Cyclic peptides for inhibiting TNF receptor 1 activity

Abstract

The present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which inhibits TNFR1 and is contemplated to have utility as a therapeutic agent, e.g., for the treatment of inflammatory bowel disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiological central axis type spondylitis, and hidradenitis suppurativa. The invention also provides pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof. The present invention also relates to the use of said compounds or pharmaceutically acceptable salts thereof in the treatment and prevention of inflammatory bowel disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiological axial spinal arthritis and hidradenitis suppurativa, and a method for preparing a pharmaceutical product for this purpose.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to certain cyclic peptides that inhibit TNF Receptor 1 (TNFR1) activity, pharmaceutical compositions comprising such peptides, and methods of using these compounds to treat, inhibit or ameliorate one or more autoimmune and inflammatory disease states that can benefit from inhibition of TNFR1, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondylarthritis, hidradenitis suppurativa and other dermatological conditions, and other neurological, neurodegenerative, metabolic and ocular disorders. BACKGROUND

[0002] Therapeutics that target signaling of the cytokine tumor necrosis factor alpha (TNFa), including the anti-TNFa biologies that emerged in the 1990s, remain one of the standard of care (SOC) for several prevalent autoimmune and inflammatory diseases, including ulcerative colitis (UC), Crohn’s disease (CD) (collectively IBD), RA, juvenile RA, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondylarthritis, and hidradenitis suppurativa. TNFa is a pleiotropic cytokine that influences the function of multiple cell types. It triggers cellular responses ranging from induction of inflammatory gene expression programs, stimulation of cell proliferation and differentiation, to activation of cell suicide programs such as apoptosis and cell necrosis. It is expressed as a type II single-pass transmembrane protein and a soluble variant released after proteolytic processing.

[0003] TNFa self-assembles into a homotrimeric molecule and both the transmembrane and soluble forms interact with two known membrane receptors of TNFa, TNFR1 and TNFR2, each exerting different biological effects. Both receptors of TNFa are representative of a more extensive TNF receptor superfamily. Thus, TNFR1 and TNFR2 are single-pass type I transmembrane proteins characterized by several cysteine-rich domains in the extracellular domain. Soluble forms of TNFR1 and TNFR2 have also been described and arise from alternative splicing or shedding. TNFR1 is expressed by almost all cell types and mediates the well-known proinflammatory, cytotoxic, and gene-inducing signaling effects 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 on immune cells and tissue regeneration.

[0004] The mechanism of action (MOA) of anti-TNFa biologies, such as infliximab, adalimumab, golimumab, and certolizumab, involves binding to the cytokine TNFa and thus inhibiting engagement with both TNFR1 and TNFR2.

[0005] A key limitation of anti-TNFa SOC biologies as a drug class is a high rate of loss of response (>70% within one year of treatment), in many cases caused by the development of anti-drug antibodies (ADAs, ~60% of IBD patients), which leads to undesired changes in the pharmacokinetic and pharmacodynamic properties of these drugs (see Colombe 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)).

[0006] Limitations of anti-TNF therapies can depend on the pleiotropic biological functions of TNF via two different TNF receptors. In different animal disease models, genetic deletion of TNFR1 is generally associated with or reduces disease, while TNFR2 ablation worsens disease. These and other data suggest that soluble TNFa / TNFR1 signaling mainly mediates pro-apoptotic and inflammatory responses, while TNFR2 contributes to immune regulation and tissue regeneration. Thus, agents that selectively target TNFRs can be superior to global TNF blockade, as they allow differential activation and / or inhibition of TNFRs. Selective blockade of TNFa / TNFR1 signaling, which would preserve functional TNFa / TNFR2 signaling, appears sufficient to interfere with pathological TNFa signaling. Such therapeutic agents can induce milder side effects and can treat other diseases, such as MS or neurodegenerative diseases, where complete TNF inhibition is contraindicated, compared to global TNF blockers that neutralize both soluble and transmembrane TNFa (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)).

[0007] In addition to the current standard of care for anti-TNFa biologic drugs, there remains a need for additional therapeutic approaches to slow the progression of prevalent autoimmune and inflammatory diseases. SUMMARY

[0008] The present disclosure provides certain cyclic peptides that specifically attenuate the pro-inflammatory activity of TNFa mediated by TNFR1 signaling by selectively inhibiting TNFR1, and reduce inflammation by preserving / passively enabling TNFa-TNFR2 homeostatic signaling. These cyclic peptides can be valuable pharmaceutically active compounds for treating prevalent autoimmune and inflammatory diseases, including ulcerative colitis (UC), Crohn’s disease (CD) (collectively, inflammatory bowel disease (IBD)), as well as rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriasis, and other inflammatory conditions treatable by blocking TNFa signaling, such as psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, hidradenitis suppurativa and other dermatological diseases, and other neurological, neurodegenerative, metabolic, and ocular disorders.

[0009] In one aspect, the present disclosure provides a compound of Formula (I)

[0010]

[0011] and pharmaceutically acceptable salts thereof.

[0012] The compounds of the present invention have the potential to provide more durable efficacy over non-selective anti-TNFa SOCs by inhibiting TNFR1 -driven inflammation while preserving TNFR2-dependent homeostasis, mucosal / tissue healing, and immune modulation. Accordingly, in another aspect, the present disclosure provides a method for treating autoimmune and inflammatory diseases (e.g., ulcerative colitis, Crohn’s disease (collectively, IBD), rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa) comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the administration comprises oral administration of the compound.

[0013] Further, the present disclosure provides methods for preparing the compounds of the present disclosure as well as pharmaceutical compositions comprising a compound of the present disclosure and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION

[0014] The compounds of the present disclosure

[0015] In one embodiment, the present disclosure provides a compound having structural Formula (I) or a pharmaceutically acceptable salt thereof:

[0016]

[0017] R 1 selected from hydrogen, C 1-10 alkyl, (C 1-6 alkyl) 0-2 amino(C 0-10 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-10 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl)3N + (C 0-6 alkyl), aryl(C 0-10 alkyl), heteroaryl(C 0-10 alkyl), (C 3-12 )cycloalkyl(C 0-10 alkyl), heterocycloalkyl(C 0-10 alkyl), C 1-10 fluoroalkyl, C 2-10 alkenyl, (C 0-6alkyl)carbonyl(C 0-6 alkyl), (C 0-6 alkyl) 0-2 aminocarbonyl(C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 0-6 alkyl), arylcarbonyl(C 0-6 alkyl), arylaminocarbonyl(C 0-6 alkyl), heteroarylcarbonyl(C 0-6 alkyl), heteroarylaminocarbonyl(C 0-6 alkyl), C 1-6 alkoxy, (C 1-6 alkyl)oxy(C 0-6 alkyl), ((C 3-12 )cycloalkyl)oxy(C 0-6 alkyl), ((C 3-12 )cycloalkyl)C 0-6 alkyl)oxy(C 0-6 alkyl), (C 0-6 alkyl)carboxy(C 0-6 alkyl), N - =N + =N–(C 0-6 alkyl) and H2N–C(=NH)NH–(C 0-6 alkyl),

[0018] wherein R 1 is substituted with 0, 1, 2, 3 or 4 R 1a substituents, each R 1a substituent is independently selected from the group consisting of C 1-6 alkyl, amino, cyano, halogen, hydroxy, (C 3-12 )cycloalkyloxy and C 1-6 alkoxy;

[0019] each R 2a is independently selected from the group consisting of hydrogen, hydroxy, C 1-4 alkyl, fluoro and C 1-4 alkoxy;

[0020] R 2b is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein the heteroaryl contains at least one nitrogen atom,

[0021] wherein R 2b is substituted with 0, 1 or 2 R 2c , each R 2c is independently selected from the group consisting of C 1-6 alkyl, amino(C 0-6 alkyl), (C 1-6 alkyl) 0-2amino (C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 alkyl), aminocarbonyl (C 0-6 Alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 0-6 Alkyl), hydroxyl, C 1-6 Alkoxy, halogen, (C 1-6 alkyl) 0-2 amino (C 0-6 alkoxy), (C 1-6 Alkyl)3N + (C 0-6 alkoxy), (C 1-6 Alkoxy)carbonyl (C 0-6 alkyl), carboxyl (C) 0-6 Alkyl), carboxyl (C) 1-6 Alkyl)oxy(C 0-6 Alkyl), C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Alkoxy;

[0022] R 3a Selected from hydrogen, hydroxyl, hydroxyl (C 1-6 Alkyl), amino, amino (C 1-6 Alkyl), C 1-10 Alkyl, (C 3-12 )cycloalkyl (C 0-10 alkyl), (C 0-6 alkyl)thio(C 1-6 alkyl) and carboxyl (C) 1-6 alkyl), wherein R 3a Can be 0, 1 or 2 R 3c Substituent substitution;

[0023] R 3b Selected from hydrogen, C 1-10 Alkyl, hydroxyl (C 1-6 alkyl), amino (C 1-10 alkyl), (C 1-6 alkyl) 0-2 amino (C 1-10 alkyl), (C 1-6 Alkyl)3N + (C 1-6 Alkyl), C 1-6 Halogenated alkyl, aryl (C 0-10 alkyl), heteroaryl (C) 0-10 alkyl), (C 3-12 )cycloalkyl (C 0-10alkyl), heterocycloalkyl(C 0-10 alkyl), (C 1-6 alkyl)oxy(C 1-6 alkyl), (C 3-12 )carboxy(C 1-6 alkyl), carboxy(C 1-6 alkyl), aminocarbonyl(C 1-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 1-6 alkyl), aminocarbonylamino(C 1-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino(C 1-6 alkyl), (C 0-6 alkyl)thio(C 1-6 alkyl), (C 1-6 alkyl)SO2(C 1-6 alkyl), and (C 1-6 alkyl)sulfinyl(C 1-6 alkyl), wherein R 3b may be substituted with 0, 1, or 2 R 3c substituents;

[0024] each R 3c is independently selected from the group consisting of halogen, C 1-6 alkyl, amino, (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl), (C 1-6 alkyl)3N + -, (C 1-6 alkyl)SO2(C 0-6 alkyl), cyano, cyano(C 1-6 alkyl), hydroxy, hydroxy(C 1-6 alkyl), (C 1-6 alkyl)oxy(C 0-6 alkyl), aminocarbonyl(C 0-6 alkyl), and (C 0-6 )carboxy(C 0-6 alkyl);

[0025] and wherein R 3a and R 3b together with the atoms to which they are attached can form a saturated ring system, wherein said saturated ring system can be substituted with 0, 1, or 2 R 3c substituents;

[0026] R 4a is selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxy, C 1-4 alkoxy, and fluoro;

[0027] R 4b selected from bicyclic heteroaryl(C 0-3 alkyl) and bicyclic aryl(C 0-3 alkyl),

[0028] wherein R 4b is substituted with 0, 1 or 2 R 4c substituents, each R 4c substituent is independently selected from halo, hydroxy, cyano, nitro, carboxy, carboxy(C 1-6 alkyl), (C 1-6 alkoxy)carbonyl(C 0-6 alkyl), C 1-6 alkoxy, (C 1-6 alkyl)oxy(C 1-6 alkyl), C 1-6 alkyl and C 1-6 haloalkyl;

[0029] R 5a is selected from hydrogen, C 1-10 alkyl, C 1-10 fluoroalkyl, carboxy(C 1-10 alkyl), hydroxy, hydroxy(C 1-10 alkyl), cyano(C 1-10 alkyl), heterocycloalkyl(C 0-10 alkyl), aminocarbonyl(C 1-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 1-6 alkyl), (carboxy(C 1-10 alkyl))oxy(C 1-6 alkyl), aryl(C 0-6 alkyl), (C 3-12 )cycloalkyl(C 0-6 alkyl), heteroaryl(C 0-6 alkyl), (C 1-6 alkyl)oxy(C 1-6 alkyl), (C 1-6 alkoxy)carbonyl(C 0-6 alkyl), amino, amino(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl), amino(C 1-6 alkyl)carbonyl(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 1-6 alkyl)carbonyl(C 1-6 alkyl), (C 1-6 alkyl)3N+ (C 2-10 alkyl), (C 1-6 alkyl)3N + (C 1-6 alkyl)carbonyl(C 1-6 alkyl) and C 1-10 fluoroalkyl, and wherein R 5a is substituted with 0, 1 or 2 R 5d substituents;

[0030] R 5b is selected from hydrogen, C 1-10 alkyl, hydroxy(C 1-10 alkyl), carboxy(C 1-6 alkyl), (C 1-6 alkyl)oxy(C 1-6 alkyl), aminocarbonyl(C 1-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 1-6 alkyl), carboxy(C 1-10 alkyl)oxy(C 1-6 alkyl), cyano(C 1-10 alkyl), amino(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 1-6 alkyl), amino(C 1-6 alkyl)carbonyl(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 1-6 alkyl)carbonyl(C 1-6 alkyl), (C 1-6 alkyl)3N + (C 2-6 alkyl)oxy(C 1-6 alkyl), (C 1-6 alkyl)3N + (C 1-6 alkyl)carbonyl(C 1-6 alkyl), (C 1-6 alkyl)3N + (C 1-6 alkyl), (heterocycloalkyl(C 0-10 alkyl), (C 3-12 )cycloalkyl(C 0-10 alkyl) and C 1-10 haloalkyl, wherein R 5b is substituted with 0, 1, 2 or 3 R 5e substituents,

[0031] wherein R5a and R 5b together with the atom to which they are attached form a saturated monocyclic or bicyclic ring, wherein said monocyclic or bicyclic ring is substituted with 0, 1, 2, or 3 R 5d and 0, 1, 2, or 3 R 5e substituents;

[0032] each R 5d is independently selected from the group consisting of halogen, hydroxy, hydroxy(C 1-10 alkyl), C 1-10 alkyl, carboxy, carboxy(C 1-6 alkyl), C 1-6 alkoxy, (C 1-6 alkyl)oxy(C 1-6 alkyl), amino, amino(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl), amino(C 1-6 alkyl)carbonyl, (C 0-6 alkyl) 1-6 amino(C 0-2 alkyl)carbonyl, (C 1-6 alkyl)3N 0-6 (C 1-6 alkyl), (C + alkyl)3N 0-6 (C 1-6 alkyl)oxy(C + alkyl), (C 2-6 alkyl)3N 0-6 (C 1-6 alkyl)carbonyl, (C + alkyl)3N 1-6 (C 0-6 alkyl), (carboxy(C 1-6 alkyl))oxy(C 1-6 alkyl), cyano(C 0-6 alkyl), tetrazolyl(C 0-6 alkyl), and C 1-6 haloalkyl, and two R 5d substituents together with the atom to which they are attached can join to form a saturated ring;

[0033] each R 5e is independently selected from the group consisting of halogen, hydroxy, hydroxy(C 1-10 alkyl), C 1-10 alkyl, carboxy, carboxy(C 1-6 alkyl), C 1-6 alkoxy, (C 1-6 alkyl)oxy(C 1-6 alkyl), amino, amino(C1-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 alkyl), amino (C 1-6 alkyl)carbonylamino (C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 1-6 alkyl)carbonylamino (C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 2-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 1-6 alkyl)carbonylamino (C 0-6 Alkyl), (carboxyl (C) 1-6 Alkyl))oxy(C 1-6 alkyl), cyano (C 0-6 alkyl), tetrazolium (C 0-6 alkyl) and C 1-6 Halogenated alkyl, and two R 5e Substituents, together with the atoms they are attached to, can bond together to form saturated rings;

[0034] R 5c It is hydrogen, C 1-4 Alkyl, hydroxyl (C 1-4 Alkyl), C 1-4 alkoxy or (C 1-4 Alkyl)oxy(C 1-4 alkyl);

[0035] R 6a Selected from hydrogen, hydroxyl, amino, C 1-4 Alkoxy and C 1-6 alkyl;

[0036] R 6b Selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-4 Alkyl groups and fluorine;

[0037] R 6c Selected from C 1-10 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)oxy(C 1-6 alkyl),

[0038] C 1-10haloalkyl, aryl(C 0-6 alkyl), heteroaryl(C 0-10 alkyl), (C 1-6 alkyl)SO2(C 0-6 alkyl), hydroxy, hydroxy(C 1-6 alkyl), amino(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl), aminocarbonyl(C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 0-6 alkyl), (C 1-6 alkyl)carbonylamino(C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino(C 0-6 alkyl), and carboxy(C 0-6 alkyl);

[0039] R 7a is selected from hydrogen, C 1-6 alkyl, hydroxy, C 1-4 alkoxy, and fluoro;

[0040] R 7b is selected from aryl(C 0-6 alkyl), heteroaryl(C 0-6 alkyl), and (C 3-12 )cycloalkyl(C 0-6 alkyl),

[0041] wherein R 7b is substituted with 0, 1, 2, or 3 R 7c substituents, each R 7c substituent is independently selected from C 1-6 alkyl, C 1-10 fluoroalkyl, C 1-10 fluoroalkoxy, (C 1-6 alkyl) 0-2 amino(C 0-5 alkyl), (C 1-6 alkyl)3N + (C 0-5 alkyl), carboxy(C 0-6 alkyl), (C 1-6 alkoxy)carbonyl(C 0-6 alkyl), carboxy(C 1-6 alkyl)oxy(C 0-6 alkyl), aminocarbonyl(C 0-6 alkyl), (C 1-6 alkyl) 0-2amino carbonyl (C 0-6 Alkyl), hydroxyl, hydroxyl (C) 1-6 Alkyl), halogen, –(C 0-5 alkyl)–(S(=O)2OH), –(C 0-5 Alkyl)–(S(=O)2NH2), amino(C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 Alkyl)oxy(C 0-6 Alkyl), (C 1-6 Alkyl)3N + (C 0-6 Alkyl)oxy(C 0-6 alkyl), aminocarbonylamino (C 0-6 Alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino (C 0-6 Alkyl), C 1-10 Haloalkyl, C 1-10 Halogenated alkoxy groups and (C 1-6 Alkyl)oxy(C 0-6 alkyl);

[0042] R 8a Selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-4 Alkoxy, C 1-6 fluoroalkyl, C 1-4 Fluoroalkoxy and halogens;

[0043] R 8b Selected from bicyclic aryl (C 0-3 alkyl) and bicyclic heteroaryl (C 0-3 alkyl),

[0044] Where R 8b By 0, 1 or 2 R 8c Substituent substitution, the R 8c Each substituent is independently selected from C 1-4 Alkyl, halogen, cyano, nitro, carboxyl, amino, hydroxyl, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy, C 1-6 Alkoxy, amino (C 1-3 alkyl) and hydroxyl (C 1-6 alkyl);

[0045] R 9 Selected from hydrogen and C 1-4 alkyl;

[0046] R 10aselected from hydrogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy, and fluoro;

[0047] R 10b is selected from (C 3-12 )cycloalkyl(C 0-3 alkyl), aryl(C 0-3 alkyl), and heteroaryl(C 0-3 alkyl), wherein the heteroaryl contains 1, 2, or 3 nitrogen atoms;

[0048] wherein R 10b is substituted with 0, 1, or 2 R 10c , wherein each R 10c is independently selected from C 1-10 alkyl, C 1-10 fluoroalkyl, C 1-6 haloalkyl, C 1-10 fluoroalkoxy, amino, amino(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl), (C 1-6 alkyl)3N + (C 0-6 alkyl), hydroxy, hydroxy(C 1-6 alkyl), cyano, halogen, aminocarbonyl, aminocarbonyl(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl amino(C 0-6 alkyl), (C 1-6 alkyl)carbonyl amino(C 0-6 alkyl), carboxy(C 0-6 alkyl), (C 1-6 alkoxy)carbonyl(C 0-6 alkyl), carboxy(C 1-6 alkyl)oxy(C 0-6 alkyl), -(C 0-5 alkyl)-(S(=O)2OH), -(C 0-5 alkyl)-(S(=O)2NH2), amino(C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl)3N + (C0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl)oxy(C 0-6 alkyl), C 1-6 haloalkoxy, (C 3-12 )cycloalkyl(C 0-6 alkyl), and heterocycloalkyl(C 0-6 alkyl);

[0049] R 11a is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy, and fluoro;

[0050] R 11b is selected from aryl(C 0-3 alkyl), heteroaryl(C 0-3 alkyl), wherein the heteroaryl contains 1, 2, or 3 nitrogen atoms and H2N–C(=NH)NH–(C 1-6 alkyl),

[0051] wherein R 11b is substituted with 0, 1, 2, 3, or 4 R 11c substituents, each R 11c substituent is independently selected from C 1-6 alkyl, amino, amino(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl), (C 1-6 alkyl)3N + (C 0-6 alkyl), hydroxy, hydroxy(C 1-6 alkyl), cyano, halogen, aminocarbonyl, aminocarbonyl(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl), carboxy(C 0-6 alkyl), carboxy(C 1-6 alkyl)oxy(C 0-6 alkyl), amino(C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl)3N + (C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl)oxy(C0-6 Alkyl), C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, (C 3-12 )cycloalkyl (C 0-6 Alkyl), heterocyclic alkyl (C 0-6 Alkyl), ((C) 1-6 alkyl) carbonyl) heterocyclic alkyl (C 0-10 alkyl) and ((C) 1-6 alkyl) carbonyl) heterocyclic alkyl (C 0-10 alkyl);

[0052] R 12a Selected from hydrogen, hydroxyl, amino, C 1-10 Alkyl and (C 3-12 )cycloalkyl (C 0-6 alkyl);

[0053] R 12b Selected from hydrogen, C 1-10 Alkyl and (C 3-12 )cycloalkyl (C 0-6 alkyl);

[0054] Where R 12a and R 12b Together with the atoms they are attached to, they can form saturated rings;

[0055] R 13a Selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-4 Alkyl groups and fluorine;

[0056] R 13b Selected from hydrogen and C 1-4 alkyl;

[0057] R 13c Selected from bicyclic nitrogen-containing heteroaryl and bicyclic aryl groups having one or two nitrogen atoms, wherein R 13c Independently controlled by 0, 1, or 2 R 13d Substituent substitution, the R 13d The substituents are each independently selected from halogens, C 1-6 Alkyl, carboxyl (C 0-4 Alkyl), C 1-4 Halogenated alkoxy groups and C 1-4 Alkoxy;

[0058] Selected from

[0059]

[0060] Where R 14a Selected from amino, hydroxyl, (C 1-6 alkyl)0-2 amino and C 1-6 alkoxy;

[0061] m is selected from 1, 2, 3 or 4;

[0062] n is selected from 1, 2, 3 or 4; and

[0063] R 14b selected from hydrogen, C 1-8 alkyl, aryl(C 0-6 alkyl) and heteroaryl(C 0-6 alkyl), wherein R 14b is substituted with 0, 1, 2 or 3 halo groups.

[0064] In a first embodiment of the application, R 1selected from aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, phenyl, phenylmethyl, phenylethyl, phenylpropyl, styryl, biphenyl, naphthyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, imidazyl, pyrazolyl, furanyl, thienyl, oxazyl, isoxazyl, thiazyl, isothiazyl, oxadiazyl, biphenylmethyl, naphthylmethyl, pyridylmethyl, pyridazylmethyl, pyrimidylmethyl, pyrazylmethyl, imidazylmethyl, pyrazolylmethyl, furanyl methyl, thienylmethyl, oxazylmethyl, isoxazylmethyl, thiazylmethyl, isothiazylmethyl, oxadiazylmethyl, bicyclo[l. l. l.]pentyl, (bicyclo[l. l. l.]pentyl)methyl, phenylcarbonylaminoethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, aminocarbonylisopropyl, aminocarbonylbutyl, aminocarbonylamino methyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, aminocarbonylaminobutyl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, adamantyl, carboxyl, carboxymethyl, carboxyethyl, azidomethyl, azidoethyl, azidopropyl, phenylaminocarbonylmethyl, pyridylaminocarbonylmethyl, (pyridylcarbonylamino)methyl, guanidinyl, guanidinylmethyl, guanidinylethyl, guanidinylpropyl, guanidinylbutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, pentafluoropropyl, heptafluoropropyl, trifluorobutyl, N,N,N-trimethylmethylammonium, N,N,N-trimethyleth-l-ylammonium, N,N,N-trimethylprop-l-ylammonium, N,N,N-trimethylbut-l-ylammonium, methylamino, methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, ethylamino, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, ethylaminobutyl, diethylamino, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl, aminoethyloxy, aminoethyloxymethyl, isoxazylcarbonylamino methyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclopropoxymethyl, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, ethenyl, prop-2-enyl, but-3-enyl, and pent-4-enyl, and other groups as provided above in general formula (I).

[0065] In a second embodiment of the application, R 1selected from 3-aminopropyl, 4-aminobutyl, phenyl, phenylmethyl, bicyclo[1.1.1.]pentyl, phenylcarbonylaminoethyl, aminocarbonylmethyl, aminocarbonylaminoethyl, n-propyl, n-butyl, iso-butyl, iso-pentyl, n-pentyl, n-hexyl, 1-azidoethyl, 2-azidoethyl, azidopropyl, 3-azidopropyl, pyridylaminocarbonylmethyl, 3-guanidinopropyl, 2,2-difluoropropyl, 4,4,4-trifluorobutyl, N,N,N-trimethylpropan-1-ylammonium, methylaminopropyl, dimethylaminopropyl, isoxazolylcarbonylaminomethyl, ethoxy, methoxymethyl, prop-2-enyl, cyclopropylmethoxy and aminoethoxy, further radicals as provided above in general formula (I) or as provided in the first embodiment.

[0066] In a third embodiment of the present application, R 1a each substituent is independently selected from C 1-6 alkyl, amino, cyano, halo and hydroxy, further radicals as provided above in general formula (I) or as provided in the first to second embodiments.

[0067] In a fourth embodiment of the present application, each R 2a is independently selected from hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, further radicals as provided above in general formula (I) or as provided in the first to third embodiments.

[0068] In a fifth embodiment of the present application, each R 2a is independently selected from hydrogen, hydroxy and methyl, further radicals as provided above in general formula (I) or as provided in the first to fourth embodiments.

[0069] In a sixth embodiment of the present application, R 2b is selected from phenyl, benzyl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and bicyclo[1.1.1]pentyl, further radicals as provided above in general formula (I) or as provided in the first to fifth embodiments.

[0070] In a seventh embodiment, R 2b is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl and bicyclo[1.1.1]pentyl, further radicals as provided above in general formula (I) or as provided in the first to sixth embodiments.

[0071] In an eighth embodiment, each R 2cindependently selected from aminomethyl, hydroxy, methoxy, fluoro, carboxy, and aminocarbonyl, other radicals being as provided in general formula (I) above or in the first to eighth embodiments. carboxy, carboxymethoxy, (carboxymethoxy)methyl, aminocarbonyl, N,N- dimethylaminocarbonyl, and aminocarbonylmethyl, other radicals being as provided in general formula (I) above or in the first to eighth embodiments.

[0072] In a ninth embodiment of the present application, each R 2c independently selected from aminomethyl, hydroxy, methoxy, fluoro, carboxy, and aminocarbonyl, other radicals being as provided in general formula (I) above or in the first to eighth embodiments.

[0073] In a tenth embodiment of the present application, R 3a is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, 2-methylpropyl, t-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, aminoethyl, aminopropyl, aminobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, thioethyl, and thiopropyl, wherein R 3a may be substituted with 0, 1, or 2 R 3c substituents, which R 3c substituents are each independently selected from fluoro, chloro, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, sec-butyl, t-butyl, amino, aminomethyl, N-methylamino, N-methylaminomethyl, N-ethylamino, N-ethylaminomethyl, N,N-dimethylamino, N,N-dimethylaminomethyl, N,N-diethylamino, N,N-diethylaminomethyl, N,N,N-trimethylammonium, N,N,N-trimethylmethylammonium, hydroxy, hydroxymethyl, -SO2CH3, -CH2SO2CH3, -CH2CH2SO2CH3, cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxy, carboxymethyl, and carboxyethyl, other radicals being as provided in general formula (I) above or in the first to ninth embodiments.

[0074] In an eleventh embodiment of the present application, R 3a is selected from hydrogen, methyl, ethyl, propyl, 2-methylpropyl, butyl, aminoethyl, 2-aminoethyl, aminopropyl, 3-aminopropyl, hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, carboxyethyl, 2-carboxyethyl, and thioethyl, wherein R 3a may be substituted with 0, 1, or 2 R 3cSubstituent substitution, the R 3c The substituents are each independently selected from methyl, isopropyl, cyclopropyl, amino, N-methylamino, hydroxyl, –SO2CH3, –CH2SO2CH3, cyano, methoxy and carboxyl, and other groups are as in general formula (I) above or as provided in the first to tenth embodiments.

[0075] In the twelfth embodiment of the present invention, R 3b Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, bicyclo[1.1.1]pentylmethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 3-hydroxypropyl, 1-methyl-1-hydroxyethyl, hydroxyisopropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, aminomethyl, 2-aminoethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, N-methylaminoethyl, N,N-dimethylaminoethyl, N-methylaminopropyl, N,N-dimethylaminopropyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 2-aminopropyl-2-yl, fluoromethyl, difluoromethyl The following are listed: methyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, benzyl, 3-pyridylmethyl, 4-pyridylmethyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, thienylmethyl, furanylmethyl, pyrazolylmethyl, N-pyrazolylmethyl, 1-phenylethyl, 1-(4-pyridyl)ethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, (N,N-dimethyl)aminocarbonylmethyl, (N,N-dimethyl)aminocarbonylethyl, thiomethyl, thioethyl, thiopropyl, -CH2CH2SO2CH3, carboxylmethyl, carboxylethyl, 2-carboxylethyl, carboxylpropyl, 3-carboxylpropyl, carboxylbutyl, 4-carboxylbutyl, piperazinylmethyl, morpholinylmethyl, piperidinylmethyl, azacyclic butylmethyl, tetrahydropyranylmethyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, and aminocarbonylaminobutyl, wherein R 3b Can be 0, 1 or 2 R 3c Substituent substitution, the R 3ceach substituent is independently selected from fluoro, chloro, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, sec-butyl, t-butyl, amino, aminomethyl, N-methylamino, N-methylaminomethyl, N-ethylamino, N-ethylaminomethyl, N,N-dimethylamino, N,N-dimethylaminomethyl, N,N-diethylamino, N,N-diethylaminomethyl, N,N,N-trimethylammonium, N,N,N-trimethylmethylammonium, hydroxy, hydroxymethyl, -SO2CH3, -CH2SO2CH3, -CH2CH2SO2CH3, cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxy, carboxymethyl and carboxyethyl, and other groups are as provided in general formula (I) above or in the first to eleventh embodiments.

[0076] In a thirteenth embodiment of the application, R 3b is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, cyclopropyl, cyclobutyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 3-hydroxypropyl, 1-methyl-1-hydroxyethyl, methoxyethyl, aminomethyl, 2-aminoethyl, N-methylaminomethyl, 1-methyl-1-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 R 3b may be substituted with 0, 1 or 2 R 3c substituents, which R 3c substituents are each independently selected from methyl, i-propyl, cyclopropyl, amino, N-methylamino, hydroxy, SO2CH3, -CH2SO2CH3, cyano, methoxy and carboxy, and other groups are as provided in general formula (I) above or in the first to twelfth embodiments.

[0077] In a fourteenth embodiment of the application, R 3a and R 3b together with the atom to which they are attached form a saturated ring system which is substituted with 0, 1 or 2 R 3c substituents, and the ring system is selected from: and other groups are as provided in general formula (I) above or in the first to thirteenth embodiments.

[0078] In a fifteenth embodiment of the application, R 3a and R 3b together with the atom to which they are attached form a saturated ring system which is substituted with 0, 1 or 2 R 3c substituents, and the ring system is selected from:

[0079]

[0080] Further groups are as provided above in general formula (I) or as provided in the first to fourteenth embodiments.

[0081] In a sixteenth embodiment of the present application, R 4a is selected from hydrogen, methyl, ethyl, propyl, hydroxy, methoxy and fluoro, further groups are as provided above in general formula (I) or as provided in the first to fifteenth embodiments.

[0082] In a seventeenth embodiment of the present application, R 4a is hydrogen or methyl, further groups are as provided above in general formula (I) or as provided in the first to sixteenth embodiments.

[0083] In an eighteenth embodiment of the present application, R 4b is selected from indolyl, naphthyl, quinolinyl, pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrazolo[3,4-b]pyridine, indazolyl, benzothiazolyl and benzothiophenyl, wherein R 4b is substituted with 0, 1 or 2 R 4c substituents, which R 4c substituents are each independently selected from fluoro, chloro, methyl and carboxymethyl, further groups are as provided above in general formula (I) or as provided in the first to seventeenth embodiments.

[0084] In a nineteenth embodiment of the present application, R 4b is selected from indolyl, naphthyl, quinolinyl, pyrrolo[2,3-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridine and indazolyl, wherein R 4b is substituted with 0, 1 or 2 R 4c substituents, which R 4c substituents are each independently selected from fluoro, chloro, methyl and carboxymethyl, further groups are as provided above in general formula (I) or as provided in the first to seventeenth embodiments.

[0085] In a twentieth embodiment of the present application, R 5aSelected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclopentyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, phenyl, benzyl, phenylethyl, phenylpropyl, oxazolylmethyl, thiazolylmethyl, imidazolylmethyl, triazolylmethyl, oxadiazolylmethyl, thiazolylmethyl, oxazolylethyl, thiazolylethyl, imidazolylethyl, triazolylethyl, oxadiazolylethyl, thiazolylethyl, oxazolylpropyl, thiazolylpropyl, imidazolylpropyl, triazolylpropyl, oxadiazolylpropyl, thiazolylpropyl, aziridinemethyl, aziridinemethyl Ethyl, oxetane-butylmethyl, oxetane-butylmethyl, pyrrolylmethyl, pyrrolylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, tetrahydropyranylmethyl, tetrahydropyranylmethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, 3-hydroxy-2,2-dimethylpropyl, cyclopropylmethyl, 1-hydroxypropyl-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, (N-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-trifluoroethyl)ethyl, (N,N,N-dimethyl ... (N,N,N-trimethylammonium)ethyl, (N,N,N-triethylammonium)ethyl, (N,N,N-triethylammonium)propyl, (N-methylamino)methylcarbonylaminoethyl, (N-methylamino)ethylcarbonylaminoethyl, (N-methylamino)methylcarbonylaminopropyl, (N-ethylamino)methylcarbonylaminoethyl, (N-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,N-diethylamino)ethylcarbonylaminoethyl, (N,N-diethylamino)methylcarbonylaminopropyl, (N,N-dimethylamino)pentylcarbonylaminoethyl, (N,N-dimethylamino)pentylcarbonylaminoethyl, (N,N-dimethylamino)pentylcarbonylaminopropyl, N,N,N-trimethyl-ethyl-1-ammonium ... Methyl-propyl-1-ammonium, (N,N,N-trimethylammonium)methylcarbonylaminoethyl, (N,N,N-trimethylammonium)ethylcarbonylaminoethyl, (N,N,N-trimethylammonium)methylcarbonylaminopropyl, (N,N,N-trimethylammonium)ethylcarbonylaminopropyl, (N,N,N-trimethylammonium)pentylcarbonylaminoethyl, (N,N,N-trimethylammonium)pentylcarbonylaminopropyl, (carboxymethyl)oxyethyl, and (carboxymethyl)oxypropyl, wherein R, 5a By 0, 1, 2 or 3 R 5d Substituent substitution, the R 5deach substituent is independently selected from the group consisting of chloro, fluoro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, cyclobutyl, n-pentyl, i-pentyl, neopentyl, carboxy, carboxymethyl, carboxyethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, amino, aminomethyl, aminoethyl, N-methylamino, (N-methylamino)methyl, (N-methylamino)ethyl, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N-dimethylamino)ethyl, N,N-diethylamino, (N,N-diethylamino)methyl, (N,N-diethylamino)ethyl, aminomethylcarbonylamino, aminoethylcarbonylamino, aminopentylcarbonylamino, aminomethylcarbonylaminomethyl, aminoethylcarbonylaminomethyl, (N-methylamino)methylcarbonylamino, (N-methylamino)ethylcarbonylamino, (N-methylamino)methylcarbonylaminomethyl, (N-methylamino)ethylcarbonylaminomethyl, (N,N-dimethylamino)methylcarbonylamino, (N,N-dimethylamino)ethylcarbonylamino, (N,N-dimethylamino)methylcarbonylaminomethyl, (N,N-dimethylamino)ethylcarbonylaminomethyl, (N,N-diethylamino)methylcarbonylamino, (N,N-diethylamino)ethylcarbonylamino, (N,N-diethylamino)methylcarbonylaminomethyl, (N,N-diethylamino)ethylcarbonylaminomethyl, N,N,N-trimethylammonium, (N,N,N-trimethylammonium)methyl, (N,N,N-trimethylammonium)ethyl, (N,N,N-trimethylammonium)ethoxyl, (N,N,N-trimethylammonium)ethoxymethyl, (N,N,N-trimethylammonium)methylcarbonylamino, (N,N,N-trimethylammonium)methylcarbonylaminomethyl, (N,N,N-trimethylammonium)ethylcarbonylamino, (N,N,N-trimethylammonium)pentylcarbonylamino, (N,N,N-trimethylammonium)methylcarbonylaminomethyl, (N,N,N-trimethylammonium)ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazolyl, tetrazolylmethyl, tetrazolylethyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, and carboxyethoxymethyl, and other groups are provided above in general formula (I) or in the first through nineteenth embodiments.

[0086] In a twenty-first embodiment of the present application, R 5aselected from hydrogen, methyl, ethyl, n-propyl, cyclopropylmethyl, (1,3,4-oxadiazol-2-yl)ethyl, 2-hydroxyethyl, 3-hydroxypropyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-hydroxyethyl, 2-hydroxy-1 -methylethyl, hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, methoxyethyl, methoxypropyl, aminocarboxyethyl, 2-fluoroethyl, 2,2-difluoroethyl, carboxymethoxyethyl, 2-aminoethyl, 3-aminopropyl, (N,N-dimethylamino)ethyl, N,N,N-trimethyl-eth-1 -ammonium, (N,N,N-trimethylammonium)ethyloxyethyl, (N,N,N-trimethylammonium)methylcarbonylaminoethyl and (carboxymethyl)oxyethyl, wherein R 5a substituted with 0, 1, 2 or 3 R 5d substituents, each R 5d substituents are independently selected from fluorine, hydroxy, hydroxymethyl, methyl, carboxy, carboxymethyl, methoxy, amino, N,N-dimethylamino, N,N,N-trimethylammonium, (N,N,N-trimethylammonium)ethyloxy, (N,N,N-trimethylammonium)methylcarbonylamino, cyano, tetrazolyl and carboxymethoxy, further groups being provided in general formula (I) above or in the first to twentieth embodiments.

[0087] In a twenty-second embodiment of the present application, R 5bSelected from hydrogen, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopropylmethyl, oxacyclobutylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, methoxypropyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, (carboxymethoxy)methyl, (carboxymethoxy)ethyl, (carboxyethoxy)methyl, (carboxyethoxy)ethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, (N-methylamino)methyl, (N-methylamino)ethyl, (N-methylamino)propyl, (N-methylamino)butyl, (N,N-dimethylamino)methyl (N,N-Dimethylamino)ethyl, (N,N-Dimethylamino)propyl, (N,N-Dimethylamino)butyl, (N,N-Diethylamino)methyl, (N,N-Diethylamino)ethyl, (N,N-Diethylamino)propyl, (N,N-Diethylamino)butyl, N,N,N-Trimethylmethyl-1-ylammonium, N,N,N-Trimethylethyl-1-ylammonium, N,N,N-Triethylethyl-1-ylammonium, N,N,N-Trimethylpropyl-1-ylammonium, N,N,N-Trimethylbutyl-1-ylammonium, (N,N,N-Trimethylammonium)ethoxymethyl, (N,N,N-Trimethylammonium)ethoxyethyl, (N,N,N-Triethylammonium)ethoxyethyl, (N,N,N-Trimethylammonium)ethoxyethyl, (N,N,N-Trimethylammonium)ethoxyethyl propyl, (N,N,N-trimethylammonium)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, (N,N-dimethylamino)carbonylpropyl, (N,N-dimethylamino)carbonylbutyl, aminomethylcarbonylaminoethyl, aminomethylcarbonylaminopropyl, aminoethylcarbonylaminoethyl, aminoethylcarbonylaminopropyl, (N,N-dimethylamino)methylcarbonylaminoethyl, (N,N-dimethylamino)methylcarbonylaminoethyl Propyl, (N,N-dimethylamino)ethylcarbonylaminoethyl, (N,N-dimethylamino)ethylcarbonylaminopropyl, (N,N,N-trimethylammonium)methylcarbonylaminoethyl, (N,N,N-triethylammonium)methylcarbonylaminoethyl, (N,N,N-trimethylammonium)methylcarbonylaminopropyl, (N,N,N-trimethylammonium)ethylcarbonylaminoethyl, (N,N,N-trimethylammonium)ethylcarbonylaminopropyl, (N,N,N-trimethylammonium)ethoxyethyl, (N,N,N-trimethylammonium)ethoxypropyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanoisopropyl, and cyanobutyl, R 5bsubstituted with 0, 1, 2, or 3 R 5e substituted with 0, 1, 2, or 3 R 5e each R is independently selected from the group consisting of chloro, fluoro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, cyclobutyl, n-pentyl, i-pentyl, neopentyl, carboxy, carboxymethyl, carboxyethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, amino, aminomethyl, aminoethyl, N-methylamino, (N-methylamino)methyl, (N-methylamino)ethyl, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N-dimethylamino)ethyl, N,N-diethylamino, (N,N-diethylamino)methyl, (N,N-diethylamino)ethyl, aminomethylcarbonylamino, aminoethylcarbonylamino, aminopentylcarbonylamino, aminomethylcarbonylaminomethyl, aminoethylcarbonylaminomethyl, (N-methylamino)methylcarbonylamino, (N-methylamino)ethylcarbonylamino, (N-methylamino)methylcarbonylaminomethyl, (N-methylamino)ethylcarbonylaminomethyl, (N,N-dimethylamino)methylcarbonylamino, (N,N-dimethylamino)ethylcarbonylamino, (N,N-dimethylamino)methylcarbonylaminomethyl, (N,N-dimethylamino)ethylcarbonylaminomethyl, (N,N-diethylamino)methylcarbonylamino, (N,N-diethylamino)ethylcarbonylamino, (N,N-diethylamino)methylcarbonylaminomethyl, (N,N-diethylamino)ethylcarbonylaminomethyl, N,N,N-trimethylammonium, (N,N,N-trimethylammonium)methyl, (N,N,N-trimethylammonium)ethyl, (N,N,N-trimethylammonium)ethoxyl, (N,N,N-trimethylammonium)ethoxymethyl, (N,N,N-trimethylammonium)methylcarbonylamino, (N,N,N-trimethylammonium)methylcarbonylaminomethyl, (N,N,N-trimethylammonium)ethylcarbonylamino, (N,N,N-trimethylammonium)pentylcarbonylamino, (N,N,N-trimethylammonium)methylcarbonylaminomethyl, (N,N,N-trimethylammonium)ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazolyl, tetrazolylmethyl, tetrazolylethyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, and carboxyethoxymethyl, and other groups as provided above in the general formula (I) or in the first through twenty-first embodiments.

[0088] In a twenty-third embodiment of the present application, R 5bselected from hydrogen, methyl, ethyl, n-propyl, cyclopropylmethyl, hydroxymethyl, 2-hydroxyethyl, 2-carboxyethyl, 3-carboxypropyl, 2-aminoethyl, (N,N-dimethylamino)ethyl, 2-methoxyethyl, N,N,N-trimethylethan-1-aminium, (N,N,N-trimethyl-aminium)methylcarbonylaminoethyl, (N,N,N-trimethyl-aminium)ethoxyethyl, 2-fluoroethyl, 2,2-difluoroethyl and (carboxymethoxy)ethyl, wherein R 5b is substituted with 0, 1, 2 or 3 R 5e substituents, each R 5e substituents is independently selected from fluorine, hydroxyl, hydroxymethyl, methyl, carboxyl, carboxymethyl, methoxy, amino, N,N-dimethylamino, N,N,N-trimethylammonium, (N,N,N-trimethylammonium)ethoxy, (N,N,N-trimethylammonium)methylcarbonylamino, cyano, tetrazolyl and carboxymethoxy, other groups being as provided in general formula (I) above or in the first to twenty-second embodiments.

[0089] In a twenty-fourth embodiment of the present application, R 5c is hydrogen, methyl or ethyl, other groups being as provided in general formula (I) above or in the first to twenty-third embodiments.

[0090] In a twenty-fifth embodiment of the present application, R 5c is hydrogen or methyl, other groups being as provided in general formula (I) above or in the first to twenty-fourth embodiments.

[0091] In a twenty-sixth embodiment of the present application, R 5a and R 5b together with the atoms to which they are attached form a saturated monocyclic or bicyclic ring system, which is substituted with 0, 1, 2 or 3 R 5d and 0, 1, 2 or 3 R 5e substituents, wherein the monocyclic or bicyclic ring system is selected from:

[0092]

[0093] other groups being as provided in general formula (I) above or in the first to sixteenth and twenty-first to twenty-fifth embodiments.

[0094] In a twenty-seventh embodiment of the present application, R 5a and R 5b together with the atoms to which they are attached form a saturated monocyclic or bicyclic ring system, which is substituted with 0, 1, 2 or 3 R 5d and 0, 1, 2 or 3 R 5e substituents, wherein the monocyclic or bicyclic ring system is selected from:

[0095]

[0096] Other groups are as provided above in general formula (I) or as provided in the first to sixteenth and twenty first to twenty sixth embodiments.

[0097] In a twenty eighth embodiment, R 6a is selected from hydrogen, hydroxyl, methyl, ethyl, propyl and methoxy, other groups are as provided above in general formula (I) or as provided in the first to twenty seventh embodiments.

[0098] In a twenty ninth embodiment, R 6a is selected from hydrogen and methyl, other groups are as provided above in general formula (I) or as provided in the first to twenty eighth embodiments.

[0099] In a thirtieth embodiment, R 6b is selected from hydrogen, hydroxyl, methyl, ethyl, propyl, methoxy and ethoxy, other groups are as provided above in general formula (I) or as provided in the first to twenty ninth embodiments.

[0100] In a thirty first embodiment, R 6b is selected from hydrogen, hydroxyl and methyl, other groups are as provided above in general formula (I) or as provided in the first to thirtieth embodiments.

[0101] In a thirty second embodiment, R 6cselected from aminocarbonyl, (aminocarbonyl)methyl, (N,N-dimethylamino)carbonylmethyl, aminocarbonylamino, (aminocarbonylamino)ethyl, methoxymethyl, (methylsulfonyl)methyl, hydroxyl, and methyl, other groups being as provided in general formula (I) supra or in the first to thirty-second embodiments.

[0102] In a thirty-third embodiment, R 6c selected from aminocarbonyl, (aminocarbonyl)methyl, (N,N-dimethylamino)carbonylmethyl, aminocarbonylamino, (aminocarbonylamino)ethyl, methoxymethyl, (methylsulfonyl)methyl, hydroxyl, and methyl, other groups being as provided in general formula (I) supra or in the first to thirty-second embodiments.

[0103] In a thirty-fourth embodiment, R 7a selected from hydrogen, methyl, ethyl, hydroxyl, methoxy, and ethoxy, other groups being as provided in general formula (I) supra or in the first to thirty-third embodiments.

[0104] In a thirty-fifth embodiment, R 7a selected from hydrogen, methyl, and hydroxyl, other groups being as provided in general formula (I) supra or in the first to thirty-fourth embodiments.

[0105] In a thirty-sixth embodiment, R 7b selected from phenyl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 3-oxoisoindolinyl, and bicyclo[l. l. l]pentyl, other groups being as provided in general formula (I) supra or in the first to thirty-fifth embodiments.

[0106] In a thirty-seventh embodiment of the application, R 7b is selected from phenyl, pyridyl, pyrimidinyl, furanyl, thiazolyl and 3-oxoisoindolinyl, further groups being as provided above in general formula (I) or as provided in the first to thirty-sixth embodiments.

[0107] In a thirty-eighth embodiment of the application, R 7c is selected from fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, carboxy, carboxymethyl, methoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, aminocarbonyl, aminocarbonylmethyl, (N,N-dimethylamino)carbonyl, (N,N-dimethylamino)carbonylmethyl, amino, aminomethyl, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N-diethylamino)methyl, N,N,N-trimethylammonium, N,N,N-trimethylmethylammonium, N,N,N-triethylmethylammonium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, -SO2OH, -CH2SO2OH, -SO2NH2, -CH2SO2NH2, aminoethoxy, aminoethoxymethyl, (N,N-dimethylamino)ethoxy, N,N,N-trimethylethan-1-oxido- ammonium, aminocarbonylamino and aminocarbonylamino-methyl, further groups being as provided above in general formula (I) or as provided in the first to thirty-seventh embodiments.

[0108] In a thirty-ninth embodiment of the application, R 7c is selected from hydroxy, carboxymethoxy, fluorine, chlorine, methoxy, carboxy, carboxymethyl, methoxycarbonyl, aminocarbonyl, aminomethyl, -SO2OH, -SO2NH2, -CH2SO2OH, aminoethoxy and aminocarbonylamino, further groups being as provided above in general formula (I) or as provided in the first to thirty-eighth embodiments.

[0109] In a fortieth embodiment of the application, R 8a is selected from hydrogen, methyl, ethyl, hydroxy, methoxy and ethoxy, further groups being as provided above in general formula (I) or as provided in the first to thirty-ninth embodiments.

[0110] In a forty-first embodiment of the application, R 8a is selected from hydrogen and methyl, further groups being as provided above in general formula (I) or as provided in the first to fortieth embodiments.

[0111] In a forty-second embodiment of the application, R 8bis selected from indolyl, naphthyl, indolylmethyl, naphthylmethyl, quinolinyl, pyrrolo[2,3-b]pyridinyl, indazolyl, benzothiazolyl, and benzothiophenyl, other radicals being as provided in general formula (I) supra or in the first to forty-first embodiments.

[0112] In a forty-third embodiment of the present application, R 8b is selected from indolyl, naphthyl, and pyrrolo[2,3-b]pyridinyl, other radicals being as provided in general formula (I) supra or in the first to forty-second embodiments.

[0113] In a forty-fourth embodiment of the present application, each R 8c is independently selected from methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo, cyano, amino, aminomethyl, nitro, hydroxy, hydroxymethyl, carboxy, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, methoxy, ethoxy, and trifluoromethoxy, other radicals being as provided in general formula (I) supra or in the first to forty-third embodiments.

[0114] In a forty-fifth embodiment of the present application, each R 8c is independently selected from fluoro, chloro, bromo, and cyano, other radicals being as provided in general formula (I) supra or in the first to forty-fourth embodiments.

[0115] In a forty-sixth embodiment of the present application, R 9 is selected from hydrogen, methyl, ethyl, and propyl, other radicals being as provided in general formula (I) supra or in the first to forty-fifth embodiments.

[0116] In a forty-seventh embodiment of the present application, R 9 is hydrogen or methyl, other radicals being as provided in general formula (I) supra or in the first to forty-sixth embodiments.

[0117] In a forty-eighth embodiment of the present application, R 10a is selected from hydrogen, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy, other radicals being as provided in general formula (I) supra or in the first to forty-seventh embodiments.

[0118] In a forty-ninth embodiment of the present application, R 10a is selected from hydrogen and hydroxy, other radicals being as provided in general formula (I) supra or in the first to forty-eighth embodiments.

[0119] In a fiftieth embodiment of the present application, R 10bis selected from phenyl, benzyl, biphenyl, biphenylmethyl, pyridyl, pyridylmethyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, imidazolylmethyl, pyrazolyl, furanyl, furanylmethyl, oxazolyl, oxazolylmethyl, thiazolyl, indolyl, [1,2,4]triazolo[1,5-a]pyridine, and bicyclo[1.1.1]pentyl, other radicals being as provided in general formula (I) above or as provided in the first to the forty-ninth embodiments.

[0120] In a fifty-first embodiment of the present application, R 10b is selected from phenyl and pyrimidinyl, other radicals being as provided in general formula (I) above or as provided in the first to the fiftieth embodiments.

[0121] In a fifty-second embodiment, each R 10c is independently selected from methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, cyclobutyl, n-pentyl, i-pentyl, 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, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N-dimethylamino)ethyl, N,N,N-trimethylammonium, N,N,N-trimethylmethylammonium, aminocarbonyl, aminocarbonylmethyl, aminocarbonyl- ethyl, (N-methylamino)carbonyl, (N-methylamino)carbonylmethyl, (N,N-dimethylamino)carbonyl, (N,N-dimethylamino)carbonylmethyl, aminocarbonylamino, aminocarbonylaminomethyl, methylcarbonylamino, methylcarbonylamino- methyl, carboxy, carboxymethyl, carboxyethyl, methoxy carboxy, carboxymethoxy, carboxyethoxy, carboxymethyloxy, carboxymethyloxy- methyl, carboxyethyloxy-methyl, -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, (N,N-diethylamino)ethoxy, (N,N,N-trimethylammonio)ethoxy, methoxy, ethoxy, methoxymethyl, ethoxymethyl, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy, other radicals being as provided in general formula (I) above or as provided in the first to the fifty-first embodiments.

[0122] In a fifty-third embodiment, each R 10cindependently selected from fluoro, carboxy, carboxymethyl, (carboxymethyl)oxy, aminocarbonyl, amino, aminomethyl, -SO2OH, -SO2NH2, hydroxy, and aminocarbonylamino, the other radicals being as provided above in general formula (I) or as provided in the first to fifty-second embodiments.

[0123] In a fifty-fourth embodiment of the present application, R 11a is selected from hydrogen, hydroxy, methyl, ethyl, methoxy, and ethoxy, the other radicals being as provided above in general formula (I) or as provided in the first to fifty-third embodiments.

[0124] In a fifty-fifth embodiment of the present application, R 11a is selected from hydrogen and hydroxy, the other radicals being as provided above in general formula (I) or as provided in the first to fifty-fourth embodiments.

[0125] In a fifty-sixth embodiment, R 11b 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, pyridyl, pyridylmethyl, indolyl, indolylmethyl, pyridazinyl, pyridazinylmethyl, pyrimidinyl, pyrimidinylmethyl, pyrazinyl, pyrazinylmethyl, imidazolyl, imidazolylmethyl, pyrazolyl, pyrazolylmethyl, [l,2,4]triazolo[l,5-a]pyridine, oxazolyl, oxazolylmethyl, thiazolyl, and thiazolylmethyl, the other radicals being as provided above in general formula (I) or as provided in the first to fifty-fifth embodiments.

[0126] In a fifty-seventh embodiment, R 11b is selected from phenyl, (H2N-C(=NH)-NH)ethyl, pyridyl, indolyl, and imidazolyl, the other radicals being as provided above in general formula (I) or as provided in the first to fifty-sixth embodiments.

[0127] In a fifty-eighth embodiment of the present application, each R 11cindependently selected from fluoro, chloro, bromo, iodo, (carboxymethyl)oxy, (carboxymethyl)oxymethyl, (carboxyethyl)oxy, hydroxy, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, carboxy, carboxymethyl, aminocarbonyl, aminocarbonylmethyl, (N-methylamino)carbonyl, (N-methylamino)carbonylmethyl, (N,N-dimethylamino)carbonyl, (N,N-dimethylamino)carbonylmethyl, amino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, aminomethyl, (N,N-dimethylamino)methyl, (N,N-diethylamino)methyl, N,N,N-trimethylammonium, N,N,N-trimethylmeth-1-yl-ammonium, N,N,N-triethylammonium, N,N,N-triethylmeth-1-yl-ammonium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, aminoethoxy, aminopropoxy, aminoethoxymethyl, (N,N-dimethylamino)ethoxy, N,N,N-trimethylethan-1-yloxy-ammonium, cyano, and methylcarbonylpiperazinyl [(N-acetyl)piperazinyl], other groups being as provided in general formula (I) above or in the first to fifty-seventh embodiments.

[0128] In a fifty-ninth embodiment of the present application, each R 11c is independently selected from (carboxymethyl)oxy, fluoro, chloro, hydroxy, methoxy, trifluoromethoxy, carboxy, carboxymethyl, aminocarbonyl, aminocarbonylmethyl, aminomethyl, aminoethoxy, (N,N-dimethylamino)ethoxy, and methylcarbonylpiperazinyl other groups being as provided in general formula (I) above or in the first to fifty-eighth embodiments.

[0129] In a sixtieth embodiment of the present application, R 12a is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, and isopropyl, other groups being as provided in general formula (I) above or in the first to fifty-ninth embodiments.

[0130] In a sixty-first embodiment of the present application, R 12a is selected from hydrogen, methyl, ethyl, and n-propyl, other groups being as provided in general formula (I) above or in the first to sixtieth embodiments.

[0131] In a sixty-second embodiment, R 12b is selected from hydrogen, methyl, ethyl, and propyl, other groups being as provided in general formula (I) above or in the first to sixty-first embodiments.

[0132] In a sixty-third embodiment, R 12b is selected from hydrogen and methyl, other groups being as provided in general formula (I) above or in the first to sixty-second embodiments.

[0133] In a sixty-fourth embodiment of the present application, R 12a and R 12b together with the atom to which they are attached form a saturated ring selected from The other groups are as provided in the general formula (I) above or in the first to sixty-third embodiments.

[0134] In a sixty-fifth embodiment of the present application, R 12a and R 12b together with the atom to which they are attached form The other groups are as provided in the general formula (I) above or in the first to sixty-fourth embodiments.

[0135] In a sixty-sixth embodiment, R 13a is hydrogen, methyl or propyl, the other groups being as provided in the general formula (I) above or in the first to sixty-fifth embodiments.

[0136] In a sixty-seventh embodiment, R 13b is hydrogen or methyl, the other groups being as provided in the general formula (I) above or in the first to sixty-sixth embodiments.

[0137] In a sixty-eighth embodiment, R 13c is selected from indolyl, pyrrolo[2,3-b]pyridinyl, quinolinyl, indazolyl and naphthyl, the other groups being as provided in the general formula (I) above or in the first to sixty-seventh embodiments.

[0138] In a sixty-ninth embodiment, R 13c is selected from indolyl and pyrrolo[2,3-b]pyridinyl, the other groups being as provided in the general formula (I) above or in the first to sixty-eighth embodiments.

[0139] In a seventieth embodiment, each R 13d is independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, carboxyl, carboxymethyl, methoxy, difluoromethoxy, trifluoromethoxy and ethoxy, the other groups being as provided in the general formula (I) above or in the first to sixty-ninth embodiments.

[0140] In a seventy-first embodiment, each R 13d is independently selected from methyl, chloro and methoxy, the other groups being as provided in the general formula (I) above or in the first to seventieth embodiments.

[0141] In a seventy-second embodiment, each R 14a is independently selected from amino, hydroxy, N-methylamino, N,N-dimethylamino, N-ethylamino, methoxy and ethoxy, the other groups being as provided in the general formula (I) above or in the first to seventy-first embodiments.

[0142] In a seventy-third embodiment, each R 14a is independently amino, the other groups being as provided above in general formula (I) or as provided in the first through seventy-second embodiments.

[0143] In a seventy-fourth embodiment, each R 14b is independently selected from the group consisting of 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, the other groups being as provided above in general formula (I) or as provided in the first through seventy-third embodiments.

[0144] In a seventy-fifth embodiment, each R 14b is independently selected from the group consisting of hydrogen, methyl, ethyl, and phenyl, the other groups being as provided above in general formula (I) or as provided in the first through seventy-fourth embodiments.

[0145] In a seventy-sixth embodiment, the compound of formula (1) or pharmaceutically acceptable salt thereof is:

[0146]

[0147] R 1 is selected from the group consisting of hydrogen, C 1-10 alkyl, (C 1-6 alkyl) 0-2 amino(C 0-10 alkyl), (C 1-6 alkyl)3N + (C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 0-10 alkyl), aryl(C 0-10 alkyl), heteroaryl(C 0-10 alkyl), (C 3-12 )cycloalkyl(C 0-10 alkyl), heterocycloalkyl(C 0-10 alkyl), C 1-10 fluoroalkyl, C 2-10 alkenyl, (C 0-6 alkyl)carbonylamino(C 0-6 alkyl), (C 0-6 alkyl)aminocarbonyl(C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino(C0-6 alkyl), arylcarbonylamino(C 0-6 alkyl), arylcarbonylamino(C 0-6 alkyl), heteroarylcarbonylamino(C 0-6 alkyl), heteroarylcarbonylamino(C 0-6 alkyl), C 1-6 alkoxy, (C 1-6 alkyl)oxy(C 0-6 alkyl), ((C 3-12 )cycloalkyl)oxy(C 0-6 alkyl), ((C 3-12 )cycloalkyl)C 0-6 alkyl)oxy(C 0-6 alkyl), (C 0-6 alkyl)carboxy(C 0-6 alkyl), N - =N + =N–(C 0-6 alkyl) and H2N–C(=NH)NH–(C 0-6 alkyl),

[0148] wherein R 1 is substituted with 0, 1, 2, 3 or 4 R 1a substituents, each R 1a substituent is independently selected from the group consisting of C 1-6 alkyl, amino, cyano, halogen, hydroxy, (C 3-12 )cycloalkyloxy and C 1-6 alkoxy;

[0149] each R 2a is independently selected from the group consisting of hydrogen, hydroxy, C 1-4 alkyl, fluoro and C 1-4 alkoxy;

[0150] R 2b is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein the heteroaryl contains at least one nitrogen atom,

[0151] wherein R 2b is substituted with 0, 1 or 2 R 2c , each R 2c is independently selected from the group consisting of C 1-6 alkyl, amino(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl), (C 1-6 alkyl)3N + (C 0-6 alkyl), aminocarbonyl(C 0-6 alkyl), (C 1-6 alkyl)0-2 aminocarbonyl(C 0-6 alkyl), hydroxyhalo, (C 1-6 alkyl) 0-2 amino(C 0-6 alkoxy), (C 1-6 alkyl)3N + (C 0-6 alkoxy), (C 1-6 alkoxy)carbonyl(C 0-6 alkyl), carboxy(C 0-6 alkyl), carboxy(C 1-6 alkyl)oxy(C 0-6 alkyl), C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 alkoxy;

[0152] R 3a is selected from hydrogen, hydroxy, hydroxy(C 1-6 alkyl), amino, amino(C 1-6 alkyl), C 1-10 alkyl, (C 3-12 )cycloalkyl(C 0-10 alkyl) and carboxy(C 1-6 alkyl), wherein R 3a may be substituted with 0, 1 or 2 R 3c substituents;

[0153] R 3b is selected from hydrogen, C 1-10 alkyl, amino(C 1-10 alkyl), (C 1-6 alkyl) 0-2 amino(C 1-10 alkyl), (C 1-6 alkyl)3N + (C 1-6 alkyl), C 1-6 haloalkyl, aryl(C 0-10 alkyl), heteroaryl(C 0-10 alkyl), (C 3-12 )cycloalkyl(C 0-10 alkyl), heterocycloalkyl(C 0-10 alkyl), (C 1-6 alkyl)oxy(C 1-6 alkyl), (C 3-12 )cycloalkoxy(C 1-6 alkyl), carboxy(C 1-6 alkyl), aminocarbonyl(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl(C 1-6alkyl), amino(C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 1-6 alkyl), (C 1-6 alkyl)thio(C 1-6 alkyl), (C 1-6 alkyl)SO2(C 1-6 alkyl), and (C 1-6 alkyl)sulfinyl(C 1-6 alkyl), wherein R 3b may be substituted with 0, 1, or 2 R 3c substituents;

[0154] each R 3c is independently selected from the group consisting of halogen, C 1-6 alkyl, amino, (C 1-6 alkyl) 0-2 amino, (C 1-6 alkyl)3N + -, (C 1-6 alkyl)SO2(C 0-6 alkyl), cyano, cyano(C 1-6 alkyl), hydroxy, hydroxy(C 1-6 alkyl), (C 1-6 alkyl)oxy(C 0-6 alkyl), and (C 0-6 )carboxy(C 0-6 alkyl);

[0155] and wherein R 3a and R 3b together with the atoms to which they are attached can form a saturated ring system, wherein said saturated ring system can be substituted with 0, 1, or 2 R 3c substituents;

[0156] R 4a is selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxy, C 1-4 alkoxy, and fluoro;

[0157] R 4b is selected from the group consisting of bicyclic heteroaryl(C 0-3 alkyl) and bicyclic aryl(C 0-3 alkyl),

[0158] wherein R 4b is substituted with 0, 1, or 2 R 4c substituents, each R 4c substituent is independently selected from the group consisting of halogen, hydroxy, cyano, nitro, carboxy(C 0-6 alkyl), (C 1-6 alkoxy)carbonyl(C 0-6alkyl), C 1-6 alkoxy, (C 1-6 alkyl)oxy(C 1-6 alkyl), C 1-6 alkyl and C 1-6 haloalkyl;

[0159] R 5a is selected from hydrogen, C 1-10 alkyl, carboxy(C 1-10 alkyl), hydroxy, hydroxy(C 1-10 alkyl), cyano(C 1-10 alkyl), heterocycloalkyl(C 0-10 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 1-6 alkyl), (carboxy(C 1-10 alkyl))oxy(C 1-6 alkyl), aryl(C 0-6 alkyl), heteroaryl(C 0-6 alkyl), (C 1-6 alkyl)oxy(C 1-6 alkyl), (C 1-6 alkoxy)carbonyl(C 0-6 alkyl), amino(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl), (C 1-6 alkyl)3N + (C 2-10 alkyl), (C 3-12 )cycloalkyl(C 0-6 alkyl) and C 1-10 fluoroalkyl, and wherein R 5a is substituted with 0, 1 or 2 R 5d substituents;

[0160] R 5b is selected from hydrogen, C 1-10 alkyl, hydroxy(C 1-10 alkyl), carboxy(C 1-6 alkyl), (C 1-6 alkyl)oxy(C 1-6 alkyl), aminocarbonyl(C 1-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 1-6 alkyl), carboxy(C 1-10 alkyl)oxy(C 1-6 alkyl), cyano(C 1-10 alkyl), amino(C 1-6 alkyl), (C1-6 alkyl) 0-2 amino (C 1-6 Alkyl), (C 1-6 Alkyl)3N + (C 1-6 Alkyl), heterocyclic alkyl (C 0-10 Alkyl), (C 3-12 )cycloalkyl (C 0-10 alkyl) and C 1-10 Haloalkyl, wherein R 5b By 0, 1 or 2 R 5d Substituent substitution, where R 5a and R 5b Together with the atoms they are attached to, they form saturated monocyclic or bicyclic rings, wherein the monocyclic or bicyclic rings are separated by 0, 1, or 2 R atoms. 5d replace;

[0161] Each R 5d Independently selected from halogens, hydroxyl groups, and C 1-10 Alkyl, hydroxyl (C 1-10 alkyl), carboxyl (C) 1-6 Alkyl), C 1-6 Alkoxy, (C 1-6 Alkyl)oxy(C 1-6 Alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 Alkyl), (Carboxyl (C) 1-6 Alkyl))oxy(C 1-6 alkyl), cyano and C 1-6 Halogenated alkyl groups and two R groups 5d Substituents, together with the atoms they are attached to, can bond together to form saturated rings;

[0162] R 5c It is hydrogen, C 1-4 Alkyl, hydroxyl (C 1-4 Alkyl), C 1-4 Alkoxy, (C 1-4 Alkyl)oxy(C 1-4 Alkyl), hydroxyl, amino, or halogen;

[0163] R 6a Selected from hydrogen, hydroxyl, amino, C 1-4 Alkoxy and C 1-6 alkyl;

[0164] R 6b Selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-4 Alkyl groups and fluorine;

[0165] R 6c Selected from C1-6 Alkoxy, (C 1-6 Alkyl)oxy(C 1-6 Alkyl), C 1-10 Halogenated alkyl, aryl (C 0-6 alkyl), heteroaryl (C) 0-10 Alkyl), (C 1-6 Alkyl)SO2(C 0-6 Alkyl), hydroxyl, hydroxyl (C) 1-6 alkyl), amino (C 0-6 Alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 Alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 0-6 Alkyl), (C 1-6 alkyl)carbonylamino (C 0-6 Alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino (C 0-6 alkyl) and carboxyl (C) 0-6 alkyl);

[0166] R 7a Selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-4 Alkyl groups and fluorine;

[0167] R 7b Selected from aryl (C 0-6 alkyl), heteroaryl (C) 0-6 alkyl) and (C 3-12 )cycloalkyl (C 0-6 alkyl), wherein R 7b By 0, 1, 2 or 3 R 7c Substituent substitution, the R 7c Each substituent is independently selected from C 1-6 Alkyl, C 1-10 fluoroalkyl, C 1-10 Fluoroalkoxy, (C 1-6 alkyl) 0-2 amino (C 0-5 Alkyl), (C 1-6 Alkyl)3N + (C 0-5 alkyl), carboxyl (C) 0-6 Alkyl), (C 1-6 Alkoxy)carbonyl (C 0-6 alkyl), carboxyl (C) 1-6 Alkyl)oxy(C 0-6 alkyl), aminocarbonyl (C 0-6 Alkyl), (C 1-6alkyl 0-2 aminocarbonyl(C 0-6 alkyl), hydroxy, hydroxy(C 1-6 alkyl), halo, -(C 0-5 alkyl)-(S(=0)2OH), -(C 0-5 alkyl)-(S(=0)2NH2), amino(C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl)3N + (C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 0-6 alkyl), C 1-10 haloalkyl, C 1-10 haloalkoxy and (C 1-6 alkyl)oxy(C 0-6 alkyl);

[0168] R 8a is selected from hydrogen, C 1-6 alkyl, hydroxy, C 1-4 alkoxy, C 1-6 fluoroalkyl, C 1-4 fluoroalkoxy and halo;

[0169] R 8b is selected from aryl(C 0-3 alkyl) and heteroaryl(C 0-3 alkyl), wherein R 8b is substituted by 0, 1 or 2 R 8c substituents, each R 8c substituent is independently selected from C 1-4 alkyl, halo, cyano, nitro, carboxy, amino, hydroxy, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy, C 1-6 alkoxy, amino(C 0-3 alkyl) and hydroxy(C 1-6 alkyl);

[0170] R 9 is selected from hydrogen and C 1-4 alkyl;

[0171] R 10a is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy and fluoro;

[0172] R 10b Selected from (C) 3-12 )cycloalkyl (C 0-3 alkyl), aryl (C 0-3 alkyl) and heteroaryl (C 0-3 Alkyl group), wherein the heteroaryl group contains 1, 2, or 3 nitrogen atoms.

[0173] Where R 10b By 0, 1 or 2 R 10c Replacement, where each R 10c Selected independently from C 1-10 Alkyl, C 1-10 fluoroalkyl, C 1-10 Fluoroalkoxy, amino (C 0-6 Alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 Alkyl), (C 1-6 Alkyl)3N + (C 0-6 Alkyl), hydroxyl, cyano, halogen, hydroxyl (C 1-6 alkyl), aminocarbonyl (C 0-6 Alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino (C 0-6 alkyl), (C 1-6 alkyl)carbonylamino (C 0-6 Alkyl), carboxyl (C) 0-6 alkyl), (C 1-6 Alkoxy)carbonyl (C 0-6 Alkyl), carboxyl (C) 1-6 Alkyl)oxy(C 0-6 alkyl), –(C 0-5 alkyl)–(S(=O)2OH), –(C 0-5 Alkyl)–(S(=O)2NH2), amino(C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 Alkyl)oxy(C 0-6 Alkyl), (C 1-6 Alkyl)oxy(C 0-6 Alkyl), C1-6 haloalkyl, (C 1-6 haloalkyl, (C 3-12 haloalkyl, (C 0-6 haloalkyl, (C 0-6 haloalkyl, (C

[0174] R 11a is selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-4 alkoxy and fluoro;

[0175] R 11b is selected from aryl(C 0-3 alkyl) and heteroaryl(C 0-3 alkyl), wherein the heteroaryl contains 1, 2 or 3 nitrogen atoms and H2N-C(=NH)NH-(C 1-6 alkyl), wherein R 11b is substituted with 0, 1, 2, 3 or 4 R 11c substituents, each R 11c substituent is independently selected from C 1-6 alkyl, amino(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl), (C 1-6 alkyl)3N + (C 0-6 alkyl), hydroxy, cyano, halogen, hydroxy(C 1-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonyl(C 0-6 alkyl), carboxy(C 0-6 alkyl), carboxy(C 1-6 alkyl)oxy(C 0-6 alkyl), amino(C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino(C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl)3N + (C 0-6 alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl)oxy(C 0-6 alkyl), C 1-6 haloalkoxy, C 1-6 haloalkyl, (C 3-12 )ring alkyl(C 0-6 alkyl), heterocycloalkyl(C 0-6alkyl) and ((C) 1-6 Alkoxy) carbonyl) heterocyclic alkyl (C 0-10 alkyl);

[0176] R 12a Selected from hydrogen, hydroxyl, amino, C 1-10 Alkyl and (C 3-12 )cycloalkyl (C 0-6 alkyl);

[0177] R 12b Selected from hydrogen, C 1-10 Alkyl and (C 3-12 )cycloalkyl (C 0-6 alkyl);

[0178] Where R 12a and R 12b Together with the atoms they are attached to, they can form saturated rings;

[0179] R 13a Selected from hydrogen and C 1-4 alkyl;

[0180] R 13b Selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-4 Alkyl groups and fluorine;

[0181] R 13c Selected from bicyclic nitrogen-containing heteroaryl and bicyclic aryl groups having one or two nitrogen atoms, wherein R 13c Independently controlled by 0, 1, or 2 R 13d Substituent substitution, the R 13d The substituents are each independently selected from halogens, C 1-6 Alkyl, carboxyl (C 0-4 Alkyl), C 1-4 Halogenated alkoxy groups and C 1-4 Alkoxy;

[0182] Selected from

[0183]

[0184]

[0185] Where R 14a Selected from amino, hydroxyl, (C 1-6 alkyl) 0-2 amino and C 1-6 Alkoxy;

[0186] m is selected from 1, 2, 3, or 4;

[0187] n is selected from 1, 2, 3, or 4; and

[0188] R 14b selected from hydrogen, C 1-8 alkyl, aryl(C 0-6 alkyl), and heteroaryl(C 0-6 alkyl), wherein R 14b is substituted with 0, 1, 2, or 3 halo.

[0189] 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: 1-289 as listed in Table 1.

[0190] In particular embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of (in the order of appearance, respectively, SEQ ID NOs 5, 10, 18, 22, 30, 31, 41, 45, 48, 51, 52, 53, 60, 68, 77, 83, 87, 104, 183, 196, 206, 210, 214, 221, 229, 237, 247, 250, 254, 257, and 265):

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211] The mechanism of action (MOA) of anti-TNFa biologies, such as infliximab, adalimumab, golimumab, and certolizumab pegol, involves binding to the cytokine TNFa and thus inhibiting engagement with both TNFR1 and TNFR2. While not being bound by any particular theory, Applicants believe that the compounds of the present disclosure selectively inhibit TNFR1 -specific proinflammatory activity of TNFa-mediated TNFR1 signaling and preserve / passively enable TNFa-TNFR2 homeostatic signaling, which can impart better therapeutic efficacy than standard-of-care anti-TNFa biologies.

[0212] Limitations

[0213] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0214] 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 are 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 this 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, amines, pyrrolidines, or imidazoles, and an acidic moiety, such as, but not limited to, carboxylic acids, zwitterions ("inner salts") can be formed and are included within the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the compounds of Formula (I) can be formed, for example, by reacting a compound of Formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.

[0215] As "C 0-6The term "C0" or "C0-6 alkyl" used in the expressions "alkyl" and "C0-6 alkyl" refers to a direct covalent bond; or, when the term appears at the end of a substituent, C0 refers to a direct covalent bond. 0-6 Alkyl refers to hydrogen or C 1-6 Alkyl groups. Similarly, when the integer number of atoms in a defining group is zero, it means that the adjacent atoms are directly connected by bonds. For example, in structural... In the expression, s is an integer equal to 0, 1, or 2. When s is zero, the structure is:

[0216] "Acyl" refers to -C(=O)-alkyl, where alkyl is defined below. The bond to the parent group is through the carbonyl carbon atom.

[0217] "Acetyl" refers to the group -C(=O)CH3.

[0218] The term "alkyl" and other groups prefixed with "alkane" (such as alkoxy, dialkylamino, and trialkylammonium) refer to aliphatic hydrocarbon groups in which one of their hydrogen atoms is bonded and substituted. Alkyl groups can be straight-chain or branched and contain about 1 to about 10 carbon atoms. In one embodiment, the alkyl group contains about 1 to about 10 carbon atoms. In various embodiments, the alkyl group contains 1 to 6 carbon atoms (C1 to C2). 1-6 Alkyl groups are alkyl groups (or have about 1 to about 4 carbon atoms, C1-C4 alkyl groups). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl, and neohexyl. In one embodiment, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched. Unless otherwise stated, the alkyl group is unsubstituted.

[0219] "Alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be straight-chain or branched, and has a specified number of carbon atoms. Preferably, the alkenyl group contains one carbon-carbon double bond, and may contain up to four non-aromatic carbon-carbon double bonds. Examples of alkenyl groups include vinyl, propenyl, n-butenyl, 2-methyl-1-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl.

[0220] "Alkoxy" and "alkyloxy" are used interchangeably and refer to an alkyl (carbon and hydrogen chain) linked to an oxygen (RO). Non-limiting examples of alkoxy groups are methoxy (CH3O-), ethoxy (CH3CH2O-), and propoxy (CH3CH2CH2O-).

[0221] "Amino" refers to the -NH2 group, which can be substituted (where one or both hydrogen atoms are replaced), as further defined herein.

[0222] "Amino acid" refers to naturally occurring a-amino acids and stereoisomers thereof, as well as unnatural amino acids (such as a,a-disubstituted amino acids, β-substituted amino acids, β-amino acids, and substituted amino acids) and stereoisomers thereof. In the sequences given for the peptides (compounds) according to the 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" isomer is indicated by "D" or "D" in front of 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 included in the foregoing have the definitions provided in the Table of Abbreviations in the Examples section below.

[0223] "Aryloxy" means an -O-aryl group, wherein aryl is as previously defined.

[0224] "Aryloxy" means an -O-aryl group, wherein aryl is as previously defined.

[0225] "Aryloxy" means an -O-aryl group, wherein aryl is as previously defined. + "Aryloxy" means an -O-aryl group, wherein aryl is as previously defined. - "Aryloxy" means an -O-aryl group, wherein aryl is as previously defined. "Aryloxy" means an -O-aryl group, wherein aryl is as previously defined.

[0226] "Bicyclic ring system" refers to two connected rings. The rings can be fused, i.e., sharing two adjacent atoms, or "spiro", i.e., sharing only a single atom.

[0227] "Carbonyl" refers to the functional group consisting of a carbon atom double bonded to an oxygen atom (C=0).

[0228] "Carbonyl" refers to the functional group consisting of a carbon atom double bonded to an oxygen atom (C=0).

[0229] "Carboxyl" refers to the -CO2H group. The bond to the parent structure is through the carbon atom of the carbonyl moiety.

[0230] "Celite" (Fluka) is a diatomaceous earth and can be referred to as "celite".

[0231] "Cycloalkyl" or "C 3-12"Cycloalkyl" refers to any monovalent nonaromatic radical derived by the removal of one hydrogen atom from a monocyclic, bicyclic or tricyclic ring system having from three to twelve ring carbon atoms. These nonaromatic radicals having from three, four, five, six, seven, eight, or up to twelve carbon ring atoms can be completely saturated or partially unsaturated. Unless stated otherwise specifically in the specification, the cycloalkyl group can be a monocyclic, bicyclic or tricyclic ring system which can include fused or spiro ring systems. The point of attachment of a cycloalkyl group herein is at a saturated ring. Bicyclic cycloalkyl ring systems include fused ring systems wherein two rings share two atoms (e.g., decalin), including spiro ring systems wherein two rings share one atom (e.g., spiro[4.5]decyl) and bridged groups (e.g., norbornyl).

[0232] Additional examples within the above meaning include, but are not limited to, the following monovalent radicals: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octyl, bicyclo[l. l. l]pentyl, bicyclo[2.2.1]heptyl, [l. l. l]-bicyclopentane, bicyclo[3.1.0]hexyl, cyclohexenyl, cyclopentenyl, 1-decalinyl, spiro[2.4]heptyl, spiro[2.2]pentyl, and norbornyl.

[0233] The term "C 3-8 "Cycloalkyl" (or "C3-C8cycloalkyl" or "C 3-8 "Cycloalkyl") refers to a ring of an alkane having a total of three to eight carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The term "C 3-7 "Cycloalkyl", "C 3-6 "Cycloalkyl", "C 5-7 "Cycloalkyl", and the like have similar meanings.

[0234] "Dialkylamino" refers to an amino group (e.g., N,N-dimethylamino or containing two alkyl groups attached to the amino nitrogen.

[0235] "Fluoroalkyl" includes mono- and polyfluorosubstituted straight and branched chain alkyl groups up to perfluorosubstituted alkyl groups. For example, fluromethyl, 1,1-difluoroethyl, difluoromethyl, trifluoromethyl, or 3,3,4,4,4-pentafluorobutyl are included.

[0236] "Guanidinyl" refers to a radical containing a monovalent radical R2NC(=NR)NH- derived from guanidine, where R is independently C 0-6 alkyl, such as 3-guanidinylpropyl

[0237] Unless otherwise indicated, "halogen" or "halo" includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo). In one embodiment, halo is fluoro (-F) or chloro (-Cl).

[0238] "Haloalkyl" means an alkyl group as described above in which one or more, particularly 1 to 10, hydrogen atoms have been replaced by a halogen atom up to complete substitution of all hydrogen atoms by halogen. C 1-6 Haloalkyl, for example, includes -CH2F, -CHF2, CF3, -CC13, -CF2CF3, -CHFCH3, and the like.

[0239] The term "heteroalkyl" means an alkyl group in which 1, 2, 3, or 4 of the carbon atoms are replaced by heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).

[0240] As used herein, the term "heteroaryl" denotes a stable monocyclic, bicylic, or tricyclic ring system containing 5 to 14 ring atoms, including at least one ring heteroatom selected from nitrogen (N), sulfur (S) (including S=0 and S02), and oxygen (O), wherein at least one of the rings containing a heteroatom is aromatic. In the case of heteroaryl ring systems in which 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 a quaternary ammonium or quaternary ammonium cation. Bicyclic heteroaryl ring systems include fused ring systems in which two rings share two atoms, including spiro ring systems in which two rings share one atom. Heteroaryl within the scope of this definition includes, but is not limited to: azaindolyl, benzoimidazolyl, benzoisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzo[d]isothiazolyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolizine, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, pyranyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, 5H-pyrrolo[3,4-b]pyridine, thiazolyl, thiophenyl, triazolyl, triazinyl, benzothiazolyl, benzothiophenyl, quinolinyl, quinazolinyl, and isoquinolinyl, and oxazolyl. If the heteroaryl contains a nitrogen atom, it is understood that this definition also includes the corresponding N-oxides.

[0241] 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 which comprises two to twelve ring carbon atoms and 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 - in this case each integer from 3 to 12. For example "3 to 12 ring atoms" means that the heterocycloalkyl radical can consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, and so forth, up to and including 12 ring atoms. In some embodiments, it is a 5- to 10-membered ring heterocycloalkyl. In some embodiments, it is a 4- to 10-membered ring heterocycloalkyl. In some embodiments, it is a 3- to 10-membered ring heterocycloalkyl. Unless stated otherwise in the specification, the heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems. The prefixes naphtho-, benzo-, or pyrido- in front of a heterocycloalkyl radical mean that at least one of the carbon atoms of the ring radical is replaced with a nitrogen atom. In some embodiments, the nitrogen or sulfur atom of the heterocycloalkyl radical can be optionally oxidized to the corresponding N-oxide, S-oxide (S=0), or S-dioxide (S02). One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl radical can be attached through any atom of the ring.

[0242] In one embodiment, the heterocycloalkyl is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, the heterocycloalkyl is monocyclic and has from about 5 to about 8 ring atoms. In another embodiment, the heterocycloalkyl is bicyclic and has from about 8 to about 11 ring atoms. In yet another embodiment, the heterocycloalkyl is monocyclic and has 5 or 6 ring atoms. In one embodiment, the heterocycloalkyl is monocyclic. In another embodiment, the heterocycloalkyl is bicyclic. In another embodiment, the heterocycloalkyl is tricyclic. There are no adjacent oxygen and / or sulfur atoms in the ring system.

[0243] Non-limiting examples of heterocycloalkyl rings include decahydroisoquinoline, dioxaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptyl, quinuclidinyl, oxetanyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, piperidinyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 6-azaspiro[2.5]octyl, azetidinyl, 2,3-dihydro-lH-indenyl, dihydro-lH-indenyl, 3H-spiro[benzofuran-2',4'-piperidinyl, 2,3-dihydro-lH-pyrrolo[3,2,1-ij][l,6]naphthyridinyl, 3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridinyl, 3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazolyl, diazabicyclo[3.3.2]decyl, 2,3,4,5,6,7-hexahydroisothiazolo[5,4-c]pyridinyl, hexahydro-2H-pyrrolo[3,4-d]isothiazolyl, 3,9-diazabicyclo[3.3.2]decyl, bicyclo[2,2,1]heptenyl, 2',3'-dihydro-l'H-spiro[piperidine-4,4'-quinazoline], octahydropyrrolo[3,4-b][l,4]oxazolyl, (diazabicyclo[2.2.1]heptyl), 2,5-diazabicyclo[2.2.1]heptyl, tetrahydrobenzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, oxabicyclo[2.1.1]hexanyl, dihydro-5H-pyrrolo[3,4-d]thiazolyl, 4,6-dihydro-5H-pyrrolo[3,4-d]thiazolyl, dihydro-5H-pyrrolo[3,4-d]oxazolyl, 4,6-dihydro-5H-pyrrolo[3,4-d]oxazolyl, dihydrothiazolo[5,4-c]pyridin-5(4H)-yl, 6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl, benzo[d]imidazolyl, lH-benzo[d]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 application, the heterocycloalkyl ring includes: piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, azetidinyl.

[0244] "Nitro" means a -N02 group.

[0245] "Oxo" means an oxygen atom connected to another atom by a double bond, and is represented herein by "=0".

[0246] The term "oxy" means an oxygen (O) atom.

[0247] "Quaternary amine" or "quaternary ammonium" refers to a positively charged group having four functional groups attached to a nitrogen atom, such as N,N,N-trimethylammonium and N,N,N-trimethylpropan-1 -ammonium

[0248] "Sulfinyl" refers to the divalent functional group -S(=0)-.

[0249] "Sulfonyl" refers to the divalent functional group -SO2-.

[0250] "Tertiary amine" refers to an amine in which three carbon atoms are attached to the amino nitrogen.

[0251] The term "thio" refers to a sulfur (S) atom.

[0252] "Trialkylammonium" refers to an alkyl group containing three alkyl groups attached to an amino nitrogen or (C 1-6 alkyl)3N + (C 0-6 alkyl)-, such as N,N,N-trimethylammonium and N,N,N-trimethylpropan-1 -ammonium

[0253] "Urea" refers to -NR-C(=0)-NR2, where R can independently be hydrogen, alkyl, aryl, for example -NHCONH2.

[0254] "Pharmaceutically acceptable" means that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to its recipient.

[0255] In the event that any amine is present in a compound, the nitrogen (N) atom can optionally be in the form of a quaternary amine having one or more appropriate additional substitutions, as further described herein.

[0256] When any variable occurs more than one time, the definitions on each occurrence are independent of one another, such as for example, n, R a , R b , etc. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0257] When any ring atom is designated as optionally substituted or in a specified form, such as sulfur (S) substituted with oxo or nitrogen (N) in the N-oxide form, this does not preclude substitution of any ring atom that is not substituted with oxo or in the N-oxide form with other enumerated optional substituents.

[0258] 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 indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Only combinations which result in a stable compound are permissible.

[0259] A "stable compound" or "stable structure" is meant to refer to a compound, which is sufficiently robust to be isolated from a reaction mixture into a useful degree of purity, and formulated into an efficacious therapeutic agent. The compounds of the application are limited to stable compounds encompassed by Formula I.

[0260] The term "compound" refers to a compound, and in certain embodiments, to any hydrate or solvate thereof, to the extent that they are stable. Hydrates are complexes of a compound with water, solvates are complexes of a compound with an organic solvent.

[0261] The term "in substantially purified form" as used herein refers to the physical state of a compound after it has been 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 it has been obtained from one or more purification methods described herein or well known to those of ordinary skill in the art (e.g., chromatography, reverse phase preparative HPLC, recrystallization, etc.) which is sufficiently pure to be characterized by standard analytical techniques described herein or well known to those of ordinary skill in the art.

[0262] It should be noted that any carbon and heteroatom for which a valence is not indicated in the text, schemes, examples and tables herein is assumed to have sufficient number of hydrogen atoms to satisfy the valence.

[0263] When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions from occurring at the protected site during a reaction.

[0264] According to standard nomenclature for the entire disclosure, the terminal portion of the indicated side chain is preceded by the adjacent functional group toward the point of attachment. For example, the "(C 1-5 alkyl)carbonyl amino(C 1-6 alkyl)" substituent is equivalent to

[0265] Structural representations of compounds having a terminal methyl group as a substituent can show the terminal methyl using the character "Me", "-Me", "CH3", "-CH3", or using a straight line to represent the presence of a methyl group, e.g. i.e. has the equivalent meaning.

[0266] For variable definitions containing terms with repeating terms, such as (CR i R j ) r where r is the integer 2, R i is the defined variable, and R j is the defined variable, the value of R i may be different in each instance of its occurrence, and the value of R j may be different in each instance of its occurrence. For example, if R i and R j are independently selected from the group consisting of methyl, ethyl, propyl, and butyl, then (CR i R j )2may be

[0267] Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaromatic ring described as containing "1 to 4 heteroatoms" means that the ring can contain 1, 2, 3, or 4 heteroatoms. It is also to be understood that any range cited herein includes all sub-ranges within that range. For example, a heterocyclic ring described as containing "1 to 4 heteroatoms" is intended to include, as an aspect thereof, a heterocyclic ring 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. Likewise, C 1-6 or C 1-6 or C1-C6 when used in conjunction with a chain (e.g., an alkyl chain) means that the chain can contain 1, 2, 3, 4, 5, or 6 carbon atoms. It also includes all ranges subsumed therein, including C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C3-C6, C4-C6, C5-C6, and all other possible combinations.

[0268] In selecting compounds of the application, one of ordinary skill in the art will recognize the selection of various substituents (i.e., R 1 , R A , R 2b etc.) is governed by the well-known principles of chemical structure connectivity and stability.

[0269] 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 combining the specified ingredients in the specified amounts.

[0270] When any variable (e.g., R 2a) at any occurrence in any constitutional or formula (I) or other formula herein, the definition at each occurrence is independent of the definition at every other occurrence. Such combinations are permissible only if the substitution of the variable results in a stable compound. In choosing a compound of the present disclosure, one of ordinary skill in the art will recognize the importance of the selection of each substituent, e.g., R 2a ) in accordance with well-known principles of chemical structure connectivity and stability. Unless explicitly stated otherwise, substitution with a designated substituent at a ring atom (e.g., an aryl, heteroaryl ring, or saturated heteroaryl ring) is permitted provided that the ring substitution is chemically possible and results in a stable compound. A “stable” compound is one that can be prepared and isolated and the structure and properties of which remain substantially 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).

[0271] The term “substituted” is to be taken as encompassing multiple degrees of substitution with the indicated substituents. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted with one or more of the disclosed or claimed substituent moieties, alone or in multiple. Independently substituted means that the substituent(s) can be the same or different.

[0272] As used herein, a dashed line indicates the point of attachment to the remainder of the compound.

[0273] Some of the compounds described herein can exist as tautomers, which have different points of attachment for hydrogen that accompany a shift in one or more double bonds. For example, a ketone and its enol form are ketone-enol tautomers. Individual tautomers and mixtures thereof are included within the compounds of the present disclosure.

[0274] In the compounds of the present disclosure, atoms can exhibit their natural isotopic abundance, or one or more atoms can 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 mainly found in nature. The present disclosure, as described and claimed herein, is intended to include all suitable isotopic variations of the compounds of the present disclosure and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium 1 (¾ and deuterium 2H, also referred to herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching deuterium can provide certain therapeutic advantages, such as increasing the half-life in vivo or reducing the dosage requirements or can provide a compound suitable for use as a standard for characterizing a biological sample. Isotopically enriched compounds of the disclosure can be prepared without undue experimentation by conventional techniques known to those with ordinary skill in the art, or by processes similar to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0275] The term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the disclosure is acidic (or has a functional group which can be anionic), its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases 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 cations (such as Ca 2+ and Mg 2+ ), and other cations (such as Al 3+ and Zn 2+ ). Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4+ ) and substituted ammonium ions. Examples of suitable substituted ammonium ions are those derived from methylamine, ethylamine, diethylamine, triethylamine, and ethylenediamine. When the compound of the disclosure is basic, its corresponding salt can be prepared from a pharmaceutically acceptable non-toxic acid, including inorganic acid and organic acid. Examples of such acid addition salts include those formed with hydrohalogens acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid), formic acid, acetic acid, decanoic acid, and citric acid. Salts containing the acetate, formate, decanoate, chloride, or sodium salt are commonly used with the compounds of the disclosure. In some embodiments, the salt of the compound of the disclosure can be formed by exchanging, as is well known to those of ordinary skill in the art, by anion exchange, for example, by replacing a trifluoroacetate ion with a chloride ion.

[0276] In addition, the compounds of the disclosure can exist in amorphous forms and / or one or more crystalline forms, and thus all amorphous and crystalline forms of the compounds of Formula (I), including the examples, and mixtures thereof are intended to be within the scope of the disclosure. In addition, some of the compounds of the disclosure can form solvates with water (i.e., hydrates) or common organic solvents, such as, but not limited to, acetic acid or acetonitrile. Such solvates and hydrates of the compounds of the disclosure, particularly pharmaceutically acceptable solvates and hydrates, as well as non-solvated and anhydrous forms are equally encompassed by the disclosure.

[0277] Any pharmaceutically acceptable prodrug modification of a compound of the present disclosure that results in a compound within the scope of the present disclosure is also within the scope of the present disclosure.

[0278] The present disclosure also relates to methods for preparing compounds of Formula (I), which are described in the following examples and by which the compounds of the present disclosure are obtainable.

[0279] "Treatment" and "treating" refer to all methods of alleviating, abrogating, inhibiting, controlling or stopping the progression of a disease or condition described herein. The term does not necessarily imply that all symptoms of the disease or condition are completely eliminated.

[0280] "Preventing" or "prophylaxis" as used herein refers to reducing the likelihood of contracting a disease or condition described herein, or reducing the severity of a disease or condition described herein.

[0281] The terms "effective or efficacious amount" and similar descriptions, such as "an amount effective to treat" or "an effective dose" are intended to mean the amount of a compound of the present 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 "effective amount" means the amount of a compound of the present disclosure that will reduce at least one clinical symptom in a human patient. The term "prophylactically effective amount" and similar descriptions, such as "an amount effective to prevent" are intended to mean the amount of a compound of the present disclosure that will prevent or reduce the risk of occurrence of the biological or medical event in a tissue, system, animal, or human being sought by a researcher, veterinarian, medical doctor, or other clinician.

[0282] Dosage of a compound of the present disclosure

[0283] 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 potencies of the compound selected for administration; the route of administration; and the renal and hepatic function of the patient. Estimation of an appropriate therapeutic or prophylactically effective dosage is well within the capability of those skilled in the art, usually stemming from a few basic parameters, as described above. It is understood that a specific daily dosage can be administered in single or divided doses.

[0284] While individual needs vary, determination of optimal ranges of effective amount of a compound of the disclosure is within the skill of the art. For administration to humans for the curative or prophylactic treatment of the conditions and disorders identified herein, for example, a typical dosage of a compound of the disclosure can range from about 0.05 mg / kg / day to about 1000 mg / kg / day. In some embodiments, a patient is administered about 5 mg / day to about 1000 mg / day, such as 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 of a compound of the disclosure. In certain embodiments, a patient is administered about 0.2 mg / kg to about 5 mg / kg, such as 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, 3.5 mg / 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 disclosure. This dosage can be administered in a single dosage or can be divided among multiple dosages.

[0285] Pharmaceutical compositions

[0286] The compounds of the disclosure and their pharmaceutically acceptable salts can be administered as the neat chemical, in mixtures with each other, or in pharmaceutical compositions to animals, preferably mammals, and in particular, to humans. The term "subject" or "patient" includes animals, preferably mammals, and in particular, humans, who are treated with the active agents of the present application for prophylaxis or therapy of a medical condition.

[0287] Administration of a drug to a subject includes self-administration or administration to a patient by another. The subject can need or desire treatment for an existing disease or medical condition or can need or desire prophylactic treatment to prevent or reduce the risk of developing the disease or medical condition. As used herein, a subject "in need of" treatment for an existing condition or prophylactic treatment includes both a determination by a medical professional and the desire of the patient for such treatment.

[0288] The present disclosure thus also provides the compounds of the present disclosure and pharmaceutically acceptable salts thereof for use as a medicament, their use for the selective modulation of TNFR1 activity, and in particular their use for the treatment and prevention of the diseases or conditions mentioned below and their use for the manufacture of a medicament for these purposes. In certain embodiments, the compounds of the present disclosure and pharmaceutically acceptable salts thereof block TNFa signaling through TNFR1.

[0289] Furthermore, the present disclosure provides pharmaceutical compositions comprising as active ingredient an effective dose of at least one compound of the present disclosure and / or a pharmaceutically acceptable salt thereof and a conventional pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable carrier substances and / or additives.

[0290] The present disclosure thus provides the compounds and pharmaceutically acceptable salts thereof, e.g. for use as a pharmaceutical composition, comprising as active ingredient an effective dose of a compound of the present disclosure and / or a pharmaceutically acceptable salt thereof and a conventional pharmaceutically acceptable carrier, and the use of the compounds and / or pharmaceutically acceptable salts thereof for the treatment or prevention of the diseases or conditions mentioned below, such as inflammatory bowel disease (IBD), rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa, and their use for the manufacture of a medicament for these purposes.

[0291] Pharmaceutical compositions according to the present disclosure can be administered orally, e.g. 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, e.g. in the form of suppositories. Administration can also be performed parenterally, e.g. subcutaneously, intramuscularly or intravenously, in the form of solutions or suspensions for injection or infusion.

[0292] Other suitable administration forms are e.g. transdermal or topical administration, e.g. in the form of a plaster, liniment, spray or transdermal therapeutic system, or e.g. microcapsules, implants or rods. The preferred administration form depends e.g. on the disease to be treated and its severity.

[0293] 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 a pharmaceutically acceptable excipient and / or carrier. Particular pharmaceutical compositions will be suitable for the mode of administration. In a particular aspect, the pharmaceutically acceptable carrier can be water or a buffered solution.

[0294] The excipients included in the pharmaceutical compositions serve different purposes depending on, for example, the nature of the drug, and the mode of administration. Examples of excipients commonly used include, but are not limited to: saline, buffered saline, dextrose, water for injection, glycerol, ethanol, and combinations thereof, stabilizers, solubilizers and surfactants, buffers and preservatives, tonicity agents, fillers, lubricants (such as talc or silica, and fats, such as vegetable stearines, magnesium stearate or stearic acid), emulsifiers, suspending or viscosity-increasing agents, inert diluents, fillers (such as cellulose, calcium dihydrogen phosphate, vegetable fats and oils, lactose, sucrose, dextrose, mannitol, sorbitol, calcium carbonate and magnesium stearate), disintegrants (such as cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethylcellulose), binders (such as starch, gelatin, cellulose, methylcellulose or modified celluloses, such as microcrystalline cellulose, hydroxypropyl cellulose, sugars, such as sucrose and lactose, or sugar alcohols, such as xylitol, sorbitol or maltitol, polyvinylpyrrolidone and polyethylene glycol), wetting agents, antibacterial agents, chelating agents, coating agents (such as cellulose film coatings, synthetic polymers, shellac, zein or other polysaccharides, and gelatin), preservatives (including vitamins A, E, C, retinyl palmitate, and selenium, cysteine, methionine, citric acid and sodium citrate, and synthetic preservatives, including methyl and propyl parabens), sweeteners, aromatics, flavorings, colorants, absorption enhancers, administration aids, and combinations thereof.

[0295] Carriers are compounds and substances that improve and / or prolong delivery of an active ingredient to a subject in the context of a pharmaceutical composition. Using controlled release technology, carriers can be used to prolong the in vivo activity of a drug or to slow release of the drug in a subject. Carriers can also decrease drug metabolism in a subject and / or reduce toxicity of the drug. Carriers can also be used to target delivery of a drug to specific cells or tissues in a subject. Common carriers (both hydrophilic and hydrophobic) include fat emulsions, lipids, PEGylated phospholipids, PEGylated liposomes, PEGylated liposomes coated with a PEG spacer having a cyclic RGD peptide, liposomes and lipid spheres, microspheres (including those made of biodegradable polymers or albumin), polymeric matrices, biocompatible polymers, protein-DNA complexes, protein conjugates, red blood cells, vesicles, nanoparticles, and hydrocarbon- immobilized side chains. The foregoing carriers can also be used to increase cell membrane permeability of the compound of Formula (I). In addition to their use in the pharmaceutical compositions of the present disclosure, carriers can also be used in compositions for other uses (such as in vitro (e.g., for delivery to cultured cells) and / or in vivo research uses).

[0296] Pharmaceutical compositions suitable for oral administration can be presented as discrete units, such as capsules or tablets; as a powder or granules; as a solution, a syrup, or a suspension in an aqueous or non-aqueous liquid; or as an edible foam or whip; or as an emulsion. Excipients suitable for use in tablets or hard gelatin capsules include lactose, maize starch or derivatives thereof, stearic acid or salts thereof. Excipients suitable for use in soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols, and the like. For preparing solutions and syrups, excipients which can be used include, for example, water, polyols, and sugars. For preparing suspensions, oils (for example, vegetable oils), can be used to provide oil-in-water or water-in-oil suspensions. Excipients which promote gastrointestinal absorption, such as permeation enhancers, e.g., sodium caprate, can be included. In certain instances, delayed release formulations can be advantageous and compositions can also be prepared which deliver the compounds of the disclosure in a delayed or controlled release manner. Prolonged gastric residence causes problems with degradation by enzymes present in the stomach and thus enteric coated capsules can also be prepared by standard techniques in the art, wherein the active material is intended for release in the lower gastrointestinal tract.

[0297] Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches applied to the skin of the recipient and intended to remain in intimate contact with the epidermis for a prolonged period of time. For example, the active ingredient can be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6): 318 (1986).

[0298] Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated in an ointment, the active ingredient can be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions suitable 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 suitable for topical administration in the mouth include lozenges, pastilles, and mouth washes.

[0299] Pharmaceutical compositions suitable for rectal administration can be presented as suppositories or enemas.

[0300] Pharmaceutical compositions suitable for nasal administration wherein 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 administered, i.e. by rapid inhalation via the nasal passage from a container of the powder held close to the nares. Pharmaceutical compositions suitable for administration as nasal sprays or nasal drops include active ingredient dissolved or suspended in an aqueous or oil liquid.

[0301] Pharmaceutical compositions suitable for administration by inhalation include fine dusts or mists which can be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators.

[0302] Pharmaceutical compositions suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0303] Pharmaceutical compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats, and solutes which render the composition substantially isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions which can include suspending agents and thickening agents. Exemplary excipients for use in injectable solutions include, e.g., water, alcohols, polyols, glycerin, and vegetable oils. The compositions can be presented in unit-dose or multi-dose containers, e.g., sealed ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, e.g., water or saline, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The pharmaceutical compositions can contain preservatives, solubilizing agents, stabilizers, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts (the substances of the disclosure can be provided in the form of pharmaceutically acceptable salts themselves), buffers, coating agents, or antioxidants. In addition to the compounds of the disclosure, they can contain therapeutically active agents.

[0304] Methods of using the compounds of the disclosure

[0305] 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 and selectivity for human TNFR1 and TNFR2 can be evaluated by SPR. Affinity for human TNFR1 can be evaluated using time-resolved fluorescence resonance energy transfer (TR-FRET) binding assays. Inhibition of TNFR1-mediated cell signaling can be evaluated by detecting a decrease in the extent of downstream NF-κΒ signaling pathway.

[0306] The present application also provides methods of using a compound of the disclosure (or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition containing such a compound, to treat a disease condition, including but not limited to conditions involving TNFR1.

[0307] In some embodiments, the present disclosure provides a method of treating IBD and other TNFa-driven inflammatory diseases, comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the foregoing pharmaceutical compositions comprising a compound of the present disclosure (or a pharmaceutically acceptable salt thereof). 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 inflammatory disease 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, the TNFa-driven inflammatory disease is psoriatic arthritis. In some embodiments, the TNFa-driven 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.

[0308] In some embodiments, the present disclosure provides a method of treating inflammatory bowel disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the foregoing pharmaceutical compositions comprising a compound of the present disclosure (or a pharmaceutically acceptable salt thereof).

[0309] In some embodiments, the present disclosure provides a method of treating ulcerative colitis, comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the foregoing pharmaceutical compositions comprising a compound of the present disclosure (or a pharmaceutically acceptable salt thereof).

[0310] In some embodiments, the present disclosure provides a method of treating Crohn’s disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the foregoing pharmaceutical compositions comprising a compound of the present disclosure (or a pharmaceutically acceptable salt thereof).

[0311] In some embodiments, the present disclosure provides a method of treating rheumatoid arthritis, comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the foregoing pharmaceutical compositions comprising a compound of the present disclosure (or a pharmaceutically acceptable salt thereof).

[0312] In some embodiments, the present disclosure provides a method of treating juvenile rheumatoid arthritis, comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the foregoing pharmaceutical compositions comprising a compound of the present disclosure (or a pharmaceutically acceptable salt thereof).

[0313] In some embodiments, the present disclosure provides a method of treating psoriasis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound.

[0314] In some embodiments, the present disclosure provides a method of treating psoriatic arthritis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound.

[0315] In some embodiments, the present disclosure provides a method of treating ankylosing spondylitis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound.

[0316] In some embodiments, the present disclosure provides a method of treating non-radiographic axial spondylarthritis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound.

[0317] In some embodiments, the present disclosure provides a method of treating hidradenitis suppurativa, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the foregoing pharmaceutical compositions comprising such a compound.

[0318] In some embodiments, the present disclosure provides a method of treating IBD and other TNFa-driven inflammatory diseases, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof), wherein the 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 spondylarthritis, and hidradenitis suppurativa.

[0319] One embodiment of the present application relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in therapy.

[0320] One embodiment of the present application relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of IBD and other TNFα-driven inflammatory diseases selected from ulcerative colitis, Crohn's disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondylarthritis, and hidradenitis suppurativa.

[0321] One embodiment relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of IBD and other TNFα-driven inflammatory diseases selected from ulcerative colitis and Crohn's disease.

[0322] One embodiment relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of IBD and other TNFα-driven inflammatory diseases selected from rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondylarthritis, and hidradenitis suppurativa.

[0323] Combination therapy

[0324] One or more additional pharmacologically active agents can be administered in combination with the compounds of the present disclosure. The additional active agent(s) is intended to refer to a pharmaceutically active agent(s) that is active in the body, including prodrugs that are converted into a pharmaceutically active form after administration, which is different from the compound of Formula I, and also includes the free acid, free base, pharmaceutically acceptable salts of the additional active agent.

[0325] Examples of additional active agents that can be employed can include, but are not limited to, anti-TNFa biologies, such as methotrexate, azathioprine, 6-mercaptopurine, anti-IL-23 agents, anti-a4b7 agents (such as vedolizumab), biased IL-2Ra agonists in clinical development.

[0326] Synthetic methods

[0327] General procedure for obtaining building blocks and monomers

[0328] The compounds of the present application can be prepared according to the procedures of the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents, and conventional synthetic procedures and are further illustrated by the following specific examples. Variations of the reactions outlined in these schemes can also be employed in the synthesis of the compounds of the present application, but are not more specifically mentioned. The general procedures for making the compounds claimed in the present application can be readily appreciated and recognized by those skilled in the art by reviewing the following Schemes. The examples also include methods for testing such compounds in biophysical, biochemical, and cellular assays. However, the compounds set forth in the examples should not be construed as forming the only genus that is considered as the disclosure.

[0329] Unless otherwise expressly stated, all reagents are commercially available, known in the literature, or readily synthesized by one of skill in the art. General routes for the synthesis of compounds of Formula I are described in the following schemes. In some cases, the order of reaction steps carried out in the schemes can be changed to facilitate the reaction or to avoid undesired reaction products. In addition, various protecting group strategies familiar to one of skill in the art of organic synthesis and solid phase peptide synthesis can be used to facilitate the reaction, improve yields and purity, or avoid undesired reaction products.

[0330] Unless otherwise specified herein, all reagents and solvents were purchased from commercial sources and used without further purification. All temperatures are expressed in degrees Celsius (°C), ambient temperature or room temperature (RT) is 20 °C. Most compounds were purified by reverse phase preparative high performance liquid chromatography (HPLC) or medium pressure liquid chromatography (MPLC) on silica gel. The progress of reactions was followed by liquid chromatography / mass spectrometry (LC-MS) or ultra-high performance liquid chromatography / mass spectrometry (UPLC-MS); electrospray ionization (ESI); UV detection at 254 nm). Proton, fluorine, and carbon magnetic resonance (1H, 19F, and13C NMR) spectra were recorded on 300, 400, 500, or 600 MHz Varian or Bruker spectrometers and chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane and referenced to residual solvent. Coupling constants are reported in Hertz. 1 H, 19 F and 13 C NMR) spectra, and chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane and referenced to residual solvent. Coupling constants are reported in Hertz. 1 H NMR data are reported as follows: 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 (tt), doublet of doublet of doublets (ddd), multiplet (m), broad singlet (br. s)], coupling constants [Hz], and integration). Reactions sensitive to moisture or air were carried out using anhydrous solvents and reagents under nitrogen or argon. Reaction progress was determined by analytical thin layer chromatography (TLC) typically with pre-coated TLC plates (E. Merck, Darmstadt, Germany), silica gel 60 F-254, layer thickness 0.25 mm, or liquid chromatography-mass spectrometry (LC-MS).

[0331] Unless otherwise specified, when a ratio of a compound (e.g., a solvent) is given, the ratio is on a volume-to-volume basis. For example, a solvent gradient ranging from 100% hexanes to 50% EtOAc / hexanes means a gradient starting from a mixture of 100 parts by volume of hexanes to a mixture of 50 parts by volume of ethyl acetate and 50 parts by volume of hexanes.

[0332] The term "w / w" refers to the ratio of the weight of a compound to the total weight. For example, NaH 60% w / w means 60 parts by weight of NaH to 100 parts total weight.

[0333] The following examples are provided in order that the application might be more fully understood. These examples are illustrative only and should not be construed as limiting the application in any way. In cases where racemic mixtures are produced, SFC reversed phase or normal phase chiral resolution conditions can be used to separate the enantiomers after isolation of the final product or at a suitable intermediate, followed by separate handling of the individual isomers. It is understood that alternative methods can also be used to synthesize these key intermediates and examples. Where possible and appropriate, asymmetric methods (e.g. chiral catalysis, auxiliaries, biocatalytic methods) can be used. The precise choice of reagents, solvents, temperatures and other reaction conditions depends on the nature of the desired product.

[0334] Abbreviations

[0335] The following abbreviations are used throughout the text:

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353] Reaction Scheme

[0354] Intermediate and monomer synthesis:

[0355] Synthesis Scheme 1

[0356]

[0357] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indazol-1-yl)propionic acid (Fmoc-1Inda-OH) 1Inda-OH

[0358] Step 1 : To a mixture of indazole (110 g, 931 mmol) and L-serine (97.9 g, 931 mmol) in DMSO (1.1 L) and 0.2 M potassium phosphate buffer (4.4 L, pH ~ 8.0) was added PLP (3.05 g, 9.31 mmol) and PfTrpB-OB2 (7.7 g, 7 wt%) under nitrogen atmosphere. The mixture was stirred and heated at 65 °C for 18 h. Upon completion, the resulting solution was used directly in the next step.

[0359] Step 2: The mixture containing (2S)-2-amino-3-(indazol-1 -yl)propanoic acid (assay yield 191 g) was diluted with tetrahydrofuran (2.1 L). Na2CO3 (197 g, 1.86 mol) and Fmoc-OSu (314 g, 931 mmol) were added to the mixture at 15 °C under nitrogen atmosphere. The mixture was stirred at room temperature under nitrogen atmosphere for 18 h. The mixture was acidified to pH ~ 3 with 6 N HCI. The mixture was filtered and the filtrate was extracted with EtOAc (3 x 3.0 L). The organic layers were combined, washed with H2O (2 x 2.0 L) and brine (3.0 L), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with DCM / hexane (5 L / 2.5 L) four times. The solid was collected by filtration and dried under reduced pressure to give (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(indazol-1 -yl)propanoic acid. C 25 H 22 N3O4[M+H] + 428.2, found 428.2. 1HNMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), 8.10 (s, 1H), 7.97-7.89 (m, 2H), 7.79-7.69 (m, 3H), 7.60-7.52 (m, 2H), 7.47-7.21 (m, 5H), 7.14-7.09 (m, 1H), 4.77-4.60 (m, 2H), 4.57-4.52 (m, 1H), 4.29-4.10 (m, 3H).

[0360] Synthesis Scheme 2

[0361]

[0362] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indazol-1-yl)propionic acid (Fmoc-1Inda-OH) Propionic acid (Fmoc-1Inda-OH)

[0363] Step 1: DMAP (0.46 g, 3.8 mmol) and Boc20 (10.4 mL, 45.1 mmol) were added to a solution of 3-methyl-lH-pyrazolo[3,4-b]pyridine (5.0 g, 37.6 mmol) in MeCN (100 mL) at rt under Ar. The reaction was stirred at rt overnight, then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 40% to give tert-butyl 3-methyl-lH-pyrazolo[3,4-b]pyridine-l-carboxylate. MS ESI [M+H] calculated for C12H15N40 229.12, found 229.09. 12 H 16 MS ESI [M+H] calculated for C12H15N40 229.12, found 229.09. + 234.12, found 234.05. 1 HNMR (300 MHz, Chloroform-d): δ 8.74-8.73 (m, 1H), 8.03-8.01 (m, 1H), 7.2-7.28 (m, 1H), 2.61 (s, 3H), 1.73 (s, 9H).

[0364] Step 2: AIBN (0.53 g, 3.22 mmol) and NBS (5.72 g, 32.2 mmol) were added to a solution of tert-butyl 3-methyl-lH-pyrazolo[3,4-b]pyridine-l-carboxylate (7.5 g, 32.2 mmol) in trifluorotoluene (170 mL) at rt under Ar. The reaction was stirred at 80 °C for 1 h, then cooled to rt and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 25% to give tert-butyl 3-(bromomethyl)-lH-pyrazolo[3,4-b]pyridine-l-carboxylate. MS ESI [M+H] calculated for C13H17BrN30 323.05, found 323.06. 12 H 15 MS ESI [M+H] calculated for C13H17BrN30 323.05, found 323.06. +312.03 / 314.03, found 311.90 / 313.90. 1 HNMR (300 MHz, Chloroform-d): δ 8.79 - 8.78 (m, 1H), 8.29 - 8.20 (m, 1H), 7.37 - 7.35 (m, 1H), 4.77 (s, 2H), 1.73 (s, 9H).

[0365] Step 3: n-BuLi (8.6 mL, 21.5 mmol, 2.5 N in hexanes) was added dropwise to a solution of tert-butyl 3-(bromomethyl)-lH-pyrazolo[3,4-b]pyridine- 1-carboxylate (6.4 g, 20.5 mmol) in dry THF (150 mL) at -78 °C under Ar atmosphere over 30 min. Then (R)-2-isopropyl-3,6-dimethoxy-2,5- dihydropyrazine (3.8 g, 20.5 mmol) in dry THF (10 mL) was added. The resulting mixture was stirred at -78 °C for 4 h. The reaction mixture was quenched with saturated aqueous NH4Cl (200 mL) at 0 °C and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 50% to give tert-butyl 3-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazin-2-yl)methyl)-lH-pyrazolo[3,4-b]pyridine-l-carboxylate. MS ESI [M+H] calculated for C23H30N4O4, 426.22, found 426.05. 21 H 30 MS ESI [M+H] calculated for C23H30N4O4, 426.22, found 426.05. + 416.22, found 426.05. 1 H NMR (300 MHz, Chloroform-d): δ 8.71 - 8.70 (m, 1H), 8.13 - 7.98 (m, 1H), 7.33 - 7.19 (m, 1H), 4.45 (s, 1H), 3.70 (s, 3H), 3.57 - 3.55 (m, 4H), 3.35 - 3.33 (m, 1H), 2.18 (s, 1H), 1.71 (s, 10H), 0.98 (d, J = 6.9 Hz, 3H), 0.66 (d, J = 6.9 Hz, 3H).

[0366] Step 4: 0.2N HC1 (81.8 mL, 16.36 mmol) was added to a stirred solution of tert-butyl 3-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)-lH- pyrazolo[3,4-b]pyridine-l -carboxylate (3.4 g, 8.18 mmol) in MeCN (50 mL) at 0 °C. The resulting mixture was stirred at room temperature for 4 h, then concentrated under reduced pressure to give (S)-methyl 2-amino-3-(lH-pyrazolo[3,4-b]pyridin-3-yl)propanoate which was used in the next step without purification. MS ESI [M+H] calculated for C 10 H 13 MS ESI [M+H] calculated for C + 221.10, found 221.10.

[0367] Step 5: 1N aqueous LiOH (16.4 mL, 16.4 mmol) was added to a solution of (S)- methyl 2-amino-3-(lH-pyrazolo[3,4-b]pyridin-3-yl)propanoate (1.8 g, 8.2 mmol) in THF (16.4 mL) at room temperature. The mixture was stirred at room temperature for 2 h, then acidified with 1N HC1. The resulting solution was concentrated under reduced pressure to give (S)-2-amino-3-(lH-pyrazolo[3,4-b]pyridin-3-yl)propanoic acid which was used in the next step without purification. MS ESI [M+H] calculated for C 11 MS ESI [M+H] calculated for C + 207.08, found 207.10.

[0368] Step 6: NaHC03(1.9 g, 22.3 mmol) and Fmoc-OSu (5.5 g, 16.3 mmol) were added to a stirred solution of (S)-2-amino-3-(lH-pyrazolo[3,4-b]pyridin-3-yl)propanoic acid (1.7 g, 7.4 mmol) in THF (30 mL) and water (30 mL) at room temperature. After the resulting mixture was stirred at room temperature overnight, the pH was adjusted to ~3 with 1N HC1 and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was recrystallized with MeCN (50 mL) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(lH-pyrazolo[3,4-b]pyridin-3- yl)propanoic acid. MS ESI [M+H] calculated for C 24 H 21 MS ESI [M+H] calculated for C + 429.15, found 429.05. 1H NMR (400 MHz, DMSO-d6): δ 13.52 - 12.70 (m, 2H), 8.48 - 8.47 (m, 1H), 8.30 - 8.28 (m, 1H), 7.88 - 7.86 (m, 3H), 7.63 - 7.61 (m, 2H), 7.42 - 7.40 (m, 2H), 7.38 - 7.35 (m, 2H), 7.12 - 7.10 (m, 1H), 4.47 - 4.46 (m, 1H), 4.21 - 4.10 (m, 3H), 3.41 - 3.28 (m, 2H).

[0369] Synthesis Scheme 3

[0370]

[0371] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(tert- butoxycarbonyl)pyridin-3-yl)propanoic acid (Fmoc-3Pal4CO2tBu-OH)

[0372] Step 1: A mixture of NiCl2·glyme (710 mg, 3.2 mmol) and 1,10-phenanthroline (700 mg, 3.2 mmol) in anhydrous DMA (160 mL) was stirred and heated to 50 °C under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature. tert-Butyl 5-bromopicolinate (4.17 g, 16.2 mmol), (R)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- iodopropionate (8.51 g, 16.2 mmol), TBAI (6.19 g, 16.2 mmol) and activated zinc (2.11 g, 32.3 mmol) were added to the mixture. The mixture was stirred at room temperature for another 2 h, then quenched with H2O (200 mL) and extracted with EtOAc (2 x 500 mL). The combined organic phase was washed with brine (3 x 200 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 20% to give tert-butyl (S)-5-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- (benzyloxy)-3-oxopropyl)picolinate. ESI MS [M+H] calculated for C41H41NO9 697.29, found 697.34. 35 H 35 ESI MS [M+H] calculated for C41H41NO9 697.29, found 697.34. + 579.24, found 579.40.

[0373] Step 2: Dissolve (S)-5-(2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)tert-butyl pyridinecarboxylate (7.5 g, 13 mmol) in EtOAc (75 mL). Empty the flask and refill it with N2 (5 times). Add Pd / C (1.38 g, 13 mmol, dry, 10 wt%) to the flask. Empty the flask and refill it with H2 (5 times). Stir the resulting mixture at room temperature under a hydrogen atmosphere for 4 h. Empty the flask and refill it with N2 (5 times). Filter the resulting mixture. The filter cake was washed with EtOAc (2 × 25 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Rp rapid column chromatography under the following conditions: column: Flash C18 (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN (0.1% TFA); gradient elution: 5 to 95%; detector: UV 215 nm. The fraction containing the product was concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(tert-butoxycarbonyl)pyridin-3-yl)propionic acid. For C 28 H 29 MS ESI [M+H] calculated from N₂O₆ + 489.19, measured value 489.20; 1 H NMR (300MHz, methanol-d4): δ8.57(s,1H),8.03–7.91(m,1H),7.86–7.74(m,3H)7.54–7.53(m,2H),7.36–7.28 (m,4H),4.51–4.40(m,1H),4.32–4.13(m,3H),3.39–3.33(m,1H),3.06–3.05(m,1H),1.65–1.59(m,9H).

[0374] Synthesis Scheme 4

[0375]

[0376] (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(pyridazin-4-yl)propionic acid (Fmoc-4PyridaAla-OH)

[0377] Step 1: Pyridine-2-carboxamidine hydrochloride (3.58 g, 22.70 mmol) was added to a stirred solution of nickel(II) chloride ethylene glycol dimethyl ether complex (2.49 g, 11.35 mmol) in anhydrous DMA (200 mL) at rt under Ar. The solution was stirred at 50 °C for 40 min. The solution was cooled to rt. A solution of TBAI (20.96 g, 56.8 mmol), (R)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- iodopropionate (28 g, 56.8 mmol), and 3,5-dichloropyridazine (16.91 g, 114 mmol) in anhydrous DMA (200 mL) was added to the reaction mixture. Then active zinc (7.42 g, 114 mmol) was added and the mixture was stirred at rt overnight. The mixture was diluted with EtOAc (1 L) and washed with brine (3 x 500 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 35% to give (S)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6- chloropyridazin-4-yl)propanoate. MS ESI [M+H] calculated for C30H34ClN4O5, 580.22, found 580.20. 26 H 27 ClN3O4 calculated MS ESI [M+H] + 480.16, found 480.10. 1 H NMR (400 MHz, Chloroform-d): δ 8.96 (s, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 7.5 Hz, 2H), 7.46 - 7.29 (m, 5H), 5.49 (s, 1H), 4.63 - 4.36 (m, 3H), 4.24 (t, J = 6.4 Hz, 1H), 3.14 - 3.12 (m, 2H), 1.45 (s, 9H).

[0378] Step 2: (S)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6- chloropyridazin-4-yl)propanoate (20 g, 41.7 mmol) and TEA (16.87 g, 167 mmol) were dissolved in THF (400 mL). The flask was evacuated and backfilled with N2(5 times). Pd / C (4.43 g, 4.17 mmol, dry, 10 wt%) was added to the flask. The flask was evacuated and backfilled with H2(5 times). The resulting mixture was stirred at rt under a hydrogen atmosphere overnight. The flask was evacuated and backfilled with N2(5 times). The resulting mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 35% to give (S)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6- chloropyridazin-4-yl)propanoate. MS ESI [M+H] calculated for C30H34ClN4O5, 580.22, found 580.20. pad. The filter cake was washed with THF (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 50% to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridazin-4-yl)propanoic acid tert-butyl ester. MS ESI [M+H] calculated for C 26 H 28 MS ESI [M+H] calculated for C + 446.20, found 446.10.

[0379] Step 3: To a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridazin-4-yl)propanoic acid tert-butyl ester (19 g, 42.6 mmol) in DCM (140 mL) was added TFA (300 mL) at room temperature. The solution was stirred at room temperature for 6 h. The solvent was concentrated under reduced pressure. The residue was recrystallized with MeCN (200 mL) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridazin-4-yl)propanoic acid. MS ESI [M+H] calculated for C 22 H 20 MS ESI [M+H] calculated for C + 390.14, found 390.10. 1 H NMR (400 MHz, DMSO-d6): d 12.92 (s, 1H), 9.19 - 9.11 (m, 2H), 7.89 - 7.83 (m, 3H), 7.63 - 7.60 (m, 3H), 7.43 - 7.28 (m, 4H), 4.34 - 4.18 (m, 4H), 3.22 - 3.18 (m, 1H), 2.97 - 2.91 (m, 1H).

[0380] Synthesis Scheme 5

[0381]

[0382] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-7,7,7-trifluoroheptanoic acid (Fmoc-AhpF3-OH)

[0383] Step 1: NaOH (3.72 g, 93.0 mmol) was added to a stirred solution of (tert-butoxycarbonyl)-L-homoserine (20.0 g, 91.2 mmol) in EtOH (60 mL) and DI water (60 mL) at room temperature. After 30 min, the reaction mixture was concentrated under vacuum. The residue was dissolved in anhydrous DMF (60 mL). BnBr (11.1 mL, 93.0 mmol) was added to this solution. The reaction mixture was stirred at room temperature for 13 h. The reaction mixture was slowly poured into DI water (300 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EtOAc in PE at 5 to 40%, to give (tert-butoxycarbonyl)-L-homoserine methyl benzoate. (For C...) 16 H 23 MS ESI[M+Na] calculated by NO5 + 332.15, measured value 332.0. 1 H NMR (400MHz, chloroform-d): δ

[0384] 7.39–7.32(m,5H),5.41–5.39(m,1H),5.23–5.16(m,2H),4.56–4.51(m,1 H),3.75–3.61(m,2H),2.20–2.14(m,1H),1.66–1.59(m,1H),1.45(s,9H).

[0385] Step 2: At room temperature, Desmond-Martin periodide (31.1 g, 73.3 mmol) was added to a stirred solution of (tert-butoxycarbonyl)-L-homoserine benzyl ester (20.6 g, 64.6 mmol) in DCM (120 mL). After 30 min, the reaction mixture was quenched by adding a 1:1 (v / v) NaHCO3 / Na2S2O3 solution (500 mL). The resulting mixture was stirred at room temperature for 30 min and extracted with DCM (200 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutyrate benzyl ester. The crude product was used directly in the next step without further purification. 1 ¹H NMR (400MHz, chloroform-d): δ 9.72 (s, 1H), 7.39–7.32 (m, 5H), 5.42–5.40 (m, 1H), 5.18 (s, 2H), 4.65–4.63 (m, 1H), 3.14–2.99 (m, 2H), 1.43 (s, 9H).

[0386] Step 3: Stir 1,1,1-trifluoro-3-iodopropane (15.7 mL, 30.0 g, 134 mmol) and PPh3 (33.4 g, 127 mmol) at 80 °C overnight. Cool the reaction mixture at room temperature and triturate with PE (80 mL) at room temperature for 2 h. Recover the solid by filtration and dry under reduced pressure to give triphenyl(3,3,3-trifluoropropylidene)-λ 5 - phosphoranes. 1 H NMR (400 MHz, Chloroform-d): δ 7.90-7.86 (m, 9H), 7.85-7.75 (m, 6H), 4.10-4.03 (m, 2H), 2.71-2.57 (m, 3H).

[0387] Step 4: Add a solution of potassium tert-butoxide (1.0 M in THF, 79.3 mL) dropwise to a stirred solution of triphenyl(3,3,3-trifluoropropylidene)-λ 5 - phosphoranes (28.4 g, 79.3 mmol) in anhydrous THF (120 mL) at -40 °C. Then stir the solution at -20 °C for 1 h. Add (S)-benzyl 2-((tert-butoxycarbonyl)amino)-4- oxobutanoate (20.3 g, 66.1 mmol) slowly to the solution at -70 °C and stir the resulting mixture at -70 °C for 30 min. Warm the reaction mixture to room temperature. Then pour the mixture slowly into saturated aqueous NH4Cl (300 mL) and extract with EtOAc (200 mL). Wash the organic layer with brine (50 mL), dry over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the residue by silica gel column chromatography eluting with EtOAc 5 to 40% in PE to give (S,E)-benzyl 2-((tert-butoxycarbonyl)amino)-7,7,7-trifluorohept-4-enoate. 1 H NMR (400 MHz, Chloroform-d): δ 7.40-7.36 (m, 5H), 5.64-5.52 (m, 2H), 5.22-5.11 (m, 2H), 4.48-4.45 (m, 1H), 2.82-2.77 (m, 2H), 2.75-2.63 (m, 1H), 2.54-2.51 (m, 1H), 1.44 (s, 9H).

[0388] Step 5: Hydrogenate a solution of (S,E)-benzyl 2-((tert-butoxycarbonyl)amino)-7,7,7- trifluorohept-4-enoate (12.6 g, 32.5 mmol) in THF (160 mL) over Pd / C (1.30 g, 10 wt%) at room temperature under 50 psi of hydrogen overnight. Filter the reaction mixture through Celite® and concentrate in vacuo. Purify the residue by silica gel column chromatography eluting with EtOAc 5 to 40% in PE to give (S)-2-((tert-butoxycarbonyl)amino)-7,7,7-trifluoroheptan-4-ol. pad. The solids were washed with THF (3 x 200 mL) and the combined filtrates were concentrated to give the crude (S)-2-((tert-butoxycarbonyl)amino)-7,7,7- trifluoroheptanoic acid.1H NMR (400 MHz, Methanol-d4): δ 4.11 - 4.05 (m, 1H), 2.16 - 2.11 (m, 2H), 1.67 - 1.60 (m, 2H), 1.59 - 1.49 (m, 4H), 1.44 (s, 9H). 12 H 20 F3NO4 calculated MS ESI [M+Na] + 322.12, found 322.2;1H NMR (400 MHz, Methanol-d4): δ 4.11 - 4.05 (m, 1H), 2.16 - 2.11 (m, 2H), 1.67 - 1.60 (m, 2H), 1.59 - 1.49 (m, 4H), 1.44 (s, 9H). 12 F3NO2 [M - Boc + H] + 200.09, found 200.2. 1 H NMR (400 MHz, Methanol-d4): δ 4.11 - 4.05 (m, 1H), 2.16 - 2.11 (m, 2H), 1.67 - 1.60 (m, 2H), 1.59 - 1.49 (m, 4H), 1.44 (s, 9H).

[0389] Step 6: 4M HC1 in 1,4-dioxane (60 mL) was added to a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-7,7,7-trifluoroheptanoic acid (8.30 g, 27.7 mmol) in EtOAc (30 mL). The resulting solution was stirred at room temperature for 30 min. The solution was then concentrated under reduced pressure. The crude residue was triturated with MTBE (25 mL) at 15 °C for 20 min to give the crude (S)-2-amino-7,7,7-trifluoroheptanoic acid. 1 H NMR (400 MHz, Methanol-d4): δ 4.11 - 4.05 (m, 1H), 2.16 - 2.11 (m, 2H), 1.67 - 1.60 (m, 2H), 1.59 - 1.49 (m, 4H), 1.44 (s, 9H).

[0390] Step 7: NaHC03(3.71 g, 44.2 mmol) and Fmoc-OSu (7.44 g, 22.1 mmol) were added to a stirred solution of (S)-2-amino-7,7,7-trifluoroheptanoic acid (5.20 g, 22.1 mmol) in DI water (40 mL) and MeCN (40 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The pH was adjusted to 2 with 1 N aqueous HC1. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 5 to 40% followed by chiral separation (column: Daicel Chiralpak® IC, 250 x 4.6 mm, 5 pm; mobile phase: 20% i-PrOH in hexane; flow rate: 1 mL / min) to give (S)-2-((9H-fluoren-9-ylmethoxy)carbonylamino)-7,7,7-trifluoroheptanoic acid as a white solid (5.20 g, 10.3 mmol, 46.6% yield over 2 steps). OJ (250 x 50 mm, 10 pm, Daicel Chiral Technologies, West Chester, PA); mobile phase: [MeOH]; B%: 20% to 20% in 8 min) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-7,7,7-trifluoroheptanoic acid. MS ESI [M+Na] calculated for C25H27F3NNaO6: 521.16, found 521.1. 22 H 22 MS ESI [M+H] calculated for C26H26F3NNaO6: 521.16, found 521.1. + 444.14, found 444.1; MS ESI [M+H] calculated for C26H26F3NNaO6: 521.16, found 521.1. + 422.16, found 422.1. 1 H NMR (400 MHz, Acetonitrile-d3): δ 9.36 (br. s, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.67 - 7.62 (m, 2H), 7.42 (d, J = 7.6 Hz, 2H), 7.33 (d, J = 7.6 Hz, 2H), 5.98 - 5.96 (m, 1H), 4.35 - 4.25 (m, 2H), 4.23 - 4.21 (m, 1H), 4.14 - 4.10 (m, 1H), 2.17 - 2.13 (m, 2H), 1.58 - 1.56 (m, 1H), 1.55 - 1.41 (m, 5H).

[0391] Synthesis Scheme 6

[0392]

[0393] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-oxoisoindolin-5-yl)propanoic acid (Fmoc-Ala4IsoindOne-OH)

[0394] Step 1: A mixture of nickel(II) chloride ethylene glycol dimethyl ether complex (0.53 g, 2.43 mmol) and 1,10-phenanthroline (0.44 g, 2.43 mmol) in anhydrous DMA (100 mL) was heated at 50 °C for 1 h. A mixture of TBAI (4.49 g, 12.16 mmol), 6-bromoisoindolin-1-one (2.58 g, 12.16 mmol) and (R)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- iodopropionate (6 g, 12.16 mmol) in anhydrous DMA (100 mL) was added at room temperature. Then active zinc (1.59 g, 24.32 mmol) was added and stirred at room temperature for 4 h. The reaction was quenched with H2O (400 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na2SO4, and filtered. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 100% to give (S)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-oxoisoindolin-5-yl)propanoate. Calculated MS ESI [M+Na] N2O5Na 30 H 30 Calculated MS ESI [M+H] N2O5 + 521.22, found 520.95.

[0395] Step 2: TFA (100 mL, 1298 mmol) was added to a stirred solution of (S)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-oxoisoindolin-5-yl)propanoate (5.5 g, 11.03 mmol) in DCM (50 mL) at room temperature. The resulting mixture was stirred at room temperature for 2.5 h, then concentrated under reduced pressure. The residue was recrystallized with Et2O (100 mL) to give Fmoc-Ala4IsoindOne-OH. Calculated MS ESI [M+H] N2O5 26 H 23 Calculated MS ESI [M+H] N2O5 + 443.15, found 443.05. 1 H NMR (400 MHz, DMSO-d6): δ 12.78 (s, 1H), 8.52 (s, 1H), 7.88 - 7.81 (m, 3H), 7.63 - 7.60 (m, 3H), 7.51 - 7.48 (m, 2H), 7.40 - 7.38 (m, 2H), 7.30 - 7.26 (m, 2H), 4.32 (s, 2H), 4.25 - 4.10 (m, 4H), 3.21 - 3.14 (m, 1H), 3.01 - 2.94 (m, 1H).

[0396] Synthesis Scheme 7

[0397]

[0398] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(tert- butoxy)bicyclo[1.1.1]pentan-1-yl)propanoic acid (Fmoc-Alapent(OtBu)-OH)

[0399] Step 1: A solution of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (200.0 g, 680.3 mmol) in pentane (2 L) was placed in a 3-L 3 -necked round-bottom flask under N2. The mixture was cooled to -78 °C. MeLi (2.0 M in Et2O, 680.3 mL) was added dropwise at -78 °C over 2 h. The reaction mixture was allowed to warm to 0 °C over 1 h. The reaction mixture was stirred at 0 °C under N2for 1 h. NMR showed the reaction was complete. The reaction mixture was purified by distillation at 0 °C under vacuum and fractions were collected in a liquid nitrogen-ethanol bath via condensation. This resulted in tricyclo[1.1.1.0 1,3 ]pentane (2.75 wt% in a mixed solution of pentane and ether). 1 H NMR (300 MHz, Chloroform-d): δ 2.00 (d, J = 1.3 Hz, 6H).

[0400] Step 2: A solution of PPh3(67.32 g, 256.6 mmol) in DCM (1000 mL) was placed in a 2-L 3 -necked round-bottom flask under N2. Imidazole (17.47 g, 256.6 mmol) was added to the flask. The reaction mixture was cooled to 0 °C. Iodine (65.14 g, 256.60 mmol) was added to the flask in portions at 0 °C over 10 min. The resulting mixture was stirred at 0 °C for 10 min. ((Benzyl oxy)carbonyl)-L-serine methyl ester (50.00 g, 197.4 mmol) was added to the flask at 0 °C. The resulting mixture was stirred at 0 °C for an additional 4 h. LC-MS monitoring showed the reaction was complete. The resulting mixture was filtered. The filter cake was washed with DCM (3 x 1000 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EtOAc in PE (80:1 to 30:1; v / v) to give (2R)-2-[[(benzyloxy)carbonyl]amino]-3-iodopropionic acid methyl ester. MS ESI [M+Na] calculated for C 12 H 14 MS ESI [M+Na] calculated for C + 386, found 386. 1H NMR (300 MHz, Chloroform-d): δ 7.44 - 7.29 (m, 5H), 5.64 (d, J = 7.5 Hz, 1H), 5.23 - 5.09 (m, 2H), 4.61 (dt, J = 7.7, 3.8 Hz, 1H), 3.83 (s, 3H), 3.62 (t, J = 3.4 Hz, 2H).

[0401] Step 3: A solution of tricyclo[1.1.1.0 1,3]pentane (880 g, 366.66 mmol, 2.75 wt%) in a mixture of pentane and diethyl ether was placed in a 3-L 3 -necked round-bottom flask under N2. The reaction mixture was cooled to 0 °C. (R)-methyl 2-(((benzyloxy)carbonyl)amino)-3-iodopropionate (55.00 g, 151.5 mmol) was added to the flask. Triethylborane (1.0 M in ether, 15.2 mL) was added dropwise over 5 min at 0 °C under N2. The reaction mixture was allowed to return to room temperature naturally and stirred for 30 min. LC-MS monitoring showed the reaction was complete. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EtOAc in PE (100:1 to 20:1; v / v) to give (2S)-methyl 2-(((benzyloxy)carbonyl)amino)-3-(3-iodotricyclo[1.1.1]pentan-1-yl)propanoate. LC-MS calcd for C 17 H 20 MS ESI [M+Na] calculated for C + 452, found 452. 1 H NMR (300 MHz, Chloroform-d): δ 7.37 (d, J = 4.5 Hz, 5H), 5.31 (d, J = 8.3 Hz, 1H), 5.14 (t, J = 2.9 Hz, 2H), 4.39 (td, J = 7.8, 4.5 Hz, 1H), 3.75 (s, 3H), 2.30 - 2.09 (m, 7H), 1.92 (dd, J = 14.7, 7.5 Hz, 1H).

[0402] Step 4: A 2-L 3 -necked round-bottom flask was charged with (2S)-methyl 2-[[(benzyloxy)carbonyl]amino]-3-[3-iodobicyclo[l. l. l ]pentan-l - yl]propanoate (40.00 g, 93.2 mmol) in DMF (600 mL). (Pin)2B2 (35.50 g, 139.8 mmol), LiOMe (7.01 g, 184.5 mmol), and PPh3 (3.67 g, 14.0 mmol) were added to the flask sequentially at room temperature. The flask was evacuated and backfilled with N2(three times). Cul (1.77 g, 9.29 mmol) was added to the flask. The flask was evacuated and backfilled with N2(three times). The reaction mixture was stirred at 35 °C for 4 h. LC-MS monitoring showed the reaction was complete. The resulting mixture was diluted with water (900 mL). The resulting mixture was extracted with EtOAc (3 x 1000 mL). The organic layer was washed with brine (7 x 600 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. This resulted in (2S)-methyl 2-[[(benzyloxy)carbonyl]amino]-3-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)bicyclo[l. l. l ]pentan-l -yl]propanoate. The crude product was used in the next step without further purification.

[0403] Step 5: A 2-L 3 -necked round-bottom flask was charged with (2S)-methyl 2-[[(benzyloxy)carbonyl]amino]-3-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)bicyclo[l. l. l ]pentan-l -yl]propanoate (40.00 g, crude) in THF (600 mL, 15V). NaOAc (9.17 g, 111.8 mmol) and hydrogen peroxide urea (26.29 g, 279.5 mmol) were added to the flask at 0 °C. The resulting mixture was stirred at 30 °C under N2for 12 h. LC-MS monitoring showed the reaction was complete. The resulting mixture was filtered. The filter cake was washed with THF (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EtOAc in PE (80: 1 to 20: 1; v / v) to give (2S)-methyl 2-[[(benzyloxy)carbonyl]amino]-3-[3-hydroxybicyclo[l. l. l ]pentan-l - yl]propanoate. The crude product was used in the next step without further purification. 17 H 21 ESI [M+Na] calculated for C + 342, found 342. 1H NMR (400 MHz, Chloroform-d): δ 7.43 - 7.30 (m, 5H), 5.24 (d, J = 8.4 Hz, 1H), 5.14 (d, J = 2.8 Hz, 2H), 4.41 (td, J = 7.7, 4.5 Hz, 1H), 3.76 (s, 3H), 2.39 (s, 1H), 2.21 (dd, J = 14.7, 4.6 Hz, 1H), 2.00 (dd, J = 14.7, 7.3 Hz, 1H), 1.84 (s, 6H).

[0404] Step 6: A 250-mL 3-necked round-bottom flask was charged with (2S)-methyl 2-[[(benzyloxy)carbonyl]amino]-3-[hydroxybicyclo[l. l. l]pentan-l - yl]propanoate (16.00 g, 0.05 mmol). Boc2O (54.67 g, 0.25 mmol) and magnesium perchlorate (1.17 g, 0.005 mmol) were added to the flask sequentially under N2. The resulting mixture was stirred at 50 °C for 6 h. LC-MS monitoring showed the reaction was complete. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (90: 1 to 10: 1; v / v) to give (2S)-methyl 2-[[(benzyloxy)carbonyl]amino]-3-[3-(tert-butoxy)bicyclo[l. l. l]pentan-l - yl]propanoate. LC-MS calcd for C25H37NO6[M+Na] 463.27, found 463.2. 21 H 29 ESI [M+Na] calculated for C25H37NO6 463.27, found 463.2. + 398, found 398. 1 H NMR (300 MHz, Chloroform-d): δ 7.41 - 7.33 (m, 5H), 5.28 - 5.17 (m, 1H), 5.14 (d, J = 4.0 Hz, 2H), 4.41 (q, J = 7.9, 7.3 Hz, 1H), 3.76 (s, 3H), 2.28 - 2.13 (m, 1H), 1.92 (s, 7H), 1.25 (s, 9H).

[0405] Step 7: A 500-mL round-bottom flask was charged with (S)-2-(((benzyloxy)carbonyl)amino)-3-(3-(tert-butoxy)bicyclo[l. l. l]pentan-l -yl)propanoic acid (12.00 g) in MeOH (240.00 mL, 20 V). The flask was evacuated and backfilled with N2(5 times). Pd / C (anhydrous 2.40 g, 20 wt%) was added to the flask. The flask was evacuated and backfilled with H2(5 times). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 h. LC-MS monitoring showed the reaction was complete. The flask was evacuated and backfilled with N2(5 times). The resulting mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure to give (S)-2-(((benzyloxy)carbonyl)amino)-3-(3-(tert-butoxy)bicyclo[l. l. l]pentan-l -yl)propanoic acid. pad. The filter cake was washed with MeOH (2 x 100 mL). The filtrate was concentrated under reduced pressure. This resulted in (S)-2-amino-3-(3-(tert-butoxy)bicyclo[l. l. l]pentan-l - yl)propanoic acid. MS ESI [M+H] calculated for C13H25NO4, 242.2, found 242.2. 13 H 23 NO3calcd. MS ESI [M+H] + 242, found 242. 1 H NMR (400 MHz, Chloroform-d): δ 3.67 (s, 3H), 3.42 (dd, J = 6.8, 5.5 Hz, 1H), 2.00 (dd, J = 14.3, 5.5 Hz, 1H), 1.92 - 1.79 (m, 7H), 1.21 (s, 9H).

[0406] Step 8: A 500-mL 3-necked round-bottom flask was charged with (S)-2-amino-3-(3-(tert-butoxy)bicyclo[l. l. l]pentan-l -yl)propanoic acid (7.20 g, 19.2 mmol) in THF (144.00 mL, 20 V). H2O (72.00 mL, 10 V) was added to the flask. LiOH (0.60 g, 25 mmol) was added to the flask at room temperature. The resulting mixture was stirred at room temperature under N2for 2 h. LC-MS monitoring showed the reaction was complete. The reaction mixture was used in the next step without further isolation.

[0407] Step 9: The reaction mixture was cooled to 0 °C. NaHC03(7.43 g, 0.08 mmol) and Fmoc-OSu (11.93 g, 0.03 mmol) were added to the flask. The resulting mixture was stirred at 0 °C under N2for 2 h. LC-MS showed the reaction was complete. The mixture was adjusted to pH ~ 3 to 4 with 1 N HC1. The resulting mixture was extracted with EtOAc (3 x 150 mL). The organic phase was washed with water (3 x 100 mL) to remove residual HC1. The organic layer was washed with brine (200 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Rp flash chromatography using a C18 silica gel column; mobile phase: MeCN / water, 15 to 50% gradient of MeCN over 40 min; detector: UV 210 nm. The fractions containing the product were concentrated under vacuum to give (2S)-3-[3-(tert-butoxy)bicyclo[l. l. l]pentan-l -yl]-2-[[(9H-fluoren-9- ylmethoxy)carbonyl]amino]propanoic acid. MS ESI [M+H] calculated for C30H35NO6, 499.3, found 499.3. 27 H 31 NO5calcd. MS ESI [M+Na] + 472, found 472. 1H NMR (400 MHz, DMSO-d6): δ 12.57 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.73 (t, J = 6.9 Hz, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.42 (td, J = 7.5, 1.2 Hz, 2H), 7.32 (tt, J = 7.5, 1.2 Hz, 2H), 4.38 - 4.20 (m, 3H), 4.03 (q, J = 7.1 Hz, 1H), 3.93 (ddd, J = 12.7, 6.4, 2.7 Hz, 1H), 2.00 (dd, J = 14.4, 3.8 Hz, 1H), 1.92 - 1.86 (m, 1H), 1.85 - 1.75 (m, 6H), 1.16 (s, 8H).

[0408] Synthesis Scheme 8

[0409]

[0410] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(tert- butoxycarbonyl)pyrimidin-5-yl)propanoic acid (Fmoc-AlaPyrim4COOtBu-OH)

[0411] Step 1: To a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-serine (10.0 g, 30.5 mmol) in DMF (150 mL) was added NaHC03(12.8 g, 153.0 mmol) and 3-bromoprop-1-ene (11.1 g, 92.0 mmol) at 0 °C under Ar atmosphere. The resulting mixture was stirred at room temperature for 12 h. The mixture was diluted with water (500 mL) and extracted with EtOAc (1000 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 50% to give (((9H-fluoren-9-yl)methoxy)carbonyl)-L-serine allyl ester. Calculated MS ESI [M+Na] for C3oH3oN04Na, 538.20; found, 538.20. 21 H 21 Calculated MS ESI [M+Na] for C3oH3oN04Na, 538.20; found, 538.20. + 390.14, found 390.20. 1 H NMR (300 MHz, Chloroform-d): δ 7.80 - 7.21 (m, 8H), 5.99 - 5.67 (m, 2H), 5.40 - 5.19 (m, 2H), 4.69 - 4.67 (m, 2H), 4.43 - 4.41 (m, 3H), 4.22 - 4.20 (m, 1H), 4.04 - 3.79 (m, 2H), 2.17 (s, 1H).

[0412] Step 2: Imidazole (3.6 g, 52.3 mmol), PPh3(11.7 g, 44.4 mmol) and iodine (9.9 g, 39.2 mmol) were added sequentially to a mixture of ((9H-fluoren-9-yl)methoxy)carbonyl)-L-serine allyl ester (9.6 g, 26.1 mmol) in DCM (960 mL) at room temperature. The reaction was stirred at room temperature for 4 h. The resulting solution was quenched with saturated Na2S203(300 mL) and extracted with DCM (2 x 500 mL). The organic layers were combined, washed with brine (2 x 400 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in PE 0 to 25% to give (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropionic acid allyl ester. MS ESI [M+Na] calculated for C2iH2iIN203Na, 482.00 / 484.00, found 482.95 / 484.95. 21 H 20 MS ESI [M+Na] calculated for C2iH2iIN203Na, 482.00 / 484.00, found 482.95 / 484.95. + 500.04, found 500.15. 1 H NMR (400 MHz, Chloroform-d): δ

[0413] 7.78 - 7.76 (m, 2H), 7.63 - 7.61 (m, 2H), 7.41 - 7.39 (m, 2H), 7.33 - 7.31 (m, 2H), 5.94 - 5.92 (m, 1H), 5.68 - 5.66 (m, 1H), 5.49 - 5.22 (m, 2H), 4.74 - 4.73 (m, 2H), 4.62 - 4.60 (m, 1H), 4.41 - 4.40 (m, 2H), 4.25 - 4.24 (m, 1H), 3.72 - 3.52 (m, 2H).

[0414] Step 3: DMAP (0.3 g, 2.5 mmol) and Boc20 (6.5 g, 29.6 mmol) were added to a mixture of 5-bromopyrimidine-2-carboxylic acid (5.0 g, 24.6 mmol) in t-BuOH (75 mL) at room temperature under Ar atmosphere. The reaction was stirred at 50 °C overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 20% to give tert-butyl 5-bromopyrimidine-2-carboxylate. MS ESI [M-tBu+H] calculated for C9H9BrN20, 245.00 / 247.00, found 245.05 / 247.05. 11 MS ESI [M-tBu+H] calculated for C9H9BrN20, 245.00 / 247.00, found 245.05 / 247.05. + 203.00 / 205.00, found 202.95 / 204.95.

[0415] Step 4: A mixture of nickel(II) chloride ethylene glycol dimethyl ether complex (63.6 mg, 0.29 mmol) and pyridine-2-carboxamidine hydrochloride (91 mg, 0.58 mmol) in anhydrous DMA (20 mL) was heated at 50 °C for 1 h. A solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropyl allyl carbonate (1.38 g, 2.89 mmol), 5-bromopyrimidine-2-carboxylic acid tert-butyl ester (750 mg, 2.89 mmol) and TBAI (2.14 g, 5.79 mmol) in anhydrous DMA (25 mL) was added at room temperature. Then active zinc (378 mg, 5.79 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction was quenched with H2O (200 mL) and extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 45% to give (S)-5-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- (allyloxy)-3-oxopropyl)pyrimidine-2-carboxylic acid tert-butyl ester. MS ESI [M+H] calculated for C3oH35FN4O7, 590.24, found 590.25. 30 H 32 MS ESI [M+H] calculated for C3oH35FN4O7, 590.24, found 590.25. + 530.22, found 530.25.

[0416] Step 5: Pd(PPh3)4 (0.16 g, 0.14 mmol) and phenylsilane (0.59 g, 5.44 mmol) were added to a stirred solution of (S)-5-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- (allyloxy)-3-oxopropyl)pyrimidine-2-carboxylic acid tert-butyl ester (1.44 g, 2.72 mmol) in THF (25 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The solvent was concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN (0.1% TFA); gradient elution: 2 to 50%; detector: UV 215 nm. Fractions containing the product were concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(tert- butoxycarbonyl)pyrimidin-5-yl)propanoic acid. MS ESI [M+H] calculated for C3oH35FN4O7, 590.24, found 590.25. 27 H 28 MS ESI [M+H] calculated for C3oH35FN4O7, 590.24, found 590.25. + 490.19, found 490.15. 1H NMR (300 MHz, DMSO-d6): δ 8.86 (s, 2H), 7.86 - 7.85 (m, 3H), 7.69 - 7.52 (m, 2H), 7.46 - 7.24 (m, 4H), 4.33 - 4.32 (m, 1H), 4.20 - 4.18 (m, 3H), 3.23 - 3.21 (m, 1H), 2.98 - 2.97 (m, 1H), 1.55 (s, 9H).

[0417] Synthesis scheme 9

[0418]

[0419] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(bis(tert- butyloxy carbonyl)amino)pyrimidin-5-yl)propanoic acid (Fmoc-AlaPyrim4NBoc2-OH)

[0420] Step 1 : DMAP (0.17 g, 1.36 mmol) and Boc20 (7.5 mL, 32.6 mmol) were added to a mixture of 5-iodopyrimidin-2-amine (3.00 g, 13.6 mmol) in DCM (45 mL) at room temperature under Ar atmosphere. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 30% to give tert-butyl (tert- butyloxy carbonyl)(5-iodopyrimidin-2-yl)carbamate.1H NMR (300 MHz, Chloroform-d): d 8.91 (s, 2H), 1.47 (s, 18H). 14 H 21 IN3O4calcd MS ESI [M+H] + 422.05, found 422.00. 1 H NMR (300 MHz, Chloroform-d): d 8.91 (s, 2H), 1.47 (s, 18H).

[0421] Step 2: A mixture of nickel(II) chloride ethylene glycol dimethyl ether complex (0.26 g, 1.19 mmol) and pyridine-2-carboxamidine hydrochloride (0.37 g, 2.37 mmol) in anhydrous DMA (100 mL) was heated at 50 °C for 1 h. A combination of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropionic acid allyl ester (5.67 g, 11.9 mmol), tert-butyl (5-iodopyrimidin-2-yl)carbamate (5.00 g, 11.9 mmol) and TBAI (8.77 g, 23.7 mmol) in anhydrous DMA (120 mL) was added at room temperature, followed by the addition of active zinc (1.55 g, 23.7 mmol). The resulting mixture was stirred at room temperature for 4 h. The mixture was quenched with H2O (600 mL) and extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 60% to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(bis(tert- butoxycarbonyl)amino)pyrimidin-5-yl)propionic acid allyl ester. MS ESI [M+H] calculated for C41H52N7O12 822.37, found 822.36. 35 H 41 MS ESI [M+H] calculated for C41H52N7O12 822.37, found 822.36. + 645.28, found 645.10. 1 H NMR (400 MHz, DMSO-d6): d 8.78 (s, 2H), 8.02 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.65 - 7.63 (m, 2H), 7.44 - 7.37 (m, 2H), 7.32 - 7.30 (m, 2H), 5.90 - 5.88 (m, 1H), 5.34 - 5.33 (m, 1H), 5.23 - 5.22 (m, 1H), 4.62 (d, J = 5.3 Hz, 2H), 4.44 - 4.43 (m, 1H), 4.32 - 4.21 (m, 1H), 4.21 - 4.11 (m, 2H), 3.20 - 3.19 (m, 1H), 2.96 - 2.95 (m, 1H), 1.35 (s, 18H).

[0422] Step 3: Pd(PPh3)4(0.33 g, 0.29 mmol) and phenylsilane (1.24 g, 11.5 mmol) were added to a mixture of (S)-allyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(bis(tert- butoxycarbonyl)amino)pyrimidin-5-yl)propanoate (3.7 g, 5.7 mmol) in anhydrous THF (70 mL) at room temperature. The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN (0.1% TFA); gradient elution: 25 to 55%; detector: UV 215 nm. Fractions containing the product were concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(bis(tert- butoxycarbonyl)amino)pyrimidin-5-yl)propanoic acid. MS ESI [M+H] calculated for C34H45N6O10: 681.31, found 681.30. 32 H 37 MS ESI [M+H] calculated for C34H45N6O10: 681.31, found 681.30. + 605.25, found 605.10. 1 H NMR (400 MHz, DMSO-d6): δ 12.81 (s, 1H), 8.76 (s, 2H), 7.89-7.87 (m, 3H), 7.67-7.66 (m, 2H), 7.44-7.38 (m, 2H), 7.37-7.34 (m, 2H), 4.23-4.13 (m, 4H), 3.18-3.08 (m, 2H), 1.34 (s, 18H).

[0423] Synthesis Scheme 10

[0424]

[0425] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert- butoxycarbonyl)amino)-3-methylbutanoic acid (Fmoc-Bav(NHBoc)-OH)

[0426] Step 1: Sodium hydroxide (1.0 g, 25 mmol) was added to a stirred solution of (S)-methyl 2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate (1.0 g, 4.1 mmol) in DI water (40 mL) and THF (40 mL) at room temperature. The solution was stirred at room temperature for 2 h. The pH was adjusted to pH 7 by the addition of 1 N aqueous HC1.

[0427] Step 2: NaHCO3(1.0 g, 1.9 mmol) and Fmoc-OSu (1.5 g, 4.5 mmol) were added to the solution of Step 1. The reaction mixture was stirred at room temperature for 4 h. The pH was adjusted to 2 with 1 N aqueous HC1 and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0 to 10% MeOH in DCM to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert- butoxycarbonyl)amino)-3-methylbutanoic acid. MS ESI [M+Na] calculated for C28H37N2O7, 529.26; found, 529.3. 25 H 30 MS ESI [M+Na] calculated for C28H37N2O7, 529.26; found, 529.3. + 477.20, found 477.2; [M - Boc + H] + 354.16, found 355.2. 1 H NMR (600 MHz, DMSO-d6): δ 12.59 (s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.73 (m, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 6.56 (s, 1H), 4.57 (d, J = 8.4 Hz, 1H), 4.30 - 4.20 (m, 3H), 1.36 (s, 9H), 1.27 (s, 6H). 13 C NMR (151 MHz, DMSO-d6): δ 172.2, 156.1, 154.6, 143.8, 140.7, 127.7, 127.1, 125.4, 120.2, 107.0, 66.6, 65.8, 59.7, 46.6, 28.3, 24.8, 24.2.

[0428] Synthesis Scheme 11

[0429]

[0430] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(tert- butoxycarbonyl)bicyclo[l.l.l]pentan-l-yl)propanoic acid (Fmoc-BCP3COOtBu-OH)

[0431] Step 1: A 1N NaOH aqueous solution (1.0M, 47.3 mL, 47.3 mmol) was added to a solution of S-phenylmethyl-L-cysteine ​​(10.0 g, 47 mmol) in EtOH (150 mL) at room temperature. The mixture was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure. The residue was suspended in pentane (300 mL). Pteropentanal (20.4 g, 237 mmol) and active... Molecular sieves. The mixture was heated to reflux (~40°C) and stirred for 6 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was azeotropically dried with toluene (3 × 200 mL). The residue was dissolved in anhydrous DCM (300 mL) and Cb2Cl (13.5 mL, 95.0 mmol) was added at 0°C. The mixture was stirred overnight at room temperature. The mixture and residue were concentrated under reduced pressure and purified by silica gel column chromatography, eluting with EtOAc 0 to 30% in PE, to give (2S,4R)-4-((benzylthio)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylic acid benzyl ester. (For C...) 23 H 28 MS ESI[M+H] calculated by NO4S + 414.17, measured value 414.05. 1 ¹H NMR (300MHz, chloroform-d): δ 7.38–7.30 (m, 5H), 7.25–7.03 (m, 5H), 5.53 (s, 1H), 5.27–5.12 (m, 2H), 4.55–4.50 (m, 1H), 3.86–3.66 (m, 2H), 2.98–2.72 (m, 2H), 0.91 (s, 9H).

[0432] Step 2: At 0 °C, mCPBA (10.9 g, 53.8 mmol) was added to a mixture of (2S,4R)-4-((benzylsulfonyl)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylic acid benzyl ester (8.9 g, 22 mmol) in DCM (180 mL). The mixture was stirred at room temperature for 3 h. The mixture was quenched with 1 N aq. NaOH (150 mL) and extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography by elution with EtOAc 0 to 35% in PE to give (2S,4R)-4-((benzylsulfonyl)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylic acid benzyl ester. (For C...) 23 H 28 MS ESI[M+H] calculated by NO6S +446.16, found 446.05. 1 H NMR (400 MHz, Chloroform-d): δ 7.44 - 7.32 (m, 10H), 5.62 (s, 1H), 5.28 - 5.17 (m, 2H), 5.10 - 5.07 (m, 1H), 4.70 - 4.65 (m, 1H), 4.44 - 4.40 (m, 1H), 3.47 - 3.41 (m, 1H), 3.17 - 3.12 (m, 1H), 0.89 (s, 9H).

[0433] Step 3: DBU (2.89 g, 19.0 mmol) was added to a solution of (2S,4R)-4- ((benzylsulfonyl)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylic acid benzyl ester (7.70 g, 17.3 mmol) in DCM (155 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 30% to give (S)-2-(tert-butyl)-4-methylene-5-oxooxazolidine-3-carboxylic acid benzyl ester. ESI MS [M+H] calculated for C20H24NO5 360.17, found 360.15. 16 H 20 ESI MS [M+H] calculated for C20H24NO5 360.17, found 360.15. + 290.13, found 290.10. 1 H NMR (300 MHz, Chloroform-d): δ 7.38 - 7.36 (m, 5H), 5.75 - 5.63 (m, 3H), 5.29 - 5.21 (m, 2H), 0.93 (s, 9H).

[0434] Step 4: (Z)-tert-butyl N,N'-diisopropylcarbamimidate (31.0 mL, 147 mmol) was added to a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1- carboxylic acid (5.0 g, 29.4 mmol) in DCM (75 mL) at room temperature. The reaction mixture was stirred at 40 °C for 2 h. The mixture was cooled to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 3-methylbicyclo[1.1.1]pentane-1,3-dicarboxylic acid 1-(tert-butyl) ester, which was used in the next step without further purification. 1 H NMR (300 MHz, Chloroform-d): δ 3.69 (s, 3H), 2.32 (s, 6H), 1.45 (s, 9H).

[0435] Step 5: An aqueous solution of LiOH (1.0 M, 46.8 mL, 47 mmol) was added to a mixture of 3-methylbicyclo[1.1.1]pentane-1,3-dicarboxylic acid 1-(tert-butyl) (5.3 g, 23 mmol) in THF (53 mL) at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was cooled to 0 °C and the pH was adjusted to ~3 to 4 with 1 N HCl aqueous solution (46.8 mL). The mixture was extracted with EtOAc (3 × 200 mL). The organic layers were combined, washed with brine (3 × 200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid, which could be used in the next step without purification. (For C...) 11 H 15 O4[M–H] – 211.10, measured value 211.10. 1 ¹H NMR (300MHz, methanol-d4): δ 2.21 (s, 6H), 1.44 (s, 9H).

[0436] Step 6: 3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.10 g, 5.18 mmol), 1,2,3,5-tetra(carbazol-9-yl)-4,6-dicyanobenzene (0.06 g, 0.07 mmol), and K₂HPO₄ (1.51 g, 8.64 mmol) were added to a solution of (S)-2-(tert-butyl)-4-methylene-5-oxooxazolidine-3-carboxylic acid benzyl ester (1.00 g, 3.46 mmol) in DMF (33 mL). The mixture was irradiated with a 34 W blue LED lamp and stirred overnight under Ar at room temperature. The mixture was diluted with water (150 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography by elution with 0 to 25% EtOAc in PE to give (2S,4S)-4-((3-(tert-butoxycarbonyl)bicyclo[1.1.1]pent-1-yl)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylic acid benzyl ester. (For C...) 26 H 39 MS ESI [M+NH4] calculated from N2O6 + 475.25, measured value 475.30. 1H NMR (400 MHz, Chloroform-d): δ 7.44 - 7.32 (m, 5H), 5.53 (s, 1H), 5.22 - 5.11 (m, 2H), 4.28 - 4.21 (m, 1H), 2.14 - 2.08 (m, 1H), 2.01 - 1.90 (m, 7H), 1.43 (s, 9H), 0.94 (s, 9H).

[0437] Step 7: An aqueous solution of LiOH (1.0 M, 10.4 mL, 10 mmol) was added to a mixture of (2S,4S)-4-((3-(tert-butoxycarbonyl)bicyclo[l. l. l]pentan-l - yl)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylic acid benzyl ester (1.9 g, 4.2 mmol) in THF (40 mL) at 0 °C. The mixture was stirred at room temperature for 4 h. The mixture was cooled to 0 °C and the pH was adjusted to ~3 to 4 with 1 M aqueous HC1 (10 mL). The mixture was diluted with water (60 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over Na2S04and filtered. The filtrate was concentrated under reduced pressure to give (S)-2-(((benzyloxy)carbonyl)amino)-3-(3-(tert- butoxycarbonyl)bicyclo[l. l. l]pentan-l -yl)propanoic acid, which was used in the next step without further purification. MS ESI [M+NH4] calculated for C25H37N02O7 479.27, found 480.30. 21 H 31 MS ESI [M+NH4] calculated for C25H37N02O7 479.27, found 480.30. + 407.22, found 407.10. 1 H NMR (400 MHz, Chloroform-d): δ 7.39 - 7.29 (m, 5H), 5.26 - 5.23 (m, 1H), 5.12 (s, 2H), 4.44 - 4.38 (m, 1H), 2.17 - 2.09 (m, 1H), 1.98 - 1.85 (m, 7H), 1.42 (s, 9H).

[0438] Step 8: (S)-2-(((benzyloxy)carbonyl)amino)-3-(3-(tert- butoxycarbonyl)bicyclo[l. l. l]pentan-l -yl)propanoic acid (1.9 g, 4.9 mmol) was dissolved in THF (40 mL). The flask was evacuated and backfilled with N2(5 times). Pd / C (1.04 g, 0.98 mmol, dry, 10 wt%) was added to the flask. The flask was evacuated and backfilled with H2(5 times). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 2 h. The flask was evacuated and backfilled with N2(5 times). The resulting mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to give (S)-2-(((benzyloxy)carbonyl)amino)-3-(3-(tert- butoxycarbonyl)bicyclo[l. l. l]pentan-l -yl)propanoic acid, which was used in the next step without further purification. pad. The filter cake was washed with THF (2 x 25 mL). The filtrate was concentrated under reduced pressure. ((S)-2-amino-3-(3-(tert-butoxycarbonyl)bicyclo[l. l. l ]pentan-l - yl)propanoic acid (1.2 g, 4.70 mmol, 96% yield)) was used in the next step without further purification. MS ESI [M+H] calculated for C 13 H 22 MS ESI [M+Na] calculated for C + 256.15, found 256.15.

[0439] Step 9: The reaction mixture of (S)-2-amino-3-(3-(tert-butoxycarbonyl)bicyclo[l. l. l ]pentan-l - yl)propanoic acid (1.2 g, 4.7 mmol) in THF (40 mL) from Step 8 was diluted with water (40 mL). NaHC03(1.97 g, 23.5 mmol) and Fmoc-OSu (1.59 g, 4.70 mmol) were added at 0 °C. The mixture was stirred at room temperature overnight. The mixture was filtered and the filter cake was washed with THF (2 x 100 mL). The filtrate was partially concentrated under reduced pressure. The pH of the solution was adjusted to ~3 to 4 with 1 N aqueous HC1 (23.5 mL). The mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with MeOH 0 to 15% in DCM to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(tert- butoxycarbonyl)bicyclo[l. l. l ]pentan-l -yl)propanoic acid. MS ESI [M+Na] calculated for C 28 H 31 MS ESI [M+Na] calculated for C + 500.22, found 500.35. 1 HNMR (400 MHz, Methanol-d4): δ 7.79 (d, J = 7.6 Hz, 2H), 7.69 - 7.65 (m, 2H), 7.39 - 7.35 (m, 2H), 7.32 - 7.28 (m, 2H), 4.46 - 4.44 (m, 1H), 4.38 - 4.35 (m, 1H), 4.24 - 4.20 (m, 1H), 4.11 - 4.08 (m, 1H), 2.05 - 2.01 (m, 1H), 1.89 - 1.74 (m, 7H), 1.44 (s, 9H).

[0440] Synthesis Scheme 12

[0441]

[0442] (1R,2S,3R,4S) and (1S,2R,3S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 2,3-dihydroxycyclopentane-1 -carboxylic acid (Fmoc-bhcLeut45diOH-OH)

[0443] Lithium hydroxide (200 mg, 8.35 mmol) was added to a racemic mixture of (1R,2S,3R,4S)- and (1S,2R,3S,4R)-4-amino-2,3-dihydroxycyclopentane-1 -carboxylic acid hydrochloride (500 mg, 2.36 mmol) in water (15 mL). The mixture was stirred at room temperature for 2 h. The pH was adjusted to ~4 by the addition of 1 N aqueous HC1, followed by the addition of THF (15 mL). Fmoc-OSu (0.95 g, 2.8 mmol) and saturated aqueous NaHC03solution (10 mL) were added to the mixture. The mixture was stirred at room temperature for 18 h. The resulting mixture was concentrated under reduced pressure. The mixture was adjusted to pH ~3 with 1 N aqueous HC1 and extracted with EtOAc (2 x 80 mL). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH in DCM to give (1R,2S,3R,4S)- and (1S,2R,3S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2,3- dihydroxycyclopentane-1 -carboxylic acid as a racemic mixture.1H NMR (600 MHz, DMSO-d6): δ 12.19 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 7.4 Hz, 2H), 7.44 - 7.39 (m, 3H), 7.36 - 7.32 (m, 2H), 4.88 - 4.64 (m, 2H), 4.30 - 4.27 (m, 2H), 4.22 (t, J = 6.9 Hz, 1H), 4.00 (t, J = 5.2 Hz, 1H), 3.76 - 3.69 (m, 1H), 3.63 (t, J = 5.3 Hz, 1H), 2.61 - 2.56 (m, 1H), 2.21 - 2.14 (m, 1H), 1.52 - 1.45 (m, 1H). MS ESI [M+H] calculated for C3oH3oN2O7, 534.2, found 534.2. 21 H 22 MS ESI [M+H] calculated for C3oH3oN2O7, 534.2, found 534.2. + 384.1, found 384.1. 1 H NMR (600 MHz, DMSO-d6): δ 12.19 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 7.4 Hz, 2H), 7.44 - 7.39 (m, 3H), 7.36 - 7.32 (m, 2H), 4.88 - 4.64 (m, 2H), 4.30 - 4.27 (m, 2H), 4.22 (t, J = 6.9 Hz, 1H), 4.00 (t, J = 5.2 Hz, 1H), 3.76 - 3.69 (m, 1H), 3.63 (t, J = 5.3 Hz, 1H), 2.61 - 2.56 (m, 1H), 2.21 - 2.14 (m, 1H), 1.52 - 1.45 (m, 1H). MS ESI [M+H] calculated for C3oH3oN2O7, 534.2, found 534.2.

[0444] Synthesis Scheme 13

[0445]

[0446] (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2-(tert-butoxy)-2- oxoethyl)pyrrolidine-2-carboxylic acid (Fmoc-dProc4CH2COOtBu-OH)

[0447] Step 1: A mixture of (R)-4-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2- methyl ester (4.00 g, 16.4 mmol) and tert-butyl 2-(triphenyl-l5-phosphoranyl)acetate (15.47 g, 41.1 mmol) in DCM (80 mL) was stirred and heated at 40 °C overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 60% to give (R,Z)-4-(2-(tert-butoxy)-2-oxoethylidene)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester. MS ESI [M+Na] calculated for C 17 H 27 NO6 calculated MS ESI [M+Na] + 364.18, found 364.00.

[0448] Step 2: (R,Z)-4-(2-(tert-butoxy)-2-oxoethylidene)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (5.00 g, 14.7 mmol) and (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate (2.36 g, 2.93 mmol) were dissolved in DCM (100 mL). The flask was evacuated and backfilled with H2 (5 times). The resulting mixture was stirred at room temperature under a hydrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 60% to give (2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester. MS ESI [M+H] calculated for C 17 H 30 NO6 calculated MS ESI [M+H] + 344.20, found 344.10.

[0449] Step 3: Trimethylchlorosilane (18.6 mL, 146 mmol) and phenol (13.7 g, 146 mmol) were added to a mixture of (2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-methyl ester (5.00 g, 14.6 mmol) in DCM (50 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was quenched with 1N LiOH aqueous solution (50 mL, 50 mmol) to pH ~8 to 9 and then extracted with DCM (3 × 300 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2-carboxylic acid methyl ester, which could be used in the next step without purification. (For C...) 12 H 22 MS ESI[M+H] calculated using NO4 + 244.15, measured value 244.10.

[0450] Step 4: At 0°C, 29 mL (29 mmol) of 1 N LiOH aqueous solution was added to a solution of (2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2-carboxylic acid methyl ester (3.54 g, 14.6 mmol) in THF (40 mL). The mixture was stirred at room temperature for 4 h. The mixture was acidified to pH ~7 with 30 mL of 1 M HCl aqueous solution and then concentrated under reduced pressure to give (2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2-carboxylic acid, which can be used in the next step without purification. (For C...) 11 H 20 MS ESI[M+H] calculated using NO4 + 230.13, measured value 230.10.

[0451] Step 5: Fmoc-OSu (4.37 g, 13.0 mmol) and NaHC03(6.05 g, 72.0 mmol) were added to a solution of (2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2- carboxylic acid (3.3 g, 14 mmol) in THF (40 mL) and water (40 mL) at 0 °C. The mixture was stirred at room temperature overnight. The mixture was acidified to pH ~3 with 1 M aqueous HC1 (30 mL) and extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with brine (2 x 50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN; gradient elution: 30 to 80%; detector: UV 210 nm. Fractions containing the product were concentrated under reduced pressure to give (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2-(tert-butoxy)-2- oxoethyl)pyrrolidine-2-carboxylic acid. The mixture of diastereomers was separated by SFC: (column: Daicel Chiralcel® IG (250 x 30 mm, 5 pm, Daicel Chiral Technologies, West Chester, PA); mobile phase: [1 : 1 MeOH in MeCN]; B%: 35 to 35%, 5 min) to give (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2-carboxylic acid as the second eluting isomer [t IG (250 x 30 mm, 5 pm, Daicel Chiral Technologies, West Chester, PA); mobile phase: [1 : 1 MeOH in MeCN]; B%: 35 to 35%, 5 min), to give (2R,4S)-1-(((9H-fluoren-9- yl)methoxy)carbonyl)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2-carboxylic acid as the second eluting isomer [t R = 3.27 min]. MS ESI [M+H] 26 H 30 calcd for C + 452.20, found 452.20. 1 H NMR (300 MHz, Methanol-d4): d 7.81 - 7.77 (m, 2H), 7.65 - 7.60 (m, 2H), 7.41 - 7.28 (m, 4H), 4.35 - 4.17 (m, 4H), 3.79 - 3.73 (m, 1H), 3.11 - 3.06 (m, 1H), 2.57 - 2.50 (m, 2H), 2.40 - 2.35 (m, 2H), 1.70 - 1.68 (m, 1H), 1.46 - 1.45 (m, 9H).

[0452] Synthesis Scheme 14

[0453]

[0454] (R)-5-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-azaspiro[2.4]heptane-6- carboxylic acid (Fmoc-dPro4cPr-OH)

[0455] Step 1: A solution of HC1 in anhydrous dioxane (4 M, 2.6 mL, 10 mmol) was added to (R)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (0.25 g, 1.0 mmol). The resulting solution was stirred at room temperature for 4 h. The solution was then concentrated under reduced pressure. The crude product was used directly in the next step without any purification.

[0456] Step 2: To a stirred solution of the crude residue in water (5 mL) was added a suspension of Fmoc-OSu (0.35 g, 1.0 mmol) in THF (2.5 mL) followed by NaHC03(0.26 g, 3.1 mmol) until pH > 7. The resulting suspension was stirred at room temperature for 18 h. The organic volatiles were then removed under reduced pressure and 0.2 M aqueous ammonium bicarbonate solution (5 mL) was added. The mixture was extracted with EtOAc (15 mL, discarded), then acidified to pH ~ 2 by the addition of concentrated HC1 (400 μί) and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (30 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN (0.1% TFA); gradient elution: 20 to 60% over 16 column volumes; detector: UV 215 nm. Fractions containing the product were combined, concentrated under reduced pressure and freeze-dried to give (R)-5-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid. MS ESI [M+H] calculated for C28H29NO6, 479.2; found, 479.2. 22 H 21 MS ESI [M+H] calculated for C28H29NO6, 479.2; found, 479.2. + 364.15, found 364.0. 1 H NMR (DMSO-d6): δ 7.90 (d, J = 7.4 Hz, 2H), 7.69 - 7.63 (m, 2H), 7.46 - 7.40 (m, 2H), 7.38 - 7.29 (m, 2H), 4.47 - 4.16 (m, 4H), 3.44 - 3.39 (m, 1H), 3.32 - 3.21 (m, 1H), 2.46 - 2.28 (m, 1H), 1.82 - 1.71 (m, 1H), 0.64 - 0.49 (m, 4H).

[0457] Synthesis Scheme 15

[0458]

[0459] (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(dimethylamino)pyrrolidine-2- carboxylic acid hydrochloride (Fmoc-dProc4NMe2-OH)

[0460] Step 1 : DIPEA (1.77 g, 13.7 mmol) and Pd / C (300 mg, 0.28 mmol, dry, 10 wt%) were added to a solution of (2R,4R)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert- butyl) 2-methyl ester hydrochloride (3.50 g, 12.5 mmol) in MeOH (65 mL). Formaldehyde (5.5 mL, 12 mmol, 37 wt% in water) was added dropwise to the reaction mixture and the mixture was degassed with hydrogen (3 times). The mixture was stirred under hydrogen at 1 atm at room temperature overnight. The mixture was filtered through Celite. The filter cake was washed with MeOH (3 x 200 mL). The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with MeOH 10% in DCM to give (2R,4R)-4-(dimethylamino)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester. MS ESI [M+H] calculated for C15H27N2O5, 307.19, found 307.20. C15H27N2O5, 307.19, found 307.20. 13 H 25 N2O4[M–Boc+H] + 173.17, found 173.10.

[0461] Step 2: LiOH (36 mL, 36 mmol, 1 N in water) was added to a mixture of (2R,4R)-4- (dimethylamino)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (3.0 g, 11 mmol) in THF (36 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 5 with 1 N aqueous HC1. The filtrate was concentrated under vacuum to give the crude product. The crude product was used directly in the next step.

[0462] Step 3: TFA (11 mL, 140 mmol) was added to a stirred mixture of (2R,4R)-1-(tert- butyloxycarbonyl)-4-(dimethylamino)pyrrolidine-2-carboxylic acid (2.8 g, 11 mmol) in DCM (33 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to give crude (2R,4R)-4- (dimethylamino)pyrrolidine-2-carboxylic acid. MS ESI [M+H] calculated for C7H13N2O2, 159.11, found 159.20. 15 N2O2[M+H] + 173.17, found 173.10.

[0463] Step 4: NaHCO3 (0.96 g, 11 mmol) and Fmoc-OSu (3.84 g, 11.4 mmol) were added to a stirred solution of (2R,4R)-4-(dimethylamino)pyrrolidine-2-carboxylic acid (1.8 g, 11 mmol) in water (18 mL) and THF (18 mL) at room temperature. The resulting mixture was stirred for 4 h at room temperature. The pH was adjusted to 3 with 1 N HCl. The solvent and residue were concentrated under reduced pressure and purified by Rp rapid column chromatography under the following conditions: 330 g C18 column, 2% to 2% in 5 min, 2% to 60% in 30 min, MeCN in water (0.05% TFA), to give (2R,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(dimethylamino)pyrrolidine-2-carboxylic acid. For C 22 H 25 N₂O₄[M–HCl+H] + 381.17, measured value 381.10. 1 H NMR (300MHz, DMSO-d6): δ7.92–7.86(m,2H),7.69–7.63(m,2H),7.45–7.32(m,4H),4.45–4.29(m,2H),4.17– 4.11(m,2H),3.91–3.78(m,1H),3.35–3.26(m,2H),2.80–2.74(m,4H),2.62–2.47(m,3H),2.03–1.86(m,1H).

[0464] Synthesis Scheme 16

[0465]

[0466] (2R,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(((tert-butoxycarbonyl)amino)-methyl)pyrrolidine-2-carboxylic acid (Fmoc-dProt4CH2NHBoc-OH)

[0467] Step 1: Degas the solution of (2R,4S)-4-cyanopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (1.1 g, 4.3 mmol) in methanol (20 mL) using nitrogen (N2). Nickel (50 mg, 0.85 mmol) was added to the solution. The mixture was then stirred for 6 hours at room temperature under hydrogen (1 atm). The mixture was then filtered. Wash with methanol (2 × 30 mL). Concentrate the filtrate under reduced pressure to give (2R,4R)-4-(aminomethyl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester. (For C...) 12H 23 N2O4– Boc [M – Boc + H] + 159.16, found 159.15.

[0468] Step 2: NaHCO3 (1.62 g, 19.3 mmol) and Cbz-OSu (1.16 g, 4.63 mmol) were added to a solution of (2R,4R)-4-(aminomethyl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (1.05 g, 3.86 mmol) in THF (20 mL) and water (20 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in PE to give (2R,4R)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester. LCMS (ESI) m / z: 434.1 [M+H]. 20 H 29 N2O6 calculated MS ESI [M+H] + 393.19, found 393.05.

[0469] Step 3: TFA (5.0 mL, 65 mmol) was added to a solution of (2R,4R)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (1.4 g, 2.5 mmol) in DCM (10 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give (2R,4S)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-2-carboxylic acid methyl ester which was used in the next step without purification. LCMS (ESI) m / z: 320.1 [M+H]. 15 H 21 N2O6 calculated MS ESI [M+H] + 293.14, found 293.10.

[0470] Step 4: 1 N aqueous LiOH (4.9 mL, 4.9 mmol) was added to a solution of (2R,4S)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-2-carboxylic acid methyl ester (1.2 g, 2.5 mmol) in THF (10 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was then acidified to pH ~ 5 with 1 M aqueous HC1. The mixture was concentrated under reduced pressure to give (2R,4S)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-2-carboxylic acid which was used in the next step without purification. LCMS (ESI) m / z: 306.1 [M+H].14 H 19 MS ESI [M+MeCN+H] calculated from N₂O₄+MeCN + 320.13, measured value 319.75.

[0471] Step 5: NaHCO3 (0.996 g, 11.9 mmol) and Fmoc-OSu (0.720 g, 2.13 mmol) were added to a solution of (2R,4S)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-2-carboxylic acid (1.2 g, 2.4 mmol) in THF (20 mL) and water (20 mL) at room temperature. The mixture was stirred for 2 h at room temperature. The mixture was then acidified to pH ~5 with 1 M HCl aqueous solution and concentrated under reduced pressure. The residue was purified by Rp rapid column chromatography under the following conditions: column: Flash C18 (80 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN; gradient elution: 2 to 40%; detector: UV 210 nm. Concentrating the fraction containing the product under reduced pressure yielded (2R,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-2-carboxylic acid. (For C...) 29 H 29 MS ESI [M+H] calculated from N₂O₆ + 501.19, measured value 501.10.

[0472] Step 6: Dissolve (2R,4R)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-2-carboxylic acid (820 mg, 1.64 mmol) and Boc2O (536 mg, 2.46 mmol) in THF (15 mL). Empty the flask and refill it with N2 (5 times). Add Pd / C (50 mg, 0.5 mmol, dry, 10% by weight) to the flask. Empty the flask and refill it with H2 (5 times). Stir the resulting mixture for 6 h at room temperature under a hydrogen atmosphere. Empty the flask and refill it with N2 (5 times). Filter the resulting mixture. The filter cake was washed with THF (2 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Rp rapid column chromatography under the following conditions: column: Flash C18 (80 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN; gradient elution: 2 to 40%; detector: UV 210 nm. The fraction containing the product was concentrated under reduced pressure to give (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(((tert-butoxycarbonyl)amino)methyl)pyrrolidine-2-carboxylic acid. (The last sentence appears to be incomplete and requires further context.) 26H 34 Calcd MS ESI [M+NH4] 484.21, found 484.25. + Calcd MS ESI [M+NH4] 484.21, found 484.25. 1 H NMR (300 MHz, Methanol-d4): δ 7.85 - 7.74 (m, 2H), 7.71 - 7.57 (m, 2H), 7.48 - 7.23 (m, 4H), 4.57 - 4.12 (m, 4H), 3.74 - 3.57 (m, 1H), 3.25 - 3.13 (m, 1H), 3.13 - 2.99 (m, 2H), 2.64 - 2.41 (m, 1H), 2.15 - 1.96 (m, 2H), 1.51 - 1.29 (m, 9H).

[0473] Synthesis Scheme 17

[0474]

[0475] 2-(((3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxypyrolidin-3-yl)amino)-N,N,N- trimethyl-2-oxoethan-1-aminium chloride (Fmoc-dProt4NHC2acidNMe3-OH)

[0476] Step 1: A mixture of tert-butyl 2-bromoacetate (1.9 g, 9.7 mmol) in trimethylamine solution (2 N in THF, 10 mL, 20 mmol) was stirred and heated at 50 °C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure to give 2-(tert-butoxy)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride, which was used in the next step without purification. For C9H 20 NO2 + [M] + Calcd MS ESI [M+NH4] 484.21, found 484.25.

[0477] Step 2: A mixture of 2-(tert-butoxy)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride (2.0 g, 9.5 mmol) in hydrochloric acid solution (4.0 M in 1,4-dioxane, 24 mL, 95 mmol) was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure to give 1-carboxy-N,N,N-trimethylmethanaminium chloride, which was used in the next step without purification. For C5H 12 NO2 + [M] + Calcd MS ESI [M+NH4] 484.21, found 484.25.

[0478] Step 3: A mixture of 1-carboxy-N,N,N-trimethylmethanaminium chloride (3.3 g, 21 mmol), HOBt (4.94 g, 32.2 mmol), DIPEA (7.50 mL, 43.0 mmol), EDC (6.18 g, 32.2 mmol), DMAP (0.262 g, 2.15 mmol) and (2R,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (5.25 g, 21.5 mmol) in DMSO (33 mL) was stirred at room temperature overnight. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18; Mobile Phase A: water (0.1% HCL), Mobile Phase B: MeCN; Gradient Elution: 5 to 90%; Detector: UV 210 nm. Fractions containing product were concentrated under reduced pressure to give 2-(((3S,5R)-1-(tert-butoxycarbonyl)-5- (methoxycarbonyl)pyrrolidin-3-yl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride.1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 3H), 7.48 (d, J = 8.0 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 4.44 (s, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 3.62 (s, 3H), 3.59 (s, 3H), 3.48 (s, 3H), 3.44 (s, 3H), 3.42 (s, 3H), 1.45 (s, 9H). LCMS (M+H+): 460.2, found 460.2. 16 H 30 N3O5 + [M] + 344.22, found 344.05.

[0479] Step 4: 1 N aqueous LiOH (20.3 mL, 20 mmol) was added to a mixture of 2-(((3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl)amino)-N,N,N- trimethyl-2-oxoethan-1-aminium chloride (3.5 g, 10 mmol) in THF (35 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The mixture was acidified to pH ~2 to 3 with 1 M aqueous HC1 to give 2-(((3S,5R)-5-carboxypyrrolidin-3-yl)amino)-N,N,N-trimethyl-2-oxoethan-1- aminium chloride which was used directly in the next step.1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 3H), 7.48 (d, J = 8.0 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 4.44 (s, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 3.62 (s, 3H), 3.59 (s, 3H), 3.48 (s, 3H), 3.42 (s, 3H), 1.45 (s, 9H). LCMS (M+H+): 460.2, found 460.2. 10 H 20 N3O3 + [M] + 230.15, found 230.15.

[0480] Step 5: Fmoc-OSu (3.56 g, 10.6 mmol) and NaHC03(4.92 g, 58.6 mmol) were added to a solution of 2-(((3S,5R)-5-carboxypyrrolidin-3-yl)amino)-N,N,N- trimethyl-2-oxoethan-1-aminium chloride (2.7 g, 12 mmol) in THF (30 mL) and water (30 mL) at room temperature. The mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to pH ~3 with 1 M HC1 and concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18; Mobile Phase A: water (0.1% HCL), Mobile Phase B: MeCN; Gradient Elution: 5 to 70%; Detector: UV 210 nm. Fractions containing product were concentrated under reduced pressure to give 2-(((3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5- carboxypyrrolidin-3-yl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride.1H NMR (400 MHz, Methanol-d4): d 7.91 - 7.75 (m, 2H), 7.67 - 7.63 (m, 2H), 7.50 - 7.18 (m, 4H), 4.60 - 4.02 (m, 7H), 3.86 - 3.79 (m, 1H), 3.43 - 3.41 (m, 2H), 3.34 (s, 8H), 2.40 - 2.31 (m, 2H). LCMS (Method 1): RT = 1.48 min; m / z = 452.22, 452.15. 25 H 30 N3O5 + [M] + 452.22, real 452.15. 1 H NMR (400 MHz, Methanol-d4): d 7.91 - 7.75 (m, 2H), 7.67 - 7.63 (m, 2H), 7.50 - 7.18 (m, 4H), 4.60 - 4.02 (m, 7H), 3.86 - 3.79 (m, 1H), 3.43 - 3.41 (m, 2H), 3.34 (s, 8H), 2.40 - 2.31 (m, 2H).

[0481] Synthesis Scheme 18

[0482]

[0483] (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(dimethylamino)pyrrolidine-2- carboxylic acid trifluoroacetic acid (Fmoc-dProt4NMe2-OH)

[0484] Step 1: Pd / C (1.089 g, 1.0 mmol, 10 wt%) was added to a solution of (2R,4S)-4- aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (2.5 g, 10 mmol) in MeOH (30 mL). Then formaldehyde (2.5 mL, 10 mmol, 37 wt% in water) was added under N2. The reaction mixture was degassed (3 times) with hydrogen gas and stirred at room temperature under hydrogen at 1 atm overnight. The mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by RP flash column chromatography with the following conditions: Column: Flash C18; Mobile Phase A: water (0.1% HCL), Mobile Phase B: MeCN; Gradient Elution: 5 to 70%; Detector: UV 210 nm. Fractions containing product were concentrated under reduced pressure to give (2R,4S)-4-aminopyrrolidine-1,2-dicarboxylic acid 2-methyl ester. Pad. The filter cake was further washed with MeOH (3 x 50 mL). The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with MeOH 0 to 10% in DCM to give (2R,4S)-4-(dimethylamino)pyrrolidine-1,2-dicarboxylic acid 1 -(tert-butyl) 2-methyl ester. MS ESI [M+H] calculated for C 13 H 25 MSESI [M+H] calculated for C + 273.17, found 272.95. 1 H NMR (300 MHz, Chloroform-d): δ 4.49 - 4.21 (m, 1H), 3.86 - 3.83 (m, 1H), 3.74 (s, 3H), 3.25 - 3.22 (m, 1H), 2.92 - 2.78 (m, 1H), 2.25 (s, 6H), 2.18 - 1.98 (m, 2H), 1.44 (m, 9H).

[0485] Step 2: LiOH (15 mL, 15 mmol, 1 N in water) was added to a mixture of (2R,4S)-4-(dimethylamino)pyrrolidine-1,2-dicarboxylic acid 1 -(tert-butyl) 2-methyl ester (1.7 g, 6.2 mmol) in THF (15 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 5 with 1 N HCI solution. The solvent was concentrated under vacuum to provide the crude product which was used directly in the next step.

[0486] Step 3: TFA (10 mL, 5.4 mmol) was added to a stirred mixture of (2R,4S)-1 -(tert- butyloxycarbonyl)-4-(dimethylamino)pyrrolidine-2-carboxylic acid (1.4 g, 5.4 mmol) in DCM (30 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to give crude (2R,4S)-4-(dimethylamino)pyrrolidine-2-carboxylic acid. MS ESI [M+H] calculated for C 13 N2O2 [M - H] - 157.11, found 157.10.

[0487] Step 4: NaHC03 (2.12 g, 25.3 mmol) and Fmoc-OSu (1.71 g, 5.06 mmol) were added to a stirred solution of (2R,4S)-4-(dimethylamino)pyrrolidine-2-carboxylic acid (800 mg, 5.06 mmol) in THF (15 mL) and water (15 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The pH was adjusted to 3 with 1 N HC1. The solvent was concentrated under reduced pressure and the residue was purified by Rp flash column chromatography with the following conditions: 330 g C18 column, 2 to 2% in 5 min, 2 to 50% in 30 min, MeCN in water (0.05% TFA) to give (3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxy-N,N- dimethylpyrrolidin-3-aminium 2,2,2-trifluoroacetate. MS ESI [M+H] calculated for C25H30F3NN04, 461.21, found 461.20. 25 H 25 MS ESI [M+H] calculated for C25H30F3NN04, 461.21, found 461.20. + 381.17, found 381.10. 1 H NMR (300 MHz, DMSO-d6): d 10.53 (s, 1H), 7.92 - 7.86 (m, 2H), 7.69 - 7.63 (m, 2H), 7.45 - 7.32 (m, 4H), 4.56 - 4.53 (m, 1H), 4.41 - 4.29 (m, 3H), 4.17 - 3.89 (m, 2H), 3.83 - 3.62 (m, 1H), 2.83 - 2.80 (s, 6H), 2.62 - 2.47 (m, 1H), 2.40 - 2.36 (m, 1H). 19 F NMR (282 MHz, DMSO-d6): d -73.73.

[0488] Synthesis Scheme 19

[0489]

[0490] (3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxy-N,N,N- trimethylpyrrolidin-3-aminium chloride (Fmoc-dProt4NMe3-OH)

[0491] Step 1 : NaHC03 (8.3 g, 98 mmol) and iodomethane (4.6 mL, 73.7 mmol) were added to a solution of (2R,4S)-4-amino pyrrolidine-1,2-dicarboxylic acid 1-(tert- butyl) 2-methyl ester (3.0 g, 12.3 mmol) in MeOH (30 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and filtered, the filtrate was concentrated under reduced pressure to give (3S,5R)-1-(tert-butoxycarbonyl)-5- (methoxycarbonyl)-N,N,N-trimethyl pyrrolidin-3-ium iodide which was used in Step 2 without purification. For C 14 H 27 N2O4[M] + 287.20, found 287.15.

[0492] Step 2: 1 N aqueous LiOH (22 mL, 22 mmol) was added to a solution of (3S,5R)-1-(tert- butoxycarbonyl)-5-(methoxycarbonyl)-N,N,N-trimethyl pyrrolidin-3-ium iodide (6.5 g, 11 mmol) in THF (23 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The mixture was acidified to pH ~ 5 with 1 M aqueous HC1 and then concentrated under reduced pressure to give (3S,5R)-1-(tert-butoxycarbonyl)-5-carboxy-N,N,N-trimethyl pyrrolidin-3-ium chloride which was used in Step 3 without purification. For C 13 H 25 N2O4[M] + 273.18, found 273.15.

[0493] Step 3: TFA (20 mL, 260 mmol) was added to a mixture of (3S,5R)-1-(tert- butoxycarbonyl)-5-carboxy-N,N,N-trimethyl pyrrolidin-3-ium chloride (6.6 g, 11 mmol) in DCM (20 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give 2,2,2-trifluoroacetic acid, (3S,5R)-1-(tert-butoxycarbonyl)-5-carboxy-N,N,N-trimethyl pyrrolidin-3-ium salt which was used in Step 4 without purification. For C8H 17 N2O2[M] + 173.13, found 173.25.

[0494] Step 4: NaHC03(5.92 g, 70.5 mmol) and Fmoc-OSu (4.28 g, 12.7 mmol) were added to a mixture of (3S,5R)-5-carboxy-N,N,N-trimethylpyrrolidin-3-aminium trifluoroacetate (8.1 g, 14 mmol) in THF (40 mL) and water (40 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The mixture was acidified to pH ~5 with 1 N aqueous HC1 and then concentrated under reduced pressure. The residue was suspended in a 9:1 (v / v) mixture of DCM and MeOH and the solids were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water (2 mM HC1), mobile phase B: MeCN; gradient elution: 2 to 35%; detector: UV 210 nm. Fractions containing the product were concentrated under reduced pressure to give (3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxy-N,N,N-trimethylpyrrolidin-3-aminium chloride.1H NMR (300 MHz, DMSO-d6): d 13.30 (s, 1H), 7.94 - 7.89 (m, 2H), 7.72 - 7.64 (m, 2H), 7.46 - 7.33 (m, 4H), 4.57 - 4.14 (m, 5H), 3.86 - 3.78 (m, 2H), 3.12 - 3.10 (m, 9H), 2.83 - 2.73 (m, 1H), 2.50 - 2.35 (m, 1H). LCMS: m / z 460.2 (M+H)+, 462.2 (M+Na)+. 23 H 27 N2O4[M] + 395.20, found 395.20. 1 H NMR (300 MHz, DMSO-d6): d 13.30 (s, 1H), 7.94 - 7.89 (m, 2H), 7.72 - 7.64 (m, 2H), 7.46 - 7.33 (m, 4H), 4.57 - 4.14 (m, 5H), 3.86 - 3.78 (m, 2H), 3.12 - 3.10 (m, 9H), 2.83 - 2.73 (m, 1H), 2.50 - 2.35 (m, 1H).

[0495] Synthesis Scheme 20

[0496]

[0497] (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2-(tert-butoxy)-2- oxoethoxy)pyrrolidine-2-carboxylic acid (Fmoc-dProt4OAcO(tBu)-OH)

[0498] NaHCO3(22.9 g, 0.27 mmol) and CbzCl (24.3 g, 0.14 mmol) were added to a stirred solution of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid (15.6 g, 0.12 mol) in DI water (75 mL) and THF (30 mL). The reaction mixture was stirred at room temperature for 12 h. The reaction solution was diluted in DI water (100 mL) and extracted with MTBE (2 x 150 mL). The aqueous solution was adjusted to pH ~ 2 by the addition of 1 N aqueous HC1. The solution was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give (2R,4S)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid. The crude product was used directly in Step 2 without further purification. 1 H NMR (400 MHz, Chloroform-d): δ 7.28 (s, 5H), 6.82 - 6.38 (m, 1H), 5.16 - 5.11 (m, 2H), 4.70 - 4.44 (m, 2H), 4.16 - 4.11 (m, 1H), 3.63 - 3.57 (m, 2H), 2.34 - 2.06 (m, 3H), 1.27 (d, J = 12 Hz, 1H).

[0499] Step 2: To a solution of (2R,4S)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2- carboxylic acid (36.0 g, 136 mmol) in anhydrous DMF (240 mL) was added NaHCO3(34.2 g, 407 mmol), Nal (2.03 g, 13.6 mmol), and BnBr (19.3 mL, 162 mmol). The mixture was stirred at room temperature for 12 h. The reaction solution was diluted in DI water (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 60% to give (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid dibenzyl ester. 1 H NMR (400 MHz, Chloroform-d): δ 7.21 (m, 10H), 5.12 - 5.05 (m, 2H), 4.94 - 4.91 (m, 2H), 4.49 - 4.36 (m, 2H), 3.57 - 3.56 (m, 2H), 2.42 (m, 1H), 2.01 - 1.95 (m, 1H).

[0500] Step 3: Add NaH (2.45 g, 61 mmol, 60 wt% dispersion in mineral oil) to a solution of tert-butyl 2-bromoacetate (22.3 mL, 150 mmol) and TBAI (1.51 g, 4.08 mmol) in anhydrous THF (30 mL). Cool the suspension to -10 °C. Add dropwise a solution of (2R,4S)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (14.5 g, 40.8 mmol) in anhydrous THF (30 mL) to the mixture, maintaining below -10 °C. After addition, allow the reaction mixture to warm to room temperature and stir at room temperature for 12 h. Slowly pour the reaction mixture into ice-saturated NH4Cl (75 mL) and extract with EtOAc (2 × 100 mL). Wash the combined organic layers with brine (50 mL), dry to anhydrous Na2SO4, filter, and concentrate under vacuum. The residue was purified by silica gel column chromatography by elution with 1 to 50% EtOAc in PE to give (2R,4S)-4-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-1,2-dicarboxylic acid dibenzyl ester. 1 ¹H NMR (400MHz, chloroform-d): δ 7.32–7.15 (m, 10H), 5.16–4.97 (m, 4H), 4.44–4.41 (m, 1H), 3.75–3.68 (m, 1H), 3.64–3.59 (m, 1H), 2.33–2.19 (m, 2H), 1.41 (s, 9H).

[0501] Step 4: Hydrogenate a solution of (2R,4S)-4-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-1,2-dicarboxylic acid dibenzyl ester (18.0 g, 48.9 mmol) in a 1:1 (v / v) mixture of EtOAc and EtOH (460 mL) for 24 h at 50 °C and 50 psi under hydrogen atmosphere on Pd / C (1.0 g, 10 wt%). Filter the reaction mixture. The solution was concentrated to obtain the crude product (2R,4S)-4-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-2-carboxylic acid. For C... 11 H 19 MS ESI[M+H] calculated by NO5 + 246.13, measured value 246.2. 1 ¹H NMR (400MHz, methanol-d⁴): δ 4.32–4.29 (m, 1H), 4.17–4.12 (m, 1H), 4.06–4.04 (t, J = 8Hz, 2H), 3.46–3.36 (m, 1H), 2.55–2.49 (m, 1H), 2.06–1.99 (m, 1H), 1.47 (s, 9H).

[0502] Step 5: NaHC03 (6.2 g, 73 mmol) and Fmoc-OSu (12.3 g, 36.5 mmol) were added to a solution of (2R,4S)-4-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-2-carboxylic acid (9.0 g, 37 mmol) in dioxane (40 mL) and DI water (20 mL). The reaction mixture was stirred at room temperature for 5 h. The reaction solution was diluted in DI water (50 mL) and extracted with MTBE (2 x 30 mL). The pH was adjusted to 2 with 1 N aqueous HC1 and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with EtOAc in PE 1 to 100% to give (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2-(tert-butoxy)-2- oxoethoxy)pyrrolidine-2-carboxylic acid. 1 H NMR (400 MHz, Chloroform-d): δ 7.69 - 7.67 (m, 2H), 7.62 - 7.60 (m, 2H), 7.51 - 7.43 (m, 4H), 4.66 - 4.33 (m, 3H), 4.18 - 4.15 (m, 2H), 3.88 - 3.83 (m, 2H), 3.63 - 3.51 (m, 2H), 2.35 - 2.30 (m, 1H), 2.24 - 2.08 (m, 1H), 1.41 (s, 9H).

[0503] Synthesis Scheme 21

[0504]

[0505] 2-(((3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxypy rrolidin-3-yl)oxy)-N,N,N-trimethylethan-1-aminium chloride (Fmoc-dProt4OEtNMe3-OH)

[0506] Step 1: tert-Butyl (E)-N,N’-diisopropylcarbamimidate (22.7 g, 113 mmol) was added to a solution of (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4- hydroxypyrrolidine-2-carboxylic acid (10.0 g, 28.3 mmol) in DCM (100 mL) at room temperature. The mixture was stirred at 40 °C for 1 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 70% to give (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-((9H-fluoren-9- yl)methyl) 2-(tert-butyl) ester. MS ESI [M+Na] calculated for C32H37NO7Na 593.24, found 593.20. 24 H 27 MS ESI [M+Na] calculated for C32H37NO7Na 593.24, found 593.20. + 432.19, found 432.05.

[0507] Step 2: Aziridine-1-carboxylate benzyl ester (4.85 g, 27.4 mmol) was added to a mixture of (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-((9H-fluoren-9- yl)methyl) 2-(tert-butyl) ester (11.2 g, 27.4 mmol) in toluene (110 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. Trifluoroborane diethyl ether (0.776 g, 5.47 mmol) was added dropwise to the mixture at 0 °C over a period of 1 h. The mixture was stirred at room temperature for another 1 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 70% to give (2R,4S)-4-(2-(((benzyloxy)carbonyl)amino)ethoxy)pyrrolidine-1,2-dicarboxylic acid 1-((9H-fluoren-9-yl)methyl) 2-(tert-butyl) ester. MS ESI [M+Na] calculated for C42H49NO8Na 737.34, found 737.30. 34 H 38 MS ESI [M+Na] calculated for C42H49NO8Na 737.34, found 737.30. + 609.27, found 609.50. 1 H NMR (400 MHz, Methanol-d4): δ 7.74 - 7.56 (m, 2H), 7.55 - 7.41 (m, 1H), 7.37 - 7.16 (m, 10H), 5.03 (s, 2H), 4.43 - 3.96 (m, 5H), 3.70 - 3.52 (m, 1H), 3.51 - 3.19 (m, 5H), 2.38 - 2.16 (m, 1H), 2.08 - 1.91 (m, 1H), 1.39 (s, 9H).

[0508] Step 3: Sodium iodide (4.85 g, 32.4 mmol) and trimethylsilyl chloride (3.52 g, 32.4 mmol) were added to a solution of (2R,4S)-4-(2-(((benzyloxy)carbonyl)amino)ethoxy)pyrrolidine-1,2-dicarboxylic acid 1-((9H-fluoren-9- yl)methyl) 2-(tert-butyl) ester (1.9 g, 3.2 mmol) in MeCN (20 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (40 g); mobile phase A: water (0.05% TFA), mobile phase B: MeCN; gradient elution: 2 to 30%; detector: UV 210 nm. Fractions containing the product were concentrated under reduced pressure to give (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2- aminoethoxy)pyrrolidine-2-carboxylic acid. MS ESI [M+H] calculated for C28H32N2O6, 488.22, found 488.40. 22 H 25 MS ESI [M+H] calculated for C28H32N2O6, 488.22, found 488.40. + 397.17, found 397.40.

[0509] Step 4: Methyl iodide (3.04 g, 21.4 mmol) and NaHC03(1.80 g, 21.4 mmol) were added to a solution of (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2- aminoethoxy)pyrrolidine-2-carboxylic acid (1.70 g, 4.3 mmol) in MeOH (15 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water (0.1% HCL), mobile phase B: MeCN; gradient elution: 2 to 70%; detector: UV 210 nm. Fractions containing the product were concentrated under reduced pressure to give 2-(((3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5- carboxypy rrolidin-3 -yl)oxy)-N,N,N-trimethyl ethan-1 -aminium chloride. MS ESI [M+H] calculated for C32H39N3O6, 573.28, found 573.30. 25 H 31 MS ESI [M+H] calculated for C32H39N3O6, 573.28, found 573.30. + 439.22, found 439.15. 1H NMR (400MHz, methanol-d4): δ7.82–7.59(m,4H),7.41–7.26(m,4H),4.40–4.38(m,2H),4.36–4.34(m, 3H),4.07–3.90(m,2H),3.79–3.44(m,4H),3.13(s,9H),2.54–2.31(m,1H),2.10–1.92(m,1H).

[0510] Synthesis Scheme 22

[0511]

[0512] (2R,4S)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-4-(1-triphenylmethyl-1H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid (Fmoc-dProt4Tet(Trt)-OH)

[0513] Step 1: Toluenesulfonyl chloride (31.1 g, 163 mmol) and pyridine (19.8 mL, 245 mmol) were added to a solution of (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (20.0 g, 82 mmol) in CHCl3 (200 mL) at room temperature. The mixture was stirred for 24 h at room temperature. The mixture was quenched with 0.1 M HCl and extracted with DCM (2 × 350 mL). The combined organic layers were washed with brine (2 × 250 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography by elution with EtOAc in PE to give (2R,4R)-4-(toluenesulfonyloxy)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester. (The last sentence appears to be incomplete and requires further context.) 18 H 25 MS ESI [M+Na] calculated using NO7SNa + 422.14, measured value 422.05.

[0514] Step 2: A mixture of (2R,4R)-4-(toluenesulfonyloxy)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (15 g, 38 mmol) and tetrabutylammonium cyanide (25 g, 94 mmol) in DMSO (150 mL) was heated overnight at 45 °C. The mixture was quenched with water (100 mL) and extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography by elution with EtOAc in PE to give (2R,4S)-4-cyanopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester. (For C...)12 H 18 N2O4–Boc[M–Boc] + 155.13, found 155.10. 1 H NMR (300 MHz, Chloroform-d): δ 4.53 - 4.35 (m, 1H), 4.01 - 3.84 (m, 1H), 3.75 (s, 3H), 3.72 - 3.57 (m, 1H), 3.35 - 3.17 (m, 1H), 2.63 - 2.42 (m, 1H), 2.42 - 2.30 (m, 1H), 1.47 - 1.42 (m, 9H).

[0515] Step 3: A mixture of (2R,4S)-4-cyanopyrrolidine-1,2-dicarboxylic acid 1-(tert- butyl) 2-methyl ester (3.5 g, 14 mmol), dibutyltin dilaurate (4.83 g, 13.8 mmol), and azidotrimethylsilane (3.65 mL, 27.5 mmol) in toluene (30 mL) was heated and stirred at 50 °C overnight. The mixture was concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water (0.05% TFA), mobile phase B: MeCN; gradient elution: 2 to 26%; detector: UV 210 nm. Fractions containing product were concentrated under reduced pressure to give (2R,4S)-4-(1H-tetrazol-5-yl)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester. MS ESI [M+Na] calculated for C14H21N7O5Na 395.15, found 395.10. 12 H 19 MS ESI [M+Na] calculated for C14H21N7O5Na 395.15, found 395.10. + 320.14, found 320.00. 1 H NMR (300 MHz, Acetonitrile-d3): δ 4.48 - 4.38 (m, 1H), 3.99 - 3.82 (m, 2H), 3.74 (d, J = 6.1 Hz, 3H), 3.71 - 3.58 (m, 1H), 2.75 - 2.39 (m, 2H), 1.46 - 1.41 (m, 9H).

[0516] Step 4: A solution of HC1 (4.0 M in 1,4-dioxane, 30 mL, 120 mmol) was added to a solution of (2R,4S)-4-(1H-tetrazol-5-yl)pyrrolidine-1,2-dicarboxylic acid 1-(tert- butyl) 2-methyl ester (2.8 g, 9.4 mmol) in THF (30 mL) at room temperature. The mixture was stirred at room temperature for 8 h. The mixture was concentrated under reduced pressure to give (2R,4S)-4-(1H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid methyl ester, which was used in Step 5 without purification. MS ESI [M+Na] calculated for C9H10N5O3Na 255.07, found 255.10. 12N5O2calcd MS ESI [M+H] + 198.09, found 198.05.

[0517] Step 5: 1 N aqueous LiOH (16.5 mL, 16.5 mmol) was added to a solution of (2R,4S)-methyl 4-(1 H-tetrazol-5-yl)pyrrolidine-2-carboxylate (2.5 g, 8.2 mmol) in THF (17 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was acidified to pH ~5 with 1 M HC1 and concentrated under reduced pressure to give (2R,4S)-4-(1 H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid which was used in Step 6 without purification. For C6H7N5O2: calc'd MS ESI [M+H] m / z 198.0; found m / z 198.0. 10 N5O2calcd MS ESI [M+H] + 184.08, found 184.05.

[0518] Step 6: NaHC03(2.98 g, 35.5 mmol) and Fmoc-OSu (2.63 g, 7.81 mmol) were added to a solution of (2R,4S)-4-(1 H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid (2.6 g, 7.1 mmol) in THF (20 mL) and water (20 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The mixture was acidified to pH ~5 with 1 M HC1 and concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water (0.05% TFA), mobile phase B: MeCN; gradient elution: 2 to 45%; detector: UV 210 nm. Fractions containing product were concentrated under reduced pressure to give (2R,4S)-1 -(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(1 H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid. For C26H23N5O4: calc'd MS ESI [M+H] m / z 460.2; found m / z 460.2. 21 H 20 N5O4calcd MS ESI [M+H] + 406.14, found 406.05.

[0519] Step 7: TEA (1.34 mL, 9.62 mmol) and triphenylmethyl chloride (2.15 g, 7.70 mmol) were added to a solution of (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(1H- tetrazol-5-yl)pyrrolidine-2-carboxylic acid (2.6 g, 6.4 mmol) in DCM (30 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, then warmed to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water, mobile phase B: MeCN; gradient elution: 2 to 72 %; detector: UV 210 nm. Fractions containing the product were concentrated under reduced pressure to give (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(1- triphenylmethyl-1H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid.1H NMR (300 MHz, DMSO-d6): δ 12.95 (s, 1H), 7.97 - 7.80 (m, 2H), 7.70 - 7.54 (m, 2H), 7.47 - 7.14 (m, 13H), 7.07 - 6.86 (m, 6H), 4.55 - 4.08 (m, 4H), 3.96 - 3.79 (m, 2H), 3.78 - 3.65 (m, 1H), 2.73 - 2.55 (m, 1H), 2.43 - 2.24 (m, 1H). 40 H 32 N5O4[M – H] - 646.25, found 646.20. 1 H NMR (300 MHz, DMSO-d6): δ 12.95 (s, 1H), 7.97 - 7.80 (m, 2H), 7.70 - 7.54 (m, 2H), 7.47 - 7.14 (m, 13H), 7.07 - 6.86 (m, 6H), 4.55 - 4.08 (m, 4H), 3.96 - 3.79 (m, 2H), 3.78 - 3.65 (m, 1H), 2.73 - 2.55 (m, 1H), 2.43 - 2.24 (m, 1H).

[0520] Synthesis Scheme 23

[0521]

[0522] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2-amino-2- oxoethyl)phenyl)propanoic acid (Fmoc-F3MCONH2-OH)

[0523] Step 1: A solution of NiCl2-glyme (0.81 g, 3.69 mmol) and 1,10-phenanthroline (0.67 g, 3.69 mmol) in anhydrous DMA (50 mL) was heated at 50 °C for 30 min. To this solution was added a mixture of tert-butyl 2-(3-bromophenyl)acetate (5.00 g, 18.44 mmol), (R)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- iodopropanoate (9.72 g, 18.44 mmol), and TBAI (6.81 g, 18.44 mmol) in anhydrous DMA (50 mL) at rt. Active zinc (2.41 g, 36.9 mmol) was added and stirred at rt for 1 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN; gradient elution: 5 to 82%; detector: UV 210 nm. Fractions containing the product were concentrated under reduced pressure to give (S)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2-(tert-butoxy)-2- oxoethyl)phenyl)propanoate. MS ESI [M+H] calculated for C44H48N2O8, 764.32, found 764.33. 37 H 38 MS ESI [M+H] calculated for C44H48N2O8, 764.32, found 764.33. + 592.26, found 592.45. 1 H NMR (300 MHz, Chloroform-d): δ 7.76 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 7.5 Hz, 2H), 7.44 - 7.27 (m, 9H), 7.19 - 7.09 (m, 2H), 7.05 - 6.83 (m, 2H), 5.30 (s, 2H), 4.75 - 4.68 (m, 1H), 4.50 - 4.31 (m, 2H), 4.23 - 4.09 (m, 1H), 3.11 (d, J = 5.9 Hz, 2H), 2.87 - 2.61 (m, 2H), 1.42 (s, 9H).

[0524] Step 2: TFA (20 mL) was added to a stirred solution of (S)-benzyl 2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(3-(2-(tert-butoxy)-2-oxoethyl)phenyl)propanoate (4.1 g, 6.9 mmol) in DCM (20 mL) at rt. The solution was stirred at rt for 4 h. The solvent was concentrated under reduced pressure to give (S)-2-(3-(2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)phenyl)acetic acid, which was used directly in Step 3. MS ESI [M+H] calculated for C42H42N2O8, 730.29, found 730.30. 33 H 30MS ESI [M+H] calculated for N2O5 + 536.20, found 536.10.

[0525] Step 3: NH4CI (0.66 g, 12.32 mmol), HATU (3.51 g, 9.24 mmol) and DIPEA (2.15 mL, 12.32 mmol) were added to a stirred solution of (S)-2-(3-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- (benzyloxy)-3-oxopropyl)phenyl)acetic acid (3.3 g, 6.2 mmol) in DMF (35 mL) at room temperature. The mixture was stirred at room temperature for 4 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 anhydrous Na2S04and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH in DCM (10: 1; v / v) to give (S)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2- amino-2-oxoethyl)phenyl)propanoate. LCMS: [M+H] calculated for C39H39N02: 595.29, found 595.30. 33 H 31 MS ESI [M+H] calculated for N2O5 + 535.22, found 535.40.

[0526] Step 4: (S)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2- amino-2-oxoethyl)phenyl)propanoate (3.2 g, 6.0 mmol) was dissolved in THF (60 mL). The flask was evacuated and backfilled with N2(5 times). Pd / C (10% w / w, 0.637 g, 0.60 mmol) was added to the flask. The flask was evacuated and backfilled with H2(5 times). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 3 h. The flask was evacuated and backfilled with N2(5 times). The resulting mixture was filtered through a pad of Celite. The filter cake was washed with THF (2 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was recrystallized with MeCN to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2- amino-2-oxoethyl)phenyl)propanoic acid. LCMS: [M+H] calculated for C31H29N02: 479.23, found 479.24. C 26 H 25 MS ESI [M+H] calculated for N2O5 + 445.17, found 445.15. 1H NMR (300 MHz, Methanol-d4): δ 7.77 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 7.5 Hz, 2H), 7.44 - 7.09 (m, 8H), 4.53 - 4.05 (m, 4H), 3.47 (s, 2H), 3.24 - 3.17 (m, 1H), 2.98 - 2.90 (m, 1H).

[0527] Synthesis Scheme 24

[0528]

[0529] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2((dimethylamino)ethoxy)phenyl)propanoic acid (Fmoc-Me2AEF-OH)

[0530] TFA (5 mL) was added to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)propanoic acid (1.0 g, 1.8 mmol) in DCM (5 mL) at room temperature. The solution was stirred at room temperature for 1 h. The solution was then concentrated under reduced pressure and the residual TFA was co-evaporated with toluene (3 x 15 mL) under vacuum. The crude product was used directly without any further purification.

[0531] The crude product was dissolved in MeOH (20 mL). Formaldehyde (660 μL; 37 wt% in water; 8.9 mmol) and sodium triacetoxyborohydride (1.89 g, 8.90 mmol) were added at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with a few drops of 1 N HCl solution and concentrated in vacuo. The residue was purified by Rp flash column chromatography with the following conditions: C18 FR040-1 (55 g, Luknova Inc., Mansfield, MA); mobile phase A: water (0.1% TFA), mobile phase B: MeCN (0.1% TFA); gradient elution: 10 to 90% over 10 column volumes, flow rate: 40 mL / min; detector: UV 215 nm. Fractions containing the product were combined, concentrated under reduced pressure and lyophilized to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2((dimethylamino)ethoxy)phenyl)propanoic acid. The product was characterized by1H NMR and LC-MS. 28 H 30 MS ESI calculated mass [M+H] for N2O5 + 475.22, found 475.3. 1H NMR (400 MHz, DMSO-d6): δ 12.77 (br. s 1H), 9.77 (br. s, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 7.0 Hz, 2H), 7.42 (t, J = 7.3 Hz, 2H), 7.34 - 7.28 (m, 2H), 7.23 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.3 Hz, 2H), 4.30 - 4.21 (m, 2H), 4.21 - 4.08 (m, 4H), 3.51 - 3.47 (m, 2H), 3.03 (dd, J = 3.7, 13.8 Hz, 1H), 2.84 (s, 6H).

[0532] Synthesis scheme 25

[0533]

[0534] (S)-4-(((9H-fluoren-9-yl)methoxy)carbonyl)-6,6-dimethylmorpholine-3-carboxylic acid (Fmoc-Morpip6diMe-OH)

[0535] Fmoc-OSu (1.7 g, 5.1 mmol) was added to a stirred solution of (S)-6,6-dimethylmorpholine-3-carboxylic acid hydrochloride (0.82 g, 4.2 mmol) in THF (20 mL) and water (20 mL) at room temperature, followed by NaHC03(1.8 g, 21 mmol). The resulting mixture was stirred at room temperature overnight. The pH was adjusted to 5 with 1 N HC1 and extracted with EtOAc (2 x 70 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with MeOH in DCM 0 to 10% to give (S)-4-(((9H-fluoren-9-yl)methoxy)carbonyl)-6,6-dimethylmorpholine-3-carboxylic acid. ESI MS calculated for C 22 H 23 ESI MS calculated for C + 382.16, found 382.2. 1H NMR (600 MHz, DMSO-d6): δ 13.08 (s, 1H), 7.90 (t, J = 7.3 Hz, 2H), 7.67 - 7.56 (m, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.35 - 7.28 (m, 2H), 4.53 - 4.42 (m, 1H), 4.42 - 4.35 (m, 1H), 4.35 - 4.22 (m, 2H), 3.95 (t, J = 10.9 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.36 - 3.32 (m, 2H), 2.84 (m, 1H), 1.10 (s, 3H), 1.07 (s, 3H). 13 CNMR (151 MHz, DMSO-d6): δ 171.1, 155.5, 143.7, 140.8, 127.7, 127.1, 125.2, 125.0, 120.1, 70.4 / 69.9, 67.0 / 66.9, 60.4 / 60.2, 53.4 / 52.8, 49.7 / 49.3, 46.7 / 46.5, 27.3 / 27.1, 20.4 / 20.3.

[0536] Synthesis Scheme 26

[0537]

[0538] N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(triphenylmethylamino)propyl)glycine (Fmoc-NEtCONHTrtG-OH)

[0539] Step 1: Acrylamide (2.00 g, 28.1 mmol) was added to a stirred mixture of triphenylmethyl chloride (7.84 g, 28.1 mmol) and zinc (II) chloride (3.83 g, 28.1 mmol) in MeCN (50 mL). The resulting mixture was stirred at room temperature for 10 min. Subsequently, a solution of triethylamine (3.92 mL, 28.1 mmol) in MeCN (20 mL) was added to the mixture over 15 min. The reaction was stirred at room temperature for another 15 min. After quenching with 5% aqueous sodium bicarbonate solution and stirring for another 15 min, the organic solvents were concentrated in vacuo until precipitation occurred. The product was recovered by filtration, triturated with water followed by Et20, and dried to give N-triphenylmethyl acrylamide.1H NMR (600 MHz, DMSO-d6): δ 7.62 - 7.55 (m, 6H), 7.45 - 7.36 (m, 6H), 7.34 - 7.28 (m, 3H), 6.22 (d, J = 7.8 Hz, 1H), 5.82 (d, J = 10.2 Hz, 1H), 4.62 (s, 2H). 22 H 20 MS ESI [M+H] calculated 314.4, found 314.3. + 314.4, found 314.3. 1H NMR (500 MHz, Chloroform-d): δ 7.36 - 7.22 (m, 15H), 6.71 (s, 1H), 6.41 - 6.13 (m, 2H), 5.68 (dd, J = 9.1, 2.5 Hz, 1H).

[0540] Step 2: Glycine (0.766 g, 10.2 mmol) was added to a stirred solution of KOH (0.607 g, 10.8 mmol) in MeOH (55 mL) and the reaction was stirred at room temperature for 10 min. N- Trityl acrylamide (3.20 g, 10.2 mmol) was added to the mixture and the reaction was stirred at 60 °C overnight. The mixture was cooled to room temperature, acidified with AcOH (1.5 mL), and allowed to stand until precipitation occurred. The residue was filtered and triturated with MeOH followed by DCM to give (3-oxo-3-(tritylamino)propyl)glycine. MS ESI [M+H] calculated for C28H29NO5, 459.21, found 459.21. 24 H 25 MS ESI [M+H] calculated for C28H29NO5, 459.21, found 459.21. + 389.47, found 389.41. 1 H NMR (500 MHz, Methanol-d4): δ 7.36 - 7.18 (m, 15H), 3.81 (s, 2H), 3.26 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H).

[0541] Step 3: A mixture of N-(9-fluorenylmethoxycarbonyloxy)succinimide (1.28 g, 3.79 mmol), (3-oxo-3-(tritylamino)propyl)glycine (1.34 g, 3.45 mmol), and Na2CO3(0.804 g, 7.59 mmol) in a 1:1 (v / v) mixture of water and acetone (40 mL) was stirred at room temperature overnight. The mixture was partially concentrated in vacuo to remove acetone and neutralized to pH 7 by the addition of 1 N HCI. The mixture was extracted with EtOAc (2 x 50 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The solid was triturated with Et2O to give N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)glycine. MS ESI [M+H] calculated for C44H43NO7, 711.31, found 711.31. 39 H 35 MS ESI [M+H] calculated for C44H43NO7, 711.31, found 711.31. + 611.71, found 611.50. 1H NMR (500MHz, DMSO-d6): δ12.75(s,1H),8.76(s,0.5H),8.64(s,0.5H),7.90(t,J=8.4Hz,2H),7.68(d,J=7.5Hz,1H),7.62(d,J=7.5Hz,1H),7.43(q ,J=7.3Hz,2H),7.34–7.14(m,17H),4.33–4.17(m,3H),3.86(s,1H),3.83 (s,1H),3.46(t,J=6.8Hz,1H),3.38(t,J=6.8Hz,1H),2.61–2.54(m,2H).

[0542] Synthesis Scheme 27

[0543]

[0544] N-(2-(1,3,4-oxadiazol-2-yl)ethyl)-N-(((9H-fluorene-9-yl)methoxy)carbonyl)glycine(Fmoc-NEt3OxadG-OH)

[0545] Step 1: At room temperature, tert-butyl 2-bromoacetate (6.0 g, 30.8 mmol) and DIPEA (10.8 mL, 61.5 mmol) were added to a stirred solution of tert-butyl 3-aminopropionate hydrochloride (16.8 g, 92 mmol) in MeCN (60 mL). The solution was stirred for 4 h at room temperature. The reactants were concentrated under reduced pressure and purified by silica gel column chromatography, eluting with EtOAc 0 to 80% in PE, to give tert-butyl 3-((2-(benzyloxy)-2-oxoethyl)amino)propionate. (For C...) 16 H 23 MSESI[M+Na] calculated using NO4Na + 316.16, measured value 316.25. 1 ¹H NMR (400MHz, chloroform-d): δ 7.50–7.21 (m, 5H), 5.19 (s, 2H), 3.50 (s, 2H), 2.91–2.88 (m, 2H), 2.51–2.45 (m, 2H), 1.47 (s, 9H).

[0546] Step 2: Fmoc-OSu (6.4 g, 19.0 mmol) and NaHC03(8.9 g, 106 mmol) were added to a solution of tert-butyl 3-((2-(benzyloxy)-2-oxoethyl)amino)propanoate (6.2 g, 21.1 mmol) in THF (60 mL) and H20 (60 mL) at room temperature. The reaction was stirred at room temperature overnight. The mixture was extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (250 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by Rp flash column chromatography with the following conditions: column: Flash C18; mobile phase A: water (0.1% TFA), mobile phase B: MeCN; gradient elution: 5 to 70%; detector: UV 210 nm. Fractions containing the product were concentrated under reduced pressure to give tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(2-(benzyloxy)-2- oxoethyl)amino)propanoate. MS ESI [M+Na] calculated for C3oH35FN2O7Na 538.23, found 538.15. 31 H 33 NO6Na calculated MS ESI [M+Na] + 538.23, found 538.15.

[0547] Step 3: TFA (70 mL, 909 mmol) was added to a stirred solution of tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(2-(benzyloxy)-2-oxoethyl)amino)propanoate (7 g, 13.6 mmol) in DCM (70 mL) at room temperature. The solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(2-(benzyloxy)-2-oxoethyl)amino)propanoic acid, which was used in Step 4 without further purification. MS ESI [M+H] calculated for C2oH21FN2O6 460.17, found 460.30. 27 H 26 NO6 calculated MS ESI [M+H] + 460.17, found 460.30.

[0548] Step 4: Isobutyl chloroformate (1.6 g, 11.4 mmol) was added to a stirred solution of 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(2-(benzyloxy)-2-oxoethyl)amino)propanoic acid (5.0 g, 10.9 mmol) and 4-methylmorpholine (1.7 g, 16.3 mmol) in THF (50 mL) at -78 °C. After 15 min, formohydrazide (1.0 g, 16.3 mmol) was added and the resulting mixture was allowed to warm slowly to room temperature. After 1 h, the reaction mixture was quenched with 0.5 M HC1 and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na2S04, 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 give N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-(2-formylhydrazino)-3- oxopropyl)benzyl glycinate. MS ESI [M+H] calculated for C3oH34N5O7 598.24, found 598.35. 28 H 28 MS ESI [M+H] calculated for C3oH34N5O7 598.24, found 598.35. + 502.19, found 502.35.

[0549] Step 5: (Methoxycarbonyl sulfamidate)triethylammonium hydroxide (Burgess reagent, 2.5 g, 10.6 mmol) was added to a solution of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-(2-formylhydrazino)-3-oxopropyl)benzyl glycinate (5.3 g, 10.6 mmol) in toluene (53 mL) at room temperature. The mixture was stirred at 110 °C for 1 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc 0 to 70% in PE to give N-(2-(1,3,4-oxadiazol-2-yl)ethyl)-N-(((9H-fluoren-9-yl)methoxy)carbonyl)benzyl glycinate. MS ESI [M+H] calculated for C3oH34N5O7 598.24, found 598.35. 28 H 26 MS ESI [M+H] calculated for C3oH34N5O7 598.24, found 598.35. + 484.18, found 484.20.

[0550] Step 6: N-(2-(l,3,4-oxadiazol-2-yl)ethyl)-N-(((9H-fluoren-9- yl)methoxy)carbonyl)glycine benzyl ester (3.0 g, 6.2 mmol) was dissolved in EtOAc (60 mL). The flask was evacuated and backfilled with N2(5 times). Pd / C (0.66 g, 6.2 mmol, dry, 10 wt%) was added to the flask. The flask was evacuated and backfilled with H2(5 times). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 h. The flask was evacuated and backfilled with N2(5 times). The resulting mixture was filtered through Celite. The filter cake was washed with EtOAc (2 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was recrystallized from Et2O to give N-(2-(l,3,4-oxadiazol-2-yl)ethyl)-N-(((9H-fluoren-9- yl)methoxy)carbonyl)glycine. MS ESI [M+H] calculated for C28H30N4O7, 542.21, found 542.21. Celite. The filter cake was washed with EtOAc (2 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was recrystallized from Et2O to give N-(2-(l,3,4-oxadiazol-2-yl)ethyl)-N-(((9H-fluoren-9- yl)methoxy)carbonyl)glycine. MS ESI [M+H] calculated for C28H30N4O7, 542.21, found 542.21. 21 H 20 MS ESI [M+H] calculated for C28H30N4O7, 542.21, found 542.21. + 394.13, found 393.95. 1 H NMR (300 MHz, DMSO-d6): δ 12.71 (s, 1H), 9.14 (d, J = 3.8 Hz, 1H), 7.98 - 7.72 (m, 2H), 7.90 - 7.80 (m, 2H), 7.46 - 7.15 (m, 4H), 4.42 (d, J = 5.7 Hz, 1H), 4.34 - 4.15 (m, 2H), 4.04 - 4.02 (m, 1H), 3.89 (s, 1H), 3.71 - 3.60 (m, 1H), 3.47 - 3.42 (m, 1H), 3.17 - 3.11 (m, 1H), 2.78 - 2.73 (m, 1H).

[0551] Synthesis Scheme 28

[0552]

[0553] N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)-L- alanine (Fmoc-NEtCONHTrt-OH)

[0554] Step 1 : To a mixture of acrylamide (10.7 g, 150 mmol) in toluene (800 mL) was added triphenylmethanol (58.6 g, 225 mmol) and p-TsOH (7.8 g, 45.0 mmol) at room temperature. The reaction was stirred and heated at 110 °C with a Dean-Stark apparatus overnight. The resulting solution was cooled to room temperature and quenched with saturated aqueous NaHC03. The aqueous layer was extracted with EtOAc (3 x 1000 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc in PE 0 to 35% to give N-tritylacrylamide. MS ESI [M+H] calculated for C2iH2iN calculated for C2iH2iN 22 H 20 MS ESI [M+H] calculated for C2iH2iN calculated for C2iH2iN + 314.15, found 314.20. 1 H NMR (300 MHz, Chloroform-d): δ 7.37 - 7.15 (m, 15H), 6.26 - 6.12 (m, 2H), 5.62 - 5.60 (m, 1H).

[0555] Step 2: TEA (5.6 mL, 40.2 mmol) was added to a suspension of L-phenylalanine hydrochloride (8.7 g, 40.2 mmol) in toluene (150 mL) at room temperature. The resulting mixture was stirred at room temperature for 10 min. N-tritylacrylamide (8.4 g, 26.8 mmol) was then added to the mixture. The reaction mixture was stirred and heated at 100 °C overnight. The volatiles were concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc in PE 0 to 65% to give (3-oxo-3-(tritylamino)propyl)-L-phenylalanine benzyl ester. MS ESI [M+H] calculated for C3iH3iN03 calculated for C3iH3iN03 32 H 33 MS ESI [M+H] calculated for C2iH2iN calculated for C2iH2iN + 493.24, found 493.20. 1 H NMR (300 MHz, Chloroform-d): δ 9.03 (s, 1H), 7.42 - 7.22 (m, 15H), 7.22 - 7.17 (m, 5H), 5.13 (d, J = 1.8 Hz, 2H), 3.44 - 3.30 (m, 1H), 3.05 - 2.91 (m, 1H), 2.82 - 2.69 (m, 1H), 2.42 - 2.37 (m, 2H), 1.18 (d, J = 6.9 Hz, 3H).

[0556] Step 3: DIPEA (6.8 mL, 39.0 mmol) and Fmoc-OSu (5.3 g, 15.6 mmol) were added to a solution of (3-oxo-3-(tritylamino)propyl)-L-alanin benzyl ester (6.4 g, 13.0 mmol) in DCM (60 mL) at room temperature. The reaction mixture was stirred at room temperature overnight then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in PE 0 to 45% to give N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)-L-alanin benzyl ester. ESI [M+H] calculated for C64H57NO8 925.38, found 925.35. 47 H 43 ESI [M+H] calculated for C64H57NO8 925.38, found 925.35. + 715.31, found 715.35. 1 HNMR (300 MHz, Acetonitrile-d3): δ 7.89 - 7.73 (m, 2H), 7.71 - 7.51 (m, 2H), 7.47 - 6.94 (m, 24H), 5.18 - 4.87 (m, 2H), 4.55 - 4.33 (m, 2H), 4.31 - 4.12 (m, 2H), 3.52 - 3.14 (m, 2H), 2.58 - 2.25 (m, 2H), 2.05 - 1.97 (m, 3H).

[0557] Step 4: N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)-L-alanin benzyl ester (5.3 g, 7.4 mmol) was dissolved in EtOAc (40 mL). The flask was evacuated and backfilled with N2(5 times). Pd / C (2 g, 18.79 mmol, dry, 10 wt%) was added to the flask. The flask was evacuated and backfilled with H2(5 times). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 6 h. The flask was evacuated and backfilled with N2(5 times). The resulting mixture was filtered through a pad of Celite. The filter cake was washed with EtOAc (2 x 80 mL). The filtrate was concentrated under reduced pressure. The mixture of diastereoisomers was separated by SFC: (Column: CHIRALP® Cellulose-SB (250 x 30 mm, 5 pm); Mobile phase: [0.1% 2M NH3-MeOH] in MeOH; B%: 35 to 35% in 10 min). The filter cake was washed with EtOAc (2 x 80 mL). The filtrate was concentrated under reduced pressure. The mixture of diastereoisomers was separated by SFC: (Column: CHIRALP® Cellulose-SB (250 x 30 mm, 5 pm); Mobile phase: [0.1% 2M NH3-MeOH] in MeOH; B%: 35 to 35% in 10 min). The filter cake was washed with EtOAc (2 x 80 mL). The filtrate was concentrated under reduced pressure. The mixture of diastereoisomers was separated by SFC: (Column: CHIRALP® Cellulose-SB (250 x 30 mm, 5 pm); Mobile phase: [0.1% 2M NH3-MeOH] in MeOH; B%: 35 to 35% in 10 min).

[0558] Fractions at 6.23 min were combined and concentrated under vacuum to give N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)-L-alanin. ESI [M+H] calculated for C64H57NO8 925.38, found 925.35. 40 H 37MS ESI [M+H] calculated for N2O5 + 625.26, found 625.20. 1 H NMR (300 MHz, Methanol-d4) δ 7.75 (s, 2H), 7.66 - 7.57 (m, 2H), 7.42 - 7.12 (m, 19H), 4.51 - 4.12 (m, 4H), 3.59 - 3.34 (m, 2H), 2.70 - 2.31 (m, 2H), 1.38 - 1.23 (m, 3H).

[0559] Fractions at 7.62 min were combined and concentrated under vacuum to give N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)-D-alanine.1H NMR (300 MHz, Chloroform-d) δ 7.75 (s, 2H), 7.65 - 7.57 (m, 2H), 7.42 - 7.14 (m, 19H), 4.51 - 4.13 (m, 4H), 3.63 - 3.34 (m, 2H), 2.71 - 2.32 (m, 2H), 1.29 (s, 3H). 40 H 37 MS ESI [M+H] calculated for N2O5 + 625.26, found 625.15. 1 H NMR (300 MHz, Methanol-d4) δ 7.75 (s, 2H), 7.66 - 7.57 (m, 2H), 7.42 - 7.12 (m, 19H), 4.51 - 4.12 (m, 4H), 3.59 - 3.34 (m, 2H), 2.70 - 2.31 (m, 2H), 1.38 - 1.23 (m, 3H).

[0560] Synthesis Scheme 29

[0561]

[0562] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5-difluorohexanoic acid (Fmoc-NleF2-OH)

[0563] Step 1: To a solution of (S)-5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5- oxopentanoic acid (6.00 g, 19.8 mmol) in anhydrous DMF (25 mL) was added N,O- dimethylhydroxylamine hydrochloride (2.32 g, 23.7 mmol), HATU (9.02 g, 23.7 mmol) and DIPEA (10.4 mL, 59.3 mmol). The resulting solution was stirred at room temperature for 90 min. The mixture was partitioned between EtOAc (400 mL) and brine (200 mL). The organic phase was washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified on a silica gel column chromatography eluting with EtOAc in hexanes 0 to 50% to give N 2 -(tert-butoxycarbonyl)-N 5 -methoxy-N5 - methyl-L-glutamic acid tert-butyl ester. MS ESI [M+H] calculated for C 16 H 30 MS ESI [M+H] calculated for C + 347.22, found 347.2.

[0564] Step 2: A solution of methylmagnesium chloride (3.0 M in THF, 33.7 mL, 100 mmol) was added dropwise to a solution of N 2 - (tert-butoxycarbonyl)-N 5 - methoxy-N 5 - methyl-L-glutamic acid tert-butyl ester (7.0 g, 20 mmol) in anhydrous THF (30 mL) and toluene (20.0 mL). The resulting solution was stirred at -78 °C for 4 h, then allowed to warm to 0 °C for 5 min. The reaction mixture was then quenched by dropwise addition of saturated aqueous NH4Cl solution (40 mL). The mixture was partitioned between EtOAc (200 mL) and saturated aqueous NH4Cl solution (200 mL). The organic phase was washed with saturated aqueous NH4Cl solution (200 mL), water (2 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on a silica gel column chromatography eluting with EtOAc in hexanes 0 to 50% to give (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-5-oxohexanoate. MS ESI [M+H] calculated for C 15 H 27 MS ESI [M+H] calculated for C + 302.20, found 302.2.

[0565] Step 3: (Diethylamino)sulfur trifluoride (6.54 mL, 49.5 mmol) was added to a solution of (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (5.33 g, 17.7 mmol) in DCM (20 mL) at 0 °C. The resulting solution was stirred from 0 °C to room temperature overnight. The solution was poured dropwise into a mixture of saturated aqueous NaHCO3 solution (300 mL) and DCM (200 mL). The mixture was stirred at room temperature for 30 min, then extracted with DCM (2 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified on a silica gel column chromatography eluting with EtOAc in hexanes 0 to 50% to give (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate. MS ESI [M+H] calculated for C 15 H 27 MS ESI [M+H] calculated for C + 324.20, found 324.2.

[0566] Step 4: TFA (6 mL, 80 mmol) was added to a solution of (S)-tert-butyl 2-((tert- butoxycarbonyl)amino)-5,5-difluorohexanoate (1.27 g, 3.93 mmol) in DCM (20 mL). The resulting solution was stirred at room temperature for 3 h. The volatiles were removed under reduced pressure. The residue was dissolved in a 1:1 (v / v) mixture of acetonitrile and water (20 mL). The residual solution was lyophilized. The resulting solid was dissolved in acetone (10 mL) and water (10 mL). Sodium carbonate (0.83 g, 7.9 mmol) and Fmoc-OSu (1.33 g, 3.93 mmol) were added to the resulting solution. The mixture was stirred at room temperature for 2 h. The volatiles were partially evaporated under reduced pressure. The aqueous phase was acidified to pH ~ 3 by the addition of 1 N aqueous HC1. The mixture was extracted with DCM (3 x 80 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified on a silica gel column chromatography eluted with MeOH 0 to 10% in DCM to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5-difluorohexanoic acid. MS ESI [M+H] calculated for C20H22F2N02, 370.17; found 370.3. 21 H 21 MS ESI [M+H] calculated for C20H22F2N02, 370.17; found 370.3. + 390.15, found 390.3. 1 H NMR (400 MHz, DMSO-d6): d 12.61 (s, 1H), 7.90 (d, J = 5 Hz, 2H), 7.72 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 4.31 - 4.30 (m, 2H), 4.25 - 4.22 (m, 1H), 4.02 - 3.98 (m, 1H), 1.98 - 1.84 (m, 4H), 1.61 (t, J = 20 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6): d -88.6.

[0567] Synthesis Scheme 30

[0568]

[0569] (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)phenyl)-3-hydroxypropanoic acid (Fmoc-RbOHPhe4CO2tBu-OH)

[0570] Step 1 : Two batches were run in parallel. (Tert-butoxycarbonyl)glycine ethyl ester (37.0 g, 182 mmol) and anhydrous THF (1.2 L) were added to a three-necked flask. The flask was purged with N2 three times and the solution was cooled to -60 °C. Lithium bis(trimethylsilyl)amide solution (2 M in THF, 191 mL) was added dropwise, maintaining the temperature below -60 °C. The reaction was stirred at -65 °C for 1 h. Then tert-butyl 4-formylbenzoate (30.0 g, 146 mmol) was added while maintaining the mixture below -60 °C. The reaction was then allowed to warm to room temperature and stirred for 4 h. The two batches were combined and added to a saturated aqueous NH4CI solution (1.0 L) and then extracted with EtOAc (3 x 500 mL). The combined organic layers were concentrated under reduced pressure to give the crude product, which was then purified by column chromatography on silica gel eluting with EtOAc in PE (50:1 to 0:1 ; v / v) to provide tert-butyl 4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-1 -hydroxy-3- oxopropyl)benzoate as a mixture of four isomers. The mixture of isomers was separated by HPLC (column: Chiralpak IC, 250 x 4.6 mm, 5 pm; mobile phase: 80% CO2, 20% MeOH; flow rate: 1 mL / min; temperature: 25 °C) to provide the desired isomer as a white solid (21.0 g, 54 mmol, 37% yield over two steps). 21 H 31 Calcd MS ESI [M - tBu - Boc + 2H] + 254, found 254. 1 H NMR (400 MHz, Methanol-d4): d 7.92 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 5.35 - 4.90 (m, 1H), 4.50 - 4.36 (m, 1H), 4.29 - 4.00 (m, 3H), 1.62 - 1.55 (m, 9H), 1.32 (m, 9H), 1.28 - 1.13 (m, 3H).

[0571] Step 2: LiOH . H2O (12.5 g, 298 mmol) was added to a solution of tert-butyl 4-(2-((tert- butoxycarbonyl)amino)-3-ethoxy-1 -hydroxy-3-oxopropyl)benzoate (61.0 g, 149 mmol) in DI water (120 mL) and MeOH (400 mL) and the mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to remove MeOH and the pH was adjusted to 4 to 5. The aqueous solution was extracted with EtOAc (2 x 300 mL) and the combined organic phase was dried over anhydrous Na2S04, then concentrated under reduced pressure to give 2-((tert-butoxycarbonyl)amino)-3-(4-(tert- butoxycarbonyl)phenyl)-3-hydroxypropanoic acid as a mixture of four isomers. The mixture of isomers was separated by HPLC (column: Chiralpak IC, 250 x 4.6 mm, 5 pm; mobile phase: 80% CO2, 20% MeOH; flow rate: 1 mL / min; temperature: 25 °C) to provide the desired isomer as a white solid (21.0 g, 54 mmol, 37% yield over two steps). 19 H 27 Calcd MS ESI [M - Boc + H] + 282, found 282.1 HNMR (400 MHz, CDC13) δ 7.91 (d, J = 7.8 Hz, 2H), 7.54 - 7.39 (m, 2H), 5.44 - 4.95 (m, 1H), 4.46 - 4.33 (m, 1H), 1.59 (s, 9H), 1.32 (m, 9H).

[0572] Step 3: (Three reactions run in parallel, then combined for workup and purification in Step 4). 2-((tert-Butoxycarbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)-3- hydroxypropanoic acid (18.2 g, 44.6 mmol) was dissolved in HCl / dioxane (1 M, 119 mL) and stirred at room temperature for 15 h. Upon completion, the resulting mixture was used directly in the next step.

[0573] Step 4: NaHC03(14.9 g, 6.93 mL, 178 mmol) was then added to the mixture at 0 °C to adjust the pH to 8, and the aqueous phase was separated (solution 1). A solution of Fmoc-OSu (21.0 g, 62.4 mmol) in dioxane (80 mL) was then added to solution 1, and the mixture was stirred at room temperature for 2 h. The three batches were then combined and concentrated under reduced pressure to remove dioxane. The pH of the aqueous solution was adjusted to 3 to 4 using 1 M aqueous HC1. The aqueous solution was then extracted with EtOAc (2 x 200 mL), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 80:1 to 5:1; v / v) to provide 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)phenyl)-3-hydroxypropanoic acid as a mixture of four isomers. Calculated MS ESI [M+Na] 550.3, found 550.3. 29 H 29 NO7 calculated MS ESI [M+Na] + 526, found 526. 1 HNMR (400 MHz, Methanol-d4): δ 7.88 (dd, J = 8.0, 2.0 Hz, 2H), 7.77 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 10.4 Hz, 4H), 7.42 - 7.17 (m, 4H), 5.43 - 4.55 (m, 1H), 5.00 - 4.46 (m, 1H), 4.37 - 4.22 (m, 1H), 4.18 - 3.92 (m, 3H), 1.51 (m, 9H).

[0574] Step 5: NaHC03(14.0 g, 167 mmol, 6.49 mL) and BnBr (28.5 g, 19.8 mL, 167 mmol) were added to a solution of 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)phenyl)-3-hydroxypropanoic acid (28.0 g, 55.6 mmol) in DMF (210 mL). The resulting mixture was stirred at room temperature overnight. Water (200 mL) was added to quench the reaction and the aqueous phase was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with water (200 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (80:1 to 10:1; v / v) to give tert-butyl 4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-1- hydroxy-3-oxopropyl)benzoate as a mixture of four isomers.C 36 H 35 NO7calcd MS ESI [M+Na] + 616, found 616. The mixture of isomers was then separated by SFC (column: DAICEL CHIRALPAK AD (250 x 50 mm, 10 pm); mobile phase: [0.1% NH4OH in EtOH]; [0.1% NH4OH in EtOH] %: 60 to 60%, 11 min), then SFC (column: DAICEL CHIRALPAK AD (250 x 50 mm, 10 pm); mobile phase: [0.1% NH4OH in EtOH]; [0.1% NH4OH in EtOH] %: 50 to 50%, 6.5 min), then SFC (column: DAICEL CHIRALCEL OD (250 x 50 mm, 10 pm); mobile phase: [0.1% NH4OH in EtOH]; [0.1% NH4OH in EtOH] %: 60 to 60%, 10 min) to provide compounds A, B, C and D.

[0575] Step 6: Pd / C (529 mg, 2.25 mmol, 45 wt%) was added to a stirred solution of compound D (6.00 g, 10.1 mmol) in MeOH (500 mL). The resulting mixture was purged with hydrogen gas and stirred at room temperature under a hydrogen atmosphere overnight. The suspension was filtered off The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 80 x 40 mm, 3 pm; mobile phase: [water (HCL) and MeCN]; MeCN%: 45 to 75%, 7 min) to provide (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)phenyl)-3-hydroxypropanoic acid. C 29 H 29 NO7[M - tBu + 2H] + 448, found 448. 1 H NMR (400 MHz, Methanol-d4): δ 7.88 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 7.6 Hz, 2H) 7.57 - 7.47 (m, 4H), 7.55 - 7.22 (m, 4H), 5.42 (d, J = 7.8 Hz, 1H), 4.46 (d, J = 7.6 Hz, 1H), 4.31 (dd, J = 9.8, 6.0 Hz, 1H), 4.16 - 3.97 (m, 2H), 1.52 (s, 9H).

[0576] Synthesis Scheme 31

[0577]

[0578] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)-2-fluorophenyl)propanoic acid (Fmoc-Phe2F4COOtBu-OH)

[0579] Step 1: A mixture of NiCl2.glyme (0.182 g, 0.827 mmol) and 1,10-phenanthroline (0.149 g, 0.827 mmol) in anhydrous DMA (15 mL) was heated at 50 °C for 1 h. Then a mixture of tert-butyl 4-bromo-3-fluorobenzoate (1.365 g, 4.96 mmol), (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoic acid (2.18 g, 4.13 mmol) and TBAI (1.527 g, 4.13 mmol) in anhydrous DMA (20 mL) was added at room temperature. Active zinc (0.541 g, 8.27 mmol) was added to the solution and the resulting suspension was stirred at 40 °C for 4 h. The reaction mixture was quenched with DI water (80 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by Rp flash chromatography with the following conditions: Column: flash C18 (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN; (gradient: 5% B hold for 5 min, up to 52% B in 33 min, 56% B hold for 5.2 min; up to 95% B in 2 min, 95% B hold for 10 min); flow rate: 90 mL / min; detector: UV 210 nm. Fractions containing the product were collected and concentrated in vacuum to give (S)-tert-butyl 4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)-3-fluorobenzoate. ESI [M+H] calculated for C44H45FN3O9 767.30, found 767.30. 36 H 35 ESI [M+H] calculated for C44H45FN3O9 767.30, found 767.30. + 596.24, found 596.20. 1 H NMR (300 MHz, DMSO-d6): d 8.03 - 8.01 (m, 1H), 7.89 - 7.87 (m, 2H), 7.68 - 7.48 (m, 4H), 7.45 - 7.31 (m, 3H), 7.31 - 7.23 (m, 7H), 5.13 (s, 2H), 4.55 - 4.35 (m, 1H), 4.26 - 4.24 (m, 2H), 4.14 - 4.11 (m, 1H), 3.27 - 3.24 (m, 1H), 3.08 - 3.00 (m, 1H), 1.53 (s, 9H). 19 F NMR (282 MHz, DMSO-d6): d -117.39.

[0580] Step 2: Pd / C (0.372 g, 3.5 mmol, 10 wt%) was added to a stirred solution of (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)-3- fluoro-tert-butyl benzoate (3.2 g, 5.4 mmol) in EtOAc (60 mL). The resulting mixture was purged with hydrogen gas and stirred under a hydrogen atmosphere at room temperature for 1 h. The suspension was filtered off The pad and the filtrate was concentrated under reduced pressure. The residue was purified by Rp flash chromatography with the following conditions: Column: C18 (330 g); Mobile Phase A: water (0.05% TFA), Mobile Phase B: MeCN; (Gradient: 5% B hold for 5 min, up to 75% B in 30 min, 80% B hold for 7 min; up to 95% B in 2 min, 95% B hold for 10 min); Flow rate: 100 mL / min; Detector: UV 210 nm. Fractions containing product were collected and concentrated in vacuo to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)-2-fluorophenyl)propanoic acid. MS ESI [M+NH3+H] calculated for C32H34FN3O7, 603.23; found 603.23. 29 H 29 FNO6calculated for C32H34FN3O7, 603.23; found 603.23. + 523.19, found 523.15. 1 H NMR (300 MHz, DMSO-d6): δ 12.91 (s, 1H), 7.88 - 7.80 (m, 3H), 7.69 - 7.52 (m, 4H), 7.52 - 7.35 (m, 3H), 7.35 - 7.22 (m, 2H), 4.33 - 4.07 (m, 4H), 3.37 - 3.20 (m, 1H), 2.95 - 2.91 (m, 1H), 1.51 (s, 9H). 19 F NMR (282 MHz, DMSO-d6): δ -117.38.

[0581] Synthesis Scheme 32

[0582]

[0583] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxy- carbonyl)-3-chlorophenyl)propanoic acid (Fmoc-Phe3Cl4COOtBu-OH)

[0584] DMAP (3.9 g, 31.9 mmol), TEA (22.2 mL, 159 mmol), and di-tert-butyl dicarbonate (27.8 g, 127 mmol) were added to a solution of 4-bromo-2-chlorobenzoic acid (25.0 g, 106 mmol) in THF (250 mL) at room temperature under Ar conditions. The solution was stirred overnight at room temperature. The reaction mixture and residue were concentrated under reduced pressure and purified by silica gel chromatography, eluting with EtOAc 0 to 60% in PE, to give tert-butyl 4-bromo-2-chlorobenzoate. 1 ¹H NMR (400MHz, chloroform-d): δ 7.63–7.60 (m, 2H), 7.44–7.41 (m, 1H), 1.60 (s, 9H).

[0585] Step 2: A mixture of nickel(II) ethylene glycol dimethyl ether complex (1.8 g, 8.2 mmol) and 1,10-phenanthroline (7.4 g, 41.2 mmol) in anhydrous DMA (120 mL) was heated at 50 °C for 30 min. A solution of tert-butyl 4-bromo-2-chlorobenzoate (12.0 g, 41.2 mmol), methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate (14.9 g, 45.3 mmol), and tetrabutylammonium iodide (15.2 g, 41.2 mmol) in anhydrous DMA (120 mL) was added to the mixture at room temperature. Subsequently, active zinc (5.4 g, 82 mmol) was added. The mixture was stirred at 30 °C for 24 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc in PE from 0 to 100%, followed by purification by Rp rapid column chromatography under the following conditions: column: Flash C18 (330 g); mobile phase A: water (5 mM NH4HCO3), mobile phase B: MeCN; gradient elution: 0 to 75%; detector: UV 210 nm. The fraction containing the product was concentrated under reduced pressure to give (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-chlorobenzoate tert-butyl ester. (The last sentence appears to be incomplete and possibly refers to a different product, so it's left as is.) 20 H 28 MSESI[M+Na] calculated using ClNO6Na + 436.16, measured value 436.15. 1 ¹H NMR (400MHz, chloroform-d): δ 7.69–7.67 (m, 1H), 7.19 (s, 1H), 7.07–7.04 (m, 1H), 4.59–4.57 (m, 1H), 3.74 (s, 3H), 3.17–3.13 (m, 1H), 3.04–2.98 (m, 1H), 1.60 (s, 9H), 1.43 (s, 9H).

[0586] Step 3: 1 N aqueous LiOH (39 mL, 39 mmol) was added to a solution of (S)-tert- butyl 4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-chlorobenzoate (8.00 g, 19.3 mmol) in THF (80 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give (S)-3-(4-(tert-butoxycarbonyl)-3-chlorophenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid, which was used without purification in Step 4. MS ESI [M+H] calculated for C23H29ClN2O6, 449.15, found 449.15. 19 H 26 ClNO6Na calculated MS ESI [M+Na] + 422.14, found 422.10.

[0587] Step 4: A solution of hydrogen chloride in 1,4-dioxane (4.0 M, 80 mL, 320 mmol) was added to a solution of (S)-3-(4-(tert-butoxycarbonyl)-3-chlorophenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (8.0 g, 20.0 mmol) in dry THF (80 mL) at room temperature under Ar. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give (S)-2-amino-3-(4-(tert-butoxycarbonyl)-3- chlorophenyl)propanoic acid, which was used without purification in Step 5. MS ESI [M+H] calculated for C17H21ClNO4, 300.09, found 300.15. 14 H 19 ClNO4 calculated MS ESI [M+H] + 300.09, found 300.15.

[0588] Step 5: Sodium bicarbonate (7.0 g, 83 mmol) and N-(9-fluorenylmethoxycarbonyloxy)succinimide (5.06 g, 15.0 mmol) were added to a solution of (S)-2-amino-3-(4-(tert-butoxycarbonyl)-3- chlorophenyl)propanoic acid (5.0 g, 16.7 mmol) in THF (50 mL) and water (50 mL) at rt under Ar. The mixture was stirred at rt for 1 h. The pH was adjusted to ~4 with 1 N aqueous HC1. The mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure and the residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN; gradient elution: 2 to 60%; detector: UV 210 nm. Fractions containing the product were concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)-3-chlorophenyl)propanoic acid. MS ESI [M - H] calculated for C30H32C1NO6 520.16, found 520.25. 29 H 27 ClNO6 calculated MS ESI [M - H] + 520.16, found 520.25. 1 H NMR (400 MHz, Methanol-d4): d 7.78 - 7.76 (m, 2H), 7.63 - 7.49 (m, 3H), 7.38 - 7.35 (m, 3H), 7.30 - 7.20 (m, 3H), 4.47 - 4.43 (m, 1H), 4.37 - 4.33 (m, 1H), 4.23 - 4.10 (m, 2H), 3.28 - 3.23 (m, 1H), 2.98 - 2.92 (m, 1H), 1.55 (s, 9H).

[0589] Synthesis Scheme 33

[0590]

[0591] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)-3-fluorophenyl)propanoic acid (Fmoc-Phe3F4COOtBu-OH)

[0592] Step 1: Stir a mixture of nickel(II) glycol dimethyl ether complex (0.333 g, 1.517 mmol) and pyridine-2-methylamidine hydrochloride (0.478 g, 3.03 mmol) in anhydrous DMA (80 mL) and heat at 50 °C for 1 h. Cool the mixture to room temperature. Add to this solution a mixture of (R)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-iodopropionate benzyl ester (8.00 g, 15.2 mmol), tert-butyl 4-bromo-2-fluorobenzoate (8.35 g, 30.3 mmol), and TBAI (11.2 g, 30.3 mmol) in anhydrous DMA (80 mL). Subsequently, add active zinc (1.98 g, 30.3 mmol). Stir the mixture at room temperature for 2 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc in PE, to give (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)-2-fluorobenzoate tert-butyl ester. (For C...) 36 H 34 MS ESI [M+Na] calculated from FNO6Na + 618.24, measured value 618.25.

[0593] Step 2: Dissolve (S)-4-(2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)-2-fluorobenzoate tert-butyl ester (4.00 g, 6.72 mmol) in EtOAc (50 mL). Empty the flask and refill it with N2 (5 times). Add Pd / C (0.143 g, 1.34 mmol, dry, 10 wt%) to the flask. Empty the flask and refill it with H2 (5 times). Stir the resulting mixture at room temperature under a hydrogen atmosphere for 4 h. Empty the flask and refill it with N2 (5 times). Filter the resulting mixture. The filter cake was washed with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Rp rapid column chromatography under the following conditions: column: Flash C18 (330 g); mobile phase A: water, mobile phase B: MeCN; gradient elution: 0 to 50%; detector: UV 210 nm. The fraction containing the product was concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)-3-fluorophenyl)propionic acid. For C 29 H 28F2NO6Na calculated MS ESI [M+Na] + 528.19, found 528.15. 1 H NMR (300 MHz, DMSO-d6): δ 12.85 (s, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.77 - 7.70 (m, 2H), 7.67 - 7.58 (m, 2H), 7.43 - 7.37 (m, 2H), 7.32 - 7.18 (m, 4H), 4.28 - 4.13 (m, 4H), 3.20 - 3.14 (m, 1H), 2.96 - 2.88 (m, 1H), 1.51 (s, 9H).

[0594] Synthesis Scheme 34

[0595]

[0596] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)-3,5-difluorophenyl)propanoic acid (Fmoc-Phe35F24COOtBu-OH)

[0597] Step 1: A solution of nickel(II) chloride ethylene glycol dimethyl ether complex (0.33 g, 1.52 mmol) and pyridine-2-carboxamidine hydrochloride (0.48 g, 3.03 mmol) in anhydrous DMA (80 mL) was stirred and heated at 50 °C for 1 h. The mixture was cooled to room temperature and a solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropionic acid benzyl ester (8.00 g, 15.2 mmol), tert-butyl 4-bromo-2,6-difluorobenzoate (8.89 g, 30.3 mmol) and TBAI (11.2 g, 30.3 mmol) in anhydrous DMA (80 mL) was added. Then active zinc (1.98 g, 30.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in PE to give tert-butyl (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)-2,6-difluorobenzoate.1H NMR (300 MHz, CDCl3): δ 8.02 (d, J = 7.5 Hz, 2H), 7.79 - 7.73 (m, 2H), 7.68 - 7.62 (m, 2H), 7.58 - 7.52 (m, 2H), 7.45 - 7.39 (m, 2H), 7.34 - 7.28 (m, 4H), 6.82 (s, 1H), 4.62 - 4.55 (m, 2H), 4.52 - 4.45 (m, 2H), 4.42 - 4.36 (m, 2H), 4.34 - 4.28 (m, 2H), 1.48 (s, 9H), 1.44 (s, 9H). 36 H 33 F2NO6Na calculated MS ESI [M+Na] + 636.23, found 636.20.

[0598] Step 2: (S)-tert-butyl 4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- (benzyloxy)-3-oxopropyl)-2,6-difluorobenzoate (4.00 g, 6.52 mmol) was dissolved in EtOAc (40 mL). The flask was evacuated and backfilled with N2(5 times). Pd / C (0.277 g, 2.61 mmol, dry, 10 wt%) was added to the flask. The flask was evacuated and backfilled with H2(5 times). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature for 4 h. The flask was evacuated and backfilled with N2(5 times). The resulting mixture was filtered through Celite. The filter cake was washed with EtOAc (3 x 80 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); Mobile Phase A: water, Mobile Phase B: MeCN; Gradient Elution: 60 to 60%; Detector: UV 210 nm. Fractions containing product were concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)-3,5-difluorophenyl)propanoic acid. Calculated MS ESI [M+Na] C30H31FN3NaO7: 606.20, found 606.20. The residue was dissolved in EtOAc (40 mL). The flask was evacuated and backfilled with N2(5 times). Pd / C (0.277 g, 2.61 mmol, dry, 10 wt%) was added to the flask. The flask was evacuated and backfilled with H2(5 times). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature for 4 h. The flask was evacuated and backfilled with N2(5 times). The resulting mixture was filtered through Celite. The filter cake was washed with EtOAc (3 x 80 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Rp flash column chromatography with the following conditions: Column: Flash C18 (330 g); Mobile Phase A: water, Mobile Phase B: MeCN; Gradient Elution: 60 to 60%; Detector: UV 210 nm. Fractions containing product were concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)-3,5-difluorophenyl)propanoic acid. Calculated MS ESI [M+Na] C30H31FN3NaO7: 606.20, found 606.20. 29 H 27 Calculated MS ESI [M+Na] C30H31FN3NaO7: 606.20, found 606.20. + 546.18, found 546.05. 1 H NMR (300 MHz, DMSO-d6): δ 12.87 (s, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.77 (d, J = 8.4 Hz, 1H), 7.63 - 7.59 (m, 2H), 7.43 - 7.38 (m, 2H), 7.32 - 7.25 (m, 2H), 7.15 (d, J = 9.0 Hz, 2H), 4.30 - 4.17 (m, 4H), 3.19 - 3.13 (m, 1H), 2.96 - 2.87 (m, 1H), 1.51 (s, 9H).

[0599] Synthesis Scheme 35

[0600]

[0601] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(4-acetylpiperazin-1- yl)phenyl)propanoic acid (Fmoc-Phe4AcPip-OH)

[0602] Step 1: XPhos Pd G 2 (2.06 g, 2.6 mmol) was added to a stirred solution of (S)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (6.00 g, 17.4 mmol) in toluene (180 mL) at room temperature under N2. The resulting solution was stirred at 100 °C for 10 min. 1-(Piperazin-1-yl)ethan-1-one (2.24 g, 17.4 mmol) and Cs2CO3(5.04 g, 26.1 mmol) were added and the resulting suspension was stirred at 110 °C for 2 h. The reaction was cooled to room temperature and quenched with DI water (500 mL), extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with EtOAc in PE 0 to 60% to give (S)-3-(4-(4-acetylpiperazin-1-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid. MS ESI [M+H] calculated for C25H35N4O5 463.26, found 464.30. 20 H 30 MS ESI [M+H] calculated for C25H35N4O5 463.26, found 464.30. + 392.21, found 392.25. 1 H NMR (400 MHz, Methanol-d4): δ 7.12 (d, J = 8 Hz, 2H), 6.89 (d, J = 8 Hz, 2H), 4.16 - 4.13 (m, 1H), 3.72 - 3.65 (m, 4H), 3.14 - 3.04 (m, 4H), 2.93 - 2.81 (m, 2H), 2.13 (s, 3H), 1.38 - 1.29 (m, 9H).

[0603] Step 2: TFA (30 mL) was added to a stirred solution of (S)-3-(4-(4-acetylpiperazin-1-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (10.0 g, 25.5 mmol) in DCM (30 mL) at room temperature. The solution was stirred at room temperature for 1 h, then concentrated under reduced pressure. The crude product was used directly in the next step without further purification. MS ESI [M+H] calculated for C19H25N4O3 365.20, found 366.25. 15 H 22 MS ESI [M+H] calculated for C19H25N4O3 365.20, found 366.25. + 292.16, found 292.20.

[0604] Step 3: Fmoc-OSu (6.34 g, 18.8 mmol) and NaHC03(8.77 g, 104 mmol) were added to a stirred solution of (S)-3-(4-(4-acetylpiperazin-1-yl)phenyl)-2- (carboxylamino)propanoic acid (7.00 g, 20.9 mmol) in a 1:1 (v / v) mixture of THF and DI water (50 mL). The resulting mixture was stirred at room temperature for 2 h. The pH was adjusted to 5 with 1 N aqueous HC1 and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2S04and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by Rp flash chromatography with the following conditions: Column: Flash C18 (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN; (gradient: 5% B hold for 5 min, up to 55% B in 15 min, 55% B hold for 5 min; up to 95% B in 20 min, 95% B hold for 5 min); flow rate: 90 mL / min; detector: UV 210 nm. Fractions containing the product were combined and concentrated in vacuo to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(4- acetylpiperazin-1-yl)phenyl)propanoic acid. MS ESI [M+H] calculated for C34H38N4O7, 618.27, found 618.30. 30 H 32 MS ESI [M+H] calculated for C34H38N4O7, 618.27, found 618.30. + 514.23, found 514.30. 1 H NMR (400 MHz, Methanol-d4): δ 7.78 - 7.76 (m, 2H), 7.61 - 7.52 (m, 2H), 7.40 - 7.37 (m, 2H), 7.32 - 7.22 (m, 4H), 7.08 - 6.98 (m, 2H), 4.47 - 4.43 (m, 1H), 4.33 - 4.31 (m, 1H), 4.14 - 4.02 (m, 2H), 3.68 - 3.63 (m, 4H), 3.23 - 3.08 (m, 5H), 2.91 - 2.85 (m, 1H), 2.11 (s, 3H).

[0605] Synthesis Scheme 36

[0606]

[0607] (2S,5S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-(tert-butoxycarbonyl)piperidine- 2-carboxylic acid (Fmoc-Pipc5COOtBu-OH)

[0608] Step 1: H2SO4(37.6 g, 365 mmol) was added to a stirred solution of pyridine-2,5-dicarboxylic acid (100 g, 598 mmol) in MeOH (700 mL) at room temperature. The solution was heated to 60 °C for 7 h. The crude reaction mixture was poured into water (1 L) at 15 °C. The resulting precipitate was collected by filtration. The filtered solid was then washed with MeOH to give 6-(methoxycarbonyl)nicotinic acid. 1 H NMR (400 MHz, DMSO-d6): δ 9.16 (dd, J = 1.6, 7.6 Hz, 1H), 8.42-8.47 (m, 1H), 8.16 (t, J = 8.0 Hz, 1H), 3.91 (s, 3H).

[0609] Step 2: 6-(Methoxycarbonyl)nicotinic acid (40.0 g, 220 mmol) was dissolved in MeOH (280 mL) at room temperature. DMAP (13.4 g, 110 mmol) and Boc20 (120 g, 126 mL, 552 mmol) were added and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure and the solid was partitioned between brine (300 mL) and EtOAc (300 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (20:1 to 5:1; v / v) to give pyridine-2,5-dicarboxylic acid 5-(tert-butyl) 2-methyl ester. 1 H NMR (400 MHz, DMSO-d6): δ 9.24 (dd, J = 1.6 Hz, 1H), 8.37 (dd, J = 2.0, 8.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 4.03 (s, 3H), 1.62 (s, 9H).

[0610] Step 3: Pyridine-2,5-dicarboxylic acid 5-(tert-butyl) 2-methyl ester (30.0 g, 126 mmol) was added to a suspension of Pd / C (3.00 g, 17 mmol, 10 wt%) in AcOH (600 mL) at room temperature. The reaction mixture was purged with hydrogen gas (three times) and then heated at 50 °C, stirring under H2(50 Psi) for 12 h. The solids were filtered off using a pad of Celite, rinsing with AcOH. The filtrate was concentrated under reduced pressure. The solid was partitioned between EtOAc (300 mL) and brine (300 mL). The organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated under vacuum to give 5-(tert-butyl) 2-methyl ester (2S,5S)-piperidine-2,5-dicarboxylate. 1H NMR (400 MHz, Chloroform-d): δ 3.71 (s, 3H), 3.47 (m, 1H), 3.13 - 3.12 (m, 1H), 2.88 (dd, J = 3.6, 12.8 Hz, 1H), 2.36 (m, 3H), 2.03 - 1.99 (m, 3H), 1.85 - 1.80 (m, 5H), 1.43 (s, 9H).

[0611] Step 4: A solution of NaOH (4.93 g, 123 mmol) in H2O (100 mL) was added to a stirred solution of 5-(tert-butyl) 2-methyl ester (2S,5S)-piperidine-2,5-dicarboxylate (20.0 g, 82.2 mmol) in EtOH (120 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The organic volatiles were removed under reduced pressure to give (2S,5S)-5-(tert-butoxycarbonyl)piperidine-2-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6): δ 14.08 (s, 1H), 8.54 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.29 (d, J = 8.8 Hz, 1H), 3.55 (s, 3H).

[0612] Step 5: Fmoc-OSu (26.4 g, 78.5 mmol) and Na2CO3(99.8 g, 94.2 mmol) were added to a stirred solution of (2S,5S)-5-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (18.0 g, 78.5 mmol) in DI water (50 mL) and MeCN (75 mL) at room temperature. The solution was stirred at room temperature for 12 h. The organic volatiles were removed under reduced pressure and the solids were partitioned between EtOAc (150 mL) and brine (150 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250 x 70 mm, 15 μm, (Phenomenex Torrance, CA); mobile phase: [water (HCL)-MeCN]; B%: 50 to 80% in 20 min). The fractions containing the product were combined and concentrated under vacuum to give the title compound (18.0 g, 78.5 mmol, 100% yield). TM Luna TM C18 (250 x 70 mm, 15 μm, (Phenomenex Torrance, CA); mobile phase: [water (HCL)-MeCN]; B%: 50 to 80% in 20 min). The fractions containing the product were combined and concentrated under vacuum to give the title compound (18.0 g, 78.5 mmol, 100% yield). TM ,Torrance, CA); mobile phase: [water (HCL)-MeCN]; B%: 50 to 80% in 20 min). The fractions containing the product were combined and concentrated under vacuum to give the title compound (18.0 g, 78.5 mmol, 100% yield). IG (250 x 50 mm, 10 pm, Daicel Chiral Technologies, West Chester, PA); mobile phase: [0.1% NH4OH in water - EtOH]; B%: 45 to 45% in 6 min) to provide (2S,5S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-(tert- butoxycarbonyl)piperidine-2-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6): δ 7.88 - 7.86 (m, 2H), 7.67 - 7.62 (m, 2H), 7.41 - 7.32 (m, 4H), 4.59 (s, 1H), 4.37 - 4.23 (m, 3H), 4.11 - 3.94 (dd, J = 12.4, 5.4 Hz, 1H), 3.02 - 2.89 (m, 1H), 2.27 - 2.16 (m, 2H), 1.85 - 1.82 (m, 1H), 1.55 - 1.53 (m, 2H), 1.40 (m, 9H), 1.28 - 1.22 (m, 2H).

[0613] Synthesis Scheme 37

[0614]

[0615] (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4- yl)butanoic acid (Fmoc-RbMe4Pal-OH) and (2S,3S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoic acid (Fmoc-SbMe4Pal-OH)

[0616] Step 1 : BnBr (501 g, 2.93 mol) was added dropwise to a solution of (((9H-fluoren-9- yl)methoxy)carbonyl)-L-threonine (500 g, 1.46 mol) in DMF (3.00 L) at room temperature. Cs2CO3 (954 g, 2.93 mol) was added to the solution. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into DI water (20 L) at room temperature and a solid precipitated. The solid was recovered by filtration and the filter cake was rinsed with DI water (2 x 1 L). The filter cake was dried under vacuum. The crude product was triturated with MTBE (10 L) at room temperature for 2 h. The solid was recovered by filtration and the filter cake was dried under reduced pressure. The crude product was triturated with PE (10 L) at room temperature for 6 h. The solid was recovered by filtration and the filter cake was dried under reduced pressure to give (((9H-fluoren-9-yl)methoxy)carbonyl)-L-threonine benzyl ester. 1H NMR (400 MHz, Methanol-d4): δ 7.79 (d, J = 7.6 Hz, 2H), 7.66 - 7.56 (m, 2H), 7.40 - 7.27 (m, 10H), 5.19 (s, 2H), 4.42 - 4.19 (m, 5H), 1.18 (d, J = 6.4 Hz, 3H).

[0617] Step 2: NIS (547 g, 2.43 mol) was added to a solution of ((9H-fluoren-9-yl)methoxy)carbonyl)-L-threonine benzyl ester (350 g, 811 mmol) in DCM (3.5 L) at 0 °C. PPh3 (638 g, 2.43 mol) was added to the stirred solution. The reaction mixture was stirred at 30 °C for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE / DCM / EtOAc = 10:10:1; v / v / v) to give (2R,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodobutyric acid benzyl ester. 1 H NMR (400 MHz, Methanol-d4): δ 7.79 (d, J = 7.6 Hz, 2H), 7.68 (d, J = 7.2 Hz, 2H), 7.40 - 7.27 (m, 10H), 5.20 (q, J = 9.6 Hz, 2H), 4.53 - 4.50 (m, 2H), 4.42 - 4.37 (m, 2H), 4.24 - 4.21 (m, 1H), 1.84 - 1.79 (m, 3H).

[0618] Step 3: Solution A: A solution of NiCl2-glyme (4.06 g, 18.5 mmol) and 4- methoxymethylpyridine amidine hydrochloride (3.47 g, 18.5 mmol) in anhydrous DMA (500 mL) was stirred at room temperature under N2for 30 min. Solution B: A solution of (2R,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodobutyric acid benzyl ester (100 g, 185 mmol) and 4-iodopyridine (37.9 g, 185 mmol) in anhydrous DMA (250 mL) was stirred at room temperature under N2for 30 min. Solution B was added slowly to solution A at room temperature under N2. Active zinc (60.4 g, 924 mmol) was added portionwise to the solution. The suspension was stirred at room temperature under N2overnight. The solids were removed by filtration and the filter cake was rinsed with EtOAc (3 x 800 mL). The filtrate was poured into DI water (2.0 L). The suspension was extracted with EtOAc (3 x 1.5 L). The combined organic layers were washed with brine (2 x 800 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 30 x 100 mm, 5 pm; mobile phase: water (0.05% NH4OH) and ACN; flow rate: 30 mL / min) to give (2R,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4- methoxymethylpyridin-1-yl)butanoic acid benzyl ester. TMLuna TM C18250 mm, 10 pm, (Phenomenex TM Torrance, CA); mobile phase: [water (0.225% FA) - MeCN]; MeCN%: 40 to 70% in 20 min) purification to give (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- (pyridin-4-yl)butanoic acid benzyl ester and (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoic acid benzyl ester as a mixture. A portion of the mixture was separated by SFC chiral separation (column: Daicel AD (250 x 50 mm, 10 pm, Daicel Chiral Technologies, West Chester, PA); mobile phase: [0.1% NH4OH in IPA]; IPA%: 50 to 50% in 6.2 min). The two isolated products were concentrated under vacuum to give two diastereomers.

[0619] (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoic acid benzyl ester A: 1 HNMR (400 MHz, DMSO-d6): d 8.44 (d, J = 5.6 Hz, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.87 - 7.55 (m, 3H), 7.56 - 7.54 (m, 2H), 7.38 - 7.32 (m, 9H), 5.17 (d, J = 2.8 Hz, 2H), 4.37 (t, J = 9.2 Hz, 1H), 4.18 - 4.08 (m, 3H), 3.20 - 3.15 (m, 1H), 1.21 - 1.14 (m, 3H).

[0620] (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoic acid benzyl ester B: 1HNMR (400 MHz, DMSO-d6): δ 8.43 (d, J = 5.6 Hz, 2H), 8.11 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.68 (d, J = 7.2 Hz, 2H), 7.44 - 7.41 (m, 2H), 7.32 - 7.26 (m, 6H), 7.24 - 7.16 (m, 2H), 4.96 (dd, J = 35.6, 12.8 Hz, 2H), 4.41 (t, J = 8.4 Hz, 1H), 4.26 - 4.16 (m, 3H), 3.28 - 3.23 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H).

[0621] Step 4: Pd / C (5.00 g, 10 wt%) was added to a solution of (2S,3R)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoate A (52.0 g, 106 mmol) in THF (300 mL) under N2. The flask was evacuated and backfilled with H2 (3 times). The resulting mixture was stirred at room temperature under a hydrogen atmosphere (15 Psi) for 12 h. The flask was evacuated and backfilled with N2 (5 times). The resulting mixture was filtered, and the filter cake was washed with THF (10 x 200 mL). The filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE (100 mL) at room temperature for 30 min. The suspension was filtered and the filter cake was dried under vacuum to give (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoic acid.1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, J = 4.8 Hz, 2H), 7.85 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 6.4 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.32 - 7.26 (m, 4H), 4.29 - 4.10 (m, 4H), 3.21 - 3.15 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H). 24 H 22 MSESI [M+H] calculated for C + 403, found 403. 1 H NMR (400 MHz, T = 273+80 K, DMSO-d6): δ 8.44 (d, J = 4.8 Hz, 2H), 7.85 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 6.4 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.32 - 7.26 (m, 4H), 4.29 - 4.10 (m, 4H), 3.21 - 3.15 (m, 1H), 1.26 (d, J = 6.8 Hz, 3H).

[0622] Step 5: Pd / C (4.00 g, 10 wt%) was added to a solution of (2S,3S)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoate B (75.0 g, 152 mmol) in THF (380 mL) under N2. The flask was evacuated and backfilled with H2(3 times). The resulting mixture was stirred at room temperature under a hydrogen atmosphere (15 Psi) for 12 h. The flask was evacuated and backfilled with N2(5 times). The resulting mixture was filtered, and the filter cake was washed with THF (10 x 200 mL). The filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE (100 mL) at room temperature for 30 min. The suspension was filtered and the filter cake was dried under vacuum to give (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoic acid. MS ESI [M+H] calculated for C28H29N4O5, 499, found 499. 24 H 22 MSESI [M+H] calculated for C28H29N4O5, 499, found 499. + 403, found 403. 1 H NMR (400 MHz, T = 273 + 80 K, DMSO-d6): δ 8.44 (d, J = 4.8 Hz, 2H), 7.86 (d, J = 7.6 Hz, 2H), 7.68 - 7.62 (m, 2H), 7.41 (d, J = 7.6 Hz, 2H), 7.32 - 7.25 (m, 4H), 4.33 - 4.25 (m, 3H), 4.19 (q, J = 6.8 Hz, 1H), 3.30 - 3.28 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H).

[0623] Synthesis Scheme 38

[0624]

[0625] (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert- butoxycarbonyl)phenyl)butanoic acid (Fmoc-SbMePhe4CO2tBu-OH)

[0626] Step 1 : To a solution of ((9H-fluoren-9-yl)methoxy)carbonyl)-L-threonine (500 g, 1.46 mol) in DMF (3.00 L) was added BnBr (501 g, 2.93 mol) dropwise at room temperature. Cs2CO3(954 g, 2.93 mol) was added to the solution and the resulting suspension was stirred at room temperature for 3 h. The reaction mixture was poured into DI water (20 L) at room temperature. The solids were recovered by filtration. The filter cake was rinsed with DI water (2 x 1 L) and dried under vacuum to give the crude product. The crude solids were triturated with MTBE (10 L) at room temperature for 2 h. The suspension was filtered and the resulting filter cake was dried under reduced pressure. The residue was triturated with PE (10 L) at room temperature for 6 h. The suspension was filtered and the solids were dried under reduced pressure to give ((9H-fluoren-9-yl)methoxy)carbonyl)-L-threonine benzyl ester. 1 HNMR (400 MHz, Methanol-d4): d 7.79 (d, J = 7.6 Hz, 2H), 7.66 - 7.65 (m, 2H), 7.40 - 7.27 (m, 10H), 5.19 (s, 2H), 4.42 - 4.19 (m, 5H), 1.18 (d, J = 6.4 Hz, 3H).

[0627] Step 2: To a solution of ((9H-fluoren-9-yl)methoxy)carbonyl)-L-threonine benzyl ester (350 g, 811 mmol) in DCM (3.5 L) was added N-iodosuccinimide (547 g, 2.43 mol) and PPh3(638 g, 2.43 mol) at 0 °C. The solution was stirred at 30 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / DCM / EtOAc = 10:10:1; v / v / v) to give (2R,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodobutyric acid benzyl ester. 1 HNMR (400 MHz, Methanol-d4): d 7.79 (d, J = 7.6 Hz, 2H), 7.68 (d, J = 7.2 Hz, 2H), 7.40 - 7.27 (m, 10H), 5.20 (q, J = 9.6 Hz, 2H), 4.53 - 4.50 (m, 2H), 4.42 - 4.37 (m, 2H), 4.24 - 4.21 (m, 1H), 1.84 - 1.79 (m, 3H).

[0628] Step 3: (Three reactions run in parallel, then combined for workup and purification). In a nitrogen filled glovebox, NiCl2.glyme (3.25 g, 14.8 mmol) and 4,7-dimethoxy-l,10-phenanthroline (3.55 g, 14.8 mmol) were added to anhydrous DMA (500 mL). The mixture was stirred at room temperature for 30 min. Then (2R,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodobutyric acid benzyl ester (80.0 g, 148 mmol) and tert-butyl 4-iodobenzoate (44.9 g, 148 mmol) were added to the solution. Then manganese (16.2 g, 296 mmol) was added followed by TMSCl (8.03 g, 9.38 mL, 73.9 mmol). The suspension was stirred at room temperature under N2for 12 h. The three reaction suspensions were then combined and filtered, rinsing the filter cake with EtOAc (2 x 500 mL). The filtrate was poured into water (2.0 L). The organic layer and aqueous phase were separated and the aqueous phase was extracted with EtOAc (3 x 800 mL). The combined organic phases were washed with brine (2 x 1 L) and dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum to give a residue which was purified first by Rp-HPLC (Phenomenex Titan C18 Bulk 250 x 100 mm, 10 pm; mobile phase: [10 mM NH4HCO3and MeCN in water]; MeCN%: 75 to 100%, 20 min) to give the product as a mixture of two diastereoisomers. The isomers were separated by SFC chiral separation (DAICEL CHIRALPAK AD (250 x 50 mm, 10 pm); mobile phase: [EtOH]; EtOH%: 40 to 40%, 3.6 min) to provide two separated diastereoisomers.

[0629] 4-((2S,3S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(benzyloxy)-4- oxobutan-2-yl)benzoic acid tert-butyl ester (A). 1 H NMR (400 MHz, Chloroform-d): δ 7.85 (d, J = 8 Hz, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.2 Hz, 2H), 7.43 - 7.28 (m, 8H), 7.05 (d, J = 8 Hz, 2H), 5.19 - 5.03 (m, 3H), 4.70 - 4.66 (m, 1H), 4.49 - 4.44 (m, 1H), 4.37 - 4.33 (m, 1H), 4.22 - 4.18 (m, 1H), 3.45 - 3.42 (m, 1H), 1.60 (s, 9H), 1.32 (d, J = 7.2 Hz, 3H).

[0630] 4-((2R,3S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(benzyloxy)-4- oxobutan-2-yl)benzoic acid tert-butyl ester (B). 1 H NMR (400 MHz, Chloroform-d): δ 7.79 (d, J = 8 Hz, 2H), 7.72 (d, J = 7.6 Hz, 2H), 7.52 (d, J = 7.6 Hz, 2H), 7.38 - 7.25 (m, 7H), 7.11 - 6.93 (m, 3H), 5.27 (d, J = 9.2 Hz, 1H), 4.97 (q, J = 8.4 Hz, 2H), 4.57 (t, J = 7.6 Hz, 1H), 4.41 - 4.27 (m, 2H), 4.14 (t, J = 6.8 Hz, 1H), 3.22 - 3.16 (m, 1H), 1.54 (s, 9H), 1.28 (d, J = 7.2 Hz, 3H).

[0631] Step 4: To a solution of tert-butyl 4-((2S,3S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(benzyloxy)-4-oxobutan-2-yl)benzoate A (34.0 g, 57.5 mmol) in THF (180 mL) was added Pd / C (3.40 g, 10 wt%) under nitrogen atmosphere. The flask was evacuated and backfilled with H2(15 psi, 5 times). The resulting mixture was stirred at room temperature under H2(15 Psi) for 6 h. The suspension was then filtered through Celite®. The filter cake was rinsed with THF (400 mL). The filtrate was concentrated under reduced pressure to provide (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)butanoic acid. MS ESI [M+Na] calculated for C34H37NO7Na, 624.24; found, 624.24. C 30 H 31 MS ESI [M+Na] calculated for C34H37NO7Na, 624.24; found, 624.24. + 524, found 524. 1 H NMR (400 MHz, DMSO-d6): δ 7.82 (m, J = 8.0, 7.6 Hz, 4H), 7.53 - 7.50 (m, 2H), 7.43 - 7.35 (m, 4H), 7.24 (q, J = 8.4 Hz, 2H), 4.07 - 4.00 (m, 2H), 3.24 - 3.16 (m, 1H), 1.48 (s, 9H), 1.25 (d, J = 7.2 Hz, 3H).

[0632] Synthesis Scheme 39

[0633]

[0634] (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxy-3- (pyridin-4-yl)propanoic acid (Fmoc-RbOH4Pal-OH)

[0635] Step 1: In a three-necked flask, a solution of (tert-butoxycarbonyl)glycine ethyl ester (100.0 g, 492 mmol) in anhydrous THF (1.5 L) was purged with N2three times and cooled to -60 °C. A solution of LiHMDS (1.0 M, 1.01 L, 1010 mmol) in THF was added dropwise at -60 °C. The reaction mixture was stirred under N2for 1 h at -65 °C. Isoxazole aldehyde (69.3 mL, 79.1 g, 738 mmol) was added to the mixture at -60 °C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 4 h. The reaction mixture was quenched with saturated aqueous NH4Cl (1 L) and extracted with EtOAc (2 x 1 L). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc in PE 2 to 100% to give 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(pyridin-4-yl)propanoic acid ethyl ester.1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 5.8 Hz, 2H), 7.48 (d, J = 5.8 Hz, 2H), 5.38 - 4.91 (m, 1H), 4.55 - 4.38 (m, 1H), 4.34 - 4.04 (m, 2H), 1.39 - 1.27 (m, 9H), 1.26 - 1.13 (m, 3H). 15 H 22 N2O5calcd. MS ESI [M+H] + 311, found 311. 1 H NMR (400 MHz, Methanol-d4): δ 8.49 - 8.48 (m, 2H), 7.49 - 7.48 (m, 2H), 5.38 - 4.91 (m, 1H), 4.55 - 4.38 (m, 1H), 4.34 - 4.04 (m, 2H), 1.39 - 1.27 (m, 9H), 1.26 - 1.13 (m, 3H).

[0636] Step 2: A solution of LiOH.H2O (53.8 g, 1.28 mol) and 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(pyridin-4-yl)propanoic acid ethyl ester (82.0 g, 0.25 mmol) in MeOH (640 mL) and H2O (160 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (water (HCL)-MeCN]; MeCN%: 1 to 27%, 20 min) to give 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(pyridin-4-yl)propanoic acid.1H NMR (400 MHz, Chloroform-d) δ 8.48 (d, J = 5.8 Hz, 2H), 7.48 (d, J = 5.8 Hz, 2H), 5.38 - 4.91 (m, 1H), 4.55 - 4.38 (m, 1H), 4.34 - 4.04 (m, 2H), 1.39 - 1.27 (m, 9H), 1.26 - 1.13 (m, 3H). 13 H 18 N2O5calcd. MS ESI [M+H] + 283, found 283.

[0637] Step 3: The mixture of four isomers was separated by SFC (SFC (column: Daicel Chiralpak® AD (250 x 50 mm, 10 pm, Daicel Chiral Technologies, West Chester, PA); mobile phase: [0.1% NH4OH in H2O; IPA]; IPA%: 30 to 30%, 7 min)) to obtain compounds A, B, C, and D. AD (250 x 50 mm, 10 pm, Daicel Chiral Technologies, West Chester, PA); mobile phase: [0.1% NH4OH in H2O; IPA]; IPA%: 30 to 30%, 7 min).

[0638] Step 4: (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(pyridin-4- yl)propanoic acid (Compound A, 10.0 g, 35.4 mmol) was dissolved in a solution of...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen, C 1-10 Alkyl, (C 1-6 alkyl) 0-2 amino (C 0-10 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-10 Alkyl)oxy(C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 alkyl), aryl (C 0-10 alkyl), heteroaryl (C) 0-10 alkyl), (C 3-12 )cycloalkyl (C 0-10 Alkyl), heterocyclic alkyl (C 0-10 Alkyl), C 1-10 fluoroalkyl, C 2-10 alkenyl, (C 0-6 alkyl)carbonylamino (C 0-6 alkyl), (C 0-6 alkyl) 0-2 amino carbonyl (C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino (C 0-6 alkyl), aryl carbonyl amino (C 0-6 alkyl), arylaminocarbonyl (C 0-6 alkyl), heteroaryl carbonyl amino (C 0-6 alkyl), heteroarylaminocarbonyl (C 0-6 Alkyl), C 1-6 Alkoxy, (C 1-6 Alkyl)oxy(C 0-6 Alkyl), ((C) 3-12 )cycloalkyl)oxy(C 0-6 Alkyl), ((C) 3-12 )cycloalkyl C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 0-6 alkyl)carboxyl (C 0-6 alkyl), N - =N + =N–(C 0-6 alkyl) and H2N–C(=NH)NH–(C 0-6 alkyl), Where R 1 By 0, 1, 2, 3 or 4 R 1a Substituent substitution, the R 1a Each substituent is independently selected from C 1-6 Alkyl, amino, cyano, halogen, hydroxyl, (C 3-12 )cycloalkoxy and C 1-6 Alkoxy; Each R 2a Independently selected from hydrogen, hydroxyl, C 1-4 Alkyl, fluorine and C 1-4 Alkoxy; R 2b Selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups, wherein the heteroaryl group contains at least one nitrogen atom. Where R 2b By 0, 1 or 2 R 2c Instead, the R 2c Selected independently from C 1-6 Alkyl, amino (C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 alkyl), aminocarbonyl (C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 0-6 Alkyl), hydroxyl, C 1-6 Alkoxy, halogen, (C 1-6 alkyl) 0-2 amino (C 0-6 alkoxy), (C 1-6 Alkyl)3N + (C 0-6 alkoxy), (C 1-6 Alkoxy)carbonyl (C 0-6 Alkyl), carboxyl (C) 0-6 Alkyl), carboxyl (C) 1-6 Alkyl)oxy(C 0-6 Alkyl), C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Alkoxy; R 3a Selected from hydrogen, hydroxyl, hydroxyl (C 1-6 Alkyl), amino, amino (C 1-6 Alkyl), C 1-10 Alkyl, (C 3-12 )cycloalkyl (C 0-10 alkyl), (C 0-6 alkyl)thio(C 1-6 alkyl) and carboxyl (C) 1-6 alkyl), wherein R 3a Can be 0, 1 or 2 R 3c Substituent substitution; R 3b Selected from hydrogen, C 1-10 Alkyl, hydroxyl (C 1-6 alkyl), amino (C 1-10 alkyl), (C 1-6 alkyl) 0-2 amino (C 1-10 alkyl), (C 1-6 Alkyl)3N + (C 1-6 Alkyl), C 1-6 Halogenated alkyl, aryl (C 0-10 alkyl), heteroaryl (C) 0-10 alkyl), (C 3-12 )cycloalkyl (C 0-10 Alkyl), heterocyclic alkyl (C 0-10 alkyl), (C 1-6 Alkyl)oxy(C 1-6 alkyl), (C 3-12 )cycloalkoxy (C 1-6 Alkyl), carboxyl (C) 1-6 alkyl), aminocarbonyl (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 1-6 alkyl), aminocarbonylamino (C 1-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino (C 1-6 alkyl), (C 0-6 alkyl)thio(C 1-6 alkyl), (C 1-6 Alkyl)SO2(C 1-6 alkyl) and (C 1-6 alkyl)sulfinyl (C 1-6 alkyl), wherein R 3b Can be 0, 1 or 2 R 3c Substituent substitution; Each R 3c Independently selected from halogens, C 1-6 Alkyl, amino, (C 1-6 alkyl) 0-2 amino (C 0-6 alkyl), (C 1-6 Alkyl)3N + –、(C 1-6 Alkyl)SO2(C 0-6 alkyl), cyano, cyano (C 1-6 Alkyl), hydroxyl, hydroxyl (C) 1-6 alkyl), (C 1-6 Alkyl)oxy(C 0-6 alkyl), aminocarbonyl (C 0-6 alkyl) and (C 0-6 ) carboxyl group (C 0-6 alkyl); And R 3a and R 3b Together with the atoms they are attached to, they can form saturated ring systems, wherein the saturated ring system can be 0, 1 or 2 R atoms. 3c Substituent substitution; R 4a Selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-4 Alkyl groups and fluorine; R 4b Selected from bicyclic heteroaryl (C 0-3 alkyl) and bicyclic aryl (C 0-3 alkyl), Where R 4b By 0, 1 or 2 R 4c Instead, the R 4c Each substituent is independently selected from halogen, hydroxyl, cyano, nitro, carboxyl, and carboxyl (C) groups. 1-6 alkyl), (C 1-6 Alkoxy)carbonyl (C 0-6 Alkyl), C 1-6 Alkoxy, (C 1-6 Alkyl)oxy(C 1-6 Alkyl), C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 5a Selected from hydrogen, C 1-10 Alkyl, C 1-10 Fluoroalkyl, carboxyl (C 1-10 Alkyl), hydroxyl, hydroxyl (C) 1-10 alkyl), cyano (C 1-10 Alkyl), heterocyclic alkyl (C 0-10 alkyl), aminocarbonyl (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 1-6 Alkyl), (Carboxyl (C) 1-10 Alkyl))oxy(C 1-6 alkyl), aryl (C 0-6 alkyl), (C 3-12 )cycloalkyl (C 0-6 alkyl), heteroaryl (C) 0-6 alkyl), (C 1-6 Alkyl)oxy(C 1-6 alkyl), (C 1-6 Alkoxy)carbonyl (C 0-6 Alkyl), amino, amino (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 alkyl), amino (C 1-6 alkyl)carbonylamino (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 1-6 alkyl)carbonylamino (C 1-6 alkyl), (C 1-6 Alkyl)3N + (C 2-10 alkyl), (C 1-6 Alkyl)3N + (C 1-6 alkyl)carbonylamino (C 1-6 alkyl) and C 1-10 Fluoroalkyl, and wherein R 5a By 0, 1 or 2 R 5d Substituent substitution; R 5b Selected from hydrogen, C 1-10 Alkyl, hydroxyl (C 1-10 Alkyl), carboxyl (C) 1-6 alkyl), (C 1-6 Alkyl)oxy(C 1-6 alkyl), aminocarbonyl (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 1-6 Alkyl), carboxyl (C) 1-10 Alkyl)oxy(C 1-6 alkyl), cyano (C 1-10 alkyl), amino (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 1-6 alkyl), amino (C 1-6 alkyl)carbonylamino (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 1-6 alkyl)carbonylamino (C 1-6 alkyl), (C 1-6 Alkyl)3N + (C 2-6 Alkyl)oxy(C 1-6 alkyl), (C 1-6 Alkyl)3N + (C 1-6 alkyl)carbonylamino (C 1-6 alkyl), (C 1-6 Alkyl)3N + (C 1-6 Alkyl), heterocyclic alkyl (C 0-10 alkyl), (C 3-12 )cycloalkyl (C 0-10 alkyl) and C 1-10 Haloalkyl, wherein R 5b By 0, 1, 2 or 3 R 5e Substituent substitution, Where R 5a and R 5b Together with the atoms they are attached to, they form saturated monocyclic or bicyclic rings, wherein the monocyclic or bicyclic rings are separated by 0, 1, 2, or 3 R atoms. 5d And 0, 1, 2 or 3 R 5e replace; Each R 5d Independently selected from halogens, hydroxyl groups, and hydroxyl (C) 1-10 Alkyl), C 1-10 Alkyl, carboxyl, carboxyl (C 1-6 Alkyl), C 1-6 Alkoxy, (C 1-6 Alkyl)oxy(C 1-6 Alkyl), amino, amino (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 alkyl), amino (C 1-6 alkyl)carbonylamino (C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 1-6 alkyl)carbonylamino (C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 2-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 1-6 alkyl)carbonylamino (C 0-6 Alkyl), (Carboxyl (C) 1-6 Alkyl))oxy(C 1-6 alkyl), cyano (C 0-6 alkyl), tetrazolium (C 0-6 alkyl) and C 1-6 Halogenated alkyl, and two R 5d Substituents, together with the atoms they are attached to, can bond together to form saturated rings; Each R 5e Independently selected from halogens, hydroxyl groups, and hydroxyl (C) 1-10 Alkyl), C 1-10 Alkyl, carboxyl, carboxyl (C 1-6 Alkyl), C 1-6 Alkoxy, (C 1-6 Alkyl)oxy(C 1-6 Alkyl), amino, amino (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 alkyl), amino (C 1-6 alkyl)carbonylamino (C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 1-6 alkyl)carbonylamino (C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 2-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 1-6 alkyl)carbonylamino (C 0-6 Alkyl), (Carboxyl (C) 1-6 Alkyl))oxy(C 1-6 alkyl), cyano (C 0-6 alkyl), tetrazolium (C 0-6 alkyl) and C 1-6 Halogenated alkyl, and two R 5e Substituents, together with the atoms they are attached to, can bond together to form saturated rings; R 5c It is hydrogen, C 1-4 Alkyl, hydroxyl (C 1-4 Alkyl), C 1-4 Alkoxy or (C 1-4 Alkyl)oxy(C 1-4 alkyl); R 6a Selected from hydrogen, hydroxyl, amino, C 1-4 Alkoxy and C 1-6 alkyl; R 6b Selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-4 Alkyl groups and fluorine; R 6c Selected from C 1-10 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)oxy(C 1-6 Alkyl), C 1-10 Halogenated alkyl, aryl (C 0-6 alkyl), heteroaryl (C) 0-10 alkyl), (C 1-6 Alkyl)SO2(C 0-6 Alkyl), hydroxyl, hydroxyl (C) 1-6 alkyl), amino (C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 alkyl), aminocarbonyl (C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 0-6 alkyl), (C 1-6 alkyl)carbonylamino (C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino (C 0-6 alkyl) and carboxyl (C) 0-6 alkyl); R 7a Selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-4 Alkyl groups and fluorine; R 7b Selected from aryl (C 0-6 alkyl), heteroaryl (C) 0-6 alkyl) and (C 3-12 )cycloalkyl (C 0-6 alkyl), Where R 7b By 0, 1, 2 or 3 R 7c Substituent substitution, the R 7c Each substituent is independently selected from C 1-6 Alkyl, C 1-10 fluoroalkyl, C 1-10 Fluoroalkoxy, (C 1-6 alkyl) 0-2 amino (C 0-5 alkyl), (C 1-6 Alkyl)3N + (C 0-5 Alkyl), carboxyl (C) 0-6 alkyl), (C 1-6 Alkoxy)carbonyl (C 0-6 Alkyl), carboxyl (C) 1-6 Alkyl)oxy(C 0-6 alkyl), aminocarbonyl (C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 0-6 Alkyl), hydroxyl, hydroxyl (C) 1-6 Alkyl), halogen, –(C 0-5 alkyl)–(S(=O)2OH), –(C 0-5 Alkyl)–(S(=O)2NH2), amino(C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 Alkyl)oxy(C 0-6 alkyl), aminocarbonylamino (C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino (C 0-6 Alkyl), C 1-10 Haloalkyl, C 1-10 Halogenated alkoxy groups and (C 1-6 Alkyl)oxy(C 0-6 alkyl); R 8a Selected from hydrogen, C 1-6 Alkyl, hydroxyl, C 1-4 Alkoxy, C 1-6 fluoroalkyl, C 1-4 Fluoroalkoxy and halogens; R 8b Selected from bicyclic aryl (C 0-3 alkyl) and bicyclic heteroaryl (C 0-3 alkyl), Where R 8b By 0, 1 or 2 R 8c Substituent substitution, the R 8c Each substituent is independently selected from C 1-4 Alkyl, halogen, cyano, nitro, carboxyl, amino, hydroxyl, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy, C 1-6 Alkoxy, amino (C 1-3 alkyl) and hydroxyl (C) 1-6 alkyl); R 9 Selected from hydrogen and C 1-4 alkyl; R 10a Selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-4 Alkyl groups and fluorine; R 10b Selected from (C) 3-12 )cycloalkyl (C 0-3 alkyl), aryl (C 0-3 alkyl) and heteroaryl (C 0-3 Alkyl group), wherein the heteroaryl group contains 1, 2, or 3 nitrogen atoms. Where R 10b By 0, 1 or 2 R 10c Replacement, where each R 10c Selected independently from C 1-10 Alkyl, C 1-10 fluoroalkyl, C 1-6 Haloalkyl, C 1-10 Fluoroalkoxy, amino, amino (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 Alkyl), hydroxyl, hydroxyl (C) 1-6 Alkyl), cyano, halogen, aminocarbonyl, aminocarbonyl (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 0-6 alkyl), (C 1-6 alkyl) 0-2 aminocarbonylamino (C 0-6 alkyl), (C 1-6 alkyl)carbonylamino (C 0-6 Alkyl), carboxyl (C) 0-6 alkyl), (C 1-6 Alkoxy)carbonyl (C 0-6 Alkyl), carboxyl (C) 1-6 Alkyl)oxy(C 0-6 alkyl), –(C 0-5 alkyl)–(S(=O)2OH), –(C 0-5 Alkyl)–(S(=O)2NH2), amino(C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 Alkyl)oxy(C 0-6 Alkyl), C 1-6 Haloalkoxy, (C 3-12 )cycloalkyl (C 0-6 alkyl) and heterocyclic alkyl (C 0-6 alkyl); R 11a Selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-4 Alkyl groups and fluorine; R 11b Selected from aryl (C 0-3 alkyl), heteroaryl (C) 0-3 Alkyl), wherein the heteroaryl group contains 1, 2 or 3 nitrogen atoms and H2N–C(=NH)NH–(C 1-6 alkyl), Where R 11b By 0, 1, 2, 3 or 4 R 11c Substituent substitution, the R 11c Each substituent is independently selected from C 1-6 Alkyl, amino, amino (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 Alkyl), hydroxyl, hydroxyl (C) 1-6 Alkyl), cyano, halogen, aminocarbonyl, aminocarbonyl (C 1-6 alkyl), (C 1-6 alkyl) 0-2 amino carbonyl (C 0-6 Alkyl), carboxyl (C) 0-6 Alkyl), carboxyl (C) 1-6 Alkyl)oxy(C 0-6 alkyl), amino (C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 alkyl) 0-2 amino (C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 Alkyl)3N + (C 0-6 Alkyl)oxy(C 0-6 alkyl), (C 1-6 Alkyl)oxy(C 0-6 Alkyl), C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkyl, (C 3-12 )cycloalkyl (C 0-6 Alkyl), heterocyclic alkyl (C 0-6 Alkyl), ((C) 1-6 alkyl) carbonyl) heterocyclic alkyl (C 0-10 alkyl) and ((C) 1-6 alkyl) carbonyl) heterocyclic alkyl (C 0-10 alkyl); R 12a Selected from hydrogen, hydroxyl, amino, C 1-10 Alkyl and (C 3-12 )cycloalkyl (C 0-6 alkyl); R 12b Selected from hydrogen, C 1-10 Alkyl and (C 3-12 )cycloalkyl (C 0-6 alkyl); Where R 12a and R 12b Together with the atoms they are attached to, they can form saturated rings; R 13a Selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-4 Alkyl groups and fluorine; R 13b Selected from hydrogen and C 1-4 alkyl; R 13c Selected from bicyclic nitrogen-containing heteroaryl and bicyclic aryl groups having one or two nitrogen atoms, wherein R 13c Independently controlled by 0, 1, or 2 R 13d Substituent substitution, the R 13d The substituents are each independently selected from halogens, C 1-6 Alkyl, carboxyl (C 0-4 Alkyl), C 1-4 Halogenated alkoxy groups and C 1-4 Alkoxy; Selected from Where R 14a Selected from amino, hydroxyl, (C 1-6 alkyl) 0-2 amino and C 1-6 Alkoxy; m is selected from 1, 2, 3, or 4; n is selected from 1, 2, 3, or 4; and R 14b Selected from hydrogen, C 1-8 Alkyl, aryl (C 0-6 alkyl) and heteroaryl (C 0-6 alkyl), wherein R 14b It is replaced by 0, 1, 2 or 3 halogen groups.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, phenyl, phenylmethyl, phenylethyl, phenylpropyl, styryl, biphenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, imidazolyl, pyrazolyl, furanyl, thiophene, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, biphenylmethyl, naphthylmethyl, pyridinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, imidazolylmethyl, pyrazolylmethyl, furanylmethyl, thiophenemethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, isothiazolylmethyl, oxadiazolylmethyl, bicyclo[1.1.1.]pentyl, (bicyclo[1.1.]pentyl). 1.]Pentyl)methyl, phenylcarbonylaminoethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, aminocarbonylisopropyl, aminocarbonylbutyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, aminocarbonylaminobutyl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, adamantyl, carboxyl, carboxymethyl, carboxylethyl, azidomethyl, azidoethyl, azidopropyl, benzene methylaminocarbonylmethyl, pyridylaminocarbonylmethyl, (pyridylcarbonylamino)methyl, guanidinyl, guanidinylmethyl, guanidinylethyl, guanidinylpropyl, guanidinylbutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, pentafluoropropyl, heptafluoropropyl, trifluorobutyl, N,N,N-trimethylmethylammonium, N,N,N-trimethylethyl-1-ylammonium, N,N,N-trimethylpropyl-1-ylammonium, N,N,N-trimethylbutyl-1-ylammonium, methylamino, methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, dimethylamino, 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.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Each R 1a Substituents are independently selected from C 1-6 Alkyl, amino, cyano, halogen, and hydroxyl groups; Each R 2a The substituents are independently selected from hydrogen, hydroxyl, methyl, ethyl, methoxy, ethoxy, and fluorine; R 2b Selected from phenyl, benzyl, biphenyl, naphthyl, pyridinyl, pyrazinylpyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and bicyclo[1.1.1]pentyl; and Each R 2c The substituents are independently selected from aminomethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, fluorine, chlorine, bromine, iodine, aminoethoxy, N-methylaminoethoxy, N-ethylaminoethoxy, N,N-dimethylaminoethoxy, Carboxyl, carboxymethoxy, (carboxymethoxy)methyl, aminocarbonyl, N,N-dimethylaminocarbonyl and aminocarbonylmethyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 3a 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, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, thioethyl, and thiopropyl, wherein R 3a Can be 0, 1 or 2 R 3c Substituent substitution, the R 3c The substituents are each independently selected from fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, amino, aminomethyl, N-methylamino, N-methylaminomethyl, N-ethylamino, N-ethylaminomethyl, N,N-dimethylamino, N,N-dimethylaminomethyl, N,N-diethylamino, N,N-diethylaminomethyl, N,N,N-trimethylammonium, N,N,N-trimethylmethylammonium, hydroxy, hydroxymethyl, –SO2CH3, –CH2SO2CH3, –CH2CH2SO2CH3, cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxyl, carboxylmethyl, and carboxylethyl; and R 3b Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, bicyclo[1.1.1]pentylmethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 3-hydroxypropyl, 1-methyl-1-hydroxyethyl, hydroxyisopropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, aminomethyl, 2-aminoethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, N-methylaminoethyl, N,N-dimethylaminoethyl, N-methylaminopropyl, N,N-dimethylaminopropyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 2-aminopropyl-2-yl, fluoromethyl, difluoromethyl The following are listed: methyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, benzyl, 3-pyridylmethyl, 4-pyridylmethyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiophenylmethyl, furanylmethyl, pyrazolylmethyl, N-pyrazolylmethyl, 1-phenylethyl, 1-(4-pyridyl)ethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, (N,N-dimethyl)aminocarbonylmethyl, (N,N-dimethyl)aminocarbonylethyl, thiomethyl, thioethyl, thiopropyl, –CH2CH2SO2CH3, carboxylmethyl, carboxylethyl, 2-carboxylethyl, carboxylpropyl, 3-carboxylpropyl, carboxylbutyl, 4-carboxylbutyl, piperazinylmethyl, morpholinylmethyl, piperidinylmethyl, azacyclic butylmethyl, tetrahydropyranylmethyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, and aminocarbonylaminobutyl, wherein R 3b Can be 0, 1 or 2 R 3c Substituent substitution, the R 3c The substituents are each independently selected from fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, amino, aminomethyl, N-methylamino, N-methylaminomethyl, N-ethylamino, N-ethylaminomethyl, N,N-dimethylamino, N,N-dimethylaminomethyl, N,N-diethylamino, N,N-diethylaminomethyl, N,N,N-trimethylammonium, N,N,N-trimethylmethylammonium, hydroxy, hydroxymethyl, –SO2CH3, –CH2SO2CH3, –CH2CH2SO2CH3, cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxyl, carboxylmethyl and carboxylethyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b Together with the atoms they are attached to, they form a group consisting of 0, 1, or 2 R atoms. 3d Saturated ring systems substituted with substituents, wherein the saturated ring system is selected from:

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 4a Selected from hydrogen, methyl, ethyl, propyl, hydroxyl, methoxy, and fluorine; R 4b Selected from indole, naphthyl, quinolinyl, pyrrolo[2,3-b]pyridyl, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrazolo[3,4-b]pyridine, indazole, benzothiazolyl, and benzothiaphenyl, wherein R 4b By 0, 1 or 2 R 4c Substituent substitution, the R 4c Each substituent is independently selected from fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, methyl, ethyl, propyl, isopropyl, carboxyl, carboxymethyl, and carboxyethyl; R 5a Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclopentyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, phenyl, benzyl, phenylethyl, phenylpropyl, oxazolylmethyl, thiazolylmethyl, imidazolylmethyl, triazolylmethyl, oxadiazolylmethyl, thiazolylmethyl, oxazolylethyl, thiazolylethyl, imidazolylethyl, triazolylethyl, oxadiazolylethyl, thiazolylethyl, oxazolylpropyl, thiazolylpropyl, imidazolylpropyl, triazolylpropyl, oxadiazolylpropyl, thiazolylpropyl, aziridinemethyl, aziridinemethyl Ethyl, oxetane-butylmethyl, oxetane-butylmethyl, pyrrolylmethyl, pyrrolylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, tetrahydropyranylmethyl, tetrahydropyranylmethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, 3-hydroxy-2,2-dimethylpropyl, cyclopropylmethyl, 1-hydroxypropyl-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, (N-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-trifluoroethyl)ethyl, (N,N,N-dimethyl ... (N,N,N-trimethylammonium)ethyl, (N,N,N-triethylammonium)ethyl, (N,N,N-triethylammonium)propyl, (N-methylamino)methylcarbonylaminoethyl, (N-methylamino)ethylcarbonylaminoethyl, (N-methylamino)methylcarbonylaminopropyl, (N-ethylamino)methylcarbonylaminoethyl, (N-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,N-diethylamino)ethylcarbonylaminoethyl, (N,N-diethylamino)methylcarbonylaminopropyl, (N,N-dimethylamino)pentylcarbonylaminoethyl, (N,N-dimethylamino)pentylcarbonylaminoethyl, (N,N-dimethylamino)pentylcarbonylaminopropyl, N,N,N-trimethyl-ethyl-1-ammonium ... Methyl-propyl-1-ammonium, (N,N,N-trimethylammonium)methylcarbonylaminoethyl, (N,N,N-trimethylammonium)ethylcarbonylaminoethyl, (N,N,N-trimethylammonium)methylcarbonylaminopropyl, (N,N,N-trimethylammonium)ethylcarbonylaminopropyl, (N,N,N-trimethylammonium)pentylcarbonylaminoethyl, (N,N,N-trimethylammonium)pentylcarbonylaminopropyl, (carboxymethyl)oxyethyl, and (carboxymethyl)oxypropyl, wherein R, 5a By 0, 1, 2 or 3 R 5d Substituent substitution, the R 5d The substituents are each independently selected from chlorine, fluorine, hydroxyl, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, carboxyl, carboxymethyl, carboxyethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, amino, aminomethyl, aminoethyl, N-methylamino, (N-methylamino)methyl, (N-methylamino)ethyl, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N-dimethylamino)ethyl, N,N-Diethylamino, (N,N-Diethylamino)methyl, (N,N-Diethylamino)ethyl, aminomethylcarbonylamino, aminoethylcarbonylamino, aminopentylcarbonylamino, aminomethylcarbonylaminomethyl, aminoethylcarbonylaminomethyl, (N-methylamino)methylcarbonylamino, (N-methylamino)ethylcarbonylamino, (N-methylamino)methylcarbonylaminomethyl, (N-methylamino)ethylcarbonylaminomethyl, (N,N-Dimethylamino)methylcarbonylamino, (N,N-Dimethylamino)ethylcarbonyl Amino, (N,N-dimethylamino)methylcarbonylaminomethyl, (N,N-dimethylamino)ethylcarbonylaminomethyl, (N,N-diethylamino)methylcarbonylamino, (N,N-diethylamino)ethylcarbonylamino, (N,N-diethylamino)methylcarbonylaminomethyl, (N,N-diethylamino)ethylcarbonylaminomethyl, N,N,N-trimethylammonium, (N,N,N-trimethylammonium)methyl, (N,N,N-trimethylammonium)ethyl, (N,N,N-trimethylammonium)ethoxy, (N,N,N-trimethylammonium)ethoxy, (N,N,N-trimethylammonium)ethoxy (N,N,N-trimethylammonium) ethoxymethyl, (N,N,N-trimethylammonium) methyl carbonylamino, (N,N,N-triethylammonium) methyl carbonylamino, (N,N,N-trimethylammonium) ethyl carbonylamino, (N,N,N-trimethylammonium) pentyl carbonylamino, (N,N,N-trimethylammonium) methyl carbonylaminomethyl, (N,N,N-trimethylammonium) ethyl carbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazolium, tetrazolylmethyl, tetrazolylethyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl and carboxyethoxymethyl; R 5b Selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopropylmethyl, oxacyclobutylmethyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, methoxypropyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, (carboxymethoxy)methyl, (carboxymethoxy)ethyl, (carboxyethoxy)methyl, (carboxyethoxy)ethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, (N-methylamino)methyl, (N-methylamino)ethyl, (N-methylamino)propyl, (N-methylamino)butyl, (N,N-dimethylamino)methyl (N,N-Dimethylamino)ethyl, (N,N-Dimethylamino)propyl, (N,N-Dimethylamino)butyl, (N,N-Diethylamino)methyl, (N,N-Diethylamino)ethyl, (N,N-Diethylamino)propyl, (N,N-Diethylamino)butyl, N,N,N-Trimethylmethyl-1-ylammonium, N,N,N-Trimethylethyl-1-ylammonium, N,N,N-Triethylethyl-1-ylammonium, N,N,N-Trimethylpropyl-1-ylammonium, N,N,N-Trimethylbutyl-1-ylammonium, (N,N,N-Trimethylammonium)ethoxymethyl, (N,N,N-Trimethylammonium)ethoxyethyl, (N,N,N-Triethylammonium)ethoxyethyl, (N,N,N-Trimethylammonium)ethoxyethyl, (N,N,N-Trimethylammonium)ethoxy Propyl, (N,N,N-trimethylammonium)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, (N,N-dimethylamino)carbonylpropyl, (N,N-dimethylamino)carbonylbutyl, aminomethylcarbonylaminoethyl, aminomethylcarbonylaminopropyl, aminoethylcarbonylaminoethyl, aminoethylcarbonylaminopropyl, (N,N-dimethylamino)methylcarbonylaminoethyl, (N,N-dimethylamino)methylcarbonylaminopropyl , (N,N-dimethylamino)ethylcarbonylaminoethyl, (N,N-dimethylamino)ethylcarbonylaminopropyl, (N,N,N-trimethylammonium)methylcarbonylaminoethyl, (N,N,N-triethylammonium)methylcarbonylaminoethyl, (N,N,N-trimethylammonium)methylcarbonylaminopropyl, (N,N,N-trimethylammonium)ethylcarbonylaminoethyl, (N,N,N-trimethylammonium)ethylcarbonylaminopropyl, (N,N,N-trimethylammonium)ethoxyethyl, (N,N,N-trimethylammonium)ethoxypropyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanoisopropyl, and cyanobutyl, wherein R 5b By 0, 1, 2 or 3 R 5e Substituent substitution, the R 5e The substituents are each independently selected from chlorine, fluorine, hydroxyl, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, carboxyl, carboxymethyl, carboxyethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, amino, aminomethyl, aminoethyl, N-methylamino, (N-methylamino)methyl, (N-methylamino)ethyl, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N-dimethylamino)ethyl, N,N-Diethylamino, (N,N-Diethylamino)methyl, (N,N-Diethylamino)ethyl, aminomethylcarbonylamino, aminoethylcarbonylamino, aminopentylcarbonylamino, aminomethylcarbonylaminomethyl, aminoethylcarbonylaminomethyl, (N-methylamino)methylcarbonylamino, (N-methylamino)ethylcarbonylamino, (N-methylamino)methylcarbonylaminomethyl, (N-methylamino)ethylcarbonylaminomethyl, (N,N-Dimethylamino)methylcarbonylamino, (N,N-Dimethylamino)ethylcarbonylamino (N,N-dimethylamino)methylcarbonylaminomethyl, (N,N-dimethylamino)ethylcarbonylaminomethyl, (N,N-diethylamino)methylcarbonylamino, (N,N-diethylamino)ethylcarbonylamino, (N,N-diethylamino)methylcarbonylaminomethyl, (N,N-diethylamino)ethylcarbonylaminomethyl, (N,N-diethylamino)ethylcarbonylaminomethyl, N,N,N-trimethylammonium, (N,N,N-trimethylammonium)methyl, (N,N,N-trimethylammonium)ethyl, (N,N,N-trimethylammonium)ethoxy, (N,N,N-trimethylammonium)ethoxy, (N,N,N-trimethylammonium)trimethylammonium (N,N,N-trimethylammonium) ethoxymethyl, (N,N,N-trimethylammonium) methylcarbonylamino, (N,N,N-triethylammonium) methylcarbonylamino, (N,N,N-trimethylammonium) ethylcarbonylamino, (N,N,N-trimethylammonium) pentylcarbonylamino, (N,N,N-trimethylammonium) methylcarbonylaminomethyl, (N,N,N-trimethylammonium) ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazolium, tetrazolylmethyl, tetrazolylethyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl and carboxyethoxymethyl; and R 5c It is hydrogen, methyl, or ethyl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 5a and R 5b Together with the atoms they are attached to, they form groups of 0, 1, 2, or 3 R. 5d And 0, 1, 2 or 3 R 5e Saturated monocyclic or bicyclic ring systems substituted with substituents, wherein the monocyclic or bicyclic ring system is selected from:

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 6a Selected from hydrogen, hydroxyl, methyl, ethyl, propyl, and methoxy; R 6b Selected from hydrogen, hydroxyl, methyl, ethyl, propyl, methoxy, and ethoxy; R 6c Selected from aminocarbonyl, (aminocarbonyl)methyl, (aminocarbonyl)ethyl, (aminocarbonyl)propyl, (N-methylamino)carbonyl, (N-methylamino)carbonylmethyl, (N-methylamino)carbonylethyl, (N-methylamino)carbonylpropyl, (N,N-dimethylamino)carbonyl, (N,N-dimethylamino)carbonylmethyl, (N,N-dimethylamino)carbonylethyl, (N,N-dimethylamino)carbonylpropyl, (N,N-diethylamino)carbonyl, (N,N-diethylamino)carbonylmethyl, (N,N-diethylamino)carbonylethyl, (N,N-diethylamino)carbonylpropyl, aminocarbonylamino, (aminocarbonyl) (amino)methyl, (aminocarbonylamino)ethyl, (aminocarbonylamino)propyl, methoxy, methoxymethyl, methoxyethyl, ethoxy, ethoxymethyl, ethoxyethyl, methylsulfonyl, (methylsulfonyl)methyl, (methylsulfonyl)ethyl, (methylsulfonyl)propyl, amino, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, carboxyl, carboxylmethyl, carboxylethyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl and benzyl; R 7a Selected from hydrogen, methyl, ethyl, hydroxy, methoxy, and ethoxy; R 7b Selected from phenyl, biphenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, imidazolyl, pyrazolyl, furanyl, thiophene, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 3-oxoisoindolinel and bicyclic [1.1.1]pentyl; R 7c Selected from fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, carboxyl, carboxymethyl, methoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonyl, carboxylmethoxy, carboxylethoxy, carboxylmethoxymethyl, aminocarbonyl, aminocarbonylmethyl, (N,N-dimethylamino)carbonyl, (N,N-dimethylamino)carbonylmethyl, amino, aminomethyl, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N-diethylamino)amino (N,N,N-trimethylammonium, N,N,N-trimethylmethylammonium, N,N,N-triethylmethylammonium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, –SO2OH, –CH2SO2OH, –SO2NH2, –CH2SO2NH2, aminoethoxy, aminoethoxymethyl, (N,N-dimethylamino)ethoxy, N,N,N-trimethyleth-1-oxy-ammonium, aminocarbonylamino and aminocarbonylaminomethyl; R 8a Selected from hydrogen, methyl, ethyl, hydroxy, methoxy, and ethoxy; R 8b Selected from indole, naphthyl, indolemethyl, naphthylmethyl, quinolinyl, pyrrolo[2,3-b]pyridyl, indazole, benzothiazolyl, and benzothiophene; Each R 8c Independently selected from methyl, ethyl, isopropyl, fluorine, chlorine, bromine, iodine, cyano, amino, aminomethyl, nitro, hydroxy, hydroxymethyl, carboxyl, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, methoxy, ethoxy, and trifluoromethoxy; and R 9 Selected from hydrogen, methyl, ethyl and propyl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 10a Selected from hydrogen, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy; R 10b Selected from phenyl, benzyl, biphenyl, biphenylmethyl, pyridyl, pyridylmethyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, imidazolylmethyl, pyrazolyl, furanyl, furanylmethyl, oxazolyl, oxazolylmethyl, thiazolyl, indolyl, [1,2,4]triazolo[1,5-a]pyridine and bicyclo[1.1.1]pentyl. R 10c Independently selected from methyl, ethyl, n-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, fluorine, chlorine, bromine, iodine, hydroxyl, hydroxymethyl, hydroxyethyl, cyano, amino, aminomethyl, aminoethyl, N-methylamino, (N-methylamino)methyl, (N-methylamino)ethyl, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N-dimethylamino)ethyl, N,N,N-trimethylammonium, N,N,N-trimethylmethylammonium, aminocarbonyl, aminocarbonylmethyl, aminocarbonylethyl, (N-methylamino)carbonyl, (N-methylamino)carbonyl, (N-methylamino)ammonium (N,N-dimethylamino)carbonylmethyl, (N,N-dimethylamino)carbonylmethyl, aminocarbonylamino, aminocarbonylaminomethyl, methylcarbonylamino, methylcarbonylamino, carboxyl, carboxylmethyl, carboxylethyl, methoxycarboxyl, carboxylmethoxy, carboxylethoxy, carboxylmethoxymethyl, carboxylethoxymethyl, –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, (N,N-diethylamino)ethoxy, (N,N,N-trimethylammonium)ethoxy, methoxy, ethoxy, methoxymethyl, ethoxymethyl, difluoromethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy; R 11a Selected from hydrogen, hydroxyl, methyl, ethyl, methoxy, and ethoxy; R 11b Selected from (H2N–C(=NH)–NH)methyl, (H2N–C(=NH)–NH)ethyl, (H2N–C(=NH)–NH)propyl, (H2N–C(=NH)–NH)butyl, phenyl, benzyl, pyridyl, pyridylmethyl, indolyl, indolylmethyl, pyridazinyl, pyridazinylmethyl, pyrimidinyl, pyrimidinylmethyl, pyrazinyl, pyrazinylmethyl, imidazolyl, imidazolylmethyl, pyrazolyl, pyrazolylmethyl, [1,2,4]triazolo[1,5-a]pyridine, oxazolyl, oxazolylmethyl, thiazolyl and thiazolylmethyl; Each R 11c Independently selected from fluorine, chlorine, bromine, iodine, (carboxymethyl)oxy, (carboxymethyl)oxymethyl, (carboxyethyl)oxy, hydroxy, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, carboxyl, carboxymethyl, aminocarbonyl, aminocarbonylmethyl, (N-methylamino)carbonyl, (N-methylamino)carbonylmethyl, (N,N-dimethylamino)carbonyl, (N,N-dimethylamino)carbonylmethyl, amino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, aminomethyl, (N (N,N-dimethylamino)methyl, (N,N-diethylamino)methyl, N,N,N-trimethylammonium, N,N,N-trimethylmethyl-1-yl-ammonium, N,N,N-triethylammonium, N,N,N-triethylmethyl-1-yl-ammonium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, aminoethoxy, aminopropoxy, aminoethoxymethyl, (N,N-dimethylamino)ethoxy, N,N,N-trimethyleth-1-yloxy-ammonium, cyano and methylcarbonylpiperazinyl [(N-acetyl)piperazinyl; R 12a Selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, and isopropyl; and R 12b Selected from hydrogen, methyl, ethyl and propyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 12a and R 12b Together with the atoms they are attached to, they form a selection from saturated ring.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 13a It is hydrogen, methyl, or propyl; R 13b It is hydrogen or methyl; R 13c Selected from indolyl, pyrrolo[2,3-b]pyridyl, quinolinyl, indazole, and naphthyl; R 13c Selected from indolyl and pyrrolo[2,3-b]pyridyl; Each R 13d It is independently selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, carboxyl, carboxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, and ethoxy; Each R 14a Independently selected from amino, hydroxyl, N-methylamino, N,N-dimethylamino, N-ethylamino, methoxy, and ethoxy; and Each R 14b It is independently 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, indole, indoleylmethyl, imidazolyl, imidazolylmethyl, pyridyl, and pyridylmethyl.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: SEQ ID NO:1-289.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of (in order of appearance, SEQ ID NO 5, 10, 18, 22, 30, 31, 41, 45, 48, 51, 52, 53, 60, 68, 77, 83, 87, 104, 183, 196, 206, 210, 214, 221, 229, 237, 247, 250, 254, 257 and 265): SEQ ID NO.5、 SEQ ID NO.10、 SEQ ID NO.18、 SEQ ID NO.22、 SEQ ID NO.30、 SEQ ID NO.31、 SEQ ID NO.41、 SEQ ID NO.45、 SEQ ID NO.48、 SEQ ID NO.51、 SEQ ID NO.52、 SEQ ID NO.53、 SEQ ID NO.60、 SEQ ID NO.68、 SEQ ID NO.77、 SEQ ID NO.83、 SEQ ID NO.87、 SEQ ID NO.104、 SEQ ID NO.183、 SEQ ID NO.196、 SEQ ID NO.206、 SEQ ID NO.210、 SEQ ID NO.214、 SEQ ID NO.221、 SEQ ID NO.229、 SEQ ID NO.237、 SEQ ID NO.247、 SEQ ID NO.250、 SEQ ID NO.254、 SEQ ID NO.257 and SEQ ID NO.

265.

14. A pharmaceutical composition comprising a compound as described in any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A method of treating IBD and other TNFα-driven inflammatory diseases, comprising administering to a subject requiring such treatment a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-12, wherein the IBD and other TNFα-driven inflammatory diseases are selected from ulcerative colitis, Crohn's disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiological axial spondyloarthritis, and hidradenitis suppurativa.

16. The method of claim 15, wherein the IBD and other TNFα-driven inflammatory diseases are selected from ulcerative colitis and Crohn's disease.

17. The method of claim 15, wherein the IBD and other TNFα-driven inflammatory diseases are selected from rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiological axial spondyloarthritis, and hidradenitis suppurativa.

18. The method according to any one of claims 15-17, wherein an effective amount of the compound or a pharmaceutically acceptable salt thereof is orally administered to the subject.

19. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13 in a therapeutic manner.

20. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13 in the treatment of IBD and other TNFα-driven inflammatory diseases selected from ulcerative colitis, Crohn's disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiological axial spondyloarthritis, and hidradenitis suppurativa.

21. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13 in the treatment of IBD and other TNFα-driven inflammatory diseases selected from ulcerative colitis and Crohn's disease.

22. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13 in the treatment of IBD and other TNFα-driven inflammatory diseases selected from rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiological axial spondyloarthritis, and hidradenitis suppurativa.

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