Method for preparing pharmaceutically appropriate peptides

Abstract

To provide methods of generating pharmaceutically relevant peptides and intermediates thereof.SOLUTION: The present technology provides methods of generating peptides, and pharmaceutically acceptable salts of the peptides and intermediates thereof. In some embodiments, the peptide is D-Arg-2'6'-Dmt-Lys-Phe-NH2.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 129,575, filed on March 6, 2015, the contents of which are incorporated herein by reference in their entirety.

[0002] Technical field This technology generally relates to methods for producing pharmaceutically relevant peptides and their intermediates. [Overview of the project] [Means for solving the problem]

[0003] In one embodiment, a method for preparing a compound of formula VIII or a salt thereof is provided. [ka] This method involves using a compound of formula IA or a salt thereof. [ka] React with the compound of formula IB or its salt, [ka] To form a compound of formula IC or a salt thereof, [ka] Converting a compound of formula IC to a compound of formula ID or a salt thereof, [ka] The compound of formula ID or a salt thereof is reacted with the compound of formula IE or a salt thereof to form the compound of formula VIII or a salt thereof. [ka] Including, in the formula, A 1 and A 2 each independently forms, together with a carbonyl group to which each is attached, a carboxylic acid, an active ester, an anhydride, or an acid halide; for example, A 1 and A 2 each independently is -OH, -O-R 58 , -OC(O)-R 59 , F, Cl, or Br, and R 58 is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group, and R 59 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, R 1 and R 2 each independently is (i) hydrogen, (ii) substituted or unsubstituted C1-C6 alkyl, (iii) substituted or unsubstituted aralkyl, (iv) substituted or unsubstituted C3-C8 cycloalkyl or cycloalkylalkyl, (v) substituted or unsubstituted C2-C6 alkenyl, (vi) an amino protecting group, or alternatively R 1 and R 2 together form a 3-, 4-, 5-, 6-, 7-, or 8-membered substituted or unsubstituted heterocyclyl or heteroaryl group, R 8a and R 8b each independently is

Chemical formula

Chemical formula

Chemical formula

[0004] In one embodiment, a method for preparing a compound of formula VIII or a salt thereof is provided. [ka] This method involves reacting a compound of formula II-D or a salt thereof with a compound of formula IB or a salt thereof to form a compound of formula VIII or a salt thereof. [ka] [ka] Including, in the formula, A 4 However, together with the carbonyl group to which it is bonded, it forms a carboxylic acid, an active ester, an anhydride, or an acid halide, for example, A 4 However, -OH, -OR 58 -OC(O)-R 59 It may be F, Cl, or Br, R 58 However, R is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group. 59 However, these are substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, R 1 and R 2 However, each operates independently. (i) Hydrogen, (ii) Substituted or unsubstituted C1-C6 alkyl groups, (iii) Substitution or non-substitution aralkyl, (iv) Substituted or unsubstituted C3-C8 cycloalkyl or cycloalkylalkyl, (v) Substituted or unsubstituted C2-C6 alkenyl, (vi) an amino protecting group, Or R 1 and R 2 Together, they form a 3, 4, 5, 6, 7, or 8-membered substituted or unsubstituted heterocyclyl or heteroaryl group. R 8a and R 8b However, each operates independently. [ka] [ka] or [ka] Selected from, In the formula, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 55 and R 56 Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R9 is OR’ or NR’R’’, where R’ at each occurrence is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, and R’’ is hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, R 12 is hydrogen, -OH, halogen (e.g., F, Cl, Br, I), C1-C6 alkyl, -O-C1-C6 alkyl, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C4-perhaloalkyl, aralkyl, -O-aralkyl, -NH-aralkyl, -N(aralkyl)2, -N(C1-C6 alkyl)(aralkyl), -C(O)-alkyl, -C(O)-aryl, or -C(O)-aralkyl, wherein each alkyl, aryl, or aralkyl group is substituted or unsubstituted, R 22 , R 23 , and R 24 are each independently hydrogen or C1-C4 alkyl, n is 1, 2, 3, 4, or 5, m is 1, 2, 3, 4, or 5, X 1 , X 2 , and X 4 are independently at each occurrence hydrogen or an amino protecting group, e.g., an amino protecting group sensitive to acid-mediated removal, or an amino protecting group resistant to acid-mediated removal and sensitive to base-mediated or hydrogen-mediated removal, X 3 is R 2 , hydrogen, or an amino protecting group, Z 5 and Z 6 are each independently -NHX 1 , -C(N-X 4 )-NH-X 2, -NX 1 C(N - X 4 ) - NH - X 2 , -NX 1 (C1 - C6 alkyl), -NX 1 (C6 - C 10 aryl), -NX 1 (C7 - C 12 aralkyl), or a nitrogen - containing heterocyclic or heteroaryl group, and each alkyl, aryl, aralkyl, heterocyclic, or heteroaryl group is substituted or unsubstituted.

[0005] In some embodiments, the compound of formula II - D or a salt thereof is prepared by a method comprising converting a compound of formula II - C or a salt thereof to a compound of formula II - D or a salt thereof.

Chemical formula

[0006] In some embodiments, the compound of formula II - C or a salt thereof is prepared by a method comprising reacting a compound of formula II - A or a salt thereof with a compound of formula I - E or a salt thereof to form a compound of formula II - C or a salt thereof.

Chemical formula

Chemical formula

[0007] In some embodiments, a compound of formula IA or II-A or a salt thereof is prepared by converting a compound of IF or a salt thereof to a compound of IA or II-A or a salt thereof. [ka] In the formula, n, W 1 , Y 1 , Z 5 , R 22 , and R 8a However, as defined herein.

[0008] In some embodiments, a compound of formula IF or a salt thereof is prepared by a method comprising reacting a compound of formula IG or a salt thereof with a compound of formula IH or a salt thereof. [ka] [ka] In the formula, R 8a , R 22 , R 23 , W 1 , Y 1 , Z 5 , and n are as defined herein, and A 5 However, together with the carbonyl group to which it is bonded, it forms a carboxylic acid, an active ester, an anhydride, or an acid halide, for example, A 5 However, -OH, -OR 58 -OC(O)-R 59 It may be F, Cl, or Br, R 58However, R is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group. 59 However, these are substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl.

[0009] In another embodiment, a method for preparing a compound of formula VIII or a salt thereof is provided. [ka] This method involves reacting a compound of formula III-A or a salt thereof with a compound of formula III-B or a salt thereof to form a compound of formula VIII or a salt thereof. [ka] [ka] Including, in the formula, A 6 However, together with the carbonyl group to which it is bonded, it forms a carboxylic acid, an active ester, an anhydride, or an acid halide, for example, A 6 However, -OH, -OR 58 -OC(O)-R 59 It may be F, Cl, or Br, R 58 However, R is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group. 59 However, these are substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, R 1 and R 2 However, each operates independently. (i) Hydrogen, (ii) Substituted or unsubstituted C1-C6 alkyl groups, (iii) Substitution or non-substitution aralkyl, (iv) Substituted or unsubstituted C3-C8 cycloalkyl or cycloalkylalkyl, (v) Substituted or unsubstituted C2-C6 alkenyl, (vi) an amino protecting group, Or R 1 and R 2 Together, they form a 3, 4, 5, 6, 7, or 8-membered substituted or unsubstituted heterocyclyl or heteroaryl group. R 8a and R 8b However, each operates independently. [ka] [ka] or [ka] Selected from, In the formula, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 55 and R 56Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 9 However, R'' is OR' or NR'R'', where R' in each occurrence is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, and R'' is hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, R 12 However, the group is selected from hydrogen, -OH, halogen (e.g., F, Cl, Br, I), C1-C6 alkyl, -O-C1-C6 alkyl, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C4-perhaloalkyl, aralkyl, -O-aralkyl, -NH-aralkyl, -N(aralkyl)2, -N(C1-C6 alkyl)(aralkyl), -C(O)-alkyl, -C(O)-aryl, or -C(O)-aralkyl, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 22 , R 23 , and R 24 However, each is independently hydrogen or a C1-C4 alkyl group. n is 1, 2, 3, 4, or 5. m is 1, 2, 3, 4, or 5. X 1 , X 2 , and X 4However, in each instance, independently, there is a hydrogen or amino protecting group, for example, an amino protecting group that is sensitive to acid-mediated removal, or an amino protecting group that is resistant to acid-mediated removal and sensitive to base-mediated or hydrogen-mediated removal. X 3 However, R 2 , hydrogen, or amino protecting group, Z 5 and Z 6 However, each operates independently, -NHX 1 -C(NX 4 )-NH-X 2 , -NX 1 C(NX 4 )-NH-X 2 , -NX 1 (C1~C6 alkyl), -NX 1 (C6~C 10 Aryl), -NX 1 (C7~C 12 The group is an aralkyl, aralkyl, heterocyclyl, or heteroaryl group, and each alkyl, aryl, aralkyl, heterocyclyl, or heteroaryl group may be substituted or unsubstituted.

[0010] In some embodiments, the compound of formula III-A or a salt thereof is prepared by a method comprising converting the compound of formula III-C or a salt thereof to the compound of formula III-A or a salt thereof. [ka] In the formula, W 2 However, R is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, 1 , R 8a , R 22 , W 2 , X 3 , Z 6, and m are as defined herein. In some embodiments, W2 is benzyl (Bn), X3 is Boc, and the conversion of the compound of formula IIIC involves reducing and cleaving benzyl to H (e.g., H2, and using a supported transition metal such as Pd or Pt on carbon). In some embodiments, R 1 and R 22 Both are H, m is 3, Z 6 It is -NHC(NH)NH2, and R 8a This is 2,6-dimethyl-4-hydroxyphenyl. For example, the compound of formula III-C may be Boc-D-Arg-DMT-OBn.

[0011] In some embodiments, the compound of formula III-C or a salt thereof is prepared by a method comprising reacting the compound of formula III-D or a salt thereof with the compound of formula IE or a salt thereof to form the compound of formula III-C or a salt thereof. [ka] [ka] In the formula, A 2 , R 1 , R 8a , R 22 , W 2 , X 3 , Z 6 , and m are as defined herein.

[0012] In some embodiments, the compound of formula III-B or a salt thereof is prepared by a method comprising converting the compound of formula III-E or a salt thereof to the compound of formula III-B or a salt thereof. [ka] In the formula, Y 2 However, the amino protecting group is, for example, an amino protecting group that is sensitive to acid-mediated removal, or an amino protecting group that is resistant to acid-mediated removal and sensitive to base-mediated or hydrogen-mediated removal, R8b , R 9 , R 23 , R 24 , Z 5 , and n are as defined herein. In some embodiments, Y 2 is Cbz, and the conversion of the III-E compound involves reducing and cleaving Cbz to H (e.g., H2, and using a supported transition metal such as Pd or Pt on the carbon). In some embodiments, R 9 It is -NH2, and R 23 H is H, n is 4, Z 5 is -NHBoc, and R 8b is an unsubstituted phenyl compound. For example, the compound of formula III-E may be Cbz-Lys(Boc)-Phe-NH2.

[0013] In some embodiments, the compound of formula III-E or a salt thereof is prepared by a method comprising reacting the compound of formula IB or a salt thereof with the compound of formula III-F or a salt thereof to form the compound of formula III-E or a salt thereof. [ka] [ka] In the formula, R 8b , R 9 , R 23 , R 24 , W 1 , Y 2 , Z 5 , and n are as defined herein, and A 7 However, together with the carbonyl group to which it is bonded, it forms a carboxylic acid, an active ester, an anhydride, or an acid halide, for example, A 7 However, -OH, -OR 58 -OC(O)-R 59 It may be F, Cl, or Br, R 58 However, R is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group. 59However, these are substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl.

[0014] In any of the embodiments described above, the conditions for forming the compound of formula VIII or a salt thereof may include a coupling agent. Such coupling agents used in any of the embodiments and models described herein may include carbodiimides, uronium salts, aminium salts, immonium salts, carbonium salts, phosphonium salts, phosphorus reagents, pentafluorophenol reagents, and the like, all known in the art. In any of the embodiments described above, the conditions for forming the compound of formula VIII or a salt thereof may further include the solvents described herein. In any of the embodiments described above, the conditions for forming the compound of formula VIII or a salt thereof may further include a base. In any of the embodiments described above, the conditions for forming the compound of formula VIII or a salt thereof may include EDC and HOBT, EDC-HCl and HOBT, BOP and HOBT, or HATU and HOAT. In any of the embodiments described above, the coupling agent may be propylphosphonic anhydride (T3P).

[0015] In some embodiments, Y 1 is an amino protecting group that is sensitive to acid-mediated removal, and converting a compound of formula IC or a salt thereof to formula ID or a salt thereof may involve combining a compound of formula IC or a salt thereof with a cleaving acid. In some embodiments, Y 1 is an amino protecting group that is sensitive to acid-mediated removal, and converting a compound of formula IF or a salt thereof to formula II-A or a salt thereof involves combining a compound of formula IF or a salt thereof with a cleaving acid. Examples of cleaving acids are known in the art and are described herein. In any of the embodiments described above, the combination with a cleaving acid may further include a protic solvent, a polar aprotic solvent, or a mixture of the two.

[0016] In another embodiment, X in a compound of formula VIII or a salt thereof 1 , X 2 , X 3 , and X 4 If at least one of the amino protecting groups is resistant to acid-mediated removal and sensitive to hydrogen-mediated removal, this method involves reacting the compound of formula VIII or a salt thereof with a hydrogen source and a transition metal catalyst to obtain the compound of formula I or a salt thereof. [ka] or forming a pharmaceutically acceptable salt thereof, further comprising, in the formula, R 1 and R 2 However, each operates independently. (i) Hydrogen, (ii) Substituted or unsubstituted C1-C6 alkyl groups, (iii) Substitution or non-substitution aralkyl, (iv) Substituted or unsubstituted C3-C8 cycloalkyl or cycloalkylalkyl, (v) Substituted or unsubstituted C2-C6 alkenyl, (vi) an amino protecting group, Or R 1 and R 2 Together, they form a 3, 4, 5, 6, 7, or 8-membered substituted or unsubstituted heterocyclyl or heteroaryl group. R 3 , R 4 , R 6 , and R 7 Each of these is independently hydrogen, or a C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl group, where each of the alkyl, aryl, or aralkyl groups is substituted or unsubstituted. R 5is selected from hydrogen, or C1-C6 alkyl, aralkyl, -C(O)-alkyl, -C(O)-aryl, or -C(O)-aralkyl, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 8b but, [ka] [ka] or [ka] And, In the formula, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 55 and R 56 Each is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted, and R 9However, R'' is OR' or NR'R'', where R' in each occurrence is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, and R'' is hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, R 12 However, the group is selected from hydrogen, -OH, halogen (e.g., F, Cl, Br, I), C1-C6 alkyl, -O-C1-C6 alkyl, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C4-perhaloalkyl, aralkyl, -O-aralkyl, -NH-aralkyl, -N(aralkyl)2, -N(C1-C6 alkyl)(aralkyl), -C(O)-alkyl, -C(O)-aryl, or -C(O)-aralkyl, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 22 , R 23 , and R 24 However, each is independently hydrogen or a C1-C4 alkyl group. n is 1, 2, 3, 4, or 5. m is 1, 2, 3, 4, or 5. Z 1 and Z 2 However, each of these is independently a hydrogen atom, a -C(NH)-NH2 group, or a substituted or unsubstituted alkyl, aryl, or aralkyl group.

[0017] In another embodiment, X in a compound of formula VIII or a salt thereof 1 , X 2 , X 3 , and X 4 If at least one of them is an amino protecting group resistant to acid-mediated removal, the method further comprises reacting a compound of formula VIII or a salt thereof with a cleaving acid to form a compound of formula I or a salt thereof. In some embodiments, X1 , X 2 , X 3 , and X 4 One or more of these are Boc groups. In some such embodiments, the Boc groups are optionally removed with HCl under anhydrous conditions to provide HCl salts of compounds of formula VIII or I.

[0018] Alternatively, in any embodiment of this specification, a salt of a compound of formula I, formula VIII, VIII-B or any other such compound may be an aliphatic carboxylate, hydrochloride, hydrobromide, alkylsulfonate, arylsulfonate, fumarate, succinate, tartrate, oxalate, phosphate, or sulfate. [Modes for carrying out the invention]

[0019] definition Definitions of certain terms used herein are provided below. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as those commonly understood by those skilled in the art to which this art belongs.

[0020] As used herein and in the appended claims, unless the context explicitly indicates otherwise, the singular forms “a,” “an,” and “the” refer to multiple objects. For example, “a cell” refers to a combination of two or more cells, and so on.

[0021] As used herein, “approximately” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where the use of a term is not clear to those skilled in the art, “approximately” means up to ±10% of a particular term, given the context in which it is used.

[0022] As will be understood by those skilled in the art, for all purposes, and especially in relation to providing written descriptions, all scopes described herein also encompass all possible subscopes and combinations of subscopes. It will be readily apparent that any scope described herein is sufficiently descriptive and capable of enabling the division of the same scope into at least equally equal parts, such as two-thirds, three-thirds, four-thirds, five-thirds, ten-thirds, etc. As a non-limiting example, each scope discussed herein may easily be divided into the lower third, middle third, upper third, etc. Also as will be understood by those skilled in the art, all terms such as “maximum,” “at least,” “greater than,” and “less than” include the number cited and refer to a scope that can be divided into the aforementioned subscopes. Finally, as will be understood by those skilled in the art, a scope includes each individual element. Thus, for example, a group having 1 to 3 atoms refers to a group having 1, 2, or 3 atoms. Similarly, a group having 1 to 5 atoms refers to a group having 1, 2, 3, 4, or 5 atoms (and so on).

[0023] As used herein, “administration” of a drug, pharmacokinetic, or peptide to a target includes any route of introduction or delivery of the compound to the target to perform its intended function. Administration may be carried out by any preferred route, including oral, intranasal, parenteral (intravenous, intramuscular, intraperitoneal, or subcutaneous), or topical. Administration may include self-administration and administration by another person.

[0024] Generally, a reference to a particular element, such as hydrogen or H, implies the inclusion of all isotopes of that element. For example, if the R group is defined as containing hydrogen or H, it also includes deuterium and tritium. Tritium, C 14 , P 32 , and S 35 Compounds containing radioactive isotopes such as those mentioned above are therefore within the scope of the present invention. Procedures for inserting such labels into compounds of the present invention will be readily apparent to those skilled in the art based on the disclosure herein.

[0025] Generally, "substituted" refers to an organic group (e.g., an alkyl group) as defined below, in which one or more bonds to hydrogen atoms are replaced by bonds to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to carbon atoms or hydrogen atoms are replaced by one or more bonds, including double or triple bonds, to heteroatoms. Thus, unless otherwise specified, substituted groups are replaced by one or more substituents. In some embodiments, substituted groups are replaced by one, two, three, four, five, or six substituents. Examples of substituents include halogens (i.e., F, Cl, Br, and I), hydroxyl, alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkoxy groups, carbonyl (oxo), carboxyl, ester, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, thiol, sulfide, sulfoxide, sulfone, sulfonyl, sulfonamide, amine, N-oxide, hydrazine, hydrazide, hydrazone, azide, amide, urea, amidine, guanidine, enamine, imide, isocyanate, isothiocyanate, cyanate, thiocyanate, imine, nitro group, nitrile (i.e., CN), and others.

[0026] Substituted ring groups, such as substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups, also include rings and ring systems in which bonds to hydrogen atoms are replaced by bonds to carbon atoms. Thus, substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups can also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups, as defined below.

[0027] Alkyl groups include linear and branched alkyl groups having 1 to 12 carbon atoms, typically 1 to 10 carbon atoms, or in some embodiments, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of linear alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Alkyl groups may be substituted or unsubstituted. Typical substituted alkyl groups may be substituted one or more times with substituents such as those listed above, and may include, but are not limited to, haloalkyls (e.g., trifluoromethyl), hydroxyalkyls, thioalkyls, aminoalkyls, alkylaminoalkyls, dialkylaminoalkyls, alkoxyalkyls, and carbonylalkyls.

[0028] Cycloalkyl groups include monocyclic, bicyclic, or tricyclic alkyl groups having 3 to 12 carbon atoms in the ring(s), or in some embodiments, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Examples of bicyclic and tricyclic systems include, but are not limited to, bicyclo[2.1.1]hexane, adamantyl, and dekalinyl, and include both cross-linked cycloalkyl groups and fused rings. Cycloalkyl groups may be substituted or unsubstituted. Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups, as defined above. However, substituted cycloalkyl groups also include rings substituted with linear or branched alkyl groups, as defined above. Typical substituted cycloalkyl groups may be monosubstituted or, if not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above, and may also be once-supersubstituted.

[0029] A cycloalkylalkyl group is an alkyl group as defined above, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds to the cycloalkyl group as defined above. In some embodiments, a cycloalkylalkyl group has 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms. Cycloalkylalkyl groups may be substituted or unsubstituted. A substituted cycloalkylalkyl group may be substituted at the alkyl moiety, the cycloalkyl moiety, or both the alkyl and cycloalkyl moiety of the group. Typical substituted cycloalkylalkyl groups may be monosubstituted, or may be one-time supersubstituted, including but not limited to monosubstituted, disubstituted, or trisubstituted with substituents such as those listed above.

[0030] Alkenyl groups include linear and branched alkyl groups as defined above, except that at least one double bond is present between two carbon atoms. Alkenyl groups have 2 to 12 carbon atoms, typically 2 to 10 carbon atoms, or in some embodiments, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkenyl groups have one, two, or three carbon-carbon double bonds. Examples include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), and -C(CH2CH3)=CH2. Alkenyl groups may be substituted or unsubstituted. Typical substituted alkenyl groups may be monosubstituted or two or more times, for example, monosubstituted, disubstituted, or trisubstituted with substituents such as those listed above, but are not limited to these.

[0031] A cycloalkenyl group includes the cycloalkyl groups defined above, having at least one double bond between two carbon atoms. In some embodiments, the cycloalkenyl group may have one, two, or three double bonds, but may not contain aromatic compounds. The cycloalkenyl group has 4 to 14 carbon atoms, or in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkenyl group may be substituted or unsubstituted.

[0032] A cycloalkenylalkyl group is an alkyl group as defined above, in which the hydrogen or carbon bond of the alkyl group is replaced by a bond to a cycloalkenyl group as defined above. Cycloalkenylalkyl groups may be substituted or unsubstituted. A substituted cycloalkenylalkyl group may be substituted at the alkyl moiety, the cycloalkenyl moiety, or both the alkyl and cycloalkenyl moieties of the group. Typical substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above.

[0033] Alkynyl groups include linear and branched alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Alkynyl groups have 2 to 12 carbon atoms, typically 2 to 10 carbon atoms, or in some embodiments, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkynyl groups have one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to, -C≡CH, -C≡CCH3, -CH2C≡CCH3, and -C≡CCH2CH(CH2CH3)2. Alkynyl groups may be substituted or unsubstituted. Typical substituted alkynyl groups may be monosubstituted or two or more times, for example, monosubstituted, disubstituted, or trisubstituted with substituents such as those listed above, but are not limited to these.

[0034] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. The aryl groups described herein include monocyclic, bicyclic, and tricyclic systems. Therefore, aryl groups include, but are not limited to, phenyl, azlenyl, heptarenyl, biphenyl, fluorenyl, phenantrenyl, anthracenyl, indenyl, indanyl, pentarenyl, and naphthyl groups. In some embodiments, the aryl group contains 6 to 14 carbon atoms in the ring portion of the group; in other embodiments, 6 to 12 carbon atoms, or even 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. The term "aryl group" includes groups containing fused rings, such as fused aromatic aliphatic rings (e.g., indanyl, tetrahydronaphthyl, etc.). The term "aryl group" also includes substituted aryl groups. Groups such as tolyls are referred to as substituted aryl groups. Typical substituted aryl groups may be monosubstituted or once-supersubstituted. For example, a monosubstituted aryl group may include, but is not limited to, a 2, 3, 4, 5, or 6-substituted phenyl or naphthyl group, which may be substituted with substituents such as those listed above. In some embodiments, the aryl group may be a phenyl group which may be substituted or unsubstituted. In some embodiments, the substituted phenyl group may have one or two substituents. In some embodiments, the substituted phenyl group may have one substituent.

[0035] An aralkyl group is an alkyl group as defined above, in which the hydrogen or carbon bonds of the alkyl group are replaced by bonds to an aryl group as defined above. In some embodiments, an aralkyl group contains 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. An aralkyl group may be substituted or unsubstituted. A substituted aralkyl group may be substituted at the alkyl moiety, the aryl moiety, or both the alkyl and aryl moiety of the group. Typical aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and condensed (cycloalkylaryl) alkyl groups such as 4-indanylethyl. Typical substituted aralkyl groups may be substituted once or more with substituents such as those listed above.

[0036] A heterocyclyl or heterocyclic group is a non-aromatic cyclic compound containing three or more ring members, one or more of which are heteroatoms such as, but not limited to, N, O, and S. In some embodiments, a heterocyclyl group contains one, two, three, or four heteroatoms. In some embodiments, a heterocyclyl group includes monocyclic, bicyclic, and tricyclic rings having 3 to 16 ring members, while other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclyl groups include partially unsaturated and saturated cyclic systems, such as imidazolinyl and imidazolidinyl groups. This term also includes bridged polycyclic cyclic systems containing heteroatoms such as, but not limited to, quinuclidyl. This term also includes heterocyclyl groups that have another group, such as an alkyl, oxo, or halo group, bonded to one of their ring members, and are referred to as "substituted heterocyclyl groups." Examples of heterocyclyl groups include, but are not limited to, azilidinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, dioxolyl, pyrrolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranil, and tetrahydrothiopyranil groups. Typical substituted heterocyclyl groups may be monosubstituted, or two or more substituted groups such as morpholinyl groups that are 2, 3, 4, 5, or 6 substituted, or disubstituted with various substituents such as those listed above. Heteroatoms may be in oxidized form if chemically possible.

[0037] A heteroaryl group is an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms such as N, O, and S, but not limited to these. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanil, benzofuranil, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaftyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused ring compounds in which all rings are aromatic, such as indolyl groups, and fused ring compounds in which only one of the rings is aromatic, such as a 2,3-dihydroindolyl group. The term "heteroaryl group" includes fused ring compounds and also includes heteroaryl groups referred to as "substituted heteroaryl groups," which have another group, such as an alkyl group, bonded to one of the ring members. Typical substituted heteroaryl groups can be substituted one or more times with various substituents, such as those listed above. Heteroatoms can also be in oxidized form if chemically possible.

[0038] A heterocyclylalkyl group is an alkyl group as defined above, in which the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclyl group as defined above. Heterocyclylalkyl groups may be substituted or unsubstituted. A substituted heterocyclylalkyl group may be substituted at the alkyl moiety, the heterocyclyl moiety, or both the alkyl and heterocyclyl moiety of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholine-4-ylethyl and tetrahydrofuran-2-ylethyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those listed above. Heteroatoms may also be in oxidized form if chemically possible.

[0039] A heteroaralkyl group is an alkyl group as defined above, in which the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above. Heteroaralkyl groups may be substituted or unsubstituted. A substituted heteroaralkyl group may be substituted at the alkyl moiety, the heteroaryl moiety, or both the alkyl and heteroaryl moiety of the group. Typical substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above. Heteroatoms may also be in oxidized form if chemically possible.

[0040] Groups described herein that have two or more bond sites in the compounds of the present invention (i.e., divalent, trivalent, or polyvalent) are designated by the use of the suffix "ene". For example, a divalent alkyl group is an alkylene group, a divalent aryl group is an arylene group, and a divalent heteroaryl group is a divalent heteroarylene group (and so on). Substituted groups having a single bond site in the compounds of the present invention are not referred to using the "ene" designation. Therefore, for example, chloroethyl is not referred to as chloroethylene herein.

[0041] An alkoxy group is a hydroxyl group (-OH) in which the bond to the hydrogen atom is replaced by the bond to the carbon atom of a substituted or unsubstituted alkyl group as defined above. Like alkyl groups, alkoxy groups may be linear or branched. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Typical substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.

[0042] As used herein, the terms "alkanoyl" and "alkanoyloxy" may refer to -C(O)-alkyl groups and -OC(O)-alkyl groups, respectively, that contain 2 to 5 carbon atoms.

[0043] The terms "aryloxy" and "arylalkoxy" refer to substituted or unsubstituted aryl groups bonded to an oxygen atom, and substituted or unsubstituted aralkyl groups bonded to an oxygen atom via alkyl groups, respectively. Examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy. Typical substituted aryloxy and arylalkoxy groups are substituted one or more times with substituents such as those listed above.

[0044] As used herein, the term "carboxylate" refers to the -C(O)OH group or its ionized form, -C(O)O - It refers to.

[0045] As used herein, the term "ester" means -C(O)OR 60 It refers to the base. R 60This term refers to a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. The term ester is also used for -OC(O)R 60 This refers to a group. For example, an ester may be -OC(O)-alkyl, -OC(O)-aryl, or -OC(O)-aralkyl, where each alkyl, aryl, or aralkyl group may be substituted or unsubstituted.

[0046] The term "active ester" is -OR 60 This refers to esters in which the leaving group is a good leaving group and which are sensitive to reaction with primary or secondary amines to form amides. Active esters are known in the art. An example of an active ester is R 60 However, -NR 67 COR 67 And R 67 and COR 67 However, together with the nitrogen to which they are bonded, they optionally substitute with one or more oxos and optionally fused with a substituted or unsubstituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl ring to form a 5 or 6-membered heterocycle, such as 3,5-pyrrolidinedione, maleimide, 5-norbornene-2,3-dicarboximide, and phthalimide, or R 60 Examples of compounds include aryl or heteroaryl compounds substituted with one or more substituents selected from nitro, fluoro, chloro, and bromo, such as nitrophenyl, pentafluorophenyl, and 2-bromopyridinium.

[0047] The term "amide" (or "amido") refers to the C- and N-amide groups, respectively, i.e., -C(O)NR 61 R 62 and -NR 61 C(O)R 62 Includes the group R 61 and R 62This group is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. The amide group therefore includes, but is not limited to, a carbamoyl group (-C(O)NH2) and a formamide group (-NHC(O)H). In some embodiments, the amide is -NR 61 C(O)-(C 1~5 In other embodiments, the amide is -NHC(O)-alkyl, and this group is called "carbonylamino".

[0048] The term "anhydrous" is two parts R 40 and R 41 This refers to a compound in which the atoms are linked by -C(O)-OC(O)-. In some embodiments, the anhydride is a mixed anhydride, i.e., R 40 and R 41 These are different compounds.

[0049] As used herein, the terms "nitrile" or "cyano" refer to the -CN group.

[0050] The urethane group consists of N- and O-urethane groups, i.e., -NR, respectively. 63 C(O)OR 64 and -OC(O)NR 63 R 64 Includes the group R 63 and R 64 R is independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. 63 It may also be H.

[0051] As used herein, the term "amine" (or "amino") is defined as -NR 65 R 66 It refers to the base, R 65 and R 66This is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. In some embodiments, the amine is an alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0052] The term "sulfonamide" refers to the S- and N-sulfonamide groups, i.e., -SO2NR, respectively. 68 R 69 and -NR 68 SO2R 69 Includes the group R 68 and R 69 These are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. The sulfonamide group therefore includes, but is not limited to, a sulfamoyl group (-SO2NH2). In some embodiments herein, the sulfonamide is -NHSO2-alkyl and is referred to as an "alkylsulfonylamino" group.

[0053] The term "thiol" refers to the -SH group, while sulfide refers to the -SR group. 70 It contains the group, and the sulfoxide is -S(O)R 71 It contains the group, and the sulfone is -SO2R 72 It contains a group, and the sulfonyl group is -SO2OR 73 Includes R 70 , R 71 , R 72 , and R 73 Each of these is independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein. In some embodiments, the sulfide is an alkylthio group, which is an -S-alkyl.

[0054] The term "urea" is -NR 74 -C(O)-NR 75 R 76 It refers to the base. R 74 , R 75 , and R 76 The group is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0055] The term "amidine" is -C(NR 77 )NR 78 R 79 and -NR 77 C(NR 78 )R 79 It refers to R 77 , R 78 , and R 79 Each of these is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0056] The term "guanidine" is -NR 80 C(NR 81 )NR 82 R 83 It refers to R 80 , R 81 , R 82 , and R 83 Each of these is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0057] The term "enamin" is -C(R 84 )=C(R 85 )NR 86 R 87 and -NR 84 C(R 85 )=C(R 86 )R 87It refers to R 84 , R 85 , R 86 , and R 87 Each of these is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0058] As used herein, the terms "halogen" or "halo" refer to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.

[0059] As used herein, the term "hydroxy" means -OH, or its ionized form, -O - It could refer to...

[0060] The term "imide" is -C(O)NR 88 C(O)R 89 It refers to R 88 and R 89 Each of these is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0061] The term "imin" is -CR 90 (NR 71 ) and -N(CR 90 R 91 ) refers to the base, R 90 and R 91 Each is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl, or heterocyclylalkyl as defined herein, except R 90 and R 91 However, this is conditional on both not being hydrogen at the same time.

[0062] As used herein, the term "nitro" refers to the -NO2 group.

[0063] As used herein, the term “perhaloalkyl” refers to the alkyl group as defined above, in which any hydrogen bond is replaced by a halogen bond. An example of a perhaloalkyl group is the trifluoromethyl group. As used herein, the term “trifluoromethyl” is -CF3.

[0064] As used herein, the term "trifluoromethoxy" means -OCF3.

[0065] Those skilled in the art will understand that the compounds of the present invention may exhibit tautomerism, conformational isomerism, geometric isomerism, and / or stereoisomerism. While the formulaic diagrams in the specification and claims may represent only one of the possible tautomeristic, conformational isomeristic, stereoisomeristic, and / or geometric isomeristic forms, it should be understood that the present invention encompasses any tautomeristic, conformational isomeristic, stereoisomeristic, and / or geometric isomeristic forms of any compound having one or more of the usefulness described herein, as well as mixtures of various different forms thereof.

[0066] "Tautomers" refer to isomers of a compound that exist in equilibrium with each other. The presence and concentration of these isomers depend on the environment in which the compound is found, and may differ depending, for example, whether the compound is a solid or in an organic solution or aqueous solution. For example, in aqueous solution, imidazole can exhibit the following isomers, which are called tautomers of each other. [ka] As will be readily apparent to those skilled in the art, a variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds described herein are within the scope of the present invention.

[0067] The stereoisomers (also known as optical isomers) of a compound include all chiral, diastereomer, and racemic forms of the structure unless a specific stereochemistry is explicitly indicated. Therefore, the compounds used in this invention, as is evident from the description, include concentrated or decomposed optical isomers at any or all chiral atoms. Both racemic and diastereoisomer mixtures, as well as individual optical isomers, can be isolated or synthesized so as to be substantially free of their enantiomer or diastereoisomer partners, and all of these stereoisomers are within the scope of this invention.

[0068] The compounds of the present invention may exist as solvates, particularly hydrates. Hydrates may form during the preparation of the compound or a composition containing the compound, or they may form over time due to the hygroscopic nature of the compound. The compounds of the present invention may also exist as organic solvent hydrates, including, among others, amides (e.g., DMF), ethers, esters, ketones, nitriles, and alcohol solvates. The identification and preparation of any particular solvate is within the scope of the art of those skilled in synthetic organic chemistry or medicinal chemistry.

[0069] As used herein, the term “amino acid” includes naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimes that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as later modified amino acids, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids, i.e., hydrogen, a carboxyl group, an amino group, and an α-carbon bonded to an R group, such as homoserine, ornithine, homoarginine, norleucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs have a modified R group (e.g., norleucine) or a modified peptide skeleton, but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimes refer to chemical compounds that have a structure different from the general chemical structure of amino acids, but function in a manner similar to naturally occurring amino acids. In this specification, amino acids may be referred to by either their well-known three-letter symbols or one-letter symbols as recommended by the IUPAC-IUB BiochemicaL NomencLature Commission.

[0070] As used herein, the term “protecting group” refers to a chemical group having the following characteristics: 1) selectively reacts with a desired functional group in good yield to yield a protected substrate that is stable for the intended reaction in which protection is desired; 2) can be selectively removed from the protected substrate to yield the desired functional group; and 3) can be removed in good yield by a reagent compatible with other functional groups present in or generated in such intended reaction. Examples of suitable protecting groups can be found in Greene et al. (1991) Protective Groups in Organic Synthesis, 3rd Ed. (John Wiley & Sons, Inc., New York). Suitable photodissociable protecting groups include, but are not limited to, mesitylene sulfonyl (Mts), benzyloxycarbonyl (Cbz or Z), 2-chlorobenzyloxycarbonyl, t-butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBS or TBDMS), 9-fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl, 2-pyridylsulfonyl, or 6-nitroveratriloxycarbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, α-,α-dimethyldimethoxybenzyloxycarbonyl (DDZ), and 5-bromo-7-nitroindolinyl. Examples of amino protecting groups that are sensitive to acid-mediated removal include, but are not limited to, Boc, TBDMS, trityl (Trt), 3,5-dimethoxyphenyl isopropoxycarbonyl (Ddz), 2-(4-biphenyl)isopropoxycarbonyl (Bpoc), and 2-nitrophenylsulfenyl (Nps). Examples of amino protecting groups that are resistant to acid-mediated removal and sensitive to hydrogen-mediated removal include, but are not limited to, allyloxycarbonyl (Alloc), Cbz, nitro, and 2-chlorobenzyloxycarbonyl (2-ClCbz).Examples of amino protecting groups that are resistant to acid-mediated removal and sensitive to base-mediated removal include, but are not limited to, Fmoc, 2,7-di-tert-butyl-Fmoc, 2-fluoro-Fmoc (Fmoc(2F)), 2-(4-nitrophenylsulfonyl)ethoxycarbonyl (Nsc), (1,1-dioxobenzo[b]thiophen-2-yl)methyloxycarbonyl (Bsmoc), (1,1-dioxonaphtho[1,2-b]thiophen-2-yl)methyloxycarbonyl (a-Nsmoc), 1-(4,4-dimethyl-2,6-dioxocyclohexa-1-ylidene)-3-methylbutyl (ivDde), tetrachlorophthaloyl (TCP), ethanesulfonylethoxycarbonyl (Esc), and 2-[phenyl(methyl)sulfonio]ethyloxycarbonyltetrafluoroborate (Pms). Examples of hydroxyl protecting groups include, but are not limited to, Fmoc, TBS, photodissociable protecting groups (such as nitroveratrillyloxymethyl ether (Nvom)), Mom (methoxymethyl ether), Mem (methoxyethoxymethyl ether), NPEOC (4-nitrophenethyloxycarbonyl), and NPEOM (4-nitrophenethyloxymethyloxycarbonyl). Examples and methods for synthesizing the above-mentioned phosphate-substituted and / or sulfate-substituted RPBQ compounds are disclosed in U.S. Patent Application Publication No. 20070225261A1.

[0071] As used herein, the term "coupling agent" refers to any suitable chemical substance useful for forming amide bonds from primary or secondary amines and carboxylic acids. Coupling agents used in any of the embodiments and models described herein include carbodiimides, such as DCC, N,N'-diisopropylcarbodiimide (DIC), N-cyclohexyl-N'-isopropylcarbodiimide (CIC), EDC, or EDC hydrochloride (EDC-HCl), uronium salts or aminium salts, such as HATU, HBTU, O-(benzotriazol-1-yl)-1,1,3,3-tetramethyleneuronium hexafluorophosphate (HAPyU), TATU, TBTU, O-(benzotriazol-1-yl)-1,1,3,3-pentamethyluronium hexafluorophosphate (TAPipU), O-(benzotriazol-1-yl)-N,N,N',N'-bis(pentamethylene)hexafluorophosphate uronium (HBpipU), and O-(7-azabenzotrizol-1-yl) -1,3-dimethyl-1,3-hexafluorophosphate trimethyleneuronium (HAMTU), O-(N-succinimidyl)-1,1,3,3-tetramethyltetrafluoroborate uronium (TSTU), O-(5-norbornene-2,3-dicarboximide)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N' Iminium salts such as tetramethyluronium tetrafluoroborate (TOTU) and O-(1,2-dihydro-2-oxo-1-pyridyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), for example, (1H-benzotriazol-1-yloxy)-N,N-hexachloroantimonate dimethylmethaniminium (BOMI), 5-(1H-benzotriazol-1-yloxy)-3,Phosphonium salts such as pyrrolium 4-dihydro-1-methyl-2H-hexachloroantimonate (BDMP), for example, (benzotriazol-1-yloxy)tris(dimethylamino)hexafluorophosphate phosphonium (BOP), (benzotriazol-1-yloxy)tris(pyrrolidino)hexafluorophosphate phosphonium (PyBOP), (7-azabenzotriazol-1-yloxy)tris(di-methylamino)hexafluorophosphate phosphonium (AOP), (7-azabenzotriazol-1-yloxy)tris(pyrrolidino)hexafluorophosphate phosphonium (PyAOP), [ethylcyano(hydroxyimino)acetato- Examples of pentafluorophenol reagents include pyrrolidinylphosphonium tri-1-hexafluorophosphate (PyOxm), pentafluorophenol reagents such as HpyOPfp, PHySPfp, pentafluorophenyl 4-nitrobenzenesulfonate (PFNB), diphenylphosphinate (FDPP), HDMPfp, and phosphorus reagents such as T3P, FMDP, 1,2-benzisoxazole-3-yldiphenyl phosphate (BIODPP), diethyl 2-(3-oxo-2,3-dihydro-1,2-benzisosulfonazolyl)phosphonate (DEBP), and 4'-(4-pyridyl)-2,6-di(2-pyrazinyl)pyridine (PyDPP). Typical coupling agents include (7-azabenzotriazol-1-yloxy)hexafluorophosphate tripyrrolidinophosphonium (PyAOP), O-benzotriazol-1-yl-N,N,N′,N′-bis(pentamethylene)hexafluorophosphate uronium, O-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)hexafluorophosphate uronium, (benzotriazol-1-yloxy)hexafluorophosphate dipiperidinocarbenium, (benzotriazol-1-yloxy)hexafluorophosphate tripyrrolidinophosphonium (PyBOP), (benzotriazol-1-yloxy)tris(dimethylamino)hexafluorophosphate phosphonium (BOP), O-(benzotriazol-1-yl)-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU), Bromotripyrrolidinophosphonium hexafluorophosphate, Bromotris(dimethylamino)hexafluorophosphate phosphonium, O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TCTU), O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-Tetramethyluronium hexafluorophosphate (HCTU), 2-chloro-1,3-Dimethylimidazolidinium hexafluorophosphate, 2- Dimethylimidazolidinium chloro-1,3-tetrafluoroborate, 2-chloro-1,3-dimethylimidazolidinium chloride, chlorodipyrrolidinocarbenium hexafluorophosphate, tetramethylformamidinium chloro-N,N,N′,N′-hexafluorophosphate, chlorotripyrrolidinophosphonium hexafluorophosphate, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino-hexafluorophosphate carbenium (COMU), dipyrrolidino(N-succinimidyloxy)hexafluoro Carbenium phosphate, O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium hexafluorophosphate, fluoro-N,N,N′,N′-bis(tetramethylene)hexafluorophosphate formamidinium, fluoro-N,N,N′,N′-bis(tetramethylene)hexafluorophosphate formamidinium, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b ]Pyridinium 3-hexafluorophosphate oxide (HATU), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)hexafluorophosphate uronium (HBTU), 1-[(dimethylamino)(morpholino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridinium-1-ium 3-hexafluorophosphate oxide (HDMA), O-(5-norbornene-2,3-dicarboximide)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, S-(1-oxide-2-pyridyl)-N,N,N′,N′-Tetramethylthiuronium hexafluorophosphate, O-(2-oxo-1(2H)pyridyl)-N,N,N′,N′-Tetramethyluronium tetrafluoroborate, N,N,N′,N′-Tetramethyl-O-(N-succinimidyl)hexafluorophosphate uronium, N,N'-Dicyclohexylcarbodiimide (DCC), N,N'-Diisopropylcarbodiimide, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidemethiozide (EDC-MeI), Propane anhydride phosphonic acid (T3P Examples include, but are not limited to, N,N'-di-tert-butylcarbodiimide, N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 1,1'-carbonyldiimidazole, 1,1'-carbonyldi(1,2,4-triazole), bis(4-nitrophenyl)carbonate, 4-nitrophenyl chloroformate, di(N-succinimidyl)carbonate, and 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole, or combinations thereof.

[0072] "Reacting" means bringing two or more chemical molecules into very close proximity to cause or facilitate a chemical reaction between one or more molecules, for example, a chemical reaction between two or more chemical molecules. For example, reacting may include mixing chemicals together and optionally mixing them sequentially. Reacting may be done by completely or partially dissolving or suspending two or more chemicals in one or more solvents according to procedures generally known to those skilled in the art, mixing the chemicals in the solvent with another chemical in the solid phase and / or gas phase, or bound to a solid support such as a resin, or by mixing two or more chemicals in the gas phase or solid phase and / or on a solid support. Reacting compound A with compound B also includes mixing compounds A, B, and C sequentially or simultaneously so that A reacts with compound C to form an intermediate, which then reacts with compound B so that the intermediate is not isolated or separated. For example, the reaction of an amino compound with a carboxylic acid compound to form an amide involves combining the carboxylic acid compound with a coupling agent and one or more additives (e.g., EDC and HOBT) to form an active ester in situ, which then reacts with an already present or subsequently added amino compound without isolation to form an amide.

[0073] "Conversion" refers to the process of changing one compound into another through a chemical reaction, or changing a free acid or base of a compound into a salt of a compound, or changing a salt of a compound into a free acid or base of a compound or another salt of a compound under reaction conditions that can induce such a change.

[0074] As used herein, “isolated” or “purified” polypeptides or peptides are substantially free of other contaminating polypeptides, such as peptides or polypeptides derived from the drug, or substantially free of chemical precursors or other chemicals during chemical synthesis. For example, the isolated peptides of this technique do not contain substances that interfere with the diagnostic or therapeutic use of the drug. Such interfering substances include other proteinaceous and non-proteinaceous solutes.

[0075] As used herein, the term “net charge” refers to the difference between the number of positively charged and negatively charged amino acids present in a peptide. It is understood herein that the net charge is measured at physiological pH. Examples of naturally occurring amino acids that are positively charged at physiological pH include L-lysine, L-arginine, and L-histidine. Examples of naturally occurring amino acids that are negatively charged at physiological pH include L-aspartic acid and L-glutamic acid.

[0076] As used herein, the terms “polypeptide,” “peptide,” and “protein” are used synonymously and mean polymers comprising two or more amino acids linked to each other by peptide bonds or modified peptide bonds, i.e., peptide counterparts. Polypeptides refer to both short chains commonly called peptides, glycopeptides, or oligomers, and long chains commonly called proteins. Polypeptides may contain amino acids other than the 20 genetically encoded amino acids. Polypeptides contain amino acid sequences modified by either natural processes such as post-translational processing or chemical modification techniques well known in the art. In one embodiment, a peptide (as disclosed herein) includes all stereoisomers and geometric isomers of the peptide, including diastereoisomers, enantiomers, and cis / trans (E / Z) isomers. In some embodiments, the amino acids of the peptide are D amino acids.

[0077] As used herein, the term “small molecule” includes organic compounds, organometallic compounds, salts of organic compounds and organometallic compounds, monosaccharides, amino acids, and nucleotides. Small molecules may further include molecules that are considered biomolecules, except that their molecular weight is 1,000 or less. Thus, small molecules may be lipids, oligosaccharides, oligopeptides, and derivatives thereof, having a molecular weight of 1,000 or less.

[0078] Method of this technology In one embodiment, a method for synthesizing the compounds of the present technology is provided. In some embodiments, the method is intended to produce one or more intermediates as the final product, and in some embodiments, the method is intended to produce the compounds of the present technology as the final product of the method. Each embodiment may be carried out independently of any other embodiment or in combination with any other embodiment. In any of the embodiments, the method may be a solution-phase process and may not be a solid-phase process. In any of the embodiments, the purity of the product of the method may be at least about 95%, as determined by high-performance liquid chromatography (HPLC). The purity may be about 98.2%, about 98.4%, about 98.6%, about 98.8%, about 99.0%, about 99.2%, about 99.4%, about 99.6%, about 99.8%, or any range between these values ​​including any two of these values, or may exceed any one of these values. In any of the embodiments, the product of the method may have a purity of at least about 98.0%, as determined by gas chromatography analysis. The purity may be about 98.2%, about 98.4%, about 98.6%, about 98.8%, about 99.0%, about 99.2%, about 99.4%, about 99.6%, about 99.8%, or any range between them including any two of these values, or may exceed any one of these values. In any of the embodiments, the product may contain less than about 50 ppm of heavy metals. The heavy metals may be about 45 ppm, about 40 ppm, about 35 ppm, about 30 ppm, about 25 ppm, about 20 ppm, about 15 ppm, about 10 ppm, about 5 ppm, about 1 ppm, or any range between them including any two of these values, or may be below any one of these values.

[0079] Remarkably, the methods of the art described herein provide compounds of formula VIII or their salts in high purity without the need for purification by column chromatography.

[0080] In one embodiment, a method for preparing a compound of formula VIII or a salt thereof is provided. [ka] This method involves reacting a compound of formula IA or a salt thereof with a compound of formula IB or a salt thereof. [ka] [ka] To form a compound of formula IC or a salt thereof, [ka] Converting a compound of formula IC or a salt thereof to a compound of formula ID or a salt thereof, [ka] The compound of formula ID or a salt thereof is reacted with the compound of formula IE or a salt thereof to form the compound of formula VIII or a salt thereof. [ka] Including, in the formula, A 1 and A 2 However, each independently, together with the carbonyl group to which it is bonded, forms a carboxylic acid, an active ester, an anhydride, or an acid halide, for example, A 1 and A 2 However, -OH and -OR are independent of each other. 58 -OC(O)-R 59 , F, Cl, or Br, R 58 However, R is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group. 59 However, these are substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, R 1 and R 2 However, each operates independently. (i) Hydrogen, (ii) Substituted or unsubstituted C1-C6 alkyl groups, (iii) Substitution or non-substitution aralkyl, (iv) Substituted or unsubstituted C3-C8 cycloalkyl or cycloalkylalkyl, (v) Substituted or unsubstituted C2-C6 alkenyl, (vi) an amino protecting group, Or R 1 and R 2 Together, they form a 3, 4, 5, 6, 7, or 8-membered substituted or unsubstituted heterocyclyl or heteroaryl group. R 8a and R 8b However, each operates independently. [ka] [ka] or [ka] And, In the formula, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 55 and R 56Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 9 However, R'' is OR' or NR'R'', where R' in each occurrence is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, and R'' is hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, R 12 However, the group is selected from hydrogen, -OH, halogen (e.g., F, Cl, Br, I), C1-C6 alkyl, -O-C1-C6 alkyl, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C4-perhaloalkyl, aralkyl, -O-aralkyl, -NH-aralkyl, -N(aralkyl)2, -N(C1-C6 alkyl)(aralkyl), -C(O)-alkyl, -C(O)-aryl, or -C(O)-aralkyl, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 22 , R 23 , and R 24 However, each is independently hydrogen or a C1-C4 alkyl group. n is 1, 2, 3, 4, or 5. m is 1, 2, 3, 4, or 5. X 1 , X 2 , and X 4However, in each instance, independently, there is a hydrogen or amino protecting group, for example, an amino protecting group that is sensitive to acid-mediated removal, or an amino protecting group that is resistant to acid-mediated removal and sensitive to base-mediated or hydrogen-mediated removal. X 3 However, R 2 , hydrogen, or amino protecting group, Y 1 However, the amino protecting group is, for example, an amino protecting group that is sensitive to acid-mediated removal, or an amino protecting group that is resistant to acid-mediated removal and sensitive to base-mediated or hydrogen-mediated removal. Z 5 and Z 6 However, each operates independently, -NHX 1 -C(NX 4 )-NH-X 2 , -NX 1 C(NX 4 )-NH-X 2 , -NX 1 (C1~C6 alkyl), -NX 1 (C6~C 10 Aryl), -NX 1 (C7~C 12 The group is an aralkyl, aralkyl, heterocyclyl, or heteroaryl group, and each alkyl, aryl, aralkyl, heterocyclyl, or heteroaryl group may be substituted or unsubstituted.

[0081] In one embodiment, a method for preparing a compound of formula VIII or a salt thereof is provided. [ka] This method involves reacting a compound of formula II-A or a salt thereof with a compound of formula IE or a salt thereof. [ka] [ka] To form a compound of formula II-C or a salt thereof, [ka] Converting a compound of formula II-C or a salt thereof to a compound of formula II-D or a salt thereof, [ka] The compound of formula II-D or a salt thereof is reacted with the compound of formula IB or a salt thereof to form the compound of formula VIII or a salt thereof. [ka] Including, in the formula, A 2 and A 4 However, each independently, together with the carbonyl group to which it is bonded, forms a carboxylic acid, an active ester, an anhydride, or an acid halide, for example, A 2 and A 4 However, -OH and -OR are independent of each other. 58 -OC(O)-R 59 , F, Cl, or Br, R 58 However, R is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group. 59 However, these are substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, R 1 and R 2 However, each operates independently. (i) Hydrogen, (ii) Substituted or unsubstituted C1-C6 alkyl groups, (iii) Substitution or non-substitution aralkyl, (iv) Substituted or unsubstituted C3-C8 cycloalkyl or cycloalkylalkyl, (v) Substituted or unsubstituted C2-C6 alkenyl, (vi) an amino protecting group, Or R 1 and R 2 Together, they form a 3, 4, 5, 6, 7, or 8-membered substituted or unsubstituted heterocyclyl or heteroaryl group. R8a and R 8b However, each operates independently. [ka] [ka] or [ka] And, In the formula, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 55 and R 56 Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 9However, R'' is OR' or NR'R'', where R' in each occurrence is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, and R'' is hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, R 12 However, the group is selected from hydrogen, -OH, halogen (e.g., F, Cl, Br, I), C1-C6 alkyl, -O-C1-C6 alkyl, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C4-perhaloalkyl, aralkyl, -O-aralkyl, -NH-aralkyl, -N(aralkyl)2, -N(C1-C6 alkyl)(aralkyl), -C(O)-alkyl, -C(O)-aryl, or -C(O)-aralkyl, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 22 , R 23 , and R 24 However, each is independently hydrogen or a C1-C4 alkyl group. n is 1, 2, 3, 4, or 5. m is 1, 2, 3, 4, or 5. W 1 However, these are substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, X 1 , X 2 , and X 4 However, in each instance, independently, there is a hydrogen or amino protecting group, for example, an amino protecting group that is resistant to acid-mediated removal and sensitive to base-mediated or hydrogen-mediated removal. X 3 However, R 2 , hydrogen, or amino protecting group, Z5 and Z 6 However, each operates independently, -NHX 1 -C(NX 4 )-NH-X 2 , -NX 1 C(NX 4 )-NH-X 2 , -NX 1 (C1~C6 alkyl), -NX 1 (C6~C 10 Aryl), -NX 1 (C7~C 12 The group is an aralkyl, aralkyl, heterocyclyl, or heteroaryl group, and each alkyl, aryl, aralkyl, heterocyclyl, or heteroaryl group may be substituted or unsubstituted.

[0082] In some embodiments, a compound of formula IA or a salt thereof is a compound of IF or a salt thereof [ka] Prepared by converting to a compound of IA, where n, W 1 , Y 1 , Z 5 , R 22 , R 23 , and R 8a However, as defined herein.

[0083] In some embodiments, converting a compound of formula IF or a salt thereof to a compound of formula IA or a salt thereof under hydrolysis conditions involves the group OW in the compound of formula IF or a salt thereof. 1 Convert to OH, A 1 This includes forming a compound of formula IA or a salt thereof in which is OH. In some embodiments, A 1 Compounds of formula IA where OH is present, or salts thereof, are A 1 A compound of formula IA where is OH, or a salt thereof, is ClC(O)-R 59 A method including reacting with an anhydrous (e.g., a mixed anhydrous), for example, A 1 ga-OC(O)-R 59It is further converted to a compound of formula IA or a salt thereof. In some embodiments, A 1 Compounds of formula IA where OH is present, or salts thereof, are A 1 A compound of formula IA, in which is OH, or a salt thereof, is reacted with a fluorinating agent such as cyanuryl fluoride, diethylaminosulfur trifluoride, tetramethylfluoroformamidinium hexafluorophosphate (TFFH), and fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), by a method comprising this reaction. 1 It is further converted to a compound of formula IA or a salt thereof, where F is present. In some embodiments, A 1 Compounds of formula IA where OH is present, or salts thereof, are A 1 A is obtained by a method comprising reacting a compound of formula IA, in which the OH group is, or a salt thereof, with a chlorinating agent such as phosphorus pentachloride, oxalyl chloride, or thionyl chloride. 1 It is further converted to a compound of formula IA or a salt thereof, where Cl is present. In some embodiments, A 1 Compounds of formula IA where OH is present, or salts thereof, are A 1 A is produced by a method comprising reacting a compound of formula IA, in which OH is present, or a salt thereof, with a brominating agent such as phosphorus tribromide. 1 It is further converted to a compound of formula IA or a salt thereof, where Br is present. In some embodiments, A 1 Compounds of formula IA where OH is present, or salts thereof, are A 1 A compound of formula IA where is OH, or a salt thereof, Lv 1 Lv is a leaving group 1 -R 58 A method including reacting with, for example, A 1 ga-OR 58 It is further converted to the compound of formula IA or a salt thereof. Lv 1 -R 58Examples include N-hydroxysuccinimide acrylate, bis(4-nitrophenyl) carbonate, bis(4-nitrophenyl) carbonate, bis(pentafluorophenyl) carbonate, 2-bromo-1-ethylpyridinium tetrafluoroborate, N,O-dimethylhydroxylamine, N,N'-disuccinimidyl carbonate, ethyl(hydroxyimino)cyanoacetate, 1-hydroxybenzotriazole hydrate, N-hydroxymaleimide, N-hydroxy-5-norbornene-2,3-dicarboxylic acidimide, 3-(4 Examples include N-hydroxysuccinimide ester (hydroxyphenyl)propionate, N-hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxysuccinimidyl acetate, N-hydroxysulfosuccinimide, N-hydroxysuccinimide ester iodoacetate, nitrobenzyl 4-chloroformate, nitrophenyl 4-chloroformate, pentafluorophenyl trifluoroacetate, N-hydroxysuccinimide ester phenoxyacetate, and N-succinimidyl N-methylcarbamate.

[0084] In some embodiments, A 1 It is OH.

[0085] In some embodiments, the compound of formula II-A or a salt thereof is prepared by converting the compound of IF or a salt thereof to the compound of II-A or a salt thereof.

[0086] In some embodiments, A 2 is OH. In some embodiments, the compound of IE is an active ester, for example, A 2 ga-OR 58 It is a compound that is A 2 Compounds of formula IE, where OH is present, or salts thereof, as described herein, Lv 1 -R 58 It is prepared by a method that includes reacting with [a]. In some embodiments, the IE compound is an anhydride (e.g., a mixed anhydride), e.g., A 2 ga-OC(O)-R 59 It is a compound that is A 2A compound of formula IE where is OH, or a salt thereof, is called ClC(O)-R 59 It is prepared by a method that includes reacting with A. In some embodiments, A 2 The compound of formula IE where F is A 2 The compound of formula IE, in which is OH, or a salt thereof, is prepared by a method comprising reacting it with a fluorinating agent such as cyanuryl fluoride, diethylaminosulfur trifluoride, tetramethylfluoroformamidinium hexafluorophosphate (TFFH), and fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH). In some embodiments, A 2 Compounds of formula IE where Cl is A 2 It is prepared by a method comprising reacting a compound of formula IE, in which the OH group is, or a salt thereof, with a chlorinating agent such as phosphorus pentachloride, oxalyl chloride, or thionyl chloride. In some embodiments, A 2 The compound of formula IE in which Br is A 2 It is prepared by a method that involves reacting a compound of formula IE, in which the OH group is, or a salt thereof, with a brominating agent such as phosphorus tribromide.

[0087] In some embodiments, a compound of formula IF or a salt thereof is prepared by a method comprising reacting a compound of formula IG or a salt thereof with a compound of formula IH or a salt thereof. [ka] [ka] In the formula, R 8a , R 22 , R 23 , W 1 , Y 1 , Z 5 , and n are as defined herein, and A 5 However, together with the carbonyl group to which it is bonded, it forms a carboxylic acid, an active ester, an anhydride, or an acid halide, for example, A 5 However, -OH, -OR 58 -OC(O)-R 59It may be F, Cl, or Br, R 58 However, R is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group. 59 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl. In some embodiments, A 5 It is OH.

[0088] In another embodiment, a method for preparing a compound of formula VIII or a salt thereof is provided. [ka] This method involves reacting a compound of formula III-A or a salt thereof with a compound of formula III-B or a salt thereof to form a compound of formula VIII or a salt thereof. [ka] [ka] Including, in the formula, A 6 However, together with the carbonyl group to which it is bonded, it forms a carboxylic acid, an active ester, an anhydride, or an acid halide, for example, A 6 However, -OH, -OR 58 -OC(O)-R 59 , F, Cl, or Br, R 58 However, R is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group. 59 However, these are substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, R 1 and R 2 However, each operates independently. (i) Hydrogen, (ii) Substituted or unsubstituted C1-C6 alkyl groups, (iii) Substitution or non-substitution aralkyl, (iv) Substituted or unsubstituted C3-C8 cycloalkyl or cycloalkylalkyl, (v) Substituted or unsubstituted C2-C6 alkenyl, (vi) an amino protecting group, Or R 1 and R 2 Together, they form a 3, 4, 5, 6, 7, or 8-membered substituted or unsubstituted heterocyclyl or heteroaryl group. R 8a and R 8b However, each operates independently. [ka] [ka] or [ka] And, In the formula, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 55 and R 56Each of these groups is independently selected from H, or C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl groups, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 9 However, R'' is OR' or NR'R'', where R' in each occurrence is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, and R'' is hydrogen, or a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl group, R 12 However, the group is selected from hydrogen, -OH, halogen (e.g., F, Cl, Br, I), C1-C6 alkyl, -O-C1-C6 alkyl, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C4-perhaloalkyl, aralkyl, -O-aralkyl, -NH-aralkyl, -N(aralkyl)2, -N(C1-C6 alkyl)(aralkyl), -C(O)-alkyl, -C(O)-aryl, or -C(O)-aralkyl, where each alkyl, aryl, or aralkyl group is substituted or unsubstituted. R 22 , R 23 , and R 24 However, each is independently hydrogen or a C1-C4 alkyl group. n is 1, 2, 3, 4, or 5. m is 1, 2, 3, 4, or 5. X 1 , X 2 , and X 4However, in each instance, independently, there is a hydrogen or amino protecting group, for example, an amino protecting group that is sensitive to acid-mediated removal, or an amino protecting group that is resistant to acid-mediated removal and sensitive to base-mediated or hydrogen-mediated removal. X 3 However, R 2 , hydrogen, or amino protecting group, Z 5 and Z 6 However, each operates independently, -NHX 1 -C(NX 4 )-NH-X 2 , -NX 1 C(NX 4 )-NH-X 2 , -NX 1 (C1~C6 alkyl), -NX 1 (C6~C 10 Aryl), -NX 1 (C7~C 12 The group is an aralkyl, aralkyl, heterocyclyl, or heteroaryl group, and each alkyl, aryl, aralkyl, heterocyclyl, or heteroaryl group may be substituted or unsubstituted.

[0089] In some embodiments, the compound of formula III-A or a salt thereof is prepared by a method comprising converting the compound of formula III-C or a salt thereof to the compound of formula III-A or a salt thereof. [ka] In the formula, m, X 1 , X 3 , Z 6 , R 22 , R 1 , and R 8a However, as defined herein, W 2 However, these are substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl.

[0090] In some embodiments, converting a compound of formula III-C or a salt thereof to a compound of III-A or a salt thereof under hydrolysis conditions is equivalent to OW in a compound of formula III-C or a salt thereof. 2 Convert the group to OH, A 6 This includes forming a compound of formula III-A or a salt thereof in which is OH. In some embodiments, A 6 A compound of formula III-A where is OH, or a salt thereof, is A 6 The compound of formula III-A, in which is OH, or a salt thereof, is ClC(O)-R 59 A method including reacting with an anhydrous (e.g., a mixed anhydrous), for example, A 6 ga-OC(O)-R 59 It is further converted to the compound of formula III-A or a salt thereof. In some embodiments, A 6 A compound of formula III-A where is OH, or a salt thereof, is A 6 A compound of formula III-A or a salt thereof, in which the OH group is Lv as described herein. 1 -R 58 A method including reacting with an active ester (e.g., A 6 ga-OR 58 ) is further converted to A. In some embodiments, A 6 A compound of formula III-A where is OH, or a salt thereof, is A 6 A compound of formula III-A, in which is OH, or a salt thereof, is reacted with a fluorinating agent such as cyanuryl fluoride, diethylaminosulfur trifluoride, tetramethylfluoroformamidinium hexafluorophosphate (TFFH), and fluoro-dipyrrolidinocarbenium hexafluorophosphate (BTFFH), by a method comprising this reaction. 6 It is further converted to a compound of formula III-A or a salt thereof, where F is. In some embodiments, A 6 A compound of formula III-A where is OH, or a salt thereof, is A 6 A is obtained by a method comprising reacting a compound of formula III-A, in which is OH, or a salt thereof, with a chlorinating agent such as phosphorus pentachloride, oxalyl chloride, or thionyl chloride. 6 It is further converted to a compound of formula III-A or a salt thereof, where Cl is present. In some embodiments, A6 A compound of formula III-A where is OH, or a salt thereof, is A 6 A compound of formula III-A, in which is OH, or a salt thereof, is reacted with a brominating agent such as phosphorus tribromide by a method comprising this reaction. 6 It is further converted to the compound of formula III-A or a salt thereof, where Br is present.

[0091] In some embodiments, A 6 It is OH.

[0092] In some embodiments, the compound of formula III-C or a salt thereof is prepared by a method comprising reacting the compound of formula III-D or a salt thereof with the compound of formula IE to form the compound of formula III-C or a salt thereof. [ka] [ka] In the formula, m, W 2 , X 1 , X 3 , Z 6 , R 22 , R 1 , and R 8a However, as defined herein, A 2 However, together with the carbonyl group to which it is bonded, it forms a carboxylic acid, an active ester, an anhydride, or an acid halide, for example, A 2 However, -OH, -OR 58 -OC(O)-R 59 It may be F, Cl, or Br, R 58 However, R is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group. 59 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl. In some embodiments, A 2 It is OH.

[0093] In some embodiments, the compound of formula III-B or a salt thereof is prepared by a method comprising converting the compound of formula III-E or a salt thereof to the compound of formula III-B or a salt thereof. [ka] In the formula, Y 2 However, the amino protecting group is, for example, an amino protecting group that is sensitive to acid-mediated removal, or an amino protecting group that is resistant to acid-mediated removal and sensitive to base-mediated or hydrogen-mediated removal, n, Z 5 , R 23 , R 24 , R 8b , and R 9 However, as defined herein.

[0094] In some embodiments, the compound of formula III-E or a salt thereof is prepared by a method comprising reacting the compound of formula IB or a salt thereof with the compound of formula III-F or a salt thereof to form the compound of formula III-E or a salt thereof. [ka] [ka] In the formula, R 8b , R 9 , R 23 , R 24 , Y 2 , Z 5 , and n are as defined herein, and A 7 However, together with the carbonyl group to which it is bonded, it forms a carboxylic acid, an active ester, an anhydride, or an acid halide, for example, A 7 However, -OH, -OR 58 -OC(O)-R 59 , F, Cl, or Br, R 58 However, R is a substituted or unsubstituted aryl, heteroaryl, or heterocyclyl group. 59is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl. In some embodiments, A 7 It is OH.

[0095] The hydrolysis conditions may include aqueous solutions of alkali metal hydroxides (e.g., LiOH, NaOH, or KOH) or alkaline earth metal hydroxides (e.g., Ca(OH)2 or Mg(OH)2). The solution may further include organic solvents, such as miscible or partially miscible organic solvents, such as CH3OH, EtOH, DMF, DMA, CH3CN, acetone, dioxane, THF, or mixtures thereof.

[0096] In some embodiments, W 1 or W 2 It is benzyl, -OW 1 or -OW 2 The benzyl is converted to OH by a method comprising a hydrogen source and a transition metal catalyst as described herein. For example, H2 and a supported catalyst such as Pd or Pt on carbon may be used to convert (reduction cleavage) the benzyl to H.

[0097] In some embodiments, W 1 or W 2 It is tert-butyl and -OW 1 or -OW 2 It is converted to OH by a method involving a cleaving acid as described herein.

[0098] In any of the embodiments described herein, Y 1 or Y 2 If the amino protecting group is susceptible to acid-mediated removal, then X 1 , X 2 , X 3 , and X 4 None of these are amino protecting groups that are susceptible to acid-mediated removal. In some embodiments of any of the above aspects, X 1, X 2 , X 3 , and X 4 If one of them is an amino protecting group that is susceptible to acid-mediated removal, then Y 1 Y 2 It is also not an amino protecting group that is susceptible to acid-mediated removal. In any of the embodiments described above, X 1 , X 2 , X 3 , and X 4 If one of them is an amino protecting group that is susceptible to acid-mediated removal, then the remaining X 1 , X 2 , X 3 , and X 4 All of these are amino protecting groups that are sensitive to hydrogen or acid-mediated removal, Y 1 Y 2 It is not an amino protecting group that is susceptible to acid-mediated removal.

[0099] In any of the embodiments described herein, Y 1 Y is an amino protecting group that is resistant to acid-mediated removal and sensitive to hydrogen-mediated removal. In some embodiments, Y 2 This is an amino protecting group that is resistant to acid-mediated removal and sensitive to hydrogen-mediated removal. For example, Y 1 or Y 2 This may independently be Cbz, and H2, and a supported catalyst such as Pd or Pt on carbon may be used to convert Cbz to H (reductive cleavage). In some embodiments, X 1 , X 2 , X 3 , and X 4 At least one of these is an amino protecting group that is susceptible to acid-mediated removal. In some embodiments, X 3 and X 1 , X 2 , and X 4 At least one of them is an amino protecting group that is sensitive to acid-mediated removal. In other embodiments, X 3 and X 1 , X 2 , and X 4At least two of these are amino protecting groups that are susceptible to acid-mediated removal.

[0100] In any of these embodiments, Y 1 and Y 2 X can independently be allyloxycarbonyl (Alloc), 2-chlorobenzyloxycarbonyl (2-ClCbz), or benzyloxycarbonyl (Cbz), with each occurrence being X 1 , X 2 , and X 4 Each of these may independently be hydrogen, or tert-butyloxycarbonyl (Boc), trityl (Trt), 3,5-dimethoxyphenyl isopropoxycarbonyl (Ddz), 2-(4-biphenyl)isopropoxycarbonyl (Bpoc), or 2-nitrophenylsulfenyl (Nps). In any of these embodiments, Y 1 and Y 2 Independently, X can be Boc, Trt, Ddz, Bpoc, or Nps, with each occurrence being X 1 , X 2 , and X 4 Each of these can independently be hydrogen, alloc, cbz, or 2-ClCbz.

[0101] In any of the embodiments described herein, Y 1 Y is an amino protecting group that is susceptible to acid-mediated removal. In some embodiments, Y 2 X is an amino protecting group that is susceptible to acid-mediated removal. In some embodiments, X 1 , X 2 , X 3 , and X 4 At least one of these is an amino protecting group that is resistant to acid-mediated removal and sensitive to hydrogen-mediated removal. In some embodiments, X 3 and X 1 , X 2 , and X 4At least one of them is an amino protecting group that is independently resistant to acid-mediated removal and sensitive to hydrogen-mediated removal. In other embodiments, X 3 and X 1 , X 2 , and X 4 At least two of these are amino protecting groups that are independently resistant to acid-mediated removal and sensitive to hydrogen-mediated removal.

[0102] In any of these embodiments, Y 1 and Y 2 X can be Boc, Trt, Ddz, Bpoc, or Nps, with each occurrence being X 1 X can independently be hydrogen, alloc, cbz, or 2-ClCbz, with each occurrence being X 2 X can independently be hydrogen, alloc, cbz, or 2-ClCbz, with each occurrence being X 4 These can independently be hydrogen, nitro, alloc, cbz, or 2-ClCbz.

[0103] In any of these embodiments, Y 1 and / or Y 2 X can independently be an amino protecting group that is susceptible to acid-mediated removal. In any of these embodiments, X in each occurrence 1 , X 2 , and / or X 4 Y is an amino protecting group that is independently resistant to acid-mediated removal and sensitive to base-mediated or hydrogen-mediated removal. In any of these embodiments, Y 1 and / or Y 2 It can be Boc, and X in each occurrence 1 X can independently be hydrogen, alloc, cbz, or 2-ClCbz, with each occurrence being X 2 X can independently be hydrogen, alloc, cbz, or 2-ClCbz, with each occurrence being X 4 Z can independently be hydrogen, nitro, alloc, Cbz, or 2-ClCbz. In some embodiments, Z 5-C(NH)-NH-X 2 When X 1 is hydrogen. In some embodiments, Z 5 -C(NX 4 )-NH-X 2 When X 1 is hydrogen, X 2 and X 4 At least one of them is not H. In any of these embodiments, X 2 However, when the amino protecting group is resistant to acid-mediated removal and susceptible to hydrogen-mediated removal, X 1 X may be hydrogen. In any of these embodiments, X 1 However, when the amino protecting group is resistant to acid-mediated removal and susceptible to hydrogen-mediated removal, X 2 It could be hydrogen.

[0104] In any of these embodiments, Y 1 and / or Y 2 Y can be an amino protecting group that is independently resistant to acid-mediated removal and sensitive to base-mediated removal. In any of these embodiments, Y 1 and / or Y 2 This could be Fmoc. In any of these embodiments, Y 1 and / or Y 2 X can be an amino protecting group that is independently resistant to acid-mediated removal and sensitive to hydrogen-mediated removal. In any of these embodiments, X in each occurrence 1 , X 2 , and / or X 4 Y can independently be an amino protecting group that is sensitive to acid-mediated removal. In any of these embodiments, Y 1 and / or Y 2 Independently, X can be Alloc, Cbz, or 2-ClCbz, and in each occurrence X 1 , X 2 , and / or X 4 Z may independently be hydrogen or Boc. In any of these embodiments, Z5 and Z 6 Each of these is independent of -NHX 1 -C(NX 4 )-NH-X 2 , -NX 1 C(NX 4 )-NH-X 2 , or substituted or unsubstituted imidazolyl or indolyl, or other substituted or unsubstituted nitrogen-containing heterocyclic and heteroaromatic groups described herein, for example, substituted and unsubstituted pyrrolyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, thiazolyl, pyrazinyl, pyridinyl, triazolyl, tetrazolyl, piperidinyl, piperazinyl, morpholinyl, benzimidazolyl, azaindolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, and triazolopyridinyl. In some embodiments, Z 5 However, -NX 1 C(NX 4 )-NH-X 2 or -C(NH)-NH-X 2 When X 1 is hydrogen. In some embodiments, Z 5 ga-NX 1 C(NX 4 )-NH-X 2 When X 1 is hydrogen, X 2 and X 4 At least one of them is not H. In any of these embodiments, X 2 However, when the amino protecting group is susceptible to acid-mediated removal, X 1 X may be hydrogen. In any of these embodiments, X 1 However, when the amino protecting group is susceptible to acid-mediated removal, X 2 It could be hydrogen.

[0105] In any of these embodiments, X 3 X can be an amino protecting group that is sensitive to acid-mediated removal. In some embodiments, X 3is an amino protecting group that is sensitive to acid-mediated removal, such as Boc, Trt, Ddz, Bpoc, or Nps. In any of the present embodiments, Z 5 -NHX 1 It could be, Z 6 -NX 1 C(NX 4 )-NH-X 2 It is possible. In some such embodiments, X 1 In other embodiments, X 1 , X 2 , and X 4 H is H. In some embodiments, Z 5 is -NHBoc, Z 6 is -NHC(NH)-NH2. In a particular embodiment, m is 3 and n is 4.

[0106] In any of these embodiments, R 8a or R 8b teeth, [ka] It is possible. In some such embodiments, R 10 , R 11 , R 12 , R 13 , and R 14 all are hydrogen, and in other such embodiments, R 10 and R 14 It can be methyl, R 12 R can be -OH. In any of the embodiments described above, 9 Z may be NH2. In any of the embodiments described above, Z 5 or Z 6 R can be -NH2 or -NHC(NH)NH2, and n or m can be 3 or 4. In any of the above embodiments, R 8a and R 8b One of them is, [ka] It could be, and one possibility is, [ka] This is possible, and in the formula, R 9 is -NH2, and Z 5 is -NH2, and n is 3 or 4.

[0107] In any of these embodiments, R 9 R may be NR'R''. In any of the embodiments described above, R 9 This may be NH2. In any of the embodiments described above, R is present in a compound other than the compound of formula I or a salt thereof. 9 R' may be OR', and R' may not be hydrogen. In some embodiments of the compounds of formula I or their salts, R 9 It can be OH.

[0108] In any of these embodiments, R 22 , R 23 , and R 24 All of these can be hydrogen. In any of these embodiments, R 22 and R 23 It can be hydrogen, R 24 R can be a C1-C4 alkyl such as methyl. In any of these embodiments, R 22 and R 24 It can be hydrogen, R 25 R can be a C1-C4 alkyl such as methyl. In any of these embodiments, R 23 and R 24 It can be hydrogen, R 22 R can be a C1-C4 alkyl such as methyl. In any of these embodiments, R 22 and R 23 R can be a C1-C4 alkyl such as methyl, 24 R may be hydrogen. In any of these embodiments, R 22 and R 24 R can be a C1-C4 alkyl such as methyl, 25R may be hydrogen. In any of these embodiments, R 23 and R 24 R can be a C1-C4 alkyl such as methyl, 22 R may be hydrogen. In any of these embodiments, R 22 , R 23 , and R 24 All of these can be C1-C4 alkyl groups such as methyl groups.

[0109] In a particular embodiment of this method, the compound of formula VIII or a salt thereof is the compound of formula VIII-B or a salt thereof, where R 1 However, it is hydrogen, X 3 However, it is an amino protecting group that is susceptible to acid-mediated removal, Z 5 and Z 6 However, independently, -NHX 1 Or selected from -NHC(NH)-NH2, X 1 However, the amino protecting group is sensitive to acid-mediated removal, and m and n are independently selected from 2, 3, or 4, R 9 However, it is NH2, and R 8a and R 8b However, they became independent, [ka] And R in each occurrence 10 and R 14 However, independently selected from hydrogen or C1-C6 alkyl, R in each appearance 12 However, it is hydrogen or -OH. In some embodiments, X 3 is Boc, and X 1 is Boc. Surprisingly, it has been found that when the compound of formula VIII-B or its salt is exposed to acid, even in the presence of a small amount of water, deprotection may not proceed to completion, and the deprotection product may not be able to be isolated as a solid powder. For example, 0.5 wt% or even 0.1 wt% water in a hydrogen halide solution (e.g., HCl in an organic solvent) can cause the compound of formula VIII (i.e., X) to be in a non-adherent powder form. 3 H is X 1This prevents the immediate isolation of the completely deprotected tetrapeptide (where H is present). In contrast, deprotection under anhydrous conditions, for example, using isopropyl alcohol and / or isopropyl acetate, yields free tetrapeptides in good yield and high purity without chromatography or crystallization.

[0110] In some embodiments, the compound of formula VIII or a salt thereof is the compound of formula VIIIa or a salt thereof, and the compound of formula I or a salt thereof is the compound of formula Ia or a salt thereof. [ka] [ka]

[0111] In some embodiments, the compound of formula VIIIa or Ia is a salt described herein. For example, the compound of formula VIIIa or Ia is an aliphatic carboxylate (e.g., acetate, propionate, pivalate, C4-C) 18 They can be isolated as fatty acids, hydrochlorides, hydrobroms, alkyl sulfons (e.g., mesylates, esylates, trifluates), aryl sulfons (e.g., tosylates), fumarates, succinates, tartrates, oxalates, phosphates, or sulfates.

[0112] In some embodiments, the compound of formula IA or a salt thereof is the compound of formula I-Aa or I-Ab or a stereoisomer thereof, or a salt of any of the above, and the compound of formula IB or a salt thereof is the compound of formula I-Ba or a stereoisomer thereof, or a salt of any of the above. [ka] or [ka] [ka]

[0113] In some embodiments, the compound of formula IC or a salt thereof is the compound of formula I-Ca, its stereoisomer, or a salt of any of the above, and the compound of formula ID or a salt thereof is the compound of formula I-Da, its stereoisomer, or a salt of any of the above. [ka] [ka]

[0114] In some embodiments, the compound of formula IE or a salt thereof is the compound of formula I-Ea or I-Eb, its stereoisomer, or a salt of any of the above, and the compound of formula II-A or a salt thereof is the compound of formula II-Aa, its stereoisomer, or a salt of any of the above. [ka] [ka] [ka]

[0115] In some embodiments, the compound of formula II-C or a salt thereof is the compound of formula II-Ca, its stereoisomer, or a salt of any of the above, and the compound of formula II-D or a salt thereof is the compound of formula II-Da, its stereoisomer, or a salt of any of the above. [ka] [ka]

[0116] In some embodiments, the compound of formula IF or a salt thereof is the compound of formula I-Fa, its stereoisomer, or a salt of any of the above; the compound of formula IG or a salt thereof is the compound of formula I-Ga, its stereoisomer, or a salt of any of the above; and the compound of formula IH or a salt thereof is the compound of formula I-Ha, its stereoisomer, or a salt of any of the above. [ka] [ka] [ka]

[0117] In some embodiments, the compound of formula III-A or a salt thereof is the compound of formula III-Aa, its stereoisomer, or a salt of any of the above, and the compound of formula III-B or a salt thereof is the compound of formula III-Ba, its stereoisomer, or a salt of any of the above. [ka] [ka]

[0118] In some embodiments, the compound of formula III-C or a salt thereof is the compound of formula III-Ca, its stereoisomer, or a salt of any of the above, and the compound of formula III-D or a salt thereof is the compound of formula III-Da, its stereoisomer, or a salt of any of the above. [ka] [ka]

[0119] In some embodiments, the compound of formula III-E is the compound of formula III-Ea, its stereoisomer, or a salt of any of the above, and the compound of formula III-F or a salt of the same is the compound of formula III-Fa, its stereoisomer, or a salt of any of the above. [ka] [ka]

[0120] In some embodiments, A 1 A compound of formula IA, in which OH is present, or a salt thereof, is reacted with a compound of formula IB, or a salt thereof, to form a compound of formula IC, or a salt thereof. 2 A compound of formula IE, in which is OH, or a salt thereof, is reacted with a compound of formula ID, or a salt thereof, to form a compound of formula VIII, or a compound of formula II-A, or a salt thereof, A 2 Reacting a compound of formula IE, in which OH is present, or a salt thereof, to form a compound of formula II-C, or a salt thereof, A 4 A compound of formula II-D, in which the parentheses are OH, or a salt thereof, is reacted with a compound of formula IB, or a salt thereof, to form a compound of formula VIII, or a salt thereof. 5 A compound of formula IG, in which OH is present, or a salt thereof, is reacted with a compound of formula IH, or a salt thereof, to form a compound of formula IF, or a salt thereof. 6 The compound of formula III-A, in which is OH, or a salt thereof, is reacted with the compound of formula III-B, or a salt thereof, to form the compound of formula VIII, or the compound of formula III-D, or a salt thereof, A 2 Reacting a compound of formula IE, where is OH, or a salt thereof, to form a compound of formula III-C, or a compound of formula IB, or a salt thereof, with A 7The reaction of a compound of formula III-F or a salt thereof, in which the OH group is, to form a compound of formula III-E or a salt thereof is carried out under conditions containing a coupling agent. In some embodiments, the coupling agent includes DCC, EDC, HATU, HBTU, HCTU, T3P, TBTU, TCTU, PyAOP, BOP, or PyBOP. In some embodiments, the coupling agent is EDC, and the conditions optionally include HOBT. In some embodiments, the coupling agent may include BOP, and the conditions optionally include HOBT. In some embodiments, the coupling agent may include HATU, and the conditions optionally include HOAT. In some embodiments, the coupling agent is propylphosphonic anhydride (T3P).

[0121] In any of these embodiments, the conditions for reacting a compound of formula IA or a salt thereof with a compound of formula IB or a salt thereof to form a compound of formula IC, a compound of formula ID or a salt thereof with a compound of formula IE or a salt thereof to form a compound of formula VIII, a compound of formula II-A or a salt thereof with a compound of formula IE or a salt thereof to form a compound of formula II-C, a compound of formula II-D or a salt thereof with a compound of formula IB or a salt thereof to form a compound of formula VIII, a compound of formula IG or a salt thereof with a compound of formula IH or a salt thereof to form a compound of formula IF, a compound of formula III-A or a salt thereof with a compound of formula III-B or a salt thereof to form a compound of formula VIII, a compound of formula III-D or a salt thereof with a compound of formula IE or a salt thereof to form a compound of formula III-C, and a compound of formula IB or a salt thereof with a compound of formula III-F or a salt thereof to form a compound of formula III-E may further include a suitable solvent. Such solvents include alcohols (e.g., methanol (CH3OH), ethanol (EtOH), isopropanol (iPrOH), trifluorethanol (TFE), butanol (BuOH)), halogenated solvents (e.g., methylene chloride (CH2Cl2), chloroform (CHCl3), benzotrifluoride (BTF;PhCF3)), ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2Me-THF), dimethoxyethane (DME), dioxane), and esters (e.g., Examples include, but are not limited to, ethyl acetate, isopropyl acetate, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), amides (e.g., dimethylformamide (DMF), dimethylacetamide (DMA)), nitriles (e.g., acetonitrile (CH3CN), proprionitrile (CH3CH2CN), benzonitrile (PhCN)), sulfoxides (e.g., dimethyl sulfoxide), sulfones (e.g., sulfolane), water, or any two or more mixtures thereof.In any of the embodiments described above, the solvent may include CH3OH, EtOH, iPrOH, TFE, BuOH, CH2Cl2, CHCl3, PhCF3, THF, 2Me-THF, DME, dioxane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, DMF, DMA, CH3CN, CH3CH2CN, PhCN, dimethyl sulfoxide, sulfolane, water, or any two or more mixtures thereof. In some embodiments, the solvent is dimethylformamide (DMF) or CH2Cl2. In any of the embodiments described above, the conditions may further include a base. The base may be an inorganic base such as Na2CO3 or NaHCO3, or an organic base such as 1,8-diazabicyclo[5.4.0]undes-7-ene (DBU), pyridine, N,N-dimethyl-4-aminopyridine (DMAP), or a trialkylamine. Suitable trialkylamines include, but are not limited to, trimethylamine, triethylamine, dimethylethylamine, and diisopropylethylamine. When the base includes an inorganic base, the suitable solvent may further include water.

[0122] In any of the embodiments described above, the conditions are approximately -40°C to approximately 150°C, for example, approximately -40°C, approximately -35°C, approximately -30°C, approximately -25°C, approximately -20°C, approximately -15°C, approximately -10°C, approximately -5°C, approximately 0°C, approximately 5°C, approximately 10°C, approximately 15°C, approximately 20°C, approximately 25°C, approximately 30°C, approximately 35°C, approximately 40°C, approximately 45°C, approximately 50°C, approximately 55°C. This may include temperatures of approximately 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, and any range between these values, including any two of these values.

[0123] In some embodiments, Y 1 Y is an amino protecting group that is susceptible to acid-mediated removal. In some embodiments, Y 1This is tert-butyloxycarbonyl (Boc). In some embodiments, converting a compound of formula IC or a salt thereof to a compound of formula ID or a salt thereof includes combining the compound of formula IC or a salt thereof with a cleaving acid to produce the compound of formula ID or a salt thereof. In some embodiments, the method further includes isolating the compound of formula ID or a salt thereof. In some embodiments, converting a compound of formula IF or a salt thereof to a compound of formula II-A or a salt thereof includes combining the compound of formula IF or a salt thereof with a cleaving acid to produce the compound of formula II-A or a salt thereof. In some embodiments, the method further includes isolating the compound of formula II-A or a salt thereof.

[0124] In some embodiments, Y 2 Y is an amino protecting group that is susceptible to acid-mediated removal. In some embodiments, Y 2 This is tert-butyloxycarbonyl (Boc). In some embodiments, the conversion of the compound of formula III-E or a salt thereof to the compound of formula III-B or a salt thereof includes combining the compound of formula III-E or a salt thereof with a cleaving acid to produce the compound of formula III-B or a salt thereof. In some embodiments, the method further includes isolating the compound of formula III-B or a salt thereof.

[0125] The cleaving acids include halogen acids, carboxylic acids, phosphonic acids, phosphoric acids, sulfinic acids, sulfonic acids, sulfuric acid, sulfamic acid, boric acid, boronic acid, acidic resins, or any combination of two or more of these. Typical examples include, but are not limited to, hydrofluoric acid, hydrochloric acid (HCl), hydrobromic acid, hydroiodic acid, acetic acid (AcOH), fluoroacetic acid, trifluoroacetic acid (TFA), chloroacetic acid, benzoic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and sulfuric acid. In some embodiments, the method includes any two or more of the aforementioned cleaving acids. Combination with cleaving acids can occur at temperatures from about -40°C to about 150°C. Such embodiments may be carried out at approximately -40°C, approximately -35°C, approximately -30°C, approximately -25°C, approximately -20°C, approximately -15°C, approximately -10°C, approximately -5°C, approximately 0°C, approximately 5°C, approximately 10°C, approximately 15°C, approximately 20°C, approximately 25°C, approximately 30°C, approximately 35°C, approximately 40°C, approximately 45°C, approximately 50°C, approximately 55°C, approximately 60°C, approximately 65°C, approximately 70°C, approximately 75°C, approximately 80°C, approximately 85°C, approximately 90°C, approximately 95°C, approximately 100°C, approximately 105°C, approximately 110°C, approximately 115°C, approximately 120°C, approximately 125°C, approximately 130°C, approximately 135°C, approximately 140°C, approximately 145°C, approximately 150°C, and any range between them including any two of these values. In any of the embodiments described above, after being combined with a cleaving acid, the temperature is raised to approximately 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, or any range between these values, including any two of these values.

[0126] In some embodiments, the combination with the cleaving acid includes a protic solvent, a polar aprotic solvent, or a mixture of the two. The protic solvents used herein include, but are not limited to, alcohols (e.g., methanol (CH3OH), ethanol (EtOH), isopropanol (iPrOH), trifluorethanol (TFE), butanol (BuOH)), carboxylic acids (e.g., formic acid, acetic acid, propanoic acid, butanoic acid, pentanoic acid, lauric acid, stearic acid, deoxycholic acid, glutamic acid, glucuronic acid), water, or any two or more mixtures thereof. The polar aprotic solvents used herein include halogenated solvents (e.g., methylene chloride (CH2Cl2), chloroform (CHCl3), benzotrifluoride (BTF; PhCF3)), ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2Me-THF), dimethoxyethane (DME), dioxane), esters (e.g., ethyl acetate, isopropyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), amides (e.g., dimethylformamide (DMF), dimethylacetamide (DMA)), nitriles (e.g., acetonitrile (CH3CN), proprionitrile (CH3CH2CN), benzonitrile (PhCN)), sulfoxides (e.g., dimethyl sulfoxide), sulfones (e.g., sulfolane), or any two or more mixtures thereof.In any of the embodiments described above, the cleaving acid may be combined with methanol (CH3OH), ethanol (EtOH), isopropanol (iPrOH), trifluorethanol (TFE), butanol (BuOH), methylene chloride (CH2Cl2), chloroform (CHCl3), benzotrifluoride (BTF; PhCF3), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2Me-THF), dimethoxyethane (DME), dioxane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile (CH3CN), proprionitrile (CH3CH2CN), benzonitrile (PhCN), dimethyl sulfoxide, sulfolane, water, or any two or more mixtures thereof.

[0127] In some embodiments, Y 1 Y is an amino protecting group that is resistant to acid-mediated removal and sensitive to hydrogen-mediated removal. In some embodiments, Y 1 is Cbz. In some embodiments, converting a compound of formula IC or a salt thereof to a compound of formula ID or a salt thereof includes combining the compound of formula IC or a salt thereof with a hydrogen source to produce the compound of formula ID or a salt thereof. In some embodiments, the method further includes isolating the compound of formula ID or a salt thereof. In some embodiments, converting a compound of formula IF or a salt thereof to a compound of formula II-A or a salt thereof includes combining the compound of formula IF or a salt thereof with a hydrogen source to produce the compound of formula II-A or a salt thereof. In some embodiments, the method further includes isolating the compound of formula II-A or a salt thereof.

[0128] In some embodiments, Y 2 Y is an amino protecting group that is resistant to acid-mediated removal and sensitive to hydrogen-mediated removal. In some embodiments, Y 2is Cbz. In some embodiments, the conversion of a compound of formula III-E or a salt thereof to a compound of formula III-B includes combining a compound of formula III-E or a salt thereof with a hydrogen source to produce a compound of formula III-B or a salt thereof. In some embodiments, the method further includes isolating a compound of formula III-B or a salt thereof.

[0129] The term "hydrogen source" means a source of two hydrogen atoms. In any of the embodiments and aspects described herein, the hydrogen source may include a hydrogen molecule, formic acid, formate, diimide, cyclohexene, or cyclohexadiene, or any two or more combinations thereof. Formate includes, but is not limited to, NH4OC(O)H, and (M) x (OCHO) yIt may also be represented by the formula, where M is an alkali metal or alkaline earth metal, x is 1, 2, or 3, and y is 1, 2, or 3. In some embodiments, the hydrogen source is hydrogen gas. In any of the embodiments and aspects described herein, the compound combined with the hydrogen source further includes a transition metal catalyst, including but not limited to cobalt (Co), iridium (Ir), molybdenum (Mo), nickel (Ni), platinum (Pt), palladium (Pd), rhodium (Rh), ruthenium (Ru), tungsten (W), or any two or more combinations thereof. In some embodiments, the transition metal catalyst includes Pd. In any of the embodiments and aspects described herein, the transition metal catalyst includes a support material. The support material includes but is not limited to carbon, carbonate, silica, silicon, silicates, alumina, clay, or any two or more mixtures thereof. For example, in some embodiments, the transition metal catalyst is Pd-carbon (Pd / C). In some embodiments, the transition metal catalyst is Pd silicon (Pd / Si). In embodiments of the transition metal catalyst including a support material, the amount of transition metal in the combined transition metal / support material mass can be about 0.01% to about 80% by weight. The amount of transition metal can be about 0.01% by weight, 0.05% by weight, 0.1% by weight, about 0.5% by weight, about 1% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, or any range between them including any two of these values. In some embodiments, the transition metal catalyst is Pd carbon, and the amount of transition metal is 5% by weight, i.e., 5%Pd / C. In some embodiments, the transition metal catalyst is Pd-carbon, and the amount of the transition metal is 10% by weight, i.e., 10%Pd / C. In some embodiments, the transition metal catalyst is Pd-silicon, and the amount of the transition metal is 5% by weight, i.e., 5%Pd / Si. In some embodiments, the transition metal catalyst is Pd-silicon, and the amount of the transition metal is 10% by weight, i.e., 10%Pd / Si.In any of the embodiments and aspects described herein, a solvent may be included in addition to the hydrogen source and the transition metal catalyst. Typical solvents include, but are not limited to, alcohols, halogenated solvents, ethers, esters, ketones, amides, nitriles, sulfoxides, sulfones, water, or any two or more mixtures thereof. In any of the embodiments described above, the solvent may include CH3OH, EtOH, iPrOH, TFE, BuOH, CH2Cl2, CHCl3, PhCF3, THF, 2Me-THF, DME, dioxane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, DMF, DMA, CH3CN, CH3CH2CN, PhCN, dimethyl sulfoxide, sulfolane, water, or any two or more mixtures thereof. In any of the embodiments and aspects described herein, the solvent may further include an acid. The acid may be present in a suitable amount, including a catalytic amount. Examples of such acids include, but are not limited to, mineral acids (e.g., HCl, HBr, HF, H2SO4, H3PO4, HClO4), carboxylic acids (e.g., formic acid, acetic acid, propanoic acid, butanoic acid, pentanoic acid, lauric acid, stearic acid, deoxycholic acid, glutamic acid, glucuronic acid), boronic acids, sulfinic acid, sulfamic acid, or any two or more mixtures thereof. In any of the embodiments described above, the solvent may further include HCl, HBr, HF, H2SO4, H3PO4, HClO4, formic acid, acetic acid, propanoic acid, butanoic acid, pentanoic acid, lauric acid, stearic acid, deoxycholic acid, glutamic acid, glucuronic acid, boronic acid, sulfinic acid, sulfamic acid, or any two or more mixtures thereof. Note that when formic acid is included as an acid, it can also serve as a hydrogen source.

[0130] In some embodiments, Y 1 Y is an amino protecting group that is resistant to acid-mediated removal and sensitive to base-mediated removal. In some embodiments, Y 1is Fmoc. In some embodiments, converting a compound of formula IC or a salt thereof to a compound of formula ID or a salt thereof includes combining the compound of formula IC or a salt thereof with a base to produce the compound of formula ID or a salt thereof. In some embodiments, the method further includes isolating the compound of formula ID or a salt thereof. In some embodiments, converting a compound of formula IF or a salt thereof to a compound of formula II-A or a salt thereof includes combining the compound of formula IF or a salt thereof with a hydrogen source to produce the compound of formula II-A or a salt thereof. In some embodiments, the method further includes isolating the compound of formula II-A or a salt thereof.

[0131] In some embodiments, Y 2 Y is an amino protecting group that is resistant to acid-mediated removal and sensitive to base-mediated removal. In some embodiments, Y 2 This is Fmoc. In some embodiments, converting a compound of formula III-E or a salt thereof to a compound of formula III-B or a salt thereof involves combining the compound of formula III-E or a salt thereof with a base to produce the compound of formula III-B or a salt thereof. In some embodiments, the method further includes isolating the compound of formula III-B or a salt thereof.

[0132] In some embodiments, the bases mediating the removal of amino protecting groups sensitive to base-mediated removal include N-methylpyrrolidine, 1,4-bis-(3-aminopropyl)piperazine, DBU, hydrazine, DIEA, dimethylaminopyridine, NaOH, KOH, LiOH, Na2CO3, NaHCO3, K2CO3, KHCO3, Li2CO3, LiHCO3, primary or secondary amines, such as ammonia, ethanolamine, diethylamine, cyclohexylamine, pyrrolidine, piperidine, morpholine, piperazine, and dixyxlohexylamine. In any of the embodiments and aspects described herein, a solvent may be included in addition to the base. Typical solvents include, but are not limited to, alcohols, halogenated solvents, ethers, esters, ketones, amides, nitriles, sulfoxides, sulfones, water, or any two or more mixtures thereof. In any of the embodiments described above, the solvent may include CH3OH, EtOH, iPrOH, TFE, BuOH, CH2Cl2, CHCl3, PhCF3, THF, 2Me-THF, DME, dioxane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, DMF, DMA, CH3CN, CH3CH2CN, PhCN, dimethyl sulfoxide, sulfolane, water, or any two or more mixtures thereof.

[0133] In some embodiments, the method further comprises isolating the compound of formula VIII or a salt thereof. In any of the above embodiments, the conditions for isolating the compound of formula VIII or a salt thereof may further include a suitable solvent. Such solvents include alcohols (e.g., methanol (CH3OH), ethanol (EtOH), isopropanol (iPrOH), trifluorethanol (TFE), butanol (BuOH)), halogenated solvents (e.g., methylene chloride (CH2Cl2), chloroform (CHCl3), benzotrifluoride (BTF;PhCF3)), ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2Me-THF), dimethoxyethane (DME), dioxane), esters (e.g., Examples of solvents include, but are not limited to, CH3OH, EtOH, iPrOH, TFE, BuOH, CH2Cl2, CHCl3, PhCF3, THF, 2Me-THF, DME, dioxane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, DMF, DMA, CH3CN, CH3CH2CN, PhCN, dimethyl sulfoxide, sulfone, water, or any two or more mixtures thereof. In any of the embodiments described above, the solvent may include CH3OH, EtOH, iPrOH, TFE, BuOH, CH2Cl2, CHCl3, PhCF3, THF, 2Me-THF, DME, dioxane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, DMF, DMA, CH3CN, CH3CH2CN, PhCN, dimethyl sulfoxide, sulfone, water, or any two or more mixtures thereof. In some embodiments, a suitable solvent is dimethylformamide (DMF). In some embodiments, a suitable solvent is dimethylacetamide (DMA). In some embodiments, a suitable solvent is CH2Cl2.

[0134] In some embodiments of any part of the foregoing described herein, X 3 R 2 If R 1X is not hydrogen. In some embodiments, X 3 R 2 If R 1 R 2 It is not hydrogen. In some embodiments, Z 5 and / or Z 6 -NHC(NH)-NH-X 2 When X 1 is hydrogen. In some embodiments, Z 5 and / or Z 6 -NHC(NX 4 )-NH-X 2 When X 1 is hydrogen, and X 2 and X 4 At least one of them is not H. In some embodiments, X 2 However, when the amino protecting group is resistant to acid-mediated removal and susceptible to hydrogen-mediated removal, X 1 X is hydrogen. In some embodiments, X 1 However, when the amino protecting group is resistant to acid-mediated removal and susceptible to hydrogen-mediated removal, X 2 is hydrogen. In any of the embodiments described above, Y 1 X can be Boc, Trt, Bpoc, Ddz, or Nps, with each occurrence being X 1 X can independently be hydrogen, alloc, cbz, or 2-ClCbzl, with each occurrence being X 2 X can independently be hydrogen, alloc, cbz, or 2-ClCbz, with each occurrence being X 4 These can independently be hydrogen, nitro, alloc, cbz, or 2-ClCbz.

[0135] In another embodiment, a compound of formula I or a salt thereof, [ka] A method is provided for preparing a pharmaceutically acceptable salt thereof. In the formula, R 1 and R 2 However, each operates independently. (i) hydrogen, (ii) substituted or unsubstituted C1-C6 alkyl, (iii) substituted or unsubstituted aralkyl, (iv) substituted or unsubstituted C3-C8 cycloalkyl or cycloalkylalkyl, (v) substituted or unsubstituted C2-C6 alkenyl, (vi) an amino protecting group, or alternatively R 1 and R 2 together form a 3-, 4-, 5-, 6-, 7-, or 8-membered substituted or unsubstituted heterocyclyl or heteroaryl group, R 3 R 4 R 6 and R 7 each independently is hydrogen, or a C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino, C1-C4 dialkylamino, cyano, -C(O)-alkyl, -C(O)-aryl, -C(O)-aralkyl, carboxylate, ester, amide, nitro, hydroxyl, halogen, or perhaloalkyl group, wherein each of the alkyl, aryl, or aralkyl groups is substituted or unsubstituted, R 5 is hydrogen, or a C1-C6 alkyl or perhaloalkyl, aralkyl, -C(O)-alkyl, -C(O)-aryl, or -C(O)-aralkyl group, wherein each of the alkyl, aryl, or aralkyl groups is substituted or unsubstituted, R 8b is

Chemical formula

Chemical formula

Chemical formula

[0136] In some embodiments, R 1 , R 2 , R 4 , R 5 , and R 6 Each of them is hydrogen, and R 3 and R 7 Each of them is methyl, and R 8 teeth, [ka] And in the formula, R 10 , R 11 , R 12 , R 13 , and R 14 All of them are hydrogen, and R 9 NH2 and Z 1 is hydrogen, Z 2 The compound is -C(NH)-NH2, where n is 4 and m is 3.

[0137] In any of the above embodiments, R 4 , R 5 , and R 6 Each of them can be hydrogen, and R 3 and R 7 It can be methyl, R 8 teeth, [ka] This is possible, and in the formula, R10 , R 11 , R 12 , R 13 , and R 14 may all be hydrogen, Z 1 and Z 5 may be hydrogen, Z 2 may be -C(NH)-NH2, Z 6 may be -C(N-X 4 )-NH-X 2 where at least one of X 2 and X 4 may not be H, n may be 4, and m may be 3.

[0138] In any of the above embodiments, R 4 , R 5 , and R 6 may each be hydrogen, R 3 and R 7 may be methyl, R 8 is <00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​In some embodiments, the peptides prepared by this method include residues at the first and third positions selected from Arg, D-Arg, His, D-His, Lys, D-Lys, Orn (ornithine), D-OrnAah (2-amino-6-amidinohexanoic acid), and D-Aah. In certain embodiments, the residues at the second and fourth positions are selected from Phe, Tyr, His, Trp, and 2'6'-Dmt. All residues are L-configured unless otherwise indicated with respect to the D configuration. In some embodiments, the peptides prepared by this method include one or more peptides from Table A*, or their stereoisomers and / or salts. [Table 1]

[0140] In some embodiments, the peptide comprises the amino acid sequence D-Arg-2′6′-Dmt-Lys-Phe-NH2.

[0141] In some embodiments, X in the compound of formula VIII or a salt thereof 1 , X 2 , X 3 , and X 4 At least one of these is an amino protecting group that is resistant to acid-mediated removal and sensitive to hydrogen-mediated removal, and the method comprises reacting a compound of formula VIII or a salt thereof with a hydrogen source and a transition metal catalyst to form a compound of formula I.

[0142] In any of the embodiments described above, the hydrogen source and the transition metal catalyst are as described herein. In any of the embodiments described above, the combination of the compound of formula VIII or a salt thereof, the hydrogen source, and the transition metal catalyst can be subjected to temperatures from about -20°C to about 150°C. Such embodiments may be implemented in any range between approximately -20°C, approximately -15°C, approximately -10°C, approximately -5°C, approximately 0°C, approximately 5°C, approximately 10°C, approximately 15°C, approximately 20°C, approximately 25°C, approximately 30°C, approximately 35°C, approximately 40°C, approximately 45°C, approximately 50°C, approximately 55°C, approximately 60°C, approximately 65°C, approximately 70°C, approximately 75°C, approximately 80°C, approximately 85°C, approximately 90°C, approximately 95°C, approximately 100°C, approximately 105°C, approximately 110°C, approximately 115°C, approximately 120°C, approximately 125°C, approximately 130°C, approximately 135°C, approximately 140°C, approximately 145°C, approximately 150°C, and any two of these values.

[0143] In some embodiments, X in the compound of formula VIII or a salt thereof 1 , X 2 , X 3 , and X 4 At least one of these is an amino protecting group resistant to acid-mediated removal, and the method comprises reacting a compound of formula VIII or a salt thereof with a cleaving acid described herein to form a compound of formula I or a salt thereof.

[0144] In some embodiments, the method further includes isolating a compound of formula I or a salt thereof. In some embodiments, the method includes preparing a pharmaceutically acceptable salt of a compound of formula I or a salt thereof. The term “pharmaceutically acceptable salt” means a salt prepared from a base or acid that is acceptable for administration to a patient, such as a mammal (e.g., a salt that has mammalian safety acceptable for a given drug regimen). However, it should be understood that this salt does not have to be a pharmaceutically acceptable salt, such as a salt of an intermediate compound not intended for administration to a patient. A pharmaceutically acceptable salt may be derived from a pharmaceutically acceptable inorganic or organic base and a pharmaceutically acceptable inorganic or organic acid. In addition, when a peptide contains both a basic moiety such as an amine, pyridine, or imidazole and an acidic moiety such as a carboxylic acid or tetrazole, an amphoteric ion may be formed, which is included in the term “salt” as used herein. Examples of pharmaceutically acceptable inorganic base-derived salts include ammonium, alkylammonium, calcium, cupric, cuprous, nickel, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc salts. Examples of pharmaceutically acceptable salts derived from organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and natural amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, diisopropylethylamine, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, imidazole, isopropylamine, lysine, methylglucamine, morpholine, N-methylmorpholine, piperazine, piperidine, pyridine, lutidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.Examples of pharmaceutically acceptable salts derived from inorganic acids include salts of boric acid, carbonic acid, hydrohalic acids (hydrobromic acid, hydrochloric acid, hydrofluoric acid, or hydroiodic acid), nitric acid, phosphoric acid, phosphorous acid, sulfamic acid, and sulfuric acid. Examples of pharmaceutically acceptable salts derived from organic acids include aliphatic hydroxyl acids (e.g., citric acid, gluconic acid, glycolic acid, lactic acid, lactobionic acid, malic acid, and tartaric acid), aliphatic monocarboxylic acids (e.g., acetic acid, butyric acid, formic acid, propionic acid, and trifluoroacetic acid), amino acids (e.g., aspartic acid and glutamic acid), aromatic carboxylic acids (e.g., benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentisic acid, hippuric acid, and triphenylacetic acid), aromatic hydroxyl acids (e.g., o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid, and 3-hydroxynaphthalene-2-carboxylic acid), as Examples include corbic acid, dicarboxylic acids (e.g., fumaric acid, maleic acid, oxalic acid, and succinic acid), fatty acids (lauric acid, myristic acid, oleic acid, stearic acid, palmitic acid), glucoronic acid, mandelic acid, mucoic acid, nicotinic acid, orotic acid, pamoic acid, pantothenic acid, sulfonic acids (e.g., benzenesulfonic acid, camphosulfonic acid, edisylic acid, ethanesulfonic acid, isethionic acid, methanesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, and p-toluenesulfonic acid), and xinafoic acid salts.In some embodiments, pharmaceutically acceptable acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphor acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), capric acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, and glucoheptonic acid (D). Examples of salts include, but are not limited to, gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid. In some embodiments, the salt is an acetate. In addition, or in other embodiments, the salt is a trifluoroacetate. In some embodiments, the salt is a hydrochloride, tosylate, or tartrate. In other embodiments, the salt is anhydrous hydrochloride.

[0145] In another embodiment, isomers of the compounds of formula IG, (L)-IG, and III-D, (L)-III-D, or salts of any of the above, can be prepared from the compound of formula XV or a salt thereof. [ka] [ka] [ka] In the formula, R 50 and R 51 However, each is independently hydrogen, or a substituted or unsubstituted C1-C6 alkyl, aryl, or cycloalkyl group, W 2 , R 3 , R 4 , R 5 , R 6 , and R 7 However, as defined herein. In some embodiments, R 4 and R 6 Each of these is hydrogen. In some embodiments, R 3 , R 7 , R 50 , and R 51 Each of these is methyl.

[0146] In one embodiment, the compound of formula (L)-IG or a salt thereof is the -NHCOR of the compound of formula XV or a salt thereof. 50 For example, by a method that includes converting the group to -NH2, a compound of formula XV or a salt thereof is reacted with an aqueous solution of HCl or an aqueous solution of ammonia, and then the -NH2 of the resulting compound is converted to compound Y 1 -By reacting with Lv or its salt, an organic base, and a suitable solvent (wherein Lv is a halo, -OY 1 It is prepared from a compound of formula XV or a salt thereof (which is a leaving group such as -OC(O)Cl). In some embodiments, Y 1 is Boc, and Y 1 -Lv is Boc2O. In some embodiments, Y 1 This is Cbz, and Y 1-Lv is benzyl chloroformate (CbzCl). In some embodiments, the base is triethylamine (Et3N), 1,8-diazabicyclo[5.4.0]undes-7-ene (DBU), diisopropylethylamine (DIPEA), pyridine or 4-dimethylaminopyridine (DMAP), or any two or more combinations thereof. In some embodiments, the base is DMAP. The solvent may include alcohols, halogenated solvents, ethers, esters, ketones, amides, nitriles, sulfoxides, sulfones, water, or any two or more mixtures thereof. In any of the embodiments described above, the solvent may include CH3OH, EtOH, iPrOH, TFE, BuOH, CH2Cl2, CHCl3, PhCF3, THF, 2Me-THF, DME, dioxane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, DMF, DMA, CH3CN, CH3CH2CN, PhCN, dimethyl sulfoxide, sulfolane, water, or any two or more mixtures thereof. In some embodiments, the solvent is methylene chloride (CH2Cl2), chloroform (CHCl3), tetrahydrofuran (THF), 2-methyltetrahydrofuran, dimethoxyethane (DME), dioxane, or any two mixtures thereof. In some embodiments, the solvent is methylene chloride. In some embodiments, a method for converting a compound of formula XV or a salt thereof to a compound of formula (L)-IG or a salt thereof is the group COOW of the compound of formula XV or a salt thereof. 2 Converting to COOH, and / or the group OCOR of the compound of formula XV or its salt. 51 This further includes converting to OH. Such conversions are generally known in the art. In some embodiments, the conversion is carried out under conditions including an aqueous solution of an alkali metal hydroxide (e.g., LiOH, NaOH, or KOH) or an alkaline earth metal hydroxide (e.g., Ca(OH)2 or Mg(OH)2). In some embodiments, the conversion is carried out under conditions including an aqueous solution of NaOH. In some embodiments, W 2 It is benzyl, COOW 2Converting to COOH is done under conditions including a hydrogen source and transition metal catalyst as described herein. In some embodiments, the method converts the OH group to R 5 -Lv 2 The compound (wherein R is used in the formula) 5 However, as defined herein, it is not hydrogen, but Lv 2 However, when reacted with a leaving group such as Cl or Br, A 5 By forming a compound of formula (L)-IG or a salt thereof in which the OH group is OR, the obtained OH group is OR 5 This further includes converting to A 5 A compound of formula (L)-IG, where OH is present, or a salt thereof, is defined as ClC(O)-R 59 And it reacts to A 5 ga-OC(O)-R 59 A is formed by a method of forming a compound of formula (L)-IG or a salt thereof. 5 A compound of formula (L)-IG, where OH is present, or a salt thereof, in its anhydrous form, for example, A 5 ga-OC(O)-R 59 The further part includes converting to a compound of formula (L)-IG or a salt thereof. In some embodiments, A 5 Compounds of (L)-IG or salts thereof where OH is A 5 A compound of formula (L)-IG or a salt thereof, in which the OH group is Lv as described herein. 1 -R 58 By a method including reaction with, it is further converted to an active ester, for example, a compound of formula (L)-IG or a salt thereof. In some embodiments, A 5 Compounds of (L)-IG or salts thereof where OH is A 5 A is obtained by a method comprising reacting a compound of (L)-IG or a salt thereof, in which OH is present, with a fluorinating agent described herein. 5 It is further converted to a compound of (L)-IG or a salt thereof, where F is present. In some embodiments, A 5 Compounds of formula (L)-IG where OH is, A 5A compound of formula (L)-IG, in which OH is present, or a salt thereof, is reacted with a chlorinating agent described herein by a method comprising this process. 5 It is further converted to a compound of formula (L)-IG where Cl is present. In some embodiments, A 5 Compounds of formula (L)-IG, where OH is present, or salts thereof, are A 5 A is obtained by a method comprising reacting a compound of formula (L)-IG, in which OH is present, or a salt thereof, with a brominating agent described herein. 5 The compound of formula (L)-IG or a salt thereof is further converted to a compound of formula (L)-IG or a salt thereof, wherein Br is present. In some embodiments, the method further comprises isolating the compound of formula (L)-IG or a salt thereof.

[0147] In one embodiment, the compound of formula (L)-III-D or a salt thereof is the -NHCOR of the compound of formula XV or a salt thereof. 50 The compounds of formula XV or their salts are prepared by a method that includes converting the group to -NH2, for example, by reacting the compound of formula XV or its salt with an aqueous solution of HCl or an aqueous solution of ammonia. In some embodiments, the method for converting the compound of formula XV or its salt to the compound of formula (L)-III-D or its salt involves the group OCOR of the compound of formula XV or its salt. 51 It is hydrolyzed to OH, R 5 The conditions further include ester hydrolysis conditions for forming a compound of formula (L)-III-D in which is hydrogen. Such conditions are generally known in the art. In some embodiments, R 5 The compound of formula (L)-III-D, or a salt thereof, in which is hydrogen, 5 A compound of formula (L)-III-D, or a salt thereof, in which R is hydrogen, 5 -Lv 2 Compounds or salts thereof (wherein R 5 However, as defined herein, it is not hydrogen, but Lv 2 However, by reacting with a leaving group such as Cl or Br to form the compound of formula (L)-III-D or a salt thereof, R 5The compound of formula (L)-III-D or a salt thereof is further converted to a compound of formula (L)-III-D or a salt thereof, wherein the atom is not hydrogen. In some embodiments, the method further comprises isolating the compound of formula (L)-III-D or a salt thereof.

[0148] In some embodiments, the conversion yield of the compound of formula XV or a salt thereof to the compound of formula (L)-IG or (L)-III-D or a salt thereof is at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%. In some embodiments, the compound of formula (L)-IG or (L)-III-D or a salt thereof is isolated in a yield of at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, with a purity of at least about 90%, or at least about 95%, or at least about 97%, or at least about 99%.

[0149] In some embodiments, compounds of formula XV or salts thereof are prepared, for example, by the method described in PCT / US2014 / 072264, filed December 23, 2014, entitled Pharmaceutically Relevant Aromatic-Cationic Peptides and Methods of Generating the Same.

[0150] It is surprising that such compounds can be incorporated into peptides without protecting the hydroxyl group of phenol.

[0151] In another embodiment, intermediates useful in the methods of the present technology described herein are provided, such as compounds of formulas IA, IB, IC, ID, IE, IF, IG, IH, II-A, II-C, II-D, III-A, III-B, III-C, III-D, III-E, or III-F, or salts of any of the above, and methods for preparing the intermediates described herein are provided. [Examples]

[0152] The technology is further illustrated by the following examples, which should not be construed as limiting in any way. Peptides described herein may also be used for each of the following examples. As an example, and not a limitation, the peptide used in the following examples may be D-Arg-2′6′-Dmt-Lys-Phe-NH2. In one embodiment, the peptide is a pharmaceutically acceptable salt, such as, but not limited to, a tartrate, acetate, or trifluoroacetate.

[0153] Terminology and Abbreviations: ACN = Acetonitrile Atm = atmosphere BOC=Boc=tert-butoxycarbonyl BOP reagent = Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate Bn = Benzyl br=wide area t-BuOH = tert-butyl alcohol Cat. = catalyst Conc.=conc=conc. d = doublet dd = double doublet ddd = double double double doublet dt = double triplet DCM = Dichloromethane (CH2Cl2) Des-martinperiodinane=1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIAD = Diisopropyl azodicarboxylate DIPEA = N,N-diisopropylethylamine DMF = N,N-dimethylformamide DMSO = Dimethyl sulfoxide EDC = N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride Et2O = Diethyl ether Et3N = Triethylamine alkyl = ethyl acetate EtOH = ethyl alcohol eq. or equiv. = equivalent (multiple equivalents are possible) h = time (multiple values ​​are possible) HATU = N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate H2O = Water HCl = hydrochloric acid HPLC = High-Performance Liquid Chromatography HOAc = Acetic Acid HOBt = 1-hydroxybenzotriazole IPA = Isopropyl alcohol ISCO = TeLedyne ISCO-supplied normal-phase silica gel cartridges K2CO3 = potassium carbonate LiBH4 = Lithium tetrahydroborate LiBr = Lithium Bromide LiCL = Lithium Chloride LAH = Lithium tetrahydroaluminate m = multiple min. = minutes (multiple minutes allowed) MgCl2 = Magnesium Chloride MeOH = methanol 2-MeTHF = 2-methyltetrahydrofuran MsCl = Methanesulfonyl Chloride MTBE = Methyl tert-butyl ether NaHCO3 = Sodium Bicarbonate Na2SO4 = sodium sulfate NH4OH = Ammonium hydroxide NH4OAc = Ammonium acetate NH4Cl = Ammonium chloride NMR=nuclear magnetic resonance NMP = N-methylpyrrolidinone Pd-C = Palladium activated carbon p = Pentet PMB = p-methoxybenzyl PMBCL = p-methoxybenzyl chloride ret=retain rt=room temperature s = singlet sat=saturated t = triplet TFA = Trifluoroacetic Acid TBDPS = t-butyldiphenylsilyl TBS = t-butyldimethylsilyl THF = Tetrahydrofuran TLC = Thin-Layer Calculation

[0154] A protecting group for phenol OH is not required for the coupling reaction. Example 1. Preparation of Cbz-DMT(1) [ka]

[0155] Fmoc-DMT (1a, 7g, 0.0162mol) was added to a 250mL round-bottom flask, followed by N,N-dimethylformamide (DMF) (91mL). The mixture was stirred for 10 minutes. Piperidine (62mL, 53.4g, 0.628mol, 38.8 equivalents) was added to the solution at ambient temperature. Precipitation was observed after 20 minutes. The mixture was stirred for 2 hours. The bulk DMF was removed under reduced pressure at 65-70°C. Tert-butyl methyl ether (MTBE) (200mL) was added to the suspension, and the mixture was stirred for 16 hours. The solid was collected by filtration and washed with 3 × 50mL of MTBE. It was dried under vacuum at ambient temperature for 4 hours to obtain 4.3g of a white solid. The material was used "as is" for the next step. [ka]

[0156] In a 1 L round-bottom flask, DMT (1b, 6.4 g, 30.6 mmol) (e.g., available from Sigma-Aldrich), followed by water (320 mL) and 1,4-dioxane (85 mL). The mixture was stirred for 15 minutes. Sodium bicarbonate (9 g, 107.1 mmol, 3.5 equivalents) was added to the solution. After 10 minutes, benzyl chloroformate (6.6 mL, 7.9 g, 46.3 mmol, 1.5 equivalents) was added to the solution at ambient temperature. The solution was stirred for 2 hours. The water / 1,4-dioxane solution was then washed twice with 2 × 200 mL of ethyl acetate. The basic water / 1,4-dioxane layer was then slowly acidified with 1 M HCl (85 mL) until the observed cloudiness persisted. The product was extracted in ethyl acetate (200 mL). The ethyl acetate solution was washed with aqueous saline (100 mL). Next, it was stirred with sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 6.0 g of the title compound 1 as heavy oil. The structure was confirmed by the presence of a molecular ion peak (m / z+H) at 344 on MS. 1 H NMR(300 MHz,DMSO-d6)δ 2.16(s,6H);2.80-3.01(m,2H);4.10-4.13(m,1H);5.01(s,2H);6.40(s,2H);7.25-7.38(m,4H);7.66(d,1H);8.97(s,1H);12.6(br,1H) Example 3. Preparation of DMT-OBn HCl 10 [ka]

[0157] Boc-DMT(10a) (10.0 g, 32.4 mmol, 1.0 equivalent) was added to a 500 mL round-bottom flask. Anhydrous N,N-dimethylformamide (DMF) (100 mL, 10 volumes) was added to the flask. Diisopropylethylamine (DIPEA) (10 mL, 7.42 g, 57.5 mmol, 1.77 equivalents) was added to the solution at ambient temperature. Benzyl bromide (8.5 mL, 12.3 g, 72.0 mmol, 2.22 equivalents) was added to the homogeneous solution and stirred for 3 days. The solution was poured into cold water (500 mL, 5 volumes). The product was extracted with ethyl acetate (300 mL). The ethyl acetate solution was washed with 2 × 0.1 L of water. It was dried on Na₂SO₄ for 16 hours. The filter agent was removed by filtration, and the filtrate was concentrated under vacuum to obtain crude oil. Heptane (100 mL) was added to the oil and stirred for 10 minutes. It was removed by decantation to obtain 15.4 g of 10b, which was used "as is" for the next step. [ka]

[0158] Dichloromethane (DCM) was added to Boc-DMT-OBn(10b) (15.4 g, 38.5 mmol, 1 equivalent) in a 500 mL round-bottom flask. The homogeneous solution was cooled to 5°C using an ice bath. At 5°C, 4M HCl (48 mL, 192 mmol, 5.0 equivalents) in 1,4-dioxane was added to the solution. The solution was stirred at 0-5°C for 1.5 hours. The ice bath was removed, and the suspension was stirred at ambient temperature for 3 hours. The precipitated solid was collected by filtration and washed with additional DCM (3 × 40 mL). It was dried under vacuum at ambient temperature to obtain 9.70 g (90.0%, 2-step yield) of the title compound 10. The structure was confirmed by MS showing a molecular ion peak (m / z + H) at 300. 1 H NMR(300MHz,DMSO-d6)δ 2.13(s,6H);3.06-3.09(m,2H);4.00(m,1H);5.04-5.09(dd,2H);6.43 (s,2H);7.03-7.09(m,2H);7.28-7.31(m,3H);8.61(m,3H);9.12(s,1H) Example 4. Preparation of Boc-D-Arg-DMT-Lys(Boc)-Phe-NH2 via [1+2+1] [ka] Step 1: Preparation of Cbz-DMT-Lys(Boc)-OMe [ka]

[0159] In a 500 mL round-bottom flask, Cbz-DMT(1) (3.0 g, 8.75 mmol, 1.05 equivalents) in dichloromethane (DCM) (30 mL, 10 volumes) was added, followed by (Boc)-Lys-OMe HCl(2) (2.47 g, 8.32 mmol, 1.0 equivalent). To the mixed heterogeneous mixture, which was being stirred, hydroxybenzotriazole (HOBt) (1.24 g, 9.17 mmol, 1.10 equivalents), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (1.69 g, 8.75 mmol, 1.05 equivalents) and diisopropylethylamine (DIPEA) (1.45 mL, 1.08 g, 8.34 mmol, 1.00 equivalent). After 16 hours, DCM was removed under reduced pressure to obtain a foamy solid, which was dissolved in ethyl acetate (300 mL). The ethyl acetate solution was successively washed with 75 mL of saturated aqueous solution NaHCO3, 75 mL of 20% saline solution, 75 mL of 20% 0.1 M HCl, and finally 75 mL of saline solution. The ethyl acetate solution was dried with Na2SO4 (35 g). The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 3 (4.0 g, 82.1%) as a grayish-white solid. The structure was confirmed by the molecular ion peak (m / z + Na) at 608 on MS. 1H NMR(300MHz,DMSO-d6)δ 1.21-1.60(m,6H),1.35(s,9H),2.18(s,6H),2.62-(m,1H),2.82-(m,3H),3.58(s,3H),4.18-4.24 (m,2H),4.92-5.00(m,2H),6.38(s,2H),6.75(t,1H),7.22-7.41(m,5H),8.10(d,1H),8.90(s,1H). Step 2: Preparation of Cbz-DMT-Lys (Boc) [ka]

[0160] Methanol (8 mL) was added to Cbz-DMT-Lys(Boc)-OMe(3) in a 1000 mL round-bottom flask (4.0 g, 6.83 mmol). 2 M aqueous LiOH (8 mL, 16 mmol, 2.3 equivalents) was added to the homogeneous solution at ambient temperature. The solution was stirred for 16 hours. A portion of the methanol was removed under reduced pressure. The solution was then acidified with 0.1 M HCl (140 mL, 14 mmol) (pH 2-3) until the observed precipitate persisted. The white solid was collected by filtration and washed with water (15 mL). It was dried under vacuum at ambient temperature to obtain the title compound 4 (3.40 g, 87.2%). The structure was confirmed by MS, which showed a molecular ion peak (m / z+H) at 572. 1 H NMR(300MHz,CDCl3)δ 1.25-1.67(m,6H),1.43(s,9H),2.27(s,6H),3.02(br,5H),4.27(br,2H),4.78(br,1H),5.12(s,2H),5.83(br,2H),6.53(s,2H),7.34(m,5H). Step 3: Preparation of Cbz-DMT-Lys(Boc)-Phe-NH2 [ka]

[0161] In a 100 mL round-bottom flask, Cbz-DMT-Lys(Boc)(4) (2.0 g, 3.5 mmol; 1.0 equivalent) was added, followed by (L)-phenylalaninamide HCl(5) (0.700 g, 3.5 mmol, 1.0 equivalent). Anhydrous N,N-dimethylformamide (DMF) (20 mL) was added to the mixture. After complete dissolution, diisopropylethylamine (2.25 g, 3.0 mL, 17.5 mmol, 5 equivalents) was added to the homogeneous solution. After 5 minutes, propylphosphonic anhydride (T3P) (50% in DMF, 2.0 mL, 1.0 equivalent) was added to the solution at ambient temperature and stirred for 3 hours. Then, water (100 mL, 5 volumes) was added to the solution. The resulting precipitate was filtered, washed with water (20 mL), and dried under vacuum at ambient temperature for 16 hours. Next, the solid was placed in a 100 mL round-bottom flask and suspended in dichloromethane for 1 hour. This was collected by filtration and dried under vacuum at ambient temperature to obtain title compound 6 (1.80 g, 72%). The structure was confirmed by a molecular ion peak (m / z + H) at 718 on MS. 1 H NMR(300MHz,DMSO-d6)δ 1.13-1.54(m,6H);1.33(s,9H);2.14(s,6H);2.65-3.01(m,6H);4.10-4.18(m,2H);4.34-4.41(m,1H); 4.77-4.99(m,2H);6.33(s,2H);6.70-6.74(t,1H);7.05-7.48(m,12H);7.79-7.92(m,2H),8.93(br,1H) Step 4: Preparation of DMT-Lys(Boc)-Phe-NH2 [ka]

[0162] In a palladium-containing flask (10% by weight on carbon powder, 50% wet with water, Degussa type, 0.044 g), Cbz-DMT-Lys(Boc)-Phe-NH40 dissolved in methanol (4.5 mL) was added. 2(6) (0.2 g, 0.290 mmol) was added. The flask was subjected to 3 cycles of evacuating / returning with nitrogen gas, followed by 3 cycles of evacuating / returning with hydrogen gas. The mixture was stirred under 1 atm of hydrogen for 16 hours. The mixture was filtered through Celite and washed with additional methanol (20 mL). The solution was concentrated under reduced pressure to obtain oil. The oil was treated with dichloromethane (5 mL) to obtain a gray solid. Dichloromethane was removed by decantation, and the mixture was subsequently dried under vacuum to obtain the title compound 7 (0.140 g, 86.4%). The structure was confirmed by MS showing a molecular ion peak (m / z + H) at 584. 1 H NMR(300MHz,DMSO-d6)δ 1.12-1.60(m,6H);1.33(s,9H);2.15(s,6H);2.71-3.31(m,6H);4.13-4.20(m,1H);4.35-4.43(m,1H);4.77-4.99(m ,2H);6.37(s,2H);6.71-6.75(t,1H);7.05(s;1H);7.11-7.23(m,5H);7.34(s,1H);7.88-7.97(m,2H);8.93(br,1H). Step 5: Preparation of Boc-D-Arg-DMT-Lys(Boc)-Phe-NH2 [ka]

[0163] In a 50 mL round-bottom flask, DMT-Lys(Boc)-Phe-NH2(7) (0.14 g, 0.240 mmol) was added, followed by Boc-D-Arg HCl hydrate 9 (0.079 g, 0.240 mmol). N,N-dimethylformamide (DMF, 2 mL) was added to the solid mixture. After complete dissolution, diisopropylethylamine (DIPEA) (0.21 mL, 0.16 g, 1.21 mmol, 5.0 equivalents) was added to the homogeneous solution. After stirring for 5 minutes, propylphosphonic anhydride (T3P) (50% in DMF, 1 equivalent, 0.076 g of activating reagent, 0.150 g of activating reagent with DMF, and 0.14 mL of activating reagent with DMF) was added to the solution. After stirring for 3 hours, 33% T3P (0.05 mL) in an additional DMF was added. The solution was stirred for 1 hour. Water (20 mL, 10 volumes) was added to the solution. The solid was collected by filtration and washed with 2 × 2.5 mL of water. The filtrate was subjected to lyophilization for 16 hours to obtain 0.44 g of a white solid consisting of the desired product and DIPEA / T3P salt. The lyophilized solid was suspended in water (6 mL) for 5 minutes. The solid was collected by filtration to obtain approximately 0.070 g of solid, which was subjected to an additional water wash (2 mL), and after filtration and drying under vacuum at ambient temperature, the title compound 16 (0.035 g, 17.5%) was obtained. The structure was confirmed by MS showing a molecular ion peak (m / z + H) at 840. 1 H NMR(300MHz,MeOH-d4)δ 1.21-1.42(m,23H);1.65-1.67(m,5H);2.30(s,6H);2.86-3.97(m,8H);3.90(m 1H);4.14(m,1H);4.54-4.71(m,2H);6.40(s,2H);7.21-7.25(m,5H). Example 5. Preparation of Boc-D-Arg-DMT-Lys(Boc)-Phe-NH2 via [2+2] [ka] Step 1: Preparation of Boc-D-Arg-DMT-OBn [ka]

[0164] In a 250 mL round-bottom flask, DMT-OBn·HCl 10 (3.00 g, 8.93 mmol, 1.00 equivalent) was added, followed by Boc-D-Arg HCl hydrate 9 (2.95 g, 8.97 mmol, 1.00 equivalent). Anhydrous N,N-dimethylformamide (DMF) (30 mL, 10 volumes) was added to the mixture. The resulting solution was treated with diisopropylethylamine (DIPEA) (8.00 mL, 5.94 g, 45.9 mmol, 5.12 equivalents). The resulting solution was stirred for 5 minutes, and then 50% T3P solution in DMF (5.20 mL, 5.67 g, 8.91 mmol, 1.00 equivalent) was added dropwise over 15 minutes. The reaction mixture was stirred at ambient temperature for 2 hours. Next, the solution was added to cold water (300 mL, 5°C) and extracted with dichloromethane (DCM, 300 mL). The dichloromethane layer was washed with 0.1 M HCl (2 × 100 mL) and saturated saline solution (200 mL). The DCM solution was dried on anhydrous sodium sulfate (approximately 50 g) while stirring for 16 hours. The desiccant was removed by vacuum filtration, and the filtration cake was washed with DCM (4 × 25 mL). The organic layer was concentrated under vacuum to obtain the title compound 11 (4.48 g, 90%). The structure was confirmed by the presence of a molecular ion peak (m / z + H) at 556 on MS. 1 H NMR(300MHz,DMSO-d6)δ 1.30-1.50(m;4H);1.36(s,9H);2.14(s,6H);2.79-2.86(m,1H);2.96-3.03(m,3H);3.97-3.99(m,1H);4.44-4.49(m.1H);5.02(s,2 H);6.38(s,2H);6.82(d,1H);6.81-6.84(d,1H);7.15-7.18(m,2H);7.25-7.29(m,4H);7.52-7.58(m,2H);8.35(d,1H);9.05(d,1H). Step 3: Preparation of Boc-D-Arg-DMT [ka]

[0165] Boc-D-Arg-DMT-OBn 11 (1.06 g, 1.90 mmol) dissolved in methanol (20 mL) was added to a 100 mL round-bottom flask containing palladium (10 wt% carbon powder, 50% wetted with water, Degussa type, 0.044 g). The flask was subjected to 3 cycles of exhaust / return-filling with nitrogen gas, followed by 3 cycles of exhaust / return-filling with hydrogen gas. The mixture was stirred under 1 atm H2 for 16 hours. The mixture was filtered through Celite and washed with additional methanol (4 × 25 mL). The solution was concentrated under reduced pressure to obtain an oily compound. The oil was treated with ethyl acetate (25 mL) and stirred for 2 hours. The solid was collected by filtration to obtain the title compound 12 (0.74 g, 85%). The structure was confirmed by MS showing a molecular ion peak (m / z + H) at 466. 1 H NMR(300MHz,DMSO-d6)δ 1.20-1.50(m;4H);1.36(s,9H);2.20(s,6H);2.74-2.83(m,1H);2.97-3.08(m,3H);3.9 7-4.06(m,1H);4.39-4.41(m.1H);6.39(s,2H);6.82(d,1H);6.86(m,1H);8.13(m,1H). Step 4: Preparation of CBz-Lys(Boc)-Phe-NH2 [ka]

[0166] In a 50 mL round-bottom flask, (L)-phenylalanineamide HCl salt 5 (1 g, 4.97 mmol, 1.0 equivalent) and Cbz-Lys(Boc) 13 (1.98 g, 5.22 mmol, 1.05 equivalent), followed by dichloromethane (10 mL). Hydroxybenzotriazole (HOBt) (0.74 g, 0.00548 mol, 1.10 equivalent), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (1.00 g, 5.22 mmol, 1.05 equivalent). Diisopropylethylamine (DIPEA) was added in a heterogeneous mixture (0.64 g, 0.86 mL, 4.97 mmol, 1.0 equivalent). The suspension was transferred to a 250 mL round-bottom flask and diluted with additional dichloromethane (90 mL). The heterogeneous mixture was stirred for 16 hours. The solid was collected by filtration and then washed with additional dichloromethane (2 × 25 mL) to obtain a white solid. This was dried under vacuum at ambient temperature to obtain the title compound 14 (1.90 g, 72.5%). The structure was confirmed by MS, which showed a molecular ion peak of 549 (m / z + Na). 1 H NMR(300MHz,DMSO-d6)δ 1.13-1.42(m,6H);1.35(s,9H);2.76-2.82(m,3H);2.95-3.00(m,1H);3.85-3.89(m,1H);4. 41-4.43(m,1H);4.99(s,2H);6.73(t,1H);7.09-7.26(m,6H);7.33-7.39(m,7H);7.82(d,1H) Step 5: Preparation of NH2-Lys(Boc)-L-Phe-CONH2 [ka]

[0167] A 100 mL round-bottom flask containing palladium (10% by weight on carbon powder, 50% wetted with water, Degussa type, (0.140 g)) was filled with Cbz-Lys(Boc)-Phe-NH214 (0.700 g, 1.33 mmol) dissolved in 25 mL of methanol. The flask was subjected to 3 cycles of evacuation / returning with nitrogen gas, followed by 3 cycles of evacuation / returning with hydrogen gas. The mixture was stirred for 2.5 hours under 1 atm of H2. The substance was filtered through Celite (4.6 g) and washed with additional methanol (4 × 25 mL). The solution was concentrated under reduced pressure to obtain oil. The oil was treated with tert-butyl methyl ether (50 mL) and stirred for 1 hour. The resulting white solid was collected by filtration and dried under vacuum at ambient temperature to obtain title compound 15 (0.445 g, 87.2%). The structure was confirmed by MS showing a molecular ion peak (m / z + H) at 393. 1 H NMR(300MHz,DMSO-d6)δ 1.07-1.41(m,6H);1.35(s,9H);2.76-2.84(m,3H);2.96-3.01(m,1H);4.03-4.10(m,1 H);4.43-4.45(m,1H);6.73(t,1H);7.09-7.23(m,6H);7.45(s,1H);8.01-8.03(m,1H). Step 6: Preparation of Boc-D-Arg-DMT-Lys(Boc)-Phe-NH2 [ka]

[0168] In a 50 mL round-bottom flask, Boc-D-Arg-DMT(12) (0.1 g, 0.215 mmol, 1 equivalent), followed by Lys(Boc)-Phe-NH2(15) (0.084 g, 0.214 mmol, 1.0 equivalent). Anhydrous N,N-dimethylformamide (DMF) (0.5 mL, 5 volumes) was added to the mixture. Diisopropylethylamine (DIPEA) (0.138 g, 0.19 mL, 1.08 mmol, 5.0 equivalents) was added to the solution. After stirring for several minutes, propylphosphonic anhydride (T3P) (50% in DMF) (1.0 equivalent, 0.068 g of activating reagent, 0.14 g of activating reagent with DMF, 0.14 mL of activating reagent with DMF) was added to the solution. Water (10 mL) was added to the solution after 2 hours. The solid was collected by filtration, washed with water (5 mL), and dried under vacuum at ambient temperature for 3 hours. Next, it was stirred in dichloromethane (5 mL) for 30 minutes, collected by filtration, and dried under vacuum at ambient temperature for 16 hours to obtain a grayish-white solid (0.040 g, 22.2%). The structure was confirmed by the presence of a molecular ion peak (m / z + H) at 840 on MS. 1 H NMR(300MHz,MeOH-d4)δ 1.21-1.42(m,23H);1.65-1.67(m,5H);2.30(s,6H);2.86-3.97(m,8H);3.90(m 1H);4.14(m,1H);4.54-4.71(m,2H);6.40(s,2H);7.21-7.25(m,5H). Example 6. Preparation of D-arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-amide. [ka]

[0169] Palladium (10% by weight on carbon powder, dried (ALdrich 520888), 0.015 g) and N 2 -[(benzyloxy)carbonyl]-N 5 -[{[(benzyloxy)carbonyl]amino}{[(benzyloxy)carbonyl]imino}methyl]-d-ornityl-2,6-dimethyl-L-tyrosyl-N6 A flask containing -{[(2-chlorobenzyl)oxy]carbonyl}-L-lysyl-L-phenylalaninamide (0.150 g, 0.124 mmol) was mixed with methanol (5 mL) and acetic acid (0.028 mL, 0.50 mmol). The flask was subjected to two cycles of exhaust / hydrogen gas return filling, and the mixture was stirred at 50°C for 4 hours under 1 atm of H2. The mixture was cooled, filtered through SoLka-FLoc, and washed with additional methanol (50 mL). The combined washes were concentrated under reduced pressure, and the residue was freeze-dried with water (20 mL) to obtain the title compound (0.093 g, 99%) as a white amorphous powder. The compound is: 1 Integration of 1H NMR spectra revealed that it contains 16% w / w acetate. 1 H NMR(400MHz,D2O)δ 1.05-1.30(m,4H),1.43-1.67(m,6H),1.80(s,6H,acetate),2.10(s,6H),2.71-3.08(m,8H),3.82(t,J=6H C 32 H 49 N9O5m / z 640.4(M+H) + ;HPLC retention time=2.25 minutes. Example 7. Preparation of D-arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-amide. [ka]

[0170] A flask, oven-dried under nitrogen, was filled with 7 mL of isopropyl alcohol and cooled to 0-5°C. Acetyl chloride (0.85 mL, 12 mmol) was added and the mixture was stirred for 15 minutes. 2 -[(t-butyloxy)carbonyl]-D-arginyl-2,6-dimethyl-L-tyrosyl-N 6-[(t-butyloxy)carbonyl]-L-lysyl-L-phenylalaninamide (1.008 g, 1.2 mmol) was added to a flask, and the slurry was heated to 40°C and stirred for 1 hour. The mixture was cooled to room temperature, filtered, and washed with isopropyl acetate (3 × 2 mL). The collected white solid was dried overnight under vacuum. White solid (877.8 mg, 88% corrected yield) 1 1H NMR was consistent with the desired product, showing 1.7 wt% isopropyl alcohol and 8.1 wt% isopropyl acetate. HPLC showed a product purity of 98.0%.

[0171] All patents, patent applications, provisional patents, and publications mentioned or cited herein, including all drawings and tables, are incorporated herein by reference in their entirety, to the extent that they do not conflict with the express teachings herein.

[0172] Equal portions Many modifications and variations of this Art can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Methods and apparatus that are functionally equivalent within the scope of this Art, in addition to those listed herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to be within the scope of the appended claims. This Art is limited only to the entire scope of the appended claims and the equivalents to which such claims are authorized. It should be understood that this Art is not limited to any particular method, reagent, compound, composition, or biological system, which may naturally differ. It should also be understood that the terms used herein are intended solely to describe a particular embodiment and are not intended to be limiting.

[0173] In addition, if any feature or aspect of the present disclosure is described in relation to the Markush group, a person skilled in the art will recognize that the present disclosure is also described in relation to any individual member of the Markush group or a member of a subgroup.

[0174] As will be understood by those skilled in the art, for all purposes, and especially with regard to providing written descriptions, all scopes described herein also encompass all possible sub-scopes and combinations of sub-scopes. It will be readily apparent that any scope described is sufficiently descriptive and capable of enabling the division of the same scope into at least equally equal parts, such as two-thirds, three-thirds, four-thirds, five-thirds, ten-thirds, etc. As a non-limiting example, each scope discussed herein may easily be divided into the lower third, middle third, upper third, etc. Also as will be understood by those skilled in the art, all terms such as “maximum,” “at least,” “greater than,” and “less than” include the number cited and refer to a scope that can be divided into the aforementioned sub-scopes. Finally, as will be understood by those skilled in the art, a scope includes each individual element. Thus, for example, a group having 1 to 3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1 to 5 cells refers to a group having 1, 2, 3, 4, or 5 cells (and so on).

[0175] Other embodiments are shown in the following claims.

Claims

1. A compound of Boc-D-Arg-DMT or a salt thereof.

2. The compound according to claim 1, which is Boc-D-Arg-DMT.

3. A method for preparing a compound of Boc-D-Arg-DMT or a salt thereof, comprising reducing and cleaving the benzyl of Boc-D-Arg-DMT-OBn to provide Boc-D-Arg-DMT or a salt thereof.

4. The method according to claim 3, wherein the reductive cleavage of the benzyl in Boc-D-Arg-DMT-OBn is performed by reacting Boc-D-Arg-DMT-OBn with a hydrogen source and a transition metal catalyst to form Boc-D-Arg-DMT or a salt thereof.

5. The method according to claim 4, wherein the transition metal catalyst comprises cobalt (Co), iridium (Ir), molybdenum (Mo), nickel (Ni), platinum (Pt), palladium (Pd), rhodium (Rh), ruthenium (Ru), tungsten (W), or any two or more combinations thereof.

6. The method according to claim 4 or 5, wherein the transition metal catalyst comprises palladium (Pd).

7. The method according to any one of claims 4 to 6, wherein the transition metal catalyst comprises a support material.

8. The method according to claim 7, wherein the carrier material comprises carbon, carbonate, silica, silicon, silicate, alumina, clay, or any two or more mixtures thereof.

9. The method according to any one of claims 4 to 8, wherein the transition metal catalyst comprises Pd carbon.

10. The method according to any one of claims 4 to 9, wherein the transition metal catalyst contains 1% to 15% by weight of Pd carbon.

11. The hydrogen source contains hydrogen molecules (H 2 The method according to any one of claims 4 to 10, comprising ), formic acid, formate, diimide, cyclohexene, cyclohexadiene, or any two or more combinations thereof.

12. The hydrogen source is a hydrogen molecule (H 2 The method according to any one of claims 4 to 11, including )

13. The method according to any one of claims 4 to 12, comprising reacting Boc-D-Arg-DMT-OBn with a hydrogen source and a transition metal catalyst in a solvent to form Boc-D-Arg-DMT or a salt thereof.

14. where the solvent is CH 3 OH, EtOH, iPrOH, TFE, BuOH, CH 2 Cl 2 , CHCl 3 , PhCF 3 , THF, 2Me - THF, DME, dioxane, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, DMF, DMA, CH 3 CN, CH 3 CH 2 CN, PhCN, dimethyl sulfoxide, sulfolane, water, or a mixture of any two or more thereof, the method according to claim 13.

15. The solvent is CH 3 The method according to claim 13 or 14, comprising OH.

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