PCSK9 antagonist compounds

Abstract

To provide antagonists of PCSK9.SOLUTION: Provided are compounds having a particular structure or salts thereof. The compounds have properties for antagonizing PCSK9.Also described are pharmaceutical formulations comprising the compounds of formula I or their salts, and methods for treating cardiovascular diseases and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application is U.S. Patent Application No. 62 / 687,913, filed on June 21, 2018. This asserts priority over the aforementioned document, which is incorporated in its entirety by reference. Born. [Background technology]

[0002] The identification of compounds and / or agents effective in treating cardiovascular diseases is highly desirable. This is important. In clinical trials, a reduction in LDL cholesterol levels has been shown to improve coronary artery disease. It is directly related to the incidence of [unclear]; Law et al., 2003 BMJ 326:1423-14 27. Lifetime moderate reduction in plasma LDL cholesterol levels is associated with coronary events. It was found to correlate with a substantial reduction in the incidence of [the condition]; Cohen et al., 2006 NE ngl.J.Med.354:1264-1272. This is related to non-lipid-related cardiovascular risks. The same was true even in populations with a high prevalence of the factor; see above. Therefore, LDL cholesterol The benefits of controlling terror levels are significant.

[0003] Proprotein convertase subtilisin-kexin type 9 (hereinafter referred to as "PCSK9") It is also known as neuronal apoptosis-modulating convertase ("NARC-1"), and is secreted Proteinase K-like subtilase identified as the ninth member of the subtilase family It is a laxative; see Seidah et al., 2003 PNAS 100:928-933. PCSK9 is a serine protease belonging to the mammalian proprotein convertase family. It belongs to the group and contains an N-terminal signal sequence, a prodomain, a catalytic domain, and a C-terminal domain. Seidah et al., 2012 Nat. Rev. Drug Discov. 11:3 See 67-383. As seen in other genes involved in cholesterol metabolism. Furthermore, research into PCSK9 transcriptional regulation suggests that this is a sterol regulatory element-binding protein (" It has been demonstrated that it is controlled by SREBP; Maxwell et al., 2003 J. Lipid Res. 44:2109-2119, this indicates that lipoprotein metabolism Typical of other genes involved; Dubuc et al., 2004 Arterioscler .Thromb.Vasc.Biol.24:1454-1459. Statins are drugs Upregulating PCSK9 expression through a method that lowers cholesterol. This has been shown; see above. Furthermore, the PCSK9 promoter is involved in cholesterol regulation. It has been shown to have two involved preservation sites: a sterol regulatory element and an Sp1 site. It is done; see above.

[0004] While present in the endoplasmic reticulum, PCSK9, as its sole catalytic activity, interacts with Gln-152. Self-cleavage occurs between Ser-153 and Naureck. iene et al., 2003 Arch.Biochem.Biophys.420:55-6 7;Seidah et al., 2003 Proc.Natl.Acad.Sci.USA See 100:928-933. Subsequent traffic through the trans-Golgi network During the kinging process, the prodomain remains tightly associated with the catalytic domain. Through self-cleavage... This maturation process has been shown to be important for PCSK9 secretion and subsequent extracellular function. (Benjannet et al., 2012 J.Biol.Chem.287:337) See 45-33755). Therefore, several types of evidence suggest that PCSK9 is particularly... This reduces the amount of liver LDLR protein, thus reducing the circulation of LDL cholesterol. It has been shown that it impairs the liver's ability to remove it.

[0005] Adenovirus-mediated overexpression of PCSK9 in mouse liver leads to hepatic LDLR tannins. Dramatic protein loss leads to accumulation of circulating LDL-C and LDLR mRNA levels. It does not affect the genotype; Benjannet et al., 2004 J. Biol. Chem. 279 :48865-48875;Maxwell&Breslow,2004 PNAS 1 01:7100-7105; Park et al., 2004 J. Biol. Chem. 279: 50630-50638; and Lalanne et al., 2005 J. Lipid Res .46:1312-1319. PC for elevated circulating LDL-C levels in mice. The effect of SK9 overexpression is entirely dependent on LDLR expression, and this is also PCSK9 The regulation of LDL-C is mediated through the downregulation of LDLR proteins. This indicates that, consistent with these findings, mice lacking PCSK9, or anti- Mice in which PCSK9 mRNA was reduced by sense oligonucleotide inhibitors showed liver High levels of LDLR protein and superior ability to clear circulating LDL-C; R ashid et al., 2005 PNAS 102:5374-5379; and Graham E., 2007 J. Lipid Res. 48(4):763-767. In addition, cultured hi Reducing PCSK9 levels in hepatocytes with siRNA is also possible. This results in improved LDLR protein levels and the ability to take up LDL-C; Ben Jannet et al., 2004 J.Biol.Chem.279:48865-48875 ; and Lalanne et al., 2005 J. Lipid Res. 46:1312-13 19. When these data are combined, the action of PCSK9 is at the LDLR protein level. This indicates that lowering [something] leads to an increase in LDL-C.

[0006] Many mutations in the PCSK9 gene also cause autosomal dominant hypercholesterolemia (" It is definitively related to ADH, and this disease is associated with low-density lipoprotein (L) in the plasma. A hereditary metabolic disorder characterized by a significant increase in DL particles, leading to premature cardiovascular failure. It can lead to something; Abifadel et al., 2003 Nature Genetics 3 4:154-156; Timms et al., 2004 Hum. Genet. 114:349- See 353; Leren, 2004 Clin. Genet. 65:419-422. I would like to see the following study published later regarding the S127R mutation by Abifadel et al. Patients who have such mutations (1) apoB100-containing lipoprotein, for example, low density Lipoproteins ("LDL"), very low-density lipoproteins ("VLDL"), and intermediate-density lipoproteins (2) Excessive production of high-grade lipoproteins ("IDL"), and (2) the crunch of the lipoprotein Due to the associated reduction in clearance or conversion, higher plasma total cholesterol and Ouguerram et al., 2004 Ar terioscler.Thromb.Vasc.Biol.24:1448-1453 .

[0007] Therefore, there is no doubt that PCSK9 plays a role in regulating LDL. There is no PCSK9 expression or upregulation is associated with LDL cholesterol levels in the blood. Associated with increased plasma levels, inhibition or deficiency of the corresponding PCSK9 expression leads to LDL cholesterol. It is associated with a reduction in plasma levels of terol. LDL is associated with PCSK9 sequence mutations. A decrease in resterol levels has been found to provide protection against coronary heart disease. Cohen, 2006 N.Engl.J.Med.354:1264-1272.

[0008] Thus, cardiovascular diseases include antagonism of the role of PCSK9 in LDL regulation. The identification of effective compounds and / or agents in the treatment of qi is highly desirable, Generally, PCSK9 circulates in the blood and binds to LDL receptors on the cell surface. Since the price is not high, this mechanism is used in the treatment of diseases related to high serum LDL levels. Previous attempts to utilize this phenomenon have focused, for example, on the use of biomolecules such as antibodies. Therefore, to inhibit PCSK9, short peptides or small molecules were used. There are few publications that reflect the activity against this target. For example, Zhang et al., 2014. See J. Biol. Chemistry, 289(2):942-955. Furthermore, the oral administration route for such compounds involves the modulation of PCSK9 activity. This is a highly desirable route for providing treatment for symptoms that can be treated, however Only a small number of compounds can be formulated into dosage forms that utilize this pathway. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Law et al., 2003 BMJ 326:1423-1427 [Non-Patent Document 2] Cohen et al., 2006 N.Engl.J.Med.354:1264-1272 [Non-Patent Document 3] Seidah et al., 2003 Proc.Natl.Acad.Sci.USA100:928-933 [Non-Patent Document 4] Seidah et al., 2012 Nat. Rev. Drug Discov. 11:367-383 [Non-Patent Document 5] Maxwell et al., 2003 J. Lipid Res. 44:2109-2119 [Non-Patent Document 6] Dubuc et al., 2004 Arterioscler.Thromb.Vasc.Biol.24:1454-1459 [Non-Patent Document 7] Naureckiene et al., 2003 Arch.Biochem.Biophys.420:55-67 [Non-Patent Document 8] Benjannet et al., 2012 J. Biol. Chem. 287:33745-33755 [Non-Patent Document 9] Benjannet et al., 2004 J. Biol. Chem. 279:48865-48875 [Non-Patent Document 10] Maxwell&Breslow,2004 PNAS 101:7100-7105 [Non-Patent Document 11] Park et al., 2004 J. Biol. Chem. 279:50630-50638 [Non-Patent Document 12] Lalanne et al., 2005 J.Lipid Res.46:1312-1319 [Non-Patent Document 13] Rashid et al., 2005 PNAS 102:5374-5379 [Non-Patent Document 14] Graham et al., 2007 J. Lipid Res. 48(4):763-767 [Non-Patent Document 15] Lalanne et al., 2005 J.Lipid Res.46:1312-1319 [Non-Patent Document 16] Abifadel et al., 2003 Nature Genetics 34:154-156. [Non-Patent Document 17] Timms et al., 2004 Hum. Genet. 114:349-353 [Non-Patent Document 18] ;Leren,2004 Clin.Genet.65:419-422 [Non-Patent Document 19] Ouguerram et al., 2004 Arterioscler.Thromb.Vasc.Biol.24:1448-1453 [Non-Patent Document 20] Zhang et al., 2014 J.Biol.Chemistry,289(2):942-955 [Overview of the Initiative] [Means for solving the problem]

[0010] This invention inhibits the activity of PCSK9, and the administration of a PCSK9 antagonist has therapeutic effects. It is thought that it may be used to inhibit the corresponding role that PCSK9 plays in various symptoms. By providing an antagonist for PCSK9, these interests can be advanced. That is the case.

[0011] In one embodiment, the present invention relates to formula I: [Chemical formula]

[0012] a compound, wherein, X is H, F, Cl or Br; R + , , + is: (a) -H; or (b) -(CH2) z -R 14A selected from, wherein: z is from 1 to 6, and R 14A is: (i) -H; (ii) -NH2; (iii) -N + H3; (iv) -N + (H3C)3; (v) -NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B (wherein, R 14B is: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3 and exists); (vi) -NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14 B (where: y12 and y13 are not both 2 at the same time and are independently from 2 to 4 ; and R 14B is: -NH2; -N + H3; -N(CH3)2; or -N + (C H3)3); (vii) -NH-C(O)-(CH2) y R 14C (wherein, y is from 1 to 6, R 14C is -O-(CH2) za -N + (CH3)3, and wherein, za is 3 or is 4); and (viii)-NH-C(O)-(CH2) y R 14C (In the formula, y is from 1 to 6) , R 14C teeth: (ai)-O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)3; or Formula (aiii): [ka]

[0013] (This is the part) and; R 2 teeth: (a)-H; and (b)-(CH2) z -R 14A Selected from, where z is from 1 to 6, R 14A teeth: (i)-H; (ii)-NH2; (iii)-N + H3; (iv)-N + (H3C)3; (v)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B (In the formula, R 14B ha:-NH2;-N + H3;-N(CH3)2;or-N + (CH3)3 be); (vi)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14 B (In the formula, y12 and y13 are not both 2 at the same time, but independently from 2 to 4.) And, R 14B ha:-NH2;-N + H3;-N(CH3)2;or-N+ (C H3)3 is; (vii)-NH-C(O)-(CH2) y R 14C (In the formula, y is from 1 to 6, R 14C is -O-(CH2) zb -N + (CH3)3, where zb is 3 or is 4); and (viii)-NH-C(O)-(CH2) y R 14C (In the formula, y is from 1 to 6) , R 14C teeth: (ai)-O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)2R 14ca (In the formula, R 14ca -CH3 or -(CH2) 1-4 -OCH3); Formula (aiii): [ka]

[0014] part; or (aiv) formula: [ka]

[0015] The part (in the formula, R 14Cb and R 14Cc (1 to 4), selected from; or R 1 and R 2 These are combined into the expression: [ka]

[0016] The part may be formed, in the formula: G 1 , R G1a and R G1b It is defined as follows: (a)G 1 The formula is: [ka]

[0017] This is the linker part, in the formula, n q1 It ranges from 1 to 6, and m q1 is 0, 1, or 2 And together, n q1 and m q1 The value of the linker portion defined by them is Including the carbon atoms in the chain that form the carbonyl portion, and / or if The oxygen atoms are selected so that the total number of oxygen atoms does not exceed 8; R G1a (i)-H; and (ii) alkyl groups with up to four carbon atoms selected; and R G1b teeth: (i) Formula: [ka]

[0018] The part; and (ii) Formula: [ka]

[0019] Selected from the part; or (b)G 1 The formula is: [ka]

[0020] This is the linker part, and in the formula, nq2 is 0, 1, or 2, and m q2 These are from 1 to 6 Yes, in total n q2 and m q2 The value of the linker portion defined by them is Including the carbon atoms in the chain that form the rubonyl portion, and / or the carbon atoms that make up the chain and / or Selected so that the total number of oxygen atoms does not exceed 8; R G1a teeth: (i) Formula: [ka]

[0021] The part; and (ii) Formula: [ka]

[0022] Selected from the parts; and R G1b (i)-H; and (ii) alkyl groups with up to four carbon atoms selected; R 8 is -CH3 or formula: [ka]

[0023] This is the part, and in the formula, R 8a is either -H or a linear, branched, or cyclic 4 It is an alkyl group with up to 1 carbon atom; A is: (a) Formula: [ka]

[0024] The part; (b)-CH2-(CH2) y-CH2-(where y is between 1 and 6); Formula (c): [ka]

[0025] The part (in the formula, A b1 teeth: (i) Formula: [ka]

[0026] This is the part where x is from 1 to 6; or (ii) Formula: [ka]

[0027] This is the part where y ranges from 1 to 5 in the formula. (d) Formula: -CH2-(CH2) m -O-(CH2) n - part (where m is 1 to 5) (where n is 0 or 1 to 4) Selected from; B is: (a) combination; (b)-(CH2) 1-4 ;or Formula (c): [ka]

[0028] This is part of it; D is: (a) Formula: [ka]

[0029] The part (where E is -CH2- or -(CH2)) 2-4 -O-, and A and B are ; as defined above (b) formula:

Chemical formula

[0030] the part of (wherein A and B are as defined above); (c) formula:

Chemical formula

[0031] the part of (wherein n a is 1, 2 or 3, m a is 2, 3 or 4, and n a + m a is ≥ 3, wherein A and B are as defined above); (d) formula:

Chemical formula

[0032] the part of (wherein R 34b is -H or an alkyl having 4 carbon atoms in a straight chain, branched chain or cyclic form and A and B are as defined above) To provide the compound as described above, or any of their pharmaceutically acceptable salts.

[0033] In a further embodiment, the present invention provides a compound of formula I, wherein X is F the compound as described above, or any of their pharmaceutically acceptable salts. In some embodiments D is of the formula:

Chemical formula

[0034] is preferably the part, where E is -CH2- or -(CH2)2-O- and A and B are as defined herein.

[0035] In some embodiments, D is of the formula:

Chemical formula

[0036] is preferably the part, where E is -CH2- or -(CH2)2-O- and A and B are as defined herein.

[0037] In some embodiments, D is of the formula:

Chemical formula

[0038] is preferably the part, where A and B are as defined herein are.

[0039] In some embodiments, D is of the formula:

Chemical formula

[0040] is preferably the part, where A and B are as defined herein are.

[0041] In some embodiments, D is of the formula:

Chemical formula

[0042] is preferably the part, where A and B are as defined herein are.

[0043] In some embodiments, D is given by formula: [ka]

[0044] Preferably, the part is as specified herein, where A and B are as defined herein. ru.

[0045] In some embodiments, D is given by formula: [ka]

[0046] Preferably, the part is as specified herein, where A and B are as defined herein. ru.

[0047] In some embodiments, D is given by formula: [ka]

[0048] Preferably, the part is as specified herein, where A and B are as defined herein. ru.

[0049] R 1 and R 2 These bind together with the peptide ring to which they are attached, forming a ring structure. In some embodiments, R 1 and R 2 Structure: [ka]

[0050] It is preferable to form the part shown.

[0051] In one embodiment, the present invention relates to a compound of the present invention, for example, a compound of formula I, and a small A pharmaceutical composition containing at least one pharmaceutical additive, preferably a composition intended for oral administration. To provide.

[0052] In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula I to a target that needs it. Alternatively, by administering the salt, preferably in the form of a pharmaceutical composition, the PCSK9 activity can be improved. Related disease symptoms include, for example, atherosclerosis, hypercholesterolemia, and coronary heart disease. Diseases, metabolic syndrome, acute coronary syndrome, or related cardiovascular and cardiogenic diseases This invention provides a method to antagonize PCSK9 in the provision of treatment for psychotic symptoms. [Modes for carrying out the invention]

[0053] In the following explanation, conventional structural representations are used, which refer to a specific chiral carbon center. It includes the conventional stereochemical notation.

[0054] Therefore, the structural representation of the compounds of the present invention is based on several asymmetric carbons shown in the exemplary compounds. It includes the conventional stereochemical notation for elementary centers. Therefore, in such examples... In this case, the black solid "wedge-shaped" connection represents a connection that protrudes from the plane of the reproduction medium, and "H" The hashed wedge joint represents a downward joint of the replication medium to the plane, and double The "wave" line attached to the bonded carbon can be in both cis and trans orientations. It indicates inclusion. As is customary, a regular solid line indicates the depicted connection. It represents all spatial configurations. Therefore, in cases where a specific stereochemical representation is not given... In summary, the expression is intended to represent all stereochemical and spatial orientations of the structural features.

[0055] As shown in the examples of the present invention and as mentioned above, a specific chiral carbon center The structure is constructed using the conventional "solid line wedge" and "hash line wedge" combined representations. It is expressed in a manner. For most of the example compounds, the absolute configuration has not been determined, but Prepared using the same or similar reaction conditions and starting reagents, and under the same chromatographic conditions. The stereochemical configuration (determined by X-ray crystallography) of the isolated species below is known. It is assigned by similarity to a specific example compound. Therefore, structurally in this specification The specific assignment of stereochemistry expressed therein is that the specific compound prepared is one particular This means confirming the presence of an excess of stereoisomers, and is particularly noteworthy among the presented data. Unless otherwise noted, this specification does not necessarily provide for the absolute determination of the stereochemical structure of the compounds. This cannot be stated as part of the description.

[0056] If a mixture of isomers is obtained, the individual stereoisomers are obtained with a high enantiomer excess percentage. Preparation in this manner may, if desired, be achieved by separating the mixture using conventional methods, for example or by chromatography or crystallization, or for the stereochemistry described for the synthesis. This can be done by using a homogeneous starting material or by stereoselective synthesis. It is understood that this is possible. Derivatization may be performed before the separation of stereoisomers. The separation of the mixture can be carried out in an intermediate step during the synthesis of the compound of formula I, or in the final step This procedure can be performed on racemic products.

[0057] Where applicable in this specification, absolute stereochemistry refers to the X-ray crystallography of a crystalline product or crystalline intermediate. determined by analysis, which reagent contains an asymmetric center of a known configuration, if necessary is derivatized with. Unless a particular isomer, salt, solvate (including hydrate) or solvate salt of such a racemate, enantiomer or diastereomer is indicated, the present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvate salts of such racemates, enantiomers, diastereomers and mixtures thereof.

[0058] The invention also includes isotopically labeled compounds of the invention, which are structurally identical to those listed herein, but a statistically significant percentage of one or more atoms in that form of the compound have an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope normally found in nature, and the abundance of the naturally occurring isotope present in the compound of the invention is thereby changed. By the invention is meant that all suitable isotopic variations of the compounds of formula I are included.

[0059] Examples of isotopes that can be preferentially incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, fluorine and chlorine, for example, but not limited to: 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O,<了 17 O, 18 O 31 P, 32 P, 35 S, 18 F and 36 Cl, 123 I and​​​​​​125 Includes I. Others It is understood that the isotopes of this compound can also be incorporated by known means.

[0060] In particular, certain isotope-labeled compounds of the present invention (for example, 3 H, 11 C and 14 (labeled with C) are compounds and / or substrates formed using various known techniques. It is recognized as particularly useful in tissue distribution assays. In addition, it is intended for isotope substitution. The compound of the present invention is protium ( 1 H) and deuterium ( 2 Hydrogen (H or D) containing hydrogen (H It includes different isotopic forms of ) Protium is the dominant hydrogen isotope found in nature. It is a body. Concentration into deuterium offers certain therapeutic benefits, such as improved in vivo half-life or It can reduce the required dose or is useful as a standard for characterizing biological samples. Compounds can be provided. Isotope-enriched compounds within the range of Formula I are well known to those skilled in the art. By means of the art used, or as described in the schemes and examples herein. A similar process is used to remove excess isotope enrichment using appropriate isotope enrichment reagents and / or intermediates. It can be prepared without the need for experiments.

[0061] When the wavy line is at the end of an conventional bond (as opposed to connecting two atoms within the same structure), (In a literal sense), this indicates a point of connection to the structure, for example: [ka]

[0062] The secondary butyl moiety is bonded via methylene groups through bonds terminated by wavy lines. This indicates that when alphabetical notation is used to represent the substituent part, Dash The symbol 'yu' is used to indicate the binding site with the substrate shown, for example: -CH2-C (O)-CH2Cl has an acetyl chloride moiety bonded via the methylene moiety of this moiety. To indicate that.

[0063] Any variable group (for example, n, R) a , R b (etc.) in any of the components or in formula I When it appears more than once within the definition, unless otherwise specified at the time of definition, for each occurrence That definition is independent of its definition in any other appearance. Those skilled in the art will understand the structure table Currently, that is, R 1 , R A The selection of various substituent combinations defined in such areas is a matter of chemistry. The substituents should be selected in accordance with well-known principles regarding structural bonding and stability. The combination of variable groups is such that such a combination results in a stable compound. Recognize that it is acceptable.

[0064] "Stable" compounds can be prepared and isolated, and their structure and properties can be determined. , use of the compound for the purposes described herein (e.g., therapeutic administration to a subject) To remain essentially unchanged for a sufficient period of time, or to be made to remain unchanged. This is a compound that can do this. The compounds of the present invention are not limited to stable compounds included in formula I. It is determined.

[0065] Any variable group or part can take the form of a range, for example (-CH 2- ) 1-4 The place expressed by In addition, both ends of the specified range (i.e., 1 and 4 in this example) are included, and similarly All numbers in between (i.e., 2 and 3 in this example) are included.

[0066] The term "halogen" refers to fluorine, chlorine, bromine, and unless otherwise specified at the time of use. It contains iodine.

[0067] As used herein, “subject” (or “patient”) is Animals in need of treatment, preferably mammals, especially humans, or domestic animals and pets. This refers to non-human animals, including animals raised for animal husbandry, and these are not limited to cattle. This includes horses, sheep, pigs, goats, rabbits, cats, dogs, and other mammals. In that embodiment, the subject is preferably a human, as used herein. The term "administration" and its variations relating to compounds of formula I (for example, "administering a compound...") (and) delivers the compound or a pharmaceutically acceptable salt thereof to the subject in need of treatment. It means that.

[0068] As mentioned above, in one embodiment, the present invention relates to a compound of formula I or a pharmaceutically acceptable compound. The salts that are accepted contain properties that counteract the function of PCSK9.

[0069] In one embodiment, the compound of formula I is formula IA: [ka]

[0070] It has the structure, in the formula: R 1 teeth: (a)-H; or (b)-(CH2) z -R 14A Selected from, where z is from 1 to 6, R14A teeth: (i)-H; (ii)-NH2; (iii)-N + H3; (iv)-N + (H3C)3; (v)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B (In the formula, R 14B ha:-NH2;-N + H3;-N(CH3)2;or-N + (CH3)3 be); (vi)-NH-C(O)-[(CH2) y12 -O-] 1-4 -(CH2) y13 R 14B Preferably -NH-C(O)-[(CH2) y12 -O-]2-(CH2) y1 3R 14B (In the formula: y12 and y13 are not both 2 at the same time, but independently from 2 to 4) And, R 14B ha:-NH2;-N + H3;-N(CH3)2;or-N + (CH3)3; (vii)-NH-C(O)-(CH2) y R 14C (In the formula, y is from 1 to 6, R 14C is -O-(CH2) za -N + (CH3)3, where za is 3 or is 4); and (viii)-NH-C(O)-(CH2) y R 14C (In the formula, y is from 1 to 6) , R 14C teeth: (ai)-O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)3; or Formula (aiii): [ka]

[0071] (This is the part) and; R 2 teeth: (a)-H; and (b)-(CH2) z -R 14A Selected from, where z is from 1 to 6, R 14A teeth: (i)-H; (ii)-NH2; (iii)-N + H3; (iv)-N + (H3C)3; (v)-NH-C(O)-[(CH2)2-O-] 1-4 -(CH2)2R 14B , good Mashikuha -NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B (In the formula, R 14B ha:-NH2;-N + H3;-N(CH3)2;or-N + (CH3)3 be); (vi)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14 B (In the formula, y12 and y13 are not both 2 at the same time, but independently from 2 to 4.) And, R 14B ha:-NH2;-N + H3;-N(CH3)2;or-N + (C H3)3 is; (vii)-NH-C(O)-(CH2) y R 14C(In the formula, y is from 1 to 6, R 14C is -O-(CH2) zb -N + (CH3)3, where zb is 3 or is 4); and (viii)-NH-C(O)-(CH2) y R 14C (In the formula, y is from 1 to 6) , R 14C teeth: (ai)-O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)2R 14ca (In the formula, R 14ca -CH3 or -(CH2) 1-4 -OCH3); Formula (aiii): [ka]

[0072] part; or (aiv) formula: [ka]

[0073] The part (in the formula, Y 14Cb and Y 14Cc is selected from 1 to 4; also teeth R 1 and R 2 These are combined into the expression: [ka]

[0074] The part may be formed, in the formula: G 1 , R G1a and R G1b It is defined as follows: (a)G 1 The formula is: [ka]

[0075] This is the linker part, in the formula, n q1 It ranges from 1 to 6, and m q1 is 0, 1, or 2 And together, n q1 and m q1 The value of the linker portion defined by them is The carbon atoms that make up the chain, including the carbon atoms in the chain that form the carbonyl portion and / or The oxygen atoms are selected so as not to exceed 8 in total; R G1a (i)-H; and (ii) alkyl groups with up to four carbon atoms selected; and R G1b teeth: (i) Formula: [ka]

[0076] The part; and (ii) Formula: [ka]

[0077] Selected from the part; or (b)G 1 The formula is: [ka]

[0078] This is the linker part, in the formula, n q2 is 0, 1, or 2, and m q2 1 to 6 And together, n q2 and m q2The value of the linker portion defined by them is The carbon atoms that make up the chain, including the carbon atoms in the chain that form the carbonyl portion and / or The oxygen atoms are selected so as not to exceed 8 in total; R G1a teeth: (i) Formula: [ka]

[0079] The part; and (ii) Formula: [ka]

[0080] Selected from the parts; and R G1b (i)-H; and (ii) alkyl groups with up to four carbon atoms selected; R 8 is -CH3 or formula: [ka]

[0081] This is the part, and in the formula, R 8a is either -H or a linear, branched, or cyclic 4 It is an alkyl group with up to 1 carbon atom; A is: (a) Formula: [ka]

[0082] The part; (b)-CH2-(CH2) y -CH2-(where y is between 1 and 6); Formula (c): [ka]

[0083] The part (in the formula, A b1 teeth: (i) Formula: [ka]

[0084] This is the part where x is from 1 to 6; or (ii) Formula: [ka]

[0085] This is the part where y ranges from 1 to 5 in the formula. (d) Formula: -CH2-(CH2) m -O-(CH2) n - part (where m is 1 to 5) (where n is 0 or 1 to 4) Selected from; B is: (a) combination; (b)-(CH2) 1-4 ;or Formula (c): [ka]

[0086] This is part of it; D is: (a) Formula: [ka]

[0087] The part (where E is -CH2- or -(CH2)) 2-4 -O-, and A and B are , as stipulated above; Formula (b): [ka]

[0088] The part of the formula (wherein A and B are as defined above); Formula (c): [ka]

[0089] The part (in the formula, n a is 1, 2, or 3, and m a is 2, 3, or 4, and n a + m a is at least 3, where A and B are as defined above; Formula (d): [ka]

[0090] The part (in the formula, R 34b is either -H, or a linear, branched, or cyclic structure with up to 4 atoms. (The alkyl group of carbon atoms is as defined above, where A and B are as defined above.) The present invention provides the aforementioned compound, or a pharmaceutically acceptable salt thereof.

[0091] In embodiments of the compound of formula IA, R 1 is, -(CH2) z -R 14A And in the formula :z is from 1 to 6, R 14A teeth: (i)-H; (ii)-NH2; (iii)-N + H3; or (iv)-N + (H3C)3 is; R 2 is, -(CH2) z -R 14A And in the formula, z is from 1 to 6, and R 14A teeth: (i)-H; (ii)-NH2; (iii)-NH-C(O)-[(CH2)2-O-] 1-4 -(CH2)2R 14B , Preferably -NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B (In the ceremony , R 14B ha:-NH2;-N + H3;-N(CH3)2;or-N + (CH3)3 It is; (iv)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B (In the formula, y12 and y13 are not both 2 at the same time, but independently from 2 to 4; And, R 14B ha:-NH2;-N + H3;-N(CH3)2;or-N + (CH 3) It is 3); (v)-NH-C(O)-(CH2) y R 14C (In the formula, y is from 1 to 6, R 14 C is -O-(CH2) zb -N + (CH3)3, where zb is 3 or 4. (and) (vi)-NH-C(O)-(CH2) y R 14C (In the formula, y is from 1 to 6, R 1 4C teeth: (ai)-O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)2R 14ca (In the formula, R 14ca is -CH3 or - (CH2) 1-4 -OCH3); Formula (aiii): [ka]

[0092] part; or (aiv) formula: [ka]

[0093] The part (in the formula, Y 14Cb and Y 14Cc is selected from 1 to 4; also teeth R 8 is -CH3 or formula: [ka]

[0094] This is the part, and in the formula, R 8a is either -H or a linear, branched, or cyclic 4 It is an alkyl group with up to 1 carbon atom; A is: (a) Formula: [ka]

[0095] The part; (b)-CH2-(CH2) y -CH2-(where y is between 1 and 6); Formula (c): [ka]

[0096] The part (in the formula, A b1 teeth: (i) Formula: [ka]

[0097] This is the part where x is from 1 to 6; or (ii) Formula: [ka]

[0098] This is the part where y is between 1 and 5 in the formula); and (d) Formula: -CH2-(CH2) m -O-(CH2) n - part (where m is 1 to 5) (where n is 0 or 1 to 4) Selected from; B is: (a)-(CH2) 1-4 ;or Formula (b): [ka]

[0099] This is part of it; D is: (a) Formula: [ka]

[0100] The part (where E is -CH2- or -(CH2)) 2-4 -O- and A and B This is as stipulated above; Formula (b): [ka]

[0101] The part of (wherein A and B are as defined above); or Formula (c): [ka]

[0102] The part (in the formula, R 34b is either -H, or a linear, branched, or cyclic structure with up to 4 atoms. (The alkyl group of carbon atoms is as defined above, where A and B are as defined above.) The compound is the aforementioned compound, or a pharmaceutically acceptable salt thereof.

[0103] In one embodiment of the compound of formula IA, D is of formula: [ka]

[0104] In the part where E is -CH2- or -(CH2)2-O-, A and B is as defined in equation IA above.

[0105] In one embodiment of the compound of formula IA, A is: (a)-(CH2)6; Formula (b): [ka]

[0106] The part of (where x is between 1 and 3 in the expression); or Formula (c): [ka]

[0107] This is the relevant part.

[0108] In another embodiment of the compound of formula IA, R 2 teeth: (a)-(CH2) z -R 14A In the formula, z is from 1 to 6, and R 14A teeth: (a)-H; (b)-CH3; (c)-NH2; (d)-N + H3; (e)-N + (H3C)3; (f)-NH-C(O)-[(CH2) 2-4 -O-] 2-4 -(CH2) 2-4 R 1 4B (In the formula, R 14B ha:-NH2;-N + H3;-N(CH3)2;or-N + ( CH3)3 is; (g)-NH-C(O)-[(CH2) y R 14C (In the formula, y is from 1 to 6, R 14C teeth: (ai)-O-(CH2) 2-4 -N + (CH3)3; (aii)-N + (CH3)3; or Formula (aiii): [ka]

[0109] (This is the part.) ;or Formula (b) [ka] This is the relevant part.

[0110] In a further embodiment of the compound of formula IA, R 1 teeth: (a)-H; (b)-(CH2) z -R 14A (In the formula, z is from 1 to 6, R 14A teeth: (i)-H; (ii)-N + H3; or (iii)-NH-C(O)-[(CH2)2-O-]2-(CH2)2-N + (CH 3)3 (is) Selected from.

[0111] In yet another embodiment of the compound of formula IA, A is -CH2-(CH2) y -CH2 -and in the formula, y is from 3 to 5. In a further embodiment, A is -(CH 2) It is 6.

[0112] In another embodiment of the compound of formula IA, B is of formula: [ka] This is the relevant part.

[0113] In another embodiment of the compound of formula IA, R 1 is, -(CH2) z -R 14A and In the formula, z is from 1 to 6, and R 14A is -H. Another embodiment of the compound of formula IA In R 1 is, -(CH2) z -R 14A And in the formula, z is 1, R 14 A It is -H.

[0114] In another embodiment of the compound of formula IA, R 2 is, -(CH2) z -R 14A and In the formula, z is from 1 to 6, and R 14A is -NH-C(O)-(CH2) y R 14C In the formula, y is from 1 to 6, and R 14C is, -N + (CH3)2R 14ca dea In the formula, R 14ca It is -CH3.

[0115] In another embodiment of the compound of formula IA, R 8 The formula is: [ka]

[0116] This is the part where, in the formula, R 8a is either -H or a linear chain of up to 4 carbon atoms It is alkyl. In a further embodiment, R 8 The formula is: [ka]

[0117] This is the part where, in the formula, R 8b This is -H, -CH3, or -C(CH3)3.

[0118] In some embodiments, the compound of formula I has the structure of formula II or formula IIA. Preferably, it is either or a pharmaceutically acceptable salt thereof: [ka]

[0119] In the formula, A, R 1 and R 2 As defined in formula IA above, B 1 ha-(CH 2) 0-2 D 1 teeth: a) Formula: [ka]

[0120] The part; and b) Formula: [ka] It is selected from the following parts.

[0121] In some embodiments of formula II or formula IIA, D 1 The formula is: [ka]

[0122] It is preferable that it be the part of Formula II or Formula IIA. 1 The formula is: [ka]

[0123] It is preferable that it be the part of Formula II or Formula IIA. 1 The formula is: [ka]

[0124] It is preferable that it be the part of Formula II or Formula IIA. 1 The formula is: [ka]

[0125] It is preferable that it be the part shown.

[0126] In some embodiments, the compound of formula I is preferably of formula III: [ka]

[0127] A compound in which A, R1 and R 2 This is as defined in formula IA above. Ri, D 2 The formula is: [ka] This is the relevant part.

[0128] In some embodiments of formula III, D 2 The formula is: [ka]

[0129] It is preferable that it be the part of Equation III. In some embodiments of Equation III, D 2 The formula is: [ka]

[0130] It is preferable that it be the part of Equation III. In some embodiments of Equation III, D 2 The formula is: [ka] It is preferable that it be the part shown.

[0131] In some embodiments, the compound of formula I is preferably of formula IV: [ka]

[0132] A compound in which A, R 1 and R 2 This is as defined in formula IA above. ru.

[0133] In some embodiments, the compound of formula I is formula V: [ka]

[0134] A compound in which A, B, R 1 and R 2 As defined in formula IA above and D 2 teeth: (a) Formula: [ka] The part;

[0135] Formula (b): [ka] The part;

[0136] Formula (c): [ka] part; or

[0137] Formula (d): [ka] This is the relevant part.

[0138] Several embodiments of Formula I, Formula IA, Formula II, Formula IIA, Formula III, Formula IV, or Formula V In this case, A is given by equation: -(CH2) ya It is preferable that this is the part, where ya is 4 From 6. In some embodiments of formula I, formula IA, formula II, or formula IIA, A The formula is: -CH2-(CH2) ma -O-(CH2) na It is preferable that it be the - part. In the formulas, ma is 2 or 3, and na is 0 or 1. (Formulas III, IV) In some embodiments of formula V, A is formula: -CH2-(CH2) ma-O-(C H2) na It is preferable that the part is -, where ma is 2 or 4, and na is It is 0, 1, or 2. Equations I, IA, II, IIA, III, IV, or V In some embodiments, A is given by the formula: [ka]

[0139] It is preferable that this be the part, where yb is between 1 and 3. Equations I, IA, II, In some embodiments of formulas IIA, III, IV, or V, A is formula: [ka] It is preferable that it be the part shown.

[0140] Furthermore, in this specification, the compounds of formula I are referred to as compounds Ex-1, Ex-2, Ex-3, and E x-4, Ex-5, Ex-6, Ex-7, Ex-8, Ex-9, Ex-10, Ex-11 , Ex-12, Ex-13, Ex-14, Ex-15, Ex-16, Ex-17, Ex- 18, Ex-19, Ex-20, Ex-21, Ex-22, Ex-23, Ex-24, E x-25, Ex-26, Ex-27, Ex-28, Ex-29, Ex-31, Ex-35 , Ex-36, Ex-38, Ex-39, Ex-40, Ex-41, Ex-44, Ex- 47, Ex-48, Ex-49, Ex-50, Ex-51, Ex-52, Ex-53, E x-54, Ex-55, Ex-56, Ex-57, Ex-58, Ex-59, Ex-60 and Ex-61, or any pharmaceutically acceptable salt thereof, are also provided. These compounds The substances are disclosed in Table 1 and are also referred to herein as “compounds of the present invention”.

[0141] Table 1 [Table 1] TIFF0007855670000093.tif161165TIFF0007855670000094.tif167164TIFF0007855670000095.tif172165TIFF0007855670000096.tif174164 TIFF0007855670000097.tif143165TIFF0007855670000098.tif152164TIFF0007855670000099.tif146165TIFF0007855670000100.tif124168

[0142] In the formula, A - It is a pharmaceutically acceptable anion.

[0143] The term "salt(s)" and the phrase "pharmaceutically acceptable salt" as used herein. Its use in this context includes any of the following: forming with inorganic acids and / or organic acids Acidic salts formed with inorganic and / or organic bases, basic salts formed with zwitterionic bases Quaternary ammonium complex. The salt of the compound of the present invention is formed by a method known to those skilled in the art. For example, the compound of the present invention may be mixed with a certain amount of acid or base, and an equivalent amount of acid, for example. Alternatively, a base is reacted with a solvent, for example, a solvent in which a salt precipitates, or an aqueous solvent. It can then be formed by freeze-drying.

[0144] The compounds of the present invention are tri-coordinate nitrogen atoms, for example, primary, secondary, or tertiary amines. It contains the portion known as, here the lone pair of electrons present on the nitrogen atom is appropriate Under appropriate reaction conditions, it can be protonated with a suitable acid, or with a suitable reagent, such as alkyl bromide. It can be alkylated, thereby removing anions generated during the process, such as halogens. A four-coordinate charged nitrogen is provided, stabilized by an on or conjugate base. Therefore, The compounds of the present invention can be prepared in the form of a free base, or as a quaternary complex or salt complex. It can be isolated morphologically. In some cases, a suitable acidic proton is present proximal to the basic nitrogen. In this context, the formation of zwitterionic complexes is possible. As the terminology is used herein, The salts of the compounds of the present invention will be acidic salts formed using inorganic and / or organic acids. And, whether it is a basic salt formed using an inorganic base and / or an organic base, amphoteric io A salt formed by incorporating basic properties, for example, a compound in which the basic part (for example, limited to) It is not a nitrogen atom, for example, an amine, pyridine, or imidazole, and an acidic part (for example) It may be a salt containing both a carboxylic acid and a fourth carboxylic acid. Whether it is a ammonium complex or not, it is included within the scope of the compounds of the present invention as described herein. It will be done.

[0145] Therefore, the structural representation of the compound of the present invention is in the form of a free base, a salt, and an amphoteric form. Or, in either the quaternary ammonium form, other such compounds discussed above It encompasses all forms. Therefore, one aspect of the present invention relates to the pharmaceutically important aspects of the compound of the present invention. The product is provided in the form of an acceptable salt, an amphoteric complex, or a quaternary ammonium complex. Those skilled in the art will recognize examples in which the compounds of the present invention may form such complexes, and these examples , tetracoordinate nitrogen is quaternized or protonated, and the charged nitrogen form is associated with anion This includes cases where stabilization is possible. The term "pharmaceutically acceptable salt" refers to its compound Having similar or superior efficacy to the free base form of a substance, and biologically or It is not undesirable in any other respect (for example, it is not toxic to the recipient). Salts (quaternary ammonium complexes and intramolecular salts, for example) that are not harmful in any other respect. This refers to a combination of factors, including amphoteric complexes.

[0146] The formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds is, for example, S. Berge et al., Journal of Pharmaceutical Science s(1977) 66(1) 1-19;P.Gould,International J. of Pharmaceutics(1986) 33 201-217;An derson et al,The Practice of Medicinal C According to hemistry (1996), Academic Press, New York. The Orange Book (Food & Drug Administration) on, Washington, DC (on its website); and P. Hei nrich Stahl, Camille G. Wermuth (Eds.), Hand book of Pharmaceutical Salts:Properties, Selection,and Use,(2002)Int'l.Union of P This is discussed in *Cure and Applied Chemistry*, pp. 330-331. These disclosures are incorporated herein by reference.

[0147] This invention intends both the free base form and all available salts of the compound of the present invention. This salt is a salt that is generally recognized as safe for use in the preparation of pharmaceutical formulations, and And can be formed within the normal range of capabilities in the relevant technical field, in the preparation of pharmaceutical formulations "Generally recognized as safe for use" This includes those that will later be classified as "(zed as safe)" and, according to this specification, In this context, it is called a "pharmaceutically acceptable salt." As you can understand, free base compounds are synthesized. By controlling the isolation conditions of the compound at that time, or from the salt form of the compound of the present invention It can be prepared by neutralization and ion exchange.

[0148] Examples of pharmaceutically acceptable acidic salts include, but are not limited to, trifluoro Acetates, adipates, alginates, ascorbetes, and asparagus containing acetate salts. Lutate, benzoate, benzenesulfonate, bisulfate, borate, butylate Citrate, camphorate, camphor sulfonate, cyclopentanepropionate T, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, gluco Heptanoate, glycerophosphate, hemisulfate, heptanoate, hexano Eth, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfate Honate, lactate, maleate, methanesulfonate, methyl sulfate, 2-na Phthalene sulfonate, nicotinate, nitrate, oxalate, pamoate, pectin Tinate, persulfate, 3-phenylpropionate, phosphate, picrate Pivalate, propionate, salicylate, succinate, sulfate, sulfone tartates (such as those mentioned herein), tartarates, thiocyanates, It contains toluenesulfonate (also known as tosylate), undecanoate, and other compounds.

[0149] Examples of pharmaceutically acceptable basic salts include, but are not limited to, ammonium. Salts, alkali metal salts, such as sodium, lithium, and potassium salts, alkaline earth metals Salts, such as calcium and magnesium salts, aluminum salts, zinc salts, organic bases (for example) Salts with organic amines, for example, benzathine, diethylamine, dicyclohexylamine, Hydravamin (N,N-bis(dehydroabiethyl)ethylenediamine is formed using ), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, piperazine, phenylcyclohexylamine, choline, trometamine salt, and It contains salts with amino acids, such as salts with arginine and lysine. Basic nitrogen-containing groups are It can be converted to a monoium ion, or, for example, a lower alkyl halide (methyl (ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulf Sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long-chain phosphates (For example, decyl, lauryl, myristyl and stearyl chlorides, bromides and yochlorides) Agents such as argyl halides (e.g., benzyl and phenethyl bromides) It can be classified into four grades using this method.

[0150] The term "pharmaceutically acceptable anion" refers to an anion that is used to form a pharmaceutically acceptable salt. It refers to the appropriate anion.

[0151] Further examples of pharmaceutically acceptable salts that may be used in the present invention include, but are limited to, It does not contain fluoride, but it does contain fluoride, chloride, bromide, and iodide.

[0152] Generally, the salt of the compound is a pharmaceutically acceptable salt within the scope of the present invention. It is illustrated.

[0153] Terms related to compounds: "purified," "in purified form," or "in isolated and purified form" "In its natural state" means isolated from a synthetic process or natural source or a combination thereof. This refers to the physical state of the compound after purification. Therefore, the term "purified" is used for a compound. "In a purified form" or "in an isolated and purified form" means as described herein. Or obtained from a purification process or processes well known to those skilled in the art, as specified herein To reveal the characteristics using standard analytical techniques described or well known to those skilled in the art: This refers to the physical state of the compound having sufficient purity. The compound of the present invention is any form of the compound. This includes, among others, insights in the reaction mixture, as well as insights obtained by conventional techniques. This includes the isolated and purified forms obtained by the present invention. This also includes polymorphs of solvates and prodrugs.

[0154] Certain compounds of the present invention may exist in different tautomeristic forms, for example, limited to It is not a thing, but ketone / enol tautomers, imine-enamine tautomers, and For example, the complex aromatic ring form, for example, the following part: [ka]

[0155] It can exist in this form.

[0156] Similarly, unless otherwise specified, the structure of any tautomerized form of a compound exhibiting tautomerism. Presenting a representation means encompassing all compounds of such tautomeristic forms. Therefore, the compounds of the present invention, their salts, and their solvates and prodrugs If the g can exist in different tautomerized forms or in equilibrium between such forms, All such forms of compounds are encompassed by and within the scope of the present invention.

[0157] In another embodiment, the present invention provides a pharmaceutical composition comprising one or more compounds of the present invention. As used herein, the term “pharmaceutical composition” means at least one pharmaceutically active A compound comprising at least one additive and a specified amount of a specified combination of specified components. , and any consequences arising directly or indirectly from a specified combination of specified components in specified amounts It is intended to encompass both the intended product and its derivatives.

[0158] As will be understood by those skilled in the art, additives themselves exert active pharmaceutical effects. Without doing so, it helps to adapt the composition to a specific route of administration or to process the composition into a dosage form. It is any component. Generally, the composition is the active substance administered. Depending on the route of administration and characteristics, it contains two or more additives. Examples of additives that impart properties to make something easier to process are not limited to those intended for tableting. In powdered pharmaceuticals, the lubricant or press aid, and the active ingredient are in emulsion form. The composition contains an emulsion stabilizer. The composition is adapted to the desired route of administration. Examples of additives include, but are not limited to, those administered orally, from the gastrointestinal tract. It is an absorption enhancer that promotes absorption, administered transdermally. When administered orally or via mucosal administration, a penetration enhancer is used. ), for example, those used in adhesive skin "patches" or compositions for buccal administration. That is the case.

[0159] Regardless of the function that the additives perform in the composition, additives are collectively referred to as "carrying" in this specification. It is called a "formula." Typically, a formulation contains up to 95 percent active ingredients and a balance of carriers. It may contain a balance carrier, but formulations with different ratios can also be prepared. Generally, an acceptable pharmaceutical composition is one that is acceptable in the subject to which the composition is administered. During this time, it can provide therapeutic serum levels of the active ingredient, and within an acceptable temperature range. To ensure that the composition retains its biological activity during the permissible storage period, based on the route of administration... To provide an effective amount of PCSK9 antagonist in each dosage form of an acceptable volume. It contains an active substance at a suitable concentration to achieve this.

[0160] The pharmaceutical compositions used herein are bulk compositions, i.e., individual compositions for administration. Formulated materials that have not yet been formed into medication units, and contained within individual medication units This refers to both of the compositions.

[0161] The composition of the present invention can be used in bulk form, while in most applications the composition is administered to the patient. The dosage form contains individual units suitable for administration, and each dosage form contains an effective amount of the above. It is understood that the composition contains a certain amount of a selected composition containing one or more compounds of formula I. Examples of suitable dosage forms include, but are not limited to, (i) dosage forms suitable for oral administration. Examples include pharmaceutical compositions in the form of liquids, gels, powders, solids, or semi-solids, which are filled into capsules. It is filled or compressed into a tablet, and in addition, one or more coatings that modify its release properties. Formulations having a coating that imparts delayed release, for example, or having sustained-release properties. (ii) Dosage forms suitable for administration through oral tissues, e.g., rapidly dissolving tablets, lollipops , needle arrays suitable for providing liquids, gels, sachets or intramucosal administration; (ii) i) Dosage forms suitable for administration through the mucous membrane of the nose or upper respiratory cavity, e.g., nasal or intra-airway (iv) Liquid, suspension or emulsion formulations for dispersion in; (iv) Suitable for transdermal administration (v) Dosage form, e.g., patch, cream or gel; (v) Dosage form suitable for intradermal administration, e.g., cream (vi) A dosage form suitable for intravenous (IV) injection, e.g., IV injection (vii) Dosage forms suitable for intramuscular administration (IM), e.g. For example, an injectable solution or suspension that forms a depot preparation with sustained-release properties. (viii) Dosage forms suitable for intravenous infusion (IV), such as liquid formulations. Alternatively, it may be a suspension, such as an IV solution or a concentrate injected into a physiological saline IV bag. (ix) The compound is diffused into the surrounding tissue, thereby creating a sustained therapeutic serum level. This includes long-term administration by implanting the provided rod or other device. (x) a dosage form suitable for subcutaneous administration; or (x) suitable for delivery via the mucous membrane of the rectum or vagina. This includes dosage forms such as suppositories.

[0162] Pharmaceutical compositions can be solid, semi-solid, or liquid. The preparations can be adapted to various modes of administration, and these examples are limited to... These are not products that can be made into tablets, but include powders, dispersible granules, small tablets, and beads, which can be made into tablets, for example. It can be used for encapsulation or direct administration. In addition, liquid preparations and This includes, but is not limited to, solutions, suspensions, and emulsions, and these include For example, not exclusively, but intended for oral ingestion, inhalation, or intravenous administration (IV). The preparations that are administered, for example, but not limited to, via IV infusion or infusion pump. Administration, intramuscular administration (IM), for example, intramuscular bolus released over a long period of time Formulations intended for administration (IM), direct IV injection, or subcutaneous administration route It can be used in the preparation of pharmaceutical formulations.

[0163] Other possible routes of administration include intranasal administration or administration to other mucous membranes. This includes preparations prepared for administration to various mucous membranes, and also preparations suitable for such administration. It may include additional components to be combined, such as viscosity modifiers.

[0164] In some embodiments, compositions suitable for use in solid oral dosage forms are used, for example, A composition suitable for use in tablets or fast-dissolving oral formulations is the compound of the present invention. The preferred route of administration of the salt is the other route mentioned above, but the composition of the present invention can be administered via the other routes mentioned above. It can be formulated for administration by means of aerosol, for example, by inhalation. Alternatively, it includes an aerosol formulation suitable for administration via the nasal mucosa, which is available in solution and powder form. It may contain solids in a state, which are pharmaceutically acceptable sprays, for example, inert compressed gases. For example, it can be combined with nitrogen. Also, immediately before use, it can be added to a suspension or solution, for example, orally or Solid-form formulations intended to be converted into suspensions or solutions for parenteral administration. It is included. Examples of such solid forms include, but are not limited to, lyophilized preparations. This includes liquid formulations absorbed into a solid absorption medium.

[0165] For example, the compounds of the present invention may also be, for example, liquids, suppositories, creams, foams, gels, or The rapidly soluble solid form may be deliverable percutaneously or transmucosally. The percutaneous composition may be deliverable percutaneously. It can also take the form of a cream, lotion, aerosol and / or emulsion. any transdermal patch known in the relevant art, for example, a pharmaceutically active compound A matrix containing or a reservoir containing pharmaceutically active compounds in solid or liquid form It is understood that it can be provided in a unit dosage form, such as an integrated patch.

[0166] Examples of the pharmaceutically acceptable carriers and methods for producing the various compositions mentioned above are provided in AG. ennaro(ed.), Remington: The Science and Pr. Act of Pharmacy, 20 th Edition, (2000), L ippincott Williams & Wilkins,Baltimore,M This can be found in D. Additional examples of publications dealing with pharmaceutical issues can be found below: Medical Drug compositions can be formulated using a number of strategies known in the art. For example, McGoff and Scher, 2000 Solution Formula tion of Proteins / Peptides:In-McNally,EJ .,ed.Protein Formulation and Delivery.Ne w York, NY:Marcel Dekker;pp.139-158;Akers &Defilippis,2000,Peptides and Proteins a s Parenteral Solutions.In-Pharmaceutical Formulation Development of Peptides and Proteins.Philadelphia,PA:Taylor and Fra ncis;pp.145-177;Akers et al., 2002,Pharm.Biotec See hnol.14:47-127.

[0167] In another embodiment, the present invention is described herein to counteract the PCSK9 function. This provides a method using a PCSK9-specific antagonist compound; the method described above is below Further details are provided below. The use of the term “antagonistic” throughout this application refers to the affected tissue ( (Similarly) It counteracts or inhibits the action of one or more functions of PCSK9 in the affected tissue. This refers to supplying a substance that counteracts, cancels out, neutralizes, or reduces a function. Inhibition or antagonism of one or more functional properties related to PCSK9 is considered in the art. Known methodologies (for example, Barak & Webb, 1981 J. Cell Bi) ol.90:595-604;Stephan&Yurachek,1993 J.Li pid Res.34:325330; and McNamara et al., 2006 Clin See also Acta 369:158-167, and Inhibition or antagonism can be easily determined according to the methodology described herein. , a decrease in PCSK9 activity compared to that observed in the absence of an antagonist, or for example Compared to the activity observed when an irrelevant specific control antagonist is present, This achieves a decrease in PCSK9 activity. Preferably, the present invention provides a PCSK9-specific solution. The antagonist may use the functions of PCSK9, which are disclosed herein, but are not limited to those disclosed herein. Preferably, the measurement parameters encompassing the activity are reduced by at least 10%. Furthermore, the measurement parameters are at least 20%, 30%, 40%, 50%, 60%, and 70%. Antagonizing to the extent of a reduction of 80%, 90%, and 95%. PCSK9 function Such inhibition / antagonism is a specific phenotype, disease, or disorder in which PCSK9 function is adversely affected. It is particularly effective when it contributes, at least partially, to the symptoms.

[0168] In one embodiment, the present invention provides a method for antagonizing the activity of PCSK9, This method can be affected by PCSK9 (i.e., the expression of the LDL receptor and Cells, cell populations or tissue samples (including / or including) as disclosed herein by PCSK9 A specific antagonist, and when the antagonist is present, it binds to PCSK9, and P Contacting CSK9 under conditions that allow for inhibition of cellular LDL uptake inhibition Includes. In some embodiments of the present invention, such a method includes the cell being a human cell. Includes. Additional embodiments of the present invention include methods such that the cells are mouse cells. .

[0169] In one embodiment, the present invention relates to a method for antagonizing the activity of PCSK9 in a subject. This method provides a therapeutically effective amount of the PCSK9-specific antagonist of the present invention to the target. This includes administering a drug. In some embodiments, to antagonize PCSK9 function The method is for treating diseases, disorders, or symptoms related to PCSK9 as defined herein. It is for treatment purposes, or to benefit from the effects of a PCSK9 antagonist. This is intended to provide treatment for diseases, disorders, or symptoms that may be present.

[0170] Therefore, the present invention relates to various treatment methods where it is desirable to counteract the PCSK9 function. Therefore, consider using the PCSK9-specific antagonists described herein. As used in the book, the term “treatment method” refers to a change in at least one sign of a disease symptom. With regard to a series of actions that lead to this, this can be inherently preventive or therapeutic. In some embodiments, the present invention relates to and / or causes PCSK9 activity. Symptoms for which PCSK9 function is contraindicated, either due to the underlying condition or for a specific subject. Regarding a treatment method for this purpose, this method involves administering a therapeutically effective amount of formula I PCSK9 antagonist to the subject. This includes administering a nist compound or a pharmaceutically acceptable salt thereof. Several implementations In this condition, the symptoms include atherosclerosis, hypercholesterolemia, coronary heart disease, Metabolic syndrome, acute coronary syndrome, or related cardiovascular and cardiometabolic diseases It may be a symptom, or a disease state or symptom for which PCSK9 activity is contraindicated. .

[0171] The treatment method according to the present invention involves administering to an individual a therapeutically (or preventively) effective amount of P of the present invention. This includes administering a CSK9-specific antagonist. The term "therapeutably effective" is used in relation to dosage. The use of "" or "preventively effective" is intended to achieve the desired therapeutic and / or therapeutic effect at the intended dose. This refers to the amount necessary to achieve a preventative effect for a desired period of time. The desired effect is, for example, treatment. It may result in relief, remission, reduction, or cessation of at least one symptom related to the symptom being treated. As those skilled in the art will understand, these quantities are not limited to the disease state of the individual. Age, sex, and weight, as well as PCSK9-specific factors that elicit the desired effect in an individual. The response varies depending on various factors, including the antagonist's ability. The response can be measured in an in vitro assay. This may be documented by non-human animal studies of Nvivo, and / or further supported by clinical trials. It can be held.

[0172] In some embodiments, the PCSK9 antagonist compound of the present invention is used as specified herein. It is preferable to administer the pharmaceutical composition in the form described herein.

[0173] The administration of antagonist drugs is well within the scope of the skills of those skilled in the art (for example, Le Derman et al., 1991 Int.J.Cancer 47:659-664; Bag Shawe et al., 1991 Antibody, Immunoconjugates an (See Radiopharmaceuticals 4:915-922) Many factors, such as, but not limited to, the patient's symptoms, the area being treated, and the administration of the medication. Based on the route and desired treatment, for example, the factors mentioned above, including prevention or acute treatment. It changes. A physician or veterinarian with normal skills can administer a therapeutically effective dose of the antagonist. It can be easily determined and prescribed.

[0174] The subjects are those who require or desire treatment for an existing disease or medical condition. It may be. As used herein, there is a "need" to treat the symptoms that exist. The scope includes both the determination of necessity by healthcare professionals and the individual's desire to receive such treatment. It contains. When the compound or a salt thereof is provided in combination with one or more other activators, "Administration" and its variations are, respectively, simultaneous or concurrent administration of the compound or its salt with other agents. This is understood to include provision, or provision in a series of separate doses over a period of time. When combination drugs are administered simultaneously, administering them together in a single composition. They can be administered together or separately. The "combination" of activators is possible with all activators. A single composition containing, or multiple compositions, each containing one or more activators. It is understood that this is possible. In the case of two activators, the combination is a single agent containing both agents. The composition may be one of two separate compositions, each containing one agent; the three active In the case of fermentation agents, the combinations are a single composition containing all three agents, or three compositions, each containing one agent. Two separate compositions, or two compositions, one of which contains two agents and the other contains three agents. For example, it may include a second agent.

[0175] The compositions and combinations of the present invention are preferably administered in an effective amount. The term "effective amount" is defined as , by antagonizing PCSK9 and thereby eliciting the desired response (i.e., in animals or In humans, although not limited to humans, atherosclerosis and hypercholesterolemia are common. coronary heart disease, metabolic syndrome, acute coronary syndrome, and related cardiovascular conditions. Treatment of symptoms related to or affected by PCSK9 function, including disease and cardio-metabolic symptoms. This refers to a sufficient amount of the active compound to induce a therapeutic response in the administration or management of the treatment.

[0176] The actual dosage used will vary depending on the patient's requirements and the severity of their symptoms. To obtain, the determination of an appropriate medication regimen for a specific situation is described, for example, in standard literature. For example, “Physicians' Desk Reference” (PDR ), for example, the 1996 edition (Medical Economics Com Pany, Montvale, NJ 07645-1742, USA), Physici an's Desk Reference, 56 th Edition, 2002 (Me dical Economics company, Inc. Montvale, NJ (Published by 07645-1742) or Physician's Desk Reference rence,57 th Edition, 2003 (Thompson PDR, Mon As described in the publication by tvale, NJ 07645-1742, the technical part These disclosures are within the scope of the field of technology; and these disclosures are incorporated herein by reference. It is administered. For convenience, the total daily dose is divided and given little by little throughout the day as needed. They may be delivered in a continuous manner.

[0177] PCSK9-specific antagonists are, but are not limited to, administered orally or by injection. Administration (specific embodiments include intravenous injection, subcutaneous injection, intraperitoneal injection, or intramuscular injection) The technology includes administration by injection, inhalation, intranasal administration, or local administration. It can be administered alone or as an adjunct in the treatment of an individual via any route of administration understood in the field. It can be administered to an individual in combination with other agents designed for this purpose. PCSK9-specific agent Gonist also includes injection devices, injection pens, needleless devices; and subcutaneous patch delivery systems. It can also be administered by means of a m. The route of administration is not limited, but depends on the desired physiological response of the treatment. The decision should be based on many considerations that are understood by those skilled in the art, including chemical properties. be.

[0178] One or more additional pharmacological activators may be administered in combination with the compound of formula I. Activators (or groups of activators) are pharmaceutical activators that are active in the body and are different from the compound of formula I. This is intended to mean (or activators), which are converted into a pharmaceutically active form after administration. It contains a prodrug, and also contains free acids, free bases, and pharmaceutically acceptable substances of the additional activators. It also includes salts that are tolerated. Generally, though not limited to, antihypertensive drugs and anti-atherosclerotic drugs. Any suitable agent, including a curing agent, such as a lipid-modifying compound, and any other suitable agent, including antidiabetic and / or anti-obesity agents. A suitable additional activator or group of activators in any combination with the compound of formula I in a single drug formulation. It can be used in combination (fixed dose combination of drugs), or the activator can be administered simultaneously or sequentially. The target may be administered with one or more separate drug formulations that enable administration (co-administration of separate activators) ).

[0179] Examples of additional activators that may be used include, but are not limited to, angiotensin Calcium-converting enzyme inhibitors (for example, alacepril, benazepril, captopril, seropril) Lu, Cilazapril, Delapril, Enalapril, Enalaprilat, Hoshinopril, Imi Dapril, lysinopril, mobertipril, perindopril, quinapril, ramipril, Spirapril, temocapril, or trandolapril (angiotensin II receptor) Inhibitors (for example, losartan, i.e., COZAAR®, valsalta) N, candesartan, olmesartan, telmesartan, o and any of these drugs used in combination with hydrochlorothiazide, for example HYZ AAR (registered trademark), etc.); neutral endopeptidase inhibitors (for example, thiorphan Phosphoramidone, aldosterone antagonist, aldosterone synthase inhibitor , renin inhibitors (for example, dipeptide and tripeptide urea derivatives (U.S. 5, See Patent No. 116,835), amino acids and derivatives (U.S. Patent No. 5,095,1 (Nos. 19 and 5,104,869), amino acid chains linked by non-peptide bonds (U.S. Patent No. 5,114,937), dipeptides and tripeptide derivatives, peptide Luaminodiol and peptidyl β-aminoacylaminodiol carbamate, and and low molecular weight renin inhibitors (including diol sulfonamides and sulfinyl), N-morpholino derivatives, N-heterocyclic alcohols and pyrroleimidazolone; also, Fluoro and chromophoric compounds of statone derivatives and statone-containing peptides RO derivative, enalkrein, RO 42-5892, A 65 317, CP 80794, ES 1005, ES 8891, SQ 34017, Ali Skiren(2(S),4(S),5(S),7(S)-N-(2-Carbamoyl-2-Me (Tylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methylpropyl) Toxy-3-(3-methoxypropoxy)-phenyl]-octaneamide hemifmarate ) SPP600, SPP630 and SPP635), endothelin receptor antagonist Stroke, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalfil (ta) dalfil) and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, garopamil, nidipine (e.g., nimodipine, nicardipine), potassium channel activators (e.g., nicorandil) Pinacidil, Chromacam, Minoxidil, Aprilcalim , loprazolam), diuretics (e.g., hydrochlorothiazide), sympathomimetic agents (sy mpatholitic), β-adrenergic blockers (for example, propranolol) L, atenolol, bisoprolol, carvedilol, metoprolol or metoprolol (Tartate), α-adrenergic blockers (for example, Xazosin, prazosin, or α-methyldopa (central α-adrenergic agonists) Peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, e.g., HMG-Co A reductase inhibitors, such as ZOCOR® in the form of lactone prodrugs, and It is marketed as MEVACOR (registered trademark) and functions as an inhibitor after administration. mvastatin and lovastatin, and dihydroxy ring-opening acid HMG-CoA reductator Pharmacologically acceptable salts of enzyme inhibitors, such as atorvastatin (especially LIPITOR (Calcium salt sold under registered trademark), rosuvastatin (especially CRESTO Calcium salts sold under the registered trademark R, pravastatin (especially PRAVA Sodium salt sold under CHOL (registered trademark), fluvastatin (especially LE Sodium salt sold under SCOL (registered trademark), crivasstatin (crivas tatin) and pitavastatin; cholesterol absorption inhibitors, such as ezetimibe (Z ETIA®, and ezetimibe and any other lipid-lowering agent, such as HM mentioned above. Combination with G-CoA reductase inhibitors, particularly with simvastatin. (VYTORIN®) or combination with atorvastatin calcium; Immediate-release or controlled-release, and / or HMG-CoA reductase inhibitors Niacin in combination with harmful agents; niacin receptor agonists, such as acipimox and Asifran, as well as niacin receptor partial agonists; metabolic modifiers (metab (an oral altering agent), which is an insulin and insulin mime Tics (for example, insulin degludec, insulin glargine, insulin) Lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (for example, sitag) Liptin, alogliptin, omaligliptin, linagliptin, vildagliptin) Includes; an insulin sensitizer which includes (i) PPARγ agonist For example, glitazone (e.g., pioglitazone, AMG 131, MBX2044, Mitoglitazone, robeglitazone, IDR-105, rosiglitazone, and paraglitazone (n), as well as other PPAR ligands, for example, (1) PPARα / γ dual agonists St (for example, ZYH2, ZYH1, GFT505, Chiglita (zar), Muragritazaru, Allegritazaru, Soderugritazaru and Nabegritazaru) (2) PPARα agonists, for example, fenofibric acid derivatives (e.g., Gemfi Brozil, clofibrate, cyprofibrate, fenofibrate, bezafibrate (3) Selective PPARγ modulator (SPPARγM) (for example, WO0 2 / 060388, WO02 / 08188, WO2004 / 019869, WO2004 Opened during / 020409, WO2004 / 020408 and WO2004 / 066963 (i) those shown; and (4) PPARγ partial agonists; (ii) Bigua Nides, such as metformin and pharmaceutically acceptable salts thereof, in particular metformin Hydrochloride salts, and sustained-release formulations thereof, such as Glumetza® and Fortam et(trademark) and GlucophageXR(trademark); and (iii) protein Tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-1137) 15 and TTP814); insulin or insulin analog (for example, insulin Lin detemir, insulin glulisine, insulin degludec, insulin gluco Lugin, insulin lispro and their respective inhalable formulations; leptin and lepti Amylin derivatives and agonists; amylin and amylin analogs (e.g., plum lynching) (e.g., sulfonylurea and non-sulfonylurea insulin secretagogues) Tolbutamide, Glybride, Glipizide, Glimepiride, Mitiglinide, Meglitinide , nateglinide and repaglinide); α-glucosidase inhibitors (e.g., acarbobacteria) glucagon receptor antagonists (for example, voglibose and miglitol); glucagon receptor antagonists (for example) , MK-3577, MK-0893, LY-2409021 and KT6-971); Ccretin mimetics, e.g., GLP-1, GLP-1 analogs, derivatives and mimetics Iks; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide) D, Albiglutide, Exenatide, Liraglutide, Lixisenatide, Taspoglutide, CJC-1131 and BIM-51077, their intranasal formulations, transdermal formulations and once-weekly formulations Agents); Bile acid metal ion chelating agents (e.g., cholestiran, colestimide, colesebalam) (colesevalam) hydrochloride, cholestipol, cholestyramine, and cross-linked dextrin Strane's dialkylaminoalkyl derivatives), Acyl-CoA: Cholesterol Acyl Lansferase inhibitors (e.g., abasimibe); anti-obesity compounds; in inflammatory symptoms Drugs intended for use, such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), Glucocorticoids and selective cyclooxygenase-2 or Cox-2 inhibitors Agents; glucokinase activators (GKA) (e.g., AZD6370); 11β-hydro Inhibitors of xisteroid dehydrogenase type 1 (for example, U.S. 6,730,69 Those disclosed in Issue 0, and LY-2523199); CETP inhibitors (for example) anacetrapib, torcetrapib and evacetrapib); fructose 1,6- Bisphosphatase inhibitors (e.g., U.S. Patent No. 6,054,587; No. 6,11) No. 0,903; No. 6,284,748; No. 6,399,782; and No. 6,489 , as disclosed in Patent No. 476); Acetyl-CoA carboxylase-1 or 2 Inhibitors of ACC1 or ACC2; AMP-activated protein kinase (AMPK) Activators; other G protein-coupled receptor agonists: (i) GPR-109, (ii) GPR-119 (for example, MBX2982 and PSN821), and (iii) GPR-40 (for example, TAK875); SSTR3 Antagonist (for example, WO Disclosed in 2009 / 001836); neuromedin U receptor agonist ( For example, what is disclosed in WO2009 / 042053, but is not limited to this. Iga Neuromedin S (NMS) included); SCD modulator; GPR-105 Antagonists (for example, those disclosed in WO2009 / 000087); S GLT inhibitors (e.g., ASP1941, SGLT-3, empagliflozin, dapag) Liflozin, Canagliflozin, BI-10773, Erzgliflozin, Lemogliflozin Zin (remogloflozin), TS-071, tofogliflozin, ipraglif Rosin and LX-4211); Acylcoenzyme A: Diacylglycerol Acyl Inhibitors of lanceferases 1 and 2 (DGAT-1 and DGAT-2); fatty acid synthesis Enzyme inhibitors; Acylcoenzyme A: Monoacylglycerol acyltransferase Inhibitors of MGAT-1 and MGAT-2; agonists of the TGR5 receptor (Also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR) (can be done); ileal bile acid transporter inhibitor; PACAP, PACAP mimetics PACAP receptor 3 agonists; PPAR agonists; protein tyrosine phosphatase Tase-1B (PTP-1B) inhibitors; IL-1b antibodies (for example, XOMA052 and canakinumab; and bromocriptine mesylate and its rapid-release formulation; also This refers to other drugs that are beneficial for treating the above-mentioned symptoms or disorders, if chemically possible. This includes free acids, free bases, and pharmaceutically acceptable salt forms of the above-mentioned activators. nothing.

[0180] The compounds of the present invention can be easily obtained according to the following reaction scheme and examples or modifications thereof. It can be easily prepared using readily available starting materials, reagents, and conventional synthesis procedures. In these reactions, it is also possible to use known variants. Reverse-phase chromatography Compound purification using tography (either HPLC or MPLC, as described later) A C18 column was used for the preparation. Other methods for preparing the compounds of the present invention are as follows: This will be readily apparent to those skilled in the art in light of the reaction scheme and examples. The terms may be used in the exemplary schemes and / or examples herein.

[0181] ACN is acetonitrile. AcOH is acetic acid. AcO - NH4 is ammonium acetate. Boc2O is a di-tert-butyl dicarbonate. Bn stands for benzyl. BnBr is benzyl bromide. BzCl is benzoyl chloride. CBr4 is a perbromomethane. Cbz-Cl is benzyl chloroformate. DBU is 1,8-diazabicyclo[5.4.0]undeca-7-ene. DCC is dicyclohexylcarbodiimide. DCE is 1,2-dichloroethane. DCM is dichloromethane. DEA is N,N-diethylamine. DIAD is (E)-diisopropyldiazene-1,2-dicarboxylate. DIEA or DIPEA is N,N-diisopropylethylamine. DMAP is 4-dimethylaminopyridine.

[0182] DMF is N,N-dimethylformamide. DMSO is dimethyl sulfoxide. EA or toluene is ethyl acetate. EtOH is ethanol. Et2O is diethyl ether. Fmoc is a fluorenylmethyloxycarbonyl protecting group. Fmoc-Cl is (9H-fluoren-9-yl)methylcarbonochloride. . Fmoc-D-Dap(Boc)-OH is N-alpha-(9-fluorenylmethyl OH Xycarbonyl)-N-beta-t-butyloxycarbonyl-D-2,3-diaminop It is lopionic acid. Fmoc-Osu is an Fmoc N-hydroxysuccinimide ester. HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium 3-oxide hexafluorophosphate. HPLC is a high-performance liquid chromatography technique. IPA is isopropyl alcohol. LiOH is lithium hydroxide. LC / MS stands for Liquid Chromatography-Mass Spectrometry. Me3N is trimethylamine. MeOH is methanol. MPLC is a medium-pressure liquid chromatography technique. MsCl is methanesulfonyl chloride. NaBH(OAc)3 is sodium triacetoxyborohydride. NMR is nuclear magnetic resonance. NsCl is 4-nitrobenzene-1-sulfonyl chloride. PE stands for petroleum ether. Pd2(dba)3(HCl3) is Tris(dibenzylideneacetone)dipalladium It is a (0)-chloroform adduct. PPh3 is triphenylphosphine. PdCl2(dppf) or Pd(ii)(dppf)Cl2 is dichloro[1,1' -Bis(diphenylphosphino)ferrocene]palladium(II). Pd(dppf)Cl2CH2Cl2 is dichloro[1,1'-bis(diphenylphosph) It is a palladium(II) dichloromethane adduct [(ino)ferrocene]. Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium. PPT s This is pyridinium p-toluenesulfonate. [Rh(OAc)2]2 is a rhodium(II) acetate dimer. RT, rt, or rt is room temperature. tBuOAc is tert-butyl acetate. TEA is triethylamine. TFA is trifluoroacetic acid. TFE stands for tetrafluoroethylene. THF stands for tetrahydrofuran. Tf2O is trifluoromethanesulfonic anhydride. Teoc-OSu is 2,5-dioxopyrrolidine-1-yl(2-(trimethylsilyl It is an ethyl carbonate. TBAF is tetrabutylammonium fluoride. TMS is tetramethylsilane. Zhan catalyst 1B is dichloro(1,3-bis(2,4,6-trimethylphenyl)-2 -Imidazolidinylidene)((5-((dimethylamino)sulfonyl)-2-(1-meth Ruethoxy-O)phenyl)methylene-C)ruthenium(II) [1,3-bis( 2,4,6-trimethylphenyl)-4,5-dihydroimidazole-2-ylidene[2 -(i-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl[methylene] Also described as ruthenium(II) dichloride. [Examples]

[0183] Example 1: Preparation of Ex-01 and Ex-51 [ka] TIFF0007855670000103.tif90134

[0184] The salt forms of compounds Ex-01 and Ex-51 are converted to intermediate 76 according to the following scheme. Prepared from Yobi 86 (prepared as follows): [ka] TIFF0007855670000105.tif230168TIFF0007855670000106.tif79168

[0185] Step A: Preparation of intermediate 89 76 (1.56 g, 1.917 mmol, prepared as follows) in DMF (40 ml) and To the solution of 86 (1.506 g, 1.936 mmol, prepared as follows), add HATU (0.80 Add 2g (2.108 mmol) and DIEA (0.670 ml, 3.83 mmol). The resulting solution was stirred at room temperature for 50 minutes, then alkylated with alkyl (300 mL) and propyl alcohol. The mixture was divided between N (100 mL). The organic layer was washed with brine (2 × 100 mL) and N The residue was dried with a2SO4, concentrated, and the MeOH / DCM was eluted on a silica gel column. By using it as a catalyst for purification, a score of 89 was obtained. LC / MS:(M+1) + :1573. 8.

[0186] Step B: Preparation of intermediate 90 89 (0.68g, 0.432mm) in DCM (500ml) and acetic acid (40mL) The solution of (ol) was bubbled with N2 for 20 minutes, followed by Zhan catalyst-1b (0.222g). (0.302 mmol) was added. The resulting mixture was further bubbling with N2 for 20 minutes. Next, it was heated at 55°C for 5 hours. After cooling to room temperature, the mixture was filtered through Celite. The filtrate is concentrated, and the residue is eluted on a silica gel column using MeOH / DCM as the eluent. Purification yielded a 90 (cis / trans mixture). LC / MS: (M+1) + :1545.7.

[0187] Step C: Preparation of Intermediate 91 90 (cis / trans mixture) (65 mg, 0.042) in acetonitrile (2 ml) To a solution of mmol, piperidine (0.042 ml, 0.420 mmol) was added. The prepared solution was stirred at room temperature for 1 hour, then concentrated, and the residue was added to acetonitrile (4 mL). The residue was dissolved and concentrated again. The residue was dried under high vacuum for a further 30 minutes to obtain 91 (cis). A mixture of (and transformer) was given. LC / MS: (M+1) + :1324.0.

[0188] Step D: Preparation of Intermediate 92 91 (cis / trans mixture) (548 mg, 0.41 mg) in 10 ml of DMF at 0°C In a solution of 4 mmol) and 88 (227 mg, 0.455 mmol, prepared as follows), H ATU (181 mg, 0.476 mmol) and DIEA (0.166 ml, 0.95 (2 mmol) was added. The resulting solution was stirred at 0°C for 1 hour, and the solution was placed on the reverse side of the C18 column. Acetonitrile (0.05% TFA) / water (0.05% TFA) is dissolved by phase MPLC. Purification using the solvent yielded 92 (cis / trans mixture). LC / M S:(M+1) + :1803.5.

[0189] Step E: Preparation of Intermediate 93 92 (700) in THF (20 ml), MeOH (6 ml), and water (6 ml) at 0°C A solution of mg, 0.388 mmol) is mixed with 1N LiOH aqueous solution (3.11 ml, 3.11 The solution was added dropwise (mol) and stirred at 0°C for 23 hours. The solution was then 1N H The addition of Cl neutralizes the pH to 7-8, allowing the volatile components to evaporate and the aqueous layer to pH 5. The mixture was cured and then filtered by reverse-phase MPLC on a C18 column using acetonitrile (0.05% T). By purifying using FA / water (0.05% TFA) as the elution solvent, 93 is obtained from TFA It was given as salt. 93 T in 0°C water (70 mL) and acetonitrile (70 mL). To a solution of FA salt (427 mg, 0.257 mmol), add 0.1 N HCl (13.5 ml) Add 1,350 mmol dropwise, stir the resulting solution at 0°C for 5 minutes, and then freeze. By drying, 93 was obtained as an HCl salt. LC / MS:(M+1) + :1567 .1.

[0190] Step F: Preparation of intermediate 94 93 (200 mg, 0.125 mmol) as an HCl salt in DMF (30 mL) HATU (56.9 mg, 0.150 mmol) was added to the solution. The resulting solution was left at room temperature. Stir for 30 minutes, then dilute with DCM (400 mL), then DIEA (0.065 (mL, 0.374 mmol) was added. The resulting solution was stirred at room temperature for 1 hour to remove volatile components. The solution is evaporated on a rotary evaporator, and the resulting DMF solution is subjected to reverse-phase MPLC. Using acetonitrile (0.05% TFA) / water (0.05% TFA) as the elution solvent Refinement yielded a score of 94. LC / MS: (M+1) + :1549.2.

[0191] Step G: Preparation of Intermediate 95 In a solution of 94 (14 mg, 9.04 μmol) in MeOH (20 ml), add 10% Pd Add C (1.924 mg, 1.808 μmol), and the resulting mixture is heated in an H2 balloon. The mixture was subjected to hydrogenation at room temperature for 1 hour. The mixture was filtered through Celite, and the filtrate was concentrated. The compound was condensed to give intermediate compound 95. LC / MS: (M+1) + :1550.9.

[0192] Step H: Preparation of Ex-01 The intermediate compound 95 (26 mg, 0.017 mmol) prepared in the previous step is used It was dissolved in DCM (2 ml). To this solution, TFA (6 mL, 78 mmol) was added. The resulting solution was stirred at room temperature for 30 minutes, then concentrated, and the residue was dissolved in DCM (3 mL). Then, treat with 4N HCl (0.042 mL, 0.168 mmol) in dioxane, and re... By concentrating it, Ex-01 was given as the crude product. The crudely purified Ex-01 was subjected to reverse-phase H2O2. PLC uses acetonitrile (0.1% formic acid) / water (0.1% formic acid) as the elution solvent. By using this method for purification, we obtained Ex-01 in formate form. LC / MS: (M+1) + :1394.4.

[0193] Step I: Preparation of Ex-51 In a solution of intermediate compound 94 (30 mg, 0.019 mmol) in DCM (2 ml), Add TFA (4 ml, 51.9 mmol), and stir the reaction mixture at ambient temperature for 30 minutes. Next, it was concentrated. The residue was dissolved in DCM (2 mL) and HCl (4N in dioxane) (0 Ex-51 is obtained by treating it with 0.048 ml (0.194 mmol) and concentrating it, thereby converting it to an HCl salt. This resulted in the compound being analyzed by reverse-phase HPLC using acetonitrile (0.1% formic acid). By purifying the substance using water (0.1% formic acid) as the mobile phase, the formate form of Ex-51 can be obtained. Provided. LC / MS:(M+1) + :1392.0.

[0194] Using the following scheme and procedure, intermediates 76, 86 and used in the above procedure We prepared bi88.

[0195] Preparation of intermediate 68 used in the preparation of intermediate 76 [ka]

[0196] Step A: Preparation of intermediate compound 65 (2S,3S)-3-hydroxypyrrolidine-2 in 100 ml of dioxane at 0°C - Suspension of carboxylic acid (5.32 g, 40.6 mmol) with sodium hydroxide (122 ml) Add 122 mmol of benzyl chloroformate (6.50 ml, 44 ml). 6 mmol was added dropwise. The resulting suspension was stirred at 0°C for 5 hours. The volatile components were removed. After removal, the aqueous layer was acidified to pH 3, and then 30% IPA / DCM (200 mL) was added. The aqueous layer is further divided into brine (50 mL) and the aqueous layer is further divided into 30% IPA / DCM (2 × 10 Extracted with 0 mL). The combined organic layers were dried with Na2SO4 and concentrated to obtain (2 S,3S)-1-((benzyloxy)carbonyl)-3-hydroxypyrrolidine-2- A carboxylic acid (65) was obtained. LC / MS: (M+1) + :266.1.

[0197] Step B: Preparation of intermediate compound 66 In a solution of 65 (7.48g, 28.2 mmol) in MeOH (80ml), TMS- Diazomethane (70.5 ml, 141 mmol) was added dropwise, and the resulting solution was left at room temperature. The solution was stirred for 10 minutes, then quenched by dropwise addition of acetic acid (approximately 400 uL). The residue was concentrated and purified using RINKAN / hexane as the eluent on a silica gel column. This resulted in a score of 66. LC / MS:(M+1) + :280.1.

[0198] Step C: Preparation of intermediate compound 67 A solution of 66 (4.81 g, 17.22 mmol) in DCM (200 mL) is diluted with N2 for 3 minutes. Bubbling for 0 minutes, followed by rhodium(II) acetate dimer (0.761g, 1. 722 mmol) was added. The mixture was cooled in an ice bath and tert-butyldiazoacetate was added. A solution (3.58 mL, 25.8 mmol) was added dropwise at 0°C. The resulting mixture was then 0°C. The mixture was stirred at °C for 1.5 hours. The reaction mixture was quenched by adding water (100 mL) and the mixture was prepared. The mixture was extracted using DCM (3 x 100 mL), and the combined organic layer was dried with Na2SO4 and concentrated. The residue was then eluted using acetonitrile (0.05% TFA) / water (0.05% TF) as the elution solvent. The product was purified by reverse-phase MPLC using A). The fraction containing the product was concentrated. The aqueous layer was extracted with DCM (2 × 100 mL). The combined organic layers were dried with Na₂SO₄. By concentrating the solution, a score of 67 was obtained. LC / MS:(M+1) + :394.2.

[0199] Step D: Preparation of intermediate compound 68 A solution of 67 (3.72g, 9.46 mmol) in MeOH (80ml) is mixed with 10% P Add d / C (0.805 g, 0.756 mmol), and the resulting mixture is heated in an H2 balloon. The solution was subjected to hydrogenation at ambient temperature for 2 hours, and then filtered through Celite. Concentration yielded a score of 68. LC / MS:(M+1) + :259.9.

[0200] Preparation of intermediate compound 76 [ka] TIFF0007855670000109.tif158165

[0201] Step A: Preparation of Intermediate 69 ( ) in THF (20 ml), MeOH (10 ml), and water (20.00 ml) at 0°C S)-2-((((9H-Fluorene-9-yl)methoxy)carbonyl)amino)-3 -(5-fluoro-1H-indole-3-yl)propanoic acid (3g, 6.75 mmol) Add NaOH (20.25 ml, 20.25 mmol) to the solution of ) and the resulting solution The mixture was stirred at ambient temperature for 4 hours, and then the volatile components were evaporated. Dioxane (5) was added to the aqueous mixture. Add 0 ml of (and 20 ml of water), and cool the resulting solution to 0°C. 0.881 ml (8.10 mmol) was added to the above solution. The resulting solution was stirred at 0°C for 3 hours. Mix the mixture to remove volatile components, extract the aqueous layer with Et2O (3 x 40 mL), and adjust the pH to 3. First, it is converted to DCM (3 x 100 mL), followed by 30% IPA / DCM (2 x 80 mL) The combined organic layers were extracted using ) and dried with Na2SO4 and concentrated to obtain 69. . LC / MS:(M+1) + :322.9.

[0202] Step B: Preparation of Intermediate 70 In a solution of 69 (2.079 g, 6.45 mmol) in 40 ml of DMF at 0°C, Add 60% NaH (0.568 g, 14.19 mmol) to the xane and obtain the solution. Stir at 0°C for 50 minutes, then add allyl bromide (1.172 mL, 13.54 mmol) It was added dropwise. The resulting solution was stirred at 0°C for 1.5 hours, then 1N HCl (approximately 3.5%) was added. The solution was then quenched by adding 68 mL of ethyl alcohol (200 mL) and water ( The organic layer is divided between (100 mL) and washed with brine (2 × 100 mL) and Na2S The residue was dried with O4, concentrated, and eluted on a silica gel column using MeOH / DCM as the eluent. By using this method for purification, a score of 70 was obtained. LC / MS:(M+1) + :363.0.

[0203] Step C: Preparation of Intermediate 71 70 (2.239g, 6.18 mmol) and 68 (1.8) in DMF (30 ml) To a solution of 42g, 7.11 mmol, add HATU (2.82g, 7.41 mmol) Add DIEA (2.59 ml, 14.83 mmol), and allow the resulting solution to rise to ambient temperature for 1 minute. The mixture was stirred for a certain amount of time. The mixture was divided between alkyl (200 mL) and brine (100 mL). The organic layer was then washed with brine (3 x 100 mL), dried with Na2SO4, and concentrated. The residue is purified using RINKAN / hexane as the elution solvent on a silica gel column. And so, 71 was given. LC / MS:(M+1) + :604.2.

[0204] Step D: Preparation of Intermediate 72 71 (2.83) in CH2Cl2 (20 ml) and tBuOAc (30 ml) at 0°C In a solution of (g, 4.69 mmol), methanesulfonic acid (1.218 ml, 18.75 ml) Add (ol), and stir the resulting solution at 0°C for 16.5 hours, then at ambient temperature for 2.5 hours. The solution (72) was used directly in the next step. LC / MS: (M+1) + :5 04.2.

[0205] Step E: Preparation of Intermediate 73 (S)-2-((((9H-fluoren-9-yl)methoxy in DMF (10ml) )carbonyl)amino)-3-(3-(((tert-butoxycarbonyl)amino)me In a solution of phenylpropanoic acid (2.66 g, 5.16 mmol), add HATU (1 (0.961g, 5.16 mmol) and DIEA (5.32 ml, 30.5 mmol) In addition, the resulting solution was stirred at room temperature for 30 minutes, and then cooled in an ice bath with the 72 solutions prepared above. It was added to the solution. The resulting solution was stirred at ambient temperature for 1 hour. The volatile components were removed using a rotary evaporator. Evaporate on a microwave, and use acetonitrile (0.05% TFA) / water as the eluent. The solution was purified by reverse-phase MPLC using (0.05% TFA). The collected fraction was then purified. Concentration on a tally evaporator yielded a score of 73. LC / MS:(M+1) + :1002.1.

[0206] Step F: Preparation of Intermediate 74 In a solution of 73 (3.235 g, 3.23 mmol) in DCM (4 ml), TFA (7 Add 0.46 ml (97 mmol), stir the resulting solution at ambient temperature for 1 hour, then concentrate It shrunk. Dissolve the residue in DCM (10 mL) and add 4N HCl (3.23) to the dioxane. Treat with ml, 12.91 mmol), then concentrate, and the residue is treated with acetonitrile (100 ml). 74 was obtained by dissolving it in L / water (50 mL) and freeze-drying. LC / MS: (M+1) + :846.1.

[0207] Step G: Preparation of Intermediate 75 In a solution of 74 (2.85g, 3.23 mmol) in DMF (45ml), add HATU ( Add 1.474 g (3.88 mmol) and stir the resulting solution at ambient temperature for 30 minutes. Next, dilute with DCM (600 ml), then DIEA (1.692 ml, 9.69 ml) (ol) was added dropwise. The resulting solution was stirred at ambient temperature for 1 hour. The solution was concentrated, and the remaining The residue was eluted using acetonitrile (0.05% TFA) / water (0.05% TFA) as the elution solvent. The product was purified by reversed-phase MPLC on a C18 column. The fraction containing the product was then removed. The solution was concentrated, and the aqueous layer was separated between DCM (200 mL) and saturated NaHCO3 (200 mL). The aqueous layer was extracted with DCM (2 x 100 mL), and the combined organic layer was treated with Na2SO4. After drying and concentration, a value of 75 was obtained. LC / MS:(M+1) + :828.1.

[0208] Step H: Preparation of intermediate compound 76 75(1) in 0℃ THF (60ml), MeOH (30ml), and water (20ml). To a solution of 0.93g, 2.331 mmol, add 1N LiOH aqueous solution (9.9 ml, 9.9 Add 0 mmol) dropwise, stir the resulting solution at 0°C for 16 hours, then add HCl (1 Quenched by adding N (9.9 mL). Volatile components were removed by rotary evaporator. Evaporate the above solution at 0°C, then add acetone (60 ml) and sodium carbonate (0.371 g) to the above solution. (3.50 mmol) and Fmoc-Osu (0.802 g, 2.378 mmol) The solution was added. The resulting solution was stirred at 0°C for 6 hours, and the volatile components were removed from the rotary evaporator. Evaporate the solution to acidify the aqueous layer to pH 4, then add 30% IPA / DCM (3 x 100 mL) Extracted using ). The combined organic layers were dried with Na2SO4 and concentrated, and the residue was collected in silica gel. Purification using MeOH / DCM as the elution solvent on a ram yielded a score of 76. LC / MS:(M+1) + :814.2.

[0209] Alternative preparations of intermediate compound 75b and intermediate compound 76B from this compound: [ka] TIFF0007855670000111.tif54170

[0210] Step B is eliminated, and the final step G replaces the Fmoc protecting group with a Boc protecting group. Aside from including the above, the general procedure for preparing intermediate compound 75 is generally followed. Thus, intermediate compound 75a was provided. The procedure for 75a and 76B is as follows: , listed below.

[0211] Step C: Preparation of intermediate compound 71a A solution of 69 (5.00 g, 15.5 mmol) in DMF (40.0 mL) at -50°C. In addition, 68, HATU (5.90g, 15.5mmol) and DIEA (4.01g, 3 Add 1.0 mmol of water and stir the reaction mixture at -50°C for 3 hours. The final solution was then mixed with water (5 Quench with (mL), concentrate under reduced pressure, and chromatograph the residue on C18 in a reversed-phase column. (Elution by gradient of acetonitrile / water + 0.01% ammonium bicarbonate) By purifying it, 71a was obtained. LCMS(ESI) C 28 H 38 FN3O8[ Calculated value of M+H+: 564.3, measured value: 564.2.

[0212] Step D: Preparation of intermediate compound 72a Solution of 2N HCl in room temperature dioxane (100 mL) and THF (100 mL). Add 71a (8.40g, 14.9 mmol) and stir the reaction mixture for 5 hours. The final solution was concentrated under reduced pressure to obtain 72a. LC-MS(ESI) C 23 H3 Calculated value of 1ClFN3O6[M-HCl+H]+: 464.2, measured value: 464.3.

[0213] Step E: Preparation of intermediate compound 73a Dissolve 72a (800 mg, 1.60 mmol) in DMF (10.0 mL) at -50°C. In the liquid, (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amine (no)-3-(3-(((tert-butoxycarbonyl)aminomethyl)phenyl) Ropanic acid (827 mg, 1.60 mmol), HATU (608 mg, 1.60 mmol) Add ) and DIEA (620 mg, 4.80 mmol), and incubate the mixture at -50°C for 3 hours. The mixture was stirred. The resulting solution was diluted with water (50 mL), and the aqueous layer was treated with HCl (3 x 100 m³). Extracted with L). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (PE 1 Purification by elution with a %-60% ammonium gradient yielded 73a. LCMS(ESI) C 53 H 60 FN5O 11 Calculated value of [M+H]+: 962.4 Measured value: 962.6.

[0214] Step F: Preparation of intermediate compound 74a A solution of 73a (3.00 g, 3.12 mmol) in DCM (15.0 mL) at room temperature. Then, 15.0 mL of TFA was added, and the reaction mixture was stirred at room temperature for 1 hour. The resulting solution was then prepared. Concentration under reduced pressure and evaporation with toluene and DCM yielded 74a. LCM S(ESI) C 46 H 45 F4N5O 11 Calculated value of [M-TFA+H]+: 806.3 The measured value was 806.7.

[0215] Step G: Preparation of intermediate compound 75a In a solution of 74a (4.00 g, 4.35 mmol) in DMF (150 mL) at room temperature, Add HATU (1.65 g, 4.35 mmol) and stir the reaction solution for 0.5 hours. Dilute the solution with DCM (450 mL) and DIEA (1.69 g, 13.1 mmol). The mixture was then stirred at room temperature for 3 hours. The resulting solution was quenched with water (5 mL) and concentrated under reduced pressure. The residue was then subjected to reverse-phase column chromatography on C18 (acetonitrile / water + 0.05%). Purification by elution with a TFA gradient yields an Fmoc-protected intermediate. Provided. LCMS(ESI) C 44 H 42 Calculated value of FN5O8[M+H]+: 788 3. Measured value: 788.9.

[0216] The Fmoc-protected intermediate (200 mg) immediately above the DCM (5.00 mL) at room temperature. Add piperidine (1.25 mL) to a 0.250 mmol solution and allow the reaction solution to stand for 1 hour. The mixture was stirred. The final solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. Purification by elution in a gradient of 0%-5% MeOH in DCM, the amine The interbody was given. LCMS(ESI) C 29 H 32 Calculated value of FN5O6[M+H]+: 5 66.2, measured value 566.3.

[0217] The amine intermediate immediately above in THF (30.0 mL) and water (30.0 mL) at room temperature ( In a solution of 2.86 g, 5.06 mmol, add Boc2O(2.21 g, 10.1 mmol) Add ) and sodium bicarbonate (1.70 g, 20.2 mmol), and react the mixture for 3 hours. The mixture was stirred. The final solution was diluted with water (50 mL) and extracted with toluene (3 × 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried with anhydrous sodium 2SO4. The filtrate was filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. Purification by elution with a 0%-5% MeOH gradient in DCM yields 75a. Provided. LCMS(ESI) C 34 H 40 Calculated value of FN5O8[M+H]+: 666 .3, measured value 666.5; 1 1H NMR (300MHz, CD3OD) δ7.35-7 .08(m,6H),6.95-6.79(m,2H),5.01-4.91(m,1H ),4.72-4.56(m,2H),4.45-4.38(m,1H),4.45-4 .38(m,5H),3.69(s,3H),3.32-2.92(m,5H),2.1 4-1.82 (m, 2H), 1.47 (s, 9H).

[0218] Step H: Preparation of intermediate compound 75b In a solution of 75a (0.665 g, 0.99 mmol) in DMF (0.5 mL), Cs 2CO3 (1.11g, 3.40 mmol) and 3-bromopropa-1-ene (0.4 3g (3.55 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours, and 5 ml Pour into a 50% saturated brine / 10% citric acid solution, then into ethyl acetate (2 × 20 ml). Extracted with L). The organic layer was washed with brine (3 × 20 mL) and dried with anhydrous MgSO4. The solution was filtered. The filtrate was concentrated under reduced pressure. The residue was then filtered into a 1%-5% MeOH gradient in DCM. The intermediate compound 75b was purified by silica gel column chromatography using ENT elution. The fractions containing [the compound] were combined and concentrated to obtain the compound described in the title. LC-MS( ESI) C 37 H 44 FN5O8[M+H] + Calculated value: 706.3, measured value: 706. 3.

[0219] Step I: Preparation of intermediate compound 76B The hydrolysis of 75b with LiOH is carried out in the same manner as described in the preparation of intermediate 93. By following the conditions, we provided 76B.

[0220] Preparation of intermediate 77B [ka]

[0221] Step A: Preparation of intermediate 77A (S)-1-(((9H-fluorene-9-yl)methyl in 140ml of DMF at 0℃ Toxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid (6.16g, 17.5 4 mmol) and tert-butyl 4-(2-aminoethyl)benzylcarbamate In a solution of hydrochloride (5.03 g, 17.54 mmol), add HATU (8.00 g, 21.0 Add 5 mmol) and DIPEA (9.16 ml, 52.6 mmol), then react. The mixture was left as is and heated to room temperature, then stirred for 2 hours. The final mixture was diluted with water and EtO2. Extracted with Ac, washed with brine, dried with MgSO4, and filtered. The filtrate was concentrated, and the residue remained. Column chromatography of the residue on silica gel (0-60% siRNA in hexane) Purification by radiant elution yielded 77A. MS(ESI): m / z (M+H)+ 584.5.

[0222] Step B: Preparation of intermediate 77B In a solution of 77A (8.92g, 15.28 mmol) in DCM (40 ml), dioxin was added. Add HCl 4N (15.28 ml, 61.1 mmol) from the solution, and heat the resulting solution in a room. The mixture was stirred overnight at warm temperature. Concentrating the mixture yielded 77B. MS(ESI): m / z (M+H)+ 484.3.

[0223] Preparation of intermediate 86 [ka] TIFF0007855670000114.tif59166

[0224] Step A: Preparation of Intermediate 77 (S)-(9H-fluoren-9-yl)methyl 2 in 140 ml of DCM at 0°C -((4-(aminomethyl)phenethyl)carbamoyl)-2-methylpyrrolidine-1- In a solution of carboxylate hydrochloride (77B) (5.87g, 11.29mmol), DI EA (5.91 ml, 33.9 mmol) and CBZ-Cl (1.726 ml, 11. Add 85 mmol) dropwise and stir the resulting solution at 0°C for 4 hours. Dilute the reaction solution with water ( The solution is divided between 200 mL of the solution and 200 mL of DCM, and the aqueous phase is extracted with 100 mL of DCM. The combined organic layers were dried with Na2SO4, and the residue was laid on a silica gel column using EtOA. Purification using c / hexane as the eluent yielded a score of 77. LC / MS: (M +1) + :618.3.

[0225] Step B: Preparation of Intermediate 78 77 (5.5) in THF (100 ml), water (50 ml), and MeOH (30 ml) To a solution of 6g, 9.00 mmol, add 1N NaOH aqueous solution (45.0 ml, 45.0 ml) Add (mol) and stir the resulting solution at room temperature for 2 hours. Evaporate the volatile components and remove the water. Dioxane (200 ml) and Boc2O(2. 508 mL (10.80 mmol) was added. The resulting mixture was stirred overnight from 0°C to room temperature. Mixed. The volatile components were evaporated on a rotary evaporator, and the aqueous layer was converted to DCM (3×1 Extraction was performed using 50 mL. The combined organic layers were dried with Na2SO4, concentrated, and the residue was silicified. Purification using toluene / hexane as the elution solvent on a Kagel column yielded 78. I gave it. LC / MS:(M+1) + :496.2.

[0226] Step C: Preparation of Intermediate 79 A 10% solution of 78 (4.04g, 8.15 mmol) in MeOH (100ml) Add Pd / C (0.867g, 0.815 mmol) and the resulting mixture in an H2 balloon The mixture was subjected to hydrogenation at room temperature for 1.5 hours. The mixture was filtered through Celite and the filtrate was obtained. By concentrating it, a score of 79 was obtained. LC / MS:(M+1) + :362.2.

[0227] Step D: Preparation of Intermediate 80 In a solution of 79 (2.58g, 7.14 mmol) in DMF (15ml), add Penta-4 -En-1-yl 4-methylbenzenesulfonate (0.858g, 3.57mmol) Add ) and K2CO3 (1.973g, 14.27 mmol) and the resulting mixture 8 The mixture was heated at 0°C for 6 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was subjected to reverse-phase MPLC. Acetonitrile (0.05% TFA) / water (0.05% TFA) is used as the elution solvent. By purifying the product, the product is given as a TFA salt, which is then further processed in DCM (100 mL). The mixture was partitioned between a 1N NaOH aqueous solution (50 mL) and a DCM (2 × 5 Extraction is performed using 0 mL, the combined organic layer is dried with Na2SO4, and then concentrated to obtain 80. I gave it. LC / MS:(M+1) + :430.3.

[0228] Step E: Preparation of Intermediate 81 In a solution of 80 (0.95g, 2.211 mmol) in DMF (15ml), 4-methionine was added. Xy-4-oxobutanoic acid (0.321g, 2.433mmol), HATU (1.00 Add 9g (2.65 mmol) and DIEA (0.927 ml, 5.31 mmol). The resulting solution was stirred at room temperature for 1 hour. The solution was then mixed with dimethyl (200 mL) and brine ( The organic layer is divided between (100 mL) and washed with brine (2 × 100 mL) and Na2S The residue was dried in O4, concentrated, and eluted on a silica gel column using toluene / hexane as the eluent. By using it as a filtration method and purifying it, a result of 81 was obtained. LC / MS:(M+1) + :544.2.

[0229] Step F: Preparation of Intermediate 82 In a solution of 81 (1.165 g, 2.143 mmol) in DCM (12 ml), add HCl (4N in dioxane) (5.36 ml, 21.43 mmol) was added. The resulting solution The mixture was stirred at room temperature for 3 hours and then concentrated to obtain a solution of 82. LC / MS: (M+1) + :444.2.

[0230] Step G: Preparation of Intermediate 83 In a solution of 82 (1.003g, 2.089 mmol) in DMF (20ml), Fmo cL-Tyr(Me)-OH (0.959g, 2.298mmol), HATU(0. 914g, 2.403 mmol) and DIEA (1.095 ml, 6.27 mmol) Add the following and stir the resulting solution at room temperature for 50 minutes. Add ethyl acetate (200 mL) to the solution and ointment. Distribute between the line (100 mL) and wash the organic layer with brine (2 × 100 mL). The combined organic layers were dried with Na2SO4, concentrated, and the residue was traced on a silica gel column using EtO2O2. Purification using Ac / hexane as the elution solvent yielded a score of 83. LC / MS: ( M+1) + :843.4.

[0231] Step H: Preparation of Intermediate 84 In a solution of 83 (1.63 g, 1.934 mmol) in acetonitrile (10 ml), Add piperidine (0.574 ml, 5.80 mmol) and allow the resulting solution to stand at room temperature for 1 hour. The mixture was stirred and then concentrated. The residue was resuspended in acetonitrile (20 mL) and concentrated again. This cycle is repeated once, and the residue is further dried under high vacuum to obtain 84. . LC / MS:(M+1) + :621.3.

[0232] Step I: Preparation of Intermediate 85 In a solution of 84 (1.2g, 1.933 mmol) in DMF (15ml), Fmoc- L-Thr(tBu)-OH(0.922g, 2.320mmol), HATU(0.9 19g, 2.416 mmol) and DIEA (0.844 ml, 4.83 mmol) In addition, the resulting solution was stirred at room temperature for 1 hour. The solution was then mixed with ethyl acetate (200 mL) and propyl alcohol. The mixture is divided between (100 mL) and the organic layer, and the organic layer is washed with brine (2 × 100 mL) and Na The residue was dried with 2SO4, concentrated, and eluted with RINKAN / hexane on a silica gel column. Purification using the solvent yielded a score of 85. LC / MS: (M+1) + :1000 2.

[0233] Step J: Preparation of Intermediate 86 85 (1.94 g, 1) prepared in the previous step in acetonitrile (20 ml) Add piperidine (0.960 ml, 9.70 mmol) to a 0.940 mmol solution. The resulting solution was stirred at room temperature for 30 minutes and then concentrated. The residue was then treated with DCM / acetonitrile. Redissolve in 1:1 solution (20 mL), then concentrate again, and repeat this cycle once. The residue was dried under high vacuum to obtain a score of 86. LC / MS:(M+1) + :77 8.3.

[0234] Preparation of intermediate 88 [ka]

[0235] Step A - Synthesis of Intermediate 87 2-Chloro-2-chlorotrityl resin 1-1.5 mmol / g (7.0 g, 1-1.5 Anhydrous DCM (45 ml) was added to mmol / g. The resin was shaken for 20 minutes, followed by DC Half the amount of DIPEA 0.17N in M ​​(3.67 ml, 21.00 mmol), Fmoc -D-Dap(Boc)-OH (3.28g, 7.70 mmol), then the remaining DC DIPEA 0.17N was added to M (3.67 ml, 21.00 mmol). The mixture was shaken overnight at room temperature, rinsed with DCM, and dried. The resin was then placed in DCM (80 mL). Quench with 5% DIPEA and 10% MeOH, shake for 2 hours, then filter, Rinse with DCM(3×), DMF(3×), and DCM(3×), then dry under vacuum. By doing so, resin 87 was provided, which was then used as is in the next step.

[0236] Step B - Synthesis of Intermediate 88 Resin 87 (4.5g, 2.475 mmol) in 5% piperidine in DMF (30ml) The mixture was manually deprotected for 30 minutes, filtered, and then mixed with 5% piperidine in DMF (30 ml). The trees were reprocessed for another 30 minutes, filtered, then rinsed with DMF and DCM, and dried. Next to lipids, Fmoc-Ala-OH (1.541g, 4.95m) in DMF (30ml) (mol), HATU (1.694g, 4.46 mmol) and DIPEA (1.729 (ml, 9.90 mmol) is manually coupled for 2 hours, then filtered, and DMF Then rinse with DCM and dry. The resin was then mixed with 10 ml of DCM (60 ml). By treating with %AcOH and TFE for 90 minutes, filtering, and concentrating the filtrate, 88 is obtained. . LC / MS:[2M+H] + =995.01.

[0237] Alternative synthesis of Example 1A-Ex-01 and preparation of Ex-25 from this compound: The compound Ex-01 presented above can be prepared alternatively according to the following scheme, Ex-25 can be prepared from Ex-01: [ka] TIFF0007855670000117.tif231166TIFF0007855670000118.tif199163TIFF0007855670000119.tif202169

[0238] Step A - Synthesis of intermediate Int-cd1 Int-3c (synthesized from intermediate 107 below) in DMF (45 ml) at 0°C (7.0 In a solution of 9g, 10.33 mmol, Int-2d (3.63g, 9.84 mmol, Preparation involves adding the following (see below) and HATU (3.74g, 9.84mmol), followed by DMF Add the DIPEA (6.87 ml, 39.4 mmol) and leave the mixture as is in the chamber. The mixture was heated to a temperature of 12°C and stirred for 1 hour. The mixture was quenched with brine at 0°C and then ammonium. Extraction was performed. The combined organic fractions were washed with brine, dried with MgSO4, and filtered. The residue was concentrated in a vacuum. The residue was then subjected to column chromatography on silica gel (petroleum ether). Purification by elution with a gradient of 1% to 80% ethyl acetate allows Int- Given cd1, LC / MS:[M+1]+=1000.5.

[0239] Step B - Synthesis of intermediate Int-cd2 Int-cd1 (3.48g, 3.48 mmol) in acetonitrile (50ml) Add piperidine (1.72 ml, 17.40 mmol) to the solution, and allow the resulting solution to cool at room temperature. The mixture was stirred for 3 hours. The mixture was concentrated, and the residue was mixed with DCM / acetonitrile (1:1, 20 mL). By redissolving it in the solution, concentrating it again, and drying the residue under vacuum, Int-cd2 is roughly produced. The product was given as is. LC / MS:(M+1) + =778.5.

[0240] Step C - Synthesis of intermediate Int-cd3 76 (preparation is shown in Example 1 above) (2.45g) in 70ml of DMF at 0℃ In a solution of (3.01 mmol) and Int-cd2 (2.69 g, 3.46 mmol) Then, add HATU (1.37g, 3.61mmol), followed by DIEA (1.05ml, 6.02 mmol) was added. The resulting solution was stirred at room temperature for 50 minutes, and then acetone was added. The organic layer was divided between (500 mL) and brine (200 mL). Wash with 00 mL, dry with Na2SO4, concentrate, and the residue is laid on silica gel. Purification is performed by chromatography (elution with a gradient of 1%-5% MeOH in DCM). This resulted in Int-cd3 being assigned. LC / MS:(M+1) + =1574.7.

[0241] Step D - Synthesis of intermediate Int-cd4 Int-cd3 (1.91g, 1) in DCM (1500ml) and acetic acid (30mL) Bubble a 0.21 mmol) room temperature solution with N2 for 30 minutes, followed by Zhan catalyst-1B (0.445 g, 0.607 mmol) was added. The resulting mixture was left at room temperature for 30 minutes. The mixture was bubbled with N2 for 1 minute, then heated at 55°C for 5 hours. After cooling to room temperature, it was mixed. The material is filtered on Celite, the filtrate is concentrated, and the residue is subjected to column chromatography on silica gel. By purifying by (elution with a gradient of 1%-5% MeOH in DCM), In t-cd4 (as a mixture of cisolefin and transolefin) was given. LC / MS:(M+1) + =1546.8.

[0242] Step E - Synthesis of intermediate Int-cd5 Int-cd4 (cisole) in DCM (20 ml) and acetonitrile (50 ml) A solution of a mixture of fins and transolefins (5.49 g, 3.55 mmol) Then, piperidine (1.76 ml, 17.8 mmol) was added. The resulting solution was left at room temperature for 2 hours. The mixture was stirred, then concentrated, the residue was suspended in acetonitrile (20 ml), and concentrated again. The residue is then dried under vacuum to obtain Int-cd5 (cisolefin and tranoxide). A crude mixture of olefins was given. LC / MS:(M+1) + = 1323.8.

[0243] Step F - Synthesis of intermediate Int-cd6 Int-cd5 (cisolefin and transolefin) in 0°C DMF (70 ml) A mixture of (4.70g, 3.55mmol) and Int-1d (2.21g, 4 Add HATU (1.76g, 4.62 mmol) to the solution (preparation is as follows) Add DIEA (1.55 ml, 8.88 mmol). The resulting solution was warmed to room temperature. Then, stir for 1 hour, and then between alkyl (300 mL) and brine (200 mL) The mixture was divided. The aqueous layer was extracted with ethyl acetate (200 mL), and the ethyl acetate layer was combined with the brine. Wash with (3 x 200 mL), dry with Na2SO4, concentrate, and place the residue on silica gel. By column chromatography (elution with a gradient of 1%-5% MeOH in DCM) By purifying it, Int-cd6 (a mixture of cisolefin and transolefin) (As an object) was given. LC / MS:(M+1) + =1802.8

[0244] Step G - Synthesis of intermediate Int-cd7 Int in THF (100 ml), MeOH (30 ml), and water (30 ml) at 0°C -cd6 (as a mixture of cisolefin and transolefin) (5.41g, 3 To a solution of 0.00 mmol, add 1N LiOH aqueous solution (24.0 ml, 24.0 mmol) The solution was added dropwise, and the resulting solution was stirred at 0°C for 3 hours. The mixture was then heated at 0°C in 1N HCl solution. The addition neutralizes the solution, evaporates the volatile components, and adjusts the pH of the aqueous layer to 5 with 1N HCl. The mixture was neutralized. The mixture was then frozen and freeze-dried, and the residue was subjected to column chromatography on C18. Fee (Acetonitrile (0.05% TFA) / Water (0.05% TFA) gradient) Purification by elution (of cisolefin and transolefin) allows for the extraction of Int-cd7 (cisolefin and transolefin). Fins were given as a mixture of TFA salts. Acetonitrile (750 mL) and Int-cd7 TFA salt obtained in this manner in water (450 mL) (cisolefin (As a mixture of transolefins) 0°C 0.1N HCl aqueous solution (150 ml) Add 15.00 mmol dropwise, then stir the resulting solution at 0°C for 5 minutes. By freezing and freeze-drying, Int-cd7 was obtained as an HCl salt (cisolefin). (and as a mixture of transolefins). LC / MS: (M+1) + =1566.6 .

[0245] Step H - Synthesis of intermediate Int-cd8 In DMF (50 ml) and DCM (1300 ml), the Int obtained from the previous step - In a solution of cd7 HCl salt (1.01 g, 0.630 mmol), DIEA (0.33 (0 ml, 1.890 mmol) and HATU (0.287 g, 0.756 mmol) The solution was added. The resulting solution was stirred at room temperature for 2 hours to evaporate the volatile components, and the residue was acetaldehyde. The aqueous layer was divided between (400 mL) and brine (200 mL). Extract with (0 mL), wash the combined organic layer with brine (3 × 100 mL), and then Na2SO Dry in step 4, concentrate, and column chromatography of the residue on silica gel (1% in DCM). Purification by elution with a -10% MeOH gradient allows for the extraction of Int-cd8 ( (As a mixture of olefins and transolefins) was given. LC / MS: (M+ 1) +=1548.8.

[0246] Step I - Synthesis of intermediate Int-cd9 In MeOH (100 ml), the Int-cd8 (1.2) obtained in the previous step is used. In a solution of 2g, 0.788 mmol, add 10% Pd / C (0.645g, 0.607mm Add ol) and hydrogenate the resulting mixture through an H2 balloon at ambient temperature for 7 hours. The mixture was then filtered on Celite after 7 hours, the filtrate was concentrated, and the residue was placed on silica gel. By column chromatography (elution with a gradient of 1%-10% MeOH in DCM) By purifying it in this way, Int-cd9 was obtained. LC / MS:(M+1) + =1550. 9.

[0247] Synthesis of compound Ex-01 as a step J-HCl salt In a solution of Int-cd9 (1.14g, 0.735 mmol) in DCM (6 ml), Add TFA (12 ml, 156 mmol), and stir the resulting solution at ambient temperature for 30 minutes. The mixture was then concentrated, and the residue was dissolved in DCM (20 mL) and toluene (20 mL). Dissolved. The resulting mixture was concentrated, and the residue was redissolved in DCM (20 mL) and HCl ( The mixture was treated with 4N dioxane (0.919 ml, 3.68 mmol). By concentrating the product, the product was given as a solid. This solid product was converted to acetonitrile (2 Redissolve in (00 mL) and water (100 mL), and add 1N HCl aqueous solution to the above solution at 0°C. The solution (3.68 ml, 3.68 mmol) was added dropwise. The resulting solution was incubated at 0°C for 2 minutes. The mixture was stirred, then frozen and freeze-dried to obtain Ex-01 as an HCl salt. LC / MS:(M+1) + =1394.7.

[0248] Synthesis of Example Ex-25 as Step K-TFA Salt Ex-01 HCl salt (870 mg) in DMF (1.2 ml) and water (0.6 ml) , 0.608 mmol) and Int-4b (170 mg, 0.669 mmol, preparation is Add HATU (254 mg, 0.669 mmol) and DIEA (425 mg) to the solution below. (μl, 2.433 mmol) was added. The resulting solution was stirred at room temperature for 1 hour, then 1. Quenched by adding 2 mL of water. The mixture was filtered, and the filtrate was placed on a C18 column microscope. Mathography (Acetonitrile (0.05% TFA) / Water (0.05% TFA) By purification (elution with dient), Ex-25 was given as a TFA salt. LC / MS:M + =1550.6.

[0249] Preparation of Example Ex-25 as Step L-Cl salt Two columns were filled with 73.6g of AG MP-1 ion exchange resin chloride form (cat# 141-1841 BIO-RAD) so that the total amount of resin in each column is 36.8g The columns were filled. Each column was washed with water (2 x 80 ml), followed by 20% acetonitrile in water. Washed with 2 x 100 ml of water. Ex-25 TFA salt (737 mg, 0.443 mmol) prepared in the step The solution was evenly loaded into two resin columns, and then each column was filled with 20% acetonitrile water. Elution was performed using Trill (130 ml). The eluate was combined, frozen, and freeze-dried to obtain Ex -25 was given as a chloride salt. LC / MS: M + =1550.6.

[0250] The following are useful in the synthesis of Ex-01 and Ex-25 described above. Here are some descriptions of intermediates.

[0251] Preparation of intermediate Int-1d The intermediate compound Int-1d was prepared from the starting materials according to the following scheme. [ka]

[0252] Step A: Synthesis of Int-1da D-Dap(Boc)-OMe HCl salt (4.10g) in 40ml of DMF at 0℃ , 16.10mmol), Fmoc-Ala-OH (5.01g, 16.10mmol) And in a solution of HATU (6.43 g, 16.90 mmol), add DIPEA (7.03 ml) Add 1 (40.2 mmol), stir the mixture at 0°C for 2 hours, then leave it in the refrigerator overnight. The mixture was set aside. The mixture was quenched with water at room temperature and extracted with ethyl acetate. Combined organic florets The cushion was washed with half brine, dried with Na2SO4, and filtered. The residue was then concentrated in a vacuum. Column chromatography (hexane / Int-1da was obtained by purification (elution with an ethyl phosphate gradient). LC / MS:[M+H]+=512.3.

[0253] Step B-Int-1d synthesis Int-1da(8) in room temperature water (40 ml) and 2-propanol (120 ml) (0.03g, 15.70 mmol) and 0.8N calcium chloride (19.62ml, 15 In a solution of 0.70 mmol, solid sodium hydroxide (0.691 g, 17.27 mmol) l) was added. The mixture was stirred overnight at room temperature. The mixture was concentrated and the pH was adjusted to approximately 2 with 0.5N. Acidify (approximately 40 mL), extract twice with ethyl acetate, wash with brine, and dry with Na2SO4. The residue was dried and concentrated. The residue was subjected to column chromatography on C18 (acetonitrile / water+ Purification by elution with a 0.1% TFA gradient yielded Int-1d. LC / MS:[M+H]+=498.25.

[0254] The preparation of intermediate Int-1d is for use in the preparation of Ex-01 and Ex-25. As described above, this part of the molecule converts a smaller peptide ring to a larger peptide ring. It can be described as a "linker" that cyclizes. For example, although not limited to Da This involves changing the spacers used in synthesis, including the use of p and D-Ala. Therefore, other similar "linkers" can be used in place of Int-1d.

[0255] Preparation of intermediate Int-2d In the preparation of the compound of the present invention, the intermediate Int-2d, which is useful as a "linker," is described below. Prepared according to the scheme: [ka]

[0256] Step A: Synthesis of Int-2da 4-bromobenzaldehyde in degassed toluene (250 ml) and water (85 ml) 15.00g, 81 mmol), potassium tert-butyl N-[2-(trifluoro [Boranuidylate]ethyl carbamate (20.97g, 84mmol), cesium carbonate ( (52.8g, 162 mmol) and 1,1'-bis(diphenylphosphin)ferroce n-palladium(II) dichloride dichloromethane complex (Pd(II)(dppf)C The solution of (1.99 g, 2.43 mmol) was heated to 76°C and stirred overnight. The compound was quenched with a semi-saturated aqueous solution of ammonium chloride at room temperature and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried with Na2SO4, filtered, and then vacuum filtered. The residue was concentrated using column chromatography (DCM / Afg.). Purification by elution with a radiant solution yielded Int-2da. LC / MS: ( M-56+1) + =193.0.

[0257] Step B-Int-2db synthesis Int-2d in room temperature DCM (120 ml) and AcOH (3 ml) in a water bath a (12.9g, 51.7mmol) and penta-4-en-1-amine (6.61g) Add sodium triacetoxyhydroborate (32.9g, 15) to a solution of 78 mmol. Gradually add 5 mmol) and stir the mixture for 30 minutes. Add the reaction mixture to 3 ml of water at 0°C. Quench more slowly, pour into 1N NaOH (500ml), stir for 15 minutes, then The residue was extracted using DCM, dried with Na2SO4, and concentrated. The residue was then placed on silica gel. Purification by chromatography (elution with a DCM / MeOH gradient) An int-2dB was applied. LC / MS:(M+1) + =319.2.

[0258] Step C-Int-2dc synthesis Int-2db (8.48g, 20.77 mmol) and 4 in DMF (40ml) In a solution of -methoxy-4-oxobutanoic acid (3.02 g, 22.85 mmol), HAT U (9.48g, 24.92mmol) and DIPEA (8.71ml, 49.8mm) (ol) was added. The resulting solution was stirred at room temperature for 1 hour, and then saturated NaHCO3 aqueous solution ( Quenched with 10 mL of toluene. The mixture was dissolved in toluene (500 mL) and saturated NaHCO3 aqueous solution. The organic layer was separated into the liquid (200 mL) and washed with brine (3 × 200 mL), and then Na Dry with 2SO4, concentrate, and place the residue on a silica gel column (hexane / siRNA). Purification by dienthe elution yielded Int-2dc. LC / MS: (M+1) + =433.4.

[0259] Step D-Int-2d synthesis In a solution of Int-2dc (2.9g, 6.70 mmol) in DCM (15 mL), 10 mL of 4 M HCl was added to warm dioxane. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain methyl 4-((4-(2-aminoethyl)be (I)(penta-4-en-1-yl)amino)-4-oxobutanoate hydrochloride (I (nt-2d) was given. LC / MS [MHCl+H] + =333.3.

[0260] Preparation of Int-3c from 107 used in the synthesis of Ex-01 and Ex-25 described above. The intermediate Int-3c was prepared according to the following scheme: [ka]

[0261] Step A: Synthesis of Int-3ca 107 in THF (100 ml) at room temperature (its preparation is shown in the synthesis of 109, later) Although used for 116, this intermediate compound is Ex-53, E in Example 3 below. (Used in the synthesis of x-54 and Ex-55) (10.34g, 21.65mm) To the solution of (100 ml), add 2N lithium hydroxide monohydrate (43.3 ml, 87 mmol). The mixture is heated to 45°C and stirred overnight to yield Int-3ca as a crude purified solution. Okay. LC / MS:(M+1) + =464.3. Cool the reaction mixture to 0°C and bring to 1M The mixture was treated with HCl (40 mL). The mixture was used directly for the next step.

[0262] Step B-Int-3c synthesis To the crude purified Int-3ca prepared in the previous step, add NaHCO3(1.725 (g, 20.54 mmol) and Fmoc-OSu (3.81 g, 11.30 mmol) The mixture was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours and treated with 1M HCl (20.5 mL). The mixture was then extracted with ethyl acetate (2 × 200 mL). The combined organic layers were then treated with brine (2 × 1 Washed with 00 mL, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Residue The 2% to 5% MeOH in DCM was analyzed by silica gel column chromatography. Int-3c was obtained by elution and purification with dient. LC / MS: (M+1) + =686.4.

[0263] Preparation of intermediate Int-4b The intermediate Int-4b was prepared according to the following scheme: [ka]

[0264] Step A-tert-butyl-3-(2-hydroxyethoxy)proponate (pro Synthesis of Int-4ba from ponate tert-butyl 3-(2-hydroxyethoxy)propanoate in DCM (2 mL) To a solution of 500.0 mg, 2.63 mmol of CBr4, add 1395 mg, 4.2 1 mmol) and PPh3 (965 mg, 3.68 mmol) were added at 0°C. Mixture The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was collected by a silica gel column. Chromatography revealed a gradient of 1%-15% ethyl acetate in petroleum ether. The product was eluted and purified. The fractions containing the desired product were combined and concentrated to obtain t ert-butyl 6-bromohexanoate was given. The acetonitrile prepared in this manner tert-butyl 6-bromohexanoate (5g, 19.91mg) in 10ml Treat the solution (mol) with trimethylamine (13.56 ml, 59.7 mmol), The resulting solution was heated overnight at 50°C. Concentrating the solution yielded Int-4ba. LC / MS:M + =230.3.

[0265] Step B-Int-4b synthesis In a solution of Int-4ba (6.8g, 21.92 mmol) in DCM (6 ml), Add 4N HCl (27.4 ml, 110 mmol) to the oxane, and the resulting solution is heated in a room. The mixture was stirred at warm temperature for 3 hours. The mixture was then concentrated to give Int-4b. LC / M S:M + =174.3.

[0266] The preparation of intermediate Int-2d is for use in the preparation of Ex-01 and Ex-25. As described above, this part of the molecule is R 1 , R 2 and R 8 Small with substituents It can be described as a "linker" that cyclizes peptide rings. Other similar "linkers" are I It can be used in place of nt-2d. The following describes how to prepare the examples of the present invention described herein. This is a description of other "linkers" that can be used for this purpose.

[0267] Preparation of the intermediate Int-2e In the preparation of the compound of the present invention, the intermediate Int-2e, which is useful as a "linker", is described below. Prepared according to the scheme: [ka]

[0268] Step A - Synthesis of intermediate Int-2ea DCE (20 mL) contains tert-butyl(2-(3-oxoisoindorin-5-I In a solution of ethyl carbamate (1.60 g, 5.79 mmol), add NsCl(1. (93g, 8.69 mmol), triethylamine (1.76g, 17.4 mmol) Then DMAP (0.141 g, 1.16 mmol) was added. The reaction mixture was incubated at 40°C for 14 hours. The mixture was stirred. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was collected on a silica gel column. Calculation by chromatography (elution with a 1%-40% gradient of dimethyl in PE) This process yielded Int-2ea. LC / MS: (M+Na) + :=484.4.

[0269] Step B - Synthesis of the interstitial Int-2eb Int-2ea (11.3g, 24) in THF (100mL) and water (100mL) LiOH (1.76 g, 73.5 mmol) was added to a 0.5 mmol solution. The reaction mixture was then mixed. The mixture was stirred at 25°C for 5 hours, and then the resulting solution was adjusted to pH 4-5 with HCl (1M). The solution was extracted with ethyl acetate, and the combined organic layers were washed with brine and anhydrous sodium 2SO4. The mixture was dried in step 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel. Purification should be performed by fluoroscopy (elution with a gradient of 1%-6% MeOH in DCM). Then, Int-2eb was administered. LC / MS: (M+Na) + :=502.2.

[0270] Step C - Synthesis of intermediate Int-2ec In a solution of Int-2eb (1.70 g, 3.55 mmol) in THF (8 mL), Ran (0.147g, 10.6 mmol) was added at 0°C. The reaction mixture was left at 25°C for 14 hours. The mixture was stirred, and the resulting solution was concentrated under reduced pressure. The residue was then subjected to column chromatography on silica gel. Purification is performed by tography (elution with a gradient of 1%-50% ethyl acetate in PE). This resulted in Int-2ec being obtained. LC / MS:(M+NH4) + =483.2.

[0271] Step D - Synthesis of intermediate Int-2ed In a solution of Int-2ec (4.50 g, 9.67 mmol) in DMF (150 mL) , K2CO3 (2.01 g, 14.5 mmol) and 3-bromopropa-1-ene (1 (0.41g, 11.6 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours, then with water. Diluted and extracted with ethyl acetate. The combined organic layers were washed with brine and then anhydrous sodium 2SO4. The filtrate was dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel. Purify by roughing (eluting with a gradient of 1%-50% dimethyl acetate in PE). Then, I gave Int-2ed. LC / MS:(M+H) + :=506.2.

[0272] Step E - Synthesis of intermediate Int-2e In a 35 mL DMF solution containing Int-2ed (4.50 g, 8.90 mmol), DBU (1.35g, 8.90 mmol) and 2-mercaptoethanol (2.08g) (26.7 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours, and then on C18 Column chromatography (Column: 330g; Mobile phase A: Water / 0.05% TFA, mobile phase A) Phase B: ACN; Flow rate: 85 mL / min; Gradient: From 10% B to 20% B in 15 minutes From 20%B to 45%B in 15 minutes (detector: UV210nm; Rt=20 min) Purification yielded Int-2e. LC / MS: (M+H) + :=321.2. 1 H NMR(300MHz,CDCl3) δ7.21-7.13(m,2H),7 .10-7.01(m,1H),5.96-5.79(m,1H),5.30-5.09 (m,2H),4.58(s,2H),3.84(s,2H),3.43-3.19(m ,4H),2.76(t,J=7.1Hz,2H),1.41(s,9H).

[0273] Preparation of intermediate Int-2f-1 In the preparation of the compound of the present invention, an intermediate Int-2f-1, which is useful as a "linker", It was prepared according to the following scheme: [ka] TIFF0007855670000126.tif45158

[0274] Step A - Synthesis of intermediate Int-2fa 4-bromobenzaldehyde (20.0g, 108 mmol) in DCM (225mL) ), (S)-2-methylpropane-2-sulfinamide (12.5g, 103 mmol) ), in a solution of MgSO4 (130g, 1081 mmol), pyridine 4-methylbenzene Sulfonate (1.35 g, 5.40 mmol) was added under nitrogen protection. This mixture was divided into two parts. The mixture was stirred at 5°C for 72 hours, then the resulting solution was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography of the residue on silica gel (1%-15% of HCl in PE) Int-2fa was obtained by purification by elution with a radiant. LC / MS: ( M+H) + :=287.9, 289.9.

[0275] Step B - Synthesis of intermediate Int-2fb (racemic mixture) and enantiomer Int- Separation into 2fb-1 and Int-2fb-2 Dissolution of Int-2fa (20.0 g, 65.9 mmol) in anhydrous DCM (200 mL) Add 15.7g, 99mmol of buta-3-en-1-ylmagnesium bromide to the liquid. The mixture was slowly added at -48°C under nitrogen protection. The mixture was stirred at -48°C for 2 hours, then saturated. The mixture was quenched with a 400 mL aqueous solution of NH4Cl and extracted with DCM. The combined organic layers were then prepared. The solution was washed with brine, dried with anhydrous sodium 2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the solution. The residue (containing an Int-2fb racemic mixture) was subjected to column chromatography on silica gel. Purification is performed by tography (elution with a gradient of 1%-35% phenylethylamine in PE). This yielded Int-2fb-1 and Int-2fb-2. LC / MS:(M+H ) + :=344.0,346.0.

[0276] Step C - Synthesis of intermediate Int-2fc-1 In a solution of HCl (100 mL, 4N in 1,4-dioxane) at room temperature, Int-2fb- Add 1 (17.0 g, 46.9 mmol). Stir the reaction solution for 1 hour, then reduce the pressure. Concentration yielded Int-2fc-1. LC / MS: (M+H-HCl) + : =240.0,242.0.

[0277] Step D - Synthesis of intermediate Int-2fd-1 Int-2fc-1 (8.20g, 28.2m) in 1,4-dioxane (200mL) In a solution of (mol) and Teoc-OSu (8.03 g, 31.0 mmol), TEA ( 8.55 g (84 mmol) was added at 25°C. The mixture was stirred for 2 hours, and then with water. The mixture was quenched and extracted with petroleum ether (PE). The combined organic layers were concentrated under reduced pressure, and the residue was removed. Column chromatography on silica gel (1%-10% glazier of dimethyl phosphate in PE) Purification by elution (using LC / MS) yielded Int-2fd-1. (+Na+CH3CN) + :=447.3, 449.3.

[0278] Step E - Synthesis of intermediate Int-2fe-1 Int-2fd-1 (15.1g) in toluene (285mL) and water (95mL) 37.3 mmol), potassium (2-((tert-butoxycarbonyl)amino)eth (L) Trifluoroborate (18.7g, 74.6mmol), Cs2CO3 (36.5 In a solution of (g, 112 mmol), add PdCl2 (dppf) (1.37 g, 1.87 mmol) l) was added under nitrogen protection. The mixture was stirred at 80°C for 40 hours. The resulting solution was diluted with water. The mixture was entrenched and extracted with toluene. The combined organic layers were dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure, and the residue is subjected to column chromatography on silica gel (1% in PE). Purification by elution with a -40% ammonium gradient allows for Int-2fe- A value of 1 was given. LC / MS: (M+Na) + :=471.4.

[0279] Step F - Synthesis of intermediate Int-2f-1 Solution of Int-2fe1 (10.6g, 22.4 mmol) in THF (100mL) To this, 1N TBAF in THF (44.9 mL, 44.9 mmol) was added. The mixture was stirred at room temperature for 16 hours, then quenched with water and extracted with siRNA. The chamber was washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was then subjected to column chromatography on silica gel (1%-70% toluene in PE). Elution by gradient (then column chromatography on C18) :330g; Mobile phase A: Water (10mm NH4HCO3), Mobile phase B: ACN; Flow rate: 8 0 mL / min; Gradient: 10%B to 10%B in 10 minutes, then 20%B to 45%B Up to 10 minutes, from 45%B to 70%B in 20 minutes, detector: UV210nm; Rt=2 Int-2f-1 was obtained by purification using LC / MS (M+H) for 5 minutes. + :=305.1. 1 H NMR(300MHz,CD3OD) δ7.27-7.1 6(m,4H),5.85-5.75(m,1H),5.00-4.85(m,2H), 3.79(t,J=7.0Hz,1H),3.32-3.21(m,2H),2.75( t,J=7.4Hz,2H),2.98-1.72(m,4H),1.42(s,9H) .

[0280] Example 2: Preparation of Ex-50 and Ex-52 [ka]

[0281] Compound Ex-50 is prepared according to the scheme below, and its preparation is described in Example 1 herein. From compound Ex-01, this is prepared under appropriate conditions according to the following scheme. It is prepared by reacting it with the intermediate Int32: [ka]

[0282] Step A: Preparation of intermediate Int-32A tert-butyl 3-(2-(2-bromoethoxy in acetonitrile (10 ml) A solution of ethoxypropanoate (5g, 16.82 mmol) is mixed with trimethylamine. (33% ethanol, 11.46 ml, 50.5 mmol) was added, and the resulting solution was 5 The solution was heated overnight at 0°C. By concentrating the solution, 2-(2-(3-(tert-butoxy) -3-Oxopropoxy)ethoxy)-N,N,N-trimethylethaneaminium bromide I gave it a D (Int32A). LC / MS:(M) + :276.5.

[0283] Step B: Preparation of intermediate Int-32 2-(2-(3-(tert-butoxy)-3-oxopropone in DCM (20ml) Xy)ethoxy)-N,N,N-trimethylethaneaminium bromide (Int-32A (5.99g, 16.81 mmol) solution with HCl (4N in dioxane) (21. Add 0.1 ml (84 mmol) and stir the resulting solution overnight at room temperature. Concentrate the solution. Therefore, 2-(2-(2-carboxyethoxy)ethoxy)-N,N,N-trimethyl Tanaminium bromide (Int-32) was administered. LC / MS: (M) + :220.1 .

[0284] Preparation of Compound Ex-50 (Example) [ka]

[0285] Ex-01 (crude product) (17.4 mg, 0.012 mmol) in DMF (2 ml) and 2-(2-(2-carboxyethoxy)ethoxy)-N,N,N-trimethyl ethanol In a solution of aminonium bromide (Int-32) (4.49 mg, 0.015 mmol) HATU (5.69 mg, 0.015 mmol) and DIEA (6.54 μl, 0. Add 0.37 mmol) and stir the resulting solution at room temperature for 50 minutes, then perform reverse-phase HPLC. Therefore, purification was performed using acetonitrile (0.1% formic acid) / water (0.1% formic acid) as the mobile phase. This resulted in Ex-50. LC / MS:M + =1596.3.

[0286] Preparation of Compound Ex-52 (Example) Compound Ex-52 was prepared in a manner similar to that of compound Ex-50, except for Ex-01. Instead, it was prepared using Ex-51. Ex-52 was prepared according to the method described herein. It was purified using reverse-phase HPLC. LC / MS: M+ = 1593.8.

[0287] Example 3: Preparation of Ex-53, Ex-54, and Ex-55 [ka] TIFF0007855670000131.tif77146

[0288] Compounds Ex-53, Ex-54, and Ex-55 were prepared in a manner similar to that of the above compounds. Intermediate 115 (preparation details below) was prepared according to the following scheme and synthesis description: [ka]

[0289] Step A - Synthesis of Intermediate 116 115 in DMF (1.5 ml), DCM (10 ml), and water (0.5 ml) at 0°C (66.3 mg, 0.044 mmol) solution, DIPEA (0.030 ml, 0.1 Add 73 mmol, then add HATU (18.50 mg, 0.049 mmol). The mixture was stirred for 30 minutes. The mixture was concentrated in vacuum and chromatographed on C18. Fee (30g, acetonitrile + 0.05% TFA / water + 0.05% TFA 90:1) Direct purification by elution (from 0 to 40:60) yields 116 E isomer and Z isomer. As a mixture of the bodies, similarly, 116 as a pure fraction of the E isomer or Z isomer Provided. LC / MS (Major isomers) LC / MS:M + =1481.19;LC / MS (minor isomer):LC / MS:M + =1480.

[0290] Step B - Synthesis of Compound Ex-54 116 (25.1 mg, 0.017 mmol) and Pd- in MeOH (10 ml) A 10% C solution (3.61 mg, 3.39 μmol) was subjected to hydrogenation at 1 atmosphere for 1 hour. The reaction mixture was filtered and concentrated on Celite. The residue was treated with DCM / TFA 1:1 for 30 minutes. Then, concentrate it and treat it with 4N HCl in dioxane (100uL), then concentrate it again. By doing so, Ex-54 was provided in the form of an HCl salt. LC / MS: M + =1383.44 .

[0291] Step C - Synthesis of Compound Ex-55 Examples: Compound Ex-55 in the form of formate, from Ex-54 to compound Ex-50 The composition was prepared using the same method as described in Example 2. LC / MS: M + =1 583.69.

[0292] Step D - Synthesis of Compound Ex-53 The example compound Ex-53, in the form of an HCl salt, was obtained from intermediate compound 116, and compound Ex The synthesis of -51 was carried out using the same method as described in Example 1. LC / MS :M + =1381.33.

[0293] Compounds Ex-53, Ex-54, and Ex-55 are ultimately derived from intermediate compound 115. Although it is prepared, the preparation of the intermediate necessary to provide intermediate compound 115 is the intermediate compound The preparation of substance 103 is described in the scheme and synthesis below. [ka]

[0294] Step A - Synthesis of Intermediate 100 4-bromo-2-hydroxybene in degassed toluene (45 ml) and water (15 ml) Zualdehyde (3.00g, 14.92 mmol), potassium tert-butyl N-[ 2-Trifluoroboraniudyl ethyl Carbamate (3.82g, 15.22mmol), Cesium carbonate (17.02g, 52) 0.2 mmol) and 1,1'-bis(diphenylphosphin)ferrocene-palladium (ii) Solution of dichloride dichloromethane complex (0.611 g, 0.746 mmol) The mixture was heated to 75°C and stirred overnight. The mixture was then heated to a semi-saturated sodium bicarbonate aqueous solution at room temperature. The mixture was quenched and extracted with ethyl acetate. The combined organic fraction was washed with brine. The residue was dried with Na2SO4, filtered, and concentrated in a vacuum. The residue was then collected in a column on silica gel. Chromatography (elution of hexanes / siRNAs at a ratio of 99:1 to 60:40) By refining it, a value of 100 was obtained. LC / MS: (M-55) + =210.25.

[0295] Step B - Synthesis of Intermediate 101 100 (1.70 g, 6.41 mmol) and bromide in DMF (10 ml) at room temperature In a solution of lyl (0.832 ml, 9.61 mmol), potassium carbonate (1.328 g, 9 Add 0.61 mmol) and heat the mixture to 50°C, stirring for 1 hour. Let the mixture sit at room temperature for half a day. Quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The fraction was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuum. The residue was subjected to column chromatography on silica gel (hexane / Depositphotos / Depositphotos 99: Purification by LC / MS (elution ratio 1 to 70:30) yielded 101. -55) + =250.29.

[0296] Step C - Synthesis of Intermediate 102 1.76g of 101 prepared in the previous step in 100ml of MeOH at room temperature , 5.76 mmol), 4A molecular sieve (2 g) and ammonium acetate (4 (0.380g sodium cyanoborohydride) in a solution of 0.44g, 57.6 mmol. Add 6.05 mmol of [unclear compound] and shake the mixture overnight. Concentrate the mixture and dilute with water at room temperature. The mixture was requenched and extracted with DCM. The combined organic fraction was dried with Na2SO4. The residue was filtered and concentrated in a vacuum. The residue was then subjected to column chromatography (DCM) on silica gel. Purification by elution (MeOH 99:1 to 30:70) provides 102. . LC / MS:(2M+H) + =613.56.

[0297] Step D - Synthesis of Intermediate 103 102 (220 mg, 0.718 mmol) and succinate in DMF (4 ml) at room temperature In a solution of monomethyl acid ester (114 mg, 0.862 mmol), HATU (300 mg (0.790 mmol) and DIPEA (0.314 ml, 1.795 mmol) The mixture was added and stirred for 30 minutes. The mixture was then dissolved in a saturated sodium bicarbonate aqueous solution at room temperature. The mixture was requenched and extracted with toluene. The combined organic fraction was washed with brine. The residue was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was then measured on silica gel using column chromatography. Mathematical analysis (elution of hexanes / toluenes at a ratio of 99:1 to 30:70) This process yielded an intermediate, which was treated with 20% TFA in DCM for 1 hour. Reactants By concentrating it and then treating it with 4N HCl (1.5 ml) and concentrating it, 103 is provided. . LC / MS:(M+H) + =321.29.

[0298] Preparation of intermediate 109 [ka]

[0299] Step A - Synthesis of Intermediate 104 Methyl(S)-2-methylpyrrolidine-2-carbocinyl in 100 ml of DMF at 0°C Silate hydrochloride (7.00g, 39mmol) and (S)-2-((tert-butoxyl Cicarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (12.08g, 4 Add DIPEA (17.01 ml, 97.0 mmol) to a 0.9 mmol stirred solution. Next, HATU (19.26 g, 50.7 mmol) was added. The resulting mixture was then... The mixture was left as is, warmed to room temperature, and stirred overnight. The reaction mixture was then quenched with a 10% LiCl aqueous solution. The organic extract was extracted with ethyl acetate. The organic extract was washed with a 10% LiCl aqueous solution and dried with MgSO4. The residue was dried. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography on silica gel. By purifying by xanes / acetates (eluting at a ratio of 80:20 to 40:60), 1 04 was provided.

[0300] Step B - Synthesis of Intermediate 105 A solution of 104 (16.4g, 39.0 mmol) in SiO(100ml) is added. 4N HCl (48.8 ml, 195 mmol) was added to the oxane. The resulting mixture Stirring at room temperature for 18 hours and then concentrating under reduced pressure to obtain 105, which is then used in the next step. It was used without further purification.

[0301] Step C - Synthesis of Intermediate 106 105 (13.2g, 37.0 mmol) and N-((benzyl o) in DMF at 0℃ Xy(carbonyl)-O-(tert-butyl)-L-threonine (18.15g, 37 Add DIPEA (16.15 ml, 92 mmol) to a 0 mmol solution, and then HATU (18.28 g, 48.1 mmol) was added. The resulting mixture was left as is. The mixture was heated to room temperature and stirred overnight. The reaction mixture was quenched with a 10% LiCl aqueous solution and EtOA Extraction was performed using c. The organic extract was washed with a 10% LiCl aqueous solution and dried with MgSO4. Remove the solvent under reduced pressure, and the residue is subjected to column chromatography on silica gel (hexane / Purification by ethyl elution (80:20 to 40:60) yields 106. did.

[0302] Step D - Synthesis of Intermediate 107 A solution of 106 (16.5g, 27.0 mmol) in MeOH is mixed with 10% Pd / C. Larry was added, and the mixture was hydrogenated at 20 psi for 4 hours. The reaction mixture was filtered on Celite. The mixture was then concentrated under reduced pressure. The crude product was then redissolved in DCM, and the solution was filtered into 2 μm particles. By filtering through a ruter and concentrating, 107 was obtained.

[0303] Step E - Synthesis of Intermediate 108 In a solution of 107 (3.2g, 6.70 mmol) in DCM, add DIPEA (1.52m (1, 8.71 mmol) is added, followed by di-tert-butyl dicarbonate (1.90 (g, 8.71 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, then under reduced pressure. The residue was concentrated using column chromatography on silica gel (hexane / African). Purification by elution (from 100:0 to 40:60) yielded 108.

[0304] Step F - Synthesis of Intermediate 109 108 (1.43g, 2.475g) in THF (15ml) and MeOH (15ml) A solution of mmol) and 1N LiOH aqueous solution (9.90 ml, 9.90 mmol) is prepared in 4 The mixture was heated to 5°C and stirred for 4 hours, then stirred at 32°C for 48 hours. The reaction mixture was concentrated and then heated to 0°C. Quench with a 0.5M hydrochloric acid solution until the pH is approximately 2-3, then extract with ethyl acetate. The combined organic fractions were dried with Na2SO4, filtered, and concentrated in a vacuum. Column chromatography of the residue on silica gel (hexane / siRNA-EtOH By purifying by elution with 99:1 and SiO-EtOH 3:1, 109 I gave it. LC / MS:(M+H) + =564.49.

[0305] Preparation of intermediate compounds 110 to 115 Step A - Synthesis of Intermediate 110 [ka]

[0306] 109 (217 mg, 0.385 mmol) in DMF (2.5 ml), HATU (1 33 mg, 0.350 mmol) and DIPEA (0.245 ml, 1.400 mmol) The solution of l) was treated with 103 (217 mg, 0.385 mmol) at 0°C, and the mixture The mixture was left as is and heated to room temperature, then stirred for 30 minutes. The mixture was saturated with sodium bicarbonate at 0°C. The solution was quenched with an aqueous solution of ammonium and extracted with ethyl acetate. The combined organic fraction was then mixed with bran. The residue was washed with water, dried with Na2SO4, filtered, and concentrated under vacuum. The residue was then removed from silica gel. The column chromatography above (hexanes / siRNA-EtOH 3:1 99:1) Purification by elution with HCl-EtOH in a 3:1 ratio yielded 110. LC / MS:(M+H) + =866.21.

[0307] Synthesis of Step B and C-intermediate compounds 111 and 112 [ka]

[0308] In a solution of 110 (249 mg, 0.288 mmol) in 1 ml of DCM at room temperature, Add HCl 4N (0.359 ml, 1.438 mmol) to the oxane and mix the mixture 6 After stirring for a period of time and then concentrating, 111 was obtained. LC / MS:(M+H) + =7 10.19.

[0309] 111 (219 mg, 0.29 mg) in DMF (3 ml) and water (0.15 ml) at 0°C In a solution of 3 mmol) and 76 (232 mg, 0.285 mmol), DIPEA (0 (0.128 ml, 0.734 mmol) and HATU (123 mg, 0.323 mmol) Add ) and stir the mixture for 30 minutes. Quench the mixture with brine at 0°C and Et Extraction was performed using OAc. The combined organic fraction was dried with Na2SO4, filtered, and then vacuum filtered. The residue was concentrated using column chromatography on silica gel (hexane / African). -EtOH 3-1 99:1 to 30:70, followed by DCM / MeOH 99:1 Purification by elution (70:30) yielded 112. LC / MS: (M+H ) + =1506.11.

[0310] Synthesis of intermediate 113 (ID) [ka]

[0311] 112 in DCM (180 ml) and AcOH (15 ml) degassed with nitrogen for 30 minutes (173 mg, 0.115 mmol) solution with Zhan catalyst (59.0 mg, 0.08 Add 0 mmol of the mixture, heat it to 50°C, and stir for 3 hours. The mixture was then laid on Celite. The residue was filtered, washed with DCM, and then concentrated under vacuum. The residue was then subjected to column chromatography on silica gel. Purification is performed by tography (elution of DCM / MeOH at a ratio of 99:1 to 80:20). Thus, 113 was given as a mixture of the E and Z isomers. LC / MS (major) Isomers):(M) + =1477.80; LC / MS (minor isomers): (M) + =1 478.28.

[0312] Step E - Synthesis of Intermediate 114 [ka]

[0313] In a solution of 113 (141 mg, 0.095 mmol) in acetonitrile (2 ml), Add piperidine (0.066 ml, 0.668 mmol) and stir the mixture for 45 minutes. The mixture is concentrated in a vacuum and co-evaporated with acetonitrile Tris. This yielded the crude product. This crude product was obtained in DMF (2 ml) and water (0.1 ml) at 0°C. Substance (119 mg, 0.095 mmol) and intermediate compound 88 (52.0 mg, 0.1 In a slurry of 0.5 mmol, add HATU (39.7 mg, 0.105 mmol) and D IPEA (0.037 ml, 0.209 mmol) was added, and the mixture was stirred for 30 minutes. Mixture Column chromatography on C18 (acetonitrile + 0.05% TFA / water) Purification by +0.05% TFA (elution ratio from 90:10 to 30:70) results in 11 4 was given as a mixture of E and Z isomers. LC / MS Major isomers: ( M) + =1735.28; LC / MS (minor isomers): (M) + =1735.25 .

[0314] Step F - Synthesis of intermediate compound 115 [ka]

[0315] 114 (134 mg) in THF (1.5 ml) and MeOH (1.5 ml) at 0°C. To a solution of 0.077 mmol, add 0.386 ml of 1N LiOH aqueous solution (0.386 ml, 0.386 ml). The mixture was added dropwise (mol) and stirred for 2 hours. The reactants were then heated in 0.5N HCl at 0°C. Add the solution dropwise until the pH reaches approximately 7, then concentrate it from the organic solvent, and then add approximately 1 mL of the slurry. Dissolve in DMF and perform column chromatography on C18 (acetonitrile + 0.05%). Direct purification by TFA / water + 0.05% TFA (eluting at a ratio of 90:10 to 50:50). This yielded 115 as a mixture of the E and Z isomers. LC / MS measuring -Isomer: (M) + =1498.71; LC / MS (minor isomers): (M) + = 1499.48.

[0316] The R in each starting compound 2 Reaction of amide with acidic substituent precursors In the preparation of Ex-50 from -01 and Ex-55 from Ex-54, as described above... As described, by using the following intermediate compounds in similar reactions, the present invention can be achieved. It may provide compounds for use.

[0317] R 1 / R 2 Synthesis of substituent precursors: 5-carboxy-N-(3-methoxypropyl)-N,N-dimethylpentane-1-amine Preparation of nium chloride (intermediate Z-1a) Step A: Preparation of intermediate Z-1 [ka]

[0318] tert-butyl 6-(dimethylamino)hexanoe in acetonitrile (1 mL) In a stirred solution of 1-bromo-3-methoxypropyl (300 mg, 1.393 mmol), add 1-bromo-3-methoxypropyl (300 mg, 1.393 mmol). Bread (853 mg, 5.57 mmol) was added. The reaction mixture was stirred at 50°C for 16 hours. The resulting mixture was concentrated under reduced pressure to give Z-1. LC / MS: (MB r)+=288.4. 1 1H NMR (300 MHz, CDCl3): δ 3.76-3. 47(m,6H),3.38(d,J=28.9Hz,9H),2.25(t,J=7. 2Hz,2H),2.12-1.95(m,2H),1.87-1.55(m,4H), 1.45 (s, 11H).

[0319] Step B: Synthesis of intermediate compound Z-1a [ka]

[0320] In a stirred solution of Z-1 (460 mg, 1.249 mmol) in DCM (0.5 mL), 4M HCl (2 mL) was added to dioxane at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The residue was concentrated under reduced pressure. The residue was redissolved in DCM (5 mL) and concentrated under reduced pressure. Intermediate compound Z-1a was obtained. LC / MS: (M-Cl) + =232.3.

[0321] Preparation of intermediate Z-2b Step A: Preparation of intermediate Z-2 [ka]

[0322] THF (10 mL) contains tert-butyl 6-bromohexanoate (1.0 g, 3 To a stirred solution of 0.98 mmol, add dimethylamine (2M in THF) (7.96 mL, 15 (0.93 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was reduced. The solution was concentrated under pressure, and the residue was analyzed by silica gel column chromatography to obtain 1%-1% in DCM. The fraction containing the desired product was eluted and purified using a 5% MeOH gradient. By combining and concentrating the two solutions, Z-2 was obtained. LC / MS: (M+H)+=216.2. 1 H NMR(300MHz,CDCl3):δ2.35-2.17(m,J=8.5 ,6.5Hz,10H),1.67-1.47(m,4H),1.45(s,9H),1 .42-1.23 (m, 2H).

[0323] Step B: Preparation of intermediate Z-2a [ka]

[0324] In a stirred solution of Z-2 (250 mg, 1.161 mmol) in ACN (1 mL), add 1- Bromo-2-methoxyethane (645 mg, 4.64 mmol) was added to the reaction mixture. The mixture was stirred at 50°C for 16 hours. The resulting mixture was concentrated under reduced pressure to give Z-2a. LC / MS: (M-Br)+=274.3. 1 1H NMR (300MHz, CDC) l3):δ4.02-3.80(m,4H),3.70-3.54(m,2H),3.4 2(d,J=13.0Hz,9H),2.24(t,J=7.2Hz,2H),1.85 -1.75(m,2H),1.72-1.55(m,2H),1.44(s,11H).

[0325] Step C: Preparation of intermediate Z-2b [ka]

[0326] A stirred solution of Z-2a (450 mg, 1.270 mmol) in DCM (0.5 mL) 4M HCl (2 mL) was added to the dioxane at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The residue was then concentrated under reduced pressure. The residue was redissolved in DCM (5 mL) and concentrated under reduced pressure. Z-2b was given. LC / MS: (M-Cl) + =218.3.

[0327] Preparation of intermediate Z-3b Step A: Preparation of intermediate Z-3 [ka]

[0328] tert-butyl 3-(2-hydroxyethoxy)propanoate in DCM (2 mL) To a solution of 500.0 mg, 2.63 mmol of CBr4, add 1395 mg, 4.2 1 mmol) and PPh3 (965 mg, 3.68 mmol) were added at 0°C. Mixture The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and the residue was collected by a silica gel column. The product was purified by elution using a chromatographic gradient of 1%-15% EA in PE. The fractions containing the desired product were combined and concentrated to give Z-3. 1 H NMR(400MHz,CDCl3):δ3.78(dt,J=11.1,6.3 Hz,4H),3.47(t,J=6.3Hz,2H),2.53(t,J=6.4Hz ,2H),1.48(s,9H).

[0329] Step B: Synthesis of intermediate Z-3a [ka]

[0330] tert-butyl 3-(2-bromoethoxy)propanoate in ACN (2 mL) In a stirred solution of Z-3 (450 mg, 1.778 mmol), add trimethylamine (955 mg). g (5.33 mmol) (in 33% Wt, EtOH) was added. The reaction mixture was heated at 50°C for 1 The mixture was stirred for 6 hours. The resulting mixture was concentrated under reduced pressure to give Z-3a. LC / MS:(M-Br)+=232.3. 1 1H NMR (400 MHz, CDCl3): δ 5.32(s,1H),4.04-3.94(m,4H),3.73(t,J=5.7H z,2H),3.50(s,10H),2.50(t,J=5.7Hz,2H),1.4 4(s,9H).

[0331] Step C: Synthesis of intermediate Z-3b [ka]

[0332] In a solution of Z-3a (550 mg, 1.761 mmol) in DCM (0.6 mL), 4M HCl (2.5 mL) was added to the oxane at room temperature. The mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with DCM (3 mL) and toluene (3 mL). It was redissolved in the solution. The mixture was then concentrated under reduced pressure to give Z-3b. LC / M S:(M-Cl) + =176.2.

[0333] Preparation of intermediate Z-4b Step A: Preparation of intermediate Z-4 [ka]

[0334] In a solution of DIAD (1.755 mL, 9.03 mmol) in THF (30 mL), P h3P (2.368 g, 9.03 mmol) was added. The mixture was stirred at room temperature for 10 minutes. Next, methyl 2-(3-hydroxyphenyl) acetate (1.0g, 6.02mO l) and 3-(dimethylamino)propan-1-ol (0.931g, 9.03mm (ol) was added to the solution. The mixture was stirred at 50°C for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was then analyzed by silica gel column chromatography to determine 1%-10% MeO in DCM. The product was eluted and purified with a H gradient. The fractions containing the desired product were combined. Concentration yielded Z-4. LC / MS: (M+H)+=252.2. 1 HN MR(300MHz,CDCl3):δ7.23-7.18(m,1H),6.82(t d,J=8.7,4.1Hz,3H),4.01(t,J=6.4Hz,2H),3.6 9(s,3H),3.59(s,2H),2.46(t,J=7.3Hz,2H),2. 27(s,6H),1.97(dt,J=7.9,6.5Hz,2H).

[0335] Step B: Preparation of intermediate Z-4a [ka]

[0336] In a solution of Z-4 (600 mg, 2.268 mmol) in ACN (12 mL), MeI (1.288 g, 9.07 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to obtain -Z-4a. LC / MS:(MI) + =2 66.2. Step C: Preparation of intermediate Z-4b [ka]

[0337] A 2M solution of Z-4a (800 mg, 1.729 mmol) in THF (12 mL) LiOH (1.729 mL, 3.46 mmol) was added. This mixture was left at room temperature for 2 hours. The mixture was stirred. The pH of the solution was adjusted to 4 with HCl (1M), and the solution was concentrated under reduced pressure. The product was analyzed using reverse-phase chromatography on C18 (mobile phase A: water, mobile phase B: ACN; flow rate: 6 0 mL / min; gradient from 1%B to 25%B in 25 minutes; from 25%B to 95%B By purifying it in 15 minutes (from 95% B to 95% B in 10 minutes), Z-4b is obtained. Okay. LC / MS: (M-Cl)+=252.2. 1 1H NMR (300MHz, CD) 3OD):δ7.21(t,J=7.9Hz,1H),6.95-6.75(m,3H) ,4.12(t,J=5.7Hz,2H),3.63-3.50(m,4H),3.18 (s, 9H), 2.35-2.20 (m, 2H).

[0338] Example 4: Preparation of Ex-23 [ka]

[0339] Step A: Preparation of intermediate S-1b (2S,3R,4S,5S,6R)-6-(acetoxymethyl)tetrahydro-2H- Pyran-2,3,4,5-tetrayltetraacetate S-1a (5g, 12.81mm) (ol) is used in AcOH and DCM (40 mL) with 48% HBr (7.25 mL, 64. The mixture was added to 0 mmol of solvent at 0°C and stirred at 0°C for 1 hour. The reaction mixture was then cooled on ice. Pour the mixture into a saturated sodium bicarbonate aqueous solution and extract the mixture with DCM (3 x 60 mL). The organic layer was washed with brine, dried with Na2SO4, filtered, concentrated, and then the crude layer was removed. The product is dissolved on silica gel using flash chromatography (0-30% ammonium / PE). It was purified to S-1b by (extraction).

[0340] Step B: Preparation of intermediate S-1c A solution of S-1b (4.5g, 10.94 mmol) in anhydrous DMF (45mL) is added. Add sodium disoxide (0.854 g, 13.13 mmol) and react the mixture at 18°C ​​for 30 minutes. The mixture was stirred. The reaction mixture was diluted with water (30 mL) and extracted with toluene (3 × 80 mL). The organic layer was dried with Na2SO4 and evaporated to dryness. The crude product was placed on silica gel. Purify by Rush chromatography (elution with 0-30% ethyl acetate / PE). Therefore, S-1c was given.

[0341] Step C: Preparation of intermediate S-1d In a solution of S-1c (3.15 g, 8.44 mmol) in EtOH (60 mL), add 10 %Pd-C (0.898g, 0.844 mmol) was added. Air was removed from the reaction vessel. Then, H2 was added under 50 psi. The reaction mixture was stirred at 18°C ​​for 5 hours. Reaction mixture E Dilute with tOAc, filter through Celite, and concentrate to obtain S-1d, and this It was used for the next step.

[0342] Step D: Preparation of intermediate S-1e In a solution of S-1d (2.34 g, 6.74 mmol) in anhydrous THF (20 mL), Hydrofuran-2,5-dione (0.742 g, 7.41 mmol) and Et3N (0 Add 0.939 mL (6.74 mmol). Continue stirring until the starting materials are completely consumed. The mixture was stirred for 3 hours and then evaporated. The resulting crude product was flash-chromized on silica gel. Purification by tography (elution with 0-10% DCM / MeOH) results in S-1 The value e was given. MS(ESI): m / z(M+H)+ 448.1. 1 HNMR (400 MHz, CDCl3) δ:6.48(d,J=9.04Hz,1H),5.43(s, 1H),5.24(t,J=8.93Hz,1H),5.07-5.17(m,2H), 4.08-4.18(m,2H),4.04(q,J=6.69Hz,1H),2.72 -2.84(m,1H),2.58-2.69(m,2H),2.43-2.53(m, 2H),2.15(s,3H),2.06(s,3H),2.04(s,4H),2.0 0(s,3H).

[0343] Step E: Preparation of Ex-23 Ex-01 (300 mg, 0.215 mg) in DMF (8 ml) and water (0.4 ml) In a solution of (mol) and S-1e (115 mg, 0.258 mmol), DIEA (0. 150 ml (0.860 mmol) and HATU (98 mg, 0.258 mmol) In addition, the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was then mixed with 1N LiOH (2.58 ml). Add 2.58 mmol) dropwise to quench, stir the resulting solution at room temperature for 2 hours, then Filter and analyze the filtrate on a reverse-phase HPLC C18 column in water (0.05% TFA) at a concentration of 29-34%. By purifying with an acetonitrile (0.05% TFA) gradient, Ex-2 I gave 3. LC / MS:[M+1]+=1657.1.

[0344] Example 5: Preparation of Ex-14 [ka]

[0345] Compound Ex-14 was prepared in a manner similar to the procedure described in Example 1, but differently. The "linkers" were prepared using alternative synthesis steps. Synthesis of these "linkers" Alternative steps and major assemblies are listed below.

[0346] Preparation of intermediate Int-2g In the preparation of the compound of the present invention, the intermediate Int-2g, which is useful as a "linker", is used as follows: Prepared according to the scheme: [ka]

[0347] Step A - Int-2gb synthesis Int-2da (0.5g, 2 mmol) in room temperature THF (16ml) in a water bath And in a solution of 2-azidoethaneamine and HCl (0.246 g, 2 mmol), Tria Gradually add sodium cethoxyhydroborate (1.06g, 5 mmol) to the mixture. The mixture was stirred for 2 hours. The reaction was slowly quenched with saturated NaHCO3 aqueous solution, and then in a solution of DCM. Extraction and washing with brine. The combined organic layers were dried with MgSO4 and concentrated. Int-2gb was given. LC / MS:(M+1) + =320.3.

[0348] Step B-Int-2gc synthesis Int-2gb (0.64g, 2mmo) in DMF (4ml) and DCM (8ml) l) and monomethyl succinate (0.3 g, 2.3 mmol) are mixed in a solution containing HATU (0. 914g (2.4 mmol) and DIPEA (0.7 ml, 4.01 mmol) -1 It was added at 5°C. The resulting solution was stirred at -15°C for 2 hours, then quenched with water and concentrated. The residue was subjected to reverse-phase chromatography on C18 (acetonitrile / water + 0.1% TFA). Int-2gc was obtained by purification by elution. LC / MS: (M+1) + = 434.3.

[0349] Step C-Int-2g Synthesis In a solution of Int-2gc (0.52g, 1.2 mmol) in DCM (9 mL), at room temperature Then, TFA (3 mL, 38.9 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield Int-2g. LC / MS: (M+1)+ = 334.3.

[0350] Preparation of intermediate compounds 70B and 76C [ka]

[0351] Step A - Synthesis of Intermediate 70B In a solution of 69B (1.5g, 4.46 mmol) in DMF (17.8ml) at 0℃, Add 95% NaH (0.141 g, 5.56 mmol) and steep the resulting solution at 0°C for 20 minutes. Stirring intermittently, then 3-bromopropa-1-yne (80% in toluene) (0.596 ml, 5.35 mmol) was added dropwise. To the resulting solution, lithium hydroxide aqueous solution (2M) (3345 μl, 6.69 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. Filter and purify by reverse-phase HPLC (elution with acetonitrile / water + 0.1% TFA). This resulted in a value of 70B. LC / MS:(M+1) + :361.0, (M+Na) + : 383.0.

[0352] Step B - Synthesis of Intermediate 76C The conversion of 70B to intermediate 76C is described in steps C through H of the preparation of intermediate 76. The procedure followed a similar sequence to the previous one. LC / MS:[M+1]+=812.16.

[0353] Assembly to Example Ex-14: [ka] TIFF0007855670000156.tif179169

[0354] Step A - Synthesis of Intermediate 117 Intermediate 117 was obtained from intermediates Int-2g and 76C as described in Examples 1 and 1A. It was prepared using a procedure similar to that used. More specifically, Int-2g was used as intermediate 77B Functionalization is carried out according to the reagents and procedures for the preparation of Step A to B, and further intermediate 86S Follow the steps for preparing steps G through J to construct (elaborate), and then finally Intermediate 76C is coupled to the intermediate according to the procedure for preparation steps B to C of Example 1A. By doing so, 117 was provided. LC / MS:(M+1)+:1573.36.

[0355] Step B - Synthesis of Intermediate 118 Copper tetrakis(acetonitrile) in BuOH (185.00 mL) / water (93 mL) (I) Hexafluorophosphate (51.6 mg, 0.138 mmol), Tris[( 1-Benzyl-1h-1,2,3-triazole-4-yl)methylamine (73.4 (mg, 0.138 mmol) and sodium ascorbate (137 mg, 0.692 The intermediate 117 (435.3) was bubbled with nitrogen and then heated at 50°C. (mg, 0.277 mmol) was added as a solid to the reactant. After 1 hour, the reactant was pH The mixture was treated with aqueous buffer 4 and extracted with toluene. The combined organic layer was evaporated, and the residue remained. Elute with reverse-phase chromatography (acetonitrile / water + 0.1% formic acid gradient). By purification using the following method, intermediate 118 was obtained. LC / MS:(M+1)+:157 3.2.

[0356] Synthesis of Step C-Ex-14 The synthesis of intermediate example Ex-14 is similar to that described in Example 1, starting from intermediate 118. Following a similar procedure, the process proceeded, including the use of alternative spacers for assembly. C / MS:[M+1]+=1621.01.

[0357] Using the above synthesis scheme, and the preparation thereof, as sometimes described above, in our work Having appropriate substitution of specific intermediates, which involves the use of alternative spacers that are obvious to the user. As can be understood from the examples below, the following compounds of the present invention listed in Table 2 below are used to test Prepared. In addition, alternative salt forms of the compounds of the present invention may also be described in this application.

[0358] Table 2 [Table 2] TIFF0007855670000158.tif170165TIFF0007855670000159.tif162166TIFF0007855 670000160.tif235166TIFF0007855670000161.tif224165TIFF0007855670000162.t if182165TIFF0007855670000163.tif221165TIFF0007855670000164.tif227164TIF F0007855670000165.tif153165TIFF0007855670000166.tif169165TIFF00078556700 00167.tif225165TIFF0007855670000168.tif222166TIFF0007855670000169.tif20 7165TIFF0007855670000170.tif229165TIFF0007855670000171.tif241170TIFF000 7855670000172.tif219165TIFF0007855670000173.tif226165TIFF00078556700001 74.tif221165TIFF0007855670000175.tif210166TIFF0007855670000176.tif146165

[0359] Determination of activity The selected compounds of the present invention are assayed to determine their activity in relation to the antagonism of PCSK9 activity. To that end, one or more of the following procedures were performed.

[0360] The following describes the PCSK9 antagonism of the compound of the present invention and any reported comparative compound. This is a description of the assay used to determine the activity related to biotinylated PCSK9. I obtained one that was being sold.

[0361] LDLR TR-FRET The PCSK9 TR-FRET assay measures the interaction between PCSK9 and LDLR. Determined. 40nM biotinylated PCSK9 + 10nM Lance ULight Str A solution containing eptavidin, 50 mM HEPES pH 7.4, 0.15 M NaCl, 5 mM CaCl2, 0.01% BSA and 0.01% Surfac Prepared during P20. 40nM rhLDLR-6xHis+10nM Eu - Prepare another solution containing W1024 anti-6xHis in the same buffer system. Prepare the mixture. Transfer 0.750 µl of the compound to an assay plate using Echo, then 1 Add 5µl PCSK9+Ulight and 15µl LDLR+Eu. Final A The capacity is 30,750 µl, and it contains 20 nm PCSK9, 5 nm Ulight, It contains 20 nM LDLR and 5 nM Eu. Let the reaction mixture sit at room temperature for at least 2 hours. After incubation, use the Envision Multilabel Reader. Fluorescence measurements are performed. The IC50 value is plotted on a sigmoid dose-response curve using nonlinear regression. Determined by fitting. Europium-labeled LDLR cow Track the B count and observe whether the compound adversely affects LDLR. A decrease in the threshold likely indicates a false positive for inhibition.

[0362] Alexa FRET Standard TR-FRET The PCSK9 Alexa FRET Standard assay uses PCSK9 and Al Reagent A(K) is a cyclic peptide tagged with exaFluor647(AF). D =83nM) The interaction between 1nM biotinylated PCSK9 and 2.5nM Lance is measured. Solution containing Streptavidin Europium (Strep-Eu) , 50mM HEPES pH7.4, 0.15M NaCl, 5mM CaCl2, 0 Prepared in 0.01% BSA and 0.01% Surfactant P20. 40 Another solution containing nM AlexaFluor tagged cyclic peptide in the same buffer Prepare the mixture in the system. Transfer 0.750 µl of the compound to the assay plate using Echo. Next, 15 µl of PCSK9+Stept-Eu and 15 µl of AF peptide are added. The final assay volume was 30.750 µl, containing 0.5 nM PCSK9, 1.2 It contains 5 nM Strep-Eu and 20 nM AF cyclic peptide. The reaction mixture is stored at room temperature. After incubation for at least 2 hours, Envision Multilabel Fluorescence measurements are performed using a Reader. The IC50 value is calculated using a sigmoid function with nonlinear regression. It is determined by fitting the data to a dose-response curve. Ki is then A IC50 and K of F-cyclic peptides D It is calculated from Europium-labeled PCSK. Track the 9 count (B count) and observe whether the compound has an adverse effect on PCSK9. A decrease in B count likely indicates a false positive for inhibition. Data from this procedure. This is reported as "A = 'numerical value' (nanomolelic concentration)".

[0363] Reagent A was prepared according to the following method: [ka]

[0364] Step A - Synthesis of intermediate compound Int-A The peptide was measured in 0.250 mmol in CEM Liberty Blue. On a cross-wave synthesis apparatus, Fmoc / tBu on PS Rink-Amide MBHA resin Using chemistry, 0.32 mmol g -1 It was synthesized using 4 equivalents. The assembly is 4 equivalents 0.2M Fmoc protective amino acids in DMF, 0.5M HATU in 4 equivalents of DMF, 4 equivalents This was carried out using single coupling with 2M DIPEA (for Tyr (Double coupling). The Fmoc deprotection cycle involves 20% (V / V) piperi in DMF. This was done using gin.

[0365] The sequences of the Fmoc-protecting amino acids and components used are as follows: 1. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-trityl -L-cysteine 2. (S)-1((((9H-fluoren-9-yl)methoxy)carbonyl)amino )-2-methylpyrrolidine-2-carboxylic acid 3. (((9H-fluoren-9-yl)methoxy)carbonyl)-L-tyrosine 4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-trityl -L-histidine 5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amine (no)-4-(tert-butoxy)-4-oxobutanoic acid 6. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amine (no)-3-(5-fluoro-1H-indole-3-yl)propanoic acid 7. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amine (no)-3-(5-fluoro-1H-indole-3-yl)propanoic acid 8. (((9H-fluoren-9-yl)methoxy)carbonyl)glycine 9. N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N 6 -(t (ert-butoxycarbonyl)-L-lysine 10. 3-(tritylthio)propanoic acid

[0366] At the end of the assembly, the resin was washed with DMF, MeOH, DCM, and Et2O. Tydos in 50 ml of TFA solution (v / v) (91% TFA, 5% H2O, 4% TIPS) The resin was cut from the solid support at room temperature over approximately 1.5 hours using [a specific method / tool]. The resin was filtered and washed with TFA. The solution was purified, concentrated to dryness, and freeze-dried. Freeze-drying was performed on the intermediate compound Int.A(399m). g) was obtained and used in its crudely purified state in the next step. LC-MS analysis C61H Calculated value for 75F2N15O13S2: 1328.48, Measured value: 1328.2 (M+1) +

[0367] Step B - Synthesis of intermediate compound Int-B: Reagent B is described as follows. RP-HPLC (Waters Deltapak C4, double cartridge, 40 ×100mm, 15m, 300A; 15% to 35% ACN / water + 0.1% over 20 minutes Purified using a TFA modifier. The recovered fraction is freeze-dried to obtain 35 mg. The intermediate compound Int-B was obtained. LC-MS analysis yielded C69H81F2N15O13S2. Calculated value: 1430.62; Measured value: 1430.9 (M+1) +

[0368] Step C - Synthesis of Compound Reagent A: As described for Reagent B LCMS analysis C105H122F2N17O26S6 3- Calculated value: 2268.58 ;1135.8(M+2) 2+

[0369] Alexa FRET Plus TR-FRET The PCSK9 Alexa FRET Plus assay uses PCSK9 and AlexaF Reagent B(K) is a luor647(AF) tagged cyclic peptide. D Between =35nM) Measuring the interaction. 1nM biotinylated PCSK9 + 2.5nM Lance Str A solution containing eptavidin Europium (Strep-Eu) is prepared in 50 ml. M HEPES pH7.4, 0.15M NaCl, 5mM CaCl2, 0.01% Prepared in BSA and 0.01% Surfactant P20. 1920 nM Another solution containing the AlexaFluor tagged cyclic peptide, in the same buffer system Prepare it inside. Using Echo, add 0.075 µl of the compound + 0.675 µl of DMSO. Transfer to each well of the assay plate, followed by 15 µl of PCSK9 + Stept-Eu Add 15 µl of AF peptide. The final assay volume is 30.750 µl. 0.5nM PCSK9, 1.25nM Strep-Eu, and 960nM AF ring Contains peptides. After incubating the reaction mixture at room temperature for at least 2 hours, Envi Fluorescence measurements are performed using a sion Multilabel Reader. The IC50 value is By fitting the data to a sigmoid dose-response curve using nonlinear regression, This is determined. Ki is then determined by the IC50 and K of the AF cyclic peptide. D Calculated from The count of europium-labeled PCSK9 (B count) was tracked, and the compound was identified as PC Observe whether it negatively affects SK9. A decrease in B count may indicate a false positive for inhibition. This is highly probable. The data from this procedure is reported as "P = 'numerical value' (nanomolecular concentration)". It can be done.

[0370] Reagent B was prepared according to the following procedure. [ka]

[0371] Step A - Synthesis of intermediate compound Int-A The peptide was measured in 0.250 mmol in CEM Liberty Blue. On a cross-wave synthesis apparatus, Fmoc / tBu on PS Rink-Amide MBHA resin Using chemistry, 0.32 mmol g -1 It was synthesized using 4 equivalents. The assembly is 4 equivalents 0.2M Fmoc protective amino acids in DMF, 1M oxime in 4 equivalents of DMF, 0. Single coupling using 5M N,N-diisopropylcarbodiimide (DIC) The procedure was carried out using (double coupling for Y01). The Fmoc deprotection cycle was The procedure was performed using 20% ​​(V / V) piperidine in DMF.

[0372] The sequences of the Fmoc-protecting amino acids and components used are as follows: 1. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-trityl- L-cysteine 2.(S)-1((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -2-methylpyrrolidine-2-carboxylic acid 3. (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino )-3-(4-methoxyphenyl)propanoic acid 4. N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-trityl- L-histidine 5. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino )-4-(tert-butoxy)-4-oxobutanoic acid 6. (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino )-3-(5-fluoro-1H-indole-3-yl)propanoic acid 7.(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino )-3-(5-fluoro-1H-indole-3-yl)propanoic acid 8. (((9H-fluoren-9-yl)methoxy)carbonyl)-D-alanine 9.N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N 6 -(te (rt-butoxycarbonyl)-L-lysine 10,3-(tritylthio)propanoic acid

[0373] At the end of the assembly, the resin was washed with DMF, MeOH, DCM, and Et2O. Prepare 50 ml of TFA solution (v / v) (91% TFA, 5% H2O, 4% TIPS) The resin was cut from the solid support at room temperature over approximately 1.5 hours. The resin was filtered and washed with TFA. The solution was concentrated to dryness and freeze-dried. Freeze-drying was performed on the intermediate compound Int.A (300 mg). This yielded a crude solution, which was used in the next step. LC-MS analysis: C63H7 Calculated value for 9F2N15O13S2: 1356.53, Measured value: 1356.9 (M+1) +

[0374] Step B - Synthesis of intermediate compound Int-B Crudely purified Int-A (0.22 mmol) was redissolved in 24 ml of DMF. 6 ml 1 liter of 1 M sodium bicarbonate solution was added to raise the pH to 7. Then 0.26 mmol 1,3-bis(bromomethyl)benzene (0.1 M in DMF) was added dropwise. Leave the mixture at room temperature for 20 minutes under stirring, then quench it with TFA (until the pH reaches 3-4). Next, by concentrating in a vacuum, crude Int-B is obtained, which is then subjected to RP-HPLC ( Waters XBridge, C18, 50×150mm, 5μm, 130A; 20 minutes It was purified by adding 25% to 40% ACN / water + 0.1% TFA modifier. It was then recovered. The fraction was freeze-dried to yield 35 mg of the intermediate compound Int-B. CMS analysis C71H85F2N15O13S2 Calculated value: 1458.67; Measured value: 1 458.8(M+1)+

[0375] Step C - Synthesis of Compound Reagent B Intermediate compound Int-B (15 mg) was dissolved in 0.2 ml of anhydrous DMSO. Then, 15 mg of ALEXAFLUOR 647 was dissolved in 1.5 ml of anhydrous DMSO. Added NHS Ester (A37566, Life technology). 20 uL of anhydrous DIPEA was added. The reaction mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere. Placed in a dark place. Quenched with TFA (until pH 3-4), then RP-HPLC (Dr Maish, Reprosil Gold C18, 250×20mm, 120Å, 1 0 μm; 20 minutes to 20% to 35% ACN with 0.1% TFA / H2O with 0.1% T FA, then purified over 5 minutes from 35% to 40% (at a flow rate of 20 mL / min). The collected fraction was freeze-dried to yield 16.1 mg of compound reagent B. LC MS analysis C107H126F2N17O26S6 3- Calculated value: 2296.64; measured Value: 1150.6 (M+2) 2+

[0376] The activity data obtained by one or both of the above procedures is selected by the present invention. The example compounds are reported in the following format: Example No.: A(standard TR Fret) = 'number'; P(Alexa Fr et plus standard TR Fret)='numerical value' / , also note that all reported The value is the nanomolar concentration.

[0377] Alexa FRET Ultra TR-FRET The PCSK9 Alexa FRET Ultra assay uses PCSK9 and Alexa. Reagent B(K) is a cyclic peptide tagged with Fluor647(AF). D (=0.99nM) and The interaction between 1 nM biotinylated PCSK9 and 2.5 nM Lance is measured. A solution containing Streptavidin Europium (Strep-Eu) 50mM HEPES pH7.4, 0.15M NaCl, 5mM CaCl2, 0. Prepared in 0.01% BSA and 0.01% Surfactant P20. 1920 Another solution containing nM AlexaFluor tagged cyclic peptide in the same buffer Prepare the mixture within the system. Use Echo to add 0.015 µl of the compound + 0.735 µl of DM. Transfer SO to each well of the assay plate, followed by 15 µl of PCSK9+Stept- Add Eu and 15 µl of AF peptide. The final assay volume is 30.750 µl. Yes, 0.5nM PCSK9, 1.25nM Strep-Eu and 960nM A It contains an F cyclic peptide. After incubating the reaction mixture at room temperature for at least 2 hours, E Fluorescence measurements are performed using the nvision Multilabel Reader. IC5 A value of 0 means that the data is fitted to a sigmoid dose-response curve using nonlinear regression. It is determined by the IC50 and K of the AF cyclic peptide. D Calculated from The count (B count) of europium-labeled PCSK9 is tracked, and the compound Observe whether it adversely affects PCSK9. A decrease in B count indicates a false positive of inhibition. It is highly likely that it is present. The data from this procedure is "Ki Ultra='numerical value'(reported The data is reported as "nanomolar concentration."

[0378] The following compounds, shown in Table 2, were evaluated using the protocol described above. The results are shown below. show: Ex-01 Ki Plus=<0.00558, Ki Ultra=0.0046 / E x-02 Ki Plus=0.00558、Ki Ultra=0.005933 / E x-03 Ki Plus=0.02535、Ki Ultra=0.06803 / Ex -04 Ki Plus ≦0.00558、Ki Ultra=0.004711 / E x-05 Ki Plus=0.009621、Ki Ultra=0.03296 / E x-06 Ki Plus=0.00568、Ki Ultra=0.003424 / E x-07 Ki Plus=0.05914、Ki Ultra=0.06753 / Ex -08 Ki Plus=0.01574、Ki Ultra=0.06832 / Ex- 09 Ki Plus=0.09189、Ki Ultra=0.247 / Ex-10 Ki Plus=0.005743、Ki Ultra=0.02489 / Ex-11 Ki Plus=0.04334、Ki Ultra=0.2067 / Ex-12 Ki Plus=0.01448、Ki Ultra=0.02247 / Ex-13 Ki Plus=0.1454、Ki Ultra=0.4772 / Ex-14 Ki Plu s=0.01605、Ki Ultra=0.02099 / Ex-15 Ki Plus =0.1027、Ki Ultra=0.2601 / Ex-16 Ki Plus=0. 01423、Ki Ultra=0.05141 / Ex-17 Ki Plus ≦0. 00558、Ki Ultra=0.0028 / Ex-18 Ki Plus=0.03 356、Ki Ultra=0.1183 / Ex-19 Ki Plus=0.0166 2、Ki Ultra=0.01204 / Ex-20 Ki Plus=0.01303 、Ki Ultra=0.01711 / Ex-21 Ki Plus=0.005692 、Ki Ultra=0.001264 / Ex-22 Ki Plus=0.00926 、Ki Ultra=0.01519 / Ex-23 Ki Plus=0.00938、 Ki Ultra=0.00239 / Ex-24 Ki Plus=0.00812、K and Ultra=0.00767 / Ex-25 Ki Plus=0.01127、Ki Ultra=0.00463 / Ex-26 Ki Plus ≦0.00558、Ki Ultra=0.002754 / Ex-27 Ki Plus ≦0.00558、K i Ultra=0.00301 / Ex-28 Ki Plus ≦0.00558、K and Ultra=0.00078 / Ex-29 Ki Plus=0.00981、Ki Ultra=0.00614 / Ex-31 Ki Plus <0.00558、Ki Ultra=0.00074 / Ex-35 Ki Plus=0.04652、Ki Ultra=0.08434 / Ex-36 Ki Plus=0.00762、Ki U ltra=0.00507 / Ex-38 Ki Plus=0.00904、Ki Ul tra=0.01416 / Ex-39 Ki Plus=0.00716、Ki Ult ra=0.00414 / Ex-40 Ki Plus=0.30800、Ki Ultr a=0.86010 / Ex-41 Ki Plus=0.00697、Ki Ultra =0.00628 / Ex-44 Ki Plus=0.01445、Ki Ultra= 0.02194 / Ex-47 Ki Plus=0.01474、Ki Ultra=0 .01193 / Ex-48 Ki Plus=0.01169、Ki Ultra=0. 01545 / Ex-49 Ki Plus=0.00716、Ki Ultra=0.0 0414 / Ex-50 Ki Standard <1.26、Ki Plus=0.0 1052、Ki Ultra=0.00443 / Ex-51 Ki Standard <1.26、Ki Plus <0.00558、Ki Ultra=0.00597 / Ex-52 Ki Standard <1.26, Ki Plus <0.00558 、Ki Ultra=0.00359 / Ex-53 Ki Standard <1.2 6、Ki Plus=0.09629、Ki Ultra=0.21500 / Ex-54 Ki Standard<1.26、Ki Plus=0.36720、Ki Ul tra=0.48390 / Ex-55 Ki Standard <1.26、Ki P lus=0.07240、Ki Ultra=0.23800 / Ex-56 Ki St standard <1.257、Ki Plus=0.02237、Ki Ultra=0 .00481 / Ex-57 Ki Standard <1.257、Ki Plus <0.00558、Ki Ultra=0.00162 / Ex-58 Ki Stand ard <1.257、Ki Plus=0.00773、Ki Ultra=0.00 196 / Ex-59 Ki Plus=0.00788、Ki Ultra=0.004 959 / Ex-60 Ki Plus=0.006515、Ki Ultra=0.00 5312 / Ex-61 Ki Plus=0.00747、Ki Ultra=0.00 6543.

Claims

1. A combination agent comprising a compound of formula I and an additional active agent, Here, the additional active agent is an antihypertensive agent or an anti-atherosclerotic agent. And here, the compound of formula I is either a compound having the following structure, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, X is H, F, Cl, or Br; R １ The following can be selected: (a) - H; or (b) - (CH ２ ) ｚ -R １４Ａ And in the formula: z is 1-6, R １４Ａ teeth: (i) - H; (ii)-NH ２ ; ()))? ＋ H ３ 4 (iv)-N ＋ (H) ３ C) ３ ; (v)-NH-C(O)-[(CH ２ ) ２ -O-] ２ - (CH ２ ) ２ R １４Ｂ (In the formula, R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ in be); (vi)-NH-C(O)-[(CH ２ ) ｙ１２ -O-] ２ - (CH ２ ) ｙ１３ R １４Ｂ (In the formula: y12 and y13 are not both 2 at the same time, but independently from 2 to 4; and R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ (is); (vii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ is -O-(CH ２ ) ３－４ -N ＋ (CH ３ ) ３ (is); and (viii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ teeth: (ai)-O-(CH) ２ ) ２ -N ＋ (CH) ３ ) ３ ; (aii)-N ＋ (CH) ３ ) ３ ; or (aiii) Formula: 【Chemistry 2】 (This is the part) and; R ２ The following can be selected: (a)-H; and (b) - (CH ２ ) ｚ -R １４Ａ And in the formula: z is from 1 to 6, R １４Ａ teeth: (i) - H; (ii)-NH ２ ; ()))? ＋ H ３ 4 (iv)-N ＋ (H) ３ C) ３ ; (v)-NH-C(O)-[(CH ２ ) ２ -O-] ２ - (CH ２ ) ２ R １４Ｂ (In the formula, R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ (is); (vi) -NH-C(O)-[(CH ２ ) ｙ１２ -O-] ２ -(CH ２ ) ｙ１３ R １４Ｂ (where: y12 and y13 are both not 2 simultaneously and are independently from 2 to 4; and, R １４Ｂ is: -NH ２ ; -N ＋ H ３ ; -N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ );; (vii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ is -O-(CH ２ ) ３－４ -N ＋ (CH ３ ) ３ (is); and (viii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ teeth: (ai)-O-(CH) ２ ) ２ -N ＋ (CH) ３ ) ３ ; (aii)-N ＋ (CH ３ ) ２ R １４ｃａ (In the formula, R １４ｃａ is, -CH ３ or - (CH ２ ) １－４ - OCH ３ (is); (aiii) Formula: 【Transformation 3】 The part; or (aiv) Formula: 【Chemistry 4】 The part (in the formula, y １４Ｃｂ and y １４Ｃｃ (1 to 4) is selected from; also is R １ and R ２ These are combined into the expression: 【Transformation 5】 The part may be formed, in the formula: G １ , R Ｇ１ａ and R Ｇ１ｂ It is defined as follows: (a) G １ The formula is: 【Transformation 6】 This is the linker part, in the formula, n ｑ１ The range is from 1 to 6, and m ｑ１ is 0, 1, or 2, and together they make up n ｑ１ and m ｑ１ The values ​​are selected such that the length of the linker portion they define does not exceed eight carbon atoms and / or oxygen atoms in total, including the carbon atoms in the chain that form the carbonyl portion; R Ｇ１ａ a: (i) -H; and (ii) selected from alkyl groups of up to four carbon atoms; and R Ｇ１ｂ teeth: (i) Formula: 【Transformation 7】 The part; and (ii) Formula: 【Transformation 8】 Selected from the part; or (b) G １ The formula is: 【Chemistry 9】 This is the linker part, and in the formula, n ｑ２ is 0, 1, or 2, and m ｑ２ The range is from 1 to 6, and the total is n. ｑ２ and m ｑ２ The values ​​are selected such that the length of the linker portion they define does not exceed eight carbon atoms and / or oxygen atoms in total, including the carbon atoms in the chain that form the carbonyl portion; R Ｇ１ａ teeth: (i) Formula: 【Chemistry 10】 The part; and (ii) Formula: 【Chemistry 11】 Selected from the parts; and R Ｇ１ｂ a: (i) -H; and (ii) selected from alkyl groups of up to four carbon atoms; R ８ is, -CH ３ Or formula: 【Chemistry 12】 This is the part, and in the formula, R ８ａ is either -H or a linear, branched, or cyclic alkyl group of up to four carbon atoms; A is: (a) Formula: 【Chemistry 13】 The part; (b)-CH ２ - (CH ２ ) ｙ -CH ２ - (where y is between 1 and 6); (c) Formula: 【Chemistry 14】 The part (in the formula, A ｂ１ teeth: (i) Formula: 【Chemistry 15】 This is the part where x is between 1 and 6; or (ii) Formula: 【Chemistry 16】 This is the part where y is between 1 and 5 in the formula; (d) Formula: -CH ２ - (CH ２ ) ｍ -O-(CH ２ ) ｎ The part marked with a hyphen (where m is between 1 and 5, and n is between 0 and 4) Selected from; B is: (a) combination; (b) - (CH ２ ) １－２ ;or (c) Formula: 【Chemistry 17】 This is the part; D is: (a) Formula: [Chemistry 18] The part (where E is -CH) ２ - or - (CH ２ ) ２－４ (-O-, and A and B are as defined above); (b) Formula: 【Chemistry 19】 The part of the formula (wherein A and B are as defined above); (c) Formula: 【Chemistry 20】 The part (in the formula, n ａ is 1, 2, or 3, and m ａ is 2, 3, or 4, and n ａ +m ａ (wherein A and B are as defined above); or (d) Formula: 【Chemistry 21】 The part (in the formula, R ３４ｂ (wherein A is -H, or a linear, branched, or cyclic alkyl group of up to four carbon atoms, and A and B are as defined above.) The aforementioned combination agent.

2. The combination agent according to claim 1, wherein the compound of formula I is a compound having the structure of formula IIE, or a pharmaceutically acceptable salt thereof; 【Chemistry 22】 [In the formula, R １ The following can be selected: (a) - H; or (b) - (CH ２ ) ｚ -R １４Ａ And in the formula: z is 1-6, R １４Ａ teeth: (i) - H; (ii)-NH ２ ; ()))? ＋ H ３ 4 (iv)-N ＋ (H) ３ C) ３ ; (v)-NH-C(O)-[(CH ２ ) ２ -O-] ２ - (CH ２ ) ２ R １４Ｂ (In the formula, R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ in be); (vi)-NH-C(O)-[(CH ２ ) ｙ１２ -O-] ２ - (CH ２ ) ｙ１３ R １４Ｂ (In the formula: y12 and y13 are not both 2 at the same time, but independently from 2 to 4; and R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ (is); (vii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ is -O-(CH ２ ) ３－４ -N ＋ (CH ３ ) ３ (is); and (viii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ teeth: (ai)-O-(CH) ２ ) ２ -N ＋ (CH) ３ ) ３ ; (aii)-N ＋ (CH ３ ) ３ ; and R ２ The following can be selected: (a)-H; and (b) - (CH ２ ) ｚ -R １４Ａ And in the formula: z is from 1 to 6, R １４Ａ teeth: (i) - H; (ii)-NH ２ ; ()))? ＋ H ３ 4 (iv)-N ＋ (H) ３ C) ３ ; (v)-NH-C(O)-[(CH ２ ) ２ -O-] ２ - (CH ２ ) ２ R １４Ｂ (In the formula, R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ (is); (vi)-NH-C(O)-[(CH ２ ) ｙ１２ -O-] ２ - (CH ２ ) ｙ１３ R １４Ｂ (In the formula: y12 and y13 are not both 2 at the same time, but independently from 2 to 4; and R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ (is); (vii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ is -O-(CH ２ ) ３－４ -N ＋ (CH ３ ) ３ (is); and (viii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ teeth: (ai)-O-(CH) ２ ) ２ -N ＋ (CH) ３ ) ３ ; (aii)-N ＋ (CH ３ ) ２ R １４ｃａ (In the formula, R １４ｃａ is, -CH ３ or - (CH ２ ) １－４ - OCH ３ (is); and A is selected from the following: (a)-CH ２ - (CH ２ ) ｙ -CH ２ - (where y is between 1 and 6); (b) Formula: 【Chemistry 23】 The part (in the formula, A ｂ１ teeth: (i) Formula: 【Chemistry 24】 This is the part where x is between 1 and 6; or (ii) Formula: 【Chemistry 25】 This is the part where y is between 1 and 5 in the formula; (c) Formula: -CH ２ - (CH ２ ) ｍ -O-(CH ２ ) ｎ The part marked with a minus sign (where m is between 1 and 5, and n is between 0 and 4); The aforementioned combination agent.

3. R １ teeth: (a) - (CH ２ ) ｚ -R １４Ａ And in the formula: z is 1-6, R １４Ａ teeth: (i) - H; (ii)-NH ２ ; ()))? ＋ H ３ 4 (iv)-N ＋ (H) ３ C) ３ ; (v)-NH-C(O)-[(CH ２ ) ２ -O-] ２ - (CH ２ ) ２ R １４Ｂ (In the formula, R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ in be); (vi)-NH-C(O)-[(CH ２ ) ｙ１２ -O-] ２ - (CH ２ ) ｙ１３ R １４Ｂ (In the formula: y12 and y13 are not both 2 at the same time, but independently from 2 to 4; and R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ (is); (vii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ is -O-(CH ２ ) ３－４ -N ＋ (CH ３ ) ３ (is); and (viii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ teeth: (ai)-O-(CH) ２ ) ２ -N ＋ (CH) ３ ) ３ ; (aii)-N ＋ (CH ３ ) ３ ; and R ２ teeth: (a) - (CH ２ ) ｚ -R １４Ａ And in the formula: z is from 1 to 6, R １４Ａ teeth: (i) - H; (ii)-NH ２ ; ()))? ＋ H ３ 4 (iv)-N ＋ (H) ３ C) ３ ; (v)-NH-C(O)-[(CH ２ ) ２ -O-] ２ - (CH ２ ) ２ R １４Ｂ (In the formula, R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ (is); (vi)-NH-C(O)-[(CH ２ ) ｙ１２ -O-] ２ - (CH ２ ) ｙ１３ R １４Ｂ (In the formula: y12 and y13 are not both 2 at the same time, but independently from 2 to 4; and R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ (is); (vii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ is -O-(CH ２ ) ３－４ -N ＋ (CH ３ ) ３ (is); or (viii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ teeth: (ai)-O-(CH) ２ ) ２ -N ＋ (CH) ３ ) ３ ; (aii)-N ＋ (CH ３ ) ２ R １４ｃａ (In the formula, R １４ｃａ is, -CH ３ or - (CH ２ ) １－４ - OCH ３ (is); and A is: (a)-CH ２ - (CH ２ ) ｙ -CH ２ - (where y is between 1 and 6); The combination agent according to claim 2.

4. R １ teeth: (a) - (CH ２ ) ｚ -R １４Ａ And in the formula: z is 1-6, R １４Ａ teeth: (i) - H; R ２ teeth: (a) - (CH ２ ) ｚ -R １４Ａ And in the formula: z is from 1 to 6, R １４Ａ teeth: (i) - H; (ii)-NH ２ ; ()))? ＋ H ３ 4 (iv)-N ＋ (H) ３ C) ３ ; (v)-NH-C(O)-[(CH ２ ) ２ -O-] ２ - (CH ２ ) ２ R １４Ｂ (In the formula, R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ (is); (vi)-NH-C(O)-[(CH ２ ) ｙ１２ -O-] ２ - (CH ２ ) ｙ１３ R １４Ｂ (In the formula: y12 and y13 are not both 2 at the same time, but independently from 2 to 4; and R １４Ｂ ha: -NH ２ ;-N ＋ H ３ ;-N(CH ３ ) ２ ; or -N ＋ (CH ３ ) ３ (is); (vii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ is -O-(CH ２ ) ３－４ -N ＋ (CH ３ ) ３ (is); or (viii)-NH-C(O)-(CH ２ ) ｙ R １４Ｃ (In the formula, y is from 1 to 6, R １４Ｃ teeth: (ai)-O-(CH) ２ ) ２ -N ＋ (CH) ３ ) ３ ; (aii)-N ＋ (CH ３ ) ２ R １４ｃａ (In the formula, R １４ｃａ is, -CH ３ or - (CH ２ ) １－４ - OCH ３ (is); and A is: (a)-CH ２ - (CH ２ ) ｙ -CH ２ - (where y is between 1 and 6); The combination agent according to claim 3.

5. The combination agent according to claim 1, wherein the compound of formula I is selected from the following: 【Chemistry 26】 【change】 【change】 Here, A － It is a pharmaceutically acceptable anion.

6. A combination of any one of claims 1 to 5, wherein the additional active agent is a lipid-lowering agent, a cholesterol absorption inhibitor, an HMG-CoA reductase inhibitor, niacin in immediate-release or controlled-release form; a niacin receptor agonist or niacin receptor partial agonist, a PPARα agonist, or a bile acid metal ion chelating agent.

7. A combination of any two claims, 1 to 6, wherein the additional active agent is selected from simvastatin, lovastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin, cerivastatin, and pitavastatin.

8. A combination agent according to any one of claims 1 to 7, wherein the additional active agent is rosuvastatin.

9. A combination formulation of any one of claims 1 to 8, wherein the compound of formula I and an additional active agent constitute a single drug formulation.

10. A combination agent according to any one of claims 1 to 8, wherein the compound of formula I and an additional active agent are separate drug formulations.

11. A combination agent comprising a compound of formula I with the following structure, 【Chemistry 27】 Here, A － It is a pharmaceutically acceptable anion. The aforementioned combination agent comprises an additional active agent, wherein the additional active agent is an antihypertensive agent or an anti-atherosclerotic agent. Combination agent.

12. The compound of formula I is as follows: 【Chemistry 28】 The combination agent according to claim 11.

13. The combination agent according to claim 11 or 12, wherein the additional active agent is a lipid-lowering agent, a cholesterol absorption inhibitor, an HMG-CoA reductase inhibitor, niacin in immediate-release or controlled-release form, a niacin receptor agonist or niacin receptor partial agonist, a PPARα agonist or a bile acid metal ion chelating agent.

14. A combination of any one of claims 11 to 13, wherein the additional active agent is selected from simvastatin, lovastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin, cerivastatin, and pitavastatin.

15. A combination of any one of claims 11 to 14, wherein the additional active agent is rosuvastatin.

16. A combination formulation of any one of claims 11 to 15, wherein the compound of formula I and an additional active agent constitute a single drug formulation.

17. A combination formulation according to any one of claims 11 to 15, wherein the compound of formula I and an additional active agent are separate drug formulations.

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