Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles

专利摘要:
Provided herein are peptidomimetic macrocycles and methods of using such macrocycles for the treatment of disease.
公开号:AU2013221433A1
申请号:U2013221433
申请日:2013-02-14
公开日:2014-09-25
发明作者:Christopher R. Conlee；Vincent Guerlavais；Scott Paul Lentini
申请人:Aileron Therapeutics Inc；
IPC主号:A61K38-12

专利说明:
WO 2013/123267 PCT/US2013/026241 TRIAZOLE-CROSSLINKED AND THIOETHER-CROSSLINKED PEPTIDOMIMETIC MACROCYCLES BACKGROUND OF THE INVENTION [0001] The human transcription factor protein p53 induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress, and thereby plays a critical role in protecting cells from malignant transformation. The E3 ubiquitin ligase MDM2 (also known as HDM2) negatively regulates p53 function through a direct binding interaction that neutralizes the p53 transactivation activity, leads to export from the nucleus of p53 protein, and targets p53 for degradation via the ubiquitylation-proteasomal pathway. Loss of p53 activity, either by deletion, mutation, or MDM2 overexpression, is the most common defect in human cancers. Tumors that express wild type p53 are vulnerable to pharmacologic agents that stabilize or increase the concentration of active p53. In this context, inhibition of the activities of MDM2 has emerged as a validated approach to restore p53 activity and resensitize cancer cells to apoptosis in vitro and in vivo. MDMX (MDM4) has more recently been identified as a similar negative regulator of p53, and studies have revealed significant structural homology between the p53 binding interfaces of MDM2 and MDMX. The p53-MDM2 and p53-MDMX protein-protein interactions are mediated by the same 15-residue alpha-helical transactivation domain of p5 3 , which inserts into hydrophobic clefts on the surface of MDM2 and MDMX. Three residues within this domain of p53 (F19, W23, and L26) are essential for binding to MDM2 and MDMX. [0002] There remains a considerable need for compounds capable of binding to and modulating the activity of p53, MDM2 and/or MDMX. Provided herein are p53-based peptidomimetic macrocycles that modulate an activity of p53. Also provided herein are p53-based peptidomimetic macrocycles that inhibit the interactions between p53, MDM2 and/or MDMX proteins. Further, provided herein are p53-based peptidomimetic macrocycles that can be used for treating diseases including but not limited to cancer and other hyperproliferative diseases. SUMMARY OF THE INVENTION [0003] Described herein are stably cross-linked peptides related to a portion of human p53 ("p 5 3 peptidomimetic macrocycles"). These cross-linked peptides contain at least two modified amino acids that together form an intramolecular cross-link that can help to stabilize the alpha-helical secondary structure of a portion of p53 that is thought to be important for binding of p53 to MDM2 and for binding of p53 to MDMX. Accordingly, a cross-linked polypeptide described herein can have improved biological activity relative to a corresponding polypeptide that is not cross-linked. The p53 peptidomimetic macrocycles are thought to interfere with binding of p53 to MDM2 and/or of p53 to MDMX, thereby liberating functional p53 and inhibiting its destruction. The p53 peptidomimetic macrocycles described herein can be used therapeutically, for example -1- WO 2013/123267 PCT/US2013/026241 to treat cancers and other disorders characterized by an undesirably low level or a low activity of p53, and/or to treat cancers and other disorders characterized by an undesirably high level of activity of MDM2 or MDMIX. The p53 peptidomimetic macrocycles can also be useful for treatment of any disorder associated with disrupted regulation of the p53 transcriptional pathway, leading to conditions of excess cell survival and proliferation such as cancer and autoimmunity, in addition to conditions of inappropriate cell cycle arrest and apoptosis such as neurodegeneration and immunedeficiencies. In some embodiments, the p53 peptidomimetic macrocycles bind to MDM2 (e.g., GenBank@ Accession No.: 228952; GI:228952) and/or MDMX (also referred to as MDM4; GenBank@ AccessionNo.: 88702791; GI:88702791). [0004] In one aspect, provided herein is a peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60%, 80%, 90%, or 95% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Table 4, Table 4a, Table 4b, or Table 5. In some embodiments, the peptidomimetic macrocycle is not a peptide as shown in Table 6, Table 6a, Table 7, Table 7a, or Table 7b. In some embodiments, the peptidomimetic macrocycle has an amino acid sequence chosen from Table 4. In some embodiments, the peptidomimetic macrocycle has an amino acid sequence chosen from Table 4a. In some embodiments, the peptidomimetic macrocycle has an amino acid sequence chosen from Table 4b. In some embodiments, the peptidomimetic macrocycle has an amino acid sequence chosen from Table 5. [0005] Alternatively, an amino acid sequence of said peptidomimetic macrocycle is chosen as above, and further wherein the macrocycle does not include an all carbon crosslink or a triazole. In some embodiments, the peptidomimetic macrocycle comprises a helix, such as an a-helix. In other embodiments, the peptidomimetic macrocycle comprises an a,a-disubstituted amino acid. A peptidomimetic macrocycle can comprise a crosslinker linking the a-positions of at least two amino acids. At least one of said two amino acids can be an a,a-disubstituted amino acid. [0006] In some embodiments, provided are peptidomimetic macrocycle of the Formula: 0 0 -[D]vtN [A]x[B]y[C]z [E]w R1 R2 L - u Formula (I) wherein: each A, C, D, and E is independently an amino acid; -2- WO 2013/123267 PCT/US2013/026241
R
3 N B is an amino acid, 0 , [-NH-L 3 -CO-], [-NH-L 3
-SO
2 -], or [-NH-L 3 -]; each L and L' is independently a macrocycle-forming linker of the formula Li L2 NH N N
L
1 , L 2 and L 3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4
-K-R
4 -],, each being optionally substituted with
R
5 ; each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR 6 , -SOR 6 , -S0 2
R
6 , -C0 2
R
6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; each R 7 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; each Rs is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1 20 or 1-10; u is an integer from 1-10, for example 1-5, 1-3 or 1-2; x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and n is an integer from 1-5. [0007] In some embodiments, v and w are integers between 1-30. In some embodiments, w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10. [0008] In some embodiments, the sum of x+y+z is 3 or 6. In some embodiments, the sum of x+y+z is 3. In other embodiments, the sum of x+y+z is 6. [0009] In some embodiments, the peptidomimetic macrocycles are claimed with the proviso that when u=1 and w=2, the first C-terminal amino acid represented by E is not an Arginine (R) and/or the second C-terminal amino acid represented by E is not a Threonine (T). For instance, when u = 1 -3- WO 2013/123267 PCT/US2013/026241 and w= 2, the first C-terminal amino acid and/or the second C-terminal amino acid represented by E do not comprise a positively charged side chain or a polar uncharged side chain. In some embodiments, when u = 1 and w= 2, the first C-terminal amino acid and/or the second C-terminal amino acid represented by E comprise a hydrophobic side chain. For example, when w- 2, the first C-terminal amino acid and/or the second N-terminal amino acid represented by E comprise a hydrophobic side chain, for example a large hydrophobic side chain. [0010] In some embodiments, w is between 3 and 1000. For example, the third amino acid represented by E comprises a large hydrophobic side chain. [0011] Peptidomimetic macrocycles are also provided of the formula: R70 R80 [D-Xaa-N. Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 1 0 N R1 R2 wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaag, Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3
-X
4 -His 5 -Tyr-Trp 7 -Ala-Glng-Leuto-Xu 1 -Ser 1 2 , where each X is an amino acid; each D and E is independently an amino acid; RI and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula LL2 NH N N Li and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4
-K-R
4 -],, each being optionally substituted with R 5 ; each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; -4- WO 2013/123267 PCT/US2013/026241 each K is independently 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR 5 , -SOR 6 , -S0 2
R
6 , -CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; each R7 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; each Rs is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20 or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5. [0012] In some embodiments, the peptidomimetic macrocycle has the formula:
R
7 o
R
8 0 [D],-Xaa3-N Xaa -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xa 0 N [E], R1 R2 wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaag, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa7, Xaag, Xaag, and Xaaio are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3
-X
4 -Glu 5 -Tyr 6 -Trp 7 -Ala-Gln-Leuio/Cbaio-XI 1-Ala12, where each X is an amino acid; each D and E is independently an amino acid; R and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R, and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula L )NH N-N -5- WO 2013/123267 PCT/US2013/026241 Li and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4
-K-R
4 -],, each being optionally substituted with R 5 ; R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is 0, S, SO, S02, CO, C0 2 , or CONR 3 ; each R5 is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR 6 , -SOR 6 , -SO 2
R
6 , -C0 2
R
6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5. [0013] In some embodiments, provided are peptidomimetic macrocycles of the Formula I: 0
R
8 0 [D],-Xaa'3',N Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 0 N [E], X3R1 R2 L wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaag, and Xaao is individually an amino acid, wherein at least three of Xaa 3 , Xaa, Xaa 6 , Xaa 7 , Xaa 8 , Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3
-X
4 -His 5 -Tyr-Trp 7 -Ala-Gln 9 -Leuto-X 1 -Ser 1 2 , where each X is an amino acid; each D and E is independently an amino acid; R, and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R, and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; -6- WO 2013/123267 PCT/US2013/026241 each L and L' is independently a macrocycle-forming linker of the formula
L
1 L 2 S NH N= N LI and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4
-K-R
4 -],, each being optionally substituted with R 5 ; each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with Rs; each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently 0, S, SO, S02, CO, C0 2 , or CONR 3 ; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR 6 , -SOR 6 , -S0 2
R
6 , -C0 2
R
6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; each R 7 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; each R8 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; each R 9 is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with Ra and/or Rb; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20 or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5. [0014] In some embodiments, provided are peptidomimetic macrocycles of the Formula I: 7
R
8 0 [ N Xaas-Xaa 6 -Xaa 7 -Xaa 8 -Xaag-XaaN [E] [D],-Xaa 3 Xa R1 R2 wherein: -7- WO 2013/123267 PCT/US2013/026241 each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaag, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaag, Xaag, and Xaaio are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3
-X
4 -Glu 5 -Tyr 6 -Trp 7 -Alag-Gln 9 -Leuio/Cbaio-XI 1-Ala 12 , where each X is an amino acid; each D and E is independently an amino acid; RI and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R, and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula
L
1
L
2 NH N - N Li and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4
-K-R
4 -],, each being optionally substituted with
R
5 ;
R
3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is 0, S, SO, S02, CO, C0 2 , or CONR 3 ; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR 6 , -SOR 6 , -S0 2
R
6 , -C0 2
R
6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
R
7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; each R 9 is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with Ra and/or Rb; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5. -8- WO 2013/123267 PCT/US2013/026241 [0015] In some embodiments, provided are peptidomimetic macrocycles of the Formula I, comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Tables 4, 4a, or 4b, wherein the peptidomimetic macrocycle has the formula: 0 0 R7 R8 N [A]x-[B]y-[C]z R1 R2 -L -u Formula (I) wherein: each A, C, D, and E is independently an amino acid; R3 N N B is an amino acid, 0 , [-NH-L 3 -CO-], [-NH-L 3
-SO
2 -], or [-NH-L 3 -]; R and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula
L
1
L
2 NN LI, L 2 and L 3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4
-K-R
4 -],, each being optionally substituted with R 5 ; each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently 0, S, SO, SO 2 , CO, CO 2 , or CONR 3 ; each R is independently halogen, alkyl, -OR 6 , -N(R6) 2 , -SR6, -SOR 6 , -S0 2
R
6 , -CO 2 R6, a fluorescent moiety, a radioisotope or a therapeutic agent; -9- WO 2013/123267 PCT/US2013/026241 each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; each R 7 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; each Rs is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; each R 9 is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with Ra and/or Rb; v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1 20 or 1-10; u is an integer from 1-10, for example 1-5, 1-3 or 1-2; x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and n is an integer from 1-5. [0016] In some embodiments, provided are peptidomimetic macrocycle of the Formula II: 0 0 R7 R8 - - - [ D ] , N [A ].-[B ]y-[C ] - N [ ] - R1 L 1 S--L2-- 1 3 R2 - -j u Formula (II) wherein: each A, C, D, and E is independently an amino acid;
R
3 N B is an amino acid, 0 , [-NH-L 4 -CO-], [-NH-L 4
-SO
2 -], or [-NH-L 4 -]; R, and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R, and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids;
R
3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; LI, L 2 , L 3 and L 4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [-R 4
-K-R
4 -]n, each being unsubstituted or substituted with R 5 ; -10- WO 2013/123267 PCT/US2013/026241 each K is 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each R5 is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR6, -SOR6, -S02R6, -C0 2
R
6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue; v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1 20 or 1-10; u is an integer from 1-10, for example 1-5, 1-3 or 1-2; x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and n is an integer from 1-5. [0017] In some embodiments, the peptidomimetic macrocycles are claimed with the proviso that when u=1 and w=2, the first C-terminal amino acid represented by E is not an Arginine (R) and/or the second C-terminal amino acid represented by E is not a Threonine (T). For instance, when u = 1 and w= 2, the first C-terminal amino acid and/or the second C-terminal amino acid represented by E do not comprise a positively charged side chain or a polar uncharged side chain. In some embodiments, when u = 1 and w= 2, the first C-terminal amino acid and/or the second C-terminal amino acid represented by E comprise a hydrophobic side chain. For example, when w- 2, the first C-terminal amino acid and/or the second N-terminal amino acid represented by E comprise a hydrophobic side chain, for example a large hydrophobic side chain. [0018] In some embodiments, w is between 3 and 1000. For example, the third amino acid represented by E comprises a large hydrophobic side chain. [0019] Peptidomimetic macrocycles are also provided of the formula: 00 Ry N R8 [Dv Xaa 3 I-' RXaa 5 Xaa 6 Xaa 7 Xaa 8 Xaag Xaa 1 -- N [E], L1 , -2- 11 L3 R2 S-1- L 2 ~S -11- WO 2013/123267 PCT/US2013/026241 wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaag, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaag, Xaag, and Xaaio are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3
-X
4 -His 5 -Tyr 6 -Trp7-Ala 8 -Glng-Leuio-Xii-Ser1 2 , where each X is an amino acid; each D and E is independently an amino acid; R, and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R, and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; Li, L 2 , L 3 and L 4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [-R 4
-K-R
4 -]n, each being unsubstituted or substituted with R 5 ; each K is 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ;
R
3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR 6 , -SOR 6 , -SO 2
R
6 , -CO 2
R
6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
R
7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20 or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5. [0020] Peptidomimetic macrocycles are also provided of the formula: -12- WO 2013/123267 PCT/US2013/026241 0 0 Ry N R8 [D, -Xaa 3 RXaa 5 Xaa 6 Xaa 7 Xaa 8 Xaag Xaa 1 -- N Li 11 -2 S1 L3 R2 S -- L 2 -- s wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3
-X
4 -Glu 5 -Tyr 6 -Trp 7 -Alas-Gln 9 -Leuio/Cbalo-X 1 -Ala1 2 , where each X is an amino acid; each D and E is independently an amino acid; RI and R2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; Lt, L 2 , L 3 and L 4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [-R 4
-K-R
4 -]n, each being unsubstituted or substituted with R5; each K is 0, S, SO, SO 2 , CO, CO 2 , or CONR 3 ; R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each R is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR6, -SOR 6 , -SO 2
R
6 , -CO 2 R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R, or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and -13- WO 2013/123267 PCT/US2013/026241 n is an integer from 1-5. [0021] In some embodiments, each E is independently an amino acid selected from Ala (alanine), D-Ala (D-alanine), Aib (a-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine). In some embodiments, [D], is -Leu-Thr 2 . [0022] In some embodiments, w is an integer from 3-10, for example 3-6, 3-8, 6-8, or 6-10. In some embodiments, w is 3. In other embodiments, w is 6. In some embodiments, v is an integer from 1 10, for example 2-5. In some embodiments, v is 2. [0023] In some embodiments, the peptidomimetic macrocycle has improved binding affinity to MDM2 or MDMX relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In other instances, the peptidomimetic macrocycle has a reduced ratio of binding affinities to MDMX versus MDM2 relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In still other instances, the peptidomimetic macrocycle has improved in vitro anti-tumor efficacy against p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In some embodiments, the peptidomimetic macrocycle shows improved in vitro induction of apoptosis in p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In other instances, the peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle has an improved in vitro anti tumor efficacy ratio for p53 positive versus p53 negative or mutant tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In some instances the improved efficacy ratio in vitro, is 1-29, >30-49, or >50. In still other instances, the peptidomimetic macrocycle has improved in vivo anti-tumor efficacy against p53 positive tumors relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In some instances the improved efficacy ratio in vivo is -29, >30-49, or >50. In yet other instances, the peptidomimetic macrocycle has improved in vivo induction of apoptosis in p53 positive tumors relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In some embodiments, the peptidomimetic macrocycle has improved cell permeability relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In other cases, the peptidomimetic macrocycle has improved solubility relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. [0024] In some embodiments, Xaa 5 is Glu or an amino acid analog thereof. In some embodiments, Xaa 5 is Glu or an amino acid analog thereof and wherein the peptidomimetic macrocycle has an improved property, such as improved binding affinity, improved solubility, improved cellular efficacy, improved cell permeability, improved in vivo or in vitro anti-tumor efficacy, or improved induction of apoptosis relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. [0025] In some embodiments, the peptidomimetic macrocycle has improved binding affinity to MDM2 or MDMVX relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. In other -14- WO 2013/123267 PCT/US2013/026241 embodiments, the peptidomimetic macrocycle has a reduced ratio of binding affinities to MDMX vs MDM2 relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. In some embodiments, the peptidomimetic macrocycle has improved solubility relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala, or the peptidomimetic macrocycle has improved cellular efficacy relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. [0026] In some embodiments, Xaa 5 is Glu or an amino acid analog thereof and wherein the peptidomimetic macrocycle has improved biological activity, such as improved binding affinity, improved solubility, improved cellular efficacy, improved helicity, improved cell permeability, improved in vivo or in vitro anti-tumor efficacy, or improved induction of apoptosis relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. [0027] In some embodiments, the peptidomimetic macrocycle has an activity against a p53+/+ cell line which is at least 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, or 100-fold greater than its binding affinity against a p53-/- cell line. In some embodiments, the peptidomimetic macrocycle has an activity against a p53+1+ cell line which is between 1 and 29 fold, between 30 and 49-fold, or >50-fold greater than its binding affinity against a p53-/- cell line. Activity can be measured, for example, as an IC50 value. For example, the p53+/+ cell line is SJSA-1, RKO, HCT-1 16, or MCF-7 and the p53-/- cell line is RKO-E6 or SW-480. In some embodiments, the peptide has an IC50 against the p53++ cell line of less than 1 RM. [0028] In some embodiments, Xaa 5 is Glu or an amino acid analog thereof and the peptidomimetic macrocycle has an activity against a p53+/+ cell line which is at least 10-fold greater than its binding affinity against a p53-/- cell line. [0029] Additionally, a method is provided of treating cancer in a subject comprising administering to the subject a peptidomimetic macrocycle. Also provided is a method of modulating the activity of p53 or MDM2 or MDMX in a subject comprising administering to the subject a peptidomimetic macrocycle, or a method of antagonizing the interaction between p53 and MDM2 and/or MDMX proteins in a subject comprising administering to the subject such a peptidomimetic macrocycle. INCORPORATION BY REFERENCE [0030] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION [0031] As used herein, the term "macrocycle" refers to a molecule having a chemical structure including a ring or cycle formed by at least 9 covalently bonded atoms. [0032] As used herein, the term "peptidomimetic macrocycle" or "crosslinked polypeptide" refers to a compound comprising a plurality of amino acid residues joined by a plurality of peptide bonds and at least one macrocycle-forming linker which forms a macrocycle between a first naturally -15- WO 2013/123267 PCT/US2013/026241 occurring or non-naturally-occurring amino acid residue (or analog) and a second naturally occurring or non-naturally-occurring amino acid residue (or analog) within the same molecule. Peptidomimetic macrocycle include embodiments where the macrocycle-forming linker connects the a carbon of the first amino acid residue (or analog) to the a carbon of the second amino acid residue (or analog). The peptidomimetic macrocycles optionally include one or more non-peptide bonds between one or more amino acid residues and/or amino acid analog residues, and optionally include one or more non-naturally-occurring amino acid residues or amino acid analog residues in addition to any which form the macrocycle. A "corresponding uncrosslinked polypeptide" when referred to in the context of a peptidomimetic macrocycle is understood to relate to a polypeptide of the same length as the macrocycle and comprising the equivalent natural amino acids of the wild-type sequence corresponding to the macrocycle. [0033] As used herein, the term "stability" refers to the maintenance of a defined secondary structure in solution by a peptidomimetic macrocycle as measured by circular dichroism, NMR or another biophysical measure, or resistance to proteolytic degradation in vitro or in vivo. Non-limiting examples of secondary structures contemplated herein are a-helices, 310 helices, p-turns, and j pleated sheets. [0034] As used herein, the term "helical stability" refers to the maintenance of a helical structure by a peptidomimetic macrocycle as measured by circular dichroism or NMR. For example, in some embodiments, a peptidomimetic macrocycle exhibits at least a 1.25, 1.5, 1.75 or 2-fold increase in a-helicity as determined by circular dichroism compared to a corresponding uncrosslinked macrocycle. [0035] The term "amino acid" refers to a molecule containing both an amino group and a carboxyl group. Suitable amino acids include, without limitation, both the D-and L-isomers of the naturally-occurring amino acids, as well as non-naturally occurring amino acids prepared by organic synthesis or other metabolic routes. The term amino acid, as used herein, includes without limitation a-amino acids, natural amino acids, non-natural amino acids, and amino acid analogs. [0036] The term "a-amino acid" refers to a molecule containing both an amino group and a carboxyl group bound to a carbon which is designated the a-carbon. [0037] The term "p-amino acid" refers to a molecule containing both an amino group and a carboxyl group in a Q configuration. [0038] The term "naturally occurring amino acid" refers to any one of the twenty amino acids commonly found in peptides synthesized in nature, and known by the one letter abbreviations A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y and V. [0039] The following table shows a summary of the properties of natural amino acids: 3- 1- Side-chain Side-chain charge Hydropathy Amino Acid Letter Letter Polarity (pH 7.4) Index -16- WO 2013/123267 PCT/US2013/026241 Code Code Alanine Ala A nonpolar neutral 1.8 Arginine Arg R polar positive -4.5 Asparagine Asn N polar neutral -3.5 Aspartic acid Asp D polar negative -3.5 Cysteine Cys C polar neutral 2.5 Glutamic acid Glu E polar negative -3.5 Glutamine Gln Q polar neutral -3.5 Glycine Gly G nonpolar neutral -0.4 positive(10%) Histidine His H polar -3.2 neutral(90%) Isoleucine Ile I nonpolar neutral 4.5 Leucine Leu L nonpolar neutral 3.8 Lysine Lys 1 polar positive -3.9 Methionine Met M nonpolar neutral 1.9 Phenylalanine Phe F nonpolar neutral 2.8 Proline Pro P nonpolar neutral -1.6 Serine Ser S polar neutral -0.8 Threonine Thr T polar neutral -0 7 Tryptophan Trp W nonpolar neutral -0.9 Tyrosine Tyr Y polar neutral -1.3 Valine Val V nonpolar neutral 4.2 [0040] "Hydrophobic amino acids" include, without limitation, small hydrophobic amino acids and large hydrophobic amino acids. "Small hydrophobic amino acid" are glycine, alanine, proline, and analogs thereof "Large hydrophobic amino acids" are valine, leucine, isoleucine, phenylalanine, methionine, tryptophan, and analogs thereof "Polar amino acids" are shrine, threonine, asparagine, glutamine, cysteine, tyrosine, and analogs thereof "Charged amino acids" are lysine, arginine, histidine, aspartate, glutamate, and analogs thereof. [0041] The term "amino acid analog" refers to a molecule which is structurally similar to an amino acid and which can be substituted for an amino acid in the formation of a peptidomimetic macrocycle. Amino acid analogs include, without limitation, f-amino acids and amino acids where the amino or carboxy group is substituted by a similarly reactive group (e.g., substitution of the primary amine with a secondary or tertiary amine, or substitution of the carboxy group with an ester). [0042] The term "non-natural amino acid" refers to an amino acid which is not one of the the twenty amino acids commonly found in peptides synthesized in nature, and known by the one letter -17- WO 2013/123267 PCT/US2013/026241 abbreviations A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y and V. Non-natural amino acids or amino acid analogs include, without limitation, structures according to the following: S/ / / N N N N N H H H N ' H O O O H 0 o 1-Naphtalanine Indanyl glycine 2-Naphtalanine homophenylalanine F4tBu (1Nal) (Igl) (2Nal) (hF) F CI F F N N ' 'N ' N ' H 0 H 0 H F4F 0 F3CI=3cf F3F=3ff F2F=2ff F F CI F F F F F CI F F F F F N ' 'N 'N ' 'N ' N H O H O H O H O H O F345F3 F34C12 F5F F34F2 F35F2 PC-OEt S H CI OEt S N 'N N N H H N ' N N ' 0 0 H H O H 2Thi 3BthA 2qA 6cIW pmpEt -18- WO 2013/123267 PCT/US2013/026241 19 H H H FBr H POH CI OH NI N " -N -N ~ N H 0H 0H 0H 0 NI 0I 00 dl4mW dl5clW dl6fW & dl6brW dl7mW Pmp HO /N H CI //\N NK 'N N ' N ' ' N H H H N 0 0 0H 0N 3,3-diphenyl-alanine 3-pyridyl-alanine 4-pyridyl-alanine Me6c0W (Dip) (3Pal) (4Pal) homotyrosine (hY)
NH
2 HN H N H H N ' 'N - N ' ' N - "N ' H H O H 0 H O H 0 Amf Aml Amr Ams Amw Ac3c Ac5c Ac6c Aib -19- WO 2013/123267 PCT/US2013/026241 N 'N N' H 0H 0H N N o O 0 H 0 Norleucine Homoleucine tert-Butyl glycine Abu Bip (Nie) (hL) (Tle) N ' N N NN H O H O H O H O homocyclohexyl alanine cyclohexyl alanine cyclohexyl glycine Adamantyl glycine (hCha) (Cha) (Chg) (Adm) OH N N O 0 'N ' N N ' cyclobutyl alanine cyclopentyl glycine I 0 (Cba) (Cpg) NmF NmL NmT Sar HO O x X H N N N 0 H H H 0 F4cooh F2X F3X F4X X=CI, Br, CF3, CN, Me, N02 X=CI, Br, CF3, CN, Me, N02 X=CI, Br, CF3, CN, Me, NO2, I N N N ' HN 0 'NN -- *N H O H H 0 St// $/$r 'N 'N" ' H O w 0H 0 $/s8 $/r8 -20- WO 2013/123267 PCT/US2013/026241 [0043] Amino acid analogs include D-amino acid analogs. Examples of D-amino acid analogs include, but are not limited to, the following: cyclic O-amino acid analogs; P - alanine; (R) - phenylalanine; (R) - 1,2,3,4 - tetrahydro - isoquinoline - 3 - acetic acid; (R) - 3 - amino - 4 - (1 naphthyl) - butyric acid; (R) - 3 - amino - 4 - (2,4 - dichlorophenyl)butyric acid; (R) - 3 - amino 4 - (2 - chlorophenyl) - butyric acid; (R) - 3 - amino - 4 - (2 - cyanophenyl) - butyric acid; (R) - 3 - amino - 4 - (2 - fluorophenyl) - butyric acid; (R) - 3 - amino - 4 - (2 - furyl) - butyric acid; (R) 3 - amino - 4 - (2 - methylphenyl) - butyric acid; (R) - 3 - amino - 4 - (2 - naphthyl) - butyric acid; (R) - 3 - amino - 4 - (2 - thienyl) - butyric acid; (R) - 3 - amino - 4 - (2 - trifluoromethylphenyl) butyric acid; (R) - 3 - amino - 4 - (3,4 - dichlorophenyl)butyric acid; (R) - 3 - amino - 4 - (3,4 difluorophenyl)butyric acid; (R) - 3 - amino - 4 - (3 - benzothienyl) - butyric acid; (R) - 3 - amino - 4 - (3 - chlorophenyl) - butyric acid; (R) - 3 - amino - 4 - (3 - cyanophenyl) - butyric acid; (R) 3 - amino - 4 - (3 - fluorophenyl) - butyric acid; (R) - 3 - amino - 4 - (3 - methylphenyl) - butyric acid; (R) - 3 - amino - 4 - (3 - pyridyl) - butyric acid; (R) - 3 - amino - 4 - (3 - thienyl) - butyric acid; (R) - 3 - amino - 4 - (3 - trifluoromethylphenyl) - butyric acid; (R) - 3 - amino - 4 - (4 bromophenyl) - butyric acid; (R) - 3 - amino - 4 - (4 - chlorophenyl) - butyric acid; (R) - 3 amino - 4 - (4 - cyanophenyl) - butyric acid; (R) - 3 - amino - 4 - (4 - fluorophenyl) - butyric acid; (R) - 3 - amino - 4 - (4 - iodophenyl) - butyric acid; (R) - 3 - amino - 4 - (4 - methylphenyl) butyric acid; (R) - 3 - amino - 4 - (4 - nitrophenyl) - butyric acid; (R) - 3 - amino - 4 - (4 - pyridyl) - butyric acid; (R) - 3 - amino - 4 - (4 - trifluoromethylphenyl) - butyric acid; (R) - 3 - amino - 4 pentafluoro - phenylbutyric acid; (R) - 3 - amino - 5 - hexenoic acid; (R) - 3 - amino - 5 hexynoic acid; (R) - 3 - amino - 5 - phenylpentanoic acid; (R) - 3 - amino - 6 - phenyl - 5 hexenoic acid; (S) - 1,2,3,4 - tetrahydro - isoquinoline - 3 - acetic acid; (S) - 3 - amino - 4 - (1 naphthyl) - butyric acid; (S) - 3 - amino - 4 - (2,4 - dichlorophenyl)butyric acid; (S) - 3 - amino 4 - (2 - chlorophenyl) - butyric acid; (S) - 3 - amino - 4 - (2 - cyanophenyl) - butyric acid; (S) - 3 amino - 4 - (2 - fluorophenyl) - butyric acid; (S) - 3 - amino - 4 - (2 - furyl) - butyric acid; (S) - 3 amino - 4 - (2 - methylphenyl) - butyric acid; (S) - 3 - amino - 4 - (2 - naphthyl) - butyric acid; (S) - 3 - amino - 4 - (2 - thienyl) - butyric acid; (S) - 3 - amino - 4 - (2 - trifluoromethylphenyl) butyric acid; (S) - 3 - amino - 4 - (3,4 - dichlorophenyl)butyric acid; (S) - 3 - amino - 4 - (3,4 difluorophenyl)butyric acid; (S) - 3 - amino - 4 - (3 - benzothienyl) - butyric acid; (S) - 3 - amino - 4 - (3 - chlorophenyl) - butyric acid; (S) - 3 - amino - 4 - (3 - cyanophenyl) - butyric acid; (S) - 3 - amino - 4 - (3 - fluorophenyl) - butyric acid; (S) - 3 - amino - 4 - (3 - methylphenyl) - butyric acid; (S) - 3 - amino - 4 - (3 - pyridyl) - butyric acid; (S) - 3 - amino - 4 - (3 - thienyl) - butyric acid; (S) - 3 - amino - 4 - (3 - trifluoromethylphenyl) - butyric acid; (S) - 3 - amino - 4 - (4 bromophenyl) - butyric acid; (S) - 3 - amino - 4 - (4 - chlorophenyl) - butyric acid; (S) - 3 - amino - 4 - (4 - cyanophenyl) - butyric acid; (S) - 3 - amino - 4 - (4 - fluorophenyl) - butyric acid; (S) - 3 - amino - 4 - (4 - iodophenyl) - butyric acid; (S) - 3 - amino - 4 - (4 - methylphenyl) - butyric -21- WO 2013/123267 PCT/US2013/026241 acid; (S) - 3 - amino - 4 - (4 - nitrophenyl) - butyric acid; (S) - 3 - amino - 4 - (4 - pyridyl) butyric acid; (S) - 3 - amino - 4 - (4 - trifluoromethylphenyl) - butyric acid; (S) - 3 - amino - 4 pentafluoro - phenylbutyric acid; (S) - 3 - amino - 5 - hexenoic acid; (S) - 3 - amino - 5 hexynoic acid; (S) - 3 - amino - 5 - phenylpentanoic acid; (S) - 3 - amino - 6 - phenyl - 5 hexenoic acid; 1,2,5,6 - tetrahydropyridine - 3 - carboxylic acid; 1,2,5,6 - tetrahydropyridine - 4 carboxylic acid; 3 - amino - 3 - (2 - chlorophenyl) - propionic acid; 3 - amino - 3 - (2 - thienyl) propionic acid; 3 - amino - 3 - (3 - bromophenyl) - propionic acid; 3 - amino - 3 - (4 chlorophenyl) - propionic acid; 3 - amino - 3 - (4 - methoxyphenyl) - propionic acid; 3 - amino 4,4,4 - trifluoro - butyric acid; 3 - aminoadipic acid; D- P - phenylalanine; P - leucine; L - P homoalanine; L - P - homoaspartic acid y - benzyl ester; L - $ - homoglutamic acid 6 - benzyl ester; L - P - homoisoleucine; L - P - homoleucine; L - P - homomethionine; L - P homophenylalanine; L - P - homoproline; L - P - homotryptophan; L - P - homovaline; L - NO benzyloxycarbonyl - P - homolysine; No - L - 13- homoarginine; 0 - benzyl - L - P homohydroxyproline; 0 - benzyl - L - P - homoserine; 0 - benzyl - L - 1 - homothreonine; 0 benzyl - L - P - homotyrosine; y - trityl - L - P - homoasparagine; (R) - P - phenylalanine; L - p homoaspartic acid y - t - butyl ester; L - P - homoglutamic acid 6 - t - butyl ester; L - NO - p homolysine; N6 - trityl - L - P - homoglutamine; No - 2,2,4,6,7 - pentamethyl dihydrobenzofuran - 5 - sulfonyl - L - P - homoarginine; 0 - t - butyl - L - P - homohydroxy proline; 0 - t - butyl - L - 1 - homoserine; 0 - t - butyl - L - P - homothreonine; 0 - t - butyl - L P - homotyrosine; 2- aminocyclopentane carboxylic acid; and 2-aminocyclohexane carboxylic acid. [0044] Amino acid analogs include analogs of alanine, valine, glycine or leucine. Examples of amino acid analogs of alanine, valine, glycine, and leucine include, but are not limited to, the following: a - methoxyglycine; a - allyl - L - alanine; a - aminoisobutyric acid; a - methyl - leucine; 1 - (1 naphthyl) - D - alanine; - (1 - naphthyl) - L - alanine; - (2 - naphthyl) - D - alanine; 1 - (2 naphthyl) - L - alanine; - (2 - pyridyl) - D - alanine; - (2 - pyridyl) - L - alanine; 1 - (2 thienyl) - D - alanine; P - (2 - thienyl) - L - alanine; - (3 - benzothienyl) - D - alanine; - (3 benzothienyl) - L - alanine; 1 - (3 - pyridyl) - D - alanine; 1 - (3 - pyridyl) - L - alanine; - (4 pyridyl) - D - alanine; 1 - (4 - pyridyl) - L - alanine; 1 - chloro - L - alanine; 1 - cyano - L alanin; 1 - cyclohexyl - D - alanine; P - cyclohexyl - L - alanine; $ - cyclopenten - 1 - yl alanine; P - cyclopentyl - alanine; P - cyclopropyl - L - Ala - OH - dicyclohexylammonium salt; P - t - butyl - D - alanine; 1 - t - butyl - L - alanine; y - aminobutyric acid; L - a,P diaminopropionic acid; 2,4 - dinitro - phenylglycine; 2,5 - dihydro - D - phenylglycine; 2 amino - 4,4,4 - trifluorobutyric acid; 2 - fluoro - phenylglycine; 3 - amino - 4,4,4 - trifluoro butyric acid; 3 - fluoro - valine; 4,4,4 - trifluoro - valine; 4,5 - dehydro - L - leu - OH dicyclohexylammonium salt; 4 - fluoro - D - phenylglycine; 4 - fluoro - L - phenylglycine; 4 hydroxy - D - phenylglycine; 5,5,5 - trifluoro - leucine; 6 - aminohexanoic acid; cyclopentyl - D -22- WO 2013/123267 PCT/US2013/026241 - Gly - OH - dicyclohexylammonium salt; cyclopentyl - Gly - OH - dicyclohexylammonium salt; D - a, - diaminopropionic acid; D - a - aminobutyric acid; D - a - t - butylglycine; D - (2 thienyl)glycine; D - (3 - thienyl)glycine; D - 2 - aminocaproic acid; D - 2 - indanylglycine; D allylglycine-dicyclohexylammonium salt; D - cyclohexylglycine; D - norvaline; D phenylglycine; B - aminobutyric acid; P - aminoisobutyric acid; (2 - bromophenyl)glycine; (2 methoxyphenyl)glycine; (2 - methylphenyl)glycine; (2 - thiazoyl)glycine; (2 - thienyl)glycine; 2 amino - 3 - (dimethylamino) - propionic acid; L - a, - diaminopropionic acid; L - a aminobutyric acid; L - a - t - butylglycine; L - (3 - thienyl)glycine; L - 2 - amino - 3 (dimethylamino) - propionic acid; L - 2 - aminocaproic acid dicyclohexyl - ammonium salt; L - 2 - indanylglycine; L - allylglycine-dicyclohexyl ammonium salt; L - cyclohexylglycine; L phenylglycine; L - propargylglycine; L - norvaline; N - a - aminomethyl - L - alanine; D - a,y diaminobutyric acid; L - a,y - diaminobutyric acid; P - cyclopropyl - L - alanine; (N - - (2,4 dinitrophenyl)) - L - a,p - diaminopropionic acid; (N - P - 1 - (4,4 - dimethyl - 2,6 dioxocyclohex - 1 - ylidene)ethyl) - D - a, - diaminopropionic acid; (N - P - I - (4,4 - dimethyl 2,6 - dioxocyclohex - 1 - ylidene)ethyl) - L - a, - diaminopropionic acid; (N - - 4 methyltrityl) - L - a,3 - diaminopropionic acid; (N - P - allyloxycarbonyl) - L - a, diaminopropionic acid; (N - y - 1 - (4,4 - dimethyl - 2,6 - dioxocyclohex - I - ylidene)ethyl) - D a,y - diaminobutyric acid; (N - y - 1 - (4,4 - dimethyl - 2,6 - dioxocyclohex - 1 - ylidene)ethyl) - L - a,y - diaminobutyric acid; (N - y - 4 - methyltrityl) - D - a,y - diaminobutyric acid; (N - y - 4 methyltrityl) - L - a,y - diaminobutyric acid; (N - y - allyloxycarbonyl) - L - a,y - diaminobutyric acid; D - a,y - diaminobutyric acid; 4,5 - dehydro - L - leucine; cyclopentyl - D - Gly - OH; cyclopentyl - Gly - OH; D - allylglycine; D - homocyclohexylalanine; L - 1 - pyrenylalanine; L - 2 - aminocaproic acid; L - allylglycine; L - homocyclohexylalanine; and N - (2 - hydroxy - 4 methoxy - Bzl) - Gly - OH. [0045] Amino acid analogs further include analogs of arginine or lysine. Examples of amino acid analogs of arginine and lysine include, but are not limited to, the following: citrulline; L - 2 amino - 3 - guanidinopropionic acid; L - 2 - amino - 3 - ureidopropionic acid; L - citrulline; Lys(Me) 2 - OH; Lys(N 3 ) - OH; N6 - benzyloxycarbonyl - L - omithine; NO - nitro - D arginine; Nw - nitro - L - arginine; a - methyl - omithine; 2,6 - diaminoheptanedioic acid; L omithine; (N6 - I - (4,4 - dimethyl - 2,6 - dioxo - cyclohex - 1 - ylidene)ethyl) - D - ornithine; (N6 - 1 - (4,4 - dimethyl - 2,6 - dioxo - cyclohex - 1 - ylidene)ethyl) - L - ornithine; (N6 - 4 methyltrityl) - D - omithine; (N6 - 4 - methyltrityl) - L - ornithine; D - ornithine; L - ornithine; Arg(Me)(Pbf) - OH; Arg(Me)2 - OH (asymmetrical); Arg(Me)2 - OH (symmetrical); Lys(ivDde) - OH; Lys(Me)2 - OH - HCl; Lys(Me3) - OH chloride; No - nitro - D - arginine; and No - nitro L - arginine. [0046] Amino acid analogs include analogs of aspartic or glutamic acids. Examples of amino acid analogs of aspartic and glutamic acids include, but are not limited to, the following: a - methyl -23- WO 2013/123267 PCT/US2013/026241 D - aspartic acid; a - methyl - glutamic acid; a - methyl - L - aspartic acid; y - methylene glutamic acid; (N - y - ethyl) - L - glutamine; [N - a - (4 - aminobenzoyl)] - L - glutamic acid; 2,6 - diaminopimelic acid; L - a - aminosuberic acid; D - 2 - aminoadipic acid; D - a - aminosuberic acid; a - aminopimelic acid; iminodiacetic acid; L - 2 - aminoadipic acid; threo - - methyl aspartic acid; y - carboxy - D - glutamic acid y,y - di - t - butyl ester; y - carboxy - L - glutamic acid y,y - di - t - butyl ester; Glu(OAll) - OH; L - Asu(OtBu) - OH; and pyroglutamic acid. [0047] Amino acid analogs include analogs of cysteine and methionine. Examples of amino acid analogs of cysteine and methionine include, but are not limited to, Cys(famesyl) - OH, Cys(famesyl) OMe, a - methyl - methionine, Cys(2 - hydroxyethyl) - OH, Cys(3 - aminopropyl) - OH, 2 amino - 4 - (ethylthio)butyric acid, buthionine, buthioninesulfoximine, ethionine, methionine methylsulfonium chloride, selenomethionine, cysteic acid, [2 - (4 - pyridyl)ethyl] - DL penicillamine, [2 - (4 - pyridyl)ethyl] - L - cysteine, 4 - methoxybenzyl - D - penicillamine, 4 methoxybenzyl - L - penicillamine, 4 - methylbenzyl - D - penicillamine, 4 - methylbenzyl - L penicillamine, benzyl-D-cysteine, benzyl - L - cysteine, benzyl - DL - homocysteine, carbamoyl - L - cysteine, carboxyethyl - L - cysteine, carboxymethyl - L - cysteine, diphenylmethyl - L cysteine, ethyl - L - cysteine, methyl - L - cysteine, t-butyl - D - cysteine, trityl - L homocysteine, trityl - D - penicillamine, cystathionine, homocystine, L-homocystine, (2 aminoethyl) - L - cysteine, seleno - L - cystine, cystathionine, Cys(StBu) - OH, and acetamidomethyl - D - penicillamine. [0048] Amino acid analogs include analogs of phenylalanine and tyrosine. Examples of amino acid analogs of phenylalanine and tyrosine include P - methyl - phenylalanine, P hydroxyphenylalanine, a - methyl - 3 - methoxy - DL - phenylalanine, a - methyl - D phenylalanine, a - methyl - L - phenylalanine, 1,2,3,4 - tetrahydroisoquinoline - 3 - carboxylic acid, 2,4 - dichloro - phenylalanine, 2 - (trifluoromethyl) - D -phenylalanine, 2 (trifluoromethyl) - L - phenylalanine, 2 - bromo - D - phenylalanine, 2 - bromo - L phenylalanine, 2 - chloro - D - phenylalanine, 2 - chloro - L - phenylalanine, 2 - cyano - D phenylalanine, 2 - cyano - L - phenylalanine, 2 - fluoro - D - phenylalanine, 2 - fluoro - L phenylalanine, 2 - methyl - D - phenylalanine, 2 - methyl - L - phenylalanine, 2 - nitro - D phenylalanine, 2 - nitro - L - phenylalanine, 2;4;5 - trihydroxy - phenylalanine, 3,4,5 - trifluoro D - phenylalanine, 3,4,5 - trifluoro - L - phenylalanine, 3,4 - dichloro - D - phenylalanine, 3,4 dichloro - L - phenylalanine, 3,4 - difluoro - D - phenylalanine, 3,4 - difluoro - L phenylalanine, 3,4 - dihydroxy - L - phenylalanine, 3,4 - dimethoxy - L - phenylalanine, 3,5,3' triiodo - L - thyronine, 3,5 - diiodo - D - tyrosine, 3,5 - diiodo - L - tyrosine, 3,5 - diiodo - L thyronine, 3 - (trifluoromethyl) - D - phenylalanine, 3 - (trifluoromethyl) - L - phenylalanine, 3 amino - L - tyrosine, 3 - bromo - D - phenylalanine, 3 - bromo - L - phenylalanine, 3 - chloro D - phenylalanine, 3 - chloro - L - phenylalanine, 3 - chloro - L - tyrosine, 3 - cyano - D phenylalanine, 3 - cyano - L - phenylalanine, 3 - fluoro - D - phenylalanine, 3 - fluoro - L -24- WO 2013/123267 PCT/US2013/026241 phenylalanine, 3 - fluoro - tyrosine, 3 - iodo - D - phenylalanine, 3 - iodo - L - phenylalanine, 3 iodo - L - tyrosine, 3 - methoxy - L - tyrosine, 3 - methyl - D - phenylalanine, 3 - methyl - L phenylalanine, 3 - nitro - D - phenylalanine, 3 - nitro - L - phenylalanine, 3 - nitro - L - tyrosine, 4 - (trifluoromethyl) - D - phenylalanine, 4 - (trifluoromethyl) - L - phenylalanine, 4 - amino - D - phenylalanine, 4 - amino - L - phenylalanine, 4 - benzoyl - D - phenylalanine, 4 - benzoyl - L phenylalanine, 4 - bis(2 - chloroethyl)amino - L - phenylalanine, 4 - bromo - D - phenylalanine, 4 - bromo - L - phenylalanine, 4 - chloro - D - phenylalanine, 4 - chloro - L - phenylalanine, 4 cyano - D - phenylalanine, 4 - cyano - L - phenylalanine, 4 - fluoro - D - phenylalanine, 4 fluoro - L - phenylalanine, 4 - iodo - D - phenylalanine, 4 - iodo - L - phenylalanine, homophenylalanine, thyroxine, 3,3 - diphenylalanine, thyronine, ethyl-tyrosine, and methyl tyrosine. [0049] Amino acid analogs include analogs of proline. Examples of amino acid analogs of proline include, but are not limited to, 3,4-dehydro-proline, 4-fluoro-proline, cis-4-hydroxy-proline, thiazolidine-2-carboxylic acid, and trans-4-fluoro-proline. [0050] Amino acid analogs include analogs of serine and threonine. Examples of amino acid analogs of serine and threonine include, but are not limited to, 3 - amino - 2 - hydroxy - 5 - methylhexanoic acid, 2 - amino - 3 - hydroxy - 4 - methylpentanoic acid, 2 - amino - 3 - ethoxybutanoic acid, 2 amino - 3 - methoxybutanoic acid, 4 - amino - 3 - hydroxy - 6 - methylheptanoic acid, 2 - amino 3 - benzyloxypropionic acid, 2 - amino - 3 - benzyloxypropionic acid, 2 - amino - 3 ethoxypropionic acid, 4 - amino - 3 - hydroxybutanoic acid, and a-methylserine. [0051] Amino acid analogs include analogs of tryptophan. Examples of amino acid analogs of tryptophan include, but are not limited to, the following: a - methyl - tryptophan; P - (3 benzothienyl) - D - alanine; [ - (3 - benzothienyl) - L - alanine; 1 - methyl - tryptophan; 4 methyl - tryptophan; 5 - benzyloxy - tryptophan; 5 - bromo - tryptophan; 5 - chloro - tryptophan; 5 - fluoro - tryptophan; 5 - hydroxy - tryptophan; 5 - hydroxy - L - tryptophan; 5 - methoxy tryptophan; 5 - methoxy - L - tryptophan; 5 - methyl - tryptophan; 6 - bromo - tryptophan; 6 chloro - D - tryptophan; 6 - chloro - tryptophan; 6 - fluoro - tryptophan; 6 - methyl - tryptophan; 7 - benzyloxy - tryptophan; 7 - bromo - tryptophan; 7 - methyl - - tryptophan; D - 1,2,3,4 tetrahydro - norharman - 3 - carboxylic acid; 6 - methoxy - 1,2,3,4 - tetrahydronorharman - 1 carboxylic acid; 7 - azatryptophan; L - 1,2,3,4 - tetrahydro - norharman - 3 - carboxylic acid; 5 methoxy - 2 - methyl - tryptophan; and 6 - chloro - L - tryptophan. [0052] In some embodiments, amino acid analogs are racemic. In some embodiments, the D isomer of the amino acid analog is used. In some embodiments, the L isomer of the amino acid analog is used. In other embodiments, the amino acid analog comprises chiral centers that are in the R or S configuration. In still other embodiments, the amino group(s) of a P-amino acid analog is substituted with a protecting group, e.g., tert-butyloxycarbonyl (BOC group), 9 fluorenylmethyloxycarbonyl (FMOC), tosyl, and the like. In yet other embodiments, the -25- WO 2013/123267 PCT/US2013/026241 carboxylic acid functional group of a p-amino acid analog is protected, e.g., as its ester derivative. In some embodiments the salt of the amino acid analog is used. [0053] A "non-essential" amino acid residue, as used herein, is an amino acid residue present in a wild type sequence of a polypeptide that can be altered without abolishing or substantially altering essential biological or biochemical activity (e.g., receptor binding or activation) of the polypeptide. [0054] An "essential" amino acid residue, as used herein, is an amino acid residue present in a wild-type sequence of a polypeptide that, when altered, results in abolishing or a substantial reduction in the polypeptide's essential biological or biochemical activity(e.g., receptor binding or activation). [0055] A "conservative amino acid substitution" is one in which an amino acid residue is replaced with a different amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., K, R, H), acidic side chains (e.g., D, E), uncharged polar side chains (e.g., G, N, Q, S, T, Y, C), nonpolar side chains (e.g., A, V, L, I, P, F, M, W), beta-branched side chains (e.g., T, V, I) and aromatic side chains (e.g., Y, F, W, H). Thus, a predicted nonessential amino acid residue in a polypeptide, for example, is replaced with another amino acid residue from the same side chain family. Other examples of acceptable substitutions are substitutions based on isosteric considerations (e.g. norleucine for methionine) or other properties (e.g. 2-thienylalanine for phenylalanine, or 6-Cl-tryptophan for tryptophan). [0056] The term "capping group" refers to the chemical moiety occurring at either the carboxy or amino terminus of the polypeptide chain of the subject peptidomimetic macrocycle. The capping group of a carboxy terminus includes an unmodified carboxylic acid (ie -COOH) or a carboxylic acid with a substituent. For example, the carboxy terminus can be substituted with an amino group to yield a carboxamide at the C-terminus. Various substituents include but are not limited to primary and secondary amines, including pegylated secondary amines. Representative secondary amine capping groups for the C-terminus include: N %N~ N JZ''X'NN N r H H H H H isopropylamide propylamide sec-butylamide butylamide isobutylam id e (-NHPr) (-NHnPr) (-NHsBu) (-NHnBu) (-NHiBu) N N N N H H H H amylamide isoamylamide hexylamide 3,3-dimethylbutylamide (-NHAm) (-NHiAm) (-NHHex) (-NHnBu3,3Me) -26- WO 2013/123267 PCT/US2013/026241 H H H cyclohexylamide 2-cyclohexylethylamide 2-cyclopentylethylamide (-NHChx) (-NHnEt2Ch) (-NHnEt2Cp) H N ~N N H IH benzylamide phenetylamide 3-phenyl-1 -propylamide (-NHBn) (-NHPe) (-NHnPr3Ph) H H ,- N ON N n-diPeg2-amide n-diPeg4-amide (-N Hmd Peg2) (-NHmdPeg4) [0057] The capping group of an amino terminus includes an unmodified amine (ie -NH 2 ) or an amine with a substituent. For example, the amino terminus can be substituted with an acyl group to yield a carboxamide at the N-terminus. Various substituents include but are not limited to substituted acyl groups, including CI-C 6 carbonyls, C 7
-C
3 0 carbonyls, and pegylated carbamates. Representative capping groups for the N-terminus include: 0 I0 0 NC Ac- Pr Adamantylcarbonyl 1-Naphthyl Isonicotinyl (Admac) (Napac) (Isoac) 0 0 0 0 H N H- N,N-Dimethylaminoacetyl Trimethylacetyl Hexanoyl Hep/ (uncapped) (Dmaac) (Tmac) (Hexac) 0 Decanoyl Palmityl (Decac) (Pam) 0 mdPEG3 0 mdPEG7 -27- WO 2013/123267 PCT/US2013/026241 [0058] The term "member" as used herein in conjunction with macrocycles or macrocycle-forming linkers refers to the atoms that form or can form the macrocycle, and excludes substituent or side chain atoms. By analogy, cyclodecane, 1,2-difluoro-decane and 1,3-dimethyl cyclodecane are all considered ten-membered macrocycles as the hydrogen or fluoro substituents or methyl side chains do not participate in forming the macrocycle. [0059] The symbol "/" when used as part of a molecular structure refers to a single bond or a trans or cis double bond. [0060] The term "amino acid side chain" refers to a moiety attached to the a-carbon (or another backbone atom) in an amino acid. For example, the amino acid side chain for alanine is methyl, the amino acid side chain for phenylalanine is phenylmethyl, the amino acid side chain for cysteine is thiomethyl, the amino acid side chain for aspartate is carboxymethyl, the amino acid side chain for tyrosine is 4-hydroxyphenylmethyl, etc. Other non-naturally occurring amino acid side chains are also included, for example, those that occur in nature (e.g., an amino acid metabolite) or those that are made synthetically (e.g., an a,a di-substituted amino acid). [0061] The term "a,a di-substituted amino" acid refers to a molecule or moiety containing both an amino group and a carboxyl group bound to a carbon (the a-carbon) that is attached to two natural or non-natural amino acid side chains. [0062] The term "polypeptide" encompasses two or more naturally or non-naturally-occurring amino acids joined by a covalent bond (e.g., an amide bond). Polypeptides as described herein include full length proteins (e.g., fully processed proteins) as well as shorter amino acid sequences (e.g., fragments of naturally-occurring proteins or synthetic polypeptide fragments). [0063] The term "macrocyclization reagent" or "macrocycle-forming reagent" as used herein refers to any reagent which can be used to prepare a peptidomimetic macrocycle by mediating the reaction between two reactive groups. Reactive groups can be, for example, an azide and alkyne, in which case macrocyclization reagents include, without limitation, Cu reagents such as reagents which provide a reactive Cu(I) species, such as CuBr, Cul or CuOTf, as well as Cu(II) salts such as Cu(CO 2
CH
3
)
2 , CuSO 4 , and CuCl 2 that can be converted in situ to an active Cu(I) reagent by the addition of a reducing agent such as ascorbic acid or sodium ascorbate. Macrocyclization reagents can additionally include, for example, Ru reagents known in the art such as Cp*RuCl(PPh 3
)
2 , [Cp*RuCl] 4 or other Ru reagents which can provide a reactive Ru(II) species. In other cases, the reactive groups are terminal olefins. In such embodiments, the macrocyclization reagents or macrocycle-forming reagents are metathesis catalysts including, but not limited to, stabilized, late transition metal carbene complex catalysts such as Group VIII transition metal carbene catalysts. For example, such catalysts are Ru and Os metal centers having a +2 oxidation state, an electron count of 16 and pentacoordinated. In other examples, catalysts have W or Mo centers. Various catalysts are disclosed in Grubbs et al., "Ring Closing Metathesis and Related Processes in Organic Synthesis" Ace. Chem. Res. 1995, 28, 446-452, -28- WO 2013/123267 PCT/US2013/026241 U.S. Pat. No. 5,811,515; U.S. Pat. No. 7,932,397; U.S. Application No. 2011/0065915; U.S. Application No. 2011/0245477; Yu et al., "Synthesis of Macrocyclic Natural Products by Catalyst-Controlled Stereoselective Ring-Closing Metathesis," Nature 2011, 479, 88; and Peryshkov et al., "Z-Selective Olefin Metathesis Reactions Promoted by Tungsten Oxo Alkylidene Complexes," J. Am. Chem. Soc. 2011, 133, 20754. In yet other cases, the reactive groups are thiol groups. In such embodiments, the macrocyclization reagent is, for example, a linker functionalized with two thiol-reactive groups such as halogen groups. [0064] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine or a radical thereof. [0065] The term "alkyl" refers to a hydrocarbon chain that is a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C 1 -Ca indicates that the group has from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, "alkyl" is a chain (straight or branched) having I to 20 (inclusive) carbon atoms in it. [0066] The term "alkylene" refers to a divalent alkyl (i.e., -R-). [0067] The term "alkenyl" refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2 -Cio indicates that the group has from 2 to 10 (inclusive) carbon atoms in it. The term "lower alkenyl" refers to a C 2
-C
6 alkenyl chain. In the absence of any numerical designation, "alkenyl" is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it. [0068] The term "alkynyl" refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2 -Cio indicates that the group has from 2 to 10 (inclusive) carbon atoms in it. The term "lower alkynyl" refers to a C 2
-C
6 alkynyl chain. In the absence of any numerical designation, "alkynyl" is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it. [0069] The term "aryl" refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like. The term "arylalkoxy" refers to an alkoxy substituted with aryl. [0070] "Arylalkyl" refers to an aryl group, as defined above, wherein one of the aryl group's hydrogen atoms has been replaced with a CI-C 5 alkyl group, as defined above. Representative examples of an arylalkyl group include, but are not limited to, 2-methylphenyl, 3-methylphenyl, 4 methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl, 3-propylphenyl, 4 propylphenyl, 2-butylphenyl, 3-butylphenyl, 4-butylphenyl, 2-pentylphenyl, 3-pentylphenyl, 4 pentylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-isobutylphenyl, 3 isobutylphenyl, 4-isobutylphenyl, 2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl, 2-t butylphenyl, 3-t-butylphenyl and 4-t-butylphenyl. -29- WO 2013/123267 PCT/US2013/026241 [0071] "Arylamido" refers to an aryl group, as defined above, wherein one of the aryl group's hydrogen atoms has been replaced with one or more -C(O)NH 2 groups. Representative examples of an arylamido group include 2-C(O)NH 2 -phenyl, 3-C(O)NH 2 -phenyl, 4-C(O)NH 2 -phenyl, 2
C(O)NH
2 -pyridyl, 3-C(O)NH2-pyridyl, and 4-C(O)NH 2 -pyridyl, [0072] "Alkylheterocycle" refers to a Ci-C 5 alkyl group, as defined above, wherein one of the CI-C 5 alkyl group's hydrogen atoms has been replaced with a heterocycle. Representative examples of an alkylheterocycle group include, but are not limited to, -CH 2
CH
2 -morpholine, -CH 2
CH
2 piperidine, -CH 2
CH
2
CH
2 -morpholine, and -CH 2
CH
2
CH
2 -imidazole. [0073] "Alkylamido" refers to a CI-C 5 alkyl group, as defined above, wherein one of the CI-C 5 alkyl group's hydrogen atoms has been replaced with a -C(O)NH 2 group. Representative examples of an alkylamido group include, but are not limited to, -CH 2
-C(O)NH
2 , -CH 2
CH
2
-C(O)NH
2 , CH 2
CH
2
CH
2
C(O)NH
2 , -CH 2
CH
2
CH
2
CH
2
C(O)NH
2 , -CH 2
CH
2
CH
2
CH
2
CH
2
C(O)NH
2 , CH 2
CH(C(O)NH
2
)CH
3 , -CH 2
CH(C(O)NH
2
)CH
2
CH
3 , -CH(C(O)NH 2
)CH
2
CH
3 , C(CH 3
)
2
CH
2
C(O)NH
2 , -CH 2
-CH
2
-NH-C(O)-CH
3 , -CH 2
-CH
2
-NH-C(O)-CH
3 -CH3, and -CH 2 CH 2
-NH-C(O)-CH=CH
2 . [0074] "Alkanol" refers to a CI-C 5 alkyl group, as defined above, wherein one of the C 1
-C
5 alkyl group's hydrogen atoms has been replaced with a hydroxyl group. Representative examples of an alkanol group include, but are not limited to, -CH 2 OH, -CH 2
CH
2 OH, -CH 2
CH
2
CH
2 OH, CH 2
CH
2
CH
2
CH
2 OH, -CH 2
CH
2
CH
2
CH
2
CH
2 OH, -CH 2
CH(OH)CH
3 , -CH 2
CH(OH)CH
2
CH
3 , CH(OH)CH 3 and -C(CH 3
)
2
CH
2 OH. [0075] "Alkylcarboxy" refers to a CI-C 5 alkyl group, as defined above, wherein one of the CI-C 5 alkyl group's hydrogen atoms has been replaced with a --COOH group. Representative examples of an alkylcarboxy group include, but are not limited to, -CH 2 COOH, -CH 2
CH
2 COOH, CH 2
CH
2
CH
2 COOH, -CH 2
CH
2
CH
2
CH
2 COOH, -CH 2
CH(COOH)CH
3 , CH 2
CH
2
CH
2
CH
2
CH
2 COOH, -CH 2
CH(COOH)CH
2
CH
3 , -CH(COOH)CH 2
CH
3 and C(CH3) 2
CH
2 COOH. [0076] The term "cycloalkyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Some cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. [0077] The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of 0, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. -30- WO 2013/123267 PCT/US2013/026241 Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like. [0078] The term "heteroarylalkyl" or the term "heteroaralkyl" refers to an alkyl substituted with a heteroaryl. The term "heteroarylalkoxy" refers to an alkoxy substituted with heteroaryl. [0079] The term "heteroarylalkyl" or the term "heteroaralkyl" refers to an alkyl substituted with a heteroaryl. The term "heteroarylalkoxy" refers to an alkoxy substituted with heteroaryl. [0080] The term "heterocyclyl" refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of 0, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring are substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. [0081] The term "substituent" refers to a group replacing a second atom or group such as a hydrogen atom on any molecule, compound or moiety. Suitable substituents include, without limitation, halo, hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, and cyano groups. [0082] In some embodiments, one or more compounds disclosed herein contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. In one embodiment isomeric forms of these compounds are included in the present invention unless expressly provided otherwise. In some embodiments, one or more compounds disclosed herein are also represented in multiple tautomeric forms, in such instances, the one or more compounds includes all tautomeric forms of the compounds described herein (e.g., if alkylation of a ring system results in alkylation at multiple sites, the one or more compounds includes all such reaction products). All such isomeric forms of such compounds are included in the present invention unless expressly provided otherwise. All crystal forms of the compounds described herein are included in the present invention unless expressly provided otherwise. [0083] As used herein, the terms "increase" and "decrease" mean, respectively, to cause a statistically significantly (i.e., p < 0.1) increase or decrease of at least 5%. [0084] As used herein, the recitation of a numerical range for a variable is intended to convey that the invention can be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable is equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable is equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is -31- WO 2013/123267 PCT/US2013/026241 described as having values between 0 and 2 takes the values 0, 1 or 2 if the variable is inherently discrete, and takes the values 0.0, 0.1, 0.01, 0.001, or any other real values > 0 and 2 if the variable is inherently continuous. [0085] As used herein, unless specifically indicated otherwise, the word "or" is used in the inclusive sense of "and/or" and not the exclusive sense of "either/or." [0086] The term "on average" represents the mean value derived from performing at least three independent replicates for each data point. [0087] The term "biological activity" encompasses structural and functional properties of a macrocycle. Biological activity is, for example, structural stability, alpha-helicity, affinity for a target, resistance to proteolytic degradation, cell penetrability, intracellular stability, in vivo stability, or any combination thereof [0088] The term "binding affinity" refers to the strength of a binding interaction, for example between a peptidomimetic macrocycle and a target. Binding affinity can be expressed, for example, as an equilibrium dissociation constant ("KD"), which is expressed in units which are a measure of concentration (e.g. M, mM, gM, nM etc). Numerically, binding affinity and KD values vary inversely, such that a lower binding affinity corresponds to a higher KD value, while a higher binding affinity corresponds to a lower KD value. Where high binding affinity is desirable, "improved" binding affinity refers to higher binding affinity and therefoere lower KD values. [0089] The term "ratio of binding affinities" refers to the ratio of dissociation constants (KD values) of a first binding interaction (the numerator), versus a second binding interaction (denominator). Consequently, a "reduced ratio of binding affinities" to Target 1 versus Target 2 refers to a lower value for the ratio expressed as KD(Target 1)/KD(Target 2). This concept can also be characterized as "improved selectivity" for Target 1 versus Target 2, which can be due either to a decrease in the KD value for Target 1 or an increase in the value for the KD value for Target 2. [0090] The term "in vitro efficacy" refers to the extent to which a test compound, such as a peptidomimetic macrocycle, produces a beneficial result in an in vitro test system or assay. In vitro efficacy can be measured, for example, as an "IC 5 0 " or "EC 0 " value, which represents the concentration of the test compound which produces 50% of the maximal effect in the test system. [0091] The term "ratio of in vitro efficacies" or "in vitro efficacy ratio" refers to the ratio of IC 5 0 or EC 50 values from a first assay (the numerator) versus a second assay (the denominator). Consequently, an improved in vitro efficacy ratio for Assay 1 versus Assay 2 refers to a lower value for the ratio expressed as ICso(Assay 1)/ICso(Assay 2) or alternatively as ECso(Assay 1)/ECso(Assay 2). This concept can also be characterized as "improved selectivity" in Assay 1 versus Assay 2, which can be due either to a decrease in the IC 50 or EC 50 value for Target 1 or an increase in the value for the IC 50 or EC 50 value for Target 2. -32- WO 2013/123267 PCT/US2013/026241 [0092] The details of one or more particular embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. Peptidomimetic Macrocycles [0093] In some embodiments, a peptidomimetic macrocycle has the Formula (I): 0 0 R7
R
8 --- [D]v N[A]x-[~-[~.- [E]w - R1 R2 L - u Formula (I) wherein: each A, C, D, and E is independently an amino acid;
R
3 N B is an amino acid, 0 , [-NH-L 3 -CO-], [-NH-L 3
-SO
2 -], or [-NH-L 3 -]; each L and L' is independently a macrocycle -forming linker of the formula LI L2 NN LI, L 2 and L 3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4
-K-R
4 -],, each being optionally substituted with R 5 ; each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR 6 , -SOR 6 , -S0 2
R
6 , -C0 2
R
6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; -33- WO 2013/123267 PCT/US2013/026241 each R 7 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; each R is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1 20 or 1-10; u is an integer from 1-10, for example 1-5, 1-3 or 1-2; x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and n is an integer from 1-5. [0094] In some embodiments, a peptidomimetic macrocycle has the Formula: 0 0 R7 R8 - - - [ D ] , N [ A ],- [ B ] y -[ C ] .- N [ ], [D],7z L [E].
R
1 L,1 -L-S L 3 R2 -- u Formula (II) wherein: each A, C, D, and E is independently an amino acid; R3 N B is an amino acid, 0 , [-NH-L 4 -CO-], [-NH-L 4
-SO
2 -], or [-NH-L 4 -]; R and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5; LI, L 2 , L 3 and L 4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [-R 4 -K-R4-]n, each being unsubstituted or substituted with R5; each K is 0, S, SO, SO 2 , CO, CO 2 , or CONR 3 ; each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; -34- WO 2013/123267 PCT/US2013/026241 each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR, -SOR 6 , -S0 2
R
6 , -CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1 20 or 1-10; u is an integer from 1-10, for example 1-5, 1-3 or 1-2; x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and n is an integer from 1-5. [0095] In some embodiments, v and w are integers between 1-30. In some embodiments, w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10. [0096] In some embodiments, the peptidomimetic macrocycles are claimed with the proviso that when u=1 and w=2, the first C-terminal amino acid represented by E is not an Arginine (R) and/or the second C-terminal amino acid represented by E is not a Threonine (T). For instance, when u = 1 and w= 2, the first C-terminal amino acid and/or the second C-terminal amino acid represented by E do not comprise a positively charged side chain or a polar uncharged side chain. In some embodiments, when u = 1 and w= 2, the first C-terminal amino acid and/or the second C-terminal amino acid represented by E comprise a hydrophobic side chain. For example, when w- 2, the first C-terminal amino acid and/or the second N-terminal amino acid represented by E comprise a hydrophobic side chain, for example a large hydrophobic side chain. [0097] In some embodiments, w is between 3 and 1000. For example, the third amino acid represented by E comprises a large hydrophobic side chain. [0098] In some embodiments of a peptidomimetic macrocycle of Formula I, L I and L 2 , either alone or in combination, do not form an all hydrocarbon chain or a thioether. In other embodiments of a peptidomimetic macrocycle of Formula II, L I and L 2 , either alone or in combination, do not form an all hydrocarbon chain or a triazole. [0099] In one example, at least one of Ri and R 2 is alkyl, unsubstituted or substituted with halo-. In another example, both R and R 2 are independently alkyl, unsubstituted or substituted with halo-. In some embodiments, at least one of R and R 2 is methyl. In other embodiments, R and R 2 are methyl. -35- WO 2013/123267 PCT/US2013/026241 [00100] In some embodiments, x+y+z is at least 3. In other embodiments, x+y+z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, the sum of x+y+z is 3 or 6. In some embodiments, the sum of x+y+z is 3. In other embodiments, the sum of x+y+z is 6. Each occurrence of A, B, C, D or E in a macrocycle or macrocycle precursor is independently selected. For example, a sequence represented by the formula [A],, when x is 3, encompasses embodiments where the amino acids are not identical, e.g. Gln-Asp-Ala as well as embodiments where the amino acids are identical, e.g. Gln-Gln-Gln. This applies for any value of x, y, or z in the indicated ranges. Similarly, when u is greater than 1, each compound can encompass peptidomimetic macrocycles which are the same or different. For example, a compound can comprise peptidomimetic macrocycles comprising different linker lengths or chemical compositions. [00101] In some embodiments, the peptidomimetic macrocycle comprises a secondary structure which is an a-helix and R 8 is -H, allowing intrahelical hydrogen bonding. In some embodiments, at least one of A, B, C, D or E is an a,a-disubstituted amino acid. In one example, B is an a,a disubstituted amino acid. For instance, at least one of A, B, C, D or E is 2-aminoisobutyric acid. R3 0 In other embodiments, at least one of A, B, C, D or E is . [00102] In other embodiments, the length of the macrocycle-forming linker L as measured from a first Ca to a second Ca is selected to stabilize a desired secondary peptide structure, such as an a-helix formed by residues of the peptidomimetic macrocycle including, but not necessarily limited to, those between the first Ca to a second Ca. [00103] Peptidomimetic macrocycles are also provided of the formula: 7
R
8 0 [D],-Xaa'sI N Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xa 0 N [E], R1,R L wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaag, and Xaao is individually an amino acid, wherein at least three of Xaa 3 , Xaa, Xaa 6 , Xaa 7 , Xaa 8 , Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3
-X
4 -His 5 -Tyr-Trp-Ala-Gln 9 -Leuto-X 1 -Ser 1 2 , where each X is an amino acid; each D and E is independently an amino acid; R and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; -36- WO 2013/123267 PCT/US2013/026241 each L and L' is independently a macrocycle-forming linker of the formula LL2 NH N --- N; Li and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4
-K-R
4 -], each being optionally substituted with
R
5 ; each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently 0, S, SO, S02, CO, C0 2 , or CONR 3 ; each R5 is independently halogen, alkyl, -OR 6 , -N(R 6
)
2 , -SR6, -SOR 6 , -S0 2
R
6 , -C0 2
R
6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; each R7 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; each Rs is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20 or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5. [00104] In some embodiments, the peptidomimetic macrocycle has the Formula: 0 R 8 0 [D],-Xaa 3 N Xaas-Xaa 6 -Xaa 7 -Xaa 8 -Xaag-Xaa , [
R
1 R2 wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaao are the same amino acid as the amino acid at -37- WO 2013/123267 PCT/US2013/026241 the corresponding position of the sequence Phe 3
-X
4 -Glu 5 -Tyr 6 -Trp 7 -Alag-Glng-Leuio/Cbaio-XI 1-Ala[2, where each X is an amino acid; each D and E is independently an amino acid; RI and R2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula LL2 NNH Li and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4
-K-R
4 -],, each being optionally substituted with
R
5 ; R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R is independently halogen, alkyl, -OR 6 , -N(R6) 2 , -SR, -SOR6, -SO 2 R6, -CO 2 R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R, or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R, or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5. [00105] Peptidomimetic macrocycles are also provided of the formula: -38- WO 2013/123267 PCT/US2013/026241 0 0 Ry N R8 [D, -Xaa 3 RXaa 5 Xaa 6 Xaa 7 Xaa 8 Xaag Xaa 1 -- N Li 11 -2 S1 L3 R2 S -- L 2 -- s wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3
-X
4 -His 5 -Tyr-Trp 7 -Ala-Gln 9 -Leuio-Xii-Ser 1 2 , where each X is an amino acid; each D and E is independently an amino acid; RI and R2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; Lt, L 2 , L 3 and L 4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [-R 4
-K-R
4 -]n, each being unsubstituted or substituted with R5; each K is 0, S, SO, SO 2 , CO, CO 2 , or CONR 3 ; R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each R is independently halogen, alkyl, -OR 6 , -N(R6) 2 , -SR, -SOR6, -SO 2 R6, -CO 2 R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R, or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20 or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and -39- WO 2013/123267 PCT/US2013/026241 n is an integer from 1-5. [00106] Peptidomimetic macrocycles are also provided of the formula: 0 0 Ry N R8 [D,-X2 3 X 1 R1Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaag Xaa 1 0 --- N Li1 S L- -, L3 R2 S -- L 2 -s wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa7, Xaas, Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3
-X
4 -Glu 5 -Tyr-Trp 7 -Alag-Glng-Leuio/Cbaio-XI 1-Ala[2, where each X is an amino acid; each D and E is independently an amino acid; R and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; LI, L 2 , L 3 and L 4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [-R 4
-K-R
4 -]n, each being unsubstituted or substituted with R 5 ; each K is 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5; each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each R5 is independently halogen, alkyl, -OR6, -N(R 6
)
2 , -SR6, -SOR 6 , -S0 2
R
6 , -C0 2
R
6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue; -40- WO 2013/123267 PCT/US2013/026241 Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5. [00107] In one embodiment, the peptidomimetic macrocycle is: R[, R OR 1 ' R2'H 0R 1 1 R2H R 1 1 R2OH R2[ 0 R 1 0
R
1 ' R 2 H R 1 ' R 2 ' H R 1 ' 2' H L wherein each R 1 and R 2 is independently independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-. [00108] In related embodiments, the peptidomimetic macrocycle is: R,' 2 H 0 R 1 1 R 2 1 H 0R 1 1 R 2 1 0 R 1 'I R21 H 0 R 2 [D],,R O R R RN ONR [E], o R 1 ' R 2 ' O R R 2 ' O L wherein each Ri' and R2' is independently an amino acid. [00109] In other embodiments, the peptidomimetic macrocycle is a compound of any of the formulas shown below: AA o AA 0 AA 0 AA N N H 1H O AA H R 2 0 L AAH H H AA OAA O AA HOAA O RK~ O N N N NN H H H A AA L L 0 AA 0 AA 0 H N 0 AA O AA 0 AA -41- WO 2013/123267 PCT/US2013/026241 L N. 0 A 0 A H 0 A 0 AA H 0 AA 0OAA 0OAA oR , oAA H R2 H H H LL 0 AA 0 AA 0 AA 0 AA 0 AA 0O 2 0 H %- N N H N N N N N N N H 0 H " H H - A 0 OAA 0 AA 0A A 0 AA AA 0 AA H 0 AA 0 AA 0 AA H 0 AA H 0 AA 1,A, ',ANJ.N N N N (N -><N -- N -ly HH H ~ H" HH 0 0 AA OR 2 0 a 0 AA R 0 L L L AA 0 AA 0 AA 0 AA ~2 0 R H 0 AA 0 R 0 H - HI H I ' H :H HH H 0 H~ HAO A ~ 0 AA H AA H 0 AA H 0 A n AA H 0AA OAAL H 0 H 0 ~ ~ H 0 ~N %~ N -N N N N N N -l 0 R H 0 -I A.H OR 2 H 0 R A 0 A 0 j AA L n L HA A P 0 H 0 R AA H O AH 0 A 0 *0 N0QN N N )< CN 3-Y 0"~HN N> N F;C.N N H 0 H 0 AN A 0 A 0 A A 0 AA 0 AA 0 AA 0 AA 0 0 AA 0 AA 0 AA AA 0 AA2 0 A H , O R H 0 H H ~ H H HA 0H 0 0 HA AAl 0AAA A 0 RH 0~ AA 0R 2 M L L -42- WO 2013/123267 PCT/US2013/026241 L AA O A A O AA 0 AA O 0 0 Nt N N N N N ',N N N N H OR H O AH H H A H O A H O A 0~~~~~ AA AAA 0 A 0 A L AA 0 AA 0 AA 0 O A O AA O H0 H ~ 0 H H 0 Ri AA 0 AA O AA AA 0 AA O AA O R 2 wherein "AA" represents any natural or non-natural amino acid side chain and " "is [D],, [E], as defined above, and n is an integer between 0 and 20, 50, 100, 200, 300, 400 or 500. In some embodiments, n is 0. In other embodiments, n is less than 50. [00110] Exemplary embodiments of the macrocycle-forming linker L for peptidomimetic macrocycles of Formula I are shown below. -43- WO 2013/123267 PCT/US2013/026241 H N N N N N NN N N N-N N-N N-N N N /NNN N N N--N N N N NNN NNN N N NN N N N N N N NN NN NN NNN N--N N--N NRN N-N N
N
NkNNR N-N N N N N--NN N NN N N NNN N N NN NNN N- N N N N NN N N NN N-N NNN N NN RN N N N NNN N N N N N R NN N R NNN N z N N NN N-N N-N N-N N N N N N NN N N, N N N -44- WO 2013/123267 PCT/US2013/026241 N N N N N N NN N N N NN N N IN N N N -N N-N N-N N -- N N N N-N NNN N N N-NN N NsN N N N N N N N N N N N N N N N N N-N~~
N
N NN N N N N N-N N-N N N N-N N-N N N N -N N-N N N N-N N N N N NN N N N-N N-N -45- WO 2013/123267 PCT/US2013/026241 ) p >Mrn y whereX,Y=S where X,Y=S m, n, a, p = 0-10 m, n, a, p = 0-10 kX X Y 0 where X, Y = S where X, Y = S m, n, o, p = 0-10 m, n, o = 0-10 R = H, alkyl, other substituent [00111] In other embodiments, D and/or E in a compound of Formula I or II are further modified in order to facilitate cellular uptake. In some embodiments, lipidating or PEGylating a peptidomimetic macrocycle facilitates cellular uptake, increases bioavailability, increases blood circulation, alters pharmacokinetics, decreases immunogenicity and/or decreases the needed frequency of administration. [00112] In other embodiments, at least one of [D] and [E] in a compound of Formula I or II represents a moiety comprising an additional macrocycle-forming linker such that the peptidomimetic macrocycle comprises at least two macrocycle-forming linkers. In a specific embodiment, a peptidomimetic macrocycle comprises two macrocycle-forming linkers. In an embodiment, u is 2. [00113] In some embodiments, any of the macrocycle-forming linkers described herein can be used in any combination with any of the sequences shown in Tables 4, 4a, 4b, 6, and 6a and also with any of the R- substituents indicated herein. [00114] In some embodiments, the peptidomimetic macrocycle comprises at least one a-helix motif. For example, A, B and/or C in a compound of Formula I or II include one or more a-helices. As a general matter, a-helices include between 3 and 4 amino acid residues per turn. In some embodiments, the a-helix of the peptidomimetic macrocycle includes 1 to 5 turns and, therefore, 3 to 20 amino acid residues. In specific embodiments, the a-helix includes 1 turn, 2 turns, 3 turns, 4 turns, or 5 turns. In some embodiments, the macrocycle-forming linker stabilizes an a-helix motif included within the peptidomimetic macrocycle. Thus, in some embodiments, the length of the macrocycle-forming linker L from a first Ca to a second Ca is selected to increase the stability of an a-helix. In some embodiments, the macrocycle-forming linker spans from 1 turn to 5 turns of the a-helix. In some embodiments, the macrocycle-forming linker spans approximately 1 turn, 2 turns, 3 turns, 4 turns, or 5 turns of the a-helix. In some embodiments, the length of the macrocycle-forming linker is approximately 5 Ato 9 A per turn of the a-helix, or approximately 6 A to 8 A per turn of the a-helix. Where the macrocycle-forming linker spans approximately 1 -46- WO 2013/123267 PCT/US2013/026241 turn of an a-helix, the length is equal to approximately 5 carbon-carbon bonds to 13 carbon carbon bonds, approximately 7 carbon-carbon bonds to 11 carbon-carbon bonds, or approximately 9 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 2 turns of an a-helix, the length is equal to approximately 8 carbon-carbon bonds to 16 carbon-carbon bonds, approximately 10 carbon-carbon bonds to 14 carbon-carbon bonds, or approximately 12 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 3 turns of an a-helix, the length is equal to approximately 14 carbon-carbon bonds to 22 carbon-carbon bonds, approximately 16 carbon-carbon bonds to 20 carbon-carbon bonds, or approximately 18 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 4 turns of an a-helix, the length is equal to approximately 20 carbon-carbon bonds to 28 carbon-carbon bonds, approximately 22 carbon-carbon bonds to 26 carbon-carbon bonds, or approximately 24 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 5 turns of an a-helix, the length is equal to approximately 26 carbon-carbon bonds to 34 carbon-carbon bonds, approximately 28 carbon-carbon bonds to 32 carbon-carbon bonds, or approximately 30 carbon-carbon bonds. Where the macrocycle-forming linker spans approximately 1 turn of an a-helix, the linkage contains approximately 4 atoms to 12 atoms, approximately 6 atoms to 10 atoms, or approximately 8 atoms. Where the macrocycle-forming linker spans approximately 2 turns of the a-helix, the linkage contains approximately 7 atoms to 15 atoms, approximately 9 atoms to 13 atoms, or approximately 11 atoms. Where the macrocycle-forming linker spans approximately 3 turns of the a-helix, the linkage contains approximately 13 atoms to 21 atoms, approximately 15 atoms to 19 atoms, or approximately 17 atoms. Where the macrocycle-forming linker spans approximately 4 turns of the a-helix, the linkage contains approximately 19 atoms to 27 atoms, approximately 21 atoms to 25 atoms, or approximately 23 atoms. Where the macrocycle-forming linker spans approximately 5 turns of the a-helix, the linkage contains approximately 25 atoms to 33 atoms, approximately 27 atoms to 31 atoms, or approximately 29 atoms. Where the macrocycle-forming linker spans approximately 1 turn of the a-helix, the resulting macrocycle forms a ring containing approximately 17 members to 25 members, approximately 19 members to 23 members, or approximately 21 members. Where the macrocycle-forming linker spans approximately 2 turns of the a-helix, the resulting macrocycle forms a ring containing approximately 29 members to 37 members, approximately 31 members to 35 members, or approximately 33 members. Where the macrocycle-forming linker spans approximately 3 turns of the a-helix, the resulting macrocycle forms a ring containing approximately 44 members to 52 members, approximately 46 members to 50 members, or approximately 48 members. Where the macrocycle-forming linker spans approximately 4 turns of the a-helix, the resulting macrocycle forms a ring containing approximately 59 members to 67 members, approximately 61 members to 65 members, or approximately 63 members. Where the macrocycle-forming linker spans approximately 5 turns of the a-helix, the resulting macrocycle -47- WO 2013/123267 PCT/US2013/026241 forms a ring containing approximately 74 members to 82 members, approximately 76 members to 80 members, or approximately 78 members. [00115] Unless otherwise stated, any compounds (including peptidomimetic macrocycles, macrocycle precursors, and other compositions) are also meant to encompass compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the described structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by "C- or 'C-enriched carbon are contemplated herein. [00116] In some embodiments, the peptidomimetic macrocycle has improved binding affinity to MDM2 or MDMX relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In other instances, the peptidomimetic macrocycle has a reduced ratio of binding affinities to MDMX versus MDM2 relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In still other instances, the peptidomimetic macrocycle has improved in vitro anti-tumor efficacy against p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In some embodiments, the peptidomimetic macrocycle shows improved in vitro induction of apoptosis in p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In other instances, the peptidomimetic macrocycle of claim 1, wherein the peptidomimetic macrocycle has an improved in vitro anti tumor efficacy ratio for p53 positive versus p53 negative or mutant tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In still other instances, the peptidomimetic macrocycle has improved in vivo anti-tumor efficacy against p53 positive tumors relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In yet other instances, the peptidomimetic macrocycle has improved in vivo induction of apoptosis in p53 positive tumors relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In some embodiments, the peptidomimetic macrocycle has improved cell permeability relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. In other cases, the peptidomimetic macrocycle has improved solubility relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2. [00117] In some embodiments, Xaa 5 is Glu or an amino acid analog thereof. In some embodiments, Xaa 5 is Glu or an amino acid analog thereof and wherein the peptidomimetic macrocycle has an improved property, such as improved binding affinity, improved solubility, improved cellular efficacy, improved cell permeability, improved in vivo or in vitro anti-tumor efficacy, or improved induction of apoptosis relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. [00118] In some embodiments, the peptidomimetic macrocycle has improved binding affinity to MDM2 or MDMX relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. In other embodiments, the peptidomimetic macrocycle has a reduced ratio of binding affinities to MDMX vs MDM2 relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. In some -48- WO 2013/123267 PCT/US2013/026241 embodiments, the peptidomimetic macrocycle has improved solubility relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala, or the peptidomimetic macrocycle has improved cellular efficacy relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. [00119] In some embodiments, Xaa 5 is Glu or an amino acid analog thereof and wherein the peptidomimetic macrocycle has improved biological activity, such as improved binding affinity, improved solubility, improved cellular efficacy, improved helicity, improved cell permeability, improved in vivo or in vitro anti-tumor efficacy, or improved induction of apoptosis relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. [00120] In one embodiment, a compound disclosed herein can contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 ([51) or carbon-14 ( C). In another embodiment, a compound disclosed herein can have one or more carbon atoms replaced with a silicon atom. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are contemplated herein. Preparation of Peptidomimetic Macrocycles [00121] Peptidomimetic macrocycles of Formulas I and II can be prepared by any of a variety of methods known in the art. For example, macrocycles of Formula I having residues indicated by "$4rn6" or "$4a5" in Table 4, Table 4a or Table 4b can be substituted with a residue capable of forming a crosslinker with a second residue in the same molecule or a precursor of such a residue. [00122] In some embodiments, the synthesis of these peptidomimetic macrocycles involves a multi-step process that features the synthesis of a peptidomimetic precursor containing an azide moiety and an alkyne moiety; followed by contacting the peptidomimetic precursor with a macrocyclization reagent to generate a triazole-linked peptidomimetic macrocycle. Such a process is described, for example, in US Application 12/037,04 1, filed on February 25, 2008. Macrocycles or macrocycle precursors are synthesized, for example, by solution phase or solid-phase methods, and can contain both naturally-occurring and non-naturally-occurring amino acids. See, for example, Hunt, "The Non-Protein Amino Acids" in Chemistry and Biochemistry of the Amino Acids, edited by G.C. Barrett, Chapman and Hall, 1985. [00123] In some embodiments of macrocycles of Formula I, an azide is linked to the a-carbon of a residue and an alkyne is attached to the a-carbon of another residue. In some embodiments, the azide moieties are azido-analogs of amino acids L-lysine, D-lysine, alpha-methyl-L-lysine, alpha methyl-D-lysine, L-ornithine, D-ornithine, alpha-methyl-L-omithine or alpha-methyl-D ornithine. In another embodiment, the alkyne moiety is L-propargylglycine. In yet other embodiments, the alkyne moiety is an amino acid selected from the group consisting of L propargylglycine, D-propargylglycine, (S)-2-amino-2-methyl-4-pentynoic acid, (R)-2-amino-2 methyl-4-pentynoic acid, (S)-2-amino-2-methyl-5-hexynoic acid, (R)-2-amino-2-methyl-5 -49- WO 2013/123267 PCT/US2013/026241 hexynoic acid, (S)-2-amino-2-methyl-6-heptynoic acid, (R)-2-amino-2-methyl-6-heptynoic acid, (S)-2-amino-2-methyl-7-octynoic acid, (R)-2-amino-2-methyl-7-octynoic acid, (S)-2-amino-2 methyl-8-nonynoic acid and (R)-2-amino-2-methyl-8-nonynoic acid. [00124] In some embodiments, provided herein is a method for synthesizing a peptidomimetic macrocycle of Formula I, the method comprising the steps of contacting a peptidomimetic precursor of formulas: 0 0 [D]v/ [A]x-[B]y-[C]z'..- [E]w
R
1
L
1 L2 R 2 I 0 0 R7 RB [D]v N [A]x-[B]y-[C]z....... [E]w
R
1
L
1
L
2
R
2 U with a macrocyclization reagent; wherein v, w, x, y, z, A, B, C, D, E, R 1 , R 2 , R 7 , R 8 , LI and L 2 are as defined above; R 12 is -H when the macrocyclization reagent is a Cu reagent and R 12 is -H or alkyl when the macrocyclization reagent is a Ru reagent; and further wherein said contacting step results in a covalent linkage being formed between the alkyne and azide moiety in the precursor. For example, R1 2 may be methyl when the macrocyclization reagent is a Ru reagent. [00125] In some embodiments, provided herein is a method for synthesizing a peptidomimetic macrocycle of Formula II, the method comprising the steps of contacting a peptidomimetic precursor of formula:
R
7 0 R 8 0 [D NR [A]x-[B ]y-[Cz-N [E]w 1 [1 SH SH with a compound formula X-L 2 -Y, wherein v, w, x, y, z, A, B, C, D, E, R 1 , R 2 , R 7 , R 8 , Li and L 2 are as defined for the compound of formula II; and X and Y are each independently a reactive group capable of reacting with a thiol group; -50- WO 2013/123267 PCT/US2013/026241 and further wherein said contacting step results in a covalent linkage being formed between the two thiol groups in Formula III. [00126] In the peptidomimetic macrocycles disclosed herein, at least one of Ri and R 2 is alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-. In some embodiments, both R 1 and R 2 are independently alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-. In some embodiments, at least one of A, B, C, D or E is an a,a disubstituted amino acid. In one example, B is an a,-disubstituted amino acid. For instance, at least one of A, B, C, D or E is 2-aminoisobutyric acid. [00127] For example, at least one of R, and R 2 is alkyl, unsubstituted or substituted with halo-. In another example, both R, and R 2 are independently alkyl, unsubstituted or substituted with halo-. In some embodiments, at least one of R and R 2 is methyl. In other embodiments, R and R 2 are methyl. The macrocyclization reagent may be a Cu reagent or a Ru reagent. [00128] In some embodiments, the peptidomimetic precursor is purified prior to the contacting step. In other embodiments, the peptidomimetic macrocycle is purified after the contacting step. In still other embodiments, the peptidomimetic macrocycle is refolded after the contacting step. The method may be performed in solution, or, alternatively, the method may be performed on a solid support. [00129] Also envisioned herein is performing the method disclosed herein in the presence of a target macromolecule that binds to the peptidomimetic precursor or peptidomimetic macrocycle under conditions that favor said binding. In some embodiments, the method is performed in the presence of a target macromolecule that binds preferentially to the peptidomimetic precursor or peptidomimetic macrocycle under conditions that favor said binding. The method may also be applied to synthesize a library of peptidomimetic macrocycles. [00130] In some embodiments, an alkyne moiety of the peptidomimetic precursor for making a compound of Formula I is a sidechain of an amino acid selected from the group consisting of L propargylglycine, D-propargylglycine, (S)-2-amino-2-methyl-4-pentynoic acid, (R)-2-amino-2 methyl-4-pentynoic acid, (S)-2-amino-2-methyl-5-hexynoic acid, (R)-2-amino-2-methyl-5 hexynoic acid, (S)-2-amino-2-methyl-6-heptynoic acid, (R)-2-amino-2-methyl-6-heptynoic acid, (S)-2-amino-2-methyl-7-octynoic acid, (R)-2-amino-2-methyl-7-octynoic acid, (S)-2-amino-2 methyl-8-nonynoic acid, and (R)-2-amino-2-methyl-8-nonynoic acid. In other embodiments, an azide moiety of the peptidoniimetic precursor for making a compound of Formula I is a sidechain of an amino acid selected from the group consisting of s-azido-L-lysine, c-azido-D-lysine, a azido-a-methyl-L-lysine, s-azido-a -methyl-D-lysine, 6-azido-a-methyl-L-omithine, and 5-azido a -methyl-D-omithine. [00131] In some embodiments, a thiol group of the peptidomimetic precursor for making a compound of Formula II is a sidechain of an amino acid selected from the group consisting of L-cysteine, D -51- WO 2013/123267 PCT/US2013/026241 cysteine, L-N-methylcysteine, D-N-methylcysteine, L-homocysteine, D-homocysteine, L-N methylhomocysteine, D-N-methylhomocysteine, a-methyl-L-cysteine, a-methyl-D-cysteine, a methyl-L-homocysteine, a-methyl-D-homocysteine, L-penicillamine, D-penicillamine, L-N methylpenicillamine, D-N-methylpenicillamine and all forms suitably protected for liquid or solid phase peptide synthesis. [00132] In some embodiments, x+y+z is 3, and and A, B and C are independently natural or non-natural amino acids. In other embodiments, x+y+z is 6, and and A, B and C are independently natural or non-natural amino acids. [00133] In some embodiments, the contacting step is performed in a solvent selected from the group consisting of protic solvent, aqueous solvent, organic solvent, and mixtures thereof. For example, the solvent may be chosen from the group consisting of H 2 0, THF, THF/H 2 0, tBuOH/H 2 0, DMF, DIPEA, CH 3 CN or CH 2 Cl 2 , ClCH 2
CH
2 Cl or a mixture thereof. The solvent may be a solvent which favors helix formation. [00134] Alternative but equivalent protecting groups, leaving groups or reagents are substituted, and certain of the synthetic steps are performed in alternative sequences or orders to produce the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein include, for example, those such as described in Larock, Comprehensive Organic Transformations, VCH Publishers (1989); Greene and Wuts, Protective Groups in Organic Synthesis, 2d. Ed. , John Wiley and Sons (1991); Fieser and Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. [00135] The peptidomimetic macrocycles disclosed herein are made, for example, by chemical synthesis methods, such as described in Fields et al., Chapter 3 in Synthetic Peptides: A User's Guide, ed. Grant, W. H. Freeman & Co., New York, N. Y., 1992, p. 77. Hence, for example, peptides are synthesized using the automated Merrifield techniques of solid phase synthesis with the amine protected by either tBoc or Fmoc chemistry using side chain protected amino acids on, for example, an automated peptide synthesizer (e.g., Applied Biosystems (Foster City, CA), Model 430A, 431, or 433). [00136] One manner of producing the peptidomimetic precursors and peptidomimetic macrocycles described herein uses solid phase peptide synthesis (SPPS). The C-terminal amino acid is attached to a cross-linked polystyrene resin via an acid labile bond with a linker molecule. This resin is insoluble in the solvents used for synthesis, making it relatively simple and fast to wash away excess reagents and by-products. The N-terminus is protected with the Fmoc group, which is stable in acid, but removable by base. Side chain functional groups are protected as necessary with base stable, acid labile groups. -52- WO 2013/123267 PCT/US2013/026241 [00137] Longer peptidomimetic precursors are produced, for example, by conjoining individual synthetic peptides using native chemical ligation. Alternatively, the longer synthetic peptides are biosynthesized by well known recombinant DNA and protein expression techniques. Such techniques are provided in well-known standard manuals with detailed protocols. To construct a gene encoding a peptidomimetic precursor disclosed herein, the amino acid sequence is reverse translated to obtain a nucleic acid sequence encoding the amino acid sequence, preferably with codons that are optimum for the organism in which the gene is to be expressed. Next, a synthetic gene is made, typically by synthesizing oligonucleotides which encode the peptide and any regulatory elements, if necessary. The synthetic gene is inserted in a suitable cloning vector and transfected into a host cell. The peptide is then expressed under suitable conditions appropriate for the selected expression system and host. The peptide is purified and characterized by standard methods. [00138] The peptidomimetic precursors are made, for example, in a high-throughput, combinatorial fashion using, for example, a high-throughput polychannel combinatorial synthesizer (e.g., Thuramed TETRAS multichannel peptide synthesizer from CreoSalus, Louisville, KY or Model Apex 396 multichannel peptide synthesizer from AAPPTEC, Inc., Louisville, KY). [00139] The following synthetic schemes are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein. [00140] Synthetic schemes 1-5 describe the preparation of peptidomimetic macrocycles of Formula I. To simplify the drawings, the illustrative schemes depict azido amino acid analogs s-azido-a-methyl L-lysine and c-azido-a -methyl-D-lysine, and alkyne amino acid analogs L-propargylglycine, (S) 2-amino-2-methyl-4-pentynoic acid, and (S)-2-amino-2-methyl-6-heptynoic acid. Thus, in the following synthetic schemes, each R 1 , R 2 , R 7 and R 8 is -H; each L 1 is -(CH2) 4 -; and each L 2 is (CH 2 )-. However, as noted throughout the detailed description above, many other amino acid analogs can be employed in which R 1 , R 2 , R 7 , R 8 , L, and L 2 can be independently selected from the various structures disclosed herein. [00141] Synthetic Scheme 1: -53- WO 2013/123267 PCT/US2013/026241 N N 3 N o H N R I N N 1 R X = halogen N AN3 F mo = , CO H N0 N =HOH3H R=HHR R=H, CH 3 S-AA-Ni-BPB
N
3 N X=halogen N 3 INiF 0 R =HCH 3 / - 0 NH O 3 R =H, CH 3 R-AA-N -BPB N N rO X O N i N X = halogen NF N C A R. Fojc 0 0 H R =H, CH 3 S-AA-Ni-BPB HZ0 N R 0N R ANi N ~ X -halogen N F~ ~ N GC 2 H -/I / 0 R =HCH 3 0 H -- t O -OR =H, CH 3 R-AA-Nl-BPB [00142] Synthetic Scheme 1 describes the preparation of several compounds useful for preparing compounds of Formula I as disclosed herein. Ni(II) complexes of Schiff bases derived from the chiral auxiliary (S)-2-[N-(N'-benzylprolyl)amino]benzophenone (BPB) and amino acids such as glycine or alanine are prepared as described in Belokon et al. (1998), Tetrahedron Asymm. 9:4249-4252. The resulting complexes are subsequently reacted with alkylating reagents comprising an azido or alkynyl moiety to yield enantiomerically enriched compounds disclosed herein. If desired, the resulting compounds can be protected for use in peptide synthesis. [00143] Synthetic Scheme 2: -54- WO 2013/123267 PCT/US2013/026241
N
3 N 3 H3 H 3 C0 Fmqoc, Emoc-. N C0 2 H N CO 2 H H H 0 O N-al-Fmoc-C-a-methyl N-a-Fmoc-C--methyl H N E-azido-L-lysine E-azido-D-lysine [AA]n N [AA]f [AA]o S,S n R=HorMe F m c . HE o c .. , C H 3 N 3 N CO 2 H N CO 2 H H H N-a-Fmoc-L- N-a-Fmoc-(S)-2-amino- H 0 H 0 propargylglycine 2-methyl-4-pentynoic N N acid [AA]n [AAMh :-e[AA] 0 Zz R R R ~ r~ R,S n' R=HorMe N3 FmcN
CO
2 H FmNo
CO
2 H H H N-a-Fmoc-(S)-2-amino- N-a-Fmoc-(S)-2-amino- Deprotect 6-heptynoic acid 2-methyl-6-heptynoic & cleave from acid solid support 0 0 0 0 H H HH [AA]n [AA]m [AA] [AA]n [AA]N [AA]O S R R=HorMe S,S n R=HorMe N, N , N N 3 N Cu(1) H 0 H 0H 0 H 0 [AA]n [AA]m AAo [AA]N [AA]m [AA]o R R) R R,S_ n R=HorMe R R,S n R = H orMe N, -:.N
N
3 [00144] In the general method for the synthesis of peptidomimetic macrocycles of Formula I shown in Synthetic Scheme 2, the peptidomimetic precursor contains an azide moiety and an alkyne moiety and is synthesized by solution-phase or solid-phase peptide synthesis (SPPS) using the commercially available amino acid N-a-Fmoc-L-propargylglycine and the N-a-Fmoc-protected forms of the amino acids (S)-2-amino-2-methyl-4-pentynoic acid, (S)-2-amino-6-heptynoic acid, (S)-2-amino-2-methyl-6-heptynoic acid, N-methyl-a-azido-L-lysine, and N-methyl-a-azido-D lysine. The peptidomimetic precursor is then deprotected and cleaved from the solid-phase resin by standard conditions (e.g., strong acid such as 95% TFA). The peptidomimetic precursor is reacted as a crude mixture or is purified prior to reaction with a macrocyclization reagent such as a Cu(I) in organic or aqueous solutions (Rostovtsev et al. (2002), Angew. Chem. Int. Ed. 41:2596-2599; Tornoe et al. (2002), J. Org. Chem. 67:3057-3064; Deiters et al. (2003), J. Am. Chem. Soc. 125:11782-11783; Punna et al. (2005), Angew. Chem. Int. Ed. 44:2215-2220). In one embodiment, the triazole forming reaction is performed under conditions that favor a-helix -55- WO 2013/123267 PCT/US2013/026241 formation. In one embodiment, the macrocyclization step is performed in a solvent chosen from the group consisting of H 2 0, THF, CH 3 CN, DMF , DIPEA, tBuOH or a mixture thereof In another embodiment, the macrocyclization step is performed in DMF. In some embodiments, the macrocyclization step is performed in a buffered aqueous or partially aqueous solvent. [00145] Synthetic Scheme 3:
N
3 CH3 H3C QN3 FmocN
CO
2 H Fmo-N
CO
2 H H H N -a-F mo c-C-a -m ethyl N-a-Fmoc-C-c-methyl H [ s-az id o-L-lysine s-azido-D-lysine [AAL [A Aj [AA ]o SS n R = H or Me Fmo%.)CH Fmoc.C H 3 N CO 2 H N CO 2 H H H N-a-Fmoc-L- N-a-Fmoc-(S)-2-am ino- H O H O propaigylglycine 2-methyl-4-pentynoic [AA N -N % y % 4 r/ acid [ [AAjm - [AAJo N3 Fmoc- H Fmoc, COH3 N CO 2 H N CO 2 H H H N-L-Fmoc-(S)-2-amino- N-a-Fmoc-(S)-2-amino 6-heptynoic acid 2-methyl-6-heptynoic Cu (1) acid 0 0 HN N [AA]n r [AA r [AAJo [AA n N [AA] [AA R =H orMe n R= H or Me N Deprotect N. NN &cleavefrom solid support [AA]n N [AA I N A [AAJO [AA]n . [AA] [AAIo ,)[RAJn4fU%' [AAJo R R,S R R=H orMe R RS R R= H orMe N, N N N N N [00146] In the general method for the synthesis of peptidomimetic macrocycles of Formula I shown in Synthetic Scheme 3, the peptidomimetic precursor contains an azide moiety and an alkyne moiety and is synthesized by solid-phase peptide synthesis (SPPS) using the commercially available amino acid N-a-Fmoc-L-propargylglycine and the N-a-Fmoc-protected forms of the amino acids (S)-2-amino-2-methyl-4-pentynoic acid, (S)-2-amino-6-heptynoic acid, (S)-2-amino-2-methyl-6 heptynoic acid, N-methyl-s-azido-L-lysine, and N-methyl-s-azido-D-lysine. The peptidomimetic precursor is reacted with a macrocyclization reagent such as a Cu(I) reagent on the resin as a -56- WO 2013/123267 PCT/US2013/026241 crude mixture (Rostovtsev et al. (2002), Angew. Chem. Int. Ed. 41:2596-2599; Tomoe et al. (2002), J. Org. Chem. 67:3057-3064; Deiters et al. (2003), J. Am. Chem. Soc. 125:11782-11783; Punna et al. (2005), Angew. Chem. Int. Ed. 44:2215-2220). The resultant triazole-containing peptidomimetic macrocycle is then deprotected and cleaved from the solid-phase resin by standard conditions (e.g., strong acid such as 95% TFA). In some embodiments, the macrocyclization step is performed in a solvent chosen from the group consisting of CH 2 Cl 2 , ClCH 2
CH
2 Cl, DMF, THF, NMP, DIPEA, 2,6-lutidine, pyridine, DMSO, H 2 0 or a mixture thereof. In some embodiments, the macrocyclization step is performed in a buffered aqueous or partially aqueous solvent. [00147] Synthetic Scheme 4:
N
3 C, N 3
CH
3
H
3 C qmoc-. Emoc..X. N CO 2 H N CO 2 H H H O O N-a-Fmoc-C-a-methyl N-a-Fmoc-C-a-methyl N . s-azido-L-lysine e-azido-D-lysine [AA]n [AA] : [AA] R s,s n R=HorMe N3 moc..'H EmoPIDCH N CO 2 H N CO 2 H H H 00 N-a-Fmoc-L- N-a-Fmoc-(S)-2-amino- H H propargylglycine 2-methyl-4-pentynoic N N acid [AA]nA N [AA]O R m(ZR R,S n R=HorMe N3 Fmoc
CO
2 H FmoN
CO
2 H H H H 2 N-a-Fmoc-(S)-2-amino- N-cx-Fmoc-(S)-2-amino- Deprotect 6-heptynoic acid 2-methyl-6-heptynoic & cleave from acid solid support H 0 H 0 H 0 H 0 [AA]n _Nx _[AA]r - [AAl 0 [AA]n N -- [AA]r N-< [AA]O R (1 R R ()R Ro~ R R=HorMe S,S n R=HorMe N N, N..N Ru (II) H 0 H 0H 0H 0 [AA]n N [AA]m .N [AA] 0 [AA] N [AA]r< [AA]o R RS) R R In R R= HorMe R S n R=HorMe 1SN N3 NzN [00148] In the general method for the synthesis of peptidomimetic macrocycles of Formula I shown in Synthetic Scheme 4, the peptidomimetic precursor contains an azide moiety and an alkyne moiety and is synthesized by solution-phase or solid-phase peptide synthesis (SPPS) using the -57- WO 2013/123267 PCT/US2013/026241 commercially available amino acid N-a-Fmoc-L-propargylglycine and the N-a-Fmoc-protected forms of the amino acids (S)-2-amino-2-methyl-4-pentynoic acid, (S)-2-amino-6-heptynoic acid, (S)-2-amino-2-methyl-6-heptynoic acid, N-methyl-s-azido-L-lysine, and N-methyl-s-azido-D lysine. The peptidomimetic precursor is then deprotected and cleaved from the solid-phase resin by standard conditions (e.g., strong acid such as 95% TFA). The peptidomimetic precursor is reacted as a crude mixture or is purified prior to reaction with a macrocyclization reagent such as a Ru(II) reagents, for example Cp*RuCl(PPh 3
)
2 or [Cp*RuC] 4 (Rasmussen et al. (2007), Org. Lett. 9:5337-5339; Zhang et al. (2005), J. Am. Chem. Soc. 127:15998-15999). In some embodiments, the macrocyclization step is performed in a solvent chosen from the group consisting of DMF, CH 3 CN and THF. [00149] Synthetic Scheme 5:
N
3
N
3 CH3 H 3 C Fqmoc-. Fmoc. X N CO2H F N CO2H H H H 0 H 0 H H O N-a-Fmoc-C-a-methyl N--Fmoc-C-a-methyl N 0 c-azido-L-lysine s-azido-D-lysine [AA]n [AA] [AA] S,S n R=HorMe N CO2H FmocN CO2H SPS H H N-a-Fmoc-L- N-a-Fmoc-(S)-2-amino- H O H propargylglycine 2-methyl-4-pentynoic N N acid [AA]n [AA] [AA] R,S nR R=HorMe N3 Fmo. 'H Fmc C'H 3 N CO 2 H FmocsN CO 2 H H H N-a-Fmoc-(S)-2-amino- N-aT-Fmoc-(S)-2-amino 6-heptynoic acid 2-methyl-6-heptynoic Ru (II) acid H 0 0 H 00 [AA]nAA [AA] ,. [AA <-_[AA] n,S R R rn R R=HorMe NaNDe protect N-N N- & cleave from HH Osolid support H O H O [AA], kN [A] [AAJO [AA]n N [AA]m N AJ_ R R=HorMeR R, R = H or Me N-N N-N [00150] In the general method for the synthesis of peptidomimetic macrocycles of Formula I shown in Synthetic Scheme 5, the peptidomimetic precursor contains an azide moiety and an alkyne moiety and is synthesized by solid-phase peptide synthesis (SPPS) using the commercially available -58- WO 2013/123267 PCT/US2013/026241 amino acidN-a-Fmoc-L-propargylglycine and the N-a-Fmoc-protected forms of the amino acids (S)-2-amino-2-methyl-4-pentynoic acid, (S)-2-amino-6-heptynoic acid, (S)-2-amino-2-methyl-6 heptynoic acid, N-methyl-a-azido-L-lysine, and N-methyl-a-azido-D-lysine. The peptidomimetic precursor is reacted with a macrocyclization reagent such as a Ru(II) reagent on the resin as a crude mixture. For example, the reagent can be Cp*RuCl(PPh 3
)
2 or [Cp*RuCl] 4 (Rasmussen et al. (2007), Org. Lett. 9:5337-5339; Zhang et al. (2005), J. Am. Chem. Soc. 127:15998-15999). In some embodiments, the macrocyclization step is performed in a solvent chosen from the group consisting of CH 2 Cl 2 , ClCH 2
CH
2 Cl, CH 3 CN, DMF, and THF. [00151] In some embodiments, a peptidomimetic macrocycle of Formula I comprises a halogen group substitution on a triazole moiety, for example an iodo substitution. Such peptidomimetic macrocycles may be prepared from a precursor having the partial structure and using the cross linking methods taught herein. Crosslinkers of any length, as described herein, may be prepared comprising such substitutions. In one embodiment, the peptidomimetic macrocycle is prepared according to the scheme shown below. The reaction is peformed, for example, in the presence of CuI and an amine ligand such as TEA or TTTA. See, e.g., Hein et al. Angew. Chem., Int. Ed. 2009, 48, 8018-8021. [00152]
N
3 AA -AA 2
-AA
3
-AA
4
-AA
5
-AA
6 .. ___ N N N H 0H 0 N' N=N 1AA-AA 2
-AA
3
-AA
4
-AA
5
-AA
6 .-_ N H 0H 0 [00153] In other embodiments, an iodo-substituted triazole is generated according to the scheme shown below. For example, the second step in the reaction scheme below is performed using, for example, Cul and N-bromosuccinimide (NBS) in the presence of THF (see, e.g. Zhang et al., J. Org. Chem. 2008, 73, 3630-3633). In other embodiments, the second step in the reaction scheme shown below is performed, for example, using Cul and an iodinating agent such as ICl (see, e.g. Wu et al., Synthesis 2005, 1314- 1318.) -59- WO 2013/123267 PCT/US2013/026241 N3 AA -AA2-AA3-AA4-AAS;-AA6_ H 0H 0 0N N=N
AAI-AA
2
-AA
3
-AA
4
-AA
5
-AA
6 H 0H 0 N' N=N 'H AAl-AA 2
-AA
3
-AA
4
-AA
5
-AA
6 .. _ N H 0H 0 [00154] In some embodiments, an iodo-substituted triazole moiety is used in a cross-coupling reaction, such as a Suzuki or Sonogashira coupling, to afford a peptidomimetic macrocycle comprising a substituted crosslinker. Sonogashira couplings using an alkyne as shown below may be performed, for example, in the presence of a palladium catalyst such as Pd(PPh 3
)
2 Cl 2 , CuI, and in the presence of a base such as triethylamine. Suzuki couplings using an arylboronic or substituted alkenyl boronic acid as shown below may be performed, for example, in the presence of a catalyst such as Pd(PPh 3
)
4 , and in the presence of a base such as K 2
CO
3 . N N 1-AA 2 -AA3-AA 4
-AA
5
-M
6 _ N H 0H 0 R PH R / or Ar-B OH HO'B OH R R N N" 'N=N IN A 1 A 2 A 3 A A 4 A A , A A 6 O NA A -A A 2 -A A 3 -A A 4 -A A 5-A A 6 O H0H 0 H 0H 0 Ar N =N
AA
1
-AA
2
-AA
3
-AA
4
-AA
5
-AA
6
-
0 -6 0 H H 0 -60- WO 2013/123267 PCT/US2013/026241 [00155] Any suitable triazole substituent groups which reacts with the iodo-substituted triazole can be used in Suzuki couplings described herein. Example triazole substituents for use in Suzuki couplings are shown below: -(n , Aly )n Cy NRa Rb ,, A ky l - ' O H (}.CYC n n NN
R
0 0 0 R 0 0 AlkyCyc Ra - Ra nO -$ ) NRaR 'ycb "n wherein "Cyc" is a suitable aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with an R, or Rb group as described below. [00156] In some embodiments, the substituent is:
NH
2 1 [00157] Any suitable substituent group which reacts with the iodo-substituted triazole can be used in Sonogashira couplings described herein. Example triazole substituents for use in Sonogashira couplings are shown below: Ra nCyc nAlkyl OH N R NRaRb n n K'NRORb Ra 0 0 wherein "Cyc" is a suitable aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with an R. or Rb group as described below. [00158] In some embodiments, the triazole substituent is:
NH
2 [00159] In some embodiments, the Cyc group shown above is further substituted by at least one Ra or R substituent. In some embodiments, at least one of Ra and Rb is independently: 0 o 0 O 2 H Ra or Rb = H, OCH 3 , OF 3 , NH 2 , CH 2
NH
2 , F, Br, I -' OH, ONO 'NH n H 0 '20 N (4 NH2 n -61- WO 2013/123267 PCT/US2013/026241 0 - >4$NRRb [00160] In other embodiments, the triazole substituent is - and at least one of Ra and Rb is alkyl (including hydrogen, methyl, or ethyl), or: 0 [00161] The present invention contemplates the use of non-naturally-occurring amino acids and amino acid analogs in the synthesis of the peptidomimetic macrocycles of Formula I described herein. Any amino acid or amino acid analog amenable to the synthetic methods employed for the synthesis of stable triazole containing peptidomimetic macrocycles can be used in the present invention. For example, L-propargylglycine is contemplated as a useful amino acid in the present invention. However, other alkyne-containing amino acids that contain a different amino acid side chain are also useful in the invention. For example, L-propargylglycine contains one methylene unit between the a-carbon of the amino acid and the alkyne of the amino acid side chain. The invention also contemplates the use of amino acids with multiple methylene units between the a carbon and the alkyne. Also, the azido-analogs of amino acids L-lysine, D-lysine, alpha-methyl L-lysine, and alpha-methyl-D-lysine are contemplated as useful amino acids in the present invention. However, other terminal azide amino acids that contain a different amino acid side chain are also useful in the invention. For example, the azido-analog of L-lysine contains four methylene units between the a-carbon of the amino acid and the terminal azide of the amino acid side chain. The invention also contemplates the use of amino acids with fewer than or greater than four methylene units between the a-carbon and the terminal azide. The following Table 1 shows some amino acids useful in the preparation of peptidomimetic macrocycles disclosed herein. -62- WO 2013/123267 PCT/US2013/026241 TABLE 1 FmocsN
CO
2 H Fmoc N CO 2 H H H N-a-Fmoc-L-propargyl glycine N-a-Fmoc-D-propargyl glycine
N
3
N
3
H
3 C Fmoc' C Fmoc C2 N COH N C0 2 HH H H4H N-a-Fmoc-(S)-2-amino-2- N-a-Fmoc-(R)-2-amino-2- FmocsN CO2H FmocsN CO 2 H methyl-4-pentynoic acid methyl-4-pentynoic acid H H N-a-Fmoc-c-azido- N-a-Fmoc-E-azido L-lysine D-lysine CH3
H
3 C
N
3
N
3 Fmo. Fmoc-, " FmcN CO 2 H N C0 2 H H H N-a-Fmoc-(S)-2-amino-2- N-a-Fmoc-(R)-2-amino-2-
,CH
3
H
3 C, methyl-5-hexynoic acid methyl-5-hexynoic acid Fmoc N Fmo c, N CO2H N C02H H H - N-a-Fmoc-c-azido- N-a-Fmoc-s-azido a-methyl-L-lysine a-methyl-D-lysine FmoN C2H FmocsN CO 2 H N OHH H N 3
N
3 N-at-Fmoc-(S)-2-amino-2- N-ax-Fmoc-(R)-2-amino-2 methyl-6-heptynoic acid methyl-6-heptynoic acid Fo ,H FmocH Fmo COH N CO 2 H CH HH Fmoc, Fmoc-, N-a-Fmoc-6-azido- N-c-Fmoc-5-azido N CO 2 H N CO 2 H L-ornithine D-ornithine H H N-a-Fmoc-(S)-2-amino-2- N-a-Fmoc-(R)-2-amino-2 methyl-7-octynoic acid methyl-7-octynoic acid N 3 N 3
CH
3 H 3 C H3 H 3 C Fmoc 2H FmocN C2H FmocN FmocN CH H CO H H H N-a-Fmoc-e-azido- N-a-Fmoc-e-azido N--Fmoc-(S)-2-amino-2- N-a-Fmoc-(R)-2-amino-2- a-methyl-L- a-methyl-D methyl-8-nonynoic acid methyl-8-nonynoic acid ornithine ornithine Table 1 shows exemplary amino acids useful in the preparation of peptidomimetic macrocycles disclosed herein. [00162] In some embodiments the amino acids and amino acid analogs are of the D-configuration. In other embodiments they are of the L-configuration. In some embodiments, some of the amino acids and amino acid analogs contained in the peptidomimetic are of the D-configuration while some of the amino acids and amino acid analogs are of the L-configuration. In some embodiments the amino acid analogs are a,a-disubstituted, such as a-methyl-L-propargylglycine, a-methyl-D-propargylglycine, s-azido-alpha-methyl-L-lysine, and s-azido-alpha-methyl-D lysine. In some embodiments the amino acid analogs are N-alkylated, e.g., N-methyl-L -63- WO 2013/123267 PCT/US2013/026241 propargylglycine, N-methyl-D-propargylglycine, N-methyl-s-azido-L-lysine, and N-methyl-s azido-D-lysine. [00163] The preparation of macrocycles of Formula II is described, for example, in US Application 11/957,325, filed on December 17, 2007 and herein incorporated by reference. Synthetic Schemes 6-9 describe the preparation of such compounds of Formula II. To simplify the drawings, the illustrative schemes depict amino acid analogs derived from L-or D-cysteine, in which L, and L 3 are both -(CH 2 )-. However, as noted throughout the detailed description above, many other amino acid analogs can be employed in which L I and L 3 can be independently selected from the various structures disclosed herein. The symbols "[AA]m", "[AA],", "[AA]." represent a sequence of amide bond-linked moieties such as natural or unnatural amino acids. As described previously, each occurrence of "AA" is independent of any other occurrence of "AA", and a formula such as "[AA]m" encompasses, for example, sequences of non-identical amino acids as well as sequences of identical amino acids. Synthetic Scheme 6: -64- WO 2013/123267 PCT/US2013/026241 H 0 H solid [AA] N [AA]m N [AA] 0 Trt , TtRR S S S-Trt R,R S-Trt R = H or Me HC H STt R -r Fo Fmo c mo H,, 0 H 0soi N CO 2 H F N CO 2 H N N ppor H H [AA]n [AA] [AA] 0 R-1 S-1 SPPS Trt S,R S-Trt R = H or Me Trt s Trt H O H 0 solid S S N N 3 C [PH, A]l ' [AA]m .' [AA]O- Emoc. Fmoc. R R F N CO2H FmoN CO 2 H S-Trt RS S-Trt R= HorMe H H R-2 S-2 H 0 H 0 solid N N support [AA], [AA]m N [AA] 0 R R=HorMe S-Trt S,S S-Trt Deprotect & cleave from solid support H 0 H H 0
H
0 [AA] A N [AA]m [A]o [AAJn [AA]m [AA] 0 [AAln N [ NAAA] [AA]rA) A~ R R,R R=HorMe RR R=HorMe L2X-2 SH RR SH [AA]n [AAm [AA] 0 [AA]n [AA]m [AA] 0 R S, R=HorMe S R, SH R=HorMe H 0 H 0 H 0 0 N N _k[A-N N[A] [AA]n [AA]m [AA] [AA], [AA] [AA] ~R RS R SS R= HorMeS R ,S RS R= HorMe
H
0 H o 0
H
0 M R s s R R=orore S S SH S,S SH [00164] In Scheme 6, the peptidomimetic precursor contains two -SH moieties and is synthesized by solid-phase peptide synthesis (SPPS) using commercially available N-ax-Fmoc amino acids such as N-a-Fmoc-S-trityl-L-cysteine or N-a-Fmoc-S-trityl-D-cysteine. Aipha-methylated versions of D-cysteine or L-cysteine are generated by known methods (Seebach et al. (1996), Angew. Chiem. Int. Ed. Engl. 35:2708-2748, and references therein) and then converted to the appropriately protected N-a-Fmoc-S-trityl monomers by known methods ("Bioorganic Chemistry: Peptides and Proteins", Oxford University Press, New York: 1998, the entire contents of which are incorporated herein by reference). The precursor peptidomimetic is then deprotected and cleaved from the solid-phase resin by standard conditions (e.g., strong acid such as 95% IFA). The -65- WO 2013/123267 PCT/US2013/026241 precursor peptidomimetic is reacted as a crude mixture or is purified prior to reaction with X-L 2 Y in organic or aqueous solutions. In some embodiments the alkylation reaction is performed under dilute conditions (i.e. 0.15 mmol/L) to favor macrocyclization and to avoid polymerization. In some embodiments, the alkylation reaction is performed in organic solutions such as liquid
NH
3 (Mosberg et al. (1985), J. Am.Chem. Soc. 107:2986-2987; Szewczuk et al. (1992), Int. J. Peptide Protein Res. 40 :233-242), NH 3 /MeOH, or NH 3 /DMF (Or et al. (1991), J. Org. Chem. 56:3146-3149). In other embodiments, the alkylation is performed in an aqueous solution such as 6M guanidinium HCL, pH 8 (Brunel et al. (2005), Chem. Commun. (20):2552-2554). In other embodiments, the solvent used for the alkylation reaction is DMF or dichloroethane. Synthetic Scheme 7: H H solid [AMit[AA [AA] [AA] 0 Mmt s MmtRR S S Mt R,R R= H orMe SMHn HS-Mit Emc K Finoc. H 0 H 0solII d N 0 2 H F N CO 2 H N Npor H H [AA]n [AA]m [AA] 0 R-1 S-1 SPPS R R R = H or Me S-Mint S,R S-Mint Mmt S Mmt H H solid S S N N suppor 'C H 3
H
3 C [AA]N [AA] [AA]o Emoc. K Fno R R N C0 2 H F N CO 2 H S-Mmt RS S-Mmt R = H or Me H H R-2 S-2 H H solid N N support [AA] [AA] N [AA]o R R R=HorMe S-Mmt SS S-Mmt Deprotect R-S-Mmt H 0 H H 0 H solid N r N NN5U [AA]n [AA]N [AA]o [AAJn [AA]m [AAJ 0 R, R R Hre R -R SRR S RR SH RR R=HorMe
S-L
2 - SH H H 0 H 0 O solid N N _ k[A.Nr_ [AA]n N [AA]N [AA], [AA] [AA] [AA] t S S,R R=HorMe R HR R=Hor Me L2 1. X-L 2 -Y SH SR SH 0 O.O O solid H H H 0 H 0 [A.N N 2. Deprotect NN ~ spo [AA] N [AA] other Act[AA]n [AA]_ [AA] 0 R R,S R & cleavage R ('R 2 R=HorMe SH RS SH R=HorMe H 0 H 0 solid N k N [A] .
NMN
4 [AA]nN [AA]i [AA]o [AA]n [AA] [AA]or R SS R R = H orMe R R R=oe L S R SH S,S SH
L
2 -66- WO 2013/123267 PCT/US2013/026241 [00165] In Scheme 7, the precursor peptidomimetic contains two or more -SH moieties, of which two are specially protected to allow their selective deprotection and subsequent alkylation for macrocycle formation. The precursor peptidomimetic is synthesized by solid-phase peptide synthesis (SPPS) using commercially available N-a-Fmoc amino acids such as N-a-Fmoc-S-p-methoxytrityl-L cysteine or N-a-Fmoc-S-p-methoxytrityl-D-cysteine. Alpha-methylated versions of D-cysteine or L-cysteine are generated by known methods (Seebach et al. (1996), Angew. Chem. Int. Ed. Engl. 35:2708-2748, and references therein) and then converted to the appropriately protected N-a Fmoc-S-p-methoxytrityl monomers by known methods (Bioorganic Chemistry: Peptides and Proteins, Oxford University Press, New York: 1998, the entire contents of which are incorporated herein by reference). The Mmt protecting groups of the peptidomimetic precursor are then selectively cleaved by standard conditions (e.g., mild acid such as 1% TFA in DCM). The precursor peptidomimetic is then reacted on the resin with X-L 2 -Y in an organic solution. For example, the reaction takes place in the presence of a hindered base such as diisopropylethylamine. In some embodiments, the alkylation reaction is performed in organic solutions such as liquid NH 3 (Mosberg et al. (1985), J Am. Chem. Soc. 107:2986-2987; Szewczuk et al. (1992), Int. J. Peptide Protein Res. 40 :233-242), NH 3 /MeOH or NH 3 /DMF (Or et al. (1991), J. Org. Chem. 56:3146-3149). In other embodiments, the alkylation reaction is performed in DMF or dichloroethane. The peptidomimetic macrocycle is then deprotected and cleaved from the solid-phase resin by standard conditions (e.g., strong acid such as 95% TFA). Synthetic Scheme 8: -67- WO 2013/123267 PCT/US2013/026241 Mmt SI S S S H F 1 H 0soi Emoc> Fmoc [AA], N AA N SUA N 0 2 H FmocCN 0C 2 H m H H R R R-3 R-4 S-Mmt R,R S-S-tBu R = H or Me R=HorMe Deprotect R-S-S-tBu H H solid N_ N supo0 H s olid [PA], j [Am [AA] 0 - X-L 2 -Y N _N SUPPO [ A R NR [ [AA] [AA]m [AA] S-Mmt S R = H or Me S-Mmt R,R S R=HorMe X-L2 1. Deprotect R-S-Mmt 2. Cyclize H O H O solid Cleave& H O H 0 N N suppor deprotect N N [AA], - [A~ [AA], A~ A~ R R R R R, R R,R , S L2 S R=HorMe S RL2 S R=HorMe [00166] In Scheme 8, the peptidomimetic precursor contains two or more -SH moieties, of which two are specially protected to allow their selective deprotection and subsequent alkylation for macrocycle formation. The peptidomimetic precursor is synthesized by solid-phase peptide synthesis (SPPS) using commercially available N-a-Fmoc amino acids such as N-a-Fmoc-S-p-methoxytrityl-L cysteine, N-a-Fmoc-S-p-methoxytrityl-D-cysteine, N-a-Fmoc-S-S-t-butyl-L-cysteine, and N-a Fmoc-S-S-t-butyl-D-cysteine. Alpha-methylated versions of D-cysteine or L-cysteine are generated by known methods (Seebach et al. (1996), Angew. Chem. Int. Ed. Engl. 35:2708-2748, and references therein) and then converted to the appropriately protected N-a-Fmoc-S-p methoxytrityl or N-a-Fmoc-S-S-t-butyl monomers by known methods (Bioorganic Chemistry: Peptides and Proteins, Oxford University Press, New York: 1998, the entire contents of which are incorporated herein by reference). The S-S-tButyl protecting group of the peptidomimetic precursor is selectively cleaved by known conditions (e.g., 20% 2-mercaptoethanol in DMF, reference: Galande et al. (2005), J. Comb. Chem. 7:174-177). The precursor peptidomimetic is then reacted on the resin with a molar excess of X-L 2 -Y in an organic solution. For example, the reaction takes place in the presence of a hindered base such as diisopropylethylamine. The Mint protecting group of the peptidomimetic precursor is then selectively cleaved by standard conditions (e.g., mild acid such as 1% TFA in DCM). The peptidomimetic precursor is then cyclized on the resin by treatment with a hindered base in organic solutions. In some -68- WO 2013/123267 PCT/US2013/026241 embodiments, the alkylation reaction is performed in organic solutions such as NH 3 /MeOH or
NH
3 /DMF (Or et at. (1991), J. Org. Chem. 56:3146-3149). The peptidomimetic macrocycle is then deprotected and cleaved from the solid-phase resin by standard conditions (e.g., strong acid such as 95% TFA). Synthetic Scheme 9: 1. Biological H O H O H 0 H O synthesis N [A[Ar N X-L 2 -Y N N [A] of peptide -- i [~AA A] ~ [,AA] 0 [AA[A], N 2. Purification H H H R,R H of peptide SH RR SH S L2 S [00167] In Scheme 9, the peptidomimetic precursor contains two L-cysteine moieties. The peptidomimetic precursor is synthesized by known biological expression systems in living cells or by known in vitro, cell-free, expression methods. The precursor peptidomimetic is reacted as a crude mixture or is purified prior to reaction with X-L2-Y in organic or aqueous solutions. In some embodiments the alkylation reaction is performed under dilute conditions (i.e. 0.15 mmol/L) to favor macrocyclization and to avoid polymerization. In some embodiments, the alkylation reaction is performed in organic solutions such as liquid NH 3 (Mosberg et al. (1985), J. Am.Chem. Soc. 107:2986-2987; Szewczuk et al. (1992), Int. J. Peptide Protein Res. 40 :233 242), NH 3 /MeOH, or NH 3 /DMF (Or et al. (1991), J. Org. Chem. 56:3146-3149). In other embodiments, the alkylation is performed in an aqueous solution such as 6M guanidinium HCL, pH 8 (Brunel et al. (2005), Chem. Commun. (20):2552-2554). In other embodiments, the alkylation is performed in DMF or dichloroethane. In another embodiment, the alkylation is performed in non-denaturing aqueous solutions, and in yet another embodiment the alkylation is performed under conditions that favor a-helical structure formation. In yet another embodiment, the alkylation is performed under conditions that favor the binding of the precursor peptidomimetic to another protein, so as to induce the formation of the bound a-helical conformation during the alkylation. [00168] Various embodiments for X and Y are envisioned which are suitable for reacting with thiol groups. In general, each X or Y is independently be selected from the general category shown in Table 2. For example, X and Y are halides such as -Cl, -Br or -I. Any of the macrocycle forming linkers described herein may be used in any combination with any of the sequences shown and also with any of the R- substituents indicated herein. TABLE 2: Examples of Reactive Groups Capable of Reacting with Thiol Groups and Resulting Linkages X or Y Resulting Covalent Linkage acrylamide Thioether halide (e.g. alkyl or aryl Thioether halide) sulfonate Thioether -69- WO 2013/123267 PCT/US2013/026241 TABLE 2: Examples of Reactive Groups Capable of Reacting with Thiol Groups and Resulting Linkages X or Y Resulting Covalent Linkage aziridine Thioether epoxide Thioether haloacetamide Thioether maleimide Thioether sulfonate ester Thioether [00169] The present invention contemplates the use of both naturally-occurring and non-naturally occurring amino acids and amino acid analogs in the synthesis of the peptidomimetic macrocycles of Formula II. Any amino acid or amino acid analog amenable to the synthetic methods employed for the synthesis of stable bis-sulfhydryl containing peptidomimetic macrocycles can be used in the present invention. For example, cysteine is contemplated as a useful amino acid in the present invention. However, sulfur containing amino acids other than cysteine that contain a different amino acid side chain are also useful. For example, cysteine contains one methylene unit between the a-carbon of the amino acid and the terminal -SH of the amino acid side chain. The invention also contemplates the use of amino acids with multiple methylene units between the a-carbon and the terminal -SH. Non-limiting examples include a methyl-L-homocysteine and a-methyl-D-homocysteine. In some embodiments the amino acids and amino acid analogs are of the D- configuration. In other embodiments they are of the L configuration. In some embodiments, some of the amino acids and amino acid analogs contained in the peptidomimetic are of the D- configuration while some of the amino acids and amino acid analogs are of the L- configuration. In some embodiments the amino acid analogs are a,a disubstituted, such as a-methyl-L-cysteine and a-methyl-D-cysteine. [00170] The invention includes macrocycles in which macrocycle-forming linkers are used to link two or more -SH moieties in the peptidomimetic precursors to form the peptidomimetic macrocycles disclosed herein. As described above, the macrocycle-forming linkers impart conformational rigidity, increased metabolic stability and/or increased cell penetrability. Furthermore, in some embodiments, the macrocycle-forming linkages stabilize the a-helical secondary structure of the peptidomimetic macrocyles. The macrocycle-forming linkers are of the formula X-L 2 -Y, wherein both X and Y are the same or different moieties, as defined above. Both X and Y have the chemical characteristics that allow one macrocycle-forming linker -L 2 - to bis alkylate the bis sulfhydryl containing peptidomimetic precursor. As defined above, the linker -L 2 - includes alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, or heterocycloarylene, or -R 1 -K-1h-, all of which can be optionally substituted with an R 5 group, as defined above. Furthermore, one to three carbon atoms within the macrocycle-forming linkers -L 2 -, other than the carbons attached to the -SH of the sulfhydryl containing amino acid, are optionally substituted with a heteroatom such as N, S or 0. -70- WO 2013/123267 PCT/US2013/026241 [00171] The L 2 component of the macrocycle-forming linker X-L 2 -Y may be varied in length depending on, among other things, the distance between the positions of the two amino acid analogs used to form the peptidomimetic macrocycle. Furthermore, as the lengths of L 1 and/or L 3 components of the macrocycle-forming linker are varied, the length of L 2 can also be varied in order to create a linker of appropriate overall length for forming a stable peptidomimetic macrocycle. For example, if the amino acid analogs used are varied by adding an additional methylene unit to each of L 1 and L 3 , the length of L 2 are decreased in length by the equivalent of approximately two methylene units to compensate for the increased lengths of L I and L 3 . [00172] In some embodiments, L 2 is an alkylene group of the formula -(CH2)n-, where n is an integer between about I and about 15. For example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In other embodiments, L 2 is an alkenylene group. In still other embodiments, L 2 is an aryl group. [00173] Table 3 shows additional embodiments of X-L 2 -Y groups. -71- WO 2013/123267 PCT/US2013/026241 TABLE 3. Exemplary X-L 2 -Y groups. x x y x O Y x' x o x x Y x' O Y X X xY S -- Y X H X Y X N y XY o | y x N Y X Y X OY X y 0 x x o xY 0 x 0 --- 0 Y Br Br CI CI Br C I Br Br CI CI I I Br-Br CI CI Br CC: C C N Br CI Nz B- Br a C I BrrCB Br CI BrBr B BBr NNN N Brr BEB Bph Bpy Each X and Y in this table, is, for example, independently Cl-, Br- or I-. [00174] Additional methods of forming peptidomimetic macrocycles which are envisioned as suitable include those disclosed by Mustapa, M. Firouz Mohd et al., J. Org. Chem (2003), 68, pp. 8193 8198; Yang, Bin et al. Bioorg Med. Chem. Lett. (2004), 14, pp. 1403-1406; U.S. Patent No. -72- WO 2013/123267 PCT/US2013/026241 5,364,851; U.S. Patent No. 5,446,128; U.S. Patent No. 5,824,483; U.S. Patent No. 6,713,280; and U.S. Patent No. 7,202,332. In such embodiments, aminoacid precursors are used containing an additional substituent R- at the alpha position. Such aminoacids are incorporated into the macrocycle precursor at the desired positions, which can be at the positions where the crosslinker is substituted or, alternatively, elsewhere in the sequence of the macrocycle precursor. Cyclization of the precursor is then effected according to the indicated method. [00175] In some embodiments, the -NH moiety of the amino acid is protected using a protecting group, including without limitation -Fmoc and -Boc. In other embodiments, the amino acid is not protected prior to synthesis of the peptidomimetic macrocycle. Assays [00176] The properties of peptidomimetic macrocycles are assayed, for example, by using the methods described below. In some embodiments, a peptidomimetic macrocycle has improved biological properties relative to a corresponding polypeptide lacking the substituents described herein. Assay to Determine a-helicity [00177] In solution, the secondary structure of polypeptides with a-helical domains will reach a dynamic equilibrium between random coil structures and a-helical structures, often expressed as a "percent helicity". Thus, for example, alpha-helical domains are predominantly random coils in solution, with a-helical content usually under 25%. Peptidomimetic macrocycles with optimized linkers, on the other hand, possess, for example, an alpha-helicity that is at least two-fold greater than that of a corresponding uncrosslinked polypeptide. In some embodiments, macrocycles will possess an alpha-helicity of greater than 50%. To assay the helicity of peptidomimetic macrocyles, the compounds are dissolved in an aqueous solution (e.g. 50 mM potassium phosphate solution at pH 7, or distilled H 2 0, to concentrations of 25-50 pM). Circular dichroism (CD) spectra are obtained on a spectropolarimeter (e.g., Jasco J-710) using standard measurement parameters (e.g. temperature, 20'C; wavelength, 190-260 nm; step resolution, 0.5 nm; speed, 20 nm/sec; accumulations, 10; response, 1 see; bandwidth, 1 nm; path length, 0.1 cm). The a-helical content of each peptide is calculated by dividing the mean residue ellipticity (e.g. [qD]222obs) by the reported value for a model helical decapeptide (Yang et al. (1986), Methods Enzymol. 130:208)). Assay to Determine Meltine Temperature (Tm). [00178] A peptidomimetic macrocycle comprising a secondary structure such as an a-helix exhibits, for example, a higher melting temperature than a corresponding uncrosslinked polypeptide. Typically peptidomimetic macrocycles exhibit Tm of > 60 0 C representing a highly stable structure in aqueous solutions. To assay the effect of macrocycle formation on melting temperature, peptidomimetic macrocycles or unmodified peptides are dissolved in distilled H 2 0 (e.g. at a final concentration of 50 gM) and the Tm is determined by measuring the change in ellipticity over a -73- WO 2013/123267 PCT/US2013/026241 temperature range (e.g. 4 to 95 C) on a spectropolarimeter (e.g., Jasco J-710) using standard parameters (e.g. wavelength 222nm; step resolution, 0.5 nm; speed, 20 nm/sec; accumulations, 10; response, 1 see; bandwidth, 1 nm; temperature increase rate: 1WC/min; path length, 0.1 cm). Protease Resistance Assay. [00179] The amide bond of the peptide backbone is susceptible to hydrolysis by proteases, thereby rendering peptidic compounds vulnerable to rapid degradation in vivo. Peptide helix formation, however, typically buries the amide backbone and therefore can shield it from proteolytic cleavage. The peptidomimetic macrocycles can be subjected to in vitro trypsin proteolysis to assess for any change in degradation rate compared to a corresponding uncrosslinked polypeptide. For example, the peptidomimetic macrocycle and a corresponding uncrosslinked polypeptide are incubated with trypsin agarose and the reactions quenched at various time points by centrifugation and subsequent HPLC injection to quantitate the residual substrate by ultraviolet absorption at 280 nm. Briefly, the peptidomimetic macrocycle and peptidomimetic precursor (5 meg) are incubated with trypsin agarose (Pierce) (S/E -125) for 0, 10, 20, 90, and 180 minutes. Reactions are quenched by tabletop centrifugation at high speed; remaining substrate in the isolated supernatant is quantified by HPLC-based peak detection at 280 nm. The proteolytic reaction displays first order kinetics and the rate constant, k, is determined from a plot of In[S] versus time (k=-lXslope). Ex Vivo Stability Assay. [00180] Peptidomimetic macrocycles with optimized linkers possess, for example, an ex vivo half-life that is at least two-fold greater than that of a corresponding uncrosslinked polypeptide, and possess an ex vivo half-life of 12 hours or more. For ex vivo serum stability studies, a variety of assays can be used. For example, a peptidomimetic macrocycle and a corresponding uncrosslinked polypeptide (2 meg) are incubated with fresh mouse, rat and/or human serum (2 mL) at 37 0 C for 0, 1, 2, 4, 8, and 24 hours. To determine the level of intact compound, the following procedure can be used: The samples are extracted by transferring 100 gl of sera to 2 ml centrifuge tubes followed by the addition of 10 gL of 50 % formic acid and 500gL acetonitrile and centrifugation at 14,000 RPM for 10 min at 4 ± 2 0 C. The supernatants are then transferred to fresh 2 ml tubes and evaporated on Turbovap under N 2 < 10 psi, 37 0 C. The samples are reconstituted in 100gL of 50:50 acetonitrile:water and submitted to LC-MS/MS analysis. In vitro Binding Assays. [00181] To assess the binding and affinity of peptidomimetic macrocycles and peptidomimetic precursors to acceptor proteins, a fluorescence polarization assay (FPA) isused, for example. The FPA technique measures the molecular orientation and mobility using polarized light and fluorescent tracer. When excited with polarized light, fluorescent tracers (e.g., FITC) attached to molecules with high apparent molecular weights (e.g. FITC-labeled peptides bound to a large protein) emit -74- WO 2013/123267 PCT/US2013/026241 higher levels of polarized fluorescence due to their slower rates of rotation as compared to fluorescent tracers attached to smaller molecules (e.g. FITC- labeled peptides that are free in solution). [00182] For example, fluoresceinated peptidomimetic macrocycles (25 nM) are incubated with the acceptor protein (25- 10OOnM) in binding buffer (140mM NaCl, 50 mM Tris-HCL, pH 7.4) for 30 minutes at room temperature. Binding activity is measured, for example, by fluorescence polarization on a luminescence spectrophotometer (e.g. Perkin-Elmer LS50B). Kd values can be determined by nonlinear regression analysis using, for example, Graphpad Prism software (GraphPad Software, Inc., San Diego, CA). A peptidomimetic macrocycle shows, In some embodiments, similar or lower Kd than a corresponding uncrosslinked polypeptide. In vitro Displacement Assays To Characterize Antagonists of Peptide-Protein Interactions. [00183] To assess the binding and affinity of compounds that antagonize the interaction between a peptide and an acceptor protein, a fluorescence polarization assay (FPA) utilizing a fluoresceinated peptidomimetic macrocycle derived from a peptidomimetic precursor sequence is used, for example. The FPA technique measures the molecular orientation and mobility using polarized light and fluorescent tracer. When excited with polarized light, fluorescent tracers (e.g., FITC) attached to molecules with high apparent molecular weights (e.g. FITC-labeled peptides bound to a large protein) emit higher levels of polarized fluorescence due to their slower rates of rotation as compared to fluorescent tracers attached to smaller molecules (e.g. FITC-labeled peptides that are free in solution). A compound that antagonizes the interaction between the fluoresceinated peptidomimetic macrocycle and an acceptor protein will be detected in a competitive binding FPA experiment. [00184] For example, putative antagonist compounds (1 nM to 1 mM) and a fluoresceinated peptidomimetic macrocycle (25 nM) are incubated with the acceptor protein (50 nM) in binding buffer (140mM NaCl, 50 mM Tris-HCL, pH 7.4) for 30 minutes at room temperature. Antagonist binding activity is measured, for example, by fluorescence polarization on a luminescence spectrophotometer (e.g. Perkin-Elmer LS50B). Kd values can be determined by nonlinear regression analysis using, for example, Graphpad Prism software (GraphPad Software, Inc., San Diego, CA). [00185] Any class of molecule, such as small organic molecules, peptides, oligonucleotides or proteins can be examined as putative antagonists in this assay. Assay for Protein-ligand binding by Affinity Selection-Mass Spectrometrv [00186] To assess the binding and affinity of test compounds for proteins, an affinity-selection mass spectrometry assay is used, for example. Protein-ligand binding experiments are conducted according to the following representative procedure outlined for a system-wide control experiment using 1 gM peptidomimetic macrocycle plus 5 gM hMDM2. A 1 gL DMSO aliquot -75- WO 2013/123267 PCT/US2013/026241 of a 40 gM stock solution of peptidomimetic macrocycle is dissolved in 19 gL of PBS (Phosphate-buffered saline: 50 mM, pH 7.5 Phosphate buffer containing 150 mM NaCl). The resulting solution is mixed by repeated pipetting and clarified by centrifugation at 10 000g for 10 min. To a 4 gL aliquot of the resulting supernatant is added 4 gL of 10 gM hMDM2 in PBS. Each 8.0 pL experimental sample thus contains 40 pmol (1.5 gg) of protein at 5.0 gM concentration in PBS plus 1 gM peptidomimetic macrocycle and 2.5% DMSO. Duplicate samples thus prepared for each concentration point are incubated for 60 min at room temperature, and then chilled to 4 'C prior to size-exclusion chromatography-LC-MS analysis of 5.0 pL injections. Samples containing a target protein, protein-ligand complexes, and unbound compounds are injected onto an SEC column, where the complexes are separated from non binding component by a rapid SEC step. The SEC column eluate is monitored using UV detectors to confirm that the early-eluting protein fraction, which elutes in the void volume of the SEC column, is well resolved from unbound components that are retained on the column. After the peak containing the protein and protein-ligand complexes elutes from the primary UV detector, it enters a sample loop where it is excised from the flow stream of the SEC stage and transferred directly to the LC-MS via a valving mechanism. The (M + 3H) 3 ' ion of the peptidomimetic macrocycle is observed by ESI-MS at the expected m/z, confirming the detection of the protein ligand complex. Assay for Protein-ligand Kd Titration Experiments. [00187] To assess the binding and affinity of test compounds for proteins, a protein-ligand Kd titration experiment is performed, for example. Protein-ligand KAd titrations experiments are conducted as follows: 2 gL DMSO aliquots of a serially diluted stock solution of titrant peptidomimetic macrocycle (5, 2.5, ..., 0.098 mM) are prepared then dissolved in 38 gL of PBS. The resulting solutions are mixed by repeated pipetting and clarified by centrifugation at 10 000g for 10 min. To 4.0 pL aliquots of the resulting supernatants is added 4.0 gL of 10 gM hMDM2 in PBS. Each 8.0 gL experimental sample thus contains 40 pmol (1.5 gg) of protein at 5.0 [M concentration in PBS, varying concentrations (125, 62.5, ..., 0.24 pM) of the titrant peptide, and 2.5% DMSO. Duplicate samples thus prepared for each concentration point are incubated at room temperature for 30 min, then chilled to 4 'C prior to SEC-LC-MS analysis of 2.0 gL injections. The (M + H)' , (M + 2H)t , (M + 3H)3 , and/or (M + Na)'+ ion is observed by ESI-MS; extracted ion chromatograms are quantified, then fit to equations to derive the binding affinity Kd as described in "A General Technique to Rank Protein-Ligand Binding Affinities and Determine Allosteric vs. Direct Binding Site Competition in Compound Mixtures." Annis, D. A.; Nazef, N.; Chuang, C. C.; Scott, M. P.; Nash, H. M. J. Am. Chem. Soc. 2004, 126, 15495-15503; also in "ALIS: An Affinity Selection-Mass Spectrometry System for the Discovery and Characterization of Protein Ligand Interactions" D. A. Annis, C.-C. Chuang, and N. Nazef. In Mass Spectrometry in -76- WO 2013/123267 PCT/US2013/026241 Medicinal Chemistry. Edited by Wanner K, H6fner G: Wiley-VCH; 2007:121-184. Mannhold R, Kubinyi H, Folkers G (Series Editors): Methods and Principles in Medicinal Chemistry. Assay for Competitive Binding Experiments by Affinity Selection-Mass Spectrometry [00188] To determine the ability of test compounds to bind competitively to proteins, an affinity selection mass spectrometry assay is performed, for example. A mixture of ligands at 40 RM per component is prepared by combining 2 jiL aliquots of 400 gM stocks of each of the three compounds with 14 ptL of DMSO. Then, 1 jiL aliquots of this 40 jiM per component mixture are combined with 1 jL DMSO aliquots of a serially diluted stock solution of titrant peptidomimetic macrocycle (10, 5, 2.5, ..., 0.078 mM). These 2 [iL samples are dissolved in 38 jiL of PBS. The resulting solutions were mixed by repeated pipetting and clarified by centrifugation at 10 000g for 10 min. To 4.0 jiL aliquots of the resulting supernatants is added 4.0 pL of 10 [LM hMDM2 protein in PBS. Each 8.0 jiL experimental sample thus contains 40 pmol (1.5 jg) of protein at 5.0 [iM concentration in PBS plus 0.5 jiM ligand, 2.5% DMSO, and varying concentrations (125, 62.5, ..., 0.98 piM) of the titrant peptidomimetic macrocycle. Duplicate samples thus prepared for each concentration point are incubated at room temperature for 60 min, then chilled to 4 'C prior to SEC-LC-MS analysis of 2.0 jL injections. Additional details on these and other methods are provided in "A General Technique to Rank Protein-Ligand Binding Affinities and Determine Allosteric vs. Direct Binding Site Competition in Compound Mixtures." Annis, D. A.; Nazef, N.; Chuang, C. C.; Scott, M. P.; Nash, H. M. J. Am. Chem. Soc. 2004, 126, 15495-15503; also in "ALIS: An Affinity Selection-Mass Spectrometry System for the Discovery and Characterization ofProtein-Ligand Interactions" D. A. Annis, C.-C. Chuang, and N. Nazef. In Mass Spectrometry in Medicinal Chemistry. Edited by Wanner K, Hdfner G: Wiley-VCH; 2007:121-184. Mannhold R, Kubinyi H, Folkers G (Series Editors): Methods and Principles in Medicinal Chemistry. Binding Assays in Intact Cells. [00189] It is possible to measure binding of peptides or peptidomimetic macrocycles to their natural acceptors in intact cells by immunoprecipitation experiments. For example, intact cells are incubated with fluoresceinated (FITC-labeled) compounds for 4 hrs in the absence of serum, followed by serum replacement and further incubation that ranges from 4-18 hrs. Cells are then pelleted and incubated in lysis buffer (50mM Tris [H 7.6], 150 mM NaCl, 1% CHAPS and protease inhibitor cocktail) for 10 minutes at 4C. Extracts are centrifuged at 14,000 rpm for 15 minutes and supernatants collected and incubated with 10 jil goat anti-FIT C antibody for 2 hrs, rotating at 4 0 C followed by further 2 hrs incubation at 4 0 C with protein A/G Sepharose (50 l of 50% bead slurry). After quick centrifugation, the pellets are washed in lysis buffer containing increasing salt concentration (e.g., 150, 300, 500 mM). The beads are then re-equilibrated at 150 mM NaCl before addition of SDS-containing sample buffer and boiling. After centrifugation, the supernatants are optionally electrophoresed using 4%-12% gradient Bis-Tris gels followed by -77- WO 2013/123267 PCT/US2013/026241 transfer into Immobilon-P membranes. After blocking, blots are optionally incubated with an antibody that detects FITC and also with one or more antibodies that detect proteins that bind to the peptidomimetic macrocycle. Cellular Penetrability Assays. [00190] A peptidomimetic macrocycle is, for example, more cell penetrable compared to a corresponding uncrosslinked macrocycle. Peptidomimetic macrocycles with optimized linkers possess, for example, cell penetrability that is at least two-fold greater than a corresponding uncrosslinked macrocycle, and often 20% or more of the applied peptidomimetic macrocycle will be observed to have penetrated the cell after 4 hours. To measure the cell penetrability of peptidomimetic macrocycles and corresponding uncrosslinked macrocycle, intact cells are incubated with fluorescently-labeled (e.g. fluoresceinated) peptidomimetic macrocycles or corresponding uncrosslinked macrocycle (10 gM) for 4 hrs in serum free media at 37 0 C, washed twice with media and incubated with trypsin (0.25%) for 10 min at 37 0 C. The cells are washed again and resuspended in PBS. Cellular fluorescence is analyzed, for example, by using either a FACSCalibur flow cytometer or Cellomics' KineticScan @ HCS Reader. Cellular Efficacy Assays. [00191] The efficacy of certain peptidomimetic macrocycles is determined, for example, in cell-based killing assays using a variety of tumorigenic and non-tumorigenic cell lines and primary cells derived from human or mouse cell populations. Cell viability is monitored, for example, over 24 96 hrs of incubation with peptidomimetic macrocycles (0.5 to 50 RM) to identify those that kill at
EC
5 0 <10 pM. Several standard assays that measure cell viability are commercially available and are optionally used to assess the efficacy of the peptidomimetic macrocycles. In addition, assays that measure Annexin V and caspase activation are optionally used to assess whether the peptidomimetic macrocycles kill cells by activating the apoptotic machinery. For example, the Cell Titer-glo assay is used which determines cell viability as a function of intracellular ATP concentration. In Vivo Stability Assay. [00192] To investigate the in vivo stability of the peptidomimetic macrocycles, the compounds are, for example,administered to mice and/or rats by IV, IP, PO or inhalation routes at concentrations ranging from 0.1 to 50 mg/kg and blood specimens withdrawn at 0', 5', 15', 30', 1 hr, 4 hrs, 8 hrs and 24 hours post-injection. Levels of intact compound in 25 pL of fresh serum are then measured by LC-MS/MS as above. In vivo Efficacy in Animal Models. [00193] To determine the anti-oncogenic activity of peptidomimetic macrocycles in vivo, the compounds are, for example, given alone (IP, IV, PO, by inhalation or nasal routes) or in combination with -78- WO 2013/123267 PCT/US2013/026241 sub-optimal doses of relevant chemotherapy (e.g., cyclophosphamide, doxorubicin, etoposide). In one example, 5 x 106 RS4; 11 cells (established from the bone marrow of a patient with acute lymphoblastic leukemia) that stably express luciferase are injected by tail vein in NOD-SCID mice 3 hrs after they have been subjected to total body irradiation. If left untreated, this form of leukemia is fatal in 3 weeks in this model. The leukemia is readily monitored, for example, by injecting the mice with D-luciferin (60 mg/kg) and imaging the anesthetized animals (e.g., Xenogen In Vivo Imaging System, Caliper Life Sciences, Hopkinton, MA). Total body bioluminescence is quantified by integration of photonic flux (photons/sec) by Living Image Software (Caliper Life Sciences, Hopkinton, MA). Peptidomimetic macrocycles alone or in combination with sub-optimal doses of relevant chemotherapeutics agents are, for example, administered to leukemia mice (10 days after injection/day 1 of experiment, in bioluminescence range of 14-16) by tail vein or IP routes at doses ranging from 0.1mg/kg to 50 mg/kg for 7 to 21 days. Optionally, the mice are imaged throughout the experiment every other day and survival monitored daily for the duration of the experiment. Expired mice are optionally subjected to necropsy at the end of the experiment. Another animal model is implantation into NOD-SCID mice of DoHH2, a cell line derived from human follicular lymphoma, that stably expresses luciferase. These in vivo tests optionally generate preliminary pharmacokinetic, pharmacodynamic and toxicology data. Clinical Trials. [00194] To determine the suitability of the peptidomimetic macrocycles for treatment of humans, clinical trials are performed. For example, patients diagnosed with cancer and in need of treatment can be selected and separated in treatment and one or more control groups, wherein the treatment group is administered a peptidomimetic macrocycle, while the control groups receive a placebo or a known anti-cancer drug. The treatment safety and efficacy of the peptidomimetic macrocycles can thus be evaluated by performing comparisons of the patient groups with respect to factors such as survival and quality-of-life. In this example, the patient group treated with a peptidomimetic macrocyle can show improved long-term survival compared to a patient control group treated with a placebo. Pharmaceutical Compositions and Routes of Administration [00195] Pharmaceutical compositions disclosed herein include peptidomimetic macrocycles and pharmaceutically acceptable derivatives or prodrugs thereof. A "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, ester, salt of an ester, pro-drug or other derivative of a compound disclosed herein which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound disclosed herein. Particularly favored pharmaceutically acceptable derivatives are those that increase the bioavailability of the compounds when administered to a mammal (e.g., by increasing absorption into the blood of an -79- WO 2013/123267 PCT/US2013/026241 orally administered compound) or which increases delivery of the active compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Some pharmaceutically acceptable derivatives include a chemical group which increases aqueous solubility or active transport across the gastrointestinal mucosa. [00196] In some embodiments, peptidomimetic macrocycles are modified by covalently or non-covalently joining appropriate functional groups to enhance selective biological properties. Such modifications include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter rate of excretion. [00197] Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, pirate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate and undecanoate. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl) 4 ' salts. [00198] For preparing pharmaceutical compositions from the compounds provided herein, pharmaceutically acceptable carriers include either solid or liquid carriers. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which also acts as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA. [00199] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. [00200] Suitable solid excipients are carbohydrate or protein fillers include, but are not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents are added, such as the cross linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. -80- WO 2013/123267 PCT/US2013/026241 [00201] Liquid form preparations include, without limitation, solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. [00202] The pharmaceutical preparation can be in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. [00203] When one or more compositions disclosed herein comprise a combination of a peptidomimetic macrocycle and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about I to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. In some embodiments, the additional agents are administered separately, as part of a multiple dose regimen, from one or more compounds disclosed herein. Alternatively, those agents are part of a single dosage form, mixed together with one or more compounds disclosed herein in a single composition. Methods of Use [00204] In one aspect, provided herein are novel peptidomimetic macrocycles that are useful in competitive binding assays to identify agents which bind to the natural ligand(s) of the proteins or peptides upon which the peptidomimetic macrocycles are modeled. For example, in the p53/MDIX system, labeled peptidomimetic macrocycles based on p53 can be used in a MDMX binding assay along with small molecules that competitively bind to MDMX. Competitive binding studies allow for rapid in vitro evaluation and determination of drug candidates specific for the p53/MDMX system. Such binding studies can be performed with any of the peptidomimetic macrocycles disclosed herein and their binding partners. [00205] Provided herein is the generation of antibodies against the peptidomimetic macrocycles. In some embodiments, these antibodies specifically bind both the peptidomimetic macrocycle and the precursor peptides, such as p53, to which the peptidomimetic macrocycles are related. Such antibodies, for example, disrupt the native protein-protein interaction, for example, binding between p53 and MDMX. [00206] In other aspects, provided herein are both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant (e.g., insufficient or excessive) expression or activity of the molecules including p53, MDM2 or MDMX. [00207] In another embodiment, a disorder is caused, at least in part, by an abnormal level of p53 or MDM2 or MDMX, (e.g., over or under expression), or by the presence of p53 or MDM2 or -81- WO 2013/123267 PCT/US2013/026241 MDMX exhibiting abnormal activity. As such, the reduction in the level and/or activity of p53 or MDM2 or MDMX, or the enhancement of the level and/or activity of p53 or MDM2 or MDMX, by peptidomimetic macrocycles derived from p53, is used, for example, to ameliorate or reduce the adverse symptoms of the disorder. [00208] In another aspect, provided herein are methods for treating or preventing a disease including hyperproliferative disease and inflammatory disorder by interfering with the interaction or binding between binding partners, for example, between p53 and MDM2 or p53 and MDMX. These methods comprise administering an effective amount of a compound to a warm blooded animal, including a human. In some embodiments, the administration of one or more compounds disclosed herein induces cell growth arrest or apoptosis. [00209] As used herein, the term "treatment" is defined as the application or administration of a therapeutic agent to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient, who has a disease, a symptom of disease or a predisposition toward a disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease, the symptoms of disease or the predisposition toward disease. [00210] In some embodiments, the peptidomimetics macrocycles can be used to treat, prevent, and/or diagnose cancers and neoplastic conditions. As used herein, the terms "cancer", "hyperproliferative" and "neoplastic" refer to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth. Hyperproliferative and neoplastic disease states can be categorized as pathologic, i.e., characterizing or constituting a disease state, or can be categorized as non-pathologic, i.e., a deviation from normal but not associated with a disease state. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. A metastatic tumor can arise from a multitude of primary tumor types, including but not limited to those of breast, lung, liver, colon and ovarian origin. "Pathologic hyperproliferative" cells occur in disease states characterized by malignant tumor growth. Examples of non-pathologic hyperproliferative cells include proliferation of cells associated with wound repair. Examples of cellular proliferative and/or differentiative disorders include cancer, e.g., carcinoma, sarcoma, or metastatic disorders. In some embodiments, the peptidomimetics macrocycles are novel therapeutic agents for controlling breast cancer, ovarian cancer, colon cancer, lung cancer, metastasis of such cancers and the like. [00211] Examples of cancers or neoplastic conditions include, but are not limited to, a fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, rectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, uterine cancer, cancer of -82- WO 2013/123267 PCT/US2013/026241 the head and neck, skin cancer, brain cancer, squamous cell carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular cancer, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, or Kaposi sarcoma. [00212] Examples of proliferative disorders include hematopoietic neoplastic disorders. As used herein, the term "hematopoietic neoplastic disorders" includes diseases involving hyperplastic/neoplastic cells of hematopoietic origin, e.g., arising from myeloid, lymphoid or erythroid lineages, or precursor cells thereof. The diseases can arise from poorly differentiated acute leukemias, e.g., erythroblastic leukemia and acute megakaryoblastic leukemia. Additional exemplary myeloid disorders include, but are not limited to, acute promyeloid leukemia (APML), acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) (reviewed in Vaickus (1991), Crit Rev. Oncol./Hemotol. 11:267-97); lymphoid malignancies include, but are not limited to acute lymphoblastic leukemia (ALL) which includes B-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) and Waldenstrom's macroglobulinemia (WM). Additional forms of malignant lymphomas include, but are not limited to non-Hodgkin lymphoma and variants thereof, peripheral T cell lymphomas, adult T cell leukemia/lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), large granular lymphocytic leukemia (LGF), Hodgkin's disease and Reed-Stemberg disease. [00213] Examples of cellular proliferative and/or differentiative disorders of the breast include, but are not limited to, proliferative breast disease including, e.g., epithelial hyperplasia, sclerosing adenosis, and small duct papillomas; tumors, e.g., stromal tumors such as fibroadenoma, phyllodes tumor, and sarcomas, and epithelial tumors such as large duct papilloma; carcinoma of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma, and miscellaneous malignant neoplasms. Disorders in the male breast include, but are not limited to, gynecomastia and carcinoma. [00214] Exampes of cellular proliferative and/or differentiative disorders of the skin include, but are not limited to proliferative skin disease such as melanomas, including mucosal melanoma, superficial spreading melanoma, nodular melanoma, lentigo (e.g. lentigo maligna, lentigo maligna melanoma, or acral lentiginous melanoma), amelanotic melanoma, desmoplastic melanoma, melanoma with features of a Spitz nevus, melanoma with small nevus-like cells, polypoid -83- WO 2013/123267 PCT/US2013/026241 melanoma, and soft-tissue melanoma; basal cell carcinomas including micronodular basal cell carcinoma, superficial basal cell carcinoma, nodular basal cell carcinoma (rodent ulcer), cystic basal cell carcinoma, cicatricial basal cell carcinoma, pigmented basal cell carcinoma, aberrant basal cell carcinoma, infiltrative basal cell carcinoma, nevoid basal cell carcinoma syndrome, polypoid basal cell carcinoma, pore-like basal cell carcinoma, and fibroepithelioma of Pinkus; squamus cell carcinomas including acanthoma (large cell acanthoma), adenoid squamous cell carcinoma, basaloid squamous cell carcinoma, clear cell squamous cell carcinoma, signet-ring cell squamous cell carcinoma, spindle cell squamous cell carcinoma, Marjolin's ulcer, erythroplasia of Queyrat, and Bowen's disease; or other skin or subcutaneous tumors. [00215] Examples of cellular proliferative and/or differentiative disorders of the lung include, but are not limited to, bronchogenic carcinoma, including paraneoplastic syndromes, bronchioloalveolar carcinoma, neuroendocrine tumors, such as bronchial carcinoid, miscellaneous tumors, and metastatic tumors; pathologies of the pleura, including inflammatory pleural effusions, noninflammatory pleural effusions, pneumothorax, and pleural tumors, including solitary fibrous tumors (pleural fibroma) and malignant mesothelioma. [00216] Examples of cellular proliferative and/or differentiative disorders of the colon include, but are not limited to, non-neoplastic polyps, adenomas, familial syndromes, colorectal carcinogenesis, colorectal carcinoma, and carcinoid tumors. [00217] Examples of cellular proliferative and/or differentiative disorders of the liver include, but are not limited to, nodular hyperplasias, adenomas, and malignant tumors, including primary carcinoma of the liver and metastatic tumors. [00218] Examples of cellular proliferative and/or differentiative disorders of the ovary include, but are not limited to, ovarian tumors such as, tumors of coelomic epithelium, serous tumors, mucinous tumors, endometrioid tumors, clear cell adenocarcinoma, cystadenofibroma, Brenner tumor, surface epithelial tumors; germ cell tumors such as mature (benign) teratomas, monodermal teratomas, immature malignant teratomas, dysgerminoma, endodermal sinus tumor, choriocarcinoma; sex cord-stomal tumors such as, granulosa-theca cell tumors, thecomafibromas, androblastomas, hill cell tumors, and gonadoblastoma; and metastatic tumors such as Krukenberg tumors. [00219] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments described herein can be employed in practicing the invention. It is intended that the following claims define the scope and that methods and structures within the scope of these claims and their equivalents be covered thereby. -84- WO 2013/123267 PCT/US2013/026241 Examples Example 1: Synthesis of 6-chlorotryptophan Fmoc amino acids 0 OH Br 1) POCl 3 , DMF H _ NaBH 4 , ethanol PPh 3 , NBSI NH 4M NaOH N 0 2h N O CH 2 0 2 , -40DC O C - 1) BOCO, acetonitrile, 0 O 80% 0 Ol MAP (cat.), 2h - al2C CI C- -2 CI 3 quantitative Boc 0 3 (1.5 or 1.1 eq) N1)53N HCI/MeOH C H 1.5 or 1.1 eq. KOtBu ON NBoc 2) Na 2
CO
3 , 00C . NNNiO R 'OH 1.50C to rt, 1 h N 'Nu 3) EDTA disodium, DMF O Cl O hrt 45-65% 4) FocOSu in S-Ala-Ni-S-BPB R=Me R=Me toe rt 7, RH Gly-Ni-S-BRB R=H 5 R=H oengt7 70% [00220] Tert-butyl 6-chloro-3-formyl-1H-indole-1-carboxylate, 1. To a stirred solution of dry DMF (12 mL) was added dropwise POCl 3 (3.92 mL, 43 mmol, 1.3 equiv) at 0 'C under Argon. The solution was stirred at the same temperature for 20 min before a solution of 6-chloroindole (5.0 g, 33 mmol, 1 eq.) in dry DMF (30 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for an additional 2.5h. Water (50 mL) was added and the solution was neutralized with 4M aqueous NaOH (pH - 8). The resulting solid was filtered off, washed with water and dried under vacuum. This material was directly used in the next step without additional purification. To a stirred solution of the crude formyl indole (33 mmol, 1 eq.) in THF (150 mL) was added successively Boc 2 0 (7.91 g, 36.3 mmol, 1.1 equiv) and DMAP (0.4 g, 3.3 mmol, 0.1 equiv) at room temperature under N 2 . The resulting mixture was stirred at room temperature for 1.5h and the solvent was evaporated under reduced pressure. The residue was taken up in EtOAc and washed with IN HCl, dried and concentrated to give the formyl indole 1 (9 g, 98 % over 2 steps) as a white solid. 'H NMR (CDCl 3 ) 5: 1.70 (s, Boc, 9H); 7.35 (dd, 1H); 8.21 (in, 3H); 10.07 (s, 1H). [00221] Tert-butyl 6-chloro-3-(hydroxymethyl)-1H-indole-1-carboxylate, 2. To a solution of compound 1 (8.86g, 32 mmol, 1 eq.) in ethanol (150 mL) was added NaBH 4 (2.4g, 63 mmol, 2 eq.). The reaction was stirred for 3 h at room temperature. The reaction mixture was concentrated and the residue was poured into diethyl ether and water. The organic layer was separated, dried over magnesium sulfate and concentrated to give a white solid (8.7g, 98%). This material was directly used in the next step without additional purification. 'H NMR (CDCl 3 ) 6: 1.65 (s, Boc, 9H); 4.80 (s, 2H, CH 2 ); 7.21 (dd, 1H); 7.53 (m, 2H); 8.16 (bs, 1H). [00222] Tert-butyl 3-(bromomethyl)-6-chloro-1H-indole-1-carboxylate, 3. To a solution of compound 2 (4.lg, 14.6 mmol, 1 eq.) in dichloromethane (50 nL) under argon was added a solution of -85- WO 2013/123267 PCT/US2013/026241 triphenylphosphine (4.59g, 17.5 mmol, 1.2 eq.) in dichloromethane (50 mL) at -40'C. The reaction solution was stirred an additional 30 min at 40'C. Then NBS (3.38g, 19 mmol, 1.3 eq.) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight. Dichloromethane was evaporated, Carbon Tetrachloride (100 mL) was added and the mixture was stirred for lh and filtrated. The filtrate was concentrated, loaded in a silica plug and quickly eluted with 25% EtOAc in Hexanes. The solution was concentrated to give a white foam (3.84g, 77%). 'H NMR (CDCl 3 ) 6: 1.66 (s, Boc, 9H); 4.63 (s, 2H, CH2); 7.28 (dd, 1H); 7.57 (d, 1H); 7.64 (bs, 1H); 8.18 (bs, 1H). [00223] aMe-6Cl-Trp(Boc)-Ni-S-BPB, 4. To S-Ala-Ni-S-BPB (2.66g, 5.2 mmol, 1 eq.) and KO-tBu (0.87g, 7.8 mmol, 1.5 eq.) was added 50 mL of DMF under argon. The bromide derivative compound 3 (2.68g, 7.8 mmol, 1.5 eq.) in solution of DMF (5.0 mL) was added via syringe. The reaction mixture was stirred at ambient temperature for 1 h. The solution was then quenched with 5 % aqueous acetic acid and diluted with water. The desired product was extracted in dichloromethane, dried and concentrated. The oily product 4 was purified by flash chromatography (solid loading) on normal phase using EtOAc and Hexanes as eluents to give a red solid (1.78g, 45% yield). aMe-6Cl-Trp(Boc)-Ni-S-BPB, 4: M+H calc. 775.21, M+H obs. 775.26; ' H NMR (CDCl 3 ) 5:1.23 (s, 3H, aMe); 1.56 (in, 11H, Boc + CH2); 1.82-2.20 (in, 4H, 2CH2); 3.03 (in, 1H, CH,); 3.24 (in, 2H, CH 2 ); 3.57 and 4.29 (AB system, 2H, CH 2 (benzyl), J= 12.8Hz); 6.62 (d, 2H); 6.98 (d, 1H); 7.14 (in, 2H); 7.23 (in, 1H); 7.32-7.36 (in, 5H); 7.50 (in, 2H); 7.67 (bs, 1H); 7.98 (d, 2H); 8.27 (in, 2H). [00224] Fmoc-aMe-6Cl-Trp(Boc)-OH, 6. To a solution of 3N HCl/MeOH (1/3, 15 mL) at 50'C was added a solution of compound 4 (1.75g, 2.3 mmol, 1 eq.) in MeOH (5 ml) dropwise. The starting material disappeared within 3-4 h. The acidic solution was then cooled to 0C with an ice bath and quenched with an aqueous solution of Na 2
CO
3 (1.21g, 11.5 mmol, 5 eq.). Methanol was removed and 8 more equivalents of Na 2
CO
3 (1.95g, 18.4 mmol) were added to the suspension. The Nickel scavenging EDTA disodium salt dihydrate (1.68g, 4.5 mmol, 2 eq.) was then added and the suspension was stirred for 2h. A solution of Fmoc-OSu (0.84g, 2.5 mmol, 1.1 eq.) in acetone (50 mL) was added and the reaction was stirred overnight. Afterwards, the reaction was diluted with diethyl ether and IN HCl. The organic layer was then dried over magnesium sulfate and concentrated in vacuo. The desired product 6 was purified on normal phase using acetone and dichloromethane as eluents to give a white foam (0.9g, 70% yield). Fmoc-aMe-6Cl-Trp(Boc) OH, 6: M+H calc. 575.19, M+H obs. 575.37; 'H NMR (CDCl 3 ) 1.59 (s, 9H, Boc); 1.68 (s, 3H, Me); 3.48 (bs, 2H, CH2; 4.22 (in, 1H, CH); 4.39 (bs, 2H, CH 2 ); 5.47 (s, 1H, NH); 7.10 (in, 1H); 7.18 (in, 2H); 7.27 (in, 2H); 7.39 (in, 2H); 7.50 (in, 2H); 7.75 (d, 2H); 8.12 (bs, 1H). [00225] 6Cl-Trp(Boc)-Ni-S-BPB, 5. To Gly-Ni-S-BPB (4.6g, 9.2 mmol, 1 eq.) and KO-tBu (1.14g, 10.1 mmol, 1.1 eq.) was added 95 mL of DMF under argon. The bromide derivative compound 3 (3.5g, 4.6 mmol, 1.1 eq.) in solution of DMF (10 mL) was added via syringe. The reaction -86- WO 2013/123267 PCT/US2013/026241 mixture was stirred at ambient temperature for 1 h. The solution was then quenched with 5 % aqueous acetic acid and diluted with water. The desired product was extracted in dichloromethane, dried and concentrated. The oily product 5 was purified by flash chromatography (solid loading) on normal phase using EtOAc and Hexanes as eluents to give a red solid (5g, 71% yield). 6Cl-Trp(Boc)-Ni-S-BPB, 5: M+H calc. 761.20, M+H obs. 761.34; 'H NMR (CDCl 3 ) 6:1.58 (m, 11H, Boc + CH 2 ); 1.84 (m, 1H); 1.96 (m, 1H); 2.24 (m, 2H, CH 2 ); 3.00 (m, 1H, CH,); 3.22 (m, 2H, CH 2 ); 3.45 and 4.25 (AB system, 2H, CH 2 (benzyl), J= 12.8Hz); 4.27 (m, 1H, CH,); 6.65 (d, 2H); 6.88 (d, 1H); 7.07 (m, 2H); 7.14 (m, 2H); 7.28 (m, 3H); 7.35-7.39 (m, 2H); 7.52 (m, 2H); 7.96 (d, 2H); 8.28 (m, 2H). [00226] Fmoc-6Cl-Trp(Boc)-OH, 7. To a solution of 3N HCl/MeOH (1/3, 44 mL) at 50'C was added a solution of compound 5 (5g, 6.6 mmol, 1 eq.) in MeOH (10 ml) dropwise. The starting material disappeared within 3-4 h. The acidic solution was then cooled to 0C with an ice bath and quenched with an aqueous solution of Na 2
CO
3 (3.48g, 33 mmol, 5 eq.). Methanol was removed and 8 more equivalents of Na 2
CO
3 (5.57g, 52 mmol) were added to the suspension. The Nickel scavenging EDTA disodium salt dihydrate (4.89g, 13.1 mmol, 2 eq.) and the suspension was stirred for 2h. A solution of Fmoc-OSu (2.21g, 6.55 mmol, 1.1 eq.) in acetone (100 mL) was added and the reaction was stirred overnight. Afterwards, the reaction was diluted with diethyl ether and IN HCl. The organic layer was then dried over magnesium sulfate and concentrated in vacuo. The desired product 7 was purified on normal phase using acetone and dichloromethane as eluents to give a white foam (2.6g, 69% yield). Fmoc-6Cl-Trp(Boc)-OH, 7: M+H cale. 561.17, M+H obs. 561.37; 1H NMR (CDC 3 ) 1.63 (s, 9H, Boc); 3.26 (m, 2H, CH 2 ); 4.19 (m, 1H, CH); 4.39 (m, 2H, CH2); 4.76 (m, 1H); 5.35 (d, 1H, NH); 7.18 (m, 2H); 7.28 (m, 2H); 7.39 (m, 3H); 7.50 (m, 2H); 7.75 (d, 2H); 8.14 (bs, 1H). Example la: Synthesis of alkyne compounds for use in synthesis of compounds of Formula I. 1) nBuLi, 1-bromo-3-chloropropane, THF, -78 0 C phenylacetylene 2) Nal, Acetone reflux 2 days (5-iodopent-1-ynyl)benzene [00227] Synthesis of (5-iodopent-1-ynyl)benzene. To a solution of THF (200mL) into reaction flask was added (5 chloropent-1 -ynyl)benzene Phenylacetylene (10g, 97.91mmol). Then the reaction mixture was cooled to 78 0 C in a dry ice bath. nBuLi (95.95mmo, 38.39mL) was added dropwise and allowed to react for 0.5h at 78C. At -78C, 1-bromo-3-chloropropane was added. Stirred for 5 hours during which the reaction was allowed to warm up to room temperature. Then reaction was refluxed at 90'C for 3 hours. The solvent was distilled off, then water (150mL) and ether (150mL) was added. The crude product was extracted, ether was distilled off and the resulting crude mixture was dissolved in acetone. Sodium iodide (22.92mmo, 3.44g) was added into the solution. The reaction mixture, with reflux condenser attached, was heated to -87- WO 2013/123267 PCT/US2013/026241 70'C for two days. Acetone was distilled off using short path distillation apparatus. Ether (150mL) and water (1 50mL) was added and carried out extraction. Ether was then dried over magnesium sulfate and distilled off resulting in 5.00g of product (yield 98%). No further purification was carried out. H NMR (500 MHz, CDCl 3 ) 2.072 (in, 2H, CH 2 ); 2.605 (t, 2H, CH 2 ); 3.697 (in, 2H, CH 2 ); 7.276 (in, 2H, Phenyl); 7.389 (in, 2H, phenyl); 7.484 (in, 1H, phenyl). 1) 3N HCi/MeOH 0 1.5 eq. KOtBu N 70"C, 20 mn IN 'N OOC to rto 7I 0 h,2Om'n 0 0 C to rt, 1h NN 2) Na 2
CO
3 , EDTA, DMF N water / / / N3) FmocOtulIn 3)-ace one, 0C to rt OH S-Ala-Ni-S-DCBPB (1.5 eq.) overnight FmocHN [00228] Synthesis of MeS5-PhenylAlkyne-Ni-S-BPB. To S-Ala-Ni-SBPB (18.17 mmol, 9.30g) and KO-tBu (27.26mmol, 3.05g) was added 200 mL of DMF under argon. (5-iodopent-1-ynyl)benzene (27.26mmol, 7.36g) in solution of DMF (50 mL) was added via syringe. The reaction mixture was stirred at ambient temperature for lh. The solution was then quenched with acetic acid (27.26mmol, 1.58mL) and diluted with water (100mL). The product was extracted with dichloromethane (100mL), separated and dried over magnesium sulfate. The crude product was purified by flash chromatography on normal phase using acetone and dichloromethane as eluents to afford the desired product as a red solid (9.48g, 79.8 %). M--H calc. 654.22, M+H obs. 654.4; 1 H NMR (500 MHz, CDCl 3 ) E 1.17 (s, 3H, Me (E Me-Phe)); 1.57 (in, 1H,
CH
2 ); 1.67 (in, 1H, CH 2 ); 1.89 (in, 1H, CH 2 ); 2.06 (in, 1H, CH 2 ); 2.24 (in, 2H, CH 2 ); 3.05 (in, 1H); 3.18 (s, 2H); 3.26 (in, 1H); 3.56 and 4.31 (AB system, 2H, CH2 benzyll), J= 12.8Hz); 6.64 (in, 2H); 6.94 (d, 1H); 7.12 (in, 1H); 7.20 (in, 1H); 7.20-7.40 (in, 10H); 7.43 (in, 2H); 8.01 (d, 2H); 8.13 (in, 1H). [00229] Synthesis of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-methyl-7-phenylhept-6-ynoi acid. To a solution of 3N HCl/MeOH (1/1, 23 mL) at 70'C was added a solution of MeS5-PhenylAlkyne-Ni-S BPB (14.5 mmol, 9.48g) in MeOH (70 ml) dropwise. The starting material disappeared within 10-20 min. The green reaction mixture was then concentrated in vacuo. Water was added (lOOmL) and the resulting precipitate (S-BPB HCl salt) was filtered off. Sodium carbonate (116 mmol, 12.29g) and EDTA (29mmol, 10.79g) were added to the mother liquor. The mixture was stirred at room temperature for 3 hours to scavenge the free nickel. After addition of 50 mL of acetone, the reaction was cooled to 0C with an ice bath. Fmoc-OSu (1 6.68mmol, 5.62g) dissolved in acetone (50ml) was added and the reaction was allowed to warm up to ambient temperature with stirring overnight. Afterwards, the reaction was diluted with ethyl acetate (300mL). Then the organic layer was separated. The aqueous layer was acidified with conc. HCl. The desired product was extracted with dichloromethane (400mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on normal phase using 10 %MBTE/DCM as eluents to afford the desired product as a white solid (6.05g, 51 %). M+H calc. 454.53, M+H obs. 454.2; 'H NMR (CDCl 3 ) E 1.50 (bs, 2H, CH2); 1.60 (bs, 3H, CH 3 ); 2.05 (bs, 1H, CH 2 ); 2.30 (bs, 1H, CH 2 ); 2.42 (bs, 2H, CH2); 4.20 (in, 1H, CH); 4.40 (bs, 2H, CH 2 ); 5.58 (s, 1H, NH); 7.26 (in, 3H); 7.32 (in, 2H); 7.37 (n, 4H); 7.58 (d, 2H); 7.76 (d, 2H). -88- WO 2013/123267 PCT/US2013/026241 1) nBuLi, Mel, THF, -78oCd CI 5-chloro-1-pentyne 2) Nal, Acetone reflux 2 days 6-iodohex-2-yne [00230] Synthesis of 6-iodohex-2-yne. To a solution of THF (250mL) into reaction flask was added 5-chloro-1 pentyne (48.7mmol, 5.0g). Then the reaction mixture was cooled to -78 0 C in a dry ice bath. nBuLi (51.immol, 20.44mL) was added dropwise and allowed to react for 0.5h at -78 0 C and allowed to warm to room temperature. Then methyl iodide (54.5mmol, 3.39mL) was added to the reaction mixture. The reaction was stirred for 5 hours. Water was added (1.5mL) and the THF was distilled off. The crude product was extracted with pentane (lOOmL) and water(OOmL). Pentane was distilled off and the resulting crude mixture was dissolved in acetone (300mL). Sodium iodide (172.9mmol, 25.92g) was added into the solution. The reaction mixture, with reflux condenser attached, was heated to 70 0 C for two days. Acetone was distilled off using short path distillation apparatus. Ether (100mL) and water (100mL) was added and carried out extraction. Ether was then dried over magnesium sulfate and distilled off resulting in 8.35g of product (yield 83%). No further purification was carried out. H NMR (500 MHz, CDCl3) 6 1.762 (t, 3H,
CH
3 ); 1.941 (in, 2H, CH 2 ); 2.245 (in, 2H, CH 2 ); 3.286 (in, 2H, CH 2 ). O 1) 3N HCI/MeOH N 1.5 eq. KOtBu 070C, 20 min 7N.N Nt( KP or,1 ;NI'l 0 H 0" tof rh NiN 2) Na 2 C0 3 , EDTA, DMF o water O 3) FmocOSu In FmocHN acetone, /OC to rt 0 S-Ala-Ni-S-OCBPB (1.5 eq.) overnight [00231] Synthesis of MeS5-MethylAlkyne-Ni-S-BPB. To S-Ala-Ni-SBPB (19.53 mmol, 10g) and KO-tBu (29.29mmol, 3.28g) was added 200 mL of DMF under argon. 6-iodohex-2-yne (29.29mmol, 6.09g) in solution of DMF (50 mL) was added via syringe. The reaction mixture was stirred at ambient temperature for Ilh. The solution was then quenched with acetic acid (29.29mmol, 1.69mL) and diluted with water (1OOmL). The product was extracted with dichloromethane (300mL), separated and dried over magnesium sulfate. The crude product was purified by flash chromatography on normal phase using acetone and dichloromethane as eluents to afford the desired product as a red solid (8.1Og, 70 %). M+H calc. 592.2, M+H obs. 592.4; 1 H NMR (500 Mz, CDCl 3 ) 6 1.17 (s, 3H, CH 3 (ctMe-Phe)); 1.57 (in, 1H, CH 2 ); 1.67 (m, 1H, CH 2 ); 1.89 (in, 1H, CH2; 2.06 (in, 1H, CH 2 ); 2.24 (in, 2H, CH2; 3.05 (in, 1H); 3.18 (s, 2H); 3.26 (in, IH); 3.56 and 4.31 (AB system, 2H, CH 2 benzyll), J= 12.8Hz); 6.64 (in, 2H); 6.94 (d, 1H); 7.12 (in, 1H); 7.20 (in, 1H); 7.20-7.40 (m, 1OH); 7.43 (in, 2H); 8.01 (d, 2H); 8.13 (in, 1H). [00232] Synthesis of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-methyloct-6-ynoic acid. To a solution of 3N HCl/MeOH (1/1, 23 mL) at 70 0 C was added a solution of MeS5-MethylAlkyne-Ni-S-BPB (13.70 mmol, 8.1Og)) in methanol (70 ml) dropwise. The starting material disappeared within 10-20 min. The green reaction mixture was then concentrated in vacuo. Water (150mL) was added and the resulting precipitate (S-BPB HCl salt) was filtered off. Sodium carbonate (116 mmol, 12.29g) EDTA (29mmol, -89- WO 2013/123267 PCT/US2013/026241 10.79g) were added to the mother liquor. The mixture was stirred at room temperature for 3 hours to scavenge the free nickel. After addition of 75 mL of acetone, the reaction was cooled to 0 0 C with an ice bath. Fmoc-OSu (15.76mmol, 5.31g) dissolved in acetone (75 ml) was added and the reaction was allowed to warm up to ambient temperature with stirring overnight. Afterwards, the reaction was diluted with ethyl acetate (200mL). Then the organic layer was separated. The aqueous layer was acidified with conc. HC. The desired product was extracted with dichloromethane (200mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on normal phase using 10 %MBTE/DCM as eluents to afford the desired product as a white solid (2.40g, 45 %). M+H calc. 392.18, M+H obs. 392.3; 1 H NMR (500 Mz, CDCI) 6 1.38 (bs, 1H, CH 2 ); 1.50 (bs, 1H, CH 2 ); 1.60 (bs, 2H, CH 2 ); 1.75 (s, 3H, CH 3 ); 1.95 (bs, 2H, CH 2 ); 2.10 (bs, 3H, CH 3 ); 4.20 (m, 1H, CH); 4.40 (bs, 2H,
CH
2 ); 5.58 (s, 1H, NH); 7.32 (m, 2H); 7.42 (in, 2H); 7.59 (d, 2H); 7.78 (d, 2H). Example 2: Peptidomimetic macrocycles of Formula I. [00233] Peptidomimetic macrocycles are prepared as described herein and as in pending U.S. Patent Application No. 12/037,041, filed February 25, 2008, which is hereby incorporated by reference in its entirety. Peptidomimetic macrocycles are designed by replacing two or more naturally occurring amino acids with the corresponding synthetic amino acids. Substitutions are made at i and i+4, and i and i+7 positions. Peptide synthesis is performed either manually or on an automated peptide synthesizer (Applied Biosystems, model 433A), using solid phase conditions, rink amide AM resin (Novabiochem), and Fmoc main-chain protecting group chemistry. For the coupling of natural Fmoc-protected amino acids (Novabiochem), 10 equivalents of amino acid and a 1:1:2 molar ratio of coupling reagents HBTU/HOBt (Novabiochem)/DIEA are employed. Non-natural amino acids (4 equiv) are coupled with a 1:1:2 molar ratio of HATU (Applied Biosystems)/HOBt/DIEA. The N-termini of the synthetic peptides are acetylated, while the C termini are amidated. [00234] Generally, ully protected resin-bound peptides were synthesized on a PEG-PS resin (loading 0.45 mmol/g) on a 0.5 mmol scale. Deprotection of the temporary Fmoc group was achieved by 3 x 10 min treatments of the resin bound peptide with 20% (v/v) piperidine in DMF. After washing with NMP (3x), dichloromethane (3x) and NMP (3x), coupling of each successive amino acid was achieved with 1 x 60 min incubation with the appropriate preactivated Fmoc-amino acid derivative. All protected amino acids (1.0 mmol) were dissolved in NMP and activated with HCTU (1.0 mmol), Cl-HOBt (1.0 mmol) and DIEA (2.0 mmol) prior to transfer of the coupling solution to the deprotected resin-bound peptide. After coupling was completed, the resin was washed in preparation for the next deprotection/coupling cycle. Acetylation of the amino terminus was carried out in the presence of acetic anhydride/DIEA in NMP. The LC-MS analysis of a cleaved and deprotected sample obtained from an aliquot of the fully assembled resin-bound peptide was accomplished in order to verifying the completion of each coupling. -90- WO 2013/123267 PCT/US2013/026241 [00235] In a typical example for the preparation of a peptidomimetic macrocycle comprising a 1,4 triazole group (e.g. SP153), 20% (v/v) 2,6-lutidine in DMF was added to the peptide resin (0.5 mmol) in a 40ml glass vial and shaken for 10 minutes. Sodium ascorbate (0.25g, 1.25 mmol) and diisopropylethylamine (0.22ml, 1.25 mmol) were then added, followed by copper(I) iodide (0.24g, 1.25 mmol) and the resulting reaction mixture was mechanically shaken 16 hours at ambient temperature. [00236] In a typical example for the preparation of a peptidomimetic macrocycle comprising a 1,5 triazole group (SP932, SP933), a peptide resin (0.25 mmol) was washed with anhydrous DCM. Resin was loaded into a microwave vial. Vessel was evacuated and purged with nitrogen. Chloro(pentamethylcyclopentadienyl) bis(triphenylphosphine)ruthenium(II), 10% loading, (Strem 44-0117) was added. Anhydrous toluene was added to the reaction vessel. The reaction was then loaded into the microwave and held at 90'C for 10 minutes. Reaction may need to be pushed a subsequent time for completion. In other cases, Chloro(1,5 cyclooctadiene)(pentamethylcyclopentadienyl)ruthenium ("Cp*RuCl(cod)") may be used, for example at at room temperature in a solvent comprising toluene. [00237] In a typical example for the preparation of a peptidomimetic macrocycle comprising an iodo substituted triazole group (e.g. SP457), THF (2 ml) was added to the peptide resin (0.05 mmol) in a 40ml glass vial and shaken for 10 minutes. N-bromosuccimide (0.04g, 0.25 mmol), copper(I) iodide (0.05g, 0.25 mmol) and diisopropylethylamine (0.04 ml, 0.25 mmol) were then added and the resulting reaction mixture was mechanically shaken 16 hours at ambient temperature. Iodo triazole crosslinkers may be further substituted by a coupling reaction, for example with boronic acids, to result in a peptidomimetic macrocycle such as SP465. In a typical example, DMF (3 ml) was added to the iodo-triazole peptide resin (0.1 mmol) in a 40ml glass vial and shaken for 10 minutes. Phenyl boronic acid (0.04g, 0.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.006g, 0.005 mmol) and potassium carbonate (0.083g, 0.6 mmol) were then added and the resulting reaction mixture was mechanically shaken 16 hours at 700 C. Jodo-triazole crosslinkers may also be further substituted by a coupling reaction, for example with a terminal alkyne (e.g. Sonogashira coupling), to result in a peptidomimetic macrocycle such as SP468. In a typical example, 2:1 THF:triethylamine (3 ml) was added to the iodo-triazole peptide resin (0.1 mmol) in a 40ml glass vial and shaken for 10 minutes. N-BOC-4-pentyne-1-amine (0.04g, 0.2 mmol) and bis(triphenylphosphine)palladiumchloride (0.014g, 0.02 mmol) were added and shaken for 5 minutes. Copper(I) iodide (0.004g, 0.02 mmol) was then added and the resulting reaction mixture was mechanically shaken 16 hours at 700 C. [00238] The triazole-cyclized resin-bound peptides were deprotected and cleaved from the solid support by treatment with TFA/H 2 0/TIS (95/5/5 v/v) for 2.5 h at room temperature. After filtration of the resin the TFA solution was precipitated in cold diethyl ether and centrifuged to yield the desired product as a solid. The crude product was purified by preparative HPLC. For example, -91- WO 2013/123267 PCT/US2013/026241 purification of cross-linked compounds is achieved by high performance liquid chromatography (HPLC) (Varian ProStar) on a reverse phase C18 column (Varian) to yield the pure compounds. Chemical composition of the pure products is confirmed by LC/MS mass spectrometry (Micromass LCT interfaced with Agilent 1100 HPLC system) and amino acid analysis (Applied Biosystems, model 420A). [00239] Table 4 shows a list of peptidomimetic macrocycles of Formula I. Table 4 S - Sequence I Ac-F$4rn6AYWEAc3cL$4a5AAA-NH2 2 Ac-F$4rn6AYWEAc3cL$4a5AAibA-NH2 3 Ac-LTF$4rn6AYWAQL$4a5SANLe-NH2 4 Ac-LTF$4rn6AYWAQL$4a5SAL-NH2 5 Ac-LTF$4rn6AYWAQL$4a5SAM-NH2 6 Ac-LTF$4rn6AYWAQL$4a5SAhL-NH2 7 Ac-LTF$4rn6AYWAQL$4a5SAF-NH2 8 Ac-LTF$4rn6AYWAQL$4a5SA-NH2 9 Ac-LTF$4rn6AYWAQL$4a5SA~ig-NH2 10 Ac-LTF$4rn6AYWAQL$4a5SAAib-NH2 11 Ac-LTF$4rn6AYWAQL$4a5SAA-NH2 12 Ac-LTF$4rn6AYWA$4a5L$S$Nle-NH2 13 Ac-LTF$4rn6AYWA$4a5L$S$A-NH2 14 Ac-F$4rn6AYWEAc3cL$4a5AAN1e-NH2 15 Ac-F$4rn6AYWEAc3cL$4a5AAL-NH2 16 Ac-F$4rn6AYWEAc3cL$4a5AAM-NH2 17 Ac-F$4rn6AYWEAc3cL$4a5AAhL-NH2 18 Ac-F$4rn6AYWEAc3cL$4a5AAF-NH2 19 Ac-F$4rn6AYWEAc3cL$4a5AAI-NH2 20 Ac-F$4rn6AYWEAc3cL$4a5AAChg-NH2 21 Ac-F$4rn6AYWEAc3cL$4a5AACha-NH2 22 Ac-F$4rn6AYWEAc3cL$4a5AAAib-NH2 23 Ac-LTF$4rn6AYWAQL$4a5AAAibV-NH2 24 Ac-LTF$4rn6AYWAQL$4a5AAAibV-NH2 25 Ac-LTF$4rn6AYWAQL$4a5SAibAA-NH2 26 Ac-LTF$4rnCAYWAQLq4a5SAibAA-NH2 27 Ac-HLTF$4rn6HHWHQL$4a5AANleNle-NH2 28 Ac-DLTF$4rn6HHWHQL$4a5RRLV-NH2 29 Ac-HHTF$4rn6HHWHQL$4a5AAML-NH2 30 Ac-F$4rn6HHWHQL$4a5RRDCha-NH2 31 Ac-F$4rn6HHWHQL$4a5HRFV-NH2 32 Ac-HLTF$4rn6HHWHQL$4a5AAhLA-NH2 33 Ac-DLTF$4rn6HHWHQL$4a5RRChgI-NH2 34 Ac-DLTF$4rn6HHWHQL$4a5RRChgl-NH2 35 Ac-HHTF$4rn6HHWHQL$4a5AAChav-NH2 36 Ac-F$4rn6HHWHQL$4a5RRDa-NH2 37 Ac-F$4rn6HHWHQL$4a5HRAibG-NH2 38 Ac-F$4rn6AYWAQL$4a5HHNleL-NH2 39 Ac-F$4rn6AYWSAL$4a5HQANle-NH2 40 Ac-F$4rn6AYWVQL$4a5QHChgl-NH2 41 Ac-F$4rn6AYWTAL$4a5QQNlev-NH2 42 Ac-F$4rn6AYWYQL$4a5HAibAa-NH2 43 Ac-LTFS4rn6AYWAQLS4a5HHLa-NH2 44 Ac-LTF$4rn6AYWAQL$4a5HHLa-NH2 45 Ac-LTFS4rn6AYWAQLS4a5HQNlev-NH2 -92- WO 2013/123267 PCT/US2013/026241 A- Sequence 46 Ac-LTF$4rn6AYWAQL$4a5HQNlev-NH2 47 Ac-LTF$4rn6AYWAQL$4a5QQM1-NH2 48 Ac-LTF$4rn6AYWAQL$4a5QQM1-NH2 49 Ac-LTF$4rn6AYWAQL$4a5HAibhLV-NH2 50 Ac-LTF$4rn6AYWAQL$4a5AHFA-NH2 51 Ac-HLTF$4rn6HHWHQL$4a5AANlel-NH2 52 Ac-DLTF$4rn6HHWHQL$4a5RRLa-NH2 53 Ac-HHTF$4rn6HHWHQL$4a5AAMv-NH2 54 Ac-F$4rn6HHWHQL$4a5RRDA-NH2 55 Ac-F$4rn6HHWHQL$4a5HRFCha-NH2 56 Ac-F$4rn6AYWEAL$4a5AA-NHAm 57 Ac-F$4rn6AYWEAL$4a5AA-NHiAm 58 Ac-F$4rn6AYWEAL$4a5AA-NHnPr3Ph 59 Ac-F$4rn6AYWEAL$4a5AA-NHnBu33Me 60 Ac-F$4rn6AYWEAL$4a5AA-NHnPr 61 Ac-F$4rn6AYWEAL$4a5AA-NHnEt2Ch 62 Ac-F$4rn6AYWEAL$4a5AA-NHnEt2Cp 63 Ac-F$4rn6AYWEAL$4a5AA-NHHex 64 Ac-LTF$4rn6AYWAQL$4a5AAIA-NH2 65 Ac-LTF$4rn6AYWAQL$4a5AAIA-NH2 66 Ac-LTF$4rn6AYWAAL$4a5AAMA-NH2 67 Ac-LTF$4rn6AYWAAL$4a5AAMA-NH2 68 Ac-LTF$4rn6AYWAQL$4a5AANleA-NH2 69 Ac-LTF$4rn6AYWAQL$4a5AANleA-NH2 70 Ac-LTF$4rn6AYWAQL$4a5AAla-NH2 71 Ac-LTF$4rn6AYWAQL$4a5AAla-NH2 72 Ac-LTF$4rn6AYWAAL$4a5AAMa-NH2 73 Ac-LTF$4rn6AYWAAL$4a5AAMa-NH2 74 Ac-LTF$4rn6AYWAQL$4a5AANlea-NH2 75 Ac-LTF$4rn6AYWAQL$4a5AANlea-NH2 76 Ac-LTF$4rn6AYWAAL$4a5AAlv-NH2 77 Ac-LTF$4rn6AYWAAL$4a5AAlv-NH2 78 Ac-LTF$4rn6AYWAQL$4a5AAMv-NH2 79 Ac-LTF$4rn6AYWAAL$4a5AANlev-NH2 80 Ac-LTF$4rn6AYWAAL$4a5AANlev-NH2 81 Ac-LTF$4rn6AYWAQL$4a5AAll-NH2 82 Ac-LTF$4rn6AYWAQL$4a5AAll-NH2 83 Ac-LTF$4rn6AYWAAL$4a5AAMl-NH2 84 Ac-LTF$4rn6AYWAQL$4a5AANlel-NH2 85 Ac-LTF$4rn6AYWAQL$4a5AANlel-NH2 86 Ac-F$4rn6AYWEAL$4a5AAMA-NH2 87 Ac-F$4rn6AYWEAL$4a5AANleA-NH2 88 Ac-F$4rn6AYWEAL$4a5AAIa-NH2 89 Ac-F$4rn6AYWEAL$4a5AAMa-NH2 90 Ac-F$4rn6AYWEAL$4a5AANlea-NH2 91 Ac-F$4rn6AYWEAL$4a5AATV-NH2 92 Ac-F$4rn6AYWEAL$4a5AAMv-NH2 93 Ac-F$4rn6AYWEAL$4a5AANlev-NH2 94 Ac-F$4rn6AYWEAL$4a5AAIl-NH2 95 Ac-F$4rn6AYWEAL$4a5AAMl-NH2 96 Ac-F$4rn6AYWEAL$4a5AANlel-NH2 97 Ac-F$4rn6AYWEAL$4a5AANlel-NH2 98 Ac-LTF$4rn6AY6clWAQL$4a5SAA-NH2 99 Ac-LTF$4rn6AY6clWAQL$4a5SAA-NH2 100 Ac-WTF$4rn6FYWSQL$4a5AVAa-NH2 101 Ac-WTF$4rn6FYWSQL$4a5AVAa-NH2 102 Ac-WTF$4rn6VYWSQL$4a5AVA-NH2 103 Ac-WTF$4rn6VYWSQL$4a5AVA-NH2 -93- WO 2013/123267 PCT/US2013/026241 Q- Sequence 104 Ac-WTF$4rn6FYWSQL$4a5SAAa-NH2 105 Ac-WTF$4rn6FYWSQL$4a5SAAa-NH2 106 Ac-WTF$4rn6VYWSQL$4a5AVAaa-NH2 107 Ac-WTF$4rn6VYWSQL$4a5AVAaa-NH2 108 Ac-LTF$4rn6AYWAQL$4a5AVG-NH2 109 Ac-LTF$4rn6AYWAQL$4a5AVG-NH2 110 Ac-LTF$4rn6AYWAQL$4a5AVQ-NH2 112 Ac-LTF$4rn6AYWAQL$4a5AVQ-NH2 112 Ac-LTF$4rn6AYWAQL$4a5SAa-NH2 113 Ac-LTF$4rn6AYWAQL$4a5SAa-NH2 114 Ac-LTF$4rn6AYWAQhL$4a5SAA-NH2 115 Ac-LTF$4rn6AYWAQhL$4a5SAA-NH2 116 Ac-LTF$4rn6AYWEQLStSA$4a5-NH2 117 Ac-LTF$4rn6AYWAQL$4a5SLA-NH2 118 Ac-LTF$4rn6AYWAQL$4a5SLA-NH2 119 Ac-LTF$4rn6AYWAQL$4a5SWA-NH2 120 Ac-LTF$4rn6AYWAQL$4a5SWA-NH2 121 Ac-LTF$4rn6AYWAQL$4a5SVS-NH2 122 Ac-LTF$4rn6AYWAQL$4a5SAS-NH2 123 Ac-LTF$4rn6AYWAQL$4a5SVG-NH2 124 Ac-ETF$4rn6VYWAQL$4a5SAa-NH2 125 Ac-ETF$4rn6VYWAQL$4a5SAA-NH2 126 Ac-ETF$4rn6VYWAQL$4a5SVA-NH2 127 Ac-ETF$4rn6VYWAQL$4a5SLA-NH2 128 Ac-ETF$4rn6VYWAQL$4a5SWA-NH2 129 Ac-ETF$4rn6KYWAQL$4a5SWA-NH2 130 Ac-ETF$4rn6VYWAQL$4a5SVS-NH2 131 Ac-ETF$4rn6VYWAQL$4a5SAS-NH2 132 Ac-ETF$4rn6VYWAQL$4a5SVG-NH2 133 Ac-LTF$4rn6VYWAQL$4a5SSa-NH2 134 Ac-ETF$4rn6VYWAQL$4a5SSa-NH2 135 Ac-LTF$4rn6VYWAQL$4a5SNa-NH2 136 Ac-ETF$4rn6VYWAQL$4a5SNa-NH2 137 Ac-LTF$4rn6VYWAQL$4a5SAa-NH2 138 Ac-LTF$4rn6VYWAQL$4a5SVA-NH2 139 Ac-LTF$4rn6VYWAQL$4a5SVA-NH2 140 Ac-LTF$4rn6VYWAQL$4a5SWA-NH2 141 Ac-LTF$4rn6VYWAQL$4a5SVS-NH2 142 Ac-LTF$4rn6VYWAQL$4a5SVS-NH2 143 Ac-LTF$4rn6VYWAQL$4a5SAS-NH2 144 Ac-LTF$4rn6VYWAQL$4a5SAS-NH2 145 Ac-LTF$4rn6VYWAQL$4a5SVG-NH2 146 Ac-LTF$4rn6VYWAQL$4a5SVG-NH2 147 Ac-LTF$4rn6EYWAQCha$4a5SAA-NH2 148 Ac-LTF$4rn6EYWAQCha$4a5SAA-NH2 149 Ac-LTF$4rn6EYWAQCpg$4a5SAA-NH2 150 Ac-LTF$4rn6EYWAQCpg$4a5SAA-NH2 151 Ac-LTF$4rn6EYWAQF$4a5SAA-NH2 152 Ac-LTF$4rn6EYWAQF$4a5SAA-NH2 153 Ac-LTF$4rn6EYWAQCba$4a5SAA-NH2 154 Ac-LTF$4rn6EYWAQCba$4a5SAA-NH2 155 Ac-LTF3Cl$4rn6EYWAQL$4a5SAA-NH2 156 Ac-LTF3C$4rn6EYWAQL$4a5SAA-NH2 157 Ac-LTF34F2$4rn6EYWAQL$4a5SAA-NH2 158 Ac-LTF34F2$4rn6EYWAQL$4a5SAA-NH2 159 Ac-LTF34F2$4rn6EYWAQhL$4a5SAA-NH2 160 Ac-LTF34rE2$4rnEYWAQhL$4a5SAA-NH 161 Ac-ETF$4rn-EYWAQL$4a5SAA-NH2 -94- WO 2013/123267 PCT/US2013/026241 SF- Sequence 162 Ac-LTF$4rn6AYWVQL$4a5SAA-NH2 163 Ac-LTF$4rn6AHWAQL$4a5SAA-NH2 164 Ac-LTF$4rn6AEWAQL$4a5SAA-NH2 165 Ac-LTF$4rn6ASWAQL$4a5SAA-NH2 166 Ac-LTF$4rn6AEWAQL$4a5SAA-NH2 167 Ac-LTF$4rn6ASWAQL$4a5SAA-NH2 168 Ac-LTF$4rn6AF4coohWAQL$4a5SAA-NH2 169 Ac-LTF$4rn6AF4coohWAQL$4a5SAA-NH2 170 Ac-LTF$4rn6AHWAQL$4a5AAla-NH2 171 Ac-ITF$4rn6FYWAQL$4a5AAla-NH2 172 Ac-ITF$4rn6EHWAQL$4a5AAla-NH2 173 Ac-ETF$4rn6EHWAQL$4a5AAla-NH2 174 Ac-ETF$4rn6EHWAQL$4a5AAla-NH2 175 Ac-ETF$4rn6EHWAQL$4a5AAla-NH2 176 Ac-LTF$4rn6AHWVQL$4a5AAla-NH2 177 Ac-ITF$4rn6FYWVQL$4a5AAla-NH2 178 Ac-ITF$4rn6EYWVQL$4a5AAla-NH2 179 Ac-LTF$4rn6EHWVQL$4a5AAla-NH2 180 Ac-LTF$4rn6AEWAQL$a5AA~a-NH2 181 Ac-LTF$4rn6AF4coohWAQL$4a5AAla-NH2 182 Ac-LTF$4rn6AF4coohWAQL$4a5AAa-NH2 183 Ac-LTF$4rn6AHWAQL$4a5AHFA-NH2 184 Ac-ITF$4rn6FYWAQL$4a5AHFA-NH2 185 Ac-ITF$4rn6FYWAQL$4a5AHFA-NH2 186 Ac-ITF$4rn6FHWAQL$4a5AEFA-NH2 187 Ac-ITF$4rn6FHWAQL$4a5AEFA-NH2 188 Ac-ITF$4rn6EHWAQL$4a5AHFA-NH2 189 Ac-LTF$4rn6EHWAQL$4a5AHFA-NH2 190 Ac-LTF$4rn6AHWVQL$4a5AHFA-NH2 191 Ac-ITF$4rn6FYWVQL$4a5AHFA-NH2 192 Ac-ITF$4rn6EYWVQL$4a5AHFA-NH2 193 Ac-ITF$4rn6EHWVQL$4a5AHFA-NH2 194 Ac-ETF$4rn6EHWVQL$4a5AHFA-NH2 195 Ac-ETF$4rn6EYWAAL$4a5SAA-NH2 196 Ac-LTF$4rn6AYWVAL$4a5SAA-NH2 197 Ac-LTF$4rn6AHWAAL$4a5SAA-NH2 198 Ac-LTF$4rn6AEWAAL$4a5SAA-NH2 199 Ac-LTF$4rn6AEWAAL$4a5SAA-NH2 200 Ac-LTF$4rn6ASWAAL$4a5SAA-NH2 201 Ac-LTF$4rn6ASWAAL$4a5SAA-NH2 202 Ac-LTF$4rn6AYWAAL$4a5AAla-NH2 203 Ac-LTF$4rn6AYWAAL$4a5AAa-NH2 204 Ac-LTF$4rn6AYWAAL$4a5AHFA-NH2 205 Ac-LTF$4rn6EHWAQL$4a5AHTa-NH2 206 Ac-LTF$4rn6EHWAQL$4a5AHIa-NH2 207 Ac-LTF$4rn6AHWAQL$4a5AHTa-NH2 208 Ac-LTF$4rn6EYWAQL$4a5AHa-NH2 209 Ac-LTF$4rn6AYWAQL$4a5AAFa-NH2 210 Ac-LTF$4rn6AYWAQL$4a5AAFa-NH2 211 Ac-LTF$4rn6AYWAQL$4a5AAWa-NH2 212 Ac-LTF$4rn6AYWAQL$4a5AAVa-NH2 213 Ac-LTF$4rn6AYWAQL$4a5AAVa-NH2 214 Ac-LTF$4rn6AYWAQL$4a5AALa-NH2 215 Ac-LTF$4rn6AYWAQL$4a5AALa-NH2 216 Ac-LTF$4rn6EYWAQL$4a5AAla-NH2 217 Ac-LTF$4rn6EYWAQL$4a5AA~a-NH2 218 Ac-LTF$4rn6EYWAQL$4a5AAFa-NH2 219 Ac-LTF$4rn-EYWAQL$4a5AAFa-NH2 -95- WO 2013/123267 PCT/US2013/026241 SF- Sequence 220 Ac-LTF$4rn6EYWAQL$4a5AAVa-NH2 221 Ac-LTF$4rn6EYWAQL$4a5AAVa-NH2 222 Ac-LTF$4rn6EHWAQL$4a5AAla-NH2 223 Ac-LTF$4rn6EHWAQL$4a5AA~a-NH2 224 Ac-LTF$4rn6EHWAQL$4a5AAWa-NH2 225 Ac-LTF$4rn6EHWAQL$4a5AAWa-NH2 226 Ac-LTF$4rn6EHWAQL$4a5AALa-NH2 227 Ac-LTF$4rn6EHWAQL$4a5AALa-NH2 228 Ac-ETF$4rn6EHWVQL$4a5AALa-NH2 229 Ac-LTF$4rn6AYWAQL$4a5AAAa-NH2 230 Ac-LTF$4rn6AYWAQL$4a5AAAa-NH2 231 Ac-LTF$4rn6AYWAQL$4a5AAAibA-NH2 232 Ac-LTF$4rn6AYWAQL$4a5AAAibA-NH2 233 Ac-LTF$4r56AYWAQL$4a5AAAa-NH2 234 Ac-LTF$r5AYWAQL$4a5s8AAa-NH2 235 Ac-LTF$r5AYWAQL$4a55BSAA-NH2 236 Ac-LTF$4rn6AYWAQCba$4a5AANleA-NH2 237 Ac-ETF$4rn6AYWAQCba$4a5AANleA-NH2 238 Ac-LTF$4rn6EYWAQCba$4a5AANleA-NH2 239 Ac-LTF$4rn6AYWAQCba$4a5AWNleA-NH2 240 Ac-ETF$4rn6AYWAQCba$4a5AWNleA-NH2 241 Ac-LTF$4rn6EYWAQCba$4a5AWNeA-NH2 242 Ac-LTF$4rnEYWAQCba$4aSAFA-NH2 243 Ac-LTF34F2$4rn6EYWAQCba$4a5SANleA-NH2 244 Ac-LTF$4rn6EF4coohWAQCba$4a5SANleA-NH2 245 Ac-LTF$4rn6EYWSQCba$4a5SANleA-NH2 246 Ac-LTF$4rn6EYWWQCba$4a5SANeA-NH2 247 Ac-LTF$4rn6EYWAQCba$4a5AAaa-NH2 248 Ac-LTF34F2$4rncEYWAQCba$4a5AAIa-NH2 249 Ac-LTF$4rn6EF4coohWAQCba$4a5AAa-NH2 250 Pam-ETF$4rn6EYWAQCba$4a5SAA-NH2 251 Ac-LTAF$4rn6EFWAQCba$4a5SAA-NH2 252 Ac-LTA$4rn6EYWAQCba$4a5SAA-NH2 253 Ac-LTF$4rn6EYAAQCba$4a5SAA-NH2 254 Ac-LTF$4rn6EY2NalAQCba$4a5SAA-NH2 255 Ac-LTF$4rn6AYWAQCba$4a5SAA-NH2 256 Ac-LTF$4rn6EYWAQCba$4a5SAF-NH2 257 Ac-LTF$4rn6EYWAQCba$4a5SAFa-NH2 258 Ac-LTF$4rn6AYWAQCba$4a5SAF-NH2 259 Ac-LTF34F2$4rn6AYWAQCba$4a5SAF-NH2 260 Ac-LTF$4rn6AF4coohWAQCba$4a5SAF-NH2 261 Ac-LTF$4rn6EY6cIWAQCba$4a5SAF-NH2 262 Ac-LTF$4rn6AYWSQCba$4a5SAF-NH2 263 Ac-LTF$4rn6AYWWQCba$4a5SA-NH2 264 Ac-LTF$4rn6AYWAQCba$4a5AAIa-NH2 265 Ac-LTE34F2$4rn6AYWAQCba$4a5AATa-NH2 266 Ac-LTF$4rn6AYchWAQCba$4a5AAIa-NH2 267 Ac-LTF$4rn6AF4coohWAQCba$4a5AATa-NH2 268 Ac-LTF$4rn6EYWAQCba$4a5AAFa-NH2 269 Ac-LTF$4rn6EYWAQCba$4a5AAFa-NH2 270 Ac-ETF$4rn6AYWAQCba$4a5AWNlea-NH2 271 Ac-LTF$4rn6EYWAQCba$4a5AWNlea-NH2 272 Ac-ETF$4rn6EYWAQCba$4a5AWNlea-NH2 273 Ac-ETF$4rn6EYWAQCba$4a5AWNlea-NH2 274 Ac-LTF$4rn6AYWAQCba$4a5SAFa-NH2 275 Ac-LTF$4rn6AYWAQCba$4a5SAFa-NH2 276 Ac-ETF$4rn6AYWAQL$4a5AWNlea-NH2 277 Ac-LTF$4cn-EYWAQL$4a5AWNlea-NH2 -96- WO 2013/123267 PCT/US2013/026241 SF- Sequence 278 Ac-ETF$4rn6EYWAQL$4a5AWNlea-NH2 279 Dmaac-LTF$4rn6EYWAQhL$4a5SAA-NH2 280 Hexac-LTF$4rn6EYWAQhL$4a5SAA-NH2 281 Napac-LTF$4rn6EYWAQhL$4a5SAA-NH2 282 Decac-LTF$4rn6EYWAQhL$4a5SAA-NH2 283 Admac-LTF$4rn6EYWAQhL$4a5SAA-NH2 284 Tmac-LTF$4rn6EYWAQhL$4a5SAA-NH2 285 Pam-LTF$4rn6EYWAQhL$4a5SAA-NH2 286 Ac-LTF$4rn6AYWAQCba$4a5AANleA-NH2 287 Ac-LTF34F2$4rn6EYWAQCba$4a5AAIa-NH2 288 Ac-LTF34F2$4rn6EYWAQCba$4a5SAA-NH2 289 Ac-LTF34F2$4rn6EYWAQCba$4a5SAA-NH2 290 Ac-LTF$4rn6EF4coohWAQCba$4a5SAA-NH2 291 Ac-LTF$4rn6EF4coohWAQCba$4a5SAA-NH2 292 Ac-LTF$4rn6EYWSQCba$4a5SAA-NH2 293 Ac-LTF$4rn6EYWSQCba$4a5SAA-NH2 294 Ac-LTF$4rn6EYWAQhL$4a5SAA-NH2 295 Ac-LTF$4rn6AYWAQhL$4a5SAF-NH2 296 Ac-LTF$4rn6AYWAQhL$4a5SAF-NH2 297 Ac-LTF34F2$4rn6AYWAQhL$4a5SAA-NH2 298 Ac-LTF34F2$4rn6AYWAQhL$4a5SAA-NH2 299 Ac-LTF$4rn6AF4coohWAQhL$4a5SAA-NH2 300 Ac-LTF$4rn6AF4coohWAQhL$4a5SAA-NH2 301 Ac-LTF$4rn6AYWSQhL$4a5SAA-NH2 302 Ac-LTF$4rn6AYWSQhL$4a5SAA-NH2 303 Ac-LTF$4rn6EYWAQL$4a5AANleA-NH2 304 Ac-LTF34F2$4rn6AYWAQL$4a5AANleA-NH2 305 Ac-LTF$4rn6AF4coohWAQL$4a5AANleA-NH2 306 Ac-LTF$4rn6AYWSQL$4a5AANleA-NH2 307 Ac-LTF34F2$4rn6AYWAQhL$4a5AANleA-NH2 308 Ac-LTF34F2$4rn6AYWAQhL$4a5AANleA-NH2 309 Ac-LTF$4rn6AF4coohWAQhL$4a5AANleA-NH2 310 Ac-LTF$4rn6AF4coohWAQhL$4a5AANleA-NH2 311 Ac-LTF$4rn6AYWSQhL$4a5AANleA-NH2 312 Ac-LTF$4rn6AYWSQhL$4a5AANleA-NH2 313 Ac-LTF$4rn6AYWAQhL$4a5AAAAa-NH2 314 Ac-LTF$4rn6AYWAQhL$4a5AAAAa-NH2 315 Ac-LTF$4rn6AYWAQL$4a5AAAAAa-NH2 316 Ac-LTF$4rn6AYWAQL$4a5AAAAAAa-NH2 317 Ac-LTF$4rn6AYWAQL$4a5AAAAAAa-NH2 318 Ac-LTF$4rn6EYWAQhL$4a5AANleA-NH2 319 Ac-AATF$4rn6AYWAQL$4a5AANleA-NH2 320 Ac-LTF$4rn6AYWAQL$4a5AANleAA-NH2 321 Ac-ALTF$4rn6AYWAQL$4a5AANleAA-NH2 322 Ac-LTF$4rn6AYWAQCba$4a5AANleAA-NH2 323 Ac-LTF$4rn6AYWAQhL$4a5AANleAA-NH2 324 Ac-LTF$4rn6EYWAQCba$4a5SAAA-NH2 325 Ac-LTF$4rn6EYWAQCba$4a5SAAA-NH2 326 Ac-LTF$4rn6EYWAQCba$4a5SAAAA-NH2 327 Ac-LTF$4rn6EYWAQCba$4a5SAAAA-NH2 328 Ac-ALTF$4rn6EYWAQCba$4a5SAA-NH2 329 Ac-ALTF$4rn6EYWAQCba$4a5SAAA-NH2 330 Ac-ALTF$4rn6EYWAQCba$4a5SAA-NH2 331 Ac-LTF$4rn6EYWAQL$4a5AAAAAa-NH2 332 Ac-LTF$4rn6EY6clWAQCba$4a5SAA-NH2 Ac-LTF$4rn6EF4cooh6clWAQCba$4a5SANleA 333 NH2 334 Ac-LTF$4rn6EF4cooh6clWAQCba$4a5SANleA -97- WO 2013/123267 PCT/US2013/026241 SF- Sequence NH2 Ac-LTF$4rn6EF4cooh6clWAQCba$4a5AAIa 335 NH2 Ac-LTF$4rn6EF4cooh6clWAQCba$4a5AAIa 336 NH2 337 Ac-LTF$4rn6AY6clWAQL$4a5AAAAAa-NH2 338 Ac-LTF$4rn6AY6clWAQL$4a5AAAAAa-NH2 339 Ac-F$4rn6AY6clWEAL$4a5AAAAAAa-NH2 340 Ac-ETF$4rn6EYWAQL$4a5AAAAAa-NH2 341 Ac-ETF$4rn6EYWAQL$4a5AAAAAa-NH2 342 Ac-LTF$4rn6EYWAQL$4a5AAAAAAa-NH2 343 Ac-LTF$4rn6EYWAQL$4a5AAAAAAa-NH2 344 Ac-LTF$4rn6AYWAQL$4a5AANleAAa-NH2 345 Ac-LTF$4rn6AYWAQL$4a5AANleAAa-NH2 346 Ac-LTF$4rn6EYWAQCba$4a5AAAAAa-NH2 347 Ac-LTF$4rn6EYWAQCba$4a5AAAAAa-NH2 348 Ac-LTF$4rn6EF4coohWAQCba$4a5AAAAAa-NH2 349 Ac-LTF$4rn6EF4coohWAQCba$4a5AAAAAa-NH2 350 Ac-LTF$4rn6EYWSQCba$4a5AAAAAa-NH2 351 Ac-LTF$4rn6EYWSQCba$4a5AAAAAa-NH2 352 Ac-LTF$4rn6EYWAQCba$4a5SAAa-NH2 353 Ac-LTF$4rn6EYWAQCba$4a5SAAa-NH2 354 Ac-ALTF$4rn6EYWAQCba$4a5SAAa-NH2 355 Ac-ALTF$4rn6EYWAQCba$4a5SAAa-NH2 356 Ac-ALTF$4rn6EYWAQCba$4a5SAAAa-NH2 357 Ac-ALTF$4rn6EYWAQCba$4a5SAAAa-NH2 358 Ac-AALTF$4rn6EYWAQCba$4a5SAAAa-NH2 359 Ac-AALTF$4rn6EYWAQCba$4a5SAAAa-NH2 360 Ac-RTF$4rn6EYWAQCba$4a5SAA-NH2 361 Ac-LRF$4rn6EYWAQCba$4a5SAA-NH2 362 Ac-LTF$4rn6EYWRQCba$4a5SAA-NH2 363 Ac-LTF$4rn6EYWARCba$4a5SAA-NH2 364 Ac-LTF$4rn6EYWAQCba$4a5RAA-NH2 365 Ac-LTF$4rn6EYWAQCba$4a5SRA-NH2 366 Ac-LTF$4rn6EYWAQCba$4a5SAR-NH2 367 5-FAM-BaLTF$4rn6EYWAQCba$4a5SAA-NH2 368 5-FAM-BaLTF$4rn6AYWAQL$4a5AANleA-NH2 369 Ac-LAF$4rn6EYWAQL$4a5AANleA-NH2 370 Ac-ATF$4rn6EYWAQL$4a5AANleA-NH2 371 Ac-AAF$4rn6EYWAQL$4a5AANleA-NH2 372 Ac-AAAF$4rn6EYWAQL$4a5AANleA-NH2 373 Ac-AAAAF$4rn6EYWAQL$4a5AANleA-NH2 374 Ac-AATF$4rn6EYWAQL$4a5AANleA-NH2 375 Ac-AALTF$4rn6EYWAQL$4a5AANleA-NH2 376 Ac-AAALTF$4rn6EYWAQL$4a5AANleA-NH2 377 Ac-LTF$4rn6EYWAQL$4a5AANleAA-NH2 378 Ac-ALTF$4rn6EYWAQL$4a5AANleAA-NH2 379 Ac-AALTF$4rn6EYWAQL$4a5AANleAA-NH2 380 Ac-LTF$4rn6EYWAQCba$4a5AANleAA-NH2 381 Ac-LTF$4rn6EYWAQhL$4a5AANleAA-NH2 382 Ac-ALTF$4rn6EYWAQhL$4a5AANleAA-NH2 383 Ac-LTF$4rn6ANmYWAQL$4a5AANleA-NH2 384 Ac-LTF$4rn6ANmYWAQL$4a5AANleA-NH2 385 Ac-LTF$4rn6AYNmWAQL$4a5AANleA-NH2 386 Ac-LTF$4rn6AYNmWAQL$4a5AANleA-NH2 387 Ac-LTF$4rn6AYAmwAQL$4a5AANleA-NH2 388 Ac-LTF$4rn6AYAmwAQL$4a5AANleA-NH2 389 Ac-LTF$4rn6AYWAibQL$4a5AANleA-NH2 -98- WO 2013/123267 PCT/US2013/026241 Y- Sequence 390 Ac-LTF$4rn6AYWAibQL$4a5AANleA-NH2 391 Ac-LTF$4rn6AYWAQL$4a5AAibNleA-NH2 392 Ac-LTF$4rn6AYWAQL$4a5AAibNleA-NH2 393 Ac-LTF$4rn6AYWAQL$4a5AaNleA-NH2 394 Ac-LTF$4rn6AYWAQL$4a5AaNleA-NH2 395 Ac-LTF$4rn6AYWAQL$4a5ASarNleA-NH2 396 Ac-LTF$4rn6AYWAQL$4a5ASarNleA-NH2 397 Ac-LTF$4rn6AYWAQL$4a5AANleAib-NH2 398 Ac-LTF$4rn6AYWAQL$4a5AANleAib-NH2 399 Ac-LTF$4rn6AYWAQL$4a5AANleNmA-NH2 400 Ac-LTF$4rn6AYWAQL$4a5AANleNmA-NH2 401 Ac-LTF$4rn6AYWAQL$4a5AANleSar-NH2 402 Ac-LTF$4rn6AYWAQL$4a5AANleSar-NH2 403 Ac-LTF$4rn6AYWAQL$4a5AANleAAib-NH2 404 Ac-LTF$4rn6AYWAQL$4a5AANleAAib-NH2 405 Ac-LTF$4rn6AYWAQL$4a5AANleANmA-NH2 406 Ac-LTF$4rn6AYWAQL$4a5AANleANmA-NH2 407 Ac-LTF$4rn6AYWAQL$4a5AANleAa-NH2 408 Ac-LTF$4rn6AYWAQL$4a5AANleAa-NH2 409 Ac-LTF$4rn6AYWAQL$4a5AANleASar-NH2 410 Ac-LTF$4rn6CAYWAQL$Q4a5AANleASar-NH2 413 Ac-LTF$4rn6Cou4YWAQL$4a5AANleA-NH2 414 Ac-LTF$4rn6Cou4YWAQL$4a5AANleA-NH2 415 Ac-LTF$4rn6AYWCou4QL$4a5AANleA-NH2 416 Ac-LTF$4rn6AYWAQL$4a5Cou4ANleA-NH2 417 Ac-LTF$4rn6AYWAQL$4a5Cou4ANleA-NH2 418 Ac-LTF$4rn6AYWAQL$4a5ACou4NleA-NH2 419 Ac-LTF$4rn6AYWAQL$4a5ACou4NleA-NH2 420 Ac-LTF$4rn6AYWAQL$4a5AANleA-OH 421 Ac-LTF$4rn6AYWAQL$4a5AANleA-OH 422 Ac-LTF$4rn6AYWAQL$4a5AANleA-NHnPr 423 Ac-LTF$4rn6AYWAQL$4a5AANleA-NHnPr 424 Ac-LTF$4rn6AYWAQL$4a5AANleA-NHnBu33Me 425 Ac-LTF$4rn6AYWAQL$4a5AANleA-NHnBu33Me 426 Ac-LTF$4rn6AYWAQL$4a5AANleA-NHHex 427 Ac-LTF$4rn6AYWAQL$4a5AANleA-NHHex 428 Ac-LTA$4rn6AYWAQL$4a5AANleA-NH2 429 Ac-LTFL$4rn6AYWAQL$4a5AANleA-NH2 430 Ac-LTF$4rn6AYAAQL$4a5AANleA-NH2 431 Ac-LTF$4rn6AY2NaAQL$4a5AANleA-NH2 432 Ac-LTF$4rn6EYWCou4QCba$4a5SAA-NH2 433 Ac-LTF$4rn6EYWCou7QCba$4a5SAA-NH2 435 Dmaac-LTF$4rn6EYWAQCba$4a5SAA-NH2 436 Dmaac-LTF$4rn6AYWAQL$4a5AAAAAa-NH2 437 Dmaac-LTF$4rn6AYWAQL$4a5AAAAAa-NH2 438 Dmaac-LTF$4rn6EYWAQL$4a5AAAAAa-NH2 439 Dmaac-LTF$4rnGEYWAQL$4aSAAAAAa-NH2 Dmaac-LTF$4rn6EF4coohWAQCba$4a5AATa 440 NH2 Dmaac-LTF$4rn6EF4coohWAQCba$4a5AAIa 441 NH2 442 Dmaac-LTF$4rn6AYWAQL$4a5AANleA-NH2 443 Dmaac-LTF$4rn6AYWAQL$4a5AANleA-NH2 444 Ac-LTF$4rn6AYWAQL$4a5AANleA-NH2 445 Ac-LTF$4rn6EYWAQL$4a5AAAAAa-NH2 446 Cou6BaLTF$4rn6EYWAQhL$4a5SAA-NH2 447 Cou8BaLTF$4rn6EYWAQhL$4a5SAA-NH2 448 Ac-LTF41$4rn6EYWAQL$4a5AAAAAa-NH2 -99- WO 2013/123267 PCT/US2013/026241 Table 4a SP Sequence ENact Found Calc Calc Calc Mass Mass 1'+l)/1 (NI+2)/2 :AI+3)/3 449 Ac-LTF$4rn6AYWAQL$4a5AANleA-NH2 1812.01 907.89 1813.02 907.01 605.01 450 Ac-LTF$4rn6AYWAQL$4a5AAAAAa-NH2 1912.04 957.75 1913.05 957.03 638.35 451 Ac-LTF$4rn6EYWAQL$4a5AAAAAa-NH2 1970.04 986.43 1971.05 986.03 657.69 452 Ac-LTF$5rn6AYWAQL$5a5AAAAAa-NH2 1912.04 957.38 1913.05 957.03 638.35 153 Ac-LTF$4rn6EYWAQCba$4a5SAA-NH2 1784.93 894.38 1785.94 893.47 595.98 454 Ac-LTF$4rn4EYWAQCba$4a5SAA-NH2 1756.89 880.05 1757.9 879.45 586.64 455 Ac-LTF$4rn5EYWAQCba$4a5SAA-NH2 1770.91 887.08 1771.92 886.46 591.31 456 Ac-LTF$5rn6EYWAQCba$5a5SAA-NH2 1784.92 894.11 1785.93 893.47 595.98 457 Ac-LTF$4rn6EYWAQCba5I-$4a5SAA-NH2 1910.82 957.01 1911.83 956.42 637.95 459 Ac-LTA$5rn6EYWAQCba$5a5SAA-NH2 1708.89 856 1709.9 855.45 570.64 460 Ac-LTA$4rn6EYWAQCba$4a5SAA-NH2 1708.89 856 1709.9 855.45 570.64 461 5-FAM-BaLTF$4rn6EYWAQCba$4a5SAA-NH2 2172 1087.81 2173.01 1087.01 725.01 462 5-FAM-BaLTA$4rn6EYWAQCba$4a5SAA-NH2 2095.97 1049.79 2096.98 1048.99 699.66 463 5-FAM-BaLTF$5rn6EYWAQCba$5a5SAA-NH2 2172 1087.53 2173.01 1087.01 725.01 464 5-FAM-BaLTA$5rn6EYWAQCba$5a5SAA-NH2 2095.97 1049.98 2096.98 1048.99 699.66 465 Ac-LTF$4rn6EYWAQCba5Ph-$4a5SAA-NH2 1675.87 932.31 1676.88 931.48 559.63 466 Ac-LTF$4rn6EYWAQCba5Prp-$4a5SAA-NH2 1675.87 914.46 1676.88 913.48 559.63 467 Ac-LTF$4rn6AYWAAL$4a5AAAAAa-NH2 1855.01 1856.02 928.51 619.34 Ac-LTF$4rn6EYWAQCba5penNH2-$4a5SAA- 1675.87 1676.88 838.94 559.63 468 NH2 Ac-LTF$4rn6EYWAQCba5BnzNH2-$4a5SAA- 1675.87 1676.88 838.94 559.63 469 NH2 Ac-LTF$4rn6EYWAQCba5prpCMe-$4a5SAA- 928.48 470 NH2 929.17 932 Ac-LTF$5rn6EYWAQL4MeS5a5AAAAAa-NH2 1926.05 1927.06 964.03 643.02 933 Ac-LTF$5rn6EYWAQL4Ph$5a5AAAAAa-NH2 1988.07 1989.07 995.04 663.70 934 Ac-LTFS5rn6EYWAQCba4MeS5a5SAANH2 1740.93 1741.94 871.48 581.32 935 Ac-LTF$5rn6EYWAQCba4Ph$5a5SAANH2 1802.95 1803.96 902.48 601.99 [00240] In the sequences shown above and elsewhere, the following abbreviations are used: "Ne" represents norleucine, "Aib" represents 2-aminoisobutyric acid, "Ac" represents acetyl, and "Pr" represents propionyl. Amino acids represented as "$" are alpha-Me S5-pentenyl-alanine olefin amino acids connected by an all-carbon crosslinker comprising one double bond. Amino acids represented as "$r5" are alpha-Me R5-pentenyl-alanine olefin amino acids connected by an all carbon comprising one double bond. Amino acids represented as "$s8" are alpha-Me S8-octenyl alanine olefin amino acids connected by an all-carbon crosslinker comprising one double bond. Amino acids represented as "$r8" are alpha-Me R8-octenyl-alanine olefin amino acids connected by an all-carbon crosslinker comprising one double bond. "Ahx" represents an aminocyclohexyl linker. The crosslinkers are linear all-carbon crosslinker comprising eight or eleven carbon atoms between the alpha carbons of each amino acid. Amino acids represented as "$/" are alpha-Me S5 pentenyl-alanine olefin amino acids that are not connected by any crosslinker. Amino acids represented as "$/r5" are alpha-Me R5-pentenyl-alanine olefin amino acids that are not connected by any crosslinker. Amino acids represented as "$/s8" are alpha-Me S8-octenyl-alanine olefin amino acids that are not connected by any crosslinker. Amino acids represented as "S/r8" are -100- WO 2013/123267 PCT/US2013/026241 alpha-Me R8-octenyl-alanine olefin amino acids that are not connected by any crosslinker. Amino acids represented as "Amw" are alpha-Me tryptophan amino acids. Amino acids represented as "Amil" are alpha-Me leucine amino acids. Amino acids represented as "Amf' are alpha-Me phenylalanine amino acids. Amino acids represented as "2ff' are 2-fluoro phenylalanine amino acids. Amino acids represented as "3ff' are 3-fluoro-phenylalanine amino acids. Amino acids represented as "St" are amino acids comprising two pentenyl-alanine olefin side chains, each of which is crosslinked to another amino acid as indicated. Amino acids represented as "St/I" are amino acids comprising two pentenyl-alanine olefin side chains that are not crosslinked. Amino acids represented as "%St" are amino acids comprising two pentenyl alanine olefin side chains, each of which is crosslinked to another amino acid as indicated via fully saturated hydrocarbon crosslinks. Amino acids represented as "Ba" are beta-alanine. The lower-case character "e" or "z" within the designation of a crosslinked amino acid (e.g. "$er8" or "$zr8") represents the configuration of the double bond (E or Z, re ectively). In other contexts, lower-case letters such as "a" or "f' represent D amino acids (e.g. D-alanine, or D-phenylalanine, respectively). Amino acids designated as "NmW" represent N-methyltryptophan. Amino acids designated as 'NmY" represent N-methyltyrosine. Amino acids designated as "NmA" represent N-methylalanine. Amino acids designated as "Sar" represent sarcosine. Amino acids designated as "Cha" represent cyclohexyl alanine. Amino acids designated as "Cpg" represent cyclopentyl glycine. Amino acids designated as "Chg" represent cyclohexyl glycine. Amino acids designated as "Cba" represent cyclobutyl alanine. Amino acids designated as "F41" represent 4-iodo phenylalanine. Amino acids designated as "F3Cl" represent 3-chloro phenylalanine. Amino acids designated as "F4cooh" represent 4-carboxy phenylalanine. Amino acids designated as "F34F2" represent 3,4-difluoro phenylalanine. Amino acids designated as "6clW" represent 6-chloro tryptophan. The designation "iso 1" or "iso2" indicates that the peptidomimetic macrocycle is a single isomer. "Ac3c" represents a aminocyclopropane carboxylic acid residue. [00241] Amino acids designated as "Cou4", "Cou6", "Cou7" and "Cou8", respectively, represent the following structures: -101- WO 2013/123267 PCT/US2013/026241 N 0 0 N O O O 0 HN HN H 0 N ' N H H 0 0 Cou Cou2 Cou3 o HO O 0 O N OA - 0 L ~H N N H 0 0 'N H 0 Cou4 Cou6 Cou HO O a 0 Cou8 [00242] In some embodiments, a peptidomimetic macrocycle is obtained in more than one isomer, for example due to the configuration of a double bond within the structure of the crosslinker (E vs Z). Such isomers can or can not be separable by conventional chromatographic methods. In some embodiments, one isomer has improved biological properties relative to the other isomer. In one embodiment, an E crosslinker olefin isomer of a peptidomimetic macrocycle has better solubility, better target affinity, better in vivo or in vitro efficacy, higher helicity, or improved cell permeability relative to its Z counterpart. In another embodiment, a Z crosslinker olefin isomer of a peptidomimetic macrocycle has better solubility, better target affinity, better in vivo or in vitro efficacy, higher helicity, or improved cell permeability relative to its E counterpart. [00243] Amino acids forming crosslinkers are represented according to the legend indicated below. -102- WO 2013/123267 PCT/US2013/026241 [00244] Stereochemistry at the alpha position of each amino acid is S unless otherwise indicated. Amino acids labeled "4Me" were prepared using an amino acid comprising an alkyne which was methyl substituted (internal alkyne), resulting in triazole groups comprising a methyl group at the 4 position. Amino acids labeled "4Ph" were prepared using an amino acid comprising an alkyne which was phenyl-substituted (internal alkyne), resulting in triazole groups comprising a phenyl group at the 4-position. For azide amino acids, the number of carbon atoms indicated refers to the number of methylene units between the alpha carbon and the terminal azide. For alkyne amino acids, the number of carbon atoms indicated is the number of methylene units between the alpha position and the triazole moiety plus the two carbon atoms within the triazole group derived from the alkyne. $5n3 Alpha-Me azide 1,5 triazole (3 carbon) #5n3 Alpha-H azide 1,5 triazole (3 carbon) $4a5 Alpha-Me alkyne 1,4 triazole (5 carbon) S4a6 Alpha-Me alkyne 1,4 triazole (6 carbon) S5a5 Alpha-Me alkyne 1,5 triazole (5 carbon) $5a6 Alpha-Me alkyne 1,5 triazole (6 carbon) #4a5 Alpha-H alkyne 1,4 triazole (5 carbon) #5a5 Alpha-H alkyne 1,5 triazole (5 carbon) $5n5 Alpha-Me azide 1,5 triazole (5 carbon) S5n6 Alpha-Me azide 1,5 triazole (6 carbon) S4n5 Alpha-Me azide 1,4 triazole (5 carbon) $4n6 Alpha-Me azide 1,4 triazole (6 carbon) S4ra5 Alpha-Me R-alkyne 1,4 triazole (5 carbon) S4ra6 Alpha-Me R-alkyne 1,4 triazole (6 carbon) $4rn4 Alpha-Me R-azide 1,4 triazole (4 carbon) $4m5 Alpha-Me R-azide 1,4 triazole (5 carbon) $4m6 Alpha-Me R-azide 1,4 triazole (6 carbon) S5rn5 Alpha-Me R-azide 1,5 triazole (5 carbon) $5ra5 Alpha-Me R-alkyne 1,5 triazole (5 carbon) $5ra6 Alpha-Me R-alkyne 1,5 triazole (6 carbon) $5m6 Alpha-Me R-azide 1,5 triazole (6 carbon) #5m6 Alpha-H R-azide 1,5 triazole (6 carbon) $4m5 Alpha-Me R-azide 1,4 triazole (5 carbon) #4m5 Alpha-H R-azide 1,4 triazole (5 carbon) 4MeS5rn6 Alpha-Me R-azide 1,5 triazole (6 carbon); 4-Me substituted triazole 4MeS5a5 Alpha-Me alkyne 1,5 triazole (5 carbon); 4-Me substituted triazole 4Ph$5a5 Alpha-Me alkyne 1,5 triazole (5 carbon); 4-phenyl substituted triazole [00245] Amino acids designated as "5I", "5penNH2", "5BnzNH2", "5prpOMe", "5Ph", and "5prp", refer to crosslinked amino acids of the type shown in the following exemplary peptidomimetie macrocycle of Formula I: -103- WO 2013/123267 PCT/US2013/026241 N= N
N
7 0 x Glu-Tyr-HN H 0 Leu-Thr-Phe-HN G-N Ser-Ala-Ala-NH 2 AIa-GIn N N 0 0 H N. H [00246] In the above structure, X is, for example, one of the following substituents: Cyc NRRb oH OHN 0 0 R 0 0 R -Alkyl '. Cyc ' Ra Ra Raa ny Rb 00 0 o NRRRa Cyc R n .0 e Cyc iAlkyl OH h c r flC NRaRbn nn n K NRaRb RaN 0 0 wherein "Cyc" is a suitable aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with an Ra or Rb group as described above. [00247] In some embodiments, the triazole substituent is chosen from the group consisting of:
NH
2
NH
2 0 5penNH2 5BnzNH2 5prpOMe 5Ph 5prp [00248] Table 4 shows exemplary peptidomimetic macrocycles of Formula I: -104- WO 2013/123267 PCT/US2013/026241 Table 4b Structure PN N SP- A 0aT0[ '1,' H 0 SLeu-Thr-Phe-HN AAla-Gln N Ala-AlaN Ala-NH 2 449 0 H 0/ 0 H Chemical Formula: CgH133N21019 Exact Mass: 1812.01 Ac- L T F $4rn6 A Y W A Q L $4a5 A A Nle A -NH2 MolecularWeight: 1813.15 SP- N N 64 N LeuThrPheHN Ala-Tyr-HN Ala-Gn Ala-Ala-Ile, NH2 0 H 0 H 0 O Chemical Formula: CoH1 33 N21019 N Exact Mass: 1812.01 H Molecular Weight: 1813.15 Ac- L T F $4rn6 A Y W A Q L $4a5 A A I a -NH2 SP- ,qN N .. 153 Leu-Thr-Phe-HN Glu-Tyr-HN Ala-Gln N Ser-Ala-Ala-NH 2 O H SH 0 Chemical Formula: Cg7H1 2 4
N
2 0021 N . Exact Mass: 1784.92 H Molecular Weight: 1786.04 Ac- L T F $4rn6 E Y W A Q Cba $4a5 S A A -NH2 SP- N 98 N Leu-Thr-Phe-HN Ala-Tyr-HN Ala-Gln N Ser-Ala-Ala-NH 2 0 H 0 D O NChemical Formula: C 8 4
H
121
CIN
20 0 19 N a Exact Mass: 1748.88 H C Molecular Weight: 1750.44 Ac- L T F $4rn6 A Y 6clW A Q L $4a5 S A A -NH2 -105- WO 2013/123267 PCT/US2013/026241 SP- N 456 N 0 Leu-Thr-Phe-HN Glu-Tyr-HN H Il GN- NJ Ser-Ala-Ala-NH 2 Chemical Formula: C 8 7
H
124
N
20 0 21 N Exact Mass: 1784.92 H Molecular Weight: 1786.04 Ac-L T F $5rn6 E Y W A Q Cba $5a5 S AA -NH2
SP
0 470 N N 'N=N Glu-Tyr-HN H 0 Leu-Thr-Phe-HN G-H AlaGl Ser-Ala-Ala-NH 2 O 00 N H [00249] In some embodiments, peptidomimetic macrocycles exclude peptidomimetic macrocycles shown in Table 5: Table 5 # Sequence 1 Ac-QSQQTF$5rn6NLWRLL$5a5QN-NH2 2 Ac-QSQQTF$4rn5NLWRLL$4a5QN-NH2 3 Ac-QSQQTF#5rn6NLWRLL#5a5QN-NH2 4 Ac-QSQQTF#4rn5NLWRLL#4a5QN-NH2 5 Ac-QSQQTF$5rn5NLWRLL$5a5QN-NH2 6 Ac-QSQQTF$5ra5NLWRLL$5n5QN-NH2 7 Ac-QSQQTF$5ra5NLWRLL$5n6QN-NH 2 8 Ac-QSQQTF$4ra5NLWRLL$4n5QN-NH 2 9 Ac-QSQQTF$4ra5NLWRLL$4n6QN-NH2 10 Ac-QSQQTF$4rn6NLWRLL$4a5QN-NH2 11 Ac-QSQQTF$5rn6NLWRLL$5a6QN-NH2 12 Ac-QSQQTF$5ra6NLWRLL$5n6QN-NH2 13 Ac-QSQQTF$4rn6NLWRLL$4a6QN-NH2 14 Ac-QSQQTF$4ra6NLWRLL$4n6QN-NH2 15 Ac-QSQQTF$4rn5NLWRLL$4a6QN-NH2 16 Ac-QSQQTF4Me$5rn6NLWRLL4Me$5a5QN-NH2 17 Ac-LTF$4ra5HYWAQL$4n6S-NH2 18 H-F$4rn6HYWAQL$4a5S-NH2 19 Ac-LTF$4rn6HYWAQL$4a5S-NH2 20 Ac-F$4rn6HYWAQL$4a5S-NH2 21 Ac-LTF$4rn6HYWAQL$4a6S-NH2 -106- WO 2013/123267 PCT/US2013/026241 22 Ac-LTF$5ra5HYWAQL$5n6S-NH2 23 Ac-LTF$4rn6AYWAQL$4a5A-NH2 24 Ac-LTF$5ra5HYWAQL$5n6S-NH2 25 Ac-LTF$4rn6AYWAQL$4a5A-NH2 26 Ac-LTFEHYWAQLTS-NH2 [00250] Peptides shown can comprise an N-terminal capping group such as acetyl or an additional linker such as beta-alanine between the capping group and the start of the peptide sequence. [00251] In some embodiments, peptidomimetic macrocycles do not comprise a peptidomimetic macrocycle structure as shown in Table 5. Example 3: Peptidomimetic macrocycles of Formula II [00252] Peptidomimetic macrocycles were designed by replacing two or more naturally occurring amino acids with the corresponding synthetic amino acids. Substitutions were made at i and i+4, and i and i+7 positions. Macrocycles were generated by solid phase peptide synthesis followed by crosslinking the peptides via their thiol-containing side chains. Peptide synthesis is performed either manually or on an automated peptide synthesizer (Applied Biosystems, model 433A), using solid phase conditions, rink amide AM resin (Novabiochem), and Fmoc main-chain protecting group chemistry. The N-termini of the synthetic peptides are acetylated, while the C termini are amidated. [00253] The fully protected resin-bound peptides are synthesized on a Rink amide MBHA resin (loading 0.62 mmol/g) on a 0.1 mmol scale. Deprotection of the temporary Fmoc group is achieved by 2 x 20 min treatments of the resin bound peptide with 25% (v/v) piperidine in NMP. After extensive flow washing with NMP and dichloromethane, coupling of each successive amino acid was achieved with 1 x 60 min incubation with the appropriate preactivated Fmoc-amino acid derivative. All protected amino acids (1 mmol) were dissolved in NMP and activated with HCTU (1 mmol) and DIEA (1 mmol) prior to transfer of the coupling solution to the deprotected resin bound peptide. After coupling was completed, the resin was extensively flow washed in preparation for the next deprotection/coupling cycle. Acetylation of the amino terminus was carried out in the presence of acetic anhydride/DIEA in NMP /NMM. The LC-MS analysis of a cleaved and deprotected sample obtained from an aliquot of the fully assembled resin-bound peptide was accomplished in order to verifying the completion of each coupling. [00254] Purification of cross-linked compounds is achieved by high performance liquid chromatography (HPLC) (Varian ProStar) on a reverse phase C18 column (Varian) to yield the pure compounds. Chemical composition of the pure products was confirmed by LC/MS mass spectrometry (Micromass LCT interfaced with Agilent 1100 HPLC system) and amino acid analysis (Applied Biosystems, model 420A). [00255] In a typical example, a peptide resin (0.1 mmol) was washed with DCM. Deprotection of the temporary Mmt group was achieved by 3 x 3 min treatments of the resin bound peptide with 2% -107- WO 2013/123267 PCT/US2013/026241 TFA/DCM 5% TIPS, then 30min treatments until no orange color is observed in the filtrate. In between treatments the resin was extensively flow washed with DCM. After complete removal of Mmt, the resin was washed with 5% DIEA/NMP solution 3X and considered ready for bisthioether coupling. Resin was loaded into a reaction vial. DCM/DMF 1/1 was added to the reaction vessel, followed by DIEA (2.4eq). After mixing well for 5 minutes, 4,4' Bis(bromomethyl)biphenyl (1.05 eq) (TCI America B1921) was added. The reaction was then mechanically agitated at room temperature overnight. Where needed, the reaction was allowed additional time to reach completion. A similar procedure may be used in the preparation of five methylene, six-methylene or seven-methylene crosslinkers ("%c7", "%c6", or "%c5"). [00256] The bisthioether resin-bound peptides were deprotected and cleaved from the solid support by treatment with TFA/H 2 0/TIS (94/3/3 v/v) for 3 h at room temperature. After filtration of the resin the TFA solution was precipitated in cold diethyl ether and centrifuged to yield the desired product as a solid. The crude product was purified by preparative HPLC. [00257] Table 6 show a list of peptidomimetic macrocycles. Table 6 SIP Aequence 471 Ac-F%cs7AYWEAc3cL%c7AAA-NH2 472 Ac-F%cs7AYWEAc3cLc7AAibA-NH2 473 Ac-LTF%cs7AYWAQL%c7SAN1e-NH2 474 Ac-LTF%cs7AYWAQL%c7SAL-NH2 475 Ac-LTF%cs7AYWAQL%c7SAM-NH2 476 Ac-LTF%cs7AYWAQL%c7SAhL-NH2 477 Ac-LTF%cs7AYWAQL%c7SAF-NH2 478 Ac-LTF%cs7AYWAQL%c7SAT-NH2 479 Ac-LTF%cs7AYWAQL%c7SAChg-NH2 480 Ac-LTF%cs7AYWAQL%c7SAAib-NH2 481 Ac-LTF%cs7AYWAQL%c7SAA-NH2 482 Ac-LTF%cs7AYWA%c7L%c7S%c7Nle-NH2 483 Ac-LTF%cs7AYWA%c7L%c7S%c7A-NH2 484 Ac-F%cs7AYWEAc3cL%c7AANe-NH2 485 Ac-F%cs7AYWEAc3cL%c7AAL-NH2 486 Ac-F%cs7AYWEAc3cL%c7AAM-NH2 487 Ac-F%cs7AYWEAc3cL%c7AAhL-NH2 488 Ac-F%cs7AYWEAc3cL%c7AAF-NH2 489 Ac-F%cs7AYWEAc3cL%c7AAT-NH2 490 Ac-F%cs7AYWEAc3cL%c7AAChg-NH2 491 Ac-F%cs7AYWEAc3cL%c7AACha-NH2 492 Ac-F%cs7AYWEAc3cL%c7AAAib-NH2 493 Ac-LTF%cs7AYWAQL%c7AAAibV-NH2 494 Ac-LTF%cs7AYWAQL%c7AAAibV-NH2 495 Ac-LTF%cs7AYWAQL%c7SAibAA-NH2 496 Ac-LTF%cs7AYWAQL%c7SAibAA-NH2 497 Ac-HLTF%cs7HHWHQL%c7AANLeNe-NH2 498 Ac-DLTF%cs7HHWHQL%c7RRLV-NH2 499 Ac-HHTF%cs7HHWHQL%c7AAML-NH2 500 Ac-F%cs7HHWHQL%c7RRDCha-NH2 501 Ac-F%cs7HHWHQL%c7HRFV-NH2 502 Ac-HLTF%cs7HHWHQL%c7AAhLA-NH2 503 Ac-DLTF%cs7HHWHQL%c7RRChgl-NH2 -108- WO 2013/123267 PCT/US2013/026241 SI P Sequence 504 Ac-DLTF cs7HHWHQL c7RRChgl-NH2 505 Ac-HHTF cs7HHWHQL c7AAChav-NH2 506 Ac-Fcs7HHWHQLc7RRDa-NH2 507 Ac-Fcs7HHWHQLc7HRAibG-NH2 508 Ac-Fcs7AYWAQLc7HHNleL-NH2 509 Ac-Fcs7AYWSALc7HQANle-NH2 510 Ac-Fcs7AYWVQLc7QHChgl-NH2 511 Ac-Fcs7AYWTALc7QQNlev-NH2 512 Ac-Fcs7AYWYQLc7HAibAa-NH2 513 Ac-LTFcs7AYWAQLc7HHLa-NH2 514 Ac-LTFcs7AYWAQLc7HHLa-NH2 515 Ac-LTFcs7AYWAQLc7HQNlev-NH2 516 Ac-LTFcs7AYWAQLc7HQNlev-NH2 517 Ac-LTFcs7AYWAQLc7QQM1-NH2 518 Ac-LTFcs7AYWAQLc7QQM1-NH2 519 Ac-LTFcs7AYWAQLc7HAibhLV-NH2 520 Ac-LTFcs7AYWAQLc7AHFA-NH2 521 Ac-HLTFcs7HHWHQLc7AANlel-NH2 522 Ac-DLTFcs7HHWHQLc7RRLa-NH2 523 Ac-HHTF%cs7HHWHQLc7AAMv-NH2 524 Ac-Fcs7HHWHQLc7RRDA-NH2 525 Ac-F%cs7HHWHQLc7HRFCha-NH2 526 Ac-Fcs7AYWEALc7AA-NHAm 527 Ac-F%cs7AYWEALc7AA-NHiAm 528 Ac-Fcs7AYWEALc7AA-NHnPr3Ph 529 Ac-F%cs7AYWEALc7AA-NHnBu33Me 530 Ac-Fcs7AYWEALc7AA-NHnPr 531 Ac-F%cs7AYWEALc7AA-NHnEt2Ch 532 Ac-Fcs7AYWEALc7AA-NHnEt2Cp 533 Ac-F%cs7AYWEALc7AA-NHHex 534 Ac-LTFcs7AYWAQLc7AAIA-NH2 535 Ac-LTFcs7AYWAQLc7AAIA-NH2 536 Ac-LTFcs7AYWAALc7AAMA-NH2 537 Ac-LTFcs7AYWAALc7AAMA-NH2 538 Ac-LTFcs7AYWAQLc7AANleA-NH2 539 Ac-LTFcs7AYWAQLc7AANleA-NH2 540 Ac-LTFcs7AYWAQLc7AAIa-NH2 541 Ac-LTFcs7AYWAQLc7AAIa-NH2 542 Ac-LTFcs7AYWAALc7AAMa-NH2 543 Ac-LTFcs7AYWAALc7AAMa-NH2 544 Ac-LTFcs7AYWAQLc7AANlea-NH2 545 Ac-LTFcs7AYWAQLc7AANlea-NH2 546 Ac-LTFcs7AYWAALc7AAIv-NH2 547 Ac-LTFcs7AYWAALc7AATv-NH2 548 Ac-LTFcs7AYWAQLc7AAMv-NH2 549 Ac-LTFcs7AYWAALc7AANlev-NH2 550 Ac-LTFcs7AYWAAL c7AANlev-NH2 551 Ac-LTFcs7AYWAQLc7AATI-NH2 552 Ac-LTFcs7AYWAQLc7AAIl-NH2 553 Ac-LTF%cs7AYWAALc7AAMl-NH2 554 Ac-LTFcs7AYWAQLc7AANlel-NH2 555 Ac-LTF%cs7AYWAQLc7AANlel-NH2 556 Ac-F%cs7AYWEALc7AAMA-NH2 557 Ac-Fcs7AYWEALc7AANleA-NH2 558 Ac-F%cs7AYWEALc7AAla-NH2 559 Ac-Fcs7AYWEALc7AAMa-NH2 560 Ac-Fcs7AYWEALc7AANlea-NH2 561 Ac-Fcs7AYWEALc7AAlv-NH2 -109- WO 2013/123267 PCT/US2013/026241 2 P Sequence 562 Ac-F cs7AYWEAL c7AAMv-NH2 563 Ac-F cs7AYWEAL c7AANlev-NH2 564 Ac-Fcs7AYWEALc7AATl-NH2 565 Ac-Fcs7AYWEALc7AAMl-NH2 566 Ac-Fcs7AYWEALc7AANlel-NH2 567 Ac-F%cs7AYWEALc7AANLe-NH2 568 Ac-LTFcs7AY6clWAQLc7SAA-NH2 569 Ac-LTF%cs7AY6c1WAQLc7SAA-NH2 570 Ac-WTF%cs7FYWSQLc7AVAa-NH2 571 Ac-WTFcs7FYWSQLc7AVAa-NH2 572 Ac-WTFcs7VYWSQLc7AVA-NH2 573 Ac-WTFcs7VYWSQLc7AVA-NH2 574 Ac-WTFcs7FYWSQLc7SAAa-NH2 575 Ac-WTFcs7FYWSQLc7SAAa-NH2 576 Ac-WTFcs7VYWSQLc7AVAaa-NH2 577 Ac-WTFcs7VYWSQLc7AVAaa-NH2 578 Ac-LTFcs7AYWAQLc7AVG-NH2 579 Ac-LTF%cs7AYWAQLc7AVG-NH2 580 Ac-LTFcs7AYWAQLc7AVQ-NH2 581 Ac-LTF%cs7AYWAQLc7AVQ-NH2 582 Ac-LTFcs7AYWAQLc7SAa-NH2 583 Ac-LTF%cs7AYWAQL%c7SAa-NH2 584 Ac-LTFcs7AYWAQhLc7SAA-NH2 585 Ac-LTF%cs7AYWAQhLtc7SAA-NH2 586 Ac-LTFcs7AYWEQLStSALc7-NH2 587 Ac-LTF%cs7AYWAQLc7SLA-NH2 588 Ac-LTFcs7AYWAQLc7SLA-NH2 589 Ac-LTF%cs7AYWAQLc7SWA-NH2 590 Ac-LTFcs7AYWAQLc7SWA-NH2 591 Ac-LTF%cs7AYWAQLc7SVS-NH2 592 Ac-LTFcs7AYWAQLc7SAS-NH2 593 Ac-LETF%cs7AYWAQLc7SVG-NH2 594 Ac-ETF%cs7VYWAQLc7SAa-NH2 595 Ac-ETF%cs7VYWAQLc7SAA-NH2 596 Ac-ETF%cs7VYWAQLc7SVA-NH2 597 Ac-ETF%cs7VYWAQLc7SLA-NH2 598 Ac-ETF%cs7VYWAQLc7SWA-NH2 599 Ac-ETF%cs7KYWAQLc7SWA-NH2 600 Ac-ETF%cs7VYWAQLc7SVS-NH2 601 Ac-ETF%cs7VYWAQLc7SAS-NH2 602 Ac-ETF%cs7VYWAQLc7SVG-NH2 603 Ac-LTF%cs7VYWAQLc7SSa-NH2 604 Ac-ETF%cs7VYWAQLc7SSa-NH2 605 Ac-LTF%cs7VYWAQLc7SNa-NH2 606 Ac-ETF%cs7VYWAQLc7SNa-NH2 607 Ac-LTF%Cs7VYWAQLc7SAa-NH2 608 Ac-LTFcs7VYWAQLc7SVA-NH2 609 Ac-LTF%Cs7VYWAQLc7SVA-NH2 610 Ac-LTFcs7VYWAQLc7SWA-NH2 611 Ac-LTF%cs7VYWAQLc7SVS-NH2 612 Ac-LTF%cs7VYWAQLc7SVS-NH2 613 Ac-LTF%CS7VYWAQLc7SAS-NH2 614 Ac-LTF%cs7VYWAQLc7SAS-NH2 615 Ac-LTF%cs7VYWAQLc7SVG-NH2 616 Ac-LTF%cs7VYWAQLc7SVG-NH2 617 Ac-LTFcs7EYWAQChac7SAA-NH2 618 Ac-LTFcs7EYWAQChac7SAA-NH2 619 Ac-LTF cs7EYWAQCpgc7SAA-NH2 -110- WO 2013/123267 PCT/US2013/026241 SI P Sequence 620 Ac-LTF cs7EYWAQCpg c7SAA-NH2 621 Ac-LTF cs7EYWAQF c7SAA-NH2 622 Ac-LTF%cs7EYWAQF%c7SAA-NH2 623 Ac-LTF%cs7EYWAQCbac7SAA-NH2 624 Ac-LTF%cs7EYWAQCbac7SAA-NH2 625 Ac-LTF3Cl%cs7EYWAQLc7SAA-NH2 626 Ac-LTF3Cl%cs7EYWAQLc7SAA-NH2 627 Ac-LTF34F2%cs7EYWAQLc7SAA-NH2 628 Ac-LTF34F2%cs7EYWAQLc7SAA-NH2 629 Ac-LTF34F2%cs7EYWAQhLc7SAA-NH2 630 Ac-LTF34F2%cs7EYWAQhLc7SAA-NH2 631 Ac-ETF%cs7EYWAQLc7SAA-NH2 632 Ac-LTF%cs7AYWVQLc7SAA-NH2 633 Ac-LTF%cs7AHWAQLc7SAA-NH2 634 Ac-LTF%cs7AEWAQLc7SAA-NH2 635 Ac-LTF%cs7ASWAQLc7SAA-NH2 636 Ac-LTF%cs7AEWAQLc7SAA-NH2 637 Ac-LTF%cs7ASWAQLc7SAA-NH2 638 Ac-LTF%cs7AF4coohWAQLc7SAA-NH2 639 Ac-LTF%cs7AF4coohWAQLc7SAA-NH2 640 Ac-LTF%cs7AHWAQLc7AAIa-NH2 641 Ac-ITF%cs7FYWAQLc7AAIa-NH2 642 Ac-ITF%cs7EHWAQLc7AAIa-NH2 643 Ac-ITF%cs7EHWAQLc7AAIa-NH2 644 Ac-ETF%cs7EHWAQLc7AAIa-NH2 645 Ac-ETF%cs7EHWAQLc7AAIa-NH2 646 Ac-LTF%cs7AHWVQLc7AAIa-NH2 647 Ac-ITF%cs7FYWVQLc7AAIa-NH2 648 Ac-ITF%cs7EYWVQLc7AAIa-NH2 649 Ac-ITF%cs7EHWVQLc7AAIa-NH2 650 Ac-LTF%cs7AEWAQLc7AAIa-NH2 651 Ac-LTF%cs7AF4coohWAQL c7AAIa-NH2 652 Ac-LTF%cs7AF4coohWAQLc7AAIa-NH2 653 Ac-LTF%cs7AHWAQLc7AHFA-NH2 654 Ac-ITF%cs7FYWAQLc7AHFA-NH2 655 Ac-ITF%cs7FYWAQLc7AHFA-NH2 656 Ac-ITF%cs7FHWAQLc7AEFA-NH2 657 Ac-ITF%cs7FHWAQLc7AEFA-NH2 658 Ac-ITF%cs7EHWAQLc7AHFA-NH2 659 Ac-ITF%cs7EHWAQLc7AHFA-NH2 660 Ac-LTF%cs7AHWVQLc7AHFA-NH2 661 Ac-ITF%cs7FYWVQLc7AHFA-NH2 662 Ac-ITF%cs7EYWVQLc7AHFA-NH2 663 Ac-ITF%cs7EHWVQLc7AHFA-NH2 664 Ac-ITF%cs7EHWVQLc7AHFA-NH2 665 Ac-ETF%cs7EYWAALc7SAA-NH2 666 Ac-LTF%cs7AYWVALc7SAA-NH2 667 Ac-LTF%cs7AHWAALc7SAA-NH2 668 Ac-LTF%cs7AEWAALc7SAA-NH2 669 Ac-LTF%cs7AEWAALc7SAA-NH2 670 Ac-LTF%cs7ASWAALc7SAA-NH2 671 Ac-LTF%cs7ASWAALc7SAA-NH2 672 Ac-LTF%cs7AYWAALc7AAIa-NH2 673 Ac-LTF%cs7AYWAALc7AAla-NH2 674 Ac-LTF%cs7AYWAALc7AHFA-NH2 675 Ac-LTF%cs7EHWAQLc7AHIa-NH2 676 Ac-LTF%cs7EHWAQLc7AHIa-NH2 677 Ac-LTF%cs7AHWAQLc7AHIa-NH2 -111- WO 2013/123267 PCT/US2013/026241 SI P Sequence 678 Ac-LTF cs7EYWAQL c7AHIa-NH2 679 Ac-LTF cs7AYWAQL c7AAFa-NH2 680 Ac-LTF%cs7AYWAQLc7AAFa-NH2 681 Ac-LTF%cs7AYWAQLc7AAWa-NH2 682 Ac-LTF%cs7AYWAQLc7AAVa-NH2 683 Ac-LTF%cs7AYWAQLc7AAVa-NH2 684 Ac-LTF%cs7AYWAQLc7AALa-NH2 685 Ac-LTF%cs7AYWAQLc7AALa-NH2 686 Ac-LTF%cs7EYWAQLc7AAIa-NH2 687 Ac-LTF%cs7EYWAQLc7AAIa-NH2 688 Ac-LTF%cs7EYWAQLc7AAFa-NH2 689 Ac-LTF%cs7EYWAQLc7AAFa-NH2 690 Ac-LTF%cs7EYWAQLc7AAVa-NH2 691 Ac-LTF%cs7EYWAQLc7AAVa-NH2 692 Ac-LTF%cs7EHWAQLc7AAIa-NH2 693 Ac-LTF%cs7EHWAQLc7AAIa-NH2 694 Ac-LTF%cs7EHWAQLc7AAWa-NH2 695 Ac-LTF%cs7EHWAQLc7AAWa-NH2 696 Ac-LTF%cs7EHWAQLc7AALa-NH2 697 Ac-LTF%cs7EHWAQLc7AALa-NH2 698 Ac-ETF%cs7EHWVQLc7AALa-NH2 699 Ac-LTF%cs7AYWAQLc7AAAa-NH2 700 Ac-LTF%cs7AYWAQLc7AAAa-NH2 701 Ac-LTF%cs7AYWAQLc7AAAibA-NH2 702 Ac-LTF%cs7AYWAQLc7AAAibA-NH2 703 Ac-LTF%cs7AYWAQLc7AAAAa-NH2 704 Ac-LTF%c7r5AYWAQLc7s8AAla-NH2 705 Ac-LTF%c7r5AYWAQL c7s8SAA-NH2 706 Ac-LTF%cs7AYWAQCbac7AANleA-NH2 707 Ac-ETF%cs7AYWAQCbac7AANleA-NH2 708 Ac-LTF%cs7EYWAQCbac7AANleA-NH2 709 Ac-LTF%cs7AYWAQCbac7AWNleA-NH2 710 Ac-ETF%cs7AYWAQCbac7AWNleA-NH2 711 Ac-LTF%cs7EYWAQCbac7AWNleA-NH2 712 Ac-LTF%cs7EYWAQCbac7SAFA-NH2 713 Ac-LTF34F2%cs7EYWAQCbac7SANleA-NH2 714 Ac-LTF%cs7EF4coohWAQCbac7SANleA-NH2 715 Ac-LTF%cs7EYWSQCbac7SANleA-NH2 716 Ac-LTF%cs7EYWWQCbac7SANleA-NH2 717 Ac-LTF%cs7EYWAQCbac7AAla-NH2 718 Ac-LTF34F2%cs7EYWAQCbac7AAla-NH2 719 Ac-LTF%cs7EF4coohWAQCbac7AAla-NH2 720 Pam-ETF%cs7EYWAQCbac7SAA-NH2 721 Ac-LThF%cs7EFWAQCbac7SAA-NH2 722 Ac-LTA%cs7EYWAQCbac7SAA-NH2 723 Ac-LTF%cs7EYAAQCbac7SAA-NH2 724 Ac-LTF%cs7EY2NalAQCbac7SAA-NH2 725 Ac-LTF%cs7AYWAQCbac7SAA-NH2 726 Ac-LTF%cs7EYWAQCbac7SAF-NH2 727 Ac-LTF%cS7EYWAQCbac7SAFa-NH2 728 Ac-LTF%cs7AYWAQCbac7SAF-NH2 729 Ac-LTF34F2%cS7AYWAQCbac7SAF-NH2 730 Ac-LTF%cs7AF4coohWAQCbac7SAF-NH2 731 Ac-LTF%cs7EY6clWAQCbac7SAF-NH2 732 Ac-LTF%cs7AYWSQCbac7SAF-NH2 733 Ac-LTF%cs7AYWWQCbac7SAF-NH2 734 Ac-LTF%cs7AYWAQCbac7AAla-NH2 735 Ac-LTF34F2%cs7AYWAQCbac7AAla-NH2 -112- WO 2013/123267 PCT/US2013/026241 SI P Sequence 736 Ac-LTF cs7AY6clWAQCba-c7AAIa-NH2 737 Ac-LTF cs7AF4coohWAQCba c7AAla-NH2 738 Ac-LTFcs7EYWAQCbac7AAFa-NH2 739 Ac-LTF%cs7EYWAQCbac7AAFa-NH2 740 Ac-ETF%cs7AYWAQCbac7AWNlea-NH2 741 Ac-LTFcs7EYWAQCbac7AWNlea-NH2 742 Ac-ETF%cs7EYWAQCbac7AWNlea-NH2 743 Ac-ETF%cs7EYWAQCbac7AWNlea-NH2 744 Ac-LTFcs7AYWAQCbac7SAFa-NH2 745 Ac-LTF%cs7AYWAQCbac7SAFa-NH2 746 Ac-ETF%cs7AYWAQLc7AWNlea-NH2 747 Ac-LTF%cs7EYWAQLc7AWNlea-NH2 748 Ac-ETF%cs7EYWAQLc7AWNlea-NH2 749 Dmaac-LTF%cs7EYWAQhLc7SAA-NH2 750 Hexac-LTFcs7EYWAQhLc7SAA-NH2 751 Napac-LTF%cs7EYWAQhLc7SAA-NH2 752 Decac-LTFcs7EYWAQhLc7SAA-NH2 753 Admac-LTF%cs7EYWAQhLc7SAA-NH2 754 Tmac-LTFcs7EYWAQhLc7SAA-NH2 755 Pam-LTF%cs7EYWAQhLc7SAA-NH2 756 Ac-LTFcs7AYWAQCbac7AANleA-NH2 757 Ac-LTF34F2%cs7EYWAQCbac7AAla-NH2 758 Ac-LTF34F2%cs7EYWAQCbac7SAA-NH2 759 Ac-LTF34F2%cs7EYWAQCbac7SAA-NH2 760 Ac-LTFcs7EF4coohWAQCbac7SAA-NH2 761 Ac-LTF%cs7EF4coohWAQCba%c7SAA-NH2 762 Ac-LTFcs7EYWSQCbac7SAA-NH2 763 Ac-LTF%cs7EYWSQCbac7SAA-NH2 764 Ac-LTFcs7EYWAQhLc7SAA-NH2 765 Ac-LTF%cs7AYWAQhL c7SAF-NH2 766 Ac-LTFcs7AYWAQhLc7SAF-NH2 767 Ac-LTF34F2%cs7AYWAQhL c7SAA-NH2 768 Ac-LTF34F2%cs7AYWAQhLc7SAA-NH2 769 Ac-LTF%cs7AF4coohWAQhLc7SAA-NH2 770 Ac-LTF%cs7AF4coohWAQhLc7SAA-NH2 771 Ac-LTF%cs7AYWSQhL c7SAA-NH2 772 Ac-LTFcs7AYWSQhLc7SAA-NH2 773 Ac-LTF%cs7EYWAQLc7AANleA-NH2 774 Ac-LTF34F2%cs7AYWAQLc7AANleA-NH2 775 Ac-LTF%cs7AF4coohWAQL c7AANleA-NH2 776 Ac-LTFcs7AYWSQLc7AANleA-NH2 777 Ac-LTF34F2%cs7AYWAQhL c7AANleA-NH2 778 Ac-LTF34F2%cs7AYWAQhLc7AANleA-NH2 779 Ac-LTF%cs7AF4coohWAQhL%c7AANleA-NH2 780 Ac-LTFcs7AF4coohWAQhLc7AANleA-NH2 781 Ac-LTF%cs7AYWSQhL%c7AANleA-NH2 782 Ac-LTFcs7AYWSQhLc7AANleA-NH2 783 Ac-LTF%cs7AYWAQhL%c7AAAAa-NH2 784 Ac-LTFcs7AYWAQhLc7AAAAa-NH2 785 Ac-LTF%cs7AYWAQLc7AAAAAa-NH2 786 Ac-LTF%cs7AYWAQLc7AAAAAAa-NH2 787 Ac-LTF%CS7AYWAQLc7AAAAAAa-NH2 788 Ac-LTF%cs7EYWAQhLc7AANleA-NH2 789 Ac-AATFCs7AYWAQLc7AANleA-NH2 790 Ac-LTF%cs7AYWAQLc7AANleAA-NH2 791 Ac-ALTFcs7AYWAQLc7AANleAA-NH2 792 Ac-LTF%cs7AYWAQCbac7AANleAA-NH2 793 Ac-LTFcs7AYWAQhLc7AANleAA-NH2 -113- WO 2013/123267 PCT/US2013/026241 SI P Sequence 794 Ac-LTF cs7EYWAQCba c7SAAA-NH2 795 Ac-LTF cs7EYWAQCba c7SAAA-NH2 796 Ac-LTF%cs7EYWAQCbac7SAAAA-NH2 797 Ac-LTF%cs7EYWAQCbac7SAAAA-NH2 798 Ac-ALTF%cs7EYWAQCbac7SAA-NH2 799 Ac-ALTF%cs7EYWAQCbac7SAAA-NH2 800 Ac-ALTF%cs7EYWAQCbac7SAA-NH2 801 Ac-LTF%cs7EYWAQLc7AAAAAa-NH2 802 Ac-LTF%cs7EY6clWAQCbac7SAA-NH2 803 Ac-LTF%cs7EF4cooh6clWAQCbac7SANleA-NH2 804 Ac-LTF%cs7EF4cooh6clWAQCbac7SANleA-NH2 805 Ac-LTF%cs7EF4cooh6clWAQCbac7AAla-NH2 806 Ac-LTF%cs7EF4cooh6clWAQCbac7AAla-NH2 807 Ac-LTF%cs7AY6clWAQLc7AAAAAa-NH2 808 Ac-LTF%cs7AY6clWAQLc7AAAAAa-NH2 809 Ac-Fcs7AY6clWEALc7AAAAAAa-NH2 810 Ac-ETF%cs7EYWAQLc7AAAAAa-NH2 811 Ac-ETF%cs7EYWAQLc7AAAAAa-NH2 812 Ac-LTF%cs7EYWAQLc7AAAAAAa-NH2 813 Ac-LTF%cs7EYWAQLc7AAAAAAa-NH2 814 Ac-LTF%cs7AYWAQLc7AANleAAa-NH2 815 Ac-LTF%cs7AYWAQLc7AANleAAa-NH2 816 Ac-LTF%cs7EYWAQCbac7AAAAAa-NH2 817 Ac-LTF%cs7EYWAQCbac7AAAAAa-NH2 818 Ac-LTF%cs7EF4coohWAQCbac7AAAAAa-NH2 819 Ac-LTF%cs7EF4coohWAQCbac7AAAAAa-NH2 820 Ac-LTF%cs7EYWSQCbac7AAAAAa-NH2 821 Ac-LTF%cs7EYWSQCbac7AAAAAa-NH2 822 Ac-LTF%cs7EYWAQCbac7SAAa-NH2 823 Ac-LTF%cs7EYWAQCbac7SAAa-NH2 824 Ac-ALTF%cs7EYWAQCbac7SAAa-NH2 825 Ac-ALTF%cs7EYWAQCbac7SAAa-NH2 826 Ac-ALTF%cs7EYWAQCbac7SAAAa-NH2 827 Ac-ALTF%cs7EYWAQCbac7SAAAa-NH2 828 Ac-AALTF%cs7EYWAQCbac7SAAAa-NH2 829 Ac-AALTF%cs7EYWAQCbac7SAAAa-NH2 830 Ac-RTF%cs7EYWAQCbac7SAA-NH2 831 Ac-LRF%cs7EYWAQCbac7SAA-NH2 832 Ac-LTF%cs7EYWRQCbac7SAA-NH2 833 Ac-LTF%cs7EYWARCbac7SAA-NH2 834 Ac-LTF%cs7EYWAQCbac7RAA-NH2 835 Ac-LTF%cs7EYWAQCbac7SRA-NH2 836 Ac-LTF%cs7EYWAQCbac7SAR-NH2 837 5-FAM-BaLTF%cs7EYWAQCbac7SAA-NH2 838 5-FAM-BaLTF%cs7AYWAQLc7AANleA-NH2 839 Ac-LAFcs7EYWAQLc7AANleA-NH2 840 Ac-ATF%cs7EYWAQLc7AANleA-NH2 841 Ac-AAF%cs7EYWAQLc7AANleA-NH2 842 Ac-AAAF%cs7EYWAQLc7AANleA-NH2 843 Ac-AAAAF%cs7EYWAQLc7AANleA-NH2 844 Ac-AATFcs7EYWAQLc7AANleA-NH2 845 Ac-AALTF%cs7EYWAQLc7AANleA-NH2 846 Ac-AAALTF%cs7EYWAQLc7AANleA-NH2 847 Ac-LTF%cs7EYWAQLc7AANleAA-NH2 848 Ac-ALTF%cs7EYWAQLc7AANleAA-NH2 849 Ac-AALTF%cs7EYWAQLc7AANleAA-NH2 850 Ac-LTF%cs7EYWAQCbac7AANleAA-NH2 851 Ac-LTF%cs7EYWAQhLc7AANleAA-NH2 -114- WO 2013/123267 PCT/US2013/026241 5 IP Sequence 852 Ac-ALT cs7EYWAQhL c7AANleAA-NH2 853 Ac-LTF cs7ANmYWAQL c7AANleA-NH2 854 Ac-LTF%cs7ANmYWAQLc7AANleA-NH2 855 Ac-LTF%cs7AYNmWAQLc7AANleA-NH2 856 Ac-LTF%cs7AYNmWAQLc7AANleA-NH2 857 Ac-LTF%cs7AYAmwAQLc7AANleA-NH2 858 Ac-LTF%cs7AYAmwAQLc7AANleA-NH2 859 Ac-LTF%cs7AYWAibQLc7AANleA-NH2 860 Ac-LTF%cs7AYWAibQLc7AANleA-NH2 861 Ac-LTF%cs7AYWAQLc7AAibNleA-NH2 862 Ac-LTF%cs7AYWAQLc7AAibNleA-NH2 863 Ac-LTF%cs7AYWAQLc7AaNleA-NH2 864 Ac-LTF%cs7AYWAQLc7AaNleA-NH2 865 Ac-LTF%cs7AYWAQLc7ASarNleA-NH2 866 Ac-LTF%cs7AYWAQLc7ASarNleA-NH2 867 Ac-LTF%cs7AYWAQLc7AANleAib-NH2 868 Ac-LTF%cs7AYWAQLc7AANleAib-NH2 869 Ac-LTF%cs7AYWAQLc7AANleNmA-NH2 870 Ac-LTF%cs7AYWAQLc7AANleNmA-NH2 871 Ac-LTF%cs7AYWAQLc7AANleSar-NH2 872 Ac-LTF%cs7AYWAQLc7AANleSar-NH2 873 Ac-LTF%cs7AYWAQLc7AANleAAib-NH2 874 Ac-LTF%cs7AYWAQLc7AANleAAib-NH2 875 Ac-LTF%cs7AYWAQLc7AANleANmA-NH2 876 Ac-LTF%cs7AYWAQLc7AANleANmA-NH2 877 Ac-LTF%cs7AYWAQLc7AANleAa-NH2 878 Ac-LTF%cs7AYWAQLc7AANleAa-NH2 879 Ac-LIE cs7AIWAQL c7AANleASar-NH2 880 Ac-LTF%cs7AYWAQLc7AANleASar-NH2 881 Ac-LTF%c7/r8AYWAQLc7/AANleA-NH2 882 Ac-LTFAibAYWAQLAibAANleA-NH2 883 Ac-LTF%cs7Cou4YWAQLc7AANleA-NH2 884 Ac-LTF%cs7Cou4YWAQLc7AANleA-NH2 885 Ac-LTF%cs7AYWCou4QLc7AANleA-NH2 886 Ac-LTF%cs7AYWAQLc7Cou4ANleA-NH2 887 Ac-LTF%cs7AYWAQLc7Cou4ANleA-NH2 888 Ac-LTF%cs7AYWAQLc7ACcu4NleA-NH2 889 Ac-LTF%cs7AYWAQLc7ACcu4NleA-NH2 890 Ac-LTF%cs7AYWAQLc7AANleA-OH 891 Ac-LTF%cs7AYWAQLc7AANleA-OH 892 Ac-LTF%cs7AYWAQLc7AANleA-NHnPr 893 Ac-LTF%cs7AYWAQLc7AANleA-NHnPr 894 Ac-LTF%cs7AYWAQLc7AANleA-NHnBu33Me 895 Ac-LTF%cs7AYWAQLc7AANleA-NHnBu33Me 896 Ac-LTF%cs7AYWAQLc7AANleA-NHHex 897 Ac-LTF%cs7AYWAQLc7AANleA-NHHex 898 Ac-LTA%cs7AYWAQLc7AANleA-NH2 899 Ac-LThL%cs7AYWAQLc7AANleA-NH2 900 Ac-LTF%cs7AYAAQLc7AANleA-NH2 901 Ac-LTF%cS7AY2NalAQLc7AANleA-NH2 902 Ac-LTF%cs7EYWCou4QCbac7SAA-NH2 903 Ac-LTF%cs7EYWCou7QCbac7SAA-NH2 904 Dmaac-LTF%cs7EYWAQCbac7SAA-NH2 905 Dmaac-LTEcs7AYWAQLc7AAAAAa-NH2 906 Dmaac-LTF%cs7AYWAQLc7AAAAAa-NH2 907 Dmaac-LTF%cs7EYWAQLc7AAAAAa-NH2 908 Dmaac-LTF%cs7EYWAQLc7AAAAAa-NH2 909 Dmaac-LTF%cs7EF4coohWAQCbac7AAla-NH2 -115- WO 2013/123267 PCT/US2013/026241 SI P Sequence 910 Dmaac-LTF cs7EF4coohWAQCba-c7AAla-NH2 911 Dmaac-LTF cs7AYWAQLc7AANleA-NH2 912 Dmaac-LTFcs7AYWAQLc7AANleA-NH2 913 Cou6BaLTF%cs7EYWAQhLc7SAA-NH2 914 Cou8BaLTFcs7EYWAQhLc7SAA-NH2 915 Ac-LTF41%cs7EYWAQLc7AAAAAa-NH2 Table 6a shows exemplary peptidomimetic macrocycles: Table 6a Calc Exact Found Calc Calc (1+3)/ SP Sequence Mass Mlass (M+1)/1 (M1+2)/2 3 916 Ac-LTF cs7AYWAQL c7AANleA-NH2 1808.94 1809.95 905.48 603.99 917 Ac-LTF cs7AYWAQL c7AAAAAa-NH2 1908.96 1909.97 955.49 637.33 918 Ac-LTFcsBphAYWAQLcBphAANleA-NH2 1890.92 1909.97 955.49 637.33 919 Ac-LTFcsBphAYWAQL%cBphAAAAAa-NH2 1990.92 996.88 920 Ac-LTF%csBphEYWAQCbacBphSAA-NH2 1865.16 933.45 933.58 921 Ac-LTF#cs7EYWAQCba#c7SAA-NH2 1753.82 1754.83 877.92 585.61 922 Ac-LTF#csBphEYWAQCba#cBphSAA-NH2 1835.81 1836.82 918.91 612.94 923 Ac-LTFcsBphEYWAQLcBphAAAAAa-NH2 924 Ac-LTFcs5AYWAQLc5AANleA-NH2 925 Ac-LTFcs5AYWAQLc5AAAAAa-NH2 926 Ac-LTFcs6AYWAQLc6AANleA-NH2 927 Ac-LTFcs6AYWAQL%c6AAAAAa-NH2 928 Ac-LTFcs6EYWAQLc6AAAAAa-NH2 1894.94 1895.96 948.48 632.66 929 Ac-LTFcs5EYWAQLc5AAAAAa-NH2 1880.93 1881.94 941.47 627.98 930 Ac-LTFcs6EYWAQCbac6SAANH2 1709.83 1710.84 855.92 570.95 931 Ac-LTFcs5EYWAQCbac5SAANH2 1695.81 1696.82 848.92 56628 [00258] Partial structures of selected exemplary peptidomimetic macrocycles are shown below: -S Ala-Tyr-HN A)la-GIn-Leu- , O H N H SP-918 S 0 S Ala-Tyr-HN Ala-Gln-Leu
,
N N H SP-916/917 [00259] A structure of an exemplary peptidomimetic macrocycle is shown below: -116- WO 2013/123267 PCT/US2013/026241 -S S H Leu-Thr-Phe-HN Ala-Tyr-HN A- Ala-Al -Ala-A -Ala- NH 2 -H aG I<n& YIIN Chemical Formula: Cg1H 136
N
20 0 21
S
2 N -Exact Mass: 1908.96 H Molecular Weight: 1910.30 Ac- L T F %cs7 A Y W A Q L %c7 A AAAAa -NH2 SP-917 [00260] Another structure of an exemplary peptidomimetic macrocycle is shown below: 0 S 0 Leu-Thr-Phe-HN Glu-Tyr-HN H Ser-Ala-Ala-NH 2 Le-Tr-heHNAla-Gln__-N N2 00 N / H SP-920 [00261] Amino acids represented as "#cs5" are D-cysteine connected by an i to i+7, five-methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "#c5" are L cysteine connected by an i to i+7, five- methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "#cs6" are D-cysteine connected by an i to i+7, six- methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "#c6" are L cysteine connected by an i to i+7, six- methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "#cs7" are D-cysteine connected by an i to i+7, seven methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "#c7 are L-cysteine connected by an i to i+7, seven- methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "#cs8" are D-cysteine connected by an i to i+7, eight methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "#c8" are L-cysteine connected by an i to i+7, eight- methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "%cs7" are alpha-methyl-D-cysteine connected by an i to i+7, seven-methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "%c 7 " are alpha-methyl-L-cysteine connected by an i to i+7, seven-methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "ocs 8 " are alpha -117- WO 2013/123267 PCT/US2013/026241 methyl-D-cysteine connected by an i to i+7, eight-methylene crosslinker to another thiol containing amino acid. Amino acids represented as "%c 8 " are alpha-methyl-L-cysteine connected by an i to i+7, eight- methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "%cs9" are alpha-methyl-D-cysteine connected by an i to i+7, nine-methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "%c 9 " are alpha methyl-L-cysteine connected by an i to i+7, nine- methylene crosslinker to another thiol containing amino acid. Amino acids represented as "%cs 10" are alpha-methyl-D-cysteine connected by an i to i+7, ten-methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "%c10" are alpha-methyl-L-cysteine connected by an i to i+7, ten methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "pen8" are D-penicillamine connected by an i to i+7, eight-methylene crosslinker to another thiol containing amino acid. Amino acids represented as "Pen8" are L-penicillamine connected by an i to i+7, eight- methylene crosslinker to another thiol-containing amino acid. Amino acids represented as "#csBph" are D-cysteine connected by an i to i+7, Bph (4,4'-bismethyl-biphenyl) crosslinker to another thiol-containing amino acid. Amino acids represented as "#cBph" are L cysteine connected by an i to i+7, Bph (4,4'-bismethyl-biphenyl) crosslinker to another thiol containing amino acid. Amino acids represented as "%csBph" are alpha-methyl-D-cysteine connected by an i to i+7, Bph (4,4'-bismethyl-biphenyl) crosslinker to another thiol-containing amino acid. Amino acids represented as "%cBph" are alpha-methyl-L-cysteine connected by an i to i+7, Bph (4,4'-bismethyl-biphenyl) crosslinker to another thiol-containing amino acid. Amino acids represented as "#csBpy" are D-cysteine connected by an i to i+7, Bpy (6,6'-bismethyl [3,3']bipyridine) crosslinker to another thiol-containing amino acid. Amino acids represented as "#cBpy" are L-cysteine connected by an i to i+7, Bpy (6,6'-bismethyl-[3,3']bipyridine) crosslinker to another thiol-containing amino acid. Amino acids represented as "ocsBpy" are alpha-methyl-D-cysteine connected by an i to i+7, Bpy (6,6'-bismethyl-[3,3']bipyridine) crosslinker to another thiol-containing amino acid. Amino acids represented as "ocBpy" are alpha-methyl-L-cysteine connected by an i to i+7, Bpy (6,6'-bismethyl-[3,3']bipyridine) crosslinker to another thiol-containing amino acid. The number of methylene units indicated above refers to the number of methylene units between the two thiol groups of the crosslinker. [00262] In some embodiments, a peptidomimetic macrocycle is obtained in more than one isomer, for example due to the configuration of a double bond within the structure of the crosslinker (E vs Z). Such isomers can or can not be separable by conventional chromatographic methods. In some embodiments, one isomer has improved biological properties relative to the other isomer. In one embodiment, an E crosslinker olefin isomer of a peptidomimetic macrocycle has better solubility, better target affinity, better in vivo or in vitro efficacy, higher helicity, or improved cell permeability relative to its Z counterpart. In another embodiment, a Z crosslinker olefin isomer of -118- WO 2013/123267 PCT/US2013/026241 a peptidomimetic macrocycle has better solubility, better target affinity, better in vivo or in vitro efficacy, higher helicity, or improved cell permeability relative to its E counterpart. [00263] In some embodiments, peptidomimetic macrocycles exclude peptidomimetic macrocycles shown in Table 7: Table 7 Sequence 1 QSQQTF%csNLWLL%cs6QN 2 QSQQTF%csNLWLL%cs7QN 3 QSQQTF%csNLWLL%cs8QN 4 QSQQTF%csNLWLL%cs9QN [00264] Peptides shown can comprise an N-terminal capping group such as acetyl or an additional linker such as beta-alanine between the capping group and the start of the peptide sequence. [00265] In some embodiments, peptidomimetic macrocycles do not comprise a peptidomimetic macrocycle structure as shown in Table 7. [00266] In other embodiments, peptidomimetic macrocycles exclude peptidomimetic macrocycles shown in Table 7a: Table 7a Number Sequence 1 Ac-QSQQTF#cs5NLWRLL#c5QN-NH2 2 Ac-QSQQTF#cs6NLWRLL#c6QN-NH2 3 Ac-QSQQTF#cs7NLWRLL#c7QN-NH2 4 Ac-QSQQTF#cs8NLWRLL#c8QN-NH2 5 Ac-QSQQTF#cs9NLWRLL#c9QN-NH2 6 Ac-QSQQTF%cs8NLWRLL%c8QN-NH2 7 Ac-QSQQTF#cs8NLWRLLPen8QN-NH2 8 Ac-QSQQTF#c8NLWRLL#c8QN-NH2 9 Ac-QSQQTF#c8NLWRLL#cs8QN-NH2 10 Ac-QSQQTF#cs8NLWALL#c8AN-NH2 11 Ac-QAibQQTF#cs8NLWALL#c8AN-NH2 12 Ac-QAibQQTF#cs8ALWALL#c8AN-NH2 13 Ac-QSQQTFpen8NLWRLLPen8QN-NH2 14 Ac-QSQQTFpen8NLWRLL#c8QN-NH2 15 Ac-QSQQTF%cs9NLWRLL%c9QN-NH2 16 Ac-LTF#cs8HYWAQL#c8S-NH2 17 Ac-LTF#cs8HYWAQI#c8S-NH2 18 Ac-LTF#cs8HYWAQNle#c8S-NH2 19 Ac-LTF#cs8HYWAQL#c8A-NH2 20 Ac-LTF#cs8HYWAbuQL#c8S-NH2 -119- WO 2013/123267 PCT/US2013/026241 21 Ac-LTF#cs8AYWAQL#c8S-NH2 22 Ac-LTF#cs8AYWAQL#c8A-NH2 23 Ac-LTF#cs8HYWAQLPen8S-NH2 24 Ac-LTFpen8HYWAQLPen8S-NH2 25 Ac-LTFpen8HYWAQL#c8S-NH2 26 Ac-LTF#cs7HYWAQL#hc7S-NH2 27 Ac-LTF%cs8HYWAQL%c8S-NH2 28 Ac-LTF%cs9HYWAQL%c9S-NH2 29 Ac-LTF%cs1OHYWAQL%clOS-NH2 30 Ac-LTF%cs7HYWAQL%c7S-NH2 31 Ac-LTF%cs4BEBHYWAQL%c4BEBS-NH2 32 Ac-Fpen8AYWEAc3cL#c8A-NH2 33 Ac-F#cs8AYWEAc3cL#c8A-NH2 34 Ac-F%cs8AYWEAc3cL%c8A-NH2 35 Ac-LTFEHYWAQLTS-NH2 [00267] In some embodiments, peptidomimetic macrocycles do not comprise a peptidomimetic macrocycle structure as shown in Table 7a. [00268] In other embodiments, peptidomimetic macrocycles exclude peptidomimetic macrocycles shown in Table 7b and disclosed in Muppidi et al., Chem. Commun. (2011) DOI: 10.1039/clccl3320a: Table 7b Number Sequence 1 LTFEHYWAQLTS 2 LTFCHYWAQLCS 3 LTF#cBphHYWAQL#cBphS 4 LTF#cBpyHYWAQLtcBpyS 5 LTFCRYWARLCS 6 LTF#cBphRYWARL#cBphS 7 LTF#cBpyRYWARL#cBpyS 8 LTFcHYWAQLCS 9 LTF#csBphHYWAQL#cBphS 10 LTF#csBpyHYWAQL#csBpyS 11 LTF#csBphRYWARL#cBphS 12 LTF#csBpyRYWARL#cBpyS wherein C denotes L-cysteine and c denotes D-cysteine in Table 7b; and #cBph, #cBpy, #csBph, and #csBpy are as defined herein. [00269] In some embodiments, peptidomimetic macrocycles do not comprise a peptidomimetic macrocycle structure as shown in Table 7b. -120- WO 2013/123267 PCT/US2013/026241 Example 4: Circular Dichroism (CD) analysis of alpha-helicity [00270] Peptide solutions are analyzed by CD spectroscopy using a Jasco J-815 spectropolarimeter (Jasco Inc., Easton, MD) with the Jasco Spectra Manager Ver.2 system software. A Peltier temperature controller is used to maintain temperature control of the optical cell. Results are expressed as mean molar ellipticity [0] (deg cm2 dmol-1) as calculated from the equation [0]=Oobs.MRW/10*l*c where Oobs is the observed ellipticity in millidegrees, MRW is the mean residue weight of the peptide (peptide molecular weight/number of residues), 1 is the optical path length of the cell in centimeters, and c is the peptide concentration in mg/ml. Peptide concentrations are determined by amino acid analysis. Stock solutions of peptides are prepared in benign CD buffer (20 mM phosphoric acid, pH 2). The stocks are used to prepare peptide solutions of 0.05 mg/ml in either benign CD buffer or CD buffer with 50% trifluoroethanol (TFE) for analyses in a 10 mm pathlength cell. Variable wavelength measurements of peptide solutions are scanned at 4 'C from 195 to 250 nm, in 0.2 nm increments, and a scan rate 50 nm per minute. The average of six scans is reported. Example 5: Direct binding assay MDM2 with Fluorescence polarization (FP) [00271] The assay is performed according to the following general protocol: 1. Dilute MDM2 (In-house, 41kD) into FP buffer (High salt buffer-200mM Nacl,5mM CHAPS, pH 7.5) to make 1O M working stock solution. 2. Add 30g1 of 10gM of protein stock solution into Al and BI well of 96-well black HE microplate (Molecular Devices). 3. Fill in 301 of FP buffer into column A2 to A12, B2 to B12, C1 to C12, and D1 to D12. 4. 2 or 3 fold series dilution of protein stock from Al, BI into A2, B2; A2, B2 to A3, B3; ... to reach the single digit nM concentration at the last dilution point. 5. Dilute 1mM (in 100% DMSO) of FAM labeled linear peptide with DMSO to 100gM (dilution 1: 10). Then, dilutefrom 100gM to 10 M with water (dilution 1:10) and then dilute with FP buffer from 10 M to 40nM (dilution 1:250). This is the working solution which will be a lOnM concentration in well (dilution 1:4). Keep the diluted FAM labeled peptide in the dark until use. 6. Add Ogl of 1OnM of FAM labeled peptide into each well and incubate, and read at different time points. Kd with 5-FAM-BaLTFEHYWAQLTS-NH 2 is ~13.38 nM. Example 6: Competitive Fluorescence polarization assay for MDM2 [00272] The assay is performed according to the following general protocol: 1. Dilute MDM2 (In-house, 4lkD) into FP buffer (High salt buffer-200mM Nacl,5mM CHAPS, pH 7.5) to make S4nM (2X) working stock solution. 2. Add 20g1 of 84nM (2X) of protein stock solution into each well of 96-well black HE microplate (Molecular Devices) -121- WO 2013/123267 PCT/US2013/026241 3. Dilute 1mM (in 100% DMSO) of FAM labeled linear peptide with DMSO to 100gM (dilution 1: 10). Then, dilute from 100gM to 10 M with water (dilution 1:10) and then dilute with FP buffer from 10 M to 40nM (dilution 1:250). This is the working solution which will be a l0nM concentration in well (dilution 1:4). Keep the diluted FAM labeled peptide in the dark until use. 4. Make unlabeled peptide dose plate with FP buffer starting with 1 M (final) of peptide and making 5 fold serial dilutions for 6 points using following dilution scheme. Dilute 10mM (in 100% DMSO) with DMSO to 5mM (dilution 1: 2). Then, dilute from 5mM to 500pM with H 2 0 (dilution 1:10) and then dilute with FP buffer from 500 M to 20gM (dilution 1:25). Making 5 fold serial dilutions from 4gM (4X) for 6 points. 5. Transfer Ogl of serial diluted unlabeled peptides to each well which is filled with 20 1 of 84nM of protein. 6. Add 1 Ogl of 1 OnM (4X) of FAM labeled peptide into each well and incubate for 3hr to read. Example 7: Direct binding assay MDMX with Fluorescence polarization (FP) [00273] The assay is performed according to the following general protocol: 1. Dilute MDMX (In-house, 40kD) into FP buffer (High salt buffer-200mnM Nacl,5mM CHAPS, pH 7.5) to make 10 M working stock solution. 2. Add 30g1 of 10gM of protein stock solution into Al and BI well of 96-well black HE microplate (Molecular Devices). 3. Fill in 301 of FP buffer into column A2 to A12, B2 to B12, Cl to C12, and D1 to D12. 4. 2 or 3 fold series dilution of protein stock from Al, BI into A2, B2; A2, B2 to A3, B3; ... to reach the single digit nM concentration at the last dilution point. 5. Dilute 1mM (in 100% DMSO) of FAM labeled linear peptide with DMSO to 100gM (dilution 1: 10). Then, dilute from 100gM to 10 M with water (dilution 1:10) and then dilute with FP buffer from 10 M to 40nM (dilution 1:250). This is the working solution which will be a lOnM concentration in well (dilution 1:4). Keep the diluted FAM labeled peptide in the dark until use. 6. Add 1Ol of 1OnM of FAM labeled peptide into each well and incubate, and read at different time points. Kd with 5-FAM-BaLTFEHYWAQLTS-NH 2 is -51 nM. Example 8: Competitive Fluorescence polarization assay for MDMVX [00274] The assay is performed according to the following general protocol: 1. Dilute MDMX (In-house, 40kD) into FP buffer (High salt buffer-200mM Nacl,5mM CHAPS, pH 7.5.) to make 300nM (2X) working stock solution. 2. Add 20g1 of 300nM (2X) of protein stock solution into each well of 96-well black HE microplate (Molecular Devices) -122- WO 2013/123267 PCT/US2013/026241 3. Dilute 1mM (in 100% DMSO) of FAM labeled linear peptide with DMSO to 100gM (dilution 1: 10). Then, dilute from 100gM to 10 M with water (dilution 1:10) and then dilute with FP buffer from 10 M to 40nM (dilution 1:250). This is the working solution which will be a lOnM concentration in well (dilution 1:4). Keep the diluted FAM labeled peptide in the dark until use. 4. Make unlabeled peptide dose plate with FP buffer starting with 5gM (final) of peptide and making 5 fold serial dilutions for 6 points using following dilution scheme. 5. Dilute 1OmM (in 100% DMSO) with DMSO to 5mM (dilution 1: 2). Then, dilute from 5mM to 500pM with H 2 0 (dilution 1:10) and then dilute with FP buffer from 500gM to 20gM (dilution 1:25). Making 5 fold serial dilutions from 20gM (4X) for 6 points. 6. Transfer 1Ol of serial diluted unlabeled peptides to each well which is filled with 20 1 of 300nM of protein. 7. Add 1 Ogl of 1 OnM (4X) of FAM labeled peptide into each well and incubate for 3hr to read. [00275] Results from Examples 4-7 are shown in Table 8. The following scale is used for IC50 and Ki values: "+" represents a value greater than 1000 nM, "++" represents a value greater than 100 and less than or equal to 1000 nM, "+++" represents a value greater than 10 nM and less than or equal to 100 nM, and "++++" represents a value of less than or equal to 10 nM. Cell viability assay results (performed as in Example 9) are also included in Table 8 using the following scale: "+" represents a value greater than 30 pM, "++" represents a value greater than 15 pM and less than or equal to 30 pM, "+++" represents a value greater than 5 gM and less than or equal to 15 gM, and "++++" represents a value of less than or equal to 5 pM. "IC50 ratio" represents the ratio of average IC50 in p53+/+ cells relative to average IC50 in p53-/- cells. Table 8 SJSA-1 IC50 EC50 Ratio SP IC50 (MDM2) IC50 (MDMIX) Ki (MDM2) Ki (MDMX) (7h) 449 ++ +++ ++±+ + + +±++ 450 ++ ++ 451 ++ ++ 452 + 456 +++ + ++ 457 ++++ ++++ ++++ 461 459 + + + 460 + + + 463 ++ 464 + 153 ++++ +++ +++ 1-29 465 ++++ ++++ 466 +.+++ ++ 470 +.+++ 916 +++ +++ ++++ ++++ ++ 917 + +±+ +++ ++ + -123- WO 2013/123267 PCT/US2013/026241 919 +++ Example 9: Competition Binding ELISA (MDM2 & MDMX) [00276] p53-His6 protein (30 nM/well) is coated overnight at room temperature in the wells of a 96-well Immulon plates. On the day of the experiment, plates are washed with 1X PBS-Tween 20 (0.05%) using an automated ELISA plate washer, blocked with ELISA Micro well Blocking for 30 minutes at room temperature; excess blocking agent is washed off by washing plates with IX PBS-Tween 20 (0.05%). Peptides are diluted from 10 mM DMSO stocks to 500 RM working stocks in sterile water, further dilutions made in 0.5% DMSO to keep the concentration of DMSO constant across the samples. The peptides are added to wells at 2X desired concentrations in 50 1tl volumes, followed by addition of diluted GST-MDM2 or GST-HMDX protein (final concentration: 1OnM). Samples are incubated at room temperature for 2h, plates are washed with PBS-Tween 20 (0.05%) prior to adding 100 ptl of HRP-conjugated anti-GST antibody [Hypromatrix, INC] diluted to 0.5 jig/ml in HRP-stabilizing buffer. Post 30 min incubation with detection antibody, plates are washed and incubated with 100 Rl per well of TMB-E Substrate solution up to 30 minutes; reactions are stopped using 1M HCL and absorbance measured at 450 nm on micro plate reader. Data is analyzed using Graph Pad PRISM software. Example 10: Cell Viability assay [00277] The assay is performed according to the following general protocol: Cell Plating: Trypsinize, count and seed cells at the pre-determined densities in 96-well plates a day prior to assay. Following cell densities are used for each cell line in use: * SJSA-1: 7500 cells/ well " RKO: 5000 cells/well * RKO-E6: 5000 cells/well * HCT-116: 5000 cells/well * SW-480: 2000 cells/well * MCF-7: 5000 cells/well [00278] On the day of study, replace media with fresh media with 11% FBS (assay media) at room temperature. Add 180 L of the assay media per well. Control wells with no cells, receive 200 1il media. [00279] Peptide dilution: all dilutions are made at room temperature and added to cells at room temperature. * Prepare 10 mM stocks of the peptides in DMSO. Serially dilute the stock using 1:3 dilution scheme to get 10, 3.3, 1.1, 0.33, 0.11, 0.03, 0.01mM solutions using DMSO as diluents. Dilute -124- WO 2013/123267 PCT/US2013/026241 the serially DMSO-diluted peptides 33.3 times using sterile water. This gives range of lOX working stocks. Also prepare DMSO/sterile water (3% DMSO) mix for control wells. " Thus the working stocks concentration range ptM will be 300, 100, 30, 10, 3, 1, 0.3 and 0 ViM. Mix well at each dilution step using multichannel. * Row H has controls. HI- H3 will receive 20 ul of assay media. H4-H9 will receive 20 ul of 3% DMSO-water vehicle. H10-H12 will have media alone control with no cells. * Positive control: MDM2 small molecule inhibitor,Nutlin-3a (10 mM) is used as positive control. Nutlin was diluted using the same dilution scheme as peptides. [00280] Addition of working stocks to cells: * Add 20 tl of I OX desired concentration to appropriate well to achieve the final concentrations in total 200 l volume in well. (20 l of 300 gM peptide + 180 l of cells in media = 30 gM final concentration in 200 1il volume in wells). Mix gently a few times using pipette. Thus final concentration range used will be 30, 10, 3, 1, 0.3, 0.1, 0.03 & 0 M (for potent peptides further dilutions are included). * Controls include wells that get no peptides but contain the same concentration of DMSO as the wells containing the peptides, and wells containing NO CELLS. * Incubate for 72 hours at 37 0 C in humidified 5% CO 2 atmosphere. * The viability of cells is determined using MTT reagent from Promega. Viability of SJSA-1, RKO, RKO-E6, HCT-1 16 cells is determined on day 3, MCF-7 cells on day 5 and SW-480 cells on day 6. At the end of designated incubation time, allow the plates to come to room temperature. Remove 80 jl of assay media from each well. Add 15 l of thawed MTT reagent to each well. * Allow plate to incubate for 2h at 37 0 C in humidified 5% CO 2 atmosphere and add 100 ji solubilization reagent as per manufacturer's protocol. Incubate with agitation for 1h at room temperature and read on Synergy Biotek multiplate reader for absorbance at 570nM. * Analyze the cell viability against the DMSO controls using GraphPad PRISM analysis tools. [00281] Reagents: * Invitrogen cell culture Media i.Falcon 96-well clear cell culture treated plates (Nunc 353072) * DMSO ( Sigma D 2650) * RPMI 1640 (Invitrogen 72400) * MTT (Promega G4000) [00282] Instruments: Multiplate Reader for Absorbance readout (Synergy 2). [00283] Results are shown in Table 8. Example 11: P21 ELISA assay [00284] The assay is performed according to the following general protocol: -125- WO 2013/123267 PCT/US2013/026241 Cell Plating: * Trypsinize, count and seed SJSA1 cells at the density of 7500 cells/ 100 pi/well in 96-well plates a day prior to assay. * On the day of study, replace media with fresh RPMI-1 1% FBS (assay media). Add 90gL of the assay media per well. Control wells with no cells, receive 100 pl media. [00285] Peptide dilution: * Prepare 10 mM stocks of the peptides in DMSO. Serially dilute the stock using 1:3 dilution scheme to get 10, 3.3, 1.1, 0.33, 0.11, 0.03, 0.01mM solutions using DMSO as diluents. Dilute the serially DMSO-diluted peptides 33.3 times using sterile water This gives range of 1OX working stocks. Also prepare DMSO/sterile water (3% DMSO) mix for control wells. * Thus the working stocks concentration range pM will be 300, 100, 30, 10, 3, 1, 0.3 and 0 gM. Mix well at each dilution step using multichannel. * Row H has controls. HI- H3 will receive 10 ul of assay media. H4-H9 will receive 10 ul of 3% DMSO-water vehicle. HI 0-H12 will have media alone control with no cells. * Positive control: MDM2 small molecule inhibitor,Nutlin-3a (10 mM) is used as positive control. Nutlin was diluted using the same dilution scheme as peptides. [00286] Addition of working stocks to cells: * Add 10 gi of I OX desired concentration to appropriate well to achieve the final concentrations in total 100 g1 volume in well. (10 gl of 300 gM peptide + 90 g1 of cells in media = 30 gM final concentration in 100 gl volume in wells). Thus final concentration range used will be 30, 10, 3, 1, 0.3& 0 gM. * Controls will include wells that get no peptides but contain the same concentration of DMSO as the wells containing the peptides, and wells containing NO CELLS. * 20h-post incubation, aspirate the media; wash cells with IX PBS (without Ca*/Mg) and lyse in 60 pl of IX Cell lysis buffer (Cell Signaling technologies IOX buffer diluted to IX and supplemented with protease inhibitors and Phosphatase inhibitors) on ice for 30 min. * Centrifuge plates in at 5000 rpm speed in at 4 0 C for 8 min; collect clear supernatants and freeze at -80 0 C till further use. [00287] Protein Estimation: * Total protein content of the lysates is measured using BCA protein detection kit and BSA standards from Thermofisher. Typically about 6-7 gg protein is expected per well. * Use 50 g1 of the lysate per well to set up p21 ELISA. [00288] Human Total p21 ELISA: The ELISA assay protocol is followed as per the manufacturer's instructions. 50 pl lysate is used for each well, and each well is set up in triplicate. [00289] Reagents: * -Cell-Based Assay (-)-Nutlin-3 (10 mM): Cayman Chemicals, catalog # 600034 * - OptiMEM, Invitrogen catalog # 51985 -126- WO 2013/123267 PCT/US2013/026241 * -Cell Signaling Lysis Buffer (lOX), Cell signaling technology, Catalog # 9803 * -Protease inhibitor Cocktail tablets(mini), Roche Chemicals, catalog # 04693124001 " -Phosphatase inhibitor Cocktail tablet, Roche Chemicals, catalog # 04906837001 * -Human total p21 ELISA kit, R&D Systems, DYC1047-5 * -STOP Solution (IM HCL), Cell Signaling Technologies, Catalog # 7002 [00290] Instruments: Micro centrifuge- Eppendorf 5415D and Multiplate Reader for Absorbance readout (Synergy 2). Example 12: Caspase 3 Detection assay: [00291] The assay is performed according to the following general protocol: Cell Plating: Trypsinize, count and seed SJSA1 cells at the density of 7500 cells/ 100 i1/well in 96-well plates a day prior to assay. On the day of study, replace media with fresh RPMI- 11% FBS (assay media). Add 180jL of the assay media per well. Control wells with no cells, receive 200 pl media. [00292] Peptide dilution: * Prepare 10 mM stocks of the peptides in DMSO. Serially dilute the stock using 1:3 dilution scheme to get 10, 3.3, 1.1, 0.33, 0.11, 0.03, 0.01mM solutions using DMSO as diluents. Dilute the serially DMSO-diluted peptides 33.3 times using sterile water This gives range of 1OX working stocks. Also prepare DMSO/sterile water (3% DMSO) mix for control wells. * Thus the working stocks concentration range piM will be 300, 100, 30, 10, 3, 1, 0.3 and 0 gM. Mix well at each dilution step using multichannel. Add 20 ul of I OX working stocks to appropriate wells. * Row H has controls. HI- H3 will receive 20 ul of assay media. H4-H9 will receive 20 ul of 3% DMSO-water vehicle. Hi 0-H12 will have media alone control with no cells. * Positive control: MDM2 small molecule inhibitor,Nutlin-3a (10 mM) is used as positive control. Nutlin was diluted using the same dilution scheme as peptides. [00293] Addition of working stocks to cells: * Add 10 sl of 1OX desired concentration to appropriate well to achieve the final concentrations in total 100 pl volume in well. (10 l of 300 gM peptide + 90 Rl of cells in media = 30 gM final concentration in 100 gl volume in wells). Thus final concentration range used will be 30, 10, 3, 1, 0.3& 0 gM. * Controls will include wells that get no peptides but contain the same concentration of DMSO as the wells containing the peptides, and wells containing NO CELLS. * 48 h-post incubation, aspirate 80 l media from each well; add 100 pl Caspase3/7Glo assay reagent (Promega Caspase 3/7 glo assay system, G8092)per well, incubate with gentle shaking for Ih at room temperature. * read on Synergy Biotek multiplate reader for luminescence. -127- WO 2013/123267 PCT/US2013/026241 * Data is analyzed as Caspase 3 activation over DMSO-treated cells. Example 13. Cell Lysis by Peptidomimetic Macrocycles [00294] SJSA- I cells are plated out one day in advance in clear flat-bottom plates (Costar, catalog number 353072) at 7500cells/well with 100ul/well of growth media, leaving row H columns 10-12 empty for media alone. On the day of the assay, media was exchanged with RPMI 1% FBS media, 90uL of media per well. [00295] 10 mlM stock solutions of the peptidomimetic macrocycles are prepared in 100% DMSO. Peptidomimetic macrocycles were then diluted serially in 100% DMSO, and then further diluted 20-fold in sterile water to prepare working stock solutions in 5% DMSO/water of each peptidomimetic macrocycle at concentrations ranging from 500 uM to 62.5 uM. [00296] 10 uL of each compound is added to the 90 uL of SJSA-1 cells to yield final concentrations of 50 uM to 6.25 uM in 0.5% DMSO-containing media. The negative control (non-lytic) sample was 0.5% DMSO alone and positive control (lytic) samples include 10 uM Melittin and 1% Triton X 100. [00297] Cell plates are incubated for 1 hour at 37C. After the 1 hour incubation, the morphology of the cells is examined by microscope and then the plates were centrifuged at 1200rpm for 5 minutes at room temperature. 40uL of supernatant for each peptidomimetic macrocyle and control sample is transferred to clear assay plates. LDH release is measured using the LDH cytotoxicity assay kit from Caymen, catalog# 1000882. Example 14: p53 GRIP assay [00298] Thermo Scientific* BioImage p53-MDM2 Redistribution Assay monitors the protein interaction with MDM2 and cellular translocation of GFP-tagged p53 in response to drug compounds or other stimuli. Recombinant CHO-hIR cells stably express human p53(1-312) fused to the C terminus of enhanced green fluorescent protein (EGFP) and PDE4A4-MDM2(1-124), a fusion protein between PDE4A4 and MDM2(1-124). They provide a ready-to-use assay system for measuring the effects of experimental conditions on the interaction of p53 and MDM2. Imaging and analysis is performed with a HCS platform. [00299] CHO-hIR cells are regularly maintained in Ham's F12 media supplemented with 1% Penicillin Streptomycin, 0.5 mg/ml Geneticin, 1 mg/ml Zeocin and 10% FBS. Cells seeded into 96-well plates at the density of 7000 cells/ 100 R1 per well 18-24 hours prior to running the assay using culture media. The next day, media is refreshed and PD 177 is added to cells to the final concentration of 3RM to activate foci formation. Control wells are kept without PD-177 solution. 24h post stimulation with PD 177, cells are washed once with Opti-MEM Media and 50 pL of the Opti-MEM Media supplemented with PD-177(6 ptM) is added to cells. Peptides are diluted from 10 mM DMSO stocks to 500 RM working stocks in sterile water, further dilutions made in 0.5% -128- WO 2013/123267 PCT/US2013/026241 DMSO to keep the concentration of DMSO constant across the samples. Final highest DMSO concentration is 0.5% and is used as the negative control. Cayman Chemicals Cell-Based Assay (-)-Nutlin-3 (10 mM) is used as positive control. Nutlin was diluted using the same dilution scheme as peptides.50 gl of 2X desired concentrations is added to the appropriate well to achieve the final desired concentrations. Cells are then incubated with peptides for 6 h at 37 0 C in humidified 5% C02 atmosphere. Post-incubation period, cells are fixed by gently aspirating out the media and adding 150 gi of fixing solution per well for 20 minutes at room temperature. Fixed cells are washed 4 times with 200 gi PBS per well each time. At the end of last wash, 100 gl of 1 gM Hoechst staining solution is added. Sealed plates incubated for at least 30 min in dark, washed with PBS to remove excess stain and PBS is added to each well. Plates can be stored at 4 0 C in dark up to 3 days. The translocation of p53/MDM2 is imaged using Molecular translocation module on Cellomics Arrayscan instrument using lOx objective, XF-100 filter sets for Hoechst and GFP. The output parameters was Mean- CircRINGAvelntenRatio (the ratio of average fluorescence intensities of nucleus and cytoplasm,(well average)). The minimally acceptable number of cells per well used for image analysis was set to 500 cells. Example 15: Solubility Determination for Peptidomimetic Macrocycles [00300] Peptidomimetic macrocyles are first dissolved in neat N, N-dimethylacetamide (DMA, Sigma Aldrich, 38840-IL-F) to make 20X stock solutions over a concentration range of 20-140 mg/mL. The DMA stock solutions are diluted 20-fold in an aqueous vehicle containing 2% Solutol-HS 15, 25 mM Histidine, 45 mg/mL Mannitol to obtain final concentrations of 1-7 mg/ml of the peptidomimetic macrocycles in 5% DMA, 2% Solutol-HS-15, 25 mM Histidine, 45 mg/mL Mannitol. The final solutions are mixed gently by repeat pipetting or light vortexing, and then the final solutions are sonicated for 10 min at room temperature in an ultrasonic water bath. Careful visual observation is then performed under hood light using a 7x visual amplifier to determine if precipitate exists on the bottom or as a suspension. Additional concentration ranges are tested as needed to determine the maximum solubility limit for each peptidomimetic macrocycle. -129-

权利要求:
Claims (39)
[1] 1. A peptidomimetic macrocycle of Formula: 7 O R 8 0 [D],-Xaa3-N' Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -XaaN [E], R1 R2 wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaa 9 , and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaato are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3 -X 4 -His 5 -Tyr 6 -Trp 7 -Alas-Gln 9 -Leuto-Xii-Ser 2 , where each X is an amino acid; each D and E is independently an amino acid; R, and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R, and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula LL2 NH Li and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4 -K-R 4 -],, each being optionally substituted with R 5 ; each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6 ) 2 , -SR 6 , -SOR 6 , -S0 2 R 6 , -C0 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent; -130- WO 2013/123267 PCT/US2013/026241 each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; each R7 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with Rs, or part of a cyclic structure with a D residue; each Rs is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20 or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5.
[2] 2. A peptidomimetic macrocycle of Formula: 0 Ry N R8 [D],- Xaa 3 ~ Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaag Xaa 1 O--N RLi 11 -2 S1 L3 R2 S -- L 2 -- s wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3 -X 4 -His 5 -Tyr-Trp 7 -Ala-Gln 9 -Leuio-Xii-Ser 1 2 , where each X is an amino acid; each D and E is independently an amino acid; R and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L or L' is independently a macrocycle-forming linker of the formula -LI-L 2 -; L, and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4 -K-R 4 -],, each being optionally substituted with R 5 ; R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5; -131- WO 2013/123267 PCT/US2013/026241 LI, L 2 , and L 3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [-R 4 -K-R 4 -]n, each being unsubstituted or substituted with R 5 ; each K is 0, S, SO, S02, CO, C0 2 , or CONR 3 ; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6 ) 2 , -SR 6 , -SOR 6 , -SO 2 R 6 , -C0 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R 7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20 or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5.
[3] 3. A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Tables 4, 4a, or 4b, wherein the peptidomimetic macrocycle has the formula: 0 0 R7 R 8 -- [D]v N[A]x-[B]y-[C]z [E]w- R 1 R2 -L -u Formula (I) wherein: each A, C, D, and E is independently an amino acid; -132- WO 2013/123267 PCT/US2013/026241 R 3 N B is an amino acid, 0 , [-NH-L 3 -CO-], [-NH-L 3 -SO 2 -], or [-NH-L 3 -]; R, and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R, and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula LL2 NH N-N LI, L 2 and L 3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4 -K-R 4 -],, each being optionally substituted with R 5 ; each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6 ) 2 , -SR 6 , -SOR 6 , -S0 2 R 6 , -C0 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; each R 7 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; each Rs is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1 20 or 1-10; u is an integer from 1-10, for example 1-5, 1-3 or 1-2; x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and n is an integer from 1-5.
[4] 4. A peptidomimetic macrocycle of Formula: -133- WO 2013/123267 PCT/US2013/026241 R7 0 0 R 8 0 [D] "XaIN Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 0 N [E], [D],-Xaa 3 Xa R1 R2 L wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3 -X 4 -Glu 5 -Tyr 6 -Trp 7 -Ala-Gln 9 -Leuio/Cbalo-X 1 -Ala1 2 , where each X is an amino acid; each D and E is independently an amino acid; R and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula L 2 LI NH N-N LI and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4 -K-R 4 -],, each being optionally substituted with R 5 ; R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R5 is independently halogen, alkyl, -OR 6 , -N(R 6 ) 2 , -SR6, -SOR 6 , -S0 2 R 6 , -C0 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; -134- WO 2013/123267 PCT/US2013/026241 Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5.
[5] 5. A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Tables 6 or 6a, wherein the peptidomimetic macrocycle has the formula: 0 0 R7 R8 --- [D], N [A],-[B]y-[C]z..- N[] -- [Dv [E]. R 1 LS.S- L R 2 - -u Formula (I) wherein: each A, C, D, and E is independently an amino acid; R 3 B is an amino acid, 0 , [-NH-L 4 -CO-], [-NH-L 4 -SO 2 -], or [-NH-L 4 -]; R, and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R, and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; R 3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; Lt, L 2 , L 3 and L 4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [-R 4 -K-R 4 -]n, each being unsubstituted or substituted with R 5 ; each K is 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6 ) 2 , -SR 6 , -SOR 6 , -S0 2 R 6 , -C0 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent; -135- WO 2013/123267 PCT/US2013/026241 each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue; v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1 20 or 1-10; u is an integer from 1-10, for example 1-5, 1-3 or 1-2; x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and n is an integer from 1-5, wherein the peptidomimetic macrocycle is not a peptidomimetic macrocycle of Table 7, Table 7a or Table 7b.
[6] 6. A peptidomimetic macrocycle of Formula: 0 Rr N R8 D, Xaa 3 '1-,"R1Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaag Xaa 1 --- N 1, L1 -L- 1- L3 R2 S--L 2 -s wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3 -X 4 -Glu 5 -Tyr-Trp 7 -Ala-Gln-Leuio/Cbalo-X 1 -Ala1 2 , where each X is an amino acid; each D and E is independently an amino acid; R, and R2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R, and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; LI, L 2 , and L 3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [-R 4 -K-R 4 -]n, each being unsubstituted or substituted with R 5 ; each K is 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; -136- WO 2013/123267 PCT/US2013/026241 R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5; each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each R5 is independently halogen, alkyl, -OR6, -N(R 6 ) 2 , -SR 6 , -SOR 6 , -S0 2 R 6 , -C0 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5.
[7] 7. A peptidomimetic macrocycle of Formula: 7 R 8 0 [D],-Xaas Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 0 , [E], R1 R2 wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaas, Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3 -X 4 -His 5 -Tyr-Trp 7 -Ala-Gln 9 -Leuio-Xii-Ser 1 2 , where each X is an amino acid; each D and E is independently an amino acid; R, and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula -137- WO 2013/123267 PCT/US2013/026241 L 1 L 2 NH N= N Li and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4 -K-R 4 -],, each being optionally substituted with R 5 ; each R 3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R is independently halogen, alkyl, -OR 6 , -N(R 6 ) 2 , -SR, -SOR6, -SO 2 R6, -CO 2 R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; each R is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; each Rs is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; each R 9 is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with Ra and/or Rb; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20 or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5.
[8] 8. A peptidomimetic macrocycle of Formula: 7 R 8 0 [ 'IN' Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaag-Xa N, [E], [D]v-Xaa 3 57 R1 R2 L - 138- WO 2013/123267 PCT/US2013/026241 wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaag, Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaag, Xaag, and Xaaio are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3 -X 4 -Glu 5 -Tyr 6 -Trp 7 -Alag-Gln 9 -Leuio/Cbaio-XI 1-Ala 1 2 , where each X is an amino acid; each D and E is independently an amino acid; R, and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R, and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula L 1 L 2 NH N --N . Li and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4 -K-R 4 -], each being optionally substituted with R 5 ; R 3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is 0, S, SO, S02, CO, C0 2 , or CONR 3 ; each R 5 is independently halogen, alkyl, -OR 6 , -N(R 6 ) 2 , -SR 6 , -SOR 6 , -S0 2 R 6 , -C0 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R 7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; each R 9 is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with Ra and/or Rb; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20, or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5. -139- WO 2013/123267 PCT/US2013/026241
[9] 9. A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Tables 4, 4a, or 4b, wherein the peptidomimetic macrocycle has the formula: 0 0 R7 R8 -- [D]v N [A]x-B]y[C]z [E]w- R1 R2 -L -u Formula (I) wherein: each A, C, D, and E is independently an amino acid; R3 N ( B is an amino acid, 0 , [-NH-L 3 -CO-], [-NH-L 3 -SO 2 -], or [-NH-L 3 -]; R and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L and L' is independently a macrocycle -forming linker of the formula L 1 L 2 NH N=N LI, L 2 and L 3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4 -K-R 4 -],, each being optionally substituted with R 5 ; each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently 0, S, SO, S02, CO, C0 2 , or CONR 3 ; each R is independently halogen, alkyl, -OR 6 , -N(R 6 ) 2 , -SR6, -SOR 6 , -S0 2 R 6 , -CO 2 R6, a fluorescent moiety, a radioisotope or a therapeutic agent; each R is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; -140- WO 2013/123267 PCT/US2013/026241 each R 7 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; each R is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; each R9 is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with Ra and/or Rb; v and w are independently integers from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1 20 or 1-10; u is an integer from 1-10, for example 1-5, 1-3 or 1-2; x, y and z are independently integers from 0-10, for example the sum of x+y+z is 2, 3, or 6; and n is an integer from 1-5.
[10] 10. The peptidomimetic macrocycle of claim 7, 8 or 9, wherein each each L and L' is independently a macrocycle-forming linker of the formula: R9 L N=N
[11] 11. A peptidomimetic macrocycle of Formula: 0O Ry N R8 [DIv--Xaa 3 xZ Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaag Xaa 1 0 -N [E], RL1 -2- - L3 R2 S -- L 2 -- s wherein: each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaag, and Xaaio is individually an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaag, and Xaao are the same amino acid as the amino acid at the corresponding position of the sequence Phe 3 -X 4 -His 5 -Tyr-Trp 7 -Ala-Gln 9 -Leuio-Xii-Ser 1 2 , where each X is an amino acid; each D and E is independently an amino acid; -141- WO 2013/123267 PCT/US2013/026241 R and R 2 are independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or at least one of R and R 2 forms a macrocycle-forming linker L' connected to the alpha position of one of said D or E amino acids; each L or L' is independently a macrocycle-forming linker of the formula -Li-L 2 -; LI and L 2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [-R 4 -K-R 4 -],, each being optionally substituted with R 5 ; R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; LI, L 2 , and L 3 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene or [-R 4 -K-R 4 -]n, each being unsubstituted or substituted with R 5 ; each K is 0, S, SO, SO 2 , CO, C0 2 , or CONR 3 ; each R 4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each R5 is independently halogen, alkyl, -OR 6 , -N(R 6 ) 2 , -SR6, -SOR 6 , -SO 2 R 6 , -CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent; each R 6 is independently -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent; R 7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue; Rs is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue; v is an integer from 1-1000, for example 1-500, 1-200, 1-100, 1-50, 1-30, 1-20 or 1-10; w is an integer from 3-1000, for example 3-500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10; and n is an integer from 1-5.
[12] 12. The peptidomimetic macrocycle of any one of claims 1, 2, 4, 6, 7, 8, or 11, wherein Xaa 5 is Glu or an amino acid analog thereof.
[13] 13. The peptidomimetic macrocycle of claim 12, wherein Xaa 5 is Glu or an amino acid analog thereof and wherein the peptidomimetic macrocycle has an improved property, such as improved binding affinity, improved solubility, improved cellular efficacy, improved helicity, improved cell permeability, improved in vivo or in vitro anti-tumor efficacy, or improved induction of apoptosis relative to a corresponding peptidomimetic macrocycle where Xaa 5 is Ala. -142- WO 2013/123267 PCT/US2013/026241
[14] 14. The peptidomimetic macrocycle of any one of claims 1-13, wherein the peptidomimetic macrocycle has improved binding affinity to MDM2 or MDMX relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2.
[15] 15. The peptidomimetic macrocycle of any one of claims 1-13, wherein the peptidomimetic macrocycle has a reduced ratio of binding affinities to MDMX versus MDM2 relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2.
[16] 16. The peptidomimetic macrocycle of any one of claims 1-13, wherein the peptidomimetic macrocycle has improved in vitro anti-tumor efficacy against p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2.
[17] 17. The peptidomimetic macrocycle of any one of claims 1-13, wherein the peptidomimetic macrocycle shows improved in vitro induction of apoptosis in p53 positive tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2.
[18] 18. The peptidomimetic macrocycle of any one of claims 1-13, wherein the peptidomimetic macrocycle has an improved in vitro anti-tumor efficacy ratio for p53 positive versus p53 negative or mutant tumor cell lines relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2.
[19] 19. The peptidomimetic macrocycle of any one of claims 1-13, wherein the peptidomimetic macrocycle has improved in vivo anti-tumor efficacy against p53 positive tumors relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2.
[20] 20. The peptidomimetic macrocycle of any one of claims 1-13, wherein the peptidomimetic macrocycle has improved in vivo induction of apoptosis in p53 positive tumors relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2.
[21] 21. The peptidomimetic macrocycle of any one of claims 1-13, wherein the peptidomimetic macrocycle has improved cell permeability relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2.
[22] 22. The peptidomimetic macrocycle of any one of claims 1-13, wherein the peptidomimetic macrocycle has improved solubility relative to a corresponding peptidomimetic macrocycle where w is 0, 1 or 2.
[23] 23. The peptidomimetic macrocycle of any preceding claim, wherein each E is independently an amino acid selected from Ala (alanine), D-Ala (D-alanine), Aib (a-aminoisobutyric acid), Sar (N methyl glycine), and Ser (serine). -143- WO 2013/123267 PCT/US2013/026241
[24] 24. The peptidomimetic macrocycle of any preceding claim, wherein [D], is -Leut-Thr 2 .
[25] 25. The peptidomimetic macrocycle of any one of claims 12-24, wherein w is 3-10.
[26] 26. The peptidomimetic macrocycle of claim 25, wherein w is 3-6.
[27] 27. The peptidomimetic macrocycle of claim 25, wherein w is 6-10.
[28] 28. The peptidomimetic macrocycle of claim 27, wherein w is 6.
[29] 29. The peptidomimetic macrocycle of any one of claims 12-24, wherein v is 1-10.
[30] 30. The peptidomimetic macrocycle of claim 24, wherein v is 2-10.
[31] 31. The peptidomimetic macrocycle of claim 25, wherein v is 2-5.
[32] 32. The peptidomimetic macrocycle of claim 26, wherein v is 2.
[33] 33. The peptidomimetic macrocycle of any one of claims 1-24, wherein w is 3-1000, for example 3 500, 3-200, 3-100, 3-50, 3-30, 3-20, or 3-10.
[34] 34. The peptidomimetic macrocycle of any preceding claim, wherein the peptidomimetic macrocycle is not a macrocycle of Table 5, Table 7, Table 7a, or Table 7b.
[35] 35. The peptidomimetic macrocycle of any preceding claim, wherein each E is Ser or Ala or an analog therof.
[36] 36. The peptidomimetic macrocycle of any preceding claim, comprising at least one amino acid which is an amino acid analog.
[37] 37. A method of treating cancer in a subject comprising administering to the subject a peptidomimetic macrocycle of any one of the preceding claims.
[38] 38. A method of modulating the activity of p53 and/or MDM2 and/or MDMX in a subject comprising administering to the subject a peptidomimetic macrocycle any one of the preceding claims.
[39] 39. A method of antagonizing the interaction between p53 and MDM2 and/or between p53 and MDMX proteins in a subject comprising administering to the subject a peptidomimetic macrocycle any one of the preceding claims. -144-

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法律状态:
2018-05-17| FGA| Letters patent sealed or granted (standard patent)|

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2021-09-09| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US201261599365P| true| 2012-02-15|2012-02-15||

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US201261599362P| true| 2012-02-15|2012-02-15||

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US61/599,362||2012-02-15||

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US61/599,365||2012-02-15||

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US201261723762P| true| 2012-11-07|2012-11-07||

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US201261723767P| true| 2012-11-07|2012-11-07||

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US61/723,767||2012-11-07||

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US61/723,762||2012-11-07||

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PCT/US2013/026241|WO2013123267A1|2012-02-15|2013-02-14|Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles|AU2018202579A| AU2018202579A1|2012-02-15|2018-04-12|Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles|