PRODRUGS OF MITOCHONDRIA-TARGETING OLIGOPEPTIDES
Disclosed are various prodrugs of L-Phe-D-Arg-L-Phe-L-Lys-NH 2 .
1 . A compound of Formula (I)
wherein:
X is —N(R 15 )—R 1 ,
Y is —N(R 15 )—R 2 ,
R 1 , R 2 , and R 3 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylheteroalkyl, cycloalkyl, heteroalkyl, heteroaryl, T, R 9 C(O)—, R 10 OC(O)—, R 11 R 12 NC(O)—, R 10 S(O)—, R 10 S(O) 2 —, R 10 OS(O)—, R 10 OS(O) 2 —, (R 11 O)(R 12 )P(O)—, or R 11 R 12 N(R 9 O)P(O)—;
R 4 and R 5 are independently alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, T, a side-chain of a naturally or non-naturally occurring chiral amino acid,
R 6 and R 7 are independently H, alkyl, or acyl; or R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-6-membered heterocyclic ring;
R 8 is H, alkyl, heteroalkyl, or acyl;
R 9 , R 11 , and R 12 are independently H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, heteroarylheteroalkyl, or T;
R 11 and R 12 can be taken together to form a heterocyclic ring;
R 10 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, heteroarylheteroalkyl, or T;
R 13 is H, methyl, ethyl, isopropyl, or tert-butyl;
R 14 is independently D, F, Cl, Br, I, —CH 3 , —OCH 3 , CH 2 CH 3 , —OCH 2 CH 3 , —CCl 3 , —CF 3 , —C═N, —OH, or —NO 2 ;
R 15 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or acyl;
T is —(CH 2 ) w —(O) x —[(CH 2 CH 2 )—O] q —R 13 ;
the absolute stereochemistry at each of stereocenters ∗1, ∗2, ∗3 and ∗4 is independently R (D for an amino acid) or S (L for an amino acid);
n and m are independently 1, 2, 3, 4, 5, or 6;
p is 0, 1, 2, 3, 4, or 5;
q is an integer from 1-30 inclusive; and
x is 0 or 1; and w is 0, 1 or 2; provided that: if x is 0, then w is 0; and if w is 0, then x is 0; and
at least one of R 1 , R 2 , and R 3 is R 9 C(O)—, R 10 OC(O)—, R 11 R 12 NC(O)—, R 10 S(O)—, R 10 S(O) 2 —, R 10 OS(O)—, R 10 OS(O) 2 —, (R 11 O)(R 12 O)P(O)—, or R 11 R 12 N(R 9 O)P(O)—.
2 . The compound of claim 1 , wherein each of R 1 , R 2 , and R 3 is not: Cbz, Boc, Bpoc, Bhoc, Nps, Bpoc, Ddz, Fmoc, ivDde, Msc, Nsc, Bsmoc, Sps, or Esc.
3 . The compound of claim 1 or 2 , wherein X is —N(R 15 )—R 1 .
4 . The compound of claim 1 or 2 , wherein X is
.
5 . The compound of claim 1 or 2 , wherein X is
.
6 . The compound of claim 1 or 2 , wherein X is
.
7 . The compound of any one of claims 1-6 , wherein Y is —N(R 15 )—R 2 .
8 . The compound of any one of claims 1-6 , wherein Y is
.
9 . The compound of any one of claims 1-6 , wherein Y is
.
10 . The compound of any one of claims 1-6 , wherein Y is
.
11 . The compound of any one of claims 1-10 , wherein R 1 is H.
12 . The compound of any one of claims 1-10 , wherein R 1 is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylheteroalkyl, cycloalkyl, heteroalkyl, or heteroaryl.
13 . The compound of any one of claims 1-10 , wherein R 1 is T.
14 . The compound of claim 13 , wherein R 1 is —[(CH 2 CH 2 )—O] q —R 13 .
15 . The compound of any one of claims 1-10 , wherein R 1 is R 9 C(O)—, R 10 OC(O)—, or (R 11 O)(R 12 O)P(O)—.
16 . The compound of any one of claims 1-10 , wherein R 1 is R 11 R 12 NC(O)—, R 10 S(O)—, R 10 S(O) 2 —, R 10 OS(O)—, R 10 OS(O) 2 —, or R 11 R 12 N(R 9 O)P(O)—.
17 . The compound of any one of claims 1-16 , wherein R 2 is H.
18 . The compound of any one of claims 1-16 , wherein R 2 is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylheteroalkyl, cycloalkyl, heteroalkyl, or heteroaryl.
19 . The compound of any one of claims 1-16 , wherein R 2 is T.
20 . The compound of claim 19 , wherein R 2 is —[(CH 2 CH 2 )—O] q —R 13 .
21 . The compound of any one of claims 1-16 , wherein R 2 is R 9 C(O)—, R 10 OC(O)—, or (R 11 O)(R 12 O)P(O)—.
22 . The compound of any one of claims 1-16 , wherein R 2 is R 11 R 12 NC(O)—, R 10 S(O)—, R 10 S(O) 2 —, R 10 OS(O)—, R 10 OS(O) 2 —, or R 11 R 12 N(R 9 O)P(O).
23 . The compound of any one of claims 1-22 , wherein R 3 is H.
24 . The compound of any one of claims 1-22 , wherein R 3 is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylheteroalkyl, cycloalkyl, heteroalkyl, or heteroaryl.
25 . The compound of any one of claims 1-22 , wherein R 3 is T.
26 . The compound of claim 25 , wherein R 3 is —[(CH 2 CH 2 )—O] q —R 13 .
27 . The compound of any one of claims 1-22 , wherein R 3 is R 9 C(O)—, R 10 OC(O)—, or (R 11 O)(R 12 O)P(O)—.
28 . The compound of any one of claims 1-22 , wherein R 3 is R 11 R 12 NC(O)—, R 10 S(O)—, R 10 S(O) 2 —, R 10 OS(O)—, R 10 OS(O) 2 —, or R 11 R 12 N(R 9 O)P(O)—.
29 . The compound of any one of claims 1-28 , wherein R 4 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, or arylheteroalkyl.
30 . The compound of any one of claims 1-28 , wherein R 4 is T.
31 . The compound of claim 30 , wherein R 4 is —(CH 2 )—(O)—[(CH 2 CH 2 )—O] q —R 13 .
32 . The compound of claim 30 , wherein R 4 is —(CH 2 ) 2 —(O)—[(CH 2 CH 2 )—O] q —R 13 .
33 . The compound of any one of claims 1-28 , wherein R 4 is a side-chain of a naturally or non-naturally occurring chiral amino acid.
34 . The compound of any one of claims 1-28 , wherein R 4 is
.
35 . The compound of any one of claims 1-28 , wherein R 4 is
.
36 . The compound of any one of claims 1-28 , wherein R 4 is
.
37 . The compound of claim 36 , wherein R 4 is
and each R
14 is H.
38 . The compound of any one of claims 1-37 , wherein R 5 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, or arylheteroalkyl.
39 . The compound of any one of claims 1-37 , wherein R 5 is T.
40 . The compound of claim 38 , wherein R 5 is —(CH 2 )—(O)—[(CH 2 CH 2 )—O] q —R 13 .
41 . The compound of claim 38 , wherein R 5 is —(CH 2 ) 2 —(O)—[(CH 2 CH 2 )—O] q —R 13 .
42 . The compound of any one of claims 1-37 , wherein R 5 is a side-chain of a naturally or non-naturally occurring chiral amino acid.
43 . The compound of any one of claims 1-37 , wherein R 5 is
.
44 . The compound of any one of claims 1-37 , wherein R 5 is
.
45 . The compound of any one of claims 1-37 , wherein R 5 is
.
46 . The compound of claim 45 , wherein R 5 is
and each R
14 is H.
47 . The compound of any one of claims 1-46 , wherein R 6 is H.
48 . The compound of any one of claims 1-46 , wherein R 6 is alkyl or acyl.
49 . The compound of any one of claims 1-48 , wherein R 7 is H.
50 . The compound of any one of claims 1-48 , wherein R 7 is alkyl or acyl.
51 . The compound of any one of claims 1-46 , wherein R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-6-membered heterocyclic ring.
52 . The compound of any one of claims 1-51 , wherein R 8 is H.
53 . The compound of any one of claims 1-51 , wherein R 8 is alkyl, heteroalkyl, or acyl.
54 . The compound of any one of claims 1-51 , wherein R 8 is H, methyl or ethyl.
55 . The compound of any one of claims 1-54 , wherein R 9 is H.
56 . The compound of any one of claims 1-54 , wherein R 9 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, or heteroarylheteroalkyl.
57 . The compound of claim 56 , wherein R 9 is C 1 -C 8 alkyl.
58 . The compound of any one of claims 1-54 , wherein R 9 is T.
59 . The compound of claim 58 , wherein R 9 is —[(CH 2 CH 2 )—O] q —R 13 and q is 1-20.
60 . The compound of any one of claims 1-59 , wherein R 10 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, or heteroarylheteroalkyl.
61 . The compound of claim 60 , wherein R 10 is C 1 -C 8 alkyl.
62 . The compound of any one of claims 1-59 , wherein R 10 is T.
63 . The compound of claim 62 , wherein R 10 is —[(CH 2 CH 2 )—O] q —R 13 and q is 1-20.
64 . The compound of any one of claims 1-63 , wherein R 11 is H.
65 . The compound of any one of claims 1-63 , wherein R 11 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, or heteroarylheteroalkyl.
66 . The compound of claim 65 , wherein R 11 is C 1 -C 8 alkyl.
67 . The compound of any one of claims 1-63 , wherein R 11 is T.
68 . The compound of claim 67 , wherein R 11 is —[(CH 2 CH 2 )—O] q —R 13 and q is 1-20.
69 . The compound of any one of claims 1-68 , wherein R 12 is H.
70 . The compound of any one of claims 1-68 , wherein R 12 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, or heteroarylheteroalkyl.
71 . The compound of claim 70 , wherein R 12 is C 1 -C 8 alkyl.
72 . The compound of any one of claims 1-68 , wherein R 12 is T.
73 . The compound of claim 72 , wherein R 12 is —[(CH 2 CH 2 )—O] q —R 13 and q is 1-20.
74 . The compound of any one of claims 1-73 , wherein R 13 is H.
75 . The compound of any one of claims 1-73 , wherein R 13 is methyl, ethyl, isopropyl or tert-butyl.
76 . The compound of any one of claims 1-36 , 38-45 and 47-75 , wherein R 14 is D.
77 . The compound of any one of claims 1-36 , 38-45 and 47-75 , wherein R 14 is F, Cl, Br, I, —CCl 3 , or —CF 3 .
78 . The compound of any one of claims 1-36 , 38-45 and 47-75 , wherein R 14 is —CH 3 , —OCH 3 , CH 2 CH 3 , —OCH 2 CH 3 , —C═N, —OH, or —NO 2 .
79 . The compound of any one of claims 1-3 , and 7 , wherein R 15 is H.
80 . The compound of any one of claims 1-3 , and 7 , wherein R 15 is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or acyl.
81 . The compound of claim 80 , wherein R 15 is methyl, ethyl, isopropyl or tert-butyl.
82 . The compound of any one of claims 1-81 , wherein n is 1, 2, 3 or 4.
83 . The compound of any one of claims 1-81 , wherein n is 5, or 6.
84 . The compound of any one of claims 1-83 , wherein m is 1, 2, 3 or 4.
85 . The compound of any one of claims 1-83 , wherein m is 5, or 6.
86 . The compound of any one of claims 1-85 , wherein the stereochemistry at the carbon atom labeled ∗4 is D, the stereochemistry at the carbon atom labeled ∗3 is L, the stereochemistry at the carbon atom labeled ∗2 is L, and the stereochemistry at the carbon atom labeled ∗1 is L.
87 . The compound of any one of claims 1-85 , wherein the stereochemistry at the carbon atom labeled ∗4 is L, the stereochemistry at the carbon atom labeled ∗3 is D, the stereochemistry at the carbon atom labeled ∗2 is D, and the stereochemistry at the carbon atom labeled ∗1 is D.
88 . The compound of any one of claims 1-85 , wherein the stereochemistry at the carbon atom labeled ∗4 is D, the stereochemistry at the carbon atom labeled ∗3 is D, the stereochemistry at the carbon atom labeled ∗2 is D, and the stereochemistry at the carbon atom labeled ∗1 is D.
89 . The compound of any one of claims 1-85 , wherein the stereochemistry at the carbon atom labeled ∗4 is L, the stereochemistry at the carbon atom labeled ∗3 is L, the stereochemistry at the carbon atom labeled ∗2 is L, and the stereochemistry at the carbon atom labeled ∗1 is L.
90 . The compound of any one of claims 1-85 , wherein the stereochemistry at the carbon atom labeled ∗4 is D, the stereochemistry at the carbon atom labeled ∗3 is L, the stereochemistry at the carbon atom labeled ∗2 is D, and the stereochemistry at the carbon atom labeled ∗1 is L.
91 . The compound of any one of claims 1-85 , wherein the stereochemistry at the carbon atom labeled ∗4 is L, the stereochemistry at the carbon atom labeled ∗3 is D, the stereochemistry at the carbon atom labeled ∗2 is L, and the stereochemistry at the carbon atom labeled ∗1 is D.
92 . The compound of claim 1 , wherein the compound is
.
93 . A compound of Formula (II):
wherein:
X is —N(R 15 )—,
Y is —N(R 15 )—,
W is —C(O)—, —C(S)—, —C(R 16 ) 2 —, —S(O)—, —S(O) 2 —, or —P(O)[Q(R 10 )]—;
Q is O or a bond;
R 3 is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylheteroalkyl, cycloalkyl, heteroalkyl, heteroaryl, T, R 9 C(O)—, R 10 OC(O)—, R 11 R 12 NC(O)—, R 10 S(O)—, R 10 S(O) 2 —, R 10 OS(O)—, R 10 OS(O) 2 —, (R 11 O)(R 12 O)P(O)—, or R 11 R 12 N(R 9 O)P(O)—;
R 4 and R 5 are independently alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, T, a side-chain of a naturally or non-naturally occurring chiral amino acid,
R 6 and R 7 are independently H, alkyl, or acyl; or R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-6-membered heterocyclic ring;
R 8 is H, alkyl, heteroalkyl, or acyl;
R 9 , R 11 , and R 12 are independently H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, heteroarylheteroalkyl, or T;
R 11 and R 12 can be taken together to form a heterocyclic ring;
R 10 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, heteroarylheteroalkyl or T;
R 13 is H, methyl, ethyl, isopropyl or tert-butyl;
R 14 is independently D, F, Cl, Br, I, —CH 3 , —OCH 3 , CH 2 CH 3 , —OCH 2 CH 3 , —CCl 3 , —CF 3 , —C═N, —OH, or —NO 2 ;
R 15 is H, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or acyl;
R 16 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, or arylalkyl;
T is —(CH 2 ) w —(O) x —[(CH 2 CH 2 )—O] q —R 13 ;
the absolute stereochemistry at each of stereocenters ∗1, ∗2, ∗3 and ∗4 is independently R (D for an amino acid) or S (L for an amino acid);
n and m are independently 1, 2, 3, 4, 5, or 6;
p is 0, 1, 2, 3, 4, or 5;
q is an integer from 1-30 inclusive; and
x is 0 or 1; and w is 0, 1 or 2; provided that: if x is 0, then w is 0; and if w is 0, then y is 0;
“∗∗” denotes the point of attachment of X to W; and
“∗∗∗” denotes the point of attachment of W to Y.
94 . The compound of claim 93 , wherein X is —N(R 15 )—.
95 . The compound of claim 93 , wherein X is
.
96 . The compound of claim 93 , wherein X is
.
97 . The compound of claim 93 , wherein X is
.
98 . The compound of any one of claims 93-97 , wherein Y is —N(R 15 )—.
99 . The compound of any one of claims 93-97 , wherein Y is
.
100 . The compound of any one of claims 93-97 , wherein Y is
.
101 . The compound of any one of claims 93-97 , wherein Y is
.
102 . The compound of any one of claims 93-101 , wherein W is —C(O)—.
103 . The compound of any one of claims 93-101 , wherein W is —C(S)—, or —C(R 16 ) 2 —.
104 . The compound of any one of claims 93-101 , wherein W is —S(O)—, or —S(O) 2 —.
105 . The compound of any one of claims 93-101 , wherein W is —P(O)[Q(R 10 )]—.
106 . The compound of claim 105 , wherein Q is O.
107 . The compound of claim 105 , wherein Q is a bond.
108 . The compound of any one of claims 93-107 , wherein R 3 is H.
109 . The compound of any one of claims 93-107 , wherein R 3 is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylheteroalkyl, cycloalkyl, heteroalkyl, or heteroaryl.
110 . The compound of any one of claims 93-107 , wherein R 3 is T.
111 . The compound of claim 110 , wherein R 3 is —[(CH 2 CH 2 )—O] q —R 13 .
112 . The compound of any one of claims 93-107 , wherein R 3 is R 9 C(O)—, R 10 OC(O)—, or (R 11 O)(R 12 O)P(O)—.
113 . The compound of any one of claims 93-107 , wherein R 3 is R 11 R 12 NC(O)—, R 10 S(O)—, R 10 S(O) 2 —, R 10 OS(O)—, R 10 OS(O) 2 —, or R 11 R 12 N(R 9 O)P(O)—.
114 . The compound of any one of claims 93-113 , wherein R 4 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, or arylheteroalkyl.
115 . The compound of any one of claims 93-113 , wherein R 4 is T.
116 . The compound of claim 115 , wherein R 4 is —(CH 2 )—(O)—[(CH 2 CH 2 )—O] q —R 13 .
117 . The compound of claim 115 , wherein R 4 is —(CH 2 ) 2 —(O)—[(CH 2 CH 2 )—O] q —R 13 .
118 . The compound of any one of claims 93-113 , wherein R 4 is a side-chain of a naturally or non-naturally occurring chiral amino acid.
119 . The compound of any one of claims 93-113 , wherein R 4 is
.
120 . The compound of any one of claims 93-113 , wherein R 4 is
.
121 . The compound of any one of claims 93-113 , wherein R 4 is
.
122 . The compound of claim 1232 , wherein R 4 is
and each R
14 is H.
123 . The compound of any one of claims 93-122 , wherein R 5 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, or arylheteroalkyl.
124 . The compound of any one of claims 93-122 , wherein R 5 is T.
125 . The compound of claim 124 , wherein R 5 is —(CH 2 )—(O)—[(CH 2 CH 2 )—O] q —R 13 .
126 . The compound of claim 124 , wherein R 5 is —(CH 2 ) 2 —(O)—[(CH 2 CH 2 )—O] q —R 13 .
127 . The compound of any one of claims 93-122 , wherein R 5 is a side-chain of a naturally or non-naturally occurring chiral amino acid.
128 . The compound of any one of claims 93-122 , wherein R 5 is
.
129 . The compound of any one of claims 93-122 , wherein R 5 is
.
130 . The compound of any one of claims 93-122 , wherein R 5 is
.
131 . The compound of claim 130 , wherein R 5 is
and each R
14 is H.
132 . The compound of any one of claims 93-131 , wherein R 6 is H.
133 . The compound of any one of claims 93-131 , wherein R 6 is alkyl or acyl.
134 . The compound of any one of claims 93-133 , wherein R 7 is H.
135 . The compound of any one of claims 93-133 , wherein R 7 is alkyl or acyl.
136 . The compound of any one of claims 93-131 , wherein R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-6-membered heterocyclic ring.
137 . The compound of any one of claims 93-136 , wherein R 8 is H.
138 . The compound of any one of claims 93-136 , wherein R 8 alkyl, heteroalkyl, or acyl.
139 . The compound of any one of claims 93-136 , wherein R 8 is H, methyl or ethyl.
140 . The compound of any one of claims 93-139 , wherein R 9 is H.
141 . The compound of any one of claims 93-139 , wherein R 9 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, or heteroarylheteroalkyl.
142 . The compound of claim 141 , wherein R 9 is C 1 -C 8 alkyl.
143 . The compound of any one of claims 93-139 , wherein R 9 is T.
144 . The compound of claim 143 , wherein R 9 is —[(CH 2 CH 2 )—O] q —R 13 and q is 1-20.
145 . The compound of any one of claims 93-144 , wherein R 10 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, or heteroarylheteroalkyl.
146 . The compound of claim 145 , wherein R 10 is C 1 -C 8 alkyl.
147 . The compound of any one of claims 93-144 , wherein R 10 is T.
148 . The compound of claim 145 , wherein R 10 is —[(CH 2 CH 2 )—O] q —R 13 and q is 1-20.
149 . The compound of any one of claims 93-148 , wherein R 11 is H.
150 . The compound of any one of claims 93-148 , wherein R 11 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, or heteroarylheteroalkyl.
151 . The compound of claim 150 , wherein R 11 is C 1 -C 8 alkyl.
152 . The compound of any one of claims 93-148 , wherein R 11 is T.
153 . The compound of claim 155 , wherein R 11 is —[(CH 2 CH 2 )—O] q —R 13 and q is 1-20.
154 . The compound of any one of claims 93-153 , wherein R 12 is H.
155 . The compound of any one of claims 93-153 , wherein R 12 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, or heteroarylheteroalkyl.
156 . The compound of claim 155 , wherein R 12 is C 1 -C 8 alkyl.
157 . The compound of any one of claims 93-153 , wherein R 12 is T.
158 . The compound of claim 157 , wherein R 12 is —[(CH 2 CH 2 )—O] q —R 13 and q is 1-20.
159 . The compound of any one of claims 93-158 , wherein R 13 is H.
160 . The compound of any one of claims 93-158 , wherein R 13 is methyl, ethyl, isopropyl or tert-butyl.
161 . The compound of any one of claims 93-121 , 123-130 and 132-160 , wherein R 14 is D.
162 . The compound of any one of claims 93-121 , 123-130 and 132-160 , wherein R 14 is F, Cl, Br, I, —CCl 3 , or —CF 3 .
163 . The compound of any one of claims 93-121 , 123-130 and 132-160 , wherein R 14 is —CH 3 , —OCH 3 , CH 2 CH 3 , —OCH 2 CH 3 , —C═N, —OH, or —NO 2 .
164 . The compound of any one of claims 93-163 , wherein R 15 is H.
165 . The compound of any one of claims 93-163 , wherein R 15 is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or acyl.
166 . The compound of claim 165 , wherein R 15 is methyl, ethyl, isopropyl or tert-butyl.
167 . The compound of any one of claims 93-166 , wherein R 16 is alkyl, alkenyl, alkynyl, or heteroalkyl.
168 . The compound of claim 167 , wherein R 16 is methyl, ethyl, isopropyl or tert-butyl.
169 . The compound of any one of claims 93-166 , wherein R 16 is cycloalkyl, aryl, or arylalkyl.
170 . The compound of any one of claims 93-169 , wherein n is 1, 2, 3 or 4.
171 . The compound of any one of claims 93-169 , wherein n is 5, or 6.
172 . The compound of any one of claims 93-169 , wherein m is 1, 2, 3 or 4.
173 . The compound of any one of claims 93-169 , wherein m is 5, or 6.
174 . The compound of any one of claims 93-173 , wherein the stereochemistry at the carbon atom labeled ∗4 is D, the stereochemistry at the carbon atom labeled ∗3 is L, the stereochemistry at the carbon atom labeled ∗2 is L, and the stereochemistry at the carbon atom labeled ∗1 is L.
175 . The compound of any one of claims 93-173 , wherein the stereochemistry at the carbon atom labeled ∗4 is L, the stereochemistry at the carbon atom labeled ∗3 is D, the stereochemistry at the carbon atom labeled ∗2 is D, and the stereochemistry at the carbon atom labeled ∗1 is D.
176 . The compound of any one of claims 93-173 , wherein the stereochemistry at the carbon atom labeled ∗4 is D, the stereochemistry at the carbon atom labeled ∗3 is D, the stereochemistry at the carbon atom labeled ∗2 is D, and the stereochemistry at the carbon atom labeled ∗1 is D.
177 . The compound of any one of claims 93-173 , wherein the stereochemistry at the carbon atom labeled ∗4 is L, the stereochemistry at the carbon atom labeled ∗3 is L, the stereochemistry at the carbon atom labeled ∗2 is L, and the stereochemistry at the carbon atom labeled ∗1 is L.
178 . The compound of any one of claims 93-173 , wherein the stereochemistry at the carbon atom labeled ∗4 is D, the stereochemistry at the carbon atom labeled ∗3 is L, the stereochemistry at the carbon atom labeled ∗2 is D, and the stereochemistry at the carbon atom labeled ∗1 is L.
179 . The compound of any one of claims 93-173 , wherein the stereochemistry at the carbon atom labeled ∗4 is L, the stereochemistry at the carbon atom labeled ∗3 is D, the stereochemistry at the carbon atom labeled ∗2 is L, and the stereochemistry at the carbon atom labeled ∗1 is D.
180 . The compound of claim 93 , wherein the compound is
.
181 . The compound of claim 93 , wherein the compound is
.