CA2908148A1 - Indoline compounds as granzyme b inhibitors - Google Patents

Abstract

Indoline Granzyme B inhibitor compounds, compositions that include the compounds, and methods for inhibiting Granzyme B in a subject or for treating a disease, disorder or condition treatable by inhibiting Granzyme B using said compounds. The indoline compounds of the invention have advantageous water solubility and effectively inhibit Granzyme B.

Description

INDOLINE COMPOUNDS AS GRANZYME B INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Patent Application No. 61/806,767, filed March 29, 2013, and U.S. Patent Application No. 61/941,358, filed February 18, 2014, each expressly incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention disclosure relates generally to agents for treating diseases, disorders, and conditions treatable by inhibiting Granzyme B, and more specifically to substituted indoline compounds that are inhibitors of Granyzme B.
BACKGROUND OF THE INVENTION
Granzyme B is a pro-apoptotic serine protease found in the granules of cytotoxic lymphocytes (CTL) and natural killer (NK) cells. Granzyme B is released towards target cells, along with the pore-forming protein, perforin, resulting in its perforin-dependent internalization into the cytoplasm and subsequent induction of apoptosis (see, for e.g., Medema et al., Elm i Immtmol. 27:3492-3498, 1997). However, during aging, inflammation and chronic disease, Granzyme B can also be expressed and secreted by other types of immune (e.g., mast cell, macrophage, neutrophil, and dendritic cells) or non-immune (keratinocyte, chondrocyte) cells and has been shown to possess extracellular matrix remodeling activity (Choy et al., Arterioscler. Thromb.
Vasc. Biol.
24(12):2245-2250, 2004 and Buzza et al., J. Biol. Chem. 280:23549-23558, 2005).
Inhibitors of Granzyme B in humans have been limited to (a) relatively weak, nonspecific inhibitors such as isocoumarins (Odake et al., (1991), Biochemistry, 30(8), 2217-2227); (b) biological inhibitors such as serpinB9 (Sun et al., (1996), 1 Biol. Chem., 271(44), 27802-27809); (c) covalently coupled inhibitors such as aldehydes (Willoughby et al., (2002), Bioorg. Med Chem, Lett., 12(16), 2197), halomethyl ketones (Kam et al., (2000), Biochim. Biophy. Acta, 1477(1-2), 307-323), and phosphonates (Mahrus and Craik, (2005), Chem. & Biol., 12, 567-77 and Kam et al., (2000)); and (d) tricyclic inhibitors (Willoughby et al., (2002)).
Nonspecific inhibitors (such as isocoumarins) are not sufficiently potent or specific to be effective treatments for Granzyme-B-related diseases, disorders, and conditions. Likewise, the use of biological inhibitors such as serpins is limited by the ability to deliver the inhibitor to the target mammal, the cost of manufacturing the biological agents, and other, off-target activities, such as inhibition of other serine proteases such as human neutrophil elastase (Dahlen et al., (1999), Biochim.
Biophys.
Acta, 1451(2-3), 233-41), Caspase-1 (Annaud et al., (1999), Biochem. J., Sep 15; 342 Pt3, 655-65; Krieg et al., (2001), Mol. Endocrinol., 15(11), 1971-82; and Young et al., (2000), 1 Exp. Med., 191(9), 1535-1544); Caspase-4 and Caspase-8 (Annaud et al., (1999)).
The tricyclic inhibitors (Willoughby et al. (2001)) also suffer from synthetic complexity/high manufacturing cost due to the complex core and accompanying low water solubility.
Despite the advances in development of Granzyme B inhibitors, there exists a need for compounds that inhibit Granzyme B with selectivity, that are relatively simple to manufacture at low cost, that are highly water soluble, and that do not present drug delivery challenges. The present invention seeks to fulfill this need and provides further related advantages.
SUMMARY OF THE INVENTION
The present invention provides Granzyme B inhibitor compounds, compositions that include the compounds, and methods for using the compounds.
In one aspect of the invention, the invention provides Granzyme B inhibitor compounds. In one embodiment, the invention provides the compounds having Formula (I):

¨1:46 R9 \

yea Z. N R2b ) n I
H 0 N=11 Ric7---L
Rib '1a Formula (1) its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ri a is a heteroaryl group selected from (a) 1,2,3-triazoly1 optionally substituted with C1-C2 alkyl, (b) 1,2,3,4-tetrazolyl, and (c) 1,2,3-thiadiazoly1;
Rib and Ric are independently selected from hydrogen, methyl, and halogen;

-2-R2a and R2b are independently selected from hydrogen and methyl, or R2a and R2b taken together are oxo (i.e., =0, R2a and R2b together with the carbon to which they are attached form a carbonyl group);
n is 1 or 2;
R3 is selected from hydrogen and Ci-C4 alkyl optionally substituted with a carboxylic acid or a carboxylate group (-0O2H or ¨0O2-) or an amine group (-NH2);
Z is an acyl group selected from the group R5, N=
(a) R4 R5a (b) , wherein o is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid;
H (1) N
R5a/
(c) P , wherein p is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid; and Yy1-1,/
(d) R4 , wherein Y is heteroaryl;
wherein R4 is selected from (i) Ci-C 1 2 alkyl, (ii) C1-C6 heteroalkyl optionally substituted with C1-C6 alkyl, (iii) C3-C6 cycloalkyl, (iv) C6-Cio aryl, (v) heterocyclyl, (vi) C3-Cio heteroaryl, (vii) aralkyl, and

-3-(viii) heteroalkylaryl;
R5 is ¨C(=0)-R10, wherein R10 is selected from (i) C1-C12 alkyl optionally substituted with C6-C112 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (ii) C1-C10 heteroalkyl optionally substituted with C1-C6 alkyl or carboxylic acid, (iii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (iv) C6-C10 aryl optionally substituted with C1-C6 alkyl, optionally substituted C6-Cio aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (v) heterocyclyl, (vi) C3-C10 heteroaryl, (vii) aralkyl, and (viii) heteroalkylaryl; and R6, R7, R8, and R9 are independently selected from (a) hydrogen, (b) halogen, (c) Ci-C6 alkyl, (d) -XRII, wherein X is selected from 0, C(=0), S, S=0, or S(=0)2, (e) -C(=0)N(R12)(R13), (f) -NRI 1 ) (R12)(R13), (g) -N-C(=0)-R11, and (h) -N-C(=0)0-Rii, wherein R11, R12, and RI 3 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, CI -C6 heteroalkyl, C2-C6 alkenyl, C6-C10 aryl, aralkyl, and C3-C10 heteroaryl.
In another embodiment, the invention provides compounds having Formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
RI a is a heteroaryl group selected from (a) 1,2,3-triazoly1 optionally substituted with C1-C2 alkyl, and (b) 1,2,3,4-tetrazoly1;

-4-Rib and Ric are independently selected from hydrogen and methyl;
R2a and R2b are independently selected from hydrogen and methyl;
n is 1;
R3 is selected from hydrogen and C1-C4 alkyl optionally substituted with a carboxylic acid or a carboxylate group (-0O2H or ¨0O2") or an amine group (-NH2);
Z is an acyl group selected from the group R5 ,N )4.
(a) R4 R5a 9 (b) , wherein o is 1 or 2, and Rsa is C4-acyl substituted with a carboxylic acid;
H
R5a,N
(c) )P , wherein p is 1 or 2, and R59 is C4-acyl substituted with a carboxylic acid; and YyLccss, (d) R4 , wherein Y is heteroaryl;
R4 is selected from (i) C1-Ci2 alkyl, (ii) C3-C6 cycloalkyl, (iii) C6-C10 aryl, and (iv) C3-C10 heteroaryl;
R5 is ¨C(=0)-Rio, wherein Ric) is selected from (1) Ci-C12 alkyl optionally substituted with C6-C10 aryl, optionally substituted C3-Cio heteroaryl, amino, or carboxylic acid, (ii) heteroalkyl optionally substituted with Ci-C6 alkyl or carboxylic acid,

-5-

6 PCT/CA2014/050317 (iii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, optionally substituted C6-Cio aryl, optionally substituted C3-Cio heteroaryl, amino, or carboxylic acid, (iv) C6-C10 aryl optionally substituted with Ci-C6 alkyl, optionally substituted C6-Ci0 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (v) C3-Ci0 heteroaryl; and R6, R7, Rg, and R9 are independently selected from (a) hydrogen, (b) halogen, (c) C1-C6 alkyl, (d) -XRii, wherein X is selected from 0 and C(=0), (0 -N(R11)(R12)(R13), (g) -N-C(=0)-Ri I, and wherein Rii, R12, and R13 are independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C6-C10 aryl, aralkyl, and C3-Cio heteroaryl.
In further embodiments, the invention provides compounds having Formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ri a is tetrazole or triazole; Rib and Ric are H; n is 1; R2, and R2b are H;
R3 is H
or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is ,N
1-N5 ' Ri a is tetrazole or triazole; Rib and R1, are H; n is 1; R2, and R2b are H;
R3 is H
or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is R5a 9 C--4)o =

RI, is tetrazole or triazole; Ri b and Ric are H; n is 1; R2a and R2b are H;
R3 is H
or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-1Z9 are H; and Z is R5a N
)P ;and Ria is tetrazole or triazole; Rib and Ric are H; n is 1; R2a and R2b are H; R3 is H
or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is O
R., wherein R4, R5a, o, p, and Y are as described above.
In another embodiment, the invention provides compounds having Formula OD:

R, H 0 R3 R a N, R20)11 R5NHÇ2 0' I\l`
Rib "la Formula (II) its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ri a is tetrazole or triazole; Rib and Ric are H; n is 1; R2a and R2b are H;
R3 is H
or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H;
R4 is C3-C6 cycloalkyl or Cl-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy; and R5 is ¨C(=0)-R10, wherein R10 is selected from (i) CI-Cu alkyl optionally substituted with C6-Cio aryl, optionally substituted C3-Cio heteroaryl, amino, or carboxylic acid,

-7-(ii) CI-CI heteroalkyl optionally substituted with C1-C6 alkyl or carboxylic acid, (iii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (iv) C6-C10 aryl optionally substituted with C1-C6 alkyl, optionally substituted C6-Cio aryl, optionally substituted C3-Clo heteroaryl, amino, or carboxylic acid, (v) C3-C10 heteroaryl.
In a further embodiment, the invention provides compounds having Formula (III):
171 0 R3 n 0 R4 1-1-1 O,H

Ria Formula (III) its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ri a, R3, R4, and R10 are as above for Formula (II);
wherein R10, when defined as Cl-C 1 2 alkyl substituted with a carboxylic acid or carboxylate group, is:
-(CH2)n-CO2H, where n is 2, 3, 4, 5, or 6;
optionally wherein one or more single methylene carbons are substituted with a fluoro, hydroxy, amino, C1-C3 alkyl (e.g., methyl), or C6-C 1 0 aryl group;
optionally wherein one or more single methylene carbons are substituted with two fluoro (e.g., difluoro, perfluoro) or C 1 -C3 alkyl (e.g., gem-dimethyl) groups;
optionally wherein one or more single methylene carbons are substituted with two alkyl groups that taken together with the carbon to which they are attached form a 3, 4, 5, or 6-membered carbocyclic ring (e.g., spiro groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl); and optionally wherein adjacent carbon atoms from an unsaturated carbon-carbon bond (e.g., alkenyl such as -CH=CH-) or taken form a benzene ring (e.g., 1,2-, 1,3-, and 1,4-phenylene); or wherein R10, when defined as C3-C6 cycloalkyl substituted with a carboxylic acid or carboxylate group, is:

-8-{cH2)n Co2H, wherein n is 1, 2, 3, or 4; and optionally, for n = 3 or 4, wherein adjacent carbon atoms from an unsaturated carbon-carbon bond (e.g., cyclopentenyl or cyclohexeny1).
In another embodiment, the invention provides compounds having Formula (IV):

), Ri("Y 1rN N
R4 H 0 ,H
Ni Ria Formula (IV) its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ria, R3, and R4 are as above for Formulae (II) and (III); and R11 is selected from:
(a) optionally substituted C6-C10 aryl (e.g., unsubstituted phenyl and substituted phenyl such as carboxyphenyl, am inophenyl, alkylaminophenyl, d ialkylam ino ph enyl); and (b) optionally substituted C3-C10 heteroaryl (e.g., optionally substituted pyridyl, optionally substituted thiazolyl, optionally substituted benzothiophenyl, optionally substituted tetrazolyl, and optionally substituted triazolyl (e.g., substituted).
In another aspect, the invention provides pharmaceutical compositions comprising a Granzyme B inhibitor compound of the invention and a pharmaceutically acceptable carrier.
In a further aspect of the invention, a method for inhibiting Granzyme B is provided. In one embodiment, the method comprises administering an effective amount of a Granzyme B inhibitor compound of the invention or a pharmaceutical composition of the invention to a subject in need thereof.
In a further aspect of the invention, a method for treating a disease, disorder, or condition treatable by inhibiting Granzyme B is provided. In one embodiment, the method comprises administering a therapeutically effective amount of a Granzyme B
inhibitor compound of the invention or a pharmaceutical composition of the invention to

-9-a subject in need thereof. Representative routes of administration include topical administration, oral administration, and administration by injection.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 is a schematic illustration of a representative synthetic pathway for the preparation of representative compounds of the invention P5-P4-P3-P2-P1 starting from P1.
FIGURE 2 is a schematic illustration of another representative synthetic pathway for the preparation of representative compounds of the invention P5-P4-P3-P2-P1 starting from P5.
FIGURE 3 is a schematic illustration of a further representative synthetic pathway for the preparation of representative compounds of the invention P5-P4-P3-P2-P1 starting from a component other than P1 or P5.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides Granzyme B inhibitor compounds, compositions that include the compounds, and methods for using the compounds. The compounds of the invention have advantageous water solubility and effectively inhibit Granzyme B.
In one aspect of the invention, the invention provides Granzyme B inhibitor compounds. In one embodiment, the invention provides the compounds having Formula (I):

\ -R6 ZNNR2a R2b/ n N
Rib r`la Formula (I) its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ria is a heteroaryl group selected from (a) 1,2,3-triazoly1 optionally substituted with Ci-C2 alkyl, (b) 1,2,3,4-tetrazolyl, and (c) 1,2,3-thiadiazoly1;
Rib and Ric are independently selected from hydrogen, methyl, and halogen;

-10-R2a and R2b are independently selected from hydrogen and methyl, or R2a and R2b taken together are oxo (i.e., =0, R2a and R2b together with the carbon to which they are attached form a carbonyl group);
n is 1 or 2;
R3 is selected from hydrogen and CI-CI alkyl optionally substituted with a carboxylic acid or a carboxylate group (-0O2H or ¨0O2-) or an amine group (-NH2);
Z is an acyl group selected from the group (a) R4 R52 C) (b) , wherein o is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid;

H I;
Iss=
R5a (C) )P , wherein p is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid; and Yy (d) R4 , wherein Y is heteroaryl;
wherein R4 is selected from (i) Ci-Ci2 alkyl, (ii) C1-C6 heteroalkyl optionally substituted with C1-C6 alkyl, (iii) C3-C6 cycloalkyl, (iv) C6-C10 aryl, (v) heterocyclyl, (vi) C3-Cio heteroaryl, (vii) aralkyl, and

-11-(viii) heteroalkylaryl;
R5 is ¨C(=O)-Rio, wherein R10 is selected from (i) CI-C12 alkyl optionally substituted with C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (ii) CI-Cm heteroalkyl optionally substituted with C1-C6 alkyl or carboxylic acid, (iii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (iv) C6-Ci0 aryl optionally substituted with Cl-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-Ci0 heteroaryl, amino, or carboxylic acid, (v) heterocyclyl, (vi) C3-C10 heteroaryl, (vii) aralkyl, and (viii) heteroalkylaryl; and R6, R7, R8, and R9 are independently selected from (a) hydrogen, (b) halogen, (c) C 1 -C6 alkyl, (d) -XR11, wherein X is selected from 0, C(=0), S, S=0, or S(=0)2, (e) -C(=0)N(R12)(R13), (0 -N(Ri i) (R12)(R13), (g) -N-C(=0)-Ri i, and (h) -N-C(=0)0-R11, wherein R11, R12, and R13 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C6-Ci0 aryl, aralkyl, and C3-C10 heteroaryl.
Representative compounds of the above embodiment include Examples A41 and B2.
In another embodiment, the invention provides compounds having Formula (I), its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ria is a heteroaryl group selected from

-12-(a) 1,2,3-triazoly1 optionally substituted with C1-C2 alkyl, and (b) 1,2,3,4-tetrazoly1;
Rib and Ric are independently selected from hydrogen and methyl;
R2a and R2b are independently selected from hydrogen and methyl;
n is 1;
R3 is selected from hydrogen and C1-C4 alkyl optionally substituted with a carboxylic acid or a carboxylate group (-CO2H or ¨0O2") or an amine group (-NF12);
Z is an acyl group selected from the group R5'N
(a) R4 RE,E11 , (b) D , wherein o is 1 or 2, and R5a is Ca-acyl substituted with a carboxylic acid;
o H ii R5a (c) )P , wherein p is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid; and (d) R4 , wherein Y is heteroaryl;
R4 is selected from (i) Ci -C12 alkyl, (ii) C3-C6 cycloalkyl, (iii) C6-C10 aryl, and (iv) C3-C10 heteroaryl;
R5 is ¨C(=0)-Rio, wherein Rio is selected from (i) C1-C12 alkyl optionally substituted with C6-Cio aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid,

-13-(ii) C1-C10 heteroalkyl optionally substituted with C1-C6 alkyl or carboxylic acid, (iii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, optionally substituted C6-Ci0 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (iv) C6-C10 aryl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (v) C3-C10 heteroaryl; and R6, R7, Rg, and R9 are independently selected from (a) hydrogen, (b) halogen, (c) Ci-C6 alkyl, (d) -XRii, wherein X is selected from 0 and C(=0), (f) -N(Rii)(R12)(R13), (g) -N-C(=0)-Rii, and wherein R11, R12, and R13 are independently selected from the group consisting of hydrogen, Ci-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C6-C10 aryl, aralkyl, and C3-Ci0 heteroaryl.
Representative compounds of the above embodiment include Examples C25, C26, C28, C29, C36, and C37.
Other representative compounds of the above embodiment include Examples C23, C24, and C38.
Other representative compounds of the above embodiment include Examples B3, B4,1-5, A6, A7, A15, A29 and C47.
In further embodiments, the invention provides compounds having Formula (1), its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ri a is tetrazole or triazole; Rib and Ric are H; n is 1; R2a and R2b are H;
R3 is H
or CI-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is R5 -'N yltcss!

-14-Ri a is tetrazole or triazole; Rib and Ric are H; n is I; R2a and R2b are H;
R3 is H
or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is Rb a a ;
Ria is tetrazole or triazole; Rib and Ric are H; n is 1; R2a and R2b are H; R3 is H
or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is H
R5a' N
5,=
)P ;and Ri a is tetrazole or triazole; Rib and Ric are H; n is 1; R2a and R2b are H;
R3 is H
or CI -C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is Yy R4 ;
wherein R4, R5a, o, p, and Y are as described above.
In another embodiment, the invention provides compounds having Formula (II):

\_-R5 171 R3 RR5 N a ) R22bf n H O,H
N

Rib -1' Formula (II) its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ri a is tetrazole or triazole; Rib and Ric are H; n is 1; R2a and R2b are H;
R3 is H
or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H;

R4 is C3-C6 cycloalkyl or C 1 -C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy; and R5 is ¨q=0)-Rio, wherein Rio is selected from CI-C12 alkyl optionally substituted with C6-Cio aryl, optionally substituted C3-Cio heteroaryl, amino, or carboxylic acid, (ii) C1-C10 heteroalkyl optionally substituted with Cl-C6 alkyl or carboxylic acid, (iii) C3-C6 cycloalkyl optionally substituted with Ci-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (iv) C6-C10 aryl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (v) C3-C10 heteroaryl.
Representative compounds of the above embodiment include Examples B5, B6, B7, C19, C20, C21, C22, C27, C30, C31, C32, C33, C34, and C35.
In a further embodiment, the invention provides compounds having Formula (III):
171 0 R3 1-=--0 R4 III 00 ,H
Nil Ri a Formula (III) its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ri a, R3, R4, and R10 are as above for Formula (II);
wherein Rio, when defined as C1-C12 alkyl substituted with a carboxylic acid or carboxylate group, is:
-(CH2),-CO2H, where n is 2, 3, 4, 5, or 6;
optionally wherein one or more single methylene carbons are substituted with a fluoro, hydroxy, amino, C1-C3 alkyl (e.g., methyl), or C6-C10 aryl group;
optionally wherein one or more single methylene carbons are substituted with two fluoro (e.g., difluoro, perfluoro) or C1-C3 alkyl (e.g., gem-dimethyl) groups;
optionally wherein one or more single methylene carbons are substituted with two alkyl groups that taken together with the carbon to which they are attached form a 3, 4, 5, or 6-membered carbocyclic ring (e.g., spiro groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl); and optionally wherein adjacent carbon atoms from an unsaturated carbon-carbon bond (e.g., alkenyl such as -CH=CH-) or taken form a benzene ring (e.g., 1,2-, 1,3-, and 1,4-phenylene); or wherein R10, when defined as C3-C6 cycloalkyl substituted with a carboxylic acid or carboxylate group, is:
(C1-12), H
- -2-, wherein n is 1, 2, 3, or 4; and optionally, for n = 3 or 4, wherein adjacent carbon atoms from an unsaturated carbon-carbon bond (e.g., cyclopentenyl or cyclohexeny1).
Representative compounds of the above embodiment include Examples A5, A13, A14, A16, A17-1, A17-2, A18, A19, A20-1, A20-2, A21-1, A21-2, A22-1, A22-2, A23-1, A23-2, A24, A25, A26-1, A26-2, A30-1, A30-2, A31, A32, A33, A36, A37, A38, A39, A40, A43, A44, A45, A46, A48, A51, A52, A53, A54-1, A54-2, A55, A56, A57-1, and A57-2.
In another embodiment, the invention provides compounds having Formula (IV):

R11---'-'1g' I R4 III 0 H

Formula (IV) its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
Ria, R3, and R4 are as above for Formulae (II) and (III); and R11 is selected from:
(a) optionally substituted C6-C10 aryl (e.g., unsubstituted phenyl and substituted phenyl such as carboxypheny I, am inophenyl, alky lam inophenyl, dialkylaminophenyl); and (b) optionally substituted C3-C10 heteroaryl (e.g., optionally substituted pyridyl, optionally substituted thiazolyl, optionally substituted benzothiophenyl, optionally substituted tetrazolyl, and optionally substituted triazolyl (e.g., substituted).

Representative compounds of the above embodiment include Examples Al, A2, A3, A4, A8, A9, A10, A11, Al2, A27, A28, A34, A35, A42, A49, A50, Bl, Cl, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, and C39.
Each of the inhibitor compounds of the invention contain asymmetric carbon centers and give rise to stereoisomers (i.e., optical isomers such as diastereomers and enantiomers). It will be appreciated that the present invention includes such diastereomers as well as their racemic and resolved enantiomerically pure forms. It will also be appreciated that in certain configurations, the relative stereochemistry of certain groups may be depicted as "cis" or "trans" when absolute stereochemistry is not shown.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, arc meant to include both E and Z geometric isomers.
When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
Examples of such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acids.
The invention is described using the following definitions unless otherwise indicated.
As used herein, the term "alkyl" refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne.

Representative alkyl groups include methyl; ethyls such as ethanyl, ethenyl, ethynyl;
propyls such as propan-l-yl, propan-2-yl, cyclopropan-l-yl, prop-l-en-l-yl, prop-1-en-2-yl, prop-2-en-1-y1 (ally!), cycloprop-l-en-l-yl; cycloprop-2-en-1-y1, prop-1-yn-l-yl, and prop-2-yn- 1 -yl; butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-1 -yl, 2-methyl-propan-2-yl, cyclobutan-l-yl, but-l-en-l-yl, but- 1-en-2-yl, 2-methyl-prop-1-en-1-y1, but-2-en-1-y1, but-2-en-2-yl, buta-1,3-dien-l-yl, buta-1,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-l-yl, but-l-yn-l-yl, but-1-yn-3-yl, and but-3-yn-1-yl; and the like. Where a specific level of saturation is intended, the expressions "alkanyl," "alkenyl," and "alkynyl" are used. Alkyl groups include cycloalkyl groups.
The term "cycloalkyl" refers to mono-, bi-, and tricyclic alkyl groups having the indicated number of carbon atoms.
Representative cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, eyelodociecylmethyl, and 2-ethyl-1-bicyclo[4.4.0]decyl groups. The alkyl group may be unsubstituted or substituted as described below.
"Alkanyl" refers to a saturated branched, straight-chain, or cyclic alkyl group.
Representative alkanyl groups include methanyl; ethanyl; propanyls such as propan-l-yl, propan-2-y1(isopropyl), and cyclopropan-1-y1; butanyls such as butan-l-yl, butan-2-y1 (sec-butyl), 2-methyl-propan-1-y1(isobutyl), 2-methyl-propan-2-yl(t-butyl), and cyclobutan-1 -y1; and the like. The alkanyl group may be substituted or unsubstituted.
Representative alkanyl group substituents include -R14, -0R14, -SRI4, -NR14(R15), X, -Cx3, ____________ CN, -NO2, -C(=0)R14, -C(=0)0R14, -C(=0)NR14(R15), -C(=0)SRI 4, -C(=NRI 4)R i 4, -C(=NRI4)0R14, -C(=NRI 4)NR 1 4(Ri 5). -C(=NRI 4)SR 14, -C(=S)Ri 4, -C(=S)ORI 4, -C(=S)NR14(R15), -C(=S)SR14, -NRI4C(=0)NR14(R15), -NR14(=NR14)NR14(R15), -NRI4C(=S)NR14(R15), -S(=0)2R14, _____________________ S(=0)20Ri 4, S (=0)2NR I 4(RI 5)5 OC(=0)R14, -0C(=0)0R14, -0C(=0)NR14(R15), -0C(=0)SR14, -0S(=0)20R14, -0S(=0)2NR14(R 1 5), and -0P(=0)2(0Ri4), wherein each X is independently a halogen; and RI 4 and R15 are independently hydrogen, C1-C6 alkyl, C6-C14 aryl, arylalkyl, C3-C10 heteroaryl, and heteroarylalkyl, as defined herein.
In certain embodiments, two hydrogen atoms on a single carbon atom can be replaced with =0, =NRI 2, or =S.
"Alkenyl" refers to an unsaturated branched, straight-chain, cyclic alkyl group, or combinations thereof having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s).
Representative alkenyl groups include ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1 -y1 (allyl), prop-2-en-2-yl, and cycloprop-1-en-1-y1; cycloprop-2-en-1 -yl; butenyls such as but-l-en-l-yl, but-1-en-2-yl, 2-methyl-prop-1-en-l-yl, but-2-en-1-y1, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-l-yl, buta-1,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-l-en-3-yl, and cyclobuta-1,3-dien-1-y1; and the like. The alkenyl group may be substituted or unsubstituted. Representative alkenyl group substituents include __________ R14, ¨X, ¨CX3, ¨CN, -C(=0)R14, -C(=0)0R14, ¨C(=0)NR14(R15), ¨C(3)SR14, ¨C(=NR14)R14, ¨C(=NR14)0R14, ¨C(=NR14)NR14(R15), ¨C(=NR14)SR14, ¨C(=S)Ria, ¨C(=S)ORI4, ¨C(=S)NR14(R15), -C(=S)SR14, wherein each X is independently a halogen; and Ri4 and R15 are independently hydrogen, C I -C6 alkyl, C6-C14 aryl, arylalkyl, C3-C10 heteroaryl, and heteroarylalkyl, as defined herein.
"Alkynyl" refers to an unsaturated branched, straight-chain, or cyclic alkyl group having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Representative alkynyl groups include ethynyl; propynyls such as prop-1-yn-1-y1 and prop-2-yn-1-y1; butynyls such as but-l-yn-l-yl, but-1-yn-3-yl, and but-3-yn-1-y1; and the like. The alkynyl group may be substituted or unsubstituted. Representative alkynyl group substituents include those as described above for alkenyl groups.
The term "haloalkyl" refers to an alkyl group as defined above having the one or more hydrogen atoms replaced by a halogen atom. Representative haloalkyl groups include halomethyl groups such as chloromethyl, fluoromethyl, and trifluoromethyl groups; and haloethyl groups such as chloroethyl, fluoroethyl, and perfluoroethyl groups.
The term "heteroalkyl' refers to an alkyl group having the indicated number of carbon atoms and where one or more of the carbon atoms is replaced with a heteroatom selected from 0, N, or S. Where a specific level of saturation is intended, the expressions "heteroalkanyl," "heteroalkenyl," and "heteroalkynyl" are used. Representative heteroalkyl groups include ether, amine, and thioether groups. Heteroalkyl groups include heterocyclyl groups. The term "heterocycly1" refers to a 5- to 10-membered non-aromatic mono- or bicyclic ring containing 1-4 heteroatoms selected from 0, S, and N.
Representative heteroeyely1 groups include pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropuranyl, and morpholinyl groups. The heteroalkyl group may be substituted or unsubstituted. Representative heteroalkyl substituents include R14, 0R14, __ SR14, ¨NR14(1c115), ¨X, ¨CX3, ¨CN, ¨NO2, ¨C(=0)R 14, ¨C(=0)0R14, ¨C(=0)NR14(R s), ¨C(=0)SR14, ¨C(=NR14)R14, ¨C(=-NR14)0Ria, ¨C(=NR14)NRI 4(R s), ¨C(=NRI 4)SR14, ¨C(=S)Ria, ¨C(=S)0R14, ¨C(=S)NR14(R15), ¨C(=S)SR14, ¨NRI4C(=0)NR14(Ri 5), ¨NR14(=NR14)NRI 4(R15), ¨NRI4C(=S)NR14(R15), ¨S(=0)2R14, ¨S(=-0)20Ri4, ¨S(-=0)2NR14(R15), ¨0C(=0)R14, ¨0C(=0)0R14, ¨0C(=0)NR14(R15), ¨0C(.0)SR14, ¨0S(=0)20R14, ¨0S(=0)2NR14(R15), and ¨0P(=0)2(0R14), wherein each X is independently a halogen; and R14 and R15 are independently hydrogen, CI-C6 alkyl, C6-C14 aryl, arylalkyl. C3-C10 heteroaryl, and heteroarylalkyl, as defined herein.
In certain embodiments, two hydrogen atoms on a single carbon atom can be replaced with =NR12, or =S.
The term "alkoxy" refers to an alkyl group as described herein bonded to an oxygen atom. Representative C1-C3 alkoxy groups include methoxy, ethoxy, propoxy, and isopropoxy groups.
The term "alkylamino" refers an alkyl group as described herein bonded to a nitrogen atom. The term "alkylamino" includes monoalkyl- and dialkylaminos groups.
Representative C1-C6 alkylamino groups include methylamino, dimethylamino, ethylamino, methylethylamino, diethylamino, propylamino, and isopropylamino groups.
The term "alkylthio" refers an alkyl group as described herein bonded to a sulfur atom. Representative C1-C6 alkylthio groups include methylthio, propylthio, and isopropylthio groups.
The term "aryl" refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Suitable aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In certain embodiments, the aryl group is a C5-C14 aryl group. In other embodiments, the aryl group is a C5-C10 aryl group. The number of carbon atoms specified refers to the number of carbon atoms in the aromatic ring system. Representative aryl groups are phenyl, naphthyl, and cyclopentadienyl. The aryl group may be substituted or unsubstituted.
Representative aryl group substituents include ¨R14, ¨0R14, ¨SR14, ¨NR14(R15), ¨X, ¨CX3, ¨CN, ¨NO2, ¨C(=0)R 14, ¨C(=0)OR i 4, ¨C(=0)NRI4(R1s), ¨C(=0)SR14, C(=NR14)12,14, ¨C(=NR14)0R14, ¨C(=NR14)NR14(Ri 5), ¨C(=NRI 4)SR14, ¨C(=S)R14, ¨C(=S)ORia, ¨C(=S)NR14(R13), ¨C(=S)SR14, ¨NR14C(=0)NR 14(R; 5), ¨NR14(=NRI5)NRI 4(Ri5), ¨NR 14C(=S)NR i 4(R i s), ¨S(==0)21214, ¨S(--=0)20R14, ¨S(7-10)2NRI 4(R 1 5)5 ¨0q=0)R1 4, -0q=0)0R14, -0q=0)1\1111 4(R1 5), -0C(=0)SR14, ¨0S(=0)20R14., ¨0S(=0)2NR14(R15), and ¨0P(=0)2(01Z14), wherein each X is independently a halogen; and R14 and R15 are independently hydrogen, C1-C6 alkyl, C6-C14 aryl, arylalkyl, C3-C10 heteroaryl, and heteroarylalkyl, as defined herein.
The term "aralkyl" refers to an alkyl group as defined herein with an aryl group, optionally substituted, as defined herein substituted for one of the alkyl group hydrogen atoms. Suitable aralkyl groups include benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-y1, 2-naphthylethen-1-y1, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. Where specific alkyl moieties are intended, the terms aralkanyl, aralkenyl, and aralkynyl are used. In certain embodiments, the aralkyl group is a C6-C20 aralkyl group, (e.g., the alkanyl, alkenyl, or alkynyl moiety of the aralkyl group is a C1-C6 group and the aryl moiety is a C5-C14 group). In other embodiments, the aralkyl group is a C6-C13 aralkyl group (e.g., the alkanyl, alkenyl, or alkynyl moiety of the aralkyl group is a C1-C3 group and the aryl moiety is a aryl group. In certain embodiments, the aralkyl group is a benzyl group.
The term "heteroaryl" refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system, which may be monocyclic or fused ring (i.e., rings that share an adjacent pair of atoms).
A "heteroaromatic" group is a 5- to 14-membered aromatic mono- or bicyclic ring containing 1-4 heteroatoms selected from 0, S, and N. Representative 5- or 6-membered aromatic monocyclic ring groups include pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole, oxazole, and isooxazole. Representative 9- or 10-membered aromatic bicyclic ring groups include benzofuran, benzothiophene, indole, pyranopyrrole, benzopyran, quionoline, benzocyclohexyl, and naphthyri dine. Suitable heteroaryl groups include groups derived from acridine, arsindole, carbazole, 13-carbo1ine, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.
In certain embodiments, the heteroaryl group is a 5-14 membered heteroaryl group. In other embodiments, the heteroaryl group is a 5-10 membered heteroaryl group.
Preferred heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, and pyrazine. The heteroaryl group may be substituted or unsubstituted. Representative heteroaryl group substituents include those described above for aryl groups.
The term "heteroarylalkyl" refers to an alkyl group as defined herein with a heteroaryl group, optionally substitutcd, as defined herein substituted for one of the alkyl group hydrogen atoms. Where specific alkyl moieties are intended, the terms heteroarylalkanyl, heteroarylalkenyl, or heteroarylalkynyl are used. In certain embodiments, the heteroarylalkyl group is a 6-20 membered heteroarylalkyl (e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is a C 1 -C6 group and the heteroaryl moiety is a 5-14-membered heteroaryl group. In other embodiments, the heteroarylalkyl group is a 6-13 membered heteroarylalkyl (e.g., the alkanyl, alkenyl or alkynyl moiety is C1-C3 group and the heteroaryl moiety is a 5-10-membered heteroaryl group).

The term "acyl" group refers to the -C(=0)¨R group, where R' is selected from optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, as defined herein.
The term "halogen'' or "halo" refers to fluoro, chloro, bromo, and iodo groups.
The term "substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
Representative compounds of the invention and related intermediates were prepared from commercially available starting materials or starting materials prepared by conventional synthetic methodologies. Representative compounds of the invention were prepared according to Methods A to P as described below and illustrated in FIGURES 1-3. The preparations of certain intermediates (I-1 to 1-15) useful in the preparation of compounds of the invention are described in the Synthetic Intermediate section below.
FIGURES 1-3 present schematic illustrations of representative synthetic pathways for the preparation of representative compounds of the invention P5-P4-P3-P2-Pl. As used herein, "P5-P4-P3-P2-P 1 " refers to compounds of the invention prepared from five (5) components: PI, P2, P3, P4, and P5. Protected version of the components useful in the preparation of the compounds of the invention are designated as, for example, "PG-P2," "PG-P2-P1," "PG-3," and "PG-P3-P2-P1," where "PG" is refers to a protecting group that allows for the coupling of, for example, P1 to P2 or P3 to P1-P2, and that is ultimately removed to provide, for example, P1 -P2 or Pl-P2-P3.
FIGURE 1 is a schematic illustration of a representative synthetic pathway for the preparation of representative compounds of the invention P5-P4-P3-P2-P1 starting from P1. In this pathway, compound P5-P4-P3-P2-P1 is prepared in a stepwise manner starting with P1 by sequential coupling steps, separated as appropriate by deprotection steps and other chemical modifications. As shown in FIGURE 1, 131 is coupled with PG-P2 to provide PG-P2-P1, which is then deprotected to provide P2-P1 and ready for coupling with the next component, PG-P3. The process is continued with subsequent couplings PG-P4 with P3-P2-P1 and PG-P5 with P4-P3-P2-P1 to ultimately provide P5-P4-P3-P2-P1. Examples A1-A57 were prepared by this pathway.
FIGURE 2 is a schematic illustration of another representative synthetic pathway for the preparation of representative compounds of the invention P5-P4-P3-P2-P1 starting from P5. In this pathway, compound P5-P4-P3-P2-P1 is prepared in a stepwise manner starting with P5 by sequential coupling steps, separated as appropriate by deprotection steps and other chemical modifications. As shown in FIGURE 2, P5 is coupled with PG-P4 to provide P5-P4-PG, which is then deprotected to provide P5-P4 and ready for coupling with the next component, P3-PG. The process is continued with subsequent couplings PG-P2 with P5-P4-P3 and PG-P1 with P5-P4-P3-P2 to ultimately provide P5-P4-P3-P2-P1. Examples B1-B7 were prepared by this method.
FIGURE 3 is a schematic illustration of a further representative synthetic pathway for the preparation of representative compounds of the invention P5-P4-P3-P2-P1 starting from a component other than P1 or P5. In this pathway, compound P5-P4-P3-P2-P1 is prepared in a stepwise manner starting with P2 by sequential coupling steps, separated as appropriate by deprotection steps and other chemical modifications. As shown in FIGURE 3, there are multiple pathways to P5-P4-P3-P2-P1. Pathways are shown involving representative Synthetic Intermediates (I-1, 1-2, 1-3, 1-4, 1-6, 1-7, 1-9, 1-10, I-11, and I-12). Examples C1-C39 were prepared by this method.
The preparation of representative compounds and their characterization are described in Examples AI to A57, B1 to B7, and C1 to C39. The structures of representative compounds are set forth in Table I.
Table 1. Representative Compounds.
Cmpd # Structure Cmpd # Structure \_) H o H 0 0 N N.
1-5 Ein( A3 0 NI1 -..Ntg H 0,)-r4 1,111 0 NNN=N
y o o A1 iry`y Nr --Tr") A4 N=N N=r4 17t A2 rryN) N A5 " -NJ ---"r NH 0%. '01-1 ---"=1=I
n NN

r Cm pd # Structure Cmpd # Structure ________________________________________________________________ _ ___ = ___________________________________ _ ...., 1-1.14 0 {-1 1:4, .---õ.õ..N.õ /
INõ,......---õir,......R.N.----,....N,I,. A15 11- 1..... l'j f;
I, ..._ _ N () _ H D
...... = -----.....,N .
rjr). ..-.1L-N4-= 1` .N1.1 ,..=== =r..z ,, NI

NN r " (-I NI-N.4 C ILI
_______________________________________________________________________ -r) fi 0 \'--OH H 0 .N .-A7 ' H2N ----- -.ir..il A16 rr -ii, -A
0 ....)..õ H 0 0 r H
H N r'i :
---',' 171 0 1 ! ,.., A17-1 y¨__y...----,,----...,..-1-;,,-------,,erl-/-, II
A8 0,-r-1-1--Ny ',.1.1-''il-1- ...._.....N 0 I 8 ...), H 0 ----eµNi 'NH 0' 1-12N 0 , ==
li N'" cliasier 1 1 eume. 1 f 0 , f 1 ii A, 1-10Y¨T-Thr )-= cµ,ni -i ____.. .N, A9 µ,...,......),,.--y ,,, N 0 = 0 õ.....,..... Fl 0 .., -.N.. \.' Nii [1,...1.,'NH A17-2 l',_1 =I'd N'Iµi diestereomer 2 N=N

Y W q ' \ H
A18 c ir r .5 F10.õ(---,A.---õrN,1..A.N,J..."...tr.Nõ... , _ N
_......---........N ..,... .... N.,-..r.N...,/
A10 Fi= N
N--sN21.1 c.) 0 ,.[..... H 0 ,-- N ' =,: NH
1 ;-1 NN
[', N=1,1 in.':...,.
.....k-',..
\ ¨if ',. 0 Fl 0 h ii HO, ....^. N ok,, N ..
1 it A19 u .., Cir .1'. 1;'.( ...
,,..õ..,.. _N, ..
A11 (I -.! 'if I '' Ir .N 0 V /
0 ,),...... H 0 c). ---, N-=---v---' N11-1 N.
0 ----. H 0 --.-----,./ N.-.

I 1 Ci' M 1 ; =
H N=N N--Ni --...,z diastereomer 1 417: --rk N CO ir...,- .
1.1 ,---= l H

Al2 A20-1 trans 1 T" 1. , EI ), ..._. ..N
= is, ,.I 1i 1 = -11 I

N,Ni -..' d i a s t e re o m e r 2 -.
r OH ,1 ,., ,__, Iranis,,r1.1. ',IIIrij,,.1[,N_,,,,,.
..-- .1. ,,.. . J1. _.. .,1. A20-2 A13 0 l'. 1 " ii.A N
, mi 1 1.00 0 r......... H 0 0..õ5---N; NH
-N I = H N.1'.:
.
__-, dastereomer 1 r) 0 A21-1 -- -= --- ='' N -'11.. = ' OH HO' ,N
cis 1, 11 .õ1.....1-.._ ....____ ,N, NH
A14 0_,..yõ.___,...õ11_,k_i..,1[...N...-....r.rn,õ-. --0 0 L
. N 1-,-, ...1õ,,, r ., N , "":

_____________________________________ 1 Cmpd # Structure Cm pd # Structure tho, ter enmer 2 r''..
d H
,.....,?, 0 ._ --- ji if 1 =1 n ._ ,, A21-2 oi's' .1 il"Cr ..--N"-----f1'N'/11.1 1 , diastereomer 1 r-1 0 H -.1 A22-1 ds?IR. ,H-r -1 _ A28N

N=H i I'd 114= J
f-1 _. ___________________________________ +I/
diaslereomer 2 2 i, k (J)] T
. 0 A22-2 cisr "1-1 'I' ' 'NMINL--,.... A29 01-))-iN,T-N i-, . N
Ho ..,.,0 NH 0 H 0 .,- -=-=-= ryli 0' N ' NN itit diastereomer 1 u 2 ri\

A30-1 4 .....1, 1 ic) ¨ -11- ' ...1 ii" NI N
c, 1 111 1 i 11 " n H N N
--k- _----.. .-,'=-=N''-----(1;"NµNI r HO. '..r.,n - H 0 i"
uia slereonier 1 H N-N
=
e--'' diastereomer 2 `1 A23-2 i ....", .
.-r-- 0 - ==
- \
A30-2 140-1"--'11-1. hic.1:1'tryNL-C
cis T II I i I1 õ... N, diestereomer 2D H ----IN-=Nr HO 0 1 N,ri ij--, Ei tv õIt A24 Fl A31 11 11 -1' 111' ir 1 . N
,.,,--Th a cc., Fi 0 D,-õ,,,'---\---'Nil O --..0 õ r,,..... H 0 0.,...-"--1,(------r NH N=N
H
Ili 1\1=N
---.1, ( 0 1-I II .. õ 1.1 0 OH
..Y, _n A32 HO)Y)(N-'11' NT
NY
A25 N, -,.... =I-1 0 = .N- -------',, NH
ri ---1 ,.J -II -)., OH 0 2-, ILI 0 A- jr"---cf'N1-1,11-1 l'ii i I 11=N
,diastereomer 1 c--7k/
0 OH 1., 0 HO ..".4-A- ill 1_ =N A33 ll ._ 1,i ll , ) pto - ..- - - li = i t.:= 7 1. r4 A26-1 ir- I' ' " u --ii: .,... , N OH 0 ,..... H O . '1-,N ---- C NI 1 0 0 ..----, Fl 0 N=-NH
I 11 N'N
0 , 1-1 NN :I
..--, 1 111) diastereomer 2 k 411'1112 .,-., . 0 .r='( ...õ4. - N ., .....- .. N .
cis ," .., I 1 410 -, \.... N A34 1 .1 r.l. 1 ,., li 1, A26-2 'r 1 N ir 1 .....,... _. ,-, 1, 41 0 --t.õ II-I 0 .... -N 14 NH 1 l I 0 =
1:-1 1.." N 110- ' C.

Cmpd # Structure Cmpd # Structure i/
õ_ ....z.: . . .t.:. A.. . ...v.
.., H0. ,.. ....õ r.: .... ..- . . h:.
A35 11 1- II' I 11'i 11 11, A44 ll l'i II
C ... , o ..- --, H C.) .......- -N'Th).'N'NH
0 -0 --....õ li o ,,-.31= -.,; r...õ4 f H N--Ni 1 0- .
-hl -_ ,.. 17¨) i 0 0 a 11 0 i A36 1..Ø.K...,,,,,,. N.. ....-.14,---õ,..N
1., i ' 11 N NO,-IL.,--. .- ---. ,N..L.
11.
0 ,.., -.... 1-1 0 =--- ,i------f". 'N11 A45 H N7N . ,,k.- /----= ..,1,1-t_i a , 11-i A37 Ho ------i 1-1 ' N11 -"Ti--- N ---t ' I 4 N'N 0 ..--'1,-, 11 0 0,1.
- t.l.'"---(-N=NI 1 q ---== --I

0 i Jl 1 0 ., C
11 t., II ...
Nr \
.õõ.....
t A38 110, 1-[ -, 11( --,,:.
1' I =1 ik --r, 0 r.,),,,, H 0 ...:3--N= ----s,"-N NH A47 . o .., [I o . -,., T' NH
0.1 I U 111 N94 1 I ' I N. N
, I
I, Cr a () /I
A39 "c)-171' -6r- 61 µ-1----ir CS ,.=

. ry A48 H, Hõ,..=II Y 1._ N I
0 0 '...... H 0 0 ' , NI I
'NI
1N ' NI
II I
A ../
,21, ; i H =, '1==
)1. , -, N -f.=N=
1= -11, - N
A40 Ho -1---Ti i ii= li- ---c= NI A49 V = i NH? 0 ,..., H 0 ...7---N7-116-1-1. 'NI,:
.. .,.., 0 1 a ,L, N'14 I 11 N=1µi i 11_,), ' N ,JLNry-N ( =o rlõ A O IL- -- ----,' =
A41 A50 (1------1-----if , Tr _.._ ...N Dv N , NI , 11.
F H N=N
.1\¨ --)) A42 1 . i, N'N14 -10d[i A, -.3 ,i'-,7.. 1.=1 1,1N
H
,.../ .'..
-=
'S'=. 0 I La. ...1. .. ..-.
J0 F F H 0 .)--'\ A52 li - 1[ 'I r:' ,II
ii . . N
. .,:,j 0 0 .. ,...... H 0 ,,, NH
A43 Ho- ";3; II 1 y ir =---c N I t' ;1 F .F C., ;J.... H 0 ,.:3- - Nr---÷" 'NH
r o. , i 1 r':=N
I

Cmpd # Structure Cmpd # Structure ,.
0 i1 =11- 1.= " \
JI. ,.. ,=;1 i'. 4 ,= - i= 1, 11 A53 -1 i'µ. II 1 1.1 II. A 4y B3 . =

.". 1'1 . 0 -.., H 0 --.,4 ' --y 1:1,1 E) I........ H ID ..!---., --NI, n -I ILI
N=I=.:
h ...7--., ---, k 0 -r"-,--1 1..1 1-ii=
r'=-, = g, .11 ' HO -- 1.. N, ..-II , - .1=4 ' B4 11 . II = 'i k - -, A54-1 r [I 1 ==1 II r:
0 o 11 ..,..: i.... ,...õ.
H
........4 r..3 0 ..1 =-----..- -NH
1 o. ' =
H N=N
cliaslereomer 1 != N=Ni r:=,) - , ..._-.' H 0 11 . .---r'y õ11 . . ;II..
..1 ' Y Cl 1 1-10 --- .... . NJ . ..N . i B5 ' Fi'= 11 1 A54-2 !I " 11 "I =l',1 I,: A 40 0 ..3....r. 0 c.r.¨.,., .--,,,, pH
0 a --,-, '1 0 .,"--N ;. = NH
N -N
C . 1 1-dasIerenrner 2 1 I i N=N
k i -0 Jr:.

,, i---:
1,1 C;= r ''S
r-A55 , . r.., N . ..) .N
'I " 11 1,.., B6 =H 0 , N= - ='' NH -- .
'ir s-=-- 'NH
0- = 0 H t.l -.1 I . H=C-1 __,/
0 11 0 --)----( .11 A56 ..
i I
I 1{.3' ' -'' --,,, '' 4 1 ' Thr'',.' . =
' IJ
a A., I 0 r) IL-r' ,='------.,:r-N NH B7 i_i I,;=N
..--..,... u=--,..., H
I H r,r.
_ 01.1un.,rner 1 'I/ 'µµ=
_--.
H .r. =!! µ..
_..,... .J1..,. ..,. , A57-1 Inns i -ir i N 1.1 1 N
=
' Ho--- , 0 L....õ 11 0 NH
a 6 3...1 =,. Cl H Ni=N .. ,J 0 ," 11 t J =--, J,.- NH
I) ,--.
diastereomer 2 17 /
'--i-t 0 //
)1, ./='\
I ' .
A57-2 trans N
N ,,,11. 1--4 iµj .) ',... H 0 -- r! NH C2 1. r(-ir 1 = NI-Ni 1-, 4 ,.......,0, 0 .
-r., " .1.' MI
0 1'J"
' NJ
// ' _./
" I .('--\ II ) N .,-.N !..1_ .- E I 0 r-iõ, B1 40 . N. 1-r 1 - - .... 1:
.. ., . N, =
H 0 0,...., --).." 1.4 I.. C3 1 -,'.., ..! N . n ..1 0 8.1 -7 1, i:, J.1-1.1 1 - , Ú.l 0 .1-- \ 'j I
B2 .r ii ..,.. 11 I -. ..11 H 0 tr'l - '.. -I : I 1,=

)I-=

'' I
..- _ .....:. L_) =,..,...... 1 l 0 - - N-,----f--;\ C4 1....1 I l'i (..) k..,,. ---,= I;H o i'i N=N õ: 6 ....___ =U
.i., N=N
________________________________________________________________________ I

Cmpd # Structure Cmpd # Structure -ff--,31-4 --,...
Id 0-N K r! \
C5-1:1 N.¨If-0 -- II:
I. C14 c:' 1 o' NN _, . ,..., r=:
.:., =
, 911 ii.---µ= :I' 4-1 = ==
H 0 .5 ,' ri. . '..,., 4 .,...' C15 (,. I rl I = -._.
C6 *
0 [ '( r.:=1} ,-.1,-. (---. =N r,H
i -ft 7:',, 1 (/ =-/
, . -C7 . _ H 0 r'''' H C., s --C
' = II j \
,11. C16 ( ,,, ii .1- !' I ;1 k=rq __________ ,. . _____________________ ,...:, U
i Hu , = . ..ii 7,11.
C8 li 1 ng 1 N , C17 H, A i "
= -µ-- = r ' ..,., .-- I., NH-- I
(..1 :, H a 1 'Ir='( il 0 .
C9 II 1 =P ' 'II C18 = -.. -..
N, = r.-: ..) NNH I. I rj l' ,......, 0 ....., .1 0=- ry/---i* NH
H N-N
I
___.....- C.. H
' r "
--I I
. ; 1F-.1.
0 r \

C10 11 ..1 I.1 i ,.N C19=
' H r \
..,,, 0 n. .-..... ..11-1 !1.....,:l ,-1, L, 'A
H,N
Hli 0 0 i---1., C11 1r) Li -] r, II . ,t, ...... H 0 ..: --N' -1=.' 'NH C20 I I J 1 I , 0 IL
.õ , C .,-..,..
H l ...=-, /I 'r 4 y L.1 , ' .,=K N
,)i-...j 1 A 1..,,K,N., =
....,. : u - ...õ. H 0 .., =N =(' 1:411 C21 I 0 I!, !..i, r.: 11.- I-.1' .. '''' P.N. -,i= = , .:( 0 ..,--.. l' N. =- l.
H ',. ._ H fil I. r'-c,5 i k; 4' === -C13 i.1 J E :1 V õ..,_ ,N, 1.1 V r \
...., 0 ,...,. ii 0 .õ.... -N--T" NH C22 I " N=1,1 I. I ri= .' 1 \ - '' . e: n L.., H 0 =, - ., - r" NH
¨= l :., N-I.:

Cm pd # Structure Cmpd # Structure Ni,, I ni HO)t,r N ,sst, N?'---= N----.)-,I, ,..) A .1., :i._, /
0 Il 0 o.N1/----e.-Nld .,, N1,1 1- .i., If.IL I =
S
I/
HN--/:
' .! ) kr ) 0 Ff CI .i--' -µ
C33 .
C24 . F 1 .- 11 IL li- r r) c ..z..,, Fr 0 ,...,.. .,.,1 ---{: !=;11 I . 4,-I I 4., Nzni (/ ''...
I

.N -0-..
C',1 cI =----====-N= C34 0 . =-= N ,. NH 11 ..I ,-, l ' N=N =,, c : ..õ.=,=.N
F I
N=N
,.F, C26 N1 Z1 N= ,11- II: ----( t,!I -- 4'1 C35 NL

iri ' fµ=
O =rs, , IA H 0 . .', ,r'.1, li. 1. - -__________ _ H I c __, .
..1? =---zu 1101 0 8 ro.)L.N^e'NH
N=N "T i H
õ 0 Ho- ,,,,,..11...õ4,-...ir N...õ( H 0 C28 .õ0õ N.,õN ,:l.
..."..... N ., =
\----II l'-I (3 ...,..L.N.------c=---N=NH C37 . CI 1 -1,..._ 0 õ_. = N,,N õ.= I I 0 ,='---N -v- 'Nil T cr' 4 N=q,i p 0 H 0 r-A

C29 1-10)'=-="Th-r Ne.N-M--N," 0 H 0 0 H 0 ...-... = N. -.,-, NI-I ,LI,.. _.----11,1. =J1,-.
...",,N, ) ...,,, 3 I 0 .=,..--N '------(-=- -, N
---, 1 I I =N
D.---(N-17. <4 .
C30 Cil 11 !=- ' ).. NI, `-....% G ".... ..' a .' --fµI/.--- l'IH
I-i 0 )'----I ' r4 H N= ...-- hl, Ji C39 N!lf )1..
i ;AN -N 0 ===õõ, H
0 ...!"---N".."--(''''-N11 D , h ,., - õ.. "
H ''' r-N
i C31=
1 -1-'1- 1 ':.' I \ . ,.., ,. ... ,. ,, c. _.. =.,..,, PHI
.' III r''I 'I
_.
i, ________________________________ A general kinetic enzyme assay useful for determining the inhibitory activity of the compounds of the invention is described in Example Dl.
Granzyme B enzymatic inhibition assays are described in Examples D2 and D6.
The compounds of the invention identified in Table 1 exhibited Granzyme B
inhibitory activity. In certain embodiments, select compounds exhibited IC50 <50,000 nM.
In other embodiments, select compounds exhibited IC50 <10,000 nM. In further embodiments, select compounds exhibited IC50 <1,000 nM. In still further embodiments, select compounds exhibited 1050 <100 nM. In certain embodiments, select compounds exhibited IC50 from 10 nM to 100 nM, preferably from 1 nM to 10 nM, more preferably from 0.1 nM to 1 nM, and even more preferably from 0.01 nM to 0.1 nM.
Caspase enzymatic inhibition assays are described in Examples D3 and D7. None of the compounds of the invention tested demonstrated an ability to significantly inhibit any of the caspases evaluated at a concentration of 50 M. In certain embodiments, the compounds exhibited less than 50% inhibition at 50 M. In other embodiments, the compounds exhibited greater than 50% inhibition at 50 M, but less than 10%
inhibition at 25 M. The results demonstrate that select compounds of the invention selectively inhibit Granzyme B without significantly inhibiting caspases.
A method for determining kinetic solubility is described in Example D4. The results demonstrate that select compounds of the invention have significantly greater solubility than Willoughby 20, a representative Granzyme B inhibitor known in the art.
Pharmaceutical Compositions The pharmaceutical compositions of the present invention include an inhibitor compound of the invention (e.g., a compound of Formulae (I), (II), (III), or (IV)) as an active ingredient or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable bases including inorganic bases and organic bases.

Representative salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, ammonium, potassium, sodium, and zinc salts. Representative salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and trimethamine.
Compositions can include one or more carriers acceptable for the mode of administration of the preparation, be it by topical administration, lavage, epidermal administration, sub-epidermal administration, dermal administration, subdermal administration, transdermal administration, subcutaneous administration, systemic administration, injection, inhalation, oral, or any other mode suitable for the selected treatment. Topical administration includes administration to external body surfaces (e.g., skin) as well as to internal body surfaces (e.g., mucus membranes for vaginal or rectal applications by, for example, suppositories). Suitable carriers are those known in the art thr use in such modes of administration.
Suitable compositions can be formulated by means known in the art and their mode of administration and dose determined by a person of skill in the art.
For parenteral administration, the compound can be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble compounds. For enteral administration, the compound can be administered in a tablet, capsule, or dissolved or suspended in liquid form. The tablet or capsule can be enteric coated, or in a formulation for sustained release. Many suitable formulations are known including, polymeric or protein microparticles encapsulating a compound to be released, ointments, pastes, gels, hydrogels, foams, creams, powders, lotions, oils, semi-solids, soaps, medicated soaps, shampoos, medicated shampoos, sprays, films, or solutions which can be used topically or locally to administer a compound. A sustained release patch or implant may be employed to provide release over a prolonged period of time.
Many techniques known to one of skill in the art are described in Remington:
the Science & Practice of Pharmacy by Alfonso Gennaro, 20th ed., Williams & Wilkins, (2000).
Formulations can contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of a compound. Other potentially useful delivery systems for a modulatory compound include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
Formulations can contain an excipient, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or can be an oily solution for administration in the form of drops, as a gel, or for other semi-solid formulation.
Compounds or pharmaceutical compositions in accordance with this invention or for use in the methods disclosed herein can be administered in combination with one or more other therapeutic agents as appropriate. Compounds or pharmaceutical compositions in accordance with this invention or for use in the methods disclosed herein can be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stents, and wound dressings. Also, implants can be devised that are intended to contain and release such compounds or compositions. An example would be an implant made of a polymeric material adapted to release the compound over a period of time.
One skilled in the art will appreciate that suitable methods of administering a Granzyme B inhibitor directly to the eye are available (i.e., invasive and noninvasive methods). Although more than one route can be used to administer the Granzyme B
inhibitor, a particular route can provide a more immediate and more effective reaction than another route. The present use is not dependent on the mode of administering the agent to an animal, preferably a human, to achieve the desired effect, and the described routes of administration are exemplary. As such, any route of administration is appropriate so long as the agent contacts an ocular cell. Thus, the Granzyme B
inhibitor can be appropriately formulated and administered in the form of an injection, eye lotion, ointment, and implant.
The Granzyme B inhibitor can be applied, for example, systemically, topically, intracamerally, subconjunctivally, intraocularly, retrobulbarly, peri ocularly (e.g., subtenon delivery), subretinally, or suprachoroidally. In certain cases, it can be appropriate to administer multiple applications and employ multiple routes to ensure sufficient exposure of ocular cells to the Granzyme B inhibitor (e.g., subretinal and intravitreous). Multiple applications of the Granzyme B inhibitor can also be required to achieve the desired effect.
Depending on the particular case, it may be desirable to non-invasively administer the Granzyme B inhibitor to a patient. For instance, if multiple surgeries have been performed, the patient displays low tolerance to anesthetic, or if other ocular-related disorders exist, topical administration of the Granzyme B inhibitor may be most appropriate. Topical formulations are well known to those of skill in the art.
Such formulations are suitable in the context of the use described herein for application to the skin or to the surface of the eye. The use of patches, corneal shields (see, U.S. Patent No. 5,185,152), and ophthalmic solutions (see, e.g., U.S. Patent No.
5,710,182) and ointments is within the skill in the art.
The Granzyme B inhibitor also can be present in or on a device that allows controlled or sustained release, such as an ocular sponge, meshwork, mechanical reservoir, or mechanical implant. Implants (see U.S. Patent Nos. 5,443,505, 4,853,224 and 4,997,652), devices (see U.S. Patent Nos. 5,554,187, 4,863,457, 5,098,443 and 5,725,493), such as an implantable device (e.g., a mechanical reservoir, an intraocular device or an extraocular device with an intraocular conduit, or an implant or a device comprised of a polymeric composition are particularly useful for ocular administration of the expression vector). The Granzyme B inhibitor also can be administered in the form of sustained-release formulations (see U.S. Patent No. 5,378,475) comprising, for example, gelatin, chondroitin sulfate, a polyphosphoester, such as bis-2-hydroxyethyl-terephthalate, or a polylactic-glycolic acid.
When used for treating an ocular disease the Granzyme B inhibitor is administered via an ophthalmologic instrument for delivery to a specific region of an eye.
Use of a specialized ophthalmologic instrument ensures precise administration while minimizing damage to adjacent ocular tissue. Delivery of the Granzyme B
inhibitor to a specific region of the eye also limits exposure of unaffected cells to the Granzyme B
inhibitor. A preferred ophthalmologic instrument is a combination of forceps and subretinal needle or sharp bent cannula.

Alternatively, the Granzyme B inhibitor can be administered using invasive procedures, such as, for instance, intravitreal injection or subretinal injection, optionally preceded by a vitrectomy, or periocular (e.g., subtenon) delivery. The pharmaceutical composition of the invention can be injected into different compartments of the eye (e.g., the vitreal cavity or anterior chamber).
While intraocular injection is preferred, injectable compositions can also be administered intramuscularly, intravenously, intraarterially, and intraperitoneally.
Pharmaceutically acceptable carriers for injectable compositions are well-known to those of ordinary skill in the art (see Pharmaceutics and Pharmacy Practice, J. B.
Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP
Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986)).
An "effective amount" of a Granzyme B inhibitor or a pharmaceutical composition of the invention as described herein includes a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount"
refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced levels of Granzyme B activity.
A
therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as Granzyme B activity. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.
It is to be noted that dosage values can vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens can be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that can be selected by a medical practitioner. The amount of active compound(s) in the composition can vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
In general, compounds of the invention should be used without causing substantial toxicity. Toxicity of the compounds of the invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index (i.e., the ratio between the LD50, the dose lethal to 50%
of the population, and the LD 00, the dose lethal to 100% of the population).
In some circumstances however, such as in severe disease conditions, it may be necessary to administer substantial excesses of the composition.
Methods of Use In a further aspect, the invention provides methods of using the compounds of the invention as Granzyme B inhibitors.
In one embodiment, the invention provides a method for inhibiting Granzyme B
in a subject. In the method, an effective amount of a compound of the invention (e.g., a compound of Formulae (1), (II), (III), or (IV)) is administered to a subject in need thereof.
In another embodiment, the invention provides a method for treating a disease, disorder, or condition treatable by inhibiting Granzyme B. In the method, a therapeutically effective amount of a compound of the invention (e.g., a compound of Formulae (I), (II), (III), or (IV)) is administered to a subject in need thereof As used herein, the term "disease, disorder, or condition treatable by inhibiting Granzyme B" refers to a disease, disorder, or condition in which Granzyme B is involved in the pathway related to for the disease, disorder, or condition, and that inhibiting Granzyme B results in the treatment or prevention of the disease, disorder, or condition.
Representative methods of treatment using the compounds of the invention include those described for Granzyme B inhibitors in WO 2007/101354 (Methods of Treating, Reducing, and Inhibiting the Appearance of Ageing in the Skin), WO 2009/043170 (Treatment of Dissection, Aneurysm, and Atherosclerosis Using Granzyme B Inhibitors), WO 2012/076985 (Granzyme B Inhibitor Compositions, Methods and Uses for Promoting Wound Healing), each expressly incorporated herein by reference in its entirety. The compounds of the invention are useful for treating, reducing, and inhibiting the appearance of aging of the skin; treating dissection, aneurysm, and atherosclerosis; and promoting wound healing.
Other disease and disorders described as treatable using the Granzyme B
inhibitors are disclosed in WO 2003/065987 (Granzyme B Inhibitors), expressly incorporated herein by reference in its entirety. Disease and disorders described as treatable by Granzyme B inhibitors in this reference include autoimmune or chronic inflammatory diseases, such as systemic lupus erythematosis, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, asthma, schleroderma and Sjogren's syndrome. The Granzyme B
inhibitors described in the reference are noted as more particularly useful to treat or prevent diseases or disorders including diseases or disorders resulting from transplantation of organs or tissue, graft-versus-host diseases brought about by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I
diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper-responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "acute-on-chronic" liver failure, augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infection. To the extent that the diseases and disorders noted in the reference are treatable by the Granzyme B inhibitors described in the reference, the Granzyme B
inhibitors of the present invention are also useful in treating and/or ameliorating a symptom associated with these diseases and conditions.
Elevated Granzyme B levels have been identified in cells and tissues from subjects suffering from a variety of diseases and conditions including Rasmussen encephalitis, amyotrophic lateral sclerosis (ALS), chronic inflammation, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Kawasaki disease, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), coronary artery disease (CAD), transplant vascular disease (TVD), restenosis, acute respiratory distress syndrome (ARDS), chronic obstructive sialadentis (associated with sialolithiasis), vitiligo, allergic contact dermatitis (ACD), atopic dermatitis (AD), pityriasis rosea (PR), rheumatoid arthritis (RA), osteoarthritis (OA), vasculitic neuropathy, sensory perineuritis, ischemic stroke, spinal cord injury, myasthenia gravis (MG), lymphocytic gastritis, autoimmune cholangitis (AIC), nodular regenerative hyperplasia (NRH) of the liver, achalasia, esophagitis, eosinophilic fasciitis, cryptorchidism, necrotizing lymphadenitis, Duchenne muscular dystrophy, facioscapulo humeral muscular dystrophy, and Higashi syndrome. Other diseases and conditions in which elevated Granzyme B levels have been identified include those described in WO 2009/043167 (Granzyme A and Granzyme B Diagnostics), expressly incorporated herein by reference in its entirety.
The Granzyme B inhibitors of the invention may be useful for treating, alleviating or ameliorating a symptom of, diminishing the extent of, stabilizing, or ameliorating or palliating the diseases and conditions noted above in which elevated Granzyme B levels have been identified.
In the above methods, the administration of the Granzyme B inhibitor can be a systemic administration, a local administration (e.g., administration to the site, an inflamed microenvironment, an inflamed joint, an area of skin, a site of a myocardial infarct, an eye, a neovascularized tumor), or a topical administration to a site (e.g., a site of inflammation or a wound).

The term "subject" or "patient" is intended to include mammalian organisms.
Examples of subjects or patients include humans and non-human mammals, e.g., nonhuman primates, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In specific embodiments of the invention, the subject is a human.
The term "administering" includes any method of delivery of a Granzyme B
inhibitor or a pharmaceutical composition comprising a Granzyme B inhibitor into a subject's system or to a particular region in or on a subject. In certain embodiments, a moiety is administered topically, intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, transcutaneously, intrathecal, intravitreally, intracerebral, or mucosally.
As used herein, the term "applying" refers to administration of a Granzyme B
inhibitor that includes spreading, covering (at least in part), or laying on of the inhibitor.
For example, a Granzyme B inhibitor may be applied to an area of inflammation on a subject or applied to, for example the eye or an area of inflammation by spreading or covering the surface of the eye with an inhibitor, by injection, oral or nasal administration.
As used herein, the term "contacting" includes contacting a cell or a subject with a Granzyme B inhibitor. Contacting also includes incubating the Granzyme B
inhibitor and the cell together in vitro (e.g., adding the inhibitor to cells in culture) as well as administering the inhibitor to a subject such that the inhibitor and cells or tissues of the subject are contacted in vivo.
As used herein, the terms "treating" or "treatment" refer to a beneficial or desired result including, but not limited to, alleviation or amelioration of one or more symptoms, diminishing the extent of a disorder, stabilized (i.e., not worsening) state of a disorder, amelioration or palliation of the disorder, whether detectable or undetectable.
"Treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment.
Each reference cited is incorporated herein by reference in its entirety.
Abbreviations As used herein, the following abbreviations have the indicated meanings.

'H NMR: proton nuclear magnetic resonance 19F NMR: fluorine-19 nuclear magnetic resonance %Inh: Percent inhibition Ac-IEPD-AMC: acetyl-isoleucyl-glutamyl-prolyl-aspartyl-(7-amino-4-methylcoumarin) substrate ACN: acetonitrile BHET: bis-2-hydroxyethyl-terephthalate Boc: tert-butoxycarbonyl CHAPS: 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate DCM: dichloromethane DIPEA: diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: dimethylformamide DMSO: dimethylsulfoxide DMSO-d6: dimethylsulfoxide-d6 DTT: dithiothreitol EDC: 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride EDTA: 2-({2-[Bis(carboxymethyl)amino]ethyll (carboxymethyDamino)acetic acid ESI: Electrospray ionization Et0Ac: ethyl acetate eq.: equivalent(s) GzmB: Granzyme B
HATU: 2-(7-aza-1H-benzotriazole-1-y1)-1,1,1,1-tetramethyluronium hexafluorophosphate HCI: hydrochloric acid HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid hGzmB: human Granzyme B
HPLC: high performance liquid chromatography HOBt: 1-hydroxy-benzotriazol IC50: inhibitory concentration that provides 50% inhibition LC/MS: liquid chromatography / mass spectrometry MeOH: methanol mGzmB: murine Granzyme B
MS: mass spectrometry m/z: mass to charge ratio.
Oxyma: ethyl 2-cyano-2-(hydroxyimino)acetate PBS: phosphate buffered saline (pH 7.4) RPM: revolution per minute RT: room temperature THE: tetrahydrofuran TFA: trifluoroacetic acid General Methods A-P
Representative compounds of the invention were prepared according to Methods A to P as described below and illustrated in FIGURES 1-3.
The Willoughby 20 compound was synthesized by published procedures (see Willoughby et al., Bioorg. Med. Chem. Lett. 12 (2002) 2197-2200 and WO
03/065987).
It will be appreciated that in the following general methods and preparation of synthetic intermediates, reagent levels and relative amounts or reagents/intermediates can be changed to suit particular compounds to be synthesized, up or down by up to 50%
without significant change in expected results.
Method A: General method for deprotection followed bv coupling reaction using EDC ( HOBt / DIPEA.
H 0 1) HCI (4M) .0 Dioxane 0 P,,A2 u 0 R, _______________________________________________________ ki 0 N Ra 0 AA1 2) EDC, HOBt, DIPEA
CH2Cl2 0 AA1 N

HCI Solution in dioxane (4M, 5 ml) was added to respective carbamate compound (0.125 mmol) and stirred for 2 hrs at RT. The reaction mixture was concentrated to dryness under vacuum and swapped with Me014 (5 ml) three times. Resulting residue was dried well under vacuum and subjected to next reaction as it is. The residue obtained above, respective acid moiety (0.125 mmol), EDC (0.19 mmol), HOBt (0.16 mmol) and FNMA (0.5 mmol) were stirred in anhydrous DCM (5 ml) for 16 hrs. The reaction mixture was concentrated under vacuum to give the crude product which was purified on a C18 column using 10-50% Me0H in water to yield product as an off-white solid (35-55%).
Method B: General method for tiehrotect ion followed by reaction with anhydride.
HO 1) HCI (4M) __________________ Dioxane HONT y Ra Ra 0 AA1 2) Triethylamine C AA1 CH2Cl2 Ra=
AAi=
==-\

HN
HO Solution in dioxane (4M, 5 ml) was added to a representative Boc-protected compound (0.125 mmol) and stirred for 2 hrs at RT. The reaction mixture was concentrated to dryness under vacuum and washed with Me0H (5 ml) three times.
Resulting residue was dried well under vacuum and subjected to next reaction as it is.
The residue obtained above, the respective anhydride moiety (0.125 mmol), and triethylamine (0.5 mmol) were added to anhydrous DCM (5 mL) and stirred for 16 hrs.
The mixture was concentrated under vacuum to give the crude product which was purified on a C18 column using 10-50% Me0H in water to yield product as an off-white solid (40-60%).

Method C: General method of coupling reaction using HATU/DIPEA.
O
O 0 Ny-Li- OH

HN 0 AA i n HATU, DIPEA, ' NH
0 'NH
CH2C12 \---cr\j NH
NH N=N
The respective acid moiety (0.125 mmol), HATU (0.17 mmol), DIPEA
(0.5 mmol) and respective amine moiety (0.125 mmol) were stirred in anhydrous DCM (5 ml) for 16 hrs. The reaction mixture was concentrated under vacuum to give the crude product which was purified on a C18 column using 10-50% Me0H in water (or similar ratio as needed) to yield product as an off-white solid (35-55%).
Method D: General method of hydrolysis using Li0H.
0 O AA1 ' EtO LiOH Et0H Ficri'Lf-ryN'TFLLN----H-rN
)j-(---ry ri6rN

AA2 0 NH 0 AA (-)C-111 HN
HN, To the stirring solution of the ester compound (0.08 mmol) in ethanol (1 ml) was added solution of lithium hydroxide monohydrate (0.4 mmol) in water (0.5 ml).
After stirring the reaction mixture for 5 hrs at RT, the mixture was acidified using citric acid (saturated solution) and concentrated under vacuum to give the crude product which was purified on a C18 column using 10-40% Me0H in water to yield product as an off-white solid (50-65%).
Method E: General method for Boc deprotection.
0 1) HCI (4M) N Ra ______ Dioxane H2N.TAR, HCI Solution in dioxane (4M, 0.5 ml) was added to the respective carbamate compound (0.06 mmol) and stirred for 3 hrs at RT. The reaction mixture was concentrated under vacuum to give the crude product which was purified on a column using 10-40% Me0H in water to yield product as an off-white solid (50-60%).
Method F: General method for methanesulfonyl (mesyl) chloride mediated amino acid coupling.

OH 1) µC1 11 R N

THF -40 C O CO2Me 2) A solution of an appropriate acid (1.0 mmol) in THF (10 mL) was cooled to -40 'C. To this solution was added DIPEA (1.7 mmol) followed by CH3S02C1 l 0 (1.3 mmol). The reaction mixture was allowed to stir for 20 minutes before addition of an appropriate amine (such as (S)-methyl indoline-2-carboxylate) (1.1 mmol).
After stirring for further 10 min at the same temperature the ice bath was removed and reaction mixture was allowed to warm up to room temperature. The reaction mixture was diluted with Et0Ac and then washed with saturated aqueous solution of NaHCO3. The aqueous layer was then extracted with Et0Ac (2x20 mL). Combined organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Flash chromatography (MeOH: DCM 2-5%) afforded final compound.
Method G: EDC/Oxyma amino acid coupling.

EDC, Oxyma -DIPEA DMSO
Ph N _______________ - Ph r H
0 nO CO2H0 HN

NH
To a mixture of an appropriate acid (0.05 mmol) in DMSO (0.5 mL) DIPEA
(0.23 mmol), an appropriate acid (0.075 mmol), EDC (0.1 mmol), and oxyma (0.1 mmol) were added at RT. After stirring for 16 h the reaction mixture was purified by preparative HPLC (column: Ascentis C18, 25 cm x 21.2 mm, lOurn, gradient 0%¨>100%
methanol/water with 0.1% TFA, 10 mLimin or similar) to furnish ll mg of powder.
Method H: General method of acid chloride synthesis followed by amide formation.
,\OH
OH 1) thionyl chloride 2) NaOH (2N) H
-Xd -OH

Acid compound (1.5 mmol) and thionyl chloride (90 mmol) were stirred together for 1 hr. at room temperature. Thionyl chloride was removed by distillation under vacuum. The acid chloride was added to the stirring solution of L-isoleucine (1.35 mmol) in NaOH (2N, 1.8 ml) at 0 C. The resulting reaction mixture was warmed to RT
and stirred overnight. The reaction mixture was diluted with water (2 ml) and washed with diethyl ether (3 m1). Separated aqueous layer was acidified to pH 2 by adding mixture of 1:1 HC1-water. The precipitated solid was filtered and washed with water to get the product as a white to off-white solid (45-75%).
Method 1: (iieneraI method for dcprotectioi-i followed by reaction with anhydride).
0 1) HCI (4M) H
.Ra Dioxane 0 H
HO N, 'Ra 0 AA 2) Triethylamine 0 AA1 CH2Cl2 1 5 3) Acidify with formic acid This method is an improved procedure for the method B. HC1 Solution in dioxane (4M, 5 ml) was added to a representative Boc-protected compound (0.125 mmol) and stirred for 2 hrs at RT. The reaction mixture was concentrated to dryness under vacuum and swapped with Me0H (5 ml) three times. The resulting residue was dried well under vacuum and subjected to next reaction as it was. The residue obtained above, the respective anhydride moiety (0.19 mmol, 1.5 eq.), and triethylamine (0.5 mmol, 4 eq.) were added to anhydrous DCM (5 mL) and stirred for 16 hrs. The mixture was acidified with formic acid and then concentrated under vacuum to give the crude product which was purified on a C18 column using 25-65% Me0H in water to yield product as an off-white solid (30-80%).
Method .1: General method for deproteetion followed by reaction with a di-acid.
0 HC1(4M) Dioxane 0 OH 0 'I y __________________________________________ IR, HO-Th. Ra 0 AA1 2) EDC, HOBt, DIPEA
CH2Cl2 OH 0 AA1 OH
HoyyL'oH
o oH
3) Acidify with formic acid HCI Solution in dioxane (4M, 5 ml) was added to a representative Boc-protected compound (0.125 mmol) and stirred for 2 hrs at RT. The reaction mixture was concentrated to dryness under vacuum and swapped with Me0H (5 ml) three times.
Resulting residue was dried well under vacuum and subjected to next reaction as it was.
The residue obtained above, the respective di-acid moiety (0.62 mmol, 5 eq.), EDC
(0.19 mmol), HOBt (0.15 mmol) and DIPEA (1.6 mmol, 13 eq.) were added to anhydrous DCM (5 mL) and stirred for 4 hrs. The mixture was acidified with formic acid and then concentrated under vacuum to give the crude product which was purified on a column using 25-65% Me0H in water to yield product as an off-white solid (30-80%).
Method K: General method for Boc protection.
NaOH (0.5M), di-tert-butyl H2N,R dicarbonate Dioxane 0 To respective amine compound (6.1 mmol) in dioxane (6 ml) and NaOH solution (0.5M, 12 ml) was added slowly solution of di-tert-butyl diearbonate (6.7 mmol) in dioxane (6 ml) at 0 C. The reaction mixture was warmed to RT and stirred overnight.
The reaction mixture was then washed with hexanes (10 m1). The separated water layer was acidified using saturated solution of citric acid and extracted with ethyl acetate (3 x

15 m1). The organic layer was washed with brine, separated, dried over sodium sulfate and concentrated to give Boc protected amine compound as off-white solid (65-90 %).
Method L: General method of hydrolysis followed bv counlina reaction using EDC
/
HOBt / DIPEA.

- TI-C) LiOhHO ciEDO Hr)St DIPEA
P.)1,0H 11-RACDPci 11 "C.
To the stirring solution of the ester compound (0.11 mmol) in ethanol (4 ml) was added solution of lithium hydroxide monohydrate (0.23 mmol) in water (2 m1).
After stirring the reaction mixture for 5 hrs at RT, the mixture was acidified using sat. citric acid solution and concentrated under vacuum to remove ethanol. The aqueous residue obtained was extracted with Et0Ac (2 X 15 ml). Combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Resulting residue was dried well under vacuum and subjected to next reaction as it was. The residue obtained above, the respective amine moiety (0.11 mmol), EDC (0.17 mmol), HOBT (0.15 mmol) and DIPEA (0.46 mmol) were stirred in DMF (4 ml) for 16 hrs. The mixture was concentrated under vacuum to give the crude product which was purified on a column using 10-50% Me0H in water to yield product as an off-white solid (50-60%).
Method M: General method for EDC/HOBt/DIPEA couplina of an intermediate existina as an HC1 salt Lind a free carboxylic acid.
RNH2 'HCI
O EDC, HOBt, DIPEA 0 ROH
DCM
RXN.R' To an intermediate collected as an HC1 salt (0.125 mmol) were added the carboxylic acid (0.125 mmol), EDC (0.19 mmol), HOBt (0.16 mmol), and anhydrous DCM (5 m1). The flask was purged with N2, sonicated for 20 s and DIPEA (0.5 mmol) was added. The reaction was stirred at room temperature for 6 hrs then concentrated under reduced pressure. The residue was purified on a C18 column using 10-80%
Me0H
in water to yield the product as an off-white solid (40-90%).
Method 1\1: Gerieral method for anhydride ri nu opening by an intermediate existing as an HCI salt.
R'¨NH2.HCI

0 triethylamine DCM

To an intermediate collected as an HCI salt (0.11 mmol) were added the respective anhydride (0.13 mmol), and anhydrous DCM (6 mL). The flask was purged with N2, sonicated for 20 s and triethylamine (0.44 mmol) was added. The reaction was stirred at room temperature for 5.5 hrs. The reaction was acidified to approximately pH 5 using citric acid (aqueous, saturated solution), and then concentrated under reduced pressure. The residue was purified on a C18 column using 10-75% Me0H in water to yield the product as an off-white solid (40-67%).
Method 0: General method for coupling (21-1-Tetrazo1-5-yl)methylamine and a li-ec carboxylic acid.
N, NH
H2N 1 i 0 0 N=N
ROH 11 EDC, HOBt, DIPEA IR'-it.
N--z:N
DMF
To the carboxylic acid (0.18 mmol), were added the (2H-tetrazol-5-yl)methylamine (0.22 mmol), EDC (0.275 mmol), HOBt (0.22 mmol), and anhydrous DMF (15 m1). The flask was purged with N2, sonicated for 20 s and DIPEA (0.73 mmol) was added. The reaction was stirred at room temperature for 16 hrs. Analysis of the reaction by LC/MS showed approximately 75% conversion of the acid. An additional one half of the portion of the amine, EDC, HOBt, and DIPEA were added and the reaction was heated at 45 C for another 6 hrs then concentrated under reduced pressure.
The residue was purified on a C18 column using 10-70% Me0H in water to yield the product as an off-white solid (40-95%).

Method P: GPneral method for (a) preparation of oncvmme.tric anhydride ring oilening products with proximal substitution (vio anhydride riiiti opcnin g with Me01-1) Followed by (b) coupling...to un amine (ex. 1-15 ) and c) subsequent hydrolvsis.
o Me0H 0 triethylamine R-NH2 (ex. 1-15) EDC, HOBt, DIPEA
DMF
Li0H.1-120 Me0H/ H20 0 To the respective anhydride (2.8 mmol) were added methanol (5.6 mmol), anhydrous DCM (28 mL) and triethylamine (11 mmol). The reaction was stirred at RT
for 4 hrs then diluted with diethyl ether (30 mL) and HC1 (1M, aqueous, 30 mL) and transferred to a separatory funnel. The organic layer was collected, washed with a NaC1 solution (saturated, aqueous) and then dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude ring-opened product was collected as a colourless oil and as a mixture of isomers. The ring-opened product mixture was used in the subsequent step without further purification. To the crude ring-opened product (0.11 mmol) were added the amine (ex. 1-15) (0.11 mmol) EDC (0.17 mmol), HOBt (0.13 mmol) and anhydrous DCM (6 mL). The flask was purged with N2, sonicated for 20 s and triethylamine (0.44 mmol) was added. The reaction was stirred at RT
for 3 hrs.
The reaction mixture was concentrated under reduced pressure and the residue was purified on a C18 column using 10-70% Me0H in water to yield the methyl ester product as an off-white solid and as a mixture of isomers (49-65%). To the mixture of isomers (0.12 mmol) were added LiOH H20 (0.23 mmol), methanol (3 mL), and H20 (4.5 mL).
The reaction was stirred at room temperature in air for 10h. The reaction was acidified to approximately pH 5 using citric acid (aqueous, saturated), and then concentrated under reduced pressure. The residue was purified on a C18 column using 10-75% Me0H
in water to yield the product as an off-white solid (17-54%).
The following examples are provided for the purpose of illustrating, not limiting, the invention.
EXAMPLES
Synthetic Intermediates The following is a description of synthetic intermediates (I-1 to 1-15) useful for making representative compounds of the invention.
Intermediate 1-1 e ) NaOH (0 5M) / H2NíNNH ÇI' Dioxane N.=- _c) ,-T di-tert-butyl ' EDC, HOBt, 0 I
¨N
O OH dicarbamate --' -0H DIPEA, DMF N T¨ 'NH

tert-Bu tyl (2S)-2-[(2H-1,2,3,4-tetrazol-5-ylmethyDearbamoy11-2,3-dihydro-1H-indole-1-earboxylate (1-1):
To (2S)-2,3-dihydro-1H-indole-2-carboxylic acid (1 g, 6.13 mmol) in dioxane (6 ml) and NaOH solution (0.5M, 12 ml) was added slowly di-tert-butyl dicarbonate (1.47 g, 6.74 mmol) in dioxane (6 ml) at 0 C. The reaction mixture was warmed to RT and stirred overnight. The reaction mixture was then washed with hexanes (10 ml). The separated water layer was acidified using saturated solution of citric acid and extracted with ethyl acetate (3 x 15 ml). The organic layer was washed with brine, separated, dried over sodium sulfate and concentrated to give (2S)-1-[(tert-butoxy)carbony1]-2,3-dihydro-1H-indole-2-carboxylic acid, as light orange colored solid (1.45 g, 90 %), used further as described. 1H NMR (400 MHz, DMSO-d6) 6 1.41 (9H, s), 2.99-3.04 (1H, d, J=20 Hz), 3.48-3.55 (1H, dd, .J=12, 16 Hz), 4.74-4.78 (1H, dd, J=4, 12 Hz), 6.91-6.95 (1H, t, J=8 Hz), 7.14-7.18 (2H, m), 7.72-7.74 (1H, d, J=8 Hz), 12.85 (1H, bs), MS (LC/MS) m/z observed 285.89, expected 286.11 [M+Na].
(2S)-1-[(tert-Butoxy)carbony1]-2,3-dihydro-1H-indole-2-carboxylie acid (3 g, 11.40 mmol), 2H-1,2,3,4-tetrazol-5-ylmethanamine (1.16 g, 11.40 mmol), EDC

(2.4 g, 12.53 mmol), HOBt (1.54 g, 11.40 mmol) and DIPEA (15.9 ml, 91.15 mmol) were stirred in anhydrous DMF (60 ml) for 16 hrs. The reaction mixture was concentrated under vacuum and re-dissolved in ethyl acetate (180 ml) and washed with citric acid (aqueous, saturated solution), water and brine. The organic layer was separated, dried over sodium sulfate and concentrated to give the crude product as an orange-red oil. The crude compound recrystallized in diethyl ether (80 ml) to yield tert-butyl (2S)-2-[(2H-1,2,3,4-tetrazol-5-ylmethyl)carbamoy1]-2,3-dihydro-1H-indole-1-carboxylate (1-1) as an off-white solid (2.8 g, 71%). 11-1 NMR (400 MHz, DMSO-d6) ö 1.32 (9H, s), 2.94-2.99 (1H, dd, J=4, 15 Hz), 3.41-3.48 (1H, dd, J=12, 20 Hz), 4.50-4.64 (2H, dq, J=4, 20 Hz), 4.73-4.77 (1H, dd, J=4, 12 Hz), 6.89-6.83 (1H, t, J=8 Hz ), 7.12-7.16 (2H, t, J=8 Hz), 7.71 (1H, bs), 7.86 (1H, bs), MS (LC/MS) nilz observed 344.73, expected 345.17 [M+H].
Intermediate 1-2 HCI (4M) / Dioxane NCI. HN,, N N

(2S)-N-(2H-1,2,3,4-Tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide hydrochloride (1-2):
HCI Solution in dioxane (4M, 28 ml) was added to 1-1 (1.4 g, 4.07 mmol) and stirred for 2 hrs at RT. Precipitated solid was filtered under nitrogen and washed with diethyl ether (2 X 15 ml) to yield (25')-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide hydrochloride(I-2) as a light pink colored solid (1.1 g, 96%), 1H NMR (400 MHz, DMSO-d6) 5 2.93-2.99 (1H, dd, J=8, 16 Hz), 3.26-3.33 (1H, dd, J=I2, 16 Hz), 4.24-4.29 (1H, t, J=8 Hz), 5.56-5.58 (2H, dd, J=1.6, 8 Hz), 5.89 (1H, bs), 6.55-6.59 (2H, t, J=8 Hz), 6.91-6.95 (1H, t, J=8 Hz), 6.99-7.01 (1H, d, J=8 Hz), 8.59-8.62 (1H, t, J=8 Hz), MS (LC/MS) m/z observed 244.97, expected 245.12[M+H].
Intermediate 1-3 >'0AOH
H

HClHN EDC, HOBt, DIPEA ,N
N DCM H

NH 1\_1 1\1==1 Nzri tert-Butyl N-12-oxo-2- [(2S)-2-[(2H-1,2,3,4-tetrazol-5-y1 m ethyl)carbam oyl] -2,3-d i hyd ro-1H-indo1-1-yl] ethyl) carbam ate (1-3):
1-2 (0.5 g, 1.78 mmol), N-Boc-glycine (0.37g, 2.14 mmol), EDC (2.4 g, 12.5 mmol), HOBt (0.75 g, 3.92 mmol) and DIPEA (1.24 ml, 7.125 mmol) were stirred in anhydrous DCM (20 ml) for 16 hrs. The reaction mixture was diluted using DCM (15 ml) and washed with citric acid (aqueous, saturated solution), followed by water and then brine. The organic layer was separated, dried over sodium sulfate and concentrated to give the crude product as a yellow-orange colored oil. The crude compound was purified on a C18 column using 10-50% Me0H in water to yield tert-butyl N-{2-oxo-2-[(2S)-2-[(2H-1,2,3,4-tetrazol-5-ylmethyl)carbamoy1]-2,3-dihydro-1H-indo1-1-yl]ethylIcarbamate (1-3) as an off-white solid (0.4 g, 56%), 111 NMR
(400 MHz, DMSO-d6) 6 1.39 (9H, s), 3.08-3.12 (2H, d, J=16 Hz), 3.56-3.63(1H, dd, J12, 20 Hz), 3.92-3.97 (1H, dd, J=4, 16 Hz), 4.56-4.62 (2H, m), 5.09-5.12 (1H, d, 12 Hz), 6.96-7.00 (2H, t, J=8 Hz), 7.13-7.17 (1H, t, J=8 Hz), 7.19-7.21 (1H, d, J=8 Hz), 8.00-8.02 (1H, d, J=8 Hz), 9.06 (1H, s), MS (LC/MS) m/z observed 401.82, expected 402.19 [M+H], and observed 424.04, expected 424.17 [M+Na].

Intermediate 1-4 \
0 HCI (4M) / Dioxane ¨

0 N ' (2S)-1-(2-Am in oacety1)-N-(2H-1,2,3,4-tetrazol-5-y 1m ethyl)-2,3-dihyd ro-1H-indole-2-carboxamide hydrochloride(I-4):
HC1 Solution in dioxane (4M, 5 ml) was added to 1-3 (0.24 g, 0.6 mmol) and stirred for 2 hrs at RT. The precipitated solid was filtered under nitrogen and washed with diethyl ether (2 X 5 ml) and dried to yield (2S)-1-(2-aminoacety1)-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide hydrochloride (I-4) as an off-white solid (0.11 g, 54%), 1H NMR (400 MHz, DMSO-d6) ö 2.20-2.24 (2H, d, J=16 Hz), 3.46-3.50(1H, d, J=16 Hz), 3.56-3.65 (IH, m), 4.05-4.09 (1H, d, J=16 Hz), 5.09-5.12 (1H, d, 12 Hz), 4.60-4.61 (2H, d, J=4 Hz), 5.19-5.22 (1H, d, J=12 Hz), 7.04-7.08 (1H, t, j=8 Hz), 7.19-7.23 (1H, t, J=8 Hz), 7.25-7.27 (1H, d, J=8 Hz), 8.03-8.05 (1H, d, J=8 Hz), 8.30 (211, bs), 9.30 (2H, s), MS (LC/MS) m/z observed 301.98, expected 302.14 [M+11].
n Le r racd iate 1-5 m 0 EDC, HOBt, DIPEA
HCI N'NHDCM H N
0- = 1\1" 'NH
Oz N- H Ojf \N 11 tert-Bu tyl N-R1S,2S)-2-methy1-1-({2-oxo-2-[(2S)-2-1(2H-1,2,3,4-tetrazol-5-ylmethyl)carbamoy1]-2,3-dihydro-1H-indo1-1-yl]ethylIcarbamoyl)butyl]carbamate (I-5):
1-4 (0.15 g, 0.44 mmol), N-Boc-Isoleucine (0.10 g, 0.44 mmol), EDC (0.13 g, 0.67 mmol), HOBt (0.078 g, 0.58 mmol) and DIPEA (0.31 ml, 1.78 mmol) were stirred in anhydrous DCM (15 ml) for 16 hrs. The reaction mixture was diluted using DCM (15 ml) and washed consecutively with citric acid (aqueous, saturated solution), water and brine. The organic layer was separated, dried over sodium sulfate and concentrated to give the crude product as a yellow-orange colored oil. The crude compound was purified on a C18 column using 10-50% Me0H in water to yield tert-butyl N-[(1S,25)-2-methy1-1-({2-oxo-2-[(2S)-2-[(2H-1,2,3,4-tetrazol-5-ylmethyl)carbamoy1]-2,3-dihydro-1H-indo1-1-yl]ethyll carbamoyDbutylicarbamate (1-5) as an off-white solid (0.14 g, 60%). 1H NMR (400 MHz, DMSO-d6) 8 0.80-0.84 (3H, t, J=8 Hz), 0.85-0.87 (3H, d, J=8 Hz), 1.39 (9H, s), 1.40-1.46 (1H, m), 1.69-1.75 (1H, m), 3.02-3.12 (2H, m), 3.52-3.66 (3H, m), 3.89-3.93 (1H, t, J=8 Hz), 4.12-4.16 (1H, d, J=16 Hz), 4.33-4.38 (1H, dd, J=4, 16 Hz), 4.50-4.55 (1H, dd, J=4,

16 Hz), 5.13-5.16 (1H, d, J=12 Hz), 6.73-6.75 (1H, d, J=8 Hz), 6.98-7.02 (1H, t, J=8 Hz), 7.15-7.22 (2H, m), 8.04-8.06 (1H, d, J=8 Hz), 8.10 )1H, s), 8.73 (1H, s), MS
(LC/MS) nilz observed 514.86, expected 515.27[M+H].
Intermediate 1-6 NaOH, Me0H OH

2-Phenylacetic acid (1-6):
A solution of methyl 2-phenylacetate (10 g, 64 mmol) in methanol (60 nril) was treated with solution of sodium hydroxide (5.1 g, 127 mmol) in water (40 ml) at 70 C for 3 hrs. The resulting mixture was concentrated under vacuum to remove the methanol. The residue was diluted with water (40 ml) and washed with diethyl ether (40 ml). The separated water layer was acidified to pH 2 using a mixture of water and HC1 (1:1) and extracted with DCM (3 X 80 m1). Combined organic extracts were washed with brine, 80 ml, separated, dried over sodium sulfate and concentrated to give 2-phenylacetic acid (1-6) as a white solid (9 g, 96%) used without further characterization. 1H NMR (400 MHz, CDC13) 8 3.64 (2H, s), 7.27-7.35 (5H, m), 11.5 (1H, bs).

Intermediate 1-7 1) Thionyl chloride (excess) H
CIF" N
-OH

2) NaOH (2N), 0 C->RT

H2N,j-LOH
, 1-7 (2S,3S)-3-Methyl-2-(2-phenylacetamido)pentanoic acid (1-7):
1-6 (2.0 g, 14.7 mmol) and thionyl chloride (6.6 ml, 90.3 mmol) were stirred together for 1 hr at RT. Thionyl chloride was removed by distillation under vacuum.
The acid chloride was added to the stirring solution of L-isoleucine (1.75 g, 13.37 mmol) in NaOH (2N, 17 ml) at 0 C. The resulting mixture was warmed to RT
and stirred overnight. The mixture was washed with diethyl ether (20 ml) and acidified to pH 4-5 by adding citric acid (aqueous, saturated solution). The precipitated solid was filtered, washed with diethyl ether and dried to yield (2S,3S)-3-methyl-2-(2-phenylacetamido)pentanoic acid (1-7) as a white solid (1.6 g, 44%). 1H
NMR (400 MHz, DMSO-d6) 8 0.78-0.82 (6H, t, J=8 Hz), 1.12-1.18 (1H, m), 1.34-1.40 (1H, m), 1.72-1.78 (1H, m), 3.41-3.53 (2H, q, J=16 Hz), 4.13-4.16 (1H, dd, J=4,12 Hz), 7.15-7.19 (1H, m), 7.22-7.28 (1H, m), 8.19-8.21(1H, d, J=8 Hz), 12.54 (1H, s), MS (LC/MS) m/z observed 250.02, expected 250.14 [M+1-1].
Intermediate 1-8 , ,03H CIH H2N.õ--y0Et OH
L
0 Ph n Li __________________________________________________ Ph Tr hl EDC, oxyma 0 0 Mve1200H, 0 õ DIPEA, DCM

2-1(2S,35)-3-Methy1-2-(2-pheny1acetamido)pentanamidolacetic acid (1-8):
To a suspension of 1-7 (24 g, 96.3 mmol) in DCM (400 mL) was added DIPEA (87 mL, 500 mmol) at 0 C. The reaction mixture was allowed to stir for 10 min, upon which a homogeneous mixture was obtained. To this was added glycine ethyl ester hydrochloride (15.1 g, 108 mmol). After stirring a further 5 min at the same temperature, EDC (24.5 g, 116 mmol) and oxyma (18.8 g 116 mmol) were added. The reaction mixture was then allowed to stir overnight (approximately 15 hr) while allowed to slowly warm to RT. Another batch of glycine ethyl ester hydrochloride (2.1 g) was added and the reaction mixture was allowed to stir a further 4 hr at ambient temperature. Reaction mixture was transferred to a separatory funnel and washed with NaHCO3 (300 mL, aqueous, saturated), followed by HC1 (3M, 50 mL), and brine (200 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Ethyl 2-[(2S,3S)-3-methy1-2-(2-phenylacetam ido)pentanamido] acetate was obtained from flash column chromatography (MeOH: DCM 1-5%) followed by recrystallization from acetonitrile (16 g, colourless crystals) and used further as described. Ill NMR (300 MHz, CD30D) 8 7.32-7.21 (m, 5H), 4.34 (m, 1H), 4.17 (q, 2H), 4.03-3.96 (m, 1H), 3.89-3.81 (m,1H), 3.68-3.52 (m, 2H), 1.98-1.89 (m, 1H), 1.62-1.35 (m, 1H), 1.26 (t, 3H), 1.21-1.09 (m, 1H), 0.96-0.86 (m, 6H), MS (ESI) m/z observed 357.29, expected 357.18 [M+Na].
Intermediate 1-8 was obtained from hydrolysis of ethyl 2-[(2S,3S)-3-methy1-2-(2-phenylacetamido)pentanamido]acetate (8.1 g, 24 mmol) using Method D (6 g, white powder). 1H NMR (300 MHz, CD30D) 8 12.40 (br s, 1H), 7.31-7.16 (m, 5H), 4.23-4.18 (m, 1H), 3.76-3.70 (m, 2H), 3.57-3.40 (m, 2H), 1.83-1.68 (m, 1H), 1.48-1.35 (m, 1H), 1.13-0.99 (m, 1H), 0.83-0.75 (m, 6H), MS (ESI) m/z observed 305.20, expected 305.15 [M-H].

Intermediate 1-9 ) Method F
y, , H
0 N,.,., 0 CO2Me N\
CO2Me Method D
\) FNJ- ..-= :1 Ph-Thr 1 y ) 0 n 0 COOH

(2S)-1-12-[(2S,3S)-3-Methyl-2-(2-phenylacetamido)pentanamido]acety1}-2,3-dihydro-1H-indole-2-carboxylic acid (1-9):
Intermediate 1-9 was obtained from 1-8 (170 mg, 0.37 mmol) using Method F
followed by Method D (120 mg, white powder) and used further as is. 11-1 NMR
(300 MHz, DMSO-d6) 6 8.37-8.18 (m, 1H), 8.06 (d, 1H), 7.28-7.08 (m, 7H), 6.95-6.90 (m, 1H), 4.57-4.53 (m, 1H), 4.44-4.24 (m, 1H), 4.13-3.89 (m, 2H), 3.59-3.18 (m, 4H), 1.92-1.71 (m, 1H), 1.47-1.22 (m, 1H), 1.13-0.99 (m, I H), 0.84-0.75 (m, 6H).
Intermediate 1-10 o )c ¨ Et0H, S0Cl2 ii =,-Ø--C[,r--.1r-NV\
NH? ______________________ HS ___________ i Method C
COOH COOEt a COOEt Ethyl (25)-1-(2-{[(tert-butoxy)carbony1]amino}acetyl)-2,3-dihydro-1H-indole-2-carboxylate (1-10) (2S)-2,3-dihydro-1H-indole-2-carboxylic acid (500 mg, 306 mmol) was suspended in Et0H (5 mL) at 0 C and thionyl chloride (0.45 mL, 6.13 mmol, 2 eq.) was added. The resulting clear mixture was allowed to come to RT and stirred for 16 hours. The reaction mixture was then concentrated to dryness and swapped with Et0H (2 x 10 mL). The solid obtained was dried well under reduced pressure to give ethyl (2S)-2,3-dihydro-1H-indole-2-carboxylate hydrochloride as a light brown solid (0.58 g, quantitative).1H NMR (400 MHz, DMSO-d6) 8 1.18 (3H, s), 3.10-3.18 (1H, m), 3.30-3.40 (1H, m), 4.05-4.17 (2H, m), 4.55 (I H, bs), 6.80 (2H, bs), 7.02-7.08 (2H, m), 7.7 (2H, bs). Compound was used further as described.
1-10 was prepared from ethyl (25)-2,3-dihydro-1H-indole-2-carboxylate hydrochloride and 2-((tert-butoxycarbonyl)amino)acetic acid using method C
however the purification was performed on normal phase using 0 % to 50 % ethyl acetate in hexanes as the eluent. 1H NMR (400 MHz, DMSO-d6) 81.18 (3H, t, J=6Hz), 1.38 (9H, s), 3.19 (1H, d, J=16Hz), 3.48-3.62 (2H, m), 3.95-4.20 (3H, m), 5.35 (1H, d, J=11Hz), 7.00 (2H, t, J=8Hz), 7.15-7.25 (2H, m), 8.01 (1H, d, J=8Hz), MS (LC/MS) m/z 370.95 [M+Nal Intermediate 1-11 ¨ 1) H2SO4, HNO3 Pd/C, Et0H ¨
HN
2) Et0H, SOCl2 HN H N

Ethyl (2S)-6-amino-2,3-dihydro-1H-indole-2-carboxylate (1-11) (25)-2,3-Dihydro-1H-indole-2-carboxylic acid (5 g, 30.640 mmol) was dissolved in sulfuric acid (concentrated, 40 ml) at 0 C. The resulting reaction mixture was chilled to -20 C and nitric acid (concentrated, 1.4 ml, 33.1 mmol) was then added dropwise. The reaction mixture was stirred at -20 C for 1 hr and then allowed to warm to RT and stirred for 2 hrs. The reaction mixture was diluted with cold water (100 ml), neutralized to pH 4 using Na0I4 solution (10N) and extracted with Et0Ac (3 X 200 m1). The combined organic layers were dried over sodium sulphate and concentrated to give an orange solid. This solid was dissolved in ethanol (200 mL) and treated with thionyl chloride (4.45 nil, 61.3 mmol) at 0 C and stirred overnight at RT. The reaction mixture was concentrated and purified by column chromatography on silica gel using 0 % to 50 % ethyl acetate in hexanes as the eluent to give ethyl (2S)-6-nitro-2,3-dihydro-1H-indole-2-carboxylate, as a yellow solid (1.61 g, 22%). 11-1 NMR (400 MHz, CDC13) 6 1.30-1.34 (3H, t, J=8 Hz), 3.30-3.57 (2H, m), 4.21-4.27 (2H, q, J=8 Hz), 4.47-4.52 (1H, q, J=8 Hz), 4.70 (1H, bs), 7.16-7.18 (1H, d, J=8 Hz), 7.47-7.48 (1H, d, J=4 Hz), 7.62-7.65 (1H, dd, J=8, 4 Hz), MS (LC/MS) m/z observed 237.00, expected 237.08 [M+11].
Ethyl (28)-6-nitro-2,3-dihydro-1H-indole-2-carboxylate (2 g, 8.474 mmol) and 10% Pd on activated carbon (0.4 g, 20% wt./wt.) in ethanol (60 ml) was stirred under hydrogen (balloon) for 3 hrs. The reaction mixture was filtered through a bed of CELITE and washed with ethanol (4 X 30 m1). Collected filtrate was concentrated and dried well under vacuum to yield 1-11 as pale yellow oil (1.4 g, 80%). 1H
NMR
(400 MHz, CDC13) 6 1.14-1.18 (3H, t, J=8 Hz), 2.94-3.01 (3H, m), 3.30 (1H, s), 4.57-4.61 (1H, t, J=8 Hz), 7.45-7.48 (1H, q, J=4 Hz), 8.03 (1H, s), 8.06-8.09 (1H, m), 8.41-8.42 (1H, d, J=4 Hz), 8.96-8.97 (1H, d, J=4 Hz), MS (LC/MS) m/z observed 207.09, expected 207.11 [M+H].

Intermediate 1-12 -----'----.-I----'---.1 -1) .-i,\ 01 rNiFi 0 Boc.N OH
H II

/ \
HN. A Method C
.1 111 HN ) Boc, 0 0 J 11----)rN j 1_7 Method A
i Boc 40 0 (I) HIN' I / N
/2 1) Hydrazine 0 0 0.-/ dicarbonate ¨ :_: NThr-N
` ' r=-," 0 X ) 0. 0 (S)-Ethyl 6-((tert-butoxycarbonyl)amino)-1-(24(2S,38)-3-methy1-2-(2-phenylacetamido)pentanamido)acetyl)indoline-2-carboxylate (1-12) 1-11 (0.6 g, 2.91 mmol) and isoindoline-1,3-dione (0.43 g, 2.91 mmol) in toluene was heated at 90 C for 4 hrs. Resulting reaction mixture was concentrated and purified by column chromatography on silica gel using 0 % to 30 % ethyl acetate in hexanes as the eluent to give (S)-6-(1,3-dioxo-1,3-dihydro-isoindolin-2-y1)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester, as an off-white solid (0.7 g, 72%).
ill NMR (400 MHz, CDC13) 3 1.29-1.33 (3H, t, J=8 Hz), 3.38-3.44 (2H, m), 4.20-4.26 (2H, m), 4.42-4.46 (1H, d , J-12,8 Hz), 4.56 (1H, bs), 6.72 (1H, s), 6.75-6.78 (1H, dd, J=12,4 Hz), 7.17-7.19 (1H, d, ./=12 Hz), 7.76-7.78 (2H, m), 7.92-7.95 (2H, m), MS (LC/MS) rn/z observed 337.07, expected 337.11 [MH-H].
(S)-1-(2-tert-B utoxycarbonylamino-acety1)-6-(1,3-dioxo-1,3-dihydro-isoindol-2-y1)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester was prepared from (S)-6-(1,3-dioxo-1,3-dihydro-isoindolin-2-y1)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester and Boc-glycine using method C and purified by column chromatography on silica gel using 0 % to 50 % ethyl acetate in hexanes as the eluent to give (S)-1-(2-tert-Butoxycarbonylamino-acety1)-6-(1,3-dioxo-1,3-dihydro-isoindol-2-y1)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester, as an off-white solid (42%).
MS
(LC/MS) nilz observed 493.87, expected 494.19[M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(8)-1 -(2-tert-B utoxy carbonylamino-acety0-6-( 1 ,3 -d ioxo-1,3-dihydro-i soindol-2-y1)-2,3-d ihydro-1H-i ndol e-2-carboxy 1 ic acid ethyl ester and 1-7 were combined using method A to produce (S)-6-(1,3-dioxo-1,3-dihydro-isoindo1-2-y1)-142-(3-methyl-2-phenylacetylam ino-pentanoylam ino)-acety1]-2,3 -dihydro-1H-i ndole-2-carboxylic acid ethyl ester. MS (LC/MS) m/z observed 625.09, expected 625.26 [M+1-11. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-6-(1,3-Dioxo-1,3-dihydro-isoindo1-2-y1)-112-(3-methy1-2-phenylacetylamino-pentanoylamino)-acety1]-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (0.3 g, 0.48 mmol) was dissolved in 1:4 mixture of DMF:dioxane (10 ml) and hydrazine monohydrate (0.026 ml, 0,53 mmol) was added. The reaction mixture was heated at 50 C for 2 hr., concentrated and dried well under vacuum to give a yellow solid. This solid was dissolved in 1:5 mixture of water:dioxane (12 mL, v/v) and treated with DIPEA (0.67 ml, 3.85 mmol) and di-tert-butyl dicarbonate (0.42 g, 1.92 mmol) and stirred overnight at RT. The reaction mixture was concentrated and purified by column chromatography on silica gel using 0 % to 50 % ethyl acetate in hexanes as the eluent to give 1-12, as a pale yellow solid (0.16 g, 56%). MS
(LC/MS) m/z observed 595.09, expected 595.31 [M+I-1] used further as needed.

Intermediates 1-13 and 1-14 No2 / \ 7 ________________ /\ 0,N / \
_ 1) Et0H, S0Cl2 nitric acid /
HN 2)i triethylamine, )----11 acetic anhydride 0 j anhydride 0 '0 /1) HCI (1N aq ) 2) 50Cl2, Et0H
/
A

. 02N --c¨/}
HN,, HN
J ) 0 . 0 .

(S)-Ethyl 5-nitroindoline-2-carboxylate (I-12) and (S)-ethyl 7-nitroindoline-2-carboxylate (1-13) (S)-2,3-Dihydro-1H-indole-2-carboxylic acid (20 g, 0.123 mol) was suspended in absolute ethanol (200 mL) and the suspension was cooled to 0 C. SOCl2 (18 mL, 0.25 mol) was then added dropwise to the reaction mixture and it was allowed to warm to RT and was stirred for 16 hrs. The solvent was then evaporated and the residue was swapped twice with ethanol (100 mL) to get a brown solid. This solid was dissolved triethylamine (34.2 mL, 0.245 mol) and acetic anhydride (170 mL) and the mixture was stirred at RT for 2 hrs. Then it was diluted with Et0Ac (500 mL) and washed with NaHCO3 (2 x 200 mL, aqueous, saturated solution) and citric acid (2 x 200 mL, aqueous, saturated solution). The combined organic layers were dried over sodium sulphate and concentrated to give a brown solid. This solid was dissolved in acetic anhydride (200 mL) and a solution of nitric acid (11.1 mL) in acetic anhydride (161 mL) was added dropwise at 0 C. The reaction mixture was left at 0 C for 15 min then warm to RT and stirred for 3 hrs. Cold water (250 mL) was added to the reaction mixture and the product was extracted with EtOAC (3 x 450 mL). The combined organic layers were dried over sodium sulphate and concentrated. The two isomers obtained were separated by normal phase column chromatography using % to 30 % ethyl acetate in hexanes as the eluent to give first, (S)-1-acety1-5-nitro-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester as a yellow solid (18.49 g, 54%) 5 and second, (S)-1-acety1-7-nitro-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester as an orange oil (8.21 g, 24 %).
(S)-1-Acetyl-5-nitro-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester: 111 NMR (400 MHz, CDCI3) 8 1.30 (3H, t, J=7.0Hz), 2.22 (3H, bs), 3.34 (1H, m), 3.65 (1H, m), 4.19-4.34 (2H, m), 5.02 (1H, bs), 8.03 (1H, s), 8.17 (1H, dd, J=2, 9Hz), 8.34 10 (1H, bs), MS (LC/MS) m/z observed 279.01, expected 279.10 [M+H].
(S)-1-Acetyl-7-nitro-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester: 11-1 NMR (400 MHz, CDCI3) 1.28 (3H, t, J=7.0Hz), 2.28 (3H, bs), 3.41 (1H, d, J=16Hz), 3.62 (1H, dd, J=10, 17Hz), 4.19-4.30 (2H, m), 5.05 (1H, dd, J=2, 10Hz), 7.16 (1H, t, J=8Hz), 7.42 (1H, dd, J=2, 9Hz), 7.67 (1H, d, J=8Hz), MS (LC/MS) m/z observed 279.01, expected 279.10 [M+H].
1-13: (S)-1-Acety1-5-nitro-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (18.49 g) was refluxed in a aqueous HC1 solution (IN, 500 mL) for 2 hrs until the compound dissolved completely. Then, the reaction mixture was concentrated to dryness and the residue was dissolved in ethanol (500 mL). SOC12 (60 mL) was then added dropwise and the reaction was left at RT for 16 hrs. The solvent was then evaporated and the product was purified by normal phase column chromatography using 5 % to 20 % ethyl acetate in hexanes as the eluent to give intermediate 1-13 as a yellow solid (10.81 g, 69 %). 111 NMR (400 MHz, CDCI3) 8 1.32 (3H, t, J=7.0Hz), 3.35-3.52 (2H, m), 4.22-4.30 (2H, q, J=7Hz), 4.57 (1H, dd, J=5, 10Hz), 5.01 (1H, bs,), 6.63 (1H, d, J= 9Hz), 7.98 (1H, bs), 8.05 (1H, dd, J=2, 9Hz), MS (LC/MS) m/z observed 237.03, expected 237.09 [M+H].
1-14: (S)-1-Acety1-7-nitro-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (1.6 g) was refluxed in a HC1 solution (1N, aqueous, 80 mL) for 2 hrs until the compound dissolved completely. Then, the reaction mixture was concentrated to dryness and the residue was dissolved in ethanol (60 mL). SOC12 (10 mL) was then added dropwise and the reaction was left at RT for 16 hrs. The solvent was then evaporated and the product was purified by normal phase column chromatography using 5 % to 20 % ethyl acetate in hexanes as the eluent to give intermediate 1-14 as a yellow solid (0.97 g, 71 %). NMR (400 MHz, CDC13) 6 1.31 (3H, t, J=7.0Hz), 3.37-3.53 (2H, m), 4.19-4.30 (2H, q, J=7Hz), 4.69 (1H, dd, J=4, 10Hz), 6.66 (1H, dd, J=7, 8Hz), 7.03 (1H, bs), 7.24 (1H, d, Jr= 7Hz), 7.83 (1H, d, J=8Hz), MS
(LC/MS) ni/z observed 237.03, expected 237.09 [M+11].
Intermediate 1-15 Method E
H
0 )NH 0 o 14.
1-5 =N1,1,1 (1S,2S)-2-Methy1-1-(2-oxo-2-{(2S)-2-[(2H-1,2,3,4-tetrazol-5-ylmethyl)-carbamoy1]-2,3-dihydro-indo1-1-y1}-ethylcarbamoy1)-butyl-ammonium; chloride (I-15) 1-15 was collected as a faint pink solid from deprotection of 1-5 using method E. MS (LC/MS) m/z observed 415.09, expected 415.22 [M-C1]. The compound was confirmed using LC/MS and moved to next step as it was.
Representative Granzyme B Inhibitor Compounds The following is a description of representative Granzyme B inhibitor compounds of the invention.
Examples A1-A57 were prepared by the representative synthetic pathway illustrated schematically in FIGURE 1.

EXAMPLE Al (2S)-1-{2-[(2S,3S)-3-METHYL-2-(2-PHENvLAcETAmmo)PENTANAmmo]AcETv0-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Title compound Al was prepared from 1-5 and 1-6 using method A: 111 NMR
(400 MHz, DMSO-d6) 6 0.76-0.80 (3H, t, J=8 Hz), 0.82-0.84 (3H, d, ./=8 Hz), 1.04-1.11 (1H, m), 1.39-1.45 (1H, m), 1.70-1.76 (1H, m), 3.10-3.14 (2H, d, J=16 Hz), 3.42-3.45 (1H, d, J=8 Hz), 3.53-3.56 (1H, d, J=8 Hz), 3.62-3.65 (1H, m), 3.66-3.69 (1H, m), 4.14-4,16 (1H, t, J=4 Hz), 4.24-4.28 (1H, t, J=8 Hz), 4.47-4.51 (1H, d, J=16 Hz), 4.59-4.63 (1H, d, J=16 Hz), 5.14-5.16 (1H, d, ./=16 Hz), 6.97-7.01 (IH, t, J=8 Hz), 7.15-7.30 (7H, m), 8.08-8.11 (1H, d, J=12 Hz), 8.24(1H, bs), 8.99(1H, bs), MS (LC/MS) m/z observed 533.05, expected 533.26 [M H] and observed 555.17, expected 555.24 [M+Na].

(2S)-1-{2-1(2S,3S)-3-METHYL-2-[2-(1'YRIDIN-4-YL)AcETAmmo]PENTANAmmo]AcETYL)-N-(21/-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-Title compound A2 was prepared from 1-5 and 4-pyridineacetic acid using method A: 1H NMR (400 MHz, DMSO-d6) 6 0.76-0.80 (3H, t, J=8 Hz), 0.82-0.84 (3H, d, J=8 Hz), 1.04-1.11 (1H, m), 1.38-1.46 (1H, m), 1.71-1.77 (1H, m), 3.07-3.11 (2H, t, J=8 Hz), 3.48-3.61 (2H, m), 4.11-4.15 (1H, d, J-16 Hz), 4.25-4.29 (1H, t, J=8 Hz), 4.39-4.43 (1H, d, J=16 Hz), 4.52-56 (1H, d, Hz), 5.12-5.15 (1H, d, J=12 Hz), 6.95-6.99 (1H, t, J=8 Hz), 7.13-7.22 (2H, m), 7.25-7.26 (2H, d, J=4 Hz), 7.25-7.28 (1H, d, J=8 Hz), 7.30 (1H, bs), 8.44-8.45(2H, d, J=4 Hz), 8.81(1H, bs), MS (LC/MS) m/z observed 534.11, expected 534.26 [M+1-1].

(2S)-1-{2-[(2S,3S)-3-METHYL-2-12-(PYRIDIN-3-YOACETAMIDO]PENTANAMIDO]ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-Title cornpound A3 was prepared from 1-5 and 3-pyridineacetic acid using method A: 11-1 NMR (400 MHz, DMSO-d6) 6 0.76-0.80 (3H, t, J=8 Hz), 0.82-0.84 (3H, d, J=8 Hz), 1.04-1.12 (1H, m), 1.37-1.46 (1H, m), 1.72-1.77 (1H, m), 3.06-3.12 (2H, m), 3.47-3.62 (2H, m), 4.12-4.16 (111, d, J=I6 Hz), 4.24-4.28 (1H, t, J=8 Hz), 4.39-4.43 (1H, d, J=16 Hz), 4.53-4.57 (1H, d, J=16 Hz), 5.13-5.15 (1H, d, J=8 Hz), 6.97-7.01 (1H, t, J=8 Hz), 7.14-7.18 (1H, t, J=8 Hz), 7.19-7.21 (1H, d, J=8 Hz), 7.28-7.31 (1H, q, J=8 Hz), 7.65-7.67 (1H, d, J=8 Hz), 8.02-8.04(1H, d, J=8 Hz), 8.23-8.26(111, d, J=12 Hz), 8.29 (1H, bs), 8.40-8.41 (1H, d, J=4 Hz), 8.44 (1H, s), 8.82 (1H, bs), MS (LC/MS) ni/z observed 534.15, expected 534.26 [M+H].

(2S)-1-12-1(2S,3S)-3-METHYL-2-[2-(PYRIDIN-2-YL)ACETAMIDO]PENTANAMIDO]ACETY0-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-Title compound A4 was prepared from 1-5 and 2-pyridineacetic acid using method A: 111 NMR (400 MHz, DMSO-d6) 0.77-0.81 (3H, t, J-8 Hz), 0.83-0.85 (3H, d, J=8 Hz), 1.06-1.13 (1H, m), 1.42-1.47 (1H, m), 1.74-1.81 (1H, m), 3.06-3.12 (2H, m), 3.53-3.62 (2H, m), 4.15-4.19 (1H, d, J=16 Hz), 4.24-4.28 (1H, t, J=8 Hz), 4.25-4.29 (1H, q, J=12 Hz), 4.44-4.47 (1H, d, J=8 Hz), 4.59-4.63 (1H, d, J=16 Hz), 5.11-5.14 (1H, d, J=12 Hz), 6.94-6.98 (1H, t, J=8 Hz), 7.12-7.22 (3H, m), 7.68-7.72 (1H, td, J=4, 8 Hz), 8.01-8.03 (1H, d, J=8 Hz), 8.18-8.20(1H, d, J=8 Hz), 8.34 (1H, bs), 8.43-8.45 (1H, d, J=8 Hz), 8.87 (1H, bs), MS (LC/MS) ni/z observed 534.12, expected 534.26 [M+H].

5-{[(1S,2S')-2-METHYL-1-(12-0x0-2-[(2S)-2-[(2H-1,2,3,4-TETRAzoL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YL]ETHYLICARBAMOYL)BUTYLICARBAMOYL}PENTANOIC ACID
The starting compound (5-{[(1S,2S)-2-methy1-1-(12-oxo-2-[(25)-2-[(2H-1,2,3,4-tetrazol-5-y Imethyl)carbamoy1]-2,3-dihydro-1H-indo1-1 -yl]ethyl carbamoyObutyllcarbamoyl } pentanoic acid, ethyl ester) was prepared from 1-5 and adipic acid, monoethyl ester using method A: MS (LC/MS) rn/z observed 571.02, expected 571.29 [M+H], Compound was confirmed using LCMS and moved to next step as it was.
Title compound A5 was prepared from 5-{[(1S,2S)-2-methy1-1-({2-oxo-2-[(2S)-2-[(2H-1,2,3,4-tetrazol-5-ylmethypcarbamoyl]-2,3-dihydro-lH-indol-1-yl]ethyl}carbamoyl)butyl]carbamoyllpentanoic acid, ethyl ester using method D:

NMR (400 MHz, DMSO-d6) 8 0.78-0.82 (3H, t, J=8 Hz), 0.84-0.86 (3H, d, J=8 Hz), 1.06-1.13 (1H, m), 1.41-1.50 (51-1, m), 1.68-1.75 (1H, m), 2.08-2.20 (4H, m), 3.10-3.14 (1H, d, J=16 Hz), 3.50-3.62 (2H, m), 4.11-4.13 (1H, d, J=8 Hz), 4.22-4.26 (1H, m), 4.52-4,56 (1H, d, J=16 Hz), 4.62-4.66 (1H, d, J=16 Hz), 5.14-5.17 (1H, d, J=12 Hz), 6.97-7.01 (1H, t, J=8 Hz), 7.13-7.17 (1H, t, J=8 Hz), 7.20-7.22 (1H, d, J=8 Hz), 7.82-7.85 (1H, q, J=8 Hz), 8.00-8.02 (1H, d, J=8 Hz), 8.13 (1H, bs), 8.22-8.25 (1H, t, J=6 Hz) 9.09 (1H, bs), MS (LC/MS) nr/z observed 542.99, expected 543.27 [M+H] and observed 565.09, expected 565.25 [M+Na]

(2S)-1-{2-R2S,3S)-2-(3-AMINOPROPANAMIDO)-3-METHY LP EN'l ANAMIDO] ACETYLI-N-l 0 (2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(2S)-1-12-[(2S,35)-2-(3-(tert-Butoxylcarbonypaminopropanam ido)-3-methylpentanamido]acetyll -N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide was prepared from 1-5 and 3-((tert-butoxycarbonyl)amino)propanoic acid using method A: 1H NMR (400 MHz, DMSO-d6) 8 0.78-0.82 (3H, t, J=8 Hz), 0.84-0.86 (3H, d, J=8 Hz), 1.05-1.12 (1H, m), 1.35 (9H, s), 1.39-1.46 (1H, m), 1.70-1.75 (1H, m), 2.23-2.34 (2H, m), 3.06-3.12 (3H, m), 3.53-3.59 (2H, m), 4.10-4.14 (1H, d, J=16 Hz), 4.22-4.26 (1H, t, J=8 Hz), 4.37-4.42 (1H, dd, J=4, 16 Hz), 4.52-4.57 (1H, dd, J=8, 16 Hz), 5.12-5.14 (1H, d, J=8 Hz), 6.96-7.00 (1H, t, J=8 Hz), 7.12-7.16 (1H, t, J=8 Hz), 7.18-7.20 (1H, d, J=8 Hz), 7.87-7.89 (1H, d, J=8 Hz), 8.01-8.03 (1H, d, J=8 Hz), 8.16 (I H, bs), 8.80 (1H, bs), MS (LC/MS) rn/z observed 585.98, expected 586.31 [M+H] and observed 608.16, expected 608.29 [M+Na]. The compound was used further as described.
Title compound A6 was prepared from (2S)-1-{24(2S,35)-2-(3-(tert-butoxylcarbonynaminopropanamido)-3-methylpentanamido]acetyll-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide using method E: 111 NMR
(400 MHz, DMSO-d6) ö 0.80-0.84 (3H, t, J=8 Hz), 0.87-0.89 (3H, d, J=8 Hz), 1.07-1.15 (1H, m), 1.43-1.52 (1H, m), 1.72-1.78 (1H, m), 2.52-2.60 (2H, m), 2.97-3.09 (3H, m), 3.51-3.64 (2H, m), 4.09-4.12 (1H, d, J=12 Hz), 4.19-4.23 (1H, t, J=8 Hz), 4.33-4.41 (2H, m), 5.10-5.13 (1H, d, J=12 Hz), 6.96-7.00 (1H, t, J=8 Hz), 7.12-7.16 (1H, t, J=8 Hz), 7.18-7.20 (1H, d, J=8 Hz), 7.72 (2H, bs), 8.01-8.03 (1H, d, J=8 Hz), 8.22 (1H, s), 8.24 (1H, bs), 8.59 (1H, bs), MS (LC/MS) m/z observed 486.14, expected 486.26 [M+H].

(2S)-1-{2-R2S,35)-2-(4-AMINOBUTANAMIDO)-3-METHYLPENTANAMIDO]ACETYL)-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
HYDROCHLORIDE
(2S)-1-{2-[(2S,3S)-2-(4-(tert-Butoxycarbonyl)aminobutanamido)-3-methyl pentanam ido] acetyl } -N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide was prepared from 1-5 and 4-((tert-butoxycarbonypamino)butanoic acid using method A: MS (LC/MS) tn/z observed 599.97, expected 600.32 [M+H], observed 622.15, expected 622.31 [M+Na]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound A7 was prepared from (2S)-1-{2-[(2S,3S)-2-(4-(tert-butoxycarbonyl)aminobutanamido)-3-methylpentanamido]acety1}-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide using method E: 111 NMR
(400 MHz, DMSO-d6) 0.80-0.84 (3H, t, J=8 Hz), 0.88-0.90 (3H, d, J=8 Hz), 1.08-1.16 (1H, m), 1.47-1.53 (1H, m), 1.72-1.84 (3H, m), 1.18-1.34 (2H, m), 2.75-2.79 (2H, t, J=6 Hz), 3.03-3.07 (1H, d, J=8 Hz), 3.51-3.64 (2H, m), 4.07-4.11 (1H, m), 4.12-4.16 (1H, t, J=12 Hz), 4.30-4.35 (1H, dd, J=6,16 Hz), 4.41-4.46 (1H, dd, J=6,16 Hz), 5.08-5.11 (1H, d, J=12 Hz), 6.96-7.00 (1H, t, J=8 Hz), 7.12-7.16 (1H, t, J=8 Hz), 7.18-7.20 (1H, d, J=8 Hz), 7.92 (3H, bs), 8.00-8.02 (1H, d, J=8 Hz), 8.13-8.16 (1H, t, J=6 Hz), 8.60 (1H, bs), MS (LC/MS) m/z observed 500.13, expected 500.27 [M+H].

(28)-1-{2-[(2S,3S)-2-12-(4-AmiNOPHENYL)ACETAMID01-3-METHYLPENTANAMIDO1ACETYL)-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-(2S)-1-{2-[(2S,35)-242-(4-(tert-Butoxycarbonyl)aminophenyl)acetamido]-3-methylpentanamido]acety1)-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide was prepared from 1-5 and 2-(4-((tert-butoxycarbonypamino)phenypacetic acid using method A: MS (LC/MS) m/z observed 648.03, expected 648.31 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.

Title compound A8 was prepared from (2S)-1-{2-[(2S,38)-242-(4-(tert-butoxycarbonypaminophenypacetamido]-3-methylpentanamido]acetyl}-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide using method E: 1H
NMR
(400 MHz, DMSO-d6) 8 0.75-0.79 (3H, t, J=8 Hz), 0.81-0.83 (3H, d, J=8 Hz), 1.01-1.06 (1H, m), 1.32-1.43 (1H, m), 1.62-1.74 (1H, m), 3.09-3.13 (2H, d, J=16 Hz), 3.19-3.26 (2H, m), 3.55-3.62 (2H, m), 4.10-4.15 (1H, dd, J=4, 16 Hz), 4.21-4.25 (1H, t, J=8 Hz), 4.51-4.55 (1H, d, J=16 Hz), 4.62-4.66 (1H, d, J=16 Hz), 5.13-5.15 (1H, d, J=8 Hz), 6.44-6,46 (2H, d, J=8 Hz), 6.88-6.90 (2H, d, J=8 Hz), 6.96-7.00 (1H, t, J=8 Hz), 7.14-7.18 (1H, t, J=8 Hz), 7.19-7.21 (1H, d, J=8 Hz), 7.79-7.81 (1H, d, J=8 Hz), 8.01-8.03 (1H, d, J=8 Hz), 8.20(1H, bs), 9.06(1H, bs), MS (LC/MS) m/z observed 548.06, expected 548.62 [M+H] and observed 570.17, expected 570.26 [M+Na].

(2S)-1-{2-[(2S,3S)-2-[2-(3-AMINOPHENYL)ACETAMID0]-3-METHYLPENTANAMIDO] ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-(2S)-1-{24(2S,3S)-242-(3-(tert-Butoxylcarbonypaminophenypacetamido]-3-methylpentanamido]acety1}-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide was prepared from 1-5 and 2-(3-((tert-butoxycarbonyl)amino)phenyl)acetic acid using method A: MS (LC/MS) nilz observed 647.96, expected 648.33 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound A9 was prepared from (2S)-1-{2-[(2S,35)-2-[2-(3-(tert-butoxylcarbonyl)aminophenyl)acetamido]-3-methylpentanamidolacety1}-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide using method E: 1H
NMR
(400 MHz, DMSO-d6) 8 0.76-0.80 (311, t, J=8 Hz), 0.82-0.84 (3H, d, J=8 Hz), 1.03-1.11 (1H, m), 1.39-1.46 (1H, m), 1.68-1.74 (1H, m), 3.08-3.12 (2H, d, J=16 Hz), 3.17-3.25 (2H, m), 3.54-3.61 (2H, m), 4.10-4.15 (1H, dd, J=4, 16 Hz), 4.22-4.27 (1H, m), 4.42-4.48 (1H, m), 4.51-4.56 (1H, d, m), 5.12-5.14 (1H, d, J=8 Hz), 6.36-6.40 (2H, t, J=8 Hz), 6.43 (1H, s), 6.86-6.90 (1H, t, J=8 Hz), 6.96-7.00 (1H, t, J=8 Hz), 7.13-7.17 (1H, t, J=8 Hz), 7.19-7.21 (1H, d, J=8 Hz), 7.92-7.96 (1H, t, J=8 Hz), 8.01-8.03(1H, d, J=8 Hz), 8.23(1H, bs), 8.36(1H, bs), 8.88(1H, bs), MS (LC/MS) m/z observed, 548.03, expected 548.27 [M+H].

(2S)-1-12-[(2S,35)-242-(2-AMINO-1,3-ThiAzoL-4-YL)AcETAmmo]-3-METHYLPENTANAMIDO] ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-Thionyl chloride (0.460 mL, 6.321 mmol, 2 eq) was added to a stirred mixture of 2-(2-aminothiazol-4-ypacetic acid (500 mg, 3.2 mmol) and ethanol (5 mL) at 0 C. The resulting clear reaction mixture was stirred at RT for 16 hr and then concentrated under vacuum to dryness and then swapped with ethanol twice. Ethyl 2-(2-aminothiazol-yl)acetate was obtained as a brown oil in a quantitative yield (588 mg). 111 NMR
(400 MHz, DMSO-d6) 8 1.17 (3H, bs), 3.72 (2H, bs), 4.08 (2H, bs), 6,68 (1H, bs), 9.43 (2H, bs). The compound was used further as described.
Ethyl 2-(2-aminothiazol-4-yl)acetate (250 mg, 1.123 mmol) was treated with triethylamine (0.630 mL, 4.494 mmol, 4 eq.), N,N-dimethylaminopyridine (30 mg, 0.225 mmol, 0.2 eq.) and di-tert-butyl dicarbonate (300 mg, 1.348 mmol, 1.2 eq.) in dichloromethane (10 mL) for 4 hr. The reaction mixture was diluted with dichloromethane (10 mL) and sequentially washed with water (1 x 10 mL), saturated citric acid solution (1 x 10 mL) and brine (1 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a brown residue that was purified by column chromatography using a gradient hexanes/ethyl acetate (0% ethyl acetate to 50%
ethyl acetate). Ethyl 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetate was obtained as a yellow oil (130 mg, 34%). 1H NMR (400 MHz, CDC13) 8 1.22 (3H, t, J=7Hz), 1.55 (9H, s), 3.72 (2H, s), 4.11 (2H, q, J=7Hz), 6.75 (1H, s), 9.55 (1H, bs).
Ethyl 2-(2-((tert-butoxycarbonypamino)thiazol-4-ypacetate (100 mg, 0.350 mmol) was dissolved in ethanol (2 mL) and water (1 mL) and treated with lithium hydroxide (44 mg, 1.05 mmol, 3 eq.) at RT for 2 hrs. The reaction mixture was acidified by adding a saturated solution of citric acid to pH 5 and then concentrated to remove all ethanol. The residue was then extracted with ethyl acetate (2 x 15 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give 2-(2-((tert-butoxycarbonypamino)thiazol-4-ypacetic acid as a yellow oil (80 mg, 89%). MS

(LC/MS) m/z observed 258.74, expected 259.08 [M+H]. Compound was confirmed using LC/MS and moved to next step as is.
(2S)-1-{2-[(2S,3S)-242-(2-(tert-Butoxycarbonypamino-1,3-thiazol-4-ypacetamido]-3-methylpentanamido]acety1}-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-earboxamide was prepared from 2-(2-((tert-butoxycarbonypamino)thiazol-4-yl)acetic acid and 1-5 using method A: MS
(LC/MS) m/z observed 654.97, expected 655.28 [M+H]. The compound was confirmed using LC/MS and moved to next step as it was.
Title compound A10 was prepared from (25)-1-{2-[(2S,3S)-242-(2-(tert-butoxycarbonyl)amino-1,3-thiazol-4-ypacetamido]-3-methylpentanamido]acetyll-N-(2H-1,2,3,4-tetrazol-5-ylmethyl)-2,3-dihydro-1H-indole-2-carboxamide using method E: 111 NMR (400 MHz, DMSO-d6) 6 0.77-0.92 (6H, m), 1.05-1.15 (1H, m), 1.40-1.52 (1H, m), 1.72-1.82 (1H, m), 3.00-3.65 (5H, m), 4.17 (1H, d, J=15Hz), 4.30 (1H, t, J=7Hz), 4.51-4,72 (2H, m), 5.20 (1H, d, J=10Hz), 6.27 (1H, s), 6.85 (2H, m), 7.02 (1H, t, J=7Hz), 7.10-7.30 (2H, m), 7.88 (1H, d, J=9Hz), 8.10 (1H, d, J=8Hz), 8.25-8.35 (1H, m), 9.10 (1H, bs), MS (LC/MS) m/z observed 555.08, expected 555.23 [M+H].

(2S)-1-{2-[(2S)-2-CYcLotExYL-2-(2-PHENYLAcETAmmo)AcETAmmolAcETvq-N-(2H-1,2,3,4-TETRAzoL-5-YLmETHYL)-2,3-minamo-1H-INDoLE-2-cARBoxAmiDE
tert-Butyl ((S)-24(24(S)-2-(((2H-tetrazol-5-yl)methypcarbamoypindolin-1-y1)-2-oxoethypamino)-1-cyclohexyl-2-oxoethyl)carbamate was prepared from 1-3 and (S)-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid using method A: MS
(LC/MS) m/z observed 540.84, expected 541.29 [M+H], Compound was confirmed using LC/MS and moved to next step as it was.
Title compound A11 was prepared from tert-butyl ((S)-24(24(S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)indol in-1-y1)-2-oxoethypami no)-1-cyclohexy1-2-oxoethyl)carbamate and 1-6 using method A: 1H NMR (400 MHz, DMSO-d6) 6 0.93-1.00- (2H, m), 1.05-1.14 (3H, m), 1.55-1.67 (6H, m), 3.05-3.11 (2H, q, J=8 Hz), 3.52 (1H, s), 3.55-3.59 (2H, m), 4.11-4.15 (1H, d, J=16 Hz), 4.23-4.27 (1H, t, J=8 Hz), 4.37-4.41 (1H, d, J=16 Hz), 4.52-4.56 (1H, d, J=16 Hz), 5.12-5.14 (1H, d, J=8 Hz), 6.96-7.00 (1H, t, J=8 Hz), 7.14-7.21 (3H, m), 7.24-7.29 (4H, m), 8.02-8.04 (1H, d, J=8 Hz), 8.06-8.08 (1H, d, J=8 Hz), 8.27 (1H, bs), 8.78 (1H, bs), MS (LC/MS) m/z observed 559.01, expected 559.28 [M+H] and observed 581.13, expected 581.26 [M+Na].
EXAMPLE Al2 (2S)-1-12-[(2S)-2-CYCLOPENTYL-2-(2-PHENYLACETAMIDO)ACETAMIDO]ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
tert-Butyl ((3)-24(2-((S)-2-(((21/-tetrazol-5-yOmethyl)carbamoypindolin-1-y1)-oxoethypamino)-1-cyclopentyl-2-oxoethyl)carbamate was prepared from 1-3 and (S)-2-((tert-butoxycarbonypamino)-2-cyclopentylacetic acid using method A: MS
(LC/MS) m/z observed 526.81, expected 527.27 [M+H]. Compound was confirmed using LC/MS
and moved to next step as it was.
Title compound Al2 was prepared from tert-butyl ((S)-24(24(S)-2-(((2H-tetrazol-5-yl)methyl)carbamoypindolin-1-y1)-2-oxoethyDamino)-1-cyclopentyl-2-oxoethyl)carbamate and 1-6 using method A: 1H NMR (400 MHz, DMSO-d6) 8 1.36-1,44 (4H, m), 1.47-1.64 (4H, m), 2.12-2.18 (1H, m), 3.03-3.09 (2H, q, J=8 Hz), 3.39-3.43 (1H, d, J=16 Hz), 3.48-3.58 (2H, m), 4.09-4.17 (1H, t, J=16 Hz), 4.25-4.29 (1H, t, J=8 Hz), 4.35-4.43 (1H, t, J=16 Hz), 4.47-4.55 (1H, t, J=16 Hz), 5.09-5.13 (1H, T, J=8 Hz), 6.96-7,00 (1H, t, J=8 Hz), 7.13-7.20 (3H, m), 7.23-7.28 (4H, m), 8.02-8.04 (1H, d, J=8 Hz), 8.18-8.21 (1H, d, J-12 Hz), 8.26 (1H, bs), 8.73 (1H, bs), MS
(LC/MS) m/z observed 544.99, expected 545.26 [M+H].

3-{[(1S,25)-2-METHYL-1-({2-oxo-2-[(2S)-2-R2H-1,2,3,4-TETRAzoL-5-YLMETHYL)CARBAMOYLI-2,3-DIHYDRO-1H-INDOL-1-YIIETHYL}CARBAMOYL)BUTYLACARBAMOYL}PROPANOIC ACID
Title compound A13 was prepared from 1-5 and succinic anhydride using method B: 1H NMR (400 MHz, DMSO-d6) 8 0.79-0.83 (3H, t, J=8 Hz), 0.85-0.87 (3H, d, J=8 Hz), 1.10-1.16 (1H, m), 1.23-1.25 (4H, d, J=8 Hz), 1.43-1.52 (1H, m), 1.73-1.82 (1H, m), 3.05-3.09 (2H, d, J=16 Hz), 3.55-3.63 (2H, m), 4.13-4.22 (2H, m), 4.46-4.50 (2H, d, J=16 Hz), 5.11-5.13 (1H, d, J=8 Hz), 6.97-7.01 (1H, t, J=8 Hz), 7.15-7.19 (1H, d, J=16 Hz), 7.94-7.96 (1H, d, J=8 Hz), 8.02 (1H, s), 8.15 (1H, bs), 8.86 (1H, bs), MS
(LC/MS) m/z observed 515.07, expected 515.24 [M+H] and observed 537.11, expected 537.22 [M+Na].

EXAMPLE Al4 4-1R1S,2S)-2-METHYL-1-({2-0X0-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YLIETHYL}CARBAMOYLALTYLJCARBAMOYLIBUTANOIC ACID
Title compound A14 was prepared from 1-5 and glutaric anhydride using method B: NMR (400 MHz, DMSO-d6) 6 0.78-0.82 (3H, t, J=8 Hz), 0.84-0.86 (3H, d, J=8 Hz), 1.06-1.13 (1H, m), 1.40-1.47 (1H, m), 1.66-1.75 (3H, m), 2.13-2.19 (4H, q, J=8 Hz), 3.03-3.07 (1H, d, J=16 Hz), 3.51-3.61 (2H, m), 4.09-4.11 (1H, d, J=8 Hz), 4.21-4,25 (1H, t, J=8 Hz), 4.28-4.32 (1H, d, J=12 Hz), 4.42-4.45 (1H, d, J=12 Hz), 5.10-5.12 (1H, d, J=8 Hz), 6.95-6.99 (1H, t, J=8 Hz), 7.12-7.16 (1H, t, J=8 Hz), 7.18-7.20 (1H, d, J=8 Hz), 7.85-7.87 (1H, d, J=8 Hz), 8.02-8.04 (1H, d, J=8 Hz), 8.19 (1H, bs), 8.58 (1H, bs), MS (LC/MS) nilz observed 528.97, expected 529.24 [M+H] and observed 551.11, expected 551.23 [M+Na].

(2S)-1-[2-1(2S,3S)-2-AcETAmmo-3-mETHYLPENTANAmiD0JACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
To 1-5 (0.12 mmol) was added HC1 (4M) solution in dioxane (4 ml) and the reaction mixture was stirred for 2 hr at RT, then concentrated to dryness under vacuum and swapped with Me0H (5 ml) three times. The resulting residue was dried well under vacuum and treated with a mixture of acetic anhydride/pyridinc (1:1, 1.5 mL) for 15 minutes at RT. Then the reaction mixture was concentrated and the residue was submitted to reverse phase C18 column using 10-50% Me0H in water to yield the title compound A15 as an off-white solid (5 mg): 111 NMR (400 MHz, DMSO-d6) 6 0.77-0,92 (6H, m), 1.05-1.15 (1H, m), 1.40-1.50 (1H, m), 1.68-1.77 (1H, m), 1.87 (3H, s), 3.08-3.15 (1H, m), 3.51-3.65 (2H, in), 4.10-4.18 (1H, m), 4.24 (1H, t, J=9Hz), 4.48-4.68 (2H, m), 5.15 (1H, d, J=10Hz), 6.95 (1H, t, J=7Hz), 7.15-7.27 (2H, m), 7.90 (1H, d, J=7Hz), 8.10 (1H, d, J=8Hz), 8.18-8.33 (1H, m), 9.05 (1H, bs), MS (LC/MS) m/z observed 456.99, expected 457.23 [M+H].

EXAMPLE Al6 3-{R1S,28)-2-METHYL-1-({2-0X0-2-1(2S)-2-[(1H-1,2,3-TRIAZOL-4-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-VIA ETHYL} CARBAMOYOBUTYL]CARBA MOYL}PROPANOIC ACID
(S)-tert-Butyl 2-(((2H- L2,3-triazol-4-y1)methyl)carbamoyl)indoline- 1 -carboxylate was prepared from (S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid, and (2H-1,2,3-triazol-4-yOmethyl-amine following the same procedure for the preparation of 1-1. MS
(LC/MS) m/z observed 365.99, expected 366.15 [M+Na]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-tert-Butyl (2-(2-(((2H-1,2,3-triazol-4-yl)methypcarbamoypindol in-l-y1)-2-oxoethyl)carbamate was prepared from (S)-tert-butyl 2-4(2H-1,2,3-triazol-4-y1)methyl)carbamoyl)indoline-1-carboxylate following the same procedure for the preparation of 1-2 followed by the same procedure for the preparation of 1-3.
MS
(LC/MS) m/z observed 400.83, expected 401.19 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound A16 was prepared from (S)-tert-butyl (2-(2-(((2H-1,2,3-triazol-yl)methyl)carbamoyl)indolin-1-y1)-2-oxoethyl)earbamate and (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-methylpentanoic acid using method A followed reaction with succinic anhydride using method B: 1H NMR (400 MHz, DMSO-d6) 6 0.79-0.83 (3H, t, J=8 Hz), 0.85-0.87 (3H, d, J=8 Hz), 1.15-1.20 (1H, m), 1.40-1.50 (1H, m), 1.68-1.80 (1H, m), 2.31-2.45 (4H, m), 3.01-3.10 (1H, m), 3.50-3.63 (2H, m), 4.05-4.15 (1H, m), 4.25 (1H, t, J= 7Hz), 4.30-4.45 (2H, m), 5.11 (1H, d, J=9 Hz), 6.98 (1H, t, J=8 Hz), 7.10-7.25 (2H, m), 7.90 (1H, d, J=9 Hz), 8.02 (1H, d, J=8 Hz), 8.13 (1H, bs), 8.86 (1H, bs), 12.02 (1H, bs), MS (LC/MS) m/z observed 514.02, expected 514.24 [M+H].

3-METHYL-4-11(1S,2S)-2-METHYL-1-(12-0X0-2-[(28)-2-R2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL1-2,3-DIHYDRO-1H-INDOL-1-YLIETHYL}CARBAMOYL)BUTYLICARBAMOYLIBUTANOIC ACID
Title compound A17 was prepared from 1-5 and 3-methylglutaric anhydride using method I and was separated by chromatography, into two diastereomers, A17-1 and A17-2, each characterized as below:

A17-1:
1H NMR (400 MHz, DMSO-d6) 8 0.82 (3H, t, J=7.4Hz), 0.84-0.90 (6H, m), 1.12 (1H, m), 1.45 (1H, m), 1.75 (1H, m), 2.05 (1H, m), 2.15-2.30 (4H, m), 3.10 (1H, m), 3.55-3.65 (2H, m), 4.15 (1H, dd, J=4, 18Hz), 4.28 (1H, t, J=15Hz), 4.55 (1H, dd, J=4, 16Hz), 4,65 (1H, dd, J=6, 16Hz), 5.16 (1H, d, J=11Hz), 7.00 (1H, t, J=8Hz), 7.16 (1H, t, J=8Hz), 7.22 (1H, d, J=8Hz), 7.87 (1H, d, J=9Hz), 8.03 (1H, d, J=8Hz), 8.17 (1H, bs), 9.08 (1H, bs), MS (LC/MS) m/z observed 543.10, expected 543.27 [M+H].

1H NMR (400 MHz, DMSO-d6) 8 0.82 (3H, t, J=7.4Hz), 0.84-0.90 (6H, m), 1.12 (1H, m), 1.45 (1H, m), 1.75 (1H, m), 2.05 (1H, m), 2.08-2.15 (2H, m), 120-2.30 (2H, m), 3.10 (1H, m), 3.55-3.65 (2H, m), 4.13 (1H, d, J=17Hz), 4.28 (1H, t, J=19Hz), 4.53 (1H, dd, J=4, 16Hz), 4,65 (1H, dd, J=6, 16Hz), 5.15 (1H, d, J=11Hz), 7.00 (1H, t, J=8Hz), 7.16 (1H, t, J=8Hz), 7.22 (1H, d, J=8Hz), 7.87 (1H, d, J=9Hz), 8.03 (1H, d, J=8E1z), 8.17 (1H, bs), 9.08 (1H, bs), MS (LC/MS) m/z observed 543.07, expected 543.27 [M+H]
.
EXAMPLE Al8 3,3-DIMETHYL-4-1[(1S,2S)-2-METHYL-1-(12-0X0-2-R2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOY1]-2,3-DIHYDRO-1H-INDOL-1-YLIETHYLICARBAMOYL)BUTYL]CARBAMOYLI BU'FANOIC ACID
Title compound A18 was prepared from 1-5 and 3,3-dimethylglutaric anhydride using method 1 without acidification with formic acid. The product was obtained as a triethylammonium salt: 1H NMR (400 MHz, DMSO-d6) 6 0.82 (3H, t, J=7.4Hz), 0.87 (3H, d, J=7Hz), 1.02 (6H, s), 1.05-1.10 (10H, m), 1.45 (1H, m), 1.75 (1H, m), (4H, m), 2.77-2.90 (6H, m), 3.05 (1H, d, J=17Hz), 3.55-3.65 (2H, m), 4.13 (1H, d, J=16Hz), 4.26-4.33 (2H, m), 4.53 (1H, m), 5.15 (1H, d, J=11Hz), 6.98 (1H, t, J=8Hz), 7.12-7-24 (2H, m), 7.97 (1H, d, J=9Hz), 8.03 (1H, d, J=8Hz), 8.21 (1H, bs), 8.62 (1H, bs), MS (LC/MS) m/z observed 557.14, expected 557.28 [M+H]

EXAMPLE Al9 241-({[(1S,2S)-2-METHYL-1-({2-0X0-2-R2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYLI-2,3-DIHYDRO-1H-INDOL-1-Y L] ETHYL} CARBAMOYOBUTYLI CARBAMOYLI METHYL)CYCLOPENTYLIACETIC ACID
Title compound A19 was prepared from 1-5 and 3,3-tetramethyleneglutaric anhydride using method 1 without acidification with formic acid. The product was obtained as a triethylammonium salt: 111 NMR (400 MHz, DMSO-d6) 8 0.82 (3H, t, J=7.4Hz), 0.87 (3H, d, J=7Hz), 1.07-1.13 (10H, m), 1.40-1.62 (9H, m), 1.75 (1H, m), 2-31-2-38 (3H, m), 2.45 (1H, d, J=15Hz), 2.86-2.93 (6H,m), 3.05 (1H, d, J-17Hz), 3.55-3.65 (2H, m), 4.13 (1H, d, J=16Hz), 4.26-4.33 (2H, m), 4.49 (1H, dd, J=6, 15Hz), 5.15 (1H, d, J=11Hz), 6.98 (1H, t, J=8Hz), 7.12-7-24 (2H, m), 7.97 (1H, d, J=9Hz), 8.03 (1H, d, J=8Hz), 8.23 (1H, bs), 8.65 (1H, bs), MS (LC/MS) m/z observed 583.11, expected 583.30 [M+H]

2- {[(1S,2S)-2-METHYL-1-(12-0X0-2- R2S)-2- R2H-1,2,3,4-TETRAZOL-5-VLMETHYL)CARBAMOYI4-2,3-DIHYDRO-1H-INDOL-1-Y14ETHYL}CARBAMOYOBUTYLICARBAMOYL)-TRANS-CYCLOHEXANE-1-CARBOXYLIC
ACID
Title compound A20 was prepared from 1-5 and trans-1,2-cyclohexanedicarboxylic anhydride using method I without acidification with formic acid and was separated by chromatography, into two diastereomers, A20-1 and A20-2, each characterized below as triethylammonium salts:
A20-1:
11-1 NMR (400 MHz, DMSO-d6) 8 0.79 (3H, t, ./=7.4Hz), 0.85 (3H, d, J=7Hz), 1.06-1.26 (14H, m), 1.46 (1H, m), 1.65-1.77 (3H, m), 1.85 (1H, m), 1.95 (I H, m), 2.40-2.45 (2H, m), 2.85-2.99 (3H, m), 3.05 (1H, d, J=17Hz), 3.32-3.47 (3H, m), 3.52-3.65 (2H, m), 4.08-4.24 (2H, m), 4.34 (1H, m), 4.47 (1H, m), 5.13 (1H, d, J=11Hz), 6.98 (1H, t, J=8Hz), 7.12-7-24 (2H, m), 7.75 (1H, d, J=9Hz), 8.00-8-10 (2H, m), 8.65 (1H, bs), MS
(LC/MS) nt/z observed 569.11, expected 569.28 [M+H].
A20-2:

1H NMR (400 MHz, DMSO-d6) 8 8 0.80 (3H, t, J=7.4Hz), 0.85 (3H, d, J=7Hz), 1.10-1-30 (14H, m), 1.50 (1H, m), 1.68-1.77 (3H, m), 1.91 (1H, m), 2.11 (1H, m), 2.43 (1H, m), 2.65 (1H, t, J=10.7Hz), 2.90-3.06 (4H, m), 3.32-3.50 (3H, m), 3.60 (1H, d, J=11, 17Hz), 3.85 (1H, dd, J=5, 17Hz), 4.08 (1H, dd, J=5, 9Hz), 4.22 (1H, dd, J=6, 17Hz), 4.35 (I H, dd, J=6, 17Hz), 4.47 (1H, dd, J=6, 15Hz), 5.07 (1H, d, J=11Hz), 6.97 (1H, t, J=8Hz), 7.11-7-21 (2H, m), 7.95-8-06 (3H, m), 8.85 (1H, bs), MS
(LC/MS) nilz observed 569.12, expected 569.28 [M+H] .

6-{[(1S,2S)-2-METHYL-1-({2-ox0-2-1(2S)-2-[(2H-1,2,3,4-TETRAzoL-5-YLMETHYL)CARBAMOYL1-2,3-DIIIYDRO-1H-INDOL-1-YL] ETHYL} CARBAMOYLAUTYL] CARBAMOYLI-C/S-CYCLOHEX-3-ENE-1-CARBOXYLIC
ACID
Title compound A21 was prepared from 1-5 and cis-1,2,3,6-tetrahydrophtalic anhydride using method I and was separated by chromatography, into two diastereomers, A21-1 and A21-2, each characterized as below:
A21-1:
111 NMR (400 MHz, DMSO-d6) S 0.81 (3H, t, J=7.4Hz), 0.86 (3H, d, J=7Hz), 1.10 (1H, m), 1.48 (1H, m), 1.75 (1H, m), 2.15-2.25 (2H, m), 2.33 (1H, m), 2.43 (1H, m), 2.82-2.95 (2H, m), 3.11 (1H, m), 3.54-3.66 (2H, m), 4.11 (1H, d, J=17Hz), 4.23 (1H, t, J=8Hz), 4.54 (1H, dd, J=6, 17Hz), 4.65 (1H, dd, J=6, 15Hz), 5.16 (1H, d, J=11Hz), 5.60 (m, 2H), 7.00 (1H, t, J=8Hz), 7.11-7-26 (2H, m), 7.65 (1H, d, J=9Hz), 8.02 (1H, d, J=9Hz), 8.16 (1H, m), 9.07 (1H, bs), MS (LC/MS) nilz observed 567.11, expected 567.27 [M+H].
A21-2:
111 NMR (400 MHz, DMSO-d6) 6 0.81 (3H, t, J=7.411z), 0.86 (3H, d, J=7Hz), 1.11 (1H, m), 1.45 (1H, m), 1.81 (1H, m), 2.22 (1H, m), 2.30-2.36 (2H, m), 2.46 (1H, m), 2.82 (1H, m), 2.94 (1H, m), 3.11 (1H, d, J=17Hz), 3.54-3.66 (2H, m), 4.12-4.25 (2H, m), 4.50-4.65 (2H, m), 5.15 (1H, d, J=11Hz), 5.62 (m, 2H), 7.00 (1H, t, J=8Hz), 7.11-7-26 (2H, m), 7.71 (IH, d, J=9Hz), 8.02 (1H, d, J=9Hz), 8.16 (1H, bs), 9.05 (1H, bs), MS
(LC/MS) nilz observed 567.11, expected 567.27 [M+H].

2-1[(1S,2S)-2-METHYL-1-({2-0X0-21(28)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYI]-2,3-DIHYDRO-1H-INDOL-1-YlIETHYLICARBAMOYLAUTYLICARBAMOYL)-C/S-CYCLOPENTANE-1-CARBOXYLIC
ACID
Title compound A22 was prepared from 1-5 and cis-1,2-cyclopentanedicarboxylic anhydride using method I and was separated by chromatography, into two diastereomers, A22-1 and A22-2, each characterized as below:
A22-1:
11-1 NMR (400 MHz, DMSO-d6) 6 0.81 (3H, t, J=7.4Hz), 0.86 (3H, d, J=7Hz), 1.11 (1H, m), 1.44-1.55 (2H, m), 1.66-1.85 (5H, m), 1.95 (1H, m), 2.82 (1H, m), 3.05 (1H, m), 3.11 (1H, m), 3.54-3.66 (2H, m), 4.10-4.23 (2H, m), 4.45-4.70 (2H, m), 5.16 (1H, d, J=11Hz), 7.00 (1H, t, J=8Hz), 7.14-7-26 (2H, m), 7.71 (1H, d, J=9Hz), 7.99-8.10 (2H, m), 9.08 (1H, bs), MS (LC/MS) m/z observed 555.10, expected 555.27 [M+H].
A22-2:
111 NMR (400 MHz, DMSO-d6) 6 0.81 (3H, t, J=7.4Hz), 0.85 (3H, d, J=7Hz), 1.14 (1H, m), 1.43 (1H, m), 1.52 (1H, m), 1.66-1.87 (5H, m), 1.96 (1H, m), 2.82 (1H, m), 3.08 (1H, m), 3.14 (1H, m), 3.56-3.69 (2H, m), 4.15-4.27 (2H, m), 4.52-4.68 (2H, m), 5.16 (1H, d, J=11Hz), 7.00 (1H, t, J=8Hz), 7.14-7-26 (2H, m), 7.77 (1H, d, J=9Hz), 8.00-8.08 (2H, m), 9.08 (1H, bs), MS (LC/MS) m/z observed 555.09, expected 555.27 [M+H].

2-1R1S,2S)-2-METHYL-1-({2-0X0-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YL1ETHYL}CARBAMOYL)BUTYL]CARBAMOYL}-0S-CYCLOHEXANE-1-CARBOXYLIC ACID
Title compound A23 was prepared from 1-5 and cis-1,2-cyclohexanedicarboxylic anhydride using method 1 and was separated by chromatography, into two diastereomers, A23-1 and A23-2, each characterized as below:
A23-1:
111 NMR (400 MHz, DMSO-d6) 8 0.79 (3H, t, J=7.4Hz), 0.83 (3H, d, J=7Hz), 1.08 (1H, m), 1.20-1.32 (2H, m), 1.34-1.57 (4H, m), 1.63 (1H, m), 1.73 (1H, m), 1.87 (1H, m), 1.99 (1H, m), 2.55 (1H, m), 2.77 (1H, m), 3.10 (1H, m), 3.54-3.65 (2H, m), 4.10-4.23 (2H, m), 4.48-4.67 (2H, m), 5.14 (1H, d, J=11Hz), 6.99 (1H, t, .J=8Hz), 7.12-7-24 (2H, m), 7.56 (1H, d, J=9Hz), 7.97-8.08 (2H, m), 9.07 (1H, bs), MS (LC/MS) nilz observed 569.08, expected 569.28 [M+H].
A23-2:
1H NMR (400 MHz, DMSO-d6) 8 0.78 (3H, t, J=7.4Hz), 0.84 (3H, d, J=7Hz), 1.11 (1H, m), 1.20-1.48 (4H, m), 1.50-1.69 (3H, m), 1.77 (1H, m), 1.90 (1H, m), 2.03 (1H, m), 2.53 (1H, m), 2.82 (1H, m), 3.10 (1H, m), 3.54-3.65 (2H, m), 4.12-4.23 (2H, m), 4.46-4.64 (2H, m), 5.13 (1H, d, J=11Hz), 6.97 (1H, t, J=8Hz), 7.12-7-24 (2H, m), 7.62 (1H, d, J=9Hz), 8.00 (1H, d, J=8Hz), 8.11 (1H, bs), 9.03 (1H, bs), MS (LC/MS) m/z observed 569.06, expected 569.28 [M+H] .

(2Z)-3- {[(1S,2S)-2-METHYL-1-({2-0x0-2- R2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YLI ETHYL} CARBAMOYL)BUTYL] CARBA MOYL}PROP-2-ENOIC ACID
Title compound A24 was prepared from 1-5 and maleic anhydride using method I
without acidification with formic acid: 1H NMR (400 MHz, DMSO-d6) 8 0.82 (3H, t, J=7.4Hz), 0.88 (3H, d, J=7Hz), 1.08 (1H, m), 1.12 (9H, t, J=7Hz), 1.47 (1H, m), 1.82 (1H, m), 2.96 (6H, q, J=7Hz), 3.05 (1H, d, J=17Hz), 3.50-3.65 (2H, m), 4.13 (1H, d, J=16Hz), 4.26 (1H, t, J=7Hz), 4.38 (1H, m), 4.50 (1H, dd, J=6, 15Hz), 5.13 (1H, d, J=I1Hz), 6.11-6.15 (2H, m), 6.98 (IH, t, J=8Hz), 7.12-7-24 (2H, m), 8.04 (1H, d, J=8Hz), 8.37 (IH, bs), 8.85 (1H, bs), MS (LC/MS) m/z observed 513.08, expected 513.22 [M+H]

2-{R1S,2S)-2-METHYL-1-({2-0X0-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLIVIETHYL)CARBAMOY1]-2,3-DIHYDRO-1H-INDOL-1-YLJETHYLICARBAMOYL)BUTYLICARBAMOYL}BENZOIC ACID
Title compound A25 was prepared from 1-7 and phthalic anhydride using method I without acidification with formic acid: 1H NMR (400 MHz, DMSO-d6) 6 0.82 (3H, t, J=7.4Hz), 0.93 (3H, d, J=7Hz), 1.10 (9H, t, J=7Hz), 1.25 (1H, m), 1.55 (1H, m), 1.97 (1H, m), 2.90 (6H, q, J=7Hz), 3.00 (1H, d, J=17Hz), 3.56 (1H, m), 3.73 (1H, m), 4.16 (1H, dd, J=6, 16Hz), 4.25 (1H, dd, J=6, 8Hz), 4.47-4.51 (2H, m), 5.18 (1H, d, J=11Hz), 6.98 (1H, t, J=8Hz), 7.12-7-20 (2H, m), 7.28 (1H, d, J=8Hz), 7.42-7-50 (2H, m), 7.88 (1H, d, J=9Hz), 8.03 (1H, d, J=8Hz), 8.62 (1H, d, J=8Hz), 8.71 (1H, bs), 9.21 (1H, bs), MS (LC/MS) m/z observed 563.10, expected 563.24 [M+H]

2- { [(1S,2S)-2-METHYL-1-(12-oxo-2- [(2S)-2- [(2H-1,2,3,4-TETRA zo L-5-Y LM ET HYL)CARBA MOYL]-233-DIHYDRO-1H-INDOL-1-YL1ETHYLICARBAMOYLIBUTYWARBAMOYL)-CIS-CYCLOPROPANE-1-CARBOXYLIC
ACID
Title compound A26 was prepared from 1-5 and cis-3-oxabicyclo[3.1.0]hexane-2,4-dione using method I and was separated by chromatography, into two diastereomers, A26-1 and A26-2, each characterized as below:
A26-1:
1H NMR (400 MHz, DMSO-d6) 8 0.81 (3H, t, J=7.4Hz), 0.87 (3H, d, J=7Hz), 1.04-1.14 (2H, m), 1.31 (1H, m), 1.47 (1H, m), 1.75 (1H, m), 1.92 (1H, m), 2.13 (1H, m), 3.11 (1H, m), 3.55-3.66 (2H, m), 4.15 (1H, dd, J=6, 16Hz), 4.25 (1H, dd, J=7, 9Hz), 4.54 (1H, m), 4.65 (1H, m), 5.17 (1H, d, J=11Hz), 7.01 (1H, t, J=8Hz), 7.14-7-26 (2H, m), 8.03 (1H, d, J=8Hz), 8.18-8.30 (2H, m), 9.10 (1H, bs), MS (LC/MS) m/z observed 527.07, expected 527.24 [M+H].
A26-2:
111 NMR (400 MHz, DMSO-d6) 6 6 0.81 (3H, t, J=7.4Hz), 0.87 (3H, d, J=7Hz), 1.06-1.17 (2H, m), 1.31 (1H, m), 1.47 (1H, m), 1.76 (1H, m), 1.91 (1H, m), 2.13 (1H, m), 3.11 (1H, m), 3.55-3.66 (2H, m), 4.16 (1H, dd, J=6, 16Hz), 4.29 (1H, dd, J=7, 9Hz), 4.54 (1H, m), 4.65 (1H, m), 5.17 (1H, d, J=11Hz), 7.01 (1H, t, J=8Hz), 7.14-7-26 (2H, m), 8.03 (1H, d, J=8Hz), 8.18-8.30 (2H, m), 9.10 (1H, bs), MS (LC/MS) ni/z observed 527.06, expected 527.24 [M+H].

(2S)-1-{2-1(2S,3S)-242-(1-BENZOTHIOPHEN-3-YL)ACETAMID0]-3-METHYLPENTANAMIDO1ACETYLI-N-(21/-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-Title compound A27 was prepared from 1-5 and 2-(benzo[b]thiophen-3-yl)acetic acid using method A except a 2:1 ratio DCM/DMF as solvent, was used for the coupling reaction: 1H NMR (400 MHz, DMSO-d6) 6 0.80 (3H, t, J=7.4Hz), 0.86 (3H, d, J=7Hz), 1.10 (1H, m), 1.47 (1H, m), 1.76 (1H, m), 3.11 (1H, m), 3.55-3.66 (2H, m), 3.73 (1H, d, 1=5Hz), 3.83 (1H, d, J=5Hz), 4.15 (1H, dd, J=6, 16Hz), 4.30 (1H, dd, .1=7, 9Hz), 4.54 (1H, m), 4.65 (1H, m), 5.17 (1H, d, J=11Hz), 7.01 (1H, t, J=8Hz), 7.14-7-26 (2H, m), 7.32-7.40 (2H, m), 7.52 (1H, s), 7.86 (1H, m), 7.95 (1H, m), 8.04 (1H, d, J=8Hz), 8.23-8.32 (2H, m), 9.08 (1H, bs), MS (LC/MS) m/z observed 589.05, expected 589.23[M+H]

(2S)-1-{2-1(2S,3S)-3-METHYL-242-(2H-1,2,3,4-TETRAzoL-5-YL)ACETAMIDO]PENTANAMIDOjACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-Title compound A28 was prepared from 1-5 and 2-(2H-tetrazol-5-yl)acetic acid using method A but with DMF as solvent for the coupling reaction: 'H NMR (400 MHz, DMSO-d6) 6 0.82 (3H, t, J=7.4Hz), 0.88 (3H, d, J=7Hz), 1.12 (1H, m), 1.50 (1H, m), 1.77 (1H, m), 3.12 (1H, m), 3.56-3.67 (2H, m), 3.95-4.05 (2H, m), 4.16 (1H, dd, J=6, 16Hz), 4.31 (1H, t, J=8Hz), 4.56 (1H, m), 4.65 (1H, m), 5.17 (1H, d, J=11Hz), 7.01 (1H, t, J=8Hz), 7.14-7-26 (2H, m), 8.04 (1H, d, J=8Hz), 8.34 (1H, bs), 8.43 (1H, d, J=9Hz), 9.08 (1H, bs), MS (LC/MS) m/z observed 525.08, expected 525.24 [M+1-11 METHYL (3R)-3-METHYL-3-{[(1S,2S)-2-METHYL-1-({2-oxo-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YL1ETHYL)CARBAMOYL)BUTYLJCARBAMOYL}PROPANOATE
Title compound A29 was prepared from 1-5 and (R)-4-methoxy-2-methy1-4-oxobutanoic acid using method E, followed by method C: 111 NMR (400 MHz, DMS0-d6) 6 0.83 (3H, t, J=7.4Hz), 0.89 (3H, d, J=7Hz), 1.05 (3H, d, J 7Hz), 1.14 (1H, m), 1.47 (1H, m), 1.77 (1H, m), 2.33 (1H, dd, J=6, 16Hz), 2.57 (1H, dd, J=8, 16Hz), 2.87 (1H, m), 3.12 (1H, m), 3.56 (3H, s), 3.58-3.67 (2H, m), 4.16 (1H, m), 4.25 (1H, t, J=8Hz), 4.56 (1H, m), 4.66 (1H, m), 5.17 (1H, d, J=11Hz), 7.01 (1H, t, J=8IIz), 7.14-7-26 (2H, m), 7.91 (1H, d, J=9Hz), 8.02-8.12 (2H, m), 9.10 (1H, bs), MS (LC/MS) m/z observed 543.13, expected 543.27 [M+H]

3-METHYL-3-1R1S,2S)-2-METHYL-1-({2-0X0-2-[(2S)-2-[(211-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-11-1-INDOL-1-YL]ETHYL}CARBAMOYL)BUTYL]CARBAMOYL}PROPANOIC ACID
Title compound A30 was prepared from A29 using method D with 3 eq. of LiOITH20 and was separated by chromatography, into two diastereomers, A30-1 and A30-2, each characterized as below:
A30-1:
1H NMR (400 MHz, DMSO-d6) 8 0.79 (3H, t, J=7.4Hz), 0.85 (3H, d, J=7Hz), 1.01 (3H, d, J= 7Hz), 1.10 (1H, m), 1.45 (1H, m), 1.74 (1H, m), 2.17 (1H, dd, J=6, 16Hz), 2.43 (1H, m), 2.79 (1H, m), 3.08 (1H, m), 3.54-3.64 (2H, m), 4.12 (1H, m), 4.22 (1H, t, J=8Hz), 4.50 (1H, m), 4.62 (1H, m), 5.14 (1H, d, J=11Hz), 6.98 (1H, t, J=8Hz), 7.11-7-23 (2H, m), 7.82 (1H, d, J=9Hz), 7.98-8.08 (2H, m), 9.01 (1H, bs), MS
(LC/MS) m/z observed 529.08, expected 529.25 [M+H].
A310-2:
1H NMR (400 MHz, DMSO-d6) 0.79 (3H, t, J=7.4Hz), 0.85 (3H, d, J=7Hz), 1.03 (3H, d, J= 7Hz), 1.10 (1H, m), 1.44 (1H, m), 1.72 (I H, m), 2.22 (1H, dd, J=7, 15Hz), 2.51 (1H, m), 2.68 (1H, m), 3.08 (1H, m), 3.54-3.64 (2H, m), 4.11 (1H, m), 4.22 (1H, t, J=8Hz), 4.48 (1H, m), 4.60 (1H, m), 5.14 (1H, d, J=11Hz), 6.98 (1H, t, J=8Hz), 7.11-7-23 (2H, m), 7.82 (IH, d, J=9Hz), 8.02 (1H, m), 8.15 (1H, bs), 8.96 (1H, bs), MS
(LC/MS) rn/z observed 529.10, expected 529.25 [M+H]

243-({[(1S,2S)-2-METHYL-1-({2-0X0-2-[(28)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YLIETHYL}CARBAMOYL)BUTYL]CARBAMOYL}METHYL)PHENYL]ACETIC ACID
Title compound A31 was prepared from 1-5 and 1-cyclohexene-1,2-dicarboxylic anhydride using method I without acidification with formic acid: 111 NMR (400 MHz, DMSO-d6) 3 0.78 (3H, t, J=7.4Hz), 0.84 (3H, d, J=7Hz), 1.08 (IH, m), 1.13 (9H, t, J=7Hz), 1.17-1.25 (2H, m), 1.43-1.63 (3H, m), 1.99 (1H, m), 2.17-2.25 (3H, in), 2.28 (1H, m), 2.97-3.05 (7H, m), 3.54-3.65 m), 4.07-4.18 (2H, m), 4.38-4.50 (2H, m), 5.12 (1H, d, J=11Hz), 6.95 (1H, t, J=8Hz), 7.12-7-20 (2H, m), 7.97 (1H, d, J=8Hz), 8.07 (1H, d, J=8Hz), 8.45 (1H, bs), 9.05 (1H, bs), MS (LC/MS) m/z observed 566.96, expected 567.27 [M+H]

(2R,3R)-2,3-DmvpRoxy-3-{[(1S,2S)-2-mETHYL-1-02-oxo-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-11LM ETHYL)CARBAMOY14-2,3-DIHYDRO-1H-INDOL-1-YLIETHYLICARBAMOYOBUTYWARBAMOYLIPROPANOIC ACID
Title compound A32 was prepared from 1-5 and L-(+)-tartaric acid using method J in DMF: 'H NMR (400 MHz, DMSO-d6) 6 0.83 (3H, t, J=7.4Hz), 0.87 (3H, d, J=7Hz), 1.08 (1H, m), 1.48 (1H, m), 1.80 (1H, m), 3.11 (1H, m), 3.56-3.68 (2H, m), 4.17 (1H, m), 4.26 (1H, s), 4.30-4.37 (2H, m), 4.55 (1H, m), 4.66 (1H, m), 5.16 (1H, d, J=11Hz), 7.00 (1H, t, J=8Hz), 7.15-7-24 (2H, m), 7.57 (1H, d, J=9Hz), 8.07 (1H, d, J=8Hz), 8.33 (1H, bs), 9.10 (1H, bs), MS (LC/MS) m/z observed 547.06, expected 547.23 [M+H]

(2S,3S)-2,3-DmvpRoxy-3-{[(1S,2S)-2-METHYL-1-(12-oxo-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YL]ETHYL}CARBAMOYL)BUTYLJCARBAMOYL}PROPANOIC ACID
Title compound A33 was prepared from 1-5 and D-(-)-tartaric acid using method J
in DMF: 'H NMR (400 MHz, DMSO-d6) 6 0.83 (3H, t, J=7.4Hz), 0.87 (3H, d, J=7Hz), 1.06 (IH, m), 1.51 (1H, m), 1.73 (1H, m), 3.11 (1H, m), 3.55-3.67 (2H, m), 4.17 (1H, m), 4.22 (1H, s), 4.31 (1H, s), 4.37 (1H, dd, j=7, 9Hz), 4.55 (1H, m), 4.63 (IH, m), 5.16 (1H, d, ./=11Hz), 7.00 (111, t, J=8Hz), 7.15-7-24 (2H, m), 7.44 (1H, d, J=9Hz), 8.02 (1H, d, J=8Hz), 8.47 (1H, bs), 9.10 (1H, bs), MS (LC/MS) nilz observed 546.92, expected 547.23 [M+H]

2-14-({R1S,2S)-2-METHYL-1-({2-0X0-2-R2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YLJETHYL}CARBAMOYL)BUTYLJCARBAMOYL}METHYL)PHENYIAACETIC ACID
Title compound A34 was prepared from 1-7 and 1,4-phenylenediacetic acid using method J: 111 NMR (400 MHz, DMSO-d6) 6 0.80 (3H, t, J=7.4Hz), 0.86 (3H, d, J=7Hz), 1.10 (1H, m), 1.44 (1H, m), 1.75 (1H, m), 3.11 (1H, m), 3.43 (2H, d, J=14Hz), 3.53 (2H, d, J=14Hz), 3.56-3.65 (2H, m), 4.15 (1H, m), 4.27 (1H, t, J=8Hz), 4.54 (1H, m), 4.65 (1H, m), 5.17 (1H, d, ./=11Hz), 7.01 (1H, t, J=814z), 7.14-7-24 (6H, m), 8.04 (1H, d, J=8Hz), 8.10 (1H, d, J=9Hz), 8.25 (1H, bs), 9.08 (1H, bs), MS (LC/MS) m/z observed 591.15, expected 591.27 [M+H]

243-({1(1S,2S)-2-METHYL-1-({2-0X0-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLIVIETHYL)CARBAMOYL]-2,3-DIHYDROAH-INDOL-1-YL1ETHYL}CARBAMOYL)BUTYL}CARBAMOYL}METHYL)PHENYLJACETIC ACID
Title compound A35 was prepared from 1-7 and 1,3-phenylenediacetic acid using method J: 111 NMR (400 MHz, DMSO-d6) 6 0.80 (3H, t, J=7.4Hz), 0.86 (3H, d, J=7Hz), 1.10 (1H, m), 1.44 (1H, m), 1.75 (1H, m), 3.11 (1H, m), 3.43 (2H, d, J=14Hz), 3.55 (2H, d, J=14Hz), 3.57-3.66 (2H, m), 4.15 (1H, m), 4.27 (1H, t, J=8Hz), 4.55 (1H, m), 4.65 (1H, m), 5.17 (1H, d, J=11Hz), 7.01 (1H, t, J=8Hz), 7.08-7-24 (6H, m), 8.04 (1H, d, J=8Hz), 8.12 (1H, d, J=9Hz), 8.25 (1H, bs), 9.08 (1H, bs), MS (LC/MS) m/z observed 590.98, expected 591.27 [M+H]

(2E)-3-{[(1S,2S)-2-METHYL-1-(12-oxo-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YLIETHYLICARBAMOYL)BUTYL}CARBAMOYLIPROP-2-ENOIC ACID
Title compound A36 was prepared from 1-5 and fumaric acid using method J: 1H
NMR (400 MHz, DMSO-d6) 6 0.83 (3H, t, J=7.4Hz), 0.90 (3H, d, J=7Hz), 1.13 (1H, m), 1.46 (1H, m), 1.78 (1H, m), 3.11 (1H, m), 3.57-3.66 (2H, m), 4.15 (1H, m), 4.37 (1H, t, J=8Hz), 4.55 (1H, m), 4.65 (1H, m), 5.17 (1H, d, J=11Hz), 6.52 (1H, d, J=15Hz), 7.01 (1H, t, J=8Hz), 7.12-7-24 (3H, m), 8.04 (1H, d, J=8Hz), 8.35 (1H, bs), 8.60 (1H, d, J=9Hz), 9.08 (1H, bs), MS (LC/MS) m/z observed 513.46, expected 513.22 [M+H]

(3S)-3-AMINO-3-1[(1S,2S)-2-mETHYL-1-({2-0x0-2-[(2S)-2-[(2H-1,2,3,4-TETRAzoL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-11-1-INDOL-1-Y L] ETHYL} CARBAMOYL)BUTYL] CARBAMOYLI PROPANOIC ACID
The intermediate compound ((S)-tert-Butyl 4-(((2S,3S)-1-((2-(2-(((2H-tetrazol-yl)methyl)carbamoyl)indolin-1-y1)-2-oxoethyl)amino)-3 -methyl-1 -oxopentan-2-yl)amino)-3-(S)-((tert-butoxycarbonyl)amino)-4-oxobutanoate) was prepared from and Boc-L-aspartic acid-13-tert-buty1 ester using method A. MS (LC/MS) m/z observed 685.99, expected 686.36 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-tert-Butyl 4-(((2S,3S)-1-((2-(2-(((2H-tetrazol-5-yl)methyl)carbamoyl)indolin-1-y1)-2-oxoethyl)am ino)-3-methyl-1-oxopentan-2-yl)am ino)-3-(S)-((tert-butoxycarbonypamino)-4-oxobutanoate (30mg) was dissolved in a 1:1 mixture TFA/DCM (4 mL) and left under stirring at RT for 2 h. The solvents were evaporated and the product was purified on a C18 column using 10-30% Me0H in water to give title compound A37 as an off-white solid: 111 NMR (400 MHz, DMSO-d6) 8 0.83 (3H, t, J=7.4Hz), 0.90 (3H, d, J=7Hz), 1.15 (1H, m), 1.55 (1H, m), 1.82 (1H, m), 2.68-2.84 (2H, m), 3.17 (1H, d, J=16Hz), 3.57-3.67 (2H, m), 4.07-4.18 (311, m), 4.44 (1H, m), 4.56 (1H, m), 5.08 (11-1, d, J=11Hz), 6.99 (1H, t, J=8Hz), 7.12-7-24 (2H, m), 8.04 (1H, d, J=8Hz), 8.32 (1H, bs), 8.45 (1H, m), 9.08 (1H, bs), MS (LC/MS) ni/z observed 530.17, expected 530.25 [M+H]

(3R)-3-AMINO-3-1[(1S,2S)-2-METHYL-1-({2-0X0-2-1(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YL] ETHYLICARBAMOYL)BUTYL]CARBAMOYL}PROPANOIC ACID
(S)-tert-Butyl 4-(((2S,3S)-14(2-(2-(((2H-tetrazol-5-yl)methypearbamoypindolin-1-y1)-2-oxoethypamino)-3-methyl- I -oxopentan-2-yl)amino)-3-(R)-((tert-butoxycarbonyl)amino)-4-oxobutanoate was prepared from 1-7 and Boc-D-aspartic acid-13-tert-butyl ester dicyclohexylammonium salt using method A. MS (LC/MS) m/z observed 686.07, expected 686.36 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-tert-Butyl 4-(((2S,35)-1 -((2-(2-(((2H-tetrazol-5-yl)methyl)carbamoy I) ind o I in-1-y1)-2-oxoethyl)am ino)-3-methyl- 1 -oxopentan-2-yl)am ino)-3-(R)-((tert-butoxycarbonyl)amino)-4-oxobutanoate (30 mg) was dissolved in a 1:1 mixture trifluoroacetic acid/DCM (4 mL) and left under stirring at RT for 2 h. The solvents were evaporated and the product was purified on a C18 column using 10-30% Me0H in water to give title compound A38 as an off-white solid: 111 NMR (400 MHz, DMSO-d6) 6 0.83 (3H, t, J=7.4Hz), 0.90 (3H, d, J=7Hz), 1.13 (1H, m), 1.46 (1H, m), 1.78 (1H, m), 2.55-2.72 (2H, m), 3.08 (1H, d, J=16Hz), 3.52-3.65 (2H, m), 4.05 (1H, m), 4.18 (1H, m), 4.27 (1H, m), 4.44-4.49 (2H, m), 5.14 (1H, d, J=11Hz), 7.00 (1H, t, J=8Hz), 7.12-7-24 (2H, m), 8.03 (1H, d, J=8Hz), 8.35 (1H, bs), 8.52 (1H, m), 8.87 (1H, bs), MS
(LC/MS) m/z observed 530.16, expected 530.25 [M+H]

(2S)-2-AMINO-3-{[(IS,25)-2-METHYL-1-({2-0X0-24(2S)-2-1(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL1-2,3-DIHYDRO-1H-INDOL-1-YE] ETHYL}CARBAMOYLIBUTYL]CARBAMOY LIPROPANOIC ACID
(S)-tert-B utyl 4-((14(2-(2-(5)-(((2H-tetrazol-5-yl)methyl)carbamoy Dindoli n-1-y I)-2-oxoethyl)am ino)-3-(S)-methy1-1-oxopentan-2-yl)amino)-2-(5)-((tert-butoxyearbonyl)amino)-4-oxobutanoate was prepared from 1-5 and Boc-L-aspartic acid-a-tert-butyl ester using method A. MS (LC/MS) m/z observed 686.09, expected 686.36 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-tert-Butyl 44(14(2-(2-(S)-(((2H-tetrazol-5-yl)methyl)carbamoy I)indol in-1 -y1)-2-oxoethyl)amino)-3 -(9-methyl-1-oxopentan-2-yDam ino)-2-(S)-((tert-butoxycarbonyl)amino)-4-oxobutanoate (30mg) was dissolved in a 1:1 mixture trifluoroacetic acid/DCM (4 mL) and left under stirring at RT for 2 h. The solvents were evaporated and the product was purified on a C18 column using 10-30% Me0H in water to give title compound A39 as an off-white solid: 111 NMR (400 MHz, DMSO-d6) 6 0.83 (3H, t, J=7.4Hz), 0.88 (3H, d, J=7Hz), 1.20 (1H, m), 1.51 (1H, m), 1.86 (1H, m), 2.37 (1H, d, J=15Hz), 2.88 (1H, dd, J=10, 14Hz), 3.01 (1H, d, J=16Hz), 3.52-3.63 (2H, m), 3.86 (1H, m), 4.10-4.20 (2H, m), 4.49 (1H, m), 4.61 (1H, m), 5.11 (1H, d, J=11Hz), 6.98 (1H, t, J=8Hz), 7.12-7-23 (2H, m), 8.03 (1H, d, J=8Hz), 8.35 (1H, d, J=8Hz), 8.52 (1H, m), 9.30 (1H, bs), MS (LC/MS) m/z observed 530.10, expected 530.25 [M+H]

(2R)-2-AmINO-3-{[(/S,2S)-2-METHYL-1-({2-0x0-2-[(25)-2-[(2H-1,2,3,4-TETRAzoL-5-YLMETHYOCARBAMOY14-2,3-DIHYDRO-1H-INDOL-1-YLlETHYLICARBAMOYOBUTYL]CARBAIVIOYLIPROPANOIC ACID
(S)-tert-Butyl 4-((1-42-(2-(S)-(((2H-tetrazol -5-yl)methyl)earbamoyl)indolin-1-y1)-2-oxoethy Dam ino)-3-(S)-methy1-1-oxopentan-2-yeam ino)-2-(R)-((tert-butoxyearbony Damino)-4-oxobutanoate was prepared from 1-5 and Boe-D-aspartic acid-a-tert-butyl ester using method A. MS (LC/MS) m/z observed 686.05, expected 686.36 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-tert-B utyl 4-((1-((2-(2-(S)-(((2H-tetrazol -5-y Omethyl)carbamoyl)indol i n-1-yI)-2-oxoethy Dam ino)-3-(S)-methyl-1-oxopentan-2-yl)amino)-2-(R)-((tert-butoxycarbonyl)amino)-4-oxobutanoate (30mg) was dissolved in a 1:1 mixture trifluoroacetic acid/DCM (4 mL) and left under stirring at RT for 2 h. The solvents were evaporated and the product was purified on a C18 column using 10-30% Me0H in water to give title compound A40 as an off-white solid: 1H NMR (400 MHz, DMSO-d6) 6 0.82 (3H, t, J=7.4Hz), 0.86 (3H, d, J=7Hz), 1.20 (1H, m), 1.50 (1H, m), 1.81 (1H, m), 2.50 (1H, m), 2.97-3.11 (2H, m), 3.55 (1H, m), 3.70 (1H, m), 3.82 (1H, m), 4.03 (1H, t, Jr= 8Hz), 4.18 (1H, dd, J=7, 16Hz), 4.49 (1H, dd, J=5, 6Hz), 4.66 (1H, dd, J=6, 17Hz), 5.08 (1H, d, J=11Hz), 6.98 (1H, t, J=8Hz), 7.12-7-23 (2H, m), 8.03 (1H, d, J=8Hz), 8.35 (1H, m), 8.48 (1H, d, J=8Hz), 9.34 (1H, bs), MS (LC/MS) m/z observed 530.13, expected 530.25 [M+H]

(2S)-1-12,43-FLuoR0-3-METHYL-2-(2-PHENYLAcETAmmo)BuTANAmmolAcETYL)-N-(2H-1,2,3,4-TETRAzoL-5-YLmETHYL)-2,3-DIHYDR0-1H-INDoLE-2-cARBoxAmmE
3-Fluoro-3-methy1-2-(2-phenylacetamido)butanoic acid was prepared from 1-6 and 3-fluoro-DL-valine using method H: 111 NMR (400 MHz, DMSO-d6) 6 1.33 (3H, d, J=219Hz), 1.39 (3H, d, J=19Hz), 3.52 (1H, d, J=14Hz), 3.59 (1H, d, J=14Hz), 4.41, 4.46 (1H, 2 x d, J=19Hz), 7.20 (1H, m), 7.22-7.29 (3H, m), 8.50 (1H, d, J=9Hz), 12.90 (1H, bs), MS (LC/MS) nilz observed 254.02, expected 254.12 [M+H]. Compound was used further as described.
Title compound A41 was prepared from 1-4 and 3-fluoro-3-methy1-2-(2-phenylacetamido)butanoic acid using method C (as a mixture of diastereomers):
MS
(LC/MS) nilz observed 537.09, expected 537.24 [M+H].

(2S)-1-{2-[(2S,3R)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO]ACETYL)-N-(2H-172,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(2S,3R)-3-Methyl-2-(2-phenylacetamido)pentanoic acid was prepared from 1-6 and a//o-isoleucine using method H: 1H NMR (400 MHz, DMSO-d6) 6 0.75-0.90 (6H, m), 1.10 (1H, m), 1.25 (1H, m), 1.85 (1H, m), 3.47 (1H, d, J=14Hz), 3.56 (1H, d, J=14Hz), 4.35 (1H, m), 7.20 (1H, m), 7.24-7.30 (3H, m), 8.15 (1H, d, J=9Hz), 12.57 (1H, bs), MS (LC/MS) m/z observed 250.04, expected 250.14 [M+H]. Compound was used further as described.
Title compound A42 was prepared from 1-3 and (2S,3R)-3-methy1-2-(2-phenylacetamido)pentanoic acid using method A: 1H NMR (400 MHz, Me0H-d4) 0.87-0.97 (6H, m), 1.18 (1H, m), 1.45 (1H, m), 1.99 (1H, m), 3.21 (1H, d, J=8Hz), 3.23 (1H, d, J=8Hz), 3.55-3.67 (2H, m), 3.69-3.76 (2H, m), 4.51 (1H, d, J=5Hz), 4.58-4.74 (2H, m), 5.16 (1H, d, J=11Hz), 7.05 (1H, t, J=8Hz), 7.15-7-35 (7H, m), 8.13 (1H, bs), MS (LC/MS) nilz observed 533.12, expected 533.26 [M+H].

2,2,3,3-TETRA FLuoR0-3-1[(1S,2S)-2-METHYL-1-(12-0x0-2- [(2S)-2- [(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL1-2,3-DIHYDRO-1H-INDOL-1-YL]ETHYLICARBAMOYL)BUTYLiCARBAMOYL}PROPANOIC ACID
Title compound A43 was prepared from 1-5 and 2,2,3,3-tetrafluorosuccinic acid using method J in DMF: 111 NMR (400 MHz, DMSO-d6) 6 0.80-0.84 (3H, t, J=8 Hz), 0.88-0.90 (3H, d, J=-8 Hz), 1.08-1.15 (1H, m), 1,45-1.51 (1H, m), 1.83-1.91 (1H, m), 2.92-3.12 (2H, m), 3.56-3.64 (2H, m), 3.13-3.17 (1H, d, J=16 Hz), 4.27-4.31 (1H, t, J8 Hz), 4.42-4.46 (1H, d, J=8 Hz), 4.58-4.62 (1H, d, J=16 Hz), 5.13-5.15 (1H, d, J=8 Hz), 6.98-7.02 (1H, t, J=8 Hz), 7.15-7.22 (2H, m), 8.03-8.05 (1H, d, J=8 Hz), 8.39(1H, s), 8.97(1H, bs), 9.90 (1H, bs) 19F NMR (376 MHz, DMSO-d6) 6 -114.28 , -115.00 , -115.62, -116.35, -116.56, -117.28 , -118.35, -119.06., MS (LC/MS) tn/z observed 587.01, expected 587.19 [M+H].

2-IMETHvg{[(1S,2S)-2-mETHYL-1-({2-0x0-2-[(2S)-2-[(2H-1,2,3,4-TETRAzoL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YL] ETHYL}CARBAMOYL)BUTYL] CARBA MOYL) METHYL)AMINO1ACETIC ACID
Title compound A44 was prepared from 1-5 and 4-methylmorpholine-2,6-dione using method I: 11-1 NMR (400 MHz, DMSO-d6) 8 0.82-0.86 (3H, t, J=8 Hz), 0.88-0.90 (3H, d, J=8 Hz), 1.04-1.11 (1H, m), 1.47-1.53 (1H, m), 1.77-1.84 (1H, m), 2.73 (1H,$), 2.89 (1H, s), 2.98-3.04 (4H, q, J=8 Hz), 3.53-3.67 (2H, m), 4.13-4.17 (1H, d, J=16 Hz), 4.30-4.34 (1H, t, J=8 Hz), 4.36-4.40 (1H, dd, J=12, 4 Hz), 4.48-4,52 (1H, dd, J=12, 4 Hz), 5.10-5.13 (1H, d, J=12 Hz), 6.97-7.01 (1H, t, J=8 Hz), 7.14-7.18 (1H, t, J=8 Hz), 7.20-7.22 (1H, d, J=8 Hz), 7.95 (1H, s), 7.98-8.04 (1H, m), 8.42(1H, bs), 8.79(1H, bs), MS (LC/MS) m/z observed 544.17, expected 544.26 [M+H].

3-{[(S)-CYCLOPENTYL(12-0X0-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLIVIETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-tert-Butyl ((5)-2-((24(S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)indolin-1-y1)-oxoethypamino)-1-cyclopenty1-2-oxoethypcarbamate was prepared from 1-3 and (S)-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid using general method A.
MS
(LC/MS) m/z observed 527.03, expected 527.27 [M+H], Compound was confirmed using LC/MS and moved to next step as is.
Title compound A45 was prepared from tert-butyl ((S)-24(24(S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)indol in-1 -y1)-2-oxoethyl)amino)-1 -cyclopenty1-2-oxoethy Dcarbamate and succinic anhydride using method I: NMR (400 MHz, DMSO-d6) 6 1.26-1.34 (2H, m), 1.41-1.48 (2H, m), 1.51-1.67 (4H, m), 2.14-2.20 (1H, m), 2.37-2.44 (3H, m), 3.54-3.67 (3H, m), 4.16-4.26 (3H, m), 4.34-4.38 (1H, d, J=16 Hz), 4.44-4.48 (1H, d, J=16 Hz), 5.09-5.11 (1H, d, J=8 Hz), 6.96-7.00 (1H, t, J=8 Hz), 7.13-7.17 (1H, t, J=8 Hz), 7.19-7.21 (1H, d, J=8 Hz), 8.02-8.09 (2H, dd, J=20, 8 Hz), 8.16 (1H, bs), 8.72 (1H, bs), MS (LC/MS) m/z observed 527.10, expected 527.23 [M+H].

3-{[(1S)-2-METHYL-1-({2-oxo-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YL]ETHYL}CARBAMOYL)PROPYL]CARBAMOYL}PROPANOIC ACID
tert-Butyl ((S)-14(24(S)-2-(((211-tetrazol-5-yl)methyl)carbamoyl)indolin-l-y1)-oxocthyl)amino)-3-methyl-l-oxobutan-2-y1)carbamate was prepared from 1-3 and (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid using general method A. MS
(LC/MS) nilz observed 500.98, expected 501.25 [M+H]. Compound was confirmed using LC/MS and moved to next step as is.
Title compound A46 was prepared from tert-butyl ((S)-1-((2-((S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)indol in-1 -y1)-2-oxoethyl)ami no)-3-methyl-l-oxobutan-2-y 1)carbamate and succinic anhydride using method I: 1H NMR (400 MHz, DMSO-d6) 0.90-0.96 (6H, m), 2.01-2.08 (1H, m), 2.44-2.50 (2H, m), 3.15-3.22 (2H, m), 3.57-3.66 (2H, m), 4.18-4.22 (1H, d, J=16 Hz), 4.26-4.30 (1H, t, J=8 Hz), 4.57-4.61 (1H, d, J=16 Hz), 4.64-4.68 (1H, d, J=16 Hz), 5.20-5.23 (1H, d, J=12 Hz), 7.03-7.07 (1H, t, J=8 Hz), 7.18-7.22 (1H, t, J=8 Hz), 7.26-7.28 (1H, d, J=8 Hz), 7.91-7.95 (1H, dd, J=16, 4 Hz), 8.06-8.08 (1H, d, J=8 Hz), 8.21 (1H, bs), 8.27-8.31 (1H, t, J=8 Hz), 9.14 (1H, bs), MS (LC/MS) m/z observed 501.07, expected 501.21 [M+H] and observed 523.19, expected 523.21 [M+Na].

2-[(2,2-DIMETHYLPROPANOYL)OXY]ETHYL 3-{R1S,2S)-2-METHYL-1-({2-0X0-24(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-11-1-INDOL-1-YLIETHYL}CARBAMOYL)BUTYLJCARBAMOYLIPROPANOATE
Triethylamine (4.13 mL, 29.63 mmol) was added to ethylene glycol (22.5 mL).
Pivaloyl chloride (3.1 mL, 25.19 mL) was then added slowly to this mixture and it was left at RT for 2 hrs. The reaction mixture was diluted with water (25 mL) and the product was extracted with DCM (4 x 20 mL). The combined organic layers were dried over sodium sulphate and concentrated. The product was purified on normal phase using 0 %
to 40 % ethyl acetate in hexanes as the eluent to give a 2-hydroxyethyl pivalate as a colorless oil (3.99 g, 97%). 1H NMR (400 MHz, CDC13) 6 1.22-1.25 (9H, s), 2.02 (1H, bs), 3.80-3.85 (2H, m), 4.19-4.23 (2H, m).

Title compound A47 (75 mg, 0.146 mmol), 2-hydroxyethyl pivalate (32 mg, 0.219 mmol), EDC (42 mg, 0.219 mmol), DMAP (3.6 mg, 0.0292 mmol) were dissolved in DMF (5 mL). DIPEA (59 111,, 0.584 mmol) was then added and the reaction was heated to 50 for 6 hrs. The reaction mixture was concentrated and the product was purified on a C18 column using 10-65% Me0H in water to yield A47 as an off-white solid (35 mg, 37%). 1H NMR (400 MHz, DMSO-d6) 6 0.81 (3H, t, J=7.4Hz), 0.87 (3H, d, J=7Hz), 1.06-1.16 (10H, m), 1.45 (1H, m), 1.75 (1H, m), 2.35-2.48 (4H, m), 3.11 (1H, m), 3.55-3.65 (2H, m), 4.11-4.28 (6H, m), 4.52 (1H, m), 4.65 (1H, m), 5.13 (1H, d, J=11Hz), 7.01 (111, t, J=81-Iz), 7.14-7-26 (2H, m), 7.92 (1H, d, J=9Hz), 8.03 (1H, d, J=8Hz), 8.18 (1H, bs), 9.08 (1H, bs), MS (LC/MS) m/z observed 643.15, expected 643.32 [M+H].

(1S,25)-2-{R1S,25)-2-METHYL-1-({2-0X0-2-1(2S)-2-[(21/-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YL]ETHYL}CARBAMOYL)BUTYL1CARBAMOYLICYCLOPROPANE-1-CARBOXYLIC ACID
To the stirring mixture of (IS,2S)-diethyl cyclopropane-1,2-dicarboxylate (0.5 gm, 2.69 mmol) in 1:1 mixture of water:THF (2.7 ml) was added ammonium hydroxide (28%, 3.8 m1). The resulting reaction mixture was sealed in a flask and stirred at RT for 16hrs.
The reaction mixture was concentrated to dryness under vacuum. The resulting residue of (1S,2S)-cyclopropane-1,2-dicarboxylic acid, was dried well under vacuum and subjected to next reaction as it is.
Title compound A48 was prepared from 1-5 and (1S,2S)-cyclopropane-1,2-dicarboxylic acid using method J. MS (LC/MS) m/z observed 525.99, expected 527.55 [M+H]. Compound was confirmed using LCMS.

(2S)-1- {2- [(2S,3S)-3-METHYL-2- [(2R)-2-PHE1NYLPROPANAMIDO]PENTANAMIDO]ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDROAH-INDOLE-2-CARBOXAMIDE
Title compound A49 (7 mg, 0.01 mmol, 10%) was collected as an off white solid from intermediate 1-15 (60 mg, 0.13 mmol) using general method M via reaction with (R)-2-phenyl-propionic acid. 11-1 NMR (400 MHz, DMSO-d6) 6 9.00 (1H, bs), 8.23 (1H, bs), 8.04 (1H, d, J=7Hz), 7.96 (1H, d, J=9Hz), 7.35 (2H, d, J=7Hz), 7.28 (2H, t, J=7Hz), 7.25-7.15 (3H, m), 7.01 (1H, t, J=7Hz), 5.17 (1H, d, J=9Hz), 4.64 (1H, d, J=16Hz), 4.50 (1H, d, J=16Hz), 4.23 (1H, t, J=8Hz), 4.10 (1H, dd, .1=10, 5Hz), 3.81 (1H, q, J=7Hz), 3.70-3.55 (2H, m), 3.16 (1H, d, J=5Hz), 1.68 (1H, m), 1.31 (3H, d, J=7Hz), 1.25 (1H, m), 0.97 (1H, m), 0.72 (3H, d, J=7Hz), 0.66 (3H, t, J=7Hz), MS (LC/MS) m/z observed 547.09, expected 547.28 [M+14].

(2S)-1-{2-[(2S,3S)-3-METHYL-2-[(2S)-2-PHENYLPROPANAMIDO]PENTANAMIDOJACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Title compound A50 (10 mg, 0.01 mmol, 15%) was collected as an off white solid from intermediate 1-15 (60 mg, 0.13 mmol) using general method M via reaction with (S)-2-phenyl-propionic acid. `1-1 NMR (400 MHz, DMSO-d6) 8 9.06 (1H, bs), 8.15 (1H, bs), 8.00 (2H, d, J=9Hz), 7.32 (2H, d, J=7Hz), 7.27 (2H, t, J=7Hz), 7.23-7.13 (3H, m), 7.00 (1H, t, J=7Hz), 5.13 (1H, d, ./=10Hz), 4.64 (1H, dd, J=16, 514z), 4.53 (1H, dd, J=16, 514z), 4.30 (1H, t, J=8Hz), 4.10 (1H, dd, J=16, 5Hz), 3.81 (1H, q, J=7Hz), 3.67-3.50 (2H, in), 3.13 (1H, d, J=16Hz), 1.77 (1H, m), 1.47 (1H, m), 1.33 (3H, d, J=7Hz), 1.18 (1H, m), 0.88 (3H, d, J=7Hz), 0.84 (3H, t, J=7Hz), MS (LC/MS) m/z observed 547.05, expected 547.28 [M+H].

4-11(1S,2S)-2-METHYL-1-({2-0X0-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOY1]-2,3-DIHYDRO-1H-INDOL-1-YLIETHYL}CARBAMOYL)BUTYLiCARBAMOYL1-2-PHENYLBUTANOIC ACID
Title compound A51 (20 mg, 0.035 mmol, 49%) was collected as an off white solid from intermediate 1-15 (30 mg, 0.07 mmol) using general method N via reaction with 3-phenyl-dihydro-pyran-2,6-dione, as an inseparable mixture of diastereomers. 111 NMR (400 MHz, DMSO-d6) S 9.06 (1H, bs), 8.14 (1H, bs), 8.03 (1H, bs), 7.87 (1H, t, J=7Hz), 7.40-7.10 (7H, m), 7.01 (1H, t, J=7Hz), 5.16 (1H, m), 4.65 (1H, d, J=16Hz), 4.53 (1H, d, J=16Hz), 4.25 (1H, t, J=7Hz), 4.14 (1H, m), 3.60 (2H, m), 3.50 (1H, t, J=7Hz), 3.13 (1H, d, J=12Hz), 2.25-2.00 (3H, m), 1.86 (111, m), 1.73 (1H, m), 1.43 (1H, m), 1.10 (1H, m), 0.86 (3H, d, J=6Hz), 0.82 (3H, t, J=6Hz), (MS (LC/MS) nilz observed 605.06, expected 605.28 [M+H].

2,2-DimETHYL-4-([(1S,2S)-2-METHYL-1-02-0x0-2-[(2S)-2-[(2H-1,2,3,4-TETRAzot,-5-YLMETHYL)CARBAMOYLF2,3-DIHYDRO-1H-INDOL-1-YL]ETHYLICARBAMOYOBUTYL]CARBAMOYOBUTANOIC ACID
Title compound A52 (24 mg, 0.04 mmol, 40%) was collected as an off white solid from intermediate 1-15 (50 mg, 0.11 mmol) using general method N via reaction with 3,3-dimethyl-dihydro-pyran-2,6-dione. NMR (400 MHz, DMSO-d6) 8 9.05 (1H, bs), 8.15 (1H, bs), 8.03 (1H, d, J=8Hz), 7.89 (1H, d, J=9Hz), 7.22 (IH, d, J=7Hz), 7.17 (1H, t, J=7Hz), 7.01 (1H, t, J=8Hz), 5.17 (1H, d, J=10Hz), 4.65 (1H, dd, J=16, 6Hz), 4.53 (1H, dd, J=16, 4Hz), 4.24 (1H, t, J=8Hz), 4.15 (1H, dd, J16, 4Hz), 3.60 (2H, m), 3.14 (1H, d, J=16Hz), 2.14 (2H, m), 1.80-1.62 (3H, m), 1.45 (1H, m), 1.20-1.10 (7H, m), 0.86 (3H, d, J=7Hz), 0.81 (3H, t, J=8Hz), MS (LC/MS) m/z observed 557.16, expected 557.28 [M+H].

2,2-DimETHyL-3-{[(1S,25)-2-METHYL-1-(12-oxo-2-[(2S)-2-1(2H-1,2,3,4-TETRAzoL-5-YLMETHYOCARBAMOYL1-2,3-DIHYDRO-1H-INDOL-1-YL]ETHYOCARBAMOYOBUTYWARBAMOYLIPROPANOIC ACID
Title compound A53 (22 mg, 0.04 mmol, 62%) was collected as an off white solid from intermediate 1-15 (30 mg, 0.07 mmol) using general method N via reaction with 3,3-dimethyl-dihydro-furan-2,5-dione. 1H NMR (400 MHz, DMSO-d6) 8 9.09 (1H, bs), 8.17 (1H, bs), 8.02 (1H, d, J=9Hz), 7.81 (111, d, J=9Hz), 7.22 (1H, d, J=7Hz), 7.17 (1H, t, J=8Hz), 7.01 (1H, t, J=8Hz), 5.17 (1H, d, J=12Hz), 4.66 (1H, dd, J=16, 5Hz), 4.55 (1H, dd, J=16, 4Hz), 4.26 (1H, t, J=8Hz), 4.14 (1H, dd, J-16, 5Hz), 3.60 (2H, m), 3.14 (1H, d, J=16Hz), 2.46 (1H, d, J=11Hz), 2.41 (1H, d, J=11Hz), 1.74 (IH, m), 1.45 (1H, m) 1.19 (1H, m), 1.12 (3H, s), 1.11 (3H, s), 0.86 (3H, d, J-6Hz), 0.81 (3H, t, J=7Hz), MS
(LC/MS) m/z observed 543.04, expected 543.27 [M+H].

4-{R1S,2S)-2-METHYL-1-({2-0X0-2-R2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL1-2,3-DIHYDRO-1H-INDOL-1-YL]ETHYL}CARBAMOYLIBUTYLICARBAMOYL}-4-PHENYLBUTANOIC ACID
Title compound A54 (25mg, 0.08 mmol, 37%) was prepared from 1-15 (100mg, 0.22 mmol) and 3-phenyl-dihydro-pyran-2,6-dione using method P, where the hydrolysis step was stopped after 8h. A54 was separated by chromatography, into two diastereomers, A54-1 (eluted at 63% Me0H in water) and A54-2 (eluted at 65%
Me0H
ill water), each characterized as below:
A54-1:
NMR (400 MHz, DMSO-d6) 6 8.70 (1H, bs), 8.22-8.10 (2H, bs), 8.01 (1H, d, J=8Hz), 7.37-7.10 (7H, m), 6.99 (1H, t, J=8Hz), 5.08 (1H, d, J=9Hz), 4.51 (1H, d, J=14Hz), 4.40-4.20 (2H, m), 4.06 (1H, d, J=13Hz), 3.66 (1H, m), 3.51 (1H, m), 3.38 (1H, m), 3.06 (1H, d, J=18Hz), 2.20-2.05 (3H, m), 1.83 (1H, m), 1.77 (1H, m), 1.45 (1H, m), 1.12 (1H, m), 0.89 (3H, d, J=7Hz), 0.84 (3H, t, J=7Hz), MS (LC/MS) m/z observed 605.09, expected 605.28 [M+H].
A54-2:
111 NMR (400 MHz, DMSO-d6) 6 9.07 (1H, bs), 8.20 (1H, bs), 8.10-8.00 (2H, m), 7.40-7.10 (7H, m), 7.01 (1H, t, J=7Hz), 5.17 (1H, d, J=10Hz), 4.65 (1H, dd, J=16, 5Hz), 4.54 (1H, dd, J=16, 4Hz), 4.28-4.12 (2H, m), 3.68 (1H, t, J=6Hz), 3.61 (1H, m), 3.39 (1H, m), 3.14 (1H, d, J=16Hz), 2.25-2.00 (3H, m), 1.84 (1H, m), 1.70 (1H, m), 1.23 (1H, m), 0.89 (1H, m), 0.70 (3H, d, J=6Hz), 0.82 (3H, t, J=7Hz), MS (LC/MS) m/z observed 605.13, expected 605.28 [M+1-11.

4,4-DIMETHYL-4-{[(1S,2S)-2-METHYL-1-(12-0X0-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YL] ETHYL]. CARBA MOYL)BUTYL] CARBA MOYL} BUTANOIC ACID
Title compound A55 (9mg, 0.03 mmol, 30%) was prepared from 1-15 (51 mg, 0.11 mmol) and 3,3-dimethyl-dihydro-pyran-2,6-dione using method P, where the hydrolysis step was stopped after 20h. 111 NMR (400 MHz, DMSO-d6) 6 9.06 (1H, bs), 8.15 (1H, bs), 8.05 (1H, d, J=8Hz), 7.30-7.15 (3H, m) 7.02 (1H, t, j=81Iz), 5.17 (1H, d, J=10Hz), 4.64 (1H, dd, J=16, 5Hz), 4.54 (1H, dd, J=16, 5Hz), 4.24 (1H, t, J=8Hz), 4.19 (1H, m), 3.61 (2H, m), 3.39 (1H, m), 3.14 (1H, d, J=16Hz), 2.12 (2H, m), 1.86 (1H, m), 1.75 (1H, m), 1.48 (1H, m), 1.20-1.05 (7H, m), 0.89 (3H, d, J=7Hz), 0.83 (3H, t, J=7Hz), MS (LC/MS) m/z observed 557.10, expected 557.28 [M+H]

3,3-DIMETHYL-3-{[(1S,2S)-2-METHYL-1-({2-0X0-2-1(2S)-2-[(211-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YLIETHYLICARBAMOYL)BUTYLICARBAMOYLIPROPANOIC ACID
Title compound A56 (11 mg, 0.02 mmol, 11%) was prepared as an off-white solid, from 1-15 (80 mg, 0.18 mmol) and 3,3-dimethyl-dihydro-furan-2,5-dione using method P, where the hydrolysis step was stopped after 7h. 111 NMR (400 MHz, DMSO-d6) 8 9.04 (1H, bs), 8.17 (1H, bs), 8.02 (1H, d, J=8Hz), 7.82 (1H, d, J=9Hz), 7.22 (1H, d, J=7Hz), 7.17 (1H, t, J=8Hz), 7.01 (1H, t, J=8Hz), 5.17 (1H, d, J=10Hz), 4.63 (1H, dd, J=16, 5Hz), 4.53 (1H, dd, J=16, 4Hz), 4.25 (1H, t, J=8Hz), 4.14 (1H, dd, J=16, 4Hz), 3.62 (2H, m), 3.14 (1H, d, J=16Hz), 2.48 (1H, d, J=16Hz), 2.42 (1H, d, J=16Hz), 1.76 (1H, m), 1.45 (1H, m), 1.25-1.05 (7H, m), 0.86 (3H, d, J=6Hz), 0.82 (3H, t, J=7Hz), MS
(LC/MS) m/z observed 543.10, expected 543.27 [M+H]

2-{[(1S,2S)-2-METHYL-1-({2-0x0-2-[(2S)-2-[(2H-1,2,3,4-TETRAzoL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDROAH-INDOL-1-ETHYLICARBAMOYL)BUTYLICARBAMOYLI-TRANS-CYCLOPENTANE-1-CARBOXYLIC
ACID
Title compound A57 was prepared from 1-15 (71 mg, 0.16 mmol) and cis-cyclopentane-1,2-dicarboxylic acid using method J without HC1 treatment and was further separated by chromatography, into two diastereomers, A57-1 (9.9 mg, 0.04 mmol, 23%) and A57-2 (6.7 mg, 0.02 mmol, 15%), each characterized as below:
A57-1:
1H NMR (400 MHz, DMSO-d6) 8 8.90 (1H, bs), 8.15 (1H, bs), 8.03 (1H, d, J=8Hz), 7.80 (1H, d, J=9Hz), 7.22 (1H, d, J=7Hz), 7.17 (1H, t, J=8Hz), 7.00 (1H, t, J=7Hz), 5.15 (1H, d, J=9Hz), 4,57 (1H, d, J=12Hz), 4.45 (1H, d, J=12Hz), 4.27 (1H, t, J=8Hz), 4.16 (1H, dd, J=9, 5Hz), 3.69 (1H, dd, J=8, 4Hz), 3.64 (1H, m), 3.11 (1H, d, J=14Hz), 3.06-2.85 (2H, m), 2.10-1.82 (2H, m), 1.80-1.66 (2H, m), 1.66-1.52 (3H, m), 1.46 (1H, m), 1.09 (1H, m), 0.86 (3H, d, J=6Hz), 0.81 (3H, t, J=7Hz), MS
(LC/MS) m/z observed 554.94, expected 555.27 [M+H].
A57-2:
11-1 NMR (400 MHz, DMSO-d6) 6 8.81 (1H, bs), 8.13 (1H, bs), 8.10-7.95 (2H, m), 7.21 (1H, d, J=7Hz), 7.16 (1H, t, J=8Hz), 6.99 (1H, t, J=8Hz), 5.15 (1H, d, J=10Hz), 4.49 (1H, dd, J=17, 6Hz), 4.45 (1H, d, J=17, 6Hz), 4.25 (1H, t, J=8Hz), 4.17 (1H, dd, J=14, 5Hz), 3.69 (1H, dd, J=13, 4Hz), 3.58 (1H, dd, J=15, 8Hz), 3.05 (1H, d, J=16Hz), 2.97 (2H, m), 2.00-1.85 (2H, m), 1.85-153 (5H, m), 1.13 (1H, m), 0,87 (3H, d, J=6Hz), 0.82 (3H, t, J=7Hz), MS (LC/MS) m/z observed 554.98, expected 555.27 [M+H].
Examples B1-B7 were prepared by the representative synthetic pathway illustrated schematically in FIGURE 2, (28)-1-{24(2S,3S)-3-METHYL-2-(2-PHENvLAcETAmmo)PENTANAmmo]AcETYLI-N-(1H-1,2,3-TRIAZOL-4-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Title compound B1 was prepared from 1-9 and (1 H41,2,3]triazol-4-yOmethanamine using method G followed by purification by preparative HPLC
(Column:
ASCENTISTm C18, 25 cm x 21.2 mm, 10um, gradient 0%->100% Methanol/water with 0.1% TFA, 10 mL/min) (11 mg, cream-coloured powder). 114 NMR, (300 MHz, DMS0-d6) 6 8.91-8.83 (m, 1H), 8.29-8.02 (m, 2H), 7.74-7.64 (m, 1H), 7.30-7.15 (m, 7H), 7.03-6,97 (m, 1H), 5.15-5.04 (m, 1H), 4.44-4.07 (m, 4H), 3.63-3.02 (m, 5H), 1.90-1.68 (m, 1H), 1.50-1.21 (m, 1H), 1.16-1.01 (m, 1H), 0.85-0.76 (m, 6H). MS (ESI) m/z observed 532.33 observed, expected 532.27 [M+H].

(2S)-1-{2-1(2S,38)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDOJACETYL)-N-(1,2,3-THIADIAZOL-4-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Title compound B2 was prepared from 1-9 and ([1,2,3]thiadiazol-4-yl)methanamine using method G. 1H NMR, (300 MHz, DMSO-d6) 6 9.15-8.96 (m, 1H), 8.26-7.98 (m, 2H), 7.31-7.15 (m, 8H), 7.04-6.94 (m, 1H), 5.19-5.10 (m, 1H), 4.87-4.68 (m, 2H), 4.31-4.22 (m, 1H), 4.18-4.01 (m, 1H), 3.66-3.43 (m, 4H), 3.12-3.02 (m, 1H), 1.82-1.66 (m, 1H), 1.51-1.37 (m, 1H), 1.18-1.03 (m, 1H), 0.89-0.76 (m, 6H). MS
(ES1) nilz observed 583.20, expected 583.19 [M+Cl] and observed 549.20, expected 549.23 [M+H] and observed 571.20, expected 571.21 [M+Na].

(28)-1-12-1(2S,3S)-3-METHYL-2-(2-PHENYLACETAIVIIDO)PENTANAMIDO]ACETYLI-N-[1-(1H-1,2,3-TRIAZOL-4-YL)ETHYL]-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Title compound B3 was prepared from 1-9 and 1-(2H-tetrazol-5-yl)ethanamine using method G as a mixture of diastereomers. 1H NMR, (300 MHz, CD30D) 8 7.35-7,21 (m, 8H), 7.09-7.03 (m, 1H), 5.39-5.32 (m, 1H), 5.17-5.09 (m, 1H), 4.38-4.32 (m, 2H), 3.62-3.58 (m, 3H), 3.26-3.14 (m, 2H), 1.95-1.84 (m, 1H), 1.68-1.61 (m, 3H), 1.59-1.47 (m, 1H), 1.22-1.09 (m, 1H), 0.98-0.86 (m, 6H). MS (ESI) m/z observed 545.48, expected 545.26 [M-H].

(2S)-N-[(4-METHYL-1H-1,2,3-TRIAZOL-5-YOMETHYL]-1-{2-[(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO1ACETYLI-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Title compound B4 was prepared from 1-9 and (4-methy1-1H-[1,2,31triazol-5-yOmethanamine using method C. 1H NMR, (300 MHz, DMSO-d6) 6 8.76 (br s, 1H), 8.20 (br s, 1H), 8.11-8.00 (m, 1H), 7.31-7.15 (m, 8H), 7.03-6.97 (m, 1H), 4.43-4.24 (m, 3H), 4.19-4.05 (m, 1H), 3.61-3.34 (m, 5H), 3.04-2.98 (m, 1H), 2.17 (s, 3H), 1.89-1.69 (m, 111), 1.48-1.19 (m, 2H), 0.85-0.77 (m, 6H). MS (ESI) m/z observed 544.52, expected 544.27 [M-H].

(2S)-1-{2-[(2S,38)-3-METHYL-2-(2-PHENYLAcurAmmo)PENTANAmiDo]AcErvLI-N-(1H-1,2,3-TRIAZOL-4-YLMETHYL)-1,2,3,4-TETRAHYDROQUINOLINE-2-CARBOXAMIDE
Title compound B5 was prepared from 1-8 and 1,2,3,4-tetrahydroquinoline-2-carboxylic acid using method F followed by addition of 1-(1H41,2,3]triazol-4-yl)methanamine using method C, as a mixture of diastereomers. 111 NMR, (300 MHz, acetone-do) 6 7.83 (br s, 1H), 7.61-7.17 (m, 9H), 5.18 (t, 1H), 4.45-4.33 (m, 4H), 3.85-3,76 (m, 1H), 3.67-3.55 (m, 2H), 2.79-2.69 (m, 1H), 2.62-2.45 (m, 2H), 1.96-1.78 (m, 2H), 1.53-1.40 (m, 1H), 1.15-1.04 (m, 1H), 0.88-0.78 (m, 6H). MS (ESI) m/z observed 546.60, expected 546.28 [M-H].

6-METHOXY-1-12-[(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO1ACETYLI-N-(1H-1,2,3-TRIAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Title compound B6 was prepared from 1-8 and 5-methoxy-indoline-2-carboxylic acid methyl ester using method F followed by ester hydrolysis using method D
and finally addition of 1-(1H41,2,31triazol-4-yl)methanamine using method C. 1H
NMR, (300 MHz, DMSO-d6) 6 8.87-8.78 (m, 1H), 8.26-7.98 (m, 2H), 7.74-7.64 (m, 1H), 7.30-7,24 (m, 5H), 7.24-7.16 (m, 1H), 7.12-7.06 (m, 1H), 6.63-6.56 (m, 1H), 5.15-5.06 (m, 1H), 4.44-4.24 (m, 3H), 3.72 (s, 3H), 3.62-3.43 (m, 4H), 3.16 (s, 1H), 3.01-2.92 (m, 1H), 1.90-1.70 (m, 1H), 1.49-1.26 (m, 1H), 1.15-1.02 (m, 1H), 0.85-0.77 (m, 6H). MS
(ESI) nilz observed 560.59, expected 560.26 [M+H].

5-METHYL-1-{2-1(25,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO]ACETYL)-N-(1H-1,2,3-TRIAZOL-4-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Title compound B7 was prepared from 1-8 and 6-methoxy-indoline-2-carboxylic acid ethyl ester using method C followed by ester hydrolysis using method D
and finally addition of 1-(1H41,2,3]triazol-4-yl)methanamine using method C as a mixture of diastereomers. 111 NMR, (300 MHz, CD30D) 8 8.86-8.62 (m, 1H), 8.32-7.93 (m, 2H), 7.68 (m, 1H), 7.37-6.95 (m, 8H), 5.18-5.02 (m, 2H), 4.55-4.44 (m, 3H), 4.38-4.29 (m, I H), 3.70-3.54 (m, 3H), 3.22-3.05 (m, 1H), 2.30 (s, 3H), 2.03-1.84 (m, 1H), 1.60-1.49 (m, 1H), 1.25-1.10 (m, 1H), 0.96-0.86 (m, 6H). MS (ESI) m/z observed 544.53, expected 544.27 [M-H].
Examples C1-C39 were prepared by the representative synthetic pathway illustrated schematically in FIGURE 3.
EXAMPLE Cl (2S)-1-12-[(2S)-3-METHYL-2-(2-PHENYLACETAMIDO)BUTANAMIDOJACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
1-6 (0.5 g, 3.67 mmol) and thionyl chloride (1.6 ml, 22 mmol) were stirred together for 1 hr at room temperature. Thionyl chloride was removed by distillation under vacuum. The acid chloride was added to the stirring solution of L-valine (0.39 g, 3.305 mmol) in NaOH (2N, 4.2 ml) at 0 C. The resulting reaction mixture was warmed to RT and stirred overnight. The mixture was washed with diethyl ether (5 ml) and acidified to pH 4-5 by adding citric acid (aqueous, saturated solution). The precipitated solid was filtered, washed with diethyl ether and dried to yield (S)-3-methyl-2-(2-phenylacetamido)butanoic acid as a white solid (0.64 g, 74%). 111 NMR (400 MHz, DMSO-d6) 6 0.82-0.84 (3H, d, J=8 Hz), 0.85-0.87 (3H, d, J=8 Hz), 1.99-2.06 (1H, m), 3.44-3.55 (2H, q, J=12 Hz), 4.10-4.14 (1H, dd, J=8,12 Hz), 7.16-7.21 (1H, m), 7.24-7.29 (4H, m), 7.19-7.21 (1H, d, J=8 Hz), 12.55 (1H, s), MS (LC/MS) m/z observed 236.04, expected 236.13 [M+H]. The compound was used further as described.
Title compound C1 was prepared from 1-3 and (S)-3-methy1-2-(2-phenylacetamido)butanoic acid using method A: '11 NMR (400 MHz, DMSO-d6) 6 0.81-0.85 (6H, m), 1.94-2.01 (1H, m), 3.04-3.10 (2H, m), 3.42-3.45 (1H, d, J=12 Hz), 3.53-3.58 (3H, m), 4.11-4.15 (1H, d, J=16 Hz), 4.22-4.26 (1H, q, J=12 Hz), 4.37-4.43 (1H, t, J=12 Hz), 4.47-4.54 (111, m), 5.12-5.14 (1H, d, J=8 Hz), 6.96-7.00 (1H, t, J=8 Hz), 7.13-7.21 (3H, m), 7.25-7.26 (4H, d, J=4 Hz), 8.02-8.03 (1H, d, J=4 Hz), 8.05-8.13 (1H, m), 8.26(1H, bs), 8.77(1H, bs), MS (LC/MS) nilz observed 519.01, expected 519.25 [M+H] and observed 541.11, expected 541.23 [M+Na].

(2S)-142-[(2S,3R)-3-HYDROXY-2-(2-PHENYLACETAMIDO)BUTANAMIDO]ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO4H-INDOLE-2-CARBOXAMIDE
1-6 (0.5 g, 3.67 mmol) and thionyl chloride (1.6 ml, 22 mmol) were stirred together for 1 hr at room temperature. Thionyl chloride was removed by distillation under vacuum. The acid chloride was added to the stirring solution of L-threonine (0.39 g, 3.305 mmol) in NaOH (2N, 4.2 ml) at 0 C. The resulting reaction mixture was warmed to RT and stirred overnight. The reaction mixture was washed with diethyl ether (5 ml) and acidified to pH 4-5 by adding citric acid (aqueous, saturated solution). The precipitated solid was filtered, washed with diethyl ether and dried to yield (2S,3R)-3-hydroxy-2-(2-phenylacetamido)butanoic acid as a white solid (0.71 g, 82%). 111 NMR
(400 MHz, DMSO-d6) 8 0.99-1.01 (3H, d, J=8 Hz), 3.49-3.60 (2H, q, J=12 Hz), 4.08-4.13 (1H, m), 4.17-4.20 (1H, dd, J=4,8 Hz), 4.89 (1H,bs), 7.16-7.31 (5H, m), 7.97-7.99 (1H, d, J=8 Hz), 12.42 (1H, bs), MS (LC/MS) m/z observed 238.00, expected 238.11 [M+H]. The compound was used further as described.
Title compound C2 was prepared from 1-3 and (2S,3R)-3-hydroxy-2-(2-phenylacetamido)butanoic acid using method A: 1H NMR (400 MHz, DMSO-d6) 6 1.00-1.02 (3H, d, J=8 Hz), 1.66-1.74 (1H, m), 3.06-3.12 (2H, m), 3.49-3.53 (1H, t, J=8 Hz), 3.55-3.62 (2H, m), 3.98-4.02 (1H, t, J=8 Hz), 4.14-4.18 (1H, d, J=16 Hz), 4.24-4.27 (1H, dd, J=4, 8 Hz), 4.44-4.49 (1H, m), 4.54-4.62 (1H, m), 5.12-5.18 (1H, m), 6.96-7.02 (1H, m), 7.16-7.22(3H, m), 7.26-7.28 (411, q, J=4 Hz), 7.99-8.03 (1H, t, J=8 Hz), 8.08 (1H, bs), 8.99 (1H, bs), MS (LC/MS) m/z observed 521.04, expected 521.23 [M+H]
and observed 543.11, expected 543.21 [M+Na].

(2S)-1-12- R2S,3S)-3-HYDROXY-2-(2-PHENYLACETA MIDO)BUTANA MIDO1ACETYL)-N-(2H-1,2,3,4-T ETRAZOL-5-1' LMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(2S,38)-3-Hydroxy-2-(2-phenylacetamido)butanoic acid was prepared from 1-6 and (2S,3S)-2-amino-4-hydroxybutanoic acid using method H: 1H NMR (400 MHz, DMSO-d6) 6 1.05 (3H, d, J=6.4 Hz), 3.55 (2H, s), 3.85 (1H, m), 4.17 (1H, dd, J=4.0, 8.4 Hz), 4.89 (1H,bs), 7.13-7.30 (5H, m), 8.19 (1H, d, J=8.4 Hz), 12.35 (1H, bs), MS
(LC/MS) m/z observed 237.86, expected 238.11 [M+H]. Compound was used further as described.
Title compound C3 was prepared from (2S,35)-3-hydroxy-2-(2-phenylacetamido)butanoic acid and 1-4 using method A: 1H NMR (400 MHz, DMSO-d6) 6 0.97-1.07 (3H, m), 2.93-3.15 (2H, m), 3.45-3.70 (3H, m), 3.82-3.88 (1H, m), 4.11-4.20 (1H, m), 4.22-4.30 (1H, m), 4.32-4.42 (1H, m), 4.45-4.55 (1H, m), 5.15 (1H, d, J=9.5Hz), 6.97 (1H, t, J=7.4Hz), 7.13-7.30 (7H, m), 7.92-8.28 (3H, m), 8.75 (1H, bs), MS (LC/MS) m/z observed 521.00, expected 521.23 [M+H].

(2S)-1-12- R25)-4-METHYL-2-(2-PHENYLACETAMIDO)PENTAN A MIDOIACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(S)-4-Methyl-2-(2-phenylacetamido)pentanoic acid was prepared from 1-6 and (S)-2-amino-4-methylpentanoic acid using method H: 1H NMR (400 MHz, DMSO-d6) 6 0.85 (3H, d, J=6.4 Hz), 1.05 (3H, d, 1=6.4 Hz), 1.45-1.53 (2H, m), 1.56-1.66 (1H, m), 3.40-3.50 (2H, m), 4.15-4.25 (1H, m), 7.13-7.30 (5H, m), 8.30 (1H, d, J=8.1 Hz), 12.50 (1H, bs), MS (LC/MS) m/z observed 249.98, expected 250.14 [M+H]. Compound was used further as described.
Title compound C4 was prepared from (S)-4-methyl-2-(2-phenylacetamido)pentanoic acid and 1-3 using method A: 1H NMR (400 MHz, DMS0-d6) 8 0.77 (3H, d, J=6.4 Hz), 0.88 (3H, d, J=6.4 Hz), 1.45-1.53 (2H, m), 1.55-1.66 (1H, m), 2.95-3.12 (2H, m), 3.40-3.65 (3H, m), 4.07-4.15 (1H, m), 4.31-4.43 (2H, m), 4.45-4,55 (1H, m), 5.12 (1H, m), 7.01 (1H, t, J=7Hz), 7.15-7.33 (7H, m), 7.97-8.10 (1H, d, J=8Hz), 8.20-8.38 (2H, m), 8.72 (1H, bs), MS (LC/MS) m/z observed 533.00, expected 533.26 [M+H].

(2S)-1-12-R2S)-2-(2-PHENYLACETAMIDO)PENTANAMIDO]ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(S)-2-(2-Phenylacetamido)pentanoic acid was prepared from 1-6 and (S)-2-aminopentanoic acid using method H: 1H NMR (400 MHz, DMSO-d6) 8 0.85 (3H, d, J=7 Hz), 1.25-1.35 (2H, m), 1.52-1.70 (2H, m), 3.42-3.50 (2H, m), 4.13-4.20 (1H, m), 7.15-7.32 (5H, m), 8.30 (1H, d, J=8 Hz), 12.50 (1H, bs), MS (LC/MS) m/z observed 235.97, expected 236.13 [M+H]. The compound was used further as described.
Title compound C5 was prepared from (S)-2-(2-phenylacetamido)pentanoic acid and 1-3 using method A: 1H NMR (400 MHz, DMSO-d6) 8 0.83 (3H, d, J=6.4 Hz), 1.25-1.35 (2H, m), 1.45-1.57 (1H, m), 1.61-1.73 (1H, m), 2.95-3.12 (2H, m), 3.42-3.65 (3H, m), 4.07-4.18 (1H, m), 4.31-4.43 (2H, m), 4.45-4.55 (1H, m), 5.12 (1H, m), 7.01 (1H, t, J=7Hz), 7.15-7.33 (7H, m), 7.97-8.10 (1H, d, J=8Hz), 8.20-8.38 (2H, m), 8.75 (1H, bs), MS (LC/MS) m/z observed 518.99, expected 519.25 [M+H].

(2S)-1-{2-[(2S)-3,3-DimETHYL-2-(2-PHENYLAcETAmmo)BuTANAmiDNACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(S)-3,3-Dimethy1-2-(2-phenylacetamido)butanoic acid was prepared from 1-6 and (S)-2-amino-3,3-dimethylbutanoic acid using method H: 1H NMR (400 MHz, DMS0-d6) 8 0.93 (9H, s), 3.47 (1H, d, J=-14Hz), 3.57 (1H, d, J=14Hz), 4.10 (1H, d, J=9Hz), 7.10-7.22 (1H, m), 7.24-7.32 (4H, m), 8.15 (1H, d, J=9 Hz), 12.58 (1H, bs), MS

(LC/MS) m/z observed 249.96, expected 250.14 [M+H]. The compound was used further as described.
Title compound C6 was prepared from (S)-3,3-dimethy1-2-(2-phenylacetamido)butanoic acid and 1-3 using method A: 111 NMR (400 MHz, DMS0-d6) 6 0.91 (9H, s), 2.95-3.12 (2H, m), 3.40-3.70 (3H, m), 4.07-4.18 (1H, m), 4.28-4.40 (2H, m), 4.45-4.55 (111, m), 5.12 (1H, m), 6.99 (1H, t, J=7Hz), 7.12-7.31 (7H, m), 7.95-8.07 (1H, m), 8.30-8.50 (2H, m), 8.73 (1H, bs), MS (LC/MS) nilz observed 533.03, expected 533.26 [M+H].

(25)-1-{2-[(2S,3R)-3-METHoxv-2-(2-PHENvLAcETAmmo)BuTANAmmo]ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(2S,3R)-3-Methoxy-2-(2-phenylacetamido)butanoie acid was prepared from 1-6 and (2S,3R)-2-amino-3-methoxybutanoic acid using method H: 111 NMR (400 MHz, DMSO-d6) 8 1.01 (3H, d, J=6Hz), 3.34 (3H, s), 3.51 (1H, d, J=14Hz), 3.61 (1H, d, J=14Hz), 3.81-3.85 (1H, m), 4.35 (1H, dd, J=3Hz, 9Hz), 7.16-7.22 (1H, m), 7.24-7.32 (4H, m), 8.17 (1H, d, J=9 Hz), 12.61 (1H, bs), MS (LC/MS) m/z observed 252.01, expected 252.12 [M+H]. The compound was used further as described.
Title compound C7 was prepared from (2S,3R)-3-methoxy-2-(2-phenylacetamido)butanoic acid and 1-4 using method C: 1H NMR (400 MHz, DMS0-d6) 3 1.04 (3H, m), 3.10-3.16 (2H, m), 3.24 (3H, s), 3.45-3.75 (4H, m), 4.11-4.25 (1H, m), 4.37-4.42 (1H, m), 4.50-4.70 (2H, m), 5.15 (1H, d, J=9.5Hz), 6.97 (1H, t, J=7.4Hz), 7.13-7.30 (7H, m), 7.97-8.18 (3H, m), 9.12 (1H, bs), MS (LC/MS) m/z observed 535.04, expected 535.24 [M+H].

(2S)-1-{2-R2S)-3-(TERT-BUTOXY)-2-(2-PHENYLACETAMIDO)PROPANAMIDNACETYL)-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(S)-3-(tert-Butoxy)-2-(2-phenylacetamido)propanoic acid was prepared from 1-6 and (S)-2-amino-3-(tert-butoxy)propanoic acid using method H: 111 NMR (400 MHz, DMSO-d6) 6 1.06 (9H, s), 3.48 (I H, m), 3.49-3.57 (2H, m), 3.63 (1H, dd, J=5Hz, 9Hz), 4.36 (1H, m), 7.16-7.22 (1H, m), 7.24-7.32 (4H, m), 8.15 (I H, d, J=9 Hz), 12.61 (1H, bs), MS (LC/MS) nilz observed 279.86, expected 280.16 [M+H]. The compound was used further as described.
Title compound C8 was prepared from (S)-3-(tert-butoxy)-2-(2-phenylacetamido)propanoic acid and 1-3 using method A: 1H NMR (400 MHz, DMS0-d6) 6 1.08 (9H, ms), 2.93-3.15 (2H, m), 3.43-3.70 (5H, m), 4.11-4.20 (1H, m), 4.30-4.55 (3H, m), 5.15 (1H, m), 6.97 (1H, t, J=7.4Hz), 7.13-7.33 (7H, m), 7.95-8.25 (3H, m), 8.75 (1H, bs), MS (LC/MS) rn/z observed 563.00, expected 563.27 [M+H].

(2S)-1-{2-[(2S,3R)-3-(TERT-Buiroxv)-2-(2-PHENYLACETAMIDO)BUTANAMIDNACETYL)-N-(2H-1,2,3,4-TETRAZOL-5-YLMETFIYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(2S,3R)-3-(tert-Butoxy)-2-(2-phenylacetamido)butanoic acid was prepared from 1-6 and (2S,3R)-2-amino-3-(tert-butoxy)butanoie acid using method H: 1H NMR
(400 MHz, DMSO-d6) 6 1.06 (3H, d, J=6Hz), 1.09 (9H, s), 3.48 (1H, d, J=14Hz), 3.56 (1H, d, J=14Hz), 3.93 (1H, m), 4.33 (1H, dd, J=5Hz, 9Hz), 7.16-7.22 (1H, m), 7.24-7.32 (4H, m), 8.18 (1H, d, J=9 Hz), 12.61 (1H, bs), MS (LC/MS) m/z observed 293.85, expected 294.17 [M+H]. The compound was used further as described.
Title compound C9 was prepared from (2S,3R)-3-(tert-butoxy)-2-(2-phenylacetamido)butanoic acid and 1-4 using method C: 1H NMR (400 MHz, DMS0-d6) 6 1.02 (3H, m), 1.13 (9H, s), 3.10-3.16 (2H, m), 3.50-3.70 (3H, m), 3.88-3.95 (1H, m), 4.11-4.25 (HI, m), 4.30-4.37 (1H, m), 4.47-4.67 (2H, m), 5.15 (IH, d, J=9.5Hz), 6.97 (1H, t, J=7.4Hz), 7.13-7.30 (7H, m), 7.85 (1H, d, J=8Hz), 8.00-8.10 (2H, m), 9.12 (1H, bs), MS (LC/MS) ni/z observed 577.11, expected 577.29 [M+H].

(2,V)-1-{2-[(2S,3S)-3-(TERT-BUTOXY)-2-(2-PHENYLACETAMIDO)BUTANAMIDOJACETYL)-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(2S,3S)-3-(tert-Butoxy)-2-(2-phenylacetamido)butanoic acid was prepared from 1-6 and (25,3S)-2-amino-3-(tert-butoxy)butanoie acid using method H: 1H NMR
(400 MHz, DMSO-d6) 6 1.03 (3H, d, J=6Hz), 1.09 (9H, s), 3.52 (1H, d, J=14Hz), 3.62 (1H, d, J=14Hz), 4.10 (1H, m), 4.27 (1H, dd, J=3Hz, 9Hz), 7.16-7.22 (1H, m), 7.24-7.32 (4H, m), 7.83 (1H, d, J=9 Hz), 12.53 (1H, bs), MS (LC/MS) m/z observed 293.92, expected 294.17 [M+H]. The compound was used further as described.
Title compound C10 was prepared from (2S,35)-3-(tert-butoxy)-2-(2-phenylacetamido)butanoic acid and 1-4 using method C: MS (LC/MS) m/z observed 577.04, expected 577.29 [M+H].

(2S)-1-[(2S)-2-[(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO]PROPANOYL]-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-IN1)OLE-2-CARBOXAMIDE
tert-Butyl ((S)-14(S)-2-(((2H-tetrazol-5-yOmethyl)carbamoypindolin-1-y1)-1-oxopropan-2-y1)carbamate was prepared from 1-2 and (S)-2-((tert-butoxycarbonyl)amino)propanoic acid using method C: MS (LC/MS) m/z observed 415.76, expected 416.20 [M+H], and observed 438.01, expected 438.19 [M+Na], Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C11 was prepared from tert-butyl ((S)-14(S)-2-(((2H-tetrazol-5-yOmethypcarbamoypindolin-1-y1)-1-oxopropan-2-y1)carbamate and (2S,3S)-3-methyl-(2-phenylacetamido)pentanoic acid using method A: 1H NMR (400 MHz, CD30D) 6 0.80-0.88 (6H, m), 1.06-1.13 (1H, m), 1.26-1.28 (3H, d, J=8 Hz), 1.42-1.48 (1H, m), 1.75-1.83 (1H, m), 3.20-3.32 (2H, m), 3.48-3.64 (2H, m), 4.20-4.22 (1H, d, J=8 Hz), 4.37-4.41 (1H, d, J=16 Hz), 4.54-4.58 (1H, d, J=16 Hz), 4.66-4.70 (1H, d, J=16 Hz), 5.49-5.51 (1H, d, J=8 Hz), 7.02-7.05 (1H, t, J=6 Hz), 7.15-7.27 (7H, m), 8.10-8.12 (1H, d, J=8 Hz), MS (LC/MS) m/z observed 546.97, expected 547.28 [M+H].

(2S)-1-[(2R)-2-[(2S,38)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDOPROPANOYLi-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
tert-Butyl ((R)-1-(0)-24(211-tetrazol-5 -yl)methyl)carbamoyl)indol in- 1 -y1)-1-oxopropan-2-yl)carbamate was prepared from 1-2 and (R)-2-((tert-butoxycarbonyl)amino)propanoic acid using method C: MS (LC/MS) m/z observed 415.79, expected 416.20 [M+H], and observed 438.03, expected 438.19 [M+Na], Compound was confirmed using LC/MS and moved to next step as it was.

Title compound C12 was prepared from tert-butyl ((R)-14(S)-2-(((2H-tetrazol-5-yl)methypearbamoypindolin-1-y1)-1-oxopropan-2-y1)carbamate and (28,3S)-3-methyl-2-(2-phenylacetamido)pentanoic acid using method A: 1H NMR (400 MHz, CD30D) 6 0.83-0.91 (6H, m), 1.10-1.13 (1H, m), 1.34-1.36 (3H, d, J=8 Hz), 1.48-1.56 (1H, m), 1.82-1.91 (1H, m), 3.18-3.28 (2H, m), 3.48-3.64 (2H, m), 4.20-4.22 (1H, d, J=8 Hz), 4.36-4.40 (1H, d, J=16 Hz), 4.54-4.58 (1H, d, J=16 Hz), 4.68-4.72 (1H, d, J=16 Hz), 5.50-5.52 (1H, d, J=8 Hz), 7.02-7.06 (1H, t, J=8 Hz), 7.20-7.34 (7H, m), 8.11-8.13 (1H, d, J=8 Hz), MS (LC/MS) m/z observed, 546.99, expected 547.28 [M+H].

(4S)-4-[(2S,38)-3-METHYL-2-(2-PHENYLAcETAmiDo)PENTANAmmo]-5-0x0-5-[(28)-2-1(2H-1,2,3,4-TETRAzOL-5-YLmETHYL)CARBAmoYL1-2,3-DiilYDR0-1H-INDOL-1-YIAPENTANOIC ACID
(S)-tert-Butyl 54(S)-2-(((2H-tetrazol-5-y1)methyl)carbamoyl)indol in-l-y1)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate was prepared from 1-2 and (S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoie acid using method C: MS
(LC/MS) m/z observed 529.83, expected 530.27 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-Ethyl 54(S)-2-(((2H-tetrazol-5-yOmethypearbamoypindolin-1-y1)-4-((2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)-5-oxopentanoate was prepared from (S)-tert-butyl 54(S)-2-(((2H-tetrazol-5-yOmethyl)carbamoyeindolin-1-y1)-4-((tert-butoxycarbonypamino)-5-oxopentanoate and 1-7 using method F: MS (LC/MS) m/z observed 633.02, expected 633.32 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C13 was prepared from (S)-ethyl 5-((S)-2-(((2H-tetrazol-5-yOmethyl)carbamoypindolin-1-y1)-4-((2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)-5-oxopentanoate using method D: 111 NMR (400 MHz, DMSO-d6) 6 0.74-0.81 (6H,m), 1.01-1.05 (1H, m), 1.20-1.27 (1H, m), 1.70-1.81 (2H, m), 2.25-2.31 (1H, m), 3.11-3.19 (1H, t, J=16 Hz), 3.36-3.61 (4H, m), 4.19-4.25 (1H, m), 4.32-4.38 (1H, m), 4.42-4.48 (1H, dd, J=8, 16 Hz), 4.54-4.60 (1H, dd, J=8, 16 Hz), 4.62-4.68 (1H, dd, J=8, 16 Hz), 5.17-5.20 (1H, d, J=12 Hz) 6.99-7.03 (1H, t, J=8 Hz), 7.15-7.26 (6H, m), 7.99-8.07(2H, m), 8.81 (11-1, bs), 8.98 (1H, bs), MS (LC/MS) m/z observed 604.97, expected 605.28 [M+H].

(3S)-3-[(2S,3S)-3-METHYL-2-(2-PHENvLAcETAmmo)PENTANAmmo]-4-0x0-4-[(2S)-2-[(2H-1,2,3,4-TETRAzoL-5-vLmETHvOcARBAmovL1-2,3-DIHYDR0-1H-INDOL-1-vidBUTANOIC ACID
(S)-tert-Butyl 44(S)-2-(((2H-tetrazol-5-yl)m ethy 1)carbamoyl)indo I in-1 -y1)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoate was prepared from 1-2 and (S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid using method C: MS
(LC/MS) m/z observed 515.74, expected 516.26 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-Ethyl 4-(0)-2-(((2H-tetrazol-5-yl)methyl)carbamoypindolin-1-y1)-3-((2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)-4-oxobutanoate was prepared from (S)-tert-butyl 4-((S)-2-(((2H-tetrazol-5-yl)methyl)carbam oyl)indo lin-1 -yI)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoate and 1-7 using method F: MS (LC/MS) m/z observed 618.93, expected 619.30 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C14 was prepared from (S)-ethyl 44(S)-2-(((2H-tetrazol-5-yl)methypcarbamoypindolin-1-y1)-3-((2S,35)-3-methyl-2-(2-phenylacetamido)pentanamido)-4-oxobutanoate using method D: 1H NMR (400 MHz, DMSO-d6) 6 0.68-0.78 (6H,m), 0.95-1.04 (1H, m), 1.22-1.29 (1H, m), 1.66-1.73 (1H, m), 2.55-2.64 (2H, m), 3.15-3.19 (1H, d, J=16 Hz), 3.38-3.42 (1H, d, J=16 Hz), 3.48-3.56 (2H, t, J=16 Hz), 4.29-4.31 (1H, t, J=16 Hz), 4.39-4.44 (1H, dd, J=4, 16 Hz), 4.57-4.66 (2H, dt, J=4, 16 Hz), 5.61-5.63 (1H, d, J=8 Hz), 7.00-7.04 (1H, t, J=8 Hz), 7.14-7.25 (6H, m), 7.96-7.98 (1H, d, 1=8 Hz), 8.04-8.06 (1H, d, J=8 Hz), 8.75 (1H, bs), 9.07 (1H, bs), MS (LC/MS) m/z observed 590.97, expected 591.27 [M+H] and observed 613.05, expected 613.25 [M+Na].

(3R)-3-[(2S,3S)-3-METHYL-2-(2-PHENvLAcErAmiDo)PENTANAm wo]-4-oxo-4-[(2S)-2-[(2H-1,2,374-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YIABUTANOIC ACID

(R)-tert-B uty I 4-((S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)indolin-l-y1)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoate was prepared from 1-2 and (R)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid using method C: MS
(LC/MS) nilz observed 515.77, expected 516.26 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(R)-Ethyl 44(S)-2-(((2H-tetrazol-5-yOmethyl)carbamoypindolin-1-y1)-3-((2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)-4-oxobutanoate was prepared from (R)-tert-butyl 44(S)-2-(((2H-tetrazol-5-yOmethyl)carbamoyl)indolin-l-y1)-3 -((tert-butoxycarbonyl)amino)-4-oxobutanoate and 1-7 using method F: MS (LC/MS) m/z observed 618.94, expected 619.30 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C15 was prepared from (R)-ethyl 44(S)-2-4(2H-tetrazol-5-yOmethyl)carbamoyl)indolin-1-y1)-34(2S,3S)-3-methyl-2-(2-phenylacetamido)pentanarnido)-4-oxobutanoate using method D: 1H NMR (400 MHz, DMSO-d6) 6 0.66-0.76 (6H,m), 0.96-1.05 (1H, m), 1.32-1.37 (1H, m), 1.60-1.66 (1H, m), 2.57-2.63 (2H, m), 3.13-3.17 (1H, t, J=8 Hz), 3.37-3.40 (1H, d, .J=12 Hz), 3.46-3.52 (2H, t, J=12 Hz), 4.16-4.20 (1H, t, J=8 Hz), 4.39-4.42 (1H, d, J=12 Hz), 4.60-4.65 (2H, m), 5.60-5.63 (1H, d, J=12 Hz), 7.00-7.04 (1H, t, J=8 Hz), 7.14-7.23 (6H, m), 8.04-8.08 (1H, t, J=8 Hz), 8.04-8.06 (1H, d, J=8 Hz), 8.80 (1H, bs), 9.02 (1H, bs), MS
(LC/MS) m/z observed 590.95, expected 591.27 [M+H] and observed 613.08, expected 613.25 [M+Na].

(4R)-4-R2S,38)-3-METHYL-2-(2-PHENYLACETAMIDOPENTANAMID01-5-oxo-5-[(2S)-2-[(2H-1,2,3,4-TETRAzoL-5-YLmETHyL)cARBAmoyi]-2,3-DmvpRo-1H-INDoL-1-)(LI PENTANOIC ACID
(R)-tert-Butyl 54(S)-2-(((2H-tetrazol-5-yl)methypcarbamoyl)indol in-l-y1)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate was prepared from 1-2 and (R)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid using method C: MS
(LC/MS) ni/z observed 529.86, expected 530.27 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(R)-Ethyl 54(5)-2-(((2H-tetrazol-5-yl)methyl)carbamoypindolin-1-y1)-44(2S,3S)-3 -methyl-2-(2-pheny lacetamido)pentanam ido)-5-oxopentanoate was prepared from (R)-tert-butyl 54(S)-2-(((2H-tetrazol-5-yl)methypcarbamoypindolin-1-y1)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate and 1-7 using method F: MS (LC/MS) m/z observed 633.01, expected 633.32 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C16 was prepared from (R)-ethyl 54(S)-2-(((2H-tetrazol-5-yOmethypdarbamoypindolin-1-y1)-44(2S,3S)-3-methy1-2-(2-phenylacetamido)pentanamido)-5-oxopentanoate using method D: 111 NMR (400 MHz, DMSO-d6) 8 0.75-0.82 (6H,m), 1.00-1.05 (1H, m), 1.21-1.27 (1H, m), 1.73-1.83 (2H, m), 2.27-2.33 (1H, m), 3.12-3.20 (1H, t, ./=16 Hz), 3.36-3.61 (4H, m), 4.20-4.24 (1H, t, J=8 Hz), 4.32-4.36 (1H, t, J=8 Hz), 4.42-4.48 (1H, dd, J=8, 16 Hz), 4.54-4.60 (1H, dd, J=8, 16 Hz), 4.62-4.68 (1H, dd, J=8, 16 Hz), 5.17-5.20 (1H, d, J=12 Hz) 6.99-7.03 (1H, t, J=8 Hz), 7.12-7.26 (6H, m), 7.99-8.07(2H, m), 8.80 (1H, bs), 9.02 (1H, bs), MS

(LC/MS) nilz observed 604.95, expected 605.28 [M+H] and observed 627.08, expected 627.27 [M+Na].

(5S)-5-[(2S,3S)-3-METHYL-2-(2-PHENviAcETAmmo)PENTANAmipol-6-oxo-6-[(2S)-2-R2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOY11-2,3-DIHYDRO-1H-INDOL-1-YLDIEXANOIC ACID
(S)-tert-Butyl 64(S)-2-4(2H-tetrazol-5-yl)methyl)carbamoyl)indolin-l-y1)-5-((tert-butoxycarbonyl)amino)-6-oxohexanoate was prepared from 1-2 and (S)-6-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-6-oxohexanoic acid using method C: MS
(LC/MS) m/z observed 543.87, expected 544.29 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-Ethyl 64(S)-2-(((2H-tetrazol-5-yl)m ethy Dcarbamoy Dindo 1 in-l-y1)-5-((2S,3S)-3-methy1-2-(2-phenylacetamido)pentanamido)-6-oxohexanoate was prepared from (S)-tert-butyl 64(S)-2-(((2H-tetrazol-5-yl)methyl)carbamoypindolin-1-y1)-5-((tert-butoxycarbonyl)amino)-6-oxohexanoate and 1-7 using method F: MS (LC/MS) m/z observed 647.01, expected 647.33 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C17 was prepared from (S)-ethyl 6-((S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)indolin-1-y1)-5-((2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)-6-oxohexanoate using method D: 111 NMR (400 MHz, DMSO-d6) 6 0.68-0.83 (6H, m), 0.95-1.08 (1H, m), 1.16-1.25 (1H, m), 1.30-1.40 (1H, m), 1.45-1.80 (4H, m), 2.00-2.25 (2H, m), 3.10-3.55 (4H, m), 4.18 (1H, bs), 4.35 (1H, dd, ,I= 6Hz, 9Hz), 4.50 (1H, m), 4.65 (1H, dd, J=6Hz, 16Hz), 5.56 (1H, dd, J=3Hz, 12 Hz), 6.93-7.02 (1H, m), 7.10-7.25 (7H, m), 7.90 (1H, d, J=9 Hz), 8.05 (1H, d, J=8 Hz), 8.52 (1H, d, J=7Hz 9.10 (1H, bs), MS (LC/MS) m/z observed 618.98, expected 619.30 [M+H].

(2S)-1-R2S)-6-AMINO-2-[(2S,35)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO1HEXANOY*N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
(S)-(5-Allyloxycarbonylamino-1- {(S)-2-[(2H-tetrazol-5-ylmethyl)-carbamoy 1] -2,3-dihydro-indole-1-carbonyl}-penty1)-carbamic acid tert-butyl ester was prepared from 1-2 and (S)-6-(((al lyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate dicyclohexylammonium salt using method C: MS (LC/MS) m/z observed 556.86, expected 557.28 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-146-(1 -Allyloxy-v inylamino)-((S)-24(2S,3S)-3-methy1-2-(2-phenylacetamido)pentanamido)hexanoylkindoline-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide was prepared from (S)-(5-allyloxycarbonylamino-1-{(S)-2-[(2H-tetrazol-5-ylmethyl)-carbamoy1]-2,3-dihydro-indole-1-carbonyl} -penty1)-carbamic acid tert-butyl ester and 1-7 using method A: MS (LC/MS) m/z observed 688.04, expected 688.36 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
To a stirred solution of (S)-1-[6-(1-allyloxy-vinylamino)-((S)-2-((2S,3S)-3-methy1-2-(2-phenylacetamido)pentanamido)hexanoy1)]-indoline-2-carboxylic acid (2H-tetrazol-5-ylmethyl)-amide (0.145 mmol) and palladium on charcoal (10%, 10 mg) in methanol (2 mL), was added triethylsilane (145 mmol, 10 equivalents) under nitrogen.
The reaction mixture was stirred at RT for 1 hr then concentrated to give a residue that was purified by reverse phase column chromatography to give the title compound C18.
(1.5 mg): MS (LC/MS) m/z observed 604.24, expected 604.34 [M+H].

TERT-BUTYL N-R2S)-1-{2-[(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDOJACETYLI-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-6-YL] CARBA MATE
Title compound C19 was prepared from 1-12 and (2H-tetrazol-5-yOmethyl-amine using general method L. 11-1 NMR (400 MHz, CD30D) 6 0.88-0.98 (6H, m), 1.14-1.22 (1H, m), 1.30-1.41 (1H, m), 1.52 (9H, s), 1.87-2.01 (1h, m), 3.12-3.21 (1H, m), 3.59-3.69 (2H, m), 3.84-3.92 (1H, t, J=16 Hz), 4.16-4.24 (1H, t, J=16 Hz), 4.34-4.36 (1H, d, J=8 Hz), 4.51-4.53 (1H, d, J=8 Hz), 4.63-4.72 (2H, m), 5.15-5.17 (1H, d, J=8 Hz), 7.06-7.15 (2H, m), 7.18-7.22 (1H, m), 7.20-7.27 (1H, m), 7.29-7.34 (4H, m), 7.55 (1H, bs), 8.21 (1H, bs), 8.91 (1H, bs) MS (LC/MS) m/z observed 648.13, expected 648.32 [M+H]

(2S)-6-AMINO-1-{2-[(2S,38)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO]ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Title compound C20 was prepared from C19 using general method E. 1H NMR
(400 MHz, CD30D) 6 0.76-0.85 (6H, m), 1.05-1.10 (1H, m), 1.30-1.42 (1H, m), 1.72-1,86 (1H, m), 3.13-3.17 (1H, d, J=16 Hz), 3.39-3.47 (2H, m), 3.54-3.71 (3H, m), 4.10-4,15 (1H, dd, J=16, 4 Hz), 4.19-4.26 (1H, m), 4.38-4.41 (1H, dd, J=8, 4 Hz), 4.53-4.69 (2H, m), 5.23-5.26 (1H, d, J=12 Hz), 6.96-6.98 (1H, d, J=8 Hz), 7.21-7.29 (5H, m), 8.01-8.12 (2H, m), 8.27-8.33 (1H, m), 9.17-9.22 (1H, m), 10.01 (1H, bs) MS (LC/MS) m/z observed 548.12, expected 548.32 [M+H]

(25)-6-(BENzviAmiN0)-1-{2-1(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO]ACETYL)-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
A solution of compound C20 (0.025 g, 0.0385 mmol), DIPEA (0.032 ml, 0.23 mmol) and benzyl bromide (0.015 ml, 0.116 mol) in DCM (4 ml) was sealed in a microwave tube and heated to 70 C for 10 hr. by microwave irradiation. The reaction mixture was concentrated to dryness and dried well under vacuum to give the crude product, which was purified on preparative HPLC using 0-80% Me0H in water to yield product as an off-white solid 0.0022 g (9%). MS (LC/MS) m/z observed 638.11, expected 638.31 [M+H]. Compound was confirmed using LC/MS and used as directed.

3- {[(2S)-1- {2- [(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDNACETYLI-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-6-YIACARBAMOYLIPROPANOIC ACID
Title compound C22 was prepared from C19 and succinic anhydride using method B: 1H NMR (400 MHz, DMSO-d6) 6 0.78-0.87 (6H, m), 1.06-1.13 (1H, m), 1.30-1.42 (1H, m), 1.75-1.86 (1H, m), 3.03-3.07 (1H, d, J=16 Hz), 3.44-3.61 (5H, m), 4.09-4.19 (1H, m), 4.23-4.27 (1H, t, J=8 Hz), 4.40-4.44 (1H, t, J=8 Hz), 4.48-4.61 (2H, m), 5.14-5.17 (1H, d, J=12 Hz), 7.09-7.11 (1H, d, J=8 Hz), 7.18-7.22 (1H, m), 7.25-7.31 (4H, m), 7.40-7.44 (1H, t, J=8 Hz), 8.04-8.06 (1H, d, J=8 Hz), 8.12-8.14 (1H, t, J=8 Hz), 8.22 (1H, bs), 8.28-8.32 (1H, t, J=8 Hz), 8.95 (1H, bs), 9.96 (1H, s) 12.10 (1H, bs) MS
(LC/MS) m/z observed 648.12, expected 648.28 [M+H]

3-{[(S)-({2-0xo-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOVL1-2,3-DIHYDRO-1H-INDOL-1-YLIETHYL}CARBAMOYLYTHIOPHEN-3-(S)-2-((tert-Butoxycarbonyl)amino)-2-(thiophen-3-yl)acetic acid was prepared from (S)-2-amino-2-(thiophen-3-yl)acetic acid using general method K. MS
(LC/MS) nilz observed 279.92, expected 280.07 [M+Na]. Compound was confirmed using LC/MS
and moved to next step as it was.
(S)-Ethyl 1-(2-((S)-2-((tert-butoxycarbonyl)amino)-2-(thiophen-3-yl)acetamido)acetyl)indoline-2-carboxylate was prepared from 1-10 and (R)-2-((tert-butoxycarbonyl)amino)-2-(thiophen-3-yl)acetie acid using general method A. The purification was performed by column chromatography on silica gel using 0 % to 50 %
ethyl acetate in hexanes as the eluent. MS (LC/MS) m/z observed 487.84, expected 488.18 [M+H], observed 510.06, expected 510.18 [M+Na]. Compound was confirmed using LC/MS and moved to next step as it was.
tert-Butyl ((S)-24(24(S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)indolin-1-y1)-oxoethyl)amino)-2-oxo-1-(thiophen-3-yl)ethyl)carbamate was prepared from (S)-ethyl 1-(2-((R)-2-((tert-butoxycarbonyl)amino)-2-(thiophen-3 -yl)acetam ido)acetyl)indol ine-2-carboxy late and (2H-tetrazol-5-yl)methyl-amine using general method L. MS
(LC/MS) m/z observed 541.02, expected 541.19 [M+H]. Compound was confirmed using LC/MS

and moved to next step as it was.
Title compound C23 was prepared from tert-butyl ((S)-24(24(S)-2-(((2H-tetrazol-5-yOmethypcarbamoypindol in-1 -y1)-2-oxoethyl)amino)-2-oxo-1-(th iophen-3-yl)ethyl)carbamate and succinic anhydride using method I: 1H NMR (400 MHz, DMSO-d6) 5 2.39-2.48 (2H, m), 3.12-3.16 (2H, d, J=16 Hz), 3.58-3.66 (3H, t, J=16 Hz), 4.20-4.24 (1H, d, J=16 Hz), 4.55-4.59 (1H, m), 4.62-4.69 (1H, m), 5.15-5.18 (I H, d, J=12 Hz), 5.64-5.68 (1H, t, J=8 Hz), 7.00-7.04 (1H, t, J=8 Hz), 7.18-7.22 (3H, m), 7.48-7.52 (2H, m), 8.04-8.06 (1H, d, J=8 Hz), 8.53-8.55 (1H, d, J=8 Hz), 8.61-8.64 (1H, m), 9.10 (1H, bs), MS (LC/MS) m/z observed 541.03, expected 541.15 [M+H]

3-{[(R)-({2-0x0-2-[(2S)-2-[(2H-1 ,2,3,4-TETRAzoL-5-viLmETHYL)cARBAmovL]-2,3-D IHYDRO-1H-INDOL- 1 -YLI ETHYL} CARBAMOYL)(THIOPHEN-2-YL)METHYL] CARBAMOYLIPROPANOIC ACID
(R)-2-((tert-Butoxycarbonyl)amino)-2-(thiophen-2-yDacetic acid was prepared from (R)-2-amino-2-(thiophen-2-yl)acetic acid using general method K. MS
(LC/MS) m/z observed 279.92, expected 280.07 [M+Na]. Compound was confirmed using LC/MS
and moved to next step as it was.
(S)-Ethyl 1-(24(R)-2-((tert-butoxycarbonypamino)-2-(thiophen-yl)acetamido)acetyl)indoline-2-carboxylate was prepared from 1-10 and (R)-2-((tert-butoxycarbonyl)amino)-2-(thiophen-2-yl)acetic acid using general method A. The purification was performed on normal phase using 0 % to 50 % ethyl acetate in hexanes as the eluent. MS (LC/MS) m/z observed 487.89, expected 488.18 [M+H], observed 510.06, expected 510.18 [M+Na]. Compound was confirmed using LC/MS and moved to next step as it was.
tert-Butyl ((S)-24(2-((S)-2-(((2H-tetrazol-5-yl)methypearbamoyl)indol in-l-y1)-oxoethyDamino)-2-oxo-1-(thiophen-2-ypethypcarbamate was prepared from (S)-ethyl 1-(2-((R)-2-((tert-butoxycarbonyl)amino)-2-(thiophen-2-y 1)acetamido)acetyl)indol ine-2-carboxylate and (2H-tetrazol-5-yl)methyl-amine using general method L. MS
(LC/MS) nilz observed 541.04, expected 541.19 [M+H]. Compound was confirmed using LC/MS
and moved to next step as it was.
Title compound C24 was prepared from tert-butyl ((S)-24(24(S)-2-(((2H-tetrazol-5-yl)methyl)carbamoypindolin-1-y1)-2-oxoethypamino)-2-oxo-1-(thiophen-ypethyl)carbamate and succinic anhydride using method I: 1H NMR (400 MHz, DMSO-d6) a 2.41-2.45 (2H, m), 3.10-3.14 (2H, d, J=16 Hz), 3.56-3.64 (3H, t, J=16 Hz), 4.19-4.23 (1H, d, J=16 Hz), 4.52-4.62 (2H, m), 5.14-5.17 (1H, d, J=12 Hz), 5.80-5.84 (1H, t, J=8 Hz), 6.95-6.98 (1H, m), 7.18-7.22 (3H, m), 6.99-7.01(1H, d, J=8 Hz), 7.13-7.18 (2H, m), 7.20-7.22 (1H, d, J=8 Hz), 7.40-7.42 (1H, d, J=8 Hz), 8.01-8.03 (1H, d, J=8 Hz), 8.62-8.64 (2H, d, J=8 Hz), 9.04 (1H, bs), MS (LC/MS) m/z observed 541.01, expected 541.15 [M+H]

4-0xo-4-[(2S)-2-({2-oxo-2-[(2S)-2-[(2H-1,2,3,4-TETRAzoL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-(S)-1-(tert-Butoxycarbonyl)piperidine-2-carboxylic acid was prepared from (S)-piperidine-2-carboxylic acid using general method K. MS (LC/MS) m/z observed 251.99, expected 252.13 [M+Na]. Compound was confirmed using LC/MS and moved to next step as it was.
1- {2-[(1-tert-Butoxycarbonyl-piperidine-(2S)-2-carbonyl)-am inol-acetyl -(25)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester was prepared from I-10 and (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid using general method A. The purification was performed by column chromatography on silica gel using 0 % to 50 %
ethyl acetate in hexanes as the eluent. MS (LC/MS) m/z observed 459.96, expected 460.24 [M+H] observed 482.16, expected 482.24 [M+Na]. Compound was confirmed using LC/MS and moved to next step as it was.
(2S)-2-(2-0xo-2-1(2S)-2-[(2H-tetrazol-5-ylmethyl)-carbamoyl]-2,3-dihydro-indo1-1-y1l-ethylcarbamoy1)-piperidine-1-carboxylic acid tert-butyl ester was prepared from 1-{2-[(1-tert-butoxycarbonyl-piperidine-(25)-2-carbonyl)-amino]-acetyll-(2S)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester and (2H-tetrazol-5-yl)methyl-amine using general method L. MS (LC/MS) m/z observed 513.08, expected 513.25 [M+H].

Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C25 was prepared from (25)-2-(2-oxo-2-{(25)-2-[(2H-tetrazol-5-ylmethyl)-carbamoy1]-2,3-dihydro-indo1-1-y1) -ethyl carbamoyI)-p iperidine-l-carboxyl ic acid tert-butyl ester and succinic anhydride using method I: NMR (400 MHz, DMSO-d6) El 1.32-1.40 (2H, m), 1.55-1.64 (2H, m), 3.56-3.64 (3H, t, J=16 Hz), 2.19-2.22 (1H, d, J=12 Hz), 2.39-2.47 (2H, m), 2.60-2.64 (2H, t, J=8 Hz), 3.12-3.16 (1H, d, J=16 Hz), 3.79-3.83 (2H, d, J=16 Hz), 4.18-4.26 (1H, m), 4.32-4.35 (1H, d, J=12 Hz), 4.53-4.56 (2H, m), 5.10 (1H, s), 5.16-5.19 (1H, d, J=12 Hz), 6.99-7.03 (1H, t, J=8 Hz), 7.15-7.19 (1H, t, J=8 Hz), 7.22-7.24 (1H, d, J=8 Hz), 7.99-8.04 (2H, m), 9.09 (1H, bs), MS (LC/MS) m/z observed 512.99, expected 513.21 [M+H]

(2S)-1-12-[(2S,3S)-3-METHYL-2-[(1'YRimiDiN-2-YL)AmiNo]PENTANAMIDOlACETYLI-N-(2H-1,2,3,4-TETRAzoL-5-vimEmvL)-2,3-DitivDR0-1H-IND0LE-2-cARBoxAmiDE
(25)-Ethyl 1 -(24(2S,35)-2-((tert-butoxycarbonyl)am ino)-3-methylpentanam ido)acety pindoline-2-carboxyl ate was prepared from 1-10 and Boc-L-isoleucine using method A. MS (LC/MS) rrilz observed 461.98, expected 462.26 [M+H].
Compound was confirmed using LC/MS and moved to next step as it was.
(2S)-142-((2S,35)-2-Amino-3-methyl-pentanoylamino)-acety11-2,3-dihyd ro-1H-indole-2-carboxylic acid ethyl ester hydrochloride was prepared from (2S)-ethyl 1-(2-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-methylpentanamido)acetyl)indol ine-2-carboxylate using method E. MS (LC/MS) m/z observed 362.08, expected 362.20 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
A solution of (2S)-1424(2S,3S)-2-amino-3-methyl-pentanoylamino)-acety1]-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester hydrochloride (0.3 g, 0.7537 mmol), DIPEA (0.46 ml, 2.638 mmol) and 2-chloropyrimidine (0.18 g, 1.131 mol) in ACN
(9 ml) was sealed in a microwave tube and heated to 130 C for 16 hrs by microwave irradiation.
The reaction mixture was concentrated to dryness and dried well under vacuum to give the crude product, which was purified by column chromatography on silica gel to get the pure product, (25)-1- { 2-[(S)-3-Methyl-(S)-2-(pyrim idin-2-ylam ino)-pentanoylam ino]-acety1}-2,3-dihydro-IH-indole-2-carboxylic acid ethyl ester, as off-white solid, 0.07 g (21%).. MS (LC/MS) ni/z observed 440.10, expected 440.22 [M+H]. Compound was confirmed using LC/MS and moved to next step as is.
Title compound C26 was prepared from (25)-1-{2-[(S)-3-Methyl-(S)-2-(pyrimidin-2-ylamino)-pentanoylaminoFacety11-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester and (2H-tetrazol-5-yl)methyl-amine using general method L. 1H
NMR
(400 MHz, DMSO-d6) 5 0.82-0.86 (3H, t, J=8 Hz), 0.92-0.94 (3H, d, J=8 Hz), 1.16-1.25 (1H, m), 1.50-1.58 (1H, m), 1.84-1.92 (1H, m), 3.11-3.15 (2H, d, J=16 Hz), 3.52-3.60 (2H, m), 4.15-4.19 (1H, d, J=16 Hz), 4.37-4.41 (1H, t, J=8 Hz), 4.50-4.54 (1H, d, J=16 Hz), 4.62-4.66 (1H, d, J=16 Hz), 5.14-5.17 (1H, d, J=16 Hz), 6.60-6.62 (1h, t, J=4 Hz), 6.92-6.94 (1H, d, J=8 Hz), 6.98-7.02 (1H, t, J=8 Hz), 7.14-7.18 (1H, t, J=8 Hz), 7.21-7.23 (1H, d, J=8 Hz), 8.00-8.02 (1H, d, J=8 Hz), 8.14(1H, bs), 8.27-8.29(2H, d, j=8 Hz), 9.05 (1H, bs), MS (LC/MS) m/z observed 493.14, expected 493.23 [M+H].

(28)-6-Ac ETAMIDO- 1- {21(2S,38)-3-METII YL-2-(2-PHENYLACETAMIDO)PENTANAMIDO] A CETYL}-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHY L)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Acetic acid (0.3 g, 4.854 mmol), EDC (1.02 g, 5.339 mmol), HOBt (0.74 g, 4.854 mmol), DIPEA (2.5 ml, 14.560 mmol) and 1-11 (1 g, 4.845 mmol) were stirred in anhydrous DCM (100 ml) for 16 hrs. The reaction mixture was concentrated under vacuum to give the crude product, which was purified by column chromatography on silica gel using 0 % to 50 % ethyl acetate in hexanes as the eluent to give (S)-ethyl 6-acetamidoindoline-2-carboxylate as a pale yellow solid (72%). 1H NMR (400 MHz, CDC13) 6 1.27-1.31 (3H, t, J=8 Hz), 2.12 (3H, s), 3.32-3.37 (2H, m), 4.17-4.23 (2H, q, J=8 Hz), 4.35-4.38 (1H, q, J=4 Hz), 4.51 (1H, s), 6.71-6.73 (1H, d, J=8 Hz), 6.97-6.99 (1H, d, .1=8 Hz), 7.05 (1H, s), 7.47 (1H, s), MS (LC/MS) m/z observed 249.07, expected 249.12[M+H].
(S)-Ethyl 6-acetamido-1-(2-((tert-butoxycarbonypamino)acetyl)indoline-2-carboxylate was prepared from (S)-ethyl 6-acetamidoindoline-2-carboxylate and Boc-glycine using method C and purified by column chromatography on silica gel using 0 %
to 80 % ethyl acetate in hexanes as the eluent to give (S)-ethyl 6-acetamido-1-(2-((tert-butoxycarbonyl)amino)acetyl)indoline-2-carboxylate, as an off-white solid (62%). MS
(LC/MS) m/z observed 405.86, expected 406.19[M+H], observed 428.10, expected 428,19[M+Na], Compound was confirmed using LC/MS and moved to next step as it was.
(S)-Ethyl 6-acetamido-1-(24(2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)acetyl)indoline-2-carboxylate was prepared from the intermediate (S)-ethyl 6-acetamido-1-(2-((tert-butoxycarbonypamino)acetypindoline-2-carboxylate and 1-7 using method A. MS (LC/MS) m/z observed 537.03, expected 537.26 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.

Title compound C27 was prepared from (S)-ethyl 6-acetamido-1-(24(2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)acetypindol ine-2-carboxylate and (2H-tetrazol-5-yl)methyl-amine using general method L. 1H NMR (400 MHz, DMSO-d6) 8 0.78-0.86 (6H, m), 1.06-1.13 (1H, m), 1.29-1.44 (1H, m), 1.75-1.86 (1H, m), 2.01 (3H, s), 3.05-3.09 (2H, d, J=16 Hz), 3.43-3.61 (4H, m), 4.09-4.13 (1H, d, J=16 Hz), 4.19-4.28 (1H, m), 4.38-4.44 (1H, m), 4.51-4.59 (2H, m), 5.15-5.18 (1H, d, J=8 Hz), 7.09-7.11 (1H, d, J=8 Hz), 7.18-7.22 (1H, m), 7.27-7.31 (3H, m), 7.40-7.44 (1H, t, J=8 Hz), 8.02-8.04 (1H, d, J=8 Hz), 8.15-8.23 (1H, m), 8.26-8.31 (1H, m), 9.04 (1H, bs), 9.93 (1H, bs), MS
(LC/MS) ni/z observed 590.15, expected 590.28 [M+H], rn/z observed 612.28, expected 612.28 [M+Na].

4-0xo-4-[(2S)-2-({2-oxo-2-[(2S)-2-[(2H-1,2,3,4-TETRAzoL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-1-YLIETHYL}CARBAMOYLPYRROLIDIN-1-YOBUTANOIC ACID
1- {2- [(1-tert-Butoxycarbonyl -pyrrolidine-(2S)-2-carbonyl)-aminol-acetyl} -(2S)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester was prepared from 1-10 and Boc-L-proline using method A. MS (LC/MS) m/z observed 445.94, expected 446.23 [M+H].

Compound was confirmed using LC/MS and moved to next step as it was.
1 - {2-[(1 -tert-B utoxycarbonyl -pyrrolidine-(2S)-2-carbonyl)-am inoFacetyl -(2S)-2,3-dihydro-1H-indole-2-carboxylic acid was prepared from 1-{2-[(1-tert-butoxycarbonyl-pyrrolidine-(2S)-2-carbony1)-aminol-acetyll-(2S)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester using method D with 2 eq. of LiOH H20. MS

(LC/MS) m/z observed 417.90, expected 418.20 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-tert-Butyl 24(2-((S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyDindolin-1-y1)-2-oxoethypcarbamoyl)pyrrolidine-1-carboxylate was prepared from 1-{2-[(1-tert-butoxycarbonyl-pyrrol id ine-(2S)-2-carbonyl)-aminol-acetyl } -(2S)-2,3-d i hydro-1H-in dole-2-carboxyl ic acid and 2H-tetrazol-5-yl)methyl-amine using method A in DMF but without HC1 treatment. MS (LC/MS) m/z observed 498.94, expected 499.24 [M+H].
Compound was confirmed using LC/MS and moved to next step as it was.

Title compound C28 was prepared from (S)-tert-butyl 2-((2-((S)-2-(((2H-tetrazol-5-yl)methyl)carbamoyl)indolin-1-y1)-2-oxoethyl)carbamoyl)pyrrolidine-1-carboxylate and succinic anhydride using method I. 1H NMR (400 MHz, DMSO-d6) 8 1.86-1.91 (2H, m), 1.95-2.05 (2H, m), 2.40-2.65 (4H, m), 3.11 (1H, m), 3.36 (1H, m), 3.46 (1H, m), 3.63 (1H, m), 4.15 (1H, dd, Jr=6, 17 Hz), 4.32 (1H, d, J=7Hz), 4.48 (1H, dd, ../=3, 9Hz), 4.56 (1H, m), 4.65 (1H, m), 5.17 (1H, d, J=11Hz), 7.01 (1H, t, J=8Hz), 7.12-7-25 (2H, m), 8.00-8.10 (2H, m), 9.08 (1H, bs), MS (LC/MS) m/z observed 499.11, expected 499.21 [M+H]

3-{[1 -([2-0X0-2-[(2S)-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-ladETHYL}CARBAMOYLICYCLOPENTYLICARBAMOYLIPROPANOIC ACID
1- {2-[(1-tert-Butoxycarbonylamino-cyclopentanecarbony l)-amino]-acetyl -(2S)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester was prepared from 1-10 and Boc-L-cycloleucine using method A. MS (LC/MS) m/z observed 459.95, expected 460.24 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
1- {2-[(1-tert-Butoxycarbonylamino-cyclopentanecarbony1)-amino]-acetyll 2,3-dihydro-1H-indole-2-carboxylic acid was prepared from 1-{2-[(1 -tert-Butoxycarbonylamino-cyclopentanecarbony1)-amino]-acetyll-(2S)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester using method D with 2 eq. of LiOH H20. MS
(LC/MS) m/z observed 431.93, expected 432.21 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(2S)-[1-(2-0xo-2-{2-[(2H-tetrazol-5-ylmethyl)-carbamoyl]-2,3-dihydro-indol-1-yll-ethylcarbamoy1)-eyclopentylFcarbamic acid tert-butyl ester was prepared from 1-{2-[(1-tert-butoxycarbonylamino-cyclopentanecarbony1)-am ino]-acetyl } -(2S)-2,3-dihydro-1H-indole-2-carboxylic acid and (2H-tetrazol-5-yOmethyl-amine using method A
in DMF but without HC1 treatment. MS (LC/MS) m/z observed 512.90, expected 513.26 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C29 was prepared from (2S)41-(2-0xo-2-{2-[(2H-tetrazol-5-ylmethyl)-earbamoy1]-2,3-dihydro-indol-1-yll-ethylcarbamoy1)-cyclopentyl]-carbamic acid tert-butyl ester and succinic anhydride using method I. 1H NMR (400 MHz, DMSO-d6) 8 1.55-1.67 (4H, m), 1.83-1.93 (2H, m), 1.98-2.14 (2H, m), 2.34-2.39 (2H, m), 2.41-2.46 (2H, m), 3.11 (1H, m), 3.50-3.63 (2H, m), 4.05 (1H, m), 4.52 (1H, dd, J=7, 16Hz), 4.68 (1H, dd, J=7, 16Hz), 5.17 (1H, d, J=11Hz), 7.01 (1H, t, J=8Hz), 7.13-7-25 (2H, m), 7.65 (1H, t, J=5Hz), 8.02 (1H, d, J=8Hz), 8.12 (1H, bs), 9.10 (1H, bs), MS
(LC/MS) m/z observed 513.06, expected 513.22 [M+H]

(2S)-7-Ac ETAMIDO-1-12-1(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO[ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Intermediate 1-14 (500 mg, 2.427 mmol) and palladium on charcoal (100 mg) were placed in a round bottom flask under nitrogen. Ethanol (10 mL) was then added and hydrogen was bubbled in the reaction mixture for 4 hrs. Then the reaction mixture was filtered over CELITE and the CELITE was washed with ethanol (3 x 15 mL). The filtrate and washings were concentrated to give a brown oil that was further dissolved in DCM (50 mL) and to this was added acetic acid (140 uL, 2.427 mmol) , HOBt (372 mg, 2.427 mmol), EDC (512 mg, 2.670 mmol) and DIPEA (845 uL, 4.854 mmol). The reaction was left at RT for 16 hrs and the solvent was evaporated. The product was purified by normal phase column chromatography using 25 % to 55 c1/0 ethyl acetate in hexanes as the eluent to give (S)-ethyl 7-acetamidoindoline-2-carboxylate as an off white solid (103 mg, 17 %). 111 NMR (400 MHz, CDC13) 8 1.32 (3H, t, J=7.0Hz), 2.19 (3H, s), 3.31 (1H, dd, J=8, 16Hz), 3.45 (1H, dd, J=11, 16Hz), 4.19-4.30 (2H, qd, J=2, 7Hz), 4.51 (1H, dd, J=7, 10Hz), 5.20 (1H, bs), 6.70 (1H, t, J=8Hz), 6.85 (1H, d, J=8Hz), 6.96 (1H, d, J= 8Hz), 7.40 (1H, bs), MS (LC/MS) m/z observed 249.07, expected 249.12 [M+H].
(S)-Ethyl 7-acetam ido-1-(2-((tert-butoxycarbonyl)amino)acetypindoline-2-carboxylate was prepared from (S)-ethyl 7-acetamidoindoline-2-carboxylate and Boc-glycine using method C but purified by normal phase column chromatography using 25 % to 55 % ethyl acetate in hexanes as the eluent. MS (LC/MS) m/z observed 406.09, expected 406.20 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-Ethyl 7-acetamido-1-(24(2S,35)-3-methyl-2-(2-phenylacetamido)pentanamido)acetypindoline-2-carboxylate was prepared from (S)-ethyl 7-acetamido-1-(2-((tert-butoxycarbonyl)amino)acetyl)indoline-2-carboxylate and using method A but the product was purified by normal phase column chromatography using 20 % to 80 % ethyl acetate in hexanes as the eluent. MS (LC/MS) rn/z observed 537.08, expected 537.27 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
The intermediate ((S)-7-Acetamido-1-(24(2S,3S)-3-methyl-2-(2-phenylacetamido)pentanamido)acetyl)indoline-2-carboxylic acid) was prepared from (S)-ethyl 7-acetamido-1-(24(2S,3S)-3-methy1-2-(2-phenylaeetamido)pentanamido)acetyl)indoline-2-carboxylate using method D with 2 eq.
of LiOH H20. MS (LC/MS) nilz observed 509.08, expected 509.24 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C30 was prepared from (S)-7-acetamido-1-(24(2S,3S)-3-methy1-2-(2-phenylacetamido)pentanamido)acetyl)indoline-2-carboxylic acid and (2H-tetrazol-5-y1)methyl-amine using method A in DMF but without HC1 treatment. 1H NMR
(400 MHz, CD30D) 6 0.88-0.92 (3H, t, J= 7Hz), 0.99 (3H, d, J=7Hz), 1.15 (1H, m), 1.45 (1H, m), 1.92 (1H, m), 2.07 (3H, s), 3.25 (1H, d, J=16Hz), 3.53-3.70 (3H, m), 4.05 (1H, m), 4.21-4.35 (2H, m), 4.51 (1H, dd, J=6, 12Hz), 4.80 (1H, m), 5.28 (1H, t, ./=-9 Hz), 7.12-7.18 (3H, m), 7.23 (1H, m), 7.26-7.34 (4H, m), MS (LC/MS) m/z observed 590.17, expected 590.28 [M+H].

TER T-BUTYL N-R2S)-1-{2-1(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAM1DOJACETYL1-2-1(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL11-2,3-DIHYDRO-1H-INDOL-5-YLiCARBAMATE
Intermediate 1-13 (1 g, 4.850 mmol) and palladium on charcoal (200 mg) were placed in a round bottom flask under nitrogen. Ethanol (20 mL) was then added and hydrogen was bubbled in the reaction mixture for 4 hrs. Then the reaction mixture was filtered over CELITE and the CEL1TE was washed with ethanol (3 x 25 mL). The filtrate and washings were concentrated to give a brown oil. This brown oil was the dissolved in toluene (50 mL) and phtalic anhydride (718 mg, 4.85 mmol) was added. The reaction was heated to 80 C for 7 hrs and the solvent was evaporated. The product was purified by normal phase column chromatography using 5 % to 20 % ethyl acetate in hexanes as the eluent to give (S)-Ethyl 5-(1,3-dioxoisoindolin-2-yl)indoline-2-carboxylate as an off white solid (750 mg, 46 %). 1H NMR (400 MHz, CDCI3) 8 1.31 (3H, t, J=7.0Hz), 3.38 (1H, dd, J=6, 17Hz), 3.45 (1H, dd, 17Hz), 4.19-4.27 (2H, qd, J=2, 7Hz), 4.43 (1H, dd, J=7, 10Hz), 4.58 (1H, bs), 6.78 (1H, d, J=8Hz), 7.05 (1H, dd, J=2, 8Hz), 7.08 (1H, bs), 7.76-738 (2H, m), 7.91-7.95 (2H, m), MS (LC/MS) m/z observed 337.10, expected 337.12 [M+H].
(S)-Ethyl 1-(2-((tert-butoxyearbonyl)amino)acety1)-5-(1,3-dioxoisoindolin-2-y1)indol i ne-2-carboxyl ate was prepared from (S)-ethyl 541,3 -d ioxoi soi ndol i n-2-yl)indol ine-2-carboxylate and Boc-glycine using method C. MS (LC/MS) m/z observed 493.87, expected 494.19[M+1-1]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-Ethyl 5-(1,3-dioxoisoindolin-2-y1)-1-(24(2S,3S)-3-methy1-2-(2-phenylacetamido)pentanamido)acetyl)indoline-2-carboxylate was prepared from (S)-ethyl 1-(2-((tert-butoxycarbonyl)amino)acety1)-5-(1,3-dioxoisoindolin-2-ypindoline-2-carboxylate and 1-7 using method A but the product was purified by filtration of the reaction mixture. The solid obtained was the pure compound. MS (LC/MS) m/z observed 625.07, expected 625.27 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-Ethyl 5-(1,3-dioxoisoindolin-2-y1)-1-(24(2S,3S)-3-methy1-2-(2-phenylacetamido)pentanamido)acetyl)indoline-2-carboxylate (420 mg, 0.672 mmol) was dissolved in a 2:1 mixture DMF/ Et0H (90 mL) and hydrazine hydrate 60%
solution in water was added (75uL 1.01 mmol). The reaction was heated to 40 C for 1 hr and then to 80 C for 5 hrs. LC/MS showed that the starting material was converted to the desired free amine. The solvents were evaporated and the residue was dissolved in Et0H
(25 mL) and lithium hydroxide monohydrate (141 mg, 3.360 mmol) dissolved in water (25 mL) was added. The reaction was left at RT for 4 hrs and then acidified to pH 4 with a saturated solution of citric acid. The mixture was concentrated to dryness and the residue was suspended in water (25 mL) and the solid in suspension was filtered and washed with water (3 x 10 mL). (S)-5-amino-1-(24(2S,35)-3-methy1-2-(2-phenylacetamido)pentanamido)acetyl)indoline-2-carboxylic acid hydrochloride was obtained as a brown solid (325 mg, 96 %). MS (LC/MS) m/z observed 466.99, expected 467.23 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-5-Amino-1-(24(2S,3S)-3-methy1-2-(2-phenylacetamido)pentanamido)acetyl)indoline-2-carboxylic acid hydrochloride (325 mg, 0.646 mmol) was dissolved in dioxane (20 mL) and NaOH (1M, 2 mL, 1.938 mmol) was added, followed by a solution of Boe20 (1.41 g, 6.461 mmol) in dioxane (5 mL).
The reaction was left at RT for 16 hrs and then acidified to pH 4 with citric acid (aqueous, saturated solution). The mixture was concentrated and the product was purified on a C18 column using 10-55% Me0H in water to yield (S)-5-((tert-butoxyearbonyl)amino)-1-(2-((2S,3S)-3-methy1-2-(2-phenylacetamido)pentanamido)acetypindoline-2-carboxylic acid as an off-white solid (255 mg, 70%). MS (LC/MS) m/z observed 567.10, expected 567.28 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C31 was prepared from (S)-5-((tert-butoxycarbonyl)amino)-1-(2-((23,38)-3-methyl-2-(2-phenylacetamido)pentanamido)acetypindoline-2-carboxylie acid and (2H-tetrazol-5-yOmethyl-amine using method A in DMF but without HC1 treatment.
1H NMR (400 MHz, DMSO-d6) 5 0.65-0.87 (6H, m), 1.10 (1H, m), 1.43 (1H, m), 1.75 (1H, m), 3.00 (1H, d, J=16Hz), 3.42-3.63 (4H, m), 4.10 (1H, m), 4.25 (1H, m), 4.45-4.67 (2H, m), 5.05 (1H, d, J=11 Hz), 6.35 (1H, d, J=8 Hz), 6.44 (1H, m), 7.23 (1H, m), 7.26-7.32 (4H, m), 7.72 (1H, d, J=9 Hz), 8.00-8.25 (2H, m), 8.95 (1H, bs), MS
(LC/MS) ni/z observed 648.10, expected 648.33 [M+H].

(2S)-5-AMINO-1-{2-[(2S,3S)-3-mETHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO1ACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLIVIETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE HYDROCHLORIDE
Title compound C32 was prepared from C31 using method E. 1H NMR
(400 MHz, DMSO-d6) E. 0.75-0.87 (6H, m), 1.08 (1H, m), 1.40-1.50 (10H, m), 1.74 (1H, m), 3.10 (1H, d, J=16Hz), 3.42-3.63 (4H, m), 4.10 (1H, m), 4.25 (1H, t, J=11 Hz), 4.40-4.67 (2H, m), 5.13 (1H, d, J=11 Hz), 7.14-7.21 (2H, m), 7.24-7.30 (4H, m), 7.36 (1H, m), 7.88 (1H, d, J=9 Hz), 8.11 (1H, d, J=9Hz), 8.24 (1H, m), 9.00 (1H, bs), 9.27 (1H, bs), MS (LC/MS) rn/z observed 548.05, expected 548.27 [M+H].

(2S)-5-(TERT-BUTYLAMINO)-1-{2-[(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDOJACETYL)-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
Title compound C32 (25 mg, 0.0428 mmol) was dissolved in DMF (5mL) in a microwaved vial. Triethylamine (2 mL) and 2-bromo-2-methyl bromide (500uL) were then added. The reaction was then microwaved at 100 C for 15 minutes.
Additional triethylamine (3 mL) and 2-bromo-2-methyl bromide (1mL) were added and the reaction was microwaved for an additional 50 minutes at 100 C. Additional triethylamine (2mL) 2-bromo-2-methyl bromide (1 mL) were added and the reaction was microwaved for an additional 30 minutes at 100 C. The reaction mixture was then filtered to remove salts and the filtrate was concentrated. The product was purified on a C18 column using 10-55% Me0H in water to yield title compound C33 as a brown solid (1.2 mg, 5%). MS
(LC/MS) nilz observed 604.20, expected 604.34 [M+H].

(2S)-N,N,N-TRimETHYL-1-{2-[(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDO]ACETYLI-2-[(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)CARBAMOYL]-2,3-DIHYDRO-1H-INDOL-5-AMINIUM IODIDE
C32 (25 mg, 0.0428 mmol) was dissolved in DMF (8mL) in a microwavable vial.
Triethylamine (500 uL) and methyl iodide (150uL) were then added. The reaction was then microwaved at 75 C for 35 minutes. The reaction mixture was then concentrated and the product was purified on a C18 column using 10-55% Me0H in water to yield title compound C34 as an off-white solid (4 mg, 13%). 111 NMR (400 MHz, DMSO-d6) 0.75-0.87 (6H, m), 1.08 (1H, m), 1.33 (1H, m), 1.74 (1H, m), 2.80-2.86 (9H, m), 3.03 (1H, d, J.-16Hz), 3.42-3.62 (4H, m), 4.10 (1H, m), 4.40 (1H, m), 4.54 (1H, m), 4.63 (1H, m), 5.10 (1H, m), 6.54 (11-1, m), 6.64 (1H, bs), 7.20 (1H, m), 7.25-7.32 (4H, m), 7.86 (1H, m), 8.03 (1H, m), 8.09-8.18 (2H, m), 9.07 (1H, bs), MS (LC/MS) nilz observed 590.11, expected 590.32[M].

(2S)-5-(BENZYLAMINO)-1-{2-1(2S,3S)-3-METHYL-2-(2-PHENYLACETAMIDO)PENTANAMIDOJACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-DIHYDRO-1H-INDOLE-2-CARBOXAMIDE
C32 (36 mg, 0.0616 mmol) was dissolved in DMF (5mL) in a microwaved vial.
Triethylamine (1 mL) and benzyl bromide (8 uL, 0.0678 mmol) were then added.
The reaction was then microwaved at 50 C for 35 minutes. Additional benzyl bromide (15 uL, 0.126 mmol) was added and the reaction was then microwaved at 50 C
for 30 additional minutes. The reaction mixture was then concentrated and the product was purified on a C18 column using 10-55% Me0H in water to yield title compound C35 as an off-white solid (5 mg, 13%). 111 NMR (400 MHz, DMSO-d6) 8 0.73-0.85 (6H, m), 1.08 (1H, m), 1.44 (1H, m), 1.75 (1H, m), 2.90 (1H, d, ./-16Hz), 3.42-3.62 (6H, m), 4.08 (1H, m), 4.41 (1H, m), 4.56 (1H, m), 4.68 (1H, m), 5.05 (1H, d, ./=11Hz), 6.35 (1H, m), 6.45 (1H, m), 7.19 (1H, m), 7.21-7.32 (6H, m), 7.33-7.39 (3H, m), 7.78 (1H, m), 8.03 (I H, m), 8.09-8.18 (2H, m), 9.10 (1H, bs), MS (LC/MS) rn/z observed 637.99, expected 638.32 [M+H].

(2S)-1-12-[(2S,3S)-2-[(DIMETHOXY-1,3,5-TRIAZIN-2-YL)AMIN0]-3-METHYLPENTANAMIDOJACETYL)-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-A solution of (2S)-1-[2-((2S,3S)-2-amino-3-methyl-pentanoylamino)-acety1]-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester hydrochloride (0.1 gm, 0.1941 mmol) that was prepared as in Example C26, DIPEA (0.085 ml, 0.291 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.051 gm, 0.291 mmol) in ACN (3 ml) was sealed in a microwave tube and heated to 100 C for 10 min by microwave irradiation. The reaction mixture was concentrated to dryness and dried well under vacuum to give the crude product, which was purified by column chromatography on silica gel to get the pure product (S)-1-(24(2S,3S)-24(4,6-dimethoxy-1,3,5-triazin-2-yDamino)-3-methylpentanamido)acetyl)indoline-2-carboxylic acid ethyl ester as an off-white solid, 0.1 gm (80%). MS (LC/MS) m/z observed 501.15, expected 501.24 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.

Title compound C36 was prepared from (S)-1-(24(2S,3S)-24(4,6-dimethoxy-1,3,5-triazin-2-yl)amino)-3-methylpentanamido)acetypindoline-2-carboxylic acid ethyl ester and (2H-tetrazol-5-yl)methyl-amine using general method L. 1H NMR (400 MHz, DMSO-d6) 8 0.82-0.86 (3H, t, J=8 Hz), 0.90-0.92 (3H, d, J=8 Hz), 1.16-1.24 (1H, m), 1.46-1.53 (1H, m), 1.80-1.87 (1H, m), 3.11-3.15 (2H, d, J=16 Hz), 3.52-3.60 (2H, m), 3.84 (6H, s), 4.16-4.20 (1H, t, J=8 Hz), 4.35-4.42 (1H, m), 4.56-4.62 (1H, d, J=16 Hz), 5.16 (1H, s), 5.14-5.17 (1H, d, J=16 Hz), 6.60-6.62 (1h, t, J=4 Hz), 6.99-7.03 (1H, t, J=8 Hz), 7.17-7.23 (2H, m), 7.81-7.85 (1H, t, J=8 Hz), 8.02 (1H, s), 8.20 (1H, bs), 8.28 (1H, bs), 9.06 (1H, bs) MS (LC/MS) m/z observed 554.18, expected 554.25 [M+H].

(2S)-1-{2-[(2S)-2-[(DIMETHOXY-1,3,5-TRIAZIN-2-YL)AMIN0]-3-METHYLBUTANAMIDNACETYLI-N-(2H-1,2,3,4-TETRAZOL-5-YLMETHYL)-2,3-A solution of (S)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (0.5 g, 2.8 mmol), DIPEA (1.16 ml, 6.7 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.4 g, 1.9 mmol) in ACN (10 ml) was sealed in a microwave tube and heated to 100 C
for 10 min by microwave irradiation. The reaction mixture was concentrated to dryness and dried well under vacuum to give the crude product, which was purified by column chromatography on silica gel to get the pure product (S)-tert-butyl 2-((4,6-dimethoxy-1,3,5-triazin-2-yl)amino)-3-methylbutanoate as an off-white solid, 0.45 g (76%). 111 NMR (400 MHz, CDC13) 8 0.96-1.00 (6H, tõ J=8 Hz), 1.45 (9H, s), 2.19-2.27 (1H, m), 3.94 (3H, s), 3.95 (3H, s), 4.58-4.61 (1H, q, J=4H), 5.76-5.78 (1H, d, J=8 Hz). MS
(LC/MS) m/z observed 313.06, expected 313.18 [M+Hl. Compound was confirmed using LC/MS and moved to next step as it was.
(S)-tert-Butyl 2((4,6-dimethoxy-1,3,5-triazin-2-yDamino)-3-methylbutanoate (0.1 g, 0.32 mmol) was stirred in 1:1 mixture of DCM:TFA (4 ml) for 2 hrs at RT. The reaction mixture was concentrated to dryness under vacuum and swapped with DCM

(4 ml) three times. Resulting residue was dried well under vacuum and subjected to next reaction as it is. The residue obtained above, 1-4 (0.11 g, 0.32 mmol), EDC
(0.092 g, 0.48 mmol), HOBt (0.064 g, 0.42 mmol) and DIPEA (0.22 ml, 1.28 mmol) were stirred in anhydrous DCM (5 ml) for 16 hrs. The reaction mixture was concentrated under vacuum to give the crude product which was purified on a C18 column using 10-50% Me0H
in water to yield the title compound C37 as an off-white solid (45%). 1H NMR (400 MHz, DMSO-d6) 8 0.92-0.98 (6H, m), 2.08-2.06 (1H, m), 1.80-1.87 (1H, m), 2.98-3.11 (2H, m), 3.52-3.58 (2H, m), 3.83 (6H, s), 4.13-4.17 (1H, t, J=8 Hz), 4.32-4.40 (2H, m), 4.47-4.52 (1H, m), 5.13-5.16 (1H, d, J=12 Hz), 6.98-7.02 (1H, t, J=8 Hz), 7.14-7.22 (2H, m), 7.77-7.81 (1H, t, J=8 Hz), 8.03-8.05 (1H, d, J=8 Hz), 8.23 (1H, bs), 8.34 (1H, bs), 8.72 (1H, bs) MS (LC/MS) m/z observed 540.17, expected 540.24 [M+H].

3-{[(S)-({2-0xo-2-[(19-2-[(2H-1,2,3,4-TE FRAZOL-5- YLMETH Y L)CARBAMOYLI-2,3-YL] ETHYL} CARBAMOYL)(PHENYL)METHYL]CARBAMOYLIPROPANOIC ACID
(2S)-2-{[(tert-Butoxy)carbonyllamino}-2-phenylacetic acid (3.0 g, 12.1 mmol, 92%) was collected as a colorless oil from (S)-phenylglycine (2.0 g, 13.2 mmol) using general method K. 1H NMR (400 MHz, CDC13) 8 7.98 (1H, bs), 7.44 (2H, d, ./=7Hz), 7.34 (3H, m), 5.14 (1H, d, J=7Hz), 1.23 (9H, s), MS (LC/MS) m/z observed 273.96, expected 274.10 [M+Na]
(2S)-Ethyl 1- {2-[(2S)-2-{ Wert-butoxy)carbonyllamino}

phenylacetamido]acety1}-2,3 -dihydro-1H-indole-2-carboxylate (131 mg, 0.27 mmol, 96%) was collected as an off white solid from the coupling of I-10 (80 mg, 0.28 mmol) with (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-phenylacetic acid (71 mg 0.28 mmol) using general method M. MS (LC/MS) m/z observed 481.88, expected 482.23 [M+H].

Compound was confirmed using LC/MS and moved to next step as it was.
(2S)-1-{2-[(2S)-2-{[(tert-Butoxy)earbonyl]aminol-2-phenylacetamido]acety11-2,3-dihydro-1H-indole-2-carboxylic acid (130 mg, 0.28 mmol, 98%) was collected as an off white solid from (25)-ethyl 1-{2-[(2S)-2-{ [(tert-butoxy)carbonyl]amino} -phenylacetamido]acety1}-2,3-dihydro-1H-indole-2-carboxylate (137 mg, 0.285 mmol) using general method D. In this example, the reaction was stopped after 30 min and a gradient of 10-70% Me0H in H20 was used during purification. MS (LC/MS) m/z observed 453.89, expected 454.20 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
tert-Butyl N-RS)-({2-oxo-2-[(25)-2-[(211-1,2,3,4-tetrazol-5-ylmethyl)carbamoyl]-2,3-dihydro-1H-indo1-1-yl]ethyl}carbamoy1)(phenyl)methyl]carbamate (96 mg, 0.18 mmol, 63%) was collected as an off white solid from (2S)-1-{2-R2S)-2-{[(tert-butoxy)carbonyl]am ino} -2-phenylacetamido]acetyl} -2,3-dihydro-1H-indole-2-carboxy I ic acid (130 mg, 028 mmol) using general method O. MS (LC/MS) m/z observed 534.91, expected 535.24 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C38 (41 mg, 0.08 mmol, 43%) was collected as an off white solid from tert-butyl N-RS)-({2-oxo-2-R2S)-2-[(2H-1,2,3,4-tetrazol-5-ylmethyl)carbamoy0-2,3 -d hydro-1H-indo1-1-yllethyl carbamoy1)(phenyemethyl]carbamate (96 mg, 0.18 mmol) using general method I. 11-1 NMR (400 MHz, DMSO-d6) ö 9.08 (1H, bs), 8.65 (1H, bs), 8.56 (1H, d, J=8Hz), 8.05 (1H, d, J=8Hz), 7.47 (2H, d, J=7Hz), 7.34 (2H, t, J=7Hz), 7.28 (1H, d, J=7Hz), 7.26-7.15 (2H, m), 7.01 (1H, d, J=7Hz), 5.60 (1H, d, J=6Hz), 5.17 (1H, d, J=10Hz), 4.65 (1H, dd, J=16, 5Hz), 4.53 (1H, dd, J=16, 4Hz), 4.22 (1H, dd, J=16, 5Hz), 3.68-3.50 (2H, m), 3.14 (1H, d, J=16Hz), 2.48-2.39 (4H, m), MS
(LC/MS) m/z observed 534.97, expected 535.20 [M+H].

(2S)-1-{2-R2S,3S)-3-METHYL-2-12-(2H-1,2,3,4-TETRAZOL-5-YOACETAMIDOPENTANAMIDNACETYL)-N-(1H-1,2,3-TRIAZOL-4-YLMETHYL)-2,3-(2S)-1424(2S,35)-2-tert-Butoxycarbonylamino-3-methyl-pentanoylamino)-acety1]-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester was prepared from 1-10 and Boc-L-isoleucine using method A. MS (LC/MS) m/z observed 461.98, expected 462.26 [M+H].
Compound was confirmed using LC/MS and moved to next step as it was.
(25)-1424(2S,35)-2-tert-Butoxycarbonylamino-3 -methyl-pen tanoy lam ino)-acety1]-2,3-dihydro-1H-indole-2-carboxylic acid was prepared from (2S)-14242S,3S)-2-tert-butoxycarbonylamino-3-methyl-pentanoylamino)-acety1]-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester using method D with 2 eq. of LiOH H20. MS (LC/MS) m/z observed 433.96, expected 434.23 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
N-R1S,2S)-2-Methy1-1-([2-oxo-2-[(2S)-2-[(1H-1,2,3-triazol-4-y I methyl)carbamoy1]-2,3-dihydro-1H-indo1-1-y I]ethyl learbamoyDbutyl]carbam ic acid tert-butyl ester was prepared from (25)-142-((2S,3S)-2-tert-Butoxycarbonylamino-3-methyl-pentanoylamino)-acety1]-2,3-dihydro-1H-indole-2-carboxylic acid and (2H-1,2,3-triazol-4-yl)methyl-amine) using method A in DMF but without HC1 treatment. MS
(LC/MS) nilz observed 513.97, expected 514.28 [M+H]. Compound was confirmed using LC/MS and moved to next step as it was.
Title compound C39 was prepared from N-R1S,2S)-2-methy1-1-({2-oxo-2-[(2S)-2-[(1H-1,2,3-triazol-4-ylmethypcarbamoyl]-2,3-dihydro-1H-indo1-1-yllethyl}carbamoyDbutyl]carbamic acid tert-butyl ester and 2-(2H-tetrazol-5-yl)acetic acid using method A but with DMF as solvent for the coupling reaction: 1H NMR
(400 MHz, DMSO-d6) 0.82 (3H, t, J=7.4Hz), 0.88 (3H, d, J=7Hz), 1.12 (1H, m), 1.50 (1H, m), 1.78 (1H, m), 3.05 (1H, m), 3.56-3.67 (2H, m), 3.92-4.02 (2H, m), 4.13 (1H, m), 4.31 (1H, t, J=8Hz), 4.37-4.43 (2H, m), 5.13 (1H, d, J=8Hz), 7.01 (1H, t, J=8Hz), 7.14-7-28 (2H, m), 7.70 (1H, s), 8.04 (1H, d, J=8Hz), 8.34 (1H, bs), 8.47 (1H, d, J=9Hz), 8.88 (1H, bs), MS (LC/MS) m/z observed 524.62, expected 524.25 [M+H].

GENERAL KINETIC ENZYME ASSAY PROTOCOL
A specific 2X assay buffer was prepared for the enzyme to be tested (see Table for final 1X assay buffer compositions). If the assay buffer included DTT, it was added immediately prior to running the assay. A 2X enzyme mix was prepared (see Table 3 for enzyme assay conditions) at 80 uL per well. Compounds were screened at one or two appropriate concentrations (to determine the percent inhibition at those concentrations) and/or a full dose response curve (typically 8 points, to identify the IC50) in duplicate, triplicate, or higher replicates as needed. An appropriate control was also assessed in full dose response, in duplicate for each assay/plate. Background control wells consisted of 1X assay buffer, DMSO (5% v/v) and substrate. Positive control wells consisted of enzyme, DMSO (5% v/v) and substrate. Test compounds and control compounds were diluted in DMSO to 40X the final desired concentration. For example, a test compound may be tested in dose response, in serial, tripling dilution condition starting at 20uM and ending at 9.1 nM (or any appropriate concentration range and dilution scheme).
Control compounds were prepared similarly. Diluted compounds were prepared in a dilution plate and transferred to the reaction plate (96-well medium binding plate (Greiner Bio-One FLUOTRACTm)) to allow for the desired final concentrations when added to the enzyme with AB. After mixing, the reaction plate was placed on a shaker (at 300 RPM) for 5 min, followed by incubation (covered) on the bench, for 20 min. Plates were warmed to reaction temperature (see Table 3) for a total incubation time of 30 min.
Plates so prepared were ready for addition of substrate and the subsequent reaction.
An appropriate substrate for each assay was prepared in advance at 2X the final desired concentration (see Table 2) in DMSO. The appropriate substrate mix was added to each appropriate well on the reaction plate, and the plate was read immediately in the TECAN plate reader (TECAN INFINITE M1000 Pro), set to the correct wavelength as needed for each assay (see Table 3) using 25 cycles, kinetic interval of lmin, number of reads per well of 20 with shaking set to ls, double orbital, 2mm amplitude.
For fluorescent assays the gain was set to optimal (50%).
Table 2. Assay Buffer Composition.

Assay Buffer Composition Enzyme _________________________________________ 50 mM HEPES pH 7.2 50 mM NaC1 Caspase 1, 3, 4, 5, 7, 8*, 9 & 10/a 0.1% (w/v) CHAPS
(General caspase assay buffer) mM EDTA
5% (v/v) Glycerol 10 mM DTT
50 mM HEPES pH 7.5 10% (w/v) sucrose GzmB & Caspase 8 0.2% (w/v) CHAPS _________________________________________________ 5 mM DTT
*Can also use GzmB assay buffer for the Caspase-8 assay; Assay buffer components were sourced as follows: HEPES, DTT, Glycerol and sucrose: Sigma-Aldrich, St. Louis, MO, USA, NaC1 and EDTA: Fisher Scientific, Pittsburgh, PA, USA, CHAPS: Calbiochem, Billerica, MA, USA.
5 Table 3. Enzyme assay conditions.
Enzyme Substrate Assay Ex/Em Control Conc. Temp Name Conc. Name (nm) Inhibitor 1 (PM) ( C) Ac-IEPD-hGzmB 10 nM 150 380/460 30 Ac-IEPD-CHO
AMC
Caspase-1 6.25 mU/ 1 YVAD-AFC 25 400/505 37 Z-VAD-FMK
Caspase-3 and Ac-DEVD-6.25 mU/111 20 380/460 37 Z-VAD-FMK
Caspase 7 AMC __ Caspase-4 and Ac-WEHD-3.125 mU/u1 100 400/505 37 Z-WEHD-FMK
Caspase-5 AFC
Ac-IEPD-Caspase-8 3.125 mU/u1 75 380/460 30 Ac-IEPD-CHO
_______________________ AMC
Caspase-9 3.125 mU/u1 LEHD-AFC 50 400/505 37 Q-LEHD-Oph __ Ac-IETD-Caspase-10/a 6.25 mU/R1 100 400/505 30 Ac-AEVD-CHO
AMC =

* Ex/Em X is the excitation and emission wavelengths at which to measure fluorescence. Enzyme and substrate concentrations are the final concentrations in the well. Note that most protocols require preparing 2X enzyme and substrate mixes, as they are diluted 2-fold in the well.
Enzymes were sourced as follows: hGzmB, Froelich Lab, Northshore University Health Systems Research Institute, Evanston, IL, USA; Caspases, Biovision Inc., Milpitas, CA, USA. Substrates were sourced as follows: Ac-IEPD-AMC, California Peptide Research Inc., Napa, CA, USA; YVAD-AFC, Biovision Inc., Milpitas, CA, USA;
Ac-DEVD-AMC, LEHD-AFC, AC-WEHD-AFC and Ac-IETD-AMC, Enzo Life Sciences Inc, Farmingdale, NY, USA. Control inhibitors were sourced as follows: Ac-IEPD-CHO, Ac-WEHD-FMK and Q-LEHD-Oph, Biovision Inc., Milpitas, CA, USA;
Z-VAD-FMK, R&D Systems, Minneapolis, MN, USA; and Ae-AEVD-CHO, Enzo Life Sciences Inc, Farmingdale, NY, USA.

An in vitro fluorogenic detection assay for assessing the IC50 and/or percent inhibition at a given concentration of inhibitors against human Granzyme B
(hGzmB) enzyme was performed as described in Example D 1 . When appropriate, percent inhibition data was collected and fitted to generate IC50 data using GraphPad Prism 5 (GraphPad Software, La Jolla California USA, www.graphpad.com) and its non-linear regression analysis tools or other equivalent tools.
Select compounds of Examples A1-A57, B1-B7 and C1-C39 exhibited inhibitory activity against hGzmB. Each of the compounds of the invention identified in Table 1 exhibited Granzyme B inhibitory activity.
In certain embodiments, select compounds exhibited IC50 <50,000 nM. In other embodiments, select compounds exhibited IC50 <10,000 nM. In further embodiments, select compounds exhibited IC50 <1,000 nM. In still further embodiments, select compounds exhibited IC50 <100 nM. In certain embodiments, select compounds exhibited IC50 from 10 nM to 100 nM, preferably from 1 nM to 10 nM, more preferably from 0.1 nM to 1 nM, and even more preferably from 0.01 nM to 0.1 nM.

HUMAN CASPASE ENZYMATIC INHIBITION ASSAY
In vitro fluorogenic detection assays for assessing the IC50 and/or percent inhibition at a given concentration of inhibitors, against a set of human Caspase enzymes, was performed as described in Example DI. Representative compounds of the invention do not significantly inhibit any caspase enzyme tested at a concentration of 50 M.
In certain embodiments, the compounds exhibited less than 50% inhibition at 50 M. In other embodiments, the compounds exhibited greater than 50%
inhibition at 50 M, but less than 10% inhibition at 25 M.

KINETIC SOLUBILITY DETERMINATION
Kinetic solubility buffer (phosphate buffered saline (PBS, 1X) at pH 7.4) was prepared from PBS (10X) solution, (Fisher Scientific, Pittsburgh, PA, USA, 10X), by adding PBS (50mL, 10X) to approximately water (450mL HPLC grade). The volume of the solution was then adjusted to 500mL for a total dilution factor of 1:10 and a final PBS
concentration of 1X. The pH of the final solution (PBS (1X)) was measured and found to be 7.4.
A DMSO stock solution (typically 10mM or greater) was used for each compound to be tested. A final DMSO concentration of 2.0% and maximum theoretical compound concentration of typically 200 M (or greater) was achieved by diluting an aliquot (6 1.d) of each stock with kinetic solubility buffer (294 11, PBS (1x) at pH 7.4) using a liquid handling system (Hamilton STARlet, Hamilton Robotics, Inc., Reno, NV, USA) and incubated directly in a solubility filter plate (Millipore, Billerica, MA, USA). Following 24 hour incubation at ambient temperature (20.5-21.7 C), each sample was vacuum filtered. The filtrate was injected into the chemiluminescent nitrogen detector for quantification (Automated Discovery Workstation, Analiza, Inc., Cleveland, OH, USA).
Each result was reported both in KM and .i.g/mL units. Three separate on-board performance indicating standards were assayed in triplicate with each test compound to ensure test results were within the acceptable range.

The equimolar nitrogen response of the detector was calibrated using standards which spanned the dynamic range of the instrument from 0.08 to 4500 1.1.g/m1 nitrogen.
Each filtrate was quantified with respect to this calibration curve. Each calculated solubility value was corrected for background nitrogen present in the DMSO, and buffer used to prepare each sample. All reported values for samples containing adjacent nitrogen atoms in a ring structure were corrected for the expected non-equimolar response. Each calculated solubility result assumed that each sample was free of nitrogen containing impurities and was stable under the assay conditions. Analyses were performed at Analiza Inc. (Cleveland, OH, USA) by published methods (Bliallachar, S.N., et al, J Pharma. BioMed Anal. 41:152-7 2006).
Table 4. Kinetic solubility in PBS.
Solubility in aqueous PBS Buffer Code (1X, pH 7.4) uM
Willoughby 20 4.2 - 4.9 2..6 - 3.0 Al 144 77 A2 >150.0 >80.0 A4 >150 >80 A6 >150 = >78 __________ A8 >150 >88 __________ A10 >750 >443 , Al2 594 323 A13 >750 >386 Al4 107 57 A16 >750 =>385 A17-1 >750 >407 A17-2 >750 >407 Solubility in aqueous PBS Buffer Code (1X, .H7.4 _____________________ uM L, i I loughby 20 4.2 -_.9 2.6 - 3.0 A20-2 = 641 = 429 A21-1 >750 >425 A21-2 _______________ >750 >425 _______ A22-1 >750 >416 A22-2 >750 >416 _______ A23-1 >750 >426 A25 __________________ 696 462 A26-1 >750 >395 A28 >750 >393 _______ A30-1 >750 >396 A30-2 >750 >396 A32 >750 >410 A34 >750 >443 _______ A44 _______ 724 467 _______ A45 682 359 A46 >750 >375 A52 __________________ >750 >418 A53 >750 >407 Solubility in aqueous PBS Buffer Code (1X, pH 7.4) uM tia/mL
Willoughby 2D 4.2 -4.9 2.6 ¨ 3 0 A54-2 >750 >454 __________ =A55 = >750 >418 A56 >750 >407 B2 12.6 8.4 C1 >150 >78 __________ C13 = >750 >454 C20 596 348 _ C22 = >750 >486 C24 >750 >405 C27 >750 >442 C32 >750 >438 GENERAL KINETIC ENZYME ASSAY PROTOCOL (384 WELL) A specific 2X assay buffer was prepared for the enzyme to be tested (see Table for final 1X assay buffer compositions). If the assay buffer included DTT, it was added immediately prior to running the assay. A 2X enzyme mix was prepared (see Table 3 for enzyme assay conditions) at 26 uL per well. Compounds were screened at one or two appropriate concentrations (to determine the percent inhibition at those concentrations) and/or a full dose response curve (typically 12 points, to identify the IC50) in duplicate, triplicate, or higher replicates as needed. An appropriate control was also assessed in full dose response, in duplicate for each assay/plate. Background control wells consisted of IX assay buffer and substrate. Positive control wells consisted of enzyme (no DMSO) and substrate. Test compounds and control compounds were diluted in 1X Assay Buffer to 15X the final desired concentration. For example, a test compound may be tested in dose response, in serial, tripling dilution condition starting at 20uM and ending at 0.1 nM
(or any appropriate concentration range and dilution scheme). Control compounds were prepared similarly. Diluted compounds were prepared in a dilution plate and transferred to the reaction plate (384-well medium binding plate (Greiner Bio-One FLUOTRACTm)) to allow for the desired final concentrations when added to the enzyme with AB. After mixing, the reaction plate was placed on a shaker (at 300 RPM) for 5 min, followed by incubation (covered) on the bench, for 20 min. Plates were warmed to reaction temperature (see Table 6) for 5 mins for a total incubation time of 30 min.
Plates so prepared were ready for addition of substrate and the subsequent reaction.
An appropriate substrate for each assay was prepared in advance at 2X the final desired concentration (see Table 5) in assay buffer. 30uL of the appropriate substrate mix was added to each appropriate well on the reaction plate, and the plate was read immediately in the TECAN plate reader (TECAN INFINITE M1000 Pro), set to the correct wavelength as needed for each assay (see Table 6) using 15 cycles, kinetic interval of lmin, number of reads per well of 20 with shaking set to ls, double orbital, 2mm amplitude. For fluorescent assays the gain was set to optimal (100% with gain regulation) for all assays except human GzmB which waswer-e set to 85 (with the z set at 23000 urn).
Table 5. Assay Buffer Composition.
_______________________________ r -Enzyme Assay Buffer Composition 50 mM HEPES pH 7.2 50 mM NaCI
Caspase 1, 3, 4, 5, 7, 8*, 9 & 10/a 0.1% (w/v) CHAPS
(General caspase assay buffer) 10 mM EDTA
5% (v/v) Glycerol 10 mM DTT
50 mM HEPES pH 7.5 GzmB & Caspase 8 0.2% (w/v) CHAPS
___________________________________________ 5 mM DTT
320mM Tris-HCL pH 7.4 Cathepsin G
3.2 M NaC1 *Can also use GzmB assay buffer for the Caspase-8 assay; Assay buffer components were sourced as follows: HEPES, DTT, Glycerol and sucrose: Sigma-Aldrich, St. Louis, MO, USA, NaC1 and EDTA: Fisher Scientific, Pittsburgh, PA, USA, CHAPS: Calbiochem, Billerica, MA, USA.

Table 6. Enzyme assay conditions.
Enzyme Substrate Assay Ex/Em Control Conc. Temp Name Conc. Name (nm) Inhibitor ___________________________________ (RNI) ( C) Ac-IEPD-hGzmB 10 nM 50 380/460 30 V2248 AMC
YVAD-Caspase-1 12.5 mU/[1.1- 5 400/505 37 Z-VAD-FMK
_______________________ AFC
Caspase-3 and 0.8mU/ L Ac-DEVD- 40 Caspase 7 8z1.5mUl pi. AMC &5 Caspase-4 and 3.125mU/uL Ac-WEHD- 40 Z-WEHD-Caspase-5 & 1.5mU/uL AFC & 100 FMK

Ac-IEPD- Ac-IEPD-Caspase-8 4 mU/uL 80 380/460 37 AMC CHO
Caspase-9 2mU/uL LEHD-AFC 50 400/505 37 Q-LEHD-Oph Ac-IETD- Ac-AEVD-Caspase-10/a 3 mU/RL , 10 400/505 37 =AMC ________________________________________________________________ CHO
Suc-AAPF- 410 Cat G
Cathepsin G 200nM 200uM 25 pNA absorbance inhibitor Human Me0Suc-Neutroph 0.125 ug/mL 50 384/500 37 S
ivelestat AAPF-AFC
Elastase * Ex/Em is the excitation and emission wavelengths at which to measure fluorescence. Enzyme and substrate concentrations are the final concentrations in the well. Note that most protocols require preparing 2X enzyme and substrate mixes, as they are diluted 2-fold in the well.
Enzymes were sourced as follows: hGzmB, Froelich Lab, Northshore University Health Systems Research Institute, Evanston, IL, USA; Caspases and Elastase, Biovision Inc., Milpitas, CA, USA; Cathepsin G, Athens Research and Technologies, Athens, GA, USA. Substrates were sourced as follows: Ac-IEPD-AMC, California Peptide Research Inc., Napa, CA, USA; YVAD-AFC and Me0Suc-AAPF-AFC Biovision Inc., Milpitas, CA, USA; LEHD-AFC and Suc-AAPF-pNA Millipore, Billerica MA, USA. Ac-DEVD-AMC, AC-WEHD-AFC and Ac-IETD-AMC, Enzo Life Sciences Inc, Farmingdale, NY, USA. Control inhibitors were sourced as follows: Ac-IEPD-CHO, Ac-WEHD-FMK, Q-LEHD-Oph and CatG inhibito,r Biovision Inc., Milpitas, CA, USA; Z-VAD-FMK, R&D

Systems, Minneapolis, MN, USA; and Ac-AEVD-CHO, Enzo Life Sciences Inc, Farmingdale, NY, USA. Sivelestat, Tocris Bioscience, Bristol, UK.

An in vitro fluorogenic detection assay for assessing the IC50 and/or percent inhibition at a given concentration of inhibitors against human Granzyme B
(hGzmB) enzyme was performed as described in Example D5. When appropriate, percent inhibition data was collected and fitted to generate IC50 data using GraphPad Prism 5 (GraphPad Software, La Jolla California USA, www.graphpad.com) and its non-linear regression analysis tools or other equivalent tools.
Select compounds of Examples A1-A57, BI-B7 and CI-C39 exhibited inhibitory activity against liGzmB. Each of the compounds of the invention identified in Table 1 exhibited Granzyme B inhibitory activity.
In certain embodiments, select compounds exhibited IC50 <50,000 nM. In other embodiments, select compounds exhibited IC50 <10,000 nM. In further embodiments, select compounds exhibited IC50 <1,000 nM. In still further embodiments, select compounds exhibited IC50 <100 nM. In certain embodiments, select compounds exhibited IC50 from 10 nM to 100 nM, preferably from 1 nM to 10 nM, more preferably from 0.1 nM to 1 nM, and even more preferably from 0.01 nM to 0.1 nM.

HUMAN CASPASE ENZYMATIC INHIBITION ASSAY
In vitro fluorogenic detection assays for assessing the IC50 and/or percent inhibition at a given concentration of inhibitors, against a set of human Caspase enzymes, was performed as described in Example D5. Representative compounds of the invention do not significantly inhibit any caspase enzyme tested at a concentration of 50 M.
In certain embodiments, the compounds exhibited less than 50% inhibition at 50 M. In other embodiments, the compounds exhibited greater than 50%
inhibition at 50 M, but less than 10% inhibition at 25 M.

Claims (17)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound having Formula (I):
its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
R1a is a heteroaryl group selected from (a) 1,2,3-triazolyl optionally substituted with C1-C2 alkyl, (b) 1,2,3,4-tetrazolyl, and (c) 1,2,3-thiadiazolyl;
R1b and R1c are independently selected from hydrogen, methyl, and halogen;
R2a and R2b are independently selected from hydrogen and methyl, or R2a and R2b taken together are oxo;
n is 1 or 2;
R3 is selected from hydrogen and C1-C4 alkyl optionally substituted with a carboxylic acid or a carboxylate group or an amine group;
Z is an acyl group selected from the group (b) , wherein o is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid;
(c) , wherein p is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid; and (d) , wherein Y is heteroaryl;
wherein R4 is selected from (i) C1-C12 alkyl, (ii) C1-C6 heteroalkyl optionally substituted with C1-C6 alkyl, (iii) C3-C6 cycloalkyl, (iv) C6-C10 aryl, (v) heterocyclyl, (vi) C3-C10 heteroaryl, (vii) aralkyl, and (viii) heteroalkylaryl;
R5 is ¨C(=O)-R10, wherein R10 is selected from (i) C1-C12 alkyl optionally substituted with C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (ii) C1-C10 heteroalkyl optionally substituted with C1-C6 alkyl or carboxylic acid, (iii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (iv) C6-C10 aryl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (v) heterocyclyl, (vi) C3-C10 heteroaryl, (vii) aralkyl, and (viii) heteroalkylaryl; and R6, R7, R8, and R9 are independently selected from (a) hydrogen, (b) halogen, (c) C1-C6 alkyl, (d) -XR11, wherein X is selected from O, C(=O), S, S=O, or S(=O)2, (e) -C(=O)N(R12)(R13), (f) -N(R11) (R12)(R13), (g) -N-C(=O)-R11, and (h) -N-C(=O)O-R11, wherein R11, R12, and R13 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C6-C10 aryl, aralkyl, and C3-C10 heteroaryl.

2. A compound having Formula (I):
its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
R1a is a heteroaryl group selected from (a) 1,2,3-triazolyl optionally substituted with C1-C2 alkyl, and (b) 1,2,3,4-tetrazolyl;
R1b and R1c are independently selected from hydrogen and methyl;
R2a and R2b are independently selected from hydrogen and methyl;
n is 1;
R3 is selected from hydrogen and C1-C4 alkyl optionally substituted with a carboxylic acid or a carboxylate group or an amine group;
Z is an acyl group selected from the group (a) (b) , wherein o is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid;
(c) , wherein p is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid; and (d) , wherein Y is heteroaryl;
wherein R4 is selected from C1-C12 alkyl, (ii) C3-C6 cycloalkyl, (iii) C6-C10 aryl, and (iv) C3-C10 heteroaryl;
R5 is ¨C(=O)-R10, wherein R10 is selected from (i) C1-C12 alkyl optionally substituted with C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (ii) C1-C10 heteroalkyl optionally substituted with C1-C6 alkyl or carboxylic acid, (iii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, (iv) C6-C10 aryl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid, and (v) C3-C10 heteroaryl; and R6, R7, R8, and R9 are independently selected from (a) hydrogen, (b) halogen, (c) C1-C6 alkyl, (d) -XR11, wherein X is selected from O and C(=O), (e) -N(R11)(R12)(R13), and (f) -N-C(=O)-R11, wherein R11, R12, and R13 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C6-C10 aryl, aralkyl, and C3-C10 heteroaryl.

3. The compound of Claims 1 or 2, wherein R1a is tetrazole or triazole; R1b and R1c are H; n is 1; R2a and R2b are H; R3 is H or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is

4. The compound of Claims 1 or 2, wherein The compound of Claims 1 or 2, wherein R1a is tetrazole or triazole; R1b and R1c are H; n is 1; R2a and R2b are H; R3 is H

or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is

5. The compound of Claims 1 or 2, wherein R1a is tetrazole or triazole; R1b and R1c are H; n is 1; R2a and R2b are H; R3 is H or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is

6. The compound of Claims 1 or 2, wherein R1a is tetrazole or triazole; R1b and R1c are H; n is 1; R2a and R2b are H; R3 is H or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group; R6-R9 are H; and Z is

7. A compound having Formula (II):
its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
R1a is tetrazole or triazole;
R1b and R1c are H;
n is 1;

R2a and R2b are H;
R3 is H or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group;
R6-R9 are H;
R4 is C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy; and R5 is ¨C(=O)-R10, wherein R10 is C1-C12 alkyl substituted with a carboxylic acid or carboxylate group, or C3-C6 cycloalkyl substituted with a carboxylic acid or carboxylate group.

8. A compound having Formula (III):
its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
R1a is tetrazole or triazole;
R3 is H or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group;
R4 is C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy; and R10 is -(CH2)n-CO2H, wherein n is 2, 3, 4, 5, or 6;
optionally wherein one or more single methylene carbons are substituted with a fluoro, hydroxy, amino, C1-C3 alkyl, or C6-C10 aryl group;
optionally wherein one or more single methylene carbons are substituted with two fluoro or C1-C3 alkyl groups;
optionally wherein one or more single methylene carbons are substituted with two alkyl groups that taken together with the carbon to which they are attached form a 3, 4, 5, or 6-membered carbocyclic ring; or optionally wherein adjacent carbon atoms from an unsaturated carbon-carbon bond or taken together form a benzene ring.

9. A compound having Formula (III):
its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
R1a is tetrazole or triazole;
R3 is H or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group;
R4 is C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy; and R10 is wherein n is 1, 2, 3, or 4; and optionally, for n = 3 or 4, wherein adjacent carbon atoms from an unsaturated carbon-carbon bond.

10. A compound having Formula (IV):
its stereoisomers and pharmaceutically acceptable salts thereof, wherein:
R1a is tetrazole or triazole;
R3 is H or C1-C4 alkyl substituted with a carboxylic acid or carboxylate group;
R4 is C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy; and R11 is selected from:

(a) optionally substituted C6-C10 aryl; and (b) optionally substituted C3-C10 heteroaryl.

11. A compound as shown in Table 1.

12. A pharmaceutical composition, comprising a compound of any one of Claims 1-11 and a pharmaceutically acceptable carrier.

13. A method for inhibiting Granzyme B in a subject, comprising administering an effective amount of a compound of any one of Claims 1-11 or a pharmaceutical composition of Claim 12 to a subject in need thereof.

14. A method for treating a disease, disorder, or condition treatable by inhibiting Granzyme B, comprising administering a therapeutically effective amount of a compound of any one of Claims 1-11 or a pharmaceutical composition of Claim 12 to a subject in need thereof.

15. The method of Claim 14, wherein the disease, disorder, or condition treatable by inhibiting Granzyme 13 is selected from treating dissection, aneurysm, and atherosclerosis.

16. The method of Claim 14, wherein the condition treatable by inhibiting Granzyme B is a wound and administering the compound or composition promotes wound healing.

17. The method of any one of Claims 13-16, wherein administering the compound comprises topical administration, oral administration, and administration by injection.