WO2011068926A1

WO2011068926A1 - Iap inhibitors

Info

Publication number: WO2011068926A1
Application number: PCT/US2010/058644
Authority: WO
Inventors: Stephen M. Condon; Matthew G. Laporte; Thomas Haimowitz
Original assignee: TetraLogic Pharmaceuticals Corp
Current assignee: TetraLogic Pharmaceuticals Corp
Priority date: 2009-12-04
Filing date: 2010-12-02
Publication date: 2011-06-09
Anticipated expiration: 2012-06-04

Abstract

The present invention describes compounds, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy.

Description

IAP INHIBITORS

[01] This application claims the benefit of and incorporates by reference U.S.

Provisional Application Serial No. 61/266,703 filed December 4, 2009; U.S. Provisional Application Serial No. 61/350,786 filed June 2, 2010; and U.S. Provisional Application Serial No. 61/409,653 filed November 3, 2010.

[02] The present invention describes compounds that are inhibitors of IAPs (inhibitors of apoptosis proteins), processes for their preparation, pharmaceutical compositions containing them, and their use in therapy. The compounds of the present invention are useful in the treatment of cancer, autoimmune diseases, neurodegenerative disorders and other developmental disorders.

[03] Apoptosis (programmed cell death) plays a central role in the development and homeostasis of all multi-cellular organisms. Apoptosis can be initiated within a cell from an external factor such as a chemokine (an extrinsic pathway) or via an intracellular event such as DNA damage (an intrinsic pathway). Alterations in apoptotic pathways have been implicated in many types of human pathologies, including developmental disorders, cancer, autoimmune diseases, as well as neurodegenerative disorders. One mode of action of chemotherapeutic drugs is cell death via apoptosis.

[04] Apoptosis is conserved across species and executed primarily by activated caspases, a family of cysteine proteases with aspartate specificity in their substrates. These cysteine containing aspartate specific proteases ("caspases") are produced in cells as catalytically inactive zymogens and are proteolytically processed to become active proteases during apoptosis. Once activated, effector caspases are responsible for proteolytic cleavage of a broad spectrum of cellular targets that ultimately lead to cell death. In normal surviving cells that have not received an apoptotic stimulus, most caspases remain inactive. If caspases are aberrantly activated, their proteolytic activity can be inhibited by a family of evolutionarily conserved proteins called IAPs (inhibitors of apoptosis proteins). [05] The IAP family of proteins suppresses apoptosis by preventing the activation of procaspases and inhibiting the enzymatic activity of mature caspases. Several distinct mammalian IAPs including XIAP, c-IAPl, C-IAP2, ML- IAP, NAIP (neuronal apoptosis inhibiting protein), Bruce, and survivin, have been identified, and they all exhibit anti-apoptotic activity in cell culture. IAPs were originally discovered in baculovirus by their functional ability to substitute for P35 protein, an anti-apoptotic gene. IAPs have been described in organisms ranging from Drosophila to human, and are known to be overexpressed in many human cancers. Generally speaking, IAPs comprise one to three Baculovirus IAP repeat (BIR) domains, and most of them also possess a carboxyl-terminal RING finger motif. The BIR domain itself is a zinc binding domain of about 70 residues comprising 4 alpha-helices and 3 beta strands, with cysteine and histidine residues that coordinate the zinc ion. It is the BIR domain that is believed to cause the anti-apoptotic effect by inhibiting the caspases and thus inhibiting apoptosis. XIAP is expressed ubiquitously in most adult and fetal tissues. Overexpression of XIAP in tumor cells has been demonstrated to confer protection against a variety of pro-apoptotic stimuli and promotes resistance to chemotherapy. Consistent with this, a strong correlation between XIAP protein levels and survival has been demonstrated for patients with acute myelogenous leukemia. Down- regulation of XIAP expression by antisense oligonucleotides has been shown to sensitize tumor cells to death induced by a wide range of pro-apoptotic agents, both in vitro and in vivo.

[06] In normal cells signaled to undergo apoptosis, however, the IAP -mediated inhibitory effect must be removed, a process at least in part performed by a mitochondrial protein named Smac (second mitochondrial activator of caspases). Smac (or, DIABLO), is synthesized as a precursor molecule of 239 amino acids; the N-terminal 55 residues serve as the mitochondria targeting sequence that is removed after import. The mature form of Smac contains 184 amino acids and behaves as an oligomer in solution. Smac and various fragments thereof have been proposed for use as targets for identification of therapeutic agents.

[07] Smac is synthesized in the cytoplasm with an N-terminal mitochondrial targeting sequence that is proteolytically removed during maturation to the mature polypeptide and is then targeted to the inter-membrane space of mitochondria. At the time of apoptosis induction, Smac is released from mitochondria into the cytosol, together with cytochrome c, where it binds to IAPs, and enables caspase activation, therein eliminating the inhibitory effect of IAPs on apoptosis. Whereas cytochrome c induces multimerization of Apaf-1 to activate procaspase-9 and -3, Smac eliminates the inhibitory effect of multiple IAPs. Smac interacts with essentially all IAPs that have been examined to date including XI AP, c-IAPl, C-IAP2, ML-IAP, and survivin. Thus, Smac appears to be a master regulator of apoptosis in mammals.

[08] It has been shown that Smac promotes not only the proteolytic activation of procaspases, but also the enzymatic activity of mature caspase, both of which depend upon its ability to interact physically with IAPs. X-ray crystallography has shown that the first four amino acids (AVPI) of mature Smac bind to a portion of IAPs. This N-terminal sequence is essential for binding IAPs and blocking their anti-apoptotic effects.

[09] Currently, there are drug discovery efforts aimed at identifying compounds that interfere with the role played by IAPs in disease states where a defect in apoptosis is implicated, such as in cancers and autoimmune diseases. Indeed, a number of IAP inhibitors that mimic the interactions of the Smac tetrapeptide are now known and possess pro-apoptotic activity in vitro and in vivo. The art continues to look for additional compounds that may function as IAP inhibitors.

SUMMARY OF THE INVENTION

[10] The present invention provides IAP inhibitors (Smac mimetics), as well as therapeutic methods of using these inhibitors to modulate apoptosis.

[11] In one embodiment, which can be practiced either separately, or in combination with the other embodiments disclosed below, the present invention provides compounds of Formula (I):

or a pharmaceutically acceptable salts thereof, wherein:

XI is O, or S;

X2 is O, or S;

R is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

Rla is H, alkyl, or substituted alkyl;

Rib is H, alkyl, or substituted alkyl

R2 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R6 is H, alkyl, substituted alkyl, alkylsulfonyl, arylsulfonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or R6 has the following formula (IA):

where R8 is H, alkyl, substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

and R9 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or R9 has the following formula

(IB):

where RlOa and RlOb are independently selected from H, alkyl, or substituted alkyl;

and Rl l is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R12 is H or hydroxy;

n is 0 or 1 ;

A is a 5-6-membered heteroaryl ring, or an 8-12-membered fused ring system that includes a 5-6-membered heteroaryl ring;

p is 0, 1, or 2;

each Y is independently selected from the group consisting of a bond, -CH₂-, -CH₂CH₂- -CH₂N(R15)-, -N(R15)CH₂- and -N(R15) -;

each Q is independently selected from the group consisting of aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, and substituted heteroaryl;

each Rl 5 is independently selected from the group consisting of H and lower alkyl;

m is 0, 1 or 2; each Z" is is independently selected from the group consisting of cyano,

hydroxyl, mercapto, amino, halogen, nitro, carboxyl, amidino

alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl;

where m+p has a value no greater than the number of substitutable positions on A;

provided that when A is 3-indolyl and n is 0, then p has a value of 1 or 2.

In another embodiment, the various elements and aspects of which can be practiced either separately, or in combination with the other embodiments disclosed above and below, the various substituents of Formula (I) (collectively or separately) are defined as follows:

R is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

Rl a is H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

Rib is H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

R2 is alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, alkoxy, cycloalkyl, aryl, heterocycloalkyl and heteroaryl;

R6 is H; alkylsulfonyl; arylsulfonyl; alkyl; substituted alkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkoxy, amino, nitro, cycloalkyl, aryl, heteroaryl optionally substituted with lower alkyl or halogen, alkylsulfonyl and arylsulfonyl; cycloalkyl; substituted cycloalkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; aryl; substituted aryl, wherein the substituents are selected from the group consisting of alkyl, halogen, hydroxy, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, nitro, alkylsulfonyl and arylsulfonyl; heterocycloalkyl; substituted heterocycloalkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; heteroaryl; or substituted heteroaryl, wherein the substituents are selected from the group consisting of halogen, hydroxy, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; or R6 has the following formula (IA):

where R8 is alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, alkoxy, mercapto, carboxyl, cycloalkyl, aryl, heterocycloalkyl, amino, nitro and heteroaryl;

and R9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

or, R9 has the following formula (IB):

where RlOa and RlOb are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; and

Rl l is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

A is a 5-membered heteroaryl ring, or an 8-9-membered fused ring system that includes a 5-membered heteroaryl ring, wherein said 5-membered heteroaryl ring or 8-9-membered fused ring system has 1 , 2, or 3 heteroatoms selected from N, O, and S, and

each Z" is independently selected from the group consisting of cyano, hydroxyl, mercapto, amino, halogen, nitro, carboxyl, amidino, guanidine, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl; wherein the substituents are selected from the group consisting of halogen, hydroxy, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro.

[13] In another embodiment, the various elements of which can be practiced either separately, or in combination with the other embodiments disclosed above and below, the present invention also provides compounds of Formula (I) where p is 1 or 2, and Y is selected from the group consisting of a bond, - CH₂- and -NH-, and, when p is 2, both Y groups are the same and both Q groups are the same.

[14] In another embodiment, the various elements of which can be practiced either separately, or in combination with the other embodiments disclosed above and below, A in the compound of Formula (I), is selected from the group consisting of a furan, thiophene, pyrrole, oxazole, isoxazole, pyrazole, imidazole, triazole, tetrazole, thiazole, isothiazole, indole, imidazopyridine, benzoimidazole, benzooxazole, benzothiazole, and thiazolopyridine.

In still another embodiment, the various elements or aspects of which can be practiced either separately, or in combination with the other embodiments disclosed above and below, A in formula I is selected from the group consisting of:

In other embodiments, the separate elements of which can be practiced either separately, or in combination with the other embodiments disclosed above and below, the present invention provides compounds of Formula (I-SA), (I- SB), (II-SA), (II-SB), (III-S), (IV-S), (V-S), or (VI-S) (and the corresponding pharmaceutically acceptable salts thereof):

with the various substituents, unless otherwise indicated, having the same definitions presented above in connection with all of the embodiments associated with formula (I) and including such compounds wherein Rl is alkyl or substituted alkyl, especially a lower alkyl or a substituted lower alkyl.

In related compounds, the elements of which can be practiced either separately, or in combination with the other embodiments disclosed above and below, the compounds and pharmaceutically acceptable salts of Formula (I) have the absolute configuration of formula (I-RA) as follows (with the various substituents having the same definitions presented above in connection with formula (I-SA):

In other embodiments, the various elements of which can be practiced either separately, or in combination with the other embodiments disclosed above and below, the various substituents (individually, or collectively in any permutation, i.e., in any combination of (1) through (14) below) are as follows:

(1) m is O; (2) Q is an optionally substituted phenyl;

(3) p is 0;

(4) R is selected from H, alkyl, substituted alkyl, alkenyl, or substituted alkenyl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro;

(5) Rla and Rib are each independently selected from H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro;

(6) R is H, or lower alkyl;

(7) Rl , Rla and Rib are independently selected from the group consisting of H and lower alkyl;

(8) R2 is H; lower alkyl; cycloalkyl, or substituted lower alkyl wherein the substituents are selected from the group consisting of hydroxy, and alkoxy;

(9) R6 is H; lower alkylsulfonyl; alkyl; substituted alkyl, wherein the alkyl substituents are selected from the group consisting of hydroxy, oxo, halogen, alkoxy, cycloalkyl, aryl, and heteroaryl optionally substituted with lower alkyl or halogen; cycloalkyl; or heteroaryl optionally substituted with lower alkyl or halogen; or R6 has the following formula (IA):

wherein R8 is H, lower alkyl, cycloalkyl, or substituted lower alkyl wherein the substituents are selected from the group consisting of hydroxy, and alkoxy; and

R9 is H, or lower alkyl; or R9 has the following formula (IB):

where RlOa and RlOb are independently selected from the group consisting of H, and lower alkyl; and

Rl 1 is H, or lower alkyl;

(10) Y is a -CH₂-, or -NH-;

(11) R15 is H;

(12) Z" is independently selected from the group consisting of cyano, hydroxyl, mercapto, amino, halogen, nitro, carboxyl, amidino

and guan no

(13) XI is O; and

(14) X2 is O.

[19] In other embodiments, the various elements of which can be practiced either separately, or in combination with the other embodiments disclosed above and below, various substituents of Formula (I) are as follows:

(1) m is 0; n is 0; Y is a bond, and p is 1 ; or

(2) m is 0; n is 0; Y is -CH₂-, or -NH-, and p is 1 ; or

(3) m is 0; n is 0; Y is a bond, and p is 2; or

(4) m is 0; n is 0; Y is -CH₂-, or -NH-, and p is 2; or

(5) m is 0; n is 1 , Y is a bond, and p is 1 ; or

(6) m is 0; n is 1 ; Y is a bond, and p is 2; or

(7) m is 0; n is 1 , Y is -CH₂- or -NH-, and p is 1 ; or

(8) m is 0; n is 1 ; Y is -CH₂-, or -NH-, and p is 2.

[20] In all of the embodiments identified above and below, dimers also can be prepared that effectively constitute the linking together of two individual monomers and such dimers also are encompassed within the scope of this invention. Dimerization of monomelic Smac mimetics has been shown to provide useful Smac mimetics. See, e.g., US7517906, US20080020986, WO200814236, WO200814238, and WO200814240, all of which are incorporated herein by reference as though fully set forth herein.

Dimeric Smac mimetics of the invention generally comprise the formula "Formula (I) -L- Formula (I)", as depicted below:

Other dimeric Smac mimetics of the invention constitute Formula (I-SA)-L- Formula (I-SA); Formula (I-SA)-L-Formula (I-RA); Formula- (I-SB)-L- Formula (I-SB); Formula (II-SA)-L-Formula (II-SA); Formula (II-SB)-L- Formula (II-SB); Formula (III-S)-L-Formula (III-S); Formula (IV-S)-L- Formula (IV-S); Formula (V-S)-L-Formula (V-S); Formula (VI-S)-L- Formula (VI-S), or other combinations i.e.,

In these formulae L is a "Linker" (L), i.e., bond or linking group whereby two chemical moieties are directly covalently linked one to the other or are indirectly linked via a chemical moiety that covalently links the two chemical moieties, in either case, to form a homo- or heterodimer. A Linker (L), therefore, is a single or double covalent bond or is a contiguous chain, branched or unbranched, substituted or unsubstituted, of 1 to about 100 atoms, typically 1 to about 30 atoms and typically up to about 500 MW, e.g., optionally substituted alkyl, alkylene, alkylyne, cycloalkyl, alkylcycloalkyl, alkylarylalkyl chain of 2 to 20 atoms with 1-4 heteroatoms selected from -0-, -NH- and -S-. Illustrative Linkers are described, e.g., in US7517906, US7309792, US20080020986, WO200814236, WO200814238, and

WO200814240, US 20050197403, US7589118, WO2010031 171,

WO2007131366, WO2007104162, and WO2008134679 all of which are incorporated herein by reference as though fully set forth.

[23] Illustrative -L- groups include the following:

1) -Cl-C10 alkyl-,

2) --C2-C6 alkenyl-,

3) --C2-C4 alkynyl-,

4) -C3-C7 cycloalkyl-,

5) -phenyl-,

6) -biphenyl-,

7) -heteroaryl-,

8) -heterocyclyl-,

9) -C1-C6 alkyl-(C2-C6 alkenyl)-Cl-C6 alkyl-,

10) -C1-C6 alkyl-(C2-C4 alkynyl)-Cl-C6 alkyl-,

11) -C1-C6 alkyl-(C3-C7 cycloalkyl)-Cl-C6 alkyl-,

12) -C1-C6 alkyl-phenyl-Cl-C6 alkyl-,

13) -C1-C6 alkyl-biphenyl-Cl-C6 alkyl-,

14) -C1 -C6 alkyl-heteroaryl-Cl-C6 alkyl-,

15) -C1-C6 alkyl-heterocyclyl-Cl-C6 alkyl-,

16) -C1-C6 alkyl-0-Cl-C6 alkyl-,

17) -C(0)-N-C(0)- wherein N is cyclohexyl, phenyl, naphthyl or biphenyl optionally substituted with Rx and Rx is C1-C6 alkyl or C6- C10 aryl optionally substituted with C1 -C6 alkyl,

18) -C(0)CH₂NHC(0)C(0)NHCH₂C(0)-.

[24] For additional linkers, see, e.g., WO2007131366 and WO2007104162.

[25] More specifically, in this and related embodiments, the invention provides compounds that are a dimers of two monomers of Formula (I), or two monomers of Formula (I-SA) or one monomer of Formula (I-SA) and one monomer of Formula (I-SR), or two monomers of Formula (I-SB), or two monomers of Formula (II-SA), or two monomers of Formula (II-SB), or two monomers of Formula (III-S), or two monomers of Formula (IV-S), or two monomers of Formula (V-S), or or two monomers of Formula (VI-S), or pharmaceutically acceptable salts thereof, wherein the various substituents can have the meanings set out in detail above for the various monomer components.

Prefereably, dimers are prepared by linking two independently substituted monovalent compounds either through the R2 positions, or through the R6 positions, such that the R2 or R6 group on one monomer and the respective R2 group or R6 group on the other monomer together form -L-. For example, in the noted dimer formulae:

XI is O, or S;

X2 is O, or S;

Rla and Rib are each independently H, alkyl, or substituted alkyl;

both R2 groups together, or both R6 groups together, form -L-, linking the two monomers;

when both R6 groups together form -L-, then each R2 independently is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

when both R2 groups together form -L-, then each R6 independently is H, alkyl, substituted alkyl, alkylsulfonyl, arylsulfonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or each R6 independently has the following formula (IA):

where R8 is H, alkyl, substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R9 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or R9 has the following formula

(IB):

where RlOa and RlOb are independently H, alkyl, or substituted alkyl; and Rl l is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

L is a single or double covalent bond, or is a contiguous chain, branched or unbranched, substituted or unsubstituted, of 1 to about 100 atoms

R12 is H or hydroxy;

n is 0 or 1 ;

p is 0, 1, or 2;

each Y is independently a bond, -CH₂-, -CH₂CH₂- -CH₂N(R15)-, -N(R15)CH₂- or -N(R15) -; each Q is independently aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl;

each R15 is independently selected from H and lower alkyl;

m is 0, 1 or 2; each Z" is independently cyano, hydroxyl, mercapto, amino, halogen, nitro, carboxyl, amidino, guanidine, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl;

provided that when A is 3-indolyl and n is 0, then p has a value of 1 or 2; and wherein each of R, Rla, Rib, R2, R6, R12, Z", Y, Q, m, n, and p of each of the separate monomers is independently selected. Thus, both homodimers and heterodimers are contemplated.

In other embodiments, the elements of which can be practiced either separately, or in combination with the other embodiments disclosed above and below, the present invention also provides a compound that is a dimer of two monomers as indicated above, or a pharmaceutically acceptable salt thereof, wherein:

XI is O;

X2 is O;

Rl a and Rib are each independently (or Rl is) H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

when both R6 groups together form -L-, then each R2 is alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, alkoxy, cycloalkyl, aryl, heterocycloalkyl and heteroaryl; when both R2 groups together form -L-, then each R6 is H; alkylsulfonyl; arylsulfonyl; alkyl; substituted alkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkoxy, amino, nitro, cycloalkyl, aryl, heteroaryl optionally substituted with lower alkyl or halogen, alkylsulfonyl and arylsulfonyl; cycloalkyl; substituted cycloalkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; aryl; substituted aryl, wherein the substituents are selected from the group consisting of alkyl, halogen, hydroxy, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, nitro, alkylsulfonyl and arylsulfonyl; heterocycloalkyl; substituted heterocycloalkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; heteroaryl; or substituted heteroaryl, wherein the substituents are selected from the group consisting of halogen, hydroxy, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; or R6 has the following formula (IA):

where R8 is alkyl, cycloalkyl, aryl, heterocycloalkyl,

heteroaryl, or substituted alkyl, wherein the substituents are

selected from the group consisting of halogen, hydroxy, oxo, alkoxy, mercapto, carboxyl, cycloalkyl, aryl, heterocycloalkyl, amino, nitro and heteroaryl;

and R9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; or, R9 has the following formula (IB):

where RlOa and RlOb are independently H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; and

Rl 1 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

A is a 5-membered heteroaryl ring, or an 8-9-membered fused ring system that includes a 5-membered heteroaryl ring, wherein said 5-membered heteroaryl ring or 8-9-membered fused ring system has 1 , 2, or 3 heteroatoms selected from N, O, and S;

L is a single or double covalent bond, or is a contiguous chain, branched or unbranched, substituted or unsubstituted, of 1 to about 100 atoms; and wherein each of R, Rla, Rib, Rl , R2, R6, R12, Z", Y, Q, m, n, and p of each of the separate monomers is independently selected. Again, both homodimers and heterodimers are contemplated.

In other embodiments, the elements of which can be practiced either separately, or in combination with the other embodiments disclosed above and below, the present invention also provides a compound that is a dimer of two monomers as indicated above, or a pharmaceutically acceptable salt thereof, wherein (together or independently):

(1) m is 0, or

(2) Q is an optionally substituted phenyl, or

(3) p is 0, or (4) R is H, alkyl, substituted alkyl, alkenyl, or substituted alkenyl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro, or

(5) Rla and Rib are each independently (or Rl is) H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro, or

(6) R is H, or lower alkyl, or

(7) Rla and Rib are independently (or Rl is) H and lower alkyl, or

(8) R2 is H; lower alkyl; cycloalkyl, or substituted lower alkyl wherein the substituents are selected from the group consisting of hydroxy, and alkoxy, or

R9 is H, or lower alkyl; or R9 has the following formula (IB):

where RlOa and RlOb are independently H, or lower alkyl; and Rl 1 is selected from H, or lower alkyl, or (13) Y is a -CH₂- or -NH-, or

(14) R15 is H, or

(15) Z" is independently cyano, hydroxyl, mercapto, amino, halogen, nitro,

carboxyl,

any combination of (1) through (12) above;

(16) XI is O and X2 is O;

L is a single or double covalent bond, or is a contiguous chain, branched or unbranched, substituted or unsubstituted, of 1 to about 100 atoms; and wherein each of R, Rl a, Rib, Rl, R2, R6, R12, Z, Y, Q, m, n, and p of each of the separate monomers is independently selected. Again, both homodimers and heterodimers are contemplated.

[29] In all of the embodiments identified above, the pharmaceutically acceptable salts of the compounds embraced by the foregoing formulae are also included in each of the embodiments.

[30] For simplicity and illustrative purposes, the principles of the invention are described by referring mainly to specific illustrative embodiments thereof. In addition, in the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. It will be apparent however, to one of ordinary skill in the art, that the invention may be practiced without limitation to these specific details. In other instances, well known methods and structures have not been described in detail so as not to unnecessarily obscure the invention.

DEFINITIONS

[31] "Alkyl" (monovalent) and "alkylene" (divalent) when alone or as part of another term (e.g., alkoxy) mean branched or unbranched, saturated aliphatic hydrocarbon group, having up to 12 carbon atoms unless otherwise specified. Examples of particular alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2- methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2- methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, and the like. The term, "lower," when used to modify alkyl, alkenyl, etc., means 1 to 4 carbon atoms, branched or linear so that, e.g.,the terms "lower alkyl", "Q-C₄ alkyl" and "alkyl of 1 to 4 carbon atoms" are synonymous and used interchangeably to mean methyl, ethyl, 1- propyl, isopropyl, 1 -butyl, sec-butyl or t-butyl. Examples of alkyl ene groups include, but are not limited to, methylene, ethylene, n-propylene, n-butylene and 2-methyl- butylene.

The term substituted alkyl refers to alkyl moieties having substituents replacing one or more hydrogens on one or more (often no more than four) carbon atoms of the hydrocarbon backbone. Such substituents are independently selected from the group consisting of: a halogen (e.g., I, Br, CI, or F, particularly fluoro (F)), hydroxy, amino, cyano, mercapto, alkoxy (such as a Q-C₆ alkoxy, or a lower (Q-C4) alkoxy, e.g., methoxy or ethoxy to yield an alkoxyalkyl), aryloxy (such as phenoxy to yield an aryloxyalkyl), nitro, oxo (e.g., to form a carbonyl), carboxyl (which is actually the combination of an oxo and hydroxy substituent on a single carbon atom), carbamoyl (also known as an aminocarbonyl such as NH₂C(0)-, which is the substitution of an oxo and an amino (NH₂) on a single carbon atom), cycloalkyl (e.g., a cycloalkylalkyl), aryl (resulting for example in aralkyls such as benzyl or phenylethyl), heterocyclolalkyl (e.g., heterocycloalkylalkyl), heteroaryl (e.g., heteroarylalkyl), alkylsulfonyl (including lower alkylsulfonyl such as methylsulfonyl), arylsulfonyl (such as phenylsulfonyl), and -OCF3 (which is a halogen substituted alkoxy). The invention further contemplates that several of these alkyl substituents, including specifically alkoxy, cycloalkyl, aryl, heterocyclyalkyl and heteroaryl, are optionally further substituted as defined in connection with each of their respective definitions provided below. In addition, certain alkyl substituent moieties result from a combination of such substitutions on a single carbon atom. For example, an ester moiety, e.g., an alkoxycarbonyl such as methoxycarbonyl, or tert-butoxycarbonyl (Boc) results from such multiple substitution on a single carbon atom. In particular, methoxycarbonyl and Boc are substituted alkyls that result from the substitution on a methyl group (-CH₃) of both an oxo (=0) and an unsubstituted alkoxy, e.g., a methoxy (CH -0) or a tert-butoxy ((CH₃)₃C-0-), respectively replacing the three hydrogens. Similarly, an amide moiety, e.g., an alkylaminocarbonyl, such as dimethlyaminocarbonyl or methylaminocarbonyl, is a substituted alkyl that results from the substitution on a methyl group (-CH₃) of both an oxo (=0) and a mono- unsubstitutedalkyl amino or, diunsubstitutedalkylamino, e.g., dimethylamino (- N-(CH₃)₂), or methylamino (-NH-(CH₃)) replacing the three hydrogens (similarly an arylaminocarbonyl such as diphenylaminocarbonyl is a substituted alkyl that results from the substitution on a methyl group (-CH₃) of both an oxo (=0) and a mono-unsubstitutedaryl(phenyl)amino). Exemplary substituted alkyl groups further include cyanomethyl, nitromethyl, hydroxyalkyls such as hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminoalkyls such as aminomethyl, carboxylalkyls such as carboxymethyl, carboxyethyl, carboxypropyl, 2,3-dichloropentyl, 3-hydroxy-5-carboxyhexyl, acetyl (e.g., an alkanoyl, where in the case of acetyl the two hydrogen atoms on the -CH₂ portion of an ethyl group are replaced by an oxo (=0)), 2- aminopropyl, pentachlorobutyl, trifluoromethyl, methoxyethyl, 3- hydroxypentyl, 4-chlorobutyl, 1 ,2-dimethyl-propyl, pentafluoroethyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t- butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6- hydroxyhexyl, 2,4-dichloro (n-butyl), 2-amino (iso-propyl), cycloalkylcarbonyl (e.g., cuclopropylcarbonyl) and 2-carbamoyloxyethyl. Particular substituted alkyls are substituted methyl groups. Examples of substituted methyl groups include groups such as hydroxymethyl, protected hydroxymethyl (e.g., tetrahydropyranyl- oxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl, carboxyl (where the three hydrogen atoms on the methyl are replaced, two of the hydrogens are replaced by an oxo (=0) and the other hydrogen is replaced by a hydroxy (-OH)), tert- butoxycarbonyl (where the three hydrogen atoms on the methyl are replaced, two of the hydrogens are replaced by an oxo (=0) and the other hydrogen is replaced by a tert-butoxy (-0-C(CH₃)₃), bromomethyl and iodomethyl. When the specification and especially the claims refer to a particular substuituent for an alkyl, that substituent can potentially occupy one or more of the substitutable positions on the alkyl. For example, reciting that an alkyl has a fluoro substituent, would embrace mono-, di-, and possibly a higher degree of substitution on the alkyl moiety.

[33] The term substituted alkylene refers to alkylene moieties having substituents replacing one or more hydrogens on one or more (often no more than four) carbon atoms of the hydrocarbon backbone where the alkylene is similarly substituted with groups as set forth above for alkyl.

[34] Alkoxy is -O-alkyl. A substituted alkoxy is -O-substituted alkyl, where the alkoxy is similarly substituted with groups as set forth above for alkyl. One substituted alkoxy is acetoxy where two of the hydrogens on one of the carbon atoms in ethoxy (e.g., ~0-CH₂-CH₃) are replaced by an oxo, (=0) to yield -O- C(0)-CH₃; another is an aralkoxy where one of the hydrogens on a carbon atom in the alkoxy is replaced by an aryl, such as benzyloxy, and another is a carbamate where two of the hydrogens on methoxy (e.g., -0-CH₃) are replaced by oxo (=0) and the other hydrogen is replaced by an amino (e.g., -NH₂, - NHR or -NRR) to yield, for example, -0-C(0)-NH₂. A lower alkoxy is -O- lower alkyl.

[35] "Alkenyl" (monovalent) and "alkenylene" (divalent) when alone or as part of another term mean an unsaturated hydrocarbon group containing at least one carbon-carbon double bond, typically 1 or 2 carbon-carbon double bonds, which hydrocarbon group may be linear or branched and which have at least 2 and up to 12 carbon atoms unless otherwise specified. Representative alkenyl groups include, by way of example, vinyl, allyl, isopropenyl, but-2-enyl, n- pent-2-enyl, and n-hex-2-enyl.

[36] The terms substituted alkenyl and substituted alkenylene refer to alkenyl and alkenylene moieties having substituents replacing one or more hydrogens on one or more (often no more than four) carbon atoms of the hydrocarbon backbone. Such substituents are independently selected from the group consisting of: halo (e.g., I, Br, CI, F), hydroxy, amino, cyano, alkoxy (such as Q-C alkoxy), aryloxy (such as phenoxy), nitro, mercapto, carboxyl, oxo, carbamoyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl and -OCF₃.

[37] "Alkynyl" means a monovalent unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, typically 1 carbon-carbon triple bond, which hydrocarbon group may be linear or branched and which have at least 2 and up to 12 carbon atoms unless otherwise specified. Representative alkynyl groups include, by way of example, ethynyl, propargyl, and but-2-ynyl.

[38] "Cycloalkyl" when alone or as part of another term means a saturated or partially unsaturated cyclic aliphatic hydrocarbon group (carbocycle group), having up to 12 carbon atoms unless otherwise specified, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and further includes polycyclic, including fused cycloalkyls such as 1 ,2,3,4-tetrahydonaphthalenyls (1 ,2,3,4- tetrahydonaphthalen-l-yl, and l ,2,3,4-tetrahydonaphthalen-2-yl), indanyls (indan-lyl, and indan-2-yl), isoindenyls (isoinden-l-yl, isoinden-2-yl, and isoinden-3-yl) and indenyls (inden-l-yl, inden-2-yl and inden-3-yl). A lower cycloalkyl has from 3 to 6 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[39] The term substituted cycloalkyl refers to cycloalkyl moieties having substituents replacing one or more hydrogens on one or more (often no more than four) carbon atoms of the hydrocarbon backbone. Such substituents are independently selected from the group consisting of: halo (e.g., I, Br, CI, F), hydroxy, amino, cyano, alkoxy (such as C]-C₆ alkoxy), substituted alkoxy, aryloxy (such as phenoxy), nitro, mercapto, carboxyl, oxo, carbamoyl, alkyl, substituted alkyls such as trifluoromethyl, aryl, substituted aryls, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl and -OCF₃. When the specification and especially the claims refer to a particular substuituent for a cycloalkyl, that substituent can potentially occupy one or more of the substitutable positions on the cycloalkyl. For example, reciting that a cycloalkyl has a fluoro substituent, would embrace mono-, di-, and a higher degree of substitution on the cycloalkyl moiety. Examples of cycloalkyls include cyclopropy, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl and indanyl.

[40] "Amino" denotes primary (i.e., -NH₂), secondary (i.e., -NHR) and tertiary (i.e., -NRR) amines, where the R groups can be the same or different and can be selected from a variety of moieties, usually an alkyl, a substituted alkyl, an aryl, a substituted aryl, a cycloalkyl, or a substituted cycloalkyl and especially a lower alkyl and an aryl (phenyl), including substituted phenyl. Particular secondary and tertiary aminos are alkylaminos, dialkylaminos, arylaminos, diarylaminos, aralkylaminos and diaralkylaminos. Particular secondary and tertiary amines are methylamino, ethylamino, propylamino, isopropylamino, phenylamino, benzylamino dimethylamino, diethylamino, dipropylamino and disopropylamino.

[41] "Aryl" when used alone or as part of another term means an aromatic carbocyclic group whether or not fused having the number of carbon atoms designated, or if no number is designated, from 6 up to 14 carbon atoms. Particular aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e. g. Lang's Handbook of Chemistry (Dean, J. A., ed) 13^th ed. Table 7-2 [1985]). Phenyl and naphthyl groups are generally preferred.

[42] The term substituted aryl refers to aryl moieties having substituents replacing one or more hydrogens on one or more (usually no more than six) carbon atoms of the aromatic hydrocarbon core. Such substituents are independently selected from the group consisting of: halo (e.g., I, Br, CI, F), hydroxy, amino, cyano, alkoxy (such as Ci-C₆ alkoxy and particularly lower alkoxy), substituted alkoxy, aryloxy (such as phenoxy), nitro, mercapto, carboxyl, carbamoyl, alkyl, substituted alkyl (such as trifluoromethyl), aryl, -OCF₃, alkylsulfonyl (including lower alkylsulfonyl), arylsulfonyl, heterocyclyl and heteroaryl. Examples of such substituted phenyls include but are not limited to a mono-or di (halo)-substituted phenyl groups such as 2-chlorophenyl, 2- bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4- dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl; 3 -fluorophenyl, 4- fluorophenyl, 3,4-diflurorphenyl, a mono-or di (hydroxy) phenyl group such as 4-hydroxyphenyl, 3- hydroxyphenyl, 2,4-dihydroxyphenyl, the protected- hydroxy derivatives thereof; a nitrophenyl group such as 3-or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono-or di (lower alkyl) phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2- methylphenyl, 4- (iso-propyl) phenyl, 4-ethylphenyl, 3- (n-propyl) phenyl; a mono or di (alkoxy) phenyl group, for example, 3,4-dimethoxyphenyl, 3-methoxy-4- benzyloxyphenyl, 3- methoxy-4- (1-chloromethyl) benzyloxy-phenyl, 3- ethoxyphenyl, 4- (isopropoxy) phenyl, 4- (t-butoxy) phenyl, 3-ethoxy-4- methoxyphenyl; 3 -or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy) phenyl group such 4-carboxyphenyl,; a mono-or di (hydroxym ethyl) phenyl or (protected hydroxymethyl) phenyl such as 3- (protected hydroxymethyl) phenyl or 3,4-di (hydroxymethyl) phenyl; a mono- or di (aminomethyl) phenyl or (protected aminomethyl) phenyl such as 2- (aminomethyl) phenyl or 2, 4- (protected aminomethyl) phenyl; or a mono-or di (N- (methylsulfonylamino)) phenyl such as 3- (N- methylsulfonylamino) phenyl. Also, the substituents, such as in disubstituted phenyl groups, can be the same or different, for example, 3-methyl-4-hydroxyphenyl, 3- chloro-4- hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3- hydroxy-4- nitrophenyl, 2-hydroxy-4-chlorophenyl, as well as for trisubstituted phenyl groups where the substituents are different, as for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino, 3- methoxy-4- benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy-4-benzyloxy-5-methyl-6- phenyl sulfonylamino. Particular substituted phenyl groups are 2- chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3- methoxyphenyl, 3-ethoxy- phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4- benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4- (1- chloromethyl) benzyloxy-phenyl, 3-methoxy-4- (1-chloromethyl) benzyloxy- 6-methyl sulfonyl aminophenyl groups. When the specification and especially the claims refer to a particular substuituent for an aryl, that substituent can potentially occupy one or more of the substitutable positions on the aryl. For example, reciting that an aryl has a fluoro substituent, would embrace mono-, di-, tri, tetra and a higher degree of substitution on the aryl moiety. Fused aryl rings may also be substituted with the substituents specified herein, for example with 1, 2 or 3 substituents, in the same manner as substituted alkyl groups. The terms aryl and substituted aryl do not include moieties in which an aromatic ring is fused to a saturated or partially unsaturated aliphatic ring. [43] Aryloxy is -O-aryl. A substituted aryloxy is -O-substituted aryl, where the suitable substituents are those described for a substituted aryl.

[44] "Heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl", "heterocycloalkyl" or "heterocyclo" alone and when used as a moiety in a complex group, are used interchangeably and refer to any mono-, bi-, or tricyclic, saturated or unsaturated, non-aromatic hetero-atom-containing ring system having the number of atoms designated, or if no number is specifically designated then from 5 to about 14 atoms, where the ring atoms include both carbon atoms and at least one heteroatom and usually not more than four heteroatoms (i.e., nitrogen, sulfur or oxygen). Included in the definition are any bicyclic groups where any of the above heterocyclic rings are fused to an aromatic ring (i.e., an aryl (e.g., benzene) or a heteroaryl ring). The heterocycloalkyl can be bonded to a core structure through either a ring carbon or a ring heteroatom, as appropriate. In a particular embodiment the group incorporates 1 to 4 heteroatoms. Typically, a 5- membered ring has 0 to 1 double bonds and a 6-or 7-membered ring has 0 to 2 double bonds and the nitrogen or sulfur heteroatoms may optionally be oxidized (e. g. SO, S0₂), and any nitrogen heteroatom may optionally be quaternized. Particular unsubstituted non-aromatic heterocycles include morpholinyl (morpholino), pyrrolidinyls, oxiranyl, indolinyls (e.g., 2,3-dihydroindolyl), isoindolinyls, tetrahydroquinolinyls, tetrahydroisoquinolinyls, oxetanyl, tetrahydrofuranyls, 2,3- dihydrofuranyl, 2H-pyranyls, tetrahydropyranyls, aziridinyls, azetidinyls, 1 -methyl-2-pyrrolyl, piperazinyls and piperidinyls.

[45] The term substituted heterocycloalkyl (and the like) refers to heterocycloalkyl moieties having substituents replacing one or more hydrogens on one or more (usually no more than six) atoms of the heterocycloalkyl backbone. Such substituents are independently selected from the group consisting of: halo (e.g., I, Br, CI, F), hydroxy, amino, cyano, alkoxy (such as C|-C₆ alkoxy), substituted alkoxy, aryloxy (such as phenoxy), nitro, carboxyl, oxo, carbamoyl, alkyl, substituted alkyl (such as trifluoromethyl), -OCF₃, aryl, substituted aryl, alkylsulfonyl (including lower alkylsulfonyl), and arylsulfonyl. When the specification and especially the claims refer to a particular substuituent for a heterocycloalkyl, that substituent can potentially occupy one or more of the substitutable positions on the heterocycloalkyl. For example, reciting that a heterocycloalkyl has a fluoro substituent, would embrace mono-, di-, tri, tetra and a higher degree of substitution on the heterocycloalkyl moiety.

"Heteroaryl" alone and when used as a moiety in a complex group refers to any mono-, bi-, or tricyclic aromatic ring system having the number of atoms designated, or if no number is specifically designated then at least one ring is a 5-, 6- or 7-membered ring and the total number of atoms is from 5 to about 14 and containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur (Lang's Handbook of Chemistry, supra). Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to a benzene ring. The heteraryl can be bonded to a core structure through either a ring carbon or a ring heteroatom, as appropriate. The following ring systems are examples of the heteroaryl groups denoted by the term "heteroaryl": thienyls (alternatively called thiophenyl), furyls, imidazolyls, pyrazolyls, thiazolyls, isothiazolyls, oxazolyls, isoxazolyls, triazolyls, thiadiazolyls, oxadiazolyls, tetrazolyls, thiatriazolyls, oxatriazolyls, pyridyls, pyrimidinyls (e.g., pyrimidin-2-yl), pyrazinyls, pyridazinyls, thiazinyls, oxazinyls, triazinyls, thiadiazinyls, oxadiazinyls, dithiazinyls, dioxazinyls, oxathiazinyls, tetrazinyls, thiatriazinyls, oxatriazinyls, dithiadiazinyls, imidazolinyls, dihydropyrimidyls, tetrahydropyrimidyls, tetrazolo [1, 5-b] pyridazinyl and purinyls, as well as benzo-fused derivatives, for example benzoxazolyls, benzofuryls, benzothienyls, benzothiazolyls, benzothiadiazolyl, benzotriazolyls, benzoimidazolyls, isoindolyls, indazolyls, indolizinyls, indolyls, naphthyridines, pyridopyrimidines, phthalazinyls, quinolyls, isoquinolyls and quinazolinyls.

The term substituted heteroaryl refers to heteroaryl moieties (such as those identified above) having substituents replacing one or more hydrogens on one or more (usually no more than six) atoms of the heteroaryl backbone. Such substituents are independently selected from the group consisting of: halo (e.g., I, Br, CI, F), hydroxy, amino, cyano, alkoxy (such as Ci-C₆ alkoxy), aryloxy (such as phenoxy), nitro, mercapto, carboxyl, carbamoyl, alkyl, substituted alkyl (such as trifluoromethyl), -OCF₃, aryl, substituted aryl, cycloalkyl, heterocycloalkyl, heteroaryl alkylsulfonyl (including lower alkylsulfonyl), and arylsulfonyl. When the specification and especially the claims refer to a particular substuituent for a heteroaryl, that substituent can potentially occupy one or more of the substitutable positions on the heteroaryl. For example, reciting that a heteroaryl has a fluoro substituent, would embrace mono-, di-, tri, tetra and a higher degree of substitution on the heteroaryl moiety.

Particular "heteroaryls" (including "substituted heteroaryls") include; 1H- pyrrolo[2,3-6]pyridine, 1 , 3-thiazol-2-yl, 4- (carboxymethyl)-5-methyl-l , 3- thiazol-2-yl, 1 ,2,4-thiadiazol-5-yl, 3- methyl-1, 2,4-thiadiazol-5-yl, 1 ,3,4- triazol-5-yl, 2-methyl-l , 3, 4-triazol-5-yl, 2-hydroxy-l ,3,4- triazol-5-yl, 2- carboxy-4-methyl-l ,3,4-triazol-5-yl , 1 , 3-oxazol-2-yl, 1 , 3,4-oxadiazol-5-yl,

2- methyl-l, 3,4-oxadiazol-5-yl, 2- (hydroxymethyl)- 1, 3,4-oxadiazol-5-yl, 1 ,

2.4- oxadiazol-5-yl, 1, 3,4-thiadiazol-5-yl, 2-thiol-l, 3,4-thiadiazol-5-yl, 2- (methylthio)-l , 3,4-thiadiazol-5-yl, 2-amino-l, 3,4-thiadiazol-5-yl, 1H- tetrazol-5-yl, 1-methyl-lH- tetrazol-5-yl, 1-(1 -(dimethyl amino) eth-2-yl)-l H- tetrazol-5-yl, l -(carboxymethyl)-l H-tetrazol-5-yl, 1- (methylsulfonic acid)- lH-tetrazol-5-yl, 2-methyl-lH-tetrazol-5-yl, 1, 2,3-triazol-5-yl, 1 -methyl-1, 2,3- triazol-5-yl, 2-methyl-l, 2,3-triazol-5-yl, 4-methyl-l, 2,3-triazol-5-yl, pyrid-2- yl N- oxide, 6-methoxy-2- (n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl, 1- methylpyrid-2-yl, 1- methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1 ,4, 5,6- tetrahydro-5, 6-dioxo-4-methyl-as-triazin-3-yl, 1 , 4,5, 6-tetrahydro-4- (formylmethyl)-5, 6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy- astriazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl , 2,5-dihydro-5- oxo-6- hydroxy-2-methyl-astriazin-3-yl , 2,5-dihydro-5-oxo-6-hydroxy-2- methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl,

2.5- dihydro-5-oxo-as-triazin-3-yl, 2,5- dihydro-5-oxo-2-methyl-as-triazin-3- yl, 2,5-dihydro-5-oxo-2, 6-dimethyl-as-triazin-3-yl, tetrazolo [1 , 5-b] pyridazin-6-yl, 8-aminotetrazolo [1, 5-b] -pyridazin-6-yl, quinol-2-yl, quinol-

3- yl, quinol-4-yl, quinol-5-yl, quinol-6-yl, quinol-8-yl, 2-methyl-quinol-4-yl, 6-fluoro-quinol-4-yl, 2-methyl,8-fluoro-quinol-4-yl, isoquinol-5-yl, isoquinol- 8-yl, isoquinol-l -yl, and quinazolin-4-yl. An alternative group of "heteroaryl" includes: 5-methyl-2-phenyl-2H-pyrazol-3-yl, 4- (carboxymethyl)-5-methyl-l, 3-thiazol-2-yl, 1, 3,4-triazol-5-yl, 2-methyl-l, 3,4-triazol-5-yl, lH-tetrazol-5- yl, 1 -methyl- lH-tetrazol-5-yl, l-(l-(dimethylamino) eth-2-yl)-lH-tetrazol-5-yl, l-(carboxymethyl)- lH-tetrazol-5-yl, 1- (methylsulfonic acid)-lH- tetrazol-5- yl, 1, 2,3-triazol-5-yl, 1,4, 5,6- tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1, 4,5, 6-tetrahydro-4- (2-formylmethyl)-5, 6-dioxo- as-triazin-3-yl, 2, 5- dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl , 2,5-dihydro-5- oxo-6- hydroxy-2-methyl-as-triazin-3-yl, tetrazolo [1, 5-b] pyridazin-6-yl, and 8- aminotetrazolo [1 , 5- b] pyridazin-6-yl.

[49] "IAP Inhibitor" or "IAP antagonist" means a compound (1) which interferes with the physiological function of an IAP protein, including the binding of IAP proteins to caspase proteins, for example by reducing or preventing the binding of IAP proteins to caspase proteins, or (2) which reduces or prevents the inhibition of apoptosis by an IAP protein, or (3) which binds to an IAP BIR domain in a manner similar to the binding of the amino terminal portion of Smac, or (4) has any two, or all three of the preceding functions.

[50] As used herein, the terms "pharmaceutically acceptable", "physiologically tolerable" and grammatical variations thereof, as they refer to compositions, excipients, carriers, diluents and reagents, are used interchangeably and represent that the materials can be administered to a subject or patient, especially a human patient.

[51] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[52] "Pharmaceutically acceptable acid addition salt" refers to those non-toxic salts which retain the biological effectiveness and essential properties of the associated free bases and which are not biologically or otherwise undesirable, and are formed with inorganic acids and with organic acids. The acid addition salts of the basic compounds are prepared by contacting the free base form of the compound with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms generally differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents.

[53] "Pharmaceutically acceptable base addition salts" refer to those non-toxic salts which retain the biological effectiveness and essential properties of the associated free acids and which are not biologically or otherwise undesirable and are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or with organic amines. The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms usually differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents.

[54] The terms "treating", "treat" or "treatment" and the like include preventative (e.g., prophylactic) and palliative treatment.

[55] As used herein "subject" or "patient" refers to an animal or mammal including, but not limited to, human, dog, cat, horse, cow, pig, sheep, goat, chicken, monkey, rabbit, rat, and mouse.

[56] As used herein, the term "therapeutic" refers to the amelioration of, the prevention of, an improvement of, or a delay in the onset of one or more symptoms of an unwanted condition or disease of a patient. Embodiments of the present invention are directed to therapeutic treatments by promoting apoptosis, and thus cell death.

[57] The terms "therapeutically effective amount" or "effective amount", as used herein, means an amount of a compound, or a pharmaceutically acceptable salt thereof, often as part of a pharmaceutical composition, sufficient to inhibit, halt, ameliorate, attenuate, delay the onset of, or cause ah improvement in one or more symptoms of the disease being treated when administered alone or in conjunction with another pharmaceutical agent for treatment in a particular subject or subject population. For example in a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated.

[58] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration to a patient.

DETAILED DESCRIPTION OF THE INVENTION

[59] It has been demonstrated in accordance with the present invention that the IAP -binding compounds of the present invention, which are Smac mimetics, are capable of potentiating apoptosis of cells.

[60] Compounds of the present invention can be used in their free base or free acid forms or in the form of their pharmaceutically-acceptable salts. In the practice of the present invention, compounds of the present invention in their free base or free acid forms generally will have a molecular weight of 1000 or below, most often a molecular weight of 800 or below and often a molecular weight of 600 or below.

[61] The following preparations and schemes are illustrative of synthesis of compounds of the present invention. Abbreviations which are used throughout these schemes and in the application generally, are identified in the following table:

* As is a commonly accepted convention, depending on the context, which will be apparent to those skilled in the art, a vacant terminal bond may be used to indicate either a methyl group, or the point of attachment to another structure for a radical.

[62] Abbreviations for NMR data reported in the following examples are as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, ddd=doublet of doublet of doublets, dt=doublet of triplets, app=apparent, br=broad, δ indicates the chemical shift; J and JCF indicate NMR coupling constants measured in Hertz.

[63] The binding affinities of compounds of the present invention to XIAP BIR-3 or to cIAP-1 BIR-3 (as reported below as ranges) were determined substantially as described by Nikolovska-Coleska, Z. et.al. (Analytical Biochemistry (2004), vol. 332:261-273 and incorporated herein by reference) using as the fluorogenic substrate: the fluorescently labeled peptide AbuRPF- K(5-Fam)-NH2. The binding affinities of the compounds are reported as a KD value (μΜ). Briefly, various concentrations of test peptides were mixed with 5 nM of the fluorescently labeled peptide (i.e., a mutated N-terminal Smac peptide - AbuRPF-K(5-Fam)-NH₂) and 40 nM of the respective IAP BIR3 for 15 min at RT in 100 mL of 0.1M Potassium Phosphate buffer, pH 7.5 containing 100 mg/ml bovine g-globulin. Following incubation, the polarization values (mP) were measured on a Victor2V (available from PerkinElmer Life Sciences) using a 485 nm excitation filter and a 520 nm emission filter. The reported binding affinities (KD values) are supplied as ranges (A = < 0.1 mM, B = 0.1 mM to 1 mM, C = >1 mM to 10 raM, D = >10 mM).

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims.

Scheme I

3-Hydroxy-pyrrolidine-l ,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2): A solution containing 3-hydroxy-pyrrolidine-l ,2-dicarboxylic acid \ -tert- butyl ester (1, 16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0 °C. To this solution was added K₂C0₃ (16 g, 1 16 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 °C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 14.8 g (87%) of 3- hydroxypyrrolidine-l,2-dicarboxylic acid \-tert-buty\ ester 2-methyl ester (2) as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).

Scheme II

[66] 3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-l ,2-dicarboxylic acid 1 -tert- butyl ester 2-methyl ester (3): A solution containing 3-hydroxypyrrolidine- 1 ,2-dicarboxylic acid 1-fert-butyl ester 2-methyl ester (2, 14.8 g, 60 mmol) in DCM (150 mL) was cooled to 0 °C. To this solution was added imidazole (5.4 g, 79 mmol) followed by i-butyl-dimethylsilyl-chloride (10 g, 66 mmol) in two portions. The reaction mixture was warmed to ambient temperature over 1 h. After 5 h, the reaction mixture was diluted with 1M HC1 and extracted twice with DCM. The combined organic extracts were dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 21.2 g (99%) of 3- (teri-butyldimethylsilanyloxy)pyrrolidine-l ,2-dicarboxylic acid 1 -tert-buiy\ ester 2-methyl ester (3) as a yellow oil. Ή NMR (CDC1₃, 300 MHz): 54.38- 4.34 (m, 1H), 4.18 (br s, rotomers, 0.5H), 4.04 (app d, J = 2.1 Hz, rotomers, 0.5H), 3.74 (s, 3H), 3.62-3.50 (m, 2H), 2.04-1.96 (m, 1H), 1.85-1.78 (m, 1H), 1.46 (s, minor rotomer), 1.41 (s, 9H), 0.92 (s, minor rotomer), 0.86 (s, 9H), 0.11 (s, 6H), 0.09 (s, minor rotomer) ppm.

Scheme III

3-(tert-Butyl-dimethyl-silanyloxyV2-hydroxymethyl-pytTolidine-l-carboxyli acid tert-butyl ester (4): A solution containing 3-(tert-

Butyldimethylsilanyloxy)pyrrolidine-l ,2-dicarboxylic acid 1 -tert-butyl ester 2-methyl ester (3, 12 g, 33 mmol) in THF (50 mL) was cooled to 0 °C. LiBH₄ in THF (2M, 20 mL) was added in a dropwise fashion. After 1 h, the solution was warmed to ambient temperature. After 2 h, the solution was diluted with MeOH, then H₂0, and concentrated. The residue was extracted with EtOAc, washed with 1M HC1, saturated aqueous NaHC0₃, brine, dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 9.5 g (87%) of 3~(tert- Butyldimethylsilanyloxy)-2-hydroxymethylpyrrolidine-l -carboxylic acid tert- butyl ester (4) as a colorless oil (See: Herdeis, C; Hubmann, H.P.; Lotter, H. Tetrahedron: Asymmetry, 1994, 5, 119).

3 -(tert-Butyl-dimethyl-silanyloxy)-2i?-(2-nitro-vinyl)-pyrrolidine-l- carboxylic acid tert-butyl ester (5): To a stirred solution containing alcohol 4 (5.7 g, 17.2 mmol) in DCM (60 mL) was added at ambient temperature Et₃N (14 mL, 103 mmol) and DMSO (50 mL). The reaction mixture was cooled to 0 °C and a solution of S0₃ -pyridine (1 1.0 g, 69 mmol) in DMSO (50 mL) was added in a dropwise fashion. After 1 h, the reaction was warmed to ambient temperature. After 1 h, the reaction mixture was poured onto a 30% citric acid/ice mixture. The aqueous layer was extracted with DCM (3 x 250 mL) and the combined organic extracts were washed with brine (400 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 5.6 g (99%) of crude N-Boc-(3>S'-OTBS)-2i?-prolinal as a yellow-colored oil.

[69] To a stirred solution containing crude N-Boc-(3S-OTBS)-2i?-prolinal (5.6 g, 17 mmol) in nitromethane (30 mL) was added Et₃N (1.5 mL). After 12 h, the reaction mixture was concentrated in vacuo to afford 6.6 g (99%) of the intermediate carbinol as a yellow-colored oil.

[70] To a solution containing crude carbinol (6.6 g, 17 mmol) at -78 °C in DCM (30 mL) was added thionyl chloride (2.60 g, 21.9 mmol) in CH₂C1₂ (15 mL). After 1 h, TEA (6.96 mL, 68.8 mmol) was added and, after an additional 1 h at -78 °C, the reaction mixture was quenched with MeOH (15 mL), H₂0 (20 mL), and saturated aqueous NaHC0₃ (20 mL) followed by warming to 0 °C. After 1 h, the reaction mixture was concentrated in vacuo and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 6.1 g (98%) of 5 as an orange-colored oil. Ή NMR (CDC1₃, 300 MHz): 67.04 (dd, J = 13.2, 6.5 Hz, 1H), 6.91 (d, J = 13.2 Hz, 1H), 4.08 (m, 1H), 3.54 (m, 2H), 3.37 (m, 1H), 1.80 (m, 2H), 1.35 (d, J = 13.2 Hz, 6H), 0.80 (s, 9H), 0.00 (s, 9H) ppm. Mass spectrum, m/z calcd for Ci₂H₂₄N0₃Si [M + H]⁺ 272.53, found 272.84.

Scheme V

3 -(tert-Butyl-dimethyl-silanyloxy)-2i?- l,S'-(6-F-indol-3-ylV2-nitro-ethyl1- pyrrolidine-l-carboxylic acid tert-butyl ester (6) and 3 ^,-(tert-Butyl-dimethyl- silanyloxy)-2 ?- l ?-(6-F-indol-3-yl)-2-nitro-ethyl] -pyrrolidine- 1-carboxylic acid tert-butyl ester (7): (See: Bartoli, G.; et al. J. Org. Chem. 2005, 70, 1941) A 1 L round-bottomed flask was charged with CeCl -7H₂0 (10.3 g, 27.7 mmol), Nal (4.2 g, 27.7 mmol), and reagent grade MeOH (200 mL). To the clear, water- white solution was added silica gel (Fisher Grade 60, 230-400 mesh, 45 g) and the white, heterogeneous mixture was concentrated in vacuo (rotovap bath temp: 40 °C). To the white, free-flowing CeCLVNal/SiC^ was added 5 (25.8 g, 69.2 mmol) and 6-F-indole (1 1.2 g, 83.1 mmol) in anhydrous ACN (160 mL) and the pale orange mixture was concentrated under high vacuum (bath temp: 40 °C). The orange-brown solid was allowed to stand at ambient temperature. After 16 h, the solid residue was poured atop a short column of silica gel and the products were eluted (20% EtOAc/hexanes to 40% EtOAc/hexanes). The diastereomers were separated by normal phase HPLC (2" Dynamax® Si0₂; 10-50% EtOAc/hexanes over 30 min; Flow: 40 mL/min) to afford 12 g (34%) of isomer 6, and 10 g (28%) of isomer 7 together with some recovered 5 [TLC analysis, Si0₂, 4:1 hexanes/EtOAc; R_f{5) = 0.6; R_f{6) = 0.48; R_f{7) = 0.45].

6: Ή NMR (CDC1₃, 300 MHz), -3:2 mixture of carbamate rotomers: 58.86 (br s, 0.4H, minor rotomer), 8.83 (br s, 0.6H, major rotomer), 8.15 (dd, J = 5.1 , 8.7 Hz, 0.6H, major rotomer), 8.04 (dd, J = 5.4, 9.0 Hz, 0.4H, minor rotomer), 7.55 (d, J = 2.4 Hz, 0.6H, major rotomer), 7.53 (br s, 1H), 7.50 (d, J = 2.1 Hz, 0.4H, minor rotomer), 7.40 (app t, J = 8.7 Hz, 0.6H, major rotomer), 7.39 (app t, J = 9.3 Hz, 0.4H, minor rotomer), 5.74-5.35 (m, 1H), 5.29-5.20 (m, 1H), 4.68 (app t, J= 1 1.4 Hz, 1H), 4.43 (m, 1H), 4.24-3.95 (m, 2H), 3.82 (t, J= 9.6 Hz, 1H), 2.61 (m, 1H), 2.28 (m, 1H), 2.08 (s, 3H, minor rotomer), 1.99 (s, 6H, major rotomer), 1.14 (s, 9H), 0.10 (s, 1H, minor rotomer), 0.09 (s, 2H, major rotomer), 0.01 (s, 2H, major rotomer), 0.00 (s, 1H, minor rotomer) ppm; ¹³C NMR (300 MHz, CDC1₃), -3:2 mixture of carbamate rotomers: 5171.2, 161.3, 157.5 (d, JcF = 102.4 Hz), 157.1 (d, J_CF = 164.2 Hz), 136.7 (d, J_CF = 1 1.1 Hz), 136.5 (d, JcF = 12.3 Hz), 123.3 (d, J_CF = 18.3 Hz), 122.3 (d, J_CF = 18.9 Hz), 1 19.3 (d, J_CF = 30.9 Hz), 1 1 1.3 (d, J_CF = 37.2 Hz), 108.3 (d, J_CF = 25.5 Hz), 98.1 (d, J_CF = 23.1 Hz), 97.8 (d, J_CF = 24.6 Hz), 80.8, 79.4, 74.2, 73.8, 68.9, 68.8, 60.3, 45.2, 44.9, 40.4, 39.9, 32.0, 31.1 , 28.3, 28.2, 25.2, 20.7, 17.5, 13.9, -5.6, -5.7 ppm. Mass spectrum, m/z [408.2] (M - Boc)+. 7: 1H NMR (CDCI3, 300 MHz), -3:2 mixture of carbamate rotomers: 59.03 (br s, 0.4H, minor rotomer), 8.92 (br s, 0.6H, major rotomer), 8.03 (m, 1H), 7.52- 7.44 (m, 2H), 7.36 (app t, J = 8.4 Hz, 1H), 5.42-5.19 (m, 2H), 4.79 (m, 1H), 4.63 (m, 2H), 4.07-3.86 (m, 1H), 3.63-3.46 (m, 1H), 2.06 (s, 3H, minor rotomer), 1.99 (s, 6H, major rotomer), 1.95 (m, 1H), 1.65 (m, 1H), 1.27 (s, 6H, major rotomer), 1.20 (s, 3H, minor rotomer), 0.38-0.25 (m, 6H) ppm; ¹³C NMR (300 MHz, CDC1₃), -3:2 mixture of carbamate rotomers: 5171.4, 161.5, 157.3 (d, J_CF = 151.9 Hz), 157.1 (d, J_CF = 186.9 Hz), 136.2 (d, JCF = 12.3 Hz), 123.2, 122.5 (d, J_CF = 24.9 Hz), 119.5 (d, J_CF = 36.0), 1 10.8, 108.5 (d, JCF = 24.3 Hz), 97.8 (d, J_CF = 28.9 Hz), 81.2, 79.9, 78.0, 75.1 , 68.8, 60.4, 46.3, 38.8, 37.9, 33.2, 32.5, 28.4, 25.5, 25.4, 20.9, 17.7, 14.1, -5.1 , -5.4 ppm. Mass spectrum, m/z [408.2] (M - Boc)+.

Scheme VI

2R-\2- Amino- lS-(6-F-indol-3- yl)-ethvn-35-f tert-butyl-dimethyl-silanyloxy)- pyrrolidine-l-carboxylic acid tert-butyl ester (8): A Parr bottle was charged with 7 (12 g, 23.7 mmol) and Raney Ni (20 mL, 2400 Ni slurry in H₂0) in EtOH (120 mL)_and subjected to 50 PSI H₂ pressure (379.2 KPa). Rapid absorption of H₂ was observed and the reaction was twice recharged to 50 PSI H₂ (379.2 KPa). After 1.5 h, the reaction mixture was filtered through diatomaceous earth (Celite®) and the solids were washed with EtOH. The filtrate was concentrated and the residue was dissolved in EtOAc, washed with saturated NaHC0₃, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to give 8 (10.7, 95%) as a yellow foam. Ή NMR (CDC1₃, 300 MHz), mixture of carbamate rotomers: 59.30 (br s, 0.5H), 9.07 (br s, 0.5H), 7.86-7.75 (m, 1H), 7.24 (app t, J = 6.6 Hz, 1H), 7.15 (s, 1H), 7.08 (ap t, J = 9.0 Hz, 1H), 4.38-4.30 (m, 3H), 3.86-3.61 (m, 2H), 3.44-3.28 (m, 3H), 1.71 (s, 9H), 0.96 (s, 9H), 0.06 (s, 3H), 0.001 (s, 3H) ppm; ¹³C NMR (CDCI₃, 75 MHz), mixture of carbamate rotomers: 5166.5 & 163.4, 161.3 (JCF = 13.5 Hz), 141.7 (Jc = 12.1 Hz), 129.4, 127.6 & 127.3, 125.1 (J_CF = 10.4 Hz) & 124.8 (JCF = 10.4 Hz), 119.1 & 1 18.5, 1 13.2 & 112.9, 102.8 (J_CF = 17.6 Hz) & 102.5 {JCF = 16.6 Hz), 85.1 & 84.4, 80.4 & 80.1 , 74.7 & 74.1, 51.4 & 51.1 , 48.5, 38.5 & 37.7, 33.6 & 30.7, 22.9, 0.09 ppm. Mass spectrum, m/z [478.3] (M + H)+.

Scheme VII

[75] 2i?-r2-Benzyloxycarbonylamino-15'-(6-fluoro-lH-indol-3-yl)-ethyl1-3j'-(tert- butyl-dimethyl-silanyloxy)-pyrrolidine-l -carboxylic acid tert-butyl ester (9):

To a solution of DCM (10 mL) containing crude 8 (10.7 g, 22.4 mmol) at 0 °C was added TEA (4.8 mL, 34.5 mmol) followed by Cbz-Cl (3.5 mL, 25 mmol). After 1 h, the reaction was warmed to room temperature. After 1.5 h, the reaction mixture was diluted with DCM, washed successively with IN HCl and brine, dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 9 (13.5 g, 98%). Ή NMR (CDC1₃, 300 MHz): 58.73 (br s, 1H), 7.57 (app q, J = 5.1 Hz, 1H), 7.48-7.32 (m, 5H), 7.10 (m, 1H), 6.91 (m, 1H), 6.45 (br s, 1 H), 5.20 (s, 2H), 4.24-4.09 (m, 2H), 3.65-3.40 (m, 4H), 3.02 (app t, J = 9.6 Hz, 1H), 1.57 (s, 9H), 0.87 (s, 9H), 0.00 (s, 6H) ppm. Mass spectrum, m/z [612.4] (M + H)+.

Scheme VIII

2i?-[2-Benzyloxycarbonylamino-15'-(6-fluoro-lH-indol-3-yl)-ethyl1-3 '- hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester (10): A solution of 9 (13.5 g, 22.0 mmol) in THF (60 mL) was treated with TBAF (45 mL, 1M in THF, 45 mmol) at ambient temperature. After 5 h, the reaction mixture was warmed for 1 h at 45 °C and then diluted with EtOAc, washed successively with IN HC1 and brine, dried over anhydrous Na₂S0₄, filtered, and concentrated to afford crude 10 which was purified by flash silica gel chromatography (1 :2 hexanes/EtOAc) to afford 10.1 g (93%) of 10 as light peach-colored foam. Ή NMR (CDC1₃, 300 MHz): 58.88 (s, 1H), 7.40-7.31 (m, 5H), 6.94 (app d, J = 9.6 Hz, 1H), 6.81 -6.75 (m, 1H), 6.67 (s, 1H), 6.45 (m, 1H), 5.12 (app q, J = 11.7 Hz, 2H), 4.18-4.03 (m, 2H), 3.51-3.34 (m, 4H), 2.92 (app t, J = 9.9 Hz, 1H), 2.33 (br s, 1H), 1.48 (s, 9H), 0.91-0.86 (m, 1H) ppm; ¹³C NMR (CDC1₃, 75 MHz) 5158.5, 157.2, 157.0, 136.9, 136.5, 136.3, 128.7, 128.3, 123.7, 122.8, 120.6, 1 13.6, 108.7, 108.4, 98.0, 97.7, 80.1, 75.7, 67.3, 66.9, 46.5, 43.4, 41.1 , 32.3, 28.7 ppm. Mass spectrum, m/z [498.2] (M + H)+.

Scheme IX

[77] 2R- 2-Benzyloxycarbonylamino- 1 S-( 6-fluoro- 1 H-indol-3 - vD-ethyl] -35- methanesulfonyloxy-pyrrolidine-l-carboxylic acid tert-butyl ester (11): A solution of 10 (10.0 g, 20.1 mmol) in DCM (100 mL) was cooled to 0 °C. A solution of MsCl (1.5 mL, 19.4 mmol) in DCM (3 mL) was added dropwise followed by the addition of DMAP (250 mg, 2.0 mmol). After 3 h at 0 °C, the reaction mixture was diluted with DCM, washed successively with IN HCl, water, and brine, dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 11 (10.4 g, 90%) as a light peach colored foam. Ή NMR (CDC1₃, 300 MHz): 58.71 (s, 1H), 7.50 (app q, J = 5.4 Hz, 1H), 7.38-7.32 (m, 5H), 7.00 (app d, J = 8.4 Hz, 1H), 6.89-6.81 (m, 2H), 6.29 (br s, 1H), 5.14 (s, 2H), 4.92 (app d, J = 3.9 Hz, 1H), 4.52 (s, 1H), 3.55-3.39 (m, 4H), 3.04 (app t, J = 9.9 Hz, 1H), 2.79 (s, 3H), 1.82 (app q, J = 7.5 Hz, 1H), 1.52 (s, 9H), 1.14 (m, 1H) ppm. Mass spectrum, m/z [576.3] (M + H)+.

Scheme X

SaR^a^l-e^-re-fluoro-lH-Indol-S-vn-he ahvdro-pyrrolorS^-blpyrrole-l- carboxylic acid tert-butyl ester (12): A solution of 11 (10.4 g, 18 mmol) in DMF (30 mL) was added to a suspension of NaH (1.9 g, 60%, 46 mmol) in DMF (100 mL) at 0 °C. After 1 h, the reaction mixture was diluted with H₂0, extracted with diethyl ether, washed with brine, dried over anhydrous Na₂S0₄, filtered, and concentrated to give 12 (8.3 g, 97%>) as a light tan colored solid. 1H NMR (CDC1₃, 300 MHz), mixture of carbamate rotomers: 58.25 (br s, 0.5 H), 8.16 (s, 0.5 H), 8.04 (dd, J = 8.4, 14.1 Hz, 0.5 H), 7.95 (dd, J = 7.8, 13.5 Hz, 0.5 H), 7.71 (m, 0.5 H), 7.64 (m, 0.5 H), 7.34 (m, 4H), 6.99 (app t, J = 13.2 Hz, 1H), 6.91-6.84 (m, 1H), 6.81-6.76 (m, 0.5 H), 6.68-6.61 (m, 0.5 H), 5.24-5.15 (m, 2H), 4.46-4.31 (m, 2H), 4.20-4.02 (m, 1H), 3.96 (m, 1H), 3.84- 3.68 (m, 1H), 3.63 (app q, J = 5.7 Hz, 1H), 3.25 (m, 1H), 2.31 (dd, J = 6.0, 13.5 Hz, 0.5 H), 2.14 (dd, J = 5.7, 13.5 Hz, 0.5 H), 1.94-1.84 (m, 1 H), 1.52 (s, 7H), 1.31-1.26 (m, 2H), 0.91-0.83 (m, 2H) ppm. Scheme XI

[79] Hexahydro-pyrrolo[3,2-blpyrrole-l,3,4-tricarboxylic acid 1 -benzyl ester 4- tert-butyl ester (13): A solution of 12 (0.5 g, 1.1 mmol) was dissolved in NMP (5 mL). To this solution was added ACN (10 mL), CC1₄ (10 mL), and H₂0 (20 mL). To this biphasic solution was added NaI0₄ (3.4 g, 16 mmol). After 10 min, RuCl₃ -hydrate (29 mg, 0.14 mmol) was added and the solution immediately turned dark orange. Precipitation was observed after about 10 min. After 3.5 h, the solution was diluted with EtOAc and washed with brine (2x). The combined organic extracts were dried over anhydrous Na₂S0₄, filtered and concentrated to give crude 13 as a dark brown-colored oil (470 mg) which was diluted with EtOAc (10 mL) and treated with DMSO (0.15 mL) and stirred at ambient temperature overnight. The solution was then concentrated and used without further purification. Ή NMR (CDC1₃, 300 MHz): 57.36-7.29 (m, 5H), 5.14 (m, 2H), 4.55 (m, 2H), 3.75-3.53 (m, 1H), 3.32-3.17 (m, 1H), 2.38 (app t, J = 8.4 Hz, 1H), 1.47 (s, 9H) ppm. Mass spectrum, m/z [391.2] (M + H)+.

Scheme XII

[80] Hexahvdro-pyrrolo[3,2-blpyrrole-l,3,4-tricarboxylic acid 1 -benzyl ester 4- tert-butyl ester 3 -methyl ester (14): To a solution of crude 13 (0.47 g) in EtOAc (10 mL) and Et₂0 (10 mL) was added an ethereal solution of diazomethane that was prepared by treatment of N-nitroso-N-methyl urea (0.5 g) in Et₂0 (10 mL) with 1M KOH (10 mL). After consumption of starting material (monitored by TLC), the reaction mixture was diluted with HOAc. The solution was extracted with EtOAc, washed with saturated NaHC0₃, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to give a dark oil that was purified by HPLC (2" Dynamax® Si0₂, 10% EtOAc/hexane to 100% EtOAc over 30 min) to give 14 (0.19 g) as a yellow-colored oil. Ή NMR (CDC1₃, 300 MHz): 57.40-7.29 (m, 5H), 5.23-5.09 (m, 2H), 4.56-4.52 (m, 2H), 4.11-4.04 (m, 1H), 3.69 (s, 3H), 3.45-3.42 (m, 1H), 3.22-3.12 (m, 1H), 2.27-2.10 (m, 1H), 1.96 (m, 1H), 1.47 (s, 9H) ppm. Mass spectrum, m/z [405.2] (M + H)+.

Scheme XIII

13

[81] Hexahvdro-pyrrolo S^-blpyrrole-U^-tricarboxylic acid 1 -benzyl ester 4- tert-butyl ester (13): A solution of 14 (923 mg, 2.28 mmol) in MeOH (20 mL) was treated with 1M NaOH (7.8 mL) at ambient temperature. After 1.5 h, the solution was concentrated and diluted with EtOAc and 1M HC1. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed successively with 1M HC1, and brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 13 as a yellow-colored foam (900 mg) which was used without further purification. Mass spectrum, m/z [391.4] (M + H)+.

Scheme XIV

tert-butyl ester 3 -methyl ester (16): Indole 15 (0.5 g, 1.1 mmol) [prepared from compound 6 using the procedures described in Schemes VI through X] was dissolved in ACN (5 mL), CC1₄ (5 mL), and H₂0 (10 mL). To this biphasic solution was added NaI0₄ (3.4 g, 16 mmol). After 10 min, RuCl₃-hydrate (23 mg, 0.14 mmol) was added and the solution immediately turned dark orange. Precipitation was observed after about 10 min. After 3.5 h, the solution was diluted with EtOAc and washed with brine (2x). The combined organic extracts were dried over anhydrous Na₂S0₄, filtered and concentrated to give the crude acid as a dark brown oil (460 mg) which was diluted with EtOAc (10 mL) and treated with DMSO (0.10 mL) and stirred at ambient temperature overnight. The solution was then concentrated and used without further purification.

[83] To a solution of the crude acid (0.47 g) in Et₂0 (5 mL) was added an ethereal solution of diazomethane that was prepared by treatment of TV-nitroso-N- methyl urea (0.6 g) in Et₂0 (10 mL) with 1M KOH (10 mL). After consumption of starting material (monitored by TLC), the reaction mixture was diluted with HOAc (5 mL). The solution was extracted with EtOAc, washed with saturated NaHC0₃, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to give a dark oil that was purified by HPLC (2" Dynamax® Si0₂, 10% EtOAc/hexane to 100% EtOAc over 30 min) to give 16 (0.15 g) as a yellow-colored oil. Ή NMR (CDC1₃, 300 MHz): 57.35 (m, 5H), 5.19-5.08 (m, 2H), 4.69 (m, 1H), 4.53-4.49 (m, 1H), 3.92-3.84 (m, 2H), 3.69 (s, 3H), 3.25-3.08 (m, 2H), 2.22-1.95 (m, 2H), 1.42 (s, 9H) ppm. Mass spectrum, m/z [405.2] (M + H)+. Scheme XV

[84] Hexahydro-pyrrolo[3,2-b]pyrrole-l ,3,4-tricarboxylic acid 1 -benzyl ester 4- tert-butyl ester (13): A solution of 16 (1.4 g, 3.5 mmol) in MeOH (20 mL) was added to a solution of NaOMe (0.34 g, 6.3 mmol) in MeOH at ambient temperature. The reaction mixture was stirred for 16 h and then concentrated. The residue was diluted with EtOAc, washed successively with 1M HCl, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 13 as an orange-colored foam (1.39 g) that was used without further purification.

Scheme XVI

[85] Hexahvdro-pyrrolo[3,2-b pyrrole-l ,3,4-tricarboxylic acid 1 -benzyl ester 4- tert-butyl ester (13): A solution of 17 (mixture of diastereomers, 1.5 g, 3.1 mmol) [The mixture of diastereomers was prepared from the mixture of diastereomers (6 and 7) generated in Scheme V using the procedures described in Schemes VI through X on the diastereomeric mixture produced in each step] in NMP (5 mL), MeCN (10 mL), CC1₄ (10 mL) and ¾0 (20 mL) was treated with NaI0₄ (9.3 g, 44 mmol) in one portion. After 10 min, RuCl₃-H₂0 (57 mg, 0.28 mmol) was added and the solution immediately turned dark orange. After ~10 min, the reaction mixture became warm and precipitation was observed. After 7.5 h, the solution was diluted with EtOAc and 1M HCl and filtered through Celite®, and rinsed with EtOAc. The filtrate was extracted with EtOAc, washed successively with 1M HC1, 10% Na₂S₂0₃, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to give a mixture of crude acids as a dark brown oil (1.4 g) which was used without further purification.

[86] A solution of crude acids (1.4 g, 3.6 mmol) in DMF (20 mL) was cooled to 0 °C and treated with K₂C0₃ (2.5 g, 18.1 mmol). After 10 min, this suspension was treated with CH₃I (0.65 mL, 10.4 mmol) and the reaction mixture was allowed to warm to ambient temperature. After consumption of starting material (approximately 2 h, monitored by TLC), the reaction mixture was diluted with EtOAc, and 1M HC1. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed successively with 1M HC1, 10% Na₂S₂0₃, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to give a dark brown residue. The dark residue was absorbed onto Si0₂ and purified by flash chromatography (1 : 1 hexane/EtOAc) to afford 0.69 g of a mixture of methyl esters (55%, 2 steps) as a yellow-colored foam.

[87] To a suspension of NaOMe (2.0 g, 37 mmol) in MeOH (20 mL) was added a solution of methyl esters (1.3 g, 3.2 mmol) in a dropwise fashion at ambient temperature. The reaction mixture was stirred for 16 h and then concentrated. The residue was diluted with EtOAc, washed successively with 1M HC1, and brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 13 as an orange-colored foam (1.1 g) that was used without further purification.

Scheme XVII

13 18

3-(2-Diazo-acetyl)-hexahydro-pyrrolo[3 ,2-b]pyrrole- 1 ,4-dicarboxylic acid 1 - benzyl ester 4-tert-butyl ester (18): To a suspension of 13 (2.0 g, 5.12 mmol) in diethyl ether (10 mL) and THF (10 mL) at ambient temperature was added Et₃N (785 μΕ, 5.63 mmol). The resulting reaction mixture was cooled to -30 °C and ethyl chloroformate (515 μί, 5.38 mmol) was added dropwise over 3 min during which time white solids precipitated from solution. After 1 h, a solution of CH₂N₂ (25.6 mmol) in Et₂0 (50 mL) was distilled into the reaction mixture in a dropwise fashion over 1 h. The reaction mixture was allowed to stir an additional 18 h while warming gradually to ambient temperature. The pale yellow-colored solution was concentrated, and the residue was dissolved in EtOAc and washed successively with aqueous NaHC0₃ (sat.) and brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 18 (2.08 g, 98%) as a viscous orange-colored oil which was taken forward without further purification. Mass spectrum, m/z [415.2] (M)+.

Scheme XVIII

18 19

[89] 3-(2-Bromo-acetyl)-hexahvdro-pyrrolo[3,2-b]pyrrole-l ,4-dicarboxylic acid 1 - benzyl ester 4-tert-butyl ester (19): To a solution of 18 (2.08 g, 5.01 mmol) in 1 ,4-dioxane (50 mL) at 0 °C was added HBr (1.12 mL, 8.93 M) dropwise over 2 min during which time vigorous gas evolution was observed. The reaction mixture was stirred for an additional 30 min while warming to ambient temperature then quenched by the addition of 50 mL aqueous NaHC0₃ (sat.) and concentrated. The aqueous layer was extracted three times with DCM and the combined organic extracts were washed with brine, dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 19 (2.35 g, quant.) as a viscous orange-colored oil which was taken forward without further purification. Mass spectrum, m/z [469.0] (M + H)+.

Scheme XIX

[90] 3-(8-Bromo-imidazo[l,2-a]pyridin-2-yiy^

dicarboxylic acid 1 -benzyl ester 4-tert-butyl ester (20): A solution of 19 (2.34 g, 5.01 mmol) and 2-amino-3-bromopyridine (1.04 g, 6.01 mmol) in EtOH (20 mL) was heated to reflux in a pre-heated oil bath for 19 h. The reaction mixture was cooled to ambient temperature and concentrated to afford an off- white foam. The residue was adsorbed onto Si0₂ and purified via flash silica gel chromatography (20-100% EtOAc/hexanes, rinsing column with 5% MeOH/DCM) to afford 20 (1.45 g, 54%) as a pale brown-colored foam. ^]H NMR (300 MHz, CDC1₃), mixture of amide rotomers: 67.95 (d, J = 6.3 Hz, 1H), 7.46-7.25 (m, 7H), 6.64 (m, 1H), 5.18 (m, 2H), 4.59 (m, 2H), 4.14 (t, J = 8.7 Hz, 1H), 3.94-3.78 (m, 2H), 3.66 (dd, J = 6.0, 10.8 Hz, 1H), 3.27 (m, 1H), 3.28 (m, 0.5H), 2.17 (m, 0.5H), 1.99 (m, 1H), 1.64-1.46 (m, 9H) ppm. Mass spectrum, m/z [543.0] (M + H)+.

Scheme XX

3-(8-Phenyl-imidazo l ,2-alpyridin-2-yl)-hexahydro-pyrrolo[3,2-b]pyrrole-l,4- dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (21): To a solution of 20 (650 mg, 1.2 mmol) in EtOH (4 mL), toluene (8 mL) and H₂0 (150 μΐ were added K₂C0₃ (331 mg, 2.4 mmol), phenylboronic acid (220 mg, 1.8 mmol) and Pd(PPh₃)₄ (69 mg, 0.06 mmol) and the mixture was heated to a gentle reflux in a pre-heated oil bath. After 3 h, the reaction mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with water, brine, dried over anhydrous Na₂S0₄, filtered, and concentrated. The resultant brown-colored foam was dissolved in 1 :1 EtOAc/hexanes and purified via normal phase HPLC (Dynamax® 2" silica column, 40-100% EtOAc/hexanes over 30 min; Flow rate: 40 mL/min) to afford 21 (510 mg, 79%) as a pale yellow-colored foam. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 58.09 (t, J = 7.5 Hz, 2H), 7.97 (t, J = 7.2 Hz, 1H), 7.49-7.26 (m, 10H), 6.83 (t, J = 6.9 Hz, 1H), 5.22 (t, J = 12.6 Hz, 1H), 5.13 (m, 1H), 4.67-4.47 (m, 2H), 4.17 (d, J = 1 1.4 Hz, 1H), 3.78 (m, 1H), 3.62 (ddd, J= 5.1, 10.8, 5.7 Hz, 1H), 3.25 (ddd, J = 5.7, 1 1.4, 5.7 Hz, 1H), 2.32 (m, 0.5H), 2.18 (dd, J = 5.4, 13.8 Hz, 0.5H), 1.93 (m, 1H), 1.75 (s, 1H), 1.51 (s, 9H) ppm. Mass spectrum, m/z [539.1 ] (M + H)+.

Scheme XXI

[92] 3-(8-Phenyl-imidazo[l,2-a]pyridin-2-yl)-hexahvdro-pyrrolo[3,2-b1pyrrole-l- carboxylic acid benzyl ester (22): To a solution of 21 (500 mg, 0.93 mmol) in DCM (5 mL) at 0 °C was added TFA (3 mL) and the resultant orange-colored reaction mixture was stirred for 3 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc, washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 22 (400 mg, 98%) as a light brown-colored foam which was taken forward without further purification. Mass spectrum, m/z [576.2] (M + H)+.

Scheme XXII

[93] 4-(2-tert-Butoxycarbonylamino-3,3-dimem^

imidazo|^rl,2-a]pyridin-2-yi)-faexafaydro-^

acid benzyl ester (23): To a mixture of Boc-Tle-OH (231 mg, 1.0 mmol) and HATU (380 mg, 1.0 mmol) in NMP (2 mL) at 0 °C was added DIPEA (238 uL, 1.37 mmol) and the resulting yellow-colored solution was stirred for 20 min. To the reaction mixture was added a solution of 22 (400 mg, 0.91 mmol) in NMP (5 mL) and the reaction mixture was allowed to warm gradually to ambient temperature. After 16 h, the reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic extracts were washed successively with 1M HCl, brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The residue was absorbed onto Si0₂ and purified via flash silica gel chromatography (1 :1 EtOAc/hexanes, flush with 5% MeOH/CH₂Cl₂) to afford 23 (640 mg, quant.) as a brown-colored foam which was taken forward without further purification. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 58.04 (t, J = 7.2 Hz, 2H), 7.53-7.26 (m, 11H), 6.85 (t, J = 6.6 Hz, 1H), 5.31 (m, 1H), 5.12 (s, 1H), 4.70 (m, 1H), 4.33 (m, 1H)(, 4.07 (m, 1H), 3.85 (m, 1H), 3.49 (m, 1H), 3.38 (m, 1 H), 2.86 (m, 1H), 2.39 (m, 1H), 2.03 (m, 1H), 1.82 (m, 1H), 1.44 (s, 9H), 1.01 (s, 9H) ppm. Mass spectrum, m/z [652.3] (M + H)+.

Scheme XXIII

[94] (2,2-Dimethyl- 1 -Γ6-Γ 8-phenyl-imidazor 1.2-a]pyridin-2-ylVhexahvdro- pyrrolo[^"3,2-b1pyrrole-l-carbonyl]-propyl}-carbamic acid tert-butyl ester (24):

To a solution of 23 (593 mg, 0.91 mmol) in MeOH (20 mL) in a Parr bottle was added 10% Pd/C (75 mg). The flask was evacuated and flushed with H₂ five times, then charged to 50 PSI H₂ and shaken. After 4 h, the reaction mixture was filtered through a Millipore filter and concentrated to afford 24 (470 mg, quant.) as an off-white-colored foam that was used without further purification. Mass spectrum, m/z [518.2] (M + H)+.

Scheme XXIV

[95] { 1 -[4-Methanesulfonyl-6-(8-phenyl-imidazo[ 1 ,2-a]pyridin-2-yl)-hexahvdro- pyrrolo[3.2-b]pyrrole-l -carbonyl]-2,2-dimethyl-propyll-carbamic acid tert- butyl ester (25): To a solution of 24 (157 mg, 0.30 mmol) in DCM (3 mL) at 0 °C was added TEA (85 μί, 0.61 mmol) and MsCl (28 μί, 0.36 mmol) and the reaction mixture was allowed to warm to ambient temperature. After 4 h, the reaction mixture was diluted with DCM and washed successively with 1M HC1, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 25 (190 mg, quant.) as a yellow-colored foam which was used without further purification. Mass spectrum, m/z [596.2] (M + H)+.

Scheme XXV

25 2-Amino-l-[4-methanesulfonyl-6-(8-phenyl-imidazo[l,2-a]pyridin-2-yl)- hexahydro-pyrrolo[3 ,2-b]pyrrol- 1 -yl] -3 ,3 -dimethyl -butan- 1 -one (26): To a solution of 25 (150 mg, 0.30 mmol) in DCM (4 mL) at ambient temperature was added TFA (2 mL). After 3 h, the reaction mixture was concentrated and the residue was dissolved in EtOAc, washed successively with aqueous NaHC0₃, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 26 (140 mg, 93%) as a pale yellow-colored foam which was taken forward without further purification. Mass spectrum, m/z [496.2] (M + H)+.

Scheme XXVI

(1 - { 1 -[4-Methanesulfonyl-6-(8-phenyl-imidazo[ 1 ,2-a]pyridin-2-yl)- hexahvdro-pyrrolo[3,2-b]pyrrole-l-carbonyl]-2,2-dimethyl-propylcarbamoyl}- ethvD-methyl-carbamic acid tert-butyl ester (27): To a mixture of Boc- N(Me)Ala-OH (63 mg, 0.31 mmol) and HATU (118 mg, 0.31 mmol) in NMP (1 mL) at 0 °C was added TEA (146 uL, 0.84 mmol) and the resultant pale yellow-colored solution was stirred for an additional 20 min. To the reaction mixture was added a solution of 26 (140 mg, 0.28 mmol) in NMP (3 mL) and the reaction mixture was allowed to warm to ambient temperature. After 3 h, the reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic extracts were washed successively with 1M HC1, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 27 (200 mg, quant.) as a yellow-colored solid that was used without further purification. Mass spectrum, m/z [681.2] (M + H)+.

Scheme XXVII

[98] N- { 1 -r4-Methanesulfonyl-6-( 8-phenyl-imidazo[ 1 ,2-a]pyridin-2-yl)- hexahydro-pyrrolo[3,2-b1pyrrole-l-carbonyl]-2,2-dimethyl-propyl}-2- methylamino-propionamide (28): To a solution of 27 (192 mg, 0.28 mmol) in DCM (4 mL) at 0 °C was added TFA (2 niL). After 3 h, the reaction mixture was concentrated and the residue was dissolved in EtOAc, washed successively with aqueous NaHC0₃, brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The residue was dissolved in 1 : 1 MeOH/H₂0 and purified by reverse-phase HPLC (2" Dynamax® CI 8, 20-100% MeOH/H₂0 containing 0.1% HOAc over 30 min; Flow: 40 mL/min). The product- containing fractions were combined, concentrated to remove MeOH, and lyophilized to afford 28 (73 mg, 45%) as a white solid.

[99] EXAMPLE 1 N- ( 1 -[4-Methanesulfonyl-6-(8-phenyl-imidazo[ 1 ,2-alpyridin- 2-yl)-hexahvdro-pyrrolo[3 ,2-b]pyrrole-l -carbonyl]-2,2-dimethyl -propyl} -2- methylamino-propionamide (28): Ή NMR (300 MHz, CDC1₃): 58.10 (d, J = 6.6 Hz, 1H), 7.85 (m, 3H), 7.71 (s, 1H), 7.47 (m, 3H), 7.25 (d, J = 6.9 Hz, 1H), 6.89 (t, J = 6.9 Hz, 1H), 4.66 (m, 2H), 4.54 (t, J = 4.5 Hz, 1H), 4.17 (t, J = 9.6 Hz, 1H), 3.92 (m, 2H), 3.74 (m, 2H), 3.20 (dd, J = 7.5, 14.4 Hz, 1H), 2.82 (br s, 3H), 2.60 (m, 3H), 2.42 (m, 3H), 2.08 (m, 2H), 1.35 (d, J = 6.9 Hz, 3H), 1.08 (m, 9H) ppm; ^I3C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.0, 170.3, 146.4, 144.0, 136.5, 130.3, 129.0, 128.9, 128.3, 124.6, 123.1 , 1 12.6, 109.9, 69.9, 63.5, 59.9, 57.0, 53.6, 47.0, 41.7, 35.7, 35.6, 34.6, 33.1, 26.6, 19.0 ppm. Mass spectrum, m/z [581.2] (M + H)+.

Scheme XXVIII

[100] { 1 -[4-Isopropylcarbamoyl-6-(8-phenyl-imidazo[ 1 ,2-a]pyridin-2-yl)- hexahydro-pyrrolo[3 ,2-b^"|pyrrole- 1 -carbonyl]-2,2-dimethyl -propyl } -carbamic acid tert-butyl ester (29): To a solution of 24 (157 mg, 0.30 mmol) in DCM (3 mL) at ambient temperature were added TEA (127 uL, 0.91 mmol) and /^'Propyl isocyanate (59 uL, 0.606 mmol). After 4 h the reaction was quenched with MeOH (2 mL) and NH₄OH (10 drops, 15 M) and allowed to stir for 10 min. The mixture was diluted with DCM and washed successively with NaHC0₃ (sat) and brine, dried over Na₂S0₄, filtered and concentrated to afford 29 (230 mg, quant) as a tan foamy solid which was used without further purification. Mass spectrum, m/z [603.2] (M + H)+.

Scheme XXIX

[101] {l-[4-Cyclopropanecarbonyl-6-(8-phenyl-imidazo[l ,2-a1pyridin-2-yl)- hexahydro-pyrrolo[3,2-b]pyrrole-l-carbonyl]-2,2-dimethyl -propyl} -carbamic acid tert-butyl ester (30): To a solution of 24 (157 mg, 0.30 mmol) in DCM (3 mL) at ambient temperature was added TEA (85 μί, 0.61 mmol) and cyclopropylcarbonyl chloride (33 μΕ, 0.36 mmol). After 4 h, the reaction mixture was diluted with DCM and washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 30 (180 mg, quant.) as a yellow-colored foam which was taken forward without further purification. Mass spectrum, m/z [586.2] (M + H)+.

[102] EXAMPLES 2 and 3 were prepared from intermediates 29 and 30, respectively using the chemistries outlined in Schemes XXV through XXVII.

[103] EXAMPLE 2 4-[3 ,3 -Dimethyl-2-(2-methylamino-propionylamino)-butyryl1 - 3-(8-phenyl-imidazo[l,2-a]pyridin-2-yl)-hexahydro-pyrrolo 3,2-blpyrrole-l- carboxylic acid isopropyl amide; Ή NMR (300 MHz, CDC1A mixture of amide rotomers: 58.13 (d, J = 6.9 Hz, 0.3H), 8.08 (d, J = 6.0 Hz, 0.2H), 8.03 (dd, J = 0.9, 6.6 Hz, 0.8H), 7.97 (d, J = 6.9 Hz, 1.4H), 7.79 (m, 1H), 7.57 (s, 1H), 7.48 (m, 2H), 7.39 (m, 1H), 7.25 (m, 1H), 6.84 (t, J = 6.9 Hz, 1H), 4.92 (m, 0.2H), 4.77 (m, 0.8H), 4.62 (m, 2H), 4.14 (t, J = 7.8 Hz, 2H), 4.04 (d, J = 9.9 Hz, 2H), 3.96 (app dd, J= 6.3, 13.2 Hz, 1H), 3.87 (d, J= 5.7 Hz, 1H), 3.51 (m, 2H), 3.13 (app dd, J = 6.6, 13.8 Hz, 1H), 2.76 (br s, 3H), 2.38 (m, 2H), 1.30 (d, J = 6.9 Hz, 3H), 1.13 (m, 6H), 1.02 (s, 9H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.2, 170.0, 155.7, 146.3, 143.5, 136.4, 129.8, 129.0, 128.9, 128.4, 128.2, 124.8, 124.6, 123.0, 122.4, 1 12.4, 1 12.2, 109.4, 68.2, 67.2, 62.1 , 60.2, 59.9, 56.8, 56.7, 51.0, 50.7, 47.5, 45.6, 44.7, 42.8, 42.4, 36.0, 35.6, 34.8, 34.6, 31.7, 30.9, 26.5, 23.6, 23.5, 23.4, 21.0, 19.3, 19.1 ppm. Mass spectrum, m/z [588.3] (M + H)+.

[104] EXAMPLE 3 N- ( 1 -[4-Cvclopropanecarbonyl-6-(8-phenyl-imidazon ,2- a]pyridin-2-yl)-hexahydro-pyrrolo[3,2-b]pyrrole-l-carbonyl]-2,2-dimethyl- propyl}-2-methylamino-propionamide: Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 58.12 (m, 1H), 8.02 (m, 2H), 7.87 (m, 1H), 7.59-7.34 (m, 4H), 7.27 (m, 1H), 6.83 (app dd, J = 7.2, 13.8 Hz, 1H), 4.93 (m, 1H), 4.76 (m, 1H), 4.65 (dd, J = 6.3, 9.3 Hz, 0.5H), 4.55 (d, J = 10.8 Hz, 0.5H), 4.30 (m, 0.5H), 4.18 (m, 0.5H), 4.06 (m, 0.5H), 3.95 (d, J = 6.3 Hz, 0.5H), 3.86 (d, J = 6.0 Hz, 0.5H), 3.76 (dd, J = 6.0, 10.2 Hz, 0.5H), 3.50 (m, 1H), 3.1 1 (m, 1H), 2.39 (m, 7H), 2.02 (m, 1H), 1.69 (m, 1H), 1.32 (m, 2H), 1.04 (m, 9H) ppm; 1³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.5, 172.5, 172.3, 170.1, 169.9, 146.5, 146.0, 143.6, 136.4, 136.3, 129.8, 128.9, 128.4, 128.2, 128.1, 124.5, 122.8, 122.6, 112.4, 112.3, 109.4, 109.1, 68.3, 66.6, 62.5, 60.8, 60.4, 60.1, 56.7, 51.6, 47.5, 47.3, 44.9, 43.0, 41.2, 36.1, 35.6, 34.9, 33.0, 31.2, 26.6, 19.4, 13.1, 12.5, 8.5, 7.7, 7.3 ppm. Mass spectrum, m/z [571.2] (M + H)+.

Scheme XXX

[105] 3- 2-(4-Fluoro-phenylamino)-thia2ol-4-yl -hexahvdro-pyrrolo[3,2-b]pyrrole- 1-carboxylic acid benzyl ester (31): A solution of 19 (1.46 g, 3.12 mmol) and 4-fluorophenyl thiourea (585 mg, 3.44 mmol) in EtOH (50 mL) was heated to reflux in a pre-heated oil bath. After 17 h, the reaction mixture was cooled to ambient temperature and concentrated. The residue was dissolved in DCM (10 mL), cooled to 0 °C, and treated with TFA (4 mL). After 5 h, the reaction mixture was concentrated. The residue was diluted with EtOAc, washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na- ₂S0₄, filtered and concentrated to afford 31 (1.44 g, quant.) as a brown- colored foam. Mass spectrum, m/z [439.1] (M + H)+.

Scheme XXXI

4-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-3-[2-(4-fluoro- phenylamino)-thiazol-4-yl]-hexahvdro-pyrrolo[3,2-b]pyrrole-l-carboxylic acid benzyl ester (32): To a solution of Boc-Tle-OH (865 mg, 3.74 mmol) and HATU (1.42 g, 3.74 mmol) in NMP (4 mL) at 0 °C was added DIPEA (1.63 mL, 9.36 mmol) and the resultant pale yellow-colored solution was stirred for 20 min. To the reaction mixture was added a solution of 31 (1.37 g, 3.12 mmol) in NMP (10 mL) and the reaction mixture was allowed to warm to ambient temperature. After 18 h, the reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic extracts were washed successively with 1 M HC1, brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue was dissolved in 20% EtOAc/hexanes and purified via normal phase HPLC (2" Dynamax® Si0₂, 20-100% EtOAc/hexanes over 30 min; Flow: 40 mL/min) to afford 32 (1.38 g, 68%) as a light brown-colored foam. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.35 (m, 7H), 7.01 (m, 2H), 6.30 (s, 1H), 5.34 (m, 1H), 5.17 (m, 2H), 4.62 (m, 2H), 4.35 (m, 1H), 4.06 (m, 2H), 3.60 (m, 1H), 3.48 (m, 2H), 2.45 (m, 0.5H), 2.86 (m, 0.5H), 2.05 (m, 2H), 1.43 (m, 9H), 1.04 (m, 9H) ppm. Mass spectrum, m/z [652.2] (M + H)+.

Scheme XXXII

4-(2-Amino-3,3-dimethyl-but ^

hexahvdro-pyrrolo[3,2-b1pyrrole-l-carboxylic acid benzyl ester (33): To a solution of 32 (900 mg, 1.38 mmol) in DCM (6 mL) at ambient temperature was added TFA (3 mL). After 3 h, the reaction mixture was concentrated and the residue was dissolved in EtOAc and washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The residue was dissolved in 1 : 1 MeOH/H₂0 and purified via reverse-phase HPLC (2" Dynamax® CI 8, 20-100% MeOH/H₂0 containing 0.1% HOAc over 30 min; Flow: 40 mL/min). The product-containing fractions were combined, concentrated to remove MeOH, diluted with aqueous NaHC0₃ (sat.), and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 33 as a white foam. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.43-7.26 (m, 7H), 6.99 (m, 2H), 6.30 (s, 1H), 5.16 (m, 2H), 4.62 (m, 2H), 4.04 (dd, J = 1 1.4, 15 Hz, 1H), 3.86 (m, 1H), 3.63 (d, J = 6.0 Hz, 1H), 3.42 (m, 3H), 2.43 (dd, J = 6.0, 13.8 Hz, 0.5H), 2.27 (dd, J = 6.3, 13.5 Hz, 0.5H), 2.02 (m, 1H), 1.60 (br s, 2H), 1.01 (m, 9H) ppm. Mass spectrum, m/z [552.1] (M + H)+.

Scheme XXXIII

[108] 4-{2-[2-(^'tert-Butoxycarbonyl-methyl-amino^")-propionylamino1-3,3-dimethyl- butyryl}-3-[2-(4-fluoro-phenylamino)-thiazol-4-yl -hexahydro-pyrrolo[3,2- b ^"[pyrrole- 1 -carboxylic acid benzyl ester (34): To a solution of Boc-N(Me)Ala- OH (300 mg, 1.48 mmol) and HATU (563 mg, 1.48 mmol) in NMP (2 mL) at 0 °C was added DIPEA (700 μΐ, 4.02 mmol) and the resultant yellow-colored solution was stirred for 20 min. To the reaction mixture was added a solution of 33 (740 mg, 1.34 mmol) in NMP (5 mL) and the reaction mixture was allowed to warm to ambient temperature. After 3 h, the reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic extracts were washed successively with 1 M HC1, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 34 (1.02 g, quant.) as a white foam. Mass spectrum, m/z [737.3] (M + H)+.

Scheme XXXIV

[109] 4-[3,3-Dimethyl-2-(2-methylamino-propionylamino)-butyryl]-3-[2-(4-fluoro- phenylamino)-thiazol-4-yl]-hexahydro-pyrrolo[3,2-b]pyrrole- 1 -carboxylic acid benzyl ester (35): To a solution of 34 (800 mg, 1.09 mmol) in DCM (5 mL) at 0 °C was added TFA (3 mL) and the reaction mixture was allowed to warm to ambient temperature. After 2.5 h, the reaction mixture was concentrated and the residue was dissolved in EtOAc, washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The residue was dissolved in 1 : 1 MeOH/H₂0 and purified via reverse-phase HPLC (2" Dynamax® CI 8, 20-100% MeOH/H₂0 containing 0.1% HOAc over 30 min; Flow: 40 mL/min). The product-containing fractions were combined, concentrated to remove MeOH and lyophilized to afford 35 (354 mg, 51 %) as a white solid. EXAMPLE 4 4-r3.3-Dimethyl-2-(2-methylamino-propionylaminoVbutyrvn- 3-[2-(4-fluoro-phenylamino^')-thiazol-4-yl]-hexahvdro-pyrrolo[3 ,2-b]pyrrole- 1 - carboxylic acid benzyl ester (35): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.92 (m, 1H), 7.44-7.29 (m, 6H), 6.99 (app dd, J= 8.4, 19.2 Hz, 2H), 6.22 (d, J = 2.4 Hz, 1H), 5.16 (m, 2H), 4.63 (m, 3H), 4.16-3.96 (m, 2H), 3.58 (d, J = 6.0 Hz, 1H), 3.48 (m, 2H), 3.27 (ddd, J = 6.9, 13.8, 13.5 Hz, 1H), 2.41 (m, 3H), 2.04 (m, 2H), 1.34 (d, J = 6.9 Hz, 3H), 1.03 (m, 9H) ppm. ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.2, 170.0,

165.8, 160.3, 157.1, 154.9, 151.5, 136.9, 128.8, 128.7, 128.3, 128.2, 128.1 ,

127.9, 120.4, 120.3, 120.2, 120.1, 1 16.3, 116.0, 102.1, 68.0, 67.4, 67.2, 61.3, 60.6, 59.9, 57.2, 51.4, 51.1, 47.5, 44.8, 44.2, 36.5, 35.8, 34.7, 34.5, 32.2, 31.2, 26.8, 19.1 ppm. Mass spectrum, m/z [637.2] (M + H)+.

Table 2

Scheme XXXV

[111] 3- 2-(3-Trifluoromethyl-phenyl)-thiazol-4-yl]-hexahvdro-pyrrolo[3,2- b]pyrrole-l -carboxylic acid benzyl ester (36): Intermediate 36 was prepared in two steps from common intermediate 19 using the procedure outlined in Scheme XXX. Mass spectrum, m/z [474.0] (M + H)+.

Scheme XXXVI

[112] 4-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-3-[2-(4-fluoro- phenylamino)-thiazol-4-yll-hexahvdro-pyrrolo[3,2-b1pyrrole-l-carboxylic acid benzyl ester (37 : Intermediate 37 was prepared in one step from 36 using the procedure outlined in Scheme XXXI. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 58.14 (m, 1H), 8.06 (m, 1H), 7.75 (d, J = 7.8 Hz, 0.2H), 7.64 (d, J = 7.8 Hz, 0.8 Hz), 7.52 (m, 1H), 7.35-7.21 (m, 5H), 7.14 (s, 1H), 5.33 (d, J= 9.9 Hz, 0.7H), 5.24 (d, J = 9.6 Hz, 0.3H), 5.15 (m, 2H), 4.69 (s, 2H), 4.54 (m, 0.2H), 4.35 (m, 0.8H), 4.17 (d, J= 5.7 Hz, 1H), 4.07 (m, 1H), 3.83 (d, J = 5.4 Hz, 1H), 3.59-3.44 (m, 2H), 2.43 (m, 0.5H), 2.32 (m, 0.5H), 2.05 (m, 1H), 1.42 (m, 9H), 1.03 (m, 9H) ppm. Mass spectrum, m/z [687.2] (M + H)+.

Scheme XXXVII

4-(2-Amino-3,3-dimethyl-but yl)-3- 2-(3-trifluoromethyl-phenyl)-thiazol-4- yl]-hexahvdro-pyrrolo[3,2-b]pyrroIe-l-carboxylic acid benzyl ester (38): To a solution of 37 (370 mg, 0.539 mmol) in DCM (10 mL) at 0 °C was added TFA (4 mL) and the reaction mixture was allowed to warm to ambient temperature. After 1.5 h, the reaction mixture was concentrated. The residue was dissolved in EtOAc and washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 38 (310 mg, 98%) as an off-white foam which was taken forward without further purification. Mass spectrum, m/z [587.1] (M + H)+.

Scheme XXXVIII

[114] 4-{2-[2-(tert-Butoxycarbonyl-methyl-amino)-propionylamino ]-3,3-dimethyl- butyryl}-3-[2-(3-trifluoromethyl-phenyl)-thiazol-4-yl]-hexah

b]pyrrole-l-carboxylic acid benzyl ester (39): Intermediate 39 was prepared in one step from 38 using the procedure outlined in Scheme XXXIII. Mass spectrum, m/z [772.3] (M + H)+.

Scheme XXXIX

[115] 4-[3,3 -Dimemyl-2-(2-methylamino-propionylamino)-butyryl]-3-[2-(3- trifluoromethyl-phenylVthiazol-4-yl]-hexahydro-pyrrolo 3.2-b]pyrrole-l- carboxylic acid benzyl ester (40): Compound 40 was prepared in one step from intermediate 39 using the procedure outlined in Scheme XXXIV.

[116] EXAMPLE 5 4-[3,3 -Dimethyl-2-(2-methylamino-propionylamino)-butyryl1- 3-[2-(3- trifluoromethyl-phenyl)-thiazol-4-yl]-hexahvdro-pyrrolo[3.2- b1pyrrole-l-carboxylic acid benzyl ester (40): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: δ 8.14 (s, 1H), 8.05 (m, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.52 (m, 1H), 7.35-7.23 (m, 4H), 7.15 (s, 1H), 5.17 (m, 2H), 4.68 (m, 2H), 4.09 (m, 2H), 3.83 (m, 1H), 3.55 (m, 2H), 3.10 (m, 1H), 2.39 (m, 3H), 1.93 (m, 3H), 1.36 (d, J= 6.9 Hz, 1H), 1.32 (d, J= 6.9 Hz, 2H), 1.05 (m, 9H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.7, 170.4, 166.5, 157.3, 155.1, 136.8, 134.4, 131.8, 131.1, 129.8, 129.7, 128.7, 128.6, 128.2, 128.1, 127.9, 127.9, 126.5, 123.3, 115.0, 68.4, 68.2, 67.5, 67.4, 67.1, 61.4, 61.0, 60.4, 57.0, 51.9, 51.5, 47.5, 45.7, 44.8, 44.1, 36.3, 35.8, 35.1, 32.2, 31.4, 26.7, 19.6 ppm. Mass spectrum, m/z [672.2] (M + H)+. Scheme XL

(2,2-Dimethyl- 1 - {6- 2-(^"3-trifluoromethyl-phenyl)-thiazol-4-yll-hexahydro- pyrrolo[3,2-b1pyrrole-l-carbonyl}-propyl)-carbamic acid tert-butyl ester (41):

To a solution of 37 in MeOH (50 mL) in a Parr bottle was added 10% Pd/C (200 mg) and the bottle was evacuated and flushed with ¾ five times, then charged to 55 PSI H₂ and shaken. After 2 h, the reaction mixture was filtered through a Millipore filter, concentrated and resubmitted to the reaction conditions. This cycle was repeated five times after which the crude residue was dissolved in 4:1 MeOH/H₂0 and purified via reverse-phase HPLC (2" Dynamax® CI 8, 20-100% MeOH/H₂0 containing 0.1% HO Ac over 30 min; Flow: 40 niL/min). The product-containing fractions were concentrated, diluted with EtOAc, washed successively with aqueous NaHC0₃, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 41 (330 mg, 24%) as a foamy white solid. ^lU NMR (300 MHz, CDC1₃), mixture of amide rotomers: 58.17 (s, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.56 (app dd, J = 6.9, 15 Hz, 1H), 7.28 (s, 1H), 5.36 (m, 1H), 4.59 (d, J = 5.1 Hz, 0.8H), 4.50 (d, J = 9.9 Hz, 0.2H), 4.43 (d, J = 6.3 Hz, 0.2 H), 4.34 (d, J = 9.9 Hz, 0.8H), 4.16 (m, 1H), 3.96 (m, 1H), 3.66 (m, 1H), 3.55 (m, 1H), 3.31 (dt, J = 4.2, 1 1.4 Hz, 1H), 3.18 (m, 1H), 2.05 (m, 2H), 1.41 (m, 9H), 1.03 (m, 9H) ppm. Mass spectrum, m/z [553.1] (M + H)+.

Scheme XLI

[118] (l-l4-Methanesulfonyl-6-r2-(3-trifluoromethyl-phenylVthiazol-4-yl1- hexahvdro-pyrrolo 3.,2-blpyrrole-l-carbonyl)-2,2-dimethyl-propyl)-carbamic acid tert-butyl ester (42): To a solution of 41 (165 mg, 0.30 mmol) in DCM (3 mL) at ambient temperature was added TEA (83 μΐ,, 0.60 mmol) and MsCI (28 μί, 0.36 mmol). After 4 h, the reaction mixture was diluted with DCM and washed successively with 1M HCl, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 42 which was taken forward without further purification. Mass spectrum, m/z [631.1] (M + H)+.

Scheme XLII

[119] 2-Amino-l- {4-methanesulfonyl-6-[2-(3-trifluoromethyl-phenyl)-thiazol-4-yl]- hexahydro-p yrrolo[3 ,2-b]pyrrol- 1 -yl } -3 ,3 -dimethyl -butan- 1 -one (43):

Intermediate 43 was prepared in one step from intermediate 42 using the procedure outlined in Scheme XXXVII. Mass spectrum, m/z [531.1] (M + H)+.

Scheme XLIII

[120] [1-(1 - (4-Methanesulfonyl-6-r2-(3-trifluoromethyl-phenylVthiazol-4-yll- hexahvdro-pyrrolo[3,2-blpyrrole-l-carbonyl}-2,2-dimethyl-propylcarbamoyl)- ethyl]-methyl-carbamic acid tert-butyl ester (44): Intermediate 44 was prepared in one step from 43 using the procedure outlined in Scheme XXXIII. Mass spectrum, m/z [716.2] (M + H)+.

Scheme XLIV

[121] N-(l-{4-Methanesulfonyl-6-r2-(3-trifluoromethyl-phenyl)-thiazol-4-yll- hexahydro-pyrrolo[3,2-b]pyrrole-l -carbonyl}-2,2-dimethyl-propyl)-2- methylamino-propionamide (45): Compound 45 was prepared in one step from intermediate 44 using the procedure outlined in Scheme XXXIV.

[122] EXAMPLE 6 N-(l - {4-Methanesulfonyl-6-r2-(3-trifluoromethyl-phenyl)- thiazol-4-yl]-hexahydro-pyrrolo[3,2-b1pyrrole- 1 -carbonyl} -2,2-dimethyl- propyl)-2-methylamino-propionamide (45): Ή NMR (300 MHz, CDCl₃),mixture of amide rotomers: 68.12 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.32 (s, 1H), 4.75 (d, J = 5.1 Hz, 1H), 4.65 (d, J = 9.6 Hz, 1H), 4.60 (t, J = 4.5 Hz, 1H), 4.22 (t, J= 9.9 Hz, 1H), 3.88 (m, 3H), 3.70 (dt, J= 5.7, 1 1.7 Hz, 1H), 3.13 (m, 1H), 2.76 (s, 3H), 2.60 (m, 4H), 3.40 (s, 3H), 1.32 (d, J = 6.6 Hz, 3H), 1.07 (s, 9H) ppm; ^l3C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.5, 170.4, 157.0, 133.9, 131.9, 131.4, 129.7, 129.4, 126.7, 123.0, 116.0, 68.8, 63.6, 60.0, 56.9, 53.9, 46.9, 44.3, 35.7, 35.6, 35.5, 34.7, 33.2, 26.6, 16.2 ppm. Mass spectrum, m/z [616.1] (M + H)+.

Scheme XLV

[123] (l-{4-Isopropylcarbamoyl-6-[2-(3-trifluoromethyl-phenyl)-thiazol-4-yl]- hexahydro-pyrrolo 3,2-b]pyrrole-l-carbonyl}-2,2-dimethyl-propyl)-carbamic acid tert-butyl ester (46): To a solution of 41 (165 mg, 0.30 mmol) in DCM (3 mL) was added TEA (125 μί, 0.90 mmol) and isopropyl isocyanate (59 μί, 0.60 mmol). After 4 h, the reaction mixture was quenched with MeOH (2 mL) and NH₄OH (15 M, 20 drops). After 10 min, the reaction mixture was diluted with DCM and washed successively with 1 M HC1, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 46 (180 mg, 94%) as a white foam that was taken forward without further purification. Mass spectrum, m/z [638.2] (M + H)+.

Scheme XLVI

[124] 4-(2-Amino-3,3-dimethyl-butyryl)-3-[2-(3-trifluoromethyl-phenyl)-thiazol-4- yl]-hexahydro-pyrrolo[3,2-b]pyrrole-l-carboxylic acid isopropylamide (47):

Intermediate 47 was prepared in one step from intermediate 46 using the procedure outlined in Scheme XXXVII. Mass spectrum, m/z [538.1] (M + H)+.

Scheme XLVII

[125] l-fl-{4-Isopropylcarbamoyl-6-[2-(3-trifluoromethyl-phenyl)-thiazol-4-yl]- hexahvdro-cvclopenta[b]pyrrole-l-carbonyl}-2,2-dimethyl-propylcarbamoyl)- ethyl]-methyl-carbamic acid tert-butyl ester (48): Intermediate 48 was prepared in one step from 47 using the procedure outlined in Scheme XXXIII. Mass spectrum, m/z [723.3] (M + H)+.

Scheme XLVIII

[126] l-[3,3-Dimethyl-2-(2-methylamino-propionylamino^')-butyryl]-6-[2-(3- trifluoromethyl-phenyl)-thiazol-4-yl]-octahydro-cyclopenta[b]pyrrole-4- carboxylic acid isopropylamide (49): Compound 49 was prepared in one step from intermediate 48 using the procedure outlined in Scheme XXXIV.

[127] EXAMPLE 7 l-r3.3-Dimethyl-2-(2-methylamino-propionylamino)-butyryl]- 6-[2-(3-trifluoromethyl-phenyl)-thiazol-4-yl]-octahydro-cyclopenta[b1pyrrole- 4-carboxylic acid isopropylamide (49): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 58.20 (s, 0.2H), 8.14 (s, 0.8H), 8.09 (d, J = 7.5 Hz, 1H), 7.92 (d, J= 9.6 Hz, 0.2H), 7.85 (d, J= 9.6 Hz, 0.8H), 7.64 (t, J = 7.8 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 4.67 (m, 3H), 4.19-3.95 (m, 2H), 3.86 (d, J = 5.7 Hz, 1H), 3.56 (m, 2H), 3.18 (q, J = 7.2 Hz, 1H), 2.59 (br s, 2H), 2.42 (m, 4H), 2.04 (m, 1H), 1.37 (d, J = 7.2 Hz, 0.8H), 1.34 (d, J = 7.2 Hz, 2.2H), 1.18 (t, J = 5.4 Hz, 6H), 1.06 (m, 9H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.0, 170.1 , 169.9, 166.2, 157.2, 156.9, 155.7, 134.2, 131.6, 131.1, 129.7, 129.4, 126.4, 123.1, 1 15.5, 114.9, 68.5, 67.8, 62.1, 60.2, 59.9, 56.9, 51.0, 50.2, 47.4, 47.1, 45.6, 44.5, 42.5, 36.1, 35.6, 34.7, 34.6, 31.7, 31.1 , 26.6, 23.6, 34.4, 19.2, 19.1 ppm. Mass spectrum, m/z [623.2] (M + H)+.

Scheme XLIX

3-[2-(4-Fluoro-phenyl)-thiazol-4-yl]-hexahvdro-pyrrolo[3,2-b]pyrrole-l - carboxylic acid benzyl ester (50): Intermediate 50 was prepared in two steps from common intermediate 19 using the procedure outlined in Scheme XXX. Mass spectrum, m/z [424.0] (M + H)+.

Scheme L

[129] 4-(2-tert-Butoxycarbonylamino-3 -dimethyl-butyryl)-3-[2-(^'4-fluoro-phenylV thiazol-4-yl]-hexahydro-pyrrolo[3,2-b]pyrrole-l-carboxylic acid benzyl ester (51): Intermediate 51 was prepared in one step from 50 using the procedure outlined in Scheme XXXI. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.88 (m, 2H), 7.29 (m, 5H), 7.07 (m, 3H), 5.34 (d, J= 9.3 Hz, 1H), 5.21 (m, 1H), 5.10 (d, J = 12.6 Hz, 1H), 4.69 (m, 2H), 4.35 (d, J = 9.6 Hz, 1H), 4.1 1 (m, 2H), 3.81 (d, J = 6.0 Hz, 1H), 3.53 (m, 2H), 2.47 (dd, J = 5.7, 13.5 Hz, 0.5H), 2.31 (m, 0.5H), 2.05 (m, 1H), 1.42 (m, 9H), 1.03 (m, 9H) ppm. Mass spectrum, m/z [637.2] (M + H)+.

Scheme LI

[130] 4-(2-Amino-3.3-dimethyl-butyryl)-3-r2-(4-fluoro-phenyl -thiazol-4-yll- hexahydro-pyrrolor3,2-blpyrrole-l-carboxylic acid benzyl ester (52):

Intermediate 52 was prepared in one step from intermediate 51 using the procedure outlined in Scheme XXXVII. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.43-7.26 (m, 7H), 6.98 (m, 2H), 6.30 (s, 1H), 5.16 (m, 2H), 4.62 (m, 2H), 4.04 (dd, J= 1 1.4, 15.0 Hz, 1H), 3.86 (m, 1H), 3.63 (d, J = 6.0 Hz, 1H), 3.40 (m, 3H), 2.43 (dd, J= 6.0, 13.8 Hz, 0.5H), 2.27 (dd, J = 6.3, 13.5 Hz, 0.5H), 2.08-1.90 (m, 2H), 1.60 (br s, 2H), 1.00 (m, 9H) ppm. Mass spectrum, m/z [552.1] (M + H)+.

Scheme LII

[131] 4-{2-[2-(tert-Butoxycarbonyl-methyl-amino)- propionylamino]-3,3-dimethyl- butyryl } -3 -[2-(4-fluoro-phenyl)-thiazol-4-yl]-hexahydro-pyrrolo[3.2- b]pyrrole-1-carboxylic acid benzyl ester (53): Intermediate 53 was prepared in one step from 52 using the procedure outlined in Scheme XXXIII. Mass spectrum, m/z [772.2 ] (M + H)+.

Scheme LIII

[132] 4- [3 ,3 -Dimethyl-2-(2-methylamino-propionylamino)-butyryl]-3-[2-(4-fluoro- phenylVthiazol-4-yl]-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester (54): Compound 54 was prepared in one step from intermediate 53 using the procedure outlined in Scheme XXXIV.

[133] EXAMPLE 8 4-[3,3-Dimethyl-2-(2-methylamino-propionylamino -butyryll- 3 - [2-(4-fluoro-phenyl)-thiazol-4-yl]-hexahydro-pyrrolo[3,2-blpyrrole-1- carboxylic acid benzyl ester (54): ¹ H NMR (300 MHz, CDC1₃), mixture of amide rotomers: δ 7.95 (m, 1H), 7.46-7.29 (m, 6H), 7.02 (m, 2H), 6.22 (d, J= 2.4 Hz, 1H), 5.16 (m, 2H), 4.64 (m, 3H), 4.16-3.91 (m, 2H), 3.58 (d, J = 6.0 Hz, 1H), 3.48 (m, 2H), 3.27 (m, 1H), 2.41 (m, 3H), 2.04 (m, 2H), 1.22 (d, J = 6.9 Hz, 3H), 1.03 (m, 9H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 8174.2, 170.3, 166.0, 165.8, 160.3, 157.1, 154.9, 151.5, 136.9, 128.8, 128.7, 128.3, 128.2, 128.1, 127.9, 120.4, 120.3, 120.2, 120.1, 116.3, 1 16.0, 102.1, 68.0, 67.4, 67.2, 61.3, 60.6, 59.9, 57.2, 51.4, 51.1 , 57.5, 44.8, 44.2, 36.5, 35.8, 34.5, 32.2, 31.2, 26.8, 19.1 ppm. Mass spectrum, m/z [622.2] (M + H)+.

Scheme LIV

[l-(l-{6-[2-(4-Fluoro^henyl)-thiazol-4-yl]-hexahydro^yrrolo[3,2-b]pyrrole- l-carbonyl}-2,2-dimethyl-propylcarbamoyl)-ethyl]-methyl-carbamic acid tert- butyl ester (55): To a solution of 53 (1.16 g, 1.6 mmol) in MeOH (20 mL) in a Parr bottle was added 10% Pd/C (100 mg) and the bottle was evacuated and flushed with H₂ five times. The bottle was charged to 55 PSI H₂ and shaken. After 2 h, the reaction mixture was filtered through a Millipore filter, concentrated, and resubmitted to the reaction conditions. This cycle was completed 5 times after which the residue was dissolved in 1 :1 MeOH/H₂0 and purified via reverse-phase HPLC (2" Dynamax® CI 8, 20-100% MeOH/H₂0 containing 0.1% HOAc over 30 min; Flow: 40 mL/min). The product-containing fractions were concentrated, diluted with EtOAc, washed successively with aqueous NaHC0₃, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 55 (250 mg, 27%) as a white foam. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.91 (m, 2H), 7.13 (m, 3H), 4.89 (dd, J = 9.9 Hz, 0.3H), 4.69 (d, J = 9.3 Hz, 1.7H), 4.56 (d, J = 6.3 Hz, 1H), 4.40 (m, 1H), 4.15 (m, 1H), 4.00 (m, 1H), 3.84 (m, 0.2H), 3.66 (m, 1H), 3.56 (m, 1H), 3.30 (dd, J = 2.7, 1 1.4 Hz, 1H), 3.19 (m, 2H), 2.85-2.68 (m, 5H), 2.04 (m, 3H), 1.48 (m, 9H), 1.31 (d, J = 6.9 Hz, 3H), 1.02 (s, 9H) ppm. Mass spectrum, m/z [588.2] (M + H)+.

Scheme LV

[135] [l-(l-{6-[2-(4-Fluoro-phenyl)-thiazol-4-yl1-4-methanesulfonyl-hexahvdro- pyrrolo[3,2-blpyrrole-l-carbonyl|-2,2-dimethyl-propylcarbanioyl)-ethyl]- methyl-carbamic acid tert-butyl ester (56): To a solution of 55 (125 mg, 0.21 mmol) in DCM (2 mL) at ambient temperature was added TEA (59 μί,, 0.43 mmol) and MsCl (20 μί, 1.47 mmol). After 4 h, the reaction mixture was diluted with DCM, washed successively with 1 M HCl, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 56 (240 mg, quant.) as a yellow-colored foam that was taken forward without further purification. Mass spectrum, m/z [666.2] (M + H)+.

Scheme LVI

[136] N-(l-{6-[2-(4-Fluoro-phenyl)-thiazol-4-yl]-4-methanesulfonyl-hexahvdro- pyrrolo[3,2-b1pyrrole-l -carbonyll-2,2-dimethyl-propyl)-2-methylamino- propionamide (57): Compound 57 was prepared in one step from intermediate 56 using the procedure outlined in Scheme XXXIV.

[137] EXAMPLE 9 N-(l-{6-r2-(4-Fluoro-phenyl)-thiazol-4-yl1-4- methanesulfonyl-hexahydro-pyrrolo[3,2-b1pyrrole-l-carbonyl|-2,2-dimethyl- propyl)-2-methylamino-propionamide (57): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.86 (m, 3H), 7.28 (s, 0.2H), 7.23 (s, 0.8H), 7.14 (t, J = 8.7 Hz, 2H), 4.76 (d, J= 5.7 Hz, 1H), 4.64 (m, 2H), 4.21 (t, J= 9.9 Hz, 1H), 3.91-3.73 (m, 3H), 3.62 (m, 4H), 3.22 (app dd, J = 6.6, 13.8 Hz, 1H), 2.71 (s, 2H), 2.59 (dd, J = 5.4, 13.5 Hz, 1H), 2.41 (s, 3H), 2.13 (m, 1H), 2.04 (s, 1H), 1.34 (d, J = 7.2 Hz, 3H), 1.06 (s, 9H) ppm; ¹³C NMR (75 MHz, CDCI₃), mixture of amide rotomers: 8179.0, 170.3, 167.3, 165.6, 162.2, 156.4, 129.4, 128.3, 128.2, 1 16.3, 116.0, 1 15.0, 68.6, 63.7, 59.7, 57.1, 54.0, 47.0, 44.3, 35.7, 35.5, 34.4, 33.2, 26.6, 26.5, 19.0 ppm. Mass spectrum, m/z [566.1] (M + H)+.

Scheme LVII

[l-(l-{6-[2-(4-Fluoro-phenyl)-thiazol-4-yl]-4-isopropylcarbamoyl-hexahvdro- pyrrolo[3.2-b]pyrrole- 1 -carbonyll -2,2-dimethyl-propylcarbamoyl)-ethyl]- methyl-carbamic acid tert-butyl ester (58): To a solution of 55 (125 mg, 0.21 mmol) in DCM (2 mL) at ambient temperature were added TEA (89 μί,, 0.64 mmol) and isopropyl isocyanate (42 μί, 0.43 mmol). After 4 h, the reaction mixture was quenched with MeOH (2 mL) and NH₄OH (15 M, 10 drops). After 10 min, the reaction mixture was diluted with DCM, washed successively with 1 M HC1, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 58 (190 mg, quant.) which was taken forward without further purification. Mass spectrum, m/z [673.2] (M + H)+.

Scheme LVIII

[139] 4-[3 -Dimethyl-2-(2-mel3iylamino-propionylamino)-butyryl1-3-[2-(4-flu^ phenyl)-thiazol-4-yl] -hexahydro-pyrrolo [3 ,2-b]pyrrole- 1 -carboxylic acid isopropylamide (59): Compound 59 was prepared in one step from intermediate 58 using the procedure outlined in Scheme XXXIV.

[140] EXAMPLE 10 4-[3.3 -Dimethyl-2-a-methylamino-propionylamino V butyryl] -3 - [2-(4-fluoro-phenyl)-thiazol-4-yl] -hexahydro-pyrrolo [3,2- b]pyrrole-l -carboxylic acid isopropylamide (59): 1H NMR (300 MHz, CDC1₃), mixture of amide rotomers: 67.89 (m, 3H), 7.10 (m, 2H), 4.64 (m, 2H), 4.19-3.75 (m, 4H), 3.53 (m, 1H), 3.15 (m, 1H), 2.71 (m, 2H), 2.39 (m, 3H), 2.04 (m, 1H), 1.32 (d, J = 6.9 Hz, 3H), 1.18 (t, J = 6.0 Hz, 6H), 1.05 (m, 9H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.3, 171.5, 166.8, 165.4, 162.1, 156.7, 156.5, 155.8, 129.9, 128.4, 128.3, 128.3, 116.0, 115.7, 114.7, 113.9, 68.6, 67.9, 62.3, 60.2, 60.0, 56.8, 51.0, 50.5, 47.4, 47.1, 45..5, 44.4, 42.5, 36.2, 35.6, 34.7, 31.6, 31.1, 26.6, 26.5, 23.6, 23.5, 23.5, 1 .3 ppm. Mass spectrum, m/z [573.2] (M + H)+.

Example

Scheme LIX

13 60 3 -Carbamoyl-hexahvdro-pyrrolo[3 ,2-b]pyrrole- 1 ,4-dicarboxylic acid 1 -benzyl ester 4-tert-butyl ester (60): To a solution of 13 (1.78 g, 4.56 mmol) in THF (25 mL) at 0 °C was added TEA (763 μί, 5.47 mmol) and ethyl chloroformate (458 nL, 4.79 mmol). After 1.5 h, cone. NH₄OH (15 M, 2 mL) was added and the reaction mixture was allowed to warm to ambient temperature. After 4 h, the reaction mixture was concentrated and the residue was partitioned between DCM and 1 M HC1. The layers were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue was dissolved in EtOAc and washed successively with aqueous NaHC0₃, brine, dried over anhydrous Na₂S04, filtered and concentrated to afford 60 (1.43 g, 81%) as a white-colored foam which was taken forward without further purification. Mass spectrum, m/z [390.1] (M + H)+.

Scheme LX

3-Thiocarbamoyl-hexahvdro-pyrrolo[3,2-b]pyrrole- 1 ,4-dicarboxylic acid 1 - benzyl ester 4-tert-butyl ester (61): To a solution of 60 (1.43 g, 3.67 mmol) in toluene (20 mL) was added Lawesson's Reagent (772 mg, 1.91 mmol) and the resulting suspension was heated to 50 °C in a pre-heated oil bath. After 1.5 h, the reaction mixture was cooled to ambient temperature and concentrated. The residue was absorbed onto Si0₂, purified via flash silica gel chromatography (1 :2 to 1 :1 EtOAc/hexanes) and the product-containing fractions were combined and concentrated to afford 61 (1.1 1 g, 74%) as a white solid. Ή NMR (300 MHz, CDC1₃), mixture of rotomers: 58.94-8.67 (br m, 2H), 7.55-7.09 (m, 5H), 5.18 (q, J = 12.3, 18.9 Hz, 2H), 4.57 (dt, J = 2.7, 6.3 Hz, 1 H), 4.48 (dd, 7 = 3.3, 1 1.7 Hz, 1H), 4.30 (d, J = 6.9 Hz, 1H), 3.60 (m, 2H), 3.39 (m, 1H), 3.28 (m, 1H), 2.26-1.97 (m, 2H), 1.48 (m, 9H) ppm. Mass spectrum, m/z [406.0] (M + H)+.

Scheme LXI

3-(4-Phenyl-thia2ol-2-yl)-hexahvdro-p olo 3,2-b]pyrrole-l-carboxylic acid benzyl ester (62): To a solution of 61 (750 mg, 1.85 mmol) in EtOH (25 mL) was added 2-bromoacetophenone and the reaction mixture was heated to reflux in a pre-heated oil bath. After 1 h, the reaction mixture was cooled to ambient temperature and concentrated to afford an off-white foam. The residue was dissolved in DCM (10 mL), cooled to 0 °C and TFA was added. After 2 h, the reaction mixture was concentrated and the resultant residue was dissolved in EtOAc, washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude product was dissolved in 1 : 1 MeOH/H₂0 and purified via reverse-phase HPLC (2" Dynamax® CI 8, 20-100% MeOH/H₂0 containing 0.1 % HOAc over 30 min; Flow: 40 mL/min). The product- containing fractions were combined, concentrated, and the residue was dissolved in EtOAc and washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na- ₂S0₄, filtered and concentrated to afford 62 (280 mg, 37%) as a white foam. Ή NMR (300 MHz, CDC1₃), mixture of rotomers: 67.87 (dd, J = 1.5, 8.4 Hz, 2H), 7.35 (m, 9H), 5.18 (m, 2H), 4.53 (q, J = 4.8, 10.8 Hz, 1H), 4.16 (m, 1H), 4.00 (m, 1H), 3.93 (d, J = 6.6 Hz, 0.7H), 3.89 (d, J = 6.3 Hz, 0.3H), 3.66 (ddd, J = 3.6, 6.9, 6.0 Hz, 1H), 3.03 (m, 2H), 2.05 (m, 3H) ppm. Mass spectrum, m/z [406.1] (M + H)+.

Scheme LXII

[144] 4-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-3-(4-phenyl-thiazol-2- yl)-hexahvdro-pytTolor3,2-b]pyrrole-l-carboxylic acid benzyl ester (63):

Intermediate 63 was prepared in one step from 62 using the procedure outlined in Scheme XXXI. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.87 (d, J = 6.9 Hz, 2H), 7.33 (m, 9H), 4.39 (d, J = 9.9 Hz, 1H), 5.20 (m, 2H), 4.85 (dd, J = 5.4, 8.7 Hz, 1H), 4.71 (d, J = 2.1 Hz, 1H), 4.34 (m, 2H), 4.1 1 (m, 1H), 4.03 (d, J = 5.7 Hz, 1H), 3.61-3.44 (m, 2H), 2.49 (dd, J = 5.1, 12.9 Hz, 0.5H), 2.33 (dd, J = 5.1 , 13.8 Hz, 0.5H), 2.07 (m, 1H), 1.43 (m, 9H), 1.02 (m, 9H) ppm. Mass spectrum, m/z [619.1] (M + H)+.

Scheme LXIII

[145] 4-(2-Amino-3,3-dimethyl-butyryl)-3-(4-phenyl-thiazol-2-yl)-hexahydro- pyrrolo 3,2-b1pyrrole-l -carboxylic acid benzyl ester (64): Intermediate 64 was prepared in one step from intermediate 63 using the procedure outlined in Scheme XXXVII. Mass spectrum, m/z [519.1] (M + H)+.

Scheme LXIX

[146] 4-{2-[2-(tert-Butoxycarbonyl-methyl-amino)-propionylamino -3,3-dimethyl- butyryl } -3 -(4-phenyl-thiazol-2-yl)-hexahydro-pyrrolo[3.2-b]pyrrole- 1 - carboxylic acid benzyl ester (65): Intermediate 65 was prepared in one step from 64 using the procedure outlined in Scheme XXXIII. Mass spectrum, m/z [704.2] (M + H)+.

Scheme LXX

[147] 4-[3,3-Dimethyl-2-(2-methylamino-propionylamino)-butyryll-3-(4-phenyl- thiazol-2-yl)-hexahvdro-pyrrolor3,2-blpyrrole-l -carboxylic acid benzyl ester (66): Compound 66 was prepared in one step from intermediate 65 using the procedure outlined in Scheme XXXIV.

[148] EXAMPLE 11 4-[3,3-Dimethyl-2-(2-methylamino-propionylamino)- butyryl1-3-(4-phenyl-thiazol-2-yl)-hexahvdro-pyrrolo[3.2-b]pyrrole-l- carboxylic acid benzyl ester (66V. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 67.86 (m, 3H), 7.39-7.27 (m, 8H), 5.20 (m, 2H), 4.83 (t, J = 5.1 Hz, 1H), 4.75 (q, J= 6.0 Hz, 1H), 4.65 (dd, J= 4.8, 9.6 Hz, 1H), 4.28 (t, J = 11.4 Hz, 1H), 4.19 (q, J = 9.0 Hz, 1H), 4.03 (s, 1H), 3.53 (m, 2H), 3.14 (m, 1H), 2.72 (br s, 1H), 2.54-2.30 (m, 4H), 2.04 (m, 1.5H), 1.32 (d, J = 6.6 Hz, 3H), 1.05 (s, 9H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.7, 170.5, 168.8, 168.7, 155.3, 157.9, 154.8, 136.7, 134.5, 129.2, 128.9, 128.7, 128.7, 128.3, 128.2, 127.9, 127.8, 126.5, 1 12.7, 68.4, 67.8, 67.4, 67.2, 61.3, 60.9, 60.4, 60.2, 57.0, 52.1 , 51.4, 47.6, 47.5, 45.6, 45.8, 35.8, 32.1, 35.0, 32.1, 31.2, 26.8, 19.5 ppm. Mass spectrum, m/z [603.9] (M + H)+.

Scheme LXXI

[149] N-(2,2-Dimethyl-l-[6-(4-phenyl-thiazol-2-vn-hexahvdro-pyrrolo 3,2- blpyrrole- 1 -carbonyl] -propyl} -2-methylamino-propionamide (67): To a solution of 66 (260 mg, 0.43 mmol) in MeOH (20 mL) in a Parr bottle was added 10% Pd/C (50 mg). The bottle was evacuated and flushed with H₂ five times, then charged to 55 PSI H₂ and shaken. After 19 h, the reaction mixture was filtered through Celite® and concentrated. The residue was dissolved in 1 : 1 MeOH/H₂0 and purified via reverse-phase HPLC (2" Dynamax® CI 8, 40-100% MeOH/H₂0 containing 0.1% HOAc over 30 min; Flow: 40 mL/min). The product-containing fractions were combined, concentrated to remove MeOH, and lyophilized to afford 67 (96 mg, 48%) as a white solid.

[150] EXAMPLE 12 N- {2.2-Dimethyl-l -[6-(4-phenyl-thiazol-2-yl)-hexahydro- pyrrolo[3,2-b]pyrrole-l -carbonyl]-propyl) -2-methylamino-propionamide (67):

Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.85 (m, 3H), 7.40 (m, 3H), 7.34 (d, J= 6.9 Hz, 1H), 5.65 (br s, 6H), 4.70 (s, 1H), 4.67 (d, J= 5.1 Hz, 1H), 4.28 (t, J= 5.1 Hz, 1H), 4.08 (t, J = 9.0 Hz, 1H), 3.86 (d, J= 5.1 Hz, 1H), 3.70 (ddd, J = 7.2, 10.5, 6.6 Hz, 1H), 3.51 (d, J = 1 1.1 Hz, 1H), 3.27 (m, 2H), 2.41 (s, 3H), 2.19 (m, 2H), 2.03 (s, 6H), 1.33 (d, J = 6.6 Hz, 3H), 1.06 (s, 9H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5176.8, 173.8, 173.7, 170.2, 169.9, 169.5, 169.4, 155.1 , 134.2, 129.7, 128.1 , 126.3, 126.2, 112.6, 69.3, 63.9, 61.2, 59.7, 59.4, 57.0, 56.9, 52.7, 51.9, 49.9, 47.9, 46.4, 35.7, 34.3, 34.0, 31.8, 31.1, 26.6, 21.7, 19.0, 18.6 ppm. Mass spectrum, m/z [470.3] (M + H)+.

Scheme LXXII

[151] 3-(^"4,5-Diphenyl-thiazol-2-yl)-hexahydro-p rolo 3,2-b]pyrrole-l-carboxylic acid benzyl ester (68): Intermediate 68 was prepared in two steps from intermediate 61 using the procedure outlined in Scheme LXI. Ή NMR (300 MHz, CDC1₃), mixture of rotomers: 57.49 (m, 2H), 7.30 (m, 13H), 5.20 (m, 2H), 4.53 (q, J = 5.1 , 9.9 Hz, 1H), 4.20 (m, 1H), 4.02 (m, 1H), 3.94 (d, J= 6.3 Hz, 0.7H), 3.90 (d, J= 6.3 Hz, 0.3H), 3.65 (dd, J = 3.33, 6.0 Hz, 1H), 3.04 (m, 2H), 2.10 (m, 4H) ppm. Mass spectrum, m/z [482.0] (M + H)+.

Scheme LXXIII

[152] 4-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-3-(4,5-diphenyl-thiazol- 2-yl)-hexahydro-pyrrolo[3,2-b]pyrrole-l-carboxylic acid benzyl ester (69):

Intermediate 69 was prepared in one step from 68 using the procedure outlined in Scheme XXXI. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.49 (m, 2H), 7.35-7.23 (m, 13H), 5.37 (d, J = 9.9 Hz, 1H), 5.20 (m, 2H), 4.90 (m, 1H), 4.73 (m, 1H), 4.33 (m, 2H), 4.1 1 (m, 1H), 4.01 (d, J = 5.7 Hz, 1H), 3.57 (m, 1H), 3.47 (m, 1H), 2.50 (m, 0.5H), 2.31 (m, 0.5H), 2.07 (m, 1H), 1.43 (m, 9H), 1.02 (m, 9H) ppm. Mass spectrum, m/z [695.2] (M + H)+.

Scheme LXXIX

[153] 4-(2-Amino-3,3-dimethyl-butyryl)-3-(4-phenyl-thiazol-2-yl)-hexahydro- pyrrolo[3,2-b]pyrrole-l-carboxylic acid benzyl ester (70): Intermediate 70 was prepared in one step from intermediate 69 using the procedure outlined in Scheme XXXVII. Mass spectrum, m/z [595.1] (M + H)+.

Scheme LXXX

[154] 4-(2-[2-(tert-Butoxycarbonyl-methyl-amino)-propionylamino]-3,3-dimethyl- butyryl|-3-(4,5-diphenyl-thiazol-2-yl)-hexahydro-pyrrolo[3,2-b pyrrole-l - carboxylic acid benzyl ester (71): Intermediate 71was prepared in one step from 70using the procedure outlined in Scheme XXXIII. Mass spectrum, m/z [780.3] (M + H)+.

Scheme LXXXI

[155] 4-[3 -Dimethyl-2-(2-methylamino-propionylamino)-butyryl]-3-(4,5- diphenyl-thiazol-2-yl)-hexahvdro-pyrrolo[3,2-b]pyrrole-l-carboxylic acid benzyl ester (72): Compound 72 was prepared in one step from intermediate 71 using the procedure outlined in Scheme XXXIV.

[156] EXAMPLE 13 4-r3,3-Dimethyl-2-(^'2-methylamino-propionylamino^')- butyryll-3-(4,5-diphenyl-thiazol-2-yl)-hexahydro-pyrrolo[3.2-blpyrrole-l- carboxylic acid benzyl ester (72): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 67.87 (dd, J = 3.3, 9.0 Hz, 1H), 7.48 (q, J = 2.4 Hz, 2H), 7.36-7.24 (m, 12H), 5.21 (m, 2H), 4.88 (d, J = 5.4 Hz, 1H), 4.77 (dt, J = 5.1, 13.5 Hz, 1H), 4.64 (dd, J = 4.8, 9.9 Hz, 1H), 4.04 (t, J = 11.4 Hz, 1H), 4.21 (m, 1H), 4.02 (d, J= 3.9 Hz, 1H), 3.54 (m, 2H), 3.10 (dd, J= 2.4, 6.6 Hz, 1H), 2.50 (dd, J = 5.4, 13.5 Hz, 0.5H), 2.43-2.30 (m, 3.5H), 2.14 (m, 4H), 1.31 (d, J = 6.9 Hz, 3H), 1.05 (s, 9H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.7, 170.2, 166.4, 154.7, 154.5, 149.2, 136.5, 134.6, 132.9, 132.8, 131.9, 129.7, 129.6, 128.9, 128.7, 128.5, 128.4, 128.1, 128.0, 127.9, 127.9, 127.7, 127.6, 67.9, 67.3, 67.2, 67.0, 61.0, 60.7, 60.2, 56.7, 52.0, 51.1, 47.3, 47.2, 46.4, 45.6, 35.7, 35.6, 34.9, 31.9, 31.0, 26.6, 19.4 ppm. Mass spectrum, m/z [679.97] (M + H)+.

Scheme LXXXII

[157] N-ll-re-^.S-Diphenyl-thiazol^-ylVhexahvdro-pyrrolorS^-blpyrrole-l- carbonyll-2,2-dimethyl-propyl}-2-methylamino-propionamide (93):

Compound 73 was prepared in one step from intermediate 72 using the procedure outlined in Scheme LXXI.

[158] EXAMPLE 14 N- ( 1 - 6-(^'4,5-Diphenyl-thiazol-2-vn-hexahvdro-pyrrolor3.2- b]pyrrole-l -carbonyl]-2,2-dimethyl-propyll-2-methylamino-propionamide (73): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.80 (d, J = 9.6 Hz, 1H), 7.49 (m, 2H), 7.34-7.24 (m, 8H), 4.74 (d, J = 6.3 Hz, 1H), 4.68 (d, J = 9.9 Hz, 1H), 4.24 (m, 1H), 4.07 (ddd, J = 5.7, 10.5, 10.2 Hz, 1H), 3.81 (d, J = 5.1 Hz, 1H), 3.69 (q, J = 8.7 Hz, 1H), 3.49 (m, 6H), 3.20 (dd, J = 6.0, 12.0 Hz, 1H), 3.12 (q, J = 6.6 Hz, 1H), 2.38 (s, 3H), 2.12 (m, 2H), 2.02 (m, 2H), 1.31 (d, J = 6.9 Hz, 3H), 1.05 (s, 9H) ppm; ^,3C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.5, 174.4, 170.1, 169.9, 167.8, 167.6, 149.2, 134.8, 132.7, 132.0, 129.7, 129.6, 128.9, 129.9, 128.6, 128.2, 128.1 , 128.0, 127.7, 69.1 , 63.8, 61.3, 60.2, 60.0, 56.7, 56.6, 53.0, 52.4, 51.9, 50.2, 47.9, 46.4, 35.8, 35.7, 34.9, 34.7, 32.4, 31.8, 26.6, 19.5, 19.3 ppm. Mass spectrum, m/z [546.1] (M + H)+.

3-Hydroxymethyl-hexahydro-pyrrolo[3,2-b1pyrrole- 1 ,4-dicarboxylic acid 1 - benzyl ester 4-tert-butyl ester (74): A solution of ester 14 (2.7 g, 6.7 mmol) in THF (15 mL) was cooled to 0 °C and treated with LiBH₄ (10 niL, 2M in THF). Afer 3 h, the solution was slowly treated with MeOH followed by H₂0. The solution was then concentrated and diluted with EtOAc. The solution was slowly treated with 1M HC1 until gas generation ceased. The solution was extracted with EtOAc, washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The residue was absorbed onto Si0₂ and purified by flash chromatography (1 : 1 hexane/EtOAc to 1 :2 hexane/EtOAc) to afford alcohol 74 (1.9 g, 75%) as a light yellow-colored oil. Ή NMR (CDC1₃, 300 MHz): 57.39-7.27 (m, 5H), 5.13-5.09 (m, 2H), 4.43-4.41 (m, 1H), 4.13-4.08 (m, 2H), 3.70-3.29 (m, 6H), 2.48-2.46 (m, 1H), 2.53-2.05 (m, 1H), 2.03-1.99 (m, 1H), 1.48 (s, 9H) ppm. Mass spectrum, m/z [377.5] (M + H)+.

Scheme LXXXIV

74 75

[160] 6-Methanesulfonyloxymethyl-hexahydro-pyrrolo[3,2-b]pyrrole-l-carboxylic acid tert-butyl ester (75V. A solution of alcohol 74 (0.78 g, 2.1 mmol) in DCM (12 mL) was cooled to 0 °C and treated with DIPEA (0.55 mL, 3.2 mmol) followed by methanesulfonyl chloride (0.22 mL, 2.8 mmol). After 1 h, the solution was diluted with DCM, washed successively with 1M HC1, and brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford mesylate 75 as a light yellow-colored foam which was used without further purification. 1H NMR (CDCI₃, 300 MHz): 57.36-7.31 (m, 5H), 5.19-5.09 (m, 2H), 4.45 (m, 1H), 4.29-4.04 (m, 3H), 3.71-3.44 (m, 4H), 3.22-3.12 (m, 1H), 2.96 (s, 3H), 2.85-2.70 (m, 1H), 2.21-1.99 (m, 2H), 1.49 (s, 9H) ppm. Mass spectrum, m/z

[455.1] (M + H)+.

Scheme LXXXV

75 76

[161] 3-Azidomethyl-hexahydro-pyrrolo 3,2-b]pynOle- 1.4-dicarboxylic acid 1 - benzyl ester 4-tert-butyl ester (76): A solution of 75 (1.69 g, 3.72 mmol) and NaN₃ (290 mg, 4.46 mmol) in DMF (20 mL) was heated to 80 °C in a preheated oil bath. After 2 h, the reaction mixture was cooled to ambient temperature and diluted with water. The reaction mixture was extracted with EtOAc (3x) and the combined organic extracts were washed successively with 1 M HC1, brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue was dissolved in 20% EtOAc/hexanes and purified via silica gel HPLC (2" Dynamax® Si0₂, 20-100% EtOAc/hexanes over 30 min; Flow: 40 niL/min) to afford 76 (1.23 g, 83%) as a pale yellow-colored oil. Ή NMR (300 MHz, CDC1₃): 57.37 (m, 5H), 5.15 (m, 2H), 4.42 (m, 1H), 4.12 (m, 1H), 3.70 (d, J = 12.6 Hz, 0.5H), 3.60 (d, J = 11.7 Hz, 1.5H), 3.45 (m, 1H), 3.31- 3.16 (m, 2H), 2.64 (m, 0.5H), 2.52 (m, 0.5H), 2.24 (m, 0.5H), 2.16-1.92 (m, 1.5H), 1.49 (m, 9H) ppm. Mass spectrum, m/z [402.2] (M + H)+.

Scheme LXXXVI

76 77

[162] 3-Azidomethyl-hexahydro-pyrrolo[3,2-b1pyrrole-l -carboxylic acid benzyl ester (77): To a solution of 76 (1.23 g, 3.06 mmol) in DCM (15 mL) at 0 °C was added TFA (5 mL). After 3 h, the reaction mixture was concentrated and the residue was dissolved in EtOAc, washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 77 (830 mg, 90%) as a brown-colored oil which was taken forward without further purification. Mass spectrum, m/z [302.1] (M + H)+.

Scheme LXXXVII

[163] 3-Azidomethyl-4-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)- hexahydro-pyrrolo 3,2-b]pyrrole-l -carboxylic acid benzyl ester (78): To a solution of Boc-Tle-OH (701 mg, 3.03 mmol) and HATU (1.15 g, 3.03 mmol) in NMP (4 mL) at 0 °C was added DIPEA (1.4 4 mL) and the mixture turned pale yellow in color. After 20 min, a solution of 77 (830 mg, 2.75 mmol) in NMP (8 mL) was added and the reaction mixture was allowed to warm to ambient temperature. After 16 h, the reaction mixture was diluted with water, extracted with EtOAc (3x), and the combined organic extracts were washed successively with 1 M HCI, and brine, dried over Na₂S0₄, filtered and concentrated. The crude reside was dissolved in 1 : 1 EtOAc/hexanes, purified via flash chromatography (Si0₂, eluting 1 :1 EtOAc/hexanes) and the product- containing fractions were combined and concentrated to afford 78 (1.29 g, 90%) as a foamy white solid. Mass spectrum, m/z [515.2] (M + H)+.

Scheme LXXXVIII

4-(2-tert-Butoxycarbonylamino-3,3-dimethyl-butyryl)-3-[4-(4-fluoro-phenyl - L2 ltriazol-l-ylmethyl]-hexahvdro-pyrrolo|^"3,2-b]pyrrole-l -carboxylic acid benzyl ester (79): To a solution of 78 (645 mg, 1.25 mmol), l -ethynyl-4- fluorobenzene (143 μΕ, 1.25 mmol) and TBTA (7 mg, 0.01 mmol) in EtOH (3 mL) and tBuOH (3 mL) at ambient temperature were added a solution of CuS0₄-5H₂0 (31 mg, 0.13 mmol) in water (1.5 mL) and a solution of sodium ascorbate (124 mg, 0.63 mmol) in water (1.5 mL) and the reaction mixture became yellow-colored and cloudy. After 4 h, the reaction mixture was diluted with water, extracted with EtOAc (2x), and the combined organic extracts were washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue was purified by flash silica gel chromatography (1 :1 to 2: 1 EtOAc/hexanes) and the product-containing fractions were combined and concentrated to afford 79 (790 mg, 99%) as an off-white foam. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.96-7.82 (m, 2H), 7.27 (m, 4H), 7.12 (m, 2H), 5.17 (m, 2H), 4.44 (m, 2H), 4.27 (m, 1H), 3.96 (m, 1H), 3.74 (m, 1H), 3.35 (m, 1H), 3.15 (m, 0.5H), 2.97 (m, 0.5H), 2.41 (m, 0.5H), 2.13 (m, 1.5H), 1.40 (m, 9H), 0.94 (m, 9H), 0.74 (d, J 31.2 Hz, 2H) ppm. Mass spectrum, m/z [635.2] (M + H)+.

Scheme LXXXIX

[165] 4-(^,2-Amino-3 -dimethyl-butyryl)-3-r4-(^'4-fluoro-phenvn-[L2,31tria2ol-l- ylmethyl1-hexahvdro-pyrrolo[3,2-b]pyrrole-l-carboxylic acid benzyl ester (80): To a solution of 79 (140 mg, 0.22 mmol) in DCM (5 mL) at 0 °C was added TFA (2 mL). After 3 h, the reaction mixture was concentrated and the residue was dissolved in EtOAc and washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 80 (100 mg, 85%) as a white foam which was taken forward without further purification. Mass spectrum, m/z [535.1] (M + H)+.

Scheme XC

[166] 4-{2-[2-(tert-Butoxycarbonyl-methyl-amino)-propionylamino]-3,3-dimethyl- butyryl}-3-[4-(4-fluoro-phenyl)-[l,2,3]triazol-l-ylmethyl]-hexahydro- pyrrolo[3,2-b]pyrrole-l-carboxylic acid benzyl ester (81): To a mixture of Boc-N(Me)Ala-OH (42 mg, 0.21 mmol) and HATU (78 mg, 0.21 mmol) in NMP (1 mL) at 0 °C was added DIPEA (97 iL, 0.56 mmol). After 20 min, a solution of 80 (100 mg, 0.19 mmol) in NMP (2 mL) was added. After 5 h, the reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic extracts were washed successively with 1 M HCl, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 81 (200 mg, quant.) as a brown-colored oil which was taken forward without further purification. Mass spectrum, m/z [720.2] (M + H)+.

Scheme XCI

[167] 4-(2-Amino-3,3-dimethyl-butyrylV3-r4-(4-fluoro-phenylVri.2.31tria2ol-l- ylmethyl1-hexahvdro-pyrrolo 3,2-b]pyrrole-l-carboxylic acid benzyl ester (82): To a solution of 81 (135 mg, 019 mmol) in DCM (4 mL) at 0 °C was added TFA (2 mL). After 3.5 h, the reaction mixture was concentrated and the residue was dissolved in EtOAc and washed successively with aqueous NaHC0₃ (sat.), brine, dried over anhydrous Na₂S0₄, filtered and concentrated. The crude residue was dissolved in ~1 : 1 MeOH/H₂0 and purified via reverse- phase HPLC (2" Dynamax® CI 8, 20-100% MeOH/H₂0 containing 0.1 % HOAc over 30 min; Flow: 40 mL/min). The product-containing fractions were combined, concentrated to remove MeOH and lyophilized to afford 82 (74 mg, 63%) as a white solid.

[168] EXAMPLE 15 4-(2-Amino ,3-dimethyl-but yl)-3-r4-(4-fluorO-phenvn- l ,2,31triazol-l-ylmethyl -hexahydro-pyrrolo[3,2-b]pyrrole-l-carboxylic acid benzyl ester (82): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.93 (t, J = 9.3 Hz, 2H), 7.82 (m, 2H), 7.35 (m, 4H), 7.1 1 (t, J = 8.7 Hz, 2H), 5.17 (m, 2H), 4.60 (d, J= 9.6 Hz, 1H), 4.38 (m, 4H), 4.03 (m, 2H), 3.63 (dd, J = 12.0, 30.9 Hz, 1H), 3.43 (m, 3H), 2.98 (m, 1H), 2.47 (m, 3H), 2.04 (m, 3H), 1.36 (d, J = 6.6 Hz, 3H), 1.00 (s, 9H), 0.70 (d, J = 1 1.4 Hz, 1H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5175.3, 173.4, 172.8, 170.2, 169.3, 169.2, 164.3, 161.0, 154.3, 154.2, 154.1, 151.1, 147.5, 147.2, 136.2, 136.0, 128.5, 128.4, 128.2, 128.0, 127.9, 127.7, 127.5, 127.4, 126.6, 126.5, 121.8, 121.6, 120.3, 120.0, 1 15.9, 1 15.8, 1 15.6, 1 15.5, 67.6, 67.3, 65.2,

64.1, 63.2, 61.8, 61.3, 60.0, 59.6, 59.1 , 57.2, 56.6, 51.3, 51.0, 50.7, 49.1, 48.9, 48.6, 48.3, 47.1 , 45.7, 45.5, 44.9, 43.5, 42.2, 35.5, 35.3, 33.5, 32.0, 31.4, 31.1 ,

30.2, 28.4, 27.3, 26.5, 26.0, 21.1, 18.8, 18.1 ppm. Mass spectrum, m/z [620.2] (M + H)+.

Scheme XCII

(l-|6-r4-(4-Fluoro-phenyl)-[K2,31triazol-l-ylmethyll-hexahvdro-pyrrolor3.2- b]pyrrole-l-carbonyl I -2,2-dimethyl -propyl Vcarbamic acid tert-butyl ester (83): To a solution of 79 (650 mg, 1.02 mmol) in MeOH (20 mL) in a Parr bottle was added 10% Pd/C (75 mg). The bottle was evacuated and purged with H₂ five times, then charged to 55 PSI H₂ and shaken. After 1.5 h, the reaction mixture was filtered through a Millipore filter and concentrated to afford 83 (470 mg, 92%) as a white-colored foam which was taken forward without further purification Mass spectrum, m/z [501.2] (M + H)+.

Scheme XCIII

[170] (1-{6-[4-(4-Fluoro-phenyl)-[ 1,2,3]triazol-1-ylmethyl]-4-methanesulfonyl- hexahvdro-pyrrolo[3 ,2-blpyrrole- 1 -carbonyl } -2,2-dimethyl-propyl)-carbamic acid tert-butyl ester (84 : To a solution of 83 (157 mg, 0.31 mmol) in DCM (3 mL) at 0 °C was added TEA (88 yH, 0.63 mmol) and MsCl (29 μΐ,, 0.38 mmol). After 4 h, the reaction mixture was diluted with DCM and washed successively with 1 M HCl, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 84 (240 mg, quant.) which was taken forward without further purification. Mass spectrum, m/z [579.1] (M + H)+.

Scheme XCIV

[171] 2-Amino- (1-{6-[4-(4-Fluoro-phenyl)-[ 1,2,3]triazol-1-ylmethyl]-4- methanesulfonyl-hexahydro-pyrrolo[3,2-b]pyrrol-l-yl1-3,3-dimethyl-butan-1- one (85): Intermediate 85 was prepared in one step from intermediate 84 using the procedure outlined in Scheme LXXXIX. Mass spectrum, m/z [479.1] (M + H)+.

Scheme XCV

[172] [ 1 -( 1 - (6-[4-(4-Fluoro-phenyl)-[ 1,2,3]triazol- 1 -ylmethvn-4-methanesulfonyl- hexahydro-pyrrolo[3 ,2-b]pyrrole- 1 -carbonyl } -2,2-dimethyl-propylcarbamoyl)- ethyl] -methyl-carbamic acid tert-butyl ester (86): Intermediate 86 was prepared in one step from 85 using the procedure outlined in Scheme XC. Mass spectrum, m/z [664.2] (M + H)+.

Scheme XCVI

[173] N-( 1 - {6-[4-(4-Fluoro-phenyl)-[ 1.2.3]triazol- 1 -ylmethyll-4-methanesulfonyl- hexahydro-pyrrolo 3 ,2-b]pyrrole- 1 -carbonyl) -2,2-dimethyl-propyl)-2- methylamino-propionamide (87): Compound 87 was prepared in one step from intermediate 86 using the procedure outlined in Scheme XCI.

[174] EXAMPLE 16 N-(l - {6-[4-(4-Fluoro-phenyl)-n .2,31triazol-l -ylmethyl]-4- methanesulfonyl-hexahvdro-pyrrolo[3,2-b]pyrrole-l-carbonyl)-2,2-dimethyl- propyl)-2-methylamino-propionamide ( 87) : Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 68.01 (s, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.81 (m, 2H), 7.12 (t, J = 9.0 Hz, 2H), 4.68 (dd, J = 4.5, 14.1 Hz, 1H), 4.57 (d, J = 9.0 Hz, 1H), 4.45 (m, 1H), 4.34 (m, 1H), 4.18 (t, J = 8.7 Hz, 1H), 3.58 (m, 1H), 3.45 (m, 2H), 3.25-2.94 (m, 6H), 2.49 (dd, J = 6.0 Hz, 1H), 2.43 (m, 3H), 2.05 (m, 2H), 1.33 (d, J = 6.9 Hz, 3H), 1.03 (m, 9H), 0.77 (s, 1H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.6, 174.4, 170.6, 169.3,

164.4, 161.1, 147.6, 147.2, 127.5, 127.4, 127.3, 126.6, 126.4, 126.4, 121.6,

120.5, 116.0, 115.9, 115.7, 115.6, 65.0, 64.5, 63.7, 62.1 , 60.1, 59.9, 56.9, 56.4, 50.4, 50.3, 50.1 , 49.9, 46.8, 46.4, 45.5, 44.4, 39.5, 37.3, 35.4, 35.3, 34.8, 34.6, 32.8, 26.5, 26.1 , 19.3, 19.1 ppm. Mass spectrum, m/z [564.1 ] (M + H)+.

Scheme XCVII

[175] (1-{6-[4-(4-Fluoro-phenyl)-[ 1,2,3]triazol-l-ylmethyll-4-isopropylcarbamoyl- hexahydro-pyrrolo[3,2-b]pyrrole-l-carbonyl}-2,2-dimethyl-propyl)-carbamic acid tert-butyl ester (88): To as solution of 83 (157 mg, 0.31 mmol) in DCM (3 niL) at 0 °C was added TEA (131 μL, 0.94 mmol) and iPr-isocyanate (62 μΐ,, 0.63 mmol). After 4 h, the reaction mixture was diluted with MeOH and quenched with NH₄OH (15 M, 10 drops). After 10 min, the reaction mixture was diluted with DCM and washed successively with 1 M HCl, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 88 (180 mg, 98%) as a white foam which was taken forward without further purification. Mass spectrum, m/z [586.2] (M + H)+.

Scheme XCVIII

[176] 4-(2-Amino-3.3-dimethyl-butyryl)-3-[4-(4-fluoro-phenylV[ 1,2,3]triazol-l- ylmethyl]-hexahvdro-pyrrolo 3,2-b]pyrrole-l -carboxylic acid isopropylamide (89): Intermediate 89 was prepared in one step from intermediate 88 using the procedure outlined in Scheme LXXXIX. Mass spectrum, m/z [486.2] (M + H)+.

Scheme XCIX

[177] ri-(l-{6-r4-(4-Fluoro-phenvn-ri.2.31triazol-l-ylmethyl1-4- isopropylcarbamoyl-hexahvdro-pyrrolor3,2-b]pyrrole-l-carbonyl)-2,2- dimethyl-propylcarbamoyl)-ethyl]-methyl-carbamic acid tert-butyl ester (90):

Intermediate 90 was prepared in one step from 89 using the procedure outlined in Scheme XC. Mass spectrum, m/z [671.3] (M + H)+.

Scheme C

[178] 4-[3,3 -Dimethyl-2-(2-methylamino-propionylamino)-butyryll-3- 4-(4-fluoro- phenyl)-[ 1 ,2,3^"|triazol- 1 -ylmethyll-hexahydro-pyrrolo[3,2-b1pyrrole- 1 - carboxylic acid isopropylamide (91): Compound 91 was prepared in one step from intermediate 90 using the procedure outlined in Scheme XCI.

[179] EXAMPLE 17 4-r3,3-Dimethyl-2-(2-methylamino-propionylamino)- butyryl1-3-r4-(4-fluoro-phenyl)-[l ,2,3]triazol-l-ylmethyll-hexahydro- pyrrolo[^"3,2-b1pyrrole-l -carboxylic acid isopropylamide (91): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 58.59 (s, 0.3H), 8.00 (s, 0.7H), 7.89 (d, J = 9.3 Hz, 1H), 7.82 (m, 2H), 8.12 (t, J = 8.4 Hz, 1H), 4.59 (d, J= 9.3 Hz, 0.7H), 4.53 (d, J = 5.1 Hz, 0.3H), 4.47 (t, J = 7.2 Hz, 2H), 4.24 (t, J = 4.5 Hz, 1H), 4.14-3.81 (m, 4H), 3.59 (d, J = 11.1 Hz, 1H), 3.45 (ddd, J = 6.6, 10.5, 6.3 Hz, 1H), 3.32 (dd, J = 6.6, 10.8 Hz, 1H), 3.42 (m, 4H), 2.94 (m, 1H), 2.42 (m, 3H), 2.26 (m, 1H), 2.05 (m, 1H), 1.33 (d, J = 6.9 Hz, 3H), 1.40 (dd, J = 1.8, 6.3 Hz, 6H), 1.04 (m, 9H), 0.76 (s, 2H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.4, 174.3, 170.4, 169.3, 164.3, 161.0, 155.4, 155.0, 147.5, 147.1 , 127.5, 127.4, 127.4, 127.3, 126.7, 126.5, 126.5, 121.6, 120.3, 1 15.9, 1 15.8, 115.7, 1 15.5, 64.7, 64.0, 60.8, 60.2, 59.9, 59.3, 56.7, 56.3, 51.3, 48.2, 47.2, 45.7, 45.6, 43.5, 42.6, 42.6, 42.2, 35.4, 34.8, 34.6, 31.7, 30.9, 26.5, 26.1, 23.5, 23.4, 23.3, 23.1, 19.3, 19.1 ppm. Mass spectrum, m/z [571.2] (M + H)+.

Scheme CI

(l-|4-Cvclopropanecarbonyl-6-[4-(4-fluoro-phenyl)-|^"l ,2,31triazol-l - ylmethyll-hexahydro-pyrrolo[3,2-b]pyrrole-l-carbonyl}-2,2-dimethyl-propyl)- carbamic acid tert-butyl ester (92): To a solution of 83 (157 mg, 0.31 mmol) in DCM (3 mL) at 0 °C were added TEA (86 μί, 0.38 mmol) and cyclopropanecarbonyl chloride (88 μΐ., 0.63 mmol). After 4 h, the reaction mixture was diluted with DCM and washed successively with 1 M HCl, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford 92 (180 mg, quant.) as an off-white foam which was taken forward without further purification. Mass spectrum, m/z [569.2] (M + H)+.

Scheme CII

[181] 2 -Amino- 1 - {4-cydopropanecarbonyl-6-[4-(4-fluoro-phenyl)-[ 1 ,2,3]triazol-l - ylmethyll-hexahydro-pyrrolo[3,2-b1pyrrol-l-yl}-3,3-dimethyl-butan-l-one (93): Intermediate 93 was prepared in one step from intermediate 92 using the procedure outlined in Scheme LXXXIX. Mass spectrum, m/z [469.1] (M + H)+.

Scheme CIII

[182] Π-Π- {4-Cvclopropanecarbonyl-6-r4-f 4-fluoro-phenyl)-r 1.2,3 ]triazol- 1 - ylmethyl1-hexahydro-pyrrolo[3,2-b]pyrrole-l-carbonyl|-2,2-dimethyl- propylcarbamovD-ethylj-methyl-carbamic acid tert-butyl ester (94):

Intermediate 94 was prepared in one step from 93 using the procedure outlined in Scheme XC. Mass spectrum, m/z [654.2] (M + H)+.

Scheme CIV

[183] N-( 1 - {4-Cvclo^propanecarbonyl-6-[4-(4-fluoro-phenyl)-r 1 ,2,31triazol-l - ylmethyll-hexahydro-pyrc

2-methylamino-propionamide (95): Compound 95 was prepared in one step from intermediate 94 using the procedure outlined in Scheme XCI.

[184] EXAMPLE 18 N-( 1 - {4-Cvclopropanecarbonyl-6-r4-(4-fluoro-phenyl)- [1 ,2,3]triazol-l -ylmethyll-hexahydro-pyrrolo[3,2-blpyrrole-l -carbonyl}-2,2- dimethyl-propyl)-2-methylamino-propionamide (95): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 58.58(d, J = 18.1 Hz, 0.3H), 7.98 (d, J = 15.3 Hz, 0.7H), 7.81 (m, 2H), 7.1 1 (m, 2H), 4.62 (m, 2H), 4.45 (m, 1H), 4.32 (m, 1H), 4.15 (m, 1H), 3.97 (m, 1H), 3.49 (m, 3H), 3.36 (m, 1H), 3.20 (m, 1H), 3.01 (m, 1H), 2.41 (t, J = 5.1 Hz, 2H), 2.53 (m, 1H), 2.20 (m, 1H), 2.05 (s, 1H), 1.59 (m, 1H), 1.34 (dd, J = 2.7, 6.9 Hz, 3H), 1.02 (m, 9H), 0.80 (s, 1.2H), 0.71 (s, 0.8H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.9, 174.5, 174.3, 174.3, 174.2, 172.5, 172.5, 172.2, 170.6,

170.2, 169.4, 169.2, 164.3, 161.1, 147.5, 147.2, 127.6, 127.5, 127.4, 127.4,

127.3, 126.8, 126.5, 121.9, 121.4, 120.3, 120.1 , 1 16.0, 1 15.9, 115.8, 1 15.7, 1 15.6, 65.8, 64.4, 63.4, 62.9, 61.5, 61.3, 60.1 , 59.8, 59.6, 56.9, 56.8, 56.4, 56.3, 51.7, 51.5, 50.8, 50.4, 48.8, 48.7, 48.5, 48.4, 47.5, 47.0, 46.5, 45.7, 45.5, 44.3, 41.7, 35.5, 35.4, 35.4, 35.3, 34.8, 34.7, 34.5, 34.4, 33.2, 32.6, 31.3, 26.5, 26.2, 26.1 , 21.1 , 19.4, 19.3, 19.1 , 13.0, 12.8, 12.4, 12.3, 8.8, 8.8, 8.2, 8.1 , 7.9, 7.8 ppm. Mass spectrum, m/z [554.2] (M + H)+.

Scheme CV

[185] 3-(4-Benzyl-rL2,31triazol-l-ylmethyl -4-(2-tert-butoxycarbonylamino-3.3- dimethyl-but ylVhexahvdro-pyrrolo 3,2-b]pyrrole-l -carboxylic acid benzyl ester (96): Intermediate 96 was prepared in one step from intermediate 78 using the procedure outlined in Scheme LXXXVIII. Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.36-7.26 (m, 11H), 5.24-5.07 (m, 3H), 4.38^1.22 (m, 4H), 4.08 (s, 1H), 3.99 (m, 2H), 3.62 (m, 1H), 3.23 (m, 2H), 2.89 (m, 1H), 2.38 (m, 0.5H), 2.18 (m, 0.5H), 2.05 (m, 1H), 1.66 (s, 1H), 1.43 (m, 9H), 0.96 (m, 9H) ppm. Mass spectrum, m/z [631.3] (M + H)+.

Scheme CVI

[186] 4-(2-Amino-3.3-dimethyl-butyryl)-3-(4-benzyl-n ,2,31triazol-l-ylmethyl >- hexahvdro-pyrrolo[3,2-b]pyrrole-l -carboxylic acid benzyl ester (97):

Intermediate 97 was prepared in one step from intermediate 96 using the procedure outlined in Scheme LXXXIX. Mass spectrum, m/z [531.2] (M + H)+.

Scheme CVII

[187] 3-(4-Benzyl-ri,2.31triazol-l-ylmethyl)-4-i2-r2-(tert-butoxycarbonyl-methyl- amino)-propionylamino]-3,3-dimethyl-butyryl}-hexahydro-pyrrolo[3,2- b]pyrrole-l-carboxylic acid benzyl ester (98): Intermediate 98 was prepared in one step from 97 using the procedure outlined in Scheme XC. Mass spectrum, m/z [716.3] (M + H)+.

Scheme CVIII

[188] 3-(4-Benzyl-[K2 1triazol-l-ylmethyl)-4-r3,3-dimethyl-2-(2-methylamino- propionylamino)-butyryl]-hexahydro-pyrrolo[3.2-b]pyrrole-l -carboxylic acid benzyl ester (99): Compound 99 was prepared in one step from intermediate 98 using the procedure outlined in Scheme XCI.

[189] EXAMPLE 19 3-(4-Benzyl-[L2,31triazol-l-ylmethyl)-4-r3 J-dimethyl-2-(2- methylamino-propionylamino)-butyryl]-hexahydro-pyrrolo[3,2-b]pyrrole-l- carboxylic acid benzyl ester (99): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: δ 7.86 (m, 1H), 7.37-7.20 (m, 10H), 5.12 (m, 2H), 4.55 (d, J = 9.6 Hz, 1H), 4.36 (m, 2H), 4.26 (m, 1H), 4.07 (m, 3H), 3.63 (m, 1H), 3.33 (m, 2H), 3.17 (q, J = 6.9 Hz, 1H), 2.95 (m, 4H), 2.40 (m, 3H), 2.04 (m, 2H), 1.32 (d, J = 6.9 Hz, 3H), 0.98 (m, 9H), 0.83 (d, J = 24.3 Hz, 2H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.3, 174.2, 170.2, 154.3, 148.1 , 147.8, 138.9, 136.2, 128.8, 128.8, 128.7, 128.6, 128.2, 128.0, 127.9, 127.8, 126.4, 122.0, 67.2, 65.0, 64.2, 63.5, 61.8, 61.3, 60.0, 59.9, 59.5,

56.7, 56.2, 51.1 , 50.8, 49.0, 48.3, 47.0, 45.8, 45.3, 44.6, 43.6, 42.4, 35.5, 35.4,

34.8, 34.6, 32.3, 32.1 , 31.3, 31.1 , 30.2, 26.5, 26.2, 26.1 , 19.4, 19.3 ppm. Mass spectrum, m/z [616.2] (M + H)+.

Scheme CIX

[190] { l-[6-(4-Benzyl-[l,2 ]triazol-l-ylmethyl)-hexahydro-pyrrolo|^"3,2-b1pyrrole- l-carbonyl1-2,2-dimethyl-propyl}-carbamic acid tert-butyl ester (100):

Intermediate 100 was prepared in one step from intermediate 96 using the procedure outlined in Scheme XCII. Mass spectrum, m/z [491.2] (M + H)+.

Scheme CX

[191] { l- 6-(4-Benzyl-[l ,2,31triazol-l-ylmethyl)-4-isopropylcarbamoyl-hexahydro- pyrrolo[3,2-blpyrrole-l -carbonyl]-2,2-dimethyl-propyl}-carbamic acid tert- butyl ester (101): Intermediate 101 was prepared in one step from intermediate 100 using the procedure outlined in Scheme XCVII. Mass spectrum, m/z [582.2] (M + H)+.

Scheme CXI

[192] 4-(2-Amino-3,3-dimethyl-butyryl)-3-(4-benzyl-[ 1,2,3]triazol-1-ylmethyl)- hexahvdro-pyrrolo 3,2-b]pyrrole-1-carboxylic acid isopropylamide (102): Intermediate 102 was prepared in one step from intermediate 101 using the procedure outlined in Scheme LXXXIX. Mass spectrum, m/z [482.1] (M +

H)+.

Scheme CXII

[193] (1-{1-[6-(4-Benzyl-[1,2,3]triazol-1-ylmethyl)-4-isopropylcarbamoyl- hexahydro-pyrrolo[3 ,2-blpyrrole- 1 -carbonyl]-2,2-dimethyl-propylcarbamoyl } - ethyl)-methyl-carbamic acid tert-butyl ester (103): Intermediate 103 was prepared in one step from 102 using the procedure outlined in Scheme XC. Mass spectrum, m/z [667.3] (M + H)+.

Scheme CXIII

[194] 3-(^'4-Benzyl-ri,2,31triazol-l-ylmethvn-4-r3.3-dimethyl-2-(2-methylamino- propionylamino)-butyryl]-hexahydro-pmolor3,2-b]pyrrole-l-carboxylic acid isopropylamide (104): Compound 104 was prepared in one step from intermediate 103 using the procedure outlined in Scheme XCI.

[195] EXAMPLE 20 3-(^'4-Benzyl-[1.2.31triazol-l-ylmethyl)-4-r3.3-dimethyl-2-r2- methylamino-propionylamino)-butyryl] -hexahydro-pyrrolo [3 ,2-b]pyrrole- 1 - carboxylic acid isopropylamide (104): Ή NMR (300 MHz, CDC1₃), mixture of amide rotomers: 57.92 (m, 1H), 7.40 (s, 1H), 7.30 (m, 3H), 4.59 (d, J = 9.6 Hz, 1H), 4.79 (dd, J = 4.5, 13.5 Hz, 1H), 4.36 (m, 3H), 4.1 1 (m, 3H), 3.85 (q, J = 6.0 Hz, 3H0, 3.45 (m, 1H), 3.27 (m, 1H), 3.15 (q, J = 6.6 Hz, 1H), 2.89 (m, 1H), 2.52-2.37 (m, 6H), 2.08 (m, 3H), 1.35 (d, J = 6.9 Hz, 3H), 1.18-1.02 (m, 15H) ppm; ¹³C NMR (75 MHz, CDC1₃), mixture of amide rotomers: 5174.5, 170.3, 169.4, 157.1, 155.5, 155.2, 148.0, 147.8, 138.8, 138.4, 128.7, 128.6, 128.6, 126.5, 122.3, 63.3, 60.1, 59.3, 56.6, 50.9, 48.2, 47.2, 43.9, 42.5, 42.1 , 35.4, 34.9, 32.1, 31.8, 26.5, 26.2, 23.4, 23.3, 19.3 ppm. Mass spectrum, m/z [567.2] (M + H)+.

[196] As noted above, dimers of the compounds generally and specifically described above can be prepared by a person of skill in the art. Illustrative dimers of the invention can be prepared, e.g., in accordance with the following general synthetic schemes and examples.

[197] In the following schemes monomers are prepared by linking two

independently substituted monovalent compounds through the R6 positions, such that the R6 group on one monomer and the R6' group on the other monomer together from -L-, as described by formula X, where the various substituents are as described above.

Scheme CXIV (Imidazopyridines)

Scheme CXV (4-Thiazoles)

Scheme CXVI (2-Tliiazoles)

Scheme CXVII (Triazoles)

[198] Additional bivalent ("dimeric") compounds can be prepared by linking two independently substituted monovalent compounds through the R2 positions, such that the R2 group on one monomer and the R2' group on the other monomer together form -L- as described by formula XI, where the various substituents are as described above.

[199] The synthetic preparation of such R2 -linked bivalent compounds is described in Schemes CXVIII through CXXV following chemistry outlined in this application and US7517906, and US7309792 which are herein incorporated by reference in their entireties.

III

Scheme CXIX

Scheme CXXII

TFA, DCM

Scheme CXXV

[200] It is intended that the present invention encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.

[201] The present invention also includes isotopically-enriched compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁶0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1.

[202] Compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically enriched compounds of this invention can generally be prepared by substituting a readily available isotopically labelled reagent for a non- isotopically enriched reagent.

[203] The compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. The compounds of the present invention (e.g., compounds of Formula I, IS, and IR, etc.) also are capable of forming both pharmaceutically acceptable salts, including but not limited to acid addition and/or base addition salts. Furthermore, compounds of the present invention may exist in various solid states includiung an amorphous form (noncrystalline form), and in the form of clathrates, prodrugs, polymorphs, bio-hydrolyzable esters, racemic mixtures, non-racemic mixtures, or as purified stereoisomers including, but not limited to, optically pure enantiomers and diastereomers. In general, all of these forms can be used as an alternative form to the free base or free acid forms of the compounds, as described above and are intended to be encompassed within the scope of the present invention.

[204] A "polymorph" refers to solid crystalline forms of a compound. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability). Different physical properties of polymorphs can affect their processing.

[205] A "clathrate" means a compound or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.

[206] As noted above, the compounds of the present invention can be administered, inter alia, as pharmaceutically acceptable salts, esters, amides or prodrugs. The term "salts" refers to inorganic and organic salts of compounds of the present invention. The salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. The salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66: 1-19 (1977).

[207] Examples of pharmaceutically acceptable esters of the compounds of the present invention include Ci -C₈ alkyl esters. Acceptable esters also include C₅ -C₇ cycloalkyl esters, as well as arylalkyl esters such as benzyl. C_\ -C₄ alkyl esters are commonly used. Esters of compounds of the present invention may be prepared according to methods that are well known in the art.

[208] Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary C]-C₈ alkyl amines, and secondary C]-C dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom. Amides derived from ammonia, C1 -C3 primary alkyl amines and Ci-C₂ dialkyl secondary amines are commonly used. Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art.

[209] The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[210] To illustrate, if the compound of the invention contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-Q alkyl, (C₂- Ci₂)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C₂)alkylamino(C₂- C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci -C₂)alkyl, N,N-di(Ci -C₂)alkylcarbamoyl-(Ci -C₂)alkyl and piperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

[211] Similarly, if a compound of the present invention comprises an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci -C₆)alkanoyloxymethyl, 1- ((C] -C₆)alkanoyloxy)ethyl, 1 -methyl- l-((Ci -C₆)alkanoyloxy)ethyl, (Q - C₆)alkoxycarbonyloxymethyl, N-(Ci -C6)alkoxycarbonylaminomethyl, succinoyl, (C_\ -C₆)alkanoyl, a-amino(C] -C₄)alkanoyl, arylacyl and a- aminoacyl, or α-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, - P(0)(OH)₂, -P(0)(0(Ci -C₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[212] Compounds and salts of the present invention may also exist in tautomeric forms, such as an enol and an imine form, and the corresponding keto and enamine forms and geometric isomers and mixtures thereof. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though only one tautomer may be described by the formulae above, the present invention includes all tautomers of the present compounds.

[213] The compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both the cis and trans forms (designated as Z and E, respectively), as well as mixtures, are contemplated.

[214] Mixture of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods such as chromatography and/or fractional crystallization. Enantiomers can can also be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some compounds may be atropisomers (e.g., substituted biaryls).

[215] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The present invention contemplates and encompasses both the solvated and unsolvated forms.

[216] The compounds of the present invention can be administered to a patient either alone or a part of a pharmaceutical composition in a therapeutically effective amount. A variety of non-limiting methods for administering the compounds and related compositions to patients include orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray. In addition, the substance or compositions containing the active substances can be administered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the substances can be varied over time.

[217] The compounds and related compositions of the present invention can be administered alone, or in combination with other pharmaceutically active substances. The other pharmaceutically active substances can be intended to treat the same disease or condition as the substances of the present invention or a different disease or condition. If the patient is to receive, or is receiving multiple pharmaceutically active substances, the substances can be administered simultaneously, or sequentially. For example, in the case of tablets, the active substances may be found in one tablet or in separate tablets, which can be administered at once or sequentially in any order. In addition, it should be recognized that the compositions may be different forms. For example, one or more substance may be delivered via a tablet, while another is administered via injection or orally as a syrup. All combinations, delivery methods and administration sequences are contemplated.

[218] Pharmaceutical compositions to be used comprise a therapeutically effective amount of a compound as described above, or a pharmaceutically acceptable salt or other form thereof together with one or more pharmaceutically acceptable excipients. The phrase "pharmaceutical composition" refers to a composition suitable for administration in medical or veterinary use. It should be appreciated that the determinations of proper dosage forms, dosage amounts, and routes of administration for a particular patient are within the level of ordinary skill in the pharmaceutical and medical arts.

[219] Compositions suitable for parenteral administration conveniently comprise a sterile aqueous preparation of a compound or composition of the invention, which is preferably isotonic with the blood of the recipient. This aqueous preparation may be formulated according to known methods using suitable dispersing or wetting agents, emulsifying and suspending agents. Various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, and sorbic acid also may be included. The sterile injectable preparation also may be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 , 3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or di-glycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Carrier formulation suitable for subcutaneous, intravenous, intramuscular, etc. administrations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA which is incorporated herein in its entirety by reference thereto.

[220] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is admixed with at least one inert pharmaceutically acceptable excipient such as (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin,

(f) absorption accelerators, as for example, quaternary ammonium compounds,

(g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate,

(h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid dosage forms such as tablets, dragees, capsules, pills, and granules also can be prepared with coatings and shells, such as enteric coatings and others well known in the art. The solid dosage form also may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. Such solid dosage forms may generally contain from 1% to 95% (w/w) of the active compound. In certain embodiments, the active compound ranges from 5% to 70% (w/w).

Since one aspect of the present invention contemplates the treatment of the disease/conditions with a combination of pharmaceutically active agents that may be administered separately, the invention further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a substance of the present invention, and a second pharmaceutical substance. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes and bags. Typically, the kit comprises directions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician or veterinarian.

[222] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[223] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . . " etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a substance of the present invention can consist of one tablet or capsule, while a daily dose of the second substance can consist of several tablets or capsules and vice versa. The memory aid should reflect this and aid in correct administration of the active agents.

[224] In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory- aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

[225] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound or composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3 -butyl eneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances. Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[226] Compositions for rectal administrations are preferably suppositories which can be prepared by mixing compounds of the present invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a low-melting, suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active compound.

[227] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active compound is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

[228] The compounds and compositions of the present invention also may benefit from a variety of delivery systems, including time-released, delayed release or sustained release delivery systems. Such option may be particularly beneficial when the compounds and composition are used in conjunction with other treatment protocals as described in more detail below.

[229] Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No. 5,075,109. Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di-and tri-glycerides; hydrogel release systems; sylastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like. Specific examples include, but are not limited to: (a) erosional systems in which the active compound is contained in a form within a matrix such as those described in U.S. Pat. Nos. 4,452,775, 4,667,014, 4,748,034 and 5,239,660 and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer such as described in U.S. Pat. Nos. 3,832,253, and 3,854,480. In addition, pump-based hardware delivery systems can be used, some of which are adapted for implantation.

[230] Use of a long-term sustained release implant may be desirable. Long-term release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active compound for at least 30 days, and preferably 60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.

[231] In practicing the methods of the present invention, the compounds and compositions of the presnt invention are administered in a therapeutically effective amount. Generally, doses of active compounds would be from about 0.01 mg/kg per day to 1000 mg/kg per day. It is expected that doses ranging from 50-500 mg/kg will be suitable, preferably intravenously, intramuscularly, or intradermally, and in one or several administrations per day. The compounds of the present invention may also be used in combination with radiation therapy, hormone therapy, surgery and immunotherapy, which therapies are well know to those skilled in the art.

[232] When practicing the conjoint or combination therapy described in more detail below, the administration of the compounds and compositions of the presnt invention can occur simultaneous with, subsequent to, or prior to chemotherapy or radiation, so long as the chemotherapeutic agent or radiation sensitizes the system to the compounds and compositions of the presnt invention.

[233] In general, routine experimentation in clinical trials will determine specific ranges for optimal therapeutic effect for a particular compound and composition of the presnt invention and each administrative protocol, and administration to specific patients will be adjusted to within effective and safe ranges depending on the patient condition and responsiveness to initial administrations. However, the ultimate administration protocol will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient, the potency of the compound or composition, the duration of the treatment and the severity of the disease being treated. For example, a dosage regimen of the compound or composition can be an oral administration of from 1 mg to 2000 mg/day, preferably 1 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses, to reduce tumor growth. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.

[234] In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that the patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds. Generally, a maximum dose is used, that is, the highest safe dose according to sound medical judgment. Those of ordinary skill in the art will understand, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reason. [235] The compounds of the present invention and pharmaceutical compositions comprising a compound of the present invention can be administered to a subject suffering from cancer, an autoimmune disease or another disorder where a defect in apoptosis is implicated. In connection with such treatments, the patient can be treated prophylactically, acutely, or chronically using compounds and compositions of the present invention, depending on the nature of the disease. Typically, the host or subject in each of these methods is human, although other mammals may also benefit from the administration of a compound of the present invention.

[236] As described in US 7,244,851 , the disclosure of which is incorporated herein by reference, IAP antagonists can be used for the treatment of all cancer types which fail to undergo apoptosis. Thus, compounds of the present invention can be used to provide a therapeutic approach to the treatment of many kinds of solid tumors, including but not limited to carcinomas, sarcomas including Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Treatment or prevention of non-solid tumor cancers such as leukemia is also contemplated by this invention. Indications may include, but are not limited to brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, colon cancers, blood cancers, lung cancers and bone cancers. Examples of such cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tong carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidea carcinoma, papillary thyroidea carcinoma, renal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma.

[237] The inventors believe that the IAP antagonists of the present invention will be particularly active for treating human malignancies where cIAPl and cIAP2 are over-expressed (e.g., lung cancers, see Dai et al, Hu. Molec. Genetics, 2003 v 12 pp791-801 ; leukemias (multiple references), and other cancers (Tamm et al, Clin Cancer Res, 2000, v 6, 1796-1803). The inventors also expect that the IAP antagonists of the present invention will be active in disorders that may be driven by inflammatory cytokines such as TNF playing a pro-survival role (for example, there is a well defined role for TNF acting as a survival factor in ovarian carcinoma, similarly for gastric cancers (see Kulbe, et al, Cancer Res 2007, 67, 585-592).

[238] In addition to apoptosis defects found in tumors, defects in the ability to eliminate self-reactive cells of the immune system due to apoptosis resistance are considered to play a key role in the pathogenesis of autoimmune diseases. Autoimmune diseases are characterized in that the cells of the immune system produce antibodies against its own organs and molecules or directly attack tissues resulting in the destruction of the latter. A failure of those self-reactive cells to undergo apoptosis leads to the manifestation of the disease. Defects in apoptosis regulation have been identified in autoimmune diseases such as systemic lupus erthematosus or rheumatoid arthritis.

[239] Examples of such autoimmune diseases include collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sharp's syndrome, CREST syndrome (calcinosis, Raynaud's syndrome, esophageal dysmotility, telangiectasia), dermatomyositis, vasculitis (Morbus Wegener's) and Sjogren's syndrome, renal diseases such as Goodpasture's syndrome, rapidly-progressing glomerulonephritis and membrano-proliferative glomerulonephritis type II, endocrine diseases such as type-I diabetes, autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED), autoimmune parathyroidism, pernicious anemia, gonad insufficiency, idiopathic Morbus Addison's, hyperthyreosis, Hashimoto's thyroiditis and primary myxedema, skin diseases such as pemphigus vulgaris, bullous pemphigoid, herpes gestationis, epidermolysis bullosa and erythema multiforme major, liver diseases such as primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis type- 1, autoimmune hepatitis type-2, primary sclerosing cholangitis, neuronal diseases such as multiple sclerosis, myasthenia gravis, myasthenic Lambert- Eaton syndrome, acquired neuromyotony, Guillain-Barre syndrome (Miiller- Fischer syndrome), stiff-man syndrome, cerebellar degeneration, ataxia, opsoklonus, sensoric neuropathy and achalasia, blood diseases such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (Morbus Werlhof), infectious diseases with associated autoimmune reactions such as AIDS, Malaria and Chagas disease.

[240] The present invention also is directed to the use of the compounds and compositions as a chemopotentiating agent with other treatment approaches. The term "chemopotentiating agent" refers to an agent that acts to increase the sensitivity of an organism, tissue, or cell to a chemical compound, or treatment namely "chemo therapeutic agents" or "chemo drugs" or to radiation treatment. Thus, compounds and compositions of the present invention can be used for inhibiting tumor growth in vivo by administering them in combination with a biologic or chemotherapeutic agent or by using them in combination with chemoradiation. In these applications, the administration of the compounds and compositions of the present invention may occur prior to, and with sufficient time, to cause sensitization of the site to be treated. Alternatively, the compounds and compositions of the present invention may be used contemporaneously with radiation and/or additional anti-cancer chemical agents (infra). Such systems can avoid repeated administrations of the compounds and compositions of the present invention, increasing convenience to the subject and the physician, and may be particularly suitable for certain compositions of the present invention.

[241] Biological and chemotherapeutics/anti-neoplastic agents and radiation induce apoptosis by activating the extrinsic or intrinsic apoptotic pathways, and, since the compounds and compositons of the present invention relieve antagonists of apoptotic proteins (IAPs) and, thus, remove the block in apoptosis, the combination of chemotherapeutics/anti-neoplastic agents and radiation with the compounds and compositons of the present invention should work synergistically to facilitate apoptosis.

[242] A combination of a compound of the present invention and a chemotherapeutic/anti neoplastic agent and/or radiation therapy of any type that activates the intrinsic pathway may provide a more effective approach to destroying tumor cells. Compounds of the present invention interact with IAP's, such as XIAP, cIAP-1 , cIAP-2, ML-IAP, etc., and block the IAP mediated inhibition of apoptosis while chemotherapeutics/anti neoplastic agents and/or radiation therapy kills actively dividing cells by activating the intrinsic apoptotic pathway leading to apoptosis and cell death. As is described in more detail below, embodiments of the invention provide combinations of a compound of the present invention and a chemotherapeutic/anti-neoplastic agent and/or radiation which provide a synergistic action against unwanted cell proliferation. This synergistic action between a compound of the present invention and a chemotherapeutic/anti- neoplastic agent and/or radiation therapy can improve the efficiency of the chemotherapeutic/anti-neoplastic agent and/or radiation therapies. This will allow for an increase in the effectiveness of current chemotherapeutic/anti- neoplastic agents or radiation treatments allowing the dose of the chemotherapeutic/anti-neoplastic agent to be lowered, therein providing both a more effective dosing schedule as well as use of a more tolerable dose of chemotherapeutic/anti-neoplastic agent and/or radiation.

[243] In an embodiment of the present invention, the patient is treated by administering a compound or a pharmaceutical composition of the present invention at a time the patient is subject to concurrent or antecedent radiation or chemotherapy for treatment of a neoproliferative pathology of a tumor such as, but not limited to, bladder cancer, breast cancer, prostate cancer, lung cancer, pancreatic cancer, gastric cancer, colon cancer, ovarian cancer, renal cancer, hepatoma, melanoma, lymphoma, sarcoma, and combinations thereof.

[244] In another embodiment of the present invention, the compound or composition of the present invention can be administered in combination with a chemotherapeutic and/or for use in combination with radiotherapy, immunotherapy, and/or photodynamic therapy, promoting apoptosis and enhancing the effectiveness of the chemotherapeutic, radiotherapy, immunotherapy, and/or photodynamic therapy.

[245] Embodiments of the invention also include a method of treating a patient afflicted with cancer by the contemporaneous or concurrent administration of a chemotherapeutic agent. Such chemotherapeutic agents include but are not limited to the chemotherapeutic agents described in "Modern Pharmacology with Clinical Applications", Sixth Edition, Craig & Stitzel, Chpt. 56, pg 639- 656 (2004), herein incorporated by reference. The chemotherapeutic agent can be, but is not limited to, alkylating agents, antimetabolites, anti-tumor antibiotics, plant-derived products such as taxanes, enzymes, hormonal agents, miscellaneous agents such as cisplatin, monoclonal antibodies, glucocorticoids, mitotic inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, immunomodulating agents such as interferons, cellular growth factors, cytokines, and nonsteroidal anti-inflammatory compounds, cellular growth factors and kinase inhibitors. Other suitable classifications for chemotherapeutic agents include mitotic inhibitors and nonsteroidal antiestrogenic analogs.

[246] Specific examples of suitable biological and chemotherapeutic agents include, but are not limited to, cisplatin, carmustine (BCNU), 5-fluorouracil (5-FU), cytarabine (Ara-C), gemcitabine, methotrexate, daunorubicin, doxorubicin, dexamethasone, topotecan, etoposide, paclitaxel, vincristine, tamoxifen, TNF- alpha, TRAIL, interferon (in both its alpha and beta forms), thalidomide, and melphalan. Other specific examples of suitable chemotherapeutic agents include nitrogen mustards such as cyclophosphamide, alkyl sulfonates, nitrosoureas, ethylenimines, triazenes, folate antagonists, purine analogs, pyrimidine analogs, anthracyclines, bleomycins, mitomycins, dactinomycins, plicamycin, vinca alkaloids, epipodophyllotoxins, taxanes, glucocorticoids, L- asparaginase, estrogens, androgens, progestins, luteinizing hormones, octreotide actetate, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, carboplatin, mitoxantrone, monoclonal antibodies, levamisole, interferons, interleukins, filgrastim and sargramostim. Chemotherapeutic compositions also comprise other members, i.e., other than TRAIL, of the TNF superfamily of compounds.

[247] Another embodiment of the present invention relates to the use of a compound or composition of the present invention in combination with topoismerase inhibitors to potentiate their apoptotic inducing effect. Topoisomerase inhibitors inhibit DNA replication and repair, thereby promoting apoptosis and have been used as chemothemotherapeutic agents. Topoisomerase inhibitors promote DNA damage by inhibiting the enzymes that are required in the DNA repair process. Therefore, export of Smac from the mitochondria into the cell cytosol is provoked by the DNA damage caused by topoisomerase inhibitors. Topoisomerase inhibitors of both the Type I class (camptothecin, topotecan, SN-38 (irinotecan active metabolite)) and the Type II class (etoposide) are expected to show potent synergy with compounds of the present invention. Further examples of topoisomerase inhibiting agents that may be used include, but are not limited to, irinotecan, topotecan, etoposide, amsacrine, exatecan, gimatecan, etc. Other topoisomerase inhibitors include, for example, Aclacinomycin A, camptothecin, daunorubicin, doxorubicin, ellipticine, epirubicin, and mitaxantrone.

[248] In another embodiment of the invention, the chemotherapeutic/anti-neoplastic agent for use in combination with the compounds and compositions of the present invention may be a platinum containing compound. In one embodiment of the invention, the platinum containing compound is cisplatin. Cisplatin can synergize with a compound of the present invention and potentiate the inhibition of an IAP, such as but not limited to XIAP, cIAP-1 , c- IAP-2, ML-IAP, etc. In another embodiment a platinum containing compound is carboplatin. Carboplatin can synergize with a compound of the present invention and potentiate the inhibition of an IAP, including, but not limited to, XIAP, cIAP-1 , c-IAP-2, ML-IAP, etc. In another embodiment a platinum containing compound is oxaliplatin. The oxaliplatin can synergize with a compound of the present invention and potentiate the inhibition of an IAP, including, but not limited to, XIAP, cIAP-1 , c-IAP-2, ML-IAP, etc.

[249] Platinum chemotherapy drugs belong to a general group of DNA modifying agents. DNA modifying agents may be any highly reactive chemical compound that bonds with various nucleophilic groups in nucleic acids and proteins and cause mutagenic, carcinogenic, or cytotoxic effects. DNA modifying agents work by different mechanisms, disruption of DNA function and cell death; DNA damage/the formation of cross-bridges or bonds between atoms in the DNA; and induction of mispairing of the nucleotides leading to mutations, to achieve the same end result. Three non-limiting examples of a platinum containing DNA modifying agents are cisplatin, carboplatin and oxaliplatin.

[250] Cisplatin is believed to kill cancer cells by binding to DNA and interfering with its repair mechanism, eventually leading to cell death. Carboplatin and oxaliplatin are cisplatin derivatives that share the same mechanism of action. Highly reactive platinum complexes are formed intracellularly and inhibit DNA synthesis by covalently binding DNA molecules to form intrastrand and interstrand DNA crosslinks.

[251] Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to induce apoptosis in colorectal cells. NSAIDs appear to induce apoptosis via the release of Smac from the mitochondria (PNAS, November 30, 2004, vol. 101 : 16897-16902). Therefore, the use of NSAIDs in combination with the compounds and compositions of the present invention would be expected to increase the activity of each drug over the activity of either drug independently.

[252] Many naturally occurring compounds isolated from bacterial, plant, and animals can display potent and selective biological activity in humans including anticancer and antineoplastic activities. In fact, many natural products, or semi-synthetic derivatives thereof, which possess anticancer activity, are already commonly used as therapeutic agents; these include paclitaxel, etoposide, vincristine, and camptothecin amongst others. Additionally, there are many other classes of natural products such as the indolocarbazoles and epothilones that are undergoing clinical evaluation as anticancer agents. A reoccurring structural motif in many natural products is the attachment of one or more sugar residues onto an aglycone core structure. In some instances, the sugar portion of the natural product is critical for making discrete protein-ligand interactions at its site of action (i.e., pharmacodynamics) and removal of the sugar residue results in significant reductions in biological activity. In other cases, the sugar moiety or moieties are important for modulating the physical and pharmacokinetic properties of the molecule. Rebeccamycin and staurosporine are representative of the sugar-linked indolocarbazole family of anticancer natural products with demonstrated anti-kinase and anti-topoisomerase activity.

[253] Taxanes are anti-mitotic, mitotic inhibitors or microtubule polymerization agents. Taxanes are characterized as compounds that promote assembly of microtubules by inhibiting tubulin depolymerization, thereby blocking cell cycle progression through centrosomal impairment, induction of abnormal spindles and suppression of spindle microtubule dynamics. Taxanes include but are not limited to, docetaxel and paclitaxel. The unique mechanism of action of taxane is in contrast to other microtubule poisons, such as Vinca alkaloids, colchicine, and cryptophycines, which inhibit tubulin polymerization. Microtubules are highly dynamic cellular polymers made of alpha-beta-tubulin and associated proteins that play key roles during mitosis by participating in the organization and function of the spindle, assuring the integrity of the segregated DNA. Therefore, they represent an effective target for cancer therapy.

[254] Yet another embodiment of the present invention is the therapeutic combination or the therapeutic use in combination of a compound or composition of the present invention with TRAIL or other chemical or biological agents which bind to and activate the TRAIL receptor(s). TRAIL has received considerable attention recently because of the finding that many cancer cell types are sensitive to TRAIL-induced apoptosis, while most normal cells appear to be resistant to this action of TRAIL. TRAIL-resistant cells may arise by a variety of different mechanisms including loss of the receptor, presence of decoy receptors, or overexpression of FLIP which competes for zymogen caspase-8 binding during DISC formation. In TRAIL resistance, a compound or composition of the present invention may increase tumor cell sensitivity to TRAIL leading to enhanced cell death, the clinical correlations of which are expected to be increased apoptotic activity in TRAIL resistant tumors, improved clinical response, increased response duration, and ultimately, enhanced patient survival rate. In support of this, reduction in XIAP levels by in vitro antisense treatment has been shown to cause sensitization of resistant melanoma cells and renal carcinoma cells to TRAIL (Chawla-Sarkar, et al., 2004). The compounds of the present invention bind to IAPs and inhibit their interaction with caspases, therein potentiating TRAIL- induced apoptosis.

[255] Compounds and compositions of the present invention also can be used to augment radiation therapy (or radiotherapy), i.e., the medical use of ionizing radiation as part of cancer treatment to control malignant cells. Although radiotherapy is often used as part of curative therapy, it is occasionally used as a palliative treatment, where cure is not possible and the aim is for symptomatic relief. Radiotherapy is commonly used for the treatment of tumors. It may be used as the primary therapy. It is also common to combine radiotherapy with surgery and/or chemotherapy. The most common tumors treated with radiotherapy are breast cancer, prostate cancer, rectal cancer, head & neck cancers, gynecological tumors, bladder cancer and lymphoma. Radiation therapy is commonly applied just to the localized area involved with the tumor. Often the radiation fields also include the draining lymph nodes. It is possible but uncommon to give radiotherapy to the whole body, or entire skin surface. Radiation therapy is usually given daily for up to 35-38 fractions (a daily dose is a fraction). These small frequent doses allow healthy cells time to grow back, repairing damage inflicted by the radiation. Three main divisions of radiotherapy are external beam radiotherapy or teletherapy, brachytherapy or sealed source radiotherapy and unsealed source radiotherapy, which are all suitable examples of treatment protocol in the present invention. The differences relate to the position of the radiation source; external is outside the body, while sealed and unsealed source radiotherapy has radioactive material delivered internally. Brachytherapy sealed sources are usually extracted later, while unsealed sources are injected into the body.

[256] Administration of the compounds and compositions of the present invention may occur prior to, concurrently with, or subsequent to the combination treatment protocol. A variety of administration routes are available. The particular mode selected will depend, of course, upon the particular chemotherapeutic drug selected, the severity of the condition being treated and the dosage required for therapeutic efficacy. The methods of the invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include, but are not limited to, oral, rectal, topical, nasal, intradermal, inhalation, intra-peritoneal, or parenteral routes. The term "parenteral" includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous or intramuscular routes are particularly suitable for purposes of the present invention.

Claims

CLAIMS:

What is claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

XI is O, or S;

X2 is O, or S;

Rla is H, alkyl, or substituted alkyl;

Rib is H, alkyl, or substituted alkyl;

R6 is H, alkyl, substituted alkyl, alkyl sulfonyl, arylsulfonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or R6 has the following formula (IA):

(IB):

where RlOa and RlOb are independently selected from the group consisting of H, alkyl, and substituted alkyl;

and Rl 1 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R12 is H or hydroxy;

n is 0 or 1 ;

p is 0, 1, or 2;

each Y is independently selected from the group consisting of a bond, -CH₂-, -CH2CH₂-, -CH₂N(R15K -N(R15)CH₂- and -N(R15) -;

each Q is independently selected from the group consisting of aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, and substituted heteroaryl; each R15 is independently selected from the group consisting of H and lower alkyl;

m is 0, 1 or 2; each Z" is independently selected from the group consisting of cyano, hydroxyl, mercapto, amino, halogen, nitro, carboxyl, amidino, guanidine, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl;

provided that when A is 3-indolyl and n is 0, then p has a value of 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein m is 0.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

R6 is H; alkylsulfonyl; arylsulfonyl; alkyl; substituted alkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkoxy, amino, nitro, cycloalkyl, aryl, alkylsulfonyl, arylsulfonyl and heteroaryl optionally substituted with lower alkyl or halogen; cycloalkyl; substituted cycloalkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; aryl; substituted aryl, wherein the substituents are selected from the group consisting of alkyl, halogen, hydroxy, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, nitro, alkylsulfonyl and arylsulfonyl; heterocycloalkyl; substituted heterocycloalkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; heteroaryl; or substituted heteroaryl, wherein the substituents are selected from the group consisting of halogen, hydroxy, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; or R6 has the following formula (IA):

or, R9 has the following formula (IB):

where RlOa and RlOb are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; and

4. The compound of claim 1, 2, or 3 or a pharmaceutically acceptable salt thereof, where p is 1 or 2, and Y is selected from the group consisting of a bond, - CH₂- and -NH-, and, when p is 2, both Y groups are the same and both Q groups are the same.

5. The compound of claim 1 , 2, 3 or 4, or a pharmaceutically acceptable salt thereof,

wherein n is 0; Y is a bond, and p is 1 ; or

wherein n is 0; Y is -CH₂-, or -NH-, and p is 1 ; or

wherein n is 0; Y is a bond, and p is 2; or

wherein n is 0; Y is -CH₂-, or -NH-, and p is 2; or

wherein n is 1 , Y is a bond, and p is 1 ; or

wherein n is 1 ; Y is a bond, and p is 2; or

wherein n is 1 , Y is— CH₂— , or -NH-, and p is 1 ; or

wherein n is 1 ; Y is -CH₂-, or -NH-, and p is 2.

6. The compound of claim 1 , 2, 3, 4 or 5, or a pharmaceutically acceptable salt thereof, wherein A is furan, thiophene, pyrrole, oxazole, isoxazole, pyrazole, imidazole, triazole, tetrazole, thiazole, isothiazole, indole, imidazopyridine, benzoimidazole, benzooxazole, benzothiazole, or thiazolopyridine.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof,

8. The compound of claim 1 , 2, 3, 4, 5, 6, or 7 or a pharmaceutically acceptable salt thereof, wherein Q is phenyl, or a substituted phenyl.

9. The compound of claim 8 wherein the substituted phenyl is substituted with fluoro or trifluoromethyl.

10. The compound of claim 1 , 2, 3, 4, 5, 6, 7, 8 or 9, or a pharmaceutically acceptable salt thereof, wherein:

R is H, alkyl, substituted alkyl, alkenyl, or substituted alkenyl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro;

Rla is H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro; and Rib is H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro.

11. The compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or a pharmaceutically acceptable salt thereof, wherein:

R is H, or lower alkyl;

Rl a is H or lower alkyl;

Rib is H or lower alkyl;

R2 is H; lower alkyl; cycloalkyl, or substituted lower alkyl wherein the substituents are selected from the group consisting of hydroxy, and alkoxy;

R6 is H; lower alkylsulfonyl; alkyl; substituted alkyl, wherein the alkyl substituents are selected from the group consisting of hydroxy, oxo, halogen, alkoxy, cycloalkyl, aryl, and heteroaryl optionally substituted with lower alkyl or halogen; cycloalkyl; or heteroaryl optionally substituted with lower alkyl or halogen; or R6 has the following formula (IA):

R9 is H, or lower alkyl; or R9 has the following formula (IB):

where RlOa and RlOb are independently selected from the group consisting of H, and lower alkyl; and Rl 1 is H, or lower alkyl.

12. The compound of claim 1 1 , or a pharmaceutically acceptable salt thereof, where Y is a -CH₂- or -NH-; and p is 1 or 2.

13. The compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, or a pharmaceutically acceptable salt thereof, wherein one of Rla and Rib is H and the other is lower alkyl.

14 The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of formula (I-SA):

wherein Rl is lower alkyl or substituted lower alkyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of formula (II-SB):

wherein Rl is lower alkyl, or substituted lower alkyl.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of formula (III-S):

wherein Rl is lower alkyl, or substituted lower alkyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of formula (IV-S):

wherein Rl is lower alkyl, or substituted lower alkyl.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of formula (V-S):

wherein Rl is lower alkyl, or substituted lower alkyl.

19. The compound of claim 14, 15, 16, 17, or 18 wherein

XI is O;

X2 is O;

R is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; Rl is H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

T? l-ii_*

substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkoxy, amino, nitro, cycloalkyl, aryl, alkylsulfonyl, arylsulfonyl and heteroaryl optionally substituted with lower alkyl or halogen; cycloalkyl; substituted cycloalkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; aryl; substituted aryl, wherein the substituents are selected from the group consisting of alkyl, halogen, hydroxy, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, nitro, alkylsulfonyl and arylsulfonyl; heterocycloalkyl; substituted heterocycloalkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; heteroaryl; or substituted heteroaryl, wherein the substituents are selected from the group consisting of halogen, hydroxy, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; or R6 has the following formula (IA):

where R8 is alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, alkoxy, mercapto, carboxyl, cycloalkyl, aryl, heterocycloalkyl, amino, nitro and heteroaryl; and 9 is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

or, R9 has the following formula (IB):

where Rl Oa and RlOb are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; and

Rl l is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; and

p is 1 or 2, and Y is selected from the group consisting of a bond, -CH₂- and - NH-, and, when p is 2, both Y groups are the same and both Q groups are the same.

The compound of claim 1 which is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

21. A compound that is a homodimer or a heterodimer of two monomers, wherein one monomer is selected from the group consisting of compounds of Formula (I), (I-SA), (I-SB), (II-SA), (II-SB), (III-S), (IV-S), (V-S) and (VI-S), and the other monomer is selected from the group consisting of compounds of Formula (I), (I-SA), (I-SB), (II-SA), (II-SB), (III-S), (IV-S), (V-S), (VI-S) and (I-RA):

or a pharmaceutically acceptable salt of any such dimer,

wherein each of the two monomers is linked together by a linker L, both R2 groups together, or both R6 groups together, form -L-, linking the two monomers;

each XI is independently O, or S;

each X2 is independently O or S;

each R is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

each Rl is independently H, alkyl, or substituted alkyl;

each Rla is independently H, alkyl, or substituted alkyl;

each Rib is independently H, alkyl, or substituted alkyl;

when both R6 groups together form -L-, then each R2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

when both R2 groups together form -L-, then each R6 is independently H, alkyl, substituted alkyl, alkylsulfonyl, arylsulfonyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or each R6 independently has the following formula (IA):

where each R8 is independently H, alkyl, substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

and each R9 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl; or each R9 independently has the following formula (IB):

where each Rl Oa and Rl Ob are independently selected from the group consisting of H, alkyl, and substituted alkyl;

and each Rl l is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

each independently R12 is H or hydroxy;

each n is independently 0 or 1 ;

each A is independently a 5-6-membered heteroaryl ring, or an 8-12- membered fused ring system that includes a 5-6-membered heteroaryl ring; p is 0, 1, or 2;

each Y is independently selected from the group consisting of a bond, -CH₂-, -CH2CH₂-, -CH₂N(R15)-, -N(R15)CH₂- and -N(R15) -;

each R15 is independently H and lower alkyl;

m is 0, 1 or 2;

each Z" is independently selected from the group consisting of cyano, hydroxyl, mercapto, amino, halogen, nitro, carboxyl, amidino, guanidine, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl;

where each m+p has a value no greater than the number of substitutable positions on the A;

L is a single or double covalent bond, or is a contiguous chain, branched or unbranched, substituted or unsubstituted, of 1 to about 100 atoms, and provided that when an A is 3-indolyl and n is 0, then p has a value of 1 or 2.

22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein:

each R is independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

each Rl is independently H, alkyl, or substituted alkyl, wherein the

substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; each Rla is independently H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; each Rib is independently H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; when both R6 groups together form -L-, then each R2 is independently alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, alkoxy, cycloalkyl, aryl, heterocyclo alkyl and heteroaryl

when both R2 groups together form -L-, then each R6 is independently H; alkylsulfonyl; arylsulfonyl; alkyl; substituted alkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkoxy, amino, nitro, cycloalkyl, aryl, alkylsulfonyl, arylsulfonyl and heteroaryl optionally substituted with lower alkyl or halogen; cycloalkyl; substituted cycloalkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; aryl; substituted aryl, wherein the substituents are selected from the group consisting of alkyl, halogen, hydroxy, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, nitro, alkylsulfonyl and arylsulfonyl; heterocycloalkyl; substituted heterocycloalkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; heteroaryl; or substituted heteroaryl, wherein the substituents are selected from the group consisting of halogen, hydroxy, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; or each R6 independently has the following formula (IA):

where each R8 is independently alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or substituted alkyl, wherein the substituents are selected from the group consisting of halogen, hydroxy, oxo, alkoxy, mercapto, carboxyl, cycloalkyl, aryl, heterocycloalkyl, amino, nitro and heteroaryl;

and each R9 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

or, each R9 independently has the following formula (IB):

where each RlOa and RlOb is independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro; and

each Rl 1 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, or substituted heteroaryl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cycloalkyl, aryl, alkoxy, amino, heteroaryl, and nitro;

each A is independently a 5-membered heteroaryl ring, or an 8-9-membered fused ring system that includes a 5-membered heteroaryl ring, wherein said 5- membered heteroaryl ring or 8-9-membered fused ring system has 1 , 2, or 3 heteroatoms selected from N, O, and S, and

23. The compound of claim 21. 22, or a pharmaceutically acceptable salt thereof, wherein:

each p is independently 1 or 2, and aech Y is independently a bond, -CH₂- or -NH-, and, when p is 2, both Y groups are the same and both Q groups are the same, and L is optionally substituted alkyl, alkylene, alkylyne, cycloalkyl, alkylcycloalkyl, or alkylarylalkyl chain of 2 to 20 atoms with 1-3 heteroatoms selected from the group consisting of -0-, -NH- and -S-.

24. The compound of claim 21 , 22, or 23, or a pharmaceutically acceptable salt thereof, wherein:

n is 0; each Y is a bond, and p is 1 ; or

n is 0; each Y is -CH₂-, or -NH-, and p is 1 ; or

n is 0; each Y is a bond, and p is 2; or

n is 0; each Y is -CH₂- or -NH-, and p is 2; or

n is i, each Y is a bond, and p is 1 ; or

n is 1 ; each Y is a bond, and p is 2; or

n is 1 , each Y is -CH₂- or -NH-, and p is 1 ; or

n is 1 ; each Y is -CH₂- or -NH-, and p is 2; and

L is an optionally substituted alkyl, alkylene, alkylyne, cycloalkyl, alkylcycloalkyl, or alkylarylalkyl chain of 2 to 20 atoms with 1-3 heteroatoms selected from -0-, -NH- and -S-.

25. The compound of claim 21 , 22, 23, or 24, or a pharmaceutically acceptable salt thereof, wherein:

each XI is O;

each X2 is O;

each A is furan, thiophene, pyrrole, oxazole, isoxazole, pyrazole, imidazole, triazole, tetrazole, thiazole, isothiazole, indole, imidazopyridine, benzoimidazole, benzooxazole, benzothiazole, or thiazolopyridine

L is -C(0)CH₂NHC(0)C(0)NHCH₂C(0) -, and

Each R12 is H.

26. The compound of claim 21 , 22, 23, 24, or 25, or a pharmaceutically acceptable salt thereof, wherein each A is selected from the group consisting of:

L is -C(0)CH₂NHC(0)C(0)NHCH₂C(0) -, and

each R12 is H.

27. The compound of claim 21, 22, 23, 24, 25, or 26, wherein

each R is independently H, alkyl, substituted alkyl, alkenyl, or substituted alkenyl; wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro; each Rl is independently H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro. each Rla is independently H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro each Rib is independently H, alkyl, or substituted alkyl, wherein the substitutents are selected from the group consisting of halogen, hydroxy, oxo, mercapto, carboxyl, alkyl, cyclopropyl, alkoxy, amino, and nitro

28. The compound of claim 21, 22, 23, 24, 25, 26, or 27, or a pharmaceutically acceptable salt thereof, wherein: each R is independently H, or lower alkyl; each Rl is independently H or lower alkyl; each Rla is independently H or lower alkyl; each Rib is independently H or lower alkyl; when both R6 groups together form -L-, then each R2 is independently H; lower alkyl; cycloalkyl, or substituted lower alkyl wherein the substituents are selected from the group consisting of hydroxy, and alkoxy; when both R2 groups together form -L-, then each R6 is independently H; lower alkylsulfonyl; alkyl; substituted alkyl, wherein the alkyl substituents are selected from the group consisting of hydroxy, oxo, halogen, alkoxy, cycloalkyl, aryl, and heteroaryl optionally substituted with lower alkyl or halogen; cycloalkyl; or heteroaryl optionally substituted with lower alkyl or halogen; or independently each R6 has the following formula (IA):

wherein each R8 is independently H, lower alkyl, cycloalkyl, or substituted lower alkyl wherein the substituents are selected from the group consisting of hydroxy, and alkoxy; and each R9 is independently H, or lower alkyl; or independently each R9 has the following formula (IB):

where each RlOa and RlOb is independently selected from the group consisting of H, and lower alkyl; and each Rl 1 is independently H, or lower alkyl,

L is -C(0)CH₂NHC(0)C(0)NHCH₂C(0) -, and

each R12 is H.

29. The compound of claim 21, 22, 23, 24, 25, 26, 27, or 28, or a pharmaceutically acceptable salt thereof wherein m is 0.

30. The compound of claim 21, or a pharmaceutically acceptable salt thereof, that is a homodimer wherein L is an optionally substituted alkyl, alkylene, alkylyne, cycloalkyl, alkylcycloalkyl, or alkylarylalkyl chain of 2 to 20 atoms with 1-3 heteroatoms selected from -0-, -NH-, and -S-.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein L is -C(0)CH₂NHC(0)C(0)NHCH₂C(0)-.

32. The compound of claim 21, or a pharmaceutically acceptable salt thereof, that is a homodimer wherein m is 0.

33. The compound of claim 21 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, selected from any of claims 1 to 30 and a pharmaceutically acceptable excipient.

35. A method for inducing apoptosis in a cell comprising contacting the cell with a compound, or a pharmaceutically acceptable salt thereof, selected from any of claims 1 to 33, or with the composition of claim 34, in an amount sufficient to induce apoptosis in the cell.

36. The method of claim 35 wherein the cell is a cancer cell.

37. A method of treating cancer selected from the group consisting of: sarcomas, bladder cancers, ovarian cancers, breast cancers, brain cancers, pancreatic cancers, colon cancers, blood cancers, skin cancers, lung cancers and bone cancers, the method comprising administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from any of claims 1 to 33, or with the composition of claim 34, to a patient in need thereof.

38. The method of claim 37 wherein the cancers are selected from the group consisting of colorectal cancer, renal carcinoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, breast carcinoma, melanoma, glioblastoma, acute myeloid leukemia (AML), small cell lung carcinoma, non-small cell lung carcinoma, rhabdomyosarcoma, and basal cell carcinoma.

39. The method of claim 38 further comprising administering a second therapy selected from radiation, chemotherapy, immunotherapy, photodynamic therapy, or combinations thereof.

40. A method of treating an autoimmune disease selected from the group consisting of: systemic lupus erythematosus, psoriasis and idiopathic thrombocytopenic purpura (Morbus Werlhof); the method comprising administering a

1

thereof, selected from any of claims 1 to 33, or with the composition of claim 34, to a patient in need thereof.