Long-acting cyclic peptides for inhibiting TNF receptor 1 activity

Abstract

Provided are compounds of the Formula (I), or their pharmaceutically acceptable salts, can inhibit TNFR1 and are expected to have utility as long-acting therapeutic agents, for example, for treating inflammatory bowel diseases, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis and hidradenitis suppurativa. The disclosure also provides pharmaceutical compositions which comprise the compounds disclosed herein or pharmaceutically acceptable salts thereof. The disclosure also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of inflammatory bowel diseases, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis and hidradenitis suppurativa, and for preparing pharmaceuticals for this purpose.

Description

LONG-ACTING CYCLIC PEPTIDES FOR INHIBITING TNF RECEPTOR 1 ACTIVITYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 678,279 filed August 1, 2024, the entire contents of which are incorporated by reference herein.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The contents of the electronic sequence listing (25953-WO-PCT_SL.xmh Size: 638,976 bytes; and Date of Creation: March 5, 2025) are herein incorporated by reference in their entirety.FIELD OF THE INVENTION

[0003] The present disclosure relates to certain cyclic peptides that inhibit TNF receptor 1 (TNFR1) activity', pharmaceutical compositions comprising such peptides, and methods for using the compounds for treating, inhibiting, or ameliorating one or more autoimmune and inflammatory disease states that could benefit from inhibiting TNFR1, including inflammatory bowel diseases (IBD), rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, hidradenitis suppurativa and other dermatological disorders, as well as other neurological, neurodegenerative, metabolic and ocular disorders.BACKGROUND OF THE INVENTION

[0004] Therapeutics which target the signaling of the cytokine tumor necrosis factor alpha (TNF a), comprising the anti-TNFa biologies which emerged in the 1990s, continue to be among the standard of care (SOC) for several prevalent autoimmune and inflammatory diseases including ulcerative colitis (UC), Crohn's disease (CD), collectively referred to as IBD, RA. juvenile RA, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa. TNFa is a pleiotropic cytokine that affects the function of a variety of cell types. It triggers cellular responses from the induction of inflammatory gene expression programs, the stimulation of cellular proliferation and differentiation, to the activation of cellular suicide programs such as apoptosis and necroptosis. It is expressed as a ty pe II single spanning transmembrane protein and as a soluble variant released after proteolytic processing.

[0005] TNFa self-assembles into homo-trimeric molecules and both the transmembrane and soluble form interact with the two known membrane receptors of TNFa, TNFR1 and TNFR2, each exerting distinct biological effects. Both receptors of TNFa are typical representatives of the broader TNF receptor superfamily. As such. TNFR1 and TNFR2 are single-spanning type I transmembrane proteins characterized by having several cysteine-rich domains in their extracellular domains. Soluble forms of TNFR1 and TNFR2 have also been described and result from alternative splicing or shedding. TNFR1 is expressed by almost all cell types and mediates the well-known pro-inflammatory, cytotoxic, and gene inductive signaling actions of TNFa. TNFR2 is expressed by more restricted cell types, including myeloid cells, regulatory T-cells, glial cells, some endothelial cell types, epithelial cells, fibroblasts, and certain T- and B-cell subsets and induces immunosuppressive / homeostatic effects of the cytokine on immune cells and in tissue regeneration.

[0006] The mechanism of action (MO A) of anti-TNFa biologies such as infliximab, adalimumab. golimumab and certolizumab, involves binding to the cytokine TNFa and thus, inhibition of engagement with both TNFR1 and TNFR2.

[0007] A key limitation of anti-TNFa SOC biologies as a medicine class is the high rate of loss of response (upwards of >70% within one year of treatment), which in many cases is caused by the development of anti-drug antibodies (ADA, -60% among IBD patients), which lead to undesirable changes in the pharmacokinetic and pharmacodynamic properties of these drugs (See, Colombel et al., ‘Adalimumab for Maintenance of Clinical Response and Remission in Patients with Crohn’s Disease'’, Gastroenterology 132 (1): 52-65 (2007); and Vaisman-Mentesh, A. et al., “The Molecular Mechanisms that underlie the Immune Biology of Anti-drug Antibody Formation following Treatment with Monoclonal Antibodies”, Frontiers in Immunology, 11 : 1951(2020)).

[0008] The limitations of anti-TNF therapy may depend on TNF’s pleiotropic biological functions via two distinct TNF receptors. In different animal disease models, genetic deletion of TNFR1 is typically associated with or reduced disease, whereas TNFR2 ablation exacerbates disease. These and other data indicate that TNFa / TNFRl signaling mainly mediates pro- apoptotic and inflammatory responses, whereas TNFR2 contributes to immune regulation and tissue regeneration. Therefore, reagents that selectively target TNFRs might be superior to global TNF blockade because they allow a differential activation and / or inhibition of TNFRs. Selective blocking of TNFa / TNFRl signaling, which will preserve functional TNFa / TNFR2 signaling, seems to be sufficient to interfere with pathological TNFa signaling. In contrast to global TNF blockers that neutralize soluble and transmembrane TNFa, this class of therapeutics may induceless severe side-effects and may be therapeutic for other diseases such as MS or neurodegenerative diseases, where complete TNF inhibition is contraindicative (See, Fischer et al., “Selective Targeting of TNF Receptors as a Novel Therapeutic Approach”, Front. Cell Dev. Biol. 8:401(2020); Dong et al., “Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders”, Antibodies, 4:4 (2015))

[0009] There is a need for additional, therapeutic approaches beyond the standard of care of current anti-TNFa biologies medications for slowing the progression of prevalent autoimmune and inflammatory diseases.SUMMARY OF THE DISCLOSURE

[0010] The present disclosure provides certain cyclic peptides that reduce inflammation by selectively inhibiting TNFR1 to specifically attenuate the proinflammat ory activities of TNFa mediated by TNFR1 signaling, and to spare / passively enable TNFa-TNFR2 pro-homeostatic signaling. These cyclic peptides can be valuable pharmaceutically active compounds for the treatment of prevalent autoimmune and inflammatory diseases including ulcerative colitis (UC), Crohn’s disease (CD), collectively referred to as inflammatory bowel diseases (IBD), as well as rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriasis and other inflammatory conditions that can be treated by blockade of TNFa signaling like psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, hidradenitis suppurativa, and other dermatological disorders, as well as other neurological, neurodegenerative, metabolic, and ocular disorders.

[0011] In one aspect, the present disclosure provides compounds of Formula (I)and their pharmaceutically acceptable salts.

[0012] The compounds of the present invention have the potential to provide superior, more durable efficacy over non-selective anti-TNFa SOC, through inhibition of TNFR1 -driveninflammation that concomitantly spares TNFR2-dependent homeostasis, mucosal and tissue healing, and immune regulation. Accordingly, in another aspect, the present disclosure provides a method for treating autoimmune and inflammatory diseases (e.g., ulcerative colitis, Crohn’s disease, collectively referred to as IBD, RA. JRA, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis and hidradenitis suppurativa) comprising administering a therapeutically effective amount of the compound of the disclosure to a subject in need thereof. In some embodiments, the administration comprises an oral administration of the compound. The present invention also provides optimized compounds and compositions to provide an increased half-life over compounds in co-pending US application 18 / 429.587, filed on February 1, 2024. The compounds of the instant invention maintain an improved pharmacokinetic profile and prolonged pharmaceutical action over the compounds of the copending application. The disclosure furthermore provides processes for preparing compounds of the disclosure and pharmaceutical compositions which comprise compounds of the disclosure and a pharmaceutically acceptable carrier.DETAILED DESCRIPTION OF THE INVENTION Compounds of the Disclosure

[0013] In one embodiment, the present disclosure provides a compound having structural Formula (I) or a pharmaceutically acceptable salt thereof:R.1 is selected from hydrogen, C1 -20 alkyl, amino(Co-10 alkyl), (C1 -6 alkyl)o-2 amino(Co-10 alkyl), (C1 -6 alkyl)o-2 amino(Co-10 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)3N+(C0-6 alkyl),aryl(Co-l 0 alkyl), heteroaryl(Co-10 alkyd), (C3-i2)cycloalkyl(Co-10 alkyd), heterocycloalkyl(Co-10 alkyl), C1-1Q fluoroalkyd, C2-10 alkenyl, (C0-6 alk l)carbonylamino(C0-6 alkyl), (Cl-6 alkyl)o-2 aminocarbonyl(C0-6 alkyl). (Cl -6 alkyl)o-2 aminocarbonylamino(C0-6 alkyl), ary dcarbonylamino(C0-6 alkyl), arylaminocarbonyl(C0-6 alkyl), heteroarylcarbonylamino(C0-6 alkyd), heteroarydaminocarbonyl(C0-6 alkyl), Cfl-6 alkydoxy, (Cl-6 alkyl)oxy(C0-6 alkyl), ((C3- 12)cycloalkyl)oxy(C0-6 alkyl), ((C3-i2)cycloalkyl C0-6 alkyl)oxy(C0-6 alkyl), (CQ-6 alkyl)carboxy(C0-6 alkyl), N'=N+=N-(C0-6 alkyl), and H2N-C(=NH)NH-(C0-6 alkyl), wherein R1 is substituted by 0, 1, 2, or 3 Rlasubstituents each independently selected from C1-6 alkyl, amino, azido, cyano, halo, hydroxy, (C3-12)cycloalky doxy, Cl-6 alkyloxy, and - (CH2)0-6-NH-(X1) 1 ^-X^-U^-Z ; each R3ais independently selected from hydrogen, hydroxy, C1 -4 alkyl, fluoro, and C1 -4 alkyloxy;R2b is selected from ary l, heteroaryl, cycloalkyl, and heterocycloalky 1, wherein said heteroary I contains at least one nitrogen atom, wherein R3b is substituted by 0, 1, or 2 R3c independently selected from Cl-6 alkyl, amino(Co- 6 alkyl), (C 1 -6 alky d)o-2amino(C0-6 alkyl). (Cl-6 alkyl)3N+(C0-6 alkyl), aminocarbonyl (C0-6 alkyl), (Cl-6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), hydroxy, Cl-6 alky doxy, halo, (Cl-6 alkyl)o-2 amino(C0-6 alkyloxy), (C1 -6 alkyl)3N+(C0-6 alkyloxy), (C1-6 alkyloxy)carbonyl(C0-6 alkyl), carboxy(C0-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6 alkyd), halo, C1 -6 haloalkyl, C1 -6 haloalky doxy, C1 -6 alkyloxy, -0(CH2)o-6~NH-(X1)i- 2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X1) 1 -2-X2-X3-U1-U2-Z;R3a is selected from hydrogen, hydroxy, hydroxy(C1 -6 alkyl), amino, amino(C1 -6 alkyl), C1 -io alkyl, (C3-i2)cycloalkyl(Co-10 alkyl), (C0-6 alkyl)thio(C1 -6 alkyl), and carboxy(C1 -6 alkyl), wherein R3amay be substituted by 0, 1, or 2 R3csubstituents;R3b is selected from hydrogen, Cl-10 alkyl, hydroxy(Cl-6 alkyd), amino(Cl-6 alkyl), (Cl-6 alkyd)o-2 amino(C1 -6 alkyl), (Cl-6 alkyl)3N'(C1 -6 alkyl), halo, Cl-6 haloalkyl. aryl(Co- 10 alkyd), heteroaryd(C0-6 alkyd), (C3-i2)cycloalkyl(C0-6 alkyl), heterocycloalkyl(C0-6 alkyd), (C1 -6 alkyl)oxy(C1 -6 alkyl), (C3-i2)cycloalkyloxy(C1-6 alkyl). carboxy(C1 -6 alkyl), aminocarbony d(C1 -6 alkyl), (C 1-6 alky d)o-2 aminocarbonyl(C1 -6 alkyl),aminocarbonylamino(C1 -6 alkyl). (C1 -6 alkyl)o-2 aminocarbony damino(C 1 -6 alkyl), (Co- 6 alky l)thio(C 1-6 alkyl), (C1 -6 alkyl)SO2(C1 -6 alkyd), and (C1 -6 alkyd)sulfmyl(C1 -6 alkyl), wherein R3bmay be substituted by 0, 1 , or 2 R3csubstituents; each R3C is independently selected from halo. C1 -6 alkyl, amino. (C1 -6 alkyl)o-2 amino(C0-6 alkyl), (C1 -6 alkyl)sN+-, (Cl -6 alkyl)SO2(C0-6 alkyl), cyano, cyano(Cl-6 alkyl), hydroxy, hydroxy(Cl-6 alkyl), (Cl -6 alkyl)oxy(C[)-6 alkyl), aminocarbonyl(C()-6 alkyl), and (C0-6) carboxy(C0-6 alkyl), whereinR3a and R3b. together with the atoms to which they are attached, may form a saturated ring system, wherein said saturated ring system may be substituted by 0, 1, or 2 R3csubstituents;R4a is selected from hydrogen, Cl -6 alkyl, hydroxy, C1.4 alkyloxy, and fluoro;R4bis selected from bicyclic heteroaryl(Co-3 alkyl), and bicyclic aiyl(Co-3 alkyl), wherein R4bis substituted with 0. 1, or 2R4C substituents each R4cindependently selected from halo, hydroxy, cyano, nitro, carboxy, carboxy(C1 -6 alkyl), (C1 -6 alky doxy)carbonyl(C0-6 alkyd), C1 -6 alkydoxy, (C1 -6 alkyl)oxy(C1 -6 alkyl), C1 -6 alkyl, C1 -6 haloalkyl, and - (CH2)0-6-NH-(X1) 1 -2-X2-X3-U1-U2-Z;R5a is selected from hydrogen, Cl-10 alkyd, Cl-10 fluoroalkyl, carboxy(Cl-K) alkyl), hydroxy, hydroxy(C1 -io alkyl), cyano(C1 -K) alkyl), (C3-i2)heterocycloalkyl(C0-10 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C1 -6 alkyl), (carboxy(C1 -io alkyl))oxy(C1 -6 alkyl), amino(C0-6 alky l)aryl(C 1-6 alkyl), aryl(CQ-6 alkyl), (C3-i2)cycloalkyl(C0-6 alkyl), heteroaryl(C0-6 alkyd), (Cl -6 alkyl)oxy(Cl-6 alkyl), (Cl -6 alkyd oxy)carbonyl(C0-6 alkyl), amino, amino(C1 -6 alkyl). (Cl -6 alkyl)o-2 amino(C0-6 alkyl). amino(C2-6 alkyl)oxy(C1 -6 alkyl), (Cl -6 alkyl)o-2 amino(C2-6 alkyl)oxy(Cl-6 alkyl), amino(Cl-6 alky d)carbony damino(Cl- 6 alkyl), amino(Cl-6 alkyl)carbonylamino(Cl-6 alkyl), (Cl -6 alkyl)o-2 amino(Cl-6 alkyl)carbonylamino(C1 -6 alkyl), (C1 -6 alkyl)?N+(C2-10 alkyd), (C1 -6 alky d)3N+(C1 -6 alkyd)carbonylamino(Cl-6 alkyl), Cl-10 fluoroalkyd, -(CH2)0-6-NH-(X1)i-2-X2-X3- U'-LP-Z. -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-Ph- (CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z and wherein R3ais substituted by 0, 1, or 2 R5d substituents;R5b is selected from hydrogen, C1 -io alkyl, hydroxy(C1 -iQ alkyl), carboxy(C1 -6 alkyd), (C1 -6 alkyl)oxy(C1-6 alkyl), aminocarbonyl(C1 -6 alkyl), (C 1-6 alkyl)o-2 aminocarbonyl(C1 -6 alkyl), carboxy(C1 -io alky l)oxy(C 1-6 alkyl), cyano(C1 -6 alkyl), amino(C1 -6 alkyl), (C 1- 6 alky l)o-2 amino(Cl-6 alkyl), (Cl -6 alky d)o-2 amino(C2-6 alky l)oxy(C 1-6 alkyl), amino(C1 -6 alkyl)carbonylamino(C1-6 alkyl), (amino(C2-6 alkyl)oxy(C1 -6 alkyl), C1 -6 alky l)o-2 amino(Cl-6 alky l)carbonylamino(C 1 -6 alkyl), (Cl -6 alkyl)3N+(C2-6 alkyl)oxy(C1-6 alkyl), (C1 -6 alkyl)3N+(C1 -6 alkyl)carbonylamino(C1 -6 alkyl). (Cl -6 alkyl)3N+(Cl-6 alkyl), (heterocycloalkyl(C()-10 alky l), (C3-12)cycloalkyl(Co-10 alkyd), C1 -10 haloalkyl, -(CH2)l-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)1- 6-NH-(X1)i-2-X2-X3-U1-U2-Z, wherein R$b is substituted by 0, 1, 2, or 3 R$esubstituents, whereinR5a and R3b, together with the atoms to which they are attached, form a saturated mono- or bi-cyclic ring, wherein said mono- or bi-cyclic ring is substituted with 0, 1. or 2, R3d and 0, 1, 2, or 3 R3esubstituents; eachR5d is independently selected from selected from halo, hydroxy, hydroxy(C1 -6 alkyl), C1 - 10 alkyl, carboxy, carboxy (C 1-6 alkyd), C1 -6 alkyloxy, (C1 -6 alkyl)oxy(C1-6 alkyl), amino, amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl), amino(C1 -6 alkyl)carbonylamino(C0-6 alkyl), (C1 -6 alkyl)o-2 amino(C1 -6 alkyl)carbonylamino(C0-6 alkyl), (C1 -6 alkyl)3N+(C0-6 alkyl), (Cl -6 alkyl)3N+(C2-6 alkyl)oxy(C0-6 alkyl). (C1-6 alkyl)3N+(C1 -6 alkyl)carbonylamino(C0-6 alkyl), (carboxy(C1 -6 alkyl))oxy(C0-6 alkyl), cyano(C0-6 alkyl), tetrazolyl(C0-6 alkyd), and C1 -6 haloalky l, amino(C2-6 alky d)oxy(Co- 6 alkyl), (C1 -6 alkyd)o-2 amino(C2-6 alkyl)oxy(C0-6 alkyl), -(CH2)0-6-O(CH2)0-6-NH- (X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z; and two R5dsubstituents together with the atom they are attached to may join together to form a saturated ring; eachR5e is independently selected from halo, hydroxy, hydroxy(C1 -io alkyl), C1 -io alkyl, carboxy, carboxy(C1 -6 alkyd), C1 -6 alkydoxy, (C1-6 alkyl)oxy(C1 -6 alkyl), amino, amino(C1 -6 alkyl). (C1-6 alkyl)o-2 amino(C0-6 alkyl). amino(C1 -6 alky l)carbonylamino(C 0-6 alkyl), (C1 -6 alkyl)o-2 amino(Cl-6 alkyl)carbonylamino(C0-6 alkyd), (C1 -6 alkyd)3N+(C0-6 alkyl), (C1 -6 alkyl)sN+(C2-6 alkyl)oxy(C0-6 alkyl). (C1-6alkyl)3N+(C1 -6 alkyl)carbonylarmno(C0-6 alkyl), (carboxy(C 1 -6 alkyl))oxy(C1 -6 alkyl). cyano(C0-6 alkyl), tetrazolyl(C0-6 alkyl), C1 -6 haloalkyl, (CH2)0-6 O(CH2)0-6 NH (X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z and two R5esubstituents together with the atom they are attached to may join together to form a saturated ring;R5C is hydrogen, Cl -4 alkyd, hydroxy(Cl-4 alkyd), Cl -4 alky doxy, or (Cl -4 alky d)oxy(Cl-4 alkyl);R6a is selected from hydrogen, hydroxy, amino, C1-4 alkyloxy, and C1 -6 alkyl;R6b is selected from hydrogen, C1 -6 alkyl, hydroxy, C1 -4 alkyloxy, and fluoro;R6C is selected from C1 -i o alkyl, C1 -6 alkyloxy, (C1 -6 alkyl )oxy(C 1 -6 alkyl). C1 -i o haloalkyl. aryl(C0-6 alkyl), heteroary d(C()-10 alkyl), (C1 -6 alkyl)S02(C0-6 alkyl), hydroxy, hydroxy(C1 -6 alkyl). amino(C0-6 alkyd), (Cl -6 alkyl)o-2 amino(C0-6 alkyd), aminocarbonyl(C0-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), (C1 -6 alky l)carbonylamino(C 0-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonylamino(C0-6 alkyl), and carboxy(C0-6 alkyl);R7a is selected from hydrogen, Cl -6 alkyl, hydroxy, C1 -4 alkyloxy, and fluoro;R3b isselected from aryl(Co-4 alkyl), heteroary l(Co-4 alkyl) wherein said heteroaryl contains at least one nitrogen, and (C3-12)cycloalkyl(Co-4 alkyd), whereinR7b is substituted by 0. 1, or 2. R3csubstituents each independently selected from C1 -6 alkyl, C1 -6 fluoroalkyl, C1-6 fluoroalkyloxy, (C1 -6 alkyl)o-2 amino(Co-5 alkyl), (C1 -6 alkyd)3N+(Co-5 alkyl), carboxy(C0-6 alkyl), (C1-6 alkyloxy)carbonyl(C0-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6 alkyl), aminocarbonyl(C0-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), halo, -(CQ-5 alkyl)- (S(=O)2OH), -(CO-5 alkyl )-(S(=O)2NH2), amino(C0-6 alkyl)oxy(C0-6 alkyl), (Cl -6 alkyl)o-2 amino(C0-6 alkyl)oxy(C0-6 alkyd), (C1 -6 alkyl)3\ (C'o-6 alkyl)oxy(CQ-6 alkyd), aminocarbonylamino(C0-6 alkyl). (C1 -6 alkyl)o-2 aminocarbonylamino(C0-6 alkyl), C1- 10 haloalkyl, C1 -io haloalkyloxy, (C1 -6 alkyd)oxy(C0-6 alkyd), and (C1 -6 haloalkyl)oxy(C0-6 alkyl);RSa is selected from hydrogen, Cl -6 alkyl, hydroxy, C1 -4 alkyloxy, C1 -6 fluoroalky l, C1 -4 fluoroalkyloxy, and halo;R8b is selected from bicyclic aryl(Co-3 alkyl) and bicyclic heteroaryl(Co-3 alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms, wherein R3b is substituted by 0, 1, or 2 R3csubstituents each independently selected from C1 -4 alkyd, halo, cyano, nitro, carboxy, carboxy (C 1-6 alkyl), amino, amino(C1 -3 alkyl), hydroxy, hydroxy(C1 -6 alkyl), C1 -6 fluoroalkyl, C1 -6 fluoroalkyloxy, and C1 -6 alkyloxy; is selected from hydrogen, and Cl-4 alkyl;R10a is selected from hydrogen, hydroxy. C] -6 alkyl, C]-4 alkyloxy, and fluoro;R10b is selected from (C3-i2)cycloalkyl(Co-3 alkyl). aryl(Co-3 alkyl), and heteroaryl(Co-3 alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms, wherein R10b is substituted by 0, 1, or 2 RIOC wherein eachRl°c is independently selected from C1 -1o alkyl, C1 -io fluoroalkyl, C1 -6 haloalkyl, C 1 > 1 o fluoroalkyloxy, amino, amino(C1 -6 alkyd), (C1-6 alkyl)o-2 amino(C0-6 alkyd), (Cl -6 alky l)sN+(C0-6 alkyd), hydroxy, hydroxy(C1 -6 alkyl), cyano, cyano(C1 -6 alkyl), halo, aminocarbonyl. aminocarbonyl(C1 -6 alkyl), (C1 -6 alkyl)o-2 aminocarbony d(C0-6 alkyl), (C 1 -6 alkyd)o-2 aminocarbonydamino(C0-6 alkyl), (C 1-6 alkyl)carbonylamino(C0-6 alkyl), carboxy (C0-6 alkyl), ( C1 -6 alkoxy)carbony 1(CQ-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6 alkyl), -(CQ-5 alky d)-(S(=O)2OH), -(CQ-5 alky d)-(S(=O)2NH2), amino(C0-6 alky d)oxy(C0-6 alkyd), (C1 -6 alkyl)o-2 amino(C0-6 alkyl)oxy(C0-6 alkyl), (Cl -6 alkyl)3N+(C0-6 alkyl)oxy(C0-6 alkyd), (C1 -6 alky d)oxy(C0-6 alkyl), C1 -6 haloalkyloxy, (C3-i2)cycloalkyl(C0-6 alkyd), heterocycloalkyl(C0-6 alkyd), -(CH2)0-6-O(CH2)0-6-NH-(X1)] -2-X2-X3-U1-U2-Z. and -(CH2)0-6-NH-(X1)i-2-X2-X?-U1-U2-Z;Rlla is selected from hydrogen, hydroxy, C1 -6 alkyl, C1 -4 alkyloxy, and fluoro;Rllb is selected from aryl(Co-3 alkyl), heteroaryl(Co-3 alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms, and H2N-C(=NH)NH-(C1 -6 alkyl), wherein Rllb is substituted by 0, 1, or 2, 3, or 4 Rlld substituents each independently selected from C1 -6 alkyl, amino, amino(C1 -6 alkyl), (C1-6 alkyl)o-2 amino(C0-6 alkyl), (C1-6 alkyl)3N+(C0-6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), cyano, cyano(C1 -6 alkyl), halo, amino(C0-6 alkyl)aminocarbony 1, aminocarbonyl, aminocarbonyl(C1-6 alkyl), (C1 -6 alky d)o-2 aminocarbonyl(C0-6 alkyl), carboxy(CQ-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6alkyl), ammo(C0-6 alkyl)oxy(C0-6 alkyl). (C1 -6 alkyl)o-2 amino(C0-6 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)3N+(C0-6 alkyl)oxy(C0-6 alkyl), -(C0-5 alkyl)-(S(=O)2NH2), (C1 -6alkyl)oxy(C0-6 alkyl), (C1 -6 fluoroalkyl)oxy(C0-6 alkyl), C1 -6 haloalkyloxy, C1 -6 haloalkyl, (C3-i2)cycloalkyl(C0-6 alkyl), heterocycloalkyl(C0-6 alky l), ((C 1-6 alkyl)carbonyl)heterocycloalkyl(Co-10 alkyl). ((C i -6 alkyl)carbonyloxy)heterocycloalkyl(CQ-io alkyl), -C(=O)NH-(CH2)2-6-NH-(X1)i-2- X2-X3-U1-U2-Z, -(CH2)0-6-O(CH2)0-6-NH-(X,)i-2-X2-X?-U1-U2-Z, -(CH2)0-6-R12a is selected from hydrogen, hydroxy, amino, C1 -io alkyl and (C3-i2)cycloalkyl(C0-6 alkyl);R12b fsselected from hydrogen, Cl- 10 alkyl and (C3-12)cycloalkyl(C0-6 alkyl), wherein Ri2aand R12b, together with the atoms to which they are attached, may form a saturated ring;R13a is selected from hydrogen, hydroxy, C1 -6 alkyl, C1 -4 alkyloxy, and fluoro;R13b is selected from hydrogen, and C1 -4 alkyl;R13C is selected from a bicyclic nitrogen-containing heteroaryl having 1 or 2 nitrogen and bicyclic-aryl and wherein Rl3cis substituted independently by 0, 1, or 2 R13d substituents each independently selected from Cl-6 alkyd, amino(C0-6 alkyl), carboxy(Co-4 alkyl), halo, C1 -4 haloalkyl, C1 -4 haloalkyloxy, C1 -4 alkyloxy, and - (CH2)0-6-NH-(X1) 1 _2-X2-X3-U1-U2-Z;R14 is selected from hydrogen, amino(C0-6 alkyl), and -(CH2)0-6~NH-(X1)i-2-X2-X3-U1-U2-Z;R14a is selected from amino, hydroxy, (C1 -6 alkyl)o-2amino, and C1 -6 alkyloxy;R14b is selected from hydrogen, C1 -8 alkyl, arjd(C0-6 alkyl), and heteroaryl(C0-6 alkyl), wherein R14b is substituted by 0, 1, 2. or 3 halo groups, q1is selected from 0, 1, 2, 3, or 4; p1is selected from 0, 1, 2, 3, or 4; p is selected from 0, 1, or 2; q is selected from 0, 1 or 2;Each X1is independently absent or selected fromC(=O) (CH2)a(O(CH2)2)b N+(CH3)2(CH2)e NH }, C(=O) (CH2)a (O(CH2)2)d-NH-} , -C(=O)-(CH2)e-N (C H3)2-(CH2)I-NH-} , -C(=O)-(CH2)a- (O(CH2)2)b-N (CH3)2-(O(CH2)2)g-NH-}, and -C(=O)-(CH2)h-phenyl-(CH2)i- NH-}, where -} is point of attachment with the group X2;Each X2is independently absent or selected from-C(=O)-(CH2)a-(O(CH2)2)d-NH-},and - C(=O)-(CH2)h-phenyl-(CH2)i-NH-}, where -} is point of attachment with the group X3;Each X3is independently absent or -C(=O)-(CH2)a-(O(CH2)2)d-NH-}, where -} is point of attachment with the group U1;point of attachment with the group U2;Each U2is independently absentpoint of attachment with the group Z;Each Z is selected from1) C(=O)CH32) -C(=O)-(CH2)m-C(=O)-OH,3) -C(=O)-(CH2)m-CH3,4) -C(=O)-(CH2)m-CH2-OH,5) -C(=O)-(CH2)m-S(=O)2-OH,6) -C(=O)-(CH2)m-tetrazolyl,), wherein Z1is selected from hydrogen, halo, Cl -6 alkyd, Cl-6 haloalkyl, Cl-6 haloalky doxy, (C3-12)cycloalky d(C0-6 alkyd), (C3-i2)cycloalkyl(C0-6 alkyloxy), aryl(C0-6 alkyl), and aryl(C0-6 alkydoxy)., wherein Z2is selected from hydrogen, halo, Cl-6 alkyl. Cl -6 haloalkyl, aryl(CQ-6 alkyl), and aryl(CQ-6 alkyloxy),Each a is independently 1 or 2;Each b is independently 0 through 6;Each c is independently 2 through 6;Each d is independently 1 through 24;Each e is independently 1 through 6;Each f is independently 2 through 6;Each g is independently 0 through 6;Each h is independently 0 through 2;Each i is independently 0 throgh 2;Each j is independently 1 through 6;Each k is independently 0 through 4;Each 1 is independently 0 through 2;Each m is independently 10 through 20;Each n is independently 0 through 4; and provided that: a) only 1, 2 or 3 of the substituents selected from Rla, R3b R4C R5U R?b R5d R5C RIOC Rllb, Rlld R13danc| R14 ha\ e a -(X1)i-2-X2-X3-U1-U2-Z component. b) only one of R3a, R3b, R3dorR5e has a -(X1)i-2-X2-X3-U1-U2-Z component, and c) only one ofR"c. or R^ has a-(X1)j-2-X2-X3-U1-U2-Z component.

[0014] In a first embodiment of the invention, R1 is selected from hydrogen, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, phenyl, phenylmethyl, phenylethyl, phenylpropyl, styryl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidyl. pyrazinyl, imidazolyl, pyrazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, biphenylmethyl, naphthylmethyl, pyridylmethyl, pyridazinylmethyl, pyrimidylmethyl, pyrazinylmethyl, imidazolylmethyl, pyrazolylmethyl, furylmethyl, thiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, oxadiazolylmethyl, bicyclo[l. 1.1 Jpentyl, (bicyclo[l .1. 1 ,]pentyl)methyl, phenylcarbonylaminoethyl,aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, aminocarbonylisopropyl, aminocarbonylbutyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, aminocarbonylaminobutyl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, w-pentyl, isopentyl, neopentyl, w-hexyl, isohexyl, n-heptyl, w-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, adamantyl, carboxy, carboxymethyl, carboxyethyl, azidomethyl, azidoethyl, azidopropyl, phenylaminocarbonylmethyl, pyridylaminocarbonylmethyl, (pyridylcarbonylamino)methyl, guanidino, guanidinomethyl, guanidinoethyl, guanidinopropyl, guanidinobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, pentafluoropropyl, heptafluoropropyl, trifluorobutyl, N.N.N- trimethylmethy lammonium, N, N,N-tri methyl eth- 1 -ylammonium, AtyV,N-tri methyl propan- 1 - ylammonium, N,N.N-trimethylbut-l -ylammonium, methylamino, methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, dimethyl amino, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, ethylamino, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, ethylaminobutyl, diethylamino, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl, aminoethoxy, aminoethoxymethyl, isoxazolylcarbonylaminomethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclopropoxymethyl, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, vinyl, prop-2-enyl, but-3-enyl, and pent-4-enyl, and the other groups are as provided in the general Formula (I) above.

[0015] In a second embodiment of the invention, R1 is selected from hydrogen, 3-aminopropyl, 4-aminobutyl, phenyl, phenylmethyl, bicyclofl. l.l.]pentyl, phenylcarbonylaminoethyl, aminocarbonylmethyl, aminocarbonylaminoethyl, methyl, ethyl, w-propyl, / / -butyl, isobutyl, isopentyl, M-pentyl, «-hexyl. 1 -azidoethyl. 2-azidoethyl. azidopropyl. 3-azidopropyl, pyridylaminocarbonylmethyl, 3-guanidinopropyl, 2,2-difluoropropyl, 4,4,4-trifluorobutyl, NJ JV- trimethylpropan-1 -ylammonium, methylaminopropyl, dimethylaminopropyl, isoxazolylcarbonylaminomethyl, ethoxy, methoxymethyl, prop-2-enyl, cyclopropylmethoxy, and aminoethoxy, and the other groups are as provided in the general Formula (I) above or as in the first embodiment.

[0016] In a third embodiment of the invention,Rla substituents are each independently selected from C1-6 alkyl, amino, cyano, halo, hydroxy, -(CH2)0-6-NH-(X1)]-2-X2-X3-U1-U2-Z, -(CH2)0-6-NH-(X1)I.2-Z, -(CH2)0-6-NH-(X1)i-2-U1-Z. and -(CH2)0-6-NH-(X1)i-2- X2L'1L'2Z. and the other groups are as provided in the general Formula (I) above or as in the first through second embodiments.

[0017] In a fourth embodiment of the invention, eachR2a is independently selected from hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, and the other groups are as provided in the general Formula (I) above, or as in the first through third embodiments.

[0018] In a fifth embodiment of the invention, eachR2a is hydrogen or methyl, and the other groups are as provided in the general Formula (I) above, or as in the first through fourth embodiments.

[0019] In a sixth embodiment of the invention,R2b is selected from phenyl, benzyl, biphenyl, naphthyl, pyridyl, pyridazinylpyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and bicyclo[l.l.l]pentyl, and the other groups are as provided in the general Formula (I) above, or as in the first through fifth embodiments.

[0020] In a seventh embodiment,R2b is selected from phenyl, pyridyl, and the other groups are as provided in the general Formula (I) above, or as in the first through sixth embodiments.

[0021] In an eighth embodiment, each R2C is independently selected from aminomethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tertbutyl, fluoro, chloro, bromo, iodo, aminoethoxy, N-methvlaminoethoxv, 'V-ethvlaminoethoxy. N,N-dimethylaminoethoxy,, carboxy, carboxymethoxy,(carboxymethoxy )methyl, aminocarbonyl, MAMimethylaminocarbonyL aminocarbonylmethyl, - 0(CH2)o-6-NH-(X1)i-2-X2-X?-U1-U2-Z, -(CH2)o-6-NH-(X1)i-2-X2-X3-U1-U2-Z, -(CH2)O- 6-NH-X1-Z, -(CH2)O-6-NH-(X1)1-2-X2-U2-Z, -(CH2)O-6-NH-(X1)1-2-X2-U1-U2-Z, - O(CH2) 0-6-NH-Z, -O(CH2) 0-6-NH-(X1)I_2-X2-X3-U2-Z, -O(CH2) 0-6-NH-(X1)i-2-X2- U^U^Z, -O(CH2) o-b-NH-X’-X^XMj’-l^-Z, and -O(CH2) o-fi-NH-X^X^U^Z, and the other groups are as provided in the general Formula (I) above, or as in the first through seventh embodiments.

[0022] In a ninth embodiment, each R2C is independently selected from aminomethyl, aminoethoxy ,-O(CH2) 0-6-NH-(X1) | .2-X2-X3-U’-U2-Z, -(CH2)Q-6-NH-(X1)I ^-X^X3^1- U2-Z, -(CI I2)0-6-NI I-X'-Z. -(CH2)0-6-NH-(X1)i-2-X2-U2-Z, -(CH2)o-6-NH-(X1)i-2-X2- U^U^Z, -O(CH2) 0-6-NH-Z, -O(CH2) 0-6-NH-(X1)l-2-X2-X3-U2-Z, -O(CH2) 0-6-NH-(X’li^-XW-l^-Z, -O(CH2) 0-6-NH-X1-X2-X3-U1-U2-Z, and -O(CH2) o^-NH-.X'-.X2- L1Z. and the other groups are as provided in the general Formula (I) above, or as in the first through eighth embodiments.

[0023] In a tenth embodiment of the invention,R3a is selected from hydrogen, methyl, ethyl, n- propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, aminoethyl, aminopropyl, aminobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy methyl, carboxy ethyl, carboxypropyl, carboxybutyl, thioethyl, and thiopropyl, wherein R3amay be substituted by 0, 1, or 2 R3C substituents each independently selected from fluoro, chloro, methyl, ethyl, w-propyl. isopropyl, cyclopropyl, w-butyl, sec-butyl, tert-butyl, amino, aminomethyl, iV-methylamino, N- methylaminomethyl, A-ethylamino. X-ethylaminomethyl, AAV-dimethylamino. N,N- dimethylaminomethyl, N,N-diethylamino, A'.A'-diethylarninomethyl. AAAAV-trimethylammonium. A'.A'.A'-trimethylmethylammonium. hydroxy, hydroxymethyl. -SChCHs, -CH2SO2CH?, - CH2CH2SO2CH3, cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxy, carboxymethyl, and carboxyethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through ninth embodiments.

[0024] In a eleventh embodiment of the invention,R3a is selected from hydrogen, methyl, ethyl, propyl, 2-methylpropyl, butyl, aminoethyl, 2-aminoethyl, aminopropyl, 3-aminopropyl, hydroxyethyl, 2-hydroxyethyl, hydroxy propyl, 2-hydroxypropyl, 3-hydroxypropyl, carboxyethyl, 2-carboxyethyl, and thioethyl, wherein R3amay be substituted by 0, 1 , or 2 R3csubstituents each independently selected from methyl, isopropyl, cyclopropyl, amino, N-methylamino, hydroxy ,-SO2CH3. -CH2SO2CH3, cyano, methoxy, and carboxy, and the other groups are as provided in the general Formula (I) above, or as in the first through tenth embodiments.

[0025] In a twelfth embodiment of the invention,R3b is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, w-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmetyl, cyclopentylmethyl, cyclohexylmethyl, bicyclo[I.I. I]pentylmethyl, hydroxymethyl, 1- hydroxy ethyl, 2-hydroxyethyl, hydroxypropyl, 3-hydroxypropyl, 1 -methyl- 1 -hydroxy ethyl, hydroxyisopropyl, hydroxybutyl, methoxymethyl, methoxy ethyl, methoxypropyl, ethoxymethyl, ethoxy ethyl, aminomethyl. 2-aminoethyl, A'-methylaminomethyl. N,N-dimethylaminomethyl, N- methylaminoethyl. A'.A'-dimeths laminoethyl. N-methylaminopropyl, A’.A’-dimethylaminoprops l. 1 -aminopropyl, 2-aminopropyl, 3-aminopropyl, 2-aminoprop-2-yl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, benzy l, 3-pyridinylmethyl, 4-pyridinylmethyl. imidazolylmethyl, thiazolylmethyl, oxazolylmethyl. thiophenylmethyl, furanylmethyl, pyrazolylmethyl, A'-pyra / oly I methyl. 1 -phenylethyl, l-(4-pyridinyl)ethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, (N,N- dimethyl)aminocarbonylmethyl, (N,jV-dimethyl)aminocarbonylethyl, thiomethyl, thioethyl, thiopropyl. -CH2CH2SO2CH3. carboxymethyl, carboxyethyl, 2-carboxyethyl, carboxypropyl, 3- carboxypropyl, carboxybutyl, 4-carboxybutyl, piperazinylmethyl, morpholinomethyl, piperidinylmethyl, azetidinylmethyl, tetrahydropyranylmethyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, and aminocarbonylaminobutyl, wherein R3b may be substituted by 0, 1, or 2 R3csubstituents each independently selected from fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, ra-butyl, .sec-but l, tert-butyl, amino, aminomethyl, N-methylamino. N-methylaminomethyl, N-ethylamino, / V-ethylaminomethyl. N,N- dimethylamino, N,jV-dimethylaminomethyl, N,N-diethylamino, / V.A'-diethylaminomethyl. N,N.N- trimethylammonium, N.ACV-trmiethyl methyl ammonium, hydroxy, hydroxymethyl, -SO2CH3, - CH2SO2CH3, -CH2CH2SO2CH3, cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxy, carboxymethyl, and carboxy ethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through eleventh embodiments.

[0026] In a thirteenth embodiment of the invention,R3b is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, rc-butyl, cyclopropyl, cyclobutyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl. hydroxypropyl, 3 -hydroxy propyl, 1 -methyl- 1 -hydroxy ethyl, methoxy ethyl, aminomethyl. 2-aminoethyl, / V-methylaminomethyl. 1-methyl-l -aminoethyl, 2- aminoprop-2-yl, 1 -phenylmethyl, benzyl, imidazolylmethyl, thiazolylmethyl, aminocarbonylmethyl, aminocarbonylethyl, thiomethyl, -CH2CH2SO2CH3, carboxymethyl, 2- carboxyethyl, 3-carboxypropyl, 4-carboxybutyl. piperazinylmethyl. and aminocarbonylaminopropyl, wherein R3bmay be substituted by 0, 1, or 2 R3C substituents each independently selected from methyl, isopropyl, cyclopropyl, amino, / V-methyl amino, hydroxy, -SO2CH3, -CH2SO2CH3, cyano, methoxy, and carboxy, and the other groups are as provided in the general Formula (I) above, or as in the first through twelfth embodiments.

[0027] In a fourteenth embodiment of the invention,R3a and R3b together with the atoms to which they are attached, form a saturated ring system substituted by 0, 1, or 2, R3csubstituents and the unsubstituted or substituted ring system is selected from:Formula (I) above, or as in the first through thirteenth embodiments.

[0028] In a fifteenth embodiment of the invention,R3a and R3b. together with the atoms to which they are attached, form a saturated ring system substituted by 0, 1, or 2, R3csubstituents and the unsubstituted or substituted ring system is selected from:the other groups are as provided in the general Formula(I) above, or as in the first through fourteenth embodiments.

[0029] In a sixteenth embodiment of the invention,R4a is selected from hydrogen, methyl, ethyl, propyl, hydroxy, methoxy, and fluoro, and the other groups are as provided in the general Formula (I) above, or as in the first through fifteenth embodiments.

[0030] In a seventeenth embodiment of the invention,R4a is hydrogen, and the other groups are as provided in the general Formula (I) above, or as in the first through sixteenth embodiments.

[0031] In an eighteenth embodiment of the invention,R4b is selected from indolyl, naphthyl, quinolinyl, pyrrolo[2,3-6]pyridinyl, [l,2,4]triazolo[l,5-«]pyridine, 17 / -pyrazolo [3, 4- >] pyridine, indazolyl, benzothiazolyl, and benzothiophenyl, wherein R4bsubstituted with 0, 1, or 2 R4C substituents each independently selected from fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, methyl, ethyl, propyl, isopropyl, aminoethyl, aminopropyl, aminobutyl, carboxy, carboxymethyl, and carboxy ethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through seventeenth embodiments.

[0032] In a nineteenth embodiment of the invention, R4bis selected from indolyl, and pyrrolo[2,3-Z?]pyridinyl, R4bsubstituted with 0, 1, or 2 R4Csubstituents each independently selected from aminopropyl and carboxymethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through eighteenth embodiments.

[0033] In a twentieth embodiment of the invention,R5a is selected from hydrogen, methyl, ethyl, w-propyl. isopropyl, cyclopropyl, / 7-butyl. isobutyl, cyclobutyl, w-pentyl, isopentyl, neopentyl, cy clopentyl, cy clobutyl, cyclopropylmethyl, cyclopropy lethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, phenyl, benzyl, phenylethyl, phenylpropyl, oxazolylmethyl, thiazolylmethyl, imidazolylmethyl, triazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl, oxazolyl ethyl, thiazolylethyl, imidazolylethyl, triazolylethyl, oxadiazolylethyl, thiadiazolylethyl, oxazolylpropyl, thiazolylpropyl, imidazolylpropyl, triazolylpropyl, oxadiazolylpropyl, thiadiazolylpropyl, azetidinylmethyl, azetidinylethyl, oxetanylmethyl, oxetanylmethyl. pyrrolidinylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, tetrahydropyranylmethyl, tetrahydropyranylmethyl, hydroxy ethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, 3- hydroxy-2.2-dimethylpropyl, cyclopropylmethyl, 1 -hydroxypropan-2-yl, 2-hydroxy ethyl, 3- hydroxypropyl, 2-hydroxyisopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-aminoethyl,3-aminopropyl, 3-amino-2,2-dimethylpropyl, cyclopropylmethyl. 4-aminobutyl, aminomethylcarbonylaminoethyl, aminoethylcarbonylaminoethyl, aminomethylcarbonylaminopropyl, aminoethylaminocarbonylmethyl, aminoethylaminocarbonylethyl, aminoethylaminocarbonylpropyl, aminohexylcarbonylaminoethyl, aminohexylcarbonylaminoethyl. (N-methylamino)ethyl, (N- methylamino)propyl, (W-ethylamino)ethyl. (MA-diethylamino)propyL (N,N- dimethylamino)ethyl, (N^V-dimethylamino)propyl, (N,N-diethylamino)ethyl, (N,N- diethylamino)propyl, (XJVrX-trimethylammonium)ethyl, (A\AdAA-trimethylarmnonium)propyl. (N,jVW-triethylammonium)ethyl, (A'.A'.A'-triethylammonium)propyl. (N- methylamino)methylcarbonylaminoethyl, (A-methylamino)ethylcarbonylaminoethyl. (N- methylamino)methylcarbonylaminopropyl, (A’-ethylamino)methylcarbonylaminoethyl. (N- ethylamino)ethylcarbonylaminoethyl, (N-ethylamino)methylcarbonylaminopropyl, (N- methylamino)pentylcarbonylaminoethyl, (N-methylamino)pentylcarbonylaminoethyl, (N- methylamino)pentylcarbonylaminopropyl. (X.A'-dimethylamiiio)methylcarbonylaminoethyl. (,V.,'V-dimethylamino)ethylcarbonylaminoethyl. (N,N- dimethylamino)methylcarbonylaminopropyl, (N,N-diethylamino)methylcarbonylaminoethyl, (NN-diethylamino)ethylcarbonylaminoethyl, (Ar,N-diethylamino)methylcarbonylaminopropyl. (AAA-dimethylamino)penlylcarbonylaminoethyl. (A'. / V-dimethylammo)pentylcarbonylaminoethyl. (AAV-dimethy lamino)penty Icarbonylaminopropy 1, N, AOV-trimethy 1-ethan- 1 -ammonium, NJ'LN- trimethyl-propan- 1 -ammonium, (N,N,N-trimethyl ammoni um)methyl carbonyl aminoethyl , (N,jV,N-trimethylammonium)ethylcarbonylaminoethyl,trimethylammonium)methylcarbonylaminopropyl, (N,N,N- trimethylammonium)ethylcarbonylaminopropyl,trimethylammonium)pentylcarbonylaminoethyl, (N,N,N- tnmethylammonium)pentylcarbonylaminopropyl. (carboxymethyl)oxyethyl, (carboxymethyl)oxypropyl, -(C H2)0-6~NH-(X1) 1 -2-X2-X3-U1-U2-Z, -(CH2)0-6-O(CH2)0-6- NH-CX^i^-X^X3-!!1-!!2- / , and -(CH2)0-6-Ph-(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, wherein R3ais substituted by 0. 1, 2, or 3substituents each independently selected from chloro, fluoro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, «-propyl, isopropyl, n- butyl, isobutyl, cyclobutyl, w-pentyl, isopentyl, neopentyl, carboxy, carboxymethyl, carboxyethyl, methoxy, ethoxy, methoxymethyl, methoxy ethyl, methoxypropyl, amino, aminomethyl, aminoethyl, / V-methylamino. (N-methylamino)methyl, (N-methylamino)ethyl. A’.A-dimethylamino. (N,N-dimethylamino)methyl, (MAMmielhylamino)ethyl. / V.X-diethylamino.(NJV-diethylamino)methyl, (A / .A'-dielhylamino)ethyl. aminopropyl, aminobutyl, aminomethylcarbonylamino, aminoethylcarbonylamino, aminopentylcarbonylamino, aminomethylcarbonylaminomethyl, aminoethylcarbonylaminomethyl, (N- methylamino)methylcarbonylamino. (jV-methylamino)ethylcarbonylamino. (N- methylamino)methylcarbonylaminomethyl, (N-methylamino)ethylcarbonylaminomethyl, (N,N- dimethylamino)methylcarbonylamino, (MAMmiethylamino)ethylcarbonylamino. (N,N- dimethylamino)methylcarbonylaminomethyl, (N,N-dimethylamino)ethylcarbonylaminomethyl, (N,jV-diethylamino)methylcarbonylamino, (N,N-diethylamino)ethylcarbonylamino,diethylamino)methylcarbonylaminomethyl, (N,N-diethylamino)ethylcarbonylaminomethyl, NNN-trimethylammonium, (ACVjV-trmiethylammonium)methyl. (N,N,N- trimethylammonium)ethyl, (MAA.Af-lrimethylammonium)ethoxy.trimethylammonium)ethoxymethyl, (N,N,jV-trimethylammonium)methylcarbonylamino, (N,N,N- triethylammonium)methylcarbonylamino, (N,jV.N-trimethylammonium)ethylcarbonylamino. (NJVJV-trimethylammonium)pentsdcarbonylamino, (N,N,N- trimethylammonium)methylcarbonylaminomethyl, (N,NN- trimethylammonium)ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazoyl, tetrazoylmethyl, tetrazoylethyl, carboxymethoxy, carboxy ethoxy, carboxymethoxymethyl, carboxy ethoxymethyl, -(CH2)0-6-O(CH2)0-6-NH-(X1)l-2-X2-X3-U1-U2-Z, and -(CH2)0-6~ NH-(X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (I) above, or as in the first through nineteenth embodiments.

[0034] In a twenty-first embodiment of the invention, R$ais selected from hydrogen, methyl, ethyl, n-propyl, 2-hydroxy ethyl, 3-hydroxypropyl, carboxymethyl, 2-carboxy ethyl, 3- carboxypropyl. 2-hydroxy ethyl, 2-hydroxy- 1 -methylethyl, hydroxypropyl, 3-hydroxy-2,2- dimethylpropyl, 2-aminoethyl. 3-aminopropyl, (X.A'-dimethylaminolethyl. aminoethoxyethyl, (carboxymethyl)oxyethyl, -(CH2)0-6~NH-(X1)i-2-X2-X3-U1-U2-Z, -(CH2)0-6-O(CH2)0-6- NH-CX^I^-X^X’-U'-U^Z, and -(CH2)0-6-Ph-(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, wherein R3ais substituted by 0, 1 , 2, or 3 R3d substituents each independently selected from fluoro, hydroxy, hydroxymethyl, methyl, amino, N,jV-dimethylamino,-(CH2)0-6-O(CH2)0-6~ NH-CX^i^-X^-U^-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (I) above, or as in the first through twentieth embodiments.

[0035] In a twenty-second embodiment of the invention, R$b isselected from hydrogen, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl,cyclobutyl, cyclopropylmethyl, oxetanylmethyl. tetrahydrofurylmethyl, tetrahydropyranylmethyl, hydroxymethyl, hydroxyethyl, hydroxy propyl, methoxy methyl, methoxyethyl, methoxypropyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, (carboxymethoxy )methyl, (carboxy methoxy )ethyl, (carboxyethoxy)methyl, (carboxyethoxy)ethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, GV-methylamino)methyl. ( / V-methylamino)ethyl. (N- methylamino)propyl, (iV-methylamino)butyl, (MA'-dimethylamino)methyl. (N,N- dimethylamino)ethyl, (iV^V-dimethylamino)propyl, (N,N-dimethylamino)butjd, (N,N- diethylamino)methyl, (Nr / V-diethylamino)ethyl, (N,N-diethylamino)propyl, (N,N- diethylamino)buty 1, AGV. / V-trimethylmethan- 1 -ylammonium, N,N,N-trimethylethan- 1 - ylammonium, NWW-triethylethan- 1 -ylammonium, / V.AGAr-trimethylpropan- l -ylammonium, N, N, N-tri methylbutan- 1 -ylammonium, (N,N, Af- tri methyl ammoni um)ethoxy methyl, (NJVJV- trimethylammonium)ethoxyethyl, (N,N,jV-triethylammonium)ethoxyethyl, (N,N,N- trimethylammonium)ethoxypropyl, (A'.A'.Af-trimethylammonium)ethoxybutyl. aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, aminocarbonylbutyl, (N- methylamino)carbonylmethyl, (N-methylamino)carbonylethyl, (A'-methylamino)carbony 1 propyl, ( / V-methylamino)carbonylbutyl. (N,N-dimethylamino)carbonylmethyl, (N,N- dimethylamino)carbonylethyl, (N,N-dimethylamino)carbonylpropyl, (NN- dimethylaminofcarbonylbutyl. aminomethylcarbonylaminoethyl, aminomethylcarbonylaminopropyl, aminoethylcarbonylaminoethyl, aminoethylcarbonylaminopropyl, ( A.Ar-dimethylamino)methylcarbonylaminoethyl. (NJV- dimethylamino)methylcarbonylaminopropyl, (Ar.Ar-dimethylamino)ethylcarbonylaminoethyl. (N,jV-dimethylamino)ethylcarbonylaminopropyl, (NNN- trimethylammonium)methylcarbonylaminoethyl, (N,NJ^ / - triethylammonium)methylcarbonylaminoethyl, (N,N,N- trimethylammonium)methylcarbonylaminopropyl, (N,N,N- trimethylammonium)ethylcarbonylaminoethyl, (N,N,N- trimethylammonium)ethylcarbonylaminopropyl, (A / .A'.A,-trimeth\iammonium)ethoxyethyl. (NNN-trimethylammonium)ethoxypropyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3, 3, 3 -trifluoropropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanoisopropyl, cyanobutyl, - (CH2) 1 -e-NH-tX1) 1 -2-X2-X3-Ul-U2-Z, and -(CH2) 1 -6-O(CH2)0-6-NH-(X1) i .2~X2-X3-Ul- U2-Z, whereinR5b is substituted by 0, 1, 2, or 3 R3esubstituents each independently selected from chloro, fluoro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, isopropyl, w-butyl. isobutyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, carboxy, carboxymethyl, carboxyethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxy propyl, amino,aminomethyl, aminoethyl. N-methylamino, (A'-methylamino)methyl. (N-methylamino)ethyl. A’.X-dimethylamino. (N,N-dimethylamino)methyl, (NN-dimethylamino)ethyl, AtyV-diethylamino, ( / V.,V-diethylamino)methyl. (jV,N-diethylamino)ethyl, aminomethylcarbonylamino, aminoethylcarbonylamino, aminopentylcarbonylamino, aminomethylcarbonylaminomethyl, aminoethylcarbonylaminomethyl, (N-methylamino)methylcarbonylamino, (N- methylamino)ethylcarbonylamino, (.'V-methylamino)methylcarbonylaminomethyl. (N- methylamino)ethylcarbonylaminomethyl, (N,N-dimethylamino)methylcarbonylamino, (N,N- dimethylamino)ethylcarbonylamino. (.'V.A'-dimethylamino)methylcarbonylaminomethyl. (N,N- dimethylamino)ethylcarbonylaminomethyl, (N,N-diethylamino)methylcarbonylamino, (NN- diethylamino)ethylcarbonylamino, (TVW-diethylamino)methylcarbonylaminomethyl, (N,N- diethylamino)ethylcarbonylaminomethyl, N,N,N-trimethylammonium,trimethylammonium)methyl, (NNrX-trimethylammonium)ethyl, (Aty\tyV- trimethylammonium)ethoxy. ( N.N, N-trimethylammonium)ethoxy methyl, (AtyVW- trimethylammonium)methylcarbonylamino. (AGV. / V-trielhylammonium)melhylcarbonylamino. (NNN-trimethylammonium)ethylcarbonylamino, (NJVJV- tnmethylammonium)pentylcarbonylamino. (Aty\tyV- trimethylammonium)methylcarbonylaminomethyl, (NNN- trimethylammonium)ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazoyl. tetrazoylmethyl, tetrazoylethyl, carboxy methoxy, carboxy ethoxy, carboxymethoxymethyl, carboxy ethoxymethyl, -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6- NH-(X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-first embodiments.

[0036] In a twenty-third embodiment of the invention, R3b is selected from hydrogen, 2- hydroxyethyl, 2-carboxyethyL 2-aminoethyl, 4-aminobutyl. (AtyV-dimethylamino)ethyl, aminoethoxy ethyl, -(CH2)l-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)l-6-O(CH2)0-6-NH- (X1)i-2-X2-X3-U1-U2-Z. wherein R3b is substituted by 0. 1, 2, or 3 R3esubstituents each independently selected from fluoro, hydroxy, hydroxymethyl, methyl, carboxy, amino, ACX- dimethylamino-(CH2)0-6-O(CH2)0-6-NH-(X')i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH- (X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-second embodiments.

[0037] In a twenty-fourth embodiment of the invention, R5C is hydrogen, methyl, or ethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-third embodiments.

[0038] In a twenty-fifth embodiment of the invention, R3cis hydrogen, or methyl, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty - fourth embodiments.

[0039] In a twenty-sixth embodiment of the invention, R3aand R3b together with the atoms to which they are attached, form a saturated mono- or bi-cyclic ring system substituted with 0, 1, 2, or 3 R3d and 0, 1, 2, or 3 R$esubstituents, wherein said mono- or bi-cyclic unsubstituted or substituted ring system is selected from:NH-CX^i^-X^-U^U2- / , or -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixteenth and the twenty -first through the twenty-fifth embodiments.

[0040] In a twenty-seventh embodiment of the invention, R3aand R3b, together with the atoms to which they are attached, form a saturated mono- or bi-cyclic ring system substituted wi th 0, 1 , 2, or 3 R5dand 0, 1, 2, or 3 R5« substituents, wherein said mono- or bi-cyclic unsubstituted or substituted ring system is selected from:the other groups are as provided in the general Formula (I) above, or as in the first through the sixteenth and the twenty-first through the twenty-sixth embodiments.

[0041] In a twenty-eighth embodiment, R3ais selected from hydrogen, hydroxy, methyl, ethyl, propyl, and methoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the twenty-seventh embodiments.

[0042] In a twenty-ninth embodiment. R3ais selected from hydrogen, and the other groups are as provided in the general Formula (I) above, or as in the first through the twenty -eighth embodiments.

[0043] In a thirtieth embodiment,R6b is selected from hydrogen, hydroxy, methyl, ethyl, propyl, methoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the twenty -ninth embodiments.

[0044] In a thirty-first embodiment, R3b is selected from hydrogen, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirtieth embodiments.

[0045] In a thirty-second embodiment. R3cis selected from aminocarbonyl, (aminocarbonyl)methyl, (aminocarbonyl)ethyl, (aminocarbonyl)propyl, (N- methylamino)carbonyl, (N-methylamino)carbonylmethyl, (N-methylamino)carbonylethyl, (N- methylamino)carbonylpropyl, (AfA imethylamino)carbonyl. (NN- dimethylamino)carbonylmethyl, (N,N-dimethylamino)carbonylethyl, (N,N- dimethylamino)carbonylpropyl, (N,N-diethylamino)carbonyl. (N.N- diethylamino)carbonylmethyl, (#.;V-diethylamino)carbonylethyl. (N,N- diethylamino)carbonylpropyl, aminocarbonylamino, (aminocarbonylamino)methyl, (aminocarbonylamino)ethyl, (aminocarbonylamino)propyl, methoxy, methoxymethyl, methoxyethyl, ethoxy, ethoxymethyl, ethoxyethyl, methylsulfonyl, (methylsulfonyl)methyl, (methylsulfonyl)ethyl, (methylsulfonyl)propyl, amino, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, carboxy, carboxymethyl, carboxyethyl, hydroxy, hydroxymethyl, hydroxy ethyl, hydroxypropyl, hydroxyisopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methyl,ethyl, isopropyl, n-propyl. isobutyl, / r-butyl. sec-butyl, isobutyl, tert-butyl, phenyl, and benzyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty -first embodiments.

[0046] In a thirty -third embodiment. R3cis aminocarbonyl and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-second embodiments.

[0047] In a thirty -fourth embodiment,R7a is selected from hydrogen, methyl, ethyl, hydroxy, methoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty -third embodiments.

[0048] In a thirty-fifth embodiment,R7a is selected from hydrogen, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-fourth embodiments.

[0049] In a thirty-sixth embodiment, R3b is selected from phenyl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 3-oxoisoindolinyl, and bicyclo[l.l.l]pentyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-fifth embodiments.

[0050] In a thirty -seventh embodiment, R3b is selected from phenyl, and pyridyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-sixth embodiments.

[0051] In a thirty -eighth embodiment of the invention, R3cis selected from fluoro, chloro, bromo, iodo, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, carboxy, carboxymethyl, methoxycarbonyl, methoxy carbonylmethyl, ethoxycarbonyl, carboxy methoxy, carboxyethoxy, carboxymethoxymethyl, aminocarbonyl, aminocarbonylmethyl, (N,N- dimethylamino)carbonyl, (W.A-dimethylamino)carbonylmethyl. amino, aminomethyl, N,N- dimethylamino, (N,N-dimethylamino)methyl, (NrV-diethylamino)methyl. N,N,N- trimethylammonium, A,.A'..'V-tnmethylmethylammonium. AfACAMriethyhuethylammonium. methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, -SO2OH -CH2SO2OH, - SO2NH2, -CH2SO2NH2, aminoethoxy, aminoethoxymethyl, (NJV-dimethylamino)ethoxy, NJVJV- trimethyleth-l-oxy-ammonium, aminocarbonylamino, and aminocarbonylaminomethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirtyseventh embodiments.

[0052] In a thirty-ninth embodiment of the invention, R3cis carboxy, and aminocarbonylamino, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-eighth embodiments.

[0053] In a fortieth embodiment,R8a is selected from hydrogen, methyl, ethyl, hydroxy, methoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty -ninth embodiments.

[0054] In a forty -first embodiment, R3ais hydrogen, and the other groups are as provided in the general Formula (I) above, or as in the first through the fortieth embodiments.

[0055] In a forty-second embodiment of the invention,R8b is selected from indolyl, naphthyl, indolylmethyl, naphthylmethyl, quinolinyl, pyrrolo[2,3-6]pyridinyl, indazolyl, benzothiazolyl, and benzothiophenyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty -first embodiments.

[0056] In a forty-third embodiment of the invention, R3b is indolyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty -second embodiments.

[0057] In a forty-fourth embodiment of the invention, each R3cindependently is selected from methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, cyano, amino, aminomethyl, nitro, hydroxy, hydroxymethyl, carboxy, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, methoxy, ethoxy, and trifluoromethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-third embodiments.

[0058] In a forty-fifth embodiment of the invention, each R3cindependently is selected from chloro, and cyano, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty- fourth embodiments.

[0059] In a forty-sixth embodiment of the invention, R3 is selected from hydrogen, methyl, ethyl, and propyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty- fifth embodiments.

[0060] In a forty-seventh embodiment of the invention, R3 is hydrogen or methyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-sixth embodiments.

[0061] In a forty-eighth embodiment of the invention. R ^a isselected from hydrogen, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy, and the other groups are asprovided in the general Formula (1) above, or as in the first through the forty-seventh embodiments.

[0062] In a forty-ninth embodiment of the invention, R *0ais hydrogen and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-eighth embodiments.

[0063] In a fiftieth embodiment of the invention, R10b is selected from phenyl, benzyl, biphenyl, biphenylmethyl, pyridyl, pyridylmethyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, imidazolylmethyl, pyrazolyl, furyl, furylmethyl, oxazolyl, oxazolylmethyl, thiazolyl, indolyl, [ 1 ,2,4]triazolo[ 1 ,5-fl| pyridine, and bicyclofl. l.l]pentyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-ninth embodiments.

[0064] In a fifty-first embodiment of the invention, R10b is selected from phenyl, and pyrimidyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the fiftieth embodiments.

[0065] In a fifty-second embodiment, each R10C is independently selected from methyl, ethyl, nl-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, fluoro, chloro, bromo, iodo, hydroxy, hydroxymethyl, hydroxyethyl, cyano, amino, aminomethyl, aminoethyl, N-methylamino, (N- methylamino)methyl, (N-methylamino)ethyl, AtyV-di methyl amino, (AtyV-dimethylamino)methyl, (NN-dimethylamino)ethyl,N,N,N-trimethylammonium, N,N,N-l-nmethylmethan-ylammonium. aminocarbonyl, aminocarbonylmethyl, aminocarbonylethyl, (N-methylamino)carbonyl, (N- methylamino)carbonylmethyl, N,N,-Ndi-methylamino)carbonyl. (N,N- dimethylamino)carbonylmethyl, aminocarbonylamino, aminocarbonylaminomethyl, methylcarbonylamino, methylcarbonylaminomethyl, carboxy, carboxymethyl, carboxyethyl, methoxycarboxy, carboxymethoxy, carboxy ethoxy, carboxymethoxymethyl, carboxyethoxymethyl, -S(=O)2OH, -CH2(S(=O)2OH), -S(=O)2NH2, -CH2(S(=O)2NH2), aminoethoxy, aminopropoxy, (N-methylamino)ethoxy, (N-ethylamino)ethoxy, (N,N- dimethylamino)ethoxy, ( / V.A-dielhylamino)ethoxy. (N,N,N-trimethylammonium)ethoxy. methoxy, ethoxy, methoxymethyl, ethoxymethyl, difluoromethoxy, trifluoromethoxy, and 2,2,2- trifluoroethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the fifty-first embodiments.

[0066] In a fifty -third embodiment, each RIOC is independently selected from carboxy, aminocarbonyl, amino, aminomethyl, and -SO2NH2, and the other groups are as provided in the general Formula (1) above, or as in the first through the fifty-second embodiments.

[0067] In a fifty -fourth embodiment of the invention,Rlla is selected from hydrogen, hydroxy, methyl, ethyl, methoxy, and ethoxy, and the other groups are as provided in the general Formula (1) above, or as in the first through the fifty -third embodiments.

[0068] In a fifty -fifth embodiment of the invention,Rlla is hydrogen and the other groups are as provided in the general Formula (I) above, or as in the first through the fifty -fourth embodiments.

[0069] In a fifty -sixth embodiment, Rl l bis selected from (H2N-C(=NH)-NH)methyl, (H2N- C(=NH)-NH)ethyl, (H2N-C(=NH)-NH)propyl, (H2N-C(=NH)-NH)butyl, phenyl, benzyl, pyridinyl, pyridinylmethyl, indolyl, indolylmethyl, pyridazinyl, pyridazinylmethyl, pyrimidyl, pyrimidylmethyl, pyrazinyl, pyrazinylmethyl, imidazolyl, imidazolylmethyl, pyrazolyl, pyrazolylmethyl. | l.2.4|tnazolo| l.5-o|pyndme. oxazolyl. oxazolylmethyl, thiazolyl, and thiazolylmethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the fifty-fifth embodiments.

[0070] In a fifty-seventh embodiment. Rllb is phenyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the fifty -sixth embodiments.

[0071] In a fifty-eighth embodiment of the invention, each RH3 is independently selected from fluoro, chloro, bromo, iodo, (carboxymethyl)oxy, (carboxymethyl)oxymethyl, (carboxyethyl)oxy, hydroxy, hydroxymethyl, hydroxy ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, carboxy, carboxymethyl, aminocarbonyl, aminocarbonylmethyl, (methylcarbonyl)aminomethyl, (methylcarbonyl)aminoethyl, (TV-methylamino)carbonyl, (N- methylamino)carbonylmethyl, (N,jV-dimethylamino)carbonyl, (N.N- dimethylamino)carbonylmethyl, amino, X-methylamino. AtyV-dimethylamino, AtyV-diethylamino. aminomethyl, (NN-dimethylamino)methyl, (NrV-diethylamino)methyl, N,N,N- trimethylammonium, N,N,N-trimethylmeth- 1 -yl-ammonium, N,N,N-tri ethylammonium, N,N,N- triethylmeth-l-yl-ammonium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, aminoethoxy, aminopropoxy, aminoethoxymethyl. (AtyV-dimethylamino)ethoxy, A’.N.#-tnmethyleth-l-ylo\y-ammonium. cyano, methyl carbonylpiperazyl [(iV-acetyl)piperazyl ], -C(=O)NH-(CH2)2-6-NH-(X1) 1.2-X2-X3-UJ-U2-Z, -(CH2)0-6-O(CH2)0-6-NH-(X1) 1 _2-hydrogen or -(X1)i-2-X2-X?-U1-U2-Z, and the other groups are as provided in the general Formula (I) above, or as in the first through the fiftyseventh embodiments.

[0072] In a fifty -ninth embodiment of the invention, each Rlld is independently selected from hydroxy, aminomethyl, aminoethoxy, carboxy, -C(=O)NH-(CH2)2-6-NH-(X1)i-2-X2-X3-U1- U2-Z, -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X?-U1-U2-Z, -(CH2)0-6-NH-(X1)i-2-X2-X?-U2-Z, and the other groups are as provided in the general Formula (I) above, or as in the first through the fifty-eighth embodiments.

[0073] In a sixtieth embodiment of the invention,R12a is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, and isopropyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the fifty-ninth embodiments.

[0074] In a sixty-first embodiment of the invention, R^a jsmethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixtieth embodiments.

[0075] In a sixty-second embodiment, Rl3b selected from hydrogen, methyl, ethyl, and propyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty-first embodiments.

[0076] In a sixty-third embodiment, R * 2b jshydrogen, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty -second embodiments.

[0077] In a sixty-forth embodiment of the invention,R12a and R12b together with the atoms to which they are attached form a saturated ring selected from, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty -third embodiments.

[0078] In a sixty-fifth embodiment of the invention,ancj Rl2b together with the atoms to which they are attached formthe other groups are as provided in the generalFormula (I) above, or as in the first through the sixty-forth embodiments.

[0079] In a sixty-sixth embodiment, R^3ais hydrogen or methyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty -fifth embodiments.

[0080] In a sixty-seventh embodiment, Ris hydrogen or methyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty-sixth embodiments.

[0081] In a sixty-eighth embodiment, R13Cis selected from indolyl, pyrrolo[2,3-6]pyridinyl, quinolinyl, indazolyl, and naphthyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty -seventh embodiments.

[0082] In a sixty -ninth embodiment, R13C is indolyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty-eighth embodiments.

[0083] In a seventieth embodiment, each Ri33 independently is selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxy, carboxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty-ninth embodiments.

[0084] In a seventy -first embodiment, each R^d independently is selected from aminopropyl, and methoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the seventieth embodiments.

[0085] In a seventy -second embodiment, each R *4a independently is selected from amino, hydroxy, N-methyl amino, 7f,N-dimethylamino, .V-ethylamino. methoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the seventy-first embodiments.

[0086] In a seventy -third embodiment, each R'4a independently is amino, and the other groups are as provided in the general Formula (I) above, or as in the first through the seventy-second embodiments.

[0087] In a seventy -fourth embodiment, each R*4b independently is selected from hydrogen, methyl, ethyl, propyl, isopropyl, w-butyl. sec-butyl, isobutyl, w-pentyl, isopentyl, neopentyl, trifluoromethyl, trifluoroethyl, phenyl, benzyl, chlorophenyl, dichlorophenyl, fluorophenyl, difluorophenyl, bromophenyl, iodophenyl, chlorobenzyl, di chlorobenz l, fluorobenzyl, difluorobenzyl. bromobenzyl, iodobenzyl, naphthyl, naphthylmethyl, pyrazolyl, pyrazolylmethyl, indolyl, indolylmethyl. imidazolyl, imidazolylmethyl, pyridyl, and pyridylmethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the seventy- third embodiments.

[0088] In a seventy-fifth embodiment, each R* 4b independently is selected from hydrogen, methyl, ethyl, and phenyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the seventy -fourth embodiments.In a seventy-sixth embodiment, each R* 4 independently is selected from hydrogen, and - (CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (I) above, or as in the first through the seventy-fourth embodiments.

[0089] In a seventy-seventh embodiment, the compound of Formula (la) or a pharmaceutically acceptable salt thereof is:R1 is selected from hydrogen, C1 -20 alkyl, amino(Co-10 alkyl), aryl(C()-10 alkyl), heteroaryl(Co-10 alkyl), (C3-i2)cycloalkyl(Co-10 alkyl), heterocycloalkyl(Co-10 alkyl). C1 -io fluoroalkyl, wherein R1 is substituted by 0. 1, 2, or 3 Rlasubstituents each independently selected from Cl-6 alkyl, amino, azido, cyano, halo, hydroxy, (C3- 12)cycloalkyloxy, Cl-6 alkyloxy, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z ; eachR2a is independently selected from hydrogen, methyl, ethyl and propyl;R2b is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said heteroaryl contains at least one nitrogen atom, wherein R3b issubstituted by 0. 1, or 2 R3cindependently selected from Cl-6 alkyl, amino(Co- 6 alkyl), (Cl-6 alkyl)o-2amino(C0-6 alkyl), (Cl -6 al yd)3N+(C0-6 alkyl), aminocarbonyl(C0-6 alkyl), (C 1-6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), hydroxy, C l-6 alkyloxy, halo, (Cl-6 alkyl)o-2 amino(C0-6 alkyloxy), (Cl-6 alkyl)?N+(C0-6 alkyloxy), (C1-6 alkyloxy)carbonyl(C0-6 alkyl), carboxy(C0-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6 alkyl), halo, Cl-6 haloalkyl, Cl-6 haloalkyloxy. C1 -6 alkyloxy. -O(CH2) 0-6-NH-(X1)i- 2-X2-X3-U1-U2-Z, and -(CH2)O-6-NH-(X1)I.2-X2-X3-U1-U2-Z;R3 is selected from hydrogen, hydroxy, hydroxy(Cl-6 alkyl), amino, amino(Cl-6 alkyl), Cl -10 alky l, (C3-i2)cycloalkyl(Co-10 alkyl). (C0-6 alkyl)thio(C1 -6 alkyl), and carboxy(C1 -6 alkyd), wherein R3amay be substituted by 0, 1, or 2 R3csubstituents;R3b is selected from hydrogen, C1 -10 alkyl, hydroxy(C1 -6 alkyl), amino(C1 -6 alkyl), (Cl-6 alkyl)o-2 amino(Cl-6 alkyd), (Cl-6 alkyd)3N+(Cl-6 alkyl), halo, Cl-6 haloalky l, aryl(C0- 10 alkyl). heteroaryl(C0-6 alkyl), (C3-i2)cycloalkyl(C0-6 alkyl), heterocycloalkyl(C0-6 alkyl), (Cl-6 alkyl)oxy(Cl-6 alkyl), (C3-12)cycloalkyloxy(Cl-6 alkyl), carboxy(Cl-6 alkyd), aminocarbonyl(C 1 -6 alkyl), (Cl-6 alkyl)o-2 aminocarbonyl(C1 -6 alkyl),aminocarbonylamino(C1 -6 alkyl). (C1 -6 alkyl)o-2 aminocarbonylamino(C 1 -6 alkyl), (Co-6 alky l)thio(C 1-6 alkyl), (C1 -6 alkyl)SO2(C1 -6 alkyd), and (C1 -6 alkyd)sulfmyl(C1 -6 alkyl), wherein R3bmay be substituted by 0, 1 , or 2 R3csubstituents, each R3cis independently selected from halo, C1 -6 alky l, amino, (C1 -6 alkyl)o-2 amino(C()-6 alkyl), (C1-6 alkyl)sN+-, (C 1 _g alkyl)S02(C0-6 alkyl), cyano, cyano(C1 -6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), (C 1 -6 alky l)oxy(C0-6 alky l), aminocarbonyl(C0-6 alkyl), and (CQ. 6) carboxy(C0-6 alky l); whereinR3a and R3b. together with the atoms to which they are attached, may form a saturated ring system, wherein said saturated ring system may be substituted by 0, 1, or 2 R3csubstituents;R4ais hydrogen;R4b is selected from bicyclic heteroaryl(Co-3 alkyl), and bicyclic aryd(Co-3 alky l), wherein R4b is substituted with 0, 1, or 2 R4c substituents each R4c independently selected halo, hydroxy, cyano, nitro, carboxy, carboxy(Cl-6 alkyd), (Cl -6 alkyd oxy)carbonyl(C0-6 alkyd), Cl -6 alkyloxy, (Cl -6 alkyl)oxy(Cl-6 alkyl), Cl -6 alkyl, Cl -6 haloalkyl, and -(CH2)0-6-NH-(X1) 1 -2-X2-X3-U1-U2-Z;R5a is selected from hydrogen, Cl- 10 alkyd, C1 -io fluoroalkyl, carboxy(C1 -io alkyl), hydroxy, hydroxy(C1 -io alkyl), cyano(C1 -io alkyl), (C3-i2)heterocycloalkyl(Co-10 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C1 -6 alkyl), (carboxy(C1 -io alkyl))oxy(C1 -6 alkyl), amino(C0-6 alky l)aryl(C 1 -6 alkyl), aryl(CQ-6 alkyl), (C3-i 2)cycloalkyl(C0-6 alkyl), heteroaryl(C0-6 alkyd), (C1 -6 alkyl)oxy(C1 -6 alkyl), (C1 -6 alkyd oxy)carbonyl(C0-6 alkyl), amino, amino(C1 -6 alkyl). (C1-6 alkyl)o-2 amino(C0-6 alkyl). amino(C2-6 alkyl)oxy(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C2-6 alkyl)oxy(C1 -6 alkyd), amino(C1 -6 alky d)carbony damino(C1 - 6 alkyl), amino(C1 -6 alkyl)carbonylamino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C1 -6 alkyl)carbonylamino(C1 -6 alkyl), (C1 -6 alkyl)3N+(C2-10 alkyd), (C1 -6 alky d)3N+(C1 -6 alkyd)carbonylamino(C1 -6 alkyl), C1 -io fluoroalkyl, -(CH2)0-6~NH-(X1)i-2-X2-X3- U'-U2-Z. -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-Ph- (CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z and wherein R3ais substituted by 0, 1, or 2 R5d substituents;R5b is selected from hydrogen, C1 -io alkyl, hydroxy(C1 -iQ alkyl), carboxy(C1 -6 alkyd), (C1 -6 alkyl)oxy(C1-6 alkyl), aminocarbonyl(C1 -6 alkyl), (C 1-6 alkyl)o-2 aminocarbonyl(C1 -6 alkyl), carboxy(C1 -io alky l)oxy(C 1-6 alkyl), cyano(C1 -6 alkyl), amino(C1 -6 alkyl), (C 1- 6 alky l)o-2 amino(Cl-6 alkyl), (Cl -6 alky d)o-2 amino(C2-6 alky l)oxy(C 1-6 alkyl), amino(C1 -6 alkyl)carbonylamino(C1-6 alkyl), (amino(C2-6 alkyl)oxy(C1 -6 alkyl), C1 -6 alky l)o-2 amino(Cl-6 alky l)carbonylamino(C 1 -6 alkyl), (Cl -6 alkyl)3N+(C2-6 alkyl)oxy(C1-6 alkyl), (C1 -6 alkyl)3N+(C1 -6 alkyl)carbonylamino(C1 -6 alkyl). (Cl -6 alkyl)3N+(Cl-6 alkyl), (heterocycloalkyl(C()-10 alky l), (C3-12)cycloalkyl(Co-10 alkyd), C1 -10 haloalkyl,-(CH2)l-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z. and -(CH2)1- 6-NH-(X1)i-2-X2-X3-U1-U2-Z, wherein R$b is substituted by 0, 1, 2, or 3 R$esubstituents, whereinR5a and R3b, together with the atoms to which they are attached, form a saturated mono- or bi-cyclic ring, wherein said mono- or bi-cyclic ring is substituted with 0, 1. or 2, R3d and 0, 1, 2, or 3 R3esubstituents; eachR5d is independently selected from selected from halo, hydroxy, hydroxy(C1 -6 alkyl), C1 - 10 alkyl, carboxy, carboxy (C 1-6 alkyd), C1 -6 alkyloxy, (C1 -6 alkyl)oxy(C1-6 alkyl), amino, amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl), amino(C1 -6 alkyl)carbonylamino(C0-6 alkyl), (C1 -6 alkyl)o-2 amino(C1 -6 alkyl)carbonylamino(C0-6 alkyl), (C1 -6 alkyl)3N+(C0-6 alkyl), (Cl -6 alkyl)3N+(C2-6 alkyl)oxy(C0-6 alkyl). (C1-6 alkyl)3N+(C1 -6 alkyl)carbonylamino(C0-6 alkyl), (carboxy(C1 -6 alkyl))oxy(C0-6 alkyl), cyano(C0-6 alkyl), tetrazolyl(C0-6 alkyd), and C1 -6 haloalky 1, amino(C2-6 alky d)oxy(Co- 6 alkyl), (C1 -6 alkyd)o-2 amino(C2-6 alkyl)oxy(C0-6 alkyl), -(CH2)0-6-O(CH2)0-6-NH- (X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z; and two R5dsubstituents together with the atom they are attached to may join together to form a saturated ring; eachR5e is independently selected from halo, hydroxy, hydroxy(C1 -io alkyl), C1 -io alkyl, carboxy, carboxy(C1 -6 alkyd), C1 -6 alkydoxy, (C1-6 alkyl)oxy(C1 -6 alkyl), amino, amino(C1 -6 alkyl). (C1-6 alkyl)o-2 amino(C0-6 alkyl). amino(C1 -6 alky l)carbonylamino(C 0-6 alkyl), (C1 -6 alkyl)o-2 amino(Cl-6 alkyl)carbonylamino(C0-6 alkyd), (C1 -6 alkyd)3N+(C0-6 alkyl), (C1 -6 alkyl)sN+(C2-6 alkyl)oxy(C0-6 alkyl). (C1-6alkyl)3N+(C1 -6 alkyl)carbonylarmno(C0-6 alkyl), (carboxy(C 1 -6 alkyl))oxy(C1 -6 alkyl). cyano(C0-6 alkyl), tetrazolyl(C0-6 alkyl), C1 -6 haloalkyl, (CH2)0-6 O CH2)0-6 NH (X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and two R5esubstituents together with the atom they are attached to may join together to form a saturated ring;R6C is selected from Cl-10 alky l, Cl-6 alkyloxy, (Cl-6 alkyl)oxy(Cl-6 alkyl), Cl-10 haloalkyl, aryl(C0-6 alkyl), heteroaryl(Co-lt) alkyl), (Cl-6 alkyl)S02(C0-6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), amino(C0-6 alkyl), (Cl-6 alkyl)o-2 amino(CQ-6 alkyl), aminocarbonyl(C0-6 alkyl), (C 1-6 alkyl)o-2 aminocarbonyl(C0-6 alkyl). (Cl-6 alkyl)carbonylamino(C0-6 alkyl), (Cl-6 alkyl)o-2 aminocarbonylamino(CQ-6 alkyl), and carboxy(C0-6 alkyl);R3b isselected from aryl(C0-4 alkyl), heteroaryl(C )-4 alky l) wherein said heteroaryl contains at least one nitrogen, and (C3-i2)cycloalkyl(C0-4 alkyl), wherein R3b is substituted by 0, 1, or 2, R3csubstituents each independently selected from Cl-6 alkyl, Cl-6 fluoroalkyl, carboxy(C0-6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), amino, aminocarbonylamino(C0-6 alkyd), and halo;R8a is hydrogen;R8b is selected from bicyclic aryl(Co-3 alkyl) and bicyclic heteroaryl(Co-3 alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms, wherein R3b issubstituted by 0. 1, or 2 Rcsubstituents each independently selected from C1 -4 alkyl, halo, cyano, nitro, carboxy, carboxy(C1 -6 alkyl), amino, amino(C1 -3 alkyl), amino, hydroxy, hydroxy(Cl-6 alkyl). Cl-6 fluoroalkyl, Cl-6 fluoroalkyloxy, and Cl-6 alkyloxy;R10b is selected from (C3-12)cycloalkyl(Co-3 alkyl). aryl(Co-3 alkyl), and heteroaryl(C()-3 alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms, wherein R10b is substituted by 0, 1 , or 2 RIOC wherein each RIOC is independently selected from C1 - 10 alkyl, C1 -io fluoroalkyl, Cl-6 haloalkyl, C1 -io fluoroalkyloxy, amino, amino(Cl-6 alkyd), (Cl-6 alkyl)o-2 amino(C0-6 alkyd), (Cl-6 alkyl)sN+(C0-6 alkyd), hydroxy, hydroxy(C1 -6 alkyl), cyano, cyano(C1 -6 alkyl), halo, aminocarbonyl. aminocarbonyl(C1 -6 alkyl), (Cl-6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), (Cl-6 alkyl)o-2aminocarbonylarmno(C0-6 alkyl). (C1 -6 alkyl)carbonylamino(C0-6 alkyl), carboxy (C0-6 alkyd), (C1 -6 alkoxy)carbonyl(C0-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6 alkyl), -(CQ-5 alky 1)-(S(=O)2OH), -(CO-5 alkyl)-(S(=O)2NH2), amino(C0-6 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)3N+(C0-6 alky l)oxy(C0-6 alkyd), (C 1-6 alkyd)oxy(C0-6 alkyl), C1 -6 haloalkyloxy. (C3-i2)cycloalkyl(C0-6 alkyd), heterocycloalkyl(C0-6 alkyd), -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X’ ) i-2-X2-X3-U’-U2-Z;Rllb is selected from aryl(Co-3 alkyd), heteroary d(Co-3 alkyl), wherein said heteroary 1 contains 1. 2, or 3 nitrogen atoms, and H2N-C(=NH)NH-(C1 -6 alkyl), wherein Rllb is substituted by 0, 1, or 2, 3, or 4 Rlld substituents each independently selected from Cl -6 alkyl, amino, amino(C1 -6 alkyl), (Cl -6 alkyl)o-2 amino(C0-6 alkyl), (Cl -6 alky l)sN+(C 0-6 alkyl), hydroxy, hydroxy(Cl-6 alkyl), cyano, cyano(Cl-6 alkyl), halo, amino(C0-6 alkyl)aminocarbonyl, aminocarbonyl, aminocarbonyl(C1-6 alkyl), (Cl -6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), carboxy(C0-6 alkyd), carboxy(C1 -6 alky d)oxy(C0-6 alkyd), amino(C0-6 alkyl)oxy(C0-6 alkyl), (Cl -6 alkyl)o-2 amino(C0-6 alkyl)oxy(CQ-6 alkyl), (Cl -6 alkyl)3N+(C0-6 alkyl)oxy(C0-6 alkyl), -(CO-5 alkyl)-(S(=O)2NH2), (Cl -6 alkyd)oxy(C0-6 alkyl), (C1 -6 fluoroalkyl)oxy(C0-6 alkyl), C1 -6 haloalkyloxy, C1 -6 haloalkyl, (C3-i2)cycloalkyl(C0-6 alkyl), heterocycloalkyl(C0-6 alkyl), ((Cl -6 alkyd)carbonyl)heterocycloalkyl(Co-10 alkyl), ((C1 -6 alkyl)carbonyloxy)heterocycloalkyl(Co-10 alkyl), -C(=O)NH-(CH2)2-6-NH-(X1)i-2- X^-U^-Z, -(CH2)0-6-O(CH2)0-6-NH-(X1) 1 _2-X2-X3-U1-U2-Z, -(CH2)0-6-2-Z;R12ais C1 -10 alkyl;R12b jsselected from hydrogen, C1 -6 alkyl, and (C3-i2)cycloalkyl(C0-6 alkyl), wherein Rl2aand R> 2b together with the atoms to which they are attached, may form a saturated ring;R13a is selected from hydrogen, hydroxy, C1 -6 alkyl, C1 -4 alkyloxy, and fluoro;R!3C is selected from a bicyclic nitrogen-containing heteroaryl having 1 or 2 nitrogen and bicyclic-aryl and wherein Rl3cis substituted independently by 0. 1, or 2 Rl3d substituents each independently selected from C1 -6 alkyd. amino(C0-6 alkyl), carboxy(Co-4 alkyd), halo, C1 -4 haloalkyl, C1 -4 haloalkyloxy, C1 -4 alkydoxy, and -(CH2)0-6-NH-(X1) 1 -2-X2-X3-U1-U2-Z;R14 is selected from hydrogen, amino(C0-6 alkyl), and -(CH2)0-6~NEI-(X1)I.2-X2-X?-U1-U2-Z; p is selected from 0, 1, or 2; q is selected from 0, 1 or 2;Each X1is independently absent or selected from(O(CH2)2)b-N+(CH3)2-(CH2)e-NH-} ,-C(=O)-(CH2)a-(O(CH2)2)d-NH-} , -C(=O)-(CH2)c-N+(CH3)2-(CH2>NH-}, -C(=O)-(CH2)a-(O(CH2)2)b-N+(CH3)2-(O(CH2)2)g-NH-}, and -C(=O)-(CH2)h-phenyl-(CEl2)i-NH-}, where -} is point of atachment with the group X2;Each X2is independently absent or selected from-C(=O)-(CH2)a-(O(CH2)2)d-NH-},and - C(=O)-(CH2)h-phenyl-(CH2)i-NH-}, where -} is point of atachment with the group X3;Each X3is independently absent or -C(=O)-(CH2)a-(O(CH2)2)d-NH-} where -} is point of atachment with the group U1;point of attachment with the group U2;Each U2is independently absentpoint of attachment with the group Z ;Each Z is selected from1 C(=O)CH3,, wherein Z1is selected from hydrogen, halo, Cl -6 alkyl.Cl-6 haloalkyl, Cl-6 haloalkyloxy, (C3-12)cycloalkyl(C0-6 alkyl), (C3- 12)cycloalkyl(C0-6 alkyloxy), aryl(C0-6 alkyl), and aryl(C0-6 alkyloxy),, wherein Z2is selected from hydrogen, halo, Cl-6 alkyl, C1 -6 haloalkyl, aryl(C0-6 alkyl), and aryl(CQ-6 alkyloxy),Each a is independently 1 or 2;Each b is independently 0 through 6;Each c is independently 2 through 6;Each d is independently 1 through 24;Each e is independently 1 through 6;Each f is independently 2 through 6;Each g is independently 0 through 6;Each h is independently 0 through 2;Each i is independently 0 throgh 2;Each j is independently 1 through 6;Each k is independently 0 through 4;Each 1 is independently 0 through 2;Each m is independently 10 through 20;Each n is independently 0 through 4; and provided that: a) only 1, 2 or 3 of the substituents selected from Rla, R3b R4C R5a R5b R5d R3e. R!®C. RUb, Rlld R13danc] R14 havea -(X1)i-2-X2-X3-U1-U2-Z component. b) only one of R3a, R3b R3d. or R3ehas a -(X1)i-2-X2-X3-U1-U2-Z component, and c) only one of RUb RHC, or RUd has a-(X1)i-2-X2-X3-U1-U2-Z component.

[0090] In a seventy-eighth embodiment, R1 is selected from hydrogen, C1 -20 alkyl, and amino(Co-10 alkyl), wherein R1 is substituted or unsubstituted by a -(CH2)0-6-NH-(X1)i-2- X2-X3-Ul-\J2-Z group, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh embodiment.

[0091] In a seventy -ninth embodiment, each R3ais independently hydrogen or methyl, and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the seventy -eighth embodiments.

[0092] In an eightieth embodiment,R2b is aryl or heteroaryl, wherein said heteroaryl contains at least one nitrogen atom, such as pyridyl, wherein R3b jssubstituted by 0 or I R3c. and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the seventy -ninth embodiments.

[0093] In an eighty-first embodiment, R3cis independently amino(C0-6 alkyl), amino(C0-6 alkyloxy), -0(CH2)O-6-NH-(X1)1-2-X2-X3-U1-U2-Z, or -(CH2)0-6-NH-(X1)i-2-X2-X3-U1- U2-Z, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the eightieth embodiments. In a variant of this embodiment, R3cis independently aminomethyl, aminoethoxy, -0(CH2)o-6-NH-(X1)l-2-X2-X3-U1-U2-Z, or - (CH2)o-6-NH-(X1)i-2-X2-X3-U1-U2-Z. and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the eightieth embodiments

[0094] In an eighty-second embodiment,R3a is selected from hydrogen, hydroxy(C]-6 alkyl). amino(C1 -6 alkyl), and Cj-io alkyd, wherein R3amay be substituted by 0. 1, or 2 R3csubstituents, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the eighty-first embodiments. In variant of this embodiment, R3ais selected from hydrogen, methyl, ethyl, propyl, 2-methylpropyL butyl, aminoethyl, 2-aminoethyl, aminopropyl, 3-aminopropyl, hydroxyethyl, 2-hydroxy ethyl, hydroxypropyl, 2-hydroxypropyl, and 3-hydroxypropyl.

[0095] In an eighty-third embodiment. R3bis selected from hydrogen, hydroxy(C]-6 alkyl). (Cj-6 alkyl)S02(C0-6 alkyl), and amino(C1 -6 alkyl), C1 -io alkyl, wherein R3bmay be substituted by 0, 1, or 2 R3C substituents, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the eighty-second embodiments. In a variant of this embodiment,R3b is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, / 7-but l. hydroxymethyl, 1 -hydroxy ethyl, 2-hydroxy ethyl, hydroxypropyl, 3- hydroxypropyl, 1 -methyl- 1 -hydroxy ethyl, aminomethyl, 2-aminoethyl, 1 -methyl- 1 -aminoethyl, 2-aminoprop-2-yl. and -CH2CH2SO2CH3.

[0096] In an eighty-fourth embodiment, each R3cis selected from Cl-10 alky l, (Cl-6 alky 1)0- 2amino(C0-6 alkyl), (C]-6 alkyl)SO2(C()-6 alkyl), hydroxy, and hydroxy(C]-6 alkyl), and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the eighty-third embodiments. In a variant of this embodiment. R3csubstituents are each independently selected from methyl, isopropyl, cyclopropyl, amino, N-methylamino, hydroxy,-SO2CH3, and -CH2SO2CH3.

[0097] In an eighty-fifth embodiment, R3b is bicyclic heteroary l(Co-3 alkyl), and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the eighty -fourth embodiments. In a variant of this embodiment, R3b is indolyl or 1H- pyrrolo[2,3-d]pyridinyl.

[0098] In an eighty -sixth embodiment, R3cis carboxy, carboxy(C1 -6 alkyl) or -(CH2)o-6~NH- (X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the eighty -fifth embodiments. In a variant of this embodiment. R3cis aminopropyl, and carboxy methyl. In an eighty-seventh embodiment. R3ais selected from hydrogen. C1 -io alkyl, carboxy(C1 -io alkyl), hydroxy, hydroxy(C1 -io alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C1 -6 alkyl), (carboxy(C1 -K) alkyl))oxy(C 1 -6 alkyd), (C1 -6 alkyl)oxy(C1-6 alkyl), (C1 -6 alkyloxy )carbonyl(C0-6 alkyl), amino, amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl), amino(C2-6 alkyl)oxy(C 1 -6 alkyl), (Cl -6 alkyl)o-2 amino(C2-6 alky l)oxy(C 1-6 alkyl), -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, -(CH2)0-6-O(CH2)0-6-NH- (X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-Ph-(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the eighty-sixth embodiments. In a variant of this embodiment, R3ais selected from hydrogen, methyl, ethyl, w-propyl, 2-hydroxy ethyl, 3 -hydroxy propyl, carboxymethyl, 2- carboxyethyl, 3-carboxypropyl, 2-hydroxy ethyl, 2-hydroxy-l-methylethyl, hydroxypropyl, 3- hydroxy-2.2-dimethylpropyl, 2-aminoethyl, 3-aminopropyl, ( / V-dimethylamino)elhyl. aminoethoxyethyl, (carboxymethyl)oxy ethyl, -(CH2)0-6-NH-(X1)l-2-X2-X3-U1-U2-Z, - (CH2)0-6-O(CH2)0-6-NH-(X1)l-2-X2-X3-U1-U2-Z, and -(CH2)0-6-Ph-(CH2)0-6-NH- (X1)l-2-X2-X3-U1-U2-Z.

[0099] In an eighty-eighth embodiment, R3ais selected from hydrogen, methyl, ethyl, hydroxy ethyl, aminoethyl, dimethylaminoethyl,-(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, - (CH2)O-6-0(CH2)O-6-NH-(X1) 1 ^-X^-U’-U^Z, and -(CH2)o-6-Ph-(CH2)o-6-NH- (X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the eighty-sixth embodiments.

[0100] In an eighty-ninth embodiment, R3b is selected from hydrogen, C1 -io alkyl, hydroxy(C1 -6 alkyl), carboxy(C1 -6 alkyl), amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl), (C1 -6 alkyl)o-2 amino(C2-6 alkyl)oxy(C1 -6 alkyl), (CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and-(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the eighty-eighth embodiments.

[0101] In an ninetieth embodiment,R5b is selected from hydrogen, 2-hydroxy ethyl, 2- carboxyethyl, 2-aminoethyl, 4-aminoethyl, (tyX-dimethylamino)ethyl. (Cltyo-fi NH (X')|-2 X^-U^U2- / , and -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z. and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the eighty -eighth embodiments.

[0102] In an ninety-first embodiment, R3d is selected from hydroxy, hydroxy(C1 -6 alkyl), C1 - 10 alkyl, amino, amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl), (C1 -6 alkyl)o-2 amino(C2- 6 alkyl)oxy(C1 -6 alkyl). (CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z. and -(CH2)0-6-O(CH2)0-6- NH-(X1)i-2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the ninetieth embodiments.

[0103] In an ninety -first embodiment, R3eis selected from fluoro, hydroxy, hydroxy(C1 -6 alkyl), C1 -io alkyl, carboxy, carboxy(C1 -6 alkyl), (Cty6 alkyl)oxy, amino. amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl), (CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6~ O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z. and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the ninetieth embodiments. In a variant of this embodiment,R5e is selected from fluoro, hydroxy, hydroxymethyl, methyl, carboxy, amino. XA'-dimethylamino. (CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z. and -(CH2)0-6~ O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z.

[0104] In a ninety-second embodiment of the invention,R5a and R3b together with the atoms to which they are attached, form a saturated mono- or bi-cyclic ring system substituted with 0, 1, 2, or 3R5d and 0, 1. 2, or 3 R$esubstituents, wherein said mono- or bi-cyclic unsubstituted or substituted ring system is selected fromU2-Z, and the other groups are as provided in the general Formula (la) above, or as in the and the other groups are as provided in the seventy-seventh through the ninety-first embodiments. In a variant of this embodiment,R5a and R5b, together with the atoms to which they are attached, form a saturated mono- or bi-cyclic ring system substituted with 0, 1. 2, or 3 R3d and 0, 1. 2, or 3 R5e substituents, wherein said mono- or bi-cyclic unsubstituted or substituted ring system is

[0105] In a ninety -third embodiment of the invention, R6C is selected from C1 -io alkyl, C1 -6 alkyloxy, (C1-6 alkyl)S02(C0-6 alkyd), hydroxy, hydroxy(C1 -6 alkyl), amino(C0-6 alkyl), (CI-6 alkyl)o-2 amino(C0-6 alkyl), aminocarbonyl(C0-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonylamino(C0-6 alkyl), and carboxy(C0-6 alkyl), and the other groups are as provided in the general Formula (la) above, or as in the and the other groups are as provided in the seventy-seventh through the ninety-second embodiments. In a variant of this embodiment, R6C is aminocarbonyl(C0-6 alkyl).

[0106] In a ninety-fourth embodiment of the invention, R3b is aryl(Co-4 alkyd) or heteroaryl(Co-4 alkyl) wherein said heteroaryl contains at least one nitrogen, and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the ninety-second embodiments. In a variant of this embodiment, R3b jsphenyl or pyridyl.

[0107] In a ninety-fifth embodiment of the invention, R3cis selected from C l-6 alkyl, Cl -6 fluoroalkyl, carboxy(C0-6 alkyl), hydroxy, and hydroxy(C1 -6 alkyl), and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the ninety fourth embodiments. In a variant of this embodiment, R3cis carboxy or aminocarbonylamino.

[0108] In a ninety-sixth embodiment of the invention,R8b is selected from indolyl(Co-3 alkyl), naphthyl(Co-3 alkyl), indolyl, naphthyl, quinolinyl(Co-3 alkyl), and pyrrolo[2,3-6]pyridinyl(Co- 3 alkyl), and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the ninety-fifth embodiments. In a variant of this embodiment, R3b is indolyl.

[0109] In a ninety-seventh embodiment of the invention, each R3cindependently is selected from C1 -4 alkyl, halo, cyano, hydroxy, C] -6 fluoroalkyl, and hydroxy(C1 -6 alkyl), and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the ninety-sixth embodiments. In a variant of this embodiment,R8C is chloro or cyano. In a ninety-eighth embodiment of the invention, R^Ob is aryl(Co-4 alky l) or heteroaryl(Co-4 alkyd) wherein said heteroaryl contains 1, 2, or 3 nitrogens, and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the ninety-seventh embodiments. In a variant of this embodiment, R10b is pheny l or pyrimidyl.

[0110] In a ninety -ninth embodiment of the invention, each R1 independently selected from amino, amino(C1 -6 alky l), aminocarbony l, aminocarbonyl(C1-6 alkyl), carboxy(C0-6 alky l), - (Co-5 alkyl)-(S(=O)2NH2), -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and - (CH2)0-6-NH-(X1) -2-X2-X3-U1-U2-Z, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the ninety-eighth embodiments. In a variant of this embodiment, R10C is selected from amino, aminomethyl, carboxy, aminocarbony 1, and -(S(=O)2NH2.[OHl] In an one hundredth embodiment of the invention, Rllb is ary l(Co-4 alkyl) or heteroaryl(Co-4 alkyl) wherein said heteroaryl contains at least one nitrogen, and the othergroups are as provided in the general Formula (la) above, or as in the seventy-seventh through the ninety' -ninth embodiments. In a variant of this embodiment, Rllb is aryl(Co-4 alkyl). In another variant, Rllb is phenyl.

[0112] In an one hundred-first embodiment of the invention, each RUd independently is selected from C1 -6 alkyl, amino, amino(C1 -6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), cyano, cyano(Cl-6 alkyl), halo, amino(C()-6 alkyl)aminocarbonyl, aminocarbonyl, aminocarbonyl(Cl-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), carboxy (C0-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6 alkyl), amino(C0-6 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)o-2 amino(C()-6 alkyl)oxy(C0-6 alkyl), -C(=O)NH-(CH2)2-6-NH-(X1)i-2-X2-X3-U1-U2-Z, -(CH2)0-6- O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z,U2-Z, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the one hundredth embodiments. In a variant of this embodiment, each Rl ' independently is selected from hydroxy, aminomethyl, aminoethoxy, carboxy, -C(=O)NH- (CH2)2-6-NH-(X1)i-2-X2-X3-U1-U2-Z. -(CH2)0-6-O(CH2)0-6-NH-(X1)i.2-X2-X3-U1-U2-where R^cis hydrogen or -(X1)i-2-X2-X3-U1-U2-Z

[0113] In a one hundredth-second embodiment of the invention,R12a is hydrogen or C1 -io alkyd, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the one hundredth-first embodiments. In a variant of this embodiment,R12a is hydrogen, methyl, ethyl, propyl, butyl, isobutyl tert-butyl, isopentyd, or pentyl. In another variant,R12a is methyl.

[0114] In a one hundredth-third embodiment of the invention,R12b is hydrogen or Cl-10 alkyl, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the one hundredth-second embodiments. In a variant of this embodiment,R12b is hydrogen, methyl, ethyl, propyl, butyl, isobutyl tert-butyl, isopentyd, or penty l. In another variant, Rl3b1Shydrogen.

[0115] In a one hundredth-fourth embodiment of the invention, R13C is selected from indolyl, pyrrolo| 2.3- / dpyridinyl. quinolinyl, indazolyl. and naphthyl, and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the one hundredth-third embodiments.

[0116] In a one hundredth-fifth embodiment of the invention. R13C is selected from indolyl, and pyrrolo[2,3-Zi]pyridinyd, and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the one hundredth-third embodiments. In a variant of this embodiment, R13C is indolyl.

[0117] In a one hundredth-sixth embodiment of the invention,R13d is selected from C1 -4 alkyloxy. and -(CH2)0-6 NH-(X') |-2-X2-X3-U'-U2-Z. and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the one hundredth-third embodiments. In a variant of this embodiment,R13d is methoxy or aminopropyl, and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the one hundredth-fifth embodiments.

[0118] In a one hundredth-seventh embodiment of the invention,R13a is selected from hydrogen, and C1 -6 alkyl, and the other groups are as provided in the general Formula (la) above, or as in the seventy-seventh through the one hundredth-sixth embodiments. In a variant ofthis embodiment,R13a is hydrogen or methyl, and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the one hundredth-sixth embodiments.

[0119] In a one hundredth-eighth embodiment of the invention, R3ais hydrogen and the other groups are as provided in the general Formula (la) above, or as in the seventy -seventh through the one hundredth-seventh embodiments.

[0120] The mechanism of action (MOA) of anti-TNFa biologies such as infliximab, adalimumab, golimumab and certolizumab, involves binding to the cytokine TNFa and thus, inhibition of engagement with both TNFR1 and TNFR2. While not being bound by any specific theory, the Applicants believe that the compounds of the disclosure selectively inhibit TNFR1 to specifically attenuate the proinfl ammatory activities of TNFa-mediated TNFR1 signaling, and to spare / passively enable TNFa-TNFR2 pro-homeostatic signaling, which may confer better therapeutic efficacy than the standard of care anti-TNFa biologies.

[0121] In certain embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is selected from the group consisting of SEQ ID NOS: 2-112 as set forth in Table 1.

[0122] In specific embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is selected from the group consisting of (SEQ ID NOS 10, 14, 26, 30, 37, 42, 45, 65, 67, and 69) respectively, in order of appearance):SEQ ID NO 10,SEQ ID NO 14,SEQ ID NO 26,SEQ ID NO 30,SEQ ID NO 42,SEQ ID NO 45,SEQ ID NO 65,SEQ ID NO 67,SEQ ID NO 69, or a pharmaceutically acceptable salt thereof.DEFINITIONS

[0123] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0124] As used throughout this disclosure. ”a compound of the disclosure”. ”a compound of the present disclosure” and “a compound disclosed herein” are used interchangeably and to be understood to include the disclosed cyclic peptides and compounds of Formula (I). The compounds of Formula (I) can form salts which are also within the scope of the present disclosure. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. In addition, when a compound of Formula (I) contains both a basic moiety, such as, but not limited to an amino group, pyrrolidine or imidazole, and an acidic moiety’, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., nontoxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the compounds of Formula (I) may be formed, for example, by reacting a compound of Formula (I) with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by' lyophilization.

[0125] The term “Co” or “CO” or “Co” as employed in expressions such as “Co-6 alky l” and “C0-6 alkyl” means a direct covalent bond; or when the term appears at the terminus of a substituent, Co-6 alky l means hydrogen or C1-6 alkyl. Similarly, when an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond. For example, in the structurewherein s is an integer equal to zero, 1 or 2, the structure is T when s is zero.

[0126] “Acyl” means a -C(=O)-alkyl group, wherein alkyd is as defined below. The bond to the parent group is through the carbon atom of the carbonyl group.

[0127] “Acetyl” means the radical -C(=O)CH3.

[0128] The term “alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, dialkylamino, and trialkylammonium. and the like, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or branched and contain from about 1 to about 10 carbon atoms. In one embodiment, an alkyd group contains from about 1 to about 10 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C 1 -6 alkyl) or from about 1 to about 4 carbon atoms (C1-C4 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propy 1, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopenty l, w-hexy 1, isohexy 1 and neohexy l. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.

[0129] “Alkeny l” refers to an aliphatic hydrocarbon group containing at least one carboncarbon double bond and which may be straight or branched and having the indicated number of carbon atoms. Preferably alkenyl contains one carbon to carbon double bond, and up to four nonaromatic carbon-carbon double bonds may be present. Examples of alkenyl groups include ethenyl, propenyl, w-butenyl, 2-methyl-l-buteny 1, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

[0130] “Alkoxy” and “alkyloxy” are used interchangeably and refer to an alkyl (carbon and hydrogen chain) group linked to oxygen (R-O). Non-limiting examples of alkoxy are methoxy (CH?O-), ethoxy (CH3CH2O-) and propoxy (CH3CH2CH2O-).

[0131] "Amino’’ means a -NH2 group, which may be substituted (wherein one or both of the hydrogen atoms are replaced), as further defined herein.

[0132] “Amino acid” refers to naturally-occurring a-amino acids and their stereoisomers, as well as unnatural amino acids (such as a,a-disubstituted amino acids, P-substituted amino acids, P-amino acids and substituted amino acids) and their stereoisomers. In the sequences given for the peptides (compounds) according to the present disclosure, the amino acid residues have their conventional meaning. Thus, “G” or “Gly” is glycine, “W” or “Trp” is tryptophan, “A” or “Ala” is alanine, “S” or “Ser” is serine, and so on. It is to be understood that “d” or “D” or “D” isomers are designated by a “D” or “D” before the three-letter code or amino acid abbreviation or amino acid name, such that for example D-Ala or D-Ala or dA is the D isomer of L-alanine. Amino acid residues not encompassed by the foregoing have the definitions provided in the Abbreviation Table in the Examples section below.

[0133] “Aminocarbony l” means -C(=O)NH2, wherein the amino moiety may be substituted (wherein one or both of the hydrogen atoms are replaced), as further defined herein.

[0134] “Aryl” means a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 5-14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl, biphenyl, and naphthyl. In one embodiment of the present invention, aryl is phenyl.

[0135] “Azido” means a radical derived from an azide anion having the structure -N=N+=N\ such as, for example, 2-azidoethyland 3-azidopropyl

[0136] “Bicyclic ring system” refers to two joined rings. The rings may be fused, i.e., share two adjacent atoms, or “spirocyclic”. i.e., share only a single atom.

[0137] “Carbonyl” means a functional group composed of a carbon atom double-bonded to an oxygen atom (C=O).

[0138] “Carbonylamino” means -NHC(=O)H, wherein the amino moiety may be substituted (wherein one or both of the hydrogen atoms are replaced), as further defined herein.

[0139] “Carboxy” means a -CO2H group. The bond to the parent group is through the carbon atom of the carbonyl component.

[0140] “Celite®” (Fluka) diatomite is diatomaceous earth and can be referred to as "celite".

[0141] “Cycloalkyl” or “C3 2 cycloalkyl” means any univalent non-aromatic radical derived from a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having 3 to 12 ring carbons atoms. These non-aromatic radicals, which have 3, 4, 5, 6, 7, 8, or up to 12 carbon ring atoms may be fully saturated, or partially unsaturated. Unless stated specifically in the specification, thecy cloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Here, the point of attachment for a “cycloalkyl” to the rest of the molecule is on the saturated ring. Bicyclic cycloalkyl ring systems include fused ring systems, where two rings share two atoms (e.g, decalin), spiro ring systems where two rings share one atom (e.g.. spiro[4.5]decanyl) and bridged groups (e.g.. norbomyl).

[0142] Additional examples within the above meaning include, but are not limited to univalent radicals of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octanyl, bicyclofl. l. l]pentanyl, bicyclo[2.2.1]heptanyl, [1.1.1] -bicyclo pentane, bicyclo[3. 1.0]hexanyl, cyclohexenyl, cyclopentenyl, 1-decalinyl, spiro[2.4]heptyl, spiro[2.2]pentyl, and norbomyl.

[0143] The term “C3-8 cycloalkyl” (or “C3-C8 cycloalkyl” or “C3-8 cycloalkyl”) means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl. cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The terms “C3-7 cycloalkyl”, “C3-6 cycloalkyl”, “C5-7 cycloalkyl” and the like have analogous meanings.CH3\ _N

[0144] “Dialkylamino” means an amino (such as AJV-dimethylamino or \3( containing two alkyl groups attached to the amino nitrogen.

[0145] “Fluoroalkyl” includes mono-substituted as well as multiple fluoro-substituted linear and branched alkyl groups, up to perfluoro substituted alkyl. For example, fluoromethyl, 1,1- difluoroethyl, difluoromethyl, trifluoromethyl or 3,3,4,4,4-pentafluorobutyl are included.

[0146] “Guanidino” means a radical containing the univalent group R.2NC(=NR)NH- derived from guanidine where R independently is CQ-6 alkyl, such as 3-guanidinopropyl

[0147] “Halogen” or “halo”, unless otherwise indicated, includes fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In one embodiment, halo is fluoro ( F) or chloro (- Cl).

[0148] “Haloalky 1” refers to an alkyl group as described above wherein one or more (in particular, 1 to 10 hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups. C1 -6 haloalky I. for example, includes - CH2F, -CHF2, CF3. -CCI3. -CF2CF3, -CHFCH3. and the like.

[0149] The term “heteroalkyl” refers to an alkyl group where 1, 2, 3, or 4 of the carbon atoms is substituted by a heteroatom independently chosen from nitrogen (N), oxygen (O), or sulfur (S).

[0150] The term "heteroary . as used herein, represents a stable monocyclic, bicyclic or tricyclic ring system containing 5 to 14 ring atoms, including at least one ring heteroatom selected from nitrogen (N), sulfur (S) (including S=O and SO2) and oxygen (O), wherein at least one of the heteroatoms containing rings is aromatic. In the case of a heteroaryl ring system where one or more of the rings are saturated and contain one or more nitrogen (N) atoms, the nitrogen (N) can be in the form of quaternary amine or quaternary ammonium cation. Bicyclic heteroaryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. Heteroaryl groups within the scope of this definition include but are not limited to: azaindolyl, benzoimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzo|c / |isothiazolyl. benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, pyranyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrazolopyrimidinyl, pyridazinyl. pyridyl, pyrimidyl, pyrimidinyl. pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, 577-pyrrolo[3,4-| pyridine, thiazolyl, thienyl, triazolyl, triazinyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, and isoquinolinyl, and oxazolyl. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding / V-oxides thereof are also encompassed by this definition.

[0151] The term “heterocycloalkyl” as used herein refers to a stable and non-aromatic (including not fully aromatic, e.g., one double bond) 3- to 12-membered ring radical that comprises two to twelve ring carbon atoms and from one to six ring heteroatoms selected from nitrogen, oxygen, and sulfur. Whenever it appears herein, a numerical range such as ”3 to 12’' or “3-12” refers to each integer in the given range. For example. “3 to 12 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, etc., up to and including 12 ring atoms. In some embodiments, it is a 5 to 10 ring heterocycloalkyl. In some embodiments, it is a 4 to 10 ring heterocycloalkyl. In some embodiments, it is a 3 to 10 ring heterocycloalkyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. In some embodiments, the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding / V-o.\ide. S-oxide (S=O) or S-dioxide (SO2). One or more nitrogen atoms, if present, are optionally quatemized. The heterocycloalkyl radical is partially or fullysaturated. The heterocycloalkyl may be attached to the rest of a molecule through any atom of the ring(s).

[0152] In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 5 to about 8 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 8 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. In another embodiment, a heterocycloalkyl group is tricyclic. There are no adjacent oxygen and / or sulfur atoms present in the ring system.

[0153] Non-limiting examples of heterocycloalkyl rings include decahydroisoquinoline, dioxaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptyl, quinuclidinyl, oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenylb, eta-lactam. gamma-lactam. de / ta-lactam, Ac / a-lactone. gamma-lactone, aW / a-lactone. piperidinyl, 3-azabixyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 6-azaspiro[2.5]octanyl, azetidinyl, 2,3-dihydro-177-indenyl, dihydro- 177-indenyl, 3H- spiro[benzofuran-2’,4'-piperidinyl, 2,3-dihydro-177-pyrrolo[3,2,l-z;][l,6]naphthyridinyl, 3,4,6,7- tetrahydro-577-imidazo[4,5-c]pyridyl, 3a,5,6,6a-tetrahydro-477-pyrrolo[3.4-<7]isoxazole, diazabicyclo[3.3.2]decanyl, 2,3,4,5,6,7-hexahydroisothiazolo[5,4-c]pyridyl, hexahydro-227- pyrrolo[3,4-< / ]isothiazolyl, 3,9-diazabicyclo[3.3.2]decanyl, bicyclo[2,2,l]heptenyl, 2',3'-dihydro- 177-spiro[piperidine-4,4'-quinazolin], octahydropyrrolo[3, 4-6] [1,4] oxazinyl, (diazabicyclo[2.2. l]heptanyl), 2.5-diazabicyclo[2.2. l]heptanyl, lelrahydrobenzo|c / |thiazolyl. 4.5.6.7-tetrahydrobenzo|c / |thiazolyl. 2,3-dihydrobenzofuranyl, oxabi cyclo[2. 1.1 ]hexyl. dihydro- 5 / / -pyrrolo[3,4-< / ]thiazolyl, 4,6-dihydro-5 / / -pyrrolo[3,4-< / |thiazolyl, dihydro-5 / / -pyrrolo[3,4- c / |oxazolyl. 4,6-dihydro-577-pyrrolo[3,4-<7]oxazolyl, dihydrothiazolo[5,4-c]pyridin-5(4TZ)-yl, 6,7- dihydrothiazolo[5,4-c]pyridin-5(477)-yl, benzo|<7|imidazolyl. 17 / -enzo|c / | imidazolyl. diazaspiro[4.4]nonanyl, and 2.7-diazaspiro[4.4]nonanyl, and pyrrolidinone, and oxides thereof and all isomers thereof. In one embodiment of the invention, heterocycloalkyl rings include: piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azeridinyl, azetidinyl.

[0154] ‘‘Nitro” means a -NO2 group.

[0155] “Oxo” means an oxygen atom connected to another atom by a double bond and is represented by “=O” herein.

[0156] The term “oxy” means an oxygen (O) atom.

[0157] “Quaternary amine” or “quaternary ammonium” means positively charged radical having four functional groups attached to a nitrogen atom, such as A.A.A-trimethyl ammonium (and A,A,A-trimethylpropan-l-aminium

[0158] “Sulfinyl” means a bivalent functional group -S(=O)-.

[0159] “Sulfonyl” means a bivalent functional group -SO2-.

[0160] '’Tertiary amine” means an amine in which three carbon atoms are attached to the amino nitrogen.

[0161] The term “thio” means a sulfur (S) atom.

[0162] “Trialkylammonium” means an amino containing three alkyl groups attached to the amino nitrogen or (Cl -6 alkyl)3N+(CQ-6 alkyl)-, such as A.A.A-trimethyl ammonium (). and A,A,A-trimethylpropan-l-aminium

[0163] “Urea” means -NR-C(=O)-NR2 where R may independently be hydrogen, alkyl, aryl, for example, NHCONH2.

[0164] By “pharmaceutically acceptable” is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.

[0165] Where any amine is present in the compound, the nitrogen (N) atom may be optionally in the form of a quaternary' amine having one or more appropriate additional substitutions, as further described herein.

[0166] When any variable (e g., n, Ra, Rb, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0167] When any ring atom is specified as being optionally substituted with, or in a specified form, for example, sulfur (S) substituted with oxo groups, or nitrogen (N) in the form of a N- oxide, this does not preclude the substitution of any ring atom with the other listed optional substituents when not substituted with oxo groups or in the form of a A-oxide.

[0168] The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0169] By ‘'stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The compounds of the present invention are limited to stable compounds embraced by Formula I.

[0170] The term “compound” refers to the compound and, in certain embodiments, to the extent they are stable, any hydrate or solvate thereof. A hydrate is the compound complexed with water, and a solvate is the compound complexed with an organic solvent.

[0171] The term “in substantially purified form”, as used herein, refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g, from a reaction mixture), a natural source, or a combination thereof. The term “in substantially purified form” also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, reversed- phase preparative HPLC, recrystallization, and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan.

[0172] It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0173] When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary7skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al.. Protective Groups in Organic Synthesis (1991). Wiley, New York.

[0174] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is preceded by the adjacent functionality toward the point of attachment. For example, a “(C 1 -5 alkyl)carbonylamino(C1 -6 alky l)” substituent is equivalent to O-C-|.6alkyl-HN'^’C-i.s alkyl

[0175] Structural representations of compounds having substituents terminating with a methyl group may display the terminal methyl group either using the characters “Me”, “-Me”, “CH3”,H H“-CH3” or using a straight line representing the presence of the methyl group, e.g. , - , , i.e..have equivalent meanings.

[0176] For variable definitions containing terms having repeated terms, e.g., (CRiRj)r, where r is the integer 2, Rj is a defined variable, and Rj is a defined variable, the value of Rj may differ in each instance in which it occurs, and the value of Rj may differ in each instance in which it occurs. For example, if Rj and Rj are independently selected from the group consisting of methyl, ethyl, propyl, and buty l, then (CRjRj)2 can

[0177] Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaromatic ring described as containing from “1 to 4 heteroatoms” means the ring can contain, 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges w ithin that range. Thus, for example, a heterocyclic ring described as containing from “1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms. 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms. Similarly, C1 -6 or C 1-6 or Ci-Ce when used with a chain, for example an alky l chains means that the chain can contain 1, 2, 3, 4, 5, or 6 carbon atoms. It also includes all ranges contained therein including Ci-Cs. C1-C4, C1-C3, C1-C2. C2-C6, Cs-Ce, C4-C6. C5-C6, and all other possible combinations.

[0178] In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e., R1, RA, R2b, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.

[0179] As used herein, the term ‘'composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts.

[0180] When any variable (e.g, R2a) occurs more than one time in any constituent or in Formula (I) or other generic formulas herein, its definition on each occurrence is independent of its definition at every' other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the vanous substituents, e.g., R2a, are to be chosen in conformity' with w ell-known principles of chemical structure connectivity and stability. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, heteroaryl ring, or saturated heteroarylring) provided such ring substitution is chemically allowed and results in a stable compound. A “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic, or prophylactic administration to a subject).

[0181] The term “substituted” shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0182] The wavy line '"u"tru"use(j herein, indicates a point of attachment to the rest of the compound.

[0183] Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present disclosure.

[0184] In the compounds of the disclosure, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of the disclosure and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium ^H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of the disclosure can be prepared without undue experimentation by conventional techniques well-known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0185] The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present disclosure is acidic (or has a functional group which may be anionic), its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganicbases and organic bases. Examples of suitable inorganic cations include, but are not limited to. alkali metal ions such as Li+, Na+, and K+, alkaline earth metal cations such as Ca2+, and Mg2+, and other cations such as A13+ and Zn2+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NEl4+) and substituted ammonium ions. Examples of suitable substituted ammonium ions are those derived from methylamine, ethylamine, diethylamine, triethylamine and ethylenediamine. When a compound of the present disclosure is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable nontoxic acids, including inorganic acids and organic acids. Example of such acid addition salts include salts formed from hydrohalic acids (e.g., hydrochloric, hydrobromic, hydroiodic), formic acid, acetic acid, capric acid, and citric acid. Salts containing acetate, formate, caprate, chloride, or sodium salts are typical for use with the compounds of the present disclosure. In some embodiments, salts of compounds of the present disclosure can be formed by exchange well- known to those of ordinary' skill in the art, such as by anion exchange, e.g., replacement of trifluoroacetate ions with chloride ions.

[0186] Furthermore, compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula (I), including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds of the instant disclosure may form solvates with water (i.e., a hydrate) or common organic solvents such as, but not limited to, acetic acid or acetonitrile. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this disclosure, along with un-solvated and anhydrous forms.

[0187] Any pharmaceutically acceptable pro-drug modification of a compound of this disclosure which results in conversion in vivo to a compound within the scope of this disclosure is also within the scope of this disclosure.

[0188] The present disclosure also relates to processes for the preparation of the compounds of Formula (I) which are described in the following Examples and by which the compounds of the disclosure are obtainable.

[0189] “Treatment” and “treating” refer to all processes in which there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of a disease or disorder described herein. The terms do not necessarily indicate a total elimination of all disease or disorder symptoms.

[0190] "Preventing” or "prophylaxis” as used herein, refers to reducing the likelihood of contracting disease or disorder described herein, or reducing the severity of a disease or disorder described herein.

[0191] The terms “therapeutically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for treatment” or “an effective dose” are intended to mean that amount of a compound of the disclosure that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician. In a preferred embodiment, the term “therapeutically effective amount” means an amount of a compound of the disclosure that alleviates at least one clinical symptom in a human patient. The terms “prophylactically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for prevention” are intended to mean that amount of a compound of the disclosure that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor, or other clinician.DOSAGES OF THE COMPOUNDS OF THE PRESENT DISCLOSURE

[0192] The dosage regimen utilizing a compound of the present disclosure is selected in accordance with a variety' of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of an immunological condition, and a prophylactically effective amount, e.g., for prevention of an immunological condition.

[0193] While individual needs vary', determination of optimal ranges of effective amounts of the compound of the present disclosure is within the skill of the art. For administration to a human in the curative or prophylactic treatment of the conditions and disorders identified herein, for example, ty pical dosages of the compounds of the present disclosure can be about 0.05 mg / kg / day to about 1000 mg / kg / day. In some embodiments, a patient is administered from about 5 mg / day to about 1000 mg / day. such as from 10 mg / day. 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day. 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, or 1000 mg / day ofa compound of the present disclosure. In certain embodiments, a patient is administered from about 0.2 mg / kg to about 5 mg / kg, such as from 0.5 mg / kg, 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.5 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5 mg / kg 5.5 mg / kg, 6.0 mg / kg, 7.0 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 9.5 mg / kg or 10 mg / kg of a compound of the present disclosure. Such doses may be administered in a single dose or may be divided into multiple doses.PHARMACEUTICAL COMPOSITIONS

[0194] The compounds of the disclosure and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and particularly to humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical compositions. The term "‘subject” or “patient” includes animals, preferably mammals and especially humans, who use the instant active agents for the prevention or treatment of a medical condition.

[0195] Administering of the drug to the subject includes both self-administration and administration to the patient by another person. The subject may be in need of or desire treatment for an existing disease or medical condition or may be in need of or desire prophylactic treatment to prevent or reduce the risk of occurrence of the disease or medical condition. As used herein, a subject “in need” of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0196] The present disclosure therefore also provides the compounds of the disclosure and their pharmaceutically acceptable salts for use as pharmaceuticals, their use for selectively modulating the activity of TNFR1, and in particular, their use in the therapy and prophylaxis of the below- mentioned diseases or disorders as well as their use for preparing medicaments for these purposes. In certain embodiments, the compounds of the disclosure and their pharmaceutically acceptable salts block TNFa signaling through TNFR1.

[0197] Furthermore, the present disclosure provides pharmaceutical compositions which comprise as active component an effective dose of at least one compound of the disclosure and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives.

[0198] Thus, the present disclosure provides, for example, said compound and its pharmaceutically acceptable salts for use as pharmaceutical compositions which comprise as active component an effective dose of the compound of the disclosure and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, and the uses of saidcompound and / or a pharmaceutically acceptable salt thereof in the therapy or prophylaxis of the below-mentioned diseases or disorders, e.g., inflammatory bowel diseases (IBD), rheumatoid arthritis, juvenile rheumatoid arthritis, psoriaris, psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis and hi dradenitis suppurativa as well as their use for preparing medicaments for these purposes.

[0199] The pharmaceutical compositions according to the disclosure can be administered orally, for example, in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic, or oily solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be carried out parenterally, for example, subcutaneously, intramuscularly, or intravenously in the form of solutions or suspension for injection or infusion.

[0200] Other suitable administration forms are, for example, percutaneous or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and on its severity.

[0201] The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I). The compound of Formula (I) can be used in combination with any suitable pharmaceutical carrier or excipient. Such pharmaceutical compositions comprise a therapeutically effective amount of one or more compounds of Formula (I), and pharmaceutically acceptable excipient(s) and / or carrier(s). The specific pharmaceutic composition will suit the mode of administration. In particular aspects, the pharmaceutical acceptable carrier may be water or a buffered solution.

[0202] Excipients included in the pharmaceutical compositions have different purposes depending, for example on the nature of the drug, and the mode of administration. Examples of generally used excipients include, without limitation: saline, buffered saline, dextrose, water-for- infection, glycerol, ethanol, and combinations thereof, stabilizing agents, solubilizing agents and surfactants, buffers and preservatives, tonicity agents, bulking agents, lubricating agents (such as talc or silica, and fats, such as vegetable stearin, magnesium stearate or stearic acid), emulsifiers, suspending or viscosity agents, inert diluents, fillers (such as cellulose, dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate), disintegrating agents (such as crosslinked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose), binding agents (such as starches, gelatin, cellulose, methyl cellulose or modified cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, sugars such as sucrose and lactose, or sugaralcohols such as xylitol, sorbitol or maltitol. polyvinylpyrrolidone and polyethylene glycol), wetting agents, antibacterials, chelating agents, coatings (such as a cellulose film coating, synthetic polymers, shellac, com protein zein or other polysaccharides, and gelatin), preservatives (including vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, cysteine, methionine, citric acid and sodium citrate, and synthetic preservatives, including methyl paraben and propyl paraben), sweeteners, perfuming agents, flavoring agents, coloring agents, absorption enhancers, administration aids, and combinations thereof.

[0203] Carriers are compounds and substances that improve and / or prolong the delivery' of an active ingredient to a subject in the context of a pharmaceutical composition. Carriers may serve to prolong the in vivo activity of a drug or slow the release of the drug in a subject, using controlled-release technologies. Carriers may also decrease drug metabolism in a subject and / or reduce the toxicity of the drug. Carriers can also be used to target the delivery' of the drug to particular cells or tissues in a subject. Common carriers (both hydrophilic and hydrophobic carriers) include fat emulsions, lipids. PEGylated phospholipids, PEGylated liposomes, PEGylated liposomes coated via a PEG spacer with a cyclic RGD peptide, liposomes and lipospheres, microspheres (including those made of biodegradable polymers or albumin), polymer matrices, biocompatible polymers, protein-DNA complexes, protein conjugates, erythrocytes, vesicles, nanoparticles, and side chains for hydrocarbon stapling. The aforementioned carriers can also be used to increase cell membrane permeability of the compounds of Formula (I). In addition to their use in the pharmaceutical compositions of the present disclosure, carriers may also be used in compositions for other uses, such as research uses in vitro (e.g., for delivery’ to cultured cells) and / or in vivo.

[0204] Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; as powders or granules; as solutions, syrups, or suspensions (in aqueous or non-aqueous liquids; or as edible foams or whips; or as emulsions). Suitable excipients for tablets or hard gelatin capsules include lactose, maize starch, or derivatives thereof, stearic acid or salts thereof. Suitable excipients for use with soft gelatin capsules include for example vegetable oils, waxes, fats, semi-solid, or liquid polyols etc. For the preparation of solutions and syrups, excipients which may be used include for example water, polyols, and sugars. For the preparation of suspensions oils, e.g., vegetable oils, may be used to provide oil-in-water or water-in-oil suspensions. Excipients which promote absorption from the gastrointestinal tract, e.g., permeation enhancers, such as sodium caprate can be included. In certain situations, delayed release preparations may be advantageous and compositions which can deliver the compounds of the present disclosure in a delayed or controlled release manner mayalso be prepared. Prolonged gastric residence brings with it the problem of degradation by the enzymes present in the stomach and so enteric-coated capsules may also be prepared by standard techniques in the art where the active substance for release lower dow n in the gastro-intestinal tract.

[0205] Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact w ith the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6):318 (1986).

[0206] Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a w ater-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions adapted for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles, and mouth washes.

[0207] Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas.

[0208] Pharmaceutical compositions adapted for nasal administration w h erein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.

[0209] Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or insufflators.

[0210] Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

[0211] Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solution which may contain antioxidants, buffers, bacteriostats and solutes w hich render the formulation substantially isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. Excipients which may be used for injectable solutions include water-for-inj ection, alcohols, polyols, glycerin, and vegetable oils, for example. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water or saline for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. The pharmaceutical compositions may contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts (substances of the present disclosure may themselves be provided in the form of a pharmaceutically acceptable salt), buffers, coating agents or antioxidants. They may also contain therapeutically active agents in addition to the compounds of the present disclosure.METHODS OF USING THE COMPOUNDS OF THE DISCLOSURE

[0212] The present application provides a method of TNFR1 -mediated cell signaling comprising contacting a cell with a compound of the disclosure or a pharmaceutically acceptable salt thereof. Binding to human TNFR1 and TNFR2 and selectivity can be assessed by surface plasmon resonance (SPR). Affinity to human TNFR1 can be assessed using a time-resolved fluorescence resonance energy transfer (TR-FRET) binding assay. Inhibition of TNFR1 -mediated cell signaling can be assessed by detecting decreases in the levels of downstream NF-KB signal transduction pathway.

[0213] The present application also provides methods of using the compounds of the disclosure (or their pharmaceutically acceptable salts) or pharmaceutical compositions containing such compounds to treat disease conditions, including but not limited to, conditions implicated by TNFR1.

[0214] In some embodiments, the present disclosure provides a method of treating IBD and other TNFa-driven inflammatory diseases, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment. In some embodiments, the TNFa-driven inflammatory disease is IBD. In some embodiments, the TNFa-driven inflammatory disease is ulcerative colitis. In some embodiments the TNFa-driven inflammatory7disease is Crohn’s disease. In some embodiments, the TNFa-driven inflammatory disease is rheumatoid arthritis. In some embodiments, the TNFa-driven inflammatory disease is juvenile rheumatoid arthritis. In some embodiments, the TNFa-driven inflammatory disease is psoriasis. In some embodiments, theTNFa- driven inflammatory disease is psoriatic arthritis. In some embodiments, the TNFa-dnven inflammatory disease is ankylosing spondylitis. In some embodiments, the TNFa-driven inflammatory disease is non-radiographic axial spondyloarthritis. In some embodiments, the TNFa- driven inflammatory disease is hidradenitis suppurativa.

[0215] In some embodiments, the present disclosure provides a method of treating an inflammatory bowel disease, the method comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0216] In some embodiments, the present disclosure provides a method of treating ulcerative colitis, the method comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereol) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0217] In some embodiments, the present disclosure provides a method of treating Crohn’s disease, the method comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereol) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0218] In some embodiments, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0219] In some embodiments, the present disclosure provides a method of treating juvenile rheumatoid arthritis, the method comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0220] In some embodiments, the present disclosure provides a method of treating psoriasis, the method comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0221] In some embodiments, the present disclosure provides a method of treating psoriatic arthritis, the method comprising administering a therapeutically effective amount a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0222] In some embodiments, the present disclosure provides a method of treating ankylosing spondylitis, the method comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0223] In some embodiments, the present disclosure provides a method of treating nonradiographic axial spondyloarthritis, the method comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0224] In some embodiments, the present disclosure provides a method of treating hidradenitis suppurativa, the method comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0225] In some embodiments, the present disclosure provides a method of treating IBD and other TNFa-driven inflammatory' diseases comprising administering a therapeutically effective amount of a compound of the disclosure (or a pharmaceutically acceptable salt thereof) to a subject in need of such treatment, wherein said IBD and other TNFa-driven inflammatory diseases are selected from ulcerative colitis, Crohn’s disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa.

[0226] One embodiment of the invention relates to the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof in therapy.

[0227] One embodiment of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating IBD and other TNFa-driven inflammatory diseases selected from ulcerative colitis. Crohn’s disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa.

[0228] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating IBD and other TNFa-driven inflammatory diseases selected from ulcerative colitis and Crohn’s disease.

[0229] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating IBD and other TNFa-driven inflammatory diseases selectedfrom rheumatoid arthritis juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa.COMBINATION THERAPIES

[0230] One or more additional pharmacologically active agents may be administered in combination with a compound of the disclosure. An additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including prodrugs that convert to pharmaceutically active form after administration, which are different from the compound of Formula I, and also includes free-acid, free-base, and pharmaceutically acceptable salts of said additional active agents.

[0231] Examples of additional active agents which may be employed include but are not limited to, anti-TNFa biologies, such as, for example, methotrexate, azathioprine, 6-mercapto purine, anti-IL-23 agents, anti-a4p7 agents like vedolizumab, biased IL-2Ra agonists in clinical development.METHODS OF SYNTHESISGeneral Procedures to Access Building Blocks and Monomers

[0232] The compounds of the present invention can be prepared according to the procedures of the following schemes and specific examples, or modifications thereof, using readily available starting materials, appropriate materials and reagents and conventional synthetic procedures and are further exemplified by the following specific examples. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following schemes. The examples also include methods for testing such compounds in biophysical, biochemical, and cellular assays. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the disclosure.

[0233] Unless otherw ise specifically indicated, all reagents are commercially available, known in the literature, or readily synthesized by one skilled in the art. The general route applied to the synthesis of compounds of Formula I is described in the Schemes that follow'. In some instances, the order of carry ing out the reaction steps in the schemes may be varied to facilitate the reaction or to avoid unw anted reaction products. Additionally, various protecting group strategies familiar to one skilled in the art of organic synthesis and solid phase peptide synthesis may be employed to facilitate the reaction, to improve yield and purity', or to avoid unwanted reaction products.

[0234] All reagents and solvents were purchased from commercial sources and used without further purification unless otherwise noted. All temperatures are in degrees Celsius (°C), and ambient temperature or room temperature (RT) is 20 °C. Most compounds were purified by reversed-phase preparative high-performance liquid chromatography (HPLC) or mediumpressure liquid chromatography (MPLC) on silica gel. The course of the reactions was followed by liquid chromatography / mass spectrometry (LC-MS) or Ultra performance liquid chromatography / mass spectrometry (UPLC-MS); electrospray ionization (ESI); UV detection at 254 nm). Proton, fluorine, and carbon magnetic resonance ('l l.19F and1?C NMR) spectra were recorded on a 300, 400, 500. or 600 MHz Varian or Bruker spectrometer, and chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane and referenced to residual solvent. Coupling constants are reported in hertz.1H NMR data are reported as given here: chemical shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublets (dd), doublet of triplets (dt), triplet of doublets (td), triplet of triplets (ft), doublet of doublet of doublets (ddd). multiplet (m), and broad singlet (br. s)]. coupling constant [Hz] and integration). Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with pre-coated TLC plates (E. Merck, Darmstadt, Germany), silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography -mass spectrometry (LC-MS).

[0235] Unless otherwise indicated, when ratios of compounds (such as for examples solvents) are given, the ratio is on a volume-to-volume basis. For example, solvent gradient ranging from 100% hexanes to 50% EtOAc / hexanes means a gradient starting from a mixture of 100 parts by volume of hexanes varying to mixture of 50 parts by volume ethyl acetate to 50 parts by volume of hexanes.

[0236] The term “w / w” means weight of compound to total weight. For example, NaH 60% w / w means 60 parts by weight NaH to 100 parts total weight.

[0237] The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. Wherein a racemic mixture is produced, the enantiomers may be separated using SFC reverse or normal phase chiral resolution conditions either after isolation of the final product or at a suitable intermediate, followed by processing of the single isomers individually. It is understood that alternative methodologies may also be employed in the synthesis of these key intermediates and examples. Asymmetric methodologies (e.g., chiral catalysis, auxiliaries, biocatalytic process) may be used where possible and appropriate. The exact choice of reagents,solvents, temperatures, and other reaction conditions depends upon the nature of the intended product.Abbreviations

[0238] The following abbreviations are used throughout the text:REACTION SCHEMESIntermediates and Monomers Syntheses:Synthetic Scheme 16y)-3-(4-(2-(2-((( Fhioren-9-yl)methoxy)carbonyl)amino)ethoxy)ethoxy)phenyl)-2-((l-(4,4-dimethyl-2,6-dioxocvclohexylidene)ethyl)amino)propanoic acid (Dde-AEEF(Fmoc)-OH) (SSI)

[0239] Step 1: DIAD (3.5 mL. 17.8 mmol) was added to a mixture of PPh? (4.7 g, 17.8 mmol) in anil, toluene (50 mL) at 0 °C under Ar. The reaction mixture was stirred at 0 °C for 30 min. (977-Fluoren-9-yl)methyl (2-(2-hydroxyethoxy)ethyl)carbamate (4.7 g, 14.2 mmol) and / c / 7-butyl (tert-butoxycarbonyl)-L-tyrosinate (4.0 g, 11.9 mmol) were then added to the mixture. The reaction mixture was stirred at RT for 2 h. then diluted with water (80 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anh. Na2SOr, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with EtOAc 0-45% in PE to afford tert-butyl (<S)-3-(4-(2-(2-((((977- fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)ethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (SSla). MS ESI calculated for C37H47N2O8 [M + H]+647.33, found 647.20. 'H NMR (300 MHz, chloroform-J): <5 7.80-7.73 (m, 2H), 7.64-7.56 (m, 2H), 7.44-7.27 (m, 4H), 7.11-7.03 (m, 2H), 6.88-6.81 (m, 2H), 5.29-5.18 (m, 1H), 5.03-4.92 (m, 2H), 4.39 (d, J= 7.2 Hz, 2H), 4.26-4. 18 (m, 1H), 4.13-4.09 (m, 2H), 3.86-3.77 (m, 2H), 3.69- 3.59 (m, 2H), 3.48-3.37 (m, 2H), 3.03-2.90 (m. 2H), 1.44-1.38 (m, 18H).

[0240] Step 2: TFA (50 mL) was added to a solution of tert-butyl (<S)-3-(4-(2-(2-((((977- fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)ethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (SSla, 4.4 g, 6.80 mmol) in DCM (50 mL) at RT. The reaction was stirred at RT for 6 h then concentrated in vacuum to afford GS)-3-(4-(2-(2-((((97 / - fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)ethoxy)phenyl)-2-aminopropanoic acid (SSlb), which was used directly in the next step. MS ESI calculated for C28H31N2O6 [M + H]+491.21, found 491.10.

[0241] Step 3: DIPEA (5.8 mL, 32.9 mmol) and 2-( 1 -hydroxy ethylidene)-5, 5- dimethylcyclohexane-l,3-dione (1.2 g, 6.6 mmol) were added to a mixture of (S)-3-(4-(2-(2- ((((9 / 7-fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)ethoxy)phenyl)-2-aminopropanoic acid (SSlb, 3.8 g, 6.6 mmol) in MeOH (60 mL) at RT. The reaction was stirred at RT for 2 h. The reaction solution was concentrated in vacuum. The residue was diluted with water (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a Cl 8 silica gel column (mobile phase: MeCN / water, 65-65% gradient of MeCN over 28 min; detector: UV 210 nm) to give (S)-3-(4-(2- (2-((((97 / -fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)ethoxy)phenyl)-2-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)propanoic acid (SSI). MS ESI calculated for C38H43N2O8 [M + H]+655.29, found 655.25. 'H NMR (300 MHz, DMSO-Je): 8 13.47 (d, J= 8.1 Hz, 1H), 7.89 (d, J= 7.5 Hz, 2H), 7.69 (d, J= 7.5 Hz, 2H), 7.46-7.28 (m, 5H), 7.09 (d, J= 8.4 Hz, 2H), 6.89-6.79 (m, 2H), 4.89-4.77 (m. 1H), 4.35-4.16 (m. 3H), 4.10-3.97 (m, 2H). 3.75-3.66 (m, 2H). 3.47 (t, J= 6.0 Hz, 2H), 3.25-3.08 (m, 3H), 3.04-2.91 (m, 1H), 2.27 (d, J= 3.6 Hz, 7H), 0.93 (s, 6H).Synthetic Scheme 2dimethyl-2,6-dioxocydohexylidene)ethyl)amino)propanoic acid (Dde-AEF(Fmoc)-OH)(SS2)

[0242] Step 1: Benzyl (2-bromoethyl)carbamate (34.4 g, 133 mmol) and K.2CO3 (18.4 g. 133 mmol) were added to a solution of tert-butyl (fert-butoxycarbonyl)-L-tyrosinate (15.0 g, 44.5 mmol) in anh. DMF (150 mL). The suspension was stirred over night at 40 °C. The reaction was quenched with water (300 mL). The mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed wi th brine (200 mL). dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in PE (1 :2; v / v) to afford tert-butyl (5)-3-(4-(2- (i(benzyloxy) carbonyl) amino) ethoxy) phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (SS2a). MS ESI calculated for C28H39N2O7 [M + H]+515.27, found 515.45. ’H NMR (400 MHz. chloroform- J): S 7.42-7.29 (m, 5H). 7.13-7.01 (m, 2H), 6.79 (d, J= 8.5 Hz, 2H), 5.22 (s, 1H).5. 11 (s. 2H), 4.02-4.00 (m, 2H). 3.62-3.58 (m, 2H), 3.04-2.94 (m. 2H), 1.42 (d. J = 3. 1 Hz, 18H).

[0243] Step 2 : tert-butyl (S)-3-(4-(2-(((benzyloxy) carbonyl)amino)elho\y)phenyl)-2-(( / e / 7- butoxycarbonyl)amino)propanoate (SS2a, 20.0 g, 38.9 mmol) was dissolved in THF (400 mL). The flask was evacuated and refilled with N2 (5 times). Pd / C (2.0 g, 18.8 mmol, dry. 10 wt. %) was added into the flask. The flask was evacuated and backfilled with H2 (5 times). The resulting mixture was stirred for 3 h at RT under an atmosphere of dihydrogen. The flask was evacuated and refilled with N2 (5 times). The resulting mixture was filtered through a Celite® pad. The filtered cake was washed with THF (2 x 50 mL). The filtrate was concentrated under reduced pressure to obtain tert-butyl (S)-3-(4-(2-aminoethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (SS2b), which w as used directly in the next step. MS ESI calculated for C20H33N2O5 [M + H]+381.23, found 381.40.

[0244] Step 3: FmocCl (9.0 g, 34.7 mmol) and TEA (8.8 mL. 63. 1 mmol) were added to a stirred solution of tert-butyl (S)-3-(4-(2-aminoethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (SS2b,12.0 g, 31.5 mmol) in DCM (120 mL) at RT. The mixture w as stirred at RT for 3 h. The mixture w as concentrated under reduced pressure. The residue w as purified by silica gel column chromatography, eluting with EtOAc in PE (1:2; v / v) to afford tert-butyl (» S)-3-(4-(2-((((97f- fl uoren-9-yl )methoxy )carbonyl )amino)ethoxy )phenyl)-2- ((terf-butoxycarbonyl)amino)propanoate (SS2c). MS ESI calculated for C35H43N2O7 [M + H]+603.30, found 603.45. ‘H NMR (300 MHz, chloroform- ): b' 7.75 (d, J= 7.5 Hz, 2H), 7.63-7.55 (m, 2H), 7.44-7.23 (m, 4H), 7.13-7.03 (m, 2H), 6.82 (d, J= 8.2 Hz, 2H), 4.43 - 4.41 (m, 3H), 4.25-4.20 (m, 1H), 4.18-3.96 (m, 2H), 3.65-3.56 (m, 2H), 3.07-2.94 (m, 2H), 1.42 (s, 18H).

[0245] Step 4: TFA (200 mL) was added to a stirred solution of tert-butyl (5)-3-(4-(2-((((9 / / - fluoren-9-yl)methoxy) carbonyl)amino)ethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (SS2c, 19.0 g, 31.5 mmol) in DCM (190 mL) at RT. The solution was stirred at RT for 4 h. The volatiles were removed under reduced pressure to give (<S’)-3-(4-(2-((((97f-fluoren-9-yl) methoxy) carbonyl)amino)ethoxy)phenyl)-2-aminopropanoic acid (SS2d), which was used directly in Step 5. MS ESI calculated for C26H27N2O5 [M + H]+447.18, found 447.35.

[0246] Step 5: 2-(l -hydroxy ethylidene)-5,5-dimethylcyclohexane-l, 3-dione (7.4 g, 40.3 mmol) and DIPEA (18.8 mL, 108 mmol) were added to a stirred solution of (5)-3-(4-(2-((((97f-fluoren- 9-yl) methoxy) carbonyl) amino)ethoxy)phenyl)-2-aminopropanoic acid (SS2d, 12.0 g, 26.9 mmol) in MeOH (120 mL) at RT. The reaction mixture w as stirred at RT for 4 h, and then concentrated under reduced pressure. The residue was purified by silica gel columnchromatography, eluting with MeOH in DCM (1:10; v / v) to afford GS')-3-(4-(2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)ethoxy)phenyl)-2-((l-(4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl)amino)propanoic acid (SS2). MS ESI calculated for C36H39N2O7 [M + H]+611.27, found 611.20. ’H NMR (300 MHz, methanol-^): <57.75 (d, J = 7.5 Hz, 2H), 7.61 (d, J= 7.5 Hz, 2H), 7.37-7.32 (m, 2H), 7.28-7.22 (m, 2H), 7.11 (d, J= 8.5 Hz, 2H), 6.84 (d, J= 8.2 Hz, 2H), 4.86- 4.82 (m, 1H), 4.34 (d, J= 6.9 Hz, 2H), 4.20-4.16 (m, 1H), 3.97-3.92 (m, 2H), 3.47-3.42 (m, 2H), 3.32-3.21 (m, 1H), 3.07-3.00 (m, 1H), 2.32-2.26 (m, 7H), 0.98 (s, 6H).Synthetic Scheme 3Step 1 Step 2 Step 3Step 9 Step 10 Step 11(L / ?3&,4A)-3-(2-((((9.H-Fluoren-9-yl)methoxy)carbonyr)amino)ethoxy)-4-((l-(4,4-dimethyl- 2,6-dioxocyclohexylidene)ethyl)amino)cyclopentane-l-carboxylic acid (Dde- bhcLeut4QC2NHFmoc-OH) (SS3)

[0247] Step 1: Benzyl bromide (16.8 g, 98 mmol) and NaHCCh (7.49 g, 89 mmol) were added to a solution of cy cl opent-3-ene-l -carboxylic acid (10.0 g, 89 mmol) in DCM (200 mL) at RT. The mixture was stirred over night at RT. The reaction mixture was quenched with water (300 mL) and extracted with DCM (3 x 500 mL). The combined organic layers were washed with brine (200 mL), dried over anh. Na2SO4,, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in PE (1:5; v / v) to afford benzyl cyclopent-3-ene-l-carboxylate (SS3a). 'H NMR (300 MHz, chloroform-c / ): 3 7.43- 7.29 (m, 5H), 5.67 (s, 2H). 5.14 (s, 2H). 3.23-3.12 (m, 1H). 2.78-2.57 (m, 4H).

[0248] Step 2 : To a solution of benzyl cyclopent-3-ene-l -carboxylate (SS3a, 17.4 g, 86 mmol) in DCM (340 mL) was added 3-chloroperoxy benzoic acid (22.7 g, 112 mmol, 85 wt. %) in three portions at 0 °C. The solution was allowed to warm to RT and stirred at RT for 4 h. The white precipitate was filtered and the solid residues were washed with DCM. The filtrate was washed with aq. sat. NaHCCb solution and aq. 10% Na2SO? solution. The organic layer was dried over MgSCL, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc in PE (1:4; v / v) to afford benzyl ( l / ?.3.s.5X)-6- oxabicyclo[3.1.0]hexane-3-carboxylate (SS3b).1H NMR (400 MHz, chloroform-c / ): <5 7.45-7.32 (m. 5H), 5.14 (s. 2H), 3.54 (s, 2H), 2.78-2.69 (m. 1H), 2.42-2.37 (m. 2H), 1.96-1.90 (m, 2H).

[0249] Step 3: To a solution of benzyl (lR,3s,51S)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (SS3b,12.0 g, 55.0 mmol) in Et20 (240 mL) was added (lA,27?)-(-)-[l,2-cyclohexanediamino- A,A’-bis(3.5-di-te / 7-butylsalicylidene)]chromium(III) chloride (0.69 g, 1.1 mmol) under N2. After 15 min, TMSN3 (8.0 mL, 60.5 mmol) was added, and the brown solution was stirred at RT for 30 h. The solution was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with EtOAc 0-15% in PE to afford benzyl ( l / ?.3,S'.4X)-3-azido- 4-((trimethylsilyl)oxy)cyclopentane-l -carboxylate (SS3c). 'H NMR (400 MHz, chloroform-t / ): 3 7.56-7.34 (m, 5H), 5.15 (s, 2H), 4.15-4.07 (m, 1H), 3.72-3.68 (m, 1H), 3.12-3.04 (m, 1H), 2.50-2.11 (m, 2H), 1.93-1.82 (m, 2H), 0.15 (s, 9H).

[0250] Step 4: TBAF (9.0 mL, 9.0 mmol, 1 N in THF) was added to a solution of benzyl (lA,3S,4S)-3-azido-4-((trimethylsilyl)oxy)cyclopentane-l-carboxylate (SS3c, 3.0 g, 9.0 mmol) in THF (60 mL) was added at RT. The solution was stirred for 3 h at RT. The solution was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with EtOAc in PE (1:2; v / v) to afford benzyl (17?,3S,4S)-3-azido-4-hydroxycyclopentane-l-carboxylate (SS3d). 'H NMR (400 MHz, chloroform-^: 3 7.42-7.32 (m. 5H), 5.16 (s, 2H), 4.24- 4.15 (m, 1H), 3.81-3.76 (m, 1H), 3.17-3.09 (m, 1H), 2.52-2.25 (m, 2H), 2.08-1.92 (m, 2H).

[0251] Step 5: PPI13 (13.1 g, 50.1 mmol) was added to a stirred solution of benzy l (L / ?,3S',4S')- 3-azido-4-hydroxycyclopentane-l -carboxylate (SS3d. 10.9 g, 41.7 mmol) in THF (110 mL) and water (11 mL) at RT. The solution was stirred at 50 °C for 4 h. The solution was cooled to RT and the volatiles were removed under reduced pressure to give benzyl (17?,3S,4S)-3-amino-4- hydroxycyclopentane-1 -carboxylate (SS3e), which was used directly in Step 5. MS ESI calculated for C13H18NO3 [M + H]+236.12, found 236.15.

[0252] Step 6: NaHCCh (15.5 g. 185.0 mmol) and Cbz-OSu (8.3 g. 33.3 mmol) were added to a solution of benzyl (U?,35, 4S)-3-amino-4-hydroxy cyclopentane- 1-carboxylate (SS3e, 8.7 g, 37.0 mmol) in THF (90 mL) and H2O (90 mL) under Ar at RT. The reaction was stirred over night at RT. The pH of the mixture was adjusted to ~3 with aq. 1 M HC1. The reaction mixture was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (400 mL). dried over anh. NazSCL, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography, eluting with EtOAc 0-60% in PE to afford benzyd ( I / ?.3,S'.4,S')-3-(((benzyloxy)carbonyl)amino)-4-hydroxy cyclopentane- 1 -carboxylate (SS3f). MS ESI calculated for C21H24NO5 [M + H]+370.16, found 370.10. ’H NMR (300 MHz, chloroform- J): 3 7.45-7.28 (m, 10H), 5.35 (s, 1H), 5.13-5.04 (m. 4H), 4.19-4.08 (m, 1H). 3.92- 3.78 (m, 1H), 3.17-3.06 (m, 1H), 2.33-2.26 (m, 1H), 2.23-2.06 (m, 1H), 1.80-1.71 (m, 2H).

[0253] Step 7: Pd(PPh?)4 (4.1 g, 3.5 mmol) and allyl methyl carbonate (8.2 g, 70.4 mmol) were added to a solution of benzy l (17?,3<S',4S')-3-(((benzyloxy)carbonyl)amino)-4- hydroxycyclopentane-l-carboxylate (SS3f, 13.0 g, 35.2 mmol) in THF (130 mL) and under N2. The solution was stirred at 65 °C for 2 h. The reaction was cooled to RT and the solvent was removed under reduced pressure. The residue was purified by a silica gel column chromatography, eluting with EtOAc 0-60% in PE to afford benzyd ( I / ?.3,S’.4,S')-3-(allyloxy)-4- (((benzyloxy)carbonyl)amino)cyclopentane-l -carboxylate (SS3g). MS ESI calculated for C26H30N2O5 [M + MeCN]1450. 19, found 450. 10.

[0254] Step 8: NMO (4.1 mL, 17.5 mmol, 50 wt. % in water) and OsO4 (4.0 mL, 1.6 mmol, 10 wt. % in water) were added to a stirred solution of benzyl ( l / ?.35’.4,S')-3-(allyloxy )-4- (((benzyloxy)carbonyl)amino)cyclopentane-l -carboxylate (SS3g, 6.5 g, 15.9 mmol) in acetone (70 mL) at 0 °C. The mixture was stirred at RT for 3 h. The reaction mixture was quenched with aq. sat. NaHSCL (150 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (250 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (70 mL). NaIO4 (3.7 g, 17.5 mmol, 10 wt.% in water) was added to the solution and stirred over night at RT. The reaction mixture was quenched with water (250 mL) and extracted with Et2O (3 x 250 mL). The combined organic layers were washed with brine (250 mL), dried over anh. Na2SO4, filered, and concentrated under reduced pressure to give benzy l (lA.3<S',4S)-3-(((benzyloxy)carbonyl)amino)-4-(2- oxoethoxy)cyclopentane-l -carboxylate (SS3h), which was immediately used in Step 9 without further purification. MS ESI calculated for C23H26NO6 [M + H]+412.17, found 412.15.

[0255] Step 9: tert-butyl carbamate (10.3 g, 87 mmol) and TFA (2.2 mL, 29.2 mmol)were added to a mixture of benzyl (17?,3S,4S)-3-(((benzyloxy)carbonyl)amino)-4-(2- oxoethoxy)cyclopentane-l -carboxylate (SS3h, 6.0 g, 14.6 mmol) in toluene (60 mL) at RT. The reaction was stirred at RT for 15 h. Dimethylphenylsilane (5.0 g, 36.5 mmol) and tris(pentafluorophenyl)borane (1.5 g, 2.9 mmol) were added to the solution and the mixture was stirred over night at RT. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with EtOAc in PE (1 :3; v / v) to afford benzyl (lA,3S.45)-3-(((benzyloxy) carbonyl) amino)-4-(2-((tert-butoxycarbonyl) amino) ethoxy) cyclopentane- 1 -carboxylate (SS3i). MS ESI calculated for C28H36N2O?Na [M + Na]+535.25, found 535.40. *H NMR (400 MHz, chloroform-r / ): d 7.44-7.30 (m, 10H), 5.46 (s, 1H), 5.16-5.13 (m, 4H), 4.86 (s, 1H), 4.07-4.05 (m, 1H), 3.86-3.84 (m, 1H), 3.65-3.49 (m, 2H). 3.30-3.28 (m, 2H), 3.12-3.08 (m. 1H), 2.45-2.37 (m, 1H). 2.09-2.06 (m, 2H), 1.87-1.74 (m, 1H), 1.46 (s, 9H).

[0256] Step 10: Benzyl (17?,35.4S)-3-(((benzyloxy)carbonyl)amino)-4-(2-((terZ- butoxycarbonyl) amino)ethoxy)cyclopentane-l-carboxylate (SS3i, 5.1 g, 10.0 mmol) was dissolved in IPA (100 mL). The flask was evacuated and refilled with N2 (5 times). Pd / C (1.0 g, 9.4 mmol, dry, 10 wt. %) was added into the flask. The flask was evacuated and backfilled with H2 (5 times). The resulting mixture was stirred for 4 h at RT under an atmosphere of dihydrogen. The flask was evacuated and refilled with N2 (5 times). The resulting mixture was filtered through a Celite® pad. The filtered cake was washed with THF (2 x 25 mL). The filtrate was concentrated under reduced pressure give (lA,3S,4S)-3-amino-4-(2-((te / 7- butoxycarbonyl)amino)ethoxy)cyclopentane-l -carboxylic acid (SS3j) which was used directly in Step 11. MS ESI calculated for C13H15N2O5 [M + H]+ 289.17, found 289.20.

[0257] Step 11: 2-(l-hydroxyethylidene)-5,5-dimethylcyclohexane-l, 3-dione (2.7 g, 14.6 mmol) and DIPEA (3.4 mL, 19.4 mmol) were added to a stirred solution of (l^SSAS^-S-amino- 4-(2-((ter / -butoxycarbonyl)amino)ethoxy)cyclopentane- 1-carboxylic acid (SS3j, 2.8 g. 9.7 mmol) in MeOH (60 mL) at RT. The mixture was stirred at RT for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH in DCM (1 : 10; v / v) to afford (17?,3S,4<S)-3-(2-((tert-butoxy carbonyl) amino)ethoxy)-4-((l-(4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl) amino) cyclopentane-1 -carboxylic acid (SS3k). MS ESI calculated for C23H37N2O7 [M + H]~ 453.25, found 453.10.

[0258] Step 12: TFA (40 mL) was added to a stirred solution of (U?,3S,4S)-3-(2-((tert- butoxycarbonyl)amino)ethoxy)-4-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)cyclopentane-l -carboxylic acid (SS3k, 4.0 g, 8.8 mmol) in DCM (40 mL) at RT. The solution was stirred at RT for 4 h. The volatiles were removed under reduced pressure to give (17?,3S',4<S)-3-(2-aminoethoxy)-4-((l-(4,4-dimethyl-2,6- dioxocy cl ohexylidene)ethyl)amino)cy cl opentane-1 -carboxy lie acid (SS31), which was used directly in Step 13. MS ESI calculated for C18H29N2O5 [M + H]+353.20, found 353.25.

[0259] Step 13: NaHCOi (3.1 g, 36.9 mmol) and Fmoc-OSu (2.2 g, 6.6 mmol) were added to a mixture of (17?,3S,4<S)-3-(2-aminoethoxy)-4-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)cyclopentane-I-carboxylic acid (SS31, 2.6 g, 7.4 mmol) in THF (30 mL) and H2O (30 mL) under Ar at RT. The reaction was stirred over night at RT. The pH of the mixture was adjusted to ~3 with aq. 1 M HC1. The reaction mixture was extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (150 mL), dried over anh. Na2SO4,, filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a C18 silica gel column (mobile phase: MeCN / water (0.1% TFA), 5-70% gradient of MeCN over 40 min; detector: UV 210 nm) to give ( 17?,3S,4S)-3-(2-((((97f- fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)-4-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)cyclopentane-l -carboxylic acid (SS3). MS ESI calculated for C33H39N2O7 [M + H]+575.27, found 575. 10. 'H NMR (400 MHz, methanol-^): 8 7.81 (d, J= 7.5 Hz. 2H), 7.71-7.58 (m, 2H). 7.47-7.22 (m, 4H), 4.36 (d, J = 6.9 Hz, 2H). 4.21 (d, J = 7.3 Hz, 2H), 3.94 (d, J = 6.1 Hz, 1H), 3.58-3.50 (m, 2H), 3.30-3.27 (m, 2H), 3.1 1-2.97 (m, 1H), 2.65- 2.44 (m, 4H), 2.32-2.22 (m, 5H), 2.08-2.05 (m, 1H), 1.91-1.84 (m, 1H), 1.00 (s, 6H).Synthetic Scheme 43-(2-((( Fliioreii-9-yl)methoxy)carbonyl)amino)ethoxy)-5-((1-(4,4-dimethyl-2.6-dioxocvclohexylidene)ethyl)amino)benzoic acid (Dde-Bz3NHFmoc5AE-OH) (SS4)

[0260] Step 1 : tert-butyl (2-hydroxyethyl)carbamate (9.6 g, 59.8 mmol) and (tributylphosphoranylidene)acetonitrile (10.8 g, 44.9 mmol) were added to a solution of methyl 3-amino-5-hydroxybenzoate (5.0 g, 29.9 mmol) in toluene (50 mL) under Ar at RT. The reaction was stirred over night at 110 °C. The reaction was cooled to RT and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluting with EtOAc 0-80% in PE to give methyl 3-amino-5-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate (SS4a). MS ESI calculated for C30H32N2O6Na [M + Na]+333.15. found 333.05.

[0261] Step 2 : An aq. 1 N LiOH solution (53.5 mL, 53.5 mmol) was added to a stirred solution of methyl 3-amino-5-(2-((ter / -butoxycarbonyl)amino)ethoxy)benzoate (SS4a, 8.3 g, 26.7 mmol) in THF (50 mL) at RT. The resulting mixture was stirred at RT for 2 h. The pH of the mixture was adjusted to ~3 with aq. 1 M HC1. The mixture was extracted with EtOAc (3 x 350 mL). The combined organic layers were washed with brine (250 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure to give 3-amino-5-(2-((terL butoxycarbonyl)amino)ethoxy)benzoic acid (SS4b, which was used directly in Step 3. MS ESI calculated for Ci-JMSfiOsNa [M + Na]+319.14, found 319.15.

[0262] Step 3: 2-(l -hydroxy ethylidene)-5,5-dimethylcyclohexane-l, 3-dione (2.8 g, 15.2 mmol) and DIPEA (2.6 g, 20.2 mmol) were added to a stirred suspension of 3-amino-5-(2-((tert-butoxy carbonyl )amino)ethoxy)benzoic acid (SS4b, 3.0 g. 10. 1 mmol) in toluene (60 mL) at RT. The reaction mixture was stirred at 110 °C for 4 h. The mixture was concentrated under reduced pressure and the residue was purified by by Rp flash chromatography using a C 18 silica gel column (mobile phase: MeCN / water (0.05% TFA), 0-73% gradient of MeCN over 30 min; detector: UV 210 nm) to give 3-(2-((te / 7-butoxycarbonyl)amino)ethoxy)-5-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)benzoic acid (SS4c). MS ESI calculated for C24H33N2O7 [M + H]+461.22, found 461.25. ‘H NMR (400 MHz, chloroform- ): 3 15.08 (s, 1H), 7.93 (s, 1H), 7.58-7.51 (m, 2H), 4.09-4.08 (m, 2H), 3.60-3.56 (m, 2H), 2.55 (s, 3H), 2.49-2.44 (m, 4H),1.46 (s, 9H). 1.09 (s, 6H).

[0263] Step 4 : TFA (30 mL) was added to a stirred solution of 3-(2-( tert- butoxycarbonyl)amino)ethoxy)-5-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)benzoic acid (SS4c, 1.9 g, 4.1 mmol) in DCM (10 mL) at RT. The solution was stirred at RT for 4 h. The volatiles were removed under reduced pressure to give 3-(2-aminoethoxy)-5-(( 1 -(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)benzoic acid (SS4d), which was used directly in Step 5. MS ESI calculated for C19H25N2O5 [M + H]+361.17, found 361.20.

[0264] Step 5: NaHCCh (0.54 g, 6.4 mmol) and Fmoc-OSu (2.2 g, 6.4 mmol) were added to a solution of 3-(2-aminoethoxy)-5-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)benzoic acid (SS4d, 2.3 g, 6.4 mmol) in THF (23 mL) and H2O (23 mL) under Ar at RT. The reaction was stirred over night at RT. The pH of the mixture was adjusted to ~3 with aq. 1 M HC1. The reaction mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anh. Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a C 18 silica gel column (mobile phase: MeCN / water (0.1% TFA), 5-55% gradient of MeCN over 25 min; detector: UV 210 nm) to give 3-(2-((((977-fluoren-9- yl)methoxy)carbonyl)amino)ethoxy)-5-((l-(4,4-dimethyl-2.6- dioxocyclohexylidene)ethyl)amino)benzoic acid (SS4). MS ESI calculated for C34H35N2O7 [M + H]+583.24, found 583.20. ‘H NMR (300 MHz, DMSO- s): 3 15.02 (s, 1H), 13.29 (s, 1H), 7.88 (d, J= 7.6 Hz, 2H), 7.68 (d, J= 7.4 Hz, 2H), 7.54-7.50 (m, 1H), 7.46-7.24 (m, 6H), 7.21 (s, 1H), 4.32 (d, J= 6.8 Hz, 2H), 4.23-4.19 (m, 1H), 4.07 (d, J= 5.8 Hz, 2H). 3.37 (d, J= 5.8 Hz, 2H), 2.44 (s, 3H), 2.39 (s, 4H), 1.00 (s, 6H).Synthetic Scheme 5(27?,4*3)-4-((((9 / 7-Fluoren-9-yl)methoxy)carbonyl)amino)-l-((allyloxy)carbonyl)pyrroli(line- 2-carboxylic acid (Alloc-dProt4NHFmoc-OH) (SS5)

[0265] Step 1: Aq. 1 N LiOH (61.4 mL, 61.4 mmol) was added to a solution of I -( / m-butyl) 2- methyl (2 / <’AS')-4-aminopyrrolidine- l .2-dicarboxylate (5.0 g, 20.5 mmol) in THF (60 mL) at RT. The mixture was stirred for 2 h at RT. The mixture was acidified to pH ~5 with aq. 1 M HC1. The volatiles were removed under vacuum and the crude material (SS5a) was used directly in Step 2 without further purification. MS ESI calculated for C10H17N2O4 [M - H]’ 229.13, found 229.05.

[0266] Step 2: NaHCOs (8.6 g, 102 mmol) and Fmoc-OSu (6.9 g, 20.4 mmol) were added to a stirred solution of (2f?,4AS)-4-amino-l-(tert-butoxy carbonyl) pyrrolidine-2-carboxylic acid (SS5a, 4.7 g, 20.4 mmol) in THF (60 mL) and water (60 mL) at RT. The resulting mixture was stirred at RT for 2 h. The pH was adjusted to ~3 with aq. 1 N HC1. The reaction mixture was extracted with EtOAc (1000 mL). The organic layer was washed with brine (3 x 250 mL). dried over anh.Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by Rp flash chromatography using a C18 silica gel column (mobile phase: MeCN / water (0.05% TFA), 2- 50% gradient of MeCN over 40 min; detector: UV 210 nm) to give (2 / ?.45')-4-((((9f / -fluoren-9- yl)methoxy)carbonyl)amino)-l-(te / 7-butoxycarbonyl)pyrrolidine-2-carboxylic acid (SS5b). MS ESI calculated for C25H29N2O6 [M - tBu + H]+397. 19, found 397.20. 'H NMR (400 MHz, DMSO-cL): 3 12.65 (s, 1H), 7.89-7.85 (m, 2H), 7.73-7.62 (m, 3H), 7.4-7.41 (m, 2H), 7.33-7.31 (m, 2H), 5.76 (s,lH). 4.36-4.34 (m, 2H), 4.21-4.18 (m, 2H), 4.09-4.00 (m. 1H), 3.54-3.53 (m, 1H), 3.17 (s, 1H), 2. 14-2.03 (m, 2H), 1.38-1.34 (m, 9H).

[0267] Step 3: TFA (15 mL) was added to a stirred solution of (27?,4<S)-4-((((97f-fluoren-9-yl) methoxyjcarbonyl) amino)- 1 -( / e / 7-bulo\y carbonyl) pyrrolidine-2-carboxylic acid (SS5b, 9.0 g, 19.9 mmol) in DCM (30 mL) at RT. The solution was stirred for 1 h at RT. The reaction mixture was concentrated under reduced pressure to give crude (2A,4<S)-4-((((9 / 7-fluoren-9-yl)methoxy)carbonyl)amino)pyrrohdine-2-carboxylic acid (SS5c). MS ESI calculated for C20H21N2O4 [M + H]+353.14, found 353.25.

[0268] Step 4: NaHCCL (8.6 g, 102 mmol) and Alloc-OSu (4. 1 g, 20.4 mmol) were added to a stirred solution of (27?,4S)-4-((((977-fluoren-9-yl)methoxy)carbonyl)amino)pyrrolidine-2- carboxylic acid (SS5c. 7.2 g. 20.4 mmol) in THF (72 mL) and water (72 mL) at RT. The resulting mixture was stirred at RT for 2 h. The pH was adjusted to ~3 with aq. 1 N HC1. The reaction mixture was extracted with EtOAc (1400 mL). the organic layer was washed with brine (3 x 300 mL), dried over Na2SO4,, filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a Cl 8 silica gel column; mobile phase: MeCN / water (0.05% TFA), 2-60% gradient of MeCN over 30 min; detector: UV 210 nm) to give (27?, 4S)-4-((((977-fluoren-9-yl)methoxy)carbonyl)amino)-l -((allyloxy )carbonyl)pyrrolidine- 2-carboxylic acid (SS5). MS ESI calculated for C24H25N2O6 [M + H]+437.16, found 437.10. 'H NMR (300 MHz, DMSO-d6): <5 7.89-7.87 (m. 2H), 7.69-7.67 (m, 3H), 7.47-7.44 (m, 2H). 7.35- 7.31 (m, 2H), 6.02-5.77 (m, 1H), 5.30-5.26 (m. 1H), 5.17-5.13 (m, 1H). 4.62-4.49 (m, 2H), 4.55-4.41 (m, 2H), 4.37-4.34 (m, 2H), 4.09 (s, 1H), 3.31-3.29 (m, 2H), 2.21-2.11 (m, 1H), 2.07 (s, 1H).Synthetic Scheme 6Alloc-dProt4OEtNHFmoc-OH (SS6)(2 / ?,4V)-4-(2-((((9 / / -Fhioren-9-yl)methoxy)carbonyl)amino)ethoxy)-l- ((allyloxy)carbonyl)pyrrolidine-2-carboxylic acid (Alloc-dProt40EtNHFmoc-OH) (SS6)

[0269] Step 1 : te / 7-butyl A'. / V'-diisopropylcarbami midate (34.7 g, 173 mmol) was added to a stirred solution of (2 / <4A)- l -( / c77-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.0 g, 43.2 mmol) in DCM (100 mL) at RT under Ar. The resulting mixture was stirred over night at 40 °C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EtOAc 0-80% in PE to afford di-tert- butyl (2 / ?.41S')-4-hydroxypyrrolidine- 1.2-dicarboxylate (SS6a). MS ESI calculated for C14H26NO5 [M + H]+288.17, found 288.25. 'H NMR (300 MHz, chloroform- J): 34.47 (d, J= 8.2 Hz, 1H), 4.34-4.26 (m, 1H), 3.69-3.32 (m, 2H), 2.40-2.14 (m, 1H), 2.14-1.97 (m, 1H), 1.45 (d, J= 5.6 Hz, 18H).

[0270] Step 2: 3-bromoprop-l-ene (5.7 g, 47.0 mmol), NaOH (10 N in water. 31.3 mL. 313 mmol), and TBAB (10. 10 g. 31.3 mmol) were added to a solution of di- / cv7-butyl (27?,45)-4-hydroxypyrrolidine-l,2-dicarboxylate (SS6a, 9.0 g. 31.3 mmol) in DCM (180 mL) and water (9 mL) at RT. The mixture was stirred over night at RT. The reaction was diluted with water (300 mL) and extracted with DCM (3 x 300 mL). The combined organic layers were washed with brine (3 x 300 mL) and dried over anh. Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography, eluted with EtOAc 0-60% in PE to afford di-tert-butyl (2R,4S)-4-(allyloxy)pyrrolidine-l,2- dicarboxylate (SS6b). MS ESI calculated for C17H30NO5 [M + H]+328.20, found 328.30. 'H NMR (300 MHz, chloroform-ci): <5 5.95-5.83 (m, 1H), 5.39-5.05 (m, 2H), 4.32-4.05 (m, 2H), 4.03-3.91 (m, 2H), 3.64-3.60 (m, 2H), 2.43-2.17 (m, 1H), 2.07-2.00 (m, 1H), 1.62-1.31 (m, 18H).

[0271] Step 3: NMO (7.2 mL, 30.9 mmol, 50 wt. % in water) and OsC>4 (0.714 g, 2.81 mmol, 5 wt. % in water) were added to a stirred solution of di-zcrz-butyl (2 / ?.4.S')-4-(allyloxy)pyrrolidinc- 1,2-dicarboxylate (SS6b, 9.2 g, 28.1 mmol) in acetone (180 mL) at 0 °C. The mixture was stirred at RT for 3 h. The reaction mixture was quenched with aq. sat. NaHSCh (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (50 mL), dried over anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue w as dissolved in MeOH (180 mL). NaIO4 (6.61 g, 30.9 mmol, 10 wt. % in water) was added to the solution and stirred over night at RT. The reaction mixture was quenched with water (200 mL) and extracted with Et20 (3 x 200 mL). The combined organic layers were washed with brine (50 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue w as purified by a silica gel column chromatography, eluted with EtOAc 0-60% in PE to afford di- / e / 7-butyl (27?,4S)-4-(2-oxoethoxy)pyrrolidine-l,2-dicarboxylate (SS6c). MS ESI calculated for C16H28NO6 [M + H]+330.18. found 330.30. 'H NMR (400 MHz. chloroform-i / ): d 9.70 (d, J= 3.0 Hz, 1H), 4.42-3.96 (m, 4H), 3.72-3.51 (m, 2H), 2.50-2.26 (m, 1H), 2.16-2.01 (m, 1H), 1.49-1.42 (m, 18H).

[0272] Step 4 : Dibenzylamine (8.1 g, 41.0 mmol) and MgSO4 (16.4 g, 137 mmol) were added to a stirred solution of di- / m-butyl (2J?,4S)-4-(2-oxoethoxy)pyrrolidine-l,2-dicarboxylate (SS6c, 9.0 g, 27.3 mmol) in DCE (90 mL) at RT. The suspension was stirred at RT for 1 h. Sodium triacetoxyborohydride (17.37 g, 82 mmol) w as then added to the mixture and the suspension was stirred over night at RT. The mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography, eluted with EtOAc 0-60% in PE to afford di-ze / V-butyl (2A,4S)-4-(2- (dibenzylamino)ethoxy)pyrrolidine-l,2-dicarboxylate (SS6d). MS ESI calculated for C30H43N2O5 [M + H]+511.31, found 511.35.

[0273] Step 5: Di- / e / 7-butyl (2A,4S)-4-(2-(dibenzylamino)ethoxy)pyrrolidine-l,2-dicarboxylate (SS6d, 6.0 g, 11.8 mmol) was dissolved in EtOH (120 mL). The flask was evacuated and refilled with N2 (5 times). Pd(0EI)2 (3.0 g, 4.3 mmol, 10 wt. %) was added into the flask. The flask was evacuated and backfilled with H2 (5 times). The resulting mixture was stirred for 2 h at RT under an atmosphere of dihydrogen. The flask was evacuated and refilled with N2 (5 times). The resulting mixture was filtered through a Celite" pad. The filtered cake was washed with EtOH (2 x 25 mL). The filtrate was concentrated under reduced pressure to give di-fert-butyl (2R.4,S')-4- (2-aminoethoxy)pyrrolidine-l,2-di carboxylate (SS6e), which was used in Step 6 without further purification. MS ESI calculated for C16H31N2O5 [M + H]+331.22, found 331.35.

[0274] Step 6: NaHCOs (4.5 g, 53.0 mmol) and Fmoc-OSu (3.2 g, 9.5 mmol) were added to a solution of di- / c77-butyl (2J?,41S)-4-(2-aminoethoxy)pyrrolidine-l,2-dicarboxylate (SS6e, 3.5 g, 10.6 mmol) in THF (35 mL) and H2O (35 mL) under Ar at RT. The reaction was stirred over night at RT. The pH of the mixture was adjusted to ~3 with 1 M HC1 and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (150 mL) and dried over anh. Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by Rp flash chromatography using a Cl 8 silica gel column (mobile phase: MeCN / water (0.1% TFA), 5-55% gradient of MeCN over 40 min; detector: UV 210 nm) to give di-tert-butyl (2A,45)-4-(2-((((97 / -fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)pyrrolidine-l,2-dicarboxylate (SS6f). MS ESI calculated for C3iH4iN2O7Na [M + Na]+575.28, found 575.40.

[0275] Step 7: TFA (200 mL) was added to a stirred solution of di-terLbutyl (2R,4S)-4-(2- ((((977-fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)pyrrolidine-l,2-dicarboxylate (SS6f, 5.8 g, 10.4 mmol) in DCM (50 mL) at RT. The solution was stirred at RT for 4 h. The solvent was concentrated under reduced pressure to give (27?,4S)-4-(2-((((9 / / -fluoren-9- yl)methoxy)carbonyl)amino)ethoxy)pyrrolidine-2-carboxylic acid (SS6g), which was used directly in Step 7. MS ESI calculated for C22H25N2O5 [M + H]+397.17, found 397.30.

[0276] Step 8: NaHCCh (3.7 g, 44. 1 mmol) and Alloc-OSu (2.6 g, 13.2 mmol) were added to a solution of (2A,4S)-4-(2-((((97 / -fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)pyrrolidine-2- carboxylic acid (SS6g, 3.5 g, 8.8 mmol) in THF (35 mL) and H2O (35 mL) under Ar at RT. The reaction was stirred at RT for 1 h. The pH of the mixture was adjusted to ~3 with 1 M HC1 and extracted with EtOAc (3 x 350 mL). The combined organic layers were washed with brine (250 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a Cl 8 silica gel column (mobile phase: MeCN / water, 5-70% gradient of MeCN over 40 min; detector: UV 210 nm) to give (27?,41S)-4-(2-((((9Ef- fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)-l-((allyloxy)carbonyl)pyrrolidine-2-carboxylicacid (SS6). MS ESI calculated for C26H29N2O7 [M + H]+481.19, found 481.20. 'H NMR (300 MHz, methanol-A): 87.79 (d, J = 7.5 Hz, 2H), 7.64 (d, J = 7.4 Hz, 2H), 7.45-7.22 (m, 4H), 5.98-5.81 (m, 1H), 5.32-5.26 (m, 1H), 5.22-5.09 (m, 1H), 4.61-4.45 (m, 2H), 4.35 (d, J= 7.2 Hz. 2H), 4.24-4.08 (m, 2H), 3.71-3.40 (m, 4H), 3.27-3.24 (m, 2H), 3.02-3.00 (m, 1H), 2.49- 2.37 (m, 1H), 2.15-1.98 (m, 1H).Synthetic Scheme 7Fmoc,(2 / ?,4‘S)-4-(2-((((9 / / -Fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)-l-((4- nitrophenyl)sulfonyl)pyrrolidine-2-carboxylic acid (Ns-dProt40EtNHFmoc-OH) (SS7)

[0277] Step 1: BF3*OEt2 (1.8 mL, 13.9 mmol) was added to a solution of di-te / 7-butyl (27?, 45)- 4-hydroxypyrrolidine-l,2-dicarboxylate (8.0 g, 27.8 mmol) in anh. toluene (160 mL) under Ar at 5 °C. After 30 min, (977-fluoren-9-yl)methyl aziridine-1 -carboxylate (9.6 g, 36.2 mmol) was added at 5 °C. The resulting mixture was stirred over night at RT. The reaction mixture was quenched with aq. sat. NaHCCh (100 mL) and extracted with EtOAc (3 x 350 mL). The combined organic layers were washed with brine (420 mL). dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc in PE (1 :3; v / v) to afford di- / e / 7-butyl (27?,4S)-4-(2-((((9 / 7- fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)pyrrolidine-l,2-dicarboxylate (SS7a). MS ESI calculated for CsiHroNzOvNa [M + Na]+575.28, found 575.20. 'l l NMR (400 MHz, chloroform- d): 8 7.79 (d, J= 7.5 Hz, 2H), 7.62 (d, J= 7.5 Hz, 2H), 7.45-7.33 (m, 4H), 4.53-4.47 (m, 1H). 4.45-4.42 (m, 1H), 4.31-4.23 (m, 2H), 4.17-4.09 (m, 1H), 3.73-3.32 (m, 6H), 2.39-2.22 (m, 1H), 2.12-2.07 (m, 1H), 1.49 (s, 18H).

[0278] Step 2: TFA (40 mL) was added to a stirred solution of di- / c / 7-butyl (2A,4S)-4-(2- ((((977-fluoren-9-yl)methoxy)carbonyl)amino(ethoxy)pyrrolidine-l,2-dicarboxylate (SS7a, 3.5 g, 6.3 mmol) in DCM (20 mL) at RT. The mixture was stirred at RT for 4 h. The volatiles were removed under reduced pressure to give (27?,45)-4-(2-((((97 / -fluoren-9- yl)methoxy)carbonyl)amino)ethoxy)pyrrolidine-2-carboxylic acid (SS7b) which was used directly in Step 3. MS ESI calculated for C22H25N2O5 [M + H]+397.17, found 397.15.

[0279] Step 3: NaHCCL (2.3 g, 27.7 mmol) and 4-nitrobenzenesulfonyl chloride (1.2 g, 5.6 mmol) were added to a solution of (2 / ?.45')-4-(2-((((9 / / -fl uoren-9-yl) methoxy) carbonyl) amino) ethoxy )pyrrolidine-2-carboxylic acid (SS7b, 2.2 g, 5.6 mmol) in THF (20 mL) and H2O (20 mL) under Ar at RT. The reaction was stirred at RT for 1 h. The reaction mixture was acidified to pH ~3 with 1 M HC1 and extracted with EtOAc (3 x 350 mL). The combined organic layer was washed with brine (5 x 50 mL), dried over anh. Na2SO4,, filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a Cl 8 silica gel column (mobile phase: MeCN / water (0.1% TFA). 5-70% gradient of MeCN over 40 min; detector: UV 210 nm) to give (2 / ?.45) -4-(2-((((9H- fl uoren-9-y I (methoxy (carbonyl (amino (ethoxy)- 1 -((4- nitrophenyl)sulfonyl)pyrrolidine-2-carboxylic acid (SS7). MS ESI calculated for C28H28N3O9S [M + H]+582.15, found 581.95. ’H NMR (300 MHz, methanol-A): d 8.18-7.99 (m, 1H), 7.90- 7.51 (m, 7H), 7.41-7.28 (m, 4H), 4.69-4.28 (m. 3H), 4.28-3.94 (m, 2H), 3.79-3.75 (m, 1H). 3.58-3.53 (m, 1H), 3.35-3.33 (m, 1H), 3.03 (d, J= 5.7 Hz, 2H), 2.92-2.70 (m, 1H), 2.47-2.40 (m, 1H), 2.14-2.03 (m, 1H).Synthetic Scheme 8ONBS-CI 1.2 eq / V-(2-((((9 / / -Fliioreii-9-yl)methoxy)carbonyl)amino)ethyl)- / V-((2-iiitrophenyl)sulfonyl) glycine (Ns-NC2NHFmoc-OH) (SS8)

[0280] Step 1 : A solution of 2-nitrobenzene sulfonyl chloride (14.7 mg, 66 mmol) in DCM (10 mL) was added to a solution of glycine methyl ester (5g, 56. 17mmol) in water (10 mL) at 0 °C. Then, triethylamine (16 mL. 112 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at RT for 12 h, diluted with water (100 mL), and extracted with EtOAc (3 x 50mL). The combined organic layers were washed with water (50 mL), aq. 1 N HC1 (50 mL), brine (50 mL), dried over anh. NazSOi. filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with EtOAc 10-90% in PE to afford methyl ((2- nitrophenyl)sulfonyl)glycinate (SS8a). MS ESI calculated for C9H10N2O6S [M + H]+275.03, found 275.26

[0281] Step 2: DIAD (885 mL, 4.38 mmol) dropwise was added to a solution of methy l ((2- nitrophenyl)sulfonyl)glycinate (SS8a, 1 g. 3.65 mmol), tert-butyl (2-hydroxyethyl)carbamate (705 mg. 4.38mmol), and PPhs (1.148 g, 4.38 mmol) in anh. THF (15 mL) at RT and under N2. The residue was diluted with DCM (100 mL), washed with aq. 1 N HC1 (50 mL) and brine (50mL). dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc 10-90% in PE to afford methyl N-(2- ((ter / ‘-butoxycarbonyl)amino)ethyl)-A-((2-nitrophenyl)sulfonyl)glycinate (SS8b) MS ESI calculated for C16H23N3O8S [M + H]+417.16, found 417.4.

[0282] Step 3: TFA (10 mL) was added to a mixture of methyl N-(2-((tert- butoxycarbonyl)amino)ethyl)-A-((2-nitrophenyl)sulfonyl)glycinate (SS8b, 945mg, 2.27 mmol) in DCM (10 mL) at RT. The reaction was stirred at RT for 1 h then concentrated in vacuum to afford methyl A-(4-(aminomethyl)benzyl)-A-((2-nitrophenyl)sulfonyl)glycinate (SS8c), which was used directly in step 4. MS ESI calculated for CnHisNsOeS [M + H]+317.32, found 317.44

[0283] Step 4: Aq. 1 N LiOH (4 mL, 4.22 mmol) was added to a solution of methyl N-(2- aminoethyl)-A-((2-nitrophenyl)sulfonyl)glycinate (SS8c, 720 mg, 2.27 mmol) in THF (10 mL) and water (10 mL) at RT. The mixture was stirred for 3 h at RT. The mixture was diluted with water (100 mL) and freeze-dried. The crude material (SS8d) was used directly in Step 5 without further purification. MS ESI calculated for C10H1 N3O6S [M + H]+303.09. found 303.20

[0284] Step 5: Fmoc-OSu (770 mg, 2.2 mmol) and potassium carbonate (940 g, 6.8 mmol) were added to a stirred solution of crude A-(2-aminoethyl)-A-((2-nitrophenyl)sulfonyl)glycine (SS8d, 690 mg, 2.27 mmol) in 1,4-di oxane (10 mL) and water (10 mL) at 0 °C. The mixture was stirred at RT for 2 h. The pH of the mixture was adjusted to ~3 with aq. 1 M HC1. The reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anh. Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by RP Flash (Column: Luknova™ SuperSep™ Cl 8 110 g (Luknova Inc, Mansfield, MA); Mobile Phase A: water (0.1%TFA), Mobile Phase B: MeCN(0.1%TFA); Flow rate: 60 mL / min; Gradient: 5-5% B in 2CV; 2-90% B in 10CV; UV 210 nm) to afford N-(2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-N-((2-nitrophenyl)sulfonyl)glycine (SS8). MS ESI calculated for C25H23N3O8S [M + H]+ 525.5, found 526. 12. ’H NMR (400 MHz, DMSO-cL): <5 13.09-12.86 (m. 1H), 13.03-12.47 (m, 1H), 7.95-7.78 (m, 4H), 7.73-7.61 (m, 2H), 7.45-7.22 (m, 5H). 7.90-6.83 (m, 1H), 6.54 (s, 1H), 4.30-4.18 (m, 3H), 3.46-3.36 (m. 3H), 3.33 (s, 6H), 3.18 (br d, J= 6.4 Hz, 2H), 3.05 (d, J= 6.0 Hz, 1H), 2.55 (br s, 1H).Synthetic Scheme 9Step 1A-(3-((((9 / 7-Fluoren-9-yl)methoxy)carbonyl)amino)propyl)-N-((allyloxy)carbonyl)glycine (Alloc-NPrNHFmocG-OH) (SS9)

[0285] Step 1: / e / 7-Butyl (3-aminopropyl)carbamate (10.7 g, 61.5 mmol) and NaHCO? (12.9 g, 154 mmol) where added to a solution of tert-butyl 2-bromoacetate (6.0 g, 30.8 mmol) in anh. DMF (60 rnL) at RT and the suspension was stirred at RT for 1 h. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (200 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc 0-100% in PE to afford tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)glycinate (SS9a). MS ESI calculated for C 14H29N2O4 [M + H]+289.20, found 289.30. 'HNMR (300 MHz, DMSO-tL): <5 6.75 (s, 1H), 3.15 (d, J= 4.4 Hz, 2H), 2.97-2.88 (m, 2H), 2.45 (d, J= 6.2 Hz, 2H), 1.95-1.77 (m, 1H), 1.50-1.35 (m, 20H).

[0286] Step 2: NaHCOs (8.7 g, 104 mmol) and Alloc-OSu (6.2 g, 31.2 mmol) were added to a solution of tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)glycinate (SS9a, 6.0 g, 20.8 mmol) in THF (60 mL) and H2O (60 mL) under Ar at RT. The reaction mixture was stirred over night at RT, and then extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (250 mL) and dried over anh. Na2SO4. After filtration, the filtrate was concentratedunder reduced pressure and the residue was purified by silica gel column chromatography, eluting with EtOAc 0-30% in PE to give / e / 7-butyl .V-((allylo\y)carbonyl)-Ar-(3-(( / i77- butoxycarbonyl)amino)propyl)glycinate (SS9b). MS ESI calculated for C18H33N2O6 [M + H]+373.23. found 373.30.

[0287] Step 3: TFA (120 mL) was added to a stirred solution of tert-butyl N- ((allyloxy)carbonyl)-A-(3-((tert-butoxycarbonyl)amino)propyl)glycinate (SS9b, 8.0 g, 21.5 mmol) in DCM (40 mL) at RT. The solution was stirred at RT for 4 h. The volatiles were removed under reduced pressure to give A'-((allyloxy)carbonyl)-Ar-(3-aminopropyl (glycine (SS9c). which was used directly in next step. MS ESI calculated for C9H17N2O4 [M + H]+217. 11, found 217.15.

[0288] Step 4: NaHCCh (8.7 g, 104 mmol) and Fmoc-OSu (6.3 g, 18.73mmol) were added to a solution of A-((allyloxy)carbonyl)-A-(3-aminopropyl)glycine (SS9c, 4.5 g, 20.8 mmol) in THF (50 mL) and H2O (50 mL) under Ar at RT. The reaction was stirred over night at RT. The pH of the mixture was adjusted to ~3 with aq. 1 M HC1 and the reaction mixture was extracted with EtOAc (3 x 350 mL). The combined organic layers were washed with brine (250 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a C18 silica gel column; mobile phase: MeCN / water (0.05% TFA), 0-63% gradient of MeCN over 30 min; detector: UV 210 nm) to give A-(3-((((97 / -fluoren-9- yl jmethoxy )carbonyl)amino)propyl)-A-((allyloxy)carbonyl)glycine (SS9). MS ESI calculated for C24H27N2O6 [M + H]+439.18, found 439.15. 'H NMR (400 MHz, DMSO-A): 8 12.67 (s, 1H), 7.91-7.89 (m, 2H). 7.70-7.68 (m, 2H), 7.44-7.40 (m, 2H), 7.36-7.33 (m, 2H), 7.32-7.27 (m, 1H), 5.95-5.84 (m. 1H), 5.29-5.23 (m, 1H). 5.17-5.13 (m, 1H), 4.53-4.49 (m, 2H), 4.31-4.29 (m. 2H), 4.24-4.22 (m, 1H). 3.94-3.90 (m, 2H). 3.26-3.23 (m, 2H), 3.02-2.97 (m. 2H), 1.64- 1.60 (m, 2H).Synthetic Scheme 10Step 110-((Allyloxy)carbonyl)-l-(9H-fluoren-9-yl)-3-oxo-2,7-dioxa-4,10-diazadodecan-12-oic acid (Alloc-NxG44(Fmoc)-OH) (SS10)

[0289] Step 1: tert -But l (2-(2-aminoethoxy)ethyl)carbamate (41.9 g, 205 mmol) and NaHCO3 (43.1 g, 513 mmol) were added to a solution of tert-butyl 2-bromoacetate (20.0 g, 103 mmol) in anh. DMF (200 mL) at RT. The suspension was stirred for 1 h at RT. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (1000 mL). The organic layer was washed with brine (400 mL), dried over anh. Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc 0- 100% in PE to afford tert -butyl (2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)glycinate (SSlOa). MS ESI calculated for C15H31N2O5 [M + H]+319.22, found 319.25. 'H NMR (400 MHz, DMSO-d6): 6.79 (d, J= 5.9 Hz, 1H), 3.45-3.28 (m, 6H), 3.08-3.04 (m, 2H), 2.64-2.61 (m, 2H), 2.10 (s, 1H), 1.39 (d, J = 15.5 Hz, 18H).

[0290] Step 2: NaHCO3 (19.8 g, 236 mmol) and Alloc-OSu (14. 1 g, 70.7 mmol) were added to a solution of tert-butyl (2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)glycinate (SSlOa, 15.0 g, 47. 1 mmol) in THF (150 mL) and H2O (150 mL) under Ar at RT. The reaction was stirred over night at RT. The reaction mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL) and dried over anh. Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with EtOAc 0-70% in PE to afford tert- butyl 11- ((allyloxy)carbonyl)-2,2-dimethyl-4-oxo-3,8-dioxa-5,l l-diazatridecan-13-oate (SSlOb). MS ESIcalculated for C19H35N2O7 [M + H]+403.24, found 403.25. 'H NMR (400 MHz, DMSO-cfe): 8 6.75 (s, 1H), 5.97-5.81 (m, 1H), 5.32-5.11 (m, 2H), 4.55-4.48 (m, 2H), 3.92 (d, J= 11.3 Hz, 2H), 3.48-3.45 (m, 2H), 3.42-3.33 (m, 4H), 3.07-3.03 (m, 2H), 1.44-1.33 (m, 18H).

[0291] Step 3 : To a stirred solution of te / 7-butyl l l-((allyloxy)carbonyl)-2,2-dimethyl-4-oxo- 3,8-dioxa-5,l 1 -diazatridecan- 13 -oate (SSlOb. 14 g. 34.8 mmol) in DCM (30 mL) was added TFA (120 mL) at RT. The solution was stirred at RT for 4 h. The volatiles were removed under reduced pressure to give A-((allyloxy)carbonyl)-A-(2-(2-aminoethoxy)ethyl)glycine (SSlOc), which was used directly in next step. MS ESI calculated for C10H19N2O5 [M + H]+247.12, found 247.15.

[0292] Step 4: NaHCCh (11.9 g, 142 mmol) and Fmoc-OSu (8.6 g, 25.6 mmol) were added to a solution of A-((allyloxy)carbonyl)-A-(2-(2-aminoethoxy)ethyl)glycine (SSlOc, 7.0 g, 28.4 mmol) in THF (70 mL) and H2O (70 mL) under Ar at RT. The reaction was stirred over night at RT. The pH of the reaction mixture was adjusted to ~3 with aq. 1 M HC1 and extracted with EtOAc (3 x 350 mL). The combined organic layers were washed with brine (250 mL), dried over anh. Na2SOr, filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a C18 silica gel column (mobile phase: MeCN / water (0.1% TFA), 5-70% gradient of MeCN over 40 min; detector: UV 210 nm) to give I ((-((ally I oxy (carbonyl)- 1 -(97 / - fluoren-9-yl)-3-oxo-2,7-dioxa-4.10-diazadodecan- 12-oic acid (SS10). MS ESI calculated for C25H29N2O7 [M + H]+469.19, found 469.15. 'H NMR (300 MHz, DMSO-rfc): 8 12.63 (s, 1H), 7.89 (d, J= 7.5 Hz, 2H), 7.69 (d, J= 7.4 Hz, 2H), 7.47-7.26 (m, 5H), 6.01-5.73 (m, 1H), 5.35- 5.08 (m, 2H), 4.58-4.45 (m, 2H), 4.30 (d, J= 6.9 Hz, 2H), 4.23-4.19 (m, 1H), 3.97 (d, J= 8.8 Hz. 2H), 3.50-3.47 (m, 2H), 3.43-3.36 (m, 4H), 3.16-3.10 (m, 2H).Synthetic Scheme 11Step 1 Step 2FmocHNSS11bl-(9 / / -Fluoren-9-yl)-10-((2-nitrophenyl)sulfonyl)-3-oxo-2,7-dioxa-4,10-diazadodecan-12-oic acid (Ns-NxG44(Fmoc)-OH) (SS11)

[0293] Step 1: 2-nitrobenzenesulfonyl chloride (8.7 g, 39.4 mmol) was added to a stirred solution of tert-butyl glycinate hydrochloride (6.0 g, 35.8 mmol) and DIPEA (18.8 mL, 107.0 mmol) in DCM (120 mL) at 0 °C under N2. The solution was stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue was purified by a silica gel column chromatography, eluting with EtOAc 0-30% in PE to afford tert-butyl ((4- nitrophenyl)sulfonyl)glycinate (SSlla). MS ESI calculated for C12H15N2O6S [M - H]’ 315.07, found 314.90. *HNMR (400 MHz, chloroform-ty): d 8.15-8.06 (m, 1H), 8.00-7.92 (m, 1H), 7.81-7.70 (m, 2H). 6.05 (t, J= 5.7 Hz, 1H), 3.92 (d, J= 5.7 Hz, 2H), 1.33 (s, 9H).

[0294] Step 2: DIAD (6.3 mL. 32.2 mmol) was added to a stirred solution of triphenylphosphine (SSlla, 8.5 g, 32.2 mmol) in anh. THF (120 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 5 min, then tert-butyl ((4-nitrophenyl)sulfonyl)glycinate (8.5 g, 26.9 mmol) and (9 / L-fluoren-9-yl)methyl (2-(2-hydroxyethoxy)ethyl)carbamate (10.6 g, 32.2 mmol) were added to the solution. The mixture was stirred at 0 °C for 1 h, then over night at RT. The solvent was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography, eluting with EtOAc 0-45% in PE to afford tert-butyl l-(977-fluoren-9- yl)-10-((4-nitrophenyl)sulfonyl)-3-oxo-2,7-dioxa-4,10-diazadodecan-12-oate (SSllb). MS ESI calculated for CsiHssNsOgNaS [M + Na]+648.21, found 648.00. 'H NMR (300 MHz, chloroform- J): d 8.12-8.02 (m, 1H). 7.81-7.70 (m, 2H), 7.70-7.54 (m. 5H), 7.45-7.36 (m. 2H), 7.36-7.28 (m, 2H), 5.26 (s, 1H), 4.42 (d, J= 6.9 Hz, 2H), 4.28-4.19 (m, 1H), 4.18 (s, 2H), 3.61 (s, 4H), 3.50-3.39 (m, 2H), 3.37-3.24 (m, 2H), 1.36 (s, 9H).

[0295] Step 3 : TFA (150 mL) was added to a stirred solution of tert-butyl l-(9 / / -fluoren-9-yl)- 10-((4-nitrophenyl)sulfonyl)-3-oxo-2,7-dioxa-4,10-diazadodecan-12-oate (SSllb, 15.0 g, 24.0 mmol) in DCM (100 mL) at RT. The solution was stirred at RT for 3 h. The volatiles were removed under reduced pressure and the residue was purified by a silica gel column chromatography, eluting with MeOH 0-5% in DCM to afford l -(9 / / -fluoren-9-yl)- l 0-((2- nitrophenyl)sulfonyl)-3-oxo-2.7-dioxa-4,10-diazadodecan-12-oic acid (SS11). MS ESI calculated for C27H28N3O9S [M + H]+570.15, found 570.30. 'H NMR (300 MHz, chloroform-J): d 8. 11- 7.99 (m, 1H), 7.76 (d, J= 7.7 Hz, 2H), 7.70-7.47 (m, 5H), 7.44-7.35 (m, 2H), 7.35-7.27 (m, 2H), 5.16 (s, 1H), 4.42 (d, 6.9 Hz, 2H), 4.27 (s, 2H), 4.20 (t, J= 6.7 Hz, 1H), 3.57 (s, 4H),3.46-3.08 (m, 4H).Synthetic Scheme 12A'-(4-(((((9 / / -Fhioren-9-yl)methoxy)carbonyl)amiiio)methyl)benzyl)- / V-((2-nitrophenyl) sulfonyl)glycine (Ns-NxG45(Fmoc)-OH) (SS12)

[0296] Step 1: 2 -Nitrobenzene sulfonyl chloride (14.7 g, 66.3 mmol) in DCM (10 mL) was added to a solution of glycine methyl ester (5.0 g, 56.2 mmol) in water (10 mL) at 0 °C. Triethylamine (16.0 mL. 112 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at RT for 12 h, then diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), aq. 1 N HC1 (50 mL), and brine (50 mL), dried over anh. Na2SOr, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with EtOAc 10-90% in PE to afford methyl ((2- nitrophenyl)sulfonyl)glycinate (SS12a). MS ESI calculated for C9H10N2O6S [M + H]+275.03. found 275.26.

[0297] Step 2: DIAD (885 pL. 4.4 mmol) was added dropwise to a solution of methyl ((2- nitrophenyl)sulfonyl)glycinate (SS12a, 1.0 g, 3.7 mmol), tert-butyl (2-hydroxyethyl)carbamate (1.2 g, 4.4 mmol), and PPhs (1. 1 g, 4.4 mmol) in anh. THF (15 mL) at RT and under N2. The residue was diluted with DCM (100 mL) and washed with aq. 1 N HC1 (50 mL) and brine (50 mL), dried over anh. Na2SOr, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc 10-90% in PE to afford methyl A'-(4-(((7e / 7-buloxycarbonyl)amino)methyl)benzyl )- '-((2-nitrophenyl )sulfonyl)glycinate (SS12b). MS ESI calculated for C22H27N3O8S [M + H]+494.16, found 494.4.

[0298] Step 3: TFA (10 mL) was added to a mixture of methylbutoxycarbonyl)amino)methyl)benzyl)-A-((2-nitrophenyl)sulfonyl)glycinate (SS12b, 1.12 g, 2.3 mmol) in DCM (10 mL) at RT. The reaction was stirred at RT for 1 h then concentrated in vacuum to afford methyl A-(4-(aminomethyl)benzyl)-A-((2-nitrophenyl)sulfonyl)glycinate (SS12c), which was used directly in Step 4. MS ESI calculated for C17H19N3O6S [M + H]+394.10. found 394.44.

[0299] Step 4: Aq. 1 N LiOH (4.0 mL, 4.2 mmol) was added to a solution of methyl A-(4- (aminomethyl)benzyl)-A-((2-nitrophenyl)sulfonyl)glycinate (SS12c, 900 mg, 2.3 mmol) in THF (10 mL) and water (10 mL) at RT. The mixture was stirred for 3 h at RT. The mixture was diluted with water (100 mL) and freeze-dried. The crude material (SS12d) was used directly in Step 5 without further purification. MS ESI calculated for CieHnNsOeS [M + H]+380.09, found 380.20.

[0300] Step 5: Fmoc-OSu (0.77 g, 2.27 mmol) and potassium carbonate (0.94 g, 6.8 mmol) were added to a stirred solution of crude A-(4-(arrdnomethyl)benzyl)-A-((2- nitrophenyl)sulfonyl)glycine (SS12d, 0.86 g, 2.3 mmol) in 1,4-dioxane (10 mL) and water (10 mL) at 0 °C. The mixture was stirred at RT for 2 h. The pH of the mixture was adjusted to ~3 with aq. 1 M HC1. The reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers w ere washed with brine (50 mL), dried over anh. Na2SO4,, filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a C18 silica gel column (mobile phase: MeCN / water (0.05% NH4HCO3). 30-80% gradient of MeCN over 25 min; detector: UV 210 nm) to afford A-(4-(((((9 / / -fluoren-9- yl)methoxy)carbonyl)amino)methyl) benzyl)-N-((2-nitrophenyl)sulfonyl)glycine (SS12). MS ESI calculated for C31H28N3O8S [M + H]+602.16, found 603.45. ’H NMR (400 MHz, DMSO-cTs): 3 8.88 (s, 1H), 8.06-7.93 (m, 1H), 7.93-7.76 (m, 3H), 7.71-7.53 (m, 10H), 7.47-7.29 (m, 2H), 7.24-7. 13 (m, 2H), 4.87-4.68 (m, 1H), 4.56 (s, 1H), 4.47-4. 19 (m, 2H), 4. 15 (br d. J= 6.0 Hz. 1H), 4.08-3.90 (m, 6 H), 3.79-3.53 (m, 2H), 1.19 (d, J= 6.3 Hz, 6H), 1.15-0.99 (m, 1H).Synthetic Scheme 132-((((9 / / -Fluoren-9-yl)methoxy)carbonyl)amino)-A-(2-(2-(2-cat boxyethoxy)ethoxy)ethyl)-AyV-dimethylethan-l-aminium chloride (Fmoc-PEG2NMe2EtNH2-OH) (SS13)

[0301] Step 1: Sodium (0.016 g, 0.702 mmol) and tert-butyl acrylate (3.0 g, 23.4 mmol) were added to a stirred solution of 2,2'-oxybis(ethan-l-ol) (6.7 mL, 70.2 mmol) in anh. THF (45 rnL) at RT and under N2. The resulting mixture was stirred over night at RT then quenched by the addition of aq. sat. NH4CI (50 mL). The resulting mixture was extracted with EtOAc (3 * 100 rnL). The combined organic layers were washed with brine (3 x 100 mL), dried over anh. Na2SO4,, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with gradient EtOAc 0-70% in PE to afford tert-butyl 3-(2-(2- hydroxyethoxy)ethoxy)propanoate (SS13a).JH NMR (300 MHz. chloroform-<7): d 3.76-3.68 (m, 4H), 3.68-3.56 (m, 6H), 2.54-2.44 (m, 3H), 1.44 (s, 9H).

[0302] Step 2: Tetrabromomethane (10.6 g, 32.0 mmol) and PPh? (8.4 g, 32.0 mmol) were added to a stirred mixture of tert-butyl 3-(2-(2-hydroxy ethoxy )ethoxy)propanoate (SS13a, 2.5 g. 10.7 mmol) in anh. DCM (25 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h then quenched by the addition of water (80 mL). The solids were removed by filtration through a pad of Celite®. The filtrate was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anh. Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EtOAc 20- 50% in PE to afford tert-butyl 3-(2-(2-bromoethoxy)ethoxy)propanoate (SS13b). 'H NMR (300 MHz, chloroform-^ ): 8 3.81-3.73 (m, 4H), 3.68-3.58 (m, 4H), 3.45 (t, J= 6.3 Hz, 2H), 2.51- 2.47 (m, 2H), 1.44 (s, 9H).

[0303] Step 3: TFA (22 mL) was added to a stirred solution of tert-butyl 3-(2-(2- bromoethoxy)ethoxy)propanoate (SS13b, 2.2 g, 7.4 mmol) in DCM (22 mL) at 0 °C. The solution was stirred at RT for 2 h. The volatiles were removed under reduced pressure to afford 3-(2-(2-bromoethoxy)ethoxy)propanoic acid (SS13c), which was used in Step 4 without further purification. MS ESI calculated for CTHuBrCL [M + H] ' 241.00 / 243.00. found 240.95 / 242.95.

[0304] Step 4: NaHCCh (2.5 g, 29.9 mmol) and iodomethane (1.9 mL, 29.9 mmol) were added to a stirred solution of 3-(2-(2-bromoethoxy)ethoxy)propanoic acid (SS13c, 1.8 g, 7.5 mmol) in anh. DMF (18 mL) at 0 °C. The suspension was stirred over night at RT, then quenched by the addition of water (80 mL). The reaction mixture was extracted with EtOAc (3 x 120 mL). The combined organic layers were washed with brine (3 x 120 mL), dried over anh. Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with gradient EtOAc 0-45% in PE to afford a mixture of methyl 3-(2-(2- iodoethoxy)ethoxy)propanoate (SS13da) and methyl 3-(2-(2-bromoethoxy)ethoxy)propanoate (SS13db) (~1 : 1 ). MS ESI calculated for CsHi6BrO4 [M + H]+255.02 / 257.02, found 254.95 / 256.95; MS ESI calculated for C8Hi6lO4[M + H]+303.00, found 302.90.

[0305] Step 5 : tert-Butyl (2-(methylamino)ethyl)carbamate (1.6 g, 9.0 mmol) was added to a solution of methyl 3-(2-(2-bromoethoxy)ethoxy)propanoate (SS13db) and methyl 3-(2-(2- iodoethoxy)ethoxy)propanoate (SS13da) (—1:1) (1 g, 1.795 mmol) in EtOH (10 mL) at RT. The resulting mixture was stirred over night at RT then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH 0-5% in DCM to afford methyl 2,2,8-trimethyl-4-oxo-3,l l,14-trioxa-5,8-diazaheptadecan-17-oate (SS13e). MS ESI calculated for C16H33N2O6 [M + H]+349.23, found 349.15. 'H NMR (400 MHz, chloroform- d) <5 5.26 (s. 1H), 3.76 (t, J = 6.5 Hz, 2H). 3.69 (s, 3H). 3.65-3.56 (m, 6H), 3.25-3.21 (m, 2H), 2.68-2.57 (m, 6H), 2.33 (s, 3H), 1.45 (s, 9H).

[0306] Step 6 : lodomethane (0.27 mL, 4.30 mmol) was added to a stirred solution of methyl 2,2,8-trimethyl-4-oxo-3,l l,14-trioxa-5,8-diazaheptadecan-l 7-oate (SS13e, 300 mg, 0.86 mmol) in MeCN (6 mL) at RT. The reaction mixture was stirred at RT for 36 h, then concentrated under reduced pressure to afford crude 2-((terZ-butoxycarbonyl)amino)-A-(2-(2-(3-methoxy-3- oxopropoxy)ethoxy)ethyl)-A, / V-dimethylethan-l-aminium iodide (SS13f). MS ESI calculated for C17H35N2O6 [M - 1 ]+363.25, found 363.15.

[0307] Step 7: Aq. 1 N LiOH solution (1.63 mL, 1.63 mmol) was added to a solution of 2- ((te / 7-butoxycarbonyl)amino)-A-(2-(2-(3-methoxy-3-oxopropoxy)ethoxy)ethyl)-jVN- dimethylethan-l-aminium iodide (SS13f, 400 mg, 0.82 mmol) in THF (4 mL) at RT. The mixture was stirred at RT for 2 h. The reaction solution was acidified to pH ~ 5 with aq. 1 M HC1 andconcentrated under reduced pressure to afford crude 2-((' / c77-butoxycarbonyl)amino)-A'-(2-(2-(2- carboxyethoxy)ethoxy)ethyl)-AL / V-dimethylethan-l -aminium iodide (SS13g). MS ESI calculated for C16H33N2O6 [M - r]+349.23, found 349.15.

[0308] Step 8: 4 M HC1 in 1 ,4-dioxane (4 mL) was added to a stirred solution of 2-((tert- butoxycarbonyl)amino)-iV-(2-(2-(2-carboxyethoxy)ethoxy)ethyl)-AL / V-dimethylethan-l-aminium iodide (SS13g, 400 mg, 0.84 mmol) in THF (4 mL) at 0 °C. The resulting mixture was stirred at RT for 4 h then concentrated under reduced pressure to afford crude 2-amino-N-(2-(2-(2- carboxyethoxy)ethoxy)ethyl)- / V..V-dimethylethan- l -aminium chloride hydrochloride (SS13h). MS ESI calculated for C11H25N2O4 [M - HC1 - CT]+249.18. found 249.10.

[0309] Step 9: NaHCOs (16.0 g, 190 mmol) and Fmoc-OSu (12.8 g, 38.0 mmol) were added to a stirred solution of 2-amino-Ar-(2-(2-(2-carboxy ethoxy )ethoxy)ethyl)-;V.,V-dimethylethan- 1 - aminium chloride hydrochloride (SS13h, 12.2 g, 38.0 mmol) in THF (150 mL) and water (150 mL) at RT. The resulting mixture was stirred over night at RT then acidified to pH ~3 with aq. 1 N HC1. The solvents were concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a C18 silica gel column (mobile phase: MeCN / water (1.5 mM HC1), 25-70% gradient of MeCN over 35 min; detector: UV 210 nm) to give 2-((((977-fluoren-9- yl)methoxy)carbonyl)amino)-N-(2-(2-(2-carboxyethoxy)ethoxy)ethyl)-ALV-dimethylethan-l- aminium chloride (SS13). MS ESI calculated for C26H35N2O6 [M - Cl ]+471.22, found 471.20. 'H NMR (300 MHz, DMSO-Js): 8 7.90-7.85 (m, 2H), 7.79-7.63 (m, 3H), 7.50-7.28 (m, 4H), 4.39-4.37 (2H), 4.24-4.22 (m, 1H), 3.82 (s, 2H), 3.67-3.48 (m, 8H), 3.42 (s, 4H), 3.11 (s, 6H), 2.44-2.41 (m, 2H).Synthetic Scheme 14Step 1 Step 2(S)-3-(4-(((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)methyl)phenyl)-2-((l-(4,4-dimethyl- 2,6-dioxocycIohexylidene)ethyl)amino)propanoic acid (Dde-Phe4CH2NHFmoc-OH) (SS14)

[0310] Step 1 : Fmoc-OSu (3.6 g, 10.7 mmol) and AlA-diisopropylethylamine (3.6 mL, 20.6 mmol) were added to a solution of 4-(aminomethyl)-A-Boc-L -phenylalanine (2.5 g, 8.5 mmol) in a mixture of DCM (30 mL) and THF (30 mL) at RT. The reaction mixture was stirred over night at RT. The volatiles were removed under reduced pressure to afford (5)-3-(4-(((((9 / 7-fluoren-9- yl)methoxy)carbonyl)amino)methyl)phenyl)-2-((Zert-butoxycarbonyl)amino)propanoic acid (SS14a), which was used directly in the next step. MS ESI calculated for C30H32N2O6Na [M + Na]+539.2, found 539.2.

[0311] Step 2: 1,4 - dioxane hydrochloride (20 mL, 80 mmol, 4 M) was added dropwise to a solution of (<S’)-3-(4-(((((97f-fluoren-9-yl)methoxy)carbonyl)amino)methyl)phenyl)-2-((ferL butoxycarbonyl)amino)propanoic acid (SS14a, 8.5 mmol) in THF (30 mL) at 0 °C. The reaction mixture was stirred at RT for 4 h. The volatiles were removed in vacuum to afford fS')-3-(4- (((((977-fluoren-9-yl)methoxy)carbonyl)amino)methyl)phenyl)-2-aminopropanoic acid (SS14b), which was used directly in Step 3 without further purification. MS ESI calculated for C25H25N2O4 [M + H]+417.2, found 417. 1.

[0312] Step 3: TEA (9 mL, 64.6 mmol) and 2-(l-hydroxyethylidene)-5,5- dimethylcyclohexane- 1,3-dione (3.2 g, 17.6 mmol) were added to a suspension of (<S)-3-(4- (((((927-fluoren-9-yl)methoxy)carbonyl)amino)methyl)phenyl)-2-aminopropanoic acid (SS14b, 8.5 mmol) in EtOH (40 mL) and DCM (50 mL) at RT. The reaction was stirred over night at RT. The reaction mixture was partially concentrated in vacuum. The residue was acidified with aq. 1 N HC1 to pH ~3-4 and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with MeOH 0-10% in DCM to afford (5)-3-(4-(((((97f-fluoren-9-yl)methoxy)carbonyl)amino)methyl)phenyl)-2-((l- (4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)propanoic acid (SS14). MS ESI calculated for C39H43N2O6 [M + H]+635.30, found 581.3. *HNMR (600 MHz, DMSO-c*): 8 13.49 (d, J = 6.4 Hz. 1H), 7.89 (d, J= 7.5 Hz. 2H), 7.83 (t, 7 = 6. 1 Hz, 1H), 7.70 (d, 7= 7.5 Hz, 2H), 7.42 (t, 7 = 7.4 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 7.22 (s, 1H), 7.17-7.10 (m, 4H), 5.75 (s, 1H), 4.88 (dt, J = 12.5, 6.3 Hz, 1H), 4.66 (d, 7= 5.5 Hz, 1H), 4.34 (d, 7= 7.0 Hz, 2H), 4.22 (t, 7= 6.8 Hz, 1H), 4.15 (d, 7= 6.1 Hz, 2H), 3.24-3.17 (m, 1H), 3.09-3.02 (m, 1H), 2.28 (s, 3H), 0.93 (s, 6H).Synthetic Scheme 15(A)-2-((((9 / / -fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((2- (((benzyloxy)carbonyl)amino)ethyl)carbamoyl)phenyl)propanoic acid (Fmoc- Phe4COEDA(Cbz)-OH) (SS15)

[0313] Step 1: HATU (1.72 g, 4.51 mmol), MeOH (0.25 mL, 6.15 mmol), and DIPEA (1.58 mL, 9.02 mmol) were added to a solution of (S)-2-((((977-fluoren-9- yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid (2.00 g, 4.10 mmol) in DMF (10 mL). The resulting solution was stirred at RT for 1.5 h. The reaction solution was partitioned between EtOAc (200 mL) and brine (200 mL). The organic phase was washed with brine (2 x 200 mL), dried over Na2SO4,, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with 0-40% EtOAc in hexane to give terLbutyl (S)- 4-(2-((((977-fluoren-9-yl)methoxy) carbonyl)amino)-3-methoxy-3-oxopropyl)benzoate (SS15a). MS ESI calculated for C30H31NO6 [M + H]+524.2, found 524.3.

[0314] Step 2: TFA (20 mL, 260 mmol) was added to a stirred solution of tert-butyl (S)-4-(2- ((((977-fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-oxopropyl)benzoate (SS15a, 2.06 g, 4. 1 mmol) in DCM (5 mL). The resulting solution was stirred at RT for 1 h, then concentrated to give the crude product (<S’)-4-(2-((((92 / -fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-oxopropyl)benzoic acid (SS15b). MS ESI calculated for C26H23NO6 [M + H]+446.2. found446.1.

[0315] Step 3: HATU (1.64 g, 4.3 mmol) and DIPEA (2.256 mL, 12.92 mmol) were added to a stirred solution of (<S)-4-(2-((((97 / -fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3- oxopropyl)benzoic acid (SS15b. 1.83 g. 4.1 mmol) and benzyl (2-aminoethyl)carbamate hydrochloride (0.99 g, 4.3 mmol) in anh. DMF (20 mL). The resulting solution was stirred at RT for 2 h. The reaction mixture was partitioned between EtOAc (200 mL) and brine (200 mL). The organic layer was washed with brine (200 mL). The product precipitated from the organic phase, and the solids were collected by filtration. The solids were washed with EtOAc (3 x 20 mL). and dried under vacuum to give methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((2- (((benzyloxy) carbonyl)amino)ethyl)carbamoyl)phenyl)propanoate (SS15c). MS ESI calculated for C36H35N3O7 [M + H]+622.2, found 622.4.

[0316] Step 4 : LiOH (15.4 mL, 15.4 mmol, 1 n in water) was added dropwise to a solution of methyl (<S’)-2-((((97 / -fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((2- (((benzyloxy)carbonyl)amino)ethyl)carbamoyl)phenyl)propanoate (SS15c, 2.4 g, 3.9 mmol) in THF (100 mL), MeOH (30 mL), and DI water (30 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h, then at RT for 2 h. The volatiles were evaporated under reduced pressure, the aqueous phase was neutralized to pH 6 by addition of aq. 1 N HC1 (~ 15 mL). Sodium carbonate (0.82 g, 7.72 mmol) and acetone (150 mL) were added followed Fmoc-OSu (1.37 g, 4.05 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched by addition of 1 N aq. HC1 (7.5 mL). The volatiles were removed under reduced pressure. The aqueous phase was acidified to pH 3 by addition of 1 N aq. HC1. The resulting precipitate was collected byfiltration. washed with water (2 x 50 mL). DCM (3 x 50 mL), and acetonitrile (2 x 50 mL), and dried under vacuum. The filtrate was extracted with DCM (3 x 100 mL). The combined organic phases were dried over Na2SO4, and concentrated in vacuum. The residue was triturated with DCM (50 mL). The solids were collected by filtration and washed with DCM (3 x 20 mL) to give (S)-2-((((9 -fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((2- (((benzyloxy)carbonyl)amino)ethyl)carbamoyl)phenyl) propanoic acid (SS15). ’H NMR (500 MHz, d6-DMSO- e): <5 8.42 (s, 1H), 7.89 (d, J= 5.0 Hz, 2H), 7.71 (d, J= 10.0 Hz, 2H), 7.63 (d, J= 10.0 Hz, 2H), 7.43-7.25 (m, 10H). 5.03 (s, 2H), 4.24-4.18 (m, 3H). 3.34-3.32 (m, 2H), 3.18- 3.16 (m, 2H), 3.13-3.10 (m,lH), 2.98-2.94 (m, 2H).MS ESI calculated for C36H35N3O7 [M + H]+608.2, found 608.4.Synthetic Scheme 16Step 11) AC2O;DI PEASS16C Fmoc-Phe4COspdiAze(Ac)-OH (SS16)(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(6-acetyl-2,6- diazaspiro [3.3] heptane-2-carbonyl)phenyl)propanoic acid (F moc-Phe4COspdiAze(Ac)-OH) (SS16)

[0317] Step 1: Acetic anhydride (125 pL, 1.3 mmol) and DIPEA (350 pL, 2.0 mmol) were added to a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (198 mg, 1 mmol) in ACN (1 mL). The reaction mixture was stirred at RT for 3 h. The volatiles were removed under reduced pressure. The solution of crude material in 4 N HC1 in dioxane (2 mL) was stirred at RT for 4 h. The volatiles were removed under reduced pressure and the crude mixture (SS16a) was used directly in Step 2 without further purification.

[0318] Step 2: To a solution of (S)-2-((((977-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(te / T- butoxycarbonyl)phenyl)propanoic acid (2.0 g. 4.1 mmol) in a 3: 1 mixture (v / v. 22 mL) of toluene and methanol at 0 °C under N2 atmosphere was added dropwise a 0.6 M solution of (trimethylsilyl)diazomethane in hexane (8.2 mL, 4.9 mmol) over a period of 10 min. The reaction was quenched by addition of AcOH (100 pL). The reaction mixture was diluted with EtOAc (100mL) and washed with aq. 1 N HC1 (30 mL). brine (30 mL), and dried over anh. Na2SO4, filtered then concentrated to dryness under vacuum.

[0319] TFA (5 mL) was added to the solution of crude material in DCM (5 mL). The mixture was stirred at RT for 1 h. The volatiles were removed under reduced pressure. The crude material was diluted with EtOAc (100 mL) and washed with aq. 1 N HC1 (30 mL) and brine (30 mL). The organic layer was dried over anh. NazSCh, filtered, and concentrated in vacuo. The residue was purified by Rp flash chromatography using a C 18 silica gel column to give (,S')-4-(2-((((9H- fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-oxopropyl)benzoic (SS16b). MS ESI calculated for C26H24NO6 [M + H]+446.2. found 446.5.

[0320] Step 3: A solution of (6 -4-(2-((((97 / -fluoren-9-yl)methoxy)carbonyl)amino)-3- meth oxy-3 -oxopropyl)benzoic acid (SS16b, 223 mg, 0.5 mmol), DIPEA (262 pL, 1.5 mmol), and HATU (209 mg, 0.55 mmol) in anh. DCM (2.5 mL) was added to a suspension of 6-acetyl-2.6-diazaspiro[3.3]heptan-2-ium (SS16a, 88 mg, 0.5 mmol) in anh. DCM (2.5 mL) under N2 atmosphere at RT. The reaction mixture was stirred at RT for 3 h. The volatiles were removed under reduced pressure, and the residue was purified by Rp flash chromatography using a Luknova™ cartridge (mobile phase: MeCN / water, 90-90% gradient of MeCN; detector: UV 210 nm) to obtain methyl (S)-2-((((9 7-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(6-acetyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)propanoate (SS16c). MS ESI calculated for C33H34N3O6 [M + H]+568.2, found 568.6.

[0321] Step 4 : A solution of lithium hydroxide (22.8 mg, 0.95 mmol) in DI water (1 mL) was added to a solution of methyl (<S)-2-((((977-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(6-acetyl-2.6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)propanoate (SS16c, 216 mg, 0.38 mmol) in a 1 : 1 (v / v; 10 mL) mixture of water and THF at 0 °C. The reaction was allowed to warm to RT and was stirred at RT for 2 h. The reaction was quenched by addition of TFA, and the volatiles were removed under reduced pressure. The crude material was purified by Rp flash chromatography using a Luknova™ cartridge (mobile phase: MeCN / water, 90-90% gradient of MeCN: detector: UV 210 nm) to afford (5)-2-((((977-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(6-acetyl-2.6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)propanoic acid (SS16). 'H NMR (400 MHz, DMSO- d6y. d 12.81 (s, 1H), 7.88 (d, J= 7.5 Hz, 2H), 7.80 (d, J= 8.6 Hz, 1H), 7.68-7.61 (m, 2H), 7.56- 7.47 (m, 2H), 7.44-7.27 (m, 6H), 4.27-4.20 (m, 4H), 4.20-4.10 (m, 5H), 4.09-3.99 (m, 1H), 3.99-3.81 (m, 2H), 3.15 (dd. J= 3.7, 13.8 Hz. 1H), 2.97-2.87 (m, 1H), 1.72 (s. 3H). MS ESI calculated for C32H32N3O6 [M + H]+554.2, found 554.7.Synthetic Scheme 17(A)-3-(4-(9-(((9H-Fluoren-9-yl)methoxy)carbonyl)-3,9-diazaspiro[5.5|undecane-3- carbonyl)phenyl)-2-((l-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)propanoic acid (Dde-Phe4COspdi4Pip(Fmoc))-OH) (SS 17)

[0322] Step 1: PPhs (17.8 g, 67.9 mmol), imidazole (5.7 g, 84.0 mmol), and iodine (15.2 g, 59.9 mmol) were added to a solution of benzyl (rerl-butoxycarbonyl)-L-serinate (11.8 g, 40.0 mmol) in DCM (150 mL) at RT. The reaction was stirred at RT for 3 h. The reaction mixture was quenched with aq. sat. Na2SOs (300 mL) and extracted with EtOAc (3 x 600 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with EtOAc 0- 35%in PE to afford benzyl (A)-2-((te / 7-butoxycarbonyl)amino)-3-iodopropanoate (SS17a). MS ESI calculated for Ci5H2oIN04Na [M + Na]+428.04, found 428.05. ‘H NMR (400 MHz, chloroform-r / ): d 7.42-7.36 (m, 5H), 5.24-5.20 (m, 2H), 4.63-4.51 (m, 1H), 3.70-3.51 (m, 2H), 1.48 (s, 9H).

[0323] Step 2: 4-Iodobenzoic acid (3.0 g, 12.0 mmol) and DMAP (0.12 g, 1.0 mmol) were added to a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2.5 g, 10.0 mmol) in DCM (30 rnL) at RT. The reaction was cooled to 0 °C, and DCC (3. 1 g, 15.0 mmol) was added to the mixture. The resulting mixture was stirred over night at RT. The resulting suspension was filtered through a pad of Celite® and washed by DCM (2 x 40 mL). The filtrate was concentrated in vacuum. The residue was purified by a silica gel chromatography, eluting with EtOAc 0-35% in PE to afford tert-butyl 9-(4-iodobenzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (SS17b). MS ESI calculated for C21H29IN2O3 [M - / Bu + H]+429. 12. found 429.00. 'l l NMR (400 MHz, chloroform- ): S 7.80-7.73 (m, 2H). 7.18-7.12 (m, 2H), 3.81-3.64 (m, 2H), 3.44-3.32 (m. 6H), 1.76-1.49 (m, 8H), 1.47 (s, 9H).

[0324] Step 3 : TFA (50 mL) was added to a solution of tert-butyl 9-(4-iodobenzoyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (SS17b, 4.8 g, 9.9 mmol) in DCM (50 mL) at RT. The reaction was stirred at RT for 2 h. The volatiles were concentrated in vacuum to afford (4- iodophenyl)(3.9-diazaspiro[5.5]undecan-3-yl)methanone (SS17c), which was used directly in Step 4. MS ESI calculated for C16H22IN2O [M + H]+385.07, found 385.00.

[0325] Step 4: NaHCCh (4.0 g, 48.0 mmol) and Fmoc-OSu (3.6 g, 10.6 mmol) were added to a mixture of (4-iodophenyl)(3,9-diazaspiro[5.5]undecan-3-yl)methanone (SS17c, 4.1 g, 9.6 mmol) in THF (40 mL) and water (40 mL) at RT. The reaction was stirred at RT for 2 h. The reaction mixture was acidified to pH ~4 with aq. 1 N HC1 and extracted with EtOAc (200 mL). The organic layer was washed with brine (2 x 80 rnL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc 0-28% in PE to afford (9H-fluoren-9-yl)melhyl 9-(4-iodobenzoyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (SS17d). MS ESI calculated for C31H32IN2O3 [M + H]+607.14, found 607.05. ‘H NMR (300 MHz, chloroform- ): b' 7.80-7.72 (m, 4H), 7.61-7.54 (m, 2H), 7.44-7.27 (m, 4H), 7.18-7.10 (m, 2H), 4.45 (d, J= 6.6 Hz, 2H), 4.23 (t, J= 6.6 Hz, 1H), 3.78-3.25 (m, 8H), 1.74-1.28 (m, 8H).

[0326] Step 5: 1.10-phenanthroline hydrochloride (0.44 g, 2.05 mmol) was added to a stirred solution of nickel (II) chloride ethylene glycol dimethyl ether complex (0.45 g, 2.05 mmol) in anh. DMA (50 mL) at RT and under N2. The solution was stirred at 50 °C for 1 h. Benzy l ( / )-2- ((tert-butoxycarbonyl)amino)-3-iodopropanoate (SS17a, 4.56 g, 11.24 mmol), (9 / / -fluoren-9- yl)methyl 9-(4-iodobenzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (SS17d, 6.20 g. 10.22 mmol), tetrabutylammonium iodide (3.92 g, 10.22 mmol), and activated zinc (1.34 g, 20.45 mmol) were added to the mixture at RT. The suspension was stirred at RT for 2 h. The reaction mixture was quenched with water (150 mL) and extracted with EtOAc (3 x 300 mL). Thecombined organic layers were washed with brine (2 x 100 mL). dried over anh. Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting EtOAc 0-32% in PE to afford (977-fluoren-9-yl)methyl (5')-9-(4-(3-(benzylo\y)-2-(( / c / 7- butoxycarbonyl)amino)-3-oxopropyl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (SS17e). MS ESI calculated for C46H52N3O7 [M + H]1758.37, found 758.35. 'H NMR (300 MHz, acetonitrile-d3): <5 7.85 (d, J= 7.5 Hz, 2H), 7.65 (d, J= 7.5 Hz, 2H), 7.48-7.33 (m, 9H), 7.33- 7.21 (m, 4H), 5.15 (s, 2H), 4.54-4.40 (m, 3H), 4.28 (t, J= 6.0 Hz, 1H), 3.79-3.22 (m, 8H), 3.22- 2.94 (m, 2H), 1.57-1.27 (m, 17H).

[0327] Step 6: (927-Fluoren-9-yl)methyl (<S)-9-(4-(3-(benzyloxy)-2-((te / 7- butoxycarbonyl)ammo)-3-oxopropyl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (SS17e, 4.6 g, 6.1 mmol)was dissolved in EtOAc (50 mL). The flask was evacuated and refilled with N2 (5 times). Pd / C (1.5 g, 14.1 mmol, dry. 10 wt. %) was added into the flask. The flask was evacuated and backfilled with H2 (5 times). The resulting mixture was stirred for 2 h at RT under an atmosphere of dihydrogen. The flask was evacuated and refilled with N2 (5 times). The resulting mixture was filtered through a Celite* pad. The filtered cake was washed with THF (2 x 50 mL). The filtrate w as concentrated under reduced pressure to afford (S)-3-(4-(9-(((977-fluoren- 9-yl)methoxy)carbonyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2-((te / 7- butoxycarbonyl)amino)propanoic acid (SS17f), which was used in Step 7 without further purification. MS ESI calculated for CssHjsNsOvNa [M + Na]+690.33, found 690.30.

[0328] Step 7: TFA (40 mL) was added to a solution of (1S)-3-(4-(9-(((977-fluoren-9- yl)methoxy)carbonyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2-((to7- butoxycarbonyl)amino)propanoic acid (SS17f, 3.5 g, 4.5 mmol) in DCM (40 mL) at RT. The reaction was stirred at RT for 2 h, then concentrated under reduced pressure to afford (S)-3-(4-(9- (((977-fluoren-9-yl)methoxy)carbonyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2- aminopropanoic acid (SS17g), which was used in Step 8 without further purification. MS ESI calculated for C34H3sN3O5[M + H]+568.27, found 568.25.

[0329] Step 8: DIPEA (3. 1 mL, 17.6 mmol) and 2-( 1 -hydroxy ethylidene)-5, 5- dimethyl cyclohexane- 1, 3-dione (1.2 g, 6.6 mmol) were added to a solution of (S)-3-(4-(9-(((97f- fluoren-9-yl)methoxy)carbonyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2- aminopropanoic acid (SS17g, 3.2 g, 4.4 mmol) in MeOH (30 mL) at RT. The reaction was stirred at RT for 4 h. the reaction mixture was then diluted with water (130 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 120 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with MeOH 0-15% in DCM to afford (<S)-3-(4-(9-(((977-fluoren-9-yl)methoxy)carbonyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)-2-((l-(4.4- dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)propanoic acid (SS17). MS ESI calculated for C44H50N3O7 [M + H]+732.16, found 732.35. 'H NMR (300 MHz, methanol-^): 8 7.79 (d, J= 7.5 Hz. 2H), 7.59 (d, J= 7.5 Hz. 2H), 7.42-7.27 (m, 8H), 4.98-4.90 (m, 1H), 4.51 (d, J= 5.7 Hz, 2H), 4.21 (t, J= 5.7 Hz, 1H), 3.75-3.62 (m, 2H), 3.45-3.37 (m. 2H), 3.36-3.32 (m, 2H). 3.25- 3.13 (m, 2H), 2.35 (s, 4H), 2.28 (s, 3H), 1.58-1.37 (m, 5H), 1.35-1.20 (m, 3H), 1.01 (s, 6H).Synthetic Scheme 18(5)-3-(4-(l-(((9 / / -Fluoren-9-yl)methoxy)carbonyl)piperidin-4-yl)phenyl)-2-((l-(4,4- dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)propanoic acid (Dde-Phe4Pip4Fmoc-OH) (SS18)

[0330] Step 1 : A solution of K2CO3 (5.0 g, 36.0 mmol) in water ( 18 mL) was added to a solution of (<S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoic acid (4.7 g, 12.0 mmol) in 1,4-dioxane (102 mL). [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.8 g, 2.4 mmol) and benzyl 4-(4.4.5.5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihy dropyri dine- l(2 / 7)-carboxy late (6.2 g, 18.0 mmol) were added to the solution at RT underAr. The reaction mixture was heated at 80 °C for 1 h. The reaction mixture was acidified with aq. 0. 1 M HC1 and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over anh. MgSO-i. filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography, eluting with MeOH 0-7% in DCM to afford (S)-3-(4-(l-((benzyloxy)carbonyl)- l,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-((to7-butoxycarbonyl)amino)propanoic acid (SS18a). MS ESI calculated for C27H33N2O6 [M + H]+481.23, found 481.10.XH NMR (300 MHz, chloroform-c / ): 87.42-7.27 (m, 7H), 7.15 (d, J= 8.0 Hz, 2H), 5.99 (s, 1H), 5.30 (s, 2H), 4.98 (d, J= 8.2 Hz, 1H), 4.66-4.55 (m, 1H), 4.19-4.09 (m, 2H), 3.76-3.64 (m, 2H), 3.25-2.99 (m, 2H), 2.52-2.50 (m, 2H), 1.24 (s, 9H).

[0331] Step 2: (5)-3-(4-(l-((Benzyloxy)carbonyl)-l,2,3,6-tetrahydropyridin-4-yl)phenyl)-2- ((ter / -butoxycarbonyl)amino)propanoic acid (SS18a, 5.0 g, 10.4 mmol) was dissolved in EtOH (50 mL). The flask was evacuated and refilled with N2 (5 times). Pd / C (1.0 g, 0.94 mmol, dry', 10 wt. %) was added into the flask. The flask was evacuated and backfilled with H2 (5 times). The resulting mixture was stirred for 6 h at RT under an atmosphere of dihydrogen. The flask was evacuated and refilled with N2 (5 times). The resulting mixture was filtered through a Celite® pad. The filtered cake was washed with MeOH (2 x 50 mL). The filtrate was concentrated under reduced pressure to afford (<S)-2-((tert-butoxycarbonyl)amino)-3-(4-(piperidin-4- yl)phenyl)propanoic acid (SS18b), which was used directly in the next step without further purification. MS ESI calculated for C19H29N2O4 [M + H]+349.20, found 349.25.

[0332] Step 3: NaHCOs (3.7 g, 44.2 mmol) and Fmoc-OSu (2.7 g, 8.0 mmol) were added to a solution of GS')-2-(0e / 7-butoxycarbonyl)amino)-3-(4-(piperidin-4-yl)phenyl)propanoic acid (SS18b, 3.5 g, 8.8 mmol) in THF (10 mL) and water (10 mL) at RT. The reaction was stirred at RT for 2 h. The resulting solution was acidified to pH ~5 with aq. 0. 1 M HC1 and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with MeOH 0-7% in DCM to afford (5)-3-(4-(l-(((977- fluoren-9-yl)methoxy)carbonyl)piperidin-4-yl)phenyl)-2-((terCbutoxycarbonyl)amino)propanoic acid (SS18c). MS ESI calculated for C34H39N2O6 [M + H]+571.27, found 571.20. 'H NMR (300 MHz, DMSO-tfe): 8 7.95-7.85 (m, 2H), 7.69-7.59 (m, 2H), 7.46-7.27 (m, 4H), 7.22-7.06 (m, 5H), 4.45-4.40 (m, 2H), 4.28 (t, J= 6.1 Hz, 1H), 4.13-3.89 (m, 5H), 3.03-2.91 (m, 1H), 2.90- 2.71 (m, 3H), 2.62-2.60 (m, 1H), 1.65-1.64 (m. 2H), 1.32 (s, 9H).

[0333] Step 4: TFA (40 mL) was added to a solution of (5)-3-(4-(l-(((9 / 7-fluoren-9- yl)methoxy)carbonyl)piperidin-4-yl)phenyl)-2-((ter / -butoxycarbonyl)amino)propanoic acid (SS18c, 3.9 g, 6.8 mmol) in DCM (40 mL) at RT. The reaction was stirred at RT for 1 h. Thevolatiles were removed in vacuum to afford (<S’)-3-(4-(l-(((9 / / -fluoren-9- yl)methoxy)carbonyl)piperidin-4-yl)phenyl)-2-aminopropanoic acid (SSlSd), which was used directly in Step 5 without further purification. MS ESI calculated for C29H31N2O4 [M + H | 471.22. found 471.15.

[0334] Step 5: DIPEA (2.2 mL, 12.5 mmol) and 2-( 1 -hydroxy ethylidene)-5, 5- dimethyl cyclohexane- 1, 3-dione (1.6 g, 8.9 mmol) were added to a solution of (S)-3-(4-(l-(((977- fluoren-9-yl)methoxy)carbonyl)piperidin-4-yl)phenyl)-2-aminopropanoic acid (SS18d, 3.5 g, 6.0 mmol) in MeOH (40 mL) at RT. The reaction was stirred at RT for 4 h. The reaction mixture was concentrated in vacuum. The residue was acidified with aq. HC1 to pH ~3-4 and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anh. Na2SO4,, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with MeOH 0-11% in DCM to afford GS')-3-(4-(l -(((9H- fluoren-9-yl)methoxy)carbonyl)piperidin-4-yl)phenyl)-2-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)propanoic acid (SS18). MS ESI calculated for C39H43N2O6 [M + H]+635.30, found 635.30. ‘H NMR (300 MHz, DMSO-Je): 6 13.61-13.39 (m, 2H), 7.88 (d, J= 7.5 Hz, 2H), 7.64 (d, J= 7.2 Hz, 2H), 7.45-7.31 (m, 4H), 7.18-7.06 (m, 4H), 4.95-4.80 (m, 1H), 4.58-4.22 (m. 3H), 4.13-3.76 (m, 2H), 3.24-3.14 (m, 1H), 3.09-2.94 (m, 1H), 2.80 (s, 2H), 2.69-2.54 (m, 1H), 2.28 (s, 7H). 1.63 (s. 2H), 1.39-1.13 (m, 2H). 0.94 (s. 6H).Synthetic Scheme 19(5)-3-(4-(4-(((9 / / -Fluoren-9-yl)methoxy)carbonyl)piperazin-l-yl)phenyl)-2-((l-(4,4- dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)propanoic acid (Dde-Phe4Piperaz(Fmoc)- OH) (SS19)

[0335] Step 1 : / c / 7-Butyl piperazine- 1 -carboxylate (4.8 g, 25.6 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-l,l'- biphenyl)]palladium(II) (1.0 g, 1.3 mmol), and CS2CO3 (12.5 g. 38.3 mmol) were added to a solution of CS>2-((to7-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoic acid (5.0 g, 12.8 mmol) in 1,4-dioxane (50 mL) at RT under Ar. The mixture was stirred over night at 100 °C. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a C18 silica gel column (mobile phase: MeCN / water (0.05% TFA), 5-95% gradient of MeCN over 35 min: detector: UV 210 nm) to afford S)-2- (tert- butoxycarbonyl)amino)-3-(4-(4-(h?ri-butoxycarbonyl)piperazin-l-yl)phenyl)propanoic acid (SS19a). MS ESI calculated for C23H36N3O6 [M + H]+450.25, found 450.20. 'H NMR (300 MHz, chloroform- ): <5 7.46 (d, J= 8.2 Hz, 2H). 7.34 (d, J= 8.2 Hz, 2H), 4.60-4.53 (m, 1H), 3.92 (s, 4H), 3.52 (s, 4H), 3.21-3.26 (m. 2H), 1.50 (s. 9H), 1.43 (s, 9H).

[0336] Step 2: TFA (20 mL) was added to a stirred solution of (S)-2-((tert- butoxycarbonyl)amino)-3-(4-(4-(terLbutoxycarbonyl)piperazin-l-yl)phenyl)propanoic acid (SS19a, 4. 1 g, 9. 1 mmol) in DCM (20 mL) at RT. The solution was stirred at RT for 4 h. The volatiles were removed under reduced pressure to give (S)-2-amino-3-(4-(piperazin-l- yl)phenyl)propanoic acid (SS19b), which was used directly in the next step. MS ESI calculated for C 13H20N3O2 [M + H]+250. 15, found 250.10.

[0337] Step 3: 2-(l-hydroxyethylidene)-5,5-dimethylcyclohexane-l, 3-dione (2.2 g, 12.0 mmol) and DIPEA (4.2 mL, 24.1 mmol) were added to a stirred solution of (S)-2-amino-3-(4-(piperazin- 1-yl) phenyl)propanoic acid (SS19b, 2.0 g, 8.0 mmol) in MeOH (40 mL) at RT. The mixture was stirred at RT for 4 h, and then concentrated under reduced pressure to afford (S)-2-((l-(4,4- dimethyl-2,6-dioxocyclohexylidene) ethyl)amino)-3-(4-(piperazin-l-yl)phenyl)propanoic acid (SS19c). MS ESI calculated for C23H32N3O4 [M + H]+414.23, found 414.35.

[0338] Step 4: NaHCOs (2.3 g, 27.8 mmol) and Fmoc-OSu (1.7 g, 5.0 mmol) were added to a solution of (5)-2-((l -(4, 4-dimethyl-2,6-di oxocyclohexylidene) ethyl)amino)-3-(4-(piperazin-l- yl)phenyl)propanoic acid (SS19c, 2.3 g, 5.6 mmol) in THF (23 mL) and H2O (23 mL) under Ar and at RT. The reaction was stirred over night at RT. The reaction mixture was acidified to pH ~3 with aq. 1 M HC1 and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (150 mL), dried over anh. Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a Cl 8 silica gel column(mobile phase: MeCN / water (0.1% TFA). 5-55% gradient of MeCN over 40 min; detector: UV 210 nm) to give (N)-3-(4-(4-(((977-fluoren-9-yl)methoxy)carbonyl)piperazin-l-yl)phenyl)-2-((l- (4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)propanoic acid (SS19). MS ESI calculated for C38H42N3O6 [M + H]+636.30, found 636.25. ’H NMR (400 MHz, methanol-^): <5 7.82 (d, J= 7.4 Hz. 2H), 7.64 (d. J= 7.4 Hz. 2H), 7.49-7.28 (m, 4H). 7.18 (d, J = 8.3 Hz, 2H). 6.99-6.97 (m, 2H), 4.88 (d, J = 4.5 Hz, 1H), 4.59 (d, J= 5.7 Hz, 2H), 4.29-4.26 (m, 1H), 3.53-3.44 (m, 4H), 3.32-3.30 (m, 1H), 3.18-2.91 (m, 5H), 2.38 (s, 4H), 2.30 (s, 3H), 1.04 (s, 6H).Synthetic Scheme 20(A')-3-(4-(3-((((9 / / -Fhioren-9-yl)methoxy)carbonyl)amino)prop-l-yn-l-yl)phenyl)-2-((l-(4,4- dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)propanoic acid (Dde-Phe4PrgNHFmoc- OH) (SS20)

[0339] Step 1: (9 / 7-Fluoren-9-yl)methyl prop-2-yn-l-ylcarbamate (7.1 g, 25.6 mmol), copper(I) iodide (0.1 g, 0.5 mmol), bis(triphenylphosphine) palladium(II) dichloride (0.5 g, 0.8 mmol), and Et?N (8.9 mL, 63.9 mmol) were added to a solution of (S)-2-((tert- butoxycarbonyl)amino)-3-(4-iodophenyl)propanoic acid (5.0 g, 12.8 mmol) in anh. DMF (50 mL) at RT and under Ar. The resulting mixture was stirred at RT for 3 h. Water (50 mL) and Fmoc-OSu (4.3 g, 12.8 mmol) were added. The resulting mixture was stirred at RT for 4 h. The resulting solution was acidified to pH 5~ with 1 M HC1 and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anh. NazSCh, filtered, and concentrated in vacuum.

[0340] The residue was purified by Rp flash chromatography using a C 18 silica gel column (mobile phase: MeCN / water (0.05% TFA), 2-55% gradient of MeCN over 28 min; detector: UV 210 nm) to give (S)-3-(4-(3-((((9 / 7-fluoren-9-yl)methoxy)carbonyl)amino)prop-l-yn-l-yl)phenyl)-2-(( / c77-butoxycarbonyl)amino)propanoic acid (SS20a). MS ESI calculated for C32H32N2O6Na [M + Na]+563.23, found 563. 15. 'H NMR (300 MHz, chloroform-^ / ): 3 7.80-7.73 (m, 2H), 7.59 (d, J= 7.7 Hz, 2H), 7.44-7.27 (m, 6H), 7.12 (d, J= 7.9 Hz, 2H), 5.19-4.91 (m, 1H), 4.66-4.34 (m. 3H), 4.25-4.17 (m, 2H), 3.24-3.02 (m, 2H), 1.50-1.29 (m, 9H).

[0341] Step 2: TFA (50 mL) was added to a solution of (5’)-3-(4-(3-((((97 / -fluoren-9- yl)methoxy (carbonyl )amino)prop- l -yn- l-yl)phenyl)-2-(( / c77-butoxycarbonyl)amino)propanoic acid (SS20a, 5.7 g, 10.5 mmol) in DCM (50 mL) at RT. The reaction was stirred at RT for 2 h. The solution was concentrated in vacuum to afford (5)-3-(4-(3-((((9 / / -fluoren-9- yl)methoxy)carbonyl)amino)prop-l-yn-l-yl)phenyl)-2-aminopropanoic acid (SS20b), which was used directly in Step 3. MS ESI calculated for C27H25N2O4 [M + H]+441. 17, found 441.15.

[0342] Step 3: DIPEA (5.3 mL, 30.2 mmol) and 2-(l-hydroxyethylidene)-5,5- dimethylcyclohexane- 1,3-dione (2.8 g, 15.1 mmol) were added to a solution of (5)-3-(4-(3- ((((97 -fluoren-9-yl)methoxy)carbonyl)amino)prop-l-yn-l-yl)phenyl)-2-aminopropanoic acid (SS20b, 6.2 g, 10. 1 mmol) in MeOH (60 mL) at 0 °C. The reaction was stirred over night at RT. The resulting solution was concentrated in vacuum.

[0343] The residue was purified by Rp flash chromatography using a C 18 silica gel column (mobile phase: MeCN / water (0.05% TFA), 2-60% gradient of MeCN over 28 min; detector: UV 210 nm) to give (5)-3-(4-(3-((((977-fluoren-9-yl)methoxy)carbonyl)amino)prop-l-yn-l- yl)phenyl)-2-((l-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)propanoic acid (SS20). MS ESI calculated for C37H37N2O6 [M + H]+605.26, found 605.50. ' H NMR (300 MHz, methanol-A): 3 7.78 (d, J= 7.5 Hz, 2H), 7.65 (d, J= 7.5 Hz, 2H), 7.39-7.26 (m, 6H), 7.18 (d, J = 8.1 Hz. 2H), 4.93-4.88 (m, 1H), 4.37 (d, J= 7.1 Hz, 2H), 4.23-4.19 (m, 1H). 4.09 (s, 2H), 3.37- 3.35 (m, 1H), 3.32-3.30 (m. 1H), 2.33-2.29 (m. 7H), 0.99 (s. 6H).Synthetic Scheme 21(2A’,3>S')-3-(l-(3-((((9 / / -Fhioren-9-yl)methoxy)carbonyl)amino)propyl)- / / 7-indol-3-yl)-2-((l- (4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)butanoic acid (Dde- SbMeWC3NHFmoc-OH) (SS21)

[0344] Step 1 : tert-Butyl (Z)-Ar.AA'-diisopropylcarbamimidate (7.2 mL, 34.1 mmol) was added to a stirred solution of (2S.3<S’)-2-((((977-fluoren-9-yl)methoxy)carbonyl)amino)-3-(177-indol-3- yl)butanoic acid (3.0 g, 6.8 mmol) in DCM (30 mL) at RT. The mixture was stirred at 40 °C for 1 h, then diluted with DCM (50 mL), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography, eluting with EtOAc 0-50% in PE to afford tert-butyl (2S,3S)-2-((((9#-fluoren-9-yl)methoxy)carbonyl)amino)-3-(177- indol-3-yl)butanoate (SS21a). MS ESI calculated for C31H33N2O4 [M + H]+497.24, found 497.20. Tf NMR (400 MHz, chloroform-^: 3 8.07 (s, 1H), 7.79 (d, J= 7.6 Hz, 3H), 7.59 (d, J =7.6 Hz. 2H). 7.46-7.30 (m, 5H). 7.24-7.14 (m, 2H). 7.03 (d, J = 2.4 Hz, 1H). 4.65-4.62 (m, 1H), 4.49-4.34 (m, 2H), 4.25-4.21 (m, 1H), 3.78-3.72 (m, 1H), 1.47-1.45 (m, 3H), 1.36 (s, 9H).

[0345] Step 2: tris(2-aminoethyl)amine (3.2 mL, 21.1 mmol) was added to a solution of tertbutyl (2S,3S)-2-((((9 / 7-fluoren-9-yl)methoxy)carbonyl)amino)-3-(17 / -indol-3-yl)butanoate (SS21a, 2. 1 g, 4.2 mmol) in MeCN (21 mL) at 0 °C. The resulting mixture was stirred at RT for 1 h, then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography, eluting with MeOH 0-15% in DCM to afford tert-butyl (25.35)-2-amino-3- (17f-indol-3-yl)butanoate (SS21b). MS ESI calculated for C16H22N2O2 [M + H]+275.17, found 275.10.

[0346] Step 3: NaHCCh (1102 mg, 13. 1 mmol) and (Boc)2O (1 . 1 mL, 4.9 mmol) were added to a stirred solution of tert-butyl (2S',3<S’)-2-amino-3-(177-indol-3-yl)butanoate (SS21b, 900 mg, 3.3 mmol) in THF (15 mL) and water (15 mL) at 0 °C. The reaction mixture was stirred over night at RT, then extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine (3 x 70 mL). dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc 0-50% in PE to afford tert-butyl (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-( 17f-indol-3-yl)butanoate (SS21c). MS ESI calculated for C21H31N2O4 [M + H]+375.22, found 375. 10. ’H NMR (300 MHz, chloroform- J): S 8.05 (s. 1H), 7.73 (d. J= 7.8 Hz. 1H), 7.37-7.31 (m, 1H), 7.22-7.08 (m, 2H). 7.04-7.03 (m, 1H), 5.07-5.04 (m, 1H), 4.53-4.48 (m, 1H), 3.69-3.65 (m, 1H), 1.45-1.41 (m, 12H), 1.31 (s, 9H).

[0347] Step 4: Benzyl (3-bromopropyl)carbamate (2.2 g, 8.0 mmol), CS2CO3 (2.6 g, 8.0 mmol), and sodium iodide (0.2 g, 1.3 mmol) were added to a stirred solution of tert-butyl (25,3S)-2- ((tert-butoxycarbonyl)amino)-3-(l / / -indol-3-yl)butanoate (SS21c, 1.0 g, 2.7 mmol) in anh. DMF (10 mL) at RT and under Ar. The suspension was stirred over night at RT. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (3 x 80 mL), dried with anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc 0-50% in PE to afford tert-butyl (2S,3S)-3-(l-(3- (((benzyloxy)carbonyl)amino)propyl)-177-indol-3-yl)-2-((tert-butoxycarbonyl)amino)butanoate (SS21d). MS ESI calculated for C32H44N3O6 [M + H]+566.32, found 566.45.

[0348] Step 5: tert-Butyl (2S,35)-3-(l-(3-(((benzyloxy)carbonyl)amino)propyl)-17f-indol-3-yl)- 2-((tert-butoxycarbonyl)amino)butanoate (SS21d, 850 mg, 1.5 mmol) was dissolved in isopropanol (15 mL). The flask was evacuated and refilled with N2 (5 times). Pd / C (160 mg, 0.150 mmol, dry, 10 wt. %) was added into the flask. The flask was evacuated and backfilledwi th H2 (5 times). The resulting mixture was stirred for 2 h at RT under an atmosphere of dihydrogen. The flask was evacuated and refilled with N2 (5 times). The resulting mixture was filtered through a Celite® pad. The filtered cake was washed with IPA (2 x 15 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl (2S,3S)-3-( l-(3-aminopropyl)- 1H- indol-3-yl)-2-((tert-butoxycarbonyl)amino)butanoate (SS21e). MS ESI calculated for C24H38N3O4 [M + H]+432.28, found 432.20.

[0349] Step 6 : NaHCOs (623 mg, 7.4 mmol) and Fmoc-Osu (500 mg, 1.5 mmol) were added to a stirred solution of tert-butyl (2S,3<S)-3-(l-(3-aminopropyl)-l / 7-indol-3-yl)-2-((tert- butoxycarbonyl)amino)butanoate (SS21e, 640 mg, 1.5 mmol) in THF (10 mL) and water (10 mL) at 0 °C. The reaction mixture was stirred over night at RT, then diluted with water (30 mL), and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over anh. Na2SO4,, filtered, and concentrated under reduced pressure. The residue w as purified by silica gel column chromatography, eluting with EtOAc 0-50% in PE to afford tertbutyl (2S,3iS’)-3-(l-(3-((((9E7-fluoren-9-yl)methoxy)carbonyl)ammo)propyl)-l / f-indol-3-yl)-2- ((tert-butoxycarbonyl)amino)butanoate (SS21 f). MS ESI calculated for C39H48N3O6 [M + H]+654.35, found 654.30. 'H NMR (400 MHz, chloroform- J): 3 7.79 (d, J= 7.6 Hz, 2H), 7.71-7.69 (m, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.42-7.27 (m, 5H), 7.25-7.07 (m, 2H). 6.97 (s, 1H), 4.76-4.71 (m. 1H), 4.49-4.42 (m, 3H), 4.26-4.08 (m, 3H). 3.16-3.09 (m, 2H), 2.06-2.02 (m, 2H), 1.46- 1.38 (m, 12H), 1.34 (s, 9H).

[0350] Step 7: TFA (21 mL) was added to a stirred solution of tert-butyl (2<S',31S)-3-(l-(3- ((((9 / 7-fluoren-9-yl)methoxy)carbonyl)amino)propyl)-177-indol-3-yl)-2-((tert- butoxycarbonyl)amino)butanoate (SS21f, 700 mg, 1.071 mmol) in DCM (7 mL) at 0 °C. The solution was stirred at RT for 4 h. The volatiles were removed under reduced pressure to afford crude (2S,35)-3-(l -(3-((((9F7-fluoren-9-yl)methoxy)carbonyl)amino)propyl)- 177-indol-3-yl)-2- aminobutanoic acid (SS21g). MS ESI calculated for C30H32N3O4 [M + H]+498.23, found 498.15.

[0351] Step 8: DIPEA (2.5 mL, 14.5 mmol) and 2-(l-hydroxyethylidene)-5,5- dimethylcyclohexane-l,3-dione (2.0 g, 10.9 mmol) were added to a stirred solution of (25,35)-3- (l-(3-((((9 / 7-fluoren-9-yl)methoxy)carbonyl)amino)propyl)-I7 / -indol-3-yl)-2-aminobutanoic acid (SS21g, 3.6 g, 7.2 mmol) in MeOH (36 mL) at 0 °C and under Ar. The resulting mixture was stirred over night at RT. The reaction was concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a Cl 8 silica gel column (mobile phase: MeCN / water (0.05% TFA), 2-80% gradient of MeCN; detector: UV 210 nm) to afford (25,35)-3-(l-(3-((((9 / / - fluoren-9-yl)methoxy)carbonyl)amino)propyl)-lF7-indol-3-yl)-2-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)butanoic acid (SS21). MS ESI calculated for C40H44N3O6 [M+ H]+662.32, found 662.30. 'H NMR (400 MHz, methanol-A): d 7.81-7.77 (m, 2H), 7.66-7.56 (m, 3H), 7.38-7.25 (m, 6H), 7.12-7.08 (m, 1H), 7.01-6.98 (m, 1H), 4.82-4.80 (m, 1H), 4.40- 4.33 (m, 2H), 4.20-4.09 (m, 3H), 3.87-3.83 (m, 1H), 3.09-2.97 (m, 2H), 2.30-2.27 (m, 7H), 2.00-1.96 (m, 2H), 1.51-1.46 (m, 3H), 0.93-0.91 (m, 6H).Synthetic Scheme 22l-(3-((((9 / 7-Fliioreii-9-yl)methoxy)carbonyl)amino)propyl)- / Va-(l-(4,4-diniethyl-2,6- dioxocy clohexylidene)ethyl)-L-try ptophan (Dde-TrpC3NHF moc-OH) (SS22)

[0352] Step 1 : A solution of Nal (0.3 g, 2.0 mmol), benzyl (3-bromopropyl) carbamate (3.3 g, 12.0 mmol) in anh. DMF (5 mL) was added to a stirred suspension of methyl (tertbutoxy carbonyl)-L -tryptophanate (1.3 g, 4.0 mmol) and CS2CO3 (3.90 g, 11.97 mmol) in anh.DMF (20 mL) at RT and under Ar atmosphere. The resulting suspension was stirred over night at RT. The reaction mixture was quenched with H2O (150 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over anh.Na2SO4, filtered, and concentrated under reduced pressure. The residue was punfied by Rp flash chromatography using a C 18 silica gel column (mobile phase: MeCN / water (0.05% TFA), 5- 52% gradient of MeCN over 33 min; detector: UV 210 nm) to give methyl l-(3-(((benzyloxy)carbon\ l)amino)propyl)-A'z-( / c77-butoxycarbonyl)-l. -tryptophanate (SS22a). MS ESI calculated for C28H36N3O6 [M + H ]+510.25, found 510.35. 'H NMR (300 MHz, chloroform-c / ): S 7.54-7.52 (m, 1H), 7.37-7.27 (m, 6H), 7.25-7.22 (m, 1H), 7.12-7.09 (m, 1H), 6.89 (s, 1H), 5.12-5.08 (m, 3H). 4.80 (s. 1H), 4.64-4.62 (m, 1H). 4.12-4.10 (m, 2H), 3.67 (s, 3H), 3.18-3.13 (m, 4H), 2.02-1.98 (m, 2H), 1.41 (s, 9H).

[0353] Step 2: Aq. 1 N LiOH solution (80 mL, 80 mmol) was added to a solution of methyl 1- (3-(((benzyloxy)carbonyl)amino)propyl)-N“-(te / 7-butoxycarbonyl)-L -tryptophanate (SS22a, 5.1 g, 10.01 mmol) in THF (80 mL). The solution was stirred at RT for 2 h. The reaction mixture was acidified to pH ~5 with aq. 1 M HC1 and extracted with EtOAc (1000 mL). The organic layer was washed with brine (3 x 300 mL), dried over anh. Na2SO4, filtered, and concentrated under vacuum to afford crude l-(3-(((benzyloxy)carbonyl)amino)propyl)-A“-(te / 7-butoxycarbonyl)-L- tryptophan (SS22b), which was used directly in Step 3 without purification. MS ESI calculated for C27H34N3O6 [M - Boc + H]+396.24, found 396.25.

[0354] Step 3 : TFA (30 mL) was added to a stirred mixture of l-(3- (((benzyloxy)carbonyl)amino)propyl)-A“-( / er / -butoxycarbonyl)-L -tryptophan (SS22b, 4.9 g, 9.9 mmol) in DCM (100 mL) at RT. The solution was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to give crude l-(3-(((benzyloxy)carbonyl)amino)propyl)-L- tryptophan (SS22c), which was used directly in Step 4. MS ESI calculated for C22H26N3O4 [M + H]+396.18, found 396.25.

[0355] Step 4: DIPEA (2.61 g, 20.23 mmol) and Dde-OH (2.8 g, 15.2 mmol) were added to a stirred solution of l-(3-(((benzyloxy)carbonyl)amino)propyl)-L -tryptophan (SS22c, 4.0 g, 10.1 mmol) in MeOH (60 mL) at 0 °C and under Ar. The solution was stirred at RT for 3 h. The pH of the solution was adjusted to ~3 with aq. 1 M HC1. The resulting mixture was extracted with EtOAc (800 mL). The organic layer was washed with brine (3 x 300 mL), dried over anh.Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with EtOAc 0-25% in PE to afford l-(3- (((benzyloxy)carbonyl)amino)propyl)-A“-(l-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)-L- tryptophan (SS22d). MS ESI calculated for C32H38N3O6 [M + H]+560.27, found 560.35. 'H NMR (300 MHz, chloroform^ / ): 8 13.72 (s, 1H), 7.56-7.53 (m, 1H), 7.33-7.29 (m, 6H), 7.19- 7.16 (m, 1H), 7.07-7.05 (m, 2H), 5.70 (s, 1H), 5.07 (s, 2H), 4.69 (s, 1H), 4.12-4.02 (m, 2H), 3.42-3.39 (m, 2H), 3.06-2.78 (m, 2H), 2.40-2.35 (m, 3H), 2.35-2.30 (m, 4H), 1.98-1.90 (m, 2H), 0.92 (s, 6H).

[0356] Step 5: l-(3-(((Benzyloxy)carbonyl)amino)propyl)-A“-(l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)- -tryptophan (SS22d, 3.8 g, 6.8 mmol) was dissolved in EtOH (80 mL). The flask was evacuated and refilled with N2 (5 times). Pd / C (700 mg, 0.658 mmol, dry', 10 wt. %) was added into the flask. The flask was evacuated and backfilled with H2 (5 times). The resulting mixture was stirred over night at RT under an atmosphere of dihydrogen. The flask was evacuated and refilled with N2 (5 times). The resulting mixture was filtered through a Celite® pad. The filtered cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure to afford crude l-(3-aminopropyl)-A“-(l-(4.4-dimethyl-2.6- dioxocyclohexylidene)ethyl)-L -tryptophan (SS22e), which was used directly in Step 6. MS ESI calculated for C24H32N3O4 [M + H]+426.23, found 426.15.

[0357] Step 6: NaHCCh (2.8 g, 32.9 mmol) and Fmoc-OSu (2.2 g, 6.6 mmol) were added to a stirred solution of l-(3-aminopropyl)-N“-(l-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)-L- tryptophan (SS22e, 2.8 g, 6.6 mmol) in THF (28 mL) and water (28 mL) at RT. The resulting mixture was stirred over night at RT. The pH of the reaction mixture was adjusted to ~3 with aq. 1 M HC1. The reaction mixture was extracted with EtOAc (400 mL). The organic layer was washed with brine (3 x 200 mL), dried over anh. Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a Cl 8 silica gel column (mobile phase: MeCN / water (0.05% TFA), 35-65% gradient of MeCN over 30 min; detector: UV 210 nm) to give l-(3-((((97 / -fluoren-9-yl)methoxy)carbonyl)amino)propyl)-A“-(l- (4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)-L-tryptophan (SS22). MS ESI calculated for C39H42N3O6 [M + H]+648.30, found 648.30. 'H NMR (400 MHz, DMSO-rfc): d 13.52-13.42 (m, 2H), 7.90-7.88 (m, 2H), 7.70-7.68 (m, 2H), 7.47-7.45 (m, 1H), 7.41-7.39 (m, 4H), 7.34-7.32 (m, 2H), 7.18-7.10 (m, 2H), 6.98-6.96 (m, 1H), 4.85-4.84 (m, 1H), 4.33-4.31 (m, 2H), 4.22- 4.20 (m, 1H), 4.09-4.08 (m, 2H), 3.31-3.30 (m. 1H), 3.20-3.18 (m, 1H), 2.96-2.94 (m, 2H). 2.24-2.22 (m, 7H), 1.86-1.78 (m, 2H), 0.90 (s, 6H).Synthetic Scheme 23(A^)-3-(4-((4-((((9 / f-fluoren-9-yl)methoxy)carbonyl)amino)but-2-en-l-yl)oxy)phenyl)-2-((l- (4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)propanoic acid (Dde- TyrOAlNHFmocAl-OH) (SS23)

[0358] Step 1 : DIPEA (7.4 mL, 42.1 mmol) and 2-acetyldimedone (5.8 g, 31.6 mmol) were added to a solution of tert-butyl L-tyrosinate (5.0 g, 21. 1 mmol) in MeOH (80 mL) at RT. The reaction mixture was stirred over night at RT. The volatiles were concentrated under reduced pressure. The residue was acidified with aq. 1 M HC1 to pH ~3 and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with EtOAc 0-50% in PE to afford tert-butyl (l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)-L-tyrosinate (SS23a). MS ESI calculated for C23H32NO5 [M + H]+402.22, found 402.30. ‘H NMR (300 MHz, chloroform- J): 3 13.74-13.71 (m, 1H), 7.08-6.96 (m, 2H), 6.81-6.71 (m. 2H), 4.48-4.46 (m, 1H), 3.26-2.89 (m, 2H), 2.39-2.30 (m, 7H), 1.46 (s, 9H), 1.02 (s. 6H).

[0359] Step 2: tert-Butyl (E)-(4-hydroxybut-2-en-l-yl)carbamate (2.1 g, 11.2 mmol) in THF (5 mL) was added to a mixture of tert-butyl (l-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)-L- tyrosinate (SS23a, 3 g, 7.47 mmol), DIAD (2.179 mL, 11.21 mmol) and PPI13 (2.94 g, 11.21 mmol) in anh. THF (65 mL) at RT under Ar. The reaction was stirred over night at RT. The resulting solution was filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with EtOAc 0-40% in PE to afford tert-butyl (<S',E)-3-(4-((4-((tert-butoxycarbonyl)amino)but-2-en-l -yl)oxy)phenyl)-2-((l - (4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)amino)propanoate (SS23b). MS ESI calculatedfor C32H47N2O7 [M + H]+571.33, found 571.50. 'H NMR (300 MHz. chloroform-c / ): d 13.79- 13.76 (m, 1H), 7.07-6.97 (m, 2H), 6.79-6.70 (m, 2H), 5.77-5.76 (m, 2H), 4.66 (s, 1H), 4.40 (s, 2H), 4.35-4.34 (m, 1H), 3.72-3.71 (m, 2H), 3.13-3.10 (m, 1H), 2.92-2.90 (m, 1H), 2.31 (s, 4H), 2.18 (s. 3H), 1.38 (s, 18H), 0.96 (s, 6H).

[0360] Step 3: TFA (45 mL) was added to a stirred solution of te / 7-butyl (S', E)-3-(4-((4-(( tert- butoxycarbonyl)amino)but-2-en-l-yl)oxy)phenyl)-2-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)propanoate (SS23b, 3.0 g, 5.3 mmol) in DCM (45 mL) at RT. The resulting mixture was stirred at RT for 3 h. The solvent was evaporated under reduced pressure to give crude (S,E)-3-(4-((4-aminobut-2-en-l-yl)oxy)phenyl)-2-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)propanoic acid (SS23c), which was used directly in Step 4. MS ESI calculated for C23H31N2O5 [M + H]+415.22, found 415.15.

[0361] Step 4: NaHCCh (2.2 g, 26.5 mmol) and Fmoc-OSu (1.8 g, 5.3 mmol) were added to a stirred solution of (S,E)-3-(4-((4-aminobut-2-en-l-yl)oxy)phenyl)-2-((l-(4,4-dimethyl-2.6- dioxocyclohexylidene)ethyl)amino)propanoic acid (SS23c, 2.2 g. 5.3 mmol) in THF (30 mL) and water (30 mL) at RT. The resulting mixture was stirred over night at RT. The pH of the mixture was adjusted to ~3 with aq. 1 N HC1. The reaction mixture was extracted with EtOAc (400 mL). The organic layer was washed with brine (3 x 150 mL), dried over anh. NazSCh, filtered, and concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a C 18 silica gel column (mobile phase: MeCN / water (0.05% TFA), 40-70% gradient of MeCN over 30 min; detector: UV 210 nm) to give a mixture product. The mixture of isomeric products was purified by Prep-SFC with the following conditions: Column: NB chiral art Cellulose-SJ, 5 x 25 cm, 5 pm; Mobile Phase A: CO2. Mobile Phase B: MeOH (0.1% 2 M NH3-MeOH): Flow rate: 200 mL / min; Gradient: isocratic 45% B; Column Temperature: 35 °C; Back Pressure: 100 bar; Wavelength: 254 nm. The faster peak was obtained at ZR = 6.51 min. The collected fractions were combined and concentrated under vacuum to give GS' 7.’)-3-(4-((4-((((97 / -nuoren-9- yl)methoxy)carbonyl)amino)but-2-en-l-yl)oxy)phenyl)-2-((l-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)amino)propanoic acid (SS23). MS ESI calculated for C38H41N2O7 [M +H]+637.28, found 637.25. ‘H NMR (400 MHz, DMSO-ufe): 3 13.48-13.46 (m, 1H), 7.89- 7.87 (m, 2H), 7.70-7.68 (m, 2H), 7.55-7.54 (m, 1H), 7.44-7.28 (m, 4H), 7.13-7.04 (m, 2H), 6.88-6.78 (m, 2H). 5.76-5.75 (m, 2H), 4.84-4.82 (m, 1H), 4.48-4.46 (m. 2H), 4.31-4.29 (m, 2H), 4.21-4.19 (m. 1H), 3.65-3.64 (m, 2H). 3.22-2.90 (m, 2H), 2.27 (s, 7H). 0.93 (s, 6H).Preparation of Final CompoundsA. Generalized Procedure for Synthesizing Linear Peptide Precursors

[0362] Peptides in Table 1 and Table 2 were synthesized using standard solid-phase synthesis using Fmoc / tBu chemistry as exemplified in Chan, W.C.; White, P.D. “Fmoc Solid-Phase Synthesis: a Practical Approach"’, Oxford University' Press, Oxford. 2000; Steward, J.; Young, J. “Solid Phase Peptide Synthesis”, Pierce Chemical Company, Rockford, 1984.; Benoiton, N.L. “Chemistry- of Peptide Synthesis”, CRC Press, New York, 2006; and Lloyd-Williams, P.;Albericio, F.; Giralt, E. “Chemical Approaches to the Synthesis of Peptides and Proteins”, CRC Press, New York, 1997.

[0363] During peptide chain elongation, the a-amino group of each amino acid was protected with a 97 / -fluoren-9-ylmethoxy carbonyl group (Fmoc). To avoid any side reactions during the chain elongation steps, any reactive amino acid side chains also cany' acid-labile protecting groups, effectively masking the reactive groups until removal upon treatment yvith strong acid. After completion of each coupling step, the Fmoc group of the .V-terminal amino acid was removed with piperidine or 4-methylpiperidine and the resin was thoroughly washed to prepare for the coupling of the subsequent Fmoc-protected amino acid derivative.

[0364] The side chain protecting groups used were: tert-butyl (tBu) for a-Me-L-Ser (aMeS), L-Ser, N-Me-L-Ser (NMeS), L-Tyr, Phe4COOH, / V-Me-i.-Glu (NMeE), TrpCH2COOH, dProt4OH, AlaPyrim4NH2, gE (alpha acid), dgE (alpha acid), eK (alpha acid), edK (alpha acid). hK (alpha acid), Phe4NH2 (alpha acid). AlaPip4 (alpha acid), and deOm (alpha acid); trity l (Trt) for L-Asn; tert-butoxy-carbonyl (Boc) forL-Trp, Pip2c. and dProt4NH2;A- Allyloxycarbonyl (Alloc) for the alpha amino group for side-chain modifications at position 5 using NxG44, dProt4OEtNH2, dProt4NH2, and NPrNH2G; o-nitrobenzenesulfonyl (oNBS or Ns) for the alpha amino group for side-chain modifications at position 5 using NxG44, dProt4OEtNH2, NC2NH2Gly, and NxG45; l-(4,4-Dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl (ivDde) for the alpha amino group for side-chain modifications of L-Lys at position 1; and, N-( l-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) (Dde) for the alpha amino group for side-chain modification of AEF at positions 2, 10, and 11, Phe4CH2NH2 at positions 2, 10. and 11, dProt4OEtNH2 at position 5, TrpC3NH2 at positions 4 and 13, SbMeWC3NH2 atposition 13, AEEF at position 11, TyrOAlNH2Al at position 11, Phe4Pip4 at position 11, Phe4PrgNH2 at position 11, Bz3NH25AE at position 0, bhcLeut4OC2NH2 at position 0, and Phe4Piperaz at position 11.

[0365] Fmoc-protected amino acids were typically obtained from vendors such as Sigma- Aldrich® (Millipore Sigma, St. Louis, MO), Novabiochem® (Millipore Sigma, St. Louis, MO), Chem-Impex (Wood Dale. IL), Combi-Blocks (San Diego, CA), Ambeed (Arlington Hts, IL), AstaTech Inc. (Bristol, PA), Iris Biotech (Marktredwitz, Germany), Acrotein BioChem Inc (Hoover, AL), Amatek (Berwyn, PA), ChemScene LLC (Monmouth Junction, NJ), BLD Pharmatech Co., Limited (C1ncinnati, OH), AchemBlock (Hayward, CA), AA Blocks LLC (San Diego, CA), abcr GmbH (Karlsruhe. Germany), Enamine Ltd. (Kyiv, Ukraine), Chem Shuttle (Burlingame. CA). or PharmaBlock (USA), Inc. (Hatfield, PA).B. Synthetic Procedures used to Prepare Macrolactam Cyclic PeptidesSynthetic Scheme 24lid-phase peptide synthesis Piperidine (20% in DMF) DIC / Oxyma, 90DCSynthetic Scheme 24 continued 24 -aSide-chain assemblySolid-phase peptide synthesis1 ) Piperidine (20% in DMF)2) DIC / Oxyma, 90 °C then 2% N2H4in DMF, 90 °C1. Procedure A a) Solid Phase Synthesis of Peptides (SPPS)

[0366] Peptides were synthesized on a Liberty Blue™ synthesizer from CEM Corporation (Matthews, NC), using standard solid-phase synthesis using Fmoc / tBu chemistry' as summarized above in Synthetic Scheme 23.

[0367] Reactions were typically performed at a 50 pmol scale using Cl-TCP(Cl) ProTide® resin (100-200 mesh, 0.37 mmol / g loading, CEM Corporation, Matthews, GA). All the amino acids were dissolved at a 0.2 M concentration in anh. DMF or NMP. The amino acids were activated with equimolar amounts of Oxyma Pure solution (0.5 M in anh. DMF containing 0.1 M of DIPEA), and a 2-fold molar excess of DIC solution (0.5 M in anh. DMF).

[0368] The loading of the initial C-terminal amino acid (25.3<Sr)-2-((((977-fluoren-9- yl)methoxy)carbonyl)amino)-3-(7-methoxy-l / 7-indol-3-yl)butanoic acid to the Cl-TCP(Cl) ProTide® resin was performed directly on the Liberty7Blue™ synthesizer by treating with 10- fold molar excess of Fmoc-protected amino acid solution (0.2 M in anh. DMF) and 20-fold molar excess of base solution (1.0 M DIPEA + 0.125 M KI in anh. DMF) and 90 °C microwave assisted heating for 10 min (repeated twice).

[0369] Every synthesis cycle included: (1) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (90 °C microwave assisted heating, 1 min); (2) Coupling (potentially repeated twice for difficult couplings) with Fmoc-protected amino acid / DIC / Oxyma (5, 5, and 10 equiv, respectively; 90 °C microwave assisted heating, 2 min). Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear protected peptide was formed. b) Side-Chain Functionalization

[0370] After coupling of ivDde-Lys(NHFmoc)-OH on resin, the Fmoc protecting group on the terminal epsilon amine was removed by treatment with 20% v / v piperidine in anh. DMF (90 °C microwave assisted heating, 1 min). The different linkers, spacers and protractor were assembled off the amino group of Lysine at position 1 by7SPPS.

[0371] Every7side-chain extension cycle included: (1) Coupling (repeated twice) with Fmoc- protected building blocks / DIC / Oxyma (5, 5, and 10 equiv, respectively; 90 °C microwave assisted heating, 2 min); (2) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (90 °C microwave assisted heating, 1 min).

[0372] The addition of the protractor (with reactive functional groups potentially protected as tert-butyl (such as C18diacid) or Boc (such as Ado) as needed) was performed by coupling(repeated twice) with (protected) protractor / DIC / Oxyma (5. 5, and 10 equiv, respectively; 90 °C microwave assisted heating, 2 min). c) Orthogonal Main-Chain Deprotection

[0373] After assembly of the side-chain modification at position 1, the ,V- terminal ivDde protecting group was removed by treatment with a solution of 2% hydrazine monohydrate in DMF (4 mL) at 90 °C (microwave assisted heating, 3 min, repeated three times). d) Completion of SPPS

[0374] The peptide sequence was completed by SPPS. Every synthesis cycle included: (1) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (50 °C microwave assisted heating, 10 min; repeated twice); (2) Coupling (potentially repeated twice for difficult couplings) with Fmoc-protected amino acid / HATU / DIPEA (5, 5, and 10 equiv, respectively; 50 °C microwave assisted heating, 10 min). Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear protected peptide was formed; (3) The peptide A-terminus was deprotected using 20% v / v piperidine in DMF (50 °C microwave assisted heating, 10 min; repeated twice). e) Cleavage of Protected Linear Peptide

[0375] After completion of the synthesis, the linear resin-bound peptide was transferred into a fritted plastic column. The resin was washed with DCM then dried under negative pressure on a Razor® peptide cleavage system from CEM Corporation (Matthews, NC). The protected peptide was cleaved off the solid support by treatment with HFIP / DCM (3:7, v / v; 5 mL) at 20 °C for 5 min. The solution was collected into a 50 mL centrifuge tube. This process was repeated twice more (three times total), and the cleavage solution was combined into the same tube. The solvents were removed under reduced pressure. The resulting crude linear peptide was dissolved in 1 : 1 (v / v) mixture of DI water / MeCN (1 mL). The solution was frozen and lyophilized.1) Solution Phase Macrolactamization

[0376] The crude protected linear peptide was dissolved in anh. THF (10 mL). To that solution was added DIPEA (45 pL. 5 equiv) followed by the dropwise addition of the solution of HO At (6 mg, 0.9 equiv) and HATU (8.4 mg, 1.3 equiv) dissolved in anh. DMF (150 pL). The solution was shaken at RT for approximately 30 min and monitored by UPLC-MS. After the reaction was complete, the reaction solution was concentrated under reduced to dryness.g) Deprotection of the Protected Cyclic Peptide

[0377] The cyclic peptide was deprotected by treatment with TFA / ThO / TIS / Phenol (93:2:3:2, v / v / v / w; 7 mL) at RT for 1 h. The crude cyclic peptide was precipitated from the TFA cleavage solution using chilled MTBE (40 mL) and collected by centrifugation (4000 rpm). The supernatant was removed. Additional cold MTBE (35 mL) was added to the peptide pellet and clarified by centrifugation. The resulting crude peptide pellet was dissolved in 1 : 1 (v / v) mixture of DI water / MeCN (10 mL). The solution was frozen and lyophilized. h) HPLC Purification

[0378] The crude residue was then dissolved in DMSO and purified by preparative reversed- phase high performance liquid chromatography on a Waters™ SunFire Prep Cl 8 OBD column (100 A, 5 pm, column size 19 x 150 mm, Milford, MA) using an Agilent MS-Directed Preparative HPLC-MS system. Mobile phase: (A) 0. 1% TFA in HPLC-grade water and (B) 0. 1% TFA in HPLC-grade acetonitrile; flow rate: 35 mL / min; UV wavelength = 215 nm; gradient: gradient: 0.5%B / min for 40 min starting at 5% B less than the calculated %B required for compound elution. In some instances, better separation was obtained by using 0.1% NH4OH as modifier.

[0379] UV absorbing fractions containing the target m / z ions were collected and the fractions containing the desired product were combined, concentrated in vacuo and freeze-dried to afford the cyclized peptide as a solid.

[0380] Confirmation of identity' and purity assessment of final compounds were performed by UPLC-MS, which was measured by a reverse phase Waters™ ACQUITY UPLC-MS system. Column: Waters™ Cortecs Cl 8+ Column (90 A, 1.6 pm, column size 2.1 x 100 mm, Milford, MA). Mobile phase: (A) 0.1% TFA in HPLC-grade water and (B) 0.1% TFA in HPLC-grade acetonitrile; injection volume: 0.5 pL; flow rate: 0.7 mL / min; Column Temperature: 60 °C; UV wavelength X = 215 nm; Two gradients were used for analysis depending on analyte polarity: 1) 2% B for 1.3 mm, 2-20% B for 1.3 mm. 20-30% B for 5.2 mm, 30-55% B for 3.9 mm, 55-95% B for 2.6 min, hold at 95% B for 2.7 min, or 2) 2% B for 1.3 min, 2-40% B for 1.3 min, 40-95% B for 10.4 min, hold at 95% B for 4 min.Synthetic Scheme 25Synthetic Scheme 25 continued25-aMacrolactamization and side chain deprotection1 ) HATU, HOAt, DIPEA, THF, RT2) TFA / TIS / H2O (+ phenol or DTT), RT2. Procedure B a) Solid Phase Synthesis of Peptides (SPPS)

[0381] Peptides were synthesized on a Liberty Blue™ synthesizer from CEM Corporation (Matthews, NC), using standard solid-phase synthesis using Fmoc / tBu chemistry' as summarized above in Synthetic Scheme 25.

[0382] Reactions were typically performed at a 50 pmol scale using Cl-TCP(Cl) ProTide® resin (100-200 mesh, 0.37 mmol / g loading, CEM Corporation, Matthews, GA). All the amino acids were dissolved at a 0.2 M concentration in anh. DMF or NMP. The amino acids were activated with equimolar amounts of Oxyma Pure solution (0.5 M in anh. DMF containing 0.1 M of DIPEA), and a 2-fold molar excess of DIC solution (0.5 M in anh. DMF).

[0383] The loading of the initial C-terminal amino acid (2S.3A)-2-((((97 / -fluoren-9- yl)methoxy)carbonyl)amino)-3-(7-methoxy-l / 7-indol-3-yl)butanoic acid to the Cl-TCP(Cl) ProTide® resin was performed directly on the Liberty7Blue™ synthesizer by treating with 10- fold molar excess of Fmoc-protected amino acid solution (0.2 M in anh. DMF) and 20-fold molar excess of base solution (1.0 M DIPEA + 0.125 M KI in anh. DMF) and 90 °C microwave assisted heating for 10 min (repeated twice).

[0384] Every synthesis cycle included: (1) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (90 °C microwave assisted heating, 1 min); (2) Coupling (potentially repeated twice for difficult couplings) with Fmoc-protected amino acid / DIC / Oxyma (5, 5, and 10 equiv, respectively; 90 °C microwave assisted heating, 2 min). Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear protected peptide was formed. b) Side-Chain Functionalization

[0385] After coupling of Dde-Phe-4(OCH2CH2-NHFmoc)-OH (AEF) or Dde-Phe- 4((OCH2CH2)2-NHFmoc)-OH (AEEF) on resin, the Fmoc protecting group on the terminal primary amine was removed by treatment with 20% v / v piperidine in anh. DMF (90 °C microw ave assisted heating, 1 min). The different linkers, spacers and protractor w ere assembled off the amino group of AEF or AEEF at position 11 by SPPS.

[0386] Every side-chain extension cycle included: (1) Coupling (repeated twice) with Fmoc- protected building blocks / DIC / Oxyma (5, 5, and 10 equiv, respectively; 90 °C microwave assisted heating, 2 min); (2) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (90 °C microw ave assisted heating, 1 min).

[0387] The addition of the protractor (with reactive functional groups potentially protected as tert-butyl (such as C 18diacid) or Boc (such as Ado) as needed) was performed by coupling (repeated twice) with (protected) protractor / DIC / Oxyma (5, 5, and 10 equiv, respectively; 90 °C microwave assisted heating, 2 min). c) Orthogonal Main-Chain Deprotection

[0388] After assembly of the side-chain modification at position 1, the A-terminal ivDde protecting group was removed by treatment with a solution of 2% hydrazine monohydrate in DMF (4 mL) at 90 °C (microwave assisted heating, 3 min, repeated three times). d) Completion of SPPS

[0389] The peptide sequence was completed by SPPS. Every synthesis cycle included: (1) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (50 °C microwave assisted heating, 10 min; repeated twice); (2) Coupling (potentially repeated twice for difficult couplings) with Fmoc-protected amino acid / HATU / DIPEA (5, 5, and 10 equiv, respectively; 50 °C microwave assisted heating, 10 min). Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling w ere repeated with the desired monomers until the full linear protected peptide w as formed; (3) The peptide A- termm us was deprotected using 20% v / v piperidine in DMF (50 °C microwave assisted heating, 10 min; repeated twice). e) Cleavage of Protected Linear Peptide

[0390] After completion of the synthesis, the linear resin-bound peptide was transferred into a fritted plastic column. The resin w as washed with DCM then dried under negative pressure on a Razor® peptide cleavage system from CEM Corporation (Matthews, NC). The protected peptide was cleaved off the solid support by treatment with HFIP / DCM (3:7, v / v; 5 mL) at 20 °C for 5 min. The solution was collected into a 50 mL centrifuge tube. This process was repeated twice more (three times total), and the cleavage solution was combined into the same tube. The solvents w ere removed under reduced pressure. The resulting crude linear peptide was dissolved in 1: 1 (v / v) mixture of DI water / MeCN (10 mL). The solution was frozen and lyophilized. f) Solution Phase Macrolactamization

[0391] The crude protected linear peptide was dissolved in anh. THF (10 mL). To that solution was added DIPEA (45 pL. 5 equiv) followed by the dropwise addition of the solution of HO At (6 mg, 0.9 equiv) and HATU (8.4 mg, 1.3 equiv) dissolved in anh. DMF (150 pL). The solution was shaken at RT for approximately 30 min and monitored by UPLC-MS. After the reaction w as complete, the reaction solution was concentrated under reduced to dry ness.g) Deprotection of the Protected Cyclic Peptide

[0392] The cyclic peptide was deprotected by treatment with TFA / ThO / TIS / Phenol (93:2:3:2, v / v / v / w; 7 mL) at RT for 1 h. The crude cyclic peptide was precipitated from the TFA cleavage solution using chilled MTBE (40 mL) and collected by centrifugation (4000 rpm). The supernatant was removed. Additional cold MTBE (35 mL) was added to the peptide pellet and clarified by centrifugation. The resulting crude peptide pellet was dissolved in 1 : 1 (v / v) mixture of DI water / MeCN (10 mL). The solution was frozen and lyophilized. h) HPLC Purification

[0393] The crude residue was then dissolved in DMSO and purified by preparative reversed- phase high performance liquid chromatography on a Waters™ SunFire Prep Cl 8 OBD column (100 A, 5 pm, column size 19 x 150 mm, Milford, MA) using an Agilent MS-Directed Preparative HPLC-MS system. Mobile phase: (A) 0. 1% TFA in HPLC-grade water and (B) 0. 1% TFA in HPLC-grade acetonitrile; flow rate: 35 mL / min; UV wavelength = 215 nm; gradient: gradient: 0.5%B / min for 40 min starting at 5% B less than the calculated %B required for compound elution. In some instances, better separation was obtained by using 0.1% NH4OH as modifier.

[0394] UV absorbing fractions containing the target m / z ions were collected and the fractions containing the desired product were combined, concentrated in vacuo and freeze-dried to afford the cyclized peptide as a solid.

[0395] Confirmation of identity' and purity assessment of final compounds were performed by UPLC-MS, which was measured by a reverse phase Waters™ ACQUITY UPLC-MS system. Column: Waters™ Cortecs Cl 8+ Column (90 A, 1.6 pm, column size 2.1 x 100 mm, Milford, MA). Mobile phase: (A) 0.1% TFA in HPLC-grade water and (B) 0.1% TFA in HPLC-grade acetonitrile; injection volume: 0.5 pL; flow rate: 0.7 mL / min; Column Temperature: 60 °C; UV wavelength X = 215 nm; Two gradients were used for analysis depending on analyte polarity: 1) 2% B for 1.3 mm, 2-20% B for 1.3 mm. 20-30% B for 5.2 mm, 30-55% B for 3.9 mm, 55-95% B for 2.6 min, hold at 95% B for 2.7 min, or 2) 2% B for 1.3 min, 2-40% B for 1.3 min, 40-95% B for 10.4 min, hold at 95% B for 4 min.Synthetic Scheme 263. Procedure C a) Solid Phase Synthesis of Peptides (SPPS)

[0396] Peptides were synthesized on a Symphony® X synthesizer from Gyros Protein Technologies (Uppsala, Sweden), using standard solid-phase synthesis using Fmoc / fBu chemistry and Fmoc-L-Phe4COEDA(Cbz)-OH, where the Cbz-protected side chain can be orthogonally deprotected for the selective late-stage functionalization of the side chain, as summarized above in Synthetic Scheme 26.

[0397] Reactions were typically performed using 2-Chlorotrityl chloride resin (100-200 mesh, 1.6 mmol / g loading, Novabiochem®). All the amino acids were dissolved at a 0.2 M concentration in anh. DMF or NMP. The amino acids were activated with equimolar amounts of HATU solution (0.5 M in anh. DMF) and a 2-fold molar excess of NMM solution (1.0 M in anh. DMF).

[0398] The loading of the initial C-terminal amino acid to the 2CTC resin was performed as follows: 2 mmol of 2CTC resin (0.62 g) was treated with DIPEA (0.84 mL, 4.8 mmol) and Fmoc-SbMeW7OMe-OH (0.57 g, 1.2 mmol) in DCM (30 mL). The slurry was shaken at RT for 3 h, then filtered. The resin was washed with a mixture of DCM / MeOH / DIPEA (17:2: 1, v / v / v; 3 x 30 mL), followed by DMF (3 x 30 mL) and DCM (3 x 30 mL), dried under vacuum.

[0399] Every synthesis cycle included: (1) Fmoc amino acid deprotection by 20% (v / v) piperidine in anh. DMF (RT; 3 x 5 min); (2) Double coupling with Fmoc-protected amino acid / HATU / NMM (4, 4. and 8 equiv, respectively; RT; 2 x 70 min). Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear peptide was formed. Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear peptide was formed; (3) The peptide A-terminus was deprotected using 20% v / v of piperidine in DMF (RT; 3 x 5 min). b) Cleavage of Protected Linear Peptide

[0400] To cleave the crude linear peptide precursor from the solid support, a 1 :3 (v / v) mixture of HFIP / DCM (40 mL) was added to the peptidyl resin and shaken for 30 min. The cleavage solution was filtered and transferred in a centrifuge tube. This process was repeated twice more (three times total), the combined cleavage solution was concentrated under reduced pressure to give the crude protected linear peptide and used in the next step directly without any further purification. MS ESI calculated for Ci42Hi65ClN24O24 [M + 2H]2+1323.1, found 1323.5.c) Solution Phase Macrolactamization

[0401] To a stirred solution of crude linear peptide (0.2 mmol) in anh. THF (200 mL) was added a solution of HATU (102 mg, 0.27 mmol) and HOAt (37 mg, 0.27 mmol) in anh. DMF (0.7 mL), and DIPEA (94 pF. 0.54 mmol). The resulting solution was stirred at RT for 1 h. The volatile was removed under reduced pressure. The residue was purified on silica gel column chromatography, eluted with MeOH 0-30% in DCM to afford the protected macrolactam. MS ESI calculated for C142H165CIN24O24 [M + 2H]2+1314.1, found 1314.6. d) Deprotection of the Protected Cyclic Peptide

[0402] A solution of TFA / Phenol / TIS (92.5 / 5 / 2.5, v / v / v; 10 mL) was added to the crude protected cyclic peptide. The mixture was stirred at RT for 1 h. Cold Et20 (30 mL) was added to the solution and the precipitated peptide was collected by centrifugation. The precipitate was washed with Et20 (2 x 30 mL) and dried under vacuum. The residue was purified by Rp chromatography with the following conditions: Gilson C8 column (Kromasil, 50 mm x 250 mm); Mobile Phase A: water (0. 1% TFA), Mobile Phase B: MeCN (0.1% TFA); Gradient Elution: 10%-90% over 6 column volumes, flow: 85 mL / min; Detector: UV 220 nm. The productcontaining fractions were combined, concentrated under reduced pressure, and freeze-dried to afford Intermediate 26A (SEQ ID NO 116: (cyclo(bhcLeu-Nle-4Pal-Pipt5OH-Trp7az-NMeE- N-4Pal-Trp7Cl-aMeS-Phe4CONH2-Phe4COEDA(Cbz)-Sar-SbMeW7OMe)). MS ESI calculated for C 115H135CIN24O24 [M + 2H]2+1137.0, found 1137.1. e) Orthogonal Side-Chain Deprotection

[0403] A stirred solution of Intermediate 26A (52 mg, 0.02 mmol) in anh. DMF (3 mL) was degassed with nitrogen for 10 min. Pd / C (anh. 42m g, 20 wt. %) was added into the flask. The flask was evacuated and backfdled with H2 (5 times). The resulting mixture was stirred for 4.5 h at RT under an atmosphere of dihydrogen. The flask was evacuated and refdled with N2 (5 times). The resulting mixture was fdtered. The fdtered cake was washed with DMF (3 x 1 mL). The fdtrate was concentrated under reduced pressure. The residue was purified by Rp chromatography with the following conditions: Gilson C8 (Kromasil. 50 mm x 250 mm); Mobile Phase A: water (0.1% TFA), Mobile Phase B: MeCN (0.1% TFA); Gradient Elution: 10%-45% over 6 column volumes, flow: 85 mL / min; Detector: UV 220 nm. The product-containing fractions were combined, concentrated under reduced pressure, and freeze-dried. The TFA salt was dissolved in acetonitrile / water (2: 1, 10 mL), treated with aq. 1 N HC1 (0.14 mL). and lyophilized to afford Intermediate 26B HC1 salt (SEQ ID NO 117: (cyclo(bhcLeu-Nle-4Pal-Pipt5OH-Trp7az-NMeE-N-4Pal-Trp7Cl-aMeS-Phe4CONH2-Phe4COEDA-Sar-SbMeW7OMe HC1 salt)). MS ESI calculated for C107H129CIN24C M + 2H]2+1070.0, found 1070.2. f) Side-Chain Functionalization

[0404] A solution of HATU (7.5 mg, 20 pmol) in DMF (200 pL) and DIPEA (7 pL, 40 pmol) was added to a solution of Intermediate 26C (25 mg, 20 pmol) in aq. DMF (400 pL). The resulting solution was stirred at RT for 30 min to give the pre-activated species.

[0405] DIPEA (12 pL. 70 pmol), and 250 uL of the above pre-activated lipid solution were added to a solution of Intermediate 26B (16 mg, 7 pmol) in anh. DMF (2.0 mL). The resulting solution was stirred at RT for 30 min. An additional 110 pL of the pre-activated lipid solution was added to the reaction mixture until consumption of Intermediate 26B. The filtrate was concentrated under reduced pressure. The residue was purified by Rp chromatography with the following conditions: Gilson (Middleton, WI) C8 (Kromasil®, 50 mm x 250 mm); Mobile Phase A: water (0.1% TFA), Mobile Phase B: MeCN (0.1% TFA); Gradient Elution: 30%-100% over 6 column volumes, flow: 85 mL / min; Detector: UV 220 nm. The product-containing fractions were combined, concentrated under reduced pressure, and freeze-dried to afford Intermediate 26D (SEQ ID NO 118: cyclo(bhcLeu-Nle-4Pal-Pipt5OH-Trp7az-NMeE-N-4Pal-Trp7Cl-aMeS- Phe4CONH2-Phe4COEDA(PEG2NMe2EtNH2-AEEA-AEEA-gGluOtBu-gGluOtBu- C18diacidOtBu)-Sar-SbMeW7OMe)). MS ESI calculated for C i7oH244ClN3o04o+[M + 2H]3+1127.9. found 1128.4. g) Deprotection

[0406] A solution of TFA / H2O / TIS (92.5 / 5 / 2.5, v / v / v; 4 mL) was added to the crude protected cyclic peptide Intermediate 26D (15 mg; 4.4 pmol). The mixture was stirred at RT for 25 min. The volatiles were removed under reduced pressure. The crude peptide was purified by Rp chromatography with the following conditions: Gilson C8 column (Kromasil®, 50 mm x 250 mm; Nouryon, Bohus, Sweden); Mobile Phase A: water (0.1% TFA). Mobile Phase B: MeCN (0.1% TFA); Gradient Elution: 10%-60% over 6 column volumes, flow: 85 mL / min; Detector: UV 220 nm. The product-containing fractions were combined, concentrated under reduced pressure, and freeze-dried to afford the final cyclized product SEQ ID NO 112 as a powder. MS ESI calculated for CissffeoCINsoC [M + 2H 1072.4, found 1071.9.Synthetic Scheme 27Cont. of Synthetic Scheme 27 27a4. Procedure D a) Solid Phase Synthesis of Peptides (SPPS)

[0407] Peptides were synthesized on a Liberty Blue™ synthesizer from CEM Corporation (Matthews, NC), using standard solid-phase synthesis using Fmoc / tBu chemistry' as summarized above in Synthetic Scheme 27.

[0408] Reactions were typically performed at a 50 pmol scale using Cl-TCP(Cl) ProTide® resin (100-200 mesh, 0.37 mmol / g loading, CEM Corporation, Matthews, GA). All the amino acids were dissolved at a 0.2 M concentration in anh. DMF or NMP. The amino acids were activated with equimolar amounts of Oxyma Pure solution (0.5 M in anh. DMF containing 0.1 M of DIPEA), and a 2-fold molar excess of DIC solution (0.5 M in anh. DMF).

[0409] The loading of the initial C-terminal amino acid (S)-2-(((( 9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid to the Cl-TCP(Cl) ProTide® resin was performed directly on the Liberty7Blue™ synthesizer by treating with 10- fold molar excess of Fmoc-protected amino acid solution (0.2 M in anh. DMF) and 20-fold molar excess of base solution (1.0 M DIPEA + 0.125 M KI in anh. DMF) and 90 °C microwave assisted heating for 10 min (repeated twice).

[0410] Every synthesis cycle included: (1) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (90 °C microwave assisted heating, 1 min); (2) Coupling (potentially repeated twice for difficult couplings) with Fmoc-protected amino acid / DIC / Oxyma (5, 5, and 10 equiv, respectively; 90 °C microwave assisted heating, 2 min). Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear protected peptide was formed. b) Side-Chain Functionalization

[0411] After coupling of ivDde-Phe-4((OCH2CH2)i-2-NHFmoc)-OH (AEF or AEEF) on resin, the Fmoc protecting group on the distal primary amine was removed by treatment with 20% v / v piperidine in anh. DMF (90 °C microwave assisted heating. 1 mm). The different linkers, spacers and protractor were assembled off the amino group of AEF or AEEF at position 11 by SPPS.

[0412] Every7side-chain extension cycle included: (1) Coupling (repeated twice) with Fmoc- protected building blocks / DIC / Oxyma (5, 5, and 10 equiv, respectively; 90 °C microwave assisted heating, 2 min); (2) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (90 °C microwave assisted heating, 1 min).The addition of the protractor (w ith reactive functional groups potentially protected as tert-butyl (such as C 18diacid) or Boc (such as Ado) as needed) was performed by coupling(repeated twice) with (protected) protractor / DIC / Oxyma (5. 5, and 10 equiv, respectively; 90 °C microwave assisted heating, 2 min). c) Orthogonal Main-Chain Deprotection

[0413] After assembly of the side-chain modification at position 11, the A-terminal ivDde protecting group was removed by treatment with a solution of 2% hydrazine monohydrate in DMF (4 mL) at 90 °C (microwave assisted heating, 3 min, repeated three times). d) Cleavage of Protected Linear Peptide

[0414] After completion of the synthesis, the linear resin-bound peptide was transferred into a fritted plastic column. The resin was washed with DCM then dried under negative pressure on a Razor® peptide cleavage system from CEM Corporation (Matthews, NC). The protected peptide was cleaved off the solid support by treatment with HFIP / DCM (3:7, v / v; 5 mL) at 20 °C for 5 min. The solution was collected into a 50 mL centrifuge tube. This process was repeated twice more (three times total), and the cleavage solution was combined into the same tube. The solvents were removed under reduced pressure. The resulting crude linear peptide was dissolved in 1: 1 (v / v) mixture of DI water / MeCN (10 mL). The solution was frozen and lyophilized. e) Solution Phase Macrolactamization

[0415] The crude protected linear peptide was dissolved in anh. THF (10 mL). To that solution was added DIPEA (45 pL. 5 equiv) followed by the dropwise addition of the solution of HO At (6 mg, 0.9 equiv) and HATU (8.4 mg, 1.3 equiv) dissolved in anh. DMF (150 pL). The solution was shaken at RT for approximately 30 min and monitored by UPLC-MS. After the reaction was complete, the reaction solution was concentrated under reduced to dryness. f) Deprotection of the Protected Cyclic Peptide

[0416] The cyclic peptide was deprotected by treatment with TFATLO / TIS / Phenol (93:2:3:2, v / v / v / w; 7 mL) at RT for 1 h. The crude cyclic peptide was precipitated from the TFA cleavage solution using chilled MTBE (40 mL) and collected by centrifugation (4000 rpm). The supernatant was removed. Additional cold MTBE (35 mL) was added to the peptide pellet and clarified by centrifugation. The resulting crude peptide pellet was dissolved in 1 : 1 (v / v) mixture of DI water / MeCN (10 mL). The solution was frozen and lyophilized. g) HPLC Purification

[0417] The crude residue was then dissolved in DMSO and purified by preparative reversed- phase high performance liquid chromatography on a Waters™ SunFire Prep Cl 8 OBD column (100 A. 5 pm, column size 19 x 150 mm; Waters Corporation, Milford. MA) using an AgilentMS-Directed Preparative HPLC-MS system (Agilent Technologies, Santa Clara. CA). Mobile phase: (A) 0.1% TFA in HPLC-grade water and (B) 0.1% TFA in HPLC-grade acetonitrile; flow rate: 35 mL / min; UV wavelength A = 215 nm; gradient: gradient: 0.5%B / min for 40 min starting at 5% B less than the calculated %B required for compound elution. In some instances, better separation was obtained by using 0. 1% NFUOH as modifier.

[0418] UV absorbing fractions containing the target m / z ions were collected and the fractions containing the desired product were combined, concentrated in vacuo, and freeze-dried to afford the cyclized peptide as a solid.

[0419] Confirmation of identity and purity assessment of final compounds were performed by UPLC-MS, which was measured by a reverse phase Waters™ ACQUITY UPLC-MS system. Column: Waters™ Cortecs Cl 8+ Column (90 A, 1.6 pm, column size 2.1 x 100 mm, Milford, MA). Mobile phase: (A) 0.1% TFA in HPLC-grade water and (B) 0.1% TFA in HPLC-grade acetonitrile; injection volume: 0.5 pL; flow rate: 0.7 mL / min; Column Temperature: 60 °C; UV wavelength A = 215 nm; Two gradients were used for analysis depending on analyte polarity: 1) 2% B for 1.3 min, 2-20% B for 1.3 mm, 20-30% B for 5.2 mm, 30-55% B for 3.9 min, 55-95% B for 2.6 min, hold at 95% B for 2.7 min, or 2) 2% B for 1.3 min, 2-40% B for 1.3 min, 40-95% B for 10.4 min, hold at 95% B for 4 min.Synthetic Scheme 285. Procedure E a) Solid Phase Synthesis of Peptides (SPPS)

[0420] Peptides were synthesized on a Liberty Blue™ synthesizer from CEM Corporation, Matthews, NC, using standard solid-phase synthesis using Fmoc / tBu chemistry as summarized above in Synthetic Scheme 28.

[0421] Reactions were typically performed at a 200 pmol scale using 2-chlorotrityl chloride resin preloaded with H2N-Tyr(OtBu)-OH (0.66 mmol / g loading / Novabiochem®, Millipore Sigma, Burlington, MA, or IRIS Biotech GmbH, Marktredwitz, DE).

[0422] Every synthesis cycle included: (1) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (50 °C micro wave assisted heating. 10 min; repeated twice); (2) Coupling (potentially repeated twice for difficult couplings) with Fmoc-protected amino acid / HATU / DIPEA (5, 5, and 10 equiv, respectively; 50 °C microwave assisted heating, 10 min).Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear protected peptide was formed; (3) The peptide A-terminus was deprotected using 20% v / v piperidine in DMF (50 °C microwave assisted heating, 10 min; repeated twice). b) Orthogonal Main-Chain Deprotection - Dde removal

[0423] After the assembly of the protractor / spacer / linker on the side chain of Bz3NH25AE, the Dde protecting group was removed from the amino acid alpha nitrogen by treatment with a solution of 4% v / v hydrazine monohydrate in DMF (5 mL; 5 min; repeated three times). The resin was washed with DMF five times to remove all traces of hydrazine. The remaining of the main-chain was assembled by SPPS using the aforementioned synthesis cycle. c) Cleavage of Protected Linear Peptide

[0424] After completion of the synthesis, the linear resin-bound peptide was transferred into a fritted plastic column. The resin was washed with DCM then the linear peptide was cleaved off the solid support by treatment with HFIP / DCM (3:7, v / v; 5 mL) at RT for 30 min. The solution was collected into a round bottom flask. The resin w as washed three times with the same cleavage solution and the washing solutions collected in the same round bottom flask. The solvents were removed under reduced pressure. The crude dissolved in 1: 1 (v / v) mixture of DI w ater / MeCN (15 mL) and freeze-dried to obtain a solid crude. d) Solution Phase Macrolactamization

[0425] The crude protected linear peptide was resuspended in anh. DMF (1.5 mg / mL) or anh. THF. DIPEA (5 equiv), HO At (0.8 equiv), and HATU (1.2 equiv) were added to the peptide solution and the solution stirred at RT for 1 h. The reaction was monitored by UPLC-MS and stopped after complete conversion of the starting material. The reaction solution was then concentrated under reduced pressure to dryness. e) Deprotection of the Protected Cyclic Peptide

[0426] The cyclic peptide was deprotected by treatment with TFA / H2O / TIS (92.5:5:2.5, v / v / v;15 mL) at RT for 1 h. The solution w as collected into a round bottom flask and the volatiles were removed under reduced pressure. The resulting crude peptide was dissolved in 1 : 1 (v / v) mixture of DI water / MeCN (10 mL) and 5% (v / v) of TFA was added to the solution to remove the tryptophan adduct, then stirred for Ih. The solution was frozen and lyophilized.f) HPLC Purification

[0427] The crude residue was then dissolved in DMSO and purified by preparative reversed- phase high performance liquid chromatography on a Waters™ Xbridge Protein BEH C4 OBD prep column (300A, 5 pm, column size 30 x 250 mm) using a Waters™ 2545 HPLC system equipped with Waters™ 2489 UV / Visible detector. Mobile phase: (A) 0.1% TFA in HPLC-grade water and (B) 0. 1% TFA in HPLC-grade acetonitrile; flow rate: 50 mL / min; UV wavelength X = 214 nm; gradient: 0.5%B / min starting at 5% B less than the calculated %B required for compound elution over 20 min. UV absorbing fractions containing the target were collected and the fractions containing the desired product were combined, concentrated in vacuo and freeze- dried to afford the cyclized peptide as a solid.

[0428] Confirmation of identity and purity assessment of final compounds were performed by UPLC-MS, which was measured by a reverse phase Waters™ ACQUITY UPLC-MS system. Column: Waters™ ACQUITY UPLC Protein BEH C4 (300 A, 1.7 pm, column size 2.1 x 100 mm). Mobile phase: (A) 0.1% TFA in HPLC-grade water and (B) 0.1% TFA in HPLC-grade acetonitrile; injection volume: 0.5 pL; flow rate: 0.4 mL / min; Column Temperature: 45 °C; UV wavelength Z = 214 nm; gradient: 20-20% B in 1 min and 20-40% in 3 min.Synthetic Scheme 296. Procedure F a) Solid Phase Synthesis of Peptides (SPPS)

[0429] Peptides were synthesized on a Liberty Blue™ synthesizer from CEM Corporation, using standard solid-phase synthesis using Fmoc / tBu chemistry' as summarized above in Synthetic Scheme 29.

[0430] Reactions were typically performed at a 200 pmol scale using 2-chlorotrityl chloride resin preloaded with H2N-Tyr(OtBu)-OH (-0.66 mmol / g loading, Novabiochem or IRIS Biotech). Every' synthesis cycle included: (1) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (50 °C micro wave assisted heating, 10 min; repeated twice); (2) Coupling (potentially repeated twice for difficult couplings) with Fmoc-protected aminoacid / HATU / DIPEA (5, 5, and 10 equiv. respectively; 50 °C microwave assisted heating. 10 min). Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear protected peptide was formed; (...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, whereinR1 is selected from hydrogen, C1-20 alkyl, amino(C0-10 alkyl), (C1 -6 alkyl)o-2 amino(C0-10 alkyl), (C1 -6 alkyl)o-2 amino(Co-10 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)3N+(C0-6 alkyl), aryl(C()-10 alkyl), heteroaryl(C()-10 alkyl), (C3-i2)cycloalkyl(C0-10 alkyl), heterocycloalkyl(Co-10 alkyl), C1-1Q fluoroalkyl, C2-10 alkenyl, (C0-6 alk l)carbonylamino(C 0-6 alkyl), (C i -6 alkyl)o-2 aminocarbonyl(C0-6 alkyl). (C1-6 alkyl)o-2 aminocarbonylamino(C0-6 alkyl), arylcarbonylamino(C0-6 alkyl), arylaminocarbonyl(C0-6 alkyl), heteroarylcarbonylamino(C0-6 alky l), heteroarylaminocarbonyl(C0-6 alkyl), C1 -6 alkyloxy, (C1-6 alkyl)oxy(C0-6 alkyl), ((C3- 12)cycloalkyl)oxy(C0-6 alkyl), ((C3-I2)cycloalkyl C0-6 alkyl)oxy(C0-6 alkyl), (CQ-6 alkyl)carboxy(C0-6 alkyl). N‘=N+=N-(C0-6 alkyl), and H2N-C(=NH)NH-(C0-6 alkyl). wherein R1 is substituted by 0, 1, 2, or 3 Rlasubstituents each independently selected from C1- 6 alkyl, amino, azido, cyano, halo, hydroxy, (C3-i2)cycloalkyloxy, C1 - alkyloxy, and - (CH2)0-6-NH-(X1) 1 -2-X2-X3-U1-U2-Z ; eachR2a is independently selected from hydrogen, hydroxy, Cl -4 alkyl, fluoro, and Cl -4 alkyloxy;R2b is selected from ary l, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said heteroaryl contains at least one nitrogen atom,wherein R3b is substituted by 0,independently selected from C1 -6 alkyl, amino(Co- 6 alkyl), (C1 -6 alkyl)o-2amino(C0-6 alkyl). (Cl -6 alkyl)3N+(C0-6 alkyl), aminocarbonyl(C0-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), hydroxy, C1 -6 alkyloxy, halo, (C 1 _g alkyl)o-2 amino(C0-6 alkyloxy), (Cl -6 alkyl)3N+(C0-6 alkyloxy), (C1 -6 alkyloxy)carbonyl(C0-6 alkyl), carboxy(C0-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6 alky l), halo, Cl -6 haloalkyl, Cl -6 haloalkyloxy, Cl -6 alkyloxy, -O(CH2)0-6~NH-(X1)i- 2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z;R3a is selected from hydrogen, hydroxy, hydroxy(C1 -6 alkyl), amino, amino(C1 -6 alkyl), C1 -io alkyl, (C3-i2)cycloalkyl(Co-10 alkyl), (C0-6 alkyl)thio(C1 -6 alkyl), and carboxy(C1 -6 alkyl), wherein R3amay be substituted by 0, 1, or 2 R3csubstituents;R3b is selected from hydrogen, C1 -io alkyl, hydroxy(C1 -6 alkyd), amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C] -6 alkyl), (C] -6 alky l)sN+(C 1 -6 alkyl), halo, Cl -6 haloalkyl. aryl(Co- 10 alky l), heteroaryl(C0-6 alky l), (C3-i2)cycloalkyl(C0-6 alkyd), heterocycloalkyl(C0-6 alkyd), (C1 -6 alkyl)oxy(C1 -6 alkyl), (C3-i2)cycloalkyloxy(C1-6 alkyl). carboxy(C1 -6 alkyl), aminocarbonyl(C 1 -6 alkyl), (C1 -6 alky d)o-2 aminocarbonyl(C1 -6 alkyl), aminocarbonylamino(C 1 -6 alkyl), (C1 -6 alkyl)o-2 aminocarbonylamino(C 1 -6 alkyl), (Co- 6 alkyd )thio(C 1-6 alkyl), (C1 -6 alkyl)SO2(C1 -6 alkyd), and (C1 -6 alkyl)sulfinyl(C1 -6 alkyl), wherein R3bmay be substituted by 0, 1, or 2R3C substituents; eachR3C is independently selected from halo, C1 -6 alkyd, amino, (Cl -6 alkyd)o-2 amino(C0-6 alkyl), (Cl -6 alkyl^N1-. (Cl -6 alkyl)SO2(C0-6 alkyl), cyano, cyano(C1 -6 alkyd), hydroxy, hydroxy(Cl-6 alkyd), (Cl -6 alkyl)oxy(C0-6 alkyd), aminocarbonyl(C0-6 alkyd), and (C0-6) carboxy(C0-6 alkyl), whereinR3a and R3b together with the atoms to which they are attached, may form a saturated ring system, wherein said saturated ring system may be substituted by 0, 1, or 2 R3csubstituents;R4a is selected from hydrogen, Cl -6 alkyl, hydroxy, C1 -4 alkyloxy, and fluoro;R4bis selected from bicyclic heteroaryl(Co-3 alkyd), and bicyclic aryl(Co-3 alkyl), wherein R4b is substituted with 0, 1, or 2 R4c substituents each R4cindependently selected from halo, hydroxy, cyano, nitro, carboxy, carboxy(Cl-6 alkyl), (Cl-6 alkydoxy)carbonyl(C0-6 alkyl), Cl-6 alkyloxy, (Cl-6 alkyl)oxy(Cl-6 alkyl), Cl-6 alkyl, Cl-6 haloalkyl, and-(CH2)0-6-NH-(X1) 1 -2-X2-X3-U '-U2-Z;R5a is selected from hydrogen, C1 -io alkyl, C1 -io fluoroalkyl, carboxy(C1 -io alkyl), hydroxy, hydroxy(C1 -io alkyl), cyano(C1 -io alkyl), (C3-i2)heterocycloalkyl(Co-10 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C 1 -6 alkyl), (carboxy(C l-10 alkyl))oxy(C 1 -6 alkyl), amino(C0-6 alky l)aryl(C 1-6 alkyl), aryl(C0-6 alkyl), (C3-i2)cycloalkyl(C0-6 alkyd), heteroaryl (C0-6 alky l), (Cl -6 alkyl)oxy(Cl-6 alkyl), (Cl -6 alky loxy)carbonyl(C0-6 alkyl), amino, amino(C1 -6 alkyl). (C1-6 alkyl)o-2 amino(C0-6 alkyl). amino(C2-6 alkyl)oxy(C1 -6 alkyl), (C1 -6 alkyl)o-2amino(C2-6 alkyl)oxy(Cl-6 alkyl), amino(Cl-6 alkyl)carbonylamino(Cl- 6 alkyl), amino(C1 -6 alkyl)carbonylamino(C1 -6 alkyl), (Cl -6 alkyl)o-2 amino(C1 -6 alkyl)carbonylamino(C1 -6 alkyl), (C1 -6 alkyl)3N+(C2-10 alky l), (C1 -6 alky d)sN+(C 1-6 alkyl)carbonylamino(C1 -6 alkyl), C1 -io fluoroalkyl, -(CH2)0-6-NH-(X1)i-2-X2-X3-(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z and wherein R3alssubstituted by 0. 1, or 2 R5d substituents;R5b is selected from hydrogen, C1 -io alkyl, hydroxy(C1 -iQ alkyl), carboxy(C1 -6 alkyd), (C1 -6 alkyl)oxy(C1-6 alkyl), aminocarbonyl(C1 -6 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C1 -6 alkyl), carboxy(C1 -io alky d)oxy(C1 -6 alkyl), cyano(C1 -6 alkyl), amino(C1 -6 alkyl), (Cl- 6 alky d)o-2amino(C1 -6 alkyl), (C1 -6 alky d)o-2amino(C2-6 alky d)oxy(C1 -6 alkyl), amino(C1 -6 alkyl)carbonylamino(C1-6 alkyl), (amino(C2-6 alkyl)oxy(C1 -6 alkyl), C1 -6 alky d)o-2 amino(C1 -6 alky d)carbony damino(C 1 -6 alkyl), (C1 -6 alkyl)3N+(C2-6 alkyl)oxy(C]-6 alkyl), (C]-6 alkyl)3N' (C] -6 alkyl)carbonylamino(C] -6 alkyl). (C] -6 alkyd)3N+(C1 -6 alkyd), (heterocycloalkyl(Co-10 alkyd), (C3-i2)cycloalkyl(Co-10 alkyd), C1 -io haloalkyl, -(CH2)l-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)1- 6-NH-(X1)i-2-X2-X3-U1-U2-Z, wherein R3b is substituted by 0, 1, 2, or 3 R3esubstituents, whereinR5a andtogether with the atoms to which they are attached, form a saturated mono- or bi-cyclic ring, wherein said mono- or bi-cyclic ring is substituted with 0, 1, or 2, R3d and 0, 1, 2, or 3 R$esubstituents; eachR5d is independently selected from selected from halo, hydroxy, hydroxy(C1 -6 alkyl), C1 - 10 alkyl, carboxy, carboxy (C 1-6 alkyl), C1 -6 alkyloxy, (C1 -6 alkyl)oxy(C1-6 alkyl),amino, amino(C1-6 alkyl). (Cl-6 alkyl)o-2 amino(C0-6 alkyl). amino(C1-6 alky l)carbonylamino(C 0-6 alkyl), (C1 -6 alkyl)o-2 amino(C1 -6 alkyl)carbonylamino(C0-6 alkyl), (C1 -6 alkyl)3N+(C0-6 alkyl), (C1 -6 alkyl)sN+(C2-6 alkyl)oxy(C0-6 alkyl). (Cl-6 alkyl)3N+(C1 -6 alkyl)carbonylamino(C0-6 alkyl), (carboxy(C 1 -6 alkyl))oxy(C0-6 alkyl), cyano(C0-6 alkyl), tetrazolyl(C0-6 alkyl), and C1 -6 haloalkyl, amino(C2-6 alkyl)oxy(Co- 6 alkyl), (C1-6 alkyl)o-2 amino(C2-6 alkyl)oxy(C0-6 alkyl), -(CH2)0-6-O(CH2)0-6-NH- (X1)i-2-X2-X3-U1-U2-Z. and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z; and two R5dsubstituents together with the atom they are attached to may join together to form a saturated ring; eachR5e is independently selected from halo, hydroxy, hydroxy(C1 -io alkyl), C1 -io alkyl, carboxy, carboxy(Cl-6 alkyl), Cl -6 alkyloxy, (Cl -6 alkyl)oxy(Cl-6 alkyl), amino, amino(C1-6 alkyl), (C1-6 alkyl)o-2 amino(C0-6 alkyl), amino(C1 -6 alky l)carbonylamino(C 0-6 alkyl), (C1 -6 alkyl)o-2 amino(Cl-6 alkyl)carbonylamino(C0-6 alkyl), (C1-6 alkyl)3N+(C0-6 alkyl), (Cl -6 alkyl)sN+(C2-6 alkyl)oxy(C0-6 alkyl). (C1-6 alkyl)3N+(Cl-6 alkyl)carbonylamino(C0-6 alkyl), (carboxy(C 1 -6 alkyl))oxy(Cl-6 alkyl), cyano(C0-6 alkyl), tetrazolyl(C0-6 alkyl), C1 -6 haloalkyl. -(CH2)0-6“O(CH2)0-6-NH- (X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z and two R5esubstituents together with the atom they are attached to may join together to form a saturated ring;R5C is hydrogen. C1 -4 alkyl, hydroxy(C1 -4 alkyl), C1-4 alkyloxy, or (C1-4 alkyl)oxy(C1 -4 alkyl);R6a is selected from hydrogen, hydroxy, amino, C1-4 alkyloxy, and Cl -6 alkyl;R6b is selected from hydrogen, Cl -6 alkyl, hydroxy, C1-4 alkyloxy, and fluoro;R6C is selected from C1 -io alky l, C1 -6 alkyloxy, (C1-6 alkyl)oxy(C1-6 alkyl), C1 -io haloalkyl, aryl(C0-6 alkyl), heteroaryl(C()-10 alkyl), (C1-6 alkyl)SO2(C0-6 alkyl), hydroxy, hydroxy(C1-6 alkyl), amino(C0-6 alkyl), (Cl-6 alkyl)o-2 amino(CQ-6 alkyl), aminocarbonyl(C0-6 alkyl), (Cl-6 alkyl)o-2 aminocarbonyl(C()-6 alkyl). (Cl-6 alkyl)carbonylamino(C0-6 alkyl), (Cl-6 alkyl)o-2 aminocarbonylamino(C0-6 alkyl), and carboxy(C()-6 alkyl);R7a is selected from hydrogen, Cl-6 alkyd, hydroxy, Cl -4 alkyloxy, and fluoro;R3b is selected from aryl(Co-4 alkyl), heteroaryl(C[)-4 alky l) wherein said heteroaryl contains at least one nitrogen, and (C3-i2)cycloalkyl(Co-4 alkyl), wherein R3b issubstituted by 0, 1, or 2, R3csubstituents each independently selected from Cl-6 alkyl. Cl -6 fluoroalkyl, Cl -6 fluoroalkyloxy, (Cl -6 alkyl)o-2 amino(C0-5 alkyl), (Cl -6 alky l)sN+(C 0-5 alkyl), carboxy(C0-6 alkyd), (Cl-6 alkyloxy)carbonyl(C0-6 alkyd), carboxy(C1 -6 alkyl)oxy(C0-6 alkyl), aminocarbonyl(C0-6 alkyl). (Cl-6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), hydroxy, hydroxy(Cl-6 alkyl), halo, -(Co-5 alkyl)- (S(=O)2OH). -(CO-5 alkyl)-(S(=O)2NH2), amino(C0-6 alkyl)oxy(C0-6 alkyl). (Cl -6 alkyl)o-2 amino(C0-6 alkyl)oxy(C0-6 alkyl), (Cl-6 alkyl)3\ (C'o-6 alkyl)oxy(CQ-6 alkyd), aminocarbonylamino(C0-6 alkyl), (Cl-6 alkyl)o-2 aminocarbonylamino(C0-6 alkyl), Cl- 10 haloalkyL C1 -io haloalkyloxy, (Cl-6 alkyl)oxy(C0-6 alkyl), and (Cl-6 haloalkyl)oxy(C0-6 alkyd);R8a is selected from hydrogen, Cl-6 alkyd, hydroxy, C1 -4 alkyloxy, Cl-6 fluoroalkyd, C1 -4 fluoroalkyloxy, and halo;R8b is selected from bicyclic aryl(Co-3 alkyl) and bicyclic heteroaryl(Co-3 alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms, wherein R3b issubstituted by 0, 1, or 2 R3csubstituents each independently selected from C1 -4 alkyl, halo, cyano, nitro, carboxy, carboxy(C1 -6 alkyl), amino, amino(C1 -3 alkyl), hydroxy, hydroxy(C1 -6 alkyl), Cl-6 fluoroalkyl, Cl-6 fluoroalkyloxy, and Cl-6 alkydoxy;R9 is selected from hydrogen, and C1.4 alkyl;R10a is selected from hydrogen, hydroxy. Cl-6 alkyl, C1 -4 alkyloxy, and fluoro;R10b is selected from (C3-i2)cycloalkyl(Co-3 alkyl). aryl(Co-3 alkyl), and heteroan d(Co-3 alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms, whereinR10b is substituted by 0, 1 , or 2R10c wherein eachRl°c is independently selected from C1 -io alkyl, C1 -io fluoroalkyl, Cl-6 haloalky 1, C1 -io fluoroalkyloxy, amino, amino(C1 -6 alkyd), (Cl-6 alkyl)o-2 amino(C0-6 alkyd), (Cl-6 alkyl)sN+(C0-6 alkyd), hydroxy, hydroxy(C1 -6 alkyl), cyano, cyano(C1 -6 alkyl), halo, aminocarbonyl. aminocarbonyl(C1 -6 alkyl), (Cl-6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), (Cl-6 alkyl)o-2 aminocarbonylamino(C0-6 alkyl), (Cl-6 alkyl)carbonylamino(C0-6 alkyl), carboxy (CQ-6alkyl), (C1 -6 alkoxy)carbonyl(C0-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6 alkyl), -(C[)-5 alkyl)-(S(=O)2OH), -(CQ-5 alky d)-(S(=O)2NH2), amino(C0-6 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl)oxy(C0-6 alkyl). (C1 -6 alkyl)3N+(C0-6 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)oxy(C0-6 alkyl), C1 -6 haloalkyloxy, (C3-i2)cycloalkyl(C0-6 alkyl), heterocycloalkyl(C0-6 alkyd), -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z;Rlla is selected from hydrogen, hydroxy. C1 -6 alkyl, C1 -4 alkyloxy, and fluoro;Rllb is selected from aryl(Co-3 alkyl), heteroaryl(Co-3 alkyl), wherein said heteroaryl contains 1 , 2, or 3 nitrogen atoms, and H2N-C(=NH)NH-(C1 -6 alkyl), wherein Rllb is substituted by 0, 1. or 2, 3. or 4 Rlld substituents each independently selected from C1 -g alkyl, amino, amino(C1 -6 alkyl), (C1-6 alkyl)o-2 amino(C0-6 alkyl), (C1-6 alky l)sN+(C 0-6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), cyano, cyano(C1 -6 alkyl), halo, amino(C0-6 alkyl)aminocarbonyl, aminocarbonyl, aminocarbonyl(C1-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C0-6 alky l), carboxy(C0-6 alky l), carboxy(C1 -6 alkyl)oxy(C0-6 alkyl), amino(CQ-6 alkyl)oxy(C0-6 alkyl). (C1 -6 alkyl)o-2 amino(C0-6 alkyl)oxy(C0-6 alkyd), (C1-6 alkyl)3N+(C0.6alkyl)oxy(C0-6 alkyl), -(C0-5 alkyd)-(S(=O)2NH2), (C1-6 alkyl)oxy(C0-6 alkyl), (C1 -6 fluoroalkyl)oxy(C0-6 alkyl), C1 -6 haloalkyloxy, C1 -6 haloalkyl, (C3-i2)cycloalkyl(C0-6 alkyl), heterocycloalkyl(C0-6 alkyd), ((C1 -6 alkyd)carbonyd)heterocycloalkyl(Co-10 alkyl), ((C1 -6 alkyl)carbonyloxy)heterocycloalkyl(Co-10 alkyl), -C(=O)NH-(CH2)2-6-NH-(X1)i-2- X^-U^U^Z, -(CH2)0-6-O(CH2)0-6-NH-(X1) i ^-X^X’-U’-U^Z, -(CH2)0-6-2-Z;R12a is selected from hydrogen, hydroxy, amino, C1-1Q alky l and (C3-i2)cycloalkyl(C0-6 alkyl);R12b jsselected from hydrogen, Cl-10 alkyd and (C3-12)cycloalkyd(C0-6 alkyl), wherein Rl3a and R12b, together with the atoms to which they are attached, may form a saturated nng;R13a is selected from hydrogen, hydroxy, C1 -6 alky l, C1 -4 alkyloxy, and fluoro;R13b is selected from hydrogen, and C1 -4 alkyd;R!3C is selected from a bicyclic nitrogen-containing heteroaryl having 1 or 2 nitrogen and bicyclic-ary 1 and wherein RI-^CISsubstituted independently by 0. 1, or 2 Rl3d substituents each independently selected from C1 -6 alkyd. amino(C0-6 alkyl), carboxy(Co-4 alkyd), halo, Cl-4 haloalkyl, Cl-4 haloalkydoxy, Cl-4 alkyloxy, and - (CH2)0-6-NH-(X1) 1 -2-X2-X3-Ul-U2-Z;R1 is selected from hydrogen, amino(C()-6 alkyl), and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z;R14a is selected from amino, hydroxy, (C1 -6 alkyl)o-2 amino, and Cj-6 alkyloxy;R14b is selected from hydrogen, C1 -8 alkyl, aryl(CQ-6 alkyl), and heteroaryl(C0-6 alkyl), wherein R14b is substituted by 0, 1, 2, or 3 halo groups, q1is selected from 0, 1, 2, 3, or 4; p1is selected from 0, 1, 2, 3, or 4; p is selected from 0, 1. or 2; q is selected from 0, 1 or 2;Each X1is independently absent or selected from-C(=O)-(CH2)a-(O(CH2)2)b-N+(CH3)2-(CH2)c-NH-} -C(=O)-(CH2)a-(O(CH2)2)d-NH-} , -C(=O)-(CH2)e-N+(C H3)2-(CH2>NH- } , -C(=O)-(CH2)a- (O(CH2)2)b N+(CH3)2(O(CH2)2)gNH } , and -C(=O)-(CH2)h-phenyl-(CH2)i- NH-}, where -} is point of attachment with the group X2;Each X2is independently absent or selected from-C(=O)-(CH2)a-(O(CH2)2)d-NH-},and - C(=O)-(CH2)h-phenyl-(CH2)i-NH-}, where -} is point of attachment with the group X3;Each X3is independently absent or -C(=O)-(CH2)a-(O(CH2)2)d-NH-}, where -} is point of attachment with the group U1;point of attachment with the group U2;Each U2is independently absentpoint of attachment with the group Z;Each Z is selected from1) -C(=O)CH3,2) -C(=O)-(CH2)m-C(=O)-OH,3) -C(=O)-(CH2)m-CH3,4) -C(=O)-(CH2)m-CH2-OH,5) -C(=O)-(CH2)m-S(=O)2-OH,6) -C(=O)-(CH2)m-tetrazolyl,alkyl, C1 -6 haloalkyl, Cj-6 haloalkyloxy, (C3-i2)cycloalkyl(C0-6 alkyl).(C3-12)cycloalkyl(C0-6 alkyloxy), aryl(C0-6 alkyl), and aryl(CQ-6 alkyloxy),Each a is independently 1 or 2;Each b is independently 0 through 6;Each c is independently 2 through 6Each d is independently 1 through 24;Each e is independently 1 through 6;Each f is independently 2 through 6;Each g is independently 0 through 6:Each h is independently 0 through 2;Each i is independently 0 throgh 2;Each j is independently 1 through 6;Each k is independently 0 through 4;Each I is independently 0 through 2;Each m is independently 10 through 20;Each n is independently 0 through 4; and provided that: a) only 1, 2 or 3 of the substituents selected from Rla. R3b R4C R5a R5b R5d R3e, R10c, RUb, Rlld R13danc] R14 have a -(Xl)|-2-X2-X?-U'-U2-Z component, b) only one of R3a. R3b R3d. or R3ehas a-(X1)i-2-X2-X3-U1-U2-Z component, and c) only one of RUb R^c, or RUd has a-(X1)i-2-X2-X3-U1-U2-Z component.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, phenyl, phenylmethyl, phenylethyl, phenylpropyl, styryl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, biphenylmethyl, naphthylmethyl, pyridylmethyl, pyridazinylmethyl, pyrimidylmethyl, pyrazinylmethyl, imidazolylmethyl, pyrazolylmethyl, furylmethyl, thiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, oxadiazolylmethyl, bicyclo[l.l.l.]pentyl, (bicyclo[l.l.l.]pentyl)methyl, phenylcarbonylaminoethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, aminocarbonylisopropyl, aminocarbonylbutyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, aminocarbonylaminobutyl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, w-pentyl, isopentyl, neopentyl, n- hexyl, isohexyl, w-heptyl, w-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, adamantyl, carboxy, carboxymethyl, carboxyethyl, azidomethyl, azidoethyl, azidopropyl, phenylaminocarbonylmethyl, pyridylaminocarbonylmethyl, (pyridylcarbonylamino)methyl, guanidino, guanidinomethyl. guanidinoethyl, guanidinopropyl, guanidinobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, pentafluoropropyl, heptafluoropropyl, trifluorobutyl, X. AC A- trimethy I methyl ammonium. X,X,X-trimethyleth-l-ylammonium, N.N.N- trimethylpropan- 1 -ylammonium, ACACX-trimethylbut- 1 -y lammonium, methylamino, methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, ethylamino, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, ethylaminobutyl, diethylamino, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl,aminoethoxy, aminoethoxy methyl, isoxazolylcarbonylaminomethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclopropoxymethyl, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, vinyl, prop-2-enyl, but-3-enyl, and pent-4-enyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: eachRla substituent is independently selected from C1 -6 alkyl, amino, azido, cyano, halo, hydroxy, (C3-i2)cycloalkyloxy, C1 -6 alkyloxy, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1- U2-Z; eachR2a is independently selected from hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy, and fluoro;Rib is selected from phenyl, benzyl, biphenyl, naphthyl, pyridyl, pyridazinylpyrimidyl, pyrazinyl, imidazolyl, pyrazolyl. oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and bicyclo[l.l.l]pentyl; and each R2C is independently selected from aminomethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, w-butyl, tert-butyl, fluoro, chloro, bromo, iodo, aminoethoxy, N-methylaminoethoxy, .V-ethvlaminoethoxv. X.Ar-dimethylaminoethoxy., carboxy, carboxymethoxy, (carboxymethoxy)methyl, aminocarbonyl, N,N- dimethylaminocarbonyl, aminocarbonylmethyl, -0(CH2) 0-6~NH-(X1)i-2-X2-X3-U1-U2-Z, - (CH2)0-6-NH-(X1) 1 ^-X^-U’-U^Z, -(CH2)0-6-NH-X1-Z, -(CH2)0-6-NH-(X1) 1 -2-X2- U2-Z, -(CH2)0-6-NH-(X1)i.2-X2-U1-U2-Z, -O(CH2) 0-6-NH-Z, -O(CH2) O-b-NH-CX1)!^- X2-X3-U2-Z, -O(CH2) 0-6-NH-(X1)i-2-X2-U1-U2-Z, -O(CH2) O-b-NH-X^X^-lA-lA-Z, and -O(CH2) o-b-NH-X^XW-Z.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, whereinR3a is selected from hydrogen, methyl, ethyl, w-propyl, isopropyl, w-butyl, 2- methylpropyl, tert-butyl. cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, aminoethyl, aminopropyl, aminobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, thioethyl, and thiopropyl, wherein R3amay be substituted by 0, 1, or 2 R3csubstituents eachindependently selected from fluoro, chloro, methyl, ethyl, w-propyl. isopropyl, cyclopropyl, n- butyl, sec'-bulyl. tert-butyl, amino, aminomethyl, / V-melhyl amino, N-methylaminomethyl, N- ethylamino, N-ethylaminomethyl, A'.A'-dimethylamino. ACA'-dimethylaminomelhyl. N,N- diethylamino, M.'V-diethylaminomethyl. ACAdAMrmiethylammonium. N.N.N- trimethylmethylammonium, hydroxy, hydroxymethyl, -SO2CH3, -CH2SO2CH3, - CH2CH2SO2CH3, cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxy, carboxymethyl, and carboxyethyl; andR3b is selected from hydrogen, methyl, ethyl, w-propyl, isopropyl, M-butyl, isobutyl, secbutyl, tert-butyl, / 7-pentyl. isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmetyl, cyclopentylmethyl, cyclohexylmethyl, bicyclo[l.l.l]pentylmethyl, hydroxymethyl, 1 -hydroxy ethyl, 2 -hydroxy ethyl, hydroxypropyl, 3- hydroxypropyl, 1 -methyl- 1 -hydroxy ethyl, hydroxyisopropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxy ethyl, aminomethyl, 2-aminoethyl, N- methylaminomethyl, A'.A'-dimethylammomethyl. N-methylaminoethyl, 2V,iV-dimethylaminoethyl, A'-mcthylammopropyl. A'.A'-dimcthylaminopropyl. 1 -aminopropyl, 2-aminopropyl, 3- aminopropyl, 2-aminoprop-2-yl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, benzyl. 3-pyridinylmethyl. 4-pyridinylmethyl. imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiophenylmethyl, furanylmethyl, pyrazolylmethyl, N- pyrazolylmethyl, 1 -phenylethyl, 1 -(4-pyridinyl)ethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, (N,N-dimethyl)aminocarbonylmethyl, (N,N- dimethyl)aminocarbonylethyl. thiomethyl, thioethyl, thiopropyl, -CH2CH2SO2CH3, carboxymethyl, carboxyethyl, 2-carboxy ethyl, carboxypropyl, 3-carboxypropyl, carboxybutyl, 4- carboxybutyl, piperazinylmethyl, morpholinomethyl, piperidinylmethyl, azetidinylmethyl, tetrahydropyranylmethyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, and aminocarbonylaminobutyl, wherein R3b may be substituted by 0, 1, or 2 R3C substituents each independently selected from fluoro, chloro, methyl, ethyl, n- propyl. isopropyl, cyclopropyl, / ?-butyl. sec-butyl, tert-butyl, amino, aminomethyl, N- methylamino, #-methylaminomethyl. 2V-ethyl amino, N-ethylaminomethyl, MA-dimethylamino. A.AMimethylaminomethyl. / V.Mdiethylamino. AAV-diethylaminomethyl. N.N.N- trimethylammonium, Ar.Ar..V-trimethylmethylammonium. hydroxy, hydroxymethyl, -SO2CH3, - CH2SO2CH3. -CH2CH2SO2CH3. cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxy, carboxymethyl, and carboxyethyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3aand R3b together with the atoms to which they are attached, form a saturated ring system substituted by 0, 1 , or 2, R3d substituents, said saturated ring system is selected from:

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof whereinR4a is selected from hydrogen, methyl, ethyl, propyl, hydroxy, methoxy, and fluoro;R4bis selected from indolyl, naphthyl, quinolinyl, pyrrolo[2,3-b]pyridinyl, [l,2,4]triazolo[l,5-a]pyridine, l / f-pyrazolo[3,4-6]pyridine, indazolyl, benzothiazolyl, and benzothiophenyl, wherein R4bsubstituted with 0, 1, or 2 R4csubstituents each independentlyselected from fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, methyl, ethyl, propyl, isopropyl, carboxy, carboxymethyl, and carboxyethyl;R5a is selected from hydrogen, methyl, ethyl, w-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, w-pentyl. isopentyl, neopentyl, cyclopentyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, phenyl, benzy l, phenylethyl, phenylpropyl, oxazolylmethyl, thiazolylmethyl, imidazolylmethyl, triazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl, oxazolylethyl, thiazolylethyl, imidazolylethyl, triazolylethyl, oxadiazolylethyl. thiadiazolylethyl, oxazolylpropyl, thiazolylpropyl, imidazolylpropyl, triazolylpropyl, oxadiazolylpropyl, thiadiazolylpropyl, azetidinylmethyl, azetidinylethyl, oxetanylmethyl, oxetanylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, tetrahydropyranylmethyl, tetrahydropyranylmethyl, hydroxy ethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, 3-hydroxy-2,2-dimethylpropyl, cyclopropylmethyl, 1- hydroxypropan-2-yl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, 2-fluoroethyl, 2.2-difluoroethyl, 2,2,2-trifluoroethyl, 2-aminoethyl, 3-aminopropyl, 3-amino-2,2-dimethylpropyl, cyclopropylmethyl, 4-aminobutyl. aminomethylcarbonylaminoethyl, aminoethylcarbonylaminoethyl, aminomethylcarbonylaminopropyl, aminoethylaminocarbonylmethyl, aminoethylaminocarbonylethyl, aminoethylaminocarbonylpropyl, aminohexylcarbonylaminoethyl, aminohexylcarbonylaminoethyl, (TV-methylamino)ethyl, (N-methylamino)propyl, (N- ethylamino)ethyl, (N,N-diethylamino)propyl, (N,N-dimethylamino)ethyl, (N,N- dimethylamino)propyl, (N.N-diethylamino)ethyl, (N,N-diethylamino)propyl, (N,N,N- trimethylammonium)ethyl, OV.A<A rmrethylammonium)propyl. (NNN-triethylammonium)ethyl, (TVNN-triethylammonium)propyl, (N-methylamino)methylcarbonylaminoethyl, (N- methylamino)ethylcarbonylaminoethyl, (N-methylamino)methylcarbonylaminopropyl, (N- ethylamino)methylcarbonylaminoethyl, (TV-ethylamino)ethylcarbonylaminoethyl, (N- ethylamino)methylcarbonylaminopropyl, (N-methylamino)pentylcarbonylaminoethyl, (N- methylamino)pentylcarbonylaminoethyl, (N-methylamino)pentylcarbonylaminopropyl, (N,N- dimethylamino)methylcarbonylaminoethyl, (N,N-dimethylamino)ethylcarbonylaminoethyl, (N,N- dimethylamino)methylcarbonylaminopropyl, (N,N-diethylamino)methylcarbonylaminoethyl, (N,jV-diethylamino)ethylcarbonylaminoethyl, (N,N-diethylamino)methylcarbonylaminopropyl.(MAMimethylamino)pentylcarbonylaminoethyl. ( / V.A'-dimethylamino)pentylcarbonylaminoethyl. (AtyV-dimethy 1 amino)pentyl carbonyl aminopropyl , NNN-trimethyl-ethan- 1 -ammonium, NNV- trimethyl-propan- 1 -ammonium, (N,N,N-trimethylammoni um)methyl carbonyl aminoethyl , (N,jV,2V-trimethylammonium)ethylcarbonylaminoethyl, (2VNN- trimethylammonium)methylcarbonylaminopropyl, (N,N,N- trimethylammonium)ethylcarbonylaminopropyl, (N.N.N- trimethylammonium)pentylcarbonylaminoethyl, (AtyV,N- trimethylammonium)pentylcarbonylaminopropyl, (carboxymethyl)oxyethyl, (carboxymethyl)oxypropyl, -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, -(CH2)0-6“O(CH2)0-6- NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-Ph-(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, whereinR5a is substituted by 0, 1 , 2, or 3R5d substituents each independently selected from chloro, fluoro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, isopropyl, n- butyl. isobutyl, cyclobutyl, «-pentyl, isopentyl, neopentyl, carboxy, carboxymethyl, carboxyethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, amino, aminomethyl, aminoethyl, A'-melhylamino. (N-methylamino)methyl, (N-methylamino)ethyl. A’.A'-dimethylamino. (N,N-dimethylamino)methyl, (MAMimethylamino)ethyl. ACAMiethylamino. (TVN-diethylamino)methyl, (NW-diethylamino)ethyl, aminomethylcarbonylamino, aminoethylcarbonylamino, aminopentylcarbonylamino, aminomethylcarbonylaminomethyl, aminoethylcarbonylaminomethyl, (N-methylamino)methylcarbonylamino, (N- methylamino)ethylcarbonylamino, ('V-methylamino)methylcarbonylaminomethyl. (N- methylamino)ethylcarbonylaminomethyl, (N,N-dimethylamino)methylcarbonylamino, (N,N- dimethylamino)ethylcarbonylamino, (AtyV-dimethylanhno)methylcarbonylaminomethyl, (N,N- dimethylamino)ethylcarbonylaminomethyl, (N,N-diethylamino)methylcarbonylamino, (NN- diethylamino)ethylcarbonylamino. (AtyV-diethylamino)methylcarbonylaminomethyl. (N.N- diethylamino)ethylcarbonylaminomethyl, A'.A’.A'-lrimethylammonium. (W.AGV- trimethylammonium)methyl, (Ar.AA.Ar-trimethylammonium)ethyl. (N,2V,N- trimethylammonium)ethoxy. (N.2V,N-trimethylammonium)ethoxymethyl, (AtyVJV- trimethylammonium)methylcarbonylamino. (N,jVW-triethylammonium)methylcarbonylamino. (NNN-trimethylammonium)ethylcarbonylamino,trimethylammonium)pentylcarbonylamino,trimethylammonium)methylcarbonylaminomethyl, (N,N,N- trimethylammonium)ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazoyl. tetrazoylmethyl, tetrazoylethyl, carboxy methoxy, carboxy ethoxy, carboxymethoxymethyl.carboxyethoxymethyl. -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-LI2-Z, and -(CH2)0-6- NH (X1) i .2 X2X3U1U2Z;R5b is selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, isobutyl, w-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopropylmethyl, oxetanylmethyl, tetrahydrofurylmethyl, tetrahydropyranylmethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, methoxypropyl, carboxy methyl, carboxyethyl, carboxypropyl, carboxybutyl, (carboxy meth oxy)methyl, (carboxymethoxy )ethyl, (carboxyethoxy )methyl, (carboxyethoxy)ethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, (N- methylamino)methyl, (N-methylamino)ethyl, (N-methylamino)propyl, (N-methylamino)butyl, (NN-dimethylamino)methyl, (N,N-,Ndm- iethylamino)ethyl. (N,N-dimethylamino)propyl, (N,N- dimethylamino)butyl, (A'’.X-diethylamino)methyl. (N,N-diethylamino)ethyl, (N,N- diethylamino)propyl, (N,N,-Ndi-ethylamino)butyl, X. N,N,N m-ethyl melhan- 1 -ylammonium, N,N,N- trimethylethan- 1 -ylammonium, >V.? / .X-tri ethy lethan- 1 -ylammonium, N'.N.N- tri methyl propan- 1 - ylammonium, / V. / V.X-trimelhylbutan- 1 -ylammonium. (N,N,jV-trimethylammonium)ethoxy methyl, (NJVJV-trimethylammonium)ethoxyethyl, (N,N,N- ethylammonium)ethoxy ethyl, (N,N,N- trimethylammonium)ethoxypropyl, (ACACAMrmiethylammonium)ethoxybutyl. aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, aminocarbonylbutyl, (N- methylamino)carbonylmethyl, (N-methylamino)carbonylethyl, (N-methylamino)carbonylpropyl. (N-methylamino)carbonylbutyl, (N,N-dimethylamino)carbonylmethyl, (N,N- dimethylamino)carbonylethyl, (ty,N-dimethylamino)carbonylpropyl, (N,N,N- dimethyl amino)carbonylbutyl, aminomethylcarbonylaminoethyl, aminomethylcarbonylaminopropyl, aminoethylcarbonylaminoethyl, aminoethylcarbonylaminopropyl, (A'.AMmrelhylamino)methylcarbonylaminoethyl. (N.N- dimethylamino)methylcarbonylaminopropyl, (A'.A,-dimethylamino)ethylcarbonylaminoethyl.(N,N,N- methyl amino)ethy Icarbony laminopropy 1, (N,N,N- trimethylammonium)methylcarbonylaminoethyl, (N,N,N- triethylammonium)methylcarbonylaminoethyl, (NNN- trimethylammonium)methylcarbonylaminopropyl, (N,N,N- trimethylammonium)ethylcarbonylaminoethyl, (N,N,N- trimethylammonium)ethylcarbonylaminopropyl, (ACA.A'-trimethylammoniumJethoxyethyl. (N,N,N--tnmetbylammonium)ethoxypropyl. 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanoisopropyl, cyanobutyl, - (CH2)1-6-NH-(X1)I.2-X2-X3-U1-U2-Z, and -(CH2)1-6-O(CH2)0-6-NH-(X1)IN,N,N-1-U2-Z, whereinR5b is substituted by 0, 1, 2, or 3 R$esubstituents each independently selected from chloro, fluoro, hy droxy , hy droxy methyl, hydroxyethy l, methyl, ethyl, n-propyl, isopropy l, w-butyl. isobutyl, cyclobutyl, M-pentyl, isopentyl, neopentyl, carboxy, carboxymethyl, carboxyethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, amino, aminomethyl, aminoethyl, N-methylamino, (N-methylamino)methyl, (N-methylamino)ethyl, MA'-dimethylammo. (N,N-dimethylamino)methyl, (NW-dimethylamino)ethyl, ACX-diethylamino. (NN-diethylamino)methyl, (MA'-diethylamino)ethyl. aminomethylcarbonylamino, aminoethylcarbonylamino, aminopentylcarbonylamino, aminomethylcarbonylaminomethyl, aminoethylcarbonylaminomethyl, (N-methylamino)methylcarbonylamino, (N- methylamino)ethylcarbonylamino, (N-methylamino)methylcarbonylaminomethyl, (N- methylamino)ethylcarbonylaminomethyl, (N,N-dimethylamino)methylcarbonylamino, (NN- dimethylamino)ethylcarbonylamino. (jVjV-dimethylamino)methylcarbonylaminomethyl, (N,N- dimethylamino)ethylcarbonylaminomethyl, (N,N-diethylamino)methylcarbonylamino, (N,N- diethylamino)ethylcarbonylamino, (.V.Mdiethylamino)methylcarbonylaminomethyl. (N,N- diethylamino)ethylcarbonylaminomethyl, X.AGV-trinicthylammonium.trimethylammonium)methyl, (,'V.A / . / V-lrimelhylammonium)elhyl. (N,N,N- trimethylammonium)ethoxy. (NJV,2V-trimethylammonium)ethoxymethyl. (N.N.N- trimethylammonium)methylcarbonylamino, (ACV.Mtriethylammonium)methylcarbonylamino. ( / V.,V.A'r-tnmethylammonium)ethylcarbonylamino. (NJVJV- trimethylammonium)pentylcarbonylamino, (NNN- trimethylammonium)methylcarbonylaminomethyl, (NNN- trimethylammonium)ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazoyl, tetrazoylmethyl, tetrazoylethyl, carboxy methoxy, carboxy ethoxy, carboxymethoxymethyl, carboxy ethoxymethyl, -(CH2)()-6-O(CH2)0-6-NH-(Xl) | -2-X2-X3-Ul-U2-Z. and -(CH2)0-6~ NH-CX^i^-X^-U^U^Z; andR5C is hydrogen, methyl, or ethyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3aand R3b together with the atoms to which they are attached, form a saturated mono- or bi-cyclic ring system substituted with 0, 1, 2, or 3R5d and 0, 1 , 2, or 3 R3esubstituents, wherein said mono- or bi-cyclic unsubstituted or substituted ring system is selected from:is hydrogen, -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, or -(^lO-b-NH-lX1)!-2-X2-X3-U1-U2-Z.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof whereinR6a is selected from hydrogen, hydroxy, methyl, ethyl, propyl, and methoxy:R6b is selected from hydrogen, hydroxy, methyl, ethyl, propyl, methoxy, and ethoxy:R6C is selected from aminocarbonyl, (aminocarbonyl)methyl, (aminocarbonyl)ethyl, (aminocarbonyl)propyl, (A'-methylamino)carbonyl. (N-methylamino)carbonylmethyl, (N- methylamino)carbonylethyl, (TV-methylamino)carbonyl propyl, (A<A-dimethylamino)carbonyl. (TVN-dimethylamino)carbonylmethyl, (NN-dimethylamino)carbonylethyl, (AOV-dimethylamino) carbonylpropyl, (ACAMiethylamino)carbonyl. (N,N-diethylamino)carbonylmethyl, (N,N- diethylamino)carbonylethyl. (N,jV-diethylamino)carbonylpropyl, aminocarbonylamino, (aminocarbonylamino)methyl, (aminocarbonylamino)ethyl, (aminocarbonylamino)propyl, methoxy, methoxymethyl, methoxyethyl, ethoxy, ethoxymethyl, ethoxyethyl, methylsulfonyl, (methylsulfonyl)methyl, (methylsulfonyl)ethyl, (methylsulfonyl)propyl, amino, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, carboxy, carboxymethyl, carboxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, isobutyl, tertbutyl, phenyl, and benzy l;R7a is selected from hydrogen, methyl, ethyl, hydroxy, methoxy, and ethoxy;is selected from phenyl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, fury l, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 3-oxoisoindolinyl, and bicyclo[l.l.l]pentyl; selected from fluoro, chloro, bromo, iodo, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, carboxy, carboxymethyl, methoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, aminocarbonyl, aminocarbonylmethyl, ( / V, / V-dimethylamino)carbonyl, (TVN-dimethylamino)carbonylmethyl, amino, aminomethyl, / V, / V-dimethylamino, (N,N- dimethylamino)methyl, (r,N-diethylamino)methyl, / V,N,N-trimethylammonium, N,N,N- trimethylmethylammonium, N, / V,N-triethylmethylammonium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, -SO2OH.-CH2SO2OH, -SO2NH2. -CH2SO2NH2, aminoethoxy, aminoethoxymethy 1, (NN-dimethylamino)ethoxy, ALV V-tnmethy leth- 1 -oxy-ammonium, aminocarbonylamino, and aminocarbonylaminomethyl;R8a is selected from hydrogen, methyl, ethyl, hydroxy, methoxy, and ethoxy;R8b is selected from indolyl, naphthyl, indolylmethyl, naphthylmethyl, quinolinyl, pyrrolo| 2.3- / ? |py ridin l. indazolyl. benzothiazolyl, and benzothiophenyl; each R8c independently is selected from methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, cyano, amino, aminomethyl, nitro, hydroxy, hydroxymethyl, carboxy, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, methoxy, ethoxy, and trifluoromethoxy; and R is selected from hydrogen, methyl, ethyl, and propyl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, whereinR10a is selected from hydrogen, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy;RlOb is selected from phenyl, benzyl, biphenyl, biphenylmethyl, pyridyl, pyridylmethyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, imidazolylmethyl, pyrazolyl, furyl, furylmethyl, oxazolyl, oxazolylmethyl, thiazolyl, indolyl, [l,2,4]triazolo[l,5-a]pyridine, and bicyclo[l .1.1] pentyl;RIOC is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n- butyl, isobutyl, cyclobutyl, «-pentyl, isopenty l, neopenty l, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexy Imethyl, fluoromethy l, difluoromethyl, trifluoromethyl. 2,2.2-trifluoroethyl, trifluoromethoxy. 2,2.2-trifluoroethoxy,fluoro, chloro, bromo, iodo, hydroxy, hydroxymethyl, hydroxyethyl, cyano, amino, aminomethyl, aminoethyl, N-methylamino, (Af-methylamino)methyl, (N-methylamino)ethyl, N,N- dimethyl amino, (N,N-dimethylamino)methyl, (N,N-dimethylamino)ethyl, N,N,N- trimethylammonium, N,N,jV-trimethylmethan-ylammonium, aminocarbonyl, aminocarbonylmethyl, aminocarbonylethyl. (N-methylamino)carbonyl. ( / V-methylamino) carbonylmethyl, (AfAMimethylamino)carbonyl. (jVN-dimethylamino)carbonylmethyl, aminocarbonyl amino, aminocarbonylaminomethyl, methylcarbonylamino, methylcarbonylaminomethyl, carboxy, carboxymethyl, carboxyethyl, methoxycarboxy, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, carboxy ethoxy methyl, -S(=O)2OH, - CH2(S(=O)2OH), -S(=O)2NH2, -CH2(S(=O)2NH2), aminoethoxy, aminopropoxy, (N- methylamino)ethoxy, (2V-ethylamino)ethoxy, (NrZV-dimethylamino)ethoxy, (ACA'-diethylamino) ethoxy. (jVW,N-trimethylammonium)ethoxy, methoxy, ethoxy, methoxymethyl, ethoxymethyl, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy;Rlla is selected from hydrogen, hydroxy, methyl, ethyl, methoxy, and ethoxy;Rllb is selected from (H2N-C(=NH)-NH)methyl, (H2N-C(=NH)-NH)ethyl, (H2N- C(=NH)-NH)propyl, (H2N-C(=NH)-NH)butyl, phenyl, benzyl, pyridinyl, pyridinylmethyl, indolyl, indolylmethyl, pyridazinyl, pyridazinylmethyl, pyrimidyl, pyrimidylmethyl, pyrazinyl, pyrazinylmethyl, imidazolyl, imidazolylmethyl, pyrazolyl, pyrazolylmethyl, [l,2,4]triazolo[l,5- a]pyridine, oxazolyl, oxazolylmethyl, thiazolyl, and thiazolylmethyl; each Rlld is independently selected from fluoro, chloro, bromo, iodo, (carboxymethyl)oxy, (carboxymethyl)oxymethyl, (carboxyethyl)oxy, hydroxy, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, difluoromethoxy. trifluoromethoxy, carboxy, carboxymethyl, aminocarbonyl, aminocarbonylmethyl, (methylcarbonyl)aminomethyl, (methylcarbonyl)aminoethyl, (N-methylamino)carbonyl, (A'-methylannno)carbonylmethyl.dimethylamino)carbonyl, (N,N-dimethylamino)carbonylmethyl, amino, N-methylamino, N,N- dimethylamino, AAV-diethylamino. aminomethyl, (NrV-dimethylamino)methyl, (N,N- diethylamino)methyl, / V.A'AV-lrimethylammonium. AAV.A / -ln methyl meth- 1 -yl-ammonium, N,N,N- tri ethyl ammonium, A,'.A / ..V-tnethylmeth-l -yl-ammonium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, aminoethoxy, aminopropoxy, aminoethoxymethyl, (TVN-dimethylamino)ethoxy, N^VN-trimethyleth-1 -yloxy-ammonium, cyano, methylcarbonylpiperazyl [(N-acetyl)pi perazyl ], -C(=O)NH-(CH2)2-6“NH-(X1)i-2-X2-X3-U1- U2-Z, -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, -(CH2)0-6-NH-(X1)i-2-X2-X3-R12a is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, and isopropyl; andR12b is selected from hydrogen, methyl, ethyl, and propyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof whereinR12a and R *2b together with the atoms to which they are attached form a saturated ring selected from11. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein:R13a is hydrogen, methyl, or propyl;R13b is hydrogen or methyl;R13C is selected from indolyl, pyrrolo[2,3-6]pyridinyl, quinolinyl, indazolyl, and naphthyl; each Rl3d independently is selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, carboxy, carboxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, and ethoxy; each R^a independently is selected from amino, hydroxy, / V-methylamino. AOV- dimethylamino, jV-ethylamino, methoxy, and ethoxy; each R *4b independently is selected from hydrogen, methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, trifluoromethyl, trifluoroethyl, phenyl.benzyl, chlorophenyl, dichlorophenyl. fluorophenyl, difluorophenyl, bromophenyl, iodophenyl, chlorobenzyl, dichlorobenzyl, fluorobenzyl, difluorobenzyl, bromobenzyl, iodobenzyl, naphthyl, naphthylmethyl, pyrazolyl, pyrazolylmethyl, indolyl, indolylmethyl, imidazolyl, imidazolylmethyl, pyridyl, and pyridylmethyl; and each R14 independently is selected from hydrogen, methyl, ethyl, propyl, and -(CH2)0- 6-NH-(X’) 1 -2-X2-X3-U1-U2-Z.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having a formula of:R1 is selected from hydrogen, Cl-20 alkyl, amino(Co-10 alkyl), aryl(C()-10 alky l), heteroaryl(Co-10 alkyl), (C3-i2)cycloalkyl(Co-10 alkyl), heterocycloalkyl(Co-10 alkyl). C1 -io fluoroalkyl, wherein R1 is substituted by 0. 1, 2, or 3 Rlasubstituents each independently selected from C 1-6 alkyl, amino, azido, cyano, halo, hydroxy, (C3- 12)cycloalkyloxy, Cl-6 alkyloxy, and -(CH2)0-6~NH-(X1)i-2-X2-X3-U1-U2-Z ; eachR2a is independently selected from hydrogen, methyl, ethyl and propyl;R2b is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said heteroaryl contains at least one nitrogen atom, wherein R3b is substituted by 0, 1, or 2 R3cindependently selected from Cl-6 alky l, amino(Co- 6 alkyl), (C1 -6 alkyl)o-2amino(C0-6 alkyl), (Cl -6 alkyl)3N+(C0-6 alkyl), aminocarbonyl(C0-6 alkyl), (Cl-6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), hydroxy, Cl-6 alkyloxy. halo, (Cl-6 alkyl)o-2 amino(C0-6 alkyloxy), (Cl-6 alkyl)3N (C0-6 alkyloxy). (Cl-6 alkyloxy)carbonyl(C0-6 alkyl), carboxy(C0-6 alkyl), carboxy(C1-6 alkyl)oxy(C0-6alkyl), halo, Cl-6 haloalkyl, Cl-6 haloalkyloxy. C1 -6 alkyloxy. -O(CH2) O-S-NH-CX1)!-2 X2X3U1U2Z. and -(CH2)O-6-NH-(X1)I.2-X2-X3-U1-U2-Z;R3a is selected from hydrogen, hydroxy, hydroxy(C1 -6 alkyl), amino, amino(C1 -6 alkyl), C1 -io alky l, (C3-i2)cycloalkyl(Co-10 alkyl). (C0-6 alkyl)thio(C1 -6 alkyl), and carboxy(C1 -6 alkyl), wherein R3amay be substituted by 0, 1, or 2 R3csubstituents;R3b is selected from hydrogen, C] -i o alkyl, hydroxy(C] -6 alkyl), amino(C]-6 alkyl), (C] -(, alkyl)o-2 amino(C1-6 alkyl), (Cl-6 alkyl)3N+(C1 -6 alkyl), halo, Cl-6 haloalky l, aryl(C()- 10 alkyl). heteroaryl(C0-6 alkyl), (C3-i2)cycloalkyl(C0-6 alkyl), heterocycloalkyl(C0-6 alkyl), (C1 -6 alkyl)oxy(C1 -6 alkyl), (C3-i2)cycloalkyloxy(C1-6 alkyl), carboxy(C1 -6 alkyd), aminocarbonyl(C 1 -6 alkyl), (C 1-6 alkyl)o-2 aminocarbonyl(C1 -6 alkyl), aminocarbonylamino(C1 -6 alkyl), (Cl-6 alkyl)o-2 aminocarbony damino(C1 -6 alkyl), (Co- 6 alky l)thio(C 1-6 alkyl), (C1 -6 alky 1)SO2(C 1-6 alky l), and (C 1-6 alky l)sulfinyl(C 1-6 alkyd), wherein R3b may be substituted by 0, 1 , or 2 R3csubstituents, each R3cis independently selected from halo, C1 -6 alkyl, amino, (C1 -6 alkyd)o-2 amino(C0-6 alkyl), (C1-6 alkyl)3N+-, (C 1 -6 alkyd)S02(C0-6 alkyl), cyano, cyano(C1 -6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), (Cl -6 alky d)oxy(C0-6 alkyd), aminocarbonyl(C0-6 alkyl), and (CQ- 6) carboxy(C0-6 alkyd); whereinR3a and R3b together with the atoms to which they are attached, may form a saturated ring system, wherein said saturated ring system may be substituted by 0, 1, or 2 R3csubstituents;R4a is hydrogen;R4b is selected from bicyclic heteroaryd(Co-3 alkyl), and bicyclic ary 1(CQ-3 alkyd), wherein R4b is substituted with 0, 1, or 2 R3c substituents each R3c independently selected halo, hydroxy, cyano, nitro, carboxy, carboxy(Cl-6 alkyd), (Cl-6 alkydoxy)carbony d(C0-6 alkyd), Cl-6 alkyloxy, (Cl-6 alkyl)oxy(Cl-6 alkyl), Cl-6 alkyl, Cl-6 haloalkyl, and -(CH2)0-6-NH-(X1) 1 -2-X2-X3-U1-U2-Z;R5a is selected from hydrogen, C1 -io alkyl, C1 -io fluoroalkyl, carboxy(C1 -io alkyl), hydroxy, hydroxy(Cl-10 alkyl), cyano(Cl-K) alkyl), (C3-12)heterocycloalky d(C0-10 alkyl), (Cl-6 alkyd)o-2 aminocarbonyl(C 1 -6 alkyl), (carboxy(C l-K) alkyl))oxy(C 1 -6 alkyl), amino(C0-6 alky l)aryl(C 1-6 alkyl), aryl(C0-6 alkyl), (C3-i2)cycloalky d(C0-6 alkyd), heteroaryl (C0-6alkyl), (C1 -6 alkyl)oxy(C1 -6 alkyl), (C1 -6 alkyloxy)carbonyl(C0-6 alkyl), amino, amino(C1 -6 alky l), (Cl-6 alkyl)o-2 amino(C0-6 alky l), amino(C2-6 alkyl)oxy(C 1 -6 alkyd), (C1 -6 alkyl)o-2 amino(C2-6 alkyl)oxy(C1 -6 alkyl). amino(C1 -6 alkyl)carbonylamino(C1 - 6 alkyl), amino(C1 -6 alkyl)carbonylamino(C1 -6 alkyl), (Cl-6 alkyl)o-2 amino(C1 -6 alkyl)carbonylamino(C1 -6 alkyl), (C1 -6 alkyl)3N+(C2-10 alkyd), (C1 -6 alkyd)3N+(C1 -6 alkyl)carbonylamino(C1 -6 alkyl), C1 -io fluoroalkyl, -(CH2)0-6-NH-(X1)i-2-X2-X3- U’-U2-Z, -(CH2)0-6-O(CH2)0-6-NH-(X,)I.2-X2-X3-U1-U2-Z, and -(CH2)0-6-Ph- (CH2)0-6 NH (X1) |-2 X2X' U1U2Z and wherein R3ais substituted by 0, 1, or 2 R5d substituents;R5b is selected from hydrogen, C1 -10 alkyl, hydroxy(C1 -io alkyl), carboxy(C1 -6 alkyd), (Cl-6 alkyl)oxy(C1-6 alkyl), aminocarbonyl (C 1-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C1 -6 alkyd), carboxy(C1 -io alkyl)oxy(C1 -6 alkyl), cyano(C1 -6 alkyd), amino(C1 -6 alkyl), (C1 - 6 alkyd)o-2 amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C2-6 alkyl)oxy(C1 -6 alkyl), amino(C1 -6 alkyl)carbonylamino(C1-6 alkyl), (amino(C2-6 alkyl)oxy(C 1 -6 alkyl), C1 -6 alkyl)o-2 amino(C1 -6 alky l)carbonylamino(C 1 -6 alkyl), (Cj -6 alkyl)sN+(C2-6 alky l)oxy(C 1-6 alkyl), (C1 -6 alkyl)sN+(C1 -6 alkyl)carbonylamino(C1 -6 alkyl), (C1 -6 alkyd)3N+(C1 -6 alkyl), (heterocycloalkyl(Co-10 alkyd), (C3-i2)cycloalkyl(Co-10 alkyd), C1 -io haloalkj d,-(CH2)l-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)1- 6-NH-(X1)i-2-X2-X3-U1-U2-Z, wherein R3b is substituted by 0, 1, 2, or 3 R$esubstituents, whereinR5a and R3b together with the atoms to which they are attached, form a saturated mono- or bi-cyclic ring, wherein said mono- or bi-cyclic ring is substituted with 0, 1, or 2, RS(1 and 0, 1, 2, or 3 R3csubstituents; eachR5d is independently selected from selected from halo, hydroxy, hydroxy(Cl-6 alkyd), Cl- 10 alkyl, carboxy, carboxy(C1 -6 alkyl), C1 -6 alkyloxy, (C1 -6 alkyl)oxy(C1-6 alkyl), amino, amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl), amino(C1 -6 alky l)carbonylamino(C 0-6 alkyl), (C l-6 alkyl)o-2 amino(Cl-6 alkyl)carbonylamino(C0-6 alkyl), (Cl-6 alkyl)3N+(C0-6 alkyl), (Cl-6 alkyl)3N+(C2-6 alkyl)oxy(C0-6 alkyl), (Cl-6 alkyd)3N+(C1 -6 alkyl)carbonylamino(C0-6 alkyl), (carboxy(C 1 -6 alkyd))oxy(C0-6 alkyl), cyano(C0-6 alkyl), tetrazolyl(C0-6 alkyl), and Cl-6 haloalkyl, amino(C2-6 alkyl)oxy(Co-6 alkyl), (C1 -6 alkyl)o-2 amino(C2-6 alkyl)oxy(C0-6 alkyl), -(CH2)0-6-O(CH2)0-6-NH- (X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z; and two R5dsubstituents together with the atom they are attached to may join together to form a saturated ring; eachR5e is independently selected from halo, hydroxy. hydroxy(C1 -io alkyl). C1 -io alkyl, carboxy, carboxy(C1 -6 alkyl), C1 -6 alky loxy, (C1-6 alkyl)oxy(C1 -6 alkyl), amino, amino(C1 -6 alkyl). (Cl-6 alkyl)o-2 amino(C0-6 alkyl). amino(C1 -6 alky l)carbonylamino(C 0-6 alkyl), (C1 -6 alkyl)o-2 amino(Cl-6 alkyl)carbonylamino(C0-6 alkyd), (C 1-6 alkyl)3N+(C0-6 alkyl), (C1 -6 alkyl)sN+(C2-6 alkyl)oxy(C0-6 alkyl). (Cl-6 alkyl)3N+(Cl- alkyl)carbonylamino(C0-6 alkyl), (carboxy(Cl-6 alky l))oxy(C 1- alkyl), cyano(C0-6 alkyl), tetrazolyl(C0-6 alky l), Cl -6 haloalkyl. -(CH2)0-6-O(CH2)0-6-NH- (X1)i-2-X2-X?-U1-U2-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and two R5esubstituents together with the atom they are attached to may join together to form a saturated ring;R6C is selected from Cl-10 alkyl, Cl-6 alkyloxy, (Cl-6 alky l)oxy(C 1-6 alkyl), C1-1Q haloalky l, aryl(C0-6 alkyl), heteroaryl(C0-10 alkyl), (Cl-6 alkyl)S02(C0-6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), amino(C0-6 alkyl), (Cl-6 alkyl)o-2 amino(C0-6 alkyl), aminocarbonyl(C0-6 alkyl), (Cl -6 alkyl)o-2 aminocarbonyl(C0-6 alkyl). (Cl -6 alky l)carbonylamino(C 0-6 alkyl), (Cl-6 alkyl)o-2 aminocarbony lamino(C0-6 alkyl), and carboxy(C0-6 alkyl);R7b is selected from aryl(Co-4 alkyl), heteroary l(Co-4 alkyl) wherein said heteroaryl contains at least one nitrogen, and (C3-i2)cycloalky d(Co-4 alkyl), wherein R3b is substituted by 0. 1, or 2. R3csubstituents each independently selected from Cl-6 alkyl, Cl-6 fluoroalkyl, carboxy(C0-6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), amino, aminocarbonylamino(C0-6 alkyl), and halo;R8a is hydrogen;R8b is selected from bicyclic aryl(Co-3 alkyl) and bicyclic heteroaryl(Co-3 alkyl), wherein said heteroary l contains 1, 2, or 3 nitrogen atoms, wherein R3b iSsubstituted by 0. 1, or 2 R3csubstituents each independently selected from C1 -4 alkyd, halo, cyano, nitro, carboxy , carboxy(C1 -6 alkyd), amino, amino(C1 -3 alkyd), amino,hydroxy. hydroxy(C1 -6 alkyl). C1 -6 fluoroalkyl, C1 -6 fluoroalkyloxy, and C1 -6 alkydoxy;RlOb is selected from (C3-i2)cycloalkyl(Co-3 alkyl). aryl(Co-3 alkyl), and heteroaryl(Co-3 alkyd), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms, wherein RlOb is substituted by 0, 1. or 2 RIOC wherein eachRl°c is independently selected from C1 -io alkyl, C1 -io fluoroalkyl, C1 -6 haloalky 1, C1 -io fluoroalkyloxy, amino, amino(C1 -6 alkyl), (C 1-6 alkyl)o-2 amino(C0-6 alkyl), (C 1 -6 alkyl)3N+(C0-6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), cyano, cyano(C1 -6 alkyl), halo, aminocarbonyl, aminocarbonyl(C 1 -6 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), (Cl -6 alkyl)o-2 aminocarbonylamino(C0-6 alkyl), (C1 -6 alkyl)carbonylamino(C0-6 alkyl), carboxy (C0-6 alkyd), (C1 -6 alkoxy)carbonyl(C0-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6 alkyl), -(CQ-5 alkyl)-(S(=O)2OH), -(Co-5 alkyl)-(S(=O)2NH2), amino(C0-6 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl)oxy(C0-6 alkyl), (Cl -6 alkyl)sN+(C0-6 alkyl)oxy(C0-6 alkyd), (C1 -6 alkyd)oxy(C0-6 alkyl), C1 -6 haloalkyloxy. (C3-i2)cycloalkyl(C0-6 alkyd), heterocycloalkyl(C0-6 alkyd), -(CH2)0-6-O(CH2)0-6-NH-(X1) -2-X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X’ ) i-2-X2-X3-U’-U2-Z;Rllb is selected from aryl(Co-3 alkyd), heteroaryd(Co-3 alkyl), wherein said heteroary 1 contains 1. 2, or 3 nitrogen atoms, and H2N-C(=NH)NH-(C1 -6 alkyl), wherein Rllb is substituted by 0, 1, or 2, 3, or 4 Rlld substituents each independently selected from C1 -6 alkyl, amino, amino(C1 -6 alkyl), (C1-6 alkyl)o-2 amino(C0-6 alkyl), (C1-6 alky l)sN+(C 0-6 alkyl), hydroxy, hydroxy(Cl-6 alkyl), cyano, cyano(Cl-6 alkyl), halo, amino(C0-6 alkyl)aminocarbonyl, aminocarbonyl, aminocarbonyl(C1-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), carboxy(C0-6 alkyl), carboxy(C1 -6 alkyl)oxy(C0-6 alkyd), amino(C0-6 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl)oxy(C0-6 alkyl), (C1 - alkyl)3N+(C0-6 alkyl)oxy(C0-6 alkyl), -(Co-5 alkyl)-(S(=O)2NH2), (C1 -6 alkyl)oxy(C0-6 alkyl), (C1 -6 fluoroalkyl)oxy(C0-6 alkyl), C1 -6 haloalkyloxy, C1 -6 haloalkyl, (C3-i2)cycloalkyl(C0-6 alkyl), heterocycloalkyl(C0-6 alkyl), ((C] -6 alkyl)carbonyl)heterocycloalkyl(Co-10 alkyl), ((C1 - alkyl)carbonyloxy)heterocycloalkyl(Co-10 alkyl), -C(=O)NH-(CH2)2-6-NH-(X1)i-2- X2-X3-U1-U2-Z, -(CH2)0-6-O(CH2)0-6-NH-(X1) I _2-X2-X3-U1-U2-Z, -(CH2)0-6-R12ais C1 -io alkyl:R12b isselected from hydrogen, Cl-6 alkyl, and (C3-12)cycloalky d(C0-6 alkyd), wherein R32aand R^b together with the atoms to which they are attached, may form a saturated ring:Ri3ais selected from hydrogen, hydroxy. Cl-6 alkyl, C1 -4 alkyloxy, and fluoro;R13C is selected from a bicyclic nitrogen-containing heteroaryl having 1 or 2 nitrogen and bicyclic-aryl and wherein R33cis substituted independently by 0, 1, or 2 R33tl substituents each independently selected from Cl-6 alkyd, amino(C0-6 alkyl), carboxy(Co-4 alkyl), halo, C1 -4 haloalkyd, C1 -4 haloalkyloxy, C1 -4 alkyloxy, and -(CH2)0-6-NH-(X1) 1 -2-X2-X3-U1-U2-Z;R14 is selected from hydrogen, amino(C0-6 alkyl), and -(CH2)0-6~NEI-(X1)I.2-X2-X?-U1-U2-Z; p is selected from 0, 1, or 2; q is selected from 0, 1 or 2;Each X1is independently absent or selected from(O(CH2)2)b-N+(CH3)2-(CH2)e-NH-} ,-C(=O)-(CH2)a-(O(CH2)2)d-NH-} , -C(=O)-(CH2)c-N+(CH3)2-(CH2>NH-}, -C(=O)-(CH2)a-(O(CH2)2)b-N+(CH3)2-(O(CH2)2)g-NH-}, and -C(=O)-(CH2)h-phenyl-(CEl2)i-NH-}, where -} is point of atachment with the group X2;Each X2is independently absent or selected from-C(=O)-(CH2)a-(O(CH2)2)d-NH-},and - C(=O)-(CH2)h-phenyl-(CH2)i-NH-}, where -} is point of atachment with the group X3;Each X3is independently absent or -C(=O)-(CH2)a-(O(CEl2)2)d-NH-} where -} is point of atachment with the group U1;point of atachment with the group U2;Each U2is independently absentpoint of atachment with the group Z ;Each Z is selected from1. C(=O)CH3,2. -C(=O)-(CH2)m-C(=O)-OH,3. -C(=O)-(CH2)m-CH3,4. -C(=O)-(CH2)m-CH2-OH,5. -C(=O)-(CH2)m-S(=O)2-OH,6. -C(=O)-(CH2)m-tetrazolyL7. -C(=O)-(CH2)m-NH2,10., wherein Z1is selected from hydrogen, halo, Cl -6 alkyl.Cl-6 haloalkyl, Cl-6 haloalkyloxy, (C3-12)cycloalkyl(C0-6 alkyl), (C3- 12)cycloalkyl(C0-6 alkyloxy), aryl(C0-6 alkyl), and aryl(C0-6 alkyloxy)Each a is independently 1 or 2;Each b is independently 0 through 6;Each c is independently 2 through 6;Each d is independently 1 through 24;Each e is independently 1 through 6;Each f is independently 2 through 6;Each g is independently 0 through 6;Each h is independently 0 through 2;Each i is independently 0 throgh 2;Each j is independently 1 through 6;Each k is independently 0 through 4;Each 1 is independently 0 through 2;Each m is independently 10 through 20;Each n is independently 0 through 4; and provided that: a) only 1, 2 or 3 of the substituents selected from Rla, R2b, R4C R5a R5b R5d R3e. R!®C. RUb, Rlld R13danc] R14 have a_(x1)i-2-X2-X3-U1-U2-Z component. b) only one of R3a, R3b R3d. or R3ehas a -(X1)i-2-X2-X3-U1-U2-Z component, and c) only one of RUb RHC, or RUd has a-(X1)j-2-X2-X3-U1-U2-Z component.

13. The compound of claim 12, or a pharmaceutially acceptable salt thereof, wherein:R1 is selected from hydrogen, Cl-20 alkyl, and amino(C()-10 alky l), wherein R1 is substituted or unsubstituted by a -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z group; each R2ais independently hydrogen or methyl;R2b is aryl or heteroaryl, wherein said heteroaryl contains at least one nitrogen atom, and R2b is substituted by 0, or 1 R2C;R2Cis amino(C0-6 alkyl), amino(C0-6 alkydoxy), -O(CH2) 0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, or -(CH2)O-6-NH-(X1) I -2-X2-X3-U1-U2-Z;R3a is selected from hydrogen, hydroxy(Cl-6 alkyd), amino(Cl-6 alkyl), C1-1Q alkyl, wherein may be substituted by 0, 1, or 2 R3csubstituents;R3b is selected from hydrogen, C1 -io alkyl, hydroxy(C i-6 alkyl), amino(C1 -6 alkyl), and (C1-6 alkyl)SO2(C1 -6 alkyl), wherein R3b may be substituted by 0, 1, or 2 R3csubstituents; each R3C is independently selected from C1-6 alkyl, amino, (C 1-6 alkyl)o-2 amino(CQ-6 alkyl), (C1 -6 alkyl)S02(C0-6 alkyl), hydroxy, and hydroxy(C1 -6 alkyl);R4a is hydrogen;R3b is bicyclic heteroaryl(CQ-3 alkyl), wherein R3b is substituted with 0, 1, or 2 R3csubstituents each R4C is carboxy, carboxy(C1 -6 alkyl), or -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z;R5a is selected from hydrogen, C1 -10 alkyl, hydroxy(C1 -6 alkyl), amino(CQ-6 alkyl)aryl(C1 -6 alkyl), amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl),-(CH2)0-6-NH-(X1)i-2- X^X’-U^U^Z, -(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0-6-Ph-(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z and wherein R3ais substituted by 0, 1, or 2R5d substituents;R5b is selected from hydrogen, C1 -10 alkyl, hydroxy(C1 -io alkyl), carboxy(C1 -6 alkyd), amino(C1 -6 alkyd), (C 1-6 alkyl)o-2 amino(C1 -6 alkyd), (C 1 -6 alkyl)o-2 amino(C2-6 alkyl)oxy(C1-6 alkyl), -(CH2)0-6-O(CH2)0-6“NH-(X1)i-2-X2-X3-U1-U2-Z, and - (CH2)0-6“NH-(X1) i-2-X2-X3-U1-U2-Z, wherein R3b issubstituted by 0, 1, 2, or 3 R3esubstituents, whereinR5a and R3b together with the atoms to which they are attached, form a saturated mono- or bi-cyclic ring system substituted with 0, 1, 2, or 3 R3d and 0, 1, 2, or 3 R5esubstituents, wherein said mono- or bi-cyclic unsubstituted or substituted ring system isX3-U3-U2-Z,; eachR5d is independently selected from selected from hydroxy, hydroxy(Cl-6 alkyl), Cl-10 alkyl, amino. amino(C1-6 alkyl). (C 1-6 alkyl)o-2 amino(C0-6 alkyl), amino(C2-6 alkyl)oxy(C0-6 alkyl), (C1 -6 alkyl)o-2 amino(C2-6 alkyl)oxy(C0-6 alkyl), -(CH2)0-6~ O(CH2)0-6-NH-(X1) 1 -2-X2-X3-U1-U2-Z, and -(CH2)0-6“NH-(X1) 1 -2-X2-X3-U1- U2-Z; eachR5e is independently selected from fluoro, hydroxy. hydroxy(C1 -io alkyl), C1 -io alkyl, carboxy, carboxy(C1 -6 alkyl), C1 -6 alky loxy, amino, amino(C1 -6 alkyl), (C1 -6 alkyl)o-2 amino(C0-6 alkyl) ,-(CH2)0-6-O(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z, and -(CH2)0- 6-NH-CX1) 1 -2-X2-X3-U1-U2-Z;R6C is selected from C1 -io alkyl, C1 -6 alkyloxy, (C1 -6 alkyl)S02(C0-6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), amino(C0-6 alkyl), (Cl -6 alkyl)o-2 amino(CQ-6 alkyl), aminocarbonyl(C0-6 alkyl), (Cl -6 alk l)o-2 aminocarbonyl(C0-6 alkyl). (C1 -6 alkyl)carbonylamino(C0-6 alkyl), (C1 -6 alkyl)o-2 aminocarbonylamino(C0-6 alkyl), and carboxy(C0-6 alkyl);R7b is selected from aryl(C()-4 alkyl), and heteroaryl(Co-4 alkyl) wherein said heteroaryl contains at least one nitrogen, wherein R3b jssubstituted by 0, 1, or 2, R3csubstituents each independently selected from Cl-6 alkyl, Cl-6 fluoroalkyl, carboxy(C0-6 alkyl), hydroxy, and hydroxy(C1 -6 alkyl);RSa is hydrogen;R8b is selected from indolyl(Co-3 alkyl), naphthyl(Co-3 alky l), quinolinyl(Co-3 alkyl), and pyrrolo[2,3-6]pyridinyl(Co-3 alkyl), whereinR8b is substituted by 0, 1, or 2 R&csubstituents each independently selected from C1 -4 alkyl, halo, cyano, hydroxy, Cl -6 fluoroalkyl, and hydroxy(C1 -6 alkyl);R10b is selected from aiyl(Co-3 alkyl), and heteroaryl(Co-3 alkyl), wherein said heteroaryl contains 1 , 2, or 3 nitrogen atoms, wherein R10b is substituted by 0, 1 , or 2 RIOC wherein eachRl°c is independently selected from C1 -io alkyl, amino, amino(C1 -6 alkyl), aminocarbonyl. aminocarbonyl(C1 -6 alkyl), carboxy(C0-6 alkyl), -(Co-5 alkyl)-(S(=O)2NH2), -(CH2)o-6-0(CH2)o-6-NH-(X1)i-2- X2-X3-U1-U2-Z, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z;Rllb is selected from aryl(Co-3 alky l) and heteroaryl(Co-3 alkyl), wherein said heteroaryl contains 1 , 2, or 3 nitrogen atoms, wherein Rllb is substituted by 0, 1, or 2, 3, or 4 Rlld substituents each independently selected from Cl -6 alkyl, amino, amino(C1 -6 alkyl), hydroxy, hydroxy(C1 -6 alkyl), cyano, cyano(C1-6 alkyl), halo, amino(C0-6 alkyl)aminocarbonyl, aminocarbonyl, aminocarbonyl(C 1 -6 alkyl), (C 1-6 alkyl)o-2 aminocarbonyl(C0-6 alkyl), carboxy (C0-6 alkyl), carboxy (C 1- alkyl)oxy(C0-6 alkyl), amino(C0-6 alkyl)oxy(C0-6 alkyl), (C1 - alkyl)o-2 amino(C0-6 alkyl)oxy(C0-6 alkyl), -C(=O)NH-(CH2)2-6“NH-(X1)i-2-X2-X3- U^U^Z, -(CH2)0-6-O(CH2)0-6-NH-(X1)l -2-X2-X3-U1-U2-Z, -(CH2)0-6-NH-R12a is hydrogen or C1 -io alkyd;R12b is selected from hydrogen, and Cl -6 alkyl;R13a is selected from hydrogen, and C1 -6 alkyl;R13C is selected from indolyl, pyrrolo[2,3-b]pyridinyl, quinolinyl, indazolyl, and naphthyl; wherein Rl3c jssubstituted independently by 0, 1 , or 2 Rl3d substituents each independently selected from C1 -4 alkyd oxy, and -(CH2)0-6-NH-(X1)i-2-X2-X3-U1-U2-Z;14. The compound of claim 1 selected from the group consisting of SEQ ID NOS: 2-112, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14 selected from the group consisting of (SEQ ID NOS 10, 14,26, 30, 37, 42, 45, 65, 67, and 69) respectively, in order of appearance):SEQ ID NO 10,SEQ ID NO 26,SEQ ID NO 30,SEQ ID NO 42,SEQ ID NO 45,SEQ ID NO 65,SEQ ID NO 67, orSEQ ID NO 69, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A method of treating IBD and other TNFa-driven inflammatory diseases comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein said IBD and other TNFa- driven inflammatory diseases are selected from ulcerative colitis, Crohn’s disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, and hidradenitis suppurativa.

18. The method according to claim 17, wherein said IBD and other TNFa-driven inflammatory diseases are selected from ulcerative colitis and Crohn's disease.

19. The method according to claim 17, wherein said IBD and other TNFa-driven inflammatory diseases are selected from rheumatoid arthritis juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, anky losing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa.

20. The method of claim 17 wherein the effective amount of the compound or a pharmaceutically acceptable salt thereof is administered orally to the subject.

21. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in therapy.

22. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for treating IBD and other TNFa-driven inflammatory diseases selected from ulcerative colitis, Crohn’s disease, rheumatoid arthritis juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa.

23. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for treating IBD and other TNFa-driven inflammatory diseases selected from rheumatoid arthritis uvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, anky losing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa.

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