next, FaSSIF-V2 powder (89.5 mg) was dissolved in maleate buffer solution to a volume of 50 mL and stored at 4°C for future use. Then, pancreatin powder (100 mg) was dissolved in 10 mL of the above FaSSIF-V2 solution.

[0193] A solution of FaSSGF containing pepsin was prepared in an NaCl / HCl buffer solution. First, the NaCl / HCl buffer solution was prepared from 1.0 g of NaCl dissolved in 0.49 L of distilled water. The pH was adjusted to 1.2 with HCl, and the volume was reduced to 0.5 L with distilled water. The NaCl / HCl buffer solution was filtered through a 0.22 μm filter. Next, FaSSGF powder (3.0 mg) was dissolved in the NaCl / HCl buffer solution, and the volume was reduced to 50 mL, which was stored at 4°C for future use. Then, pepsin powder (32 mg) was dissolved in 10 mL of the above FaSSGF solution.

[0194] Stock solutions of compounds 2, 47, 48, and 49 were prepared in DMSO at a concentration of 50 mM. From these 50 mM stock solutions, 200 μM working solutions of compounds 2, 47, 48, and 49 were prepared by diluting the stock solutions with DMSO.

[0195] A stock solution of terfenadine was prepared at 1 / 1 mg / mL in DMSO. From this 1 / 1 mg / mL stock solution, a 5 / 10 ng / mL terfenadine quench solution was prepared by diluting the stock solution with acetonitrile. Using the same procedure, a 1 / 1 mg / mL stock solution of tolbutamide in DMSO and a 5 / 10 ng / mL tolbutamide quench solution in acetonitrile were prepared.

[0196] To 199 μL of FaSSIF solution containing pancreatin or FaSSGF solution containing pepsin, 1.0 μL of the test compound / control working solution was added at 0, 5, 15, 30, 60, and 120 minutes, and incubated for 120 minutes, 60 minutes, 30 minutes, 15 minutes, 5 minutes, and 0 minutes, respectively. After 120 minutes, 600 μL of quench solution was added to 200 μL of the reaction mixture.

[0197] A 1 μM standard solution of compound 2 was prepared by adding 199 μL of buffer solution to 600 μL of quench solution. Subsequently, 1.0 μL of working solution of compound 2 was added to prepare the standard solution of compound 2.

[0198] The test solution and the standard solution of compound 2 were vortexed vigorously for 1 minute, and then centrifuged at 4000 rpm at 4°C for 15 minutes. The supernatant (300 μL) of each sample was removed for LC-MS / MS analysis.

[0199] Plasma stability assay protocol Plasma from male Sprague Dolly rats was obtained from BIOIVT and stored at -20°C. Mass spectra were obtained using a Q Trap 4500 or API 4000 mass spectrometer obtained from AB Sciex. LC-MS / MS analysis was performed in ESI positive ionization mode using an ACE Excel 5 C4 50*2.1 mm column (analysis time 3 minutes) or a Kinetex 2.6 μm C18 100 Å column (2.1 mm*30 mm, analysis time 1.5 minutes) containing mobile phase A of 0.1% formic acid in H2O and mobile phase B of 0.1% formic acid in acetonitrile.

[0200] Rat plasma was thawed in a 37°C water bath, and the pH was adjusted to 7.4 using HCl or NaOH solution as needed. A stock solution of terfenadine was prepared at 1 / 1 mg / mL in DMSO. A 5 / 10 ng / mL terfenadine quench solution was prepared from this 1 / 1 mg / mL stock solution by diluting the stock solution with acetonitrile. Using the same procedure, a 1 / 1 mg / mL stock solution of tolbutamide in DMSO and a 5 / 10 ng / mL tolbutamide quench solution in acetonitrile were prepared.

[0201] Stock solutions of compounds 2, 47, 48, and 49 were prepared in DMSO at a concentration of 50 mM. From these 50 mM stock solutions, 200 μM working solutions of compounds 2, 47, 48, and 49 were prepared by diluting the stock solutions with DMSO.

[0202] Rat plasma was preheated in a 37°C water bath for 15 minutes. A working solution of the control / test compound (2 μL) was added to 398 μL of plasma and thoroughly mixed by pipetting. 30 μL of the reaction mixture was removed from each time point (0, 5, 15, 30, 60, and 120 minutes) and added to 300 μL of quench solution. DMSO (3 μL) was added to the above solution to ensure that the concentration in DMSO was the same as that of the standard solution of compound 2.

[0203] A 1 μM standard solution of compound 2 was prepared by adding 30 μL of plasma to a 300 μL quench solution to which a working solution of compound 2 (3 μL, 10 μM) had been added.

[0204] The test sample and standard solution of compound 2 were thoroughly mixed by vortexing for 1 minute, and then centrifuged at 4,000 rpm at 4°C for 15 minutes. For LC-MS / MS analysis, the supernatant (100 μL) of each sample was thoroughly mixed with 100 μL of distilled water.

[0205] Intestinal S9 Stability Assay Protocol Rat (male) intestinal samples S9 without phenylmethyl sulfonyl fluoride (PMSF) were obtained from BioreclamationIVT and stored at -80°C. Terfenadine, tolbutamide, and tetracaine were obtained from Sigma-Aldrich. K2HPO4 was obtained from SCR. NADPH was obtained from ACROS. Mass spectra were obtained using a Q Trap 4500 or API 4000 mass spectrometer obtained from AB Sciex. LC-MS / MS analysis was performed in ESI positive ionization mode with a run time of 3 minutes using an ACE Excel 5 C4 50*2.1 mm column containing mobile phase A of 0.1% formic acid in H2O and mobile phase B of 0.1% formic acid in acetonitrile.

[0206] A phosphate buffer solution (50 mM K2HPO4, pH 7.4) was prepared by dissolving 8.709 g of K2HPO4 in 950 mL of water. The pH was adjusted to 7.4 using HCl solution. The final volume was adjusted to 1000 mL with water, filtered through a 0.22 μm filter, and stored at 4°C for future use.

[0207] A stock solution of terfenadine was prepared at 1 / 1 mg / mL in DMSO. From this 1 / 1 mg / mL stock solution, a 5 / 10 ng / mL terfenadine quench solution was prepared by diluting the stock solution with acetonitrile. Using the same procedure, a 1 / 1 mg / mL stock solution of tolbutamide in DMSO and a 5 / 10 ng / mL tolbutamide quench solution in acetonitrile were prepared.

[0208] Stock solutions of compounds 47, 48, and 49 were prepared in DMSO at a concentration of 50 mM. From these 50 mM stock solutions, 200 μM working solutions of compounds 47, 48, and 49 were prepared by diluting the stock solutions with DMSO.

[0209] Intestinal S9 was thawed in a 37°C water bath. A 5 mM NADPH working solution was prepared in phosphate buffer solution. A 1.5 μL working solution of the control / test compound was added to a 238.5 μL working solution of Intestinal S9 in a 1.1 mL tube and gently mixed. The tube was pre-incubated for 5 minutes in a 37°C shaking water bath. The reaction was initiated by adding a 60 μL NADPH working solution to the tube and mixing by pipetting. 30 μL of the reaction mixture at each time point (0 min, 5 min, 15 min, 30 min, and 60 min) was transferred to a 300 μL quench solution and thoroughly mixed by pipetting. 3 μL of DMSO was added to the above solution to ensure that the concentration in DMSO was the same as that of the standard solution of compound 2. The sample was vigorously vortexed for approximately 1 minute.

[0210] A standard solution of compound 2 was prepared in DMSO at a concentration of 50 mM. A 10 μM working solution of compound 2 was prepared by diluting the standard solution of compound 2 with DMSO from this 50 mM stock solution. Intestinal S9 working solution (24 μL) and NADPH working solution (6 μL) were added to the quenching solution (300 μL), and then 3 μL of compound 2 working solution was added and thoroughly mixed.

[0211] The test samples and standard solutions of compound 2 were centrifuged at 4000 rpm at 4°C for 15 minutes. For LC-MS / MS analysis, each supernatant (100 μL) was mixed with distilled water (100 μL).

[0212] Stability assay results Prodrug compounds 47, 48, and 49 were tested in different matrices for stability and the ability to generate parent compound 2. The assay results obtained are summarized in Tables 2 and 3 below. Prodrug glycerol linker moieties can be used to enhance the stability of prodrug compounds without impairing the biological activity of the parent compound. Such prodrug glycerol linker moieties can be used to develop prodrugs of carboxylic acids containing the parent drug that can enhance the absorption of the parent compound.

[0213] [Table 2]

[0214] [Table 3]

[0215] Example 3 - Functional and Inhibitory Assays The compounds prepared in Example 1 were evaluated using human recombinant enzyme (PPIase assay) in cyclophylline A and cyclophylline D peptidyl-prolyl isomerase functional assays, as well as in calcineurin inhibition assays with and without cyclophylline A. The compounds were also evaluated in a calcium retention capacity (CRC) assay in permeabilized HepG2. Cyclosporine A was used as a control in all assays.

[0216] The compound was supplied as a dry powder or oil and prepared as a 10 mM stock solution in 100% DMSO. Subsequent dilutions were carried out in 100% DMSO for use in all assays.

[0217] Cyclophylline peptidyl-prolyl isomerase functional assay Measurements were performed using an Agilent 8453 spectrophotometer. The assay buffer was cooled to 10°C in a precision glass cuvette (while stirring), and the inhibitor was added from the DMSO stock solution to obtain a final concentration of less than 1% DMSO. A blank spectrum was obtained, and then the enzyme and substrate were added, and the change in absorbance was measured over 5 minutes. The first-order reaction rate was fitted to the absorbance data to obtain the rate constant (the first 10-15 seconds were excluded by mixing). The catalytic rate was calculated by subtracting the background rate from the enzyme rate. The enzyme rate constants determined in two series at each inhibitor concentration were plotted against the inhibitor concentration, and a nonlinear fit was performed using SigmaPlot. i It generated.

[0218] Calcineurin phosphatase inhibition assay with and without cyclophyllin A This colorimetric 96-well assay is designed for the screening of recombinant calcineurin (CaN) inhibitors. Activity is determined using the RII phosphopeptide substrate, the most effective and selective peptide known for calcineurin, and detection of released free phosphate is based on the classic malachite green assay. CypA and CsA form a complex that binds to CaN / calmodulin, inhibiting the dephosphorylation of the RII peptide. Cyclosporine-like cyclophylline inhibitors were screened in the assay in the presence of recombinant CypA to determine inhibition of calcineurin phosphatase activity. Two dilution series were prepared in 96-well plates, one with cyclophylline A enzyme (7 points) and the other without cyclophylline A enzyme (4 points). Assay buffer / calcineurin / calmodulin master mixture was added, followed by the phosphopeptide substrate (RII). After incubation at 30°C, the reaction was stopped by the addition of malachite green / molybdate reagent. The colored complex formed using free phosphate was quantified by reading the absorbance at 620 nm. The blank-corrected data was plotted against the inhibitor concentration, and IC50 was calculated. 50 The value was determined.

[0219] Calcium uptake capacity (CRC) assay in permeabilized HepG2 HepG2 cells were permeabilized with 100 μM digitonin for 10 minutes in ice-cold buffer containing 1 mM EGTA. After two washing steps to remove digitonin, the cells were 1e per well in 180 μL of assay buffer containing 0.5 μM Calcium Green 5N. 6Cells were seeded in 96-well black and clear plates. The compound was diluted 1000-fold to its final concentration in DMSO, then diluted 1:100 in assay buffer and added to the assay at a concentration of 20 μL per well. The assay buffer contained 5 mM glutamate and 2.5 mM malate. The cell plates were immediately run on a FLIPR Tetra®, and the plate readings were taken every 3 seconds while adding 5 μL of 200 μM (5 μM) calcium chloride every 5 minutes. The under-curve region was calculated for each concentration of the compound. EC 50 The values ​​were calculated. It was determined that using the Area Under the Curve (AUC), rather than the number of calcium additions before loss of buffering capacity, was a more accurate method than analyzing the data.

[0220] Jurkat cell IL-2 induction assay Day 1. The Jurkat cell suspension was collected and resuspended in 10% FBS 1640 medium. The cells were then placed in 2 × 10⁶ well plates. 6 Cells were seeded by diluting the seed at cells / mL to 100 μL / well. A 30 μg / mL concanavalin A solution was prepared ("ConA", Sigma, catalog number C5275), and 25 μL of the solution was transferred to each well. The wells were heated at a stimulating temperature of 37°C for 30 minutes. A 10 mM stock solution of each representative compound of this disclosure (see Tables 1 and 4) was diluted to a concentration of 2 mM with DMSO, and then diluted 33.33 times with 10% FBS1640 medium to a concentration of 60 μM. 25 μL of the test compound solution was then added to the corresponding well. The final concentration of the test compound was 10 μM, and a total of 10 concentrations were investigated (3-fold dilution per concentration), with each concentration point set in two replication wells. The compounds were incubated at 37°C for 6 hours. After incubation, 120 μL of supernatant from each well was transferred to a new 96-well plate and stored overnight at 4°C. Coated ELISA plate: Capture antibody was prepared in the coating buffer from the ELISA kit, in a 100 μL / well coated 96-well plate, and stored overnight at 4°C.

[0221] Day 2. IL-2 ELISA determination. Each well was aspirated and the ELISA plate was washed with wash buffer. This process was repeated twice, for a total of three washes. Block buffer (200 μL) was added to each well. The plate was incubated at room temperature for 1 hour. The aspiration / washing process was repeated, and 100 μL of sample or standard material in reagent diluent or appropriate diluent was added to each well. The wells were covered with adhesive strips and incubated at room temperature for 2 hours. The aspiration / washing process was repeated a total of 5 times, and 100 μL of working detector (detection antibody + streptavidin-HRP reagent) was added to each well. The wells were covered with adhesive strips and incubated at room temperature for 1 hour. The aspiration / washing process was repeated a total of 7 times, and 100 μL of substrate solution was added to each well. The plate was covered and incubated at room temperature for 30 minutes, away from direct light. Stop solution (50 μL) was added to each well, and the plate was gently tapped to ensure complete mixing. OD450 / 570nm was recorded.

[0222] The assay results obtained are summarized in Table 4 below, with each column being as follows: A. Human CypA inhibitors (K i nM) B. Human CypD inhibitors (K i nM) C. Calcineurin inhibitors (IC) 50 nM) + CypA D. Calcineurin inhibitors (IC) 50 nM)-CypA E. Calcium uptake capacity (EC 50 nM) F.HRMS(ESI)m / z G. Sarcosine [3] Carboxy-α-proton (DMSO-d6, 400MHz, δppm unless otherwise specified) H. Carboxylate side chain proton (DMSO-d6, 400 MHz, δ ppm unless otherwise specified) I. IL-2 ELISA (EC 50 nM) For comparison purposes, the biological data for compound 0 and cyclosporine A (CsA), described in the background information section, are included in the last two rows of Table 4.

[0223] The compounds disclosed herein, compared to Compound 0 and cyclosporine A (CsA), possess unexpected and surprising properties, particularly regarding their water solubility, as will be discussed further below (see, for example, Table 5).

[0224] For example, compared to CsA and compound 0, and as shown in Table 4 below, certain compounds were found to be effective inhibitors of cyclophylline, particularly cyclophylline A, but surprisingly non-immunosuppressive. Other compounds were found to be effective inhibitors of cyclophylline, particularly cyclophylline A, but surprisingly immunosuppressive, with little to no effect on mitochondrial activity, and thus showing improvement over the properties of cyclosporine A (CsA) and / or compound 0. Still other compounds exhibited anti-inflammatory activity but were non-immunosuppressive and had little to no effect on mitochondrial activity. Some compounds exhibited immunosuppressive properties similar to CsA, but these were surprisingly improved compared to CsA, for example, and may have increased water solubility. CsA is a poorly water-soluble active pharmaceutical ingredient that poses problems in drug formulation and delivery. In many cases, and across various therapeutic applications, the development of specific (and complex) formulation strategies to solubilize it and facilitate its delivery has been needed.

[0225] [Table 4] JPEG2026532573000158.jpg224160JPEG2026532573000159.jpg231160JPEG20265325730 00160.jpg225160JPEG2026532573000161.jpg223160JPEG2026532573000162.jpg205160 JPEG2026532573000163.jpg223160JPEG2026532573000164.jpg236160JPEG20265325730 00165.jpg233160JPEG2026532573000166.jpg213160JPEG2026532573000167.jpg215160

[0226] water soluble The water solubility of the selected compounds disclosed herein was determined and compared with compound 0 and cyclosporine A (CsA) in Table 5. A Hypersil GOLD™ 5 μm, 4.6 × 250 mm column with mobile phase A: 0.05% formic acid in H2O and mobile phase B: 0.05% formic acid in acetonitrile was used, and a Thermo Scientific Ultimate 3000 HPLC was employed for analysis. The column temperature was 40°C, the flow rate was 1.0 mL / min, and the wavelength was 210 nm. At 0, 1, 8, 10, 10.1, and 15 minutes, the compositions of mobile phases (A:B) were 95:5, 95:5, 5:95, 5:95, 95:5, and 95:5, respectively.

[0227] Standard solutions were prepared as follows. First, the test compound was accurately weighed, and the weight data (m STD A standard solution (μg) was obtained. Next, the test compound was dissolved in acetonitrile. Acetonitrile was added to adjust the final volume in the volumetric flask, and the standard solution and its volume data were obtained (V STD (mL). Analyze the standard solution by HPLC and determine the injection volume (V STDInj Data (A) of the HPLC spectrum peak area (μL) STD ,mAU*min) was obtained.

[0228] The test solution was prepared as follows: First, the test compound was added to 0.5 mL of distilled water until the compound was completely dissolved. The solution was filtered twice through a 0.22 μm filter to obtain the test solution. The test solution was analyzed by HPLC, and the injection volume (V) was determined. TESTInj Data (A) of the HPLC spectrum peak area (μL) TEST ,mAU*min) was obtained.

[0229] The standard solution concentrations were calculated as follows.

number

[0230] Water solubility was calculated as follows:

number

[0231] Surprisingly and unexpectedly, many of the compounds are far more water-soluble than known compounds, as shown in Table 5 below. Such differences in solubility are unpredictable until the compounds are prepared and their solubility is tested.

[0232] [Table 5]

Claims

1. A compound of formula 1, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Formula 1 During the ceremony: X, 【Chemistry 2】 or 【Transformation 3】 And, n is 0, 1, 2, 3, or 4, c, d, and e are each 0 or 1, Y is CH ２ Or NR ｘ And, R ｘ However, H or C １ -C ６ It is alkyl, R １ and R ２ are each independently H, aryl, arylalkyl, C １ -C ６ alkyl, C ６ -C １０ bicyclyl, (C １ -C ６ alkyl)C(O) ２ R ９ , or R １ and R ２ are bonded together to form a C ３ -C ６ cycloalkyl ring, R ３ and R ４ However, H and C are independent of each other. １ -C ６ Selected from alkyl groups, or R ３ and R ４ However, when they combine together, C ３ -C ６ Forming a cycloalkyl ring, R ５ and R ６ However, each is independent of H or C １ -C ６ It is alkyl, R ７ However, O-R ８ And, R ８ However, H, C １ -C ６ Alkyl, CHR １０ OC(O)CHNH ２ R １１ _CHR １２ OC(O)R １３ ,CH ２ CH ２ OH, CH ２ CH(OH)CH ２ OH or 【Chemistry 4】 Selected from, where m is between 0 and 20, R ９ , R １０ , R １１ and R １２ However, each is independent of H or C １ -C ６ Selected from alkyl groups, R １３ However, O(C １ -C ６ Alkyl) or C １ -C ６ Selected from alkyl groups, R １４ However, H, NR １５ R １６ , selected from a heteroalkyl ring or a heteroaryl ring, R １５ and R １６ However, each is independent of H or C １ -C ６ Selected from alkyl groups, or R １５ and R １６ However, they are joined together as C ３ -C ６ Cycloalkyl or C ３ -C ６ A compound of formula 1, or a pharmaceutically acceptable salt thereof, that forms a heterocycloalkyl ring.

2. R ８ However, H, CH ３ , C (CH ３ ) ３ _CHR １０ OC(O)CHNH ２ R １１ or CHR １２ OC(O)R １３ The compound according to claim 1.

3. R ８ が、CH ２ CH ２ OH、CH ２ CH(OH)CH ２ OH、 【Transformation 5】 or (CH ２ ) (CH ２ ) ｍ NR １５ R １６ The compound according to claim 1, wherein m is 1 to 6.

4. R １４ but, 【Transformation 6】 or 【Transformation 7】 The compound according to claim 3.

5. X, 【Transformation 8】 And, A compound according to any one of claims 1 to 4, wherein n is 0.

6. R １ , 【Chemistry 9】 【Chemistry 10】 or 【Chemistry 11】 In the formula, f and g are each independently between 0 and 4, and R ２ The compound according to claim 5, wherein is H.

7. R １ and R ２ C ３ The compound according to claim 5, which forms a cycloalkyl ring.

8. X, 【Chemistry 12】 And, The compound according to any one of claims 1 to 4, wherein n is 1, 2, or 3.

9. -CR １ R ２ - The stereocenter defined by is the (S) enantiomer, and R １ is 【Chemistry 13】 and 【Chemistry 14】 Selected from the group consisting of R ２ H is R ８ but, 【Chemistry 15】 and 【Chemistry 16】 A compound according to any one of claims 5 to 8, selected from the group consisting of the following.

10. -CR １ R ２ The stereocenter defined by - is the (S) enantiomer, and R １ but, 【Chemistry 17】 and [Chemistry 18] Selected from the group consisting of R ２ H is R ８ but, 【Chemistry 19】 The compound according to any one of claims 5 to 8.

11. -CR １ R ２ The stereocenter defined by - is the (S) enantiomer, and R １ but, 【Chemistry 20】 and 【Chemistry 21】 Selected from the group consisting of R ２ H is R ８ but, 【Chemistry 22】 The compound according to any one of claims 5 to 8.

12. X is, 【Chemistry 23】 【Chemistry 24】 Selected from the group consisting of R ８ but 【Chemistry 25】 The compound according to claim 1.

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of any of the compounds 1 to 96 disclosed in Table 1.

14. A compound as defined in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein the compound or the pharmaceutically acceptable salt thereof comprises a cyclosporine ring, and the isobutyl group at position 4 of the cyclosporine ring is substituted with at least one hydroxy substituent.

15. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

16. Use of a compound as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the prevention and / or treatment of a disease or condition.

17. A method for treating and / or preventing a disease or condition, comprising administering a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in any one of claims 1 to 15.

18. The use or method according to claim 16 or 17, wherein the disease or condition is a cyclophylline-mediated disease or condition.

19. The use or method according to claim 18, wherein the disease or condition is a cyclophylline A-mediated disease or condition or a cyclophylline D-mediated disease or condition.

20. A compound as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

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