Cyclophilin inhibitors and uses thereof

Abstract

The compounds defined by formula 4 are used as cyclophilin inhibitors for the prevention or treatment of diseases or disorders such as organ injury or organ failure. JPEG2023518777000061.jpg77132

Description

[Technical Field]

[0001] The present invention relates to cyclosporine analogs and their use for treating or preventing diseases or disorders that can be caused by several different reasons, such as ischemia or ischemia-reperfusion injury, toxins, infection, or mechanical trauma, particularly diseases or conditions associated with cell injury or cell death. In particular, the present invention relates to compounds that can serve as potent cyclophilin D inhibitors. [Background technology]

[0002] It is now well recognized that acute inflammation involves a complex interplay of various cellular (neutrophils, macrophages) and extracellular (complement, histamine) factors that act in response to PAMP (pathogen-activating molecular pattern) and DAMP (cytotoxicity-activating molecular pattern) signals to resolve the underlying injury. Cyclophilin A has been demonstrated to function as a chemokine promoting leukocyte migration to support the inflammatory response, and blockade of cyclophilin A has been shown to be beneficial in animal models of acute inflammation. More recently, severe forms of inflammation accompanied by cell death and tissue necrosis have been described. A large body of evidence now supports the opening of a pore in the mitochondrial membrane, called the mitochondrial permeability transition pore (MPTP), as crucial for the development and maintenance of this necroinflammation. The key regulator of this MPTP opening is cyclophilin D (CypD), and inhibitors of CypD have shown potent activity in preventing tissue damage associated with necroinflammation. The opening of the MPTP and the subsequent initiation of necrotic cell death are triggered by elevated intracellular calcium levels resulting from a variety of factors, including excessive physiological signals (e.g., noise trauma, excitotoxicity), oxidative stress, hypoxia, bile salt toxins, etc. Notably, genetic disruption or pharmacological inhibition of CypD was found to be protective against tissue degradation resulting from ischemia-reperfusion injury in cardiac tissue, suggesting that CypD inhibition is a viable drug target for ischemia-reperfusion injury more generally.

[0003] In a mouse model, cyclophilin D deletion was shown to have a significant protective effect against kidney damage caused by severe ischemia-reperfusion injury (Am J Physiol Renal Physiol 297:F749-F759, 2009). This protective effect was evident in improved renal function, as measured by serum creatinine levels, and in tissue damage (measured by histology) in cyclophilin D knockout animals compared with wild-type controls. Similarly, in a mouse model of kidney injury caused by administration of a nephrotoxic drug (Am J Physiol Renal Physiol. 2019 Sep 1;317(3):F683-F694), animals in which cyclophilin D was knocked out were more resistant to oxidative stress and hypomethylation and showed fewer signs of nephrotoxicity than wild-type animals.

[0004] Studies using cyclophilin D knockout mice and pharmacological strategies with cyclophilin inhibitors have clearly demonstrated that the opening of the mitochondrial permeability transition pore (MPTP), a nonspecific channel in the inner mitochondrial membrane, is a fundamental event in cell death caused by various insults. Furthermore, inhibition of cyclophilin D can prevent the opening of the MPTP, which is protective for mitochondrial function and preserves cell survival.

[0005] Cyclosporin A is a compound well known for its immunosuppressive properties, although other biological properties have also been described. Cyclosporin A has the following chemical structure: JPEG0007776435000001.jpg106150

[0006] Biologically active derivatives of cyclosporin A have also been prepared. For example, U.S. Patent No. 6,583,265, European Patent No. 0484281, and European Patent No. 0194972 describe cyclosporin derivatives with various properties, including immunosuppressive, antiparasitic, and antiviral properties. U.S. Patent No. 6,583,265 describes cyclosporin derivatives with modifications at the 3-position of the cyclosporin macrocycle. In particular, U.S. Patent No. 6,583,265 discloses Compound 1. JPEG0007776435000002.jpg112160

[0007] WO 2019 / 016572 also describes compound 1 for use in the treatment or prevention of acute or chronic inflammatory disorders.

[0008] It is an object of the present invention to provide additional cyclosporin analogs, particularly analogs that may be useful in inhibiting cyclophilins, such as cyclophilins A, B, and D, and cyclophilin-associated diseases and conditions. Further objects of the present invention will become apparent based on the following description, examples, and claims of the invention. [Prior art documents] [Patent documents]

[0009] [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 [Non-patent literature]

[0010] (Non-patent document 1) Am J Physiol Renal Physiol 297:F749-F759,2009 (Non-patent document 2) Am J Physiol Renal Physiol.2019 Sep 1;317(3):F683-F694 Summary of the Invention

[0011] In a first aspect, the present invention relates to compounds as defined in the detailed description, namely compounds of formula 1, formula 2 or formula 3, or formula 4. In a further aspect, the present invention provides the use of the compound as a cyclophilin inhibitor. In yet a further aspect, the present invention provides the use of the compound in a method for preventing and / or treating a disease or condition associated with cell injury or cell death, such as organ injury or organ failure. In yet another aspect, the present invention may provide the use of the compound in the prevention and / or treatment of a renal condition or disease in a subject exposed to a nephrotoxin capable of inducing the renal condition or disease, wherein the nephrotoxin is a nephrotoxic drug substance or an endogenous nephrotoxin. DETAILED DESCRIPTION OF THE INVENTION

[0012] In a first aspect, the present disclosure provides a compound of Formula 1, or a pharmaceutically acceptable salt thereof: JPEG0007776435000003.jpg77133Formula: R 1 and R 2 are independently selected from H, C1-C6 alkyl, or R 1 and R 2 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; A is, -NR 3 R 4 , where R 3 and R 4 are independently selected from H, C1-C6 alkyl, or R 3 and R 4 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; - N=C(R5 )NR 6 R 7 , where R 5 , R 6 and R 7 are independently selected from H, C1-C6 alkyl, and optionally, R 6 and R 7 may be joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; Selected from; R 8 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; R 9 is expressed by formula 1a or 1b JPEG0007776435000004.jpg7678JPEG0007776435000005.jpg7678, Regarding.

[0013] In one aspect, the present disclosure provides a method for producing a compound comprising: 1 and R 2 are both H, and R 8 is selected from ethyl, isopropyl, and n-propyl; R 9 is formula 1a, and A is NR 3 R 4 If R 3 and R 4 is not H, C1-C4 alkyl, or is joined together to form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, or phthaloyl residue. 1 and R 2 are both H, or R1 is methyl and R2 is H; R 8 is selected from ethyl, isopropyl, and n-propyl; R 9 is formula 1a, and A is NR 3 R 4 If R 3 and R 4is not H, C1-C4 alkyl, or is joined together to form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, or phthaloyl residue. 1 and R 2 are both H, or R 1 is C1-C6 alkyl, and R 2 is H;R 8 is selected from ethyl, isopropyl, and n-propyl; R 9 is formula 1a, and A is NR 3 R 4 If R 3 and R 4 is not H, C1-C4 alkyl, or is joined together to form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, or phthaloyl residue. 1 and R 2 are both H, and R 8 is selected from ethyl, isopropyl, and n-propyl; R 9 is formula 1a, when A is NR 3 R 4 In a further aspect, the present disclosure relates to compounds of formula 1 wherein R 1 and R 2 are both H, or R 1 is C1-C6 alkyl, and R 2 is H and R 8 is selected from ethyl, isopropyl, and n-propyl; R 9 is formula 1a, when A is NR 3 R 4 is not a compound of formula 1.

[0014] In yet another aspect, the present disclosure provides a method for producing a compound comprising: 1 and R 2 are both H, and R 8 When is selected from ethyl, A is NR 3 R 4a compound as defined for formula 1 provided that R 1 and R 2 are both H, or R 1 is H and R 2 is C1-C6 alkyl, and R 8 is selected from ethyl, and R 9 is formula 1a, A is NR 3 R 4

[0023] The present invention relates to compounds as defined for Formula 1, with the proviso that they are not:

[0024] In particular, compounds of Formula 1 do not include Compound 1 shown above. Compounds of Formula 1 also do not include 3-[2-(aminopropoxy)]cyclosporine.

[0015] In a related aspect, the present disclosure also provides a compound of Formula 2, or a pharmaceutically acceptable salt thereof: JPEG0007776435000006.jpg78143 During the ceremony: R 1 and R 2 are independently selected from H, C1-C6 alkyl, or R 1 and R 2 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; R 3 and R 4 are independently selected from H, C1-C6 alkyl, or R 3 and R 4 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; R 8 is 1-hydroxyethyl, isopropyl or n-propyl; R 9 is expressed by formula 1a or 1b JPEG0007776435000007.jpg7678JPEG0007776435000008.jpg7678, may be related to.

[0016] In a related aspect, the present disclosure also provides a compound of Formula 3, or a pharmaceutically acceptable salt thereof: JPEG0007776435000009.jpg75147Formula: R 1 and R 2 are independently selected from H, C1-C6 alkyl, or R 1 and R 2 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; R 5 , R 6 and R 7 are independently selected from H, C1-C6 alkyl, and optionally, R 6 and R 7 may be joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; R 8 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; R 9 is expressed by formula 1a or 1b JPEG0007776435000010.jpg7678JPEG0007776435000011.jpg7678, may be related to.

[0017] In particular, the compounds of Formulas 1, 2 and 3 and Formula 4 relate to cyclosporine analogs of cyclosporine A, C, D or G.

[0018] In one embodiment, a cyclosporin compound according to the present disclosure is a cyclosporin A compound (e.g., R 9 The residue is of formula 1a, R 8In other embodiments, the cyclosporin compounds according to the present disclosure are cyclosporin C compounds (e.g., R 9 The residue is of formula 1a, R 8 is 1-hydroxyethyl), cyclosporin D compounds (e.g., R 9 The residue is of formula 1a, R 8 is isopropyl), or cyclosporin G compounds (e.g., R 9 The residue is of formula 1a, R 8 is n-propyl).

[0019] The position numbering used herein refers to the commonly used nomenclature and numbering of the 11 amino acid residues contained in the cyclosporine core. Using cyclosporine A as a base, the amino acid residues can be numbered as follows: methyl-butenyl-threonine, which can be abbreviated as MeBmt (1), aminobutyric acid (2), sarcosine, which can be abbreviated as Sar (3), N-methylleucine (4), valine (5), N-methylleucine (6), alanine (7), D-alanine (8), N-methylleucine (9), N-methylleucine (10), N-methylvaline (11).

[0020] The term "H" as used herein refers to hydrogen. The term "C1-C6 alkyl" as used herein is defined as a saturated or unsaturated alkyl hydrocarbon moiety containing 1 to 6 carbon atoms in any isomeric configuration. Included are straight-chain linear alkyls such as methyl, ethyl, n-propyl, n-butyl, 1-pentyl, and n-hexyl. Also included are branched alkyls (i.e., branched C3-C6 alkyls) such as isopropyl, sec-butyl, isobutyl, tert-butyl, 2-pentyl, 3-pentyl, isopentyl, tert-pentyl, neopentyl, and hexyl isomers. Also included within the definition of "C1-C6 alkyl" are cyclic isomers such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of unsaturated C1-C6 alkyls include, but are not limited to, vinyl, allyl, butenyl, pentenyl, and hexenyl, as well as other alkenyl or alkylene moieties containing, for example, one or more double bonds, such as pentadienyl. The term "C3-C6" should be understood similarly, but refers to moieties containing a range of 3 to 6 carbon atoms.

[0021] In preferred embodiments, C1-C6 alkyl refers to an unsubstituted hydrocarbon moiety as defined above. In optional embodiments, C1-C6 alkyl can be substituted with one or more substituents, where one or more hydrogen atoms are replaced with said substituent or a bond to a non-hydrogen moiety.

[0022] The term "substituted," such as substituted alkyl (e.g., substituted C1-C6 alkyl), can refer to a moiety or group in which one or more hydrogens are independently replaced with at least one or more (e.g., two, three, or more) substituents such as halogen, haloalkyl, hydroxyl (-OH), C1-C6 alkoxyl, amino (-NH2), monoalkylamino, dialkylamino, thioalkyl, nitro, cyano, carboxyl, alkoxycarbonyl, aryl, and heteroaryl.

[0023] The term "halogen" is interchangeable with "halo" and can refer to chloro, bromo, iodo, or fluoro atoms. "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.

[0024] The term "hydroxyl" refers to an -OH group. In some embodiments, the hydrogen can be replaced with, for example, a hydroxy protecting group known in the art. Terms such as "alkoxyl" refer to an alkylated hydroxyl substituent, i.e., where the hydrogen is replaced by an alkyl group. "C1-C6 alkoxy" refers to the replacement of the hydroxy hydrogen with a C1-C6 alkyl, as defined above. Examples include methoxy, isopropoxy, phenoxy, or t-butoxy.

[0025] The term "amino" can refer to an -NH group. In some embodiments, the hydrogen can be replaced with one or more further substituents, such as, for example, a protecting group or an alkyl. The term "monoalkylamino" refers to an amino group in which one of the hydrogens is replaced with an alkyl, for example, a C1-C6 alkyl as defined above (i.e., -NHR, where R is alkyl). "Dialkylamino" refers to an amino group in which both hydrogens are independently replaced with alkyl (i.e., -NRR', where R and R' are alkyl and can be the same (e.g., dimethylamino) or different).

[0026] "Thioalkyl" may refer to the group -SR" where R" is alkyl, e.g., C1-C6 alkyl, as defined above. As used herein, the term "carboxyl" refers to the group -C(O)-R a refers to R a may be selected from hydrogen, alkyl, aryl, hetaryl, hydroxy, alkoxy (e.g., —OCH), amino, alkylamino, dialkylamino, thioalkyl, etc. The term “alkoxycarbonyl” refers to the group —OC(O)—Ra can refer to R a is selected from alkyl (eg, C1-C6 alkyl, such as methyl), aryl, hetaryl, alkoxy, amino, alkylamino, dialkylamino, thioalkyl, and the like.

[0027] In one embodiment, the compounds described herein, e.g., R of Formula 1, Formula 2, or Formula 3, or Formula 4 1 or R 2 At least one or both of R 1 or R 2 At least one of R is C1-C6 alkyl. 1 and R 2 One or both of the is -CH3 (methyl).

[0028] In some embodiments, two adjacent R 1 and R 2 Substituents may be bonded together to form a ring, such as a C3-C6 cycloalkyl ring. As used herein, "cycloalkyl" refers to a saturated or unsaturated non-aromatic hydrocarbon ring. Adjacent R groups bonded together to form a ring, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, may be bonded together to form a ring. 1 and R 2 Examples of moieties formed by substituents. In one embodiment, two adjacent R 1 and R 2 The substituents may be joined to form a cyclopropyl ring.

[0029] The term "hetero," when used to describe a compound or substituent, means that one or more carbon atoms are replaced by an oxygen, nitrogen, or sulfur atom. In a further embodiment of the present disclosure, the substituent R 1 and R 2can be joined together to form a heterocycloalkyl ring, e.g., a C3-C6 heterocycloalkyl ring. Unless otherwise indicated, "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic ring forming at least part of the ring structure, in which at least one or more carbon atoms are replaced by an oxygen, nitrogen, or sulfur atom (and in the case of a C3-C6 heterocycloalkyl, contains 3 to 6 carbon atoms). For example, the substituent R 1 and R 2 can be joined together to form a 4-, 5-, or 6-membered saturated non-aromatic ring containing at least one heteroatom. The heterocycloalkyl ring can contain at least one heteroatom selected from O, N, or S.

[0030] Substituent R of compounds of formula 1, 2 or 3 or 4 8 may be selected from ethyl, 1-hydroxyethyl, isopropyl, and n-propyl. 8 is selected from the group consisting of 1-hydroxyethyl, isopropyl, and n-propyl. 8 is ethyl, and R 9 is Equation 1b.

[0031] The substituent R at position 1 of the cyclosporin compounds of the present disclosure 9 may correspond to formula 1a, i.e., position 1 of the compound may correspond to the amino acid residue N-methyl-butenyl threonine or MeBmt. Alternatively, R 9 may correspond to its oxidized form as shown in formula 1b.

[0032] In one embodiment, the substituent A in the compounds according to the present disclosure is an amino group NR 3 R 4 and R 3 and R 4 are independently selected from H, C1-C6 alkyl, or R 3 and R 4 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring. 3and R 4 are both -CH3 (methyl). In another embodiment, R 3 and R 4 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring. For example, the substituent R 3 and R 4 may be joined together to form a 4-, 5-, or 6-membered saturated non-aromatic ring. In the context of the compound of this formula, adjacent R 3 and R 4 The cycloalkyl ring formed by the substituents can include, for example, azetidine, pyrrolidine, or piperidine. The heterocycloalkyl ring can be a saturated or unsaturated non-aromatic ring forming at least a portion of the ring structure, in which at least one or more carbon atoms are bonded to R, as characterized, for example, in Formula 1 or 2. 3 and R 4 is replaced by an oxygen, nitrogen or sulfur atom in addition to the nitrogen to which it is attached. 3 and R 4 is the substituent R 3 and R 4 may be joined together to form a 4-, 5-, or 6-membered saturated non-aromatic ring containing at least one additional heteroatom to the nitrogen atom to which R is attached, e.g., at least one additional heteroatom selected from O, N, or S. In one particular embodiment, R 3 and R 4 are linked together to form a morpholine residue. 3 and R 4 The cycloalkyl or heterocycloalkyl moiety formed by may be substituted with one or more substituents as defined above in which one or more hydrogen atoms are replaced with a bond to said substituent.

[0033] In another embodiment, compounds according to the present disclosure comprise a substituent A, where A is an amidine, particularly a compound of the formula —N═C(R 5 )NR 6 R 7 and R is an amidine substituent defined by 5, R 6 and R 7 are independently selected from H, C1-C6 alkyl, and optionally substituted C1-C6 alkyl.

[0034] In one embodiment, R 5 is selected from H and CH3 (methyl). Amino group NR 6 R 7 is an alkylamino group, such as monoalkylamino (R 6 or R 7 one of which is hydrogen and the other is C1-C6 alkyl), or R 6 Or R 7 and R may be the same or different C1-C6 alkyl groups. 6 and R 7 In one embodiment of a compound of Formula 1, or Formula 3, or Formula 4, A is —N═C(R 5 )NR 6 R 7 and R 8 is ethyl.

[0035] Compounds according to the present disclosure may be selected from compounds 2, 3, 4, see below, as defined in Table 1, or pharmaceutically acceptable salts thereof: JPEG0007776435000012.jpg103151JPEG0007776435000013.jpg228151JPEG0007776435000014.jpg220151 JPEG0007776435000015.jpg226151

[0036] In another aspect, the present disclosure also provides a compound of formula 4, or a pharmaceutically acceptable salt thereof: JPEG0007776435000016.jpg96164wherein X and Z are independently selected substituents, such as a substituent selected from H, alkyl (e.g., C1-C6 alkyl, e.g., methyl), and substituted alkyl, such as substituted C1-C6 alkyl, or X and Z are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; where A, R 1 , R 2 , R 8 and R 9 is as defined in any one or combination of the embodiments described herein. Formula 4 also includes compounds of formula I:

[0037] In one embodiment, X and Z are both H. In another embodiment, X and Z can be both alkyl, e.g., methyl. In yet another embodiment, X is H and Z is methyl. Embodiments of Formula 4 can also include the following:

[0038] 1.1 R 1 and R 2 are both hydrogen.

[0039] 1.2 R 1 or R 2 The compound according to 1.1, wherein at least one of is C1-C6 alkyl, for example, methyl.

[0040] 1.3 R 1 and R 2 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring, or preferably a C3-C6 cycloalkyl ring, such as cyclopropyl.

[0041] 1.4 R 8 The compound according to 1.1 to 1.3, wherein is ethyl.

[0042] 1.5 R 8The compound according to any one of 1.1 to 1.4, wherein is isopropyl.

[0043] 1.6 R 8 The compound according to any one of 1.1 to 1.5, wherein is n-propyl.

[0044] 1.7 R 8 The compound according to any one of 1.1 to 1.6, wherein is 1-hydroxyethyl.

[0045] 1.8 A is -N=C(R 5 )NR 6 R 7 The compound according to any one of 1.1 to 1.7,

[0046] 1.9 R 5 , R 6 and R 7 is independently selected from H, C1-C6 alkyl, and optionally substituted C1-C6 alkyl.

[0047] 1.10 R 5 is H or CH3, and R 6 and R 7 The compound according to 1.9, wherein is CH3.

[0048] 1.11 R 9 The compound according to 1.8 to 1.10, wherein: is Formula 1a.

[0049] 1.12 R 9 The compound according to any one of 1.1 to 1.11, wherein: is formula 1b.

[0050] 1.13 A is NR 3 R 4 The compound according to any one of 1.1 to 1.7 or 1.11 to 1.12,

[0051] 1.14 R 3 and R 4 are both -CH3.

[0052] 1.15 R 3 and R 4 are linked together to form a morpholinyl residue.

[0053] 1.16 The compound according to 1.1 to 1.15, wherein X and Z are both H.

[0054] 1.17 Compounds according to 1.1 to 1.16, wherein X is alkyl (eg, C1-C6 alkyl, such as methyl) and Z is H.

[0055] 1.18 R 8 is ethyl and R 9 The compound according to 1.17, wherein: is formula 1a.

[0056] In certain embodiments of Formula 4 described herein, the provisos defined for the selection of A described for Formula I may also apply.

[0057] In yet another aspect, the present disclosure also relates to methods for preparing compounds according to formulas 1, 2, 3, and 4. In one embodiment, the compounds can be prepared by a method or process comprising a compound-forming reaction, the reaction comprising copper triflate and an amino alcohol. The amino alcohol is a compound of formula 5: JPEG0007776435000017.jpg9793 wherein the substituents, X and Z, can be independently selected from H, alkyl (e.g., C1-C6 alkyl, e.g., methyl), substituted alkyl, e.g., substituted C1-C6 alkyl, or X and Z are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; wherein A, R 1 , R 2 may be as defined in any one or combination of the embodiments described herein. In some embodiments, the provisos defined for the selection of A described for Formula I may also apply. In one embodiment, X and Z in Formula 5 are H, and A, R 1 , R2 is as defined in any one or combination of the embodiments described herein. In another embodiment, A is NR 3 R 4 and R 3 and R 4 is as defined according to any one of the aspects or examples herein. In yet another embodiment of Formula 5, X and Z are both H; R 1 and R 2 are both H, and A is NR 3 R 4 and R 3 and R 4 are all alkyl, for example, C1 to C6 alkyl, for example, methyl).

[0058] In one embodiment, compounds according to the present disclosure can be prepared or obtained by a process comprising reacting a cyclosporin compound (e.g., cyclosporin A, C, D, G, etc.) intermediate containing a leaving group at the 3-position or sarcosine position with an amino alcohol compound, such as a compound of formula 5. In another embodiment, compounds described herein can be prepared by: a) reacting a cyclosporin compound, e.g., cyclosporin A, C, D, G, etc., with a dipyridyl disulfide to form a thiopyridyl cyclosporin intermediate (e.g., [(2'-(2-thiopyridyl)-Sar] 3 -cyclosporin A or C, or D, or G, etc., and b) reacting said intermediate with an amino alcohol compound in the presence of copper triflate. The amino alcohol may be a compound defined according to Formula 5 above. Examples of amino alcohol compounds that may be used include, but are not limited to, morpholinoethanol or dimethylaminoethanol.

[0059] The compounds of the present disclosure and the present invention can exist in various stereoisomeric forms and mixtures. It is understood that the present disclosure includes, in addition to the stereocenters designated or shown in the formula, all enantiomers, diastereomers, racemates, or other mixtures thereof, as well as polymorphs, solvates, hydrates, complexes, free forms, or salt forms. Unless otherwise indicated, compounds within the scope of the present disclosure that contain one or more asymmetric centers not designated or shown in the formula or not specifically named / described also include all enantiomers, diastereomers, or mixtures thereof, racemates or otherwise. Representations of double bonds in the present disclosure refer to the isomer depicted, but can also be considered to include other Z (or E) isomers. The use of any optically pure or stereochemically pure stereoisomers, and any combination of stereoisomers, determined or prepared by methods well known in the art, is also included. Optionally, the compounds of the present invention may also include their isotopes, ie, compounds in which atoms have been replaced with isotopes such as hydrogen by deuterium or carbon by carbon-13.

[0060] As defined herein, a pharmaceutically acceptable compound is a compound that is generally safe, non-toxic, not biologically or otherwise undesirable, tolerable, and compatible for pharmaceutical use in humans. Pharmaceutically acceptable salts are salts of compounds as provided herein that retain their biological properties, are non-toxic, and are compatible for pharmaceutical use.

[0061] Salts according to the present disclosure can result from the addition of an acid to a compound of Formula 1, Formula 2, Formula 3, Formula 4, or any one of the 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, arylsulfonic acids (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, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptone, gluconic acid (e.g., D-gluconic acid), glutamic acid, glutamic acid, glutamic acid, glutamic acid, glutamic acid, glutamic acid, glutamic acid, sucralose ... uronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic 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, metaphosphoric acid, meta Acid addition salts may include those formed with arylsulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic 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, acid addition salts may include those derived from mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid; and organic acids such as tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, arylsulfonic acids, and the like.

[0062] The compounds of the present disclosure may be useful for the prevention and / or treatment of a disease or medical condition, or in the manufacture of a medicament for the prevention and / or treatment of a disease or medical condition.

[0063] As used herein, the term "therapy", which may be used interchangeably with the term "treatment", relates to a therapeutic intervention that can result in the cure, amelioration, remission, control, control of progression, prevention of progression, or prevention of recurrence of a disease, condition, or symptom associated with said disease or condition.

[0064] 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 occurrence of a disease, condition, or symptom, or to significantly reduce the likelihood of the occurrence of a disease, condition, or symptom, and, for example, to prevent the further recurrence of a disease, condition, or associated symptom. Also included within the meaning of this term is the prevention of the progression of said disease, condition, or associated symptom after initial improvement or after initial elimination of the cause of the disease, condition, or symptom.

[0065] In particular, the compounds according to the invention can be used for the prevention and treatment of cyclophilin-mediated diseases or conditions.

[0066] In particular, the compounds described herein can be used as inhibitors of cyclophilins, particularly cyclophilin A (CypA) and / or cyclophilin D (CypD). In one embodiment, the compounds are used as inhibitors of cyclophilin D, e.g., are provided or administered in a therapeutically appropriate amount for the inhibition of cyclophilin D. As generally understood herein, the term "therapeutically effective amount" is the amount of a compound that, when administered to a subject (e.g., a human subject) to treat and / or prevent, e.g., a disease or condition, is sufficient to effect such treatment and / or prevention.

[0067] Overexpression of these cyclophilins has been associated with or correlated with various diseases and conditions, particularly inflammatory disorders in humans. For example, cyclophilin A has been demonstrated to function as a chemokine that promotes leukocyte migration to support the inflammatory response, and blockade of cyclophilin A has been shown to be beneficial in animal models of acute inflammation. A growing body of evidence now supports the opening of a pore in the mitochondrial membrane called the mitochondrial permeability transition pore (MPTP) as crucial for the development and maintenance of necroinflammation, a severe form of inflammation. Cyclophilin D is a key regulator of MPTP opening, and inhibition of CypD has demonstrated potent activity in preventing tissue damage associated with necroinflammation. MPTP opening and the subsequent initiation of necrotic cell death are triggered by elevated intracellular calcium levels due to various factors, including oxidative stress, hypoxia, and bile salt toxins. Therefore, pharmacological inhibition of CypD may be protective against tissue degradation resulting from ischemia-reperfusion injury in organ tissues.

[0068] Compounds according to the present disclosure have been found to be surprisingly effective as inhibitors of cyclophilins, particularly cyclophilin D, as demonstrated in the Examples. The compounds may be useful in the treatment or prevention of diseases or conditions in which elevated levels or activity of cyclophilins are associated with, contribute to, or result in said disease or condition. In particular, a cyclophilin-mediated disease or condition that may be treated or prevented in accordance with the present invention may be a cyclophilin-D-mediated disease or condition. The disease or condition may be the result of mitochondrial dysfunction due, for example, to upregulated opening of MPTP.

[0069] In one embodiment, compounds according to the present disclosure may be used as cytoprotective agents (e.g., for preventing or reducing cell damage or cell death) or as mitochondrial protective agents (e.g., for preventing or reducing mitochondrial dysfunction or damage).

[0070] Cyclophilin-mediated diseases or conditions are typically diseases and conditions associated with inflammatory responses, cell injury, damage and / or cell death (e.g., necrosis), and may include, but are not limited to, diseases and conditions such as those further described below.

[0071] In one embodiment, the compounds according to the present invention can be used in the treatment and / or prevention of diseases or conditions associated with cell injury or cell death, such as cell necrosis (unprogrammed cell death associated with loss of cell membrane integrity and release of cellular components into the extracellular matrix). Cell injury and cell death can be the result or can be induced, for example, by injury, infection, infarction, inflammation, ischemia, exposure to toxins, thermal trauma, physical trauma, etc.

[0072] As understood herein, the term "cell" or "cellular" can also refer to a collection or aggregate of cells, i.e., cellular tissue. The tissue can be associated with or located in a particular organ, such as the kidney, liver, heart, lung, and other organs typically found in a subject to be treated.

[0073] In one embodiment, the compound according to the present invention can be used in the treatment or prevention of organ failure or organ damage, and the organ can be selected from the group consisting of kidney, liver, heart, lung, pancreas, intestine, cornea, skin, brain, and nervous tissue. Examples of nervous tissue include central nervous tissue or peripheral nervous tissue. In one embodiment, the organ is the kidney. As understood herein, organ failure or organ damage can refer to the failure or damage of one, two, or multiple organs in a subject. For example, renal failure or renal damage can refer to the condition of one kidney in a subject or patient, but can also refer to the condition of two or both kidneys. In one embodiment, the compound can be used to treat and / or prevent multiple organ failure (e.g., kidney, lung, and liver failure).

[0074] In another embodiment, the compound according to the present invention can be used for the prevention and / or treatment of kidney disease or condition, i.e. kidney disease or condition.Kidney disease or condition can be characterized by, for example, the abnormal or impaired function of kidney or renal tissue.Abnormal or impaired renal function can be determined according to standard clinical diagnostic methods in the art, for example, but not limited to, measuring renal function markers such as blood urea nitrogen and / or serum creatinine.

[0075] In a further embodiment, the compound according to the present invention can be used for the prevention and / or treatment of ischemia, i.e., ischemia in tissue or organ as described herein.Ischemia or ischemic injury generally occurs when the blood supply to a tissue region is blocked or interrupted, resulting in a lack of oxygen or insufficient supply of oxygen to tissue, among other factors.The incidence of ischemic injury can be caused and / or result from, for example, but not limited to, myocardial infarction, stroke and other thrombotic events.The length of time that tissue can survive oxygen deprivation varies, but eventually ischemic tissue can become necrotic.In one embodiment, the compound can be used for the treatment of myocardial ischemia, renal ischemia, cerebral ischemia or hepatic ischemia.

[0076] Ischemic injury can occur in organs for transplantation during surgery when blood vessels are cross-clamped. Ischemia-reperfusion (reoxygenation) injury is tissue damage caused when blood supply is restored to tissue after a period of ischemia or oxygen deprivation (anoxia, hypoxia). Without being bound by theory, it is believed that the lack of oxygen and nutrients from the blood during the ischemic period creates conditions in which restoration of circulation leads to inflammation and oxidative damage.

[0077] In one embodiment, the compounds according to the invention can be used in the prevention or treatment of ischemia-reperfusion injury, which can be associated with or result from a surgical procedure.

[0078] The surgical procedure can be a transplantation procedure.Ischemia-reperfusion injury can occur in the recipient subject or in the donor subject.In organ transplantation or organ-tissue transplantation, there is a period between removing the organ or tissue from the donor's blood supply and reconnecting the organ or tissue to the donor-recipient's blood supply.In some cases, the organ may need to be transported long distances to the surgical site, which increases the possibility of organ damage.In one aspect, the present invention relates to the use of the compounds described herein for preventing and / or treating ischemia-reperfusion injury associated with or resulting from organ transplantation.

[0079] In one embodiment, a compound of the invention is administered to an organ transplant recipient (eg, a kidney transplant recipient).

[0080] In yet a further embodiment, the ischemia-reperfusion injury is renal ischemia-reperfusion injury, which may result, for example, from a surgical procedure in which the blood vessels supplying the kidney are clamped for at least part of the surgical procedure, such as a kidney transplant. In one embodiment, the compounds described herein are used for the prevention or treatment of acute kidney injury.

[0081] Renal transplantation procedures are associated with the risk of conditions such as acute kidney injury, which can be induced or caused by renal ischemia and renal ischemia-reperfusion injury. Renal ischemia can result from arterial occlusion, shock, and renal transplantation, and can lead to renal cell death and renal failure. In a further embodiment, the compounds described herein are used for the prevention or treatment of acute kidney injury associated with or resulting from renal transplantation procedures. For example, after the removal of donor kidneys, renal tissue can suffer from oxygen deprivation as a result of loss of blood flow (ischemia), and further damage to ischemic renal tissue can occur when blood flow is restored (reperfusion injury). Preventing such damage and preventing MPTP opening after ischemic stress by administering compounds that can be used as protective agents by potently inhibiting cyclophilin D can help improve the viability of transplanted organs.

[0082] In another aspect, the present invention may relate to the use of the compounds described herein for the prevention or treatment of hepatic or cardiac ischemia-reperfusion injury, which may optionally be the result of or associated with transplantation of said organ or organ tissue.

[0083] According to the present disclosure, the compounds as defined above or pharmaceutically acceptable salts thereof may be used in the manufacture of a medicament for preserving organs and / or protecting organs from organ injury, such as during transplant surgery.

[0084] In the context of use of the compound (e.g., in the manufacture of a medicament comprising said compound), and also in the context of transplant surgery, the compound or medicament may be administered to the organ donor and / or organ recipient before, during and / or after transplantation of the organ from the organ donor to the organ recipient.

[0085] In one embodiment, the compound of the present invention can be administered to the donor subject before the removal of the donor organ, for example, by systemic administration, for example, injection or infusion. Alternatively or additionally, the compound according to the present disclosure can be administered to the organ after removal of the organ from the individual and before transplantation or reattachment. For example, the compound can be added to (or contained in) the fluid in which the organ is placed, and / or the compound described herein can be added to (or contained in) the fluid recirculated within and / or through the organ.

[0086] In another embodiment, the compound according to the present disclosure can be administered to a subject before the start of surgery, for example, to an organ transplant recipient before the start of transplant surgery.In yet a further embodiment, the compound can also be administered during and / or after surgery, for example, in the case of a transplant recipient, during and / or after transplantation of an organ or organ tissue.In still a further embodiment, the compound can also be administered to a donor (or optionally to an excised organ) and a recipient throughout the transplantation process and / or recovery period.In one embodiment, the compound is administered to a transplant recipient before the transplantation process.In another embodiment, the compound is administered to a transplant recipient or to an organ before and after transplantation.

[0087] As used herein, the term "donor" or "organ donor" refers to a subject from whom an organ (or tissue of an organ) is removed. The donor may be a living or living donor. Alternatively, the donor may be a clinically deceased donor, the term "clinically deceased" being generally understood by those skilled in the art and defined by standard clinical and / or legal guidelines in the art, e.g., as applied to human subjects.

[0088] Furthermore, the terms "subject" or "patient" may be used interchangeably and, in one embodiment, refer to a human subject. Preferably, the subject or patient is a human. Similarly, terms such as "organ donor" or "organ recipient" as used herein may refer to a human subject. These terms may also refer to other animals, such as other mammals. In further embodiments, the present invention may be applied to, for example, livestock or other veterinary subjects, particularly mammals such as cats, dogs, primates, horses, cows, and pigs. The present invention may also be applied to transgenic animals (e.g., transgenic pigs) in which such animals have organs suitable for human transplantation.

[0089] Before organ removal, organ donor can be administered a systemic dose of the compound of the present invention.This allows organ to receive a protective dose of compound before removal, thereby protecting organ from damage during removal and up to and during the process of transplantation into donor recipient, thereby preserving organ.If two or more organs are removed from donor, this systemic dose ensures that each organ receives a dose of compound.Systemic dose is also more likely to provide a uniform dose of compound to the organ tissue to be transplanted.If donor is legally dead, the dose can be larger than that usually given to living subjects.

[0090] The compounds can be administered immediately prior to or during organ removal surgery. For example, the compounds of the invention can be administered up to 8, 7, 6, 5, 4, 3, 2, or 1 hour before surgery.

[0091] Alternatively or additionally, the organ recipient can receive a dose of a compound of the invention immediately prior to receiving the organ so that their blood supply contains a protective dose of the compound, thereby preserving the transplanted organ or body part from damage after surgery.

[0092] In embodiments of the compounds (or methods or uses) described herein above, the organ may be any transplantable organ, including kidney, liver, heart, lung, pancreas, intestine, cornea, skin, brain and neural tissue.

[0093] As described above, the present disclosure provides for the administration of a compound that acts as a cyclophilin inhibitor to prevent, treat, ameliorate, and / or reduce damage to organs. Optionally, the treatment can also be applied to the prevention and treatment of damage to body parts, such as limbs, hands, feet, fingers, or toes. For example, in an accident involving limb amputation, there is a period between the body part's disconnection from the blood supply and its reconnection to the blood supply. During this period, there may be a possibility of ischemia-reperfusion injury. In some cases, the body part and the patient may need to be transported long distances to the surgical site, increasing the possibility of injury before, during, and after reattachment. In the case of body parts, they may be amputated from the same individual and reattached to the same individual, or may be given to a second individual as a graft. When a body part is amputated from a subject, the amputation may be complete or partial. A partial amputation may be, for example, a cutoff of the blood supply, but the body part remains attached, for example, via skin, bone, or muscle tissue. The compound may be administered to the subject (i) the severed body part; and / or (ii) prior to reattachment of the body part; and / or (iii) during or after reattachment of the body part.

[0094] The compounds of the present disclosure can optionally be administered with one or more additional active agents.

[0095] In a further aspect, the present disclosure provides a compound described herein (i.e., a compound of Formula 1, 2, 3, 4 or specific embodiments thereof) for use in the prevention or treatment of a renal condition or disease in a subject exposed to a nephrotoxin capable of inducing said renal condition or disease, wherein said nephrotoxin is a nephrotoxic drug substance or an endogenous nephrotoxin.

[0096] A nephrotoxin is a compound or substance that can destroy or impair the function of the kidney and its associated tissues in a subject. In one aspect of the present disclosure, a nephrotoxin that can induce kidney symptoms or disease is a nephrotoxic drug substance.

[0097] As used herein, the term "nephrotoxic drug substance" can be an active ingredient or a pharmacologically or diagnostically active compound or mixture of compounds useful for medical or therapeutic use in the prevention, diagnosis, stabilization, treatment, or management of a condition, disorder, or disease, and capable of disrupting, impairing, or reducing kidney function. A nephrotoxic drug substance can be provided or administered to a subject as a pharmaceutical product or pharmaceutical dosage form comprising said nephrotoxic drug substance or mixture of nephrotoxic substances and one or more non-pharmacologically active excipients or carriers. In particular, a nephrotoxic drug substance can be a dose-limited drug substance whose administration for its indicated therapeutic or diagnostic use is limited in terms of a threshold dose amount given in single and / or cumulative doses due to the possibility of nephrotoxic side effects. A nephrotoxic drug substance may also be further defined as a drug substance whose prescribing information lists nephrotoxicity as a side effect or adverse effect and / or whose prescribed use for its intended therapeutic / diagnostic application includes a dose concentration of the nephrotoxic drug substance in the subject to whom it is administered (e.g., its serum concentration) and / or advice to monitor the recipient subject's renal function, e.g., for signs and markers associated with nephrotoxicity.

[0098] As understood herein, "exposure to a nephrotoxin" or similar phrases can refer to exposure of a subject to a nephrotoxin during the course of treatment for a condition, symptom, or disease, wherein the subject is administered one or more doses of a nephrotoxin, such as any one or combination of nephrotoxic drug substances defined in various embodiments herein, for therapeutic or diagnostic purposes. As used herein, the phrase "exposure to a nephrotoxin" also includes any unintentional exposure of a subject to a nephrotoxin, for example, but not limited to, accidental exposure from a needlestick injury, or situational / unforeseen events such as physical trauma or prolonged physical stress that may cause the release and / or accumulation of endogenous nephrotoxins.

[0099] As understood herein, the term "drug substance" and its genus, family, or species can refer to the drug substance itself and any pharmaceutically acceptable salts, hydrates, derivatives, or prodrugs thereof. For example, the term "gentamicin" can also include its common commercial form, gentamicin sulfate. Similarly, the term "aminoglycoside" is interchangeable with, for example, the term "aminoglycoside antibiotic" and refers to any compound that falls within that general definition or classification in the art.

[0100] In another embodiment of the present disclosure, the nephrotoxin that can induce kidney symptoms or disease is endogenous nephrotoxin.As defined herein, endogenous nephrotoxin is a molecule or substance (for example, protein) that is endogenously produced by the subject, and is not administered externally, in contrast to the above-mentioned nephrotoxic drug substance that can be considered as exogenous toxin.During normal physiological and homeostatic conditions, endogenous nephrotoxin can exist in the subject or the subject's blood or serum at a non-nephrotoxic concentration or amount, but when it reaches an elevated level, i.e., exceeds a threshold or baseline concentration, it becomes nephrotoxic, and can be decomposed or broken down into nephrotoxic components, and / or induce cellular or inflammatory response events that lead to the development of nephrotoxicity and kidney tissue injury.

[0101] In one embodiment, the endogenous nephrotoxin is myoglobin, and optionally any decay or degradation products or released components associated with myoglobin. Myoglobin is an oxygen- and iron-binding protein found in muscle tissue. High levels of myoglobin and its associated components can be directly toxic to renal tubular cells and can also result in renal vasoconstriction and intratubular cast formation, among other pathologies.

[0102] Rhabdomyolysis is a condition characterized by damage or degradation of skeletal muscle tissue, resulting in the release of tissue contents into the circulation. The release of high levels of myoglobin is also associated with the related condition of myoglobinuria. Other conditions in which endogenous cellular components can be nephrotoxic include, but are not limited to, hemolysis (lysis of red blood cells, in which damaged red blood cell contents, such as heme, are released into the circulation) and conditions such as tumor lysis or myeloma. Tumors in cancer patients can lyse (e.g., during chemotherapy), releasing tumor cell contents into the circulation and into the kidney.

[0103] In one embodiment, a subject to which a compound according to the present disclosure or a pharmaceutically acceptable salt thereof can be administered can have elevated serum and / or urinary myoglobulin levels, i.e., elevated concentrations of myoglobin in the serum and / or urine. Alternatively or additionally, the subject can also have elevated serum levels, i.e., elevated serum concentrations of any one or a combination of creatine phosphokinase, lactate dehydrogenase, calcium, potassium, and phosphate, indicating the presence of muscle damage. In a further related embodiment, a subject to which a compound according to the present disclosure or a pharmaceutically acceptable salt thereof can be administered can have serum creatine phosphokinase levels at least 5-fold higher than baseline.

[0104] As defined herein, the term "baseline" used in connection with serum concentration levels of creatine phosphokinase refers to, for example, a clinically applicable or expected serum creatine phosphokinase level or range for an individual not yet exposed to a nephrotoxin, or a nephrotoxic level or concentration of an endogenous nephrotoxin, e.g., myoglobin, that takes into account variability that may be attributable to any one or combination of criteria, such as, but not limited to, age group, sex, existing comorbidities, etc. The baseline value or baseline range of serum creatine phosphokinase or any other marker may be within the knowledge of one of ordinary skill in the art or may be determined based on common methods in the art.

[0105] As defined herein, the term "baseline" used in connection with serum levels, i.e., serum concentration, of creatinine and / or blood urea nitrogen (BUN) levels, i.e., blood urea nitrogen concentration, can refer to baseline values ​​of these renal function markers determined for a subject, for example, before the onset of exposure to a nephrotoxic drug substance (e.g., before a treatment regimen including administration of a nephrotoxic drug substance). In situations where a subject does not have serum creatinine or BUN levels measured before exposure to a nephrotoxin and before the onset of reduced renal function, the term "baseline" can refer to a clinically applicable or expected serum creatinine and / or blood urea nitrogen value or range of values ​​for an individual not yet exposed to a nephrotoxin, taking into account variability that may be due to criteria such as, but not limited to, age group, sex, existing comorbidities, etc. These baseline values ​​or ranges of values ​​can be within the knowledge of one of ordinary skill in the art and / or can be determined using common methods in the art.

[0106] In one embodiment, a compound of Formula 1, or Formula 2, or Formula 3, or Formula 4, or a pharmaceutically acceptable salt thereof, can be administered to a subject prior to the subject's exposure to a nephrotoxic drug substance. As understood herein, administration of a compound of Formula 1, 2, or 3, or 4 prior to exposure refers to administration of a first dose of said compound before administration of a first dose of a nephrotoxic drug.

[0107] Furthermore, in some embodiments, a dose of a compound according to the present disclosure or a pharmaceutically acceptable salt thereof can be administered before any dose of a nephrotoxic drug substance is administered, for example, if the nephrotoxic drug substance is administered repeatedly, for example, more than once, during a given course of treatment. Thus, a dose of the compound can be administered during the period between successive doses of the nephrotoxic drug substance. Optionally, two or more doses of a compound according to the present disclosure can be administered during the period between successive doses of the nephrotoxic drug substance.

[0108] In one aspect, the present disclosure provides a compound of Formula 1, 2, or 3, or 4, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a renal condition or disease induced by a nephrotoxic drug substance (e.g., acute kidney injury), wherein the compound or a pharmaceutically acceptable salt thereof is repeatedly administered to a subject during a first period beginning before and overlapping with a second period during which the subject is repeatedly exposed to or administered the nephrotoxic drug substance. As used herein, "repeatedly" refers to at least two administrations or exposures, i.e., two or more times. The period may be understood as a course or duration of treatment that is clinically determined to be therapeutically appropriate with respect to the intended pharmacological effect, for example, in preventing, stabilizing, treating, or managing a symptom, disorder, or disease.

[0109] In one embodiment, a compound described herein, e.g., a compound of Formula 1 or Formula 2 or Formula 3 or 4, or a pharmaceutically acceptable salt thereof, can be administered to a subject after the onset of reduced renal function. The onset of reduced renal function can be characterized by elevated levels of serum creatinine and / or blood urea nitrogen (BUN) and / or oliguria, among other physiological markers. In one embodiment, the onset of reduced renal function can be characterized by blood urea nitrogen levels at least 1.5 to 3 times higher than baseline and / or serum creatinine levels at least 1.5 to 3 times higher than baseline and / or oliguria. In one embodiment, the subject has reduced renal function characterized by serum creatinine and BUN levels at least 2 times higher than baseline.

[0110] In one particular embodiment, the onset of reduced renal function can be due to exposure to a nephrotoxic drug substance. For example, during the course of treatment with a nephrotoxic drug substance, a subject may suddenly develop renal dysfunction or failure due to the accumulation of the nephrotoxic drug substance (e.g., blood concentration or localization in specific kidney cells or tissues), i.e., exposure to a cumulative dose of the nephrotoxic drug substance. Coexistence with a disease or condition that occurs or worsens during the course of treatment with a nephrotoxic drug substance can also contribute to the onset of reduced renal function, resulting in acute kidney injury. In other embodiments, the onset of reduced renal function can be due to exposure to endogenous nephrotoxins.

[0111] As used herein, unless preceded or followed by an indication of time, time interval, or amount, the term "dose" or "dosage" itself refers to a single dose or unit dose of a compound described herein or its pharmaceutically acceptable salt or drug substance. For example, "daily dose" or "daily dosage" refers to the total dose of a compound described herein or drug substance administered during one day (24 hours). A daily dose can include only one dose if only one dose is administered once per day, but it can also be a total amount based on the sum of multiple unit doses administered during one day, for example, if two or more unit doses are administered at two or more time intervals during one day. The interval between doses can be, for example, two doses administered approximately every 12 hours, or three doses administered approximately every 8 hours. As used herein, a dose of a compound may refer to a unit dose of a compound of Formula 1, 2, 3, 4, etc., or a pharmaceutically acceptable salt thereof, but may also be applicable to a pharmaceutical product, or a composition or dosage form comprising said unit dose of a compound or a pharmaceutically acceptable salt thereof.

[0112] In one embodiment, a dose of a compound according to the present disclosure or a pharmaceutically acceptable salt thereof can be administered to a subject within 24 hours before a dose of a nephrotoxic drug substance is administered to the subject. In another embodiment, a compound or a pharmaceutically acceptable salt thereof can be administered to a subject within 24 hours before a dose of an aminoglycoside, such as gentamicin, is administered to the subject.

[0113] As used herein, terms such as "about" in connection with an attribute or value, such as a dosage amount, include the exact attribute or value as well as any attribute or value that is customarily considered to fall within the normal or accepted variation associated with the art and the method of measuring or determining said attribute or value. The term allows for any variation that, in common practice, allows for the product being evaluated to be considered bioequivalent in mammals to the stated strength or dose of the claimed product.

[0114] It will be understood that the use of a compound of Formula 1, Formula 2, or Formula 3, or Formula 4, or a pharmaceutically acceptable salt thereof, or their use in a method of prevention and / or treatment of a disease or condition described in any one of the embodiments or combination of embodiments described herein, may also provide for the manufacture or preparation of a medicinal product or medicament adapted and designated for said use or method of treatment and / or prevention.

[0115] The compound according to the present disclosure or its pharmaceutically acceptable salt can be administered to a subject enterally or parenterally.In one embodiment, the compound of formula 1, or formula 2, or formula 3, or formula 4, or the composition or medicament comprising said compound or its pharmaceutically acceptable salt can be adapted for administration or can be administered parenterally, for example, by intravenous injection, or by subcutaneous injection, or by intramuscular injection, or by intravenous or subcutaneous injection.In another embodiment, the compound or the composition or medicament comprising the compound can be adapted for administration or can be administered to a subject enterally, for example, orally.

[0116] The present disclosure may also relate to a medicament or pharmaceutical composition comprising a compound according to any one or combination of the embodiments described herein above, for example, a compound of Formula 1, Formula 2, Formula 3, Formula 4, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. The medicament or composition may comprise a therapeutically effective amount or unit dose of said compound.

[0117] The medicament or pharmaceutical composition comprising the compound may be formulated in a dosage form suitable or adapted for injection or infusion by any of the above-mentioned administration methods. Alternatively, for oral administration, the medicament or pharmaceutical composition comprising the compound according to the present disclosure may be provided in a dosage form suitable or adapted for oral administration, such as, but not limited to, a tablet, capsule, gelcap, or film. The medicament or pharmaceutical composition may be used according to any of the treatment or prevention methods or uses described herein.

[0118] The following list of numbered items includes aspects according to this disclosure.

[0119] 1. A compound of formula 1 or a pharmaceutically acceptable salt thereof, JPEG0007776435000018.jpg77135In formula: R 1 and R 2 are independently selected from H, C1-C6 alkyl, or R 1 and R 2 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; A is, -NR 3 R 4 , where R 3 and R 4 are independently selected from H, C1-C6 alkyl, or R 3 and R 4 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; and - N=C(R 5 )NR 6 R 7 , where R 5 , R 6 and R 7 are independently selected from H, C1-C6 alkyl, and optionally, R 6 and R 7 may be joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; Selected from; R 8 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; R 9 is expressed by formula 1a or 1b JPEG0007776435000019.jpg7678JPEG0007776435000020.jpg7678.

[0120] 2.R 1 and R 2 are both H, and R 8 is selected from ethyl, isopropyl, and n-propyl; R 9 is formula 1a, and A is NR 3 R 4 If R 3 and R 4 is not H, C1-C4 alkyl, or is joined together to form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, or phthaloyl residue; or 1 and R 2 are both H, or R 1 is methyl, R2 is H, and R 8 is selected from ethyl, isopropyl, and n-propyl; R 9 is formula 1a, and A is NR 3 R 4 If R 3 and R 4 is not H, C1-C4 alkyl, or is joined together to form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, or phthaloyl residue.

[0121] 3.R 1 and R 2 are both H, and R 8 is selected from ethyl, isopropyl, and n-propyl; R 9 is formula 1a, A is NR 3 R4 or a compound according to item 1, provided that R 1 and R 2 are both H, or R 1 is C1-C6 alkyl, and R 2 is H and R 8 is selected from ethyl, isopropyl, and n-propyl; R 9 is formula 1a, A is NR 3 R 4 Item 1. The compound of item 1, provided that it is not

[0122] 4.R 1 and R 2 are both H, and R 8 When is selected from ethyl, A is NR 3 R 4 or a compound according to item 1, provided that R 1 and R 2 are both H, or R 1 is C1-C6 alkyl, R2 is H, and R 8 When is selected from ethyl, A is NR 3 R 4 Item 1. The compound of item 1, provided that it is not

[0123] 5.R 1 and R 2 and R are hydrogen atoms.

[0124] 6.R 1 or R 2 The compound according to item 1, wherein at least one of is C1-C6 alkyl, for example, methyl.

[0125] 7.R 1 and R 2 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring, or preferably a C3-C6 cycloalkyl ring, such as cyclopropyl.

[0126] 8.R8 8. The compound according to any one of items 1 to 7, wherein is ethyl.

[0127] 9.R 8 is selected from 1-hydroxyethyl, isopropyl and n-propyl.

[0128] 10.R 8 8. The compound according to any one of items 1 to 7, wherein is n-propyl.

[0129] 11.R 8 8. The compound according to any one of items 1 to 7, wherein is isopropyl.

[0130] 12.R 8 8. The compound according to any one of items 1 to 7, wherein is 1-hydroxyethyl.

[0131] 13.R 9 13. The compound according to any one of items 1 to 12, wherein: is formula 1a.

[0132] 14.R 9 14. The compound according to any one of items 1 to 13, wherein is formula 1b.

[0133] 15.A is NR 3 R 4 15. The compound according to any one of items 1 to 14, wherein

[0134] 16.R 3 and R 4 and n is -CH3.

[0135] 17.R 3 and R 4 are linked together to form a morpholinyl residue.

[0136] 18.R 8 18. The compound according to any one of items 15 to 17, wherein is 1-hydroxyethyl, isopropyl or n-propyl.

[0137] 19.A is -N=C(R 5 )NR 6 R 7 15. The compound according to any one of items 1 to 14, wherein

[0138] 20.R 5 , R 6 and R 7 are independently selected from H, C1-C6 alkyl and optionally substituted C1-C6 alkyl.

[0139] 21.R 5 is H or CH3, and R 6 and R 7 21. The compound according to item 20, wherein is CH3.

[0140] 22.R 8 The compound according to items 19-20, wherein is ethyl.

[0141] 23. The compound according to item 1, wherein the compound or a pharmaceutically acceptable salt thereof is of formula 2: JPEG0007776435000021.jpg94169Formula: R 1 and R 2 are independently selected from H, C1-C6 alkyl, or R 1 and R 2 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; R 3 and R 4 are independently selected from H, C1-C6 alkyl, or R 3 and R 4 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; R 8 is 1-hydroxyethyl, isopropyl or n-propyl; R 9 is expressed by formula 1a or 1b JPEG0007776435000022.jpg7678JPEG0007776435000023.jpg7678.

[0142] 24.R 1 and R 2 24. The compound according to item 23, wherein each of

[0143] 25.R 1 or R 2 24. The compound according to item 23, wherein at least one of is C1-C6 alkyl.

[0144] 26.R 1 and R 2 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring, or preferably a C3-C6 cycloalkyl ring, such as cyclopropyl.

[0145] 27.R 8 27. The compound according to any one of items 23 to 26, wherein is isopropyl.

[0146] 28.R 8 27. The compound according to any one of items 23 to 26, wherein is n-propyl.

[0147] 29.R 8 27. The compound according to any one of items 23 to 26, wherein is 1-hydroxyethyl.

[0148] 30.R 3 and R 4 and n is -CH3.

[0149] 31.R 3 and R 4 are linked together to form a morpholinyl residue.

[0150] 32.R 9The compound according to any one of items 23 to 31, wherein is formula 1a.

[0151] 33.R 9 The compound according to any one of items 23 to 31, wherein is formula 1b.

[0152] 34. The compound according to item 1, wherein the compound or a pharmaceutically acceptable salt thereof is of formula 3: JPEG0007776435000024.jpg72143Formula: R 1 and R 2 are independently selected from H, C1-C6 alkyl, or R 1 and R 2 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; R 5 , R 6 and R 7 are independently selected from H, C1-C6 alkyl, and optionally, R 6 and R 7 may be joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; R 8 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; R 9 is expressed by formula 1a or 1b JPEG0007776435000025.jpg7678JPEG0007776435000026.jpg7678.

[0153] 35.R 1 and R 2 35. The compound according to item 34, wherein each of

[0154] 36.R 1 or R 2 35. The compound according to item 34, wherein at least one of is C1-C6 alkyl, for example, methyl.

[0155] 37.R 1and R 2 are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring, or preferably a C3-C6 cycloalkyl ring, such as cyclopropyl.

[0156] 38.R 8 38. The compound according to any one of items 34 to 37, wherein is ethyl.

[0157] 39.R 8 38. The compound according to any one of items 34 to 37, wherein is isopropyl.

[0158] 40.R 8 38. The compound according to any one of items 34 to 37, wherein is n-propyl.

[0159] 41.R 8 38. The compound according to any one of items 34 to 37, wherein is 1-hydroxyethyl.

[0160] 42.R 5 , R 6 and R 7 is independently selected from H, C1-C6 alkyl and optionally substituted C1-C6 alkyl.

[0161] 43.R 5 is H or CH3, and R 6 and R 7 43. The compound according to item 42, wherein is CH3.

[0162] 44.R 9 44. The compound according to any one of items 34 to 43, wherein: is formula 1a.

[0163] 45.R 9 The compound according to any one of items 34 to 43, wherein is formula 1b.

[0164] 46. ​​A compound selected from the group of compounds shown in Table 1 above or a pharmaceutically acceptable salt thereof, or a compound according to item 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compounds in Table A, JPEG0007776435000027.jpg82141JPEG0007776435000028.jpg192151; or the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds 2, 5, 6, 9, 10, 11, 12 and 13 in Table A, a compound selected from the group of compounds shown in Table 1 above or a pharmaceutically acceptable salt thereof, or a compound according to item 1

[0165] 47. Use of a compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and / or treatment of a disease or condition, for example a kidney disease or condition.

[0166] 48. Use of a compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and / or treatment of a cyclophilin-mediated disease or condition (e.g., cyclophilin A and / or cyclophilin D); for the prevention and / or treatment of a cyclophilin-mediated disease or condition of the kidney.

[0167] 49. Use of a compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and / or treatment of a disease or condition associated with cell injury or cell death, such as a kidney disease or condition associated with cell injury or cell death.

[0168] 50. The use according to item 49, wherein the disease or condition associated with cell injury or cell death is organ failure or organ injury.

[0169] 51. The use according to item 50, wherein the organ is selected from the group consisting of kidney, liver, heart, lung, pancreas, intestine, cornea, skin, brain and nervous tissue.

[0170] 52. The use according to any one of items 47 to 51, wherein the disease or condition is ischemia-reperfusion injury.

[0171] 53. The use according to item 52, wherein the ischemia-reperfusion injury is renal ischemia-reperfusion injury.

[0172] 54. The use according to any one of items 47 to 51, wherein the disease or condition is acute kidney injury.

[0173] 55. The use according to item 54, wherein the acute kidney injury is associated with or is the result of a kidney transplant.

[0174] 56. The use according to any one of items 47 to 55, wherein the medicament is administered to an organ transplant recipient.

[0175] 57. Use according to any one of items 47 to 56, wherein the medicament is adapted for oral administration or for administration by intravenous injection or infusion.

[0176] 58. Use according to any one of items 47 to 57, wherein the medicament is administered to the organ donor and / or to the organ recipient before, during and / or after transplantation of an organ from the organ donor to the organ recipient.

[0177] 59. Use of a compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preserving and / or protecting an organ from organ injury, comprising administering the compound to an organ donor prior to removal of the organ from the organ donor, and / or to an organ recipient prior to, during or after transplantation of the organ.

[0178] 60. Use of a compound according to any one of items 1 to 46 or a pharmaceutically acceptable salt thereof for preserving and / or protecting an organ from organ injury, comprising administering the compound to an organ donor and / or to the organ prior to removal of the organ from the organ donor.

[0179] 61. A method for preserving or protecting an organ from organ injury, comprising administering a compound according to any one of items 1 to 46 or a pharmaceutically acceptable salt thereof to an organ donor and / or to the organ prior to removal of the organ from the organ donor.

[0180] 62. The use or method according to any one of items 59 to 61, wherein the organ is selected from the group consisting of kidney, liver, heart, lung, pancreas, intestine, cornea, skin, brain and nervous tissue.

[0181] 63. The use or method according to any one of items 59 to 62, wherein the donor is a living donor or the donor is a clinically deceased donor.

[0182] 64. The use or method according to any one of items 59 to 64, wherein the compound is administered to the donor and / or recipient by intravenous injection or infusion.

[0183] 65. Use of a compound according to any one of items 1 to 46 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and / or treatment of a renal condition or disease in a subject exposed to a nephrotoxin capable of inducing said renal condition or disease, wherein said nephrotoxin is a nephrotoxic drug substance or an endogenous nephrotoxin.

[0184] 66. The use according to item 65, wherein the nephrotoxic drug substance is selected from the group consisting of antibacterial agents, cancer chemotherapeutic agents, blood pressure medications including ACE inhibitors and angiotensin receptor blockers, macrolactone immunosuppressants, HIV protease inhibitors, peptic ulcer medications, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, laxatives and contrast media.

[0185] 67. The use of item 66, wherein the nephrotoxic drug substance is a chemotherapeutic agent selected from the group consisting of a platin (e.g., carboplatin, cisplatin, oxaliplatin, or nedaplatin), an anthracycline (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin), bleomycin, mitomycin, actinomycin, cyclophosphamide, cytarabine, capecitabine, gemcitabine, ifosfamide, interleukin-2, streptozocin, gemtuzumab ozogamicin, melphalan, methotrexate, pemetrexed, plicamycin, and trimetrexate.

[0186] 68. The use according to items 65 to 67, wherein the subject is undergoing treatment for cancer, and the cancer treatment comprises administering a chemotherapeutic agent to the subject.

[0187] 69. The use according to items 65 to 66, wherein the nephrotoxic drug substance is an antibacterial agent selected from the group consisting of aminoglycosides (e.g., gentamicin, tobramycin, amikacin, netilmicin, apramycin, streptomycin, kanamycin, neomycin, sisomicin), β-lactams (e.g., tazobactam, or piperacillin / tazobactam), polypeptide antibiotics (e.g., polymyxins such as polymyxin A, B, C, D, E (colistin)), glycopeptide antibiotics (e.g., vancomycin), antibiotics targeting outer membrane proteins (e.g., murepavadin), antifungals (e.g., amphotericin B), and combinations thereof.

[0188] 70. The use of any one of items 66 or 69, wherein the subject is suffering from an infection, and the infection is treated by administering the antibacterial agent to the subject.

[0189] 71. The use according to item 66, wherein the blood pressure medication is an ACE inhibitor, optionally selected from the group consisting of captopril, benazepril, enalapril, fosinopril, and ramipril, or an angiotensin receptor blocker, optionally selected from the group consisting of candesartan, valsartan, irbesartan, olmesartan, telmisartan, eprosartan, and losartan.

[0190] 72. The use according to item 66, wherein the HIV protease inhibitor is selected from the group consisting of indinavir and ritonavir.

[0191] 73. The use according to item 66, wherein the anti-ulcer drug is selected from the group consisting of cimetidine, esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole.

[0192] 74. The use according to item 66, wherein the nonsteroidal anti-inflammatory drug is selected from the group consisting of ibuprofen, ketoprofen, diclofenac and aspirin.

[0193] 75. The use according to item 66, wherein the laxative is selected from sodium phosphates.

[0194] 76. The use according to item 66, wherein the nephrotoxic drug substance is an imaging agent, which may optionally be an iodinated imaging agent (e.g., iothalamate, or iodixanol, or iohexol).

[0195] 77. The use of item 65, wherein the endogenous nephrotoxin is myoglobin, and optionally, the subject has a creatine phosphokinase serum level at least 5-fold higher than baseline.

[0196] 78. The use of any one of items 77, wherein the subject has experienced or is suffering from physical trauma or crush wounds, exposure to electric current, extreme physical exertion or activity, and extreme temperatures.

[0197] 79. The use of any one of items 77 or 78, wherein the pharmaceutical agent is administered to the subject prior to exposure to or involvement in an activity (e.g., extreme physical activity) associated with or at risk of developing rhabdomyolysis.

[0198] 80. The use of any one of items 65 to 76, wherein the nephrotoxic drug substance is administered repeatedly to the subject, optionally, the nephrotoxic drug substance may be administered at least twice, optionally at least once daily for a period of at least 3 or 7 days.

[0199] 81. The use according to any one of items 65 to 80, wherein the renal condition or disease is nephrotoxin-induced acute kidney injury or renal failure.

[0200] 82. The use according to any one of items 65 to 80, wherein the renal condition or disease is selected from rhabdomyolysis, hemolysis, myoglobinuria, or optionally from tumor lysis or myeloma-induced acute kidney injury.

[0201] 83. The use of any one of items 65 to 83, wherein the subject has a pre-existing condition or disease that increases the subject's risk of developing a kidney condition or disease if exposed to a nephrotoxin, and optionally the pre-existing kidney condition can be chronic kidney disease, and further optionally the subject has a history of kidney dysfunction or requires dialysis.

[0202] 84. The use according to item 83, wherein the subject has reduced renal function, and optionally, the subject has a blood urea nitrogen level at least 1.5 to 3 times higher than baseline, and / or a serum creatinine level at least 1.5 to 3 times higher than baseline, and / or oliguria.

[0203] 85. The use of any one of items 65 to 84, wherein the pharmaceutical agent is administered to the subject prior to the subject's exposure to the nephrotoxic drug substance, and optionally, a dose of the pharmaceutical agent is administered to the subject within 24 hours before a dose of the nephrotoxic drug substance is administered to the subject, and further optionally, a dose of the pharmaceutical agent is administered to the subject within about 6 hours, and optionally within about 2 hours, before the nephrotoxic drug substance is administered to the subject.

[0204] 86. The use according to any one of items 65 to 85, wherein the medicament is administered to the subject after the onset of reduced renal function characterized by any one or combination of blood urea nitrogen levels at least 1.5 to 3 times higher than baseline, serum creatinine levels at least 1.5 to 3 times higher than baseline, and oliguria.

[0205] 87. The use according to items 65 to 86, wherein the dose of the medicinal product is administered to the subject 1 to 24 hours after the onset of reduced renal function.

[0206] 88. The use of any one of items 65 to 87, wherein the pharmaceutical agent is repeatedly administered to the subject during a first period of time that begins before and overlaps with a second period of time during which the subject is repeatedly exposed to the nephrotoxic drug substance.

[0207] 89. The use according to any one of items 1 to 88, wherein the recipient, donor and / or subject is a human.

[0208] 90. Use according to any one of items 1 to 89, wherein the medicament is adapted or formulated for administration by infusion or by injection, preferably subcutaneous, intramuscular or intravenous injection, or by intravenous or subcutaneous injection, or adapted or formulated for oral administration.

[0209] 91. A compound according to any one of items 1 to 46 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0210] 92. A compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of a disease or condition, such as the kidney, or an organ or tissue thereof.

[0211] 93. Compounds according to item 91 for use as cyclophilin inhibitors (e.g. cyclophilin A and / or cyclophilin D inhibitors), preferably for use in the prevention or treatment of cyclophilin-mediated diseases or conditions, e.g. renal cyclophilin (e.g. cyclophilin A and / or D)-mediated diseases or conditions.

[0212] 94. A compound for use according to items 91 to 93, wherein said use comprises any one or combination of the features according to items 50 to 58.

[0213] 95. The compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, for use in organ preservation and / or protection of an organ from organ injury, wherein the use comprises administering the compound to an organ donor prior to removal of the organ from the organ donor, and / or to an organ recipient prior to, during or after transplantation of the organ.

[0214] 96. A compound for use according to item 95, wherein the use comprises any one or combination of the features according to items 62 to 64.

[0215] 97. The compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of a renal condition or disease in a subject exposed to a nephrotoxin capable of inducing said renal condition or disease, wherein the nephrotoxin is a nephrotoxic drug substance or an endogenous nephrotoxin.

[0216] 98. A compound for use according to item 97, further comprising any one or any combination of the features defined in items 66 to 90.

[0217] 99. The compound for use according to any one of items 91 to 98, wherein the compound or medicament is administered to a human subject, donor or recipient.

[0218] 100. A method for preventing and / or treating a disease or condition, comprising administering a compound according to any one of items 1 to 46 or a pharmaceutically acceptable salt thereof to a subject in need thereof, preferably wherein the subject is a human subject.

[0219] 101. The method of item 100, wherein the disease or condition is a kidney disease or condition.

[0220] 102. A method for inhibiting cyclophilin or for preventing and / or treating a cyclophilin-mediated disease or condition by inhibiting cyclophilin, comprising administering to a (human) subject in need thereof a compound according to any one of items 1 to 46 or a pharmaceutically acceptable salt thereof, wherein optionally the cyclophilin is cyclophilin A or cyclophilin D, and further optionally the cyclophilin-mediated disease or condition is a kidney disease or condition.

[0221] 103. The method according to items 100-101, wherein the method comprises any one or combination of the features defined in items 50-58.

[0222] 104. A method for preserving and / or protecting an organ from organ injury, comprising administering a compound according to any one of items 1 to 46, or a pharmaceutically acceptable salt thereof, to an organ donor before removing the organ from the organ donor, and / or to an organ recipient before, during or after transplantation of the organ.

[0223] 105. The method according to item 104, wherein the method comprises any one or combination of the features defined in items 62 to 64.

[0224] 106. A method for preventing and / or treating a renal symptom or disease in a subject exposed to a nephrotoxin capable of inducing said renal symptom or disease, wherein said nephrotoxin is a nephrotoxic drug substance or an endogenous nephrotoxin, said method comprising administering to said subject a compound according to any one of items 1 to 46 or a pharmaceutically acceptable salt thereof.

[0225] 107. The method according to item 106, wherein the method comprises any one or combination of the features defined in items 60 to 90.

[0226] 108. A pharmaceutical composition comprising a compound according to any one of items 1 to 46 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0227] 109. A compound of formula 4 or a pharmaceutically acceptable salt thereof: JPEG0007776435000029.jpg72130wherein X and Z are independently selected substituents, for example, substituents selected from H, alkyl (e.g., C1-C6 alkyl, e.g., methyl), and substituted alkyl (e.g., substituted C1-C6 alkyl), or X and Z are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; where A, R 1 , R 2 , R 8 and R 9 is as defined in any one or combination of the features described in items 1 to 22.

[0228] 110. Compounds according to item 109, wherein X and Z are both H, or X and Z are both alkyl, for example methyl, or one of X or Z is alkyl, for example C1-C6 alkyl (for example methyl).

[0229] 111.A is NR 3 R 4 For example, R 3 and R 4 are both alkyl, for example C1-C6 alkyl, for example methyl.

[0230] 112. Use of a compound according to any one of items 109 to 111 for the manufacture of a medicament according to any one or combination of the characteristics defined in items 47 to 90.

[0231] 113. A method for preparing any one of the compounds of formula 1, 2, 3 or 4 as defined in items 1-46 or 109-111, comprising reacting a cyclosporin intermediate (e.g., an intermediate of cyclosporin A, C, D, G, etc.), such as a thiopyridyl intermediate, with an amino alcohol compound and, optionally, copper triflate.

[0232] 114. The amino alcohol is a compound of formula 5: JPEG0007776435000030.jpg5757 wherein X and Z are independently selected from H, alkyl (e.g., C1-C6 alkyl, e.g., methyl), substituted alkyl (e.g., substituted C1-C6 alkyl); or wherein X and Z are joined together to form a C3-C6 cycloalkyl or heterocycloalkyl ring; or X and Z are as described in items 110-111; A, R 1 and R 2 Item 113. The method of item 113, wherein the method is as defined according to any one or combination of the features described in items 1 to 22.

[0233] The following examples serve to illustrate the present invention but should not be understood as limiting the scope of the invention. [Example]

[0234] Example 1 - Preparation of Compounds The compounds described herein can be obtained by the following general synthetic route: reacting a cyclosporin compound (e.g., cyclosporin A, C, D, G, etc.) with dipyridyl disulfide to form a thiopyridyl intermediate ([(2'-(2-thiopyridyl)-Sar] 3 -cyclosporin A or C, or D, or G, etc.), for example, a compound of formula I shown below, followed by a second step comprising reacting this intermediate with an aminoalcohol compound in the presence of copper triflate. Examples of aminoalcohol compounds used include, but are not limited to, aminoethanol compounds such as morpholinoethanol or dimethylaminoethanol.

[0235] Those skilled in the art will appreciate that different analogs can be prepared using different amino alcohol reagents, for example, in a second step where the N-amino substituent on the amino alcohol can also be varied to give additional analogs (examples of N-amino substituents include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl). JPEG0007776435000031.jpg100169

[0236] The following procedure described for the preparation of compound 2 (Table 1, see Table A above) can be applied as a general procedure for preparing compounds with similar substitutions at the 3-position of cyclosporine.

[0237] Preparation of Compound 2 Step I: A solution of cyclosporin C (100 mg, 0.082 mmol) in 1.5 mL of THF was added to a three-neck flask. Then, 106 mg of LiCl was added. The mixture was cooled to 0°C under N2. To the mixture was added dropwise an LDA solution (2 M solution in THF, 1.6 mmol). The mixture was stirred at 0°C for 1 hour. To the mixture was added dropwise a solution of dipyridyl disulfide (55 mg, 0.25 mmol) in 0.5 mL of THF. The mixture was stirred at 0°C for 1 hour. Then, 1 mL of MeOH was added to the mixture. The mixture was then stirred at -5°C for an additional 16 hours.

[0238] The mixture was quenched with 5 mL of saturated NaH2PO4 solution and then extracted three times with 5 mL of MBTE. The organic phase was dried over Na2SO4 and concentrated to give 200 mg of crude product. The thiopyridyl intermediate was obtained by purification using column chromatography.

[0239] Step II: Cu(OTf)2 (40.0 mg, 0.11 mmol) and 4A molecular sieves (40 mg) were added to a reaction flask containing 1.0 mL of THF. The mixture was stirred under N2 at 40 °C for 1 h. After the solvent was removed in vacuo, a solution of intermediate Ia (20.0 mg, 0.015 mmol) in 0.5 mL of THF was added to the residue. The mixture was stirred at room temperature for 1 h. Dimethylaminoethanol (12.6 mg, 0.14 mmol) was added dropwise to the mixture, followed by TMSCl (20.0 mg, 0.18 mmol). The resulting mixture was stirred at 30 °C for 16 h. The mixture was then quenched with 5 mL of water and extracted with iPrOAc. The organic phase was dried over sodium sulfate and concentrated. The crude product was chromatographed to give the desired product, compound 2 ( 1 H-NMR (400 MHz CDCl, δ (ppm)): 6.18, sarcosine residue; HRMS electrospray (M+1) 1306.10; 1307.10; mass from isotopic distribution: 1304.90 (100%); 1305.91 (71.4%)).

[0240] Reaction of the thiopyridyl intermediate obtained in step I with morpholinoethanol instead of dimethylaminoethanol gave the corresponding derivative compound 2b: JPEG0007776435000032.jpg149160

[0241] Preparation of compounds 3, 4, 7 and 8 Cyclosporin derivatives based on cyclosporin D and cyclosporin G can be prepared using a method similar to that described for the preparation of compound 2; a thiopyridyl intermediate is obtained in the first step, which is then reacted with the respective ethanol derivative (e.g., morpholinoethanol or dimethylaminoethanol) in the second step to give compound 3 (( 1 H-NMR (400 MHz CDCl3, δ (ppm)): 5.96, sarcosine residue; HRMS electrospray (M+1) 1304.15; 1305.10; mass by isotope distribution 1302.93 (100%) 1303.93 (72.5%)), compound 4 (( 1 H-NMR (400 MHz CDCl3, δ (ppm)): 6.01, sarcosine residue; HRMS electrospray (M+1) 1346.25; 1347.45; mass due to isotope distribution 1344.94 (100%), 1345.94 (74.6%)), compound 7 (( 1 H-NMR (400 MHz CDCl3, δ (ppm)): 5.76, sarcosine residue; HRMS electrospray (M+1) 1304.10; 1305.15; mass due to isotopic distribution 1302.93 (100%), 1303.93 (72.5%)) and compound 8 (( 1 H-NMR (400 MHz CDCl, δ (ppm)): 5.80, sarcosine residue; HRMS electrospray (M+1) 1346.25; 1346.75; isotopic distribution mass 1344.94 (100%), 1345.94 (74.6%).

[0242] Preparation of Compound 5 and Compound 6 A solution of compound 3 (6.0 mg, 0.0046 mmol) in 2.4 mL of DMSO was added to a 10 mL reaction vessel, and then 2-iodoxybenzoic acid (Dess-Martin reagent, 120.0 mg, 0.43 mmol) was added to the solution. The mixture was stirred at room temperature for 24 hours. The mixture was then quenched with 12 mL of water and extracted with iPrOAc. The organic phase was dried and concentrated. The crude product was purified by chromatography to give 3.0 mg of the desired product, compound 5 (( 1 H-NMR (400 MHz CDCl, δ (ppm)): 5.98, sarcosine residue; HRMS electrospray (M+1) 1302.30; 1303.60; mass from isotopic distribution 1300.91 (100%), 1301.91 (72.5%).

[0243] Similarly, compound 4 can be oxidized under similar reaction conditions as the Dess-Martin reagent to give compound 6 (( 1 H-NMR (400 MHz CDCl, δ (ppm)): 6.01, sarcosine residue; HRMS electrospray (M+1) 1344.30; 1345.00; isotopic distribution mass 1342.92 (100%), 1343.92 (74.6%) can be obtained.

[0244] Preparation of Compounds 9 and 10 Compounds 9 and 10 were prepared from intermediate II (2'-(2-aminoethoxy)-Sar]3-cyclosporine A), which can be prepared according to the method described in WO 2019 / 016572. JPEG0007776435000033.jpg55134

[0245] Compound II (10.0 mg, 0.0079 mmol) was dissolved in 5 mL of MeOH under N2. Dimethylacetamide, dimethyl acetal (E1 3.2 mg, 0.024 mmol) was added to the solution. The mixture was stirred at 70°C for 2 hours. The mixture was concentrated to dryness and the desired compound 9 was obtained by chromatography. 1H-NMR (400 MHz CDCl, δ (ppm)): 5.90, sarcosine residue; HRMS electrospray (M+1) 1331.15; 1332.30; mass from isotopic distribution 1329.94 (100%); 1330.94 (73.5%). JPEG0007776435000034.jpg59150

[0246] Compound 10 was similarly prepared by reaction of compound II with dimethylformamide dimethyl acetal (E2). 1 H-NMR (400 MHz CDCl, δ (ppm)): 5.91, sarcosine residue; HRMS electrospray (M+1) 1317.15; 1318.05; mass from isotopic distribution 1315.92 (100%), 1316.92 (72.5%).

[0247] Preparation of compounds 11 and 12 The preparation of intermediate III (2'-(2-thiopyridyl)-Sar) is also described in WO 2019 / 016572. 3 Compounds 11 and 12 were prepared from cyclosporin A. JPEG0007776435000035.jpg52146

[0248] Cu(OTf)2 catalyst (5.0 g, 16.39 mmol) was placed in 15 mL of THF and cooled to 0 °C. A solution of III (5.0 g, 3.81 mmol) and G25 (1.9 g, 16.39 mmol) in 35 mL of THF was added to the flask. TMSCl (1.0 g, 9.15 mmol) was finally added dropwise to the mixture. The mixture was then stirred at 20–25 °C. After 16 h, the reaction mixture was poured into 150 mL of water. The pH was adjusted to 10 by adding aqueous K2CO3 solution. i-PrOAc (50 mL) was added to the mixture, and the insoluble matter was filtered off. The filtrate was extracted with i-PrOAc (50 mL × 2). The organic phase was washed twice with aqueous malic acid solution. The aqueous phases were combined, the pH was adjusted to 8, and extracted again with i-PrOAc. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to give 1.4 g of compound 11. The product was further purified by chromatography. Compound 11(( 1 H-NMR (400 MHz CDCl, δ (ppm)): 5.90, sarcosine residue; HRMS electrospray (M+1) 1317.80; 1318.70; mass from isotopic distribution 1316.94 (100%), 1317.94 (73.5%). JPEG0007776435000036.jpg50142

[0249] Compound 12 was prepared under similar conditions by reaction of III with H25. Compound 12(( 1 H-NMR (400 MHz CDCl, δ (ppm)): 5.82, sarcosine residue; HRMS electrospray (M+1) 1315.70; 1316.60; mass from isotopic distribution: 1314.93 (100%), 1315.93 (73.5%).

[0250] Preparation of Compound 13 Step 1: To a stirred solution of III (5 g) and H25-1 (3.1 g) in 50 mL of THF at 0 °C under N2, Cu(OTf)2 (5 g) was first added, followed by TMSCl (99 mg). The resulting mixture was stirred at room temperature under N2 for 16 h. The resulting mixture was poured into 50 mL of water, and then 50 mL of i-PrOAc was added. The aqueous phase was adjusted to pH 8.0 by the addition of aqueous K2CO3 solution. The aqueous phase was separated and extracted with another portion of i-PrOAc. The combined organic phase was washed twice with aqueous malic acid (2.1 g of malic acid in 50 mL of water). After phase separation, the pH of the aqueous phase was adjusted to pH 8.0 by the addition of aqueous K2CO3 solution. The aqueous solution was then extracted twice with 50 mL of i-PrOAc. The organic phase was dried and concentrated to give 4.7 g of crude IV, which was used directly in the next step.

[0251] Step 2: Compound IV (4.7 g) obtained from step 1 was dissolved in 25 mL of DCM. TFA (25 mL) was added at 0° C. under N2. The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under vacuum. The residue was dissolved in 50 mL of EtOAc and washed twice with 50 mL of saturated NaHCO3. The organic phase was dried and concentrated to give 3.9 g of crude intermediate V. The crude product was purified by chromatography to give 1.7 g of compound V. 1 H-NMR (400 MHz CDCl, δ (ppm)): 6.02, sarcosine residue; HRMS (electrospray M+1) observed values: 1287.8 / 1289.0; calculated mass from isotope distribution: 1286.89 (100%), 1287.9 ​​(71.4%). JPEG0007776435000038.jpg55142

[0252] Step 3: V (200 mg) and E1 (103 mg) were dissolved in 2 mL of MeOH, and to this stirred solution was added MgSO4 (2 g). The resulting mixture was stirred at room temperature. After 16 h, the mixture was diluted with 10 mL of DCM and filtered. The filtrate was concentrated in vacuo to give 180 mg of crude product, which was further purified by chromatography to give compound 13 ((1 H-NMR (400 MHz CDCl, δ (ppm)): 5.91, sarcosine residue; HRMS electrospray (M+1) 1356.8; 1357.7; mass by isotope distribution: 1355.95 (100%), 1356.96 (75.7%).

[0253] Preparation of compounds 14 and 15 Compound 14: To a stirred solution of III (1 g) and R1 (338.2 mg) in 20 mL of THF, Cu(OTf)2 (1 g) was first added to the flask under N2 at 0 °C, followed by TMSCl (198 mg). The mixture was then stirred for 16 h at room temperature under N2. The resulting mixture was poured into 20 mL of water, and then 20 mL of i-PrOAc was added. The aqueous phase was adjusted to pH 8.0 by the addition of aqueous K2CO3 solution. The aqueous phase was separated and extracted with another portion of i-PrOAc. The combined organic phase was washed twice with aqueous malic acid (840 mg of malic acid in 20 mL of water). After phase separation, the aqueous phase was adjusted to pH 8.0 by the addition of aqueous K2CO3 solution. The aqueous solution was then extracted twice with 20 mL of i-PrOAc. The organic phase was dried and concentrated to give 340 mg of the desired compound 14. Compound 14: (( 1 H-NMR (400 MHz CDCl, δ (ppm)): 6.08, sarcosine residue; HRMS electrospray (M+1) 1303.7; 1304.6; mass from isotopic distribution: 1302.93 (100%), 1303.93 (72.5%). JPEG0007776435000040.jpg68170

[0254] Compound 15 was similarly prepared from compound III and R2 according to the general method described above for compound 14, and obtained after further purification by chromatography. Compound 15(( 1H-NMR (400 MHz CDCl, δ (ppm)): 6.31, sarcosine residue; HRMS electrospray (M+1) 1303.4, 1304.6; mass from isotopic distribution: 1302.93 (100%); 1303.93 (72.5%).

[0255] Example 2 - Functional and Inhibition Assays The compounds prepared in Example 1 were tested in a cyclophilin A and D peptidyl-prolyl isomerase functional assay (PPIase assay) using human recombinant enzymes, and in a calcineurin inhibition assay with and without cyclophilin A. The compounds were also tested in a calcium retention capacity (CRC) assay in permeabilized HepG2. Cyclosporin A was used as a control in all assays.

[0256] Compounds were supplied as dry powders or oils and made up as 10 mM stock solutions in 100% DMSO. Subsequent dilutions were made in 100% DMSO for use in all assays.

[0257] Cyclophilin peptidyl-prolyl isomerase functional assay Measurements were performed using an Agilent 8453 spectrophotometer. Assay buffer was cooled to 10°C (with stirring) in precision glass cuvettes, and inhibitors were added from DMSO stock solutions to give a final DMSO concentration of less than 1%. Blank spectra were obtained, then enzyme and substrate were added, and the change in absorbance was measured over a 5-minute period. First-order kinetics were fitted to the absorbance data to obtain rate constants (the first 10-15 seconds were excluded due to mixing). Catalytic rates were calculated by subtracting the background rate from the enzyme rate. Enzyme rate constants, determined in duplicate at each inhibitor concentration, were plotted against inhibitor concentration, and a nonlinear fit using SigmaPlot yielded the K. i obtained.

[0258] Calcineurin phosphatase inhibition assay with and without cyclophilin A This colorimetric 96-well assay was designed for screening inhibitors of recombinant calcineurin (CaN). Activity was determined using the RII phosphopeptide substrate, the most efficient 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 CaN / calmodulin, inhibiting dephosphorylation of the RII peptide. Cyclosporine-like cyclophilin inhibitors were screened in the assay to determine inhibition of calcineurin phosphatase activity in the presence of recombinant CypA. Two dilution series were prepared in a 96-well plate, one containing cyclophilin A enzyme (7 points) and the other without cyclophilin A enzyme (4 points). The assay buffer / calcineurin / calmodulin master mix 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 along with the liberated phosphate was quantified by reading the absorbance at 620 nm. Blank-corrected data were plotted against inhibitor concentration to obtain IC 50 value was determined.

[0259] Calcium retention capacity (CRC) assay in permeabilized HepG2 HepG2 cells were permeabilized with 100 μM digitonin for 10 min in ice-cold buffer containing 1 mM EGTA. After two washing steps to remove the digitonin, cells were permeabilized with 1 e per well in 180 μL of assay buffer containing 0.5 μM Calcium Green 5N. 6Cells were plated in 96-well black and clear plates. Compound dilutions were made in DMSO at 1000x the final concentration, diluted 1:100 in assay buffer, and added to the assay at 20 μL per well. Assay buffer contained 5 mM glutamate and 2.5 mM malate. The cell plate was immediately run on a FLIPR Tetra™, where 5 μL of 200 μM (5 μM) calcium chloride was added every 5 minutes, with the plate read every 3 seconds. The area under the curve at each compound concentration was calculated. EC 50 Values ​​were calculated. It was determined that the use of the area under the curve (ALIC) rather than the number of calcium additions before buffering was lost was a more accurate method of analyzing the data.

[0260] The assay results obtained are summarized in Tables 2-4 below. JPEG0007776435000041.jpg85146

[0261] JPEG0007776435000042.jpg190151

[0262] JPEG0007776435000043.jpg204151

[0263] JPEG0007776435000044.jpg196151

[0264] The tested compounds were observed to have unexpectedly high levels of human cyclophilin inhibition, particularly human cyclophilin D, compared to the cyclosporin A control and at levels comparable to reference compound 1 (see Table 2). It was further observed that the calcineurin inhibitory activity of the tested compounds in the presence of cyclophilin A was lower compared to the cyclosporin A control and, in some cases, reference compound 1 (see Table 3).

[0265] Binding to cyclophilin A and inhibition of calcineurin are closely related to immunosuppression. Without wishing to be bound by theory, it is believed that the prevention or treatment of cell injury or cell death caused by inflammatory processes, such as cell necrosis and related diseases or conditions, may be better achieved by compounds that have potent anti-inflammatory activity but lower immunosuppressive activity, such as those characterized by reduced affinity for binding to cyclophilin A and calcineurin.

[0266] In particular, it is believed that higher levels of inhibition, particularly of cyclophilin D, which regulates the opening of the mitochondrial permeability transition pore (PTP), may lead to improved prevention and / or treatment of cell injury or cell death, and thus the prevention or treatment of symptoms or diseases associated with mitochondrial dysfunction.

[0267] The calcium retention capacity (CRC) assay is a model of mitochondrial function based on the inhibition of mitochondrial permeability transition pore (PTP) opening. Prolonged Ca++ overload is understood to induce prolonged PTP opening and mitochondrial dysfunction, leading to cell death. The assay measures loss of inhibition based on calcium release, as determined by increased fluorescence intensity of the calcium-binding dye used in the assay. Several of the tested compounds were observed to have significantly increased calcium retention capacity compared to the cyclosporine A control, demonstrating comparable or, in some cases, improved capacity compared to reference compound 1.

Claims

1. A compound according to formula 4 or a pharmaceutically acceptable salt thereof (In the formula: R １ and R ２ are independently H, C １ ~C ６ alkyl, or R １ and R ２ are joined together, C ３ ~C ６ forming a cycloalkyl or heterocycloalkyl ring; X and Z are both alkyl, or X is alkyl or C １ ~C ６ alkyl and Z is H, or X and Z are joined together to form C ３ ~C ６ forming a cycloalkyl or heterocycloalkyl ring; A is, -NR ３ R ４ (In the formula, R ３ and R ４ are independently H or C １ ~C ６ alkyl); and - N=C(R ５ ) NR ６ R ７ (In the formula, R ５ , R ６ and R ７ are independently H, C １ ~C ６ alkyl, or R ６ and R ７ are joined together to form C ３ ~C ６ forming a cycloalkyl or heterocycloalkyl ring); Selected from: R ８ is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; R ９ is represented by formula 1a or 1b (It is).

2. A compound of formula 1 or a pharmaceutically acceptable salt thereof (In the formula: R １ and R ２ are independently H, C １ ~C ６ alkyl, or R １ and R ２ are joined together, C ３ ~C ６ forming a cycloalkyl or heterocycloalkyl ring; A is, -NR ３ R ４ (In the formula, R ３ and R ４ are independently H or C １ ~C ６ alkyl); and - N=C(R ５ ) NR ６ R ７ (In the formula, R ５ , R ６ and R ７ are independently H, C １ ~C ６ alkyl, or R ６ and R ７ are joined together to form C ３ ~C ６ forming a cycloalkyl or heterocycloalkyl ring); Selected from: R ８ is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; R ９ is represented by formula 1a or 1b and However, R １ and R ２ are both H, or R １ is methyl, and R ２ is H and R ８ is selected from ethyl, isopropyl, and n-propyl; R ９ is formula 1a, and A is NR ３ R ４ If R ３ and R ４ is H, C １ ~C ４ not alkyl).

3. a) R １ and R ２ are both hydrogen; or b) R １ or R ２ At least one of １ ~C ６ is alkyl; or c) R １ and R ２ are joined together to form C ３ ~C ６ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl or heterocycloalkyl ring.

4. R ８ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is ethyl.

5. R ９ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

6. A is NR ３ R ４ 6. The compound according to any one of claims 1 to 5, wherein:

7. R ３ and R ４ are both -CH ３ 7. The compound of claim 6, wherein:

8. A is -N=C(R ５ ) NR ６ R ７ or A is -N=C(R ５ ) NR ６ R ７ and R ５ , R ６ and R ７ But H, and C １ ~C ６ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from alkyl;

9. R ５ is H or CH ３ and R ６ and R ７ is CH ３ 9. The compound of claim 8, wherein:

10. R ８ 10. The compound of claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein is ethyl.

11. The compound is of formula 4, wherein X is C １ ~C ６ 2. The compound of claim 1, wherein Z is H, or a pharmaceutically acceptable salt thereof.

12. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, which is a compound according to formula 3, or a pharmaceutically acceptable salt thereof: (In the formula: R １ and R ２ are independently H, C １ ~C ６ alkyl, or R １ and R ２ are joined together, C ３ ~C ６ forming a cycloalkyl or heterocycloalkyl ring; R ５ , R ６ and R ７ are independently H, C １ ~C ６ alkyl, or R ６ and R ７ are joined together to form C ３ ~C ６ forming a cycloalkyl or heterocycloalkyl ring; R ８ is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; R ９ is represented by formula 1a or 1b (It is).

13. a) R １ and R ２ are both hydrogen; or b) R １ or R ２ At least one of １ ~C ６ is alkyl; or c) R １ and R ２ are joined together to form C ３ ~C ６ form a cycloalkyl or heterocycloalkyl ring, R ８ is ethyl, and R ５ , R ６ and R ７ But H, and C １ ~C ６ alkyl; or R ５ is H or CH ３ and R ６ and R ７ is CH ３ 13. The compound of claim 12, wherein:

14. The compound or a pharmaceutically acceptable salt thereof is a compound selected from the group consisting of compounds of the following formula 1 or a pharmaceutically acceptable salt thereof:

3. The compound of claim 2, wherein R<1> and R<2> are joined together to form a C<3> cycloalkyl in compounds 12 and 13, or a pharmaceutically acceptable salt thereof.

15. Compound of Formula 4 (In the formula, R ９ is formula 1a, and R ８ is ethyl, X is methyl, Z is H, and R １ and R ２ are both H, and A is -N(CH ３ ) ２ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

16. And 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

17. a) the prevention and / or treatment of kidney diseases or conditions; or b) prevention and / or treatment of a cyclophilin-mediated disease or condition, a cyclophilin A and / or D-mediated disease or condition, or a cyclophilin-mediated disease or condition of the kidney; or c) prevention and / or treatment of diseases or conditions associated with cell injury or cell death; or d) prevention and / or treatment of a disease or condition associated with cell injury or cell death, wherein said disease or condition is organ injury or organ failure; or e) prevention and / or treatment of a disease or condition associated with cell injury or cell death, wherein said disease or condition is organ injury or organ failure, and said organ is selected from the group consisting of kidney, liver, heart, lung, pancreas, intestine, cornea, skin, brain and nervous tissue; or f) prevention and / or treatment of diseases or conditions associated with cell injury or cell death, wherein said diseases or conditions are ischemia-reperfusion injury, renal ischemia-reperfusion injury, acute kidney injury; or acute kidney injury associated with or as a result of kidney transplantation; 17. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for:

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