Cyclic peptide for inhibiting TNF receptor 1 activity

Abstract

To provide a cyclic peptide that inhibits TNFR1 activity, and a pharmaceutical composition.SOLUTION: Provided is a compound of formula (I) or its pharmacologically acceptable salt, wherein (I) is capable of inhibiting TNFR1, and is useful as a therapeutic drug for IBD and rheumatic arthritis for example.SELECTED DRAWING: None

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 the 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 spondyloarthritis, hidradenitis suppurativa and other skin disorders, and other neurological, neurodegenerative, metabolic, and ocular disorders. [Background technology]

[0002] Therapeutic agents targeting the signaling of the cytokine tumor necrosis factor alpha (TNFα), including anti-TNFα biologics that emerged in the 1990s, continue to be included in the standard of care (SOC) for several common autoimmune and inflammatory diseases, including ulcerative colitis (UC), Crohn's disease (CD) (collectively known as IBD), RA, juvenile RA, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa. TNFα is a pleiotropic cytokine that affects the function of various cell types. It triggers cellular responses ranging from inducing inflammatory gene expression programs, stimulating cell proliferation and differentiation, to activating cell suicide programs such as apoptosis and necroptosis. It is expressed as a type II single-pass transmembrane protein and as a soluble variant released after proteolytic processing.

[0003] TNFα self-assembles into homotrimeric molecules and interacts with two known membrane receptors for TNFα, TNFR1 and TNFR2, both in transmembrane and soluble forms, each exerting distinct biological effects. Both TNFα receptors are typical representatives of the broader TNF receptor superfamily. TNFR1 and TNFR2 are type I single-pass transmembrane proteins characterized by several cysteine-rich domains in their extracellular domains. 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 pro-inflammatory, cytotoxic, and gene-inducing signaling actions of TNFα. 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, where it mediates the cytokine's immunosuppressive / homeostatic effects on immune cells and tissue regeneration.

[0004] The mechanism of action (MOA) of anti-TNFα biologics such as infliximab, adalimumab, golimumab and certolizumab involves binding to the cytokine TNFα and therefore inhibiting binding to both TNFR1 and TNFR2.

[0005] A key limitation of anti-TNFα SOC biologics as a class of drugs is the high loss of response rate (>70% within 1 year of treatment), often caused by the development of anti-drug antibodies (ADAs, approximately 60% of IBD patients), which result in undesirable changes in the pharmacokinetic and pharmacodynamic properties of these drugs (see Colombel et al., “Adalimumab for Maintenance of Clinical Response and Remission in Patients with Crohn's Disease”, Gastroenterology 132(1):52-65 (2007); and Vaisman-Mentesh, A. et al., “The Molecular Mechanisms that Underlie the Immune Biology of Anti-drug Antibody Formation Following Treatment with Monoclonal Antibodies”, Frontiers in Immunology, 11:1951 (2020)).

[0006] The limitations of anti-TNF therapy may depend on the pleiotropic biological functions of TNF mediated by two distinct TNF receptors. In different animal disease models, genetic deletion of TNFR1 is typically associated with or reduces disease, whereas loss of TNFR2 exacerbates disease. These and other data indicate that soluble TNFα / TNFR1 signaling primarily mediates proapoptotic and inflammatory responses, whereas TNFR2 contributes to immune regulation and tissue regeneration. Therefore, reagents that selectively target TNFRs may be superior to comprehensive TNF blockade, as they allow for differential activation and / or inhibition of TNFRs. Selective blockade of TNFα / TNFR1 signaling while preserving functional TNFα / TNFR2 signaling appears to be sufficient to disrupt pathological TNFα signaling. In contrast to global TNF blockers, which neutralize both soluble and transmembrane forms of TNFα, this class of therapeutics may induce less severe side effects and may be useful for treating other diseases in which complete TNF inhibition is contraindicated, such as MS or neurodegenerative diseases (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] Additional therapeutic approaches beyond the current standard of care of anti-TNFα biologics are needed to slow the progression of common autoimmune and inflammatory diseases. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Colombel et al., “Adalimumab for Maintenance of Clinical Response and Remission in Patients with Crohn's Disease”, Gastroenterology 132(1):52-65(2007) [Non-patent document 2] 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) [Non-patent document 3] Fischer et al., “Selective Targeting of TNF Receptors as a Novel Therapeutic Approach”, Front.Cell Dev.Biol.8:401(2020) [Non-patent document 4] Dong et al., “Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders”, Antibodies, 4:4 (2015) Summary of the Invention

[0009] The present disclosure provides certain cyclic peptides that reduce inflammation by selectively inhibiting TNFR1, specifically attenuating the pro-inflammatory activity of TNFα mediated by TNFR1 signaling and sparing / passively enabling TNFα-TNFR2 pro-homeostatic signaling. These cyclic peptides may be valuable pharmaceutically active compounds for treating common autoimmune and inflammatory diseases, including ulcerative colitis (UC), Crohn's disease (CD) (collectively known as inflammatory bowel disease (IBD)), rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriasis, and other inflammatory conditions that can be treated by blocking TNFα signaling, such as psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, hidradenitis suppurativa, and other skin disorders, as well as other neurological, neurodegenerative, metabolic, and ocular disorders.

[0010] In one aspect, the present disclosure provides a compound of formula (I) [ka] and pharmaceutically acceptable salts thereof.

[0011] The compounds of the present invention have the potential to provide superior and sustained efficacy over non-selective anti-TNFα SOCs through inhibition of TNFR1-driven inflammation while simultaneously sparing TNFR2-dependent homeostasis, mucosal / tissue healing, and immune regulation. Thus, in another aspect, the present disclosure provides a method for treating autoimmune and inflammatory diseases (e.g., ulcerative colitis, Crohn's disease (collectively known as IBD), rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa) comprising administering a therapeutically effective amount of a compound of the present disclosure to a subject in need thereof. In some embodiments, the administration comprises oral administration of the compound.

[0012] The present disclosure further provides methods for preparing compounds of the present disclosure and pharmaceutical compositions comprising compounds of the present disclosure and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF THE INVENTION

[0013] Compounds of the Disclosure In one embodiment, the present disclosure provides a compound having structural formula (I) or a pharmaceutically acceptable salt thereof: [ka] (In the formula, R 1 is 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 0~6 Alkyl)carbonylamino(C 0~6 alkyl), (C 0~6 alkyl) 0~2 Aminocarbonyl (C 0~6 alkyl), (C 1~6 alkyl) 0~2 Aminocarbonylamino (C 0~6 alkyl), arylcarbonylamino (C 0~6 alkyl), arylaminocarbonyl (C 0~6 alkyl), heteroarylcarbonylamino (C 0~6 alkyl), heteroarylaminocarbonyl (C 0~6 alkyl), C 1~6 Alkyloxy, (C 1~6 Alkyl)oxy(C 0~6 alkyl), ((C3~12 )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), where R 1 is C 1~6 Alkyl, amino, cyano, halo, hydroxy, (C 3~12 ) cycloalkyloxy, and C 1~6 0, 1, 2, 3, or 4 R, each independently selected from alkyloxy; 1a is substituted by a substituent; Each R 2a is hydrogen, hydroxy, C 1~4 Alkyl, Fluoro, and C 1~4 independently selected from alkyloxy; R 2b is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said heteroaryl contains at least one nitrogen atom; where R 2b is 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), hydroxy, C 1~6 Alkyloxy, halo, (C 1~6 alkyl) 0~2 Amino (C 0~6alkyloxy), (C 1~6 Alkyl)3N + (C 0~6 alkyloxy), (C 1~6 Alkyloxy)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 Haloalkyloxy, and C 1~6 0, 1, or 2 R independently selected from alkyloxy 2c has been replaced by; R 3a is 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), (C 0~6 alkyl)thio(C 1~6 alkyl), and carboxy (C 1~6 alkyl), where R 3a can contain 0, 1, or 2 R 3c optionally substituted by a substituent; R 3b is hydrogen, C 1~10 Alkyl, hydroxy (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 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(C1~6 alkyl), (C 3~12 )Cycloalkyloxy(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), where R 3b can contain 0, 1, or 2 R 3c optionally substituted by a substituent; Each R 3c Ha, Halo, 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); where R 3a and R 3b may, together with the atom to which they are attached, form a saturated ring system, wherein said saturated ring system is selected from the group consisting of 0, 1, or 2 R 3coptionally substituted by a substituent; R 4a is hydrogen, C 1~6 Alkyl, hydroxy, C 1~4 alkyloxy, and fluoro; R 4b is a bicyclic heteroaryl (C 0~3 alkyl), and bicyclic aryl (C 0~3 alkyl), where R 4b are halo, hydroxy, cyano, nitro, carboxy, carboxy (C 1~6 alkyl), (C 1~6 Alkyloxy)carbonyl (C 0~6 alkyl), C 1~6 Alkyloxy, (C 1~6 Alkyl)oxy(C 1~6 alkyl), C 1~6 Alkyl, and C 1~6 0, 1, or 2 R independently selected from haloalkyl 4c is substituted with a substituent; R 5a is 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 (C0-6 alkyl), heteroaryl (C 0~6 alkyl), (C 1~6 Alkyl)oxy(C 1~6 alkyl), (C 1~6 Alkyloxy)carbonyl (C 0~6Alkyl), 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, where R 5a can contain 0, 1, or 2 R 5d is substituted by a substituent; R 5b is 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)carbonylamino(C 1~6 alkyl), (C 1~6 alkyl) 0~2 Amino (C 1~6 Alkyl)carbonylamino(C 1~6 alkyl), (C 1~6Alkyl)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), heterocycloalkyl (C 0~10 alkyl), (C 3~12 ) Cycloalkyl(C 0~10 alkyl), and C 1~10 haloalkyl, where R 5b can contain 0, 1, 2, or 3 R 5e is substituted by a substituent, where R 5a and R 5b together with the atoms to which they are attached form a saturated monocyclic or bicyclic ring, wherein said monocyclic or bicyclic ring contains 0, 1, 2, or 3 R 5d Substituent and 0, 1, 2, or 3 R 5e is substituted with a substituent; Each R 5d are halo, hydroxy, hydroxy(C 1~10 alkyl), C 1~10 Alkyl, carboxy, carboxy(C 1~6 alkyl), C 1~6 Alkyloxy, (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 0~6alkyl), (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), (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 The substituents, together with the atoms to which they are attached, may be joined to form a saturated ring; Each R 5e are halo, hydroxy, hydroxy(C 1~10 alkyl), C 1~10 Alkyl, carboxy, carboxy(C 1~6 alkyl), C 1~6 Alkyloxy, (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), (carboxy(C1~6 Alkyl))oxy(C 1~6 alkyl), cyano (C 0~6 alkyl), tetrazolyl (C 0~6 alkyl), and C 1~6 haloalkyl, and two R 5e The substituents, together with the atoms to which they are attached, may be joined to form a saturated ring; R 5c is hydrogen, C 1~4 Alkyl, hydroxy (C 1~4 alkyl), C 1~4 Alkyloxy, or (C 1~4 Alkyl)oxy(C 1~4 alkyl); R 6a is hydrogen, hydroxy, amino, C 1~4 Alkyloxy, and C 1~6 alkyl; R 6b is hydrogen, C 1~6 Alkyl, hydroxy, C 1~4 alkyloxy, and fluoro; R 6c is C 1~10 Alkyl, C 1~6 Alkyloxy, (C 1~6 Alkyl)oxy(C 1~6 alkyl), C 1~10 Haloalkyl, 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), (C1-6 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), (C1~6 alkyl) 0~2 Aminocarbonylamino (C 0~6 alkyl), and carboxy (C 0~6 alkyl); R 7a is hydrogen, C 1~6 Alkyl, hydroxy, C 1~4 alkyloxy, and fluoro; R 7b is an aryl (C 0~6 alkyl), heteroaryl (C 0~6 alkyl), and (C 3~12 ) Cycloalkyl(C 0~6 alkyl), where R 7b is C 1~6 Alkyl, C 1~10 Fluoroalkyl, C 1~10 Fluoroalkyloxy, (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 Alkyloxy)carbonyl (C 0~6 alkyl), carboxy (C 1~6 Alkyl)oxy(C 0~6 alkyl), aminocarbonyl (C 0~6 alkyl), (C 1~6 alkyl) 0~2 Aminocarbonyl (C 0~6 alkyl), hydroxy, hydroxy(C 1~6 alkyl), halo, -(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 1~6Alkyl)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 haloalkyloxy, and (C 1~6 Alkyl)oxy(C 0~6 0, 1, 2, or 3 R independently selected from 7c is substituted by a substituent; R 8a is hydrogen, C 1~6 Alkyl, hydroxy, C 1~4 Alkyloxy, C 1~6 Fluoroalkyl, C 1~4 selected from fluoroalkyloxy, and halo; R 8b is a bicyclic aryl (C 0~3 alkyl) and bicyclic heteroaryl (C 0~3 alkyl), where R 8b is C 1~4 Alkyl, halo, cyano, nitro, carboxy, amino, hydroxy, C 1~6 Fluoroalkyl, C 1~6 Fluoroalkyloxy, C 1~6 Alkyloxy, amino(C 1~3 alkyl), and hydroxy (C 1~6 0, 1, or 2 R independently selected from 8c is substituted by a substituent; R 9 is hydrogen and C 1~4 alkyl; R 10a is hydrogen, hydroxy, C 1~6 Alkyl, C 1~4 alkyloxy, and fluoro; R 10b is (C 3~12) Cycloalkyl(C 0~3 alkyl), aryl (C 0~3 alkyl), and heteroaryl (C 0~3 alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms; where R 10b can contain 0, 1, or 2 R 10c are replaced by, and each R 10c is C 1~10 Alkyl, C 1~10 Fluoroalkyl, C 1~6 Haloalkyl, C 1~10 Fluoroalkyloxy, 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, halo, aminocarbonyl, aminocarbonyl (C 1~6 alkyl), (C 1~6 alkyl) 0~2 Aminocarbonyl (C 0~6 alkyl), (C 1~6 alkyl) 0~2 Aminocarbonylamino (C 0~6 alkyl), (C 1~6 Alkyl)carbonylamino(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 0~6alkyl), (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 Haloalkyloxy, (C 3~12 ) Cycloalkyl(C 0~6 alkyl), and heterocycloalkyl (C 0~6 alkyl); R 11a is hydrogen, hydroxy, C 1~6 Alkyl, C 1~4 alkyloxy, and fluoro; R 11b is an aryl (C 0~3 alkyl), heteroaryl (C 0~3 alkyl), where the heteroaryl contains 1, 2, or 3 nitrogen atoms, and HN—C(═NH)NH—(C 1~6 alkyl), where R 11b is 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, halo, aminocarbonyl, aminocarbonyl (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 0~6Alkyl)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 Haloalkyloxy, C 1~6 Haloalkyl, (C 3~12 ) Cycloalkyl(C 0~6 alkyl), heterocycloalkyl (C 0~6 alkyl), ((C 1~6 alkyl)carbonyl)heterocycloalkyl(C 0~10 alkyl), and ((C 1~6 alkyl)carbonyloxy)heterocycloalkyl(C 0~10 0, 1, 2, 3, or 4 R, each independently selected from 11c is substituted by a substituent; R 12a is hydrogen, hydroxy, amino, C 1~10 Alkyl, and (C 3~12 ) Cycloalkyl(C 0~6 alkyl); R 12b is hydrogen, C 1~10 Alkyl, and (C 3~12 ) Cycloalkyl(C 0~6 alkyl); where R 12a and R 12b may, together with the atoms to which they are attached, form a saturated ring; R 13a is hydrogen, hydroxy, C 1~6 Alkyl, C 1~4 alkyloxy, and fluoro; R 13b is hydrogen and C 1~4 alkyl; R 13c is selected from bicyclic nitrogen-containing heteroaryl and bicyclic aryl having one or two nitrogens, where R 13cHa, Halo, C 1~6 Alkyl, carboxy (C 0~4 alkyl), C 1~4 Haloalkyloxy, and C 1~4 0, 1, or 2 R independently selected from alkyloxy 13d is independently substituted by substituents; [ka] teeth, [ka] Selected from TIFF2025159726000005.tif52150; where R 14a is amino, hydroxy, (C 1~6 alkyl) 0~2 Amino, and C 1~6 alkyloxy; m is selected from 1, 2, 3, or 4; n is selected from 1, 2, 3, or 4; and R 14b is hydrogen, C 1~8 Alkyl, aryl (C 0~6 alkyl), and heteroaryl (C 0~6 alkyl), where R 14b is substituted by 0, 1, 2, or 3 halo groups; to provide.

[0014] In the first embodiment of the present invention, R 1aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, phenyl, phenylmethyl, phenylethyl, phenylpropyl, styryl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, biphenylmethyl, naphthylmethyl, pyridylmethyl, pyridazinylmethyl, pyrimidylmethyl, pyrazinylmethyl, imidazolylmethyl, pyrazolylmethyl, furyl Methyl, thiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, oxadiazolylmethyl, bicyclo[1.1.1.]pentyl, (bicyclo[1.1.1.]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, carboxy, carboxymethyl, carboxyethyl, azidomethyl, azidoethyl, azidopropyl, phenylaminocarbonylmethyl, pyridylaminocarbonylmethyl, carbonylmethyl, (pyridylcarbonylamino)methyl, guanidino, guanidinomethyl, guanidinoethyl, guanidinopropyl, guanidinobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, pentafluoropropyl, heptafluoropropyl, trifluorobutyl, N,N,N-trimethylmethylammonium, N,N,N-trimethyleth-1-ylammonium, N,N,N-trimethylpropan-1-ylammonium, N,N,N-trimethylbut-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, with other groups being as provided in general formula (I) above.

[0015] In a second embodiment of the present invention, R 1 is selected from 3-aminopropyl, 4-aminobutyl, phenyl, phenylmethyl, bicyclo[1.1.1.]pentyl, phenylcarbonylaminoethyl, aminocarbonylmethyl, aminocarbonylaminoethyl, n-propyl, n-butyl, isobutyl, isopentyl, 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, and other groups are as provided in general formula (I) above or as in the first embodiment.

[0016] In a third embodiment of the present invention, R1a The substituent is C 1~6 are each independently selected from alkyl, amino, cyano, halo, and hydroxy, and other groups are as provided in general formula (I) above, or as in the first to second embodiments.

[0017] In a fourth embodiment of the present invention, each R 2a are independently selected from hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, and other groups are as provided in general formula (I) above, or as in the first to third embodiments.

[0018] In a fifth embodiment of the present invention, each R 2a are independently selected from hydrogen, hydroxy, and methyl, and the other groups are as provided in general formula (I) above, or as in the first to fourth embodiments.

[0019] In a sixth embodiment of the present invention, R 2b is selected from phenyl, benzyl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and bicyclo[1.1.1]pentyl, and other groups are as provided in general formula (I) above, or as in the first to fifth embodiments.

[0020] In the seventh embodiment, R 2b is selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, and bicyclo[1.1.1]pentyl, and other groups are as provided in general formula (I) above, or as in the first to sixth embodiments.

[0021] In the eighth embodiment, each R 2caminomethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, fluoro, chloro, bromo, iodo, aminoethoxy, N-methylaminoethoxy, N-ethylaminoethoxy, N,N-dimethylaminoethoxy, [ka] are independently selected from carboxy, carboxymethoxy, (carboxymethoxy)methyl, aminocarbonyl, N,N-dimethylaminocarbonyl, and aminocarbonylmethyl, and other groups are as provided in general formula (I) above, or as in the first to seventh embodiments.

[0022] In the ninth embodiment, each R 2c are independently selected from aminomethyl, hydroxy, methoxy, fluoro, carboxy, and aminocarbonyl, and other groups are as provided in general formula (I) above, or as in the first to eighth embodiments.

[0023] In a tenth embodiment of the present invention, R 3a is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, aminoethyl, aminopropyl, aminobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, thioethyl, and thiopropyl; R 3ais zero, one, or two R independently selected from fluoro, chloro, 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, carboxy, carboxymethyl, and carboxyethyl; 3c It may be substituted by substituents and other groups as provided in general formula (I) above or as in the first to ninth embodiments.

[0024] In an eleventh embodiment of the present invention, 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; R 3a are each independently selected from methyl, isopropyl, cyclopropyl, amino, N-methylamino, hydroxy, -SO2CH3, -CH2SO2CH3, cyano, methoxy, and carboxy; 3c It may be substituted by substituents and other groups as provided in general formula (I) above or as in the first to tenth embodiments.

[0025] In a twelfth embodiment of the present invention, R 3bis 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-aminoprop-2-yl, fluoromethyl, difluoromethyl, thiazolinone ... trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, benzyl, 3-pyridinylmethyl, 4-pyridinylmethyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiophenylmethyl, furanylmethyl, pyrazolylmethyl, N-pyrazolylmethyl, 1-phenylethyl, 1-(4-pyridinyl)ethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, (N,N-dimethyl)aminocarbonylmethyl, (N,N-dimethyl)aminocarbonylethyl, thiomethyl, thioethyl, thiopropyl, -CH2CH2SO2CH3, carboxymethyl, carboxyethyl, 2-carboxyethyl, carboxypropyl, 3-carboxypropyl, carboxybutyl, 4-carboxybutyl, piperazinylmethyl, morpholinomethyl, piperidinylmethyl, azetidinylmethyl, tetrahydropyranylmethyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, and aminocarbonylaminobutyl; R 3bis zero, one, or two R independently selected from fluoro, chloro, 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, carboxy, carboxymethyl, and carboxyethyl; 3c It may be substituted by substituents and other groups as provided in general formula (I) above or as in the first to eleventh embodiments.

[0026] In a thirteenth embodiment of the present invention, R 3b is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, 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; R 3b are each independently selected from methyl, isopropyl, cyclopropyl, amino, N-methylamino, hydroxy, -SO2CH3, -CH2SO2CH3, cyano, methoxy, and carboxy; 3cIt may be substituted by substituents and other groups as provided in general formula (I) above or as in the first to twelfth embodiments.

[0027] In a fourteenth embodiment of the present invention, R 3a and R 3b together with the atoms to which they are attached, can contain 0, 1, or 2 R 3c form a saturated ring system substituted by substituents, the ring system being [ka] and other groups are as provided in general formula (I) above, or as in the first to thirteenth embodiments.

[0028] In a fifteenth embodiment of the present invention, R 3a and R 3b together with the atoms to which they are attached, can contain 0, 1, or 2 R 3c form a saturated ring system substituted by substituents, the ring system being [ka] and other groups are as provided in general formula (I) above, or as in the first to fourteenth embodiments.

[0029] In a sixteenth embodiment of the present invention, R 4a is selected from hydrogen, methyl, ethyl, propyl, hydroxy, methoxy, and fluoro, and other groups are as provided in general formula (I) above, or as in the first to fifteenth embodiments.

[0030] In a seventeenth embodiment of the present invention, R 4a is hydrogen or methyl, and the other groups are as provided in general formula (I) above, or as in the first to sixteenth embodiments.

[0031] In an eighteenth embodiment of the present invention, R 4bis 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; R 4b is 0, 1, or 2 R independently selected from fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, methyl, ethyl, propyl, isopropyl, carboxy, carboxymethyl, and carboxyethyl; 4c It is substituted with a substituent, and other groups are as provided in general formula (I) above, or as in the first to seventeenth embodiments.

[0032] In a nineteenth embodiment of the present invention, R 4b is selected from indolyl, naphthyl, quinolinyl, pyrrolo[2,3-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridine, and indazolyl; R 4b are each independently selected from fluoro, chloro, methyl, and carboxymethyl; 4c It is substituted with a substituent, and other groups are as provided in general formula (I) above, or as in the first to eighteenth embodiments.

[0033] In a twentieth embodiment of the present invention, R 5ais 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, thiadiazolylmethyl, oxazolylethyl, thiazolylethyl, imidazolylethyl, triazolylethyl, oxadiazolylethyl, thiadiazolylethyl, oxazolylpropyl, thiazolylpropyl, imidazolylpropyl, triazolylpropyl, oxadiazolylpropyl, thiadiazolylpropyl, azetidinylmethyl, azetidinylethyl, oxetanyl Methyl, oxetanylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, tetrahydropyranylmethyl, tetrahydropyranylmethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, 3-hydroxy-2,2-dimethylpropyl, cyclopropylmethyl, 1-hydroxypropan-2-yl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-aminoethyl, 3-aminopropyl, 3-amino-2,2-Dimethylpropyl, cyclopropylmethyl, 4-aminobutyl, aminomethylcarbonylaminoethyl, aminoethylcarbonylaminoethyl, aminomethylcarbonylaminopropyl, aminoethylaminocarbonylmethyl, aminoethylaminocarbonylethyl, aminoethylaminocarbonylpropyl, aminohexylcarbonylaminoethyl, aminohexylcarbonylaminoethyl, (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-trimethylammonium)ethyl, (N,N,N-trimethylammonium)propyl, (N,N,N-triethylammonium)ethyl, (N,N,N-triethylammonium)propyl, (N-methylamino)methylcarbonylaminoethyl, (N-methylamino)ethylcarbonylaminoethyl, (N-methylamino)methylcarbonylaminopropyl, (N-ethylamino)methyl (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)ethylcarbonylaminopropyl, (N,N-diethylamino)methylcarbonylaminoethyl carbonylaminoethyl, (N,N-diethylamino)ethylcarbonylaminoethyl, (N,N-diethylamino)methylcarbonylaminopropyl, (N,N-dimethylamino)pentylcarbonylaminoethyl, (N,N-dimethylamino)pentylcarbonylaminoethyl, (N,N-dimethylamino)pentylcarbonylaminopropyl, N,N,N-trimethyl-ethane-1-ammonium, N,N,N-trimethyl-propane-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; R, 5ais chloro, fluoro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, 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, aminoethylcarbonylaminoethylaminomethyl, (N-methylcarbonylamino)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 ammonium)methyl, (N,N,N-trimethylammonium)ethyl, (N,N,N-trimethylammonium)ethoxy, (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, tetrazoyl, tetrazoylmethyl, tetrazoylethyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, and carboxyethoxymethyl; 5d It is substituted by a substituent, and other groups are as provided in general formula (I) above, or as in the first to nineteenth embodiments.

[0034] In a 21st embodiment of the present invention, R 5a is selected 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-ethane-1-ammonium, (N,N,N-trimethylammonium)ethoxyethyl, (N,N,N-trimethylammonium)methylcarbonylaminoethyl, and (carboxymethyl)oxyethyl; R 5a is zero, one, two, or three R independently selected from fluoro, hydroxy, hydroxymethyl, methyl, carboxy, carboxymethyl, methoxy, amino, N,N-dimethylamino, N,N,N-trimethylammonium, (N,N,N-trimethylammonium)ethoxy, (N,N,N-trimethylammonium)methylcarbonylamino, cyano, tetrazoyl, and carboxymethoxy; 5dIt is substituted by a substituent, and other groups are as provided in general formula (I) above, or as in the first to twentieth embodiments.

[0035] In a 22nd embodiment of the present invention, R 5bis hydrogen, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopropylmethyl, oxetanylmethyl, tetrahydrofurylmethyl, 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-trimethylmethane-1-ylammonium, N,N,N-trimethylethan-1-ylammonium, N,N,N-triethylethan-1-ylammonium, N,N,N-trimethylpropan-1-ylammonium, N,N,N-trimethylbutan-1-ylammonium, (N,N,N-trimethylammonium)ethoxymethyl, (N,N,N-trimethylammonium)ethoxyethyl, (N,N,N-triethylammonium)ethoxyethyl, (N,N,N-trimethyl (N,N,N-trimethylammonium)ethoxypropyl, (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)methylcarbonylamino R is selected from 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; 5bchloro, fluoro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, 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-di (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)ethoxy, (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, tetrazoyl, tetrazoylmethyl, tetrazoylethyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, and carboxyethoxymethyl; 5e It is substituted by a substituent, and other groups are as provided in general formula (I) above, or as in the first to twenty-first embodiments.

[0036] In a 23rd embodiment of the present invention, R 5b is selected 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-trimethylethane-1-ammonium, (N,N,N-trimethylammonium)methylcarbonylaminoethyl, (N,N,N-trimethylammonium)ethoxyethyl, 2-fluoroethyl, 2,2-difluoroethyl, and (carboxymethoxy)ethyl; R 5b is zero, one, two, or three R independently selected from fluoro, hydroxy, hydroxymethyl, methyl, carboxy, carboxymethyl, methoxy, amino, N,N-dimethylamino, N,N,N-trimethylammonium, (N,N,N-trimethylammonium)ethoxy, (N,N,N-trimethylammonium)methylcarbonylamino, cyano, tetrazoyl, and carboxymethoxy; 5e It is substituted by a substituent, and other groups are as provided in general formula (I) above, or as in the first to twenty-second embodiments.

[0037] In a 24th embodiment of the present invention, R 5cis hydrogen, methyl, or ethyl, and the other groups are as provided in general formula (I) above, or as in the first to twenty-third embodiments.

[0038] In a 25th embodiment of the present invention, R 5c is hydrogen or methyl, and the other groups are as provided in general formula (I) above, or as in the first to twenty-fourth embodiments.

[0039] In a 26th embodiment of the present invention, R 5a and R 5b together with the atoms to which they are attached, can contain 0, 1, 2, or 3 R 5d Substituent and 0, 1, 2, or 3 R 5e forming a saturated monocyclic or bicyclic ring system substituted with a substituent, said monocyclic or bicyclic ring system being [ka] TIFF2025159726000010.tif248166 TIFF2025159726000011.tif35152, and other groups are as provided in general formula (I) above, or as in the first to sixteenth and twenty-first to twenty-fifth embodiments.

[0040] In a 27th embodiment of the present invention, R 5a and R 5b together with the atoms to which they are attached, can contain 0, 1, 2, or 3 R 5d Substituent and 0, 1, 2, or 3 R 5e forming a saturated monocyclic or bicyclic ring system substituted with a substituent, said monocyclic or bicyclic ring system being [ka] and other groups are as provided in general formula (I) above, or as in the first to sixteenth and twenty-first to twenty-sixth embodiments.

[0041] In a twenty-eighth embodiment, R 6a is selected from hydrogen, hydroxy, methyl, ethyl, propyl, and methoxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 27.

[0042] In a twenty-ninth embodiment, R 6a is selected from hydrogen and methyl, and other groups are as provided in general formula (I) above, or as in the first to twenty-eighth embodiments.

[0043] In a thirtieth embodiment, R 6b is selected from hydrogen, hydroxy, methyl, ethyl, propyl, methoxy, and ethoxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 29.

[0044] In a thirty-first embodiment, R 6b is selected from hydrogen, hydroxy, and methyl, and other groups are as provided in general formula (I) above, or as in the first to thirtieth embodiments.

[0045] In a thirty-second embodiment, R 6cHowever, 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, (aminocarbonylamino)methyl, (aminocarbonylamino)ethyl, (aminocarbonylamino)propyl propyl, methoxy, methoxymethyl, methoxyethyl, ethoxy, ethoxymethyl, ethoxyethyl, methylsulfonyl, (methylsulfonyl)methyl, (methylsulfonyl)ethyl, (methylsulfonyl)propyl, amino, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, carboxy, carboxymethyl, carboxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl, and benzyl, with other groups as provided in general formula (I) above or as in the first to thirty-first embodiments.

[0046] In a thirty-third embodiment, R 6c is selected from aminocarbonyl, (aminocarbonyl)methyl, (N,N-dimethylamino)carbonylmethyl, aminocarbonylamino, (aminocarbonylamino)ethyl, methoxymethyl, (methylsulfonyl)methyl, hydroxy, and methyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 32.

[0047] In a thirty-fourth embodiment, R7a is selected from hydrogen, methyl, ethyl, hydroxy, methoxy, and ethoxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 33.

[0048] In a thirty-fifth embodiment, R 7a is selected from hydrogen, methyl, and hydroxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 34.

[0049] In a thirty-sixth embodiment, R 7b However, phenyl, biphenyl, naphthyl, pyridyl, selected from pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 3-oxoisoindolinyl, and bicyclo[1.1.1]pentyl, with other groups as provided in general formula (I) above, or as in embodiments 1 to 35.

[0050] In a thirty-seventh embodiment, R 7b is selected from phenyl, pyridyl, pyrimidyl, furyl, thiazolyl, and 3-oxoisoindolinyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 36.

[0051] In a 38th embodiment of the present invention, R 7cFluoro, chloro, bromo, iodo, 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-trimethylamino ammonium, N,N,N-trimethylmethylammonium, N,N,N-triethylmethylammonium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, -SOOH, -CHSOOH, -SONH, -CHSONH, aminoethoxy, aminoethoxymethyl, (N,N-dimethylamino)ethoxy, N,N,N-trimethyleth-1-oxyammonium, aminocarbonylamino, and aminocarbonylaminomethyl, with other groups as provided in general formula (I) above, or as in embodiments 1 to 37.

[0052] In a thirty-ninth embodiment of the present invention, R 7c is selected from hydroxy, carboxymethoxy, fluoro, chloro, methoxy, carboxy, carboxymethyl, methoxycarbonyl, aminocarbonyl, aminomethyl, —SOOH, —SONH, —CHSOOH, aminoethoxy, and aminocarbonylamino, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 38.

[0053] In a fortieth embodiment, R 8a is selected from hydrogen, methyl, ethyl, hydroxy, methoxy, and ethoxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 39.

[0054] In a forty-first embodiment, R 8ais selected from hydrogen, and methyl, and other groups are as provided in general formula (I) above, or as in the first to fortieth embodiments.

[0055] In a forty-second embodiment of the present invention, R 8b is selected from indolyl, naphthyl, indolylmethyl, naphthylmethyl, quinolinyl, pyrrolo[2,3-b]pyridinyl, indazolyl, benzothiazolyl, and benzothiophenyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 41.

[0056] In a forty-third embodiment of the present invention, R 8b is selected from indolyl, naphthyl, and pyrrolo[2,3-b]pyridinyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 42.

[0057] In a forty-fourth embodiment of the present invention, each R 8c are 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, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 43.

[0058] In a 45th embodiment of the present invention, each R 8c are independently selected from fluoro, chloro, bromo, and cyano, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 44.

[0059] In a 46th embodiment of the present invention, R 9 is selected from hydrogen, methyl, ethyl, and propyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 45.

[0060] In a 47th embodiment of the present invention, R 9 is hydrogen or methyl, and the other groups are as provided in general formula (I) above, or as in the first to forty-sixth embodiments.

[0061] In a 48th embodiment of the present invention, R 10a is selected from hydrogen, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 47.

[0062] In a forty-ninth embodiment of the present invention, R 10a is selected from hydrogen and hydroxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 48.

[0063] In a 50th embodiment of the present invention, R 10b is selected from phenyl, benzyl, biphenyl, biphenylmethyl, pyridyl, pyridylmethyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, imidazolylmethyl, pyrazolyl, furyl, furylmethyl, oxazolyl, oxazolylmethyl, thiazolyl, indolyl, [1,2,4]triazolo[1,5-a]pyridine, and bicyclo[1.1.1]pentyl, and other groups are as provided in general formula (I) above, or as in the first to forty-ninth embodiments.

[0064] In a 51st embodiment of the present invention, R 10b is selected from phenyl and pyrimidyl, and other groups are as provided in general formula (I) above, or as in the first to fiftieth embodiments.

[0065] In the fifty-second embodiment, each R 10cmethyl, 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, 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-trimethylmethanylammonium, aminocarbonyl, aminocarbonylmethyl, aminocarbonylethyl, (N-methylamino)carbonyl, (N-methylamino)carbonyl Nylmethyl, (N,N-dimethylamino)carbonyl, (N,N-dimethylamino)carbonylmethyl, aminocarbonylamino, aminocarbonylaminomethyl, methylcarbonylamino, methylcarbonylaminomethyl, carboxy, carboxymethyl, carboxyethyl, methoxycarboxy, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, carboxyethoxymethyl, -S(=O)2OH, -CH2(S(=O)2OH), -S(=O)2NH2, -CH2(S(=O)2NH2) , aminoethoxy, aminopropoxy, (N-methylamino)ethoxy, (N-ethylamino)ethoxy, (N,N-dimethylamino)ethoxy, (N,N-diethylamino)ethoxy, (N,N,N-trimethylammonium)ethoxy, methoxy, ethoxy, methoxymethyl, ethoxymethyl, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 51.

[0066] In the fifty-third embodiment, each R 10care independently selected from fluoro, carboxy, carboxymethyl, (carboxymethyl)oxy, aminocarbonyl, amino, aminomethyl, —SOOH, —SONH, hydroxy, and aminocarbonylamino, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 52.

[0067] In a 54th embodiment of the present invention, R 11a is selected from hydrogen, hydroxy, methyl, ethyl, methoxy, and ethoxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 53.

[0068] In a 55th embodiment of the present invention, R 11a is selected from hydrogen and hydroxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 54.

[0069] In a fifty-sixth embodiment, R 11b is selected from (HN-C(=NH)-NH)methyl, (HN-C(=NH)-NH)ethyl, (HN-C(=NH)-NH)propyl, (HN-C(=NH)-NH)butyl, phenyl, benzyl, pyridinyl, pyridinylmethyl, indolyl, indolylmethyl, pyridazinyl, pyridazinylmethyl, pyrimidyl, pyrimidylmethyl, pyrazinyl, pyrazinylmethyl, imidazolyl, imidazolylmethyl, pyrazolyl, pyrazolylmethyl, [1,2,4]triazolo[1,5-a]pyridine, oxazolyl, oxazolylmethyl, thiazolyl, and thiazolylmethyl, and other groups are as provided in general formula (I) above, or as in the first to fifty-fifth embodiments.

[0070] In a fifty-seventh embodiment, R 11b is selected from phenyl, (H2N-C(=NH)-NH)ethyl, pyridinyl, indolyl, and imidazolyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 56.

[0071] In a 58th embodiment of the present invention, each R 11c 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 methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, aminoethoxy, aminopropoxy, aminoethoxymethyl, (N,N-dimethylamino)ethoxy, N,N,N-trimethyleth-1-yloxy-ammonium, cyano, and methylcarbonylpiperazyl [(N-acetyl)piperazyl], with other groups as provided in general formula (I) above, or as in embodiments 1 to 57.

[0072] In a 59th embodiment of the present invention, each R 11c (carboxymethyl)oxy, fluoro, chloro, hydroxy, methoxy, trifluoromethoxy, carboxy, carboxymethyl, aminocarbonyl, aminocarbonylmethyl, aminomethyl, aminoethoxy, (N,N-dimethylamino)ethoxy, and methylcarbonylpiperazyl [ka] and other groups are as provided in general formula (I) above, or as in embodiments 1 to 58.

[0073] In a sixtieth embodiment of the present invention, R 12a is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, and isopropyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 59.

[0074] In a 61st embodiment of the present invention, R 12a is selected from hydrogen, methyl, ethyl, and n-propyl, and other groups are as provided in general formula (I) above, or as in the first to sixth embodiments.

[0075] In a 62nd embodiment, R 12b is selected from hydrogen, methyl, ethyl, and propyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 61.

[0076] In a 63rd embodiment, R 12b is selected from hydrogen and methyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 62.

[0077] In a 64th embodiment of the present invention, R 12a and R 12b together with the atoms to which they are bonded, [ka] and the other groups are as provided in general formula (I) above, or as in the first to sixth embodiments.

[0078] In a 65th embodiment of the present invention, R 12a and R 12b together with the atoms to which they are bonded, [ka] and the other groups are as provided in general formula (I) above, or as in embodiments 1 to 64.

[0079] In a 66th embodiment, R 13a is hydrogen, methyl or propyl, and the other groups are as provided in general formula (I) above, or as in the first to sixth embodiments.

[0080] In a 67th embodiment, R 13b is hydrogen or methyl, and the other groups are as provided in general formula (I) above, or as in the first to sixth embodiments.

[0081] In a 68th embodiment, R 13c is selected from indolyl, pyrrolo[2,3-b]pyridinyl, quinolinyl, indazolyl, and naphthyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 67.

[0082] In a sixty-ninth embodiment, R 13c is selected from indolyl and pyrrolo[2,3-b]pyridinyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 68.

[0083] In a seventieth embodiment, each R 13d are independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, carboxy, carboxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, and ethoxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 69.

[0084] In the 71st embodiment, each R 13d are independently selected from methyl, chloro, and methoxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 70.

[0085] In the 72nd embodiment, each R 14a are independently selected from amino, hydroxy, N-methylamino, N,N-dimethylamino, N-ethylamino, methoxy, and ethoxy, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 71.

[0086] In a 73rd embodiment, each R 14a is independently amino, and the other groups are as provided in general formula (I) above, or as in embodiments 1 to 72.

[0087] In the 74th embodiment, each R 14b are 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, indolyl, indolylmethyl, imidazolyl, imidazolylmethyl, pyridyl, and pyridylmethyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 73.

[0088] In a 75th embodiment, each R 14b are independently selected from hydrogen, methyl, ethyl, and phenyl, and other groups are as provided in general formula (I) above, or as in embodiments 1 to 74.

[0089] In a 76th embodiment, the compound of formula (1) or a pharmaceutically acceptable salt thereof is [ka] (In the formula, R 1 is hydrogen, C 1~10Alkyl, (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 (C 0~6 alkyl), arylcarbonylamino (C 0~6 alkyl), arylaminocarbonyl (C 0~6 alkyl), heteroarylcarbonylamino (C 0~6 alkyl), heteroarylaminocarbonyl (C 0~6 alkyl), C 1~6 Alkyloxy, (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), where R1 is C 1~6 Alkyl, amino, cyano, halo, hydroxy, (C 3~12 ) cycloalkyloxy, and C 1~6 0, 1, 2, 3, or 4 R, each independently selected from alkyloxy; 1a is substituted by a substituent; Each R 2a is hydrogen, hydroxy, C 1~4 Alkyl, Fluoro, and C 1~4 independently selected from alkyloxy; R 2b is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said heteroaryl contains at least one nitrogen atom; where R 2b is 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), hydroxy, halo, (C 1~6 alkyl) 0~2 Amino (C 0~6 alkyloxy), (C 1~6 Alkyl)3N + (C 0~6 alkyloxy), (C 1~6 Alkyloxy)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 Haloalkyloxy, and C 1~6 0, 1, or 2 R independently selected from alkyloxy 2chas been replaced by; R 3a is 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), and R 3a can contain 0, 1, or 2 R 3c optionally substituted by a substituent; R 3b is 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 )Cycloalkyloxy(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 1~6 alkyl)thio(C 1~6 alkyl), (C 1~6 alkyl)SO2(C 1~6 alkyl), and (C1~6 Alkyl)sulfinyl(C 1~6 alkyl), and R 3b can contain 0, 1, or 2 R 3c optionally substituted by a substituent; Each R 3c Ha, Halo, 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); where R 3a and R 3b may, together with the atom to which they are attached, form a saturated ring system, said saturated ring system containing zero, one, or two R 3c optionally substituted by a substituent; R 4a is hydrogen, C 1~6 Alkyl, hydroxy, C 1~4 alkyloxy, and fluoro; R 4b is a bicyclic heteroaryl (C 0~3 alkyl), and bicyclic aryl (C 0~3 alkyl), where R 4b are halo, hydroxy, cyano, nitro, carboxy (C 0~6 alkyl), (C 1~6 Alkyloxy)carbonyl (C 0~6 alkyl), C 1~6 Alkyloxy, (C 1~6 Alkyl)oxy(C 1~6 alkyl), C 1~6 Alkyl, and C 1~60, 1, or 2 R independently selected from haloalkyl 4c is substituted with a substituent; R 5a is 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 Alkyloxy)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 (C0-6 alkyl), and C 1~10 fluoroalkyl; R 5a can contain 0, 1, or 2 R 5d is substituted by a substituent; R 5b is 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 1~10Alkyl)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), (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; R 5b can contain 0, 1, or 2 R 5d is substituted by a substituent, R 5a and R 5b together with the atoms to which they are attached form a saturated monocyclic or bicyclic ring, said monocyclic or bicyclic ring containing zero, one, or two R 5d is substituted with a substituent; Each R 5d are halo, hydroxy, C 1~10 Alkyl, hydroxy (C 1~10 alkyl), carboxy (C 1~6 alkyl), C 1~6 Alkyloxy, (C 1~6 Alkyl)oxy(C 1~6 alkyl), (C 1~6 alkyl) 0~2 Amino (C 0~6 alkyl), (carboxy(C 1~6 Alkyl))oxy(C 1~6 alkyl), cyano, and C 1~6 haloalkyl; and two R 5d The substituents, together with the atoms to which they are attached, may be joined to form a saturated ring; R 5c is hydrogen, C 1~4 Alkyl, hydroxy (C 1~4 alkyl), C 1~4 Alkyloxy, (C 1~4 Alkyl)oxy(C 1~4alkyl), hydroxy, amino, or halo; R 6a is hydrogen, hydroxy, amino, C 1~4 Alkyloxy, and C 1~6 alkyl; R 6b is hydrogen, C 1~6 Alkyl, hydroxy, C 1~4 alkyloxy, and fluoro; R 6c is C 1~6 Alkyloxy, (C 1~6 Alkyl)oxy(C 1~6 alkyl), C 1~10 Haloalkyl, 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), (C1-6 alkyl) 0~2 Amino (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); R 7a is hydrogen, C 1~6 Alkyl, hydroxy, C 1~4 alkyloxy, and fluoro; R 7b is an aryl (C 0~6 alkyl), heteroaryl (C 0~6 alkyl), and (C 3~12 ) Cycloalkyl(C 0~6 alkyl), and R 7b is C 1~6 Alkyl, C1~10 Fluoroalkyl, C 1~10 Fluoroalkyloxy, (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 Alkyloxy)carbonyl (C 0~6 alkyl), carboxy (C 1~6 Alkyl)oxy(C 0~6 alkyl), aminocarbonyl (C 0~6 alkyl), (C 1~6 alkyl) 0~2 Aminocarbonyl (C 0~6 alkyl), hydroxy, hydroxy(C 1~6 alkyl), halo, -(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) 0~2 Aminocarbonylamino (C 0~6 alkyl), C 1~10 Haloalkyl, C 1~10 haloalkyloxy, and (C 1~6 Alkyl)oxy(C 0~6 0, 1, 2, or 3 R independently selected from 7c is substituted by a substituent; R 8a is hydrogen, C 1~6 Alkyl, hydroxy, C 1~4 Alkyloxy, C 1~6 Fluoroalkyl, C1~4 selected from fluoroalkyloxy, and halo; R 8b is aryl (C 0~3 alkyl) and heteroaryl (C 0~3 alkyl), and R 8b is C 1~4 Alkyl, halo, cyano, nitro, carboxy, amino, hydroxy, C 1~6 Fluoroalkyl, C 1~6 Fluoroalkyloxy, C 1~6 Alkyloxy, amino(C 0~3 alkyl), and hydroxy (C 1~6 0, 1, or 2 R independently selected from 8c is substituted by a substituent; R 9 is hydrogen and C 1~4 alkyl; R 10a is hydrogen, hydroxy, C 1~6 Alkyl, C 1~4 alkyloxy, and fluoro; R 10b is (C 3~12 ) Cycloalkyl(C 0~3 alkyl), aryl (C 0~3 alkyl), and heteroaryl (C 0~3 alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms; where R 10b can contain 0, 1, or 2 R 10c are replaced by, and each R 10c is C 1~10 Alkyl, C 1~10 Fluoroalkyl, C 1~10 Fluoroalkyloxy, 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, halo, hydroxy(C1~6 alkyl), aminocarbonyl (C 0~6 alkyl), (C 1~6 alkyl) 0~2 Aminocarbonyl (C 0~6 alkyl), (C 1~6 alkyl) 0~2 Aminocarbonylamino (C 0~6 alkyl), (C 1~6 Alkyl)carbonylamino(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 + (C 0~6 Alkyl)oxy(C 0~6 alkyl), (C 1~6 Alkyl)oxy(C 0~6 alkyl), C 1~6 Haloalkyloxy, C 1~6 Haloalkyl, (C 3~12 ) Cycloalkyl(C 0~6 alkyl), and heterocycloalkyl (C 0~6 alkyl); R 11a is hydrogen, hydroxy, C 1~6 Alkyl, C 1~4 alkyloxy, and fluoro; R 11b is an aryl (C 0~3 alkyl) and heteroaryl (C 0~3alkyl), where the heteroaryl contains 1, 2, or 3 nitrogen atoms, and HN—C(═NH)NH—(C 1~6 alkyl), and R 11b is 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, halo, 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 Haloalkyloxy, C 1~6 Haloalkyl, (C 3~12 ) Cycloalkyl(C 0~6 alkyl), heterocycloalkyl (C 0~6 alkyl), and ((C 1~6 Alkyloxy)carbonyl)heterocycloalkyl(C 0~10 0, 1, 2, 3, or 4 R, each independently selected from 11c is substituted by a substituent; R 12a is hydrogen, hydroxy, amino, C 1~10 Alkyl, and (C 3~12) Cycloalkyl(C 0~6 alkyl); R 12b is hydrogen, C 1~10 Alkyl, and (C 3~12 ) Cycloalkyl(C 0~6 alkyl); R 12a and R 12b may, together with the atoms to which they are attached, form a saturated ring; R 13a is hydrogen and C 1~4 alkyl; R 13b is hydrogen, hydroxy, C 1~6 Alkyl, C 1~4 alkyloxy, and fluoro; R 13c is selected from bicyclic nitrogen-containing heteroaryls and bicyclic aryls having one or two nitrogens, and R 13c Ha, Halo, C 1~6 Alkyl, carboxy (C 0~4 alkyl), C 1~4 Haloalkyloxy, and C 1~4 0, 1, or 2 R independently selected from alkyloxy 13d is independently substituted by substituents; [ka] teeth, [ka] Selected from; R 14a is amino, hydroxy, (C 1~6 alkyl) 0~2 Amino, and C 1~6 alkyloxy; m is selected from 1, 2, 3, or 4; n is selected from 1, 2, 3, or 4; R 14b is hydrogen, C 1~8 Alkyl, aryl (C 0~6alkyl), and heteroaryl (C 0~6 alkyl), where R 14b is substituted by 0, 1, 2, or 3 halo).

[0090] In certain embodiments, the present disclosure provides a compound of formula (I) selected from the group consisting of SEQ ID NOs: 1-289 as shown in Table 1.

[0091] In specific embodiments, the present disclosure provides the following sequences: (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, respectively, in order of appearance): [ka] SEQ ID NO:5,

[0092] [ka] SEQ ID NO: 10,

[0093] [ka] SEQ ID NO: 18,

[0094] [ka] SEQ ID NO: 22,

[0095] [ka] SEQ ID NO: 30,

[0096] [ka] SEQ ID NO: 31,

[0097] [ka] SEQ ID NO: 41,

[0098] [ka] SEQ ID NO: 45,

[0099] [ka] SEQ ID NO: 48

[0100] [ka] SEQ ID NO: 51, [ka] SEQ ID NO: 52,

[0101] [ka] SEQ ID NO: 53,

[0102] [ka] SEQ ID NO: 60,

[0103] [ka] SEQ ID NO: 68,

[0104] [ka] SEQ ID NO: 77,

[0105] [ka] SEQ ID NO: 83,

[0106] [ka] SEQ ID NO: 87,

[0107] [ka] SEQ ID NO: 104,

[0108] [ka] SEQ ID NO: 183,

[0109] [ka] SEQ ID NO: 196,

[0110] [ka] SEQ ID NO: 206,

[0111] [ka] SEQ ID NO: 210,

[0112] [ka] SEQ ID NO: 214,

[0113] [ka] SEQ ID NO: 221,

[0114] [ka] SEQ ID NO: 229,

[0115] [ka] SEQ ID NO: 237,

[0116] [ka] SEQ ID NO: 247,

[0117] [ka] SEQ ID NO: 250,

[0118] [ka] SEQ ID NO: 254,

[0119] [ka] SEQ ID NO: 257, and

[0120] [ka] SEQ ID NO: 265, The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0121] The mechanism of action (MOA) of anti-TNFα biologics, such as infliximab, adalimumab, golimumab, and certolizumab, involves binding to the cytokine TNFα, and thus inhibiting binding to both TNFR1 and TNFR2. Without being bound by any particular theory, Applicants believe that the compounds of the present disclosure selectively inhibit TNFR1, specifically attenuating the pro-inflammatory activity of TNFα-mediated TNFR1 signaling, sparing / passively allowing TNFα-TNFR2 pro-homeostatic signaling, which may confer better therapeutic efficacy than standard of care anti-TNFα biologics.

[0122] definition 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 invention belongs.

[0123] As used throughout this disclosure, the terms "a compound of the disclosure," "a compound of the present disclosure," and "a compound disclosed herein" are used interchangeably and should be understood to include the disclosed cyclic peptides and compounds of Formula (I). Compounds of Formula (I) can form salts that are also within the scope of this disclosure. As used herein, the term "salt(s)" refers to acid salts formed with inorganic and / or organic acids and base salts formed with inorganic and / or organic bases. Furthermore, when a compound of Formula (I) contains both a basic moiety, such as, but not limited to, an amino group, pyrrolidine, or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") may be formed and are included in 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 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 that the salt precipitates or in an aqueous medium, followed by lyophilization.

[0124] "C 0~6 Alkyl" and "C 0~6 The term "C0" or "C0" or "C0" as used in expressions such as "alkyl" or "C0" means a direct covalent bond or, when the term appears at the terminal end of a substituent, C 0~6 Alkyl is hydrogen or C 1~6Similarly, if the integer defining the presence of a certain number of atoms in a group is equal to 0, it means that the adjacent atoms are directly connected by a bond. For example, the structure where s is an integer equal to 0, 1, or 2 [ka] So, if s is 0, the structure is [ka] is.

[0125] "Acyl" means a -C(=O)-alkyl group, where alkyl is as defined below. The bond to the parent group is through the carbon atom of the carbonyl group.

[0126] "Acetyl" refers to the radical -C(=O)CH3.

[0127] The term "alkyl," as well as other groups having the prefix "alk," such as alkoxy, dialkylamino, and trialkylammonium, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group can be straight-chained or branched and can contain from about 1 to about 10 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 10 carbon atoms. In a different embodiment, an alkyl group can contain from 1 to 6 carbon atoms (C 1~6 and alkyl groups containing from about 1 to about 4 carbon atoms (C1-C4 alkyl). 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, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise specified, an alkyl group is unsubstituted.

[0128] "Alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be linear or branched, and having the indicated number of carbon atoms. Preferably, alkenyl contains one carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds may be present. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 2-methyl-1-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl.

[0129] "Alkoxy" and "alkyloxy" are used interchangeably and refer to an alkyl (carbon and hydrogen chain) group (RO) attached to an oxygen. Non-limiting examples of alkoxy are methoxy (CHO-), ethoxy (CHCHO-), and propoxy (CHCHCHO-).

[0130] "Amino" refers to an optionally substituted -NH2 group (one or both of the hydrogen atoms replaced), as further defined herein.

[0131] "Amino acid" refers to naturally occurring α-amino acids and their stereoisomers, as well as non-naturally occurring amino acids (e.g., α,α-disubstituted amino acids, β-substituted amino acids, β-amino acids, and substituted amino acids) and their stereoisomers. In the sequences shown for peptides (compounds) according to the present disclosure, amino acid residues have their conventional meanings. Thus, "G" or "Gly" is glycine, "W" or "Trp" is tryptophan, "A" or "Ala" is alanine, "S" or "Ser" is serine, etc. It should be understood that "d" or "D" or "d" isomers are designated by "D" or "d" before the three-letter code or amino acid abbreviation or name, such as, for example, D-Ala or d-Ala or dA is the D isomer of L-alanine. Amino acid residues not encompassed by the foregoing have the definitions provided in the abbreviations table in the Examples section below.

[0132] "Aminocarbonyl" means -C(=O)NH2, in which the amino moiety is optionally substituted (one or both of the hydrogen atoms are replaced), as further defined herein.

[0133] "Aryl" means a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 5 to 14 carbon atoms, in which at least one ring is aromatic. Examples of aryl include phenyl, biphenyl, and naphthyl. In one embodiment of the present invention, aryl is phenyl.

[0134] "Azide" has the structure -N=N + =N - groups derived from azide anions having the formula: [ka] ) and 3-azidopropyl ( [ka] ) means

[0135] A "bicyclic ring system" refers to two linked rings. The rings may be fused, i.e., share two adjacent atoms, or "spirocyclic," i.e., share only a single atom.

[0136] "Carbonyl" refers to a functional group composed of a carbon atom double bonded to an oxygen atom (C=O).

[0137] "Carbonylamino" means --NHC(.dbd.O)H, wherein the amino moiety is optionally substituted (one or both of the hydrogen atoms are replaced), as further defined herein.

[0138] "Carboxy" means a -CO2H group. The bond to the parent group is through the carbon atom of the carbonyl moiety.

[0139] "Celite®" (Fluka) diatomite is a diatomaceous earth that may be referred to as "celite."

[0140] "Cycloalkyl" or "C 3~12 "Cycloalkyl" means any monovalent non-aromatic group derived from a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having 3 to 12 ring carbon atoms. These non-aromatic groups having 3, 4, 5, 6, 7, 8, or up to 12 carbon ring atoms can be fully saturated or partially unsaturated. Unless specifically stated otherwise in the specification, a cycloalkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused or bridged ring systems, where the point of attachment of the "cycloalkyl" to the rest of the molecule is on the saturated ring. Bicyclic cycloalkyl ring systems include fused ring systems in which two rings share two atoms (e.g., decalin), spiro ring systems in which two rings share one atom (e.g., spiro[4.5]decanyl), and bridging groups (e.g., norbornyl).

[0141] Additional examples within the above meaning include, but are not limited to, monovalent radicals of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, [1.1.1]-bicyclopentane, bicyclo[3.1.0]hexanyl, cyclohexenyl, cyclopentenyl, 1-decalinyl, spiro[2.4]heptyl, spiro[2.2]pentyl, and norbornyl.

[0142] "C 3~8 Cycloalkyl" (or "C3-C8 cycloalkyl" or "C 3~8 The term "cycloalkyl" means a cyclic ring of an alkane having 3 to 8 total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). 3~7 cycloalkyl," "C 3~6 cycloalkyl," "C 5~7Terms such as "cycloalkyl" have an analogous meaning.

[0143] "Dialkylamino" refers to an amino containing two alkyl groups attached to the amino nitrogen (e.g., N,N-dimethylamino, or [ka] ) means

[0144] "Fluoroalkyl" includes mono- and multiply fluoro-substituted straight-chain and branched alkyl groups, up to perfluoro-substituted alkyl, such as fluoromethyl, 1,1-difluoroethyl, difluoromethyl, trifluoromethyl, or 3,3,4,4,4-pentafluorobutyl.

[0145] "Guanidino" refers to the monovalent radical RNC(=NR)NH- derived from guanidine, where R is independently 0~6 alkyl), such as 3-guanidinopropyl ( [ka] ) means

[0146] Unless otherwise specified, "halogen" or "halo" includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo). In one embodiment, halo is fluoro (-F) or chloro (-Cl).

[0147] "Haloalkyl" refers to an alkyl group as defined above in which one or more (particularly 1 to 10) hydrogen atoms are replaced by halogen atoms, up to and including complete replacement of all hydrogen atoms with halo groups. 1~6 Haloalkyl includes, for example, -CH2F, -CHF2, CF3, -CCl3, -CF2CF3, -CHFCH3, and the like.

[0148] The term "heteroalkyl" refers to 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).

[0149] As used herein, the term "heteroaryl" refers to a stable monocyclic, bicyclic, or tricyclic ring system containing 5 to 14 ring atoms, including at least one ring heteroatom selected from nitrogen (N), sulfur (S) (including S=O and SO), and oxygen (O), in which at least one of the heteroatom-containing rings is aromatic. In heteroaryl ring systems in which one or more of the rings are saturated and contain one or more nitrogen (N) atoms, the nitrogen (N) may be in the form of a quaternary amine or a quaternary ammonium cation. Bicyclic heteroaryl ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom. Heteroaryl groups within the scope of this definition include azaindolyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzo[d]isothiazolyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthapyridinyl, l), oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, pyranyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, 5H-pyrrolo[3,4-b]pyridine, thiazolyl, thienyl, triazolyl, triazinyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, and isoquinolinyl, and oxazolyl. If heteroaryl contains a nitrogen atom, it is understood that the corresponding N-oxide is also encompassed by this definition.

[0150] The term "heterocycloalkyl," as used herein, refers to a stable, non-aromatic (not completely aromatic, e.g., containing one double bond) 3- to 12-membered ring group containing 2 to 12 ring carbon atoms and 1 to 6 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Whenever it appears herein, a numerical range such as "3 to 12" or "3 to 12" refers to each integer within the given range. For example, "3 to 12 ring atoms" means that the heterocycloalkyl group can consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, or up to 12 ring atoms. In some embodiments, it is a 5- to 10-ring heterocycloalkyl. In some embodiments, it is a 4- to 10-ring heterocycloalkyl. In some embodiments, it is a 3- to 10-ring heterocycloalkyl. Unless specifically stated otherwise in the specification, a heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused or bridged ring systems. The prefix aza, oxa, or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. In some embodiments, the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide (S=O), or S-dioxide (SO). One or more nitrogen atoms, if present, can be optionally quaternized. A heterocycloalkyl group can be partially or fully saturated. A heterocycloalkyl can be attached to the remainder of the molecule through any atom of the ring(s).

[0151] In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic and has from about 5 to about 8 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 8 to about 11 ring atoms. In yet another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. In another embodiment, a heterocycloalkyl group is tricyclic. There are no adjacent oxygen and / or sulfur atoms in the ring system.

[0152] Non-limiting examples of heterocycloalkyl rings include decahydroisoquinoline, dioxaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptyl, quinuclidinyl, oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta-lactam, gamma-lactam, delta-lactam, beta-lactone, gamma-lactone, delta-lactone, piperidinyl, 3-azabicyclo(azabixyclo)[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 6-azaspiro[2.5]octanyl, azetidinyl, 2,3-dihydro-1H-indenyl, dihydro-1H-indenyl, 3H-spiro[benzofuran-2',4'-piperidinyl, 2,3-dihydro-1H-pyrrolo[3,2,1-ij][ 1,6]naphthyridinyl, 3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridyl, 3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazole, diazabicyclo[3.3.2]decanyl, 2,3,4,5,6,7-hexahydroisothiazolo[5,4-c]pyridyl, hexahydro-2H-pyrrolo[3,4-d]isothiazolyl, 3,9-diazabicyclo[3.3.2]decanyl, bicyclo [2,2,1]heptenyl, 2',3'-dihydro-1'H-spiro[piperidine-4,4'-quinazoline], octahydropyrrolo[3,4-b][1,4]oxazinyl, (diazabicyclo[2.2.1]heptanyl), 2,5-diazabicyclo[2.2.1]heptanyl, tetrahydrobenzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, oxabicyclo[2.1.1]hexyl, 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, 1H-benzo[d]imidazolyl (1H-enzo[d]imidazolyl), diazaspiro[4.4]nonanyl, and 2,7-diazaspiro[4.4]nonanyl, and pyrrolidinone, and their oxides and all their isomers. In one embodiment of the present invention, heterocycloalkyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azelidinyl, and azetidinyl.

[0153] "Nitro" refers to the -NO2 group.

[0154] "Oxo" means an oxygen atom that is double bonded to another atom, represented herein as "=O."

[0155] The term "oxy" means an oxygen (O) atom.

[0156] A "quaternary amine" or "quaternary ammonium" is a positively charged group with four functional groups attached to a nitrogen atom, such as N,N,N-trimethylammonium ( [ka] ), and N,N,N-trimethylpropan-1-aminium ( [ka] ) means

[0157] "Sulfinyl" refers to the divalent functional group -S(=O)-.

[0158] "Sulfonyl" refers to the divalent functional group -SO2-.

[0159] "Tertiary amine" means an amine having three carbon atoms attached to the amino nitrogen.

[0160] The term "thio" refers to a sulfur (S) atom.

[0161] "Trialkylammonium" refers to an amino or (C) alkyl group containing three alkyl groups attached to the amino nitrogen. 1~6 Alkyl)3N + (C 0~6 alkyl)-, such as N,N,N-trimethylammonium ( [ka] ), and N,N,N-trimethylpropan-1-aminium ( [ka] ) means

[0162] "Urea" means -NR-C(=O)-NR2, where R can be independently hydrogen, alkyl, or aryl, e.g., -NHCONH2.

[0163] By "pharmaceutically acceptable" it is meant that the components of a pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.

[0164] If any amine is present in the compound, the nitrogen (N) atom may be in the form of a quaternary amine with one or more appropriate additional substitutions, as further described herein.

[0165] Any variable (e.g., n, R a , R bWhen any radical (e.g., aryl, aryl, aryl) occurs more than one time in any constituent or in formula I, its definition at each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0166] When any ring atom is specified as being optionally substituted in a particular form, for example, sulfur (S) substituted with an oxo group, or nitrogen (N) in the form of an N-oxide, this does not exclude any ring atom from being substituted with any of the other listed substituents when not substituted with an oxo group or in the form of an N-oxide.

[0167] The term "substituted" means that one or more hydrogens on the designated atom have been replaced with a selection from the indicated group, provided that the replacement does not exceed the normal valence of the designated atom under the circumstances, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0168] By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The compounds of the present invention are limited to stable compounds encompassed by Formula I.

[0169] The term "compound" refers to the compound and, in certain embodiments, any hydrates or solvates thereof, so long as they are stable. A hydrate is a compound complexed with water, and a solvate is a compound complexed with an organic solvent.

[0170] As used herein, the term "in substantially purified form" refers to the physical state of a compound after it has been isolated from a synthetic method (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 known to those of skill in the art (e.g., chromatography, reverse-phase preparative HPLC, recrystallization, etc.) of sufficient purity that it can be characterized by standard analytical techniques described herein or known to those of skill in the art.

[0171] It should also be noted that any carbon and heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0172] When a functional group of a compound is referred to as "protected," this means that the group is modified to prevent undesired side reactions at the protected site when the compound undergoes a reaction. Suitable protecting groups will be recognized by those skilled in the art and by reference to standard texts such as, for example, T.W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0173] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is preceded by an adjacent functional group toward the point of attachment. For example, (C 1~5 Alkyl)carbonylamino(C 1~6 The alkyl) substituents are [ka] is equal to.

[0174] Structural representations of compounds with substituents terminating in methyl groups may be expressed using the letters "Me", "-Me", "CH3", "-CH3", or a line to represent the presence of the methyl group, e.g. [ka] can be used to represent the terminal methyl group, i.e. [ka] have equivalent meanings.

[0175] For example, (CR i R j ) r (wherein r is an integer 2 and R i is a defined variable, and R j In the case of a definition of a variable containing a term with repeated terms, such as (where is the defined variable), R i The value of R may be different in each instance in which it occurs. j The value of may be different in each instance where it occurs. For example, R i and R j is independently selected from the group consisting of methyl, ethyl, propyl, and butyl, (CR i R j )2 is [ka] It could be.

[0176] Unless otherwise specified, 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. Any range cited herein should also be understood to include within its scope all subranges within that range. Thus, for example, a heterocyclic ring described as containing "1 to 4 heteroatoms" is intended to include, in its embodiments, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms. Similarly, C 1~6 or C 1~6Or C1-C6, when used with a chain, such as an alkyl chain, means that the chain can contain 1, 2, 3, 4, 5, or 6 carbon atoms. It also includes all ranges contained therein, including C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C3-C6, C4-C6, C5-C6, and all other possible combinations.

[0177] In selecting compounds of the present invention, one skilled in the art will appreciate the various substituents, i.e., R 1 , R A , R 2b It will be appreciated that the etc. should be selected according to well-known principles of chemical structure connectivity and stability.

[0178] As used herein, the term "composition" is intended to encompass products containing the specified ingredients in the specified amounts, as well as any product resulting from combining the specified ingredients in the specified amounts.

[0179] Any variable (e.g., R 2a When R occurs more than one time in any constituent or in general formula (I) or other general formulas herein, its definition at each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In selecting compounds of the present disclosure, those skilled in the art will recognize that various substituents, e.g., R 2a It will be recognized that the groups should be selected in accordance with well-known principles of chemical structure connectivity and stability. Unless specified to the contrary, substitution with a specified substituent on any atom in a ring (e.g., an aryl, heteroaryl, or saturated heteroaryl ring) is possible so long as such ring substitution is chemically permissible and results in a stable compound. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain essentially unchanged, or can be made to remain unchanged, for a period of time sufficient to permit use of the compound for the purposes described herein.

[0180] The term "substituted" should be considered to include multiple degrees of substitution by the named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound may be singly or multiply independently substituted with one or more of the disclosed or claimed substituent moieties. By independently substituted, it is meant that the (two or more) substituents may be the same or different.

[0181] Wavy lines as used herein [ka] indicates the point of attachment to the rest of the compound.

[0182] Some of the compounds described herein may exist as tautomers with different attachment points of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed by the compounds of the present disclosure.

[0183] In the compounds of the present disclosure, atoms may be present at their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly 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 H) and deuterium (also designated D herein) 2H). Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium may confer certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, or may provide compounds useful as standards for characterization of biological samples. Isotopically enriched compounds of the present disclosure can be prepared without undue experimentation by conventional techniques well known to those of skill in the art, or by methods analogous to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0184] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When a compound of the present disclosure is acidic (or has a functional group that can be anionic), its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Examples of suitable inorganic cations include Li + , Na + , and K. + Alkali metal ions such as Ca 2+ and Mg 2+ Alkaline earth metal cations such as Al 3+ and Zn 2+ Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4 +) and substituted ammonium ions. Examples of suitable substituted ammonium ions are those derived from methylamine, ethylamine, diethylamine, triethylamine, and ethylenediamine. When a compound of the present disclosure is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Examples of such acid addition salts include salts formed from hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid), formic acid, acetic acid, capric acid, and citric acid. Salts containing acetate, formate, caprate, chloride, or sodium salts are typical for use with compounds of the present disclosure. In some embodiments, salts of compounds of the present disclosure can be formed by anion exchange, such as by replacing a trifluoroacetate ion with a chloride ion, as is well known to those skilled in the art.

[0185] Furthermore, the compounds of the present disclosure may exist in amorphous form 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 present disclosure. Furthermore, some of the compounds of the present disclosure may 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, particularly pharmaceutically acceptable solvates and hydrates, are also encompassed within the scope of the present disclosure, along with unsolvated and anhydrous forms.

[0186] Pharmaceutically acceptable prodrug variants of the compounds of the present disclosure, which result in conversion in vivo to compounds within the scope of the present disclosure, are also within the scope of the present disclosure.

[0187] The present disclosure also relates to methods for preparing compounds of formula (I), which are described in the Examples below and from which compounds of the present disclosure are obtained.

[0188] "Treatment" and "treating" refer to any process that may slow, interrupt, inhibit, control, or stop the progression of a disease or disorder described herein. These terms do not necessarily indicate the complete elimination of all disease or disorder symptoms.

[0189] As used herein, "preventing" or "prevention" refers to reducing the likelihood of contracting a disease or disorder described herein or reducing the severity of a disease or disorder described herein.

[0190] The terms "therapeutically effective (or effective) amount" and similar descriptions such as "treatment effective amount" or "effective dose" are intended to mean an amount of a compound of the present disclosure that elicits a biological or medical response in a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician. In preferred embodiments, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that alleviates at least one clinical symptom in a human patient. The terms "prophylactically effective (or effective) amount" and similar descriptions such as "prophylactically effective amount" are intended to mean an amount of a compound of the present disclosure that prevents or reduces the risk of occurrence of a biological or medical event that is sought to be prevented in a tissue, system, animal, or human by a researcher, veterinarian, physician, or other clinician.

[0191] Dosage of Compounds of the Disclosure The dosage regimen utilizing the compounds of the present disclosure is selected according to various factors, including patient type, species, age, weight, sex and medical condition; the severity of the condition to be treated; the efficacy of the compound selected for administration; administration route; and the renal and hepatic function of the patient.The consideration of these factors is within the scope of a skilled clinician to determine the therapeutically effective dose or prophylactically effective dose required to prevent, counter or prevent the progression of the condition.It is understood that a specific daily dosage can be both a therapeutically effective amount for treating, for example, immunological conditions, and a prophylactically effective amount for preventing, for example, immunological conditions.

[0192] While individual needs vary, determining the optimal range of effective amounts of the compounds of the present disclosure is within the skill of one of ordinary skill in the art. For example, for administration to humans in the curative or prophylactic treatment of the conditions and disorders identified herein, a typical dosage of the compounds of the present disclosure may be about 0.05 mg / kg / day to about 1000 mg / kg / day. In some embodiments, patients are administered about 5 mg / day to about 1000 mg / day, e.g., 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 present disclosure. In certain embodiments, patients are 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 present disclosure. Such a dose may be administered in a single dose or divided into multiple doses.

[0193] Pharmaceutical Composition The compounds of the present disclosure and their pharmaceutically acceptable salts can be administered to animals, preferably mammals, particularly humans, as pharmaceuticals alone, in mixtures with each other, or in the form of pharmaceutical compositions. The term "subject" or "patient" includes animals, preferably mammals, particularly humans, who use a readily active agent for the prevention or treatment of a medical condition.

[0194] The administration of drug to subject includes both self-administration and administration to patient by other people.Subject may need or desire the treatment of existing disease or medical condition, or may need or desire the preventive treatment to prevent or reduce the risk of the occurrence of disease or medical condition.As used herein, the subject that " needs " the treatment of existing condition or preventive treatment includes both the need judged by medical professionals and the patient's desire for such treatment.

[0195] Therefore, the present disclosure also provides compounds of the present disclosure and their pharmaceutically acceptable salts for use as pharmaceuticals, their use for selectively modulating the activity of TNFR1, particularly their use in the treatment and prevention of the diseases or disorders mentioned below, and their use for preparing medicaments for these purposes. In certain embodiments, the compounds of the present disclosure and their pharmaceutically acceptable salts block TNFα signaling through TNFR1.

[0196] Furthermore, the present disclosure provides pharmaceutical compositions comprising an effective dose of at least one compound of the present disclosure and / or a pharmaceutically acceptable salt thereof as an active ingredient, and a conventional pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or excipients.

[0197] Thus, the present disclosure provides, for example, the compounds of the present disclosure and pharmaceutically acceptable salts thereof for use as pharmaceutical compositions comprising an effective dose of said compounds and / or pharmaceutically acceptable salts thereof as an active ingredient and a conventional pharmaceutically acceptable carrier, as well as the use of said compounds and / or pharmaceutically acceptable salts thereof in the treatment or prevention of the diseases or disorders 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 preparing medicaments for these purposes.

[0198] The pharmaceutical compositions according to the present disclosure can be administered, for example, in the form of pills, tablets, lacquered tablets, dragees, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be parenterally, for example subcutaneously, intramuscularly or intravenously, in the form of solutions or suspensions for injection or infusion.

[0199] Other suitable administration forms are, for example, ointments, tinctures, sprays or transdermal therapeutic systems, or transdermal or topical administration, for example in the form of microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and its severity.

[0200] The present disclosure also provides pharmaceutical compositions comprising compounds of formula (I). Compounds of formula (I) can be used in combination with any suitable pharmaceutical carrier or excipient. Such pharmaceutical compositions comprise a therapeutically effective amount of one or more compounds of formula (I) and pharmaceutically acceptable excipient(s) and / or carrier(s). The specific pharmaceutical composition is suited to the mode of administration. In certain embodiments, the pharmaceutically acceptable carrier may be water or a buffer solution.

[0201] Excipients included in pharmaceutical compositions have different purposes depending, for example, on the nature of the drug and the mode of administration. Examples of commonly used excipients include, but are not limited to, saline, buffered saline, dextrose, water-for-infection, glycerol, ethanol, and combinations thereof, stabilizers, solubilizers and surfactants, buffers and preservatives, isotonicity agents, bulking agents, lubricants (e.g., talc or silica, and fats, such as vegetable stearin, magnesium stearate, or stearic acid), emulsifiers, suspending agents or viscosity agents, inert diluents, fillers (e.g., cellulose, dibasic calcium phosphate, vegetable oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate), disintegrants (e.g., cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethylcellulose), binders (e.g., starch, The additives may include, but are not limited to, cellulose, 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), humectants, antimicrobial agents, chelating agents, coatings (e.g., cellulose film coatings, synthetic polymers, shellac, corn protein zein or other polysaccharides, and gelatin), preservatives (including vitamin A, vitamin E, vitamin C, retinyl palmitate, and synthetic preservatives including selenium, cysteine, methionine, citric acid and sodium citrate, and methylparaben and propylparaben), sweeteners, fragrances, flavorings, coloring agents, absorption enhancers, administration aids, and combinations thereof.

[0202] Carriers are compounds and substances that improve and / or prolong the delivery of active ingredients to a subject in the context of a pharmaceutical composition. Carriers can help extend the in vivo activity of a drug or delay its release in a subject using controlled-release technology. Carriers can also reduce drug metabolism and / or reduce drug toxicity in a subject. Carriers can also be used to target the delivery of a drug to specific cells or tissues in a subject. Common carriers (both hydrophilic and hydrophobic) include lipid emulsions, lipids, PEGylated phospholipids, PEGylated liposomes, PEGylated liposomes coated with cyclic RGD peptide via a PEG spacer, liposomes and lipospheres, microspheres (including those made of biodegradable polymers or albumin), polymer matrices, biocompatible polymers, protein-DNA complexes, protein conjugates, red blood cells, vesicles, nanoparticles, and hydrocarbon stapling side chains. The above carriers can also be used to increase the cell membrane permeability of the compound of Formula (I). In addition to their use in the pharmaceutical compositions of the present disclosure, carriers may also be used in compositions for other uses, such as in vitro (e.g., for delivery to cultured cells) and / or in vivo research uses.

[0203] Pharmaceutical compositions adapted for oral administration can be provided as discrete units such as capsules or tablets; as powders or granules; as solutions, syrups, or suspensions (in aqueous or non-aqueous liquids; or as edible foams or whips; or as emulsions). Suitable excipients for tablets or hard gelatin capsules include lactose, corn starch or derivatives thereof, stearic acid or salts thereof. Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semisolids, or liquid polyols. Excipients that can be used to prepare solutions and syrups include, for example, water, polyols, and sugars. For the preparation of suspensions, oils, such as vegetable oils, can be used to provide oil-in-water or water-in-oil suspensions. Excipients that promote absorption from the gastrointestinal tract, such as permeation enhancers such as sodium caprate, can be included. In certain circumstances, delayed-release preparations can be advantageous, and compositions that can deliver the compounds of the present disclosure in a delayed-release or controlled-release manner can also be prepared. Prolonged gastric retention poses the problem of degradation by enzymes present in the stomach, therefore enteric coated capsules can also be prepared by standard techniques in the art in which the active substance for release descends in the gastrointestinal tract.

[0204] Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3(6):318 (1986).

[0205] Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, liquids, pastes, gels, sprays, aerosols, or oils.When formulated into ointments, the active ingredient can be used with either a paraffinic ointment base or a water-miscible ointment base.Alternatively, the active ingredient can be formulated into a cream containing an oil-in-water cream base or a water-in-oil base.Pharmaceutical compositions suitable for topical administration to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent.Pharmaceutical compositions suitable for topical administration to the mouth include lozenges, troches, and mouthwashes.

[0206] Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas.

[0207] Pharmaceutical compositions adapted for nasal administration wherein the carrier is a solid include coarse powder having a particle size in the range, for example, 20 to 500 microns, administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close to the nose. Compositions wherein the carrier is a liquid, suitable for administration as a nasal spray or as nasal solutions, include aqueous or oily solutions of the active ingredient.

[0208] Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by various types of metered dose pressurized aerosols, nebulizers, or insufflators.

[0209] Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

[0210] Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation substantially isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Excipients that may be used for injection solutions include, for example, water for injection, alcohols, polyols, glycerin, and vegetable oils. The compositions may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection or physiological saline for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Pharmaceutical compositions may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts (the substances of the present disclosure themselves may be provided in the form of pharmaceutically acceptable salts), buffers, coatings, or antioxidants. They may also contain therapeutically active agents in addition to the compounds of the present disclosure.

[0211] Methods of Using the Disclosed Compounds The present application provides a method for TNFR1-mediated cell signaling, comprising contacting cells with the compound of the present disclosure or its pharmaceutically acceptable salt.The binding and selectivity to human TNFR1 and TNFR2 can be evaluated by SPR.The affinity to human TNFR1 can be evaluated using time-resolved fluorescence resonance energy transfer (TR-FRET) binding assay.The inhibition of TNFR1-mediated cell signaling can be evaluated by detecting a decrease in the level of the downstream NF-κB signaling pathway.

[0212] The present application also provides methods of treating disease conditions, including but not limited to conditions involving TNFR1, using the compounds of the present disclosure (or pharmaceutically acceptable salts thereof) or pharmaceutical compositions containing such compounds.

[0213] In some embodiments, the present disclosure provides methods of treating IBD and other TNFα-driven inflammatory diseases, comprising administering a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the pharmaceutical compositions comprising such a compound to a subject in need of such treatment. In some embodiments, the TNFα-driven inflammatory disease is IBD. In some embodiments, the TNFα-driven inflammatory disease is ulcerative colitis. In some embodiments, the TNFα-driven inflammatory disease is Crohn's disease. In some embodiments, the TNFα-driven inflammatory disease is rheumatoid arthritis. In some embodiments, the TNFα-driven inflammatory disease is juvenile rheumatoid arthritis. In some embodiments, the TNFα-driven inflammatory disease is psoriasis. In some embodiments, the TNFα-driven inflammatory disease is psoriatic arthritis. In some embodiments, the TNFα-driven inflammatory disease is ankylosing spondylitis. In some embodiments, the TNFα-driven inflammatory disease is axial spondyloarthritis that does not meet radiographic criteria. In some embodiments, the TNFα-driven inflammatory disease is hidradenitis suppurativa.

[0214] In some embodiments, the present disclosure provides a method of treating inflammatory bowel disease, comprising administering a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the aforementioned pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

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

[0216] In some embodiments, the present disclosure provides a method of treating Crohn's disease, comprising administering a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the aforementioned pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0217] In some embodiments, the present disclosure provides a method of treating rheumatoid arthritis, comprising administering a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the aforementioned pharmaceutical compositions comprising such a compound to a subject in need of such treatment.

[0218] In some embodiments, the present disclosure provides a method of treating juvenile rheumatoid 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 aforementioned pharmaceutical compositions comprising such a compound.

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

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

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

[0222] In some embodiments, the present disclosure provides a method for treating subradiographic axial spondyloarthritis, 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 aforementioned pharmaceutical compositions comprising such a compound.

[0223] 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 aforementioned pharmaceutical compositions comprising such a compound.

[0224] In some embodiments, the present disclosure provides methods of treating IBD and other TNFα-driven inflammatory diseases, comprising administering a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) to a subject in need of such treatment, 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-radiographic axial spondyloarthritis, and hidradenitis suppurativa.

[0225] One embodiment of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy.

[0226] One embodiment of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating 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 spondyloarthritis, and hidradenitis suppurativa.

[0227] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating IBD and other TNFα-driven inflammatory diseases selected from ulcerative colitis and Crohn's disease.

[0228] One embodiment relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating IBD and other TNFα-driven inflammatory diseases selected from rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and hidradenitis suppurativa.

[0229] Combination therapy One or more additional pharmacologically active agents may be administered in combination with the compounds of the present disclosure. Additional active agent(s) is intended to mean pharmaceutically active agent(s) that are active in the body, including prodrugs that are converted to a pharmaceutically active form after administration, that are different from the compounds of Formula I, and also includes the free acid, free base, and pharmaceutically acceptable salts of said additional active agents.

[0230] Examples of additional active agents that may be used include, but are not limited to, anti-TNFα biologics such as methotrexate, azathioprine, 6-mercaptopurine, anti-IL-23 agents, anti-α4β7 agents such as vedolizumab, and biased IL-2Rα agonists in clinical development.

[0231] Synthesis method General procedure for accessing building blocks and monomers The compounds of the present invention can be prepared according to the procedures of the following schemes and specific examples, or modifications thereof, using readily available starting materials, suitable materials and reagents, and conventional synthesis procedures, and are further exemplified by the following specific examples. In these reactions, it is also possible to use variants that are themselves known to those skilled in the art but are not mentioned in more detail. The general procedures for making the compounds claimed in the present invention can be easily understood and recognized by those skilled in the art from viewing the following schemes. Examples also include methods for testing such compounds in biophysical, biochemical, and cellular assays. However, the compounds illustrated in the examples should not be construed as forming the only genus considered in this disclosure.

[0232] Unless otherwise specifically stated, all reagents are commercially available, known in the literature, or easily synthesized by those skilled in the art. The general routes applicable to the synthesis of compounds of Formula I are described in the following schemes. In some cases, the order of reaction steps in the schemes can be changed to facilitate the reaction or avoid unwanted reaction products. Furthermore, various protecting group strategies familiar to those skilled in the art of organic synthesis and solid-phase peptide synthesis can be used to facilitate the reaction, improve yield and purity, or avoid undesired reaction products.

[0233] Unless otherwise noted, all reagents and solvents were purchased from commercial sources and used without further purification. All temperatures are in degrees Celsius (°C), and ambient or room temperature (RT) is 20°C. Most compounds were purified by reversed-phase preparative high-performance liquid chromatography (HPLC) or medium-pressure liquid chromatography (MPLC) on silica gel. The course of reactions was followed by liquid chromatography / mass spectrometry (LC-MS) or ultra-performance liquid chromatography / mass spectrometry (UPLC-MS); electrospray ionization (ESI); UV detection at 254 nm. Proton, fluorine, and carbon magnetic resonance ( 1 H, 19 F and 13 C NMR spectra were recorded on 300, 400, 500, or 600 MHz Varian or Bruker spectrometers; chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane and referenced to residual solvent. Coupling constants are reported in Hertz. 1H NMR data are reported here as follows: chemical shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublet (dd), doublet of triplet (dt), triplet of triplet (td), triplet of triplet (tt), doublet of doublet of doublet (ddd), multiplet (m), and broad singlet (br.s)], coupling constant [Hz], and integral). Moisture- or air-sensitive reactions were carried out under nitrogen or argon using anhydrous solvents and reagents. Reaction progress was determined by either analytical thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), typically performed on pre-coated TLC plates (E. Merck, Darmstadt, Germany), silica gel 60F-254, layer thickness 0.25 mm.

[0234] Unless otherwise specified, when ratios of compounds (e.g., solvents) are given, the ratios are on a volume to volume basis. For example, a solvent gradient ranging from 100% hexane to 50% EtOAc / hexane refers to a gradient starting from a mixture of 100 parts hexane by volume and varying to a mixture of 50 parts ethyl acetate:50 parts hexane by volume.

[0235] The term "w / w" refers to the weight of a compound relative to the total weight. For example, NaH 60% w / w means 60 parts by weight of NaH:100 parts by weight of total.

[0236] The following examples are provided so that the present invention may be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. If a racemic mixture is produced, the enantiomers can be separated using SFC reverse-phase or normal-phase chiral resolution conditions after isolation of the final product or on an appropriate intermediate, followed by individual processing of the single isomers. It is understood that alternative methods can be used to synthesize these key intermediates and examples. Asymmetric methods (e.g., chiral catalysts, auxiliaries, biocatalytic processes) can be used where possible and appropriate. The exact choice of reagents, solvents, temperatures, and other reaction conditions will depend on the nature of the intended products.

[0237] Abbreviation The following abbreviations are used throughout the text: [Table 1] TIFF2025159726000066.tif250166 TIFF2025159726000067.tif251165 TIFF2025159726000068.tif251165 TIFF2025159726000069.tif248165 TIFF2025159726000070.tif251165 TIFF2025159726000071.tif252166 TIFF2025159726000072.tif249166 TIFF2025159726000073.tif253166 TIFF2025159726000074.tif252166 TIFF2025159726000075.tif249165 TIFF2025159726000076.tif249166 TIFF2025159726000077.tif247165 TIFF2025159726000078.tif253166 TIFF2025159726000079.tif194166

[0238] Reaction scheme Synthesis of intermediates and monomers: Synthetic Scheme 1 [ka]

[0239] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indazol-1-yl)propanoic acid (Fmoc-1Inda-OH) Step 1: Under a nitrogen atmosphere, 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 approximately 8.0) was added PLP (3.05 g, 9.31 mmol) and PfTrpB-0B2 (7.7 g, 7 wt%). The mixture was stirred and heated at 65 °C for 18 h. Upon completion, the resulting solution was used directly in the next step.

[0240] Step 2: A 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 a nitrogen atmosphere. The mixture was stirred at RT for 18 h under a nitrogen atmosphere. The mixture was acidified to approximately pH 3 with 6 n HCl. The mixture was filtered, and the filtrate was extracted with EtOAc (3 × 3.0 L). The organic layers were combined, washed with HO (2 × 2.0 L) and brine (3.0 L), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated four times with DCM / hexane (5 L / 2.5 L). 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. 25 H 22 N3O4[M+H] + 428.2, actual value 428.2. 1H NMR(300MHz,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).

[0241] Synthetic Scheme 2 [ka]

[0242] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-pyrazolo[3,4-b]pyridin-3-yl)propanoic acid (Fmoc-1Inda7az-OH) Step 1: Under Ar at RT, DMAP (0.46 g, 3.8 mmol) and BocO (10.4 mL, 45.1 mmol) were added to a solution of 3-methyl-1H-pyrazolo[3,4-b]pyridine (5.0 g, 37.6 mmol) in MeCN (100 mL). The reaction was stirred overnight at RT and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-40% EtOAc in PE to give tert-butyl 3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate. 12 H 16 N3O2[M+H] + MS ESI calculated for 234.12, found 234.05. 1 H NMR (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).

[0243] Step 2: Under Ar at RT, 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-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (7.5 g, 32.2 mmol) in trifluorotoluene (170 mL). 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 0-25% EtOAc in PE to give tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate. 12 H 15 BrN3O2[M+H] + MS ESI calculated 312.03 / 314.03, found 311.90 / 313.90. 1 H NMR (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).

[0244] Step 3: n-BuLi (8.6 mL, 21.5 mmol, 2.5 n in hexane) was added dropwise to a solution of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (6.4 g, 20.5 mmol) in anh.THF (150 mL) over 30 minutes at −78° C. under an Ar atmosphere. Then, (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3.8 g, 20.5 mmol) in anh.THF (10 mL) was added. The resulting mixture was stirred at −78° C. for 4 hours. The reaction mixture was quenched with aq.sat. NH4Cl (200 mL) at 0° C. and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over anh.Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in PE to give tert-butyl 3-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate. 21 H 30 N5O4[M+H] + MS ESI calculated for 416.22, found 416.05. 1 H NMR (300MHz, 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=6.9Hz,3H),0.66(d,J=6.9Hz,3H).

[0245] Step 4: At 0° C., 0.2 n HCl (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)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (3.4 g, 8.18 mmol) in MeCN (50 mL). The resulting mixture was stirred at RT for 4 hours and then concentrated under reduced pressure to give methyl (S)-2-amino-3-(1H-pyrazolo[3,4-b]pyridin-3-yl)propanoate, which was used in the next step without purification. 10 H 13 N4O2[M+H] + MS ESI calculated for 221.10, found 221.10.

[0246] Step 5: At RT, an aqueous 1N LiOH solution (16.4 mL, 16.4 mmol) was added to a solution of methyl (S)-2-amino-3-(1H-pyrazolo[3,4-b]pyridin-3-yl)propanoate (1.8 g, 8.2 mmol) in THF (16.4 mL). The mixture was stirred at RT for 2 hours and then acidified with 1N HCl. The resulting solution was concentrated under reduced pressure to give (S)-2-amino-3-(1H-pyrazolo[3,4-b]pyridin-3-yl)propanoic acid, which was used in the next step without purification. CH 11 N4O2[M+H] + MS ESI calculated for 207.08, found 207.10.

[0247] Step 6: At RT, NaHCO3 (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-(1H-pyrazolo[3,4-b]pyridin-3-yl)propanoic acid (1.7 g, 7.4 mmol) in THF (30 mL) and water (30 mL). The resulting mixture was stirred at RT overnight, the pH was adjusted to approximately 3 with 1N HCl, and the mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from MeCN (50 mL) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-pyrazolo[3,4-b]pyridin-3-yl)propanoic acid. 24 H 21 N4O4[M+H] + MS ESI calculated for 429.15, found 429.05. 1 H NMR(400MHz,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).

[0248] Synthetic Scheme 3 [ka]

[0249] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(tert-butoxycarbonyl)pyridin-3-yl)propanoic acid (Fmoc-3Pal4CO2tBu-OH) Step 1: A mixture of NiCl2·glyme (710 mg, 3.2 mmol) and 1,10-phenanthroline (700 mg, 3.2 mmol) in anh.DMA (160 mL) was stirred and heated to 50 °C under a nitrogen atmosphere for 1 h. The mixture was cooled to RT. tert-Butyl 5-bromopicolinate (4.17 g, 16.2 mmol), benzyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (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 RT for an additional 2 h, then quenched with HO (200 mL) and extracted with EtOAc (2 × 500 mL). The combined organic phase was washed with brine (3 x 200 mL), dried over anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-20% EtOAc in PE to give tert-butyl (S)-5-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)picolinate. 35 H 35 N2O6[M+H] + MS ESI calculated for 579.24, found 579.40.

[0250] Step 2: tert-Butyl (S)-5-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)picolinate (7.5 g, 13 mmol) was dissolved in EtOAc (75 mL). The flask was evacuated and backfilled with N (5 times). Pd / C (1.38 g, 13 mmol, dry, 10 wt%) was added to the flask. The flask was evacuated and backfilled with H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT for 4 h. The flask was evacuated and backfilled with N (5 times). The resulting mixture was filtered through a Celite® pad. The filter cake was washed with EtOAc (2 × 25 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Rp-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN (0.1% TFA); Gradient elution: 5-95%; Detector: UV 215 nm. The product-containing fractions were concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(tert-butoxycarbonyl)pyridin-3-yl)propanoic acid. 28 H 29 N2O6[M+H] + MS ESI calculated for 489.19, found 489.20; 1 H NMR (300MHz, methanol-d4):δ 8.57(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),4.5 1-4.40(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).

[0251] Synthetic Scheme 4 [ka]

[0252] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridazin-4-yl)propanoic acid (Fmoc-4PyridaAla-OH) Step 1: At room temperature and under Ar, pyridine-2-carboximidamide 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 anh.DMA (200 mL). The solution was stirred at 50 °C for 40 min. The solution was cooled to room temperature. A solution of TBAI (20.96 g, 56.8 mmol), tert-butyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (28 g, 56.8 mmol), and 3,5-dichloropyridazine (16.91 g, 114 mmol) in anh.DMA (200 mL) was added to the reaction mixture. Activated zinc (7.42 g, 114 mmol) was then added, and the mixture was stirred at room temperature. The mixture was diluted with EtOAc (1 L) and washed with brine (3 x 500 mL). The organic layer was dried over anh. Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-35% EtOAc in PE to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-chloropyridazin-4-yl)propanoate. 26 H 27 ClN3O4[M+H] + MS ESI calculated for 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).

[0253] Step 2: tert-Butyl (S)-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 refilled with N (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 H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT. The flask was evacuated and refilled with N (5 times). The resulting mixture was filtered through a Celite® pad. The filter cake was washed with THF (2 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in PE to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridazin-4-yl)propanoate. 26 H 28 N3O4[M+H] + MS ESI calculated for 446.20, found 446.10.

[0254] Step 3: To a stirred solution of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridazin-4-yl)propanoate (19 g, 42.6 mmol) in DCM (140 mL) at RT was added TFA (300 mL). The solution was stirred at RT for 6 h. The solvent was concentrated under reduced pressure. The residue was recrystallized from MeCN (200 mL) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridazin-4-yl)propanoic acid. C 22 H 20 N3O4[M+H] + MS ESI calculated for 390.14, found 390.10. 1H NMR(400MHz,DMSO-d6):δ 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).

[0255] Synthetic Scheme 5 [ka]

[0256] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-7,7,7-trifluoroheptanoic acid (Fmoc-AhpF3-OH) Step 1: At RT, 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). After 30 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in anh.DMF (60 mL). BnBr (11.1 mL, 93.0 mmol) was added to the solution. The reaction mixture was stirred at RT for 13 h. The reaction mixture was slowly poured into DI water (300 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anh.Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-40% EtOAc in PE to give benzyl (tert-butoxycarbonyl)-l-homoserinate. C 16 H 23 NO5[M+Na] + MS ESI calculated for 332.15, found 332.0. 1H NMR (400 MHz, chloroform-d): δ 7.39-7.32 (m, 5H), 5.41-5.39 (m, 1H), 5.23-5.16 (m, 2H), 4.56-4.51 (m, 1H), 3.75-3.61 (m, 2H), 2.20-2.14 (m, 1H), 1.66-1.59 (m, 1H), 1.45 (s, 9H).

[0257] Step 2: At RT, Dess-Martin periodinane (31.1 g, 73.3 mmol) was added to a stirred solution of benzyl (tert-butoxycarbonyl)-l-homoserinate (20.6 g, 64.6 mmol) in DCM (120 mL). After 30 min, the reaction mixture was quenched by the addition of a 1:1 (v / v) NaHCO3 / Na2SO3 solution (500 mL). The resulting mixture was stirred at RT for 30 min and extracted with DCM (200 mL). The organic layer was washed with brine (50 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo to give benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate. The crude product was used directly in the next step without further purification. 1 H NMR (400 MHz, 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).

[0258] Step 3: 1,1,1-trifluoro-3-iodopropane (15.7 mL, 30.0 g, 134 mmol) and PPh3 (33.4 g, 127 mmol) were stirred at 80 °C. The reaction mixture was cooled to RT and triturated with PE (80 mL) at RT for 2 h. The solid was collected by filtration and dried under reduced pressure to give triphenyl(3,3,3-trifluoropropylidene)-λ. 5 -Phosphane was obtained. 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).

[0259] Step 4: At -40 °C, a solution of potassium tert-butoxide (1.0 m in THF, 79.3 mL) was added to triphenyl(3,3,3-trifluoropropylidene)-λ 5 To a stirred solution of 28.4 g (79.3 mmol) of tert-butoxycarbonyl-2-amino-4-oxobutanoate was added dropwise in anh.THF (120 mL). The solution was then stirred at −20° C. for 1 h. Benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (20.3 g, 66.1 mmol) was slowly added to the solution at −70° C., and the resulting mixture was stirred at −70° C. for 30 min. The reaction mixture was allowed to warm to RT. The mixture was then slowly poured into an aq. sat. NH4Cl solution (300 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (50 mL), dried over anh.Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-40% EtOAc in PE to give benzyl (S,E)-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).

[0260] Step 5: A solution of benzyl (S,E)-2-((tert-butoxycarbonyl)amino)-7,7,7-trifluorohept-4-enoate (12.6 g, 32.5 mmol) in THF (160 mL) was hydrogenated over Pd / C (1.30 g, 10 wt%) under 50 psi of dihydrogen at RT. The reaction mixture was filtered through a Celite® pad. The solid was washed with THF (3×200 mL), and the combined filtrate was concentrated to give the crude product (S)-2-((tert-butoxycarbonyl)amino)-7,7,7-trifluoroheptanoic acid. 12 H 20F3NO4[M+Na] + MS ESI calculated for 322.12, found 322.2; CH 12 F3NO2[M-Boc+H] + MS ESI calculated for 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).

[0261] Step 6: 4 m HCl 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 RT 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 product (S)-2-amino-7,7,7-trifluoroheptanoic acid. 1 H NMR (400 MHz, methanol-d4): δ 4.00-3.97 (m, 1H), 2.21-2.17 (m, 2H), 1.96-1.94 (m, 2H), 1.65-1.55 (m, 4H).

[0262] Step 7: At RT, NaHCO3 (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). The resulting mixture was stirred at RT for 12 h. The pH was adjusted to 2 with aqueous 1N HCl solution. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-40% EtOAc in PE, followed by chiral separation (Column: Daicel Chiracel® OJ (250 × 50 mm, 10 μm, Daicel Chiral Technologies, West Chester, PA); Mobile phase: [MeOH]; B%: 20%-20%, 8 min) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-7,7,7-trifluoroheptanoic acid. 22 H 22 F3NO4[M+Na] + MS ESI calculated for 444.14, found 444.1; [M+H] + 422.16, actual value 422.1. 1 H NMR (400MHz, acetonitrile-d3):δ 9.36(br.s,1H),7.83(d,J=7.2Hz,2H),7.67-7.62(m,2H),7.42(d,J=7.6Hz,2H),7.33(d,J=7.6Hz,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).

[0263] Synthetic Scheme 6 [ka]

[0264] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-oxoisoindolin-5-yl)propanoic acid (Fmoc-Ala4IsoindOne-OH) 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 anh.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 tert-butyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (6 g, 12.16 mmol) in anh.DMA (100 mL) was added at room temperature. Activated zinc (1.59 g, 24.32 mmol) was then added and stirred at room temperature for 4 h. The reaction was quenched with HO (400 mL) and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine (3 × 300 mL), dried over anh. NaSO, and filtered. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in PE to give tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-oxoisoindolin-5-yl)propanoate. 30 H 30 N2O5Na[M+Na] + MS ESI calculated for 521.22, found 520.95.

[0265] Step 2: At RT, TFA (100 mL, 1298 mmol) was added to a stirred solution of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-oxoisoindolin-5-yl)propanoate (5.5 g, 11.03 mmol) in DCM (50 mL). The resulting mixture was stirred at RT for 2.5 h and then concentrated under reduced pressure. The residue was recrystallized from EtO (100 mL) to give Fmoc-Ala4IsoindOne-OH. C26 H 23 N2O5[M+H] + MS ESI calculated for 443.15, found 443.05. 1 H NMR(400MHz,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).

[0266] Synthetic Scheme 7 [ka] (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)

[0267] Step 1: A 3 L three-necked round-bottom flask was charged with a solution of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (200.0 g, 680.3 mmol) in pentane (2 L) under N2. The mixture was cooled to -78 °C. MeLi (2.0 m in Et2O, 680.3 mL) was added dropwise over 2 h at -78 °C. The reaction mixture was warmed to 0 °C over 1 h. The reaction mixture was stirred at 0 °C under N2 for 1 h. NMR showed the reaction was complete. The reaction mixture was purified by distillation under vacuum at 0 °C, and fractions were collected by condensation in a liquid nitrogen-ethanol bath. This gave tricyclo[1.1.1.0]. 1,3 ] Pentane (2.75 wt % in a mixed solution of pentane and ether) was obtained. 1 H NMR (300 MHz, chloroform-d): δ 2.00 (d, J = 1.3 Hz, 6H).

[0268] Step 2: A 2 L three-necked round-bottom flask was charged with a solution of PPh3 (67.32 g, 256.6 mmol) in DCM (1000 mL) under N2. Imidazole (17.47 g, 256.6 mmol) was added to the flask. The reaction mixture was cooled to 0 °C. Diiodine (65.14 g, 256.60 mmol) was added to the flask in small portions over 10 minutes at 0 °C. The resulting mixture was stirred at 0 °C for 10 minutes. Methyl ((benzyloxy)carbonyl)-l-serinate (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 hours. LC-MS monitoring indicated the reaction was complete. The resulting mixture was filtered. The filter cake was washed with DCM (3 × 1000 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (80:1 to 30:1; v / v) to give methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-iodopropanoate. 12 H 14 INO4[M+Na] + MS ESI calculated for 386, found 386. 1 H 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).

[0269] Step 3: In a 3 L three-necked round-bottom flask, add tricyclo[1.1.1.0] under N2. 1,3A solution of pentane (880 g, 366.66 mmol, 2.75 wt%) in a mixture of pentane and diethyl ether was added. The reaction mixture was cooled to 0°C. Methyl (R)-2-(((benzyloxy)carbonyl)amino)-3-iodopropanoate (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 minutes at 0°C under N2. The reaction mixture was allowed to warm to RT and stirred for 30 minutes. LC-MS monitoring indicated the reaction was complete. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (100:1 to 20:1; v / v) to give methyl (2S)-2-(((benzyloxy)carbonyl)amino)-3-(3-iodobicyclo[1.1.1]pentan-1-yl)propanoate. 17 H 20 INO4[M+Na] + MS ESI calculated for 452, found 452. 1 H NMR (300MHz, chloroform-d):δ 7.37(d,J=4.5Hz,5H),5.31(d,J=8.3Hz,1H),5.14(t,J=2.9Hz,2H),4.39(td,J =7.8,4.5Hz,1H),3.75(s,3H),2.30-2.09(m,7H),1.92(dd,J=14.7,7.5Hz,1H).

[0270] Step 4: A 2 L three-necked round-bottom flask was charged with a solution of methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[3-iodobicyclo[1.1.1]pentan-1-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 in sequence at RT. The flask was evacuated and refilled with N2 (repeated three times). CuI (1.77 g, 9.29 mmol) was added to the flask. The flask was evacuated and refilled with N2 (repeated three times). The reaction mixture was stirred at 35 °C for 4 h. LC-MS monitoring indicated the reaction was complete. The resulting reaction mixture was diluted with water (900 mL). The resulting mixture was extracted with EtOAc (3 × 1000 mL). The organic layer was washed with brine (7 × 600 mL), dried over anh.Na2SO4, filtered, and concentrated under reduced pressure. This gave methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl]propanoate. The crude product was carried on to the next step without further purification.

[0271] Step 5: A 2 L three-necked round-bottom flask was charged with a solution of methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl]propanoate (40.00 g, crude) in THF (600 mL, 15 V). NaOAc (9.17 g, 111.8 mmol) and urea peroxide (26.29 g, 279.5 mmol) were added to the flask at 0 °C. The resulting mixture was stirred at 30 °C under N for 12 h. LC-MS monitoring indicated the reaction was complete. The resulting mixture was filtered. The filter cake was washed with THF (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (80:1 to 20:1; v / v) to give methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[3-hydroxybicyclo[1.1.1]pentan-1-yl]propanoate. 17 H 21 NO5[M+Na] + MS ESI calculated for 342, found 342. 1 H NMR (400MHz, chloroform-d):δ 7.43-7.30(m,5H),5.24(d,J=8.4Hz,1H),5.14(d,J=2.8Hz,2H),4.41(td,J=7.7,4.5Hz,1H),3. 76(s,3H),2.39(s,1H),2.21(dd,J=14.7,4.6Hz,1H),2.00(dd,J=14.7,7.3Hz,1H),1.84(s,6H).

[0272] Step 6: A 250 mL three-necked round-bottom flask was charged with methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[hydroxybicyclo[1.1.1]pentan-1-yl]propanoate (16.00 g, 0.05 mmol). BocO (54.67 g, 0.25 mmol) and magnesium perchlorate (1.17 g, 0.005 mmol) were added sequentially to the flask under N2. The resulting mixture was stirred at 50 °C for 6 h. LC-MS monitoring indicated 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 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[3-(tert-butoxy)bicyclo[1.1.1]pentan-1-yl]propanoate. 21 H 29 NO5[M+Na] + MS ESI calculated for 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).

[0273] Step 7: A 500 mL round-bottom flask was charged with a solution of methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(3-(tert-butoxy)bicyclo[1.1.1]pentan-1-yl)propanoate (12.00 g) in MeOH (240.00 mL, 20 V). The flask was evacuated and refilled with N (5 times). Pd / C (anh. 2.40 g, 20 wt%) was added to the flask. The flask was evacuated and backfilled with H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT for 3 h. LC-MS monitoring indicated the reaction was complete. The flask was evacuated and refilled with N (5 times). The resulting mixture was filtered through a Celite® pad. The filter cake was washed with MeOH (2 × 100 mL). The filtrate was concentrated under reduced pressure. This gave methyl (S)-2-amino-3-(3-(tert-butoxy)bicyclo[1.1.1]pentan-1-yl)propanoate. 13 H 23 NO3[M+H] + MS ESI calculated for 242, found 242. 1 H NMR (400MHz, chloroform-d): δ 3.67(s,3H),3.42(dd,J=6.8,5.5Hz,1H),2.00(dd,J=14.3,5.5Hz,1H),1.92-1.79(m,7H),1.21(s,9H).

[0274] Step 8: A 500 mL three-necked round-bottom flask was charged with a solution of methyl (S)-2-amino-3-(3-(tert-butoxy)bicyclo[1.1.1]pentan-1-yl)propanoate (7.20 g, 19.2 mmol) in THF (144.00 mL, 20 V). HO (72.00 mL, 10 V) was added to the flask. LiOH (0.60 g, 25 mmol) was added to the flask at RT. The resulting mixture was stirred under N at RT for 2 h. LC-MS monitoring indicated the reaction was complete. The reaction mixture was used in the next step without further isolation.

[0275] Step 9: The reaction mixture was cooled to 0 °C. NaHCO3 (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 under N2 at 0 °C for 2 h. LC-MS showed the reaction was complete. The mixture was adjusted to approximately pH 3-4 with 1 N HCl. The resulting mixture was extracted with EtOAc (3 × 150 mL). The organic phase was washed with water (3 × 100 mL) to remove residual HCl. The organic layer was washed with brine (200 mL) and dried over anh. Na2SO4. 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, 15-50% gradient of MeCN over 40 min; detector: UV 210 nm. The product-containing fractions were concentrated in vacuo to give (2S)-3-[3-(tert-butoxy)bicyclo[1.1.1]pentan-1-yl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoic acid. 27 H 31 NO5[M+Na] + MS ESI calculated for 472, found 472. 1 H NMR(400MHz,DMSO-d6):δ 12.57(s,1H),7.90(d,J=7.5Hz,2H),7.73(t,J=6.9Hz,2H),7.62(d,J=8.5 Hz,1H),7.42(td,J=7.5,1.2Hz,2H),7.32(tt,J=7.5,1.2Hz,2H),4.38-4.2 0(m,3H),4.03(q,J=7.1Hz,1H),3.93(ddd,J=12.7,6.4,2.7Hz,1H),2.00( dd,J=14.4,3.8Hz,1H),1.92-1.86(m,1H),1.85-1.75(m,6H),1.16(s,8H).

[0276] Synthetic Scheme 8 [ka]

[0277] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(tert-butoxycarbonyl)pyrimidin-5-yl)propanoic acid (Fmoc-AlaPyrim4COOtBu-OH) 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 NaHCO3 (12.8 g, 153.0 mmol) and 3-bromoprop-1-ene (11.1 g, 92.0 mmol) under an Ar atmosphere at 0 °C. The resulting mixture was stirred at RT 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 × 500 mL), dried over anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0 to 50% EtOAc in PE to give allyl (((9H-fluoren-9-yl)methoxy)carbonyl)-l-serinate. 21 H 21 NO5Na[M+Na] + MS ESI calculated for 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).

[0278] 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 successively to a mixture of allyl (((9H-fluoren-9-yl)methoxy)carbonyl)-l-serinate (9.6 g, 26.1 mmol) in DCM (960 mL) at RT. The reaction was stirred at RT for 4 h. The resulting solution was quenched with sat. Na2SO3 (300 mL) and extracted with DCM (2 × 500 mL). The organic layers were combined, washed with brine (2 × 400 mL), dried over anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-25% EtOAc in PE to give allyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate. 21 H 20 INO4Na[M+Na] + MS ESI calculated for 500.04, found 500.15. 1 H NMR (400MHz, chloroform-d):δ 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).

[0279] Step 3: Under an Ar atmosphere and at RT, DMAP (0.3 g, 2.5 mmol) and BocO (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). The reaction was stirred at 50 °C. The reaction was cooled to RT and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc in PE to give tert-butyl 5-bromopyrimidine-2-carboxylate. 11BrN2O2[M-tBu+H] + MS ESI calculated 203.00 / 205.00, found 202.95 / 204.95.

[0280] Step 4: A mixture of nickel(II) chloride ethylene glycol dimethyl ether complex (63.6 mg, 0.29 mmol) and pyridine-2-carboximidamide hydrochloride (91 mg, 0.58 mmol) in anh.DMA (20 mL) was heated at 50 °C for 1 h. A solution of allyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (1.38 g, 2.89 mmol), tert-butyl 5-bromopyrimidine-2-carboxylate (750 mg, 2.89 mmol), and TBAI (2.14 g, 5.79 mmol) in anh.DMA (25 mL) was added at RT. Activated zinc (378 mg, 5.79 mmol) was then added, and the mixture was stirred at RT for 2 h. The reaction was quenched with HO (200 mL) and extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anh. NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-45% EtOAc in PE to give tert-butyl (S)-5-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(allyloxy)-3-oxopropyl)pyrimidine-2-carboxylate. 30 H 32 N3O6[M+H] + MS ESI calculated for 530.22, found 530.25.

[0281] Step 5: At RT, Pd(PPh3)4 (0.16 g, 0.14 mmol) and phenylsilane (0.59 g, 5.44 mmol) were added to a stirred solution of tert-butyl (S)-5-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(allyloxy)-3-oxopropyl)pyrimidine-2-carboxylate (1.44 g, 2.72 mmol) in THF (25 mL). The resulting mixture was stirred at RT for 1 h. The solvent was concentrated under reduced pressure. The residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN (0.1% TFA); Gradient elution: 2-50%; Detector: UV 215 nm. The product-containing fractions 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. 27 H 28 N3O6[M+H] + MS ESI calculated for 490.19, found 490.15. 1 H NMR(300MHz,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),4.33-4.3 2(m,1H),4.20-4.18(m,3H),3.23-3.21(m,1H),2.98-2.97(m,1H),1.55(s,9H).

[0282] Synthetic Scheme 9 [ka]

[0283] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)propanoic acid (Fmoc-AlaPyrim4NBoc2-OH) Step 1: DMAP (0.17 g, 1.36 mmol) and BocO (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 RT under an Ar atmosphere. The mixture was stirred at RT. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-30% EtOAc in PE to give tert-butyl (tert-butoxycarbonyl) (5-iodopyrimidin-2-yl)carbamate. 14 H 21 IN3O4[M+H] + MS ESI calculated for 422.05, found 422.00. 1 H NMR (300 MHz, chloroform-d): δ 8.91 (s, 2H), 1.47 (s, 18H).

[0284] Step 2: A mixture of nickel(II) chloride ethylene glycol dimethyl ether complex (0.26 g, 1.19 mmol) and pyridine-2-carboximidamide hydrochloride (0.37 g, 2.37 mmol) in anh.DMA (100 mL) was heated at 50 °C for 1 h. A combination of allyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (5.67 g, 11.9 mmol), tert-butyl (tert-butoxycarbonyl)(5-iodopyrimidin-2-yl)carbamate (5.00 g, 11.9 mmol), and TBAI (8.77 g, 23.7 mmol) in anh.DMA (120 mL) was added at RT, followed by activated zinc (1.55 g, 23.7 mmol). The resulting mixture was stirred at RT for 4 h. The mixture was quenched with HO (600 mL) and extracted with EtOAc (2 × 400 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over anh. NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0–60% EtOAc in PE to give allyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)propanoate. 35 H 41 N4O8[M+H] + MS ESI calculated for 645.28, found 645.10. 1 H NMR (400 MHz, DMSO-d): δ 8.78(s,2H),8.02(d,J=8.6Hz,1H),7.88(d,J=7.5Hz,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=5.3Hz,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).

[0285] 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 allyl (S)-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 RT. The mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN (0.1% TFA); Gradient elution: 25-55%; Detector: UV 215 nm. The product-containing fractions 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. 32 H 37 N4O8[M+H] + MS ESI calculated for 605.25, found 605.10. 1 H NMR(400MHz,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).

[0286] Synthetic Scheme 10 [ka]

[0287] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (Fmoc-Bav(NHBoc)-OH) Step 1: Sodium hydroxide (1.0 g, 25 mmol) was added to a stirred solution of methyl (S)-2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate (1.0 g, 4.1 mmol) in DI water (40 mL) and THF (40 mL). The solution was stirred at RT for 2 h. The pH was adjusted to pH 7 by the addition of aqueous 1 n HCl solution.

[0288] Step 2: NaHCO3 (1.0 g, 1.9 mmol) and Fmoc-OSu (1.5 g, 4.5 mmol) were added to the solution from Step 1. The reaction mixture was stirred at RT for 4 h. The pH was adjusted to 2 with aq. 1N HCl solution and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid. C 25 H 30 N2O6[M+Na] + MS ESI calculated for 477.20, found 477.2; [M-Boc+H] + 354.16, actual value 355.2. 1 H NMR(600MHz,DMSO-d6):δ 12.59(s,1H),7.90(d,J=7.6Hz,2H),7.73(m,2H),7.61(d,J=8.5Hz,1H),7.42(t,J=7.5Hz,2H),7.3 2(t,J=7.4Hz,2H),6.56(s,1H),4.57(d,J=8.4Hz,1H),4.30-4.20(m,3H),1.36(s,9H),1.27(s,6H). 13 C NMR(151MHz,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.

[0289] Synthetic Scheme 11 [ka]

[0290] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)propanoic acid (Fmoc-BCP3COOtBu-OH) Step 1: Aq. 1N NaOH (1.0 m, 47.3 mL, 47.3 mmol) was added to a solution of S-benzyl-l-cysteine ​​(10.0 g, 47 mmol) in EtOH (150 mL) at RT. The mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure. The residue was suspended in pentane (300 mL). Pivalaldehyde (20.4 g, 237 mmol) and activated 3 Å molecular sieves were added at RT. The mixture was heated to reflux (ca. 40 °C) and stirred for 6 h. The mixture was cooled to RT and filtered. The filtrate was concentrated under reduced pressure. The residue was azeotropically dried with toluene (3 × 200 mL). The residue was dissolved in anh.DCM (300 mL), and CbzCl (13.5 mL, 95.0 mmol) was added at 0 °C. The mixture was stirred at RT. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-30% EtOAc in PE to give benzyl (2S,4R)-4-((benzylthio)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylate. 23 H 28 NO4S[M+H] + MS ESI calculated for 414.17, found 414.05. 1 H NMR (300 MHz, 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).

[0291] Step 2: mCPBA (10.9 g, 53.8 mmol) was added to a mixture of benzyl (2S,4R)-4-((benzylthio)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylate (8.9 g, 22 mmol) in DCM (180 mL) at 0 °C. The mixture was stirred at RT 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 anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0–35% EtOAc in PE to give benzyl (2S,4R)-4-((benzylsulfonyl)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylate. 23 H 28 NO6S[M+H] + MS ESI calculated for 446.16, found 446.05. 1 H NMR(400MHz,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).

[0292] Step 3: DBU (2.89 g, 19.0 mmol) was added to a solution of benzyl (2S,4R)-4-((benzylsulfonyl)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylate (7.70 g, 17.3 mmol) in DCM (155 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-30% EtOAc in PE to give benzyl (S)-2-(tert-butyl)-4-methylene-5-oxooxazolidine-3-carboxylate. 16 H 20 NO4[M+H] +MS ESI calculated for 290.13, found 290.10. 1 H NMR (300MHz, 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).

[0293] Step 4: tert-Butyl (Z)-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 RT. The reaction mixture was stirred at 40°C for 2 hours. The mixture was cooled to RT. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1-(tert-butyl)-3-methylbicyclo[1.1.1]pentane-1,3-dicarboxylate, 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).

[0294] Step 5: An aq. solution of LiOH (1.0 m, 46.8 mL, 47 mmol) was added to a mixture of 1-(tert-butyl)-3-methylbicyclo[1.1.1]pentane-1,3-dicarboxylate (5.3 g, 23 mmol) in THF (53 mL) at 0 °C. The mixture was stirred at RT for 3 h. The mixture was cooled to 0 °C, and the pH was adjusted to approximately 3–4 with aq. 1 N HCl (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 anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid, which was used in the next step without purification. C 11 H 15 O4[MH] - MS ESI calculated for 211.10, found 211.10. 1H NMR (300 MHz, methanol-d4): δ 2.21 (s, 6H), 1.44 (s, 9H).

[0295] Step 6: 3-(tert-Butoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.10 g, 5.18 mmol), 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (0.06 g, 0.07 mmol), and KHPO (1.51 g, 8.64 mmol) were added to a solution of benzyl (S)-2-(tert-butyl)-4-methylene-5-oxooxazolidine-3-carboxylate (1.00 g, 3.46 mmol) in DMF (33 mL). The mixture was irradiated with a 34 W blue LED lamp and stirred under Ar at RT. The mixture was diluted with water (150 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-25% EtOAc in PE to give benzyl (2S,4S)-4-((3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylate. 26 H 39 N2O6[M+NH4] + MS ESI calculated for 475.25, found 475.30. 1 H 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).

[0296] Step 7: An aq. solution of LiOH (1.0 m, 10.4 mL, 10 mmol) was added to a mixture of benzyl (2S,4S)-4-((3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-(tert-butyl)-5-oxooxazolidine-3-carboxylate (1.9 g, 4.2 mmol) in THF (40 mL) at 0 °C. The mixture was stirred at RT for 4 h. The mixture was cooled to 0 °C, and the pH value was adjusted to approximately 3–4 with aq. 1 m HCl (10 mL). The mixture was diluted with water (60 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure to give (S)-2-(((benzyloxy)carbonyl)amino)-3-(3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)propanoic acid, which was used in the next step without further purification. 21 H 31 N2O6[M+NH4] + MS ESI calculated for 407.22, found 407.10. 1 H NMR(400MHz,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).

[0297] Step 8: (S)-2-(((benzyloxy)carbonyl)amino)-3-(3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)propanoic acid (1.9 g, 4.9 mmol) was dissolved in THF (40 mL). The flask was evacuated and backfilled with N (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 H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT for 2 h. The flask was evacuated and backfilled with N (5 times). The resulting mixture was filtered through a Celite® pad. The filter cake was washed with THF (2 × 25 mL). The filtrate was concentrated under reduced pressure. The reaction mixture ((S)-2-amino-3-(3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)propanoic acid (1.2 g, 4.70 mmol, 96% yield) was used in the next step without further manipulation. 13 H 22 NO4[M+H] + MS ESI calculated for 256.15, found 256.15.

[0298] Step 9: A reaction mixture of (S)-2-amino-3-(3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)propanoic acid (1.2 g, 4.7 mmol) from Step 8 in THF (40 mL) was diluted with water (40 mL). NaHCO3 (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 RT. The mixture was filtered, and the filter cake was washed with THF (2 × 100 mL). The filtrate was partially concentrated under reduced pressure. The pH of the solution was adjusted to approximately 3–4 with aq. 1 N HCl (23.5 mL). The mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 150 mL), dried over anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-15% MeOH in DCM to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentan-1-yl)propanoic acid. 28 H 31 NO6Na[M+Na] + MS ESI calculated for 500.22, found 500.35. 1 H NMR(400MHz,methanol-d4):δ 7.79(d,J=7.6Hz,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).

[0299] Synthetic Scheme 12 [ka]

[0300] (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) 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-carboxylate hydrochloride (500 mg, 2.36 mmol) in water (15 mL). The mixture was stirred at RT for 2 h. The pH was adjusted to about 4 by adding 1 n aq. HCl, and then THF (15 mL) was added. Fmoc-OSu (0.95 g, 2.8 mmol) and saturated aqueous NaHCO3 (10 mL) were added to the mixture. The mixture was stirred at RT for 18 h. The resulting mixture was concentrated under reduced pressure. The mixture was adjusted to about pH 3 with 1 n aq. HCl, and then extracted with EtOAc (2 × 80 mL). The combined organic layers were dried over anh. Na2SO4, 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. 21 H 22 NO6[M+H] + MS ESI calculated for 384.1, found 384.1. 1 H NMR(600MHz,DMSO-d6):δ 12.19(s,1H),7.90(d,J=7.5Hz,2H),7.72(d,J=7.4Hz,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),4.2 2(t,J=6.9Hz,1H),4.00(t,J=5.2Hz,1H),3.76-3.69(m,1H),3.63(t,J=5.3Hz,1H),2.61-2.56(m,1H),2.21-2.14(m,1H),1.52-1.45(m,1H).

[0301] Synthetic Scheme 13 [ka]

[0302] (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2-carboxylic acid (Fmoc-dProc4CH2COOtBu-OH) Step 1: A mixture of 1-(tert-butyl) 2-methyl (R)-4-oxopyrrolidine-1,2-dicarboxylate (4.00 g, 16.4 mmol) and tert-butyl 2-(triphenyl-15-phosphanylidene)acetate (15.47 g, 41.1 mmol) in DCM (80 mL) was stirred and heated at 40 °C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-60% EtOAc in PE to give 1-(tert-butyl) 2-methyl (R,Z)-4-(2-(tert-butoxy)-2-oxoethylidene)pyrrolidine-1,2-dicarboxylate. 17 H 27 NO6Na[M+Na] + MS ESI calculated for 364.18, found 364.00.

[0303] Step 2: 1-(tert-butyl) 2-methyl(R,Z)-4-(2-(tert-butoxy)-2-oxoethylidene)pyrrolidine-1,2-dicarboxylate (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 H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-60% EtOAc in PE to give 1-(tert-butyl) 2-methyl(2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate. 17 H 30 NO6[M+H] + MS ESI calculated for 344.20, found 344.10.

[0304] Step 3: Chlorotrimethylsilane (18.6 mL, 146 mmol) and phenol (13.7 g, 146 mmol) were added to a mixture of 1-(tert-butyl) 2-methyl(2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (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 aqueous LiOH (50 mL, 50 mmol) to pH 8-9, then extracted with DCM (3 × 300 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anh.Na2SO4, filtered, and concentrated under reduced pressure to give methyl (2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2-carboxylate, which was used in the next step without purification. 12 H 22 NO4[M+H] + MS ESI calculated for 244.15, found 244.10.

[0305] Step 4: An aqueous 1 m LiOH solution (29 mL, 29 mmol) was added to a solution of methyl (2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2-carboxylate (3.54 g, 14.6 mmol) in THF (40 mL) at 0° C. The mixture was stirred at RT for 4 h. The mixture was acidified to approximately pH 7 with an aqueous 1 m HCl solution (30 mL) and then concentrated under reduced pressure to give (2R,4R)-4-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-2-carboxylic acid, which was used in the next step without purification. 11 H 20 NO4[M+H] + MS ESI calculated for 230.13, found 230.10.

[0306] Step 5: Fmoc-OSu (4.37 g, 13.0 mmol) and NaHCO3 (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 RT. The mixture was acidified to about pH 3 with aq. 1 m HCl solution (30 mL) and extracted with EtOAc (3 × 200 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN; Gradient elution: 30-80%; Detector: UV 210 nm. The product-containing fractions 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 ChiralPak® IG (250 × 30 mm, 5 μm, Daicel Chiral Technologies, West Chester, PA); Mobile phase: [1:1 MeOH in MeCN]; B%: 35-35%, 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]. 26 H 30 NO6[M+H] + MS ESI calculated for 452.20, found 452.20. 1H NMR(300MHz,methanol-d4):δ 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).

[0307] Synthetic Scheme 14 [ka]

[0308] (R)-5-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (Fmoc-dPro4cPr-OH) Step 1: A solution of HCl 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 RT for 4 h. The solution was then concentrated under reduced pressure. The crude product was used directly in the next step without purification.

[0309] 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 NaHCO3 (0.26 g, 3.1 mmol) until pH > 7. The resulting suspension was stirred at RT for 18 h. The organic volatiles were then removed under reduced pressure, and aq. 0.2 m ammonium bicarbonate (5 mL) was added. The mixture was extracted with EtOAc (15 mL, discarded), then acidified to approximately pH 2 by the addition of concentrated HCl (400 μL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Rp-flash column chromatography using the following conditions: Column: Flash C18 (30 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN (0.1% TFA); Gradient elution: 20-60% over 16 column volumes; Detector: UV 215 nm. Product-containing fractions were combined, concentrated under reduced pressure, and lyophilized to give (R)-5-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid. 22 H 21 NO4[M+H] + MS ESI calculated for 364.15, found 364.0. 1 H NMR(DMSO-d6):δ 7.90(d,J=7.4Hz,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).

[0310] Synthetic Scheme 15 [ka]

[0311] (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(dimethylamino)pyrrolidine-2-carboxylic acid hydrochloride (Fmoc-dProc4NMe2-OH) 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 1-(tert-butyl) 2-methyl(2R,4R)-4-aminopyrrolidine-1,2-dicarboxylate 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 RT under 1 atm. The mixture was filtered through a Celite® pad. The filter cake was washed with MeOH (3 x 200 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 10% MeOH in DCM to give 1-(tert-butyl) 2-methyl (2R,4R)-4-(dimethylamino)pyrrolidine-1,2-dicarboxylate. 13 H 25 N2O4[M-Boc+H] + MS ESI calculated for 173.17, found 173.10.

[0312] Step 2: LiOH (36 mL, 36 mmol, 1 n in water) was added to a mixture of 1-(tert-butyl) 2-methyl(2R,4R)-4-(dimethylamino)pyrrolidine-1,2-dicarboxylate (3.0 g, 11 mmol) in THF (36 mL). The resulting mixture was stirred at RT for 2 h. The mixture was acidified to pH 5 with aq. 1 n HCl. The filtrate was concentrated in vacuo to give the crude product. The crude product was used directly in the next step.

[0313] Step 3: At RT, TFA (11 mL, 140 mmol) was added to a stirred mixture of (2R,4R)-1-(tert-butoxycarbonyl)-4-(dimethylamino)pyrrolidine-2-carboxylic acid (2.8 g, 11 mmol) in DCM (33 mL). The resulting mixture was stirred at RT for 1 h. The solvent was evaporated under reduced pressure to give crude (2R,4R)-4-(dimethylamino)pyrrolidine-2-carboxylic acid. CH 15 N2O2[M+H] + MS ESI calculated for 159.11, found 159.20.

[0314] Step 4: At RT, 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). The resulting mixture was stirred at RT for 4 h. The pH was adjusted to 3 with 1 n HCl. The solvent was concentrated under reduced pressure, and the residue was purified by RP-flash column chromatography using the following conditions: 330 g C18 column, 2% to 2% in 5 min, 2% to 60% in 30 min, MeCN (0.05% TFA) in water to give (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(dimethylamino)pyrrolidine-2-carboxylic acid. 22 H 25 N2O4[M-HCl+H] + MS ESI calculated for 381.17, found 381.10. 1 H NMR(300MHz,DMSO-d6):δ 7.92-7.86(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).

[0315] Synthetic Scheme 16 [ka]

[0316] (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(((tert-butoxycarbonyl)amino)-methyl)pyrrolidine-2-carboxylic acid (Fmoc-dProtCHNHBoc-OH) Step 1: A solution of 1-(tert-butyl) 2-methyl (2R,4S)-4-cyanopyrrolidine-1,2-dicarboxylate (1.1 g, 4.3 mmol) in methanol (20 mL) was degassed with N. Raney® nickel (50 mg, 0.85 mmol) was added to the solution under N. The mixture was then stirred under hydrogen (1 atm) at RT for 6 hours. The mixture was filtered through Celite® and washed with methanol (2 × 30 mL). The filtrate was concentrated under reduced pressure to give 1-(tert-butyl) 2-methyl (2R,4R)-4-(aminomethyl)pyrrolidine-1,2-dicarboxylate. C 12 H 23 N2O4-Boc [M-Boc+H] + MS ESI calculated for 159.16, found 159.15.

[0317] Step 2: NaHCO3 (1.62 g, 19.3 mmol) and Cbz-OSu (1.16 g, 4.63 mmol) were added to a solution of 1-(tert-butyl) 2-methyl(2R,4R)-4-(aminomethyl)pyrrolidine-1,2-dicarboxylate (1.05 g, 3.86 mmol) in THF (20 mL) and water (20 mL) at RT. The mixture was stirred at RT for 4 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anh.Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in PE to give 1-(tert-butyl) 2-methyl(2R,4R)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-1,2-dicarboxylate. C20 H 29 N2O6[M+H] + MS ESI calculated for 393.19, found 393.05.

[0318] Step 3: TFA (5.0 mL, 65 mmol) was added to a solution of 1-(tert-butyl) 2-methyl(2R,4R)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-1,2-dicarboxylate (1.4 g, 2.5 mmol) in DCM (10 mL) at RT. The mixture was stirred at RT for 2 hours. The mixture was concentrated under reduced pressure to give methyl (2R,4S)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-2-carboxylate, which was used in the next step without purification. C 15 H 21 N2O4[M+H] + MS ESI calculated for 293.14, found 293.10.

[0319] Step 4: An aqueous 1 m solution of LiOH (4.9 mL, 4.9 mmol) was added to a solution of methyl (2R,4S)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-2-carboxylate (1.2 g, 2.5 mmol) in THF (10 mL) at RT. The mixture was stirred at RT for 2 h. The mixture was then acidified to approximately pH 5 with an aqueous 1 m HCl solution. 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. 14 H 19 N2O4+MeCN [M+MeCN+H] + MS ESI calculated for 320.13, found 319.75.

[0320] 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 RT. The mixture was stirred at RT for 2 h. The mixture was then acidified to approximately pH 5 with aq. 1 m HCl solution and then concentrated under reduced pressure. The residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18 (80 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN; Gradient elution: 2-40%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-2-carboxylic acid. 29 H 29 N2O6[M+H] + MS ESI calculated for 501.19, found 501.10.

[0321] Step 6: (2R,4R)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-((((benzyloxy)carbonyl)amino)methyl)pyrrolidine-2-carboxylic acid (820 mg, 1.64 mmol) and BocO (536 mg, 2.46 mmol) were dissolved in THF (15 mL). The flask was evacuated and backfilled with N (5 times). Pd / C (50 mg, 0.5 mmol, dry, 10 wt%) was added to the flask. The flask was evacuated and backfilled with H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT for 6 h. The flask was evacuated and backfilled with N (5 times). The resulting mixture was filtered through a Celite® pad. The filter cake was washed with THF (2 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Rp-flash column chromatography using the following conditions: Column: Flash C18 (80 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN; Gradient elution: 2-40%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(((tert-butoxycarbonyl)amino)methyl)pyrrolidine-2-carboxylic acid. 26 H 34 N3O6[M+NH4] + MS ESI calculated for 484.21, found 484.25. 1 H NMR (300MHz, 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).

[0322] Synthetic Scheme 17 [ka]

[0323] 2-(((3S,5R)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-5-carboxypyrrolidin-3-yl)amino)-N,N,N-trimethyl-2-oxoethan-1-aminium chloride (Fmoc-dProt4NHC2 acid NMe3-OH) Step 1: A mixture of tert-butyl 2-bromoacetate (1.9 g, 9.7 mmol) in a solution of trimethylamine (2 n in THF, 10 mL, 20 mmol) was stirred and heated on at 50 °C. The mixture was cooled to RT 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. CH 20 NO2 + [M] + MS ESI calculated for 174.15, found 174.10.

[0324] 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 RT 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. CH 12 NO2 + [M] + MS ESI calculated for 118.09, found 118.05.

[0325] 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 1-(tert-butyl) 2-methyl(2R,4S)-4-aminopyrrolidine-1,2-dicarboxylate (5.25 g, 21.5 mmol) in DMSO (33 mL) was stirred at RT. The residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18; Mobile phase A: water (0.1% HCl), Mobile phase B: MeCN; Gradient elution: 5-90%; Detector: UV 210 nm. The product-containing fractions 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. 16 H 30 N3O5 + [M] + MS ESI calculated for 344.22, found 344.05.

[0326] Step 4: An aq. 1 m LiOH solution (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 RT. The mixture was stirred at RT for 4 h. The mixture was acidified to approximately pH 2-3 with aq. 1 m HCl solution 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. 10 H 20 N3O3 + [M] + MS ESI calculated for 230.15, found 230.15.

[0327] Step 5: Fmoc-OSu (3.56 g, 10.6 mmol) and NaHCO3 (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 RT. The mixture was stirred at RT. The pH of the mixture was adjusted to approximately pH 3 with 1 m HCl and concentrated under reduced pressure. The residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18; Mobile phase A: water (0.1% HCl), Mobile phase B: MeCN; Gradient elution: 5-70%; Detector: UV 210 nm. The product-containing fractions 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. 25 H 30 N3O5 + [M] + MS ESI calculated for 452.22, found 452.15. 1 H NMR (400MHz, methanol-d4):δ 7.91-7.75(m,2H),7.67-7.63(m,2H),7.50-7.18(m,4H),4.60-4.02(m,7 H),3.86-3.79(m,1H),3.43-3.41(m,2H),3.34(s,8H),2.40-2.31(m,2H).

[0328] Synthetic Scheme 18 [ka]

[0329] (2R,4S)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-(dimethylamino)pyrrolidine-2-carboxylic acid trifluoroacetic acid (Fmoc-dProt4NMe2-OH) Step 1: Pd / C (1.089 g, 1.0 mmol, 10 wt%) was added to a solution of 1-(tert-butyl) 2-methyl(2R,4S)-4-aminopyrrolidine-1,2-dicarboxylate (2.5 g, 10 mmol) in MeOH (30 mL). Then, formaldehyde (2.5 mL, 10 mmol, 37 wt% in water) was added under N. The reaction mixture was degassed with dihydrogen (3 times) and stirred under 1 atm at RT on hydrogen. The mixture was filtered through a Celite® pad. The filter cake was further washed with MeOH (3 × 50 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give 1-(tert-butyl) 2-methyl(2R,4S)-4-(dimethylamino)pyrrolidine-1,2-dicarboxylate. C 13 H 25 N2O4[M+H] + MS ESI calculated for 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).

[0330] Step 2: LiOH (15 mL, 15 mmol, 1N in water) was added to a mixture of 1-(tert-butyl) 2-methyl(2R,4S)-4-(dimethylamino)pyrrolidine-1,2-dicarboxylate (1.7 g, 6.2 mmol) in THF (15 mL). The resulting mixture was stirred at RT for 2 h. The mixture was acidified to pH 5 with 1N HCl solution. The solvent was concentrated in vacuo to give the crude product, which was used directly in the next step.

[0331] Step 3: At RT, TFA (10 mL, 5.4 mmol) was added to a stirred mixture of (2R,4S)-1-(tert-butoxycarbonyl)-4-(dimethylamino)pyrrolidine-2-carboxylic acid (1.4 g, 5.4 mmol) in DCM (30 mL). The resulting mixture was stirred at RT for 1 h. The solvent was evaporated under reduced pressure to give crude (2R,4S)-4-(dimethylamino)pyrrolidine-2-carboxylic acid. CH 13 N2O2[MH] - MS ESI calculated for 157.11, found 157.10.

[0332] Step 4: At RT, NaHCO3 (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). The resulting mixture was stirred at RT. The pH was adjusted to 3 with 1 N HCl. The solvent was concentrated under reduced pressure and the residue was purified by Rp-flash column chromatography using the following conditions: 330 g C18 column, 2-2% in 5 min, 2-50% in 30 min, MeCN (0.05% TFA) in water to give (3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxy-N,N-dimethylpyrrolidin-3-aminium 2,2,2-trifluoroacetate. 25 H 25 N2O4[M+H] + MS ESI calculated for 381.17, found 381.10. 1 H NMR(300MHz,DMSO-d6):δ 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(282MHz,DMSO-d6):δ-73.73.

[0333] Synthetic Scheme 19 [ka]

[0334] (3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxy-N,N,N-trimethylpyrrolidine-3-aminium chloride (Fmoc-dProt4NMe3-OH) Step 1: NaHCO3 (8.3 g, 98 mmol) and iodomethane (4.6 mL, 73.7 mmol) were added to a solution of 1-(tert-butyl) 2-methyl(2R,4S)-4-aminopyrrolidine-1,2-dicarboxylate (3.0 g, 12.3 mmol) in MeOH (30 mL) at RT. The mixture was stirred at RT. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM, filtered, and the filtrate was concentrated under reduced pressure to give (3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)-N,N,N-trimethylpyrrolidin-3-aminium iodide, which was used in Step 2 without purification. 14 H 27 N2O4[M] + MS ESI calculated for 287.20, found 287.15.

[0335] Step 2: At RT, an aqueous 1 m LiOH solution (22 mL, 22 mmol) was added to a solution of (3S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)-N,N,N-trimethylpyrrolidine-3-aminium iodide (6.5 g, 11 mmol) in THF (23 mL). The mixture was stirred at RT for 4 hours. The mixture was acidified to approximately pH 5 with 1 m aqueous HCl and then concentrated under reduced pressure to give (3S,5R)-1-(tert-butoxycarbonyl)-5-carboxy-N,N,N-trimethylpyrrolidine-3-aminium chloride, which was used in Step 3 without further purification. 13 H 25 N2O4[M] +MS ESI calculated for 273.18, found 273.15.

[0336] Step 3: TFA (20 mL, 260 mmol) was added to a mixture of (3S,5R)-1-(tert-butoxycarbonyl)-5-carboxy-N,N,N-trimethylpyrrolidine-3-aminium chloride (6.6 g, 11 mmol) in DCM (20 mL) at RT. The mixture was stirred at RT 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-trimethylpyrrolidine-3-aminium salt, which was used in Step 4 without purification. CH 17 N2O2[M] + MS ESI calculated for 173.13, found 173.25.

[0337] Step 4: NaHCO3 (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 salt (8.1 g, 14 mmol) in THF (40 mL) and water (40 mL) at RT. The mixture was stirred at RT for 4 h. The mixture was acidified to approximately pH 5 with aqueous 1N HCl solution and then concentrated under reduced pressure. The residue was suspended in a 9:1 (v / v) mixture of DCM and MeOH, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (2 mM HCl), Mobile phase B: MeCN; Gradient elution: 2-35%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give (3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxy-N,N,N-trimethylpyrrolidine-3-aminium chloride. 23 H 27 N2O4[M] + MS ESI calculated for 395.20, found 395.20. 1H NMR(300MHz,DMSO-d6):δ 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).

[0338] Synthetic Scheme 20 [ka]

[0339] (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-2-carboxylic acid (Fmoc-dProt4OAcO(tBu)-OH) Step 1: 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 RT for 12 h. The reaction solution was diluted with DI water (100 mL) and extracted with MTBE (2 × 150 mL). The pH of the aqueous solution was adjusted to approximately pH 2 by the addition of aqueous 1 n HCl solution. The solution was extracted with EtOAc (2 × 150 mL). The combined organic phases were washed with brine (50 mL), dried over anh. 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).

[0340] Step 2: To a solution of (2R,4S)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (36.0 g, 136 mmol) in anh.DMF (240 mL) was added NaHCO3 (34.2 g, 407 mmol), NaI (2.03 g, 13.6 mmol), and BnBr (19.3 mL, 162 mmol). The mixture was stirred at RT for 12 h. The reaction solution was diluted with DI water (100 mL) and extracted with EtOAc (2 × 150 mL). The combined organic phases were washed with brine (50 mL), dried over anh.Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0–60% EtOAc in PE to give dibenzyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate. 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).

[0341] Step 3: NaH (2.45 g, 61 mmol, 60 wt% dispersion in mineral oil) was added to a solution of tert-butyl 2-bromoacetate (22.3 mL, 150 mmol) and TBAI (1.51 g, 4.08 mmol) in anh.THF (30 mL). The suspension was cooled to -10 °C. A solution of (2R,4S)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (14.5 g, 40.8 mmol) in anh.THF (30 mL) was added dropwise to the mixture, maintaining the temperature below -10 °C. After the addition, the reaction mixture was allowed to warm to RT and stirred at RT for 12 h. The reaction mixture was slowly poured into frozen sat. NH4Cl (75 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 1 to 50% EtOAc in PE to give dibenzyl (2R,4S)-4-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-1,2-dicarboxylate. 1 H 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).

[0342] Step 4: A solution of dibenzyl (2R,4S)-4-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-1,2-dicarboxylate (18.0 g, 48.9 mmol) in a 1:1 (v / v) mixture of EtOAc and EtOH (460 mL) was hydrogenated over Pd / C (1.0 g, 10 wt%) under 50 psi of dihydrogen at 50° C. for 24 hours. The reaction mixture was filtered through a Celite® pad, and the filtrate was concentrated to give the crude product (2R,4S)-4-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-2-carboxylic acid. 11 H 19 NO5[M+H] +MS ESI calculated for 246.13, found 246.2. 1 H NMR (400 MHz, methanol-d4): δ 4.32-4.29 (m, 1H), 4.17-4.12 (m, 1H), 4.06-4.04 (t, J = 8 Hz, 2H), 3.46-3.36 (m, 1H), 2.55-2.49 (m, 1H), 2.06-1.99 (m, 1H), 1.47 (s, 9H).

[0343] Step 5: NaHCO3 (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 RT for 5 h. The reaction solution was diluted with DI water (50 mL) and extracted with MTBE (2 × 30 mL). The pH was adjusted to 2 with aq. 1N HCl solution and extracted with EtOAc (2 × 80 mL). The combined organic layers were washed with brine (50 mL), dried over anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 1 to 100% EtOAc in PE to give (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2-(tert-butoxy)-2-oxoethoxy)pyrrolidine-2-carboxylic acid. 1 H NMR (400MHz, 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,2 H),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).

[0344] Synthetic Scheme 21 [ka]

[0345] 2-(((3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxypyrrolidin-3-yl)oxy)-N,N,N-trimethylethane-1-aminium chloride (Fmoc-dProt4OEtNMe3-OH) 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 RT. The mixture was stirred at 40 °C for 1 hour. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-70% EtOAc in PE to give 1-((9H-fluoren-9-yl)methyl) 2-(tert-butyl)(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate. 24 H 27 NO5Na[M+Na] + MS ESI calculated for 432.19, found 432.05.

[0346] Step 2: Benzyl aziridine-1-carboxylate (4.85 g, 27.4 mmol) was added to a mixture of 1-((9H-fluoren-9-yl)methyl) 2-(tert-butyl)(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (11.2 g, 27.4 mmol) in toluene (110 mL) at 0° C. The mixture was stirred at 0° C. for 30 minutes. Boron trifluoride diethyl etherate (0.776 g, 5.47 mmol) was added dropwise to the mixture over 1 hour at 0° C. The mixture was stirred at RT for an additional 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-70% EtOAc in PE to give 1-((9H-fluoren-9-yl)methyl) 2-(tert-butyl)(2R,4S)-4-(2-(((benzyloxy)carbonyl)amino)ethoxy)pyrrolidine-1,2-dicarboxylate. 34 H 38N2O7Na[M+Na] + MS ESI calculated for 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).

[0347] Step 3: Sodium iodide (4.85 g, 32.4 mmol) and chlorotrimethylsilane (3.52 g, 32.4 mmol) were added to a solution of 1-((9H-fluoren-9-yl)methyl) 2-(tert-butyl)(2R,4S)-4-(2-((benzyloxy)carbonyl)amino)ethoxy)pyrrolidine-1,2-dicarboxylate (1.9 g, 3.2 mmol) in MeCN (20 mL) at RT. The mixture was stirred at RT. The mixture was concentrated under reduced pressure, and the residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18 (40 g); Mobile phase A: water (0.05% TFA), Mobile phase B: MeCN; Gradient elution: 2-30%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(2-aminoethoxy)pyrrolidine-2-carboxylic acid. 22 H 25 N2O5[M+H] + MS ESI calculated for 397.17, found 397.40.

[0348] Step 4: Iodomethane (3.04 g, 21.4 mmol) and NaHCO3 (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 RT. The mixture was stirred at RT. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (0.1% HCl), Mobile phase B: MeCN; Gradient elution: 2-70%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give 2-(((3S,5R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-carboxypyrrolidin-3-yl)oxy)-N,N,N-trimethylethane-1-aminium chloride. 25 H 31 N2O5[M] + MS ESI calculated for 439.22, found 439.15. 1 H NMR (400MHz, methanol-d4):δ 7.82-7.59(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).

[0349] Synthetic Scheme 22 [ka]

[0350] (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(1-trityl-1H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid (Fmoc-dProt4Tet(Trt)-OH) Step 1: Tosyl chloride (31.1 g, 163 mmol) and pyridine (19.8 mL, 245 mmol) were added to a solution of 1-(tert-butyl) 2-methyl(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (20.0 g, 82 mmol) in CHCl (200 mL) at RT. The mixture was stirred at RT for 24 hours. 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 anh.NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in PE to give 1-(tert-butyl) 2-methyl(2R,4R)-4-(tosyloxy)pyrrolidine-1,2-dicarboxylate. C 18 H 25 NO7SNa[M+Na] + MS ESI calculated for 422.14, found 422.05.

[0351] Step 2: A mixture of 1-(tert-butyl) 2-methyl (2R,4R)-4-(tosyloxy)pyrrolidine-1,2-dicarboxylate (15 g, 38 mmol) and tetrabutylammonium cyanide (25 g, 94 mmol) in DMSO (150 mL) was heated 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 anh.Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in PE to give 1-(tert-butyl) 2-methyl (2R,4S)-4-cyanopyrrolidine-1,2-dicarboxylate. C 12 H 18 N2O4-Boc[M-Boc] + MS ESI calculated for 155.13, found 155.10. 1H 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).

[0352] Step 3: A mixture of 1-(tert-butyl) 2-methyl (2R,4S)-4-cyanopyrrolidine-1,2-dicarboxylate (3.5 g, 14 mmol), dibutylstannanediyl diacetate (4.83 g, 13.8 mmol), and trimethylsilyl azide (3.65 mL, 27.5 mmol) in toluene (30 mL) was heated and stirred at 50 °C. The mixture was concentrated under reduced pressure. The residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (0.05% TFA), Mobile phase B: MeCN; Gradient elution: 2-26%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give 1-(tert-butyl) 2-methyl(2R,4S)-4-(1H-tetrazol-5-yl)pyrrolidine-1,2-dicarboxylate. 12 H 19 NO4Na[M+Na] + MS ESI calculated for 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).

[0353] Step 4: HCl solution (4.0 m in 1,4-dioxane, 30 mL, 120 mmol) was added to a solution of 1-(tert-butyl) 2-methyl (2R,4S)-4-(1H-tetrazol-5-yl)pyrrolidine-1,2-dicarboxylate (2.8 g, 9.4 mmol) in THF (30 mL) at RT. The mixture was stirred at RT for 8 h. The mixture was concentrated under reduced pressure to give methyl (2R,4S)-4-(1H-tetrazol-5-yl)pyrrolidine-2-carboxylate, which was used in Step 5 without purification. CH 12 NO2[M+H] + MS ESI calculated for 198.09, found 198.05.

[0354] Step 5: An aqueous solution of LiOH (16.5 mL, 16.5 mmol) was added to a solution of methyl (2R,4S)-4-(1H-tetrazol-5-yl)pyrrolidine-2-carboxylate (2.5 g, 8.2 mmol) in THF (17 mL) at RT. The mixture was stirred at RT for 2 h. The mixture was acidified to approximately pH 5 with 1 m HCl and then concentrated under reduced pressure to give (2R,4S)-4-(1H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid, which was used in Step 6 without purification. CH 10 NO2[M+H] + MS ESI calculated for 184.08, found 184.05.

[0355] Step 6: NaHCO3 (2.98 g, 35.5 mmol) and Fmoc-OSu (2.63 g, 7.81 mmol) were added to a solution of (2R,4S)-4-(1H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid (2.6 g, 7.1 mmol) in THF (20 mL) and water (20 mL) at RT. The mixture was stirred at RT for 4 h. The mixture was acidified to approximately pH 5 with 1 m HCl and then concentrated under reduced pressure. The residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (0.05% TFA), Mobile phase B: MeCN; Gradient elution: 2-45%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(1H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid. 21 H 20 N5O4[M+H] + MS ESI calculated for 406.14, found 406.05.

[0356] Step 7: TEA (1.34 mL, 9.62 mmol) and trityl 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 RT and stirred for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by Rp-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water, Mobile phase B: MeCN; Gradient elution: 2-72%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give (2R,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(1-trityl-1H-tetrazol-5-yl)pyrrolidine-2-carboxylic acid. 40 H 32 N5O4[MH] -MS ESI calculated for 646.25, found 646.20. 1 H NMR(300MHz,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).

[0357] Synthetic Scheme 23 [ka]

[0358] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2-amino-2-oxoethyl)phenyl)propanoic acid (Fmoc-F3MCONH2-OH) Step 1: A solution of NiCl·glyme (0.81 g, 3.69 mmol) and 1,10-phenanthroline (0.67 g, 3.69 mmol) in anh.DMA (50 mL) was heated at 50 °C for 30 min. A mixture of tert-butyl 2-(3-bromophenyl)acetate (5.00 g, 18.44 mmol), benzyl (R)-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 anh.DMA (50 mL) was added at RT. Activated 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 using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN; Gradient elution: 5-82%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give benzyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2-(tert-butoxy)-2-oxoethyl)phenyl)propanoate. 37 H 38 NO6[M+H] + MS ESI calculated for 592.26, found 592.45. 1 H NMR (300MHz, chloroform-d):δ 7.76(d,J=7.5Hz,2H),7.56(d,J=7.5Hz,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=5.9Hz,2H),2.87-2.61(m,2H),1.42(s,9H).

[0359] Step 2: TFA (20 mL) was added to a stirred solution of benzyl (S)-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. C 33 H 30 NO6[M+H] + MS ESI calculated for 536.20, found 536.10.

[0360] Step 3: At RT, NH4Cl (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). The mixture was stirred at RT 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 anh.Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH in DCM (10:1; v / v) to give benzyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2-amino-2-oxoethyl)phenyl)propanoate. 33 H 31 N2O5[M+H] + MS ESI calculated for 535.22, found 535.40.

[0361] Step 4: Benzyl (S)-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 N (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 H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT for 3 h. The flask was evacuated and backfilled with N (5 times). The resulting mixture was filtered through a Celite® pad. The filter cake was washed with THF (2 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was recrystallized from MeCN to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(2-amino-2-oxoethyl)phenyl)propanoic acid. 26 H 25 N2O5[M+H] + MS ESI calculated for 445.17, found 445.15. 1 H NMR(300MHz,methanol-d4):δ 7.77(d,J=7.5Hz,2H),7.59(d,J=7.5Hz,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).

[0362] Synthetic Scheme 24 [ka]

[0363] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2(dimethylamino)ethoxy)phenyl)propanoic acid (Fmoc-Me2AEF-OH) 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 RT. The solution was stirred at RT for 1 h. The solution was then concentrated under reduced pressure and the residual TFA was co-evaporated with toluene (3 × 15 mL) in vacuo. The crude product was used directly without further purification.

[0364] 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 RT. The reaction mixture was stirred at RT. The reaction mixture was quenched with a few drops of 1N HCl solution and concentrated in vacuo. The residue was purified by RP-flash column chromatography using the following conditions: Luknova® SuperSep® 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: 10–90% over 10 column volumes, flow rate: 40 mL / min; detector: UV 215 nm. The product-containing fractions 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. 28 H 30 N2O5[M+H] + MS ESI calculated mass 475.22, found mass 475.3. 1H NMR(400MHz,DMSO-d6):δ 12.77(br.s 1H),9.77(br.s,1H),7.89(d,J=7.5Hz,2H),7.72(d,J=8.6Hz,1H),7.66(d,J=7.0Hz,2H),7.42(t,J=7.3Hz,2H),7.34-7.28(m,2H),7.23(d ,J=8.1Hz,2H),6.90(d,J=8.3Hz,2H),4.30-4.21(m,2H),4.21-4.08(m,4H),3.51-3.47(m,2H),3.03(dd,J=3.7,13.8Hz,1H),2.84(s,6H).

[0365] Synthetic Scheme 25 [ka]

[0366] (S)-4-(((9H-fluoren-9-yl)methoxy)carbonyl)-6,6-dimethylmorpholine-3-carboxylic acid (Fmoc-Morpip6diMe-OH) At RT, Fmoc-OSu (1.7 g, 5.1 mmol) was added, followed by NaHCO (1.8 g, 21 mmol), 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). The resulting mixture was stirred at RT. The pH was adjusted to 5 with 1N HCl and extracted with EtOAc (2 × 70 mL). The combined organic layers were washed with brine (50 mL), dried over anh. NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0–10% MeOH in DCM to give (S)-4-(((9H-fluoren-9-yl)methoxy)carbonyl)-6,6-dimethylmorpholine-3-carboxylic acid. 22 H 23 NO5[M+H] + MS ESI calculated for 382.16, found 382.2. 1H NMR(600MHz,DMSO-d6):δ 13.08(s,1H),7.90(t,J=7.3Hz,2H),7.67-7.56(m,2H),7.41(t,J=7.2Hz,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=10.9Hz,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 C NMR(151MHz,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.

[0367] Synthetic Scheme 26 [ka]

[0368] N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)glycine (Fmoc-NEtCONHTrtG-OH) 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 RT for 10 min. Then, 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 RT for an additional 15 min. After quenching with aq. 5% trisodium citrate dihydrate solution and stirring for an additional 15 min, the organic solvent was concentrated in vacuo, resulting in a precipitate. The product was collected by filtration, triturated with water, followed by EtO, and dried to give N-trityl acrylamide. C22 H 20 NO[M+H] + MS ESI calculated for 314.4, found 314.3. 1 H 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).

[0369] 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 RT 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. The mixture was cooled to RT and acidified with AcOH (1.5 mL), resulting in a precipitate upon standing. The residue was filtered and triturated with MeOH followed by DCM to give (3-oxo-3-(tritylamino)propyl)glycine. C 24 H 25 N2O3[M+H] + MS ESI calculated for 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).

[0370] 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 RT. The mixture was partially concentrated in vacuo to remove acetone and neutralized to pH 7 by the addition of 1 nHCI. The mixture was extracted with EtOAc (2 x 50 mL), washed with brine (50 mL), dried over anh. 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. C 39 H 35 N2O5[M+H] + MS ESI calculated for 611.71, found 611.50. 1 H NMR(500MHz,DMSO-d6):δ 12.75(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,2 H),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).

[0371] Synthetic Scheme 27 [ka]

[0372] N-(2-(1,3,4-oxadiazol-2-yl)ethyl)-N-(((9H-fluoren-9-yl)methoxy)carbonyl)glycine (Fmoc-NEt3OxadG-OH) Step 1: At RT, 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-aminopropanoate hydrochloride (16.8 g, 92 mmol) in MeCN (60 mL). The solution was stirred at RT for 4 h. The reaction was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 0-80% EtOAc in PE to give tert-butyl 3-((2-(benzyloxy)-2-oxoethyl)amino)propanoate. C 16 H 23 NO4Na[M+Na] + MS ESI calculated for 316.16, found 316.25. 1 H 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).

[0373] Step 2: At RT, Fmoc-OSu (6.4 g, 19.0 mmol) and NaHCO3 (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 HO (60 mL). The reaction was stirred at RT. The mixture was extracted with EtOAc (3 × 250 mL). The combined organic layers were washed with brine (250 mL) and dried over anh. Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18; Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN; Gradient elution: 5–70%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(2-(benzyloxy)-2-oxoethyl)amino)propanoate. 31 H 33 NO6Na[M+Na] +MS ESI calculated for 538.23, found 538.15.

[0374] Step 3: At RT, 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). The solution was stirred at RT 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. C 27 H 26 NO6[M+H] + MS ESI calculated for 460.17, found 460.30.

[0375] Step 4: Isobutyl carbonochloridate (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, formic acid hydrazide (1.0 g, 16.3 mmol) was added, and the resulting mixture was allowed to warm slowly to RT. After 1 h, the reaction mixture was quenched with 0.5 m HCl and extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (250 mL), dried over anh.NaSO, 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 benzyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-(2-formylhydrazineyl)-3-oxopropyl)glycinate. 28 H28 N3O6[M+H] + MS ESI calculated for 502.19, found 502.35.

[0376] Step 5: At RT, (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess's reagent, 2.5 g, 10.6 mmol) was added to a solution of benzyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-(2-formylhydrazinyl)-3-oxopropyl)glycinate (5.3 g, 10.6 mmol) in toluene (53 mL). The mixture was stirred at 110° C. for 1 hour. The reaction was cooled to RT and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-70% EtOAc in PE to give benzyl N-(2-(1,3,4-oxadiazol-2-yl)ethyl)-N-(((9H-fluoren-9-yl)methoxy)carbonyl)glycinate. 28 H 26 N3O5[M+H] + MS ESI calculated for 484.18, found 484.20.

[0377] Step 6: Benzyl N-(2-(1,3,4-oxadiazol-2-yl)ethyl)-N-(((9H-fluoren-9-yl)methoxy)carbonyl)glycinate (3.0 g, 6.2 mmol) was dissolved in EtOAc (60 mL). The flask was evacuated and refilled with N (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 H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT for 2 h. The flask was evacuated and refilled with N (5 times). The resulting mixture was filtered through a Celite® pad. The filter cake was washed with EtOAc (2 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was recrystallized from EtO to give N-(2-(1,3,4-oxadiazol-2-yl)ethyl)-N-(((9H-fluoren-9-yl)methoxy)carbonyl)glycine. 21 H 20 N3O5[M+H]+ MS ESI calculated for 394.13, found 393.95. 1 H NMR(300MHz,DMSO-d6):δ 12.71(s,1H),9.14(d,J=3.8Hz,1H),7.98-7.72(m,2H),7.90-7.80(m,2H),7.46-7.15(m,4H),4.42(d,J=5.7Hz,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).

[0378] Synthetic Scheme 28 [ka]

[0379] N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)-l-alanine (Fmoc-NEtCONHTrt-OH) 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 RT. The reaction was stirred and heated at 110 °C using a Dean-Stark apparatus. The resulting solution was cooled to RT and quenched with aqueous saturated NaHCO 3 . The aqueous solution was extracted with EtOAc (3 × 1000 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0–35% EtOAc in PE to give N-trityl acrylamide. C 22 H 20 NO[M+H] + MS ESI calculated for 314.15, found 314.20. 1H NMR (300 MHz, chloroform-d): δ 7.37-7.15 (m, 15H), 6.26-6.12 (m, 2H), 5.62-5.60 (m, 1H).

[0380] Step 2: At RT, TEA (5.6 mL, 40.2 mmol) was added to a suspension of benzyl l-alaninate hydrochloride (8.7 g, 40.2 mmol) in toluene (150 mL). The resulting mixture was stirred at RT for 10 minutes. Then, N-trityl acrylamide (8.4 g, 26.8 mmol) was added to the mixture. The reaction mixture was stirred and heated at 100 °C. The volatiles were concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-65% EtOAc in PE to give benzyl (3-oxo-3-(tritylamino)propyl)-l-alaninate. 32 H 33 N2O3[M+H] + MS ESI calculated for 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).

[0381] Step 3: At RT, DIPEA (6.8 mL, 39.0 mmol) and Fmoc-OSu (5.3 g, 15.6 mmol) were added to a solution of benzyl (3-oxo-3-(tritylamino)propyl)-l-alaninate (6.4 g, 13.0 mmol) in DCM (60 mL). The reaction mixture was stirred at RT and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-45% EtOAc in PE to give benzyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)-l-alaninate. 47 H 43N2O5[M+H] + MS ESI calculated for 715.31, found 715.35. 1 H NMR(300MHz,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).

[0382] Step 4: Benzyl N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)-l-alaninate (5.3 g, 7.4 mmol) was dissolved in EtOAc (40 mL). The flask was evacuated and backfilled with N (5 times). Pd / C (2 g, 18.79 mmol, dry, 10 wt%) was added to the flask. The flask was evacuated and backfilled with H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT for 6 h. The flask was evacuated and backfilled with N (5 times). The resulting mixture was filtered through a Celite® pad. The filter cake was washed with EtOAc (2 × 80 mL). The filtrate was concentrated under reduced pressure. The mixture of diastereomers was separated by SFC: (Column: CHIRAL ART® Cellulose-SB (250 × 30 mm, 5 μm); Mobile phase: [0.1% 2 m NH3-MeOH] in MeOH; B%: 35-35%, 10 min).

[0383] The 6.23 min fractions were combined and concentrated in vacuo to give N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)-l-alanine. 40 H 37 N2O5[M+H] + MS ESI calculated for 625.26, found 625.20. 1H NMR (300MHz, 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).

[0384] The 7.62 min fractions were combined and concentrated in vacuo to give N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(3-oxo-3-(tritylamino)propyl)-d-alanine. 40 H 37 N2O5[M+H] + MS ESI calculated for 625.26, found 625.15. 1 H NMR(300MHz,methanol-d4)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).

[0385] Synthetic Scheme 29 [ka]

[0386] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5-difluorohexanoic acid (Fmoc-NleF2-OH) Step 1: 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) were added to a solution of (S)-5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid (6.00 g, 19.8 mmol) in anh.DMF (25 mL). The resulting solution was stirred at RT for 90 min. The mixture was partitioned between EtOAc (400 mL) and brine (200 mL). The organic phase was washed with brine (2 × 200 mL), dried over anh.Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0–50% EtOAc in hexane to give tert-butyl N,O-dimethylhydroxylamine hydrochloride. 2 -(tert-butoxycarbonyl)-N 5 -Methoxy-N 5 C 16 H 30 N2O6[M+H] + MS ESI calculated for 347.22, found 347.2.

[0387] Step 2: Methylmagnesium chloride solution (3.0 m in THF, 33.7 mL, 100 mmol) was added to tert-butyl N 2 -(tert-butoxycarbonyl)-N 5 -Methoxy-N 5To a solution of 1-methyl-l-glutamate (7.0 g, 20 mmol) in anh.THF (30 mL) and toluene (20.0 mL) was added dropwise at -78 °C. The resulting solution was stirred at -78 °C for 4 h and then warmed to 0 °C for 5 min. The reaction mixture was then quenched by the dropwise addition of aq.sat.NH4Cl solution (40 mL). The mixture was partitioned between EtOAc (200 mL) and aq.sat.NH4Cl solution (200 mL). The organic phase was washed with aq.sat.NH4Cl (200 mL), water (2 × 200 mL), dried over anh.Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in hexane to give tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate. 15 H 27 NO5[M+H] + MS ESI calculated for 302.20, found 302.2.

[0388] Step 3: (Diethylamino)sulfur trifluoride (6.54 mL, 49.5 mmol) was added to a solution of tert-butyl (S)-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 RT overnight. The solution was poured dropwise into a mixture of aq. sat. NaHCO3 solution (300 mL) and DCM (200 mL). The mixture was stirred at RT for 30 min and then extracted with DCM (2 × 200 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-50% EtOAc in hexane to give tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate. 15 H 27 F2NO4[M+H] + MS ESI calculated for 324.20, found 324.2.

[0389] Step 4: TFA (6 mL, 80 mmol) was added to a solution of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate (1.27 g, 3.93 mmol) in DCM (20 mL). The resulting solution was stirred at RT 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 RT for 2 h. The volatiles were partially evaporated under reduced pressure. The aqueous phase was acidified to approximately pH 3 by the addition of aq. 1 n HCl solution. The mixture was extracted with DCM (3 x 80 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5,5-difluorohexanoic acid. 21 H 21 F2NO4[M+H] + MS ESI calculated for 390.15, found 390.3. 1 H NMR(400MHz,DMSO-d6):δ 12.61(s,1H),7.90(d,J=5Hz,2H),7.72(t,J=7.5Hz,2H),7.42(t,J=7.5Hz,2H),7.34(t,J=7.5Hz,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=20Hz,3H). 19 F NMR(376MHz,DMSO-d6):δ-88.6.

[0390] Synthetic Scheme 30 [ka]

[0391] (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)-3-hydroxypropanoic acid (Fmoc-RbOHPhe4CO2tBu-OH) Step 1: Two batches were run in parallel. Ethyl (tert-butoxycarbonyl)glycinate (37.0 g, 182 mmol) and anhydrous THF (1.2 L) were added to a three-neck 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. tert-Butyl 4-formylbenzoate (30.0 g, 146 mmol) was then added, maintaining the mixture below -60 °C. The reaction was then allowed to warm to RT and stirred for 4 h. The two batches were combined and added to aq. sat. NH4Cl solution (1.0 L), followed by extraction 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 silica gel column chromatography eluting with EtOAc in PE (50:1 to 0:1; v / v) to give tert-butyl 4-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-1-hydroxy-3-oxopropyl)benzoate as a mixture of four isomers. 21 H 31 NO7[M-tBu-Boc+2H] + MS ESI calculated for 254, found 254. 1 H NMR (400 MHz, methanol-d): δ 7.92(d,J=8.0Hz,2H),7.48(d,J=8.4Hz,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).

[0392] Step 2: LiOH.HO (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 RT for 2 h. The mixture was then concentrated under reduced pressure to remove MeOH, and the pH was adjusted to 4-5. The aqueous solution was extracted with EtOAc (2 x 300 mL), and the combined organic phases were dried over anh.NaSO and 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. 19 H 27 NO7[M-Boc+H] + MS ESI calculated for 282, found 282. 1 H NMR(400MHz,CDCl3)δ 7.91(d,J=7.8Hz,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).

[0393] Step 3: (Three reactions were run in parallel and 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 RT for 15 h. Upon completion, the resulting mixture was used directly in the next step.

[0394] Step 4: NaHCO3 (14.9 g, 6.93 mL, 178 mmol) was then added to the mixture to adjust the pH to 8 at 0 °C, 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 RT 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 3-4 using aq. 1 m HCl. The aqueous solution was then extracted with EtOAc (2 × 200 mL), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica column chromatography (DCM:MeOH = 80:1 to 5:1; v / v) to give 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)-3-hydroxypropanoic acid as a mixture of four isomers. 29 H 29 NO7[M+Na] + MS ESI calculated for 526, found for 526. 1 H NMR (400MHz, methanol-d4):δ 7.88(dd,J=8.0,2.0Hz,2H),7.77(d,J=7.6Hz,2H),7.52(t,J=10.4Hz,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).

[0395] Step 5: NaHCO3 (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 RT. The reaction was quenched by the addition of water (200 mL), and the aqueous phase was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with water (200 mL), dried over anh.Na2SO4, 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. 36 H 35 NO7[M+Na] + 616, actual value 616. The mixture of isomers was then separated by SFC (column: DAICEL CHIRALPAK AD (250 × 50 mm, 10 μm); mobile phase: [0.1% NH4OH in EtOH]; [0.1% NH4OH in EtOH]%: 60–60%, 11 min), followed by SFC (column: DAICEL CHIRALPAK AD (250 × 50 mm, 10 μm); mobile phase: [0.1% NH4OH in EtOH]; [0.1% NH4OH in EtOH]%: 50–50%, 6.5 min), followed by SFC (column: DAICEL CHIRALCEL OD (250 × 50 mm, 10 μm); mobile phase: [0.1% NH4OH in EtOH]; [0.1% NH4OH in EtOH]%: 60–60%, 10 min) to give compounds A, B, C, and D.

[0396] 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 dihydrogen and stirred at RT under a dihydrogen atmosphere. The suspension was filtered through a Celite® pad, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 80 × 40 mm, 3 μm; mobile phase: [water (HCl) and MeCN]; MeCN%: 45-75%, 7 min) to give (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, actual value 448. 1 H NMR (400MHz, methanol-d4):δ 7.88(d,J=8.4Hz,2H),7.77(d,J=7.6Hz,2H)7.57-7.47(m,4H),7.55-7.22(m,4H),5.42(d,J=7 .8Hz,1H),4.46(d,J=7.6Hz,1H),4.31(dd,J=9.8,6.0Hz,1H),4.16-3.97(m,2H),1.52(s,9H).

[0397] Synthetic Scheme 31 [ka]

[0398] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)-2-fluorophenyl)propanoic acid (Fmoc-Phe2F4COOtBu-OH) Step 1: A mixture of NiCl·glyme (0.182 g, 0.827 mmol) and 1,10-phenanthroline (0.149 g, 0.827 mmol) in anh.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), benzyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (2.18 g, 4.13 mmol), and TBAI (1.527 g, 4.13 mmol) in anh.DMA (20 mL) was added at RT. Activated 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 × 250 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anh.NaSO, filtered, and concentrated in vacuo. The residue was purified by Rp-flash chromatography using the following conditions: Column: flash C18 (330 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN; (Gradient: 5% B held for 5 min, to 52% B within 33 min, to 56% B held for 5.2 min; to 95% B within 2 min, to 95% B held for 10 min); Flow rate: 90 mL / min; Detector: UV 210 nm. The product-containing fractions were collected and concentrated in vacuo to give tert-butyl (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)-3-fluorobenzoate. 36 H 35 FNO6[M+H] + MS ESI calculated for 596.24, found 596.20. 1H NMR(300MHz,DMSO-d6):δ 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(282MHz,DMSO-d6):δ-117.39.

[0399] Step 2: Pd / C (0.372 g, 3.5 mmol, 10 wt%) was added to a stirred solution of tert-butyl (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)-3-fluorobenzoate (3.2 g, 5.4 mmol) in EtOAc (60 mL). The resulting mixture was purged with dihydrogen and stirred under a dihydrogen atmosphere at RT for 1 h. The suspension was filtered through a Celite® pad, and the filtrate was concentrated under reduced pressure. The residue was purified by Rp-flash chromatography using the following conditions: Column: C18 (330 g); Mobile phase A: water (0.05% TFA), Mobile phase B: MeCN; (Gradient: hold at 5% B for 5 min, to 75% B within 30 min, hold at 80% B for 7 min; to 95% B within 2 min, hold at 95% B for 10 min); Flow rate: 100 mL / min; Detector: UV 210 nm. Product-containing fractions 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. 29 H 29 FNO6[M+NH3+H] + MS ESI calculated for 523.19, found 523.15. 1H NMR(300MHz,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(282MHz,DMSO-d6):δ-117.38.

[0400] Synthetic Scheme 32 [ka]

[0401] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)-3-chlorophenyl)propanoic acid (Fmoc-Phe3Cl4COOtBu-OH) Step 1: 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 RT under Ar. The solution was stirred at RT. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 0-60% EtOAc in PE to give tert-butyl 4-bromo-2-chlorobenzoate. 1 H NMR (400 MHz, chloroform-d): δ 7.63-7.60 (m, 2H), 7.44-7.41 (m, 1H), 1.60 (s, 9H).

[0402] Step 2: A mixture of nickel(II) chloride ethylene glycol dimethyl ether complex (1.8 g, 8.2 mmol) and 1,10-phenanthroline (7.4 g, 41.2 mmol) in anh.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-iodopropanoate (14.9 g, 45.3 mmol), and tetrabutylammonium iodide (15.2 g, 41.2 mmol) in anh.DMA (120 mL) was added to the mixture at RT. Then, activated 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 0-100% EtOAc in PE, followed by Rp-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (5 mM NH4HCO3), Mobile phase B: MeCN; Gradient elution: 0-75%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give tert-butyl (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-chlorobenzoate. 20 H 28 ClNO6Na[M+Na] + MS ESI calculated for 436.16, found 436.15. 1 H 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),3.7 4(s,3H),3.17-3.13(m,1H),3.04-2.98(m,1H),1.60(s,9H),1.43(s,9H).

[0403] Step 3: An aqueous solution of LiOH (39 mL, 39 mmol) was added to a solution of tert-butyl (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-chlorobenzoate (8.00 g, 19.3 mmol) in THF (80 mL) at RT. The mixture was stirred at RT 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 in Step 4 without purification. 19 H 26 ClNO6Na[M+Na] + MS ESI calculated for 422.14, found 422.10.

[0404] 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 anh.THF (80 mL) under Ar at RT. The mixture was stirred at RT 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 in Step 5 without purification. 14 H 19 ClNO4[M+H] + MS ESI calculated for 300.09, found 300.15.

[0405] 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 approximately 4 with aq. 1 n HCl. The mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (150 mL), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure, and the residue was purified by RP-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN; Gradient elution: 2-60%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)-3-chlorophenyl)propanoic acid. 29 H 27 ClNO6[M+H] + MS ESI calculated for 520.16, found 520.25. 1 H NMR(400MHz,methanol-d4):δ 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,1 H),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).

[0406] Synthetic Scheme 33 [ka]

[0407] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)-3-fluorophenyl)propanoic acid (Fmoc-Phe3F4COOtBu-OH) Step 1: A mixture of nickel(II) chloride ethylene glycol dimethyl ether complex (0.333 g, 1.517 mmol) and pyridine-2-carboximidamide hydrochloride (0.478 g, 3.03 mmol) in anh.DMA (80 mL) was stirred and heated at 50 °C for 1 h. The mixture was cooled to RT. To this solution was added a mixture of benzyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (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 anh.DMA (80 mL). Activated zinc (1.98 g, 30.3 mmol) was then added. The mixture was stirred at RT 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 anh.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 tert-butyl (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)-2-fluorobenzoate. C 36 H 34 FNO6Na[M+Na] + MS ESI calculated for 618.24, found 618.25.

[0408] Step 2: tert-Butyl (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(benzyloxy)-3-oxopropyl)-2-fluorobenzoate (4.00 g, 6.72 mmol) was dissolved in EtOAc (50 mL). The flask was evacuated and refilled with N (5 times). Pd / C (0.143 g, 1.34 mmol, dry, 10 wt%) was added to the flask. The flask was evacuated and backfilled with H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT for 4 h. The flask was evacuated and backfilled with N (5 times). The resulting mixture was filtered through a Celite® pad. The filter cake was washed with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Rp-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water, Mobile phase B: MeCN; Gradient elution: 0-50%; Detector: UV 210 nm. The product-containing fractions were concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)-3-fluorophenyl)propanoic acid. 29 H 28 FNO6Na[M+Na] + MS ESI calculated for 528.19, found 528.15. 1 H NMR(300MHz,DMSO-d6):δ 12.85(s,1H),7.88(d,J=7.5Hz,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).

[0409] Synthetic Scheme 34 [ka]

[0410] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)-3,5-difluorophenyl)propanoic acid (Fmoc-PheFCOOtBu-OH) Step 1: A solution of nickel(II) chloride ethylene glycol dimethyl ether complex (0.33 g, 1.52 mmol) and pyridine-2-carboximidamide hydrochloride (0.48 g, 3.03 mmol) in anh.DMA (80 mL) was stirred and heated at 50 °C for 1 h. The mixture was cooled to RT, and a solution of benzyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (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 anh.DMA (80 mL) was added. Activated zinc (1.98 g, 30.3 mmol) was then added to the mixture. The mixture was stirred at RT 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 anh.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. C 36 H 33 F2NO6Na[M+Na] + MS ESI calculated for 636.23, found 636.20.

[0411] Step 2: tert-Butyl (S)-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 refilled with N (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 H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere at RT for 4 h. The flask was evacuated and backfilled with N (5 times). The resulting mixture was filtered through a Celite® pad. The filter cake was washed with EtOAc (3 × 80 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Rp-flash column chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water, Mobile phase B: MeCN; Gradient elution: 60-60%; Detector: UV 210 nm. The product-containing fractions 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. 29 H 27 F2NO6Na[M+Na] + MS ESI calculated for 546.18, found 546.05. 1 H NMR (300MHz, DMSO-d6):δ 12.87(s,1H),7.88(d,J=7.5Hz,2H),7.77(d,J=8.4Hz,1H),7.63-7.59(m,2H),7.43-7.38(m,2H),7.32-7 .25(m,2H),7.15(d,J=9.0Hz,2H),4.30-4.17(m,4H),3.19-3.13(m,1H),2.96-2.87(m,1H),1.51(s,9H).

[0412] Synthetic Scheme 35 [ka]

[0413] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(4-acetylpiperazin-1-yl)phenyl)propanoic acid (Fmoc-Phe4AcPip-OH) Step 1: At RT under N2, XPhos Pd G2 (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). 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 RT, quenched with DI water (500 mL), and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-60% EtOAc in PE to give (S)-3-(4-(4-acetylpiperazin-1-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid. 20 H 30 N3O5[M+H] + MS ESI calculated for 392.21, found 392.25. 1 H NMR (400MHz, methanol-d4):δ 7.12(d,J=8Hz,2H),6.89(d,J=8Hz,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).

[0414] Step 2: At RT, 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). The solution was stirred at RT for 1 h and then concentrated under reduced pressure. The crude product was used directly in the next step without further purification. C 15 H 22 N3O3[M+H] + MS ESI calculated for 292.16, found 292.20.

[0415] Step 3: Fmoc-OSu (6.34 g, 18.8 mmol) and NaHCO3 (8.77 g, 104 mmol) were added to a stirred solution of (S)-3-(4-(4-acetylpiperazin-1-yl)phenyl)-2-(carboxyamino)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 RT for 2 h. The pH was adjusted to 5 with aqueous 1N HCl solution and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anh. Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by Rp-flash chromatography using the following conditions: Column: Flash C18 (330 g); Mobile phase A: water (0.1% TFA), Mobile phase B: MeCN; (Gradient: hold at 5% B for 5 min, to 55% B within 15 min, hold at 55% B for 5 min; to 95% B within 20 min, hold at 95% B for 5 min); Flow rate: 90 mL / min; Detector: UV 210 nm. Product-containing fractions 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. 30 H 32 N3O5[M+H] + MS ESI calculated for 514.23, found 514.30. 1H NMR (400MHz, 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,1) H),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).

[0416] Synthetic Scheme 36 [ka]

[0417] (2S,5S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Fmoc-Pipc5COOtBu-OH) 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 RT. 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(400MHz,DMSO-d6):δ 9.16(dd,J=1.6,7.6Hz,1H),8.42-8.47(m,1H),8.16(t,J=8.0Hz,1H),3.91(s,3H).

[0418] Step 2: 6-(Methoxycarbonyl)nicotinic acid (40.0 g, 220 mmol) was dissolved in MeOH (280 mL) at RT. DMAP (13.4 g, 110 mmol) and BocO (120 g, 126 mL, 552 mmol) were added, and the reaction mixture was stirred at RT 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 anh. NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (20:1 to 5:1; v / v) to give 5-(tert-butyl) 2-methylpyridine-2,5-dicarboxylate. 1 H NMR(400MHz,DMSO-d6):δ 9.24(dd,J=1.6Hz,1H),8.37(dd,J=2.0,8.0Hz,1H),8.18(d,J=8.0Hz,1H),4.03(s,3H),1.62(s,9H).

[0419] Step 3: 5-(tert-butyl) 2-methylpyridine-2,5-dicarboxylate (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 RT. The reaction mixture was purged with dihydrogen (3 times) and then heated at 50° C. with stirring under H (50 Psi) for 12 h. The solid was filtered through a Celite® pad and rinsed 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 anh. Na SO , filtered, and concentrated in vacuo to give 5-(tert-butyl) 2-methyl(2S,5S)-piperidine-2,5-dicarboxylate. 1 H 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).

[0420] Step 4: A solution of NaOH (4.93 g, 123 mmol) in HO (100 mL) was added to a stirred solution of 5-(tert-butyl) 2-methyl(2S,5S)-piperidine-2,5-dicarboxylate (20.0 g, 82.2 mmol) in EtOH (120 mL) at RT. The reaction mixture was stirred at RT 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 (400MHz, DMSO-d6): δ 14.08(s,1H),8.54(d,J=8.8Hz,1H),7.48(s,1H),7.29(d,J=8.8Hz,1H),3.55(s,3H).

[0421] 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 RT. The solution was stirred at RT for 12 h. The organic volatiles were removed under reduced pressure, and the solid was partitioned between EtOAc (150 mL) and brine (150 mL). The organic layer was washed with brine, dried over anh. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex™ Luna™ C18 (250 × 70 mm, 15 μm, (Phenomenex™, Torrance, CA)); mobile phase: [water (HCl)-MeCN]; B%: 50-80%, 20 min). The compound was further purified by SFC (column: Daicel ChiralPak® IG (250 × 50 mm, 10 μm, Daicel Chiral Technologies, West Chester, PA); mobile phase: [0.1% NH4OH-EtOH in water]; B%: 45-45%, 6 min) to give (2S,5S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-(tert-butoxycarbonyl)piperidine-2-carboxylic acid. 1H NMR(400MHz,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=12.4,5.4Hz,1 H),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).

[0422] Synthetic Scheme 37 [ka]

[0423] (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) Step 1: At RT, 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). CsCO (954 g, 2.93 mol) was added to the solution. The reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into DI water (20 L) at RT, causing a solid to precipitate. The solid was collected by filtration, and the filter cake was rinsed with DI water (2 × 1 L). The filter cake was dried under vacuum. The crude product was triturated with MTBE (10 L) at RT for 2 h. The solid was collected by filtration, and the filter cake was dried under reduced pressure. The crude product was triturated with PE (10 L) at RT for 6 h. The solid was collected by filtration and the filter cake was dried under reduced pressure to give benzyl (((9H-fluoren-9-yl)methoxy)carbonyl)-l-threoninate. 1H NMR (400MHz, methanol-d4): δ 7.79(d,J=7.6Hz,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=6.4Hz,3H).

[0424] Step 2: NIS (547 g, 2.43 mol) was added to a solution of benzyl (((9H-fluoren-9-yl)methoxy)carbonyl)-l-threoninate (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 benzyl (2R,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodobutanoate. 1 H NMR (400MHz, methanol-d4):δ 7.79(d,J=7.6Hz,2H),7.68(d,J=7.2Hz,2H),7.40-7.27(m,10H),5.20(q,J=9.6Hz ,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).

[0425] Step 3: Solution A: A solution of NiCl2·glyme (4.06 g, 18.5 mmol) and 4-methoxypicolinimidamide hydrochloride (3.47 g, 18.5 mmol) in anh.DMA (500 mL) was stirred at RT under N2 for 30 min. Solution B: A solution of benzyl (2R,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodobutanoate (100 g, 185 mmol) and 4-iodopyridine (37.9 g, 185 mmol) in anh.DMA (250 mL) was stirred at RT under N2 for 30 min. Solution B was slowly added to solution A at RT under N2. Activated zinc (60.4 g, 924 mmol) was added portionwise to the solution. The suspension was stirred at RT under N2. The solids were removed by filtration, and the filter cake was rinsed with EtOAc (3×800 mL). The filtrate was poured into DI water (2.0 L). The suspension was extracted with EtOAc (3×1.5 L). The combined organic layers were washed with brine (2×800 mL), dried over anh.Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex™ Luna™ C18 250 mm, 10 μm, (Phenomenex™, Torrance, CA); mobile phase: [water (0.225% FA)-MeCN]; MeCN%: 40-70%, 20 min) to give a mixture of benzyl (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoate and benzyl (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoate. A portion of the mixture was separated by SFC chiral separation (column: Daicel ChiralPak® AD (250 × 50 mm, 10 μm, Daicel Chiral Technologies, West Chester, PA); mobile phase: [0.1% NH4OH in IPA]; IPA%: 50–50%, 6.2 min). The two separated products were concentrated under vacuum to give both diastereoisomers.

[0426] Benzyl (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoate A: 1 H NMR(400MHz,DMSO-d6):δ 8.44(d,J=5.6Hz,2H),7.95(d,J=8.0Hz,1H),7.87-7.55(m,3H),7.56-7.54(m,2H),7.38-7.32(m,9H), 5.17(d,J=2.8Hz,2H),4.37(t,J=9.2Hz,1H),4.18-4.08(m,3H),3.20-3.15(m,1H),1.21-1.14(m,3H). Benzyl (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoate B: 1 H NMR(400MHz,DMSO-d6):δ 8.43(d,J=5.6Hz,2H),8.11(d,J=8.0Hz,1H),7.89(d,J=7.6Hz,2H),7.68(d,J=7.2Hz,2H),7.44-7.41(m,2H),7.32-7.26(m,6H),7. 24-7.16(m,2H),4.96(dd,J=35.6,12.8Hz,2H),4.41(t,J=8.4Hz,1H),4.26-4.16(m,3H),3.28-3.23(m,1H),1.25(d,J=6.8Hz,3H).

[0427] Step 4: Pd / C (5.00 g, 10 wt%) was added to a solution of benzyl (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoate A (52.0 g, 106 mmol) in THF (300 mL) under N. The flask was evacuated and backfilled with H (3 times). The resulting mixture was stirred under a dihydrogen atmosphere (15 psi) at RT for 12 h. The flask was evacuated and refilled with N (5 times). The resulting mixture was filtered, and the filter cake was washed with THF (10 × 200 mL). The filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE (100 mL) at RT 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. 24 H 22 N2O4[M+H] + MS ESI calculated value for 403, found value 403. 1 H NMR(400MHz,T=273+80K,DMSO-d6):δ 8.44(d,J=4.8Hz,2H),7.85(d,J=7.6Hz,2H),7.58(d,J=6.4Hz,2H),7.38(d,J=7.6Hz ,2H),7.32-7.26(m,4H),4.29-4.10(m,4H),3.21-3.15(m,1H),1.26(d,J=6.8Hz,3H).

[0428] Step 5: Pd / C (4.00 g, 10 wt%) was added to a solution of benzyl (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(pyridin-4-yl)butanoate B (75.0 g, 152 mmol) in THF (380 mL) under N. The flask was evacuated and backfilled with H (3 times). The resulting mixture was stirred under a dihydrogen atmosphere (15 psi) at RT for 12 h. The flask was evacuated and refilled with N (5 times). The resulting mixture was filtered, and the filter cake was washed with THF (10 × 200 mL). The filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE (100 mL) at RT 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. 24 H 22 N2O4[M+H] + MS ESI calculated value for 403, found value 403. 1 H NMR(400MHz,T=273+80K,DMSO-d6):δ 8.44(d,J=4.8Hz,2H),7.86(d,J=7.6Hz,2H),7.68-7.62(m,2H),7.41(d,J=7.6Hz,2H),7.32-7 .25(m,4H),4.33-4.25(m,3H),4.19(q,J=6.8Hz,1H),3.30-3.28(m,1H),1.27(d,J=6.4Hz,3H).

[0429] Synthetic Scheme 38 [ka]

[0430] (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)butanoic acid (Fmoc-SbMePhe4CO2tBu-OH) 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) at RT. CsCO (954 g, 2.93 mol) was added to the solution, and the resulting suspension was stirred at RT for 3 h. The reaction mixture was poured into DI water (20 L) at RT. The solid was collected by filtration. The filter cake was rinsed with DI water (2 × 1 L) and dried under vacuum to give the crude product. The crude solid was triturated with MTBE (10 L) at RT 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 RT for 6 h. The suspension was filtered and the solid was dried under reduced pressure to give benzyl (((9H-fluoren-9-yl)methoxy)carbonyl)-l-threoninate. 1 H NMR (400MHz, methanol-d4): δ 7.79(d,J=7.6Hz,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=6.4Hz,3H).

[0431] Step 2: To a solution of benzyl (((9H-fluoren-9-yl)methoxy)carbonyl)-l-threoninate (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 benzyl (2R,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodobutanoate. 1H NMR (400MHz, methanol-d4):δ 7.79(d,J=7.6Hz,2H),7.68(d,J=7.2Hz,2H),7.40-7.27(m,10H),5.20(q,J=9.6Hz ,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).

[0432] Step 3: (Three reactions were performed in parallel and then combined for workup and purification.) In a nitrogen-filled glovebox, NiCl·glyme (3.25 g, 14.8 mmol) and 4,7-dimethoxy-1,10-phenanthroline (3.55 g, 14.8 mmol) were added to anh.DMA (500 mL). The mixture was stirred at RT for 30 min. Benzyl (2R,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodobutanoate (80.0 g, 148 mmol) and tert-butyl 4-iodobenzoate (44.9 g, 148 mmol) were then added to the solution. Manganese (16.2 g, 296 mmol) was then added, followed by TMSCl (8.03 g, 9.38 mL, 73.9 mmol). The suspension was stirred at RT under N2 for 12 h. The three reaction suspensions were then combined, filtered, and the filter cake was rinsed with EtOAc (2 × 500 mL). The filtrate was poured into water (2.0 L). The organic and aqueous layers were separated, and the aqueous layer was extracted with EtOAc (3 × 800 mL). The combined organic layers were washed with brine (2 × 1 L) and dried over anh. sodium sulfate. The organic layer was concentrated in vacuo to give a residue that was first purified by RP-HPLC (Phenomenex Titan C18 Bulk 250 × 100 mm, 10 μm; mobile phase: [10 mM aqueous NH4HCO3 and MeCN]; MeCN%: 75–100%, 20 min) to give the product as a mixture of two diastereomers. The isomers were separated by SFC chiral separation (DAICEL CHIRALPAK AD (250 × 50 mm, 10 μm); mobile phase: [EtOH]; EtOH%: 40-40%, 3.6 min) to give two separated diastereomers.

[0433] tert-Butyl 4-((2S,3S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(benzyloxy)-4-oxobutan-2-yl)benzoate (A) 1 H NMR (400MHz, chloroform-d):δ 7.85(d,J=8Hz,2H),7.78(d,J=7.6Hz,2H),7.54(t,J=7.2Hz,2H),7.43-7.28(m,8H),7.05(d,J=8Hz,2H),5.19-5.03(m,3H),4.7 0-4.66(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=7.2Hz,3H). tert-Butyl 4-((2R,3S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(benzyloxy)-4-oxobutan-2-yl)benzoate (B) 1 H NMR (400MHz, chloroform-d):δ 7.79(d,J=8Hz,2H),7.72(d,J=7.6Hz,2H),7.52(d,J=7.6Hz,2H),7.38-7.25(m,7H),7.11-6.93(m,3H),5.27(d,J=9.2Hz,1H),4.97(q ,J=8.4Hz,2H),4.57(t,J=7.6Hz,1H),4.41-4.27(m,2H),4.14(t,J=6.8Hz,1H),3.22-3.16(m,1H),1.54(s,9H),1.28(d,J=7.2Hz,3H).

[0434] Step 4: Under a nitrogen atmosphere, 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%). The flask was evacuated and backfilled with H (15 psi, 5 times). The resulting mixture was stirred under H (15 psi) at RT for 6 h. The suspension was then filtered through a Celite® pad. The filter cake was rinsed with THF (400 mL). The filtrate was concentrated under reduced pressure to give (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)butanoic acid. 30 H 31 NO6[M+Na] + MS ESI calculated for 524, found 524. 1 H NMR(400MHz,DMSO-d6):δ δ 7.82(m,J=8.0,7.6Hz,4H),7.53-7.50(m,2H),7.43-7.35(m,4H),7.24(q,J=8.4H z,2H),4.07-4.00(m,2H),3.24-3.16(m,1H),1.48(s,9H),1.25(d,J=7.2Hz,3H).

[0435] Synthetic Scheme 39 [ka]

[0436] (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxy-3-(pyridin-4-yl)propanoic acid (Fmoc-RbOH4Pal-OH) Step 1: In a three-neck flask, a solution of ethyl (tert-butoxycarbonyl)glycinate (100.0 g, 492 mmol) in anhydrous THF (1.5 L) was purged with N2 three 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 N2 at -65 °C for 1 h. Isonicotinaldehyde (69.3 mL, 79.1 g, 738 mmol) was added to the mixture at -60 °C. The reaction mixture was allowed to warm to RT and stirred at RT for 4 h. The reaction mixture was quenched with aq. sat. NH4Cl (1 L) and extracted with EtOAc (2 × 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 2-100% EtOAc in PE to give ethyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(pyridin-4-yl)propanoate. 15 H 22 N2O5[M+H] + MS ESI calculated for 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).

[0437] Step 2: A solution of LiOH·HO (53.8 g, 1.28 mol) and ethyl 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(pyridin-4-yl)propanoate (82.0 g, 0.25 mmol) in MeOH (640 mL) and HO (160 mL) was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (water (HCl)-MeCN; MeCN%: 1-27%, 20 min) to give 2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-(pyridin-4-yl)propanoic acid. 13 H 18 N2O5[M+H]+ MS ESI calculated for 283, found 283.

[0438] Step 3: The mixture of four isomers was separated by SFC (SFC (Column: Daicel ChiralPak® AD (250 × 50 mm, 10 μm, Daicel Chiral Technologies, West Chester, PA); Mobile phase: [0.1% NH4OH in HO; IPA]; IPA%: 30-30%, 7 min)) to give compounds A, B, C, and D.

[0439] 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 hydrogen chloride in EtOAc (4.0 m, 71.9 mL, 287.6 mmol), and the solution was stirred at RT for 2 h. The pH of the reaction mixture was adjusted to approximately 3-4 by slow addition of aqueous NaHCO (41.6 g, 496 mmol, 19.3 mL) at 0 °C. The aqueous layer was isolated and used in the next step.

[0440] Fmoc-OSu (16.7 g, 49.6 mmol) in dioxane (60 mL) was added to the aqueous solution. The reaction mixture was stirred at RT for 2 h and then concentrated in vacuo. The residue was purified by RP HPLC (column: Welch Xtimate® C18 250 × 70 mm (Welch, West Haven, Connecticut), 10 μm; mobile phase: [NH4HCO3 in water; MeCN]; MeCN%: 1-40%, 20 min) to give (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxy-3-(pyridin-4-yl)propanoic acid. C 23 H 20 N2O5[M+H] + MS ESI calculated for 405, found 405. 1HNMR(400MHz,DMSO-d6):δ 12.95(s,1H),8.51-8.45(m,2H),7.88(d,J=7.4Hz,2H),7.62(dd,J=20.7,7.3Hz,2H),7.46-7.3 7(m,4H),7.35-7.24(m,3H),5.96(s,1H),5.21(s,1H),4.41(d,J=9.5Hz,1H),4.15-4.03(m,3H).

[0441] Synthetic Scheme 40 [ka]

[0442] (2S,3S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-4-oxo-4-(tritylamino)butanoic acid (Fmoc-SbO(TBDMS)Asn(Trt)OH) and (2S,3R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-4-oxo-4-(tritylamino)butanoic acid (Fmoc-RbO(TBDMS)Asn(Trt)OH) Step 1: Formic acid (1.9 mL, 50.1 mmol) and AcO (4.7 mL, 50.1 mmol) were stirred in a dry flask at 55 °C for 2 h. The solution was then added dropwise to a solution of triphenylmethanamine (13.0 g, 50.1 mmol) in anh.THF (84 mL) at 0 °C under a N atmosphere. The reaction mixture was warmed to RT and stirred for 2 h. The resulting solution was quenched with aq. sat. NaCO solution and extracted with EtOAc (200 mL). The organic layer was washed with brine, dried over anh.NaSO, filtered, and concentrated in vacuo to give N-tritylformamide, which was used in Step 2 without further purification. 1 H NMR (300MHz, DMSO-d6): δ 9.01 (s, 1H), 8.13 (d, J=1.9Hz, 1H), 7.41-7.10 (m, 15H).

[0443] Step 2: A solution of N-tritylformamide (15.3 g, 53.2 mmol) and TEA (21.5 mL, 154 mmol) in anhydrous THF (96 mL) was cooled to 0 °C under a N atmosphere. POCl (8.44 mL, 91 mmol) was added dropwise to the reaction mixture and stirred for 1 h. The resulting solution was quenched with aq. sat. NaCO solution (180 mL) and extracted with DCM (3 × 200 mL). The combined organic layers were dried over anh. NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0–7% EtOAc in PE to give (isocyanomethanetriyl)tribenzene. 1 H NMR(300MHz,DMSO-d6):δ 7.54-7.10(m,15H).

[0444] Step 3: Imidazole (6.2 g, 92 mmol) and TBSCl (6.9 g, 45.8 mmol) were added to a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-d-serine (10.0 g, 30.5 mmol) in anh.DMF (100 mL) under N2 at RT. The reaction was stirred at RT for 12 h. The resulting solution was quenched with 1 m HCl and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 150 mL), dried over anh.Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with 0–5% MeOH in DCM to give N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-butyldimethylsilyl)-d-serine. 24 H 32 NO5Si[M+H] + MS ESI calculated for 442.15, found 442.20. 1H NMR (300MHz, chloroform-d):δ 7.76(d,J=7.5Hz,2H),7.63-7.59(m,2H),7.44-7.27(m,4H),5.63(d,J=8.2Hz,1H),4.53-4.32(m,3 H)4.25(t,J=7.2Hz,1H),4.16-4.13(m,1H),3.90-3.85(m,1H),0.90(s,9H),0.08(d,J=2.6Hz,6H).

[0445] Step 4: Under N2 at RT, DMAP (0.373 g, 3.06 mmol) was added to a solution of N-(((9H-Fluoren-9-yl)methoxy)carbonyl)-O-(tert-butyldimethylsilyl)-d-serine (13.5 g, 30.6 mmol) in DCM (150 mL). The reaction was cooled to 0 °C. DCC (12.6 g, 61.1 mmol) and ethanethiol (2.9 g, 45.9 mmol) were added to the mixture. The reaction was warmed to RT and stirred for 4 h. The resulting solution was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 0-12% EtOAc in PE to give S-ethyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanethioate. 26 H 36 NO4SSi[M+H] + MS ESI calculated for 486.21, found 486.25. 1 H NMR (300 MHz, chloroform-d): δ 7.76-7.22 (m, 8H), 4.53-3.96 (m, 5H), 3.76 (dd, J = 10.2, 3.6 Hz, 1H), 2.93-2.75 (m, 2H), 1.21 (t, J = 7.5 Hz, 3H), 0.85 (s, 9H), 0.01 (d, J = 6.3 Hz, 6H).

[0446] Step 5: Under Ar, Pd / C (2.5 g, 2.35 mmol, dry, 10 wt%) and triethylsilane (6.32 g, 54.4 mmol) were added to a solution of S-ethyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanethioate (13.2 g, 27.2 mmol) in DCM (130 mL). The reaction mixture was stirred at RT for 4 h. The resulting solution was filtered through a Celite® pad. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with 0-23% EtOAc in PE to give (9H-fluoren-9-yl)methyl (R)-(1-((tert-butyldimethylsilyl)oxy)-3-oxopropan-2-yl)carbamate. 24 H 32 NO4Si[M+H] + MS ESI calculated for 426.20, found 426.05. 1 H NMR (300MHz, chloroform-d):δ 9.61(s,1H),7.71(d,J=7.5Hz,2H),7.60-7.52(m,2H),7.40-7.22(m,4H),4.36(d,J=7.1H z,2H),4.32-4.24(m,1H),4.24-4.13(m,2H),3.90-3.79(m,1H),0.82(s,9H).0.04(s,6H).

[0447] Step 6: At RT, (isocyanomethanetriyl)tribenzene (7.0 g, 26.0 mmol) was added to a solution of (9H-fluoren-9-yl)methyl (R)-(1-((tert-butyldimethylsilyl)oxy)-3-oxopropan-2-yl)carbamate (8.5 g, 19.97 mmol) in toluene (80 mL). Formic acid (1.5 mL, 39.9 mmol) was added dropwise. The reaction mixture was warmed to 60 °C and stirred at 60 °C. The resulting solution was quenched with aqueous saturated Na2CO3 solution and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-15% EtOAc in PE to give (3R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((tert-butyldimethylsilyl)oxy)-1-oxo-1-(tritylamino)butan-2-ylformate. 45 H 49 N2O6Si[M+H] + MS ESI calculated for 741.33, found 741.20. 1 H NMR (300MHz, chloroform-d):δ 8.13(s,1H),7.73(d,J=7.5Hz,2H),7.59-7.48(m,2H),7.41-7.31(m,2H),7.31-7.11(m,19H),5.49(s,1H),4.4 5-4.21(m,3H),4.18-4.14(m,1H),3.64-3.62(m,1H),3.59-3.47(m,1H),0.87-0.81(m,9H),0.07-0.01(m,6H).

[0448] Step 7: At RT, CaCl (20.7 g, 186 mmol) was added to a solution of (3R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((tert-butyldimethylsilyl)oxy)-1-oxo-1-(tritylamino)butan-2-ylformate (9.2 g, 12.42 mmol) in 2-propanol (188 mL) and THF (94 mL). After dissolving the CaCl by sonication, a solution of LiOH (1.2 g, 49.7 mmol) in water (47 mL) was added dropwise. The reaction was stirred at RT for 2 h. The reaction mixture was acidified to approximately pH 5 by adding 0.1 n HCl. The mixture was partially concentrated under vacuum to remove most of the isopropanol and THF. The mixture was diluted with HO (150 mL) and extracted with DCM (3 × 300 mL). The combined organic layers were dried over anh. Na2SO4, filtered, concentrated in vacuo, and purified by silica gel flash column chromatography eluting with 0-25% EtOAc in PE to give (9H-fluoren-9-yl)methyl ((2R)-1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-4-oxo-4-(tritylamino)butan-2-yl)carbamate. 44 H 48 N2O5SiNa[M+Na] + MS ESI calculated for 736.33, found 736.35.

[0449] Step 8: At 0°C, tert-butyldimethylsilyl trifluoromethanesulfonate (2.8 g, 10.5 mmol) was added dropwise to a solution of (9H-fluoren-9-yl)methyl ((2R)-1-((tert-butyldimethylsilyl)oxy)-3-hydroxy-4-oxo-4-(tritylamino)butan-2-yl)carbamate (7.5 g, 10.5 mmol) in DCM (75 mL). The reaction was stirred at 0°C for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with 0-35% EtOAc in PE to give (9H-fluoren-9-yl)methyl ((6R)-2,2,3,3,9,9,10,10-octamethyl-5-(tritylcarbamoyl)-4,8-dioxa-3,9-disilaundecan-6-yl)carbamate. 50 H 63 N2O5Si2[M+H] + MS ESI calculated for 827.42, found 827.35. 1 H NMR (400MHz, chloroform-d):δ 7.98(s,1H),7.79-7.76(m,2H),7.62-7.58(m,2H),7.46-7.36(m,2H),7.34-7.19(m,17H),4.99-4.83(m,1H),4.50-4.32(m ,3H),4.24(t,J=7.0Hz,1H),4.03-3.94(m,1H),3.87-3.56(m,2H),0.90(d,J=11.4Hz,18H),0.23-0.08(m,6H),0.03(s,6H).

[0450] Step 9: A solution of p-toluenesulfonic acid monohydrate (1.7 g, 8.7 mmol) in MeOH (68 mL) was added dropwise to a mixture of (9H-fluoren-9-yl)methyl ((6R)-2,2,3,3,9,9,10,10-octamethyl-5-(tritylcarbamoyl)-4,8-dioxa-3,9-disilaundecan-6-yl)carbamate (7.2 g, 8.7 mmol) in MeOH (270 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and purified by silica gel flash column chromatography eluting with 0-9% EtOAc in DCM to give both diastereoisomers (A and B). (9H-Fluoren-9-yl)methyl ((2R,3S)-3-((tert-butyldimethylsilyl)oxy)-1-hydroxy-4-oxo-4-(tritylamino)butan-2-yl)carbamate (A). C 44 H 49 N2O5Si[M+H] + MS ESI calculated for 713.33, found 713.30. 1 H NMR (400 MHz, chloroform-d): δ 8.19 (s, 1H), 7.80-7.70 (m, 2H), 7.60-7.53 (m, 2H), 7.44-7.19 (m, 19H), 4.91 (d, J = 9.2 Hz, 1H), 4.54-4.30 (m, 3H), 4.24 (t, J = 6.7 Hz, 1H), 4.04-4.03 (m, 1H), 3.81-3.78 (m, 1H), 3.52-3.50 (m, 1H), 0.92 (s, 9H), 0.19 (d, J = 11.8 Hz, 6H). (9H-Fluoren-9-yl)methyl ((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-1-hydroxy-4-oxo-4-(tritylamino)butan-2-yl)carbamate (B). C 44 H 49 N2O5Si[M+H] + MS ESI calculated for 713.33, found 713.30. 1H NMR (400MHz, chloroform-d):δ 8.02(s,1H),7.75(d,J=7.5Hz,2H),7.56(d,J=7.8Hz,2H),7.45-7.11(m,19H),4.45-4. 12(m,4H),4.00-3.99(s,1H),3.69-3.59(m,2H),0.88(s,9H),0.18(s,3H),0.10(s,3H).

[0451] Step 10: Phenyl-λ at 0 °C 3 -Iodanediyldiacetate (Phenyl-λ 3 (9H-fluoren-9-yl)methyl ((2R,3S)-3-((tert-butyldimethylsilyl)oxy)-1-hydroxy-4-oxo-4-(tritylamino)butan-2-yl)carbamate (A) (2.6 g, 3.65 mmol) in DCM (26 mL) was added. The reaction was stirred at 0 °C for 2 h. Sodium chlorite (0.66 g, 7.29 mmol) and 2-methylbut-2-ene (0.51 g, 7.29 mmol) were added to the mixture at 0 °C. The reaction mixture was stirred at RT. The reaction mixture was diluted with EtOAc (100 mL) and washed with aq. sat. Na2S2O3 (2 x 50 mL) and brine (2 x 50 mL). The organic phase was dried over anh. Na2SO4, concentrated in vacuo, and purified by silica gel flash column chromatography eluting with 0-50% EtOAc in DCM to give (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-4-oxo-4-(tritylamino)butanoic acid. 44 H 47 N2O6Si[M+H] + MS ESI calculated for 727.31, found 727.30. 1H NMR (300MHz, methanol-d4):δ 7.79-7.74(m,2H),7.65-7.60(m,2H),7.41-7.16(m,19H),4.59-4.58(m,2H),4 .48-4.31(m,2H),4.22(t,J=6.6Hz,1H),0.83(s,9H),0.10(s,3H),0.01(s,3H).

[0452] Step 11: Phenyl-λ at 0°C 3 -iodanediyl diacetate (2.08 g, 6.45 mmol) and TEMPO (0.10 g, 0.65 mmol) were added to a mixture of (9H-fluoren-9-yl)methyl ((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-1-hydroxy-4-oxo-4-(tritylamino)butan-2-yl)carbamate (B) (2.3 g, 3.23 mmol) in DCM (26 mL). The reaction was stirred at 0 °C for 2 h. Sodium chlorite (0.58 g, 6.45 mmol) and 2-methylbut-2-ene (0.45 g, 6.45 mmol) were added to the mixture at 0 °C. The reaction mixture was stirred at RT. The reaction mixture was diluted with EtOAc (100 mL) and washed with aq. sat. Na2S2O3 (2 x 50 mL) and brine (2 x 50 mL). The organic phase was dried over anh. Na2SO4, concentrated in vacuo, and purified by silica gel flash column chromatography eluting with 0-50% EtOAc in DCM to give (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-4-oxo-4-(tritylamino)butanoic acid. 44 H 47 N2O6Si[M+H] + MS ESI calculated for 727.31, found 727.30. 1H NMR (300MHz, methanol-d4):δ 7.72-7.53(m,3H),7.48(d,J=7.5Hz,1H),7.31-7.21(m,2H),7.17-6.98(m,17H),4.69-4.59(m,2 H),4.43-4.33(m,1H),4.24-4.13(m,1H),4.09(t,J=6.9Hz,1H),0.75(s,9H),0.04-0.00(m,6H).

[0453] Synthetic Scheme 41 [ka]

[0454] (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxy-3-phenylpropanoic acid (Fmoc-RbOtBuPhe-OH) Step 1: N,O-Dimethylhydroxylamine hydrochloride (104 g, 1.07 mol) and N-methylmorpholine (179 g, 1.78 mol, 195 mL) were added to a solution of ((benzyloxy)carbonyl)-d-serine (170 g, 710 mmol) in DCM (1.20 L) at −15° C. EDC (143 g, 746 mmol) was added to the mixture at −15° C. The reaction mixture was stirred at 0° C. for 4 hours. The reaction mixture was quenched by adding aq. 1 n HCl (2.00 L) to the reaction at −15° C. The organic layer was isolated, and the aqueous layer was extracted with DCM (1.00 L). The combined organic layers were washed with sat. NaHCO3 (1.00 L), dried over anh. Na2SO4, filtered, and concentrated under reduced pressure to give benzyl-(R)-(3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate. 1 H NMR(400MHz DMSO-d6):δ 7.83-7.30(m,5H),5.02(s,2H),4.88(t,J=6.0Hz,1H),4.60(d,J=4.8Hz,1H),3.72(s,3H),3.60-3.56(m,1H),3.51-3.46(m,2H),3.11(s,3H).

[0455] Step 2: Crude benzyl (R)-(3-hydroxy-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (204 g, 723 mmol) was dissolved in a mixture of acetone (880 mL) and 2,2-dimethoxypropane (693 g, 6.66 mol, 816 mL). BF EtO (9.38 g, 66.1 mmol, 8.16 mL) was added to the solution. The reaction mixture was stirred at RT for 5 h. The reaction mixture was quenched by the addition of triethylamine (10.0 mL). The volatiles were removed under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with EtOAc in PE (10:1 to 3:1; v / v) to give benzyl (R)-4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate.

[0456] Step 3: A suspension of LAH (9.08 g, 239 mmol) in anh.THF (440 mL) was added to a solution of benzyl (R)-4-(methoxy(methyl)carbamoyl)-2,2-dimethyloxazolidine-3-carboxylate (145 g, 450 mmol) in anh.THF (440 mL) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched by adding an aqueous saturated solution of KHSO (1.5 L) to the mixture at −10° C. MTBE (1.0 L) was added, and the mixture was stirred at 0° C. for 30 min. The solid was removed by filtration. The organic layer was isolated, dried over anh.NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (10:1 to 2:1; v / v) to give benzyl (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate. 1 H NMR (400MHz, DMSO-d6): δ 9.57(s,1 H),7.39-7.31(m,5 H),5.15-4.99(m,2 H),4.49-4.11(m,1 H),3.95-3.90(m,2 H),1.54-1.42(m,6 H).

[0457] Step 4: Phenylmagnesium bromide (3.0 m in diethyl ether, 60.7 mL, 180 mmol) was diluted with anh.THF (200 mL) and the solution was cooled to 0 °C. A solution of benzyl (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate (40.0 g, 152 mmol) in anh.THF (50.0 mL) was added to the reaction mixture at 0 °C. The resulting solution was stirred at RT for 2 h. The reaction mixture was slowly poured into ice-cold aq.sat. NH4Cl solution (500 mL) at 0 °C and extracted with MTBE (2 × 250 mL). The combined organic layers were washed with brine (300 mL), dried over anh.Na2SO4, filtered, and concentrated under reduced pressure to give crude benzyl (4R)-4-(hydroxy(phenyl)methyl)-2,2-dimethyloxazoline-3-carboxylate, which was used in Step 5 without further purification.

[0458] Step 5: p-Toluenesulfonic acid monohydrate (11.1 g, 58.6 mmol) was added to a solution of benzyl (4R)-4-(hydroxy(phenyl)methyl)-2,2-dimethyloxazoline-3-carboxylate (40.0 g, 117 mmol) in MeOH (250 mL). The solution was stirred at 50 °C for 12 h. The reaction mixture was quenched by the slow addition of aq. sat. NaHCO3 solution (500 mL) and then extracted with DCM (2 × 350 mL). The combined organic layers were dried over anh. Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (6:1 to 0:1; v / v) to give benzyl ((2R)-1,3-dihydroxy-1-phenylpropan-2-yl)carbamate.

[0459] Step 6: The mixture of diastereomers was separated by SFC: (Column: Daicel ChiralPak® IC (250 × 50 mm, 10 μm, Daicel Chiral Technologies, West Chester, PA); Mobile phase: [0.1% NH4OH in HO; IPA]; IPA%: 40–40%, 5 min). Benzyl ((1R,2R)-1,3-dihydroxy-1-phenylpropan-2-yl)carbamate A. 1 H NMR(400MHz,DMSO-d6):δ 7.35-7.18(m,10 H),6.94(d,J=8.2Hz,1 H),5.38(d,J=5.6Hz,1 H),4.90(dd,J=13.2Hz,28.8Hz,2 H),4.57-4.47(m,2 H),3.63-3.53(m,3 H). Benzyl ((1S,2R)-1,3-dihydroxy-1-phenylpropan-2-yl)carbamate B. 1 H NMR(400MHz,DMSO-d6):δ 7.35-7.21(m,10 H),6.65(d,J=8.2Hz,1 H),5.32(d,J=5.6Hz,1 H),4.93(dd,J=13.2Hz,28.8Hz,2 H),4.81-4.72(m,2 H),3.68-3.67(m,1 H),3.51-3.49(m,1 H),3.33-3.28(m,1 H).

[0460] Step 7: Sodium hypochlorite (10.5 g, 14.1 mmol, 8.65 mL, 10% active chlorine basis) was added to a solution of benzyl ((1R,2R)-1,3-dihydroxy-1-phenylpropan-2-yl)carbamate A (18.0 g, 56.3 mmol, 94.2% purity) and TEMPO (1.77 g, 11.3 mmol) in acetone (90.0 mL) and aq. NaHCO (194 g, 116 mmol, 90.0 mL, 5 wt%). The reaction mixture was stirred under N at RT for 1 h. The reaction mixture was diluted with DI water (300 mL) and extracted with EtOAc (2 × 150 mL). The pH of the aqueous layer was adjusted to approximately pH 2 by the addition of 1N HCl solution. The mixture was extracted with EtOAc (2×150 mL) and the combined organic layers were dried over anh.NaSO, filtered and concentrated under reduced pressure to give crude (2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-hydroxy-3-phenylpropanoic acid, which was used in Step 8 without further purification. 1H NMR(400MHz,DMSO-d6):δ 12.8(s,1H),7.94-7.92(m,1H),7.92-7.39(m,1H),7.38-7.322(m,10H),7.1(m, 1H),5.67(s,1H),5.13-5.11(m,1H),5.12(s,2H),4.31(dd,J=9.6Hz,3.2Hz,1H).

[0461] Step 8: Crude (2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-hydroxy-3-phenylpropanoic acid (12.0 g, 38.0 mmol) was added to a mixture of aq. 12 m HCl solution (3.16 mL) in MeOH (60.0 mL). Pd / C (6.00 g, 10 wt%) was added to the solution under N. The flask was evacuated and backfilled with H (5 times). The resulting mixture was stirred under a dihydrogen atmosphere (15 psi) at RT for 3 h. The flask was evacuated and refilled with N (5 times). The resulting mixture was filtered. The filter cake was washed with MeOH (2 × 50 mL). The filtrate was concentrated under reduced pressure. To the crude solid was added MeCN (40.0 mL) and HO (8.00 mL) at RT, followed by the addition of NaHCO (6.39 g, 76.1 mmol) and Fmoc-OSu (10.3 g, 30.4 mmol). The reaction mixture was stirred at RT for 2 h. Upon completion of Fmoc protect...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof [Chemical Formula 1] (In the formula, R １ is 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) ３ N ＋ (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 ０～６ alkyl)carbonylamino (C ０～６ alkyl), (C ０～６ alkyl) ０～２ Aminocarbonyl (C ０～６ alkyl), (C １～６ alkyl) ０～２ Aminocarbonylamino (C ０～６ alkyl), arylcarbonylamino (C ０～６ alkyl), arylaminocarbonyl (C ０～６ alkyl), heteroarylcarbonylamino (C ０～６ alkyl), heteroarylaminocarbonyl (C ０～６ alkyl), C １～６ Alkyloxy, (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 H ２ NC(=NH)NH-(C ０～６ alkyl), Here, R １ is C １～６ Alkyl, amino, cyano, halo, hydroxy, (C ３～１２ ) cycloalkyloxy, and C １～６ 0, 1, 2, 3, or 4 R each independently selected from alkyloxy １ａ is substituted by a substituent; Each R ２ａ is hydrogen, hydroxy, C １～４ Alkyl, fluoro, and C １～４ independently selected from alkyloxy; R ２ｂ is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said heteroaryl contains at least one nitrogen atom; Here, R ２ｂ is C １～６ Alkyl, amino (C ０～６ alkyl), (C １～６ alkyl) ０～２ Amino (C ０～６ alkyl), (C １～６ alkyl) ３ N ＋ (C ０～６ alkyl), aminocarbonyl (C ０～６ alkyl), (C １～６ alkyl) ０～２ Aminocarbonyl (C ０～６ alkyl), hydroxy, C １～６ Alkyloxy, halo, (C １～６ alkyl) ０～２ Amino (C ０～６ alkyloxy), (C １～６ alkyl) ３ N ＋ (C ０～６ alkyloxy), (C １～６ alkyloxy)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 Haloalkyloxy, and C １～６ 0, 1, or 2 R independently selected from alkyloxy ２ｃ is replaced by R ３ａ is 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), (C ０～６ alkyl)thio(C １～６ alkyl), and carboxy (C １～６ alkyl), where R ３ａ is 0, 1, or 2 R ３ｃ may be substituted by a substituent; R ３ｂ is hydrogen, C １～１０ Alkyl, hydroxy (C １～６ alkyl), amino (C １～１０ alkyl), (C １～６ alkyl) ０～２ Amino (C １～１０ alkyl), (C １～６ alkyl) ３ N ＋ (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 ) cycloalkyloxy (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)SO ２ (C １～６ alkyl), and (C １～６ alkyl)sulfinyl (C １～６ alkyl), where R ３ｂ is 0, 1, or 2 R ３ｃ may be substituted by a substituent; Each R ３ｃ Ha, Halo, C １～６ Alkyl, amino, (C １～６ alkyl) ０～２ Amino (C ０～６ alkyl), (C １～６ alkyl) ３ N ＋ -, (C １～６ alkyl)SO ２ (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); Here, R ３ａ and R ３ｂ may, together with the atom to which they are attached, form a saturated ring system, wherein said saturated ring system contains zero, one, or two R ３ｃ may be substituted by a substituent; R ４ａ is hydrogen, C １～６ Alkyl, hydroxy, C １～４ selected from alkyloxy, and fluoro; R ４ｂ is a bicyclic heteroaryl (C ０～３ alkyl), and bicyclic aryl (C ０～３ alkyl), Here, R ４ｂ is halo, hydroxy, cyano, nitro, carboxy, carboxy (C １～６ alkyl), (C １～６ alkyloxy)carbonyl (C ０～６ alkyl), C １～６ Alkyloxy, (C １～６ alkyl)oxy(C １～６ alkyl), C １～６ Alkyl, and C １～６ 0, 1, or 2 R independently selected from haloalkyl ４ｃ is substituted with a substituent; R ５ａ is 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 (C0-6 alkyl), heteroaryl (C ０～６ alkyl), (C １～６ alkyl)oxy(C １～６ alkyl), (C １～６ alkyloxy)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) ３ N ＋ (C ２～１０ alkyl), (C １～６ alkyl) ３ N ＋ (C １～６ alkyl)carbonylamino (C １～６ alkyl), and C １～１０ fluoroalkyl, where R ５ａ is 0, 1, or 2 R ５ｄ is substituted by a substituent; R ５ｂ is 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)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) ３ N ＋ (C ２～６ alkyl)oxy(C １～６ alkyl), (C １～６ alkyl) ３ N ＋ (C １～６ alkyl)carbonylamino (C １～６ alkyl), (C １～６ alkyl) ３ N ＋ (C １～６ alkyl), heterocycloalkyl (C ０～１０ alkyl), (C ３～１２ ) cycloalkyl (C ０～１０ alkyl), and C １～１０ haloalkyl, where R ５ｂ is 0, 1, 2, or 3 R ５ｅ is substituted by a substituent, Here, R ５ａ and R ５ｂ together with the atoms to which they are attached form a saturated monocyclic or bicyclic ring, wherein said monocyclic or bicyclic ring contains 0, 1, 2, or 3 R ５ｄ and 0, 1, 2, or 3 R ５ｅ is substituted with; Each R ５ｄ is halo, hydroxy, hydroxy (C １～１０ alkyl), C １～１０ Alkyl, carboxy, carboxy (C １～６ alkyl), C １～６ Alkyloxy, (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) ３ N ＋ (C ０～６ alkyl), (C １～６ alkyl) ３ N ＋ (C ２～６ alkyl)oxy(C ０～６ alkyl), (C １～６ alkyl) ３ N ＋ (C １～６ alkyl)carbonylamino (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 The substituents, together with the atoms to which they are attached, may be joined to form a saturated ring; Each R ５ｅ is halo, hydroxy, hydroxy (C １～１０ alkyl), C １～１０ Alkyl, carboxy, carboxy (C １～６ alkyl), C １～６ Alkyloxy, (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) ３ N ＋ (C ０～６ alkyl), (C １～６ alkyl) ３ N ＋ (C ２～６ alkyl)oxy(C ０～６ alkyl), (C １～６ alkyl) ３ N ＋ (C １～６ alkyl)carbonylamino (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 ５ｅ The substituents, together with the atoms to which they are attached, may be joined to form a saturated ring; R ５ｃ is hydrogen, C １～４ Alkyl, hydroxy (C １～４ alkyl), C １～４ alkyloxy, or (C １～４ alkyl)oxy(C １～４ alkyl); R ６ａ is hydrogen, hydroxy, amino, C １～４ Alkyloxy, and C １～６ alkyl; R ６ｂ is hydrogen, C １～６ Alkyl, hydroxy, C １～４ selected from alkyloxy, and fluoro; R ６ｃ is C １～１０ Alkyl, C １～６ Alkyloxy, (C １～６ alkyl)oxy(C １～６ alkyl), C １～１０ Haloalkyl, aryl (C ０～６ alkyl), heteroaryl (C ０～１０ alkyl), (C １～６ alkyl)SO ２ (C ０～６ alkyl), hydroxy, hydroxy(C １～６ alkyl), amino (C ０～６ alkyl), (C1-6 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); R ７ａ is hydrogen, C １～６ Alkyl, hydroxy, C １～４ selected from alkyloxy, and fluoro; R ７ｂ is an aryl (C ０～６ alkyl), heteroaryl (C ０～６ alkyl), and (C ３～１２ ) cycloalkyl (C ０～６ alkyl), Here, R ７ｂ is C １～６ Alkyl, C １～１０ Fluoroalkyl, C １～１０ Fluoroalkyloxy, (C １～６ alkyl) ０～２ Amino (C ０～５ alkyl), (C １～６ alkyl) ３ N ＋ (C ０～５ alkyl), carboxy (C ０～６ alkyl), (C １～６ alkyloxy)carbonyl (C ０～６ alkyl), carboxy (C １～６ alkyl)oxy(C ０～６ alkyl), aminocarbonyl (C ０～６ alkyl), (C １～６ alkyl) ０～２ Aminocarbonyl (C ０～６ alkyl), hydroxy, hydroxy(C １～６ alkyl), halo, -(C ０～５ alkyl)-(S(=O) ２ OH), -(C ０～５ alkyl)-(S(=O) ２ NH ２ ), 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) ３ N ＋ (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 haloalkyloxy, and (C １～６ alkyl)oxy(C ０～６ 0, 1, 2, or 3 R ７ｃ is substituted by a substituent; R ８ａ is hydrogen, C １～６ Alkyl, hydroxy, C １～４ Alkyloxy, C １～６ Fluoroalkyl, C １～４ selected from fluoroalkyloxy, and halo; R ８ｂ is a bicyclic aryl (C ０～３ alkyl) and bicyclic heteroaryl (C ０～３ alkyl), Here, R ８ｂ is C １～４ Alkyl, halo, cyano, nitro, carboxy, amino, hydroxy, C １～６ Fluoroalkyl, C １～６ Fluoroalkyloxy, C １～６ Alkyloxy, amino (C １～３ alkyl), and hydroxy (C １～６ 0, 1, or 2 R independently selected from ８ｃ is substituted by a substituent; R ９ is hydrogen and C １～４ alkyl; R １０ａ is hydrogen, hydroxy, C １～６ Alkyl, C １～４ selected from alkyloxy, and fluoro; R １０ｂ is (C ３～１２ ) cycloalkyl (C ０～３ alkyl), aryl (C ０～３ alkyl), and heteroaryl (C ０～３ alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms; Here, R １０ｂ is 0, 1, or 2 R １０ｃ and each R １０ｃ is C １～１０ Alkyl, C １～１０ Fluoroalkyl, C １～６ Haloalkyl, C １～１０ Fluoroalkyloxy, amino, amino(C １～６ alkyl), (C １～６ alkyl) ０～２ Amino (C ０～６ alkyl), (C １～６ alkyl) ３ N ＋ (C ０～６ alkyl), hydroxy, hydroxy(C １～６ alkyl), cyano, halo, aminocarbonyl, aminocarbonyl (C １～６ alkyl), (C １～６ alkyl) ０～２ Aminocarbonyl (C ０～６ alkyl), (C １～６ alkyl) ０～２ Aminocarbonylamino (C ０～６ alkyl), (C １～６ alkyl)carbonylamino (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) ２ OH), -(C ０～５ alkyl)-(S(=O) ２ NH ２ ), 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) ３ N ＋ (C ０～６ alkyl)oxy(C ０～６ alkyl), (C １～６ alkyl)oxy(C ０～６ alkyl), C １～６ Haloalkyloxy, (C ３～１２ ) cycloalkyl (C ０～６ alkyl), and heterocycloalkyl (C ０～６ alkyl); R １１ａ is hydrogen, hydroxy, C １～６ Alkyl, C １～４ selected from alkyloxy, and fluoro; R １１ｂ is an aryl (C ０～３ alkyl), heteroaryl (C ０～３ alkyl), wherein the heteroaryl contains 1, 2, or 3 nitrogen atoms, and H ２ NC(=NH)NH-(C １～６ alkyl), Here, R １１ｂ is 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) ３ N ＋ (C ０～６ alkyl), hydroxy, hydroxy(C １～６ alkyl), cyano, halo, aminocarbonyl, aminocarbonyl (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) ３ N ＋ (C ０～６ alkyl)oxy(C ０～６ alkyl), (C １～６ alkyl)oxy(C ０～６ alkyl), C １～６ Haloalkyloxy, C １～６ Haloalkyl, (C ３～１２ ) cycloalkyl (C ０～６ alkyl), heterocycloalkyl (C ０～６ alkyl), ((C １～６ alkyl)carbonyl)heterocycloalkyl(C ０～１０ alkyl), and ((C １～６ alkyl)carbonyloxy)heterocycloalkyl(C ０～１０ 0, 1, 2, 3, or 4 R １１ｃ is substituted by a substituent; R １２ａ is hydrogen, hydroxy, amino, C １～１０ alkyl, and (C ３～１２ ) cycloalkyl (C ０～６ alkyl); R １２ｂ is hydrogen, C １～１０ alkyl, and (C ３～１２ ) cycloalkyl (C ０～６ alkyl); Here, R １２ａ and R １２ｂ may, together with the atoms to which they are attached, form a saturated ring; R １３ａ is hydrogen, hydroxy, C １～６ Alkyl, C １～４ selected from alkyloxy, and fluoro; R １３ｂ is hydrogen and C １～４ alkyl; R １３ｃ is selected from bicyclic nitrogen-containing heteroaryls and bicyclic aryls having one or two nitrogens, where R １３ｃ Ha, Halo, C １～６ Alkyl, carboxy (C ０～４ alkyl), C １～４ Haloalkyloxy, and C １～４ 0, 1, or 2 R independently selected from alkyloxy １３ｄ is independently substituted by substituents; 【Chemistry 2】 teeth, 【Chemistry 3】 【change】 Selected from: Here, R １４ａ is an amino, hydroxy, (C １～６ alkyl) ０～２ Amino, and C １～６ alkyloxy; m is selected from 1, 2, 3, or 4; n is selected from 1, 2, 3, or 4; and R １４ｂ is hydrogen, C １～８ Alkyl, aryl (C ０～６ alkyl), and heteroaryl (C ０～６ alkyl), where R １４ｂ is substituted with 0, 1, 2, or 3 halo groups).

2. R １ is aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, phenyl, phenylmethyl, phenylethyl, phenylpropyl, styryl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, biphenylmethyl, naphthylmethyl, pyridylmethyl, pyridazinylmethyl, pyrimidylmethyl, pyrazinylmethyl, imidazolylmethyl, pyrazolylmethyl, furylmethyl, thiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, oxadiazolylmethyl, bicyclo[1.1.

1. ]pentyl, (bicyclo[1.1.1.]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, cycloheptylmethyl, xylmethyl, adamantyl, carboxy, carboxymethyl, carboxyethyl, azidomethyl, azidoethyl, azidopropyl, phenylaminocarbonylmethyl, pyridylaminocarbonylmethyl, (pyridylcarbonylamino)methyl, guanidino, guanidinomethyl, guanidinoethyl, guanidinopropyl, guanidinobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, pentafluoropropyl, heptafluoropropyl, trifluorobutyl, N,N,N-trimethylmethylammonium, N,N,N-trimethyleth-1-ylammonium, N,N,The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from N-trimethylpropan-1-ylammonium, N,N,N-trimethylbut-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. Each R １ａ The substituent is C １～６ independently selected from alkyl, amino, cyano, halo, and hydroxy; Each R ２ａ the substituents are independently selected from hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy, and fluoro; R ２ｂ is selected from phenyl, benzyl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and bicyclo[1.1.1]pentyl; Each R ２ｃ The substituents may be aminomethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, fluoro, chloro, bromo, iodo, aminoethoxy, N-methylaminoethoxy, N-ethylaminoethoxy, N,N-dimethylaminoethoxy, 【Chemistry 4】 independently selected from carboxy, carboxymethoxy, (carboxymethoxy)methyl, aminocarbonyl, N,N-dimethylaminocarbonyl, and aminocarbonylmethyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. R ３ａ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, aminoethyl, aminopropyl, aminobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, thioethyl, and thiopropyl, wherein R ３ａ is fluoro, chloro, 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, -SO ２ CH ３ , -CH ２ SO ２ CH ３ , -CH ２ CH ２ SO ２ CH ３ , cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxy, carboxymethyl, and carboxyethyl; ３ｃ may be substituted by a substituent; R ３ｂ is 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-aminoprop-2-yl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, benzyl, 3-pyridinylmethyl, 4-pyridinylmethyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiophenylmethyl, furanylmethyl, pyrazolylmethyl, N-pyrazolylmethyl, 1-phenylethyl, 1-(4-pyridinyl)ethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, (N,N-dimethyl)aminocarbonylmethyl, (N,N-dimethyl)aminocarbonylethyl, thiomethyl, thioethyl, thiopropyl, -CH ２ CH ２ SO ２ CH ３ , carboxymethyl, carboxyethyl, 2-carboxyethyl, carboxypropyl, 3-carboxypropyl, carboxybutyl, 4-carboxybutyl, piperazinylmethyl, morpholinomethyl, piperidinylmethyl, azetidinylmethyl, tetrahydropyranylmethyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, and aminocarbonylaminobutyl, wherein R ３ｂ is fluoro, chloro, 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, -SO ２ CH ３ , -CH ２ SO ２ CH ３ , -CH ２ CH ２ SO ２ CH ３ , cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxy, carboxymethyl, and carboxyethyl; ３ｃ optionally substituted by a substituent; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. R ３ａ and R ３ｂ together with the atoms to which they are attached, can be 0, 1, or 2 R ３ｄ forming a saturated ring system substituted by a substituent, said saturated ring system being 【Chemistry 5】 2. The compound of claim 1, selected from: or a pharmaceutically acceptable salt thereof.

6. R ４ａ is selected from hydrogen, methyl, ethyl, propyl, hydroxy, methoxy, and fluoro; 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 are each independently selected from fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, methyl, ethyl, propyl, isopropyl, carboxy, carboxymethyl, and carboxyethyl; ４ｃ is substituted with a substituent; R ５ａ is 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, thiadiazolylmethyl, oxazolylethyl, thiazolylethyl, imidazolylethyl, triazolylethyl, oxadiazolylethyl, thiadiazolylethyl, oxazolylpropyl, thiazolylpropyl, imidazolylpropyl, triazolylpropyl, oxadiazolylpropyl, thiadiazolylpropyl, azetidinylmethyl, azetidinylethyl, oxetanyl Methyl, oxetanylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, tetrahydropyranylmethyl, tetrahydropyranylmethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, 3-hydroxy-2,2-dimethylpropyl, cyclopropylmethyl, 1-hydroxypropan-2-yl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-aminoethyl, 3-aminopropyl, 3-amino-2,2-dimethylpropyl, cyclopropylmethyl, 4-aminobutyl, aminomethylcarbonylaminoethyl, aminoethylcarbonylaminoethyl, aminomethylcarbonylaminopropyl, aminoethylaminocarbonylmethyl, aminoethylaminocarbonylethyl, aminoethylaminocarbonylpropyl, aminohexylcarbonylaminoethyl, aminohexylcarbonylaminoethyl, (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-trimethylammonium)ethyl, (N,N,N-trimethylammonium)propyl, (N,N,N-triethylammonium)ethyl, (N,N,N-triethylammonium)propyl, (N-methylamino)methylcarbonylaminoethyl, (N-methylamino)ethylcarbonylaminoethyl, (N-methylamino)methylcarbonylaminopropyl, (N-ethylamino)methyl (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)ethylcarbonylaminopropyl, (N,N-diethylamino)methylcarbonylaminoethyl carbonylaminoethyl, (N,N-diethylamino)ethylcarbonylaminoethyl, (N,N-diethylamino)methylcarbonylaminopropyl, (N,N-dimethylamino)pentylcarbonylaminoethyl, (N,N-dimethylamino)pentylcarbonylaminoethyl, (N,N-dimethylamino)pentylcarbonylaminopropyl, N,N,N-trimethyl-ethane-1-ammonium, N,N,N-trimethyl-propane-1-ammonium, (N,N,N-trimethylammonium)methylcarbonylaminoethyl, (N,N,(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 is chloro, fluoro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, 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, aminoethylcarbonylaminoethylaminomethyl, (N-methylcarbonylamino)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 (N,N,N-trimethylammonium)methyl, (N,N,N-trimethylammonium)ethyl, (N,N,N-trimethylammonium)ethoxy, (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,0, 1, 2, or 3 R, each independently selected from N-trimethylammonium)ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazoyl, tetrazoylmethyl, tetrazoylethyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, and carboxyethoxymethyl; ５ｄ is substituted by a substituent; R ５ｂ is hydrogen, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopropylmethyl, oxetanylmethyl, tetrahydrofurylmethyl, 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-trimethylmethane-1-ylammonium, N,N,N-trimethylethan-1-ylammonium, N,N,N-triethylethan-1-ylammonium, N,N,N-trimethylpropan-1-ylammonium, N,N,N-trimethylbutan-1-ylammonium, (N,N,N-trimethylammonium)ethoxymethyl, (N,N,N-trimethylammonium)ethoxyethyl, (N,N,N-triethylammonium)ethoxyethyl, (N,N,N-trimethyl (N,N,N-trimethylammonium)ethoxypropyl, (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 ethyl, (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 is chloro, fluoro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, 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-di (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) ethoxy, (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,0, 1, 2, or 3 R, each independently selected from N-trimethylammonium)ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazoyl, tetrazoylmethyl, tetrazoylethyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, and carboxyethoxymethyl; ５ｅ is substituted by a substituent; and R ５ｃ is hydrogen, methyl, or ethyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. R ５ａ and R ５ｂ together with the atoms to which they are attached, can be 0, 1, 2 or 3 R ５ｄ a substituent and 0, 1, 2, or 3 R ５ｅ forming a saturated monocyclic or bicyclic ring system substituted with a substituent, wherein said monocyclic or bicyclic ring system is 【Chemistry 6】 【change】 2. The compound of claim 1, selected from: or a pharmaceutically acceptable salt thereof.

8. R ６ａ is selected from hydrogen, hydroxy, methyl, ethyl, propyl, and methoxy; R ６ｂ is selected from hydrogen, hydroxy, methyl, ethyl, propyl, methoxy, and ethoxy; R ６ｃ Examples of the arylaminocarbonyl include 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, (aminocarbonylamino)methyl, (aminocarbonyl (aminocarbonylamino)ethyl, (aminocarbonylamino)propyl, methoxy, methoxymethyl, methoxyethyl, ethoxy, ethoxymethyl, ethoxyethyl, methylsulfonyl, (methylsulfonyl)methyl, (methylsulfonyl)ethyl, (methylsulfonyl)propyl, amino, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, carboxy, carboxymethyl, carboxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl, and benzyl; R ７ａ is selected from hydrogen, methyl, ethyl, hydroxy, methoxy, and ethoxy; R ７ｂ is selected from phenyl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 3-oxoisoindolinyl, and bicyclo[1.1.1]pentyl; R ７ｃ is fluoro, chloro, bromo, iodo, 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, —SO ２ OH, -CH ２ SO ２ OH, -SO ２ NH ２ , -CH ２ SO ２ NH ２ , aminoethoxy, aminoethoxymethyl, (N,N-dimethylamino)ethoxy, N,N,N-trimethyleth-1-oxyammonium, aminocarbonylamino, and aminocarbonylaminomethyl; R ８ａ is selected from hydrogen, methyl, ethyl, hydroxy, methoxy, and ethoxy; R ８ｂ is selected from indolyl, naphthyl, indolylmethyl, naphthylmethyl, quinolinyl, pyrrolo[2,3-b]pyridinyl, indazolyl, benzothiazolyl, and benzothiophenyl; 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; and R ９ is selected from hydrogen, methyl, ethyl, and propyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. R １０ａ is selected from hydrogen, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy; R １０ｂ is selected from phenyl, benzyl, biphenyl, biphenylmethyl, pyridyl, pyridylmethyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, imidazolylmethyl, pyrazolyl, furyl, furylmethyl, oxazolyl, oxazolylmethyl, thiazolyl, indolyl, [1,2,4]triazolo[1,5-a]pyridine, and bicyclo[1.1.1]pentyl; R １０ｃ 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, 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-trimethylmethane-ylammonium, aminocarbonyl, aminocarbonylmethyl, aminocarbonylethyl, (N-methylamino)carbonyl, (N-methylamino)carbonylmethyl, (N,N-dimethylamino)carbonyl, (N,N-dimethylamino)carbonylmethyl, aminocarbonylamino, aminocarbonylaminomethyl, methylcarbonylamino, methylcarbonylaminomethyl, carboxy, carboxymethyl, carboxyethyl, methoxycarboxy, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, carboxyethoxymethyl, —S(═O) ２ OH, -CH ２ (S(=O) ２ OH), -S(=O) ２ NH ２ , -CH ２ (S(=O) ２ NH ２ ), 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 is selected from hydrogen, hydroxy, methyl, ethyl, methoxy, and ethoxy; R １１ｂ However, (H ２ N—C(═NH)—NH)methyl, (H ２ N—C(═NH)—NH)ethyl, (H ２ N—C(═NH)—NH)propyl, (H ２ selected from N—C(═NH)—NH)butyl, phenyl, benzyl, pyridinyl, pyridinylmethyl, indolyl, indolylmethyl, pyridazinyl, pyridazinylmethyl, pyrimidyl, pyrimidylmethyl, pyrazinyl, pyrazinylmethyl, imidazolyl, imidazolylmethyl, pyrazolyl, pyrazolylmethyl, [1,2,4]triazolo[1,5-a]pyridine, oxazolyl, oxazolylmethyl, thiazolyl, and thiazolylmethyl; Each R １１ｃ 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) (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-trimethyleth-1-yloxy-ammonium, cyano, and methylcarbonylpiperazyl [(N-acetyl)piperazyl; R １２ａ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, and isopropyl; and R １２ｂ is selected from hydrogen, methyl, ethyl, and propyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. R １２ａ and R １２ｂ together with the atoms to which they are bonded, 【Chemistry 7】 forming a saturated ring selected from 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. R １３ａ is hydrogen, methyl or propyl; R １３ｂ is hydrogen or methyl; R １３ｃ is selected from indolyl, pyrrolo[2,3-b]pyridinyl, quinolinyl, indazolyl, and naphthyl; R １３ｃ is selected from indolyl and pyrrolo[2,3-b]pyridinyl; Each R １３ｄ is independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, carboxy, carboxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, and ethoxy; Each R １４ａ is independently selected from amino, hydroxy, N-methylamino, N,N-dimethylamino, N-ethylamino, methoxy, and ethoxy; and Each R １４ｂ are 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, indolyl, indolylmethyl, imidazolyl, imidazolylmethyl, pyridyl, and pyridylmethyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. 2. The compound of claim 1, selected from the group consisting of SEQ ID NOs: 1 to 289, or a pharmaceutically acceptable salt thereof.

13. (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, respectively, in order of appearance.) 【Chemistry 8】 SEQ ID NO:5, 【Chemistry 9】 SEQ ID NO: 10, 【Chemistry 10】 SEQ ID NO: 18, 【Chemistry 11】 SEQ ID NO: 22, 【Chemistry 12】 SEQ ID NO: 30, 【Chemistry 13】 SEQ ID NO: 31, 【Chemistry 14】 SEQ ID NO: 41, 【Chemistry 15】 SEQ ID NO: 45, 【Chemistry 16】 SEQ ID NO:48 【Chemistry 17】 SEQ ID NO: 51, 【Chemistry 18】 SEQ ID NO: 52, 【Chemistry 19】 SEQ ID NO: 53, 【Chemistry 20】 SEQ ID NO: 60, 【Chemical 21】 SEQ ID NO: 68, [Chemical 22] SEQ ID NO: 77, 【Chemical 23】 SEQ ID NO: 83, 【Chemistry 24】 SEQ ID NO: 87, 【Chemistry 25】 SEQ ID NO: 104, 【Chemical Formula 26】 SEQ ID NO: 183, 【Chemical 27】 SEQ ID NO: 196, 【Chemical Formula 28】 SEQ ID NO: 206, 【Chemical Formula 29】 SEQ ID NO: 210, 【Chemistry 30】 SEQ ID NO: 214, 【Chemical 31】 SEQ ID NO: 221, 【Chemical 32】 SEQ ID NO: 229, 【Chemical 33】 SEQ ID NO: 237, 【Chemical 34】 SEQ ID NO: 247, 【Chemical 35】 SEQ ID NO: 250, 【Chemical 36】 SEQ ID NO: 254, 【Chemical 37】 SEQ ID NO: 257, and 【change】 SEQ ID NO: 265, 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

14. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. 13. A method for treating IBD and other TNFα-driven inflammatory diseases, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, 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-radiographic axial spondyloarthritis, and hidradenitis suppurativa.

16. 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. 16. 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-radiographic axial spondyloarthritis, and hidradenitis suppurativa.

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

19. 14. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, in therapy.

20. 14. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for treating 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 spondyloarthritis, and hidradenitis suppurativa.

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

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

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